Tumor-targeted PROTAC prodrug nanoplatform enables precise protein degradation and combination cancer therapy.

Proteolysis targeting chimeras (PROTACs) have emerged as revolutionary anticancer therapeutics that degrade disease-causing proteins. However, the anticancer performance of PROTACs is often impaired by their insufficient bioavailability, unsatisfactory tumor specificity and ability to induce acquired drug resistance. Herein, we propose a polymer-conjugated PROTAC prodrug platform for the tumor-targeted delivery of the most prevalent von Hippel-Lindau (VHL)- and cereblon (CRBN)-based PROTACs, as well as for the precise codelivery of a degrader and conventional small-molecule drugs. The self-assembling PROTAC prodrug nanoparticles (NPs) can specifically target and be activated inside tumor cells to release the free PROTAC for precise protein degradation. The PROTAC prodrug NPs caused more efficient regression of MDA-MB-231 breast tumors in a mouse model by degrading bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinase 9 (CDK9) with decreased systemic toxicity. In addition, we demonstrated that the PROTAC prodrug NPs can serve as a versatile platform for the codelivery of a PROTAC and chemotherapeutics for enhanced anticancer efficiency and combination benefits. This study paves the way for utilizing tumor-targeted protein degradation for precise anticancer therapy and the effective combination treatment of complex diseases.

The metabolism-related lncRNA signature predicts the prognosis of breast cancer patients.

Long non-coding RNAs (lncRNAs) involved in metabolism are recognized as significant factors in breast cancer (BC) progression. We constructed a novel prognostic signature for BC using metabolism-related lncRNAs and investigated their underlying mechanisms. The training and validation cohorts were established from BC patients acquired from two public sources: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The prognostic signature of metabolism-related lncRNAs was constructed using the least absolute shrinkage and selection operator (LASSO) cox regression analysis. We developed and validated a new prognostic risk model for BC using the signature of metabolism-related lncRNAs (SIRLNT, SIAH2-AS1, MIR205HG, USP30-AS1, MIR200CHG, TFAP2A-AS1, AP005131.2, AL031316.1, C6orf99). The risk score obtained from this signature was proven to be an independent prognostic factor for BC patients, resulting in a poor overall survival (OS) for individuals in the high-risk group. The area under the curve (AUC) for OS at three and five years were 0.67 and 0.65 in the TCGA cohort, and 0.697 and 0.68 in the GEO validation cohort, respectively. The prognostic signature demonstrated a robust association with the immunological state of BC patients. Conventional chemotherapeutics, such as docetaxel and paclitaxel, showed greater efficacy in BC patients classified as high-risk. A nomogram with a c-index of 0.764 was developed to forecast the survival time of BC patients, considering their risk score and age. The silencing of C6orf99 markedly decreased the proliferation, migration, and invasion capacities in MCF-7 cells. Our study identified a signature of metabolism-related lncRNAs that predicts outcomes in BC patients and could assist in tailoring personalized prevention and treatment plans.

A mechanism study of DUSP1 in inhibiting malignant progression of endometrial carcinoma by regulating ERK/AP-1 axis and dephosphorylation of EPHA2.

