Epigenetic-based combination therapy and liposomal codelivery overcomes osimertinib-resistant NSCLC via repolarizing tumor-associated macrophages.

Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.

Exosomal MiR-381 from M2-polarized macrophages attenuates urethral fibroblasts activation through YAP/GLS1-regulated glutaminolysis.

OBJECTIVE AND DESIGN: Post-traumatic urethral stricture is a clinical challenge for both patients and clinicians. Targeting glutamine metabolism to suppress excessive activation of urethral fibroblasts (UFBs) is assumed to be a potent and attractive strategy for preventing urethral scarring and stricture. MATERIAL OR SUBJECTS: In cellular experiments, we explored whether glutaminolysis meets the bioenergetic and biosynthetic demands of quiescent UFBs converted into myofibroblasts. At the same time, we examined the specific effects of M2-polarized macrophages on glutaminolysis and activation of UFBs, as well as the mechanism of intercellular signaling. In addition, findings were further verified in vivo in New Zealand rabbits. RESULTS: It revealed that glutamine deprivation or knockdown of glutaminase 1 (GLS1) significantly inhibited UFB activation, proliferation, biosynthesis, and energy metabolism; however, these effects were rescued by cell-permeable dimethyl α-ketoglutarate. Moreover, we found that exosomal miR-381 derived from M2-polarized macrophages could be ingested by UFBs and inhibited GLS1-dependent glutaminolysis, thereby preventing excessive activation of UFBs. Mechanistically, miR-381 directly targets the 3'UTR of Yes-associated protein (YAP) mRNA to reduce its stability at the transcriptional level, ultimately downregulating expression of YAP, and GLS1. In vivo experiments revealed that treatment with either verteporfin or exosomes derived from M2-polarized macrophages significantly reduced urethral stricture in New Zealand rabbits after urethral trauma. CONCLUSION: Collectively, this study demonstrates that exosomal miR-381 from M2-polarized macrophages reduces myofibroblast formation of UFBs and urethral scarring and stricture by inhibiting YAP/GLS1-dependent glutaminolysis.

Role of Platelet to Lymphocyte Ratio and Red Cell Distribution Width in Predicting Postoperative Complications in Patients with Acute Mesenteric Ischemia.

BACKGROUND: The predictive values of the platelet to lymphocyte ratio (PLR) and red cell distribution width (RDW) have been demonstrated in different types of abdominal surgery. The aim of this study was to investigate the interest of the preoperative PLR and RDW as predictors of 30-day postoperative complications in patients with acute mesenteric ischemia (AMI). METHODS: Clinical data of 105 AMI patients were retrospectively reviewed. Postoperative complications were evaluated by the Clavien-Dindo classification. The cutoff values for neutrophil to lymphocyte ratio (NLR), PLR, and RDW were determined by receiver operating characteristic curves. Univariate and multivariate analyses evaluating the risk factors for postoperative complications were performed. RESULTS: In the univariate analyses, advanced age, female, anemia, high white blood cell (WBC), high PLR, high NLR, high RDW, Charlson comorbidity index (CCI) score ≥2, and bowel resection were associated with the postoperative complications. A multivariable analysis revealed that advanced age, high PLR, high RDW, and bowel resection were independent predictors of postoperative complications. CONCLUSIONS: The PLR and RDW might play important roles in evaluation of the risk of postoperative complications in AMI patients. The preoperative PLR and RDW are simple and useful predictors of postoperative complications in AMI patients.

An immune-related lncRNA prognostic model in papillary renal cell carcinoma: A lncRNA expression analysis.

OBJECTIVE: To screen several immune-related long non-coding RNAs (lncRNAs) and construct a prognostic model for papillary renal cell carcinoma (pRCC). METHODS: Transcriptome-sequencing data of pRCC was downloaded and a prognostic model was constructed. Time-dependent receiver operating characteristic (ROC) curve was plotted and the area under curve (AUC) was calculated. We conducted quantitative reverse transcription polymerase chain reaction (RT-PCR) to verify the model. The gene set enrichment analysis (GSEA) was used to show the connection of our model with immune pathways. RESULT: We identified four lncRNAs to constructed the model. The model was significantly associated with the survival time and survival state. The expression-levels of the four lncRNAs were measured and the prognosis of high-risk patients was significantly worse. The two immune-gene sets had an active performance in the high-risk patients. CONCLUSION: We constructed a prognostic model in pRCC which provided more reference for treatment.

