Huang Qin decoction increases SLC6A4 expression and blocks the NFκB-mediated NLRP3/Caspase1/GSDMD pathway to disrupt colitis-associated carcinogenesis.

Huang Qin decoction (HQD) is a traditional Chinese medicine formula for treating colitis, but the effects and molecular mechanism of action of HQD in colitis-associated carcinogenesis (CAC) are still unclear. Therefore, we aimed to determine the beneficial effects of HQD on CAC in mice and to reveal the underlying mechanism involved. AOM/DSS was used to induce CAC in mice, and the effects of HQD on tumorigenesis in mice were examined (with mesalazine serving as a positive control). Mesalazine or HQD treatment alleviated body weight loss and decreased the disease activity index in mice induced by AOM/DSS. Mesalazine or HQD treatment also suppressed the shortening of colon tissue length, the number of tumors, and the infiltration of inflammatory cells. The genes targeted by HQD were predicted and verified, followed by knockout experiments. Elevated SLC6A4 and inhibited serotonin production and inflammation were observed in HQD-treated mice. HQD inhibited the NFκB and NLRP3/caspase1/GSDMD pathways. The therapeutic effect of HQD was diminished in SLC6A4-deficient AOM/DSS mice. Additionally, the downregulation of SLC6A4 mitigated the inhibitory effect of HQD-containing serum on MODE-K cell pyroptosis. Our findings suggest that SLC6A4 is a pivotal regulator of HQD-alleviated CAC via its modulation of the NLRP3/caspase1/GSDMD pathway.

Comparison of downsizing strategy (HANGZHOU Solution) and standard annulus sizing strategy in type 0 bicuspid aortic stenosis patients undergoing transcatheter aortic valve replacement: Rationale and design of a randomized clinical trial.

BACKGROUND: There has not been a consensus on the prothesis sizing strategy in type 0 bicuspid aortic stenosis (AS) patients undergoing transcatheter aortic valve replacement (TAVR). Modifications to standard annular sizing strategies might be required due to the distinct anatomical characteristics. We have devised a downsizing strategy for TAVR using a self-expanding valve specifically for patients with type 0 bicuspid AS. The primary aim of this study is to compare the safety and efficacy of downsizing strategy with the Standard Annulus Sizing Strategy in TAVR for patients with type 0 bicuspid AS. TRIAL DESIGN: It is a prospective, multi-center, superiority, single-blinded, randomized controlled trial comparing the Down Sizing and Standard Annulus Sizing Strategy in patients with type 0 bicuspid aortic stenosis undergoing transcatheter aortic valve replacement. Eligible participants will include patients with severe type 0 bicuspid AS, as defined by criteria such as mean gradient across aortic valve ≥40 mmHg, peak aortic jet velocity ≥4.0 m/s, aortic valve area (AVA) ≤1.0 cm², or AVA index ≤0.6 cm2/m2. These patients will be randomly assigned, in a 1:1 ratio, to either the Down Sizing Strategy group or the Standard Sizing Strategy group. In the Down Sizing Strategy group, a valve one size smaller will be implanted if the "waist sign" manifests along with less than mild regurgitation during balloon pre-dilatation. The primary end point of the study is a composite of VARC-3 defined device success, absence of both permanent pacemaker implantation due to high-degree atrioventricular block and new-onset complete left bundle branch block. CONCLUSION: This study will compare the safety and efficacy of Down Sizing Strategy with the Standard Annulus Sizing Strategy and provide valuable insights into the optimal approach for sizing in TAVR patients with type 0 bicuspid AS. We hypothesize that the Down Sizing Strategy will demonstrate superiority when compared to the Standard Annulus Sizing Strategy. (Down Sizing Strategy (HANGZHOU Solution) vs Standard Sizing Strategy TAVR in Bicuspid Aortic Stenosis (Type 0) (TAILOR-TAVR), NCT05511792).

Telomere length in multiple cancer: insight into recurrence risk from a meta-analysis.