Background: Endometrial carcinoma is one of the most common female malignancies worldwide. Based on our preliminary investigation, DUSP1 was identified as a potential biomarker for endometrial carcinoma prognosis, but its function and mechanism remained unclear. Methods: In this study, genes highly correlated with DUSP1 in endometrial cancer were found through correlation analysis, and the promoter sequence of DUSP1 was analyzed by PROMO program. Next-generation phosphorylation mass spectrometry was used to explore new downstream target proteins and pathways of DUSP1 in endometrial carcinoma. The mRNA and protein expression levels were detected by real-time quantitative PCR, immunohistochemistry and Western blotting. The cell survival and proliferation were analyzed by CCK8 assay, cell apoptosis was analyzed by Annexin-V-APC and PI dual staining assay, and the cell invasion was analyzed by Transwell method. Results: (1) There was a high correlation between the expression of DUSP1 and the genes involved in AP-1 complex and its co-expression network. (2) Promoter sequence analysis predicted that the members of AP-1 complex might be the upstream transcriptional regulators of DUSP1. (3) Transfection experiments proved DUSP1 can inhibit tumor growth and invasion, and promote apoptosis by regulating ERK pathway. (4) The results of phosphorylation mass spectrometry showed that overexpression of DUSP1 mainly dephosphorylated EPHA2 in endometrial carcinoma, and co-immunoprecipitation verified the protein interaction between DUSP1 and EPHA2. (5) Overexpression or knockdown of EPHA2 significantly changed the phosphorylation level of EPHA2. (6) The expression of EPHA2 protein was high in patients with more aggressive endometrial cancer. (7) Using EPHA2 inhibitor could significantly slow down the growth rate of tumor cells. Conclusion: (1) There exists a mutual regulation relationship between DUSP1 and AP-1 co-expression network in endometrial carcinoma. (2) It is reported for the first time that DUSP1 phosphatase acts on the ser899 site of EphA2 in endometrial carcinoma. (3) DUSP1 can inhibit tumor growth and invasion, and promote apoptosis by regulating MAPK pathway through directly dephosphorylating ERK, or by dephosphorylating EPHA2.

Establishment of reference intervals for bone turnover markers in healthy Chinese older adults.

BACKGROUND: Reference ranges for bone turnover markers (BTMs) are still lacking in the healthy Chinese population. AIM: To establish reference intervals for BTMs and to investigate the correlations between BTMs and bone mineral density (BMD) in Chinese older adults. SUBJECTS AND METHODS: A community-based cross-sectional study was conducted among 2511 Chinese subjects aged over 50 yrs residing in Zhenjiang, Southeast China. Reference intervals for BTMs (i.e. procollagen type I N-terminal propeptide, P1NP; ß cross-linked C-terminal telopeptide of type I collagen, ß-CTX) were calculated as the central 95% range of all measurements in Chinese older adults. RESULTS: The reference intervals of P1NP, ß-CTX and P1NP/ß-CTX were 15.8-119.9 ng/mL, 0.041-0.675 ng/mL and 49.9-1261.5 for females and 13.6-111.4 ng/mL, 0.038-0.627 ng/mL and 41.0-1269.1 for males, respectively. In the multiple linear regression analysis, only ß-CTX was negatively associated with BMD after adjusting for age and body mass index (BMI) in both sex-stratified groups (all p < .05). CONCLUSION: This study established age- and sex-specific reference intervals for BTMs in a large sample of healthy Chinese participants ≥ 50 and < 80 years of age and explored the correlations between BTMs and BMD, which provides an effective reference for the assessment of bone turnover in the clinical practice of osteoporosis.

Sulforaphane suppresses skin squamous cell carcinoma cells proliferation through miR-199a-5p/Sirt1/CD44ICD signaling pathway.

BACKGROUND: The present study aimed to explore the impact of sulforaphane on the growth of sSCC cells, and the activation of miR-199a-5p/Sirt1 and CD44ICD signaling pathways. METHODS: Cell viability, count, apoptosis, and invasion assays were performed in the sSCC cell line (SCC-13) in which miR-199a-5p was over-expressed or under-expressed. The expression levels of miR-199a-5p, Sirt1 and CD44ICD mRNA were measured by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Sulforaphane significantly inhibited the cell growth and invasion of SCC-13 cells, and dramatically induced cell apoptosis. Additionally, sulforaphane also greatly increased miR-199a-5p expression and suppressed Sirt1 and CD44ICD mRNA levels. Moreover, miR-199a-5p overexpression considerably down-regulated the expressions of Sirt1 and CD44ICD mRNA, and promoted the ability of sulforaphane to represses cell growth and invasion, and to induce cell apoptosis. However, miR-199a-5p underexpression has the opposite effects. CONCLUSIONS: Sulforaphane appears to inhibit sCC progression by impacting its growth and invasion ability, and regulates miR-199a-5p/Sirt1 and CD44ICD signaling pathways, and may be utilized to develop a curative approach for sSCC.

