Mechanisms of vascular invasion after cartilage injury and potential engineering cartilage treatment strategies.

Articular cartilage injury is one of the most common diseases in orthopedic clinics. Following an articular cartilage injury, an inability to resist vascular invasion can result in cartilage calcification by newly formed blood vessels. This process ultimately leads to the loss of joint function, significantly impacting the patient's quality of life. As a result, developing anti-angiogenic methods to repair damaged cartilage has become a popular research topic. Despite this, tissue engineering, as an anti-angiogenic strategy in cartilage injury repair, has not yet been adequately investigated. This exhaustive literature review mainly focused on the process and mechanism of vascular invasion in articular cartilage injury repair and summarized the major regulatory factors and signaling pathways affecting angiogenesis in the process of cartilage injury. We aimed to discuss several potential methods for engineering cartilage repair with anti-angiogenic strategies. Three anti-angiogenic tissue engineering methods were identified, including administering angiogenesis inhibitors, applying scaffolds to manage angiogenesis, and utilizing in vitro bioreactors to enhance the therapeutic properties of cultured chondrocytes. The advantages and disadvantages of each strategy were also analyzed. By exploring these anti-angiogenic tissue engineering methods, we hope to provide guidance for researchers in related fields for future research and development in cartilage repair.

lncTIMP3 promotes osteogenic differentiation of bone marrow mesenchymal stem cells via miR-214/Smad4 axis to relieve postmenopausal osteoporosis.

BACKGROUND: Promoting the balance between bone formation and bone resorption is the main therapeutic goal for postmenopausal osteoporosis (PMOP), and bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation plays an important regulatory role in this process. Recently, several long non-coding RNAs (lncRNAs) have been reported to play an important regulatory role in the occurrence and development of OP and participates in a variety of physiological and pathological processes. However, the role of lncRNA tissue inhibitor of metalloproteinases 3 (lncTIMP3) remains to be investigated. METHODS: The characteristics of BMSCs isolated from the PMOP rat model were verified by flow cytometry assay, alkaline phosphatase (ALP), alizarin red and Oil Red O staining assays. Micro-CT and HE staining assays were performed to examine histological changes of the vertebral trabeculae of the rats. RT-qPCR and western blotting assays were carried out to measure the RNA and protein expression levels. The subcellular location of lncTIMP3 was analyzed by FISH assay. The targeting relationships were verified by luciferase reporter assay and RNA pull-down assay. RESULTS: The trabecular spacing was increased in the PMOP rats, while ALP activity and the expression levels of Runx2, Col1a1 and Ocn were all markedly decreased. Among the RNA sequencing results of the clinical samples, lncTIMP3 was the most downregulated differentially expressed lncRNA, also its level was significantly reduced in the OVX rats. Knockdown of lncTIMP3 inhibited osteogenesis of BMSCs, whereas overexpression of lncTIMP3 exhibited the reverse results. Subsequently, lncTIMP3 was confirmed to be located in the cytoplasm of BMSCs, implying its potential as a competing endogenous RNA for miRNAs. Finally, the negative targeting correlations of miR-214 between lncTIMP3 and Smad4 were elucidated in vitro. CONCLUSION: lncTIMP3 may delay the progress of PMOP by promoting the activity of BMSC, the level of osteogenic differentiation marker gene and the formation of calcium nodules by acting on the miR-214/Smad4 axis. This finding may offer valuable insights into the possible management of PMOP.

A Review on The Phytochemistry and Pharmacology of The Genus Sterculia.

The Sterculia genus is comprised of approximately 300 species, which have been widely used as traditional medicines to treat inflammation, snake bites, gastrointestinal diseases, skin diseases, microbial infections and many other diseases. To gain a comprehensive understanding of the therapeutic potential of Sterculia plants, an extensive literature search was conducted in CNKI, Bing, Wanfang Database, Springer Database, Elsevier Database, Google Scholar, Baidu Scholar, PubMed, and other similar websites from January 1971 to March 2024. The research indicated that Sterculia species predominantly contain flavonoids, terpenoids, phenylpropanoids, fatty acids, alkaloids and other chemical components. A wide range of pharmacologic activities such as anti-inflammatory, antioxidant, antibacterial and other biological activities have been reported. Nevertheless, there isn't much scholarly research on the therapeutic material basis of the genus Sterculia. This review reports the ethnobotany, phytochemicals, and biological activities of the plants in the Sterculia genus as herbal remedies.