BACKGROUND: Several studies have revealed the relationships between telomere length and the risk and mortality of numerous cancers. This meta-analysis aims to insightfully clarify the potential relationship between telomere length and the recurrence of multiple cancers. METHODS: PubMed database was used to search and identify interrelated citations. These reports investigated the relationship between telomere length and various cancer recurrences. Meta-analysis pooled data from studies that reported risk ratio (RR) of 95 (CI = 95%) confidence intervals and/or P-values. The cancer recurrence was investigated from an overall standpoint to the multiple levels of subtypes of cancers. RESULTS: The meta-analysis involved 5907 recurrent multiple cancer patients from 13 cohort studies. Compared to these cancer recurrence cases and the telomere length differences, there was no significant correlation between telomere length and cancer recurrence risk (short telomeres vs long telomeres; RR = 0.93, 95% CI: 0.72-1.20, P = 0.59). Additionally, a negative association was observed between telomere length and cancer recurrence in gastrointestinal cancer and a positive association in head and neck cancer, while telomere length had little effect on the recurrence of hematological malignancies and genitourinary cancer in this analysis. CONCLUSION: There was no significant relationship between recurrence and telomere length in 5907 cases in 13 studies. However, there was a correlation between specific tumors. These results suggested that telomere length as a recurrence marker or telomere length to determine the possibility of recurrence must be evaluated on the specific type of cancer.

Effect of Layered Aminovanadic Oxalate Phosphate on Flame Retardancy of Epoxy Resin.

To alleviate the fire hazard of epoxy resin (EP), layered ammonium vanadium oxalate-phosphate (AVOPh) with the structural formula of (NH4)2[VO(HPO4)]2(C2O4)·5H2O is synthesized using the hydrothermal method and mixed into an EP matrix to prepare EP/AVOPh composites. The thermogravimetric analysis (TGA) results show that AVOPh exhibits a similar thermal decomposition temperature to EP, which is suitable for flame retardancy for EP. The incorporation of AVOPh nanosheets greatly improves the thermal stability and residual yield of EP/AVOPh composites at high temperatures. The residue of pure EP is 15.3% at 700 °C. In comparison, the residue of EP/AVOPh composites is increased to 23.0% with 8 wt% AVOPh loading. Simultaneously, EP/6 wt% AVOPh composites reach UL-94 V1 rating (t1 + t2 =16 s) and LOI value of 32.8%. The improved flame retardancy of EP/ AVOPh composites is also proven by the cone calorimeter test (CCT). The results of CCT of EP/8 wt% AVOPh composites show that the peak heat release rate (PHHR), total smoke production (TSP), peak of CO production (PCOP), and peak of CO2 production (PCO2P) decrease by 32.7%, 20.4%, 37.1%, and 33.3% compared with those of EP, respectively. This can be attributed to the lamellar barrier, gas phase quenching effect of phosphorus-containing volatiles, the catalytic charring effect of transition metal vanadium, and the synergistic decomposition of oxalic acid structure and charring effect of phosphorus phase, which can insulate heat and inhibit smoke release. Based on the experimental data, AVOPh is expected to serve as a new high-efficiency flame retardant for EP.

Optimization of Neferine Purification Based on Response Surface Methodology and Its Anti-Metastasis Mechanism on HepG2 Cells.

Liver cancer continues to be a focus of scientific research due to its low five-year survival rate. One of its main core issues is the high metastasis of cells, for which there is no effective treatment. Neferine was originally isolated from Plumula nelumbinis and demonstrated to have a good antitumor effect. In order to extract high-purity Neferine in a more efficient and environmentally friendly manner, response surface methodology (RSM) was used to optimize the isolation and purification procedures in this study. The extract conditions of a 7:3 ratio for the eluent of dichloromethane: methanol, 1:60 for the mass ratio of the extract amount: silica gel, and 3 mL/min of the elution flow rate were shown to be the optimal conditions. These conditions resulted in the highest yield of 6.13 mg per 66.60 mg of starting material, with productivity of 8.76% and purity of 87.04%. Compared with the previous methods, this method can prepare Neferine in large quantities more quickly. We subsequently evaluated the antitumor activity of the purified Neferine against HepG2 hepatic cancer cells. The purified Neferine was found to inhibit the proliferation of HepG2 cells through the CCK-8 assay, with an IC50 of 33.80 µM in 24 h, 29.47 µM in 48 h, 24.35 µM in 72 h and 2.78 µM in 96 h of treatment. Neferine at a concentration of 3 µM could significantly inhibit the migration and invasion abilities of the HepG2 cells in vitro. We also explored the mechanism of action of Neferine via Western blot. We showed that Neferine could reduce RhoA expression by effectively inhibiting the phosphorylation of MYPT1, thereby effectively exerting anti-metastasis activity against HepG2 cells. Thus, we have optimized the isolation procedures for highly pure Neferine by response surface methodology (RSM) in this study, and purified Neferine is shown to play an essential role in the anti-metastasis process of liver cancer cells. The Neferine purification procedure may make a wide contribution to the follow-up development of other anti-metastasis lead compounds.

