ZIF-62 glass foam self-supported membranes to address CH4/N2 separations.

Membranes with ultrahigh permeance and practical selectivity could greatly decrease the cost of difficult industrial gas separations, such as CH4/N2 separation. Advanced membranes made from porous materials, such as metal-organic frameworks, can achieve a good gas separation performance, although they are typically formed on support layers or mixed with polymeric matrices, placing limitations on gas permeance. Here an amorphous glass foam, agfZIF-62, wherein a, g and f denote amorphous, glass and foam, respectively, was synthesized by a polymer-thermal-decomposition-assisted melting strategy, starting from a crystalline zeolitic imidazolate framework, ZIF-62. The thermal decomposition of incorporated low-molecular-weight polyethyleneimine evolves CO2, NH3 and H2O gases, creating a large number and variety of pores. This greatly increases pore interconnectivity but maintains the crystalline ZIF-62 ultramicropores, allowing ultrahigh gas permeance and good selectivity. A self-supported circular agfZIF-62 with a thickness of 200-330 µm and area of 8.55 cm2 was used for membrane separation. The membranes perform well, showing a CH4 permeance of 30,000-50,000 gas permeance units, approximately two orders of magnitude higher than that of other reported membranes, with good CH4/N2 selectivity (4-6).

Loop technique for anterior cruciate ligament reconstruction combined with anterolateral structure reinforcement: technical description and clinical results.

PURPOSE: We describe a surgical technique for ACL reconstruction combined with anterolateral structure reinforcement and report early clinical follow-up results. METHODS: The semitendinosus and gracilis tendons are braided into 5 strands and the ACL femoral tunnel and tibial tunnel are created. The graft is passed through the tunnel with the use of a traction suture and the tibial end is fixed with absorbable interference screws at 30° of knee flexion. The ACL graft traction suture is used as an anterolateral reconstruction structure to pass through the proximal exit of the ACL femoral tunnel and then through the depth of the iliotibial bundle to the anterior to Gerdy's tubercle, a bony tunnel is created from the anterior to Gerdy's tubercle to the goose foot, and the traction suture is passed through this bony tunnel to form a Loop structure at 20° of knee flexion. Between March 2021 and May 2022 IKDC score, Lysholm score, and Tegner score were performed preoperatively and 6-12 months postoperatively in 24 consecutive patients who met the indications for this procedure and underwent surgery. The patient's maximum flexion angle, the circumference of the thigh, and the stress X-ray between the operated and healthy knee were measured. RESULTS: Patients showed significant improvement in IKDC score, Lysholm score and Tegner score at a mean follow-up of 7 months postoperatively compared to preoperatively. No significant increase in anterior tibial displacement was found between the patient's operated side and the healthy side. CONCLUSION: The Loop technique ACLR combined with ALSA can be used in patients with an ACL tear combined with a high degree of positive pivot shift. The patient's subjective perception was significantly improved from the preoperative period and knee stability was restored. LEVEL OF EVIDENCE: IV, therapeutic study.

Effective C4 Separation by Zeolite Metal-Organic Framework Composite Membranes.

Inorganic zeolites have excellent molecular sieving properties, but they are difficult to process into macroscopic structures. In this work, we use metal-organic framework (MOF) glass as substrates to engineer the interface with inorganic zeolites, and then assemble the discrete crystalline zeolite powders into monolithic structures. The zeolites are well dispersed and stabilized within the MOF glass matrix, and the monolith has satisfactory mechanical stabilities for membrane applications. We demonstrate the effective separation performance of the membrane for 1,3-butadiene (C4H6) from other C4 hydrocarbons, which is a crucial and challenging separation in the chemical industry. The membrane achieves a high permeance of C4H6 (693.00±21.83 GPU) and a high selectivity over n-butene, n-butane, isobutene, and isobutane (9.72, 9.94, 10.31, and 11.94, respectively). This strategy opens up new possibilities for developing advanced membrane materials for difficult hydrocarbon separations.