A novel long non-coding RNA, lnc-RNU12, influences the T-cell cycle via c-JUN and CCNL2 in rheumatoid arthritis.

OBJECTIVES: Long non-coding RNAs (lncRNAs) play important roles in RA pathogenesis. However, specific lncRNAs that regulate gene expression in RA pathogenesis are poorly known. This study was undertaken to characterize a novel lncRNA (lnc-RNU12) that has a lower-than-normal expression level in RA patients. METHODS: We performed initial genome-wide lncRNA microarray screening in peripheral blood mononuclear cells from 28 RA cases and 18 controls. Multiple methods were used to validate the detected associations between lncRNAs and RA. Furthermore, we identified the source and characteristics of the highlighted lncRNAs, detected the target genes, and determined the functional effect on immune cells through lncRNA knock-down in Jurkat T cell lines. RESULTS: lnc-RNU12 was downregulated in peripheral blood mononuclear cells and T cell subtypes of RA patients and was genetically associated with RA risk. lnc-RNU12 mediates the effect of microbiome alterations on RA risk. Activation of T cells caused low expression of lnc-RNU12. Knock-down of lnc-RNU12 in Jurkat T cells caused cell cycle S-phase arrest and altered the expression of protein-coding genes related to the cell cycle and apoptosis (e.g. c-JUN, CCNL2, CDK6, MYC, RNF40, PKM, VPS35, DNAJB6 and FLCN). Finally, c-JUN and CCNL2 were identified as target genes of lnc-RNU12 at the mRNA and protein expression levels. RNA-binding protein immunoprecipitation assays verified the interaction between lnc-RNU12 and the two proteins (c-Jun and cyclin L2) in Jurkat cells. CONCLUSIONS: Our study suggested that lnc-RNU12 was involved in the pathogenesis of RA by influencing the T cell cycle by targeting c-JUN and CCNL2.

The immune factors have complex causal regulation effects on bone mineral density.

Recent evidence has gradually recognized that the immune and skeletal systems are two closely correlated systems, but the specific immune factors on bone mineral density (BMD) are largely unknown. Based on the summary-level data of genome-wide association studies (GWASs), we performed a series of analyses including two-sample Mendelian randomization (MR) analysis to test potential causal links between 731 immune traits [including median fluorescence intensities (MFIs), absolute cell (AC) counts, relative cell (RC) counts, and morphological parameters (MP)] and BMD. After false discovery rate (FDR) correction, 9 MFI-BMD, 16 AC-BMD, 22 RC-BMD, and 5 MP-BMD pairs reached the level of significance (FDR-adjusted p< 0.05). For MFI traits, the T- and B-cell panels had the largest number of significant immune trait pairs than other panels. CD40, as a molecule expressed by four subsets of monocytes, was highlighted due to its consistently positive correlation with BMD at four sites. For both AC and RC traits, immune traits from the T-cell panel were also highlighted, with CD39-positive T-cell subsets being the most frequently observed feature. For MP traits, the most significant association immune trait with BMD was SSC-A on CD14+ monocyte. Sensitivity analyses suggested that the identified immune factors were robust to pleiotropy. Multivariable MR analysis confirmed the independent causal effect of several immune traits on BMD. Mediation analyses showed that CD40 on monocytes could mediate multiple immune traits, especially the suggestive associations of CD27 on several memory B cells with BMD mediated by CD40 on CD14+ CD16- monocyte. Our study represents the first comprehensive evaluation of the causal effects of immune traits on the risk of osteoporosis. The findings highlighted the complex and important role of immune-derived factors in the pathogenesis of osteoporosis.

Correlation of Glucose Metabolism with Cancer and Intervention with Traditional Chinese Medicine.

