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Purpose: Disulfidptosis is a novel type of cell death induced by disulphide stress that depends on the accumulation of cystine disulphide, causing cytotoxicity and triggering cell death. However, the direct prognostic effect and regulatory mechanism of disulfidptosis-related genes in bladder urothelial carcinoma (BLCA) remain unclear. Methods: To explore the role of 10 disulfidptosis-related genes, the multiomic data of 10 genes were comprehensively analysed. Next, based on seven disulfidptosis-related differentially expressed genes, a novel disulfidptosis-related gene score was developed to help predict the prognosis of BLCA. Immunohistochemistry, EDU, Real-time PCR and western blot were used to verify the model. Results: Significant functional differences were found between the high- and low-risk score groups, and samples with a higher risk score were more malignant. Furthermore, the tumour exclusion and Tumour Immune Dysfunction and Exclusion scores of the high-risk score group were higher than those of the low-risk score group. The risk score was positively correlated with the expression of immune checkpoints. Drug sensitivity analyses revealed that the low-risk score group had a higher sensitivity to cisplatin, doxorubicin, docetaxel and gemcitabine than the high-risk score group. Moreover, the expression of the TM4SF1 was positively correlated with the malignancy degree of BLCA, and the proliferation ability of BLCA cells was reduced after knockdown TM4SF1. Conclusion: The present study results suggest that disulfidptosis-related genes influence the prognosis of BLCA through their involvement in immune cell infiltration. Thus, these findings indicate the role of disulfidptosis in BLCA and its potential regulatory mechanisms. [ABSTRACT FROM AUTHOR]

Eltrombopag (EPAG) can improve the efficacy of immunosuppressive therapy (IST) consisting of antithymocyte immunoglobulin (ATG) and cyclosporin in severe aplastic anemia (SAA) patients. This study explored whether patients with SAA could benefit from continuous usage of EPAG beyond 6 months. Seventy-four treatment-naive Chinese patients with SAA were administrated with rabbit ATG-based IST plus EPAG for 6 months. Patients not achieving complete remission (CR) at 6 months were treated with EPAG for another 6 months. At 1, 3, 6 and 12 months after IST, the cumulative response rates were 31%, 61%, 82% and 90%, and the cumulative CR rates were 0, 14%, 27% and 45%, respectively. The cumulative effect curve showed that 93% and 53% of all remission and CR occurred within 6 months, while 98% and 83% of all remission and CR occurred within 12 months. Thirty-seven percent of patients (11 of 30) with partial remission (PR) at 6 months continuously exposed to EPAG improved to CR within 3 (1–5) months of the extended median time. Six patients failing at 6 months continued to use EPAG. Three patients showed improved responses with an extended median time of 6 (1–6) months. The 2-year event-free survival (EFS) was better in those continuing with EPAG (89% vs. 49%, P = 0.006) for patients with PR or non-remission at 6 months. Continuous administration with EPAG could improve the hematologic response and EFS in patients without achieving CR at 6 months. This trial has been registered at the Chinese Clinical Trial Registry (ChiCTR2100045895). [ABSTRACT FROM AUTHOR]

In this work, thermal deep drawing and thermoelectric coupling drawing tests were performed on an annealed ZK60 magnesium alloy sheet to investigate the effect of the pulse current on the formability of the ZK60 magnesium alloy during the drawing process. The effects of thermal deep drawing and the thermoelectric coupling on the forming of drawn parts were studied, and the changes of the thinning rate and hardness were obtained. The results showed that the using of pulse current improved the formability of the ZK60 magnesium alloy and increased the ultimate depth of drawing. The hardness value of the drawn part showed an overall increasing trend, followed by thermoelectric coupling deep drawing, which was significantly higher than the sheet after annealing without deep drawing. The deep-drawn parts had different grain sizes in different places, and dynamic recrystallization occurred to varying degrees in each region. Furthermore, the degree of dynamic recrystallization in the punch fillet and cylinder wall was significantly higher than in other areas. [ABSTRACT FROM AUTHOR]