Benzofuran Derivatives from Cortex Mori Radicis and Their Cholinesterase-Inhibitory Activity.

The phytochemical investigation of Cortex Mori Radicis led to the isolation and identification of a new prenylated benzofuranone (1) and four ring-opening derivatives (2-5) named albaphenol A-E, as well as nigranol A (6), together with ten 2-arylbenzofuran derivatives (7-16). The characterization of the structures of the new compounds and the structural revision of nigranol A (6) were conducted using the comprehensive analysis of spectroscopic data (1D/2D NMR, HRESIMS, CD, and XRD). Compounds 1-16 were tested for their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compounds 1 and 4 showed weak BChE-inhibitory activity (IC50 45.5 and 61.0 µM); six 2-arylbenzofuran derivatives showed more-potent BChE-inhibitory activity (IC50 2.5-32.8 µM) than the positive control galantamine (IC50 35.3 µM), while being inactive or weakly inhibitory toward AChE. Cathafuran C (14) exhibited the most potent and selective inhibitory activity against BChE in a competitive manner, with a Ki value of 1.7 µM. The structure-activity relationships of the benzofuran-type stilbenes were discussed. Furthermore, molecular docking and dynamic simulations were performed to clarify the interactions of the inhibitor-enzyme complex.

Iron induces B cell pyroptosis through Tom20-Bax-caspase-gasdermin E signaling to promote inflammation post-spinal cord injury.

BACKGROUND: Immune inflammatory responses play an important role in spinal cord injury (SCI); however, the beneficial and detrimental effects remain controversial. Many studies have described the role of neutrophils, macrophages, and T lymphocytes in immune inflammatory responses after SCI, although little is known about the role of B lymphocytes, and immunosuppression can easily occur after SCI. METHODS: A mouse model of SCI was established, and HE staining and Nissl staining were performed to observe the pathological changes. The size and morphology of the spleen were examined, and the effects of SCI on spleen function and B cell levels were detected by flow cytometry and ELISA. To explore the specific mechanism of immunosuppression after SCI, B cells from the spleens of SCI model mice were isolated using magnetic beads and analyzed by 4D label-free quantitative proteomics. The level of inflammatory cytokines and iron ions were measured, and the expression of proteins related to the Tom20 pathway was quantified by western blotting. To clarify the relationship between iron ions and B cell pyroptosis after SCI, we used FeSO4 and CCCP, which induce oxidative stress to stimulate SCI, to interfere with B cell processes. siRNA transfection to knock down Tom20 (Tom20-KD) in B cells and human B lymphocytoma cell was used to verify the key role of Tom20. To further explore the effect of iron ions on SCI, we used deferoxamine (DFO) and iron dextran (ID) to interfere with SCI processes in mice. The level of iron ions in splenic B cells and the expression of proteins related to the Tom20-Bax-caspase-gasdermin E (GSDME) pathway were analyzed. RESULTS: SCI could damage spleen function and lead to a decrease in B cell levels; SCI upregulated the expression of Tom20 protein in the mitochondria of B cells; SCI could regulate the concentration of iron ions and activate the Tom20-Bax-caspase-GSDME pathway to induce B cell pyroptosis. Iron ions aggravated CCCP-induced B cell pyroptosis and human B lymphocytoma pyroptosis by activating the Tom20-Bax-caspase-GSDME pathway. DFO could reduce inflammation and promote repair after SCI by inhibiting Tom20-Bax-caspase-GSDME-induced B cell pyroptosis. CONCLUSIONS: Iron overload activates the Tom20-Bax-caspase-GSDME pathway after SCI, induces B cell pyroptosis, promotes inflammation, and aggravates the changes caused by SCI. This may represent a novel mechanism through which the immune inflammatory response is induced after SCI and may provide a new key target for the treatment of SCI.