Effects of Bedaquiline on Antimicrobial Activity and Cytokine Secretion of Macrophages Infected with Multidrug-Resistant Mycobacterium tuberculosis Strains.

Background: Bedaquiline (Bdq) exerts bactericidal effects against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains, including multidrug-resistant M. tuberculosis strains (MDR-MTBs). However, few reported investigations exist regarding Bdq effects on MDR-MTBs-infected macrophages activities and cytokine secretion. Here, Bdq bactericidal activities against MDR-MTBs and related cellular immune mechanisms were explored. Methods: Macrophages infected with MDR-MTBs or H37Rv received Bdq treatments (4 h/8 h/24 h/48 h) at 1 × the minimum inhibitory concentration (1 × MIC), 10 × MIC and 20 × MIC. Intracellular colony-forming units (CFUs) and culture supernatant IL-12/23 p40, TNF-α, IL-6, and IL-10 were determined using the Luminex® 200TM system. Normally distributed continuous data (mean ± standard deviation) were analyzed using t-test or F-test (SPSS 25.0, P < 0.05 deemed statistically significant). Results: (1) 100% of Bdq-treated macrophages (all doses applied over 4-48 h) survived with 0% inhibition of proliferation observed. (2) Intracellular CFUs of Bdq-treated MDR-MTBs-infected macrophages decreased over 4-48 h of treatment, were lower than preadministration and control CFUs, decreased with increasing Bdq dose, and resembled H37Rv-infected group CFUs (48 h). (3) For MDR-MTBs-infected macrophages (various Bdq doses), IL-12/23 p40 levels resembled preadministration group levels and exceeded controls (4 h); TNF-α levels exceeded preadministration group levels (24 h/48 h) and controls (24 h); IL-12/23 p40 and TNF-α levels resembled H37Rv-infected group levels (4 h/8 h/24 h/48 h); IL-6 levels exceeded preadministration and H37Rv-infected group levels (24 h/48 h) and controls (24 h); IL-10 levels resembled preadministration and H37Rv-infected group levels (4 h/8 h/24 h/48 h) and were lower than controls (24 h/48 h); IL-12/23 p40 and IL-10 levels remained unchanged as intracellular CFUs changed, with IL-12/23 p40 levels exceeding controls (4 h) and IL-10 levels remaining lower than controls (24 h/48 h); TNF-α and IL-6 levels increased as intracellular CFUs decreased (24 h/48 h) and exceed controls (24 h). Conclusion: Bdq was strongly bactericidal against intracellular MDR-MTBs and H37Rv in a time-dependent, concentration-dependent manner. Bdq potentially exerted immunomodulatory effects by inducing high-level Th1 cytokine expression (IL-12/23 p40, TNF-α) and low-level Th2 cytokine expression (IL-10).

[Influence of prostatic calculi on the results of prostate biopsy in patients with a PSA level of 4－10 µg/L].

OBJECTIVE: To investigate the influence of prostatic calculi on the results of prostate biopsy in patients with a PSA level of 4－10 µg/L. METHODS: We reviewed the clinical data on 317 patients with a PSA level of 4－10 µg/L on prostate biopsy performed in The First Affiliated Hospital of Fujian Medical University between May 2012 and May 2019, concerning age, body mass index (BMI), prostate volume, PSA level, FPSA/TPSA ratio, PSA density (PSAD), scores on Prostate Imaging Reporting and Data System version 2 (PI-RADS), prostatic calculi and pathological findings. Using logistic regression analysis and ROC curves, we evaluated the influence of prostatic calculi on the results of prostate biopsy. RESULTS: Multivariate analysis showed that age and the PI-RADS score were independent risk factors of positive prostate biopsy, while the prostate volume, FPSA/TPSA ratio and calculus burden were independent protective factors, and that the PI-RADS score was an independent risk factor of clinically significant PCa, while calculus burden and FPSA/TPSA ratio were independent protective factors. Subgroup analysis of the prostatic calculi revealed that the rates of positive prostate biopsy and clinically significant PCa were higher in the patients with calculi in the peripheral zone than in the other groups, but lower in those with calculi in the central or transitional zone than in the peripheral zone and non-calculus groups. CONCLUSIONS: The rates of positive prostate biopsy and clinically significant PCa are low in prostatic calculus patients with a PSA level of 4－10 µg/L, especially in those with calculi in the central or transitional zone.