Mine tailings are stored in tailings storage facilities (TSF), normally in the form of tailings dams. High-stacked tailings dams (HTD) are failure-prone for several reasons, such as overtopping, seepage failure, and strength deterioration. The investigation of compressibility and permeability of tailings material with different particle sizes under high pressure is essential for safety stability. By self-developed high-pressure consolidation permeability apparatus (HCPA), the laboratory conjoined consolidation permeability tests are carried out on tailings with different particle sizes at the maximum consolidation pressure (σ'v) of 5 MPa. For compressibility of tailings in the high-pressure stage (σ'v > 2 MPa), the void ratio e of tailings with different particle sizes has a new linear relationship with σ'v. Coarse-grained tailings have a "secondary- compression-like property" due to particle breakage under high pressure. The hydraulic conductivity of tailings under high pressure presents a piecewise linear k-σ'v relationship. With the decrease in particle size and the increase of σ'v, the seepage pattern of tailings changes from channel seepage to micropore seepage. σ'v = 2 MPa is regarded as the critical value for high-pressure compression of tailing, and the corresponding microscopic critical value of the average particle spacing is 1.2–1.8 nm. This research explored useful information on the compressibility and permeability of tailings with different particle sizes under high pressure that can provide a reference for improving the stabilization of HTD. [ABSTRACT FROM AUTHOR]

Eltrombopag (EPAG), a thrombopoietin receptor agonist, was approved for the treatment of severe aplastic anemia (SAA) combined with immunosuppressive therapy (IST). However, the effects of real-life use of low doses of EPAG combined with rabbit antithymocyte globulin (ATG)-based IST in Asian patients with SAA are yet unknown. A total of 121 previously untreated Chinese patients with SAA were enrolled in a multicenter registry of the Chinese Eastern Collaboration Group of Anemia (2014-2020): 67 patients received IST alone and 54 patients received additional EPAG. Patients receiving IST plus EPAG had a higher overall response rate (ORR) at 1 month (P = 0.002), 3 months (P = 0.028), 6 months (P = 0.006), and 12 months (P = 0.031) compared to those receiving IST alone. EPAG was the favorable factor for response efficacy at 6 months. The complete response rate in the EPAG plus IST group was 17% at 3 months, 27% at 6 months, and 32% at 12 months, compared to 7% (P = 0.069), 14% (P = 0.11), and 33% (P = 0.92) for those treated with IST alone. The 2-year overall survival rate in EPAG plus IST and IST alone groups was 98% and 88%, respectively (P = 0.078). The rate of adverse events, including clonal evolution, infection, and transaminitis, was similar in the two cohorts. The addition of EPAG to IST was well-tolerated and associated with high rates of hematologic responses among the previously untreated Chinese patients with SAA. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) comprises immune-infiltrating cells that are closely linked to tumor development. By screening and analyzing genes associated with tumor-infiltrating M0 cells, we developed a risk model to provide therapeutic and prognostic guidance in clear cell renal cell carcinoma (ccRCC). First, the infiltration abundance of each immune cell type and its correlation with patient prognosis were analyzed. After assessing the potential link between the depth of immune cell infiltration and prognosis, we screened the infiltrating M0 cells to establish a risk model centered on three key genes (TMEN174, LRRC19, and SAA1). The correlation analysis indicated a positive correlation between the risk score and various stages of the tumor immune cycle, including B-cell recruitment. Furthermore, the risk score was positively correlated with CD8 expression and several popular immune checkpoints (ICs) (TIGIT, CTLA4, CD274, LAG3, and PDCD1). Additionally, the high-risk group (HRG) had higher scores for tumor immune dysfunction and exclusion (TIDE) and exclusion than the low-risk group (LRG). Importantly, the risk score was negatively correlated with the immunotherapy-related pathway enrichment scores, and the LRG showed a greater therapeutic benefit than the HRG. Differences in sensitivity to targeted drugs between the HRG and LRG were analyzed. For commonly used targeted drugs in RCC, including axitinib, pazopanib, temsirolimus, and sunitinib, LRG had lower IC50 values, indicating increased sensitivity. Finally, immunohistochemistry results of 66 paraffin-embedded specimens indicated that SAA1 was strongly expressed in the tumor samples and was associated with tumor metastasis, stage, and grade. SAA1 was found to have a significant pro-tumorigenic effect by experimental validation. In summary, these data confirmed that tumor-infiltrating M0 cells play a key role in the prognosis and treatment of patients with ccRCC. This discovery offers new insights and directions for the prognostic prediction and treatment of ccRCC. [ABSTRACT FROM AUTHOR]