Fine mapping of KLW1 that conditions kernel weight mainly through regulating kernel length in wheat (Triticum aestivum L.).

KEY MESSAGE: KLW1 was localized to a 0.6 cM interval near the centromere of chromosome 4B and found to be dominant in conditioning longer kernels and higher kernel weight. Kernel weight is a major wheat yield component and affected by kernel dimensions, filling process and kernel density. Because of this complexity, the mechanism underlying kernel weight is still far from clear. Qtgw.nau-4B or KLW1 was a major kernel weight QTL identified in the Nanda2419 × Wangshuibai population. We showed that introduction of the Nanda2419 allele into elite cultivar Wenmai6 resulted in longer kernels as well as higher kernel weight, without affecting other traits such as spike number per plant, plant height, spike length, spikelet number per spike, and kernel number per spike. KLW1 was dominant in conditioning higher kernel weight and functioned mainly through affecting kernel length. Using F2 plants derived from KLW1 NIL, a high-density genetic map covering the QTL was constructed. KLW1 was consequently confined to the 0.6 cM Xwgrc4219-Xwgrc4067 interval by evaluating the recombinant lines in three field trials. KLW1 is complementary to KT1, the QTL on chromosome 5A of Nanda2419 for thicker and heavier kernels, in producing larger kernels with higher commercial value, augmenting its usefulness in wheat breeding.

Metal-Organic Framework Crystal-Glass Composite Membranes with Preferential Permeation of Ethane.

Metal-organic framework (MOF) glass is an easy to process and self-supported amorphous material that is suitable for fabricating gas separation membranes. However, MOF glasses, such as ZIF-62 and ZIF-4 have low porosity, which makes it difficult to obtain membranes with high permeance. Here, a self-supported MOF crystal-glass composite (CGC) membrane was prepared by melt quenching a mixture of ZIF-62 as the membrane matrix and ZIF-8 as the filler. The conversion of ZIF-62 from crystal to glass and the simultaneous partial melting of ZIF-8 facilitated by the melt state of ZIF-62 make the CGC membrane monolithic, eliminating non-selective grain boundaries and improving selectivity. The thickness of CGC membrane can be adjusted to fabricate a membrane without the need of a support substrate. CGC membranes exhibit a C2 H6 permeance of 41 569 gas permeation units (GPU) and a C2 H6 /C2 H4 selectivity of 7.16. The CGC membrane has abundant pores from the glassy state of ZIF-62 and the crystalline ZIF-8, which enables high gas permeance. ZIF-8 has preferential adsorption for C2 H6 and promotes C2 H6 transport in the membrane, and thus the GCG membrane exhibits ultrahigh C2 H6 permeance and good C2 H6 /C2 H4 selectivity.

Synthesis and biological evaluation of (4-hydroxy-2-(substitued sulfonamido)pyrimidine-5-carbonyl)glycines as oral erythropoietin secretagogues.

Erythropoietin (EPO) is the predominant regulating factor in erythropoiesis. Herein we describe the identification of (4-hydroxy-2-(substitued sulfonamido)pyrimidine-5-carbonyl) glycine-based oral EPO secretagogues. Most of these compounds obviously increased the EPO level in Hep3B cells by stabilizing the hypoxia-inducible factor-α (HIF-α). Furthermore, their potential inhibitory activities against HIF prolyl hydroxylase domain (PHD) revealed their function as PHD inhibitors in PHD-HIF pathway. Compound 6i, with a biphenyl substituent on the sulfonamido group, particularly increased plasma EPO level in mice and could serve as a candidate of EPO stimulating agent for anemia treatment.

Novel Sophoridine Derivatives Bearing Phosphoramide Mustard Moiety Exhibit Potent Antitumor Activities In Vitro and In Vivo.