Development and validation of hub genes for lymph node metastasis in patients with prostate cancer.

Lymph node metastasis is one of the most important independent risk factors that can negatively affect the prognosis of prostate cancer (PCa); however, the exact mechanisms have not been well studied. This study aims to better understand the underlying mechanism of lymph node metastasis in PCa by bioinformatics analysis. We analysed a total of 367 PCa cases from the cancer genome atlas database and performed weighted gene co-expression network analysis to explore some modules related to lymph node metastasis. Gene Ontology analysis and pathway enrichment analysis were conducted for functional annotation, and a protein-protein interaction network was built. Samples from the International Cancer Genomics Consortium database were used as a validation set. The turquoise module showed the most relevance with lymph node metastasis. Functional annotation showed that biological processes and pathways were mainly related to activation of the processes of cell cycle and mitosis. Four hub genes were selected: CKAP2L, CDCA8, ERCC6L and ARPC1A. Further validation showed that the four hub genes well-distinguished tumour and normal tissues, and they were good biomarkers for lymph node metastasis of PCa. In conclusion, the identified hub genes facilitate our knowledge of the underlying molecular mechanism for lymph node metastasis of PCa.

Bioinformatics Analysis of the Expression of Key Long Intergenic Non-Protein Coding RNA Genes in Bladder Cancer.

BACKGROUND Evidence indicates that there is an important role for long non-coding RNAs (lncRNA) in numerous cellular processes and that lncRNAs dysregulation contributes to tumor progression. Improved insight into the molecular characteristics of bladder cancer is required to predict outcomes and to develop a new rationale for targeted therapeutic strategies. Bioinformatics methods, including functional enrichment and network analysis combined with survival analysis, are required to process a large volume of data to obtain further information about differentially expressed genes (DEGs) in bladder cancer. This study aimed to explore the role of lncRNAs and their regulation network in bladder cancer. MATERIAL AND METHODS We analyzed bladder cancer data by The Cancer Genome Atlas profiling to identify differentially expressed lncRNAs in bladder cancer. The genes involved in the circlncRNAnet database were evaluated using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), evolutionary relationship analysis, and protein-protein interaction (PPI) networks. RESULTS Two new lncRNAs, ADAMTS9-AS1 and LINC00460, were shown to be differentially expressed in bladder cancer. Patients were divided into 2 groups (high expression and low expression) according to their median expression values. The overall survival and disease-free survival of patients with high ADAMTS9-AS1 bladder cancer were significantly shorter; the expression of LINC00460 had no significant correlation with survival. GO and KEGG analysis of the 2 lncRNA-related genes revealed that these lncRNAs played a vital role in tumorigenesis. Bioinformatics analysis showed that key genes related to LINC00460, including CXCL, CCL, and CSF2, may be related to the development of bladder cancer. The low expression of ADAMTS9-AS1 may influence the survival rate of bladder cancer with the hub gene as a target. CONCLUSIONS LncRNA, including LINC00460 and ADAMTS9-AS1, might play a crucial role in the biosynthesis network of bladder cancer. Differential expression results of ADAMTS9-AS1 suggests it may be correlated with a worse prognosis and a shorter survival time. We outlined the biosynthesis network that regulates lncRNAs in bladder cancer. Further experimental data is needed to validate our results.

Work engagement as a mediator between organizational commitment and job satisfaction among community health-care workers in China: a cross-sectional study.