We introduce the Gorenstein algebraic K-theory space and the Gorenstein algebraic K-group of a ring, and show the relation with the classical algebraic K-theory space, and also show the 'resolution theorem' in this context due to Quillen. We characterize the Gorenstein algebraic K-groups by two different algebraic K-groups and by the idempotent completeness of the Gorenstein singularity category of the ring. We compute the Gorenstein algebraic K-groups along a recollement of the bounded Gorenstein derived categories of CM-nite Gorenstein algebras. [ABSTRACT FROM AUTHOR]

Correction to: A real-world experience of eltrombopag plus rabbit antithymocyte immunoglobulin-based IST in Chinese patients with severe aplastic anemia The correct article title should be "A real-world experience of eltrombopag plus rabbit -antithymocyte immunoglobulin-based IST in Chinese patients with severe aplastic anemia". The original article can be found online at https://doi.org/10.1007/s00277-022-04966-w B Correction to: Annals of Hematology b https://doi.org/10.1007/s00277-022-04966-w The article "A real-word experience of eltrombopag plus rabbit -antithymocyte immunoglobulin-based IST in Chinese patients with severe aplastic anemia" was published with a mistake in the title. [Extracted from the article]

The objective of this study was to report the drug delivery system that can integrate the functional building blocks for optical pH-sensing, cancer cell imaging and controlled drug release into a single nanoparticle. The CD/SAHA-QDs-CS/FA nanoparticles were prepared by in-situ immobilization of ZnSe/ZnS quantum dots (QDs) in β-cyclodextrin (CD) and chitosan (CS) polymer loaded with suberoylanilide hydroxamic acid (SAHA). Synthetic CD/SAHA-QDs-CS/FA nanoparticles were approximately 100 nm in size and with blue fluorescence. The drug encapsulation efficiency of nanoparticles was 22.36 % and the encapsulated drug was released via a controlled release mechanism after a 9 h plateau was reached. The efficiency of the drug release in tumor microenvironments (pH 5.3 buffer solutions) was higher than that in physiological pH 7.4. In vitro cytotoxicity assay results showed that the blank nanoparticles had no cytotoxicity and therefore can be used as the fluorescence tracer, and the SAHA-encapsulated nanoparticles expressed an anticancer effect. Confocal microscopy and in vivo imaging studies showed that the developed nanoparticles had cytotoxicity in resistant cancer cells and preferentially accumulated in tumors. CD/SAHA-QDs-CS/FA nanoparticles with excellent long-term optical properties have great prospects for the development of targeting tracers and anti-tumor biomedical research. [ABSTRACT FROM AUTHOR]