Novel mustard functionalized sophoridine derivatives were synthesized and evaluated for their cytotoxicity against of a panel of various cancer cell lines. They were shown to be more sensitive to S180 and H22 tumor cells with IC50 values ranging from 1.01⁻3.65 µM, and distinctly were more cytotoxic to cancer cells than normal cell L929. In addition, compounds 7a, 7c, and 7e displayed moderate tumor suppression without apparent organ toxicity in vivo against mice bearing H22 liver tumors. Furthermore, they arrested tumor cells in the G1 phase and induced cellular apoptosis. Their potential binding modes with DNA-Top I complex have also been investigated.

High excimer-state emission of perylene bisimides and recognition of latent fingerprints.

High excimer-state emission in the H-type aggregate of a novel asymmetric perylene bisimide derivative, 6, with triethyleneglycol chains and lactose functionalization was achieved in water. Furthermore, its application for enhancing the visualization of transfer latent fingerprints from glass slides to the poly(vinylidene fluoride) (PVDF) membrane was explored, which showed clear images of the latent fingerprint in daylight and under 365 nm ultraviolet illumination.

Roles of Sagittal Anatomical Parameters of the Pelvis in Primary Total Hip Replacement for Patients with Ankylosing Spondylitis.

We examined the correlation between acetabular prostheses and sagittal anatomical parameters of the pelvis for the preoperative evaluation of total hip arthroplasty in 29 patients with ankylosing spondylitis between April 2004 and November 2011. No implant dislocation or subsidence was observed at 4.18 years. The relationship between sagittal parameters conformed to the equation Pelvic incidence (PI)=Pelvic tilt (PT)+Sacral slope (SS). Better outcomes were achieved in the SS>PT group, postoperative function was positively correlated with SS/PI. Functional abduction and anteversion were positively correlated with PT but negatively correlated with SS. Due to the compensatory changes in the pelvis and spine of patients with AS, the preoperative assessment of sagittal parameters plays pivotal roles in placing acetabular prostheses in optimal positions and preventing postoperative impingement and dislocation.

Impaired ossification coupled with accelerated cartilage degeneration in developmental dysplasia of the hip: evidences from µCT arthrography in a rat model.

BACKGROUND: Developmental dysplasia of the hip (DDH) always leads to cartilage degeneration and osteoarthritis of the hip joint. However, the diagnosis of early cartilage degeneration in DDH is still a clinical challenge. This study aims to investigate the dynamic changes of bone and cartilage in the hip of a rat model of DDH and to explore the potential application of microcomputed tomography (µCT) arthrography to detect early cartilage degeneration in DDH. METHODS: Newborn Wistar rats were used to induce DDH by hindlimb swaddling. The bone and cartilage of the hip in model and control group were analyzed by µCT arthrography and histology examination at postnatal day 10, week 4, 6 and 8. RESULTS: Hip dysplasia developed with age, became obvious at postnatal week 6 and further progressed at week 8. µCT analysis showed that bone mineral density (BMD) and bone volume density (bone volume over total volume, BV/TV) of the femoral head and neck region (FHNR) in model group were both significantly lower than those in control group, and they increased dramatically from postnatal week 4 to week 6 but maintained at a similar level at week 8. Contrast-enhanced µCT (CE-µCT) arthrography and histology data showed age-dependent increase in cartilage attenuation (CA) and decrease in safranin O staining intensity (SI) in model group, respectively. Moreover, the model group revealed remarkably higher CA and lower SI than control group, respectively. In addition, significant changes of CA and SI were both observed from postnatal week 6 to week 8 in model group. A strong linear correlation (r2=0.789, P <0.001) was found between CA and SI in model group. Furthermore, BMD was negatively correlated with SI (t=-2.683, P <0.05), whereas specific bone surface (bone surface over bone volume, BS/BV) was positively correlated with SI (t =4.501, P <0.01), in model group. CONCLUSIONS: Impaired ossification coupled with continuous loss of sGAG in cartilage matrix was found in the dysplasia hip during the disease progression of DDH. Cartilage degeneration in the dysplasia hip may occur early at childhood, accelerated with age and become irreversible at young adult stage. All these abnormal changes could be quantitatively assessed by µCT arthrography.