Cancer is a complex disease with several distinct characteristics, referred to as "cancer markers" one of which is metabolic reprogramming, which is a common feature that drives cancer progression. Over the last ten years, researchers have focused on the reprogramming of glucose metabolism in cancer. In cancer, the oxidative phosphorylation metabolic pathway is converted into the glycolytic pathway in order to meet the growth requirements of cancer cells, thereby creating a microenvironment that promotes cancer progression. The precise mechanism of glucose metabolism in cancer cells is still unknown, but it is thought to involve the aberrant levels of metabolic enzymes, the influence of the tumor microenvironment (TME), and the activation of tumor-promoting signaling pathways. It is suggested that glucose metabolism is strongly linked to cancer progression because it provides energy to cancer cells and interferes with antitumor drug pharmacodynamics. Therefore, it is critical to unravel the mechanism of glucose metabolism in tumors in order to gain a better understanding of tumorigenesis and to lay the groundwork for future research into the identification of novel diagnostic markers and therapeutic targets for cancer treatment. Traditional Chinese Medicine (TCM) has the characteristics of multiple targets, multiple components, and less toxic side effects and has unique advantages in tumor treatment. In recent years, researchers have found that a variety of Chinese medicine monomers and compound recipes play an antitumor role by interfering with the reprogramming of tumor metabolism. The underlying mechanisms of metabolism reprogramming of tumor cells and the role of TCM in regulating glucose metabolism are reviewed in this study, so as to provide a new idea for antitumor research in Chinese medicine.

Protective effects and mechanisms of Lizhong decoction against non-alcoholic fatty liver disease in a rat model.

OBJECTIVE: To investigate the protective effects and molecular mechanisms of Lizhong decoction (, LZD) against non-alcoholic fatty liver disease (NAFLD). METHODS: Male Wistar rats were fed a high-fat diet for four weeks to induce NAFLD, and were administered LZD by gavage for four weeks. Potential therapeutic targets for NAFLD were analyzed using network pharmacology. Liver pathology was evaluated using Oil Red O and hematoxylin-eosin staining. Furthermore, mitochondrial function, lipid metabolism, oxidative stress, and inflammatory response were examined. RESULTS: Rats with NAFLD exhibited high levels of hepatic damage and cholesterol deposition. Moreover, apoptosis was increased, superoxide dismutase and glutathione content were reduced, malondialdehyde content was increased, and the protein expression of inflammatory cytokines and p-c-Jun N-terminal kinase was increased. The LZD treatment ameliorated mitochondrial dysfunction, reduced liver damage, inhibited oxidative stress and inflammatory response, upregulated peroxisome proliferator-activated receptor (PPAR)-γ expression, and suppressed dipeptidyl peptidase 4 (DPP4) expression in the liver. CONCLUSION: It was found that LZD alleviates NAFLD by activating PPAR-γ and inhibiting DPP4.

Systematic Evaluation of Rheumatoid Arthritis Risk by Integrating Lifestyle Factors and Genetic Risk Scores.

Background: Effective identification of high-risk rheumatoid arthritis (RA) individuals is still a challenge. Whether the combined effects of multiple previously reported genetic loci together with lifestyle factors can improve the prediction of RA risk remains unclear. Methods: Based on previously reported results and a large-scale Biobank dataset, we constructed a polygenic risk score (PRS) for RA to evaluate the combined effects of the previously identified genetic loci in both case-control and prospective cohorts. We then evaluated the relationships between several lifestyles and RA risk and determined healthy lifestyles. Then, the joint effects of healthy lifestyles and genetic risk on RA risk were evaluated. Results: We found a positive association between PRS and RA risk (OR = 1.407, 95% confidence interval (CI) = 1.354~1.463; HR = 1.316, 95% CI = 1.257~1.377). Compared with the low genetic risk group, the group with intermediate or high genetic risk had a higher risk (OR = 1.347, 95% CI = 1.213~1.496; HR = 1.246, 95% CI = 1.108~1.400) (OR = 2.169, 95% CI = 1.946~2.417; HR = 1.762, 95% CI = 1.557~1.995). After adjusting for covariates, we found protective effects of three lifestyles (no current smoking, regular physical activity, and moderate body mass index) on RA risk and defined them as healthy lifestyles. Compared with the individuals with low genetic risks and favorable lifestyles, those with high genetic risks and unfavorable lifestyles had as high as OR of 4.637 (95%CI = 3.767~5.708) and HR of 3.532 (95%CI = 2.799~4.458). Conclusions: In conclusion, the integration of PRS and lifestyles can improve the prediction of RA risk. High RA risk can be alleviated by adopting healthy lifestyles but aggravated by adopting unfavorable lifestyles.