The efficacies of pembrolizumab and nivolumab have never been directly compared in a real-world study. Therefore, we sought to retrospectively evaluate the objective response rate (ORR) and the progression-free survival (PFS) of patients with recurrent or advanced non-small cell lung cancer (NSCLC) in a real-world setting. This study included patients with recurrent or advanced NSCLC diagnosed between September 1, 2015 and August 31, 2019, who were treated with programmed cell death 1 (PD-1) inhibitors at the Cancer Center of the Chinese People's Liberation Army. PFS was estimated for each treatment group using Kaplan–Meier curves and log-rank tests. The multivariate analysis of PFS was performed with Cox proportional hazards regression models. A total of 255 patients with advanced or recurrent NSCLC treated with PD-1 inhibitors were identified. The ORR was significantly higher in the pembrolizumab group than in the nivolumab group, while PFS was not significantly different between the two groups. Subgroup analysis showed that the ORR was significantly higher for pembrolizumab than for nivolumab in patients in the first-line therapy subgroup and in those in the combination therapy as first-line therapy subgroup. Survival analysis of patients receiving combination therapy as second- or further-line therapy showed that nivolumab had better efficacy than pembrolizumab. However, the multivariate analysis revealed no significant difference in PFS between patients treated with pembrolizumab and those treated with nivolumab regardless of the subgroup. In our study, no significant difference in PFS was noted between patients treated with pembrolizumab and those treated with nivolumab in various clinical settings. This supports the current practice of choosing either pembrolizumab or nivolumab based on patient preferences. [ABSTRACT FROM AUTHOR]

Magnetic core–shell Fe3O4@SiO2 nanoparticles were synthesized by sol–gel method. Based on the characterization and experimental results, the adsorbent was found to have an average particle size of approximately 120 nm, a pore size range of 2–5 nm and superparamagnetic properties. It exhibited electrostatic and hydrogen bonding interactions during adsorption of methyl orange (MO). The adsorption of MO on the magnetic Fe3O4@SiO2 nanoparticles exhibited pseudo-second-order kinetics, the adsorption process is a spontaneous endothermic adsorption process, which conforms to the Langmuir adsorption isotherm model. he maximum amount of MO was adsorbed at pH = 2, T = 45 °C and t = 30 min, and the highest adsorption capacity was 182.503 mg/g; The unit adsorption capacity of the Fe3O4@SiO2 nanoparticles still reached 83% of the original capacity after 5 cycles, so the material was reusable and met the requirements of environmental protection. This study reveals the great potential of magnetic mesoporous nanoparticles for removal of dyes from wastewater. [ABSTRACT FROM AUTHOR]

In a DC microgrid, the negative damping characteristics of a constant power load can deteriorate the stability of the whole system. To improve the robustness and stability of the DC microgrid, a hybrid passivity-based control of damping injection is presented in this paper. The stability of the closed-loop system is ensured by the energy dissipation property of the passivity-based control. A proportional-integral controller is integrated with the passivity-based controller to form a hybrid passivity-based control to improve control robustness. A small-signal model of a DC power system with constant power load is derived in detail, and the stability of the system is analyzed with the Lyapunov eigenvalue method. The proposed hybrid passivity-based control provides the system with a faster recovery and a larger power boundary when compared with the typical voltage-current dual-loop control. First, the proposed control is verified by simulation of the DC power system based on MATLAB/Simulink, and the feasibility and superiority of the proposed control are further verified by hardware-in-loop (HIL) experiments based on real-time laboratory (RT-Lab) and a TI DSP TMS320 F28335. [ABSTRACT FROM AUTHOR]

Microglia, as innate immune cells in the brain, closely monitor changes in the internal environment and participate in the maintenance of homeostasis in the central nervous system (CNS). Microglia can be polarized to the M1 or M2 phenotype in response to various stimuli in vivo or in vitro, affecting the functions of peripheral neurons. M2 microglia have attracted increasing attention in recent years owing to their beneficial effects on various diseases and injuries of the CNS, such as traumatic brain injury, stroke, Alzheimer's disease and multiple sclerosis. They exert neuroprotective effects by various mechanisms, e.g., suppressing inflammation, promoting the degradation of misfolded and aggregated proteins, promoting neurite growth, enhancing neurogenesis, inhibiting autophagy and apoptosis, promoting myelination, maintaining blood–brain barrier integrity, and enhancing phagocytic activity.This review summarizes the molecular mechanisms by which M2 microglia exert protective effects on neurons and provides a reference for the selection of therapeutic targets for CNS diseases. [ABSTRACT FROM AUTHOR]