The biomechanical differences of rotational acetabular osteotomy, Chiari osteotomy and shelf procedure in developmental dysplasia of hip.

BACKGROUND: Rotational acetabular osteotomy (RAO), Chiari osteotomy and shelf procedure are important treatments to delay the progression of osteoarthritis in developmental dysplasia of hip (DDH) patients, but their biomechanical differences are still unknown. This study was to evaluate the different biomechanical changes of hip joint after these three surgeries. METHODS: Sixteen DDH models of 8 human cadaver specimens were reconstructed, and treated by different surgeries, and then strain around femoral head was evaluated by strain gauges. RESULTS: Hip strain value of DDH model was decreased after treated by shelf procedure (Pleft = 0.016 and Pright = 0.021) and rotational acetabular osteotomy (P = 0.004), but not in Chiari osteotomy (P = 0.856). Moreover, the improved ratio of RAO treatment was better than shelf procedure (P = 0.015) and Chiari osteotomy (P = 0.0007), and the descendent range of shelf procedure was greater than Chiari osteotomy (P = 0.018). CONCLUSIONS: From biomechanics points, RAO was more effective in relieving hip joint stress compared with shelf procedure and Chiari osteotomy.

Exploring Derivatives of Quinolizidine Alkaloid Sophoridine in the Design and Biological Mechanistic Evaluation of Histone Deacetylase Inhibitors against Triple-Negative Breast Cancer.

As a critical epigenetic modulator of gene expression, histone deacetylases (HDACs) have been involved in the pathogenesis and therapeutic investigation of cancer. Quinolizidine alkaloid sophoridine is known to have anticancer efficacy but with limited indication. By incorporating the pharmacophore of the HDAC inhibitor into the ring-opened sophoridine core, a new series of sophoridine hydroxamic acid derivatives were synthesized. After structure-activity studies, a selected compound was found to exert significant cytotoxicity in triple-negative breast cancer CAL-51 cells (IC50 1.17 µM), and demonstrated low nanomolar inhibitory potency toward HDAC1/3/6. Cellular functional assays indicated that this compound was able to induce apoptosis and cause accumulation of cells in the S phase of the cell cycle. Western blot analysis revealed it to decrease the expression of DNMT1, DNMT3a and DNMT3b by down-regulating phosphor-ERK1/2. Furthermore, treatment with this compound proved to block the PI3K/AKT/mTOR signaling in the PI3KCA and PTEN-mutant CAL-51 cells. Collectively, this work provides a novel lead compound for the development of potential therapeutics against triple-negative breast cancers, possibly mesenchymal-like subtype.

Exploration of the effect and potential mechanism of quercetin in repairing spinal cord injury based on network pharmacology and in vivo experimental verification.

Spinal cord injury (SCI) is a highly complex neurological disease, but there is no effective repair method. Quercetin is a flavonol drug and has a variety of biological activities, such as scavenging oxygen free radicals in the body to resist oxidation, inhibiting inflammation, and so on. In this study, quercetin was firstly demonstrated to reduce tissue damage, promote neuron survival and repair motor function after SCI in rats through in vivo experiments. Then, 293 potential targets of quercetin repair for SCI were predicted by network pharmacology. GO analysis revealed that the biological processes of potential targets focused mainly on signal transduction, negative regulation of the apoptotic process, protein phosphorylation, drug response, and so on. Similarly, KEGG analysis suggested that these potential targets were involved in cell growth regulation, differentiation, apoptosis, and a few metabolic pathways. PPI network analysis predicted that the key genes were EP300, CREBBP, SRC, HSP90AA1, TP53, PIK3R1, EGFR, ESR1, and CBL. Further, the molecular docking showed that quercetin binds well with these proteins. Finally, RT-qPCR and Western blotting experiments verified that quercetin downregulated the expression levels of PIK3R1 and EGFR. It is suggested that quercetin can repair SCI in rats through PI3K-AKT signaling pathway and EGFR/MAPK pathway, which may provide a new theoretical basis for the repair of spinal cord injury.