Enhanced Polarization Properties of Holographic Storage Materials Based on RGO Size Effect.

Polarized holographic properties play an important role in the holographic data storage of traditional organic recording materials. In this study, reduced graphene oxide (RGO) was introduced into a phenanthraquinone-doped polymethylmethacrylate (PQ/PMMA) photopolymer to effectively improve the orthogonal polarization holographic properties of the material. Importantly, the lateral size of RGO nanosheets has an important influence on the polymerization of MMA monomers. To some extent, a larger RGO diameter is more conducive to promoting the polymerization of MMA monomers and can induce more PMMA polymers to be grafted on its surface, thus obtaining a higher PMMA molecular weight. However, too large of a RGO will lead to too much grafting of the PMMA chain to shorten the length of a single PMMA chain, which will lead to the degradation of PQ/PMMA holographic performance. Compared with the original PQ/PMMA, the diffraction efficiency of the RGO-doped PQ/PMMA photopolymer can reach more than 11.4% (more than 3.5 times higher than the original PQ/PMMA), and its photosensitivity is significantly improved by 4.6 times. This study successfully synthesized RGO-doped PQ/PMMA high-performance photopolymer functional materials for multi-dimensional holographic storage by introducing RGO nanoparticles. Furthermore, the polarization holographic properties of PQ/PMMA photopolymer materials can be further accurately improved to a new level.

Highly sensitive photopolymer for holographic data storage.

The insufficient photosensitivity of conventional organic recording materials such as phenanthraquinone-doped poly(methyl methacrylate) (PQ/PMMA) significantly limits the recording speed in holographic data storage. Accelerating the formation of free radicals using the photosensitizer PQ during the photoreaction process and increasing the C = C double bond concentration of the matrix are effective methods for improving the photosensitivity. Using the above methods, we doped PQ/PMMA with the co-photoinitiator triethanolamine and co-monomer acrylamide to improve the photosensitivity of the material. Compared with the original PQ/PMMA material, the photosensitivity was increased by 10 times, and the diffraction efficiency was increased by 20%. The role of each doping component was studied by characterization and analysis. In addition, the introduction of the cross-linking agent N,N'-methylene-bisacrylamide, having high sensitivity, reduced the shrinkage of the material. We verified the application of the new material in a collinear system, and its high sensitivity showed its great potential for holographic data storage.

Elevated N-terminal pro C-type natriuretic peptide is associated with mortality in patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Unlike N-terminal pro-B-type natriuretic peptide (NT-proBNP), which have been extensively studied, little is known about the role of N-terminal pro-C-type natriuretic peptide (NT-proCNP) for predicting survival post transcatheter aortic valve replacement (TAVR). METHODS: A total of 309 patients were included in the analysis. Patients were grouped into quartiles (Q1-4) according to the baseline NT-proCNP value. Blood for NT-proCNP analysis was obtained prior to TAVR procedure. The primary endpoint was mortality after a median follow-up of 32 months. Multivariable Cox proportional hazards regression models analyzed prognostic factors. The predictive capability was compared between NT-proBNP and NT-proCNP using receiver operator curve (ROC) analysis. RESULTS: A total of 309 subjects with the mean age of 76.8 ± 6.3 years, among whom 58.6% were male, were included in the analysis. A total of 58 (18.8%) patients died during follow-up. Cox multivariable analyses indicated society of thoracic surgeons (STS)-score was a strong independent predictor for mortality (hazard ratio (HR) 1.08, 95% confidential interval (CI) 1.05-1.12, P < 0.001). Elevated NT-proCNP was associated with a higher risk of cardiovascular mortality (HR 1.02, 95% CI 1.00-1.03, P = 0.025) and All-cause mortality (HR 1.01, 95% CI 1.00-1.03, P = 0.027), whereas NT-proBNP showed a small effect size on mortality. ROC analysis indicated that NT-proCNP was superior to NT-proBNP for TAVR risk evaluation in patients with left ventricular ejection fraction (LVEF) < 50% [(Area under the curve (AUC)-values of 0.79 (0.69; 0.87) vs. 0.59 (0.48; 0.69), P = 0.0453]. CONCLUSIONS: NT-proCNP and STS-Score were the independent prognostic factors of mortality among TAVR patients. Furthermore, NT-proCNP was superior to NT-proBNP for TAVR risk evaluation in patients with LVEF < 50%. Trial registration NCT02803294, 16/06/2016.