The purpose of this study was to explore levels of organizational commitment, job satisfaction and work engagement among community health-care workers in China, and to examine spatial relationships of variables. Data were collected by Organizational Commitment Scale, Job Satisfaction Scale and Utrecht Work Engagement Scale from 1404 community health-care workers in Guangzhou and Shenzhen cities. Structural equation model was used to analyze relationships among three variables. Medium levels of organizational commitment, job satisfaction and work engagement were found among community health-care workers. Organizational commitment was positively correlated to work engagement (r = 0.564) and job satisfaction (r = 0.550). The path analysis indicated that total effect (ß = 0.598) of organizational commitment on job satisfaction (R2 = 0.52) consisted of a direct effect (ß = 0.264) and an indirect effect (ß = 0.334), which was mediated positively by work engagement. Improvement in work engagement may lead to higher level of job satisfaction and organizational commitment.

Penoscrotal edema: a case report and literature review.

BACKGROUND: Penoscrotal edema is typically caused by lymphatic obstruction, which can have both primary and secondary causes. Studies describing congenital penoscrotal edema are rare. Surgery can be divided into two types: The first approach involves extensive removal of diseased tissue and tissue reconstruction. The second approach is removal of the lesions and creating additional lymphatic vascular anastomoses. CASE PRESENTATION: We present a case report of a 15-year-old patient with recurrent penoscrotal edema and swelling of both lower extremities. The literature were also reviewed to provide additional information. Physical examination revealed slow lymphatic reflux of the lower extremities and no obvious abnormalities in testicular morphology, bilaterally, or blood supply. Surgery was performed by excising the affected skin and subcutaneous tissue and the flaps was cut in the middle in Y shape to cover the penis and scrotum. Postoperative follow-up revealed wound integrity and patient satisfaction with the outcome. CONCLUSION: Excision and reconstructive surgery are the primary treatments for penoscrotal edema. The majority of reported patients undergoing excision and reconstruction achieved satisfactory reshaping and improved their life quality.

[Impact of the degrees of intravesical prostatic protrusion on the recovery of urinary continence after radical prostatectomy].

OBJECTIVE: To investigate the influence of the degrees of intravesical prostatic protrusion (IPP) on the recovery of urinary continence after radical prostatectomy. METHODS: We retrospectively analyzed the clinical data on 212 patients diagnosed with prostate cancer by biopsy and treated by laparoscopic radical prostatectomy by the same surgeon. Based on the degrees of IPP measured by MRI, we divided the patients into an IPP ≤ 10 mm group (n = 146) and an IPP > 10 mm group (n = 66) and determined the factors influencing the recovery of urinary continence by univariate and multivariate logistic regression analyses. RESULTS: At 1, 3, 6 and 12 months after surgery, the urinary continence rates of the patients were 32.5%, 50.5%, 82.1% and 91%, respectively. Univariate analysis indicated that the factors influencing the recovery of urinary continence included IPP, body mass index (BMI), bladder neck preservation (BNP), neurovascular bundle preservation (NVBP) and clinical tumor (T) stage at 3 months (P < 0.05 or P < 0.01), age, IPP, BMI, BNP and clinical T stage at 6 months (P < 0.05 or P < 0.01), and age, IPP, BMI, BNP, NVBP and clinical T stage at 12 months (P < 0.05), while multivariate logistic regression analysis showed the independent influencing factors to be IPP > 10 mm (P < 0.001), BMI ≥ 25 kg/m2 (P = 0.004) and BNP (P = 0.032) at 3 months, and IPP and BMI at 6 months (both P < 0.01) and 12 months (P < 0.01 and P = 0.033). CONCLUSIONS: IPP > 10 mm and BMI ≥ 25 kg/m2 are independent factors influencing the long-term recovery of urinary continence after radical prostatectomy.