Metformin modulates mitochondrial autophagy in renal tubular epithelial injury induced by high glucose via the Keap1/Nrf2 pathway.

The current study aimed to explore the role and underpinning molecular mechanisms of metformin in renal cellular injury induced by high glucose levels. Male C57BL/KsJ (db/db) and (db/m +) mice were utilized in this study. The experimental group was administered 1 mg/mL of metformin through drinking water. Renal tissues were harvested for hematoxylin and eosin (HE) staining, superoxide dismutase (SOD) activity detection, biochemical indices analysis, Western blotting, and qRT-PCR. HK-2 cells were utilized for Nrf2 siRNA transfection and to establish a high level of glucose-induced cell models. Metformin was administered at a concentration of 1 mmol/L in the experimental group. Cellular viability was assessed using CCK-8, whereas acridine orange (AO) staining and LC3-mitotracker co-localization staining were employed to evaluate autophagy. The expression of Nrf2, P21, LC3, PTEN-induced putative kinase 1 (PINK1), translocase of outer mitochondrial membrane 20 (TOMM20), and Kelch-like ECH-associated protein 1 (Keap1) were determined through Western blotting and qRT-PCR. Metformin mitigated renal tissue inflammatory damage in diabetic mice, as indicated by upregulated expression of Nrf2, PINK1, LC3, and TOMM20, and downregulated expression of Keap1 and P21. High level of glucose treatment in HK-2 cells resulted in decreased autophagy, and reduced expression of Nrf2, PINK1, LC3, and TOMM20 alongside elevated the expression of Keap1 and P21. Notably, metformin treatment partially counteracted these effects. Nrf2 knockdown intensified these phenomena in the high level of glucose-induced model. Protein-protein interaction network analysis indicated that Nrf2 could regulate the majority autophagy-related proteins via Keap1. Metformin modulates mitochondrial autophagy in high glucose-induced renal tubular epithelial senescence via the Keap1/Nrf2 pathway.

Bioactive Isoquinoline Alkaloids with Diverse Skeletons from Fissistigma polyanthum.

Six new isoquinoline alkaloids, including aporphine alkaloids (2, 3, 9, and 10), a benzylisoquinoline alkaloid (13), and a protoberberine alkaloid (17), were isolated from the roots of Fissistigma polyanthum, along with a new furanone (20) and 13 known isoquinoline alkaloids (1, 4-8, 11, 12, 14-16, 18, and 19). The structures of the new compounds were elucidated by the analysis of spectroscopic data. Compounds 1 and 2 are rare oxalyl-fused dehydroaporphine alkaloids. Compound 12 presented the most potent dual-target activities on AChE inhibition and Aß aggregation inhibition, while compounds 13 and 19 simultaneously exhibited discernible AChE and BChE inhibitions with antioxidant activities. The activity results indicate that F. polyanthum alkaloids have a potential of inhibition and prevention of Alzheimer's disease mainly through both ChEs and ß-amyloid pathways in addition to antioxidant activity.

Efficacy and safety of duloxetine in chronic musculoskeletal pain: a systematic review and meta-analysis.

BACKGROUND: Chronic musculoskeletal pain (CMP) is a complex condition that is mainly treated with analgesic drugs. However, antidepressant intervention is also an important factor in the treatment of CMP. Duloxetine is an effective treatment option for patients with CMP as its antidepressant effect. The purpose of this article is to evaluate the efficacy and safety of duloxetine in treating CMP. DATABASES AND DATA TREATMENT: We searched PubMed, Web of Science, Embase, Cochrane Library from inception to May, 2022. Randomized controlled trials (RCTs) evaluating the efficacy and safety of duloxetine versus placebo in patients with CMP were included. We identified 13 articles and studied a population of 4201 participants in 4 countries. RESULTS: This meta-analysis showed that the duloxetine has statistically significant compared with the placebo control, benefits on 24-hour average pain, living quality, physical function, and global impressions and there was no difference in the incidence of serious adverse event. In general, duloxetine can improve mood and pain level at the same time. CONCLUSIONS: This review shows a significant contribution of duloxetine to CMP symptom relief. This meta-analysis improved that duloxetine can significantly reduce the pain level of patients, improve depressive symptoms and global impression, and has no obvious serious adverse reactions. However, additional studies are required to confirm the relationship between psychological diseases and chronic pain and explore their internal links.