Instant diagnosis of gastroscopic biopsy via deep-learned single-shot femtosecond stimulated Raman histology.

Gastroscopic biopsy provides the only effective method for gastric cancer diagnosis, but the gold standard histopathology is time-consuming and incompatible with gastroscopy. Conventional stimulated Raman scattering (SRS) microscopy has shown promise in label-free diagnosis on human tissues, yet it requires the tuning of picosecond lasers to achieve chemical specificity at the cost of time and complexity. Here, we demonstrate that single-shot femtosecond SRS (femto-SRS) reaches the maximum speed and sensitivity with preserved chemical resolution by integrating with U-Net. Fresh gastroscopic biopsy is imaged in <60 s, revealing essential histoarchitectural hallmarks perfectly agreed with standard histopathology. Moreover, a diagnostic neural network (CNN) is constructed based on images from 279 patients that predicts gastric cancer with accuracy >96%. We further demonstrate semantic segmentation of intratumor heterogeneity and evaluation of resection margins of endoscopic submucosal dissection (ESD) tissues to simulate rapid and automated intraoperative diagnosis. Our method holds potential for synchronizing gastroscopy and histopathological diagnosis.

Identifying Active Substances and the Pharmacological Mechanism of Houttuynia cordata Thunb. in Treating Radiation-Induced Lung Injury Based on Network Pharmacology and Molecular Docking Verification.

Background: Houttuynia cordata Thunb. is a traditional Chinese herb widely used mainly because of the pharmacological effects related to heat clearance and detoxification. Emerging clinical evidence indicates that the efficacy of Houttuynia cordata Thunb. on RILI is upstanding. Nevertheless, its underlying therapeutic mechanism remains unclear and warrants further elucidation. Methods: The major active components and corresponding targets of Houttuynia cordata Thunb. were retrieved from the traditional Chinese medicine system pharmacology database (TCMSP) and literature review. The related targets of RILI were retrieved from the GeneCards database. Common targets among the active compounds and diseases were identified through Venn diagram analysis. Cytoscape was employed to construct and visualize the network relationship among the drug, active compounds, targets, and disease. The protein interaction network (PPI) was constructed by STRING. The reliability (the binding affinity) of the core targets and active compounds was verified by molecular docking. Results: A search of the TCMSP database and related literature revealed 12 active compounds of Houttuynia cordata Thunb. against RILI. The core active compounds included quercetin, kaempferol, hyperoside, and rutin. Hub nodes including TP53, VEGFA, JUN, TNF, and IL-6 were identified in the PPI network. The GO categories were classified into three functional categories: 112 biological processes, 9 molecular functions, and 32 cellular components of the active compounds of Houttuynia cordata Thunb. The KEGG pathway enrichment analysis demonstrated the enrichment of target genes in several key cancer-related signaling pathways, including the cancer pathways, TNF signaling pathway, PI3K-Akt signaling pathway, and HIF-1 signaling pathway. Molecular docking analysis validated the effective binding capacity of the main active compounds with the core targets. Conclusion: The main active components of Houttuynia cordata Thunb. have a potential pharmacological effect against RILI via the cancer pathways, TNF signaling pathway, and PI3K-Akt signaling pathway.

ATM and TP53 polymorphisms modified susceptibility to radiation-induced lens opacity in natural high background radiation area, China.