Follicular localization of growth differentiation factor 8 and its receptors in normal and polycystic ovary syndrome ovaries.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and its etiology has not been characterized. Growth differentiation factor 8 (GDF8) is a member of the transforming growth factor-ß superfamily that plays a critical role in the regulation of ovarian functions. However, the expression pattern of GDF8 in the human ovary is not yet clear. This study examined the cellular distribution of GDF8 and its putative cellular receptors (ACVR2A, ACVR2B, and ALK5) in a series of normal (n = 34) and PCOS ovaries (n = 14). The immunostaining of GDF8, ACVR2A, ACVR2B, and ALK5 was detected in the oocytes regardless of the developmental stage. All these proteins were localized in antral follicles in normal and PCOS ovaries, and the expression of these proteins increased with increasing follicle diameter. A significantly higher expression of GDF8 was detected in the granulosa cells than in the matched theca cells (TCs). These proteins were also localized in the luteal cells of the corpus luteum. Granulosa cells and TCs of large antral follicles in PCOS ovaries display a higher expression of these proteins. The higher expression levels of GDF8 and its functional receptors (ACVR2A, ACVR2B, and ALK5) in antral follicles of PCOS ovaries than those in normal ovaries suggest the possible involvement of dysregulated GDF8 in the pathogenesis of PCOS.

Can time-dependent density functional theory predict intersystem crossing in organic chromophores? A case study on benzo(bis)-X-diazole based donor-acceptor-donor type molecules.

Here we utilized new diagnostic tools in time-dependent density functional theory to explain the trend of intersystem crossing in benzo(bis)-X-diazole based donor-acceptor-donor type molecules. These molecules display a wide range of fluorescence quantum yields and triplet yields, making them excellent candidates for testing the validity of these diagnostic tools. We believe that these tools are cost-effective and can be applied to structurally similar organic chromophores to predict/explain the trends of intersystem crossing, and thus fluorescence quantum yields and triplet yields without the use of complex and expensive multireference configuration interaction or multireference pertubation theory methods.

[Study of heterologous efficient synthesis of cucurbitadienol].

Cucurbitadienol has anti-inflammation, anti-cancer activities, and acts as a precursor of traditional Chinese medicine active ingredients mogroside and cucurbitacine. For construction of a Sacchromyces cerevisiae cell factory for production of cucurbitadienol, we firstly cloned a cucurbitadienol synthase (CBS) gene from Siraitia grosvenorii. Then, through heterologous expression of CBS in the triterpenoid chassis strain WD-2091, the engineered strain could produced 27.44 mg•L ⁻¹ cucurbitadienol, which was determined by GC-MS. Further regulation of CBS expression led to cucurbitadienol's titer increasing by 202.07% and reaching 82.89 mg•L ⁻¹ in the shake flask fermentation and 1 724.10 mg•L ⁻¹ in the high cell density fermentation. Our research promotes the cucurbitane-type tetracyclic triterpenoids synthesis pathway analysis progress and provides the basis for further obtaining cell factories for production of cucurbitadienol tetracyclic triterpenoids.

Nuclear-targeting TAT-PEG-Asp8-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer.

AIM: Drug efflux-associated multidrug resistance (MDR) is a main obstacle to effective cancer chemotherapy. Large molecule drugs are not the substrates of P-glycoprotein, and can circumvent drug efflux and be retained inside cells. In this article we report a polymer-drug conjugate nanoparticulate system that can overcome MDR based on size-related exclusion effect. METHODS: Doxorubicin was coupled with the triblock polymeric material cell-penetrating TAT-PEG-poly(aspartic acid). The amphiphilic macromolecules (termed TAT-PEG-Asp8-Dox) could self-assemble into nanoparticles (NPs) in water. The antitumor activity was evaluated in drug-resistant human colon cancer HCT8/ADR cells in vitro and in nude mice bearing HCT8/ADR tumor. RESULTS: The self-assembling TAT-PEG-Asp8-Dox NPs were approximately 150 nm with a narrow particle size distribution, which not only increased the cellular uptake efficiency, but also bypassed P-glycoprotein-mediated drug efflux and improved the intracellular drug retention, thus yielding an enhanced efficacy for killing drug-resistant HCT8/ADR colon cancer cells in vitro. Importantly, the TAT-PEG-Asp8-Dox NPs enhanced the intranuclear disposition of drugs for grater inhibition of DNA/RNA biosynthesis. In nude mice bearing xenografted HCT8/ADR colon cancers, intravenous or peritumoral injection of TAT-PEG-Asp8-Dox NPs for 22 d effectively inhibited tumor growth. CONCLUSION: TAT-PEG-Asp8-Dox NPs can increase cellular drug uptake and intranuclear drug delivery and retain effective drug accumulation inside the cells, thus exhibiting enhanced anticancer activity toward the drug-resistant human colon cancer HCT8/ADR cells.