Chinese Herbal Medicine Guilu Erxian Glue Inhibits Osteoclast Formation and Activity via Mc3t3-Derived Extracellular Vesicles in vitro.

Background: Osteoporosis is a systemic bone disease characterized by decreased bone density and quality, destruction of bone microstructure, and increased bone fragility. Extracellular vesicles are lipid bilayer nanoparticles that participate in intercellular communication. Extracellular vesicles are becoming popular in the study of osteoporosis and the bone cell microenvironment. Extracellular vesicles can transmit cell signals and regulate bone homeostasis. Our previous studies revealed that the Chinese herbal medicine Guilu Erxian Glue promotes type I collagen synthesis and osteoprotegerin secretion by osteoblasts in rats, reverses the imbalance of bone homeostasis, and alleviates osteoporosis. Objective: We investigated how osteoblast-derived extracellular vesicles treated with Guilu Erxian Glue affected osteoclasts in vitro. Methods: We quantified osteoclast differentiation of RAW 264.7 using TRAP staining, cell apoptosis using flow cytometry, extracellular vesicle uptake by fluorescence tracing, bone absorption functions by bone resorption lacuna , and transcription of key genes by quantitative real-time PCR. Results: Fluorescently labeled mouse preosteoblastic MC3T3-E1 cells secreted nanoscale substances less than 1 µm in diameter. Mouse macrophage RAW 264.7 cells adsorbed these nanoparticles and PKH26-labeled extracellular vesicles derived from MC3T3-E1 cells on the cell membrane surface. Extracellular vesicles from MC3T3-E1 cells treated with Guilu Erxian Glue inhibited the differentiation of osteoclasts induced by receptor activator of nuclear factor-κB ligand and macrophage colony-stimulating factor and reduced the number of lacunae formed by osteoclasts in vitro compared with controls. Extracellular vesicles from MC3T3-E1 cells treated with Guilu Erxian Glue downregulated the relative messenger RNA expression of c-Fos, cathepsin K, nuclear factor of activated T cells 1, and tartrate-resistant acid phosphatase in osteoclasts, which may be part of the mechanism by which they regulate osteoclasts. Conclusions: Our results demonstrate that extracellular vesicles are essential for signal exchange between osteoblasts and osteoclasts. Although we do not know how Guilu Erxian Glue affects the signaling molecules carried by extracellular vesicles, we have shown for the first time, to our knowledge, that Guilu Erxian Glue can inhibit osteoclast differentiation and function via osteoblast-derived extracellular vesicles. Our findings are conducive to providing a new target for the development of osteoporosis drugs.

Adenoviral Vector for Enhanced Prostate Cancer Specific Transferrin Conjugated Drug Targeted Therapy.

Prostate cancer (PCa) is one of the leading causes of death for men worldwide. Unlike some other types of cancer, there is a lack of targeted therapy for prostate cancer patients that can kill cancer cells but do much less damage to the normal tissue. In this paper, we report on an adenoviral vector enhanced prostate cancer specific transferrin conjugated drug targeted therapy. In particular, a functional PCa-specific gene probe is introduced to drive and up-regulate the transferrin receptor expression on the PCa via adenoviral vector. As a result, significantly enhanced accumulation of nanoscale transferrin-doxorubicin (Tf-DOX) protein drug conjugates and concomitant notably elevated PCa tumor inhibition are observed. This conceptual strategy provides the proof-of-concept for the targeted therapy of PCa that is highly desired but not yet developed.

Accelerating carbon neutrality could help China's energy system align with below 1.5 °C.