Purpose: A population-based case-control study was conducted in Yangjiang and Enping areas in South China to assess whether the risk of lens opacity induced by natural high background radiation exposure is modulated by polymorphisms of ATM and TP53.Materials and methods: A total of 133 cases who were diagnosed with cortical and posterior subcapsular (PSC) opacity were recruited, and 419 healthy controls were selected through counter-matching in terms of radiation status. Genomic DNA from all the participants was genotyped with the Illumina platform for four single nucleotide polymorphisms of ATM (rs189037, rs373759, and rs4585) and TP53 (rs1042522). The cumulative lens dose received during the entire life was estimated based on annual indoor and outdoor radiation doses and gender- and age-specific occupancy factors. Non-conditional logistic regression was performed to calculate odds ratio (OR) and 95% confidence intervals (95% CI).Results:ATM rs189037 and TP53 rs1042522 were significantly related to cortical and PSC opacity. The risk of opacity was higher when individuals carried the A allele of ATM rs189037 and C allele of TP53 rs1042522, compared with GG genotype. ATM rs189037 A allele carriers (AG/AA) and TP53 rs1042522 C allele carriers (CG/CC) combined with a cumulative lens dose of 100 mGy or higher showed statistically significant opacity risks (OR = 5.51, 95% CI: 1.47-20.66; OR = 2.69, 95% CI: 1.10-6.60).Conclusion: The A allele of ATM rs189037 and C allele of TP53 rs1042522 increased the risk of lens opacity induced by radiation. These polymorphisms in ATM and TP53 might modify the risk of cortical and PSC opacity induced by chronic and prolonged low-dose radiation.

Primary Care Providers' Knowledge, Attitudes, Beliefs, and Practice Related to Lung Cancer Screening in Five High-Risk Communities in New York City.

Racial/ethnic minorities face stark inequalities in lung cancer incidence, treatment, survival, and mortality compared with US born non-Hispanic Whites. Lung cancer screening (LCS) with low-dose computed tomography (LDCT) is effective at reducing lung cancer mortality in high-risk current and former smokers and is recommended by the US Preventive Services Task Force (USPSTF). This study sought to assess primary care providers' (PCPs') knowledge, attitudes, beliefs, and practice related to LCS and the recent USPSTF guidelines in five high-risk immigrant communities in New York City. We surveyed 83 eligible PCPs between December 2016 and January 2018 through surveys sent by mail, email, and fax, administered by phone or in person. The survey included questions about providers' clinical practice, knowledge, attitudes, and beliefs related to LCS and the USPSTF guidelines. Information about patient demographics, PCPs' training background, and practice type were also collected. Sixty-seven percent of respondents reported that they did not have established guidelines for LCS at their practice, and 52% expressed that "vague" screening criteria influenced their referral processes for LCS. Barriers to LCS with LDCT included concerns that LDCT is not covered by insurance, patients' fears of screening results, and patients' concerns regarding radiation exposure. Targeted educational interventions for both PCPs and patients may increase access to recommended LCS, especially for populations at disproportionate risk for lung cancer.

Identification of causal metabolites related to multiple autoimmune diseases.

Observational studies provide evidence that metabolites may be involved in the development of autoimmune diseases (ADs), but whether it is causal is still unknown. Based on the large-scale genome-wide association studies (GWAS) summary statistics, we performed two-sample Mendelian randomization (MR) to evaluate the causal associations between human blood metabolites and multiple ADs, which were inflammatory bowel disease (IBD), ulcerative colitis (UC), crohns disease (CD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), multiple sclerosis (MS), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). After Bonferroni adjustment, we identified 6 causal features of metabolites, i.e., glycerol 2-phosphate for T1D, hexadecanedioate, phenylacetylglutamine and laurylcarnitine for RA, glycine and arachidonate (20:4n6) for CD. Comprehensive sensitive analysis was further performed to validate the robustness of associations. We also observed some overlaps of metabolites among different ADs, implying similar or shared underlying mechanisms in such pathogenic processes. Multivariable MR analysis was then conducted to avoid potential pleiotropic effect of other complex traits. After controlling for several common traits, multivariable MR analysis ruled out most of potential pleiotropic effects and validated independence of identified metabolites. Finally, metabolic pathway analysis was performed based on suggestive metabolites for each AD respectively and a total of seven metabolic pathways were identified. In conclusion, this study provided novel insights into investigating causal role of blood metabolites in development of multiple ADs through a comprehensive genetic pathway.

