Household air pollution disparities between socioeconomic groups in Chicago.

Purpose: To assess household air pollution levels in urban Chicago households and examine how socioeconomic factors influence these levels. Methods: We deployed wireless air monitoring devices to 244 households in a diverse population in Chicago to continuously record household fine particulate matter (PM2.5) concentration. We calculated hourly average PM2.5 concentration in a 24-hour cycle. Four factors-race, household income, area deprivation, and exposure to smoking-were considered in this study. Results: A total of 93085 h of exposure data were recorded. The average household PM2.5 concentration was 43.8 µg m-3. We observed a significant difference in the average household PM2.5 concentrations between Black/African American and non-Black/African American households (46.3 versus 31.6 µg m-3), between high-income and low-income households (18.2 versus 52.5 µg m-3), and between smoking and non-smoking households (69.7 versus 29.0 µg m-3). However, no significant difference was observed between households in less and more deprived areas (43.7 versus 43.0 µg m-3). Implications: Household air pollution levels in Chicago households are much higher than the recommended level, challenging the hypothesis that household air quality is adequate for populations in high income nations. Our results indicate that it is the personal characteristics of participants, rather than the macro environments, that lead to observed differences in household air pollution.

Discovery of Dehydrogenated Imipridone Derivatives as Activators of Human Caseinolytic Protease P.

Based on the founding member of imipridones, ONC201, a class of dehydrogenated imipridone derivatives was designed, synthesized, and evaluated in a series of biochemical and biological assays as human caseinolytic protease P (hClpP) activators. Mechanism studies for one of the most potent compounds, XT6, indicated that it can potently bind to both recombinant and cellular hClpP, effectively promote the formation of hClpP tetradecamer, efficiently induce the degradation of hClpP substrates, robustly upregulate the expression of ATF4, and strongly inhibit the phosphorylations of AKT and ERK. More importantly, XT6 exhibited a promising pharmacokinetic profile in rats and could penetrate the blood brain barrier. It showed highly potent in vivo antitumor activity in a MIAPACA2 cell line derived pancreatic cancer model in BALB/c nude mice.

Design, synthesis and bioactivity evaluation of isobavachin derivatives as hURAT1 inhibitors for hyperuricemia agents.

Previously, we reported a novel natural scaffold compound, isobavachin (4',7-dihydroxy-8-prenylflavanone), as a highly potent hURAT1 inhibitor with anti-hyperuricemia effect. However, the structure-activity relationship remains unknown and the poor pharmacokinetic (PK) parameters may limit further clinical use. Herein, a series of isobavachin derivatives were rationally designed and synthesized to explore the structure-activity relationship of isobavachin target hURAT1, and to improve their PK properties. Among them, compounds 15d, 15f, 15g, 27b and 27d showed promising hURAT1 inhibitory activities, which could comparable to that of isobavachin (IC50 = 0.24 µM). In addition, 27b also inhibited another urate reabsorption transporter GLUT9 with an IC50 of 4.47 µM. Compound 27b displayed greater urate-lowering activity in a hyperuricemia mouse model at a dose of 10 mg/kg compared to isobavachin and lesinurad. Overall, our results suggest that compound 27b represents a novel, safe hURAT1 and GLUT9 dual-target inhibitor with excellent drug availability and is worthy of further investigation as an anti-hyperuricemia agent.

An Electron Donor-Acceptor Structured Rhenium(I) Complex Photo-Sensitizer Evokes Mutually Reinforcing "Closed-Loop" Ferroptosis and Immunotherapy.

The hypoxic microenvironment of solid tumors severely lowers the efficacy of oxygen-dependent photodynamic therapy (PDT). The development of hypoxia-tolerant photosensitizers for PDT is an urgent requirement. In this study, a novel rhenium complex (Re-TTPY) to develop a "closed-loop" therapy based on PDT-induced ferroptosis and immune therapy is reported. Due to its electron donor-acceptor (D-A) structure, Re-TTPY undergoes energy transfer and electron transfer processes under 550 nm light irradiation and displays hypoxia-tolerant type I/II combined PDT capability, which can generate 1O2, O2 -, and ·OH simultaneously. Further, the reactive oxygen species (ROSs) leads to the depletion of 1,4-dihydronicotinamide adenine dinucleotide (NADH), glutathione peroxidase 4 (GPX4), and glutathione (GSH). As a result, ferroptosis occurs in cells, simultaneously triggers immunogenic cell death (ICD), and promotes the maturation of dendritic cells (DCs) and infiltration of T cells. The release of interferon-γ (IFN-γ) by CD8+ T cells downregulates the expression of GPX4, further enhancing the occurrence of ferroptosis, and thereby, forming a mutually reinforcing "closed-loop" therapeutic approach.