To support the achievement of the Paris Agreement's 1.5 °C global warming threshold, China aims to peak CO2 emissions before 2030 and achieve carbon neutrality before 2060. However, the specific carbon neutrality pathway remains to be designed. By applying a refined Chinese version of Global Change Analysis Model, this study examines implications of four illustrative carbon neutrality scenarios for aligning China's energy system with below 1.5 °C by 2100. The results feature a trade-off between China's ambition to transform its energy system toward mid-century and its reliance on carbon dioxide removal (CDR) after carbon neutrality. From a full time perspective until 2100, accelerating carbon neutrality could help China's energy system align with below 1.5 °C. Compared to a 2060 carbon neutrality scenario, a 2050 carbon neutrality scenario reduces China's total mitigation costs between 2021 and 2100 by 1.04% of GDP, reduces reliance on CDR by 36%, and provides some additional co-benefits, such as reduced air pollutants. However, special attention needs to be paid to the fact that accelerating carbon neutrality poses greater challenges and costs to China in overcoming development inertia and restructuring its energy system over the next 30-40 years. Compared to a 2060 carbon neutrality scenario, a 2050 scenario increases China's mitigation costs by a factor of 1.13 between 2021 and 2050. This study suggests through quantitative evidence that China could accelerate emissions reductions and energy system transformation to achieve carbon neutrality, based on its national circumstances and capabilities and international support.

Wen-Shen-Tong-Luo-Zhi-Tong Decoction regulates bone-fat balance in osteoporosis by adipocyte-derived exosomes.

CONTEXT: Wen-Shen-Tong-Luo-Zhi-Tong (WSTLZT) Decoction is a Chinese prescription with antiosteoporosis effects, especially in patients with abnormal lipid metabolism. OBJECTIVE: To explore the effect and mechanism of WSTLZT on osteoporosis (OP) through adipocyte-derived exosomes. MATERIALS AND METHODS: Adipocyte-derived exosomes with or without WSTLZT treated were identified by transmission electron microscopy, nanoparticle tracking analysis (NTA) and western blotting (WB). Co-culture experiments for bone marrow mesenchymal stem cells (BMSCs) and exosomes were performed to examine the uptake and effect of exosome in osteogenesis and adipogenic differentiation of BMSC. MicroRNA profiles, luciferase and IP were used for exploring specific mechanisms of exosome on BMSC. In vivo, 80 Balb/c mice were randomly divided into four groups: Sham, Ovx, Exo (30 µg exosomes), Exo-WSTLZT (30 µg WSTLZT-exosomes), tail vein injection every week. After 12 weeks, the bone microstructure and marrow fat distribution were analysed by micro-CT. RESULTS: ALP, Alizarin red and Oil red staining showed that WSTLZT-induced exosomes from adipocyte can regulate osteoblastic and adipogenic differentiation of BMSC. MicroRNA profiles observed that WSTLZT treatment resulted in 87 differentially expressed miRNAs (p < 0.05). MiR-122-5p with the greatest difference was screened by q-PCR (p < 0.01). The target relationship between miR-122-5p and SPRY2 was tested by luciferase and IP. MiR-122-5p negatively regulated SPRY2 and elevated the activity of MAPK signalling pathway, thereby regulating the osteoblastic and adipogenic differentiation of BMSC. In vivo, exosomes can not only improve bone microarchitecture but also significantly reduce accumulation of bone marrow adipose. CONCLUSIONS: WSTLZT can exert anti-OP effect through SPRY2 via the MAKP signalling by miR-122-5p carried by adipocyte-derived exosomes.

A new method for primary culture of microglia in rats with spinal cord injury.

At present, the primary culture method of microglia is complicated, and the culture of spinal cord microglia is rare, so we will explore to establish a new and efficient primary culture method of microglia in rats with spinal cord injury (SCI). The SCI model of SD rats was established by modified A11en's method, and the model of SCI was performed on 1 d, 3 d, 7 d and 14 d respectively. Then the injured spinal cord was removed, mechanically separated and filtered. The morphology of microglia was observed the next day and its purity was identified by CD11b and Iba1 immunofluorescence labeling. According to the above results, the morphological changes of microglia after 3 d of SCI were observed at 1 d, 2 d and 4 d. The results showed that the purity of microglia was 98%. The number of microglia after 3 d of SCI was the most. After SCI, the migration ability of microglia was enhanced, the number of microglia in the injured area increased, and the number was the highest at 3 d, then gradually decreased. In addition, the microglia after SCI would gradually change from active state to resting state with the passage of time. Therefore, we can use a simple and efficient mechanical separation method to extract primary microglia, which provides the basis for the study of microglia.

FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia.

Internal tandem duplication (ITD) mutations within the FMS-like receptor tyrosine kinase-3 (FLT3) can be found in up to 25% to 30% of acute myeloid leukemia (AML) patients and confer a poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs) have shown clinical responses, they cannot eliminate primitive FLT3-ITD+ AML cells, which are potential sources of relapse. Therefore, elucidating the mechanisms underlying FLT3-ITD+ AML maintenance and drug resistance is essential to develop novel effective treatment strategies. Here, we demonstrate that FLT3 inhibition induces histone deacetylase 8 (HDAC8) upregulation through FOXO1- and FOXO3-mediated transactivation in FLT3-ITD+ AML cells. Upregulated HDAC8 deacetylates and inactivates p53, leading to leukemia maintenance and drug resistance upon TKI treatment. Genetic or pharmacological inhibition of HDAC8 reactivates p53, abrogates leukemia maintenance, and significantly enhances TKI-mediated elimination of FLT3-ITD+ AML cells. Importantly, in FLT3-ITD+ AML patient-derived xenograft models, the combination of FLT3 TKI (AC220) and an HDAC8 inhibitor (22d) significantly inhibits leukemia progression and effectively reduces primitive FLT3-ITD+ AML cells. Moreover, we extend these findings to an AML subtype harboring another tyrosine kinase-activating mutation. In conclusion, our study demonstrates that HDAC8 upregulation is an important mechanism to resist TKIs and promote leukemia maintenance and suggests that combining HDAC8 inhibition with TKI treatment could be a promising strategy to treat FLT3-ITD+ AML and other tyrosine kinase mutation-harboring leukemias.

Optimization of idarubicin and cytarabine induction regimen with homoharringtonine for newly diagnosed acute myeloid leukemia patients based on the peripheral blast clearance rate: A single-arm, phase 2 trial (RJ-AML 2014).

Individualized chemotherapy, which is at the forefront of acute myeloid leukemia (AML) treatment, has moderately improved outcomes over the past decade. Monitoring the peripheral blood blast burden during induction by flow cytometry has shown significant value in the evaluation of treatment responses. Our previous study reported the day 5 peripheral blast clearance rate (D5-PBCR) as an indicator of early treatment response, and D5-PBCR (+) patients showed poor outcomes. We performed the present phase 2 trial of early intervention in D5-PBCR (+) patients with homoharringtonine (HHT) introduced in the traditional induction regimen with anthracycline and cytarabine. The primary endpoint was complete remission (CR). This study enrolled 151 patients, 65 patients were D5-PBCR (+) and 55 patients completed induction with HHT addition. The overall CR rate after one course of induction was 84.4%, with 87.5% and 80.0% for the D5-PBCR (-) and D5-PBCR (+) groups, respectively. The incidence of grade 3/4 adverse events was comparable between the two groups. At the median follow-up of 53.1 months, median overall survival (OS) was not reached in the entire cohort, and median event-free survival (EFS) was 42.2 months. Neither the OS nor EFS showed significant differences between the D5-PBCR (-) and D5-PBCR (+) groups. Compared to historical data, significant improvements in both OS (p = .020) and EFS (p = .020) were observed in the D5-PBCR (+) group. In conclusion, optimization of induction chemotherapy with idarubicin and cytarabine according to D5-PBCR is feasible in patients with newly diagnosed AML. The addition of HHT demonstrated a good efficacy and safety profile.

Chemotherapy or Allogeneic Stem Cell Transplantation as Salvage Therapy for Patients with Refractory Acute Myeloid Leukemia: A Multicenter Analysis.