Xiao Chai Hu Tang alleviates the pancreatic tumorigenesis via improving the mtDNA N6-Methyladenine modification mediated mitochondrial dysfunction in Syrian hamster model.

BACKGROUND: Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion of pancreatic ductal adenocarcinoma (PDAC), which is a highly malignant tumor and lack of effective treatment. Although Xiao Chai Hu Tang (XCHT) has a good therapeutic effect on pancreatic cancer patients with advanced stage, the effect and mechanism of XCHT remains unclear in pancreatic tumorigenesis. PURPOSE: To assess the therapeutic effects of XCHT on the malignant transformation from PanIN to PDAC and to reveal its mechanisms of pancreatic tumorigenesis. METHODS: Syrian golden hamster were induced by N-Nitrosobis (2-oxopropyl) amine (BOP) to establish the pancreatic tumorigenesis model. The morphological changes of pancreatic tissue were observed by H&E and Masson staining; the Gene ontology (GO) analysis the transcriptional profiling changes; the mitochondrial ATP generation, mitochondrial redox status, mitochondrial DNA (mtDNA) N6-methyladenine (6mA) level and relative mtDNA genes expressions were examined. In addition, immunofluorescence detect the cell localization of 6mA in human pancreatic cancer PANC1 cell. Using the TCGA database, the prognostic effect of mtDNA 6mA demethylation ALKBH1 expression on pancreatic cancer patients was analyzed. RESULTS: We confirmed the mtDNA 6mA levels were gradually increased with the mitochondrial dysfunction in PanINs progression. XCHT showed the effect to inhibit the occurrence and development of pancreatic cancer in Syrian hamster pancreatic tumorigenesis model. In addition, the lack of ALKBH1 mediated mtDNA 6mA increase, mtDNA coded genes down-expression and abnormal redox status were rescued by XCHT. CONCLUSIONS: ALKBH1/mtDNA 6mA mediated mitochondrial dysfunction to induce the occurrence and progression of pancreatic cancer. XCHT can improve ALKBH1 expression and mtDNA 6mA level, regulate the oxidative stress and expression of mtDNA coded genes. This study investigated a new molecular mechanism of pancreatic tumorigenesis, and revealed the therapeutic efficacy of XCHT in pancreatic tumorigenesis for the first time.

miRNA expression profile during osteogenic differentiation of human adipose-derived stem cells.

Human adipose-derived stem cells (hADSC) are capable of differentiating into an osteogenic lineage. It is believed that microRNAs (miRNAs) play important roles in regulating this osteogenic differentiation of human adipose-derived cells, although its molecular mechanism remains unclear. We investigated the miRNA expression profile during osteogenic differentiation of hADSCs, and assessed the roles of involved miRNAs during the osteogenic differentiation. We obtained and cultured human adipose-derived stems cells from donors who underwent elective liposuction or other abdominal surgery at our institution. miRNA expression profiles pre- and post-osteogenic induction were obtained using microarray essay, and differently expressed miRNAs were verified using quantitative real-time polymerase chain reaction (qRT-PCR). The expression of osteogenic proteins was detected using an enzyme-linked immunosorbent assay. Putative targets of the miRNAs were predicted using online software MiRanda, TargetScan, and miRBase. Eight miRNAs were found differently expressed pre- and post-osteogenic induction, among which four miRNAs (miR-17, miR-20a, miR-20b, and miR-106a) were up-regulated and four miRNAs (miR-31, miR-125a-5p, miR-125b, and miR-193a) were down-regulated. qRT-PCR analysis further confirmed the results. Predicted target genes of the differentially expressed miRNAs based on the overlap from three public prediction algorithms: MiRanda, TargetScan, and miRBase Target have the known functions of regulating stem cell osteogenic differentiation, self-renewal, signal transduction, and cell cycle control. We identified a group of miRNAs that may play important roles in regulating hADSC cell differentiation toward an osteoblast lineage. Further study of these miRNAs may elucidate the mechanism of hADSC differentiation into adipose tissue, and thus provide basis for tissue engineering.