Duration-sensitive association between air pollution exposure and changes in cardiometabolic biomarkers: Evidence from a predominantly African American cohort.

BACKGROUND: Ambient fine particulate matter (PM2.5) exposure has been related to cardiometabolic diseases, but the underlying biological pathways remain unclear at the population level. OBJECTIVE: To investigate the effect of PM2.5 exposure on changes in multiple cardiometabolic biomarkers across different exposure durations. METHOD: Data from a prospective cohort study were analyzed. Ten cardiometabolic biomarkers were measured, including ghrelin, resistin, leptin, C-peptide, creatine kinase myocardial band (CK-MB), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-alpha), N-terminal pro B-type natriuretic peptide (NT-proBNP), troponin, and interleukin-6 (IL-6). PM2.5 levels across exposure durations from 1 to 36 months were assessed. Mixed effect model was used to estimate changes in biomarker levels against 1 µg/m3 increase in PM2.5 level across different exposure durations. RESULTS: Totally, 641 participants were included. The average PM2.5 exposure level was 9 µg/m3. PM2.5 exposure was inversely associated with ghrelin, and positively associated with all other biomarkers. The magnitudes of these associations were duration-sensitive and exhibited a U-shaped or inverted-U-shaped trend. For example, the association of resistin were ß = 0.05 (95% CI: 0.00, 0.09) for 1-month duration, strengthened to ß = 0.27 (95% CI: 0.14, 0.41) for 13-month duration, and weakened to ß = 0.12 (95% CI: -0.03, 0.26) for 24-month duration. Similar patterns were observed for other biomarkers except for CK-MB, of which the association direction switched from negative to positive as the duration increased. Resistin, leptin, MCP-1, TNF-alpha, and troponin had a sensitive exposure duration of nearly 12 months. Ghrelin and C-peptide were more sensitive to longer-term exposure (>18 months), while NT-proBNP and IL-6 were more sensitive to shorter-term exposure (<6 months). CONCLUSION: PM2.5 exposure was associated with elevated levels in cardiometabolic biomarkers related to insulin resistance, inflammation, and heart injury. The magnitudes of these associations depended on the exposure duration. The most sensitive exposure durations of different biomarkers varied.

Air quality and cancer risk in the All of Us Research Program.

INTRODUCTION: The NIH All of Us Research Program has enrolled over 544,000 participants across the US with unprecedented racial/ethnic diversity, offering opportunities to investigate myriad exposures and diseases. This paper aims to investigate the association between PM2.5 exposure and cancer risks. MATERIALS AND METHODS: This work was performed on data from 409,876 All of Us Research Program participants using the All of Us Researcher Workbench. Cancer case ascertainment was performed using data from electronic health records and the self-reported Personal Medical History questionnaire. PM2.5 exposure was retrieved from NASA's Earth Observing System Data and Information Center and assigned using participants' 3-digit zip code prefixes. Multivariate logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI). Generalized additive models (GAMs) were used to investigate non-linear relationships. RESULTS: A total of 33,387 participants and 46,176 prevalent cancer cases were ascertained from participant EHR data, while 20,297 cases were ascertained from self-reported survey data from 18,133 participants; 9,502 cancer cases were captured in both the EHR and survey data. Average PM2.5 level from 2007 to 2016 was 8.90 µg/m3 (min 2.56, max 15.05). In analysis of cancer cases from EHR, an increased odds for breast cancer (OR 1.17, 95% CI 1.09-1.25), endometrial cancer (OR 1.33, 95% CI 1.09-1.62) and ovarian cancer (OR 1.20, 95% CI 1.01-1.42) in the 4th quartile of exposure compared to the 1st. In GAM, higher PM2.5 concentration was associated with increased odds for blood cancer, bone cancer, brain cancer, breast cancer, colon and rectum cancer, endocrine system cancer, lung cancer, pancreatic cancer, prostate cancer, and thyroid cancer. CONCLUSIONS: We found evidence of an association of PM2.5 with breast, ovarian, and endometrial cancers. There is little to no prior evidence in the literature on the impact of PM2.5 on risk of these cancers, warranting further investigation.