Introduction: In this study, the silk fibroin blended constructs were produced, scaffold performances of different kinds of scaffold were analyzed, and the better type for tissue engineering was optimized. Methods: The silk fibroin/collagen (SF/C) and silk fibroin/chitosan (SF/CS) were made using a freeze-drying technique, porosity, water absorption expansion rate, mechanical properties and pore size of different scaffold was detected. Bone marrow mesenchymal stem cells (BMSCs) of 4-week-old male Wistar rats were separated by density gradient centrifugation, third generation BMSCs were seeded onto scaffolds, cultured 14 days, proliferation and metabolize of cells were detected in different time using the thiazolyl blue tetrazolium bromide (MTT) assay method, and cell morphology and distribution were observed by histological analysis and scanning electron microscopy (SEM). Results: Porosity, water absorption expansion rate and Young's modulus of SF/C were significantly higher than SF/CS ( p < 0.05); pore size of SF/C and SF/CS was 103 ± 12 and 76 ± 11 μm and had no significant differences between two types ( p > 0.05); MTT results showed that the metabolism of cells in the SF/C was better than SF/CS; after cultivation for 14 days, in the inner zone of scaffolds, cells staining were little or absent from SF/CS, lots of cells staining were existing in SF/C; pore size was consistent, holes communicated with each other better, stem cells grew well inside the scaffolds, extended fully and secreted much extracellular matrix under SEM in SF/C scaffold; internal structure of SF/CS was disorder, holes size were not consistent, and did not communicated with each other and cells were partly dead. Conclusion: Compared with SF/CS, SF/C scaffold showed better porosity, water absorption expansion rate, elasticity modulus and pore size, cells grow well inside the scaffolds, and was more suitable for tissue engineering. [ABSTRACT FROM AUTHOR]

Mandibular defect repair has always been a clinical challenge, facing technical bottleneck. The new materials directly affect technological breakthroughs in mandibular defect repair field. Our aim is to fabricate a scaffold of advanced biomaterials for repairing of small mandibular defect. Therefore, a novel dual-channel scaffold consisting of silk fibroin/collagen type-I/hydroxyapatite (SCH) and polycaprolactone/hydroxyapatite (PCL/HA) was fabricated by cryogenic 3D printing technology with double nozzles. The mechanical properties and behaviors of the dual-channel scaffold were investigated by performing uniaxial compression, creep, stress relaxation, and ratcheting experiments respectively. The experiments indicated that the dual-channel scaffold was typical non-linear viscoelastic consistent with cancellous tissue; the Young’s modulus of this scaffold was 60.1 kPa. Finite element analysis (FEA) was employed performing a numerical simulation to evaluate the implantation effect in mandible. The stress distribution of the contact area between scaffold and defect was uniform, the maximum Mises stress of cortical bone and cancellous bone in defect area were 54.520 MPa and 3.196 MPa, and the maximum displacement of cortical bone and cancellous bone in defect area were 0.1575 mm and 0.1555 mm respectively, which distributed in the incisor region. The peak maximum Mises stress experienced by the implanted scaffold was 3.128 × 10–3 MPa, and the maximum displacement was 6.453 × 10−2 mm distributed near incisor area. The displacement distribution of the scaffold was consistent with that of cortical and cancellous bone. The scaffold recovered well when the force applied on it disappeared. Above all, the dual-channel scaffold had excellent bio-mechanical properties in implanting mandible, which provides a new idea for the reconstruction of irregular bone defects in the mandible and has good clinical development prospects.Graphical Abstract: Mandibular defect repair has always been a clinical challenge, facing technical bottleneck. The new materials directly affect technological breakthroughs in mandibular defect repair field. Our aim is to fabricate a scaffold of advanced biomaterials for repairing of small mandibular defect. Therefore, a novel dual-channel scaffold consisting of silk fibroin/collagen type-I/hydroxyapatite (SCH) and polycaprolactone/hydroxyapatite (PCL/HA) was fabricated by cryogenic 3D printing technology with double nozzles. The mechanical properties and behaviors of the dual-channel scaffold were investigated by performing uniaxial compression, creep, stress relaxation, and ratcheting experiments respectively. The experiments indicated that the dual-channel scaffold was typical non-linear viscoelastic consistent with cancellous tissue; the Young’s modulus of this scaffold was 60.1 kPa. Finite element analysis (FEA) was employed performing a numerical simulation to evaluate the implantation effect in mandible. The stress distribution of the contact area between scaffold and defect was uniform, the maximum Mises stress of cortical bone and cancellous bone in defect area were 54.520 MPa and 3.196 MPa, and the maximum displacement of cortical bone and cancellous bone in defect area were 0.1575 mm and 0.1555 mm respectively, which distributed in the incisor region. The peak maximum Mises stress experienced by the implanted scaffold was 3.128 × 10–3 MPa, and the maximum displacement was 6.453 × 10−2 mm distributed near incisor area. The displacement distribution of the scaffold was consistent with that of cortical and cancellous bone. The scaffold recovered well when the force applied on it disappeared. Above all, the dual-channel scaffold had excellent bio-mechanical properties in implanting mandible, which provides a new idea for the reconstruction of irregular bone defects in the mandible and has good clinical development prospects. [ABSTRACT FROM AUTHOR]