[Construction of cell factories for production of lupeol in Saccharomyces cerevisiae].

Lupane-type triterpenoids, such as betulinic acid, are derived from lupeol and have excellent properties in anti-HIV, anti-cancer activities and so on. For realizing heterogenous production of lupane-type triterpenoids, our research firstly integrated all the seven genes in the MVA pathway in Saccharomyces cerevisiae to increase the supply of squalene (triterpenoids universal precursor) in a single step using the DNA assembler method. Next, cell factories for production of lupeol was constructed by integrating Arabidopsis thaliana lupeol synthetic gene (AtLUP) into chromosome of triterpenoid chassis strain. Results showed that the MVA pathway, about 20 kb nucleotide length, could be assembled in one-pot process and the doubled MVA pathway could significantly improve squalene by 500-fold, reaching 354.00 mg•L⁻¹. NK2-LUP was obtained by introducing AtLUP gene on chromosome, and could produce 8.23 mg•L⁻¹ lupeol. This study supports the possibility of large-scale biosynthetic pathway assembly in S.cerevisiae and lays the foundation of obtaining cell factories for production of lupan-type triterpenoids at the same time.

Nanocomposites of sulfonic polyaniline nanoarrays on graphene nanosheets with an improved supercapacitor performance.

A new nanocomposite, poly(aniline-co-diphenylamine-4-sulfonic acid)/graphene (PANISP/rGO), was prepared by means of an in situ oxidation copolymerization of aniline (ANI) with diphenylamine-4-sulfonic acid (SP) in the presence of graphene oxide, followed by the chemical reduction of graphene oxide using hydrazine hydrate as a reductant. The morphology and structure of PANISP/rGO were characterized by field-emission (FE) SEM, TEM, X-ray photoelectron spectroscopy (XPS), Raman, FTIR, and UV/Vis spectra. The electrochemical performance was evaluated by cyclic voltammetry, galvanostatic charge-discharge, and electrochemical impedance spectroscopy. The PANISP/rGO nanocomposite showed a nanosized structure, with sulfonic polyaniline nanoarrays coated homogeneously on the surface of graphene nanosheets. This special structure of the nanocomposite also facilitates the enhancement of the electrochemical performance of the electrodes. The PANISP/rGO nanocomposite exhibits a specific supercapacitance up to 1170 F g(-1) at the current density of 0.5 A g(-1) . The as-prepared electrodes show excellent supercapacitive performance because of the synergistic effects between graphene and the sulfonic polyaniline copolymer chains.

Neolignans from Aristolochia fordiana Prevent Oxidative Stress-Induced Neuronal Death through Maintaining the Nrf2/HO-1 Pathway in HT22 Cells.

Bioassay-guided fractionation of the ethanolic extract of the stems of Aristolochia fordiana led to the isolation of six new dihydrobenzofuran neolignans (1-3 and 7-9), three new 2-aryldihydrobenzofurans (4-6), a new 8-O-4' neolignan (10), and 14 known analogues (11-24). The structures of compounds 1-10 were established by spectroscopic methods, and their absolute configurations were determined by analyses of the specific rotation and electronic circular dichroism data. The neuroprotective effects of compounds 1-24 against glutamate-induced cell death were tested in hippocampal neuronal cell line HT22. Compounds 17 and 20-24 exhibited moderate neuroprotective activity by increasing the endogenous antioxidant defense system. In addition, the neolignans activated the Nrf2 (nuclear factor E2-related factor 2) pathway, resulting in the increase of the expression of endogenous antioxidant protein HO-1 (heme oxygenase-1). The active compounds also preserved the levels of antiapoptotic protein Bcl-2 (B cell lymphoma/leukemia-2), which was decreased by glutamate. Collectively, these results suggested that the active neolignans protect neurons against glutamate-induced cell death through maintaining the Nrf2/HO-1 signaling pathway as well as preserving the Bcl-2 protein and might be promising novel beneficial agents for oxidative stress-associated diseases.