Negative regulation of tobacco cold stress tolerance by NtPhyA.

Cold stress is a non-biological stressor that adversely affects tobacco yield and leaf quality. Plant photoreceptor proteins, which function as dual light-temperature sensors, play a vital role in temperature changes, making them crucial for responses to non-biological stressors. However, the regulatory mechanisms of PhyA in tobacco remain poorly understood. Therefore, in this study, we aimed to clone the NtPhyA gene from tobacco and generate overexpression (OE-NtPhyA) and mutant (KO-NtPhyA) constructs of NtPhyA. By assessing the physiological and biochemical responses of the mutants under cold stress and performing transcriptome sequencing, we determined the signalling mechanism of NtPhyA under cold stress. Comparative analysis with wild-type (WT) NtPhyA revealed that KO-NtPhyA exhibited increased seed germination rates and reduced wilting under cold stress. In additional, the degree of damage to leaf cells, cell membranes, and stomatal structures was mitigated, and the levels of reactive oxygen species (ROS) were significantly decreased. Antioxidant enzyme activity, net photosynthetic rate, and Fv/Fm were significantly enhanced in KO-NtPhyA, whereas the opposite effects were observed in OE-NtPhyA. These findings indicate that KO-NtPhyA augments tobacco tolerance to cold stress, implying a negative regulatory role of NtPhyA in tobacco during cold stress. Transcriptome analysis revealed that NtPhyA governs the expression of a cascade of genes involved in the response to oxygen-containing compounds, hydrogen peroxide (H2O2), ROS, temperature stimuli, photosystem II oxygen-evolving complex assembly, water channel activity, calcium channel activity, and carbohydrate transport. Collectively, our findings indicate that NtPhyA activates downstream gene expression to enhance the resilience of tobacco to cold stress.

Amide-decorated carbon dots as sensitive and selective probes for fluorescence enhancement detection of cadmium ion.

As highly toxic metal ions, cadmium ions (Cd2+) are prevalent in varying concentrations around the world. The establishment of an accurate and effective method for Cd2+ determination with high sensitivity and selectivity is of particular concern. The present work fabricated a fluorescence chemosensor for the detection of Cd2+ based on functionalized carbon dots (CDs), which were hydrothermally prepared using amidated hyperbranched-polyethyleneimine (HPEI). As investigated by FTIR, NMR, and XPS, the stably grafted amide groups endowed the CDs with thermosensitivity and high cloud point due to the change in hydrophilic-hydrophobic behaviors. The CDs chemosensor with optimal amidation degree exhibited high sensitivity, selectivity, and stability in the determination of Cd2+ from various water environments. Notably, the fluorescence intensity enhanced with the increase of Cd2+ concentration, originating from the improved structure rigidity caused by the interactions between grafted amides and Cd2+. These impressive features made the CDs not only sensitive to detecting Cd2+ in low-concentration solutions with a limit of detection of 3.41 nM (the lowest known value for Cd2+ detection) but also accurate for the quantification in high-concentration solutions with a detectable Cd2+ concentration of 6.0 × 10-2 M. Owing to the broad detection range, the CDs developed in present work show great potential applications in various scenarios.

The interference between effects of PFAS exposure on thyroid hormone disorders and cholesterol levels: an NHANES analysis.

Studies have documented that per- and polyfluoroalkyl substance (PFAS) exposures are associated with thyroid hormones (TH) and lipid levels. This study investigates whether these effects interfere with each other. We analyzed data on 3954 adults in the US National Health and Nutrition Examination Survey (NHANES; 2007-2012). TH disorder was defined using thyroid hormones. Serum high-density lipoprotein (HDL) cholesterol, total cholesterol, and six types of PFAS were included. Weighted quantile sum (WQS) regression was used to estimate the overall effect of PFAS mixture on TH disorder and cholesterols, respectively. Potential confounders, including age, race, gender, education, household poverty, smoking, and alcohol drinking, were adjusted. PFAS mixture was associated increased risk for TH disorder (odds ratio = 1.21, 95% confidence interval (CI): 1.02, 1.43), higher HDL cholesterol (linear coefficient = 1.31, 95% CI: 0.50, 2.11), and higher total cholesterol (linear coefficient = 5.30, 95% CI: 3.40, 7.21). TH disorder was associated with higher HDL cholesterol (linear coefficient = 2.30, 95% CI: 0.50, 2.11), but not total cholesterol. When adjusted for TH disorder, the effect estimates of PFAS mixture remain roughly unchanged on HDL cholesterol (linear coefficient = 1.13, 95% CI: 0.28, 1.98) and total cholesterol (linear coefficient = 5.61, 95% CI: 3.58, 7.63). Sex modified the effect of PFAS mixture on HDL cholesterol (P for interaction: 0.04) but did not change the interaction between PFAS and TH disorder on cholesterols. We corroborated the adverse health effects of PFAS exposure on TH and lipids; however, these two effects appear to be independent of and not interfere with each other.