Genetic Deletion of HLJ1 Does Not Affect Blood Coagulation in Mice.

HLJ1 (also called DNAJB4) is a member of the DNAJ/Hsp40 family and plays an important role in regulating protein folding and activity. However, there is little information about the role of HLJ1 in the regulation of physiological function. In this study, we investigated the role of HLJ1 in blood coagulation using wild-type C57BL/6 mice and HLJ1-null (HLJ1-/-) mice. Western blot analysis and immunohistochemistry were used to assess the expression and distribution of HLJ1 protein, respectively. The tail bleeding assay was applied to assess the bleeding time and blood loss. A coagulation test was used for measuring the activity of extrinsic, intrinsic and common coagulation pathways. Thromboelastography was used to measure the coagulation parameters in the progression of blood clot formation. The results showed that HLJ1 was detectable in plasma and bone marrow. The distribution of HLJ1 was co-localized with CD41, the marker of platelets and megakaryocytes. However, genetic deletion of HLJ1 did not alter blood loss and the activity of extrinsic and intrinsic coagulation pathways, as well as blood clot formation, compared to wild-type mice. Collectively, these findings suggest that, although HLJ1 appears in megakaryocytes and platelets, it may not play a role in the function of blood coagulation under normal physiological conditions.

Evaluation algorithm of coastal city ecological civilization development level based on improved BP neural network.

To accurately evaluate the development level of ecological civilization in coastal cities, this paper proposes an evaluation algorithm of coastal city ecological civilization development based on Improved BP neural network, constructs the evaluation index system, and establishes the BP neural network-based evaluation model. By collecting the relevant data of 30 cities in China Line standardization, as the input learning matrix, entropy and coefficient of variation are used to evaluate the development level of ecological civilization. Through 5000 training times, the error accuracy is close to 10-7, and the cities with low ecological civilization level and less cultivated land resources per capita are found out. Based on the improved BP neural network method, according to the development level of coastal cities, the ecological culture of coastal cities is put forward as a whole. The countermeasures and suggestions of construction are given.

Phenanthraquinone-Doped Polymethyl Methacrylate Photopolymer for Holographic Recording.

Phenanthraquinone-doped polymethyl methacrylate (PQ/PMMA) photopolymers are considered to be the most promising holographic storage media due to their unique properties, such as high stability, a simple preparation process, low price, and volumetric shrinkage. This paper reviews the development process of PQ/PMMA photopolymers from inception to the present, summarizes the process, and looks at the development potential of PQ/PMMA in practical applications.

Pharmacologic targeting of the P-TEFb complex as a therapeutic strategy for chronic myeloid leukemia.