SNP identification and allelic-specific PCR markers development for TaGW2, a gene linked to wheat kernel weight.

TaGW2, an orthologous gene of rice OsGW2, has been associated with kernel width and weight of bread wheat (Triticum aestivum). Difference in TaGW2 coding sequence was not found among different wheat varieties in previous researches. In this study, we found eight exons and seven introns in TaGW2 with a full-length cDNA sequence of 1,275 bp, which contains a conserved function domain and seven splice sites that shared homology with rice OsGW2. A single T-base insertion in the eighth exon of TaGW2 on chromosome 6A was detected in a large-kernel wheat variety, Lankaodali. This insertion mutation reduces the coding protein sequence from normal 424 amino acids (~47.2 kDa) to 328 amino acids (~37.1 kDa) by truncating 96 amino acids. The result was validated by identifying histidine-tagged TaGW2 proteins encoded by both alleles of the mutant and the wild types in SDS-PAGE. Allele-specific PCR markers were developed based on the single nucleotide polymorphism (SNP) site. The SNP markers were genotyped for an F(2) segregation population from the cross of Lankaodali × Chinese Spring. Seed traits of F(2:3) families were evaluated in three different environments. The association analysis indicated that F(2:3) families with the mutated TaGW2 allele significantly increased kernel width (KW) and thousand-kernel weight (TKW), and slightly improved kernel length (KL). Using the SNP markers, another two varieties harbored the mutated TaGW2 allele were successfully identified from 22 additional wheat varieties, and they both have large KW and TKW. Cloning and sequencing of the gene further confirmed the functions of the mutated allele of TaGW2 in the two large kernel varieties. The results suggested that TaGW2 may negatively regulate kernel size variation, which shares the same function as OsGW2 in rice. The successful development of SNP markers provides a useful tool for improving kernel yield in wheat.

Effects of IL-1 receptor-associated kinase-4 gene silencing on human osteoblast-like cells.

The aim of this study is to identify the effects of interleukin-1 receptor-associated kinase-4 (IRAK-4) gene silencing on human osteoblast-like cells. The siRNA sequences of the target gene, IRAK-4, were constructed and transferred into MG63 cells (control group = MG63 cells; SC group = MG63 cells transfected with scrambled IRAK-4 siRNA; KD group = MG63 cells transfected with 75 nM IRAK-4 siRNA). The morphological changes, cell growth, cell-cycle progression, apoptosis, and the expression of various cytokines and proteins were compared. Compared with the control and SC groups, IRAK-4 gene silencing in MG63 cells caused morphological changes, inhibited growth, altered the cell-cycle distribution, increased apoptosis (p < 0.05), decreased bone alkaline phosphatase and osteocalcin levels (p < 0.05), and decreased protein expression of Bcl-2/Bax and Bcl-2, p-JNK1/2, p-ERK1/2, and p-p38MAPK (p < 0.05). The results indicated that IRAK-4 gene silencing in MG63 cells inhibited cell proliferation and function and increase apoptosis, which may be related to the decreased Bcl-2/Bax ratio and inhibition of the protein expression of various components of the mitogen-activated protein kinase pathways. The results of this study may help improve the understanding of the relationship between IRAK-4 and osteoblast-like cells and the interactions between various cytokines in the periprosthetic inflammatory environment.

The influence of body mass index on life quality and clinical improvement after total hip arthroplasty.