Background: Rationale exists for combining immune checkpoint inhibitors and PARP inhibitors (PARPi), and results of clinical trials in ovarian cancer are promising, but data in other cancers are limited. Method: Efficacy and safety of PARPi/anti-PD-1 in advanced solid tumors were retrospectively analyzed. The efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results: This retrospective study included data from 40 patients. The ORR was 27.5% (95% CI, 13.0–42.0%), with a DCR of 85.0% (95% CI, 73.4–96.6%). Except four patients in first-line treatment (three with PR and one with SD), the ORR of ≥second-line treatment, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) was 22.2%, 23.1% and 28.6%, and the DCR was 83.3%, 84.6% and 71.4%, separately. The median PFS of all patients, ≥second-line treatment, NSCLC and SCLC was 4.6 m, 4.2 m, 4.5 m and 3.7 m. The median OS was 9.4 m, 11.4 m, 12.7 m and 5.4 m, respectively. Multivariable analysis revealed that BRCA1/2 mutation was positively correlated with ORR (P = 0.008), and LDH≥250U/L was negatively correlated with lowered DCR (P = 0.018), while lymphocyte number, ECOG and LDH significantly influenced both PFS and OS. We found that the possible resistant mechanisms were sarcomatous degeneration and secondary mutation, including BRCA2 truncation mutation, A2M, JAK1,T790M, KEAP1 and mTOR mutation. 37.5% patients had ≥grade 3 adverse events. Conclusion: PARPi/anti-PD-1 is an effective and tolerable method for patients with advanced solid tumors, and BRCA1/2 is a potential biomarker. [ABSTRACT FROM AUTHOR]

The coating of phosphor-in-glass with high refractive index was successfully fabricated for enhanced light extraction efficiency of white LEDs through a multilayer screen-printing and low-temperature sintering procedure. The effects of sintering temperature on the BO-SiO-ZnO glass coating and YAG:Ce phosphor concentration on the phosphor-in-glass coating were investigated. The BO-SiO-ZnO glass matrix possesses low glass transition temperature and appropriate thermal expansion coefficient. With the addition of LaO and WO, high refractive index of 1.82 at 460 nm is acquired. The amorphous glass coating, sintered at 600 °C, yields an optimized transmittance of 50%. Furthermore, negligible thermal degradation is observed in the phosphor-in-glass coating, and the emission peak under the 460-nm excitation is at ~540 nm. When increasing the concentration of phosphor, luminous efficacy and correlated color temperature are both improved, but color rendering index is deteriorated. As the refractive index increases, the light extraction efficiency of white LEDs is enhanced due to the reason that the match of refractive index between the glass matrix and the phosphor decreases the total internal reflection at the interface. [ABSTRACT FROM AUTHOR]