Iron-Catalyzed α,ß-Dehydrogenation of Carbonyl Compounds.

An iron-catalyzed α,ß-dehydrogenation of carbonyl compounds was developed. A broad spectrum of carbonyls or analogues, such as aldehyde, ketone, lactone, lactam, amine, and alcohol, could be converted to their α,ß-unsaturated counterparts in a simple one-step reaction with high yields.

Magnolol protects against acute gastrointestinal injury in sepsis by down-regulating regulated on activation, normal T-cell expressed and secreted.

BACKGROUND: Sepsis is a major medical challenge. Magnolol is an active constituent of Houpu that improves tissue function and exerts strong anti-endotoxin and anti-inflammatory effects, but the mechanism by which it reduces intestinal inflammation in sepsis is yet unclear. AIM: To assess the protective effect of magnolol on intestinal mucosal epithelial cells in sepsis and elucidate the underlying mechanisms. METHODS: Enzyme-linked immunosorbent assay was used to measure tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, and regulated on activation, normal T-cell expressed and secreted (RANTES) levels in serum and ileal tissue in animal studies. The histopathological changes of the ileal mucosa in different groups were observed under a microscope. Cell Counting Kit-8 and cell permeability assays were used to determine the concentration of drug-containing serum that did not affect the activity of Caco2 cells but inhibited lipopolysaccharide (LPS)-induced decrease in permeability. Immunofluorescence and Western blot assays were used to detect the levels of RANTES, inhibitor of nuclear factor kappa-B kinase ß (IKKß), phosphorylated IKKß (p-IKKß), inhibitor of nuclear factor kappa-B kinase α (IκBα), p65, and p-p65 proteins in different groups in vitro. RESULTS: In rats treated with LPS by intravenous tail injection in the presence or absence of magnolol, magnolol inhibited the expression of proinflammatory cytokines, IL-1ß, IL-6, and TNF-α in a dose-dependent manner. In addition, magnolol suppressed the production of RANTES in LPS-stimulated sepsis rats. Moreover, in vitro studies suggested that magnolol inhibited the increase of p65 nucleation, thereby markedly downregulating the production of the phosphorylated form of IKKß in LPS-treated Caco2 cells. Specifically, magnolol inhibited the translocation of the transcription factor nuclear factor-kappa B (NF-κB) from the cytosol into the nucleus and down-regulated the expression level of the chemokine RANTES in LPS-stimulated Caco2 cells. CONCLUSION: Magnolol down-regulates RANTES levels by inhibiting the LPS/NF-κB signaling pathways, thereby suppressing IL-1ß, IL-6, and TNF-α expression to alleviate the mucosal barrier dysfunction in sepsis.

SASH1 Suppresses the Proliferation and Invasion of Human Skin Squamous Cell Carcinoma Cells via Inhibiting Akt Cascade.

OBJECTIVE: The SAM- and SH3-domain containing 1 gene (SASH1) has been considered as a tumor suppressor in some cancers. Nevertheless, the effect of SASH1 on the proliferation and invasion of human skin squamous cell carcinoma (cSCC) remains poorly understood. Therefore, the purpose of the present study was to observe the potential role of SASH1 in cSCC and investigate its underlying mechanisms. METHODS: The overexpression of SASH1 was constructed by transfecting the pcDNA3.1/SASH1 vector into SCL-1 and A431 cells, and SASH1 knockdown was generated by transfecting the SASH1 siRNA into cSCC cells. Then, cell proliferation, invasion, apoptosis, and Akt pathway were observed. RESULTS: The expression levels of SASH1 mRNA and protein were greatly reduced in cSCC cells. The overexpression of SASH1 inhibited the viability and invasion of cSCC cells, while its knockdown induced the viability and invasion of cSCC cells. The overexpression of SASH1 also suppressed the expression levels of p-Akt and its target genes, including cyclin D1, Bcl-2, and metal matrix proteinase 2(MMP-2). By contrast, SASH1 knockdown exerted the opposite role. Furthermore, inhibition of Akt obviously decreased the inducible effect of cSCC knockdown on the proliferation and invasion of cSCC cells. CONCLUSION: Overall, these results found that SASH1 inhibits the proliferation and invasion of cSCC cells via suppressing Akt cascade, indicating a tumor inhibitory effect of SASH1 in cSCC cells.