INTRODUCTION: The overall outcome of patients with refractory AML (rAML) remains poor. Though allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered as the only curative therapy, it is routinely recommended only for patients after remission with salvage chemotherapy. OBJECTIVE: In this study, we evaluated the impact of salvage chemotherapy or allo-HSCT on the overall outcome in rAML. METHODS: We collected the clinical data of 220 patients from 4 medical centers and performed retrospective analysis of prognosis factors, including salvage chemotherapy, intensity of chemotherapy, and allo-HSCT. RESULTS: A total of 29 patients received allo-HSCT directly without salvage chemotherapy, 26 patients achieved complete remission (CR) or complete remission with incomplete hematological recovery (CRi) after transplantation and 4-year leukemia-free survival (LFS) and overall survival (OS) were 45.0 ± 10.7 and 51.0 ± 10.6%, respectively. Another 191 patients received salvage chemotherapy and 81 (42.2%) achieved CR or CRi. Thirty-four patients among them underwent subsequent allo-HSCT with 4-year LFS and OS of 46.0 ± 8.8 and 46.2 ± 9.0%. The 4-year LFS and OS in 26 patients who failed to obtain CR or CRi but received allo-HSCT with active disease were 32.9 ± 10.0 and 36.9 ± 10.8%, respectively. For patients who received salvage chemotherapy but not allo-HSCT, few of them became long-term survivors. In multivariate analysis, salvage chemotherapy and the intensity of chemotherapy failed to have significant impact on both OS and LFS. Allo-HSCT was the only prognostic factor for improved OS and LFS in multivariate analysis. CONCLUSIONS: These results indicate the benefit of allo-HSCT in patients with rAML and direct allo-HSCT without salvage chemotherapy could be treatment option.

The association between a combination of healthy lifestyles and the risks of hypertension and dyslipidemia among adults-evidence from the northeast of China.

BACKGROUND AND AIMS: There is increasing evidence that lifestyle factors play an important role in the development of hypertension and dyslipidemia. However, existing research usually evaluated these risk factors individually (such as physical activity, smoking, drinking, obesity and so on), rather than joint evaluation. The aim of this study was to quantify the association between a combination of a healthy lifestyle and the risk of hypertension and dyslipidemia. METHODS AND RESULT: A healthy lifestyle score was created based on 4 factors: never smoking, moderate to high-intensive physical activity, no alcohol drinking, and normal body mass index. We calculated the healthy lifestyle score using the cumulative number of health factors for each individual. Also, a multivariate analysis was used to assess the relationship between healthy lifestyle and hypertension and dyslipidemia. Among 6446 participants, 650 (10.08%) had lowest healthy lifestyle score (0) and 627 (9.72%) had highest healthy lifestyle score (4), respectively. The adjustment model indicated that participants with the highest score (score: 4), which integrated the four lifestyles, had significantly lower ORs for hypertension compared with the lowest score (score: 0) (0.21; (95%CI: 0.10, 0.43 P-trend< 0.001)). In the adjustment models, compared with lowest healthy lifestyle score, the ORs of highest healthy lifestyle score was: 0.17; (95%CI: 0.07, 0.42 P-trend<0.001) for dyslipidemia. CONCLUSION: Hypertension and dyslipidemia were negatively correlated with healthy lifestyle score. Interventions with healthy lifestyle to reduce hypertension, dyslipidemia and promote population health are warranted.

Dysregulated MDR1 by PRDM1/Blimp1 Is Involved in the Doxorubicin Resistance of Non-Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma.

INTRODUCTION: The chemoresistance mechanism of diffuse large B-cell lymphoma (DLBCL) is still poorly understood, and patient prognosis remains unsatisfactory. This study aimed to investigate drug resistance mechanisms in non-germinal center B-cell-like (non-GCB) DLBCL. METHODS: Doxorubicin (DOX)-resistant OCI-Ly3 cells were generated through long-term incubation of cells in a medium with gradually increasing DOX concentrations. The expression levels of genes related to drug metabolism were determined using a functional gene grouping polymerase chain reaction (PCR) array. Drug-resistant proteins were identified using bioinformatics, and molecular association networks were subsequently generated. The association and mechanism of key genes were determined using a dual-luciferase reporter assay System and chromatin immunoprecipitation (ChIP). The expression of drug-resistant genes and target genes was then measured using Western blotting and immunohistochemistry. The correlation between gene expressions was analyzed using Spearman's rank correlation coefficient. RESULTS: Using the PCR array, MDR1 was identified as the key gene that regulates DOX resistance in OCI-Ly3/DOX-A100, a non-GCB DLBCL cell line. The dual-luciferase reporter assay system demonstrated that MDR1 transcription could be inhibited by PRDM1. ChIP results showed that PRDM1 had the ability to bind to the promoter region (-1,132 to -996) of MDR1. In OCI-Ly3/DOX cells, NF-κB activity and PRDM1 expression decreased with an increase in drug-resistant index, whereas MDR1 expression increased with enhanced drug resistance. Immunohistochemical analysis revealed that relative MDR1 expression was higher than that of PRDM1 in human DLBCL tissue samples. A negative correlation was observed between MDR1 and PRDM1. CONCLUSION: In non-GCB DLBCL cells, NF-κB downregulates PRDM1 and thereby promotes MDR1 transcription by terminating PRDM1-induced transcriptional inhibition of MDR1. Such a mechanism may explain the reason for disease recurrence in non-GCB DLBCL after R-CHOP or combined CHOP with bortezomib treatment. Our findings may provide a potential therapeutic strategy for reducing drug resistance in patients with DLBCL.