A novel antitumor drug delivery system, docetaxel (DTX)-loaded oxidized single-wall carbon nanohorns (oxSWNHs) with anti-VEGF monoclonal antibody (mAb) as a target agent was constructed. DTX was absorbed onto the oxSWNHs via the physical adsorption or π-π interaction. DSPE-PEG-COOH was non-covalently wrapped to the hydrophobic surface of oxSWNHs to improve its water solubility and biocompatibility. The mAb was bonded to the PEG through amide bond. The DTX@oxSWNHs-PEG-mAb (DDS) exhibited suitable particle size (191.2 ± 2.1 nm), good particle size distribution (PDI: 0.196), and negative zeta potential (−24.3 ± 0.85 mV). These features enhanced permeability and retention (EPR) effect and reduced the drug molecule uptake by the reticuloendothelial system. The in vitro drug release followed non-Fickian diffusion ( n = 0.6857, R = 0.9924) with the cumulative release of DTX 59 ± 1.35 % at 72 h. Compared with free DTX, the DDS enhanced the cytotoxicity in MCF-7 cell lines in vitro efficiently (IC: 2.96 ± 0.6 μg/ml), and provided higher antitumor efficacy (TGI: 69.88 %) in vivo. The histological analysis indicated that the DDS had no significant side effect. Therefore, the new DDS is promising to attain higher pharmaceutical efficacy and lower side effects than free DTX for cancer therapy. The research demonstrated that DTX@oxSWNHs-PEG-mAb might have promising biomedical applications for future cancer therapy. Graphical Abstract: [ABSTRACT FROM AUTHOR]

Estrogen and mechanical strain are two important regulators of bone remodeling. α-zearalanol (α-ZAL) is a new oomycete phytoestrogen that is similar to 17-beta estradiol, but has less adverse effects. The aim of this study was to investigate cell proliferation, differentiation, osteoprotegerin (OPG), and receptor activator of nuclear factor-κB ligand (RANKL) expression in the pre-osteoblast MC3T3-E1 cell line in response to α- ZAL, mechanical strain, or a combination of both. Cell proliferation was assessed by flow cytometry, and alkaline phosphatase (ALP) activity was measured using a spectrophotometric detection kit. mRNA expression of ALP, runt-related transcriptional factor 2 (Runx2), OPG, and RANKL genes was determined by real-time Reverse Transcription-Polymerase Chain Reaction (real-time RT-PCR). Protein expression of Runx2, OPG, and RANKL was determined by Western blotting. α-ZAL alone (10-10 M) suppressed proliferation of MC3T3-E1 cells and promoted the activity and gene expression of ALP, an early marker of osteogenesis. It also enhanced Runx2 mRNA expression and the OPG/RANKL ratio. Mechanical strain alone promoted proliferation and differentiation of MC3T3-E1 cells. In addition, Runx2 protein, but not mRNA expression, was upregulated and the OPG/RANKL ratio increased. Although a combination of α-ZAL and mechanical strain inhibited cell proliferation, high concentrations of α-ZAL (10 M) combined with a high magnitude of strain (2500 με), significantly enhanced ALP activity. α-ZAL with a high magnitude of strain increased RUNX2 protein expression, but lowered the OPG/RANKL ratio. The OPG/RANKL ratio significantly increased in response to α-ZAL combined with a low magnitude of strain (1000 με). Thus, α-ZAL might be a promising candidate for the treatment of osteoporosis. Mechanical strain was effective in inducing osteogenic differentiation. Taken together, our data suggest that α-ZAL combined with a low, but not high magnitude of strain, may provide benefits for osteogenesis. [ABSTRACT FROM AUTHOR]