BACKGROUND: The positive transcription elongation factor b (P-TEFb) kinase activity is involved in the process of transcription. Cyclin-dependent kinase 9 (CDK9), a core component of P-TEFb, regulates the process of transcription elongation, which is associated with differentiation and apoptosis in many cancer types. Wogonin, a natural CDK9 inhibitor isolated from Scutellaria baicalensis. This study aimed to investigate the involved molecular mechanisms of wogonin on anti- chronic myeloid leukemia (CML) cells. MATERIALS AND METHODS: mRNA and protein levels were analysed by RT-qPCR and western blot. Flow cytometry was used to assess cell differentiation and apoptosis. Cell transfection, immunofluorescence analysis and co-immunoprecipitation (co-IP) assays were applied to address the potential regulatory mechanism of wogonin. KU-812 cells xenograft NOD/SCID mice model was used to assess and verify the mechanism in vivo. RESULTS: We reported that the anti-CML effects in K562, KU-812 and primary CML cells induced by wogonin were regulated by P-TEFb complex. We also confirmed the relationship between CDK9 and erythroid differentiation via knockdown the expression of CDK9. For further study the mechanism of erythroid differentiation induced by wogonin, co-IP experiments were used to demonstrate that wogonin increased the binding between GATA-1 and FOG-1 but decreased the binding between GATA-1 and RUNX1, which were depended on P-TEFb. Also, wogonin induced apoptosis and decreased the mRNA and protein levels of MCL-1 in KU-812 cells, which is the downstream of P-TEFb. In vivo studies showed wogonin had good anti-tumor effects in KU-812 xenografts NOD/ SCID mice model and decreased the proportion of human CD45+ cells in spleens of mice. We also verified that wogonin exhibited anti-CML effects through modulating P-TEFb activity in vivo. CONCLUSIONS: Our study indicated a special mechanism involving the regulation of P-TEFb kinase activity in CML cells, providing evidences for further application of wogonin in CML clinical treatment. Video Abstract.

A randomized comparison of two paclitaxel-coated balloons for the treatment of in-stent restenosis: The LONGTY ISR China randomized trial (LONGTY DCB vs. SeQuent Please DCB).

OBJECTIVES: This study sought to compare the efficacy and clinical safety of the LONGTY drug-coated balloon (DCB) with those of SeQuent Please DCB in patients with in-stent restenosis (ISR). BACKGROUND: Although DCB technologies have evolved, little is known about the clinical efficacy of the new-generation LONGTY DCB. METHODS: This was a prospective, multicenter, randomized, noninferiority trial comparing LONGTY DCB with SeQuent Please DCB in patients with ISR. The primary endpoint was target lesion late lumen loss at 9 months' follow-up. RESULTS: A total of 211 patients with ISR from 13 Chinese sites were included (LONGTY DCB, n = 105; SeQuent Please DCB, n = 106). Device success was achieved in all patients. At the 9 month angiographic follow-up, target lesion late lumen loss was 0.35 ± 0.42 mm with LONGTY and 0.38 ± 0.45 mm with SeQuent Please (p for noninferiority <.001). The target lesion revascularization rates at 1 year were similar in both DCB groups (15.24 vs. 13.21%; p = .673). Over an extended follow-up of 2 years, the clinical endpoints, including cardiac death, myocardial infarction, and thrombus rate, were extremely low and similar in both groups. CONCLUSIONS: In this multicenter, head-to-head, randomized trial, the new-generation LONGTY DCB was noninferior to the SeQuent Please DCB for the primary endpoint of target lesion late lumen loss at 9 months.

LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK-eIF2α-ATF4-CHOP axis.

Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1-25 µM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC50 values of around 10 µM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP3R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK-eIF2α-ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress-related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP3R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. In NOD/SCID mice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent against CTCL.

JAV1 controls jasmonate-regulated plant defense.

Plants evolve effective mechanisms to protect themselves from environmental stresses and employ jasmonates as vital defense signals to defend against insect attack and pathogen infection. Jasmonates are also recognized as an essential growth regulator by which diverse developmental processes are mediated. Despite substantial research, there are no key signaling components reported yet to control jasmonate-regulated plant defense independent of developmental responses. We identify JAV1, a key gene in the jasmonate pathway, which functions as a negative regulator to control plant defense but does not play a detectable role in plant development. Our results suggest that when encountering insect attack and pathogen infection, plants accumulate jasmonates that trigger JAV1 degradation via the 26S proteasome to activate defensive gene expression and elevate resistances against both insects and pathogens. These findings have provided insight into the molecular mechanism by which plants integrate jasmonate signals to protect themselves from insect attack and pathogen infection.