Use of Traditional Chinese Herbal Medicine Concurrently with Conventional Cancer Treatment Among Chinese Cancer Patients.

In the U.S. and Canada, Traditional Chinese Medicine (TCM) use has become increasingly common; Chinese immigrants have particularly high rates of TCM use. In this study, we used a cross sectional survey study design to assess the specific types of Traditional Chinese Herbal Medicine (TCHM) used, the concurrent use of TCHM and conventional cancer treatment, and communication with providers about TCHM use, among Chinese immigrant cancer patients in New York City (NYC). We surveyed 114 patients from several community and clinical settings in NYC. The mean age was 63, 59% were female, and 83% originated from mainland China. Breast (18%) and lung (21%) cancer were the most common cancer diagnoses, and 60% were receiving conventional cancer treatment at the time of the survey. 75% reported ever using TCHM since their most recent primary cancer diagnosis. 68% of those who used herbs reported concurrent use of TCHM with conventional cancer treatment. Only 13% of those who used herbs reported sharing TCHM use with a provider, and only 19% reported that a provider had ever discussed TCHM use with them. Our findings demonstrated an alarmingly high rate of concurrent use of TCHM and conventional cancer treatment and low rate of communication with providers about TCHM use. A wide variety of herbs were used, including those with potentially negative interactions with conventional treatment. This study highlights the urgent need for the development of interventions to assist providers and patients in improving communication around this important topic.

Deregulation of cell adhesion molecules is associated with progression and poor outcomes in endometrial cancer: Analysis of The Cancer Genome Atlas data.

Cell adhesion molecules (CAMs) determine the behavior of cancer cells during metastasis. Although some CAMs are dysregulated in certain types of cancer and are associated with cancer progression, to the best of our knowledge, a comprehensive study of CAMs has not been undertaken, particularly in endometrial cancer (EC). In the present study the expression of 225 CAMs in EC patients with various clinicopathological phenotypes were evaluated by statistical analysis using publicly available data from The Cancer Genome Atlas database. The Kaplan-Meier method, and univariate and multivariate Cox proportional hazards regression models were used for survival analyses. Among the differentially expressed CAMs that were associated with aggressive clinicopathological phenotypes, 10 CAM genes were independent prognostic factors compared with other clinicopathological prognostic factors, including stage, grade, age, lymph node status, peritoneal cytology and histological subtype. A total of six genes (L1 cell adhesion molecule, mucin 15, cell surface associated, cell adhesion associated, oncogene regulated, immunoglobulin superfamily member 9B, protocadherin 9 and protocadherin ß1) were selected for integrative analysis. The six-gene signature was demonstrated to be an independent prognostic factor and could effectively stratify patients with different risks. Patients with more high-expression CAMs had a higher risk of poor overall survival (OS) rate. The mortality risk for patients with elevation of >4 CAMs was 11 times of that in those without elevation of these 6 CAMs. Similar results were obtained when relapse-free survival (RFS) time was used during the analysis. Prognostic reliability of the six-gene model was validated using data of an independent cohort from the International Cancer Genome Consortium. In conclusion, a combination of CAM alterations contributed to progression and aggressiveness of EC. The six-gene signature was effective for predicting worse OS and RFS in patients with EC and could be complementary to the present clinical prognostic criteria.