Knockdown of LMX1B Suppressed Cell Apoptosis and Inflammatory Response in IL-1ß-Induced Human Osteoarthritis Chondrocytes through NF-κB and NLRP3 Signal Pathway.

Osteoarthritis (OA), a chronic degenerative joint disease, always occurred in the aging population. There is evidence suggests that chondrocytes' survival, inflammation, and apoptosis play critical roles in OA pathogenesis. LMX1B has been shown to be involved in antiosteogenic function in early patterning of the calvaria. However, the role and mechanism of LMX1B in OA is not unknown. The present study observed that LMX1B was highly expressed in OA patients compared with normal patients. Besides, we found that IL-1ß increased LMX1B mRNA and protein expression in SW1353 and C28/I2 chondrocytes. LMX1B knockdown increased IL-1ß-induced cell viability and proliferation and suppressed cell apoptosis and inflammation response, including IFN-γ, TNF-α, IL-6, prostaglandin E2 (PGE2), and NO both in SW1353 and C28/I2. Furthermore, LMX1B silence inhibited MMP-3 and MMP-13 expression both in SW1353 and C28/I2 cells. Also, the activation of the NF-κB and NLRP3 signaling pathway was suppressed in LMX1B silence cells by decreasing the p-p65 and NLRP3 protein expressions. Additionally, inhibition of NF-κB by PDTC suppressed NLRP3 expression. Moreover, NLRP3 overexpression reversed the effects of LMX1B silence on chondrocytes' survival, proliferation, apoptosis, and inflammation. Finally, we confirmed that LMX1B depletion had protective effects in OA rats in vivo.

Sister centromere fusion during meiosis I depends on maintaining cohesins and destabilizing microtubule attachments.

Sister centromere fusion is a process unique to meiosis that promotes co-orientation of the sister kinetochores, ensuring they attach to microtubules from the same pole during metaphase I. We have found that the kinetochore protein SPC105R/KNL1 and Protein Phosphatase 1 (PP1-87B) regulate sister centromere fusion in Drosophila oocytes. The analysis of these two proteins, however, has shown that two independent mechanisms maintain sister centromere fusion. Maintenance of sister centromere fusion by SPC105R depends on Separase, suggesting cohesin proteins must be maintained at the core centromeres. In contrast, maintenance of sister centromere fusion by PP1-87B does not depend on either Separase or WAPL. Instead, PP1-87B maintains sister centromeres fusion by regulating microtubule dynamics. We demonstrate that this regulation is through antagonizing Polo kinase and BubR1, two proteins known to promote stability of kinetochore-microtubule (KT-MT) attachments, suggesting that PP1-87B maintains sister centromere fusion by inhibiting stable KT-MT attachments. Surprisingly, C(3)G, the transverse element of the synaptonemal complex (SC), is also required for centromere separation in Pp1-87B RNAi oocytes. This is evidence for a functional role of centromeric SC in the meiotic divisions, that might involve regulating microtubule dynamics. Together, we propose two mechanisms maintain co-orientation in Drosophila oocytes: one involves SPC105R to protect cohesins at sister centromeres and another involves PP1-87B to regulate spindle forces at end-on attachments.