Dependence of the Nanoscale Composite Morphology of Fe3O4 Nanoparticle-Infused Lysozyme Amyloid Fibrils on Timing of Infusion: A Combined SAXS and AFM Study.

Understanding the formation process and the spatial distribution of nanoparticle (NP) clusters on amyloid fibrils is an essential step for the development of NP-based methods to inhibit aggregation of amyloidal proteins or reverse the assembling trend of the proto-fibrillary complexes that prompts pathogenesis of neuro degeneration. For this, a detailed structural determination of the diverse hybrid assemblies that are forming is needed, which can be achieved by advanced X-ray scattering techniques. Using a combined solution small angle X-ray scattering (SAXS) and atomic force microscopy (AFM) approach, this study investigates the intrinsic trends of the interaction between lysozyme amyloid fibrils (LAFs) and Fe3O4 NPs before and after fibrillization at nanometer resolution. AFM images reveal that the number of NP clusters interacting with the lysozyme fibers does not increase significantly with NP volume concentration, suggesting a saturation in NP aggregation on the fibrillary surface. The data indicate that the number of non-adsorbed Fe3O4 NPs is highly dependent on the timing of NP infusion within the synthesis process. SAXS data yield access to the spatial distribution, aggregation manner and density of NP clusters on the fibrillary surfaces. Employing modern data analysis approaches, the shape and internal structural morphology of the so formed nanocomposites are revealed. The combined experimental approach suggests that while Fe3O4 NPs infusion does not prevent the fibril-formation, the variation of NP concentration and size at different stages of the fibrillization process can impose a pronounced impact on the superficial and internal structural morphologies of these nanocomposites. These findings may be applicable in devising advanced therapeutic treatments for neurodegenerative diseases and designing novel bio-inorganic magnetic devices. Our results further demonstrate that modern X-ray methods give access to the structure of-and insight into the formation process of-biological-inorganic hybrid structures in solution.

Effect of the concentration of protein and nanoparticles on the structure of biohybrid nanocomposites.

We present colloidal nanocomposites formed by incorporating magnetite Fe3 O4 nanoparticles (MNPs) with lysozyme amyloid fibrils (LAFs). Preparation of two types of solutions, with and without addition of salt, was carried out to elucidate the structure of MNPs-incorporated fibrillary nanocomposites and to study the effect of the presence of salt on the stability of the nanocomposites. The structural morphology of the LAFs and their interaction with MNPs were analyzed by atomic force microscopy and small-angle x-ray scattering measurements. The results indicate that conformational properties of the fibrils are dependent on the concentration of protein, and the precise ratio of the concentration of the protein and MNPs is crucially important for the stability of the fibrillary nanocomposites. Our results confirm that despite the change in fibrillary morphology induced by the varying concentration of the protein, the adsorption of MNPs on the surface of LAF is morphologically independent. Moreover, most importantly, the samples containing salt have excellent stability for up to 1 year of shelf-life.

LW-213, a newly synthesized flavonoid, induces G2/M phase arrest and apoptosis in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell neoplasm characterized by an uncontrolled proliferation of moderately and well differentiated cells of the granulocytic lineage. LW-213, a newly synthesized flavonoid compound, was found to exert antitumor effects against breast cancer through inducing G2/M phase arrest. We investigated whether LW-213 exerted anti-CML effects and the underlying mechanisms. We showed that LW-213 inhibited the growth of human CML cell lines K562 and imatinid-resistant K562 (K562r) in dose- and time-dependent manners with IC50 values at the low µmol/L levels. LW-213 (5, 10, 15 µM) caused G2/M phase arrest of K562 and K562r cells via reducing the activity of G2/M phase transition-related proteins Cyclin B1/CDC2 complex. LW-213 treatment induced apoptosis of K562 and K562r cells via inhibiting the expression of CDK9 through lysosome degradation, thus leading to the suppression of RNAPII phosphorylation, down-regulation of a short-lived anti-apoptic protein MCL-1. The lysosome inhibitor, NH4Cl, could reverse the anti-CML effects of LW-213 including CDK9 degradation and apoptosis. LW-213 treatment also degraded the downstream proteins of BCR-ABL1, such as oncoproteins AKT, STAT3/5 in CML cells, which was blocked by NH4Cl. In primary CML cells and CD34+ stem cells, LW-213 maintained its pro-apoptotic activity. In a K562 cells-bearing mice model, administration of LW-213 (2.5, 5.0 mg/kg, ip, every other day for 4 weeks) dose-dependently prolonged the survival duration, and significantly suppressed huCD45+ cell infiltration and expression of MCL-1 in spleens. Taken together, our results demonstrate that LW-213 may be an efficient agent for CML treatment.