BACKGROUND: The effect of body mass index (BMI) on the outcome of total hip arthroplasty (THA) remains controversial. The purpose of this study was to examine whether revision rate and postoperative outcomes following THA were influenced by BMI. MATERIALS AND METHODS: We retrospectively evaluated 714 patients (751 hips) who underwent primary THA in our department between March 1991 and April 2006. They were followed prospectively for 5-20 years with 24 deaths (24 hips) and 33 losses (34 hips). Patients were separated into three groups based on BMI: underweight, normal and obese groups. A survival analysis was performed using revision as the endpoint, and a case-matched study that was matched for age, gender, and laterality was designed; outcomes were assessed with the Harris Hip score, 36-item short-form health survey, complication rate and radiological examination. RESULTS: The preoperative scores were lower for the obese group, and the postoperative scores were higher for the normal group. Patients in the obese group obtained the greatest overall improvement in clinical scores from admission to the last follow-up. We found a significantly higher complication rate in the obese group and underweight group. It appears that being underweight was associated with an increased dislocation rate, and obese patients were more likely to have osteolysis, deep vein embolism, and pulmonary thrombosis. The log rank test for survival showed no significant differences among the three groups. CONCLUSIONS: Abnormal BMI does not prevent functional rehabilitation after THA; however, patients with abnormal BMI have to face higher complication rates and poorer clinical outcomes following this operation.

Hyaluronan size alters chondrogenesis of mesenchymal stem cells cultured on tricalcium phosphate-collagen-hyaluronan scaffolds.

Hyaluronan (HA) provides a favorable environment for chondrogenesis of bone marrow mesenchymal stem cells (BMSCs). A previous report from our group indicated that addition of HA increases the chondro-inductive capacity of scaffolds. Therefore, this study aimed to investigate whether the Mw of the HA could affect chondrogenesis of BMSCs seeded on TCP-COL-HA scaffolds. Human BMSCs (hBMSCs) and rabbit BMSCs (rBMSCs) were isolated and expanded. TCP-COL scaffolds and TCP-COL-HA scaffolds with two different HA Mws were assessed for their capacity to induce cartilage regeneration from hBMSCs in vitro and in vivo. The results showed that about 96.96% of hBMSCs expressed CD44. Moreover, Hyal-1 and chondrogenic marker genes expressions were increased in hMSCs seeded on TCP-COL-HA scaffolds, and blocking the HA-CD44 interaction with an anti-CD44 antibody reduced the expression levels of Hyal-1 and chondrogenic marker genes. Additionally, TCP-COL-HA scaffolds with 2000 kDa Mw showed greater induction of BMSC chondrogenesis induction compared with those with 80 kDa Mw. Similar results were observed in an ectopic implantation nude mouse model. In a rabbit osteochondral defect repair model, rBMSCs seeded on TCP-COL-HA scaffolds with 2000 kDa Mw showed greater cartilage regeneration than those seeded with 80 kDa Mw. In addition, hBMSC-seeded TCP-COL-HA scaffolds with 2000 kDa Mw showed a significantly higher mechanical strength than those with 80 kDa Mw. Collectively, these results indicate that the Mw of HA could affect chondrogenesis of BMSCs seeded on TCP-COL-HA scaffolds. The TCP-COL-HA scaffolds might be used as allogenic off the shelf products in cartilage tissue engineering in future.

Sophoridine Derivatives Induce Apoptosis and Autophagy to Suppress the Growth of Triple-Negative Breast Cancer through Inhibition of mTOR Signaling.

In order to improve the antitumor potency and therapeutic margins of natural product sophoridine, its novel nitrogen mustard carbamate derivatives were designed and synthesized. In screening their in vitro activity, we found all the tested compounds were more potent against the highly aggressive triple-negative breast cancer cell line MDA-MB-231. Cellular functional assays showed that representative compounds could induce G1-phase arrest and trigger apoptosis, evidenced by the alteration of Bax, Bcl-2, caspase-3 and PARP levels. Furthermore, these compounds significantly enhanced the autophagic flux with increased expression of LC3-II and Beclin-1, as well as decreased level of p62, which may attribute to simultaneously inhibition of the phosphorylation of p70S6K, 4E-BP1 and AKT, the key substrates of the mTOR signaling pathway. In vivo, two compounds revealed potent antitumor activity in mice bearing MDA-MB-231. Altogether, our work describes novel leads to yield more potent chemotherapeutics against triple-negative breast cancers, possibly mesenchymal stem-like subtype.