Mitotic catastrophe and p53-dependent senescence induction in T-cell malignancies exposed to nonlethal dosage of GL-V9.

Mitotic catastrophe of cancer cells induced by drugs is characterized by low dosage and low toxicity, representing a significant advantage in the cancer treatment. Effective therapeutic options are limited for T-cell malignancies patients who are still treated by high-dose multiagent chemotherapy, potentially followed by hematopoietic stem cell transplantation, highlighting the urgency for identification of more effective anti-T-cell malignancies drugs. The use of antineoplastic drugs which induced tumor cell mitotic catastrophe would be a new strategy for cancer therapy. Nevertheless, there is still no effective mitotic catastrophe agent in T-cell malignancies. Our study showed that nonlethal dosage (ND) of GL-V9 (5-hydroxy-8-methoxy-2-phenyl-7-(4-(pyrrolidin-1-yl) butoxy) 4 H-chromen-4-one) (2 µM), a potential anticancer drug, not only attenuated cell growth and survival, but also arrested the cell cycle in G2/M phase and induced multipolar spindles, nuclear alterations (micronucleation and multinucleation), which are the most prominent morphological characteristics of mitotic catastrophe, in T-cell malignancies cell lines including Jurkat, HuT-102, and HuT-78. Moreover, ND GL-V9 could trigger DNA damage, and significantly influence several mitosis-associated proteins. Besides, results showed that ND GL-V9 increased the activity of senescence-associated ß-galactosidase (SA-ß-Gal) following the induction of mitotic catastrophe in Jurkat and HuT-102 cells with intact p53, while causing apoptosis in p53-deficient HuT-78 cells. We concluded that the anti-T-cell malignancies effects of ND GL-V9 and clarified the precise regulation in the process of mitosis under the action of GL-V9 in T-cell malignancies. Our data provided new evidence for the study of T-cell malignancies treatment associated with mitotic catastrophe and cellular senescence induction.

A20 overexpression exerts protective effects on podocyte injury in lupus nephritis by downregulating UCH-L1.

Lupus nephritis (LN), an autoimmune kidney disease caused by systemic lupus erythematosus (SLE), is the inflammation of the kidney. Although the treatment of LN is still a therapeutic challenge for many practitioners, the present study aims to provide a new insight for the treatment and management. The study aims to explore the effect of A20 on LN in relation to the nuclear factor-kappa B (NF-κB) signaling pathway. MRL/lpr mice were used as the LN mouse model. Next, A20, UCH-L1, and NF-κB expression in LN patients and MRL/lpr mice was determined. A20 was upregulated in podocytes to assess biological functions of A20 in LN. Furthermore, to further investigate the pivotal role of the NF-κB pathway in LN, the NF-κB pathway was blocked in podocytes. Next, UCH-L1 was downregulated in MRL/lpr mice to assess biological functions of UCH-L1 in LN. A20 was downregulated, whereas UCH-L1 was upregulated in LN. Overexpressed A20 declined NF-κB, UCH-L1 expression, and the extent of p65 phosphorylation. A20 overexpression or UCH-L1 inhibition increased expression of synaptoporin and nephrin but decreased desmin expression and ubiquitin accumulation level in podocytes. Moreover, A20 overexpression or UCH-L1 inhibition increased the podocyte number but decreased protein level of cleaved caspase-3, podocyte lesion improvement, decreased foot process width, glomerulus basement membrane, and foot process fusion rate. In addition, urine protein, blood urea nitrogen, serum creatinine, and ds-DNA antibody levels decreased with elevated A20 or depleted UCH-L1. Collectively, it could be concluded that A20 protects against podocyte injury in LN via UCH-L1 by inactivating the NF-κB signaling pathway.