Levels of oxidative stress in patients with neoadjuvant chemotherapy for gastric cancer: correlation with treatment response.

Objective: The intent of this study was to investigate the relationship between oxidative stress and treatment response in gastric cancer patients undergoing neoadjuvant chemotherapy. Methods: Blood samples from 108 patients and 108 healthy subjects were collected, and all patients were enrolled in SOX chemotherapy. The patients received four cycles of neoadjuvant chemotherapy. Blood samples were collected to determine oxidative stress levels at baseline prior to beginning chemotherapy, and at the end of cycles 2 and 4. The patients receiving neoadjuvant chemotherapy were followed up for several months to years. A survival curve was created according to the follow-up information from the patients. In addition, the correlation between oxidative stress level and treatment effect was evaluated and ROC curves were plotted according to the final collected data. Results: Compared with the normal group, the levels of the antioxidant index decreased while the peroxide index increased in the patients. Conversely, when patients were compared before and after chemotherapy, the antioxidant index increased but the peroxide index decreased. Furthermore, the antioxidant index increased in the response group while the peroxide index decreased in the non-response group. Conclusion: Patients with an increased antioxidant index after chemotherapy have good treatment responsiveness. These indicators can also be used as predictors to judge the patients' response to chemotherapy.

Genome-wide identification and characterization of Glutathione S-Transferases (GSTs) and their expression profile under abiotic stresses in tobacco (Nicotiana tabacum L.).

BACKGROUND: Glutathione S-transferases (GSTs) are large and multifunctional proteases that play an important role in detoxification, protection against biotic and abiotic stresses, and secondary metabolite transportation which is essential for plant growth and development. However, there is limited research on the identification and function of NtGSTs. RESULTS: This study uses K326 and other six tobacco varieties (Hongda, HG, GDH11, Va116, VG, and GDH88) as materials to conduct comprehensive genome-wide identification and functional characterization of the GST gene in tobacco. A total of 59 NtGSTs were identified and classified into seven subfamilies via the whole-genome sequence analysis, with the Tau type serving as the major subfamily. The NtGSTs in the same branch of the evolutionary tree had similar exon/intron structure and motif constitution. There were more than 42 collinear blocks between tobacco and pepper, tomato, and potato, indicating high homology conservation between them. Twelve segmental duplicated gene pairs and one tandem duplication may have had a substantial impact on the evolution and expansion of the tobacco GST gene family. The RT-qPCR results showed that the expression patterns of NtGSTs varied significantly among tissues, varieties, and multiple abiotic stresses, suggesting that NtGST genes may widely respond to various abiotic stresses and hormones in tobacco, including NtGSTF4, NtGSTL1, NtGSTZ1, and NtGSTU40. CONCLUSIONS: This study provides a comprehensive analysis of the NtGST gene family, including structures and functions. Many NtGSTs play a critical regulatory role in tobacco growth and development, and responses to abiotic stresses. These findings offer novel and valuable insights for understanding the biological function of NtGSTs and the reference materials for cultivating highly resistant varieties and enhancing the yield and quality of crops.

The impact of neighborhood disadvantage on colorectal cancer screening among African Americans in Chicago.

Historically, colorectal cancer (CRC) screening rates have been lower among African Americans. Previous studies that have examined the relationship between community characteristics and adherence to CRC screening have generally focused on a single community parameter, making it challenging to evaluate the overall impact of the social and built environment. In this study, we will estimate the overall effect of social and built environment and identify the most important community factors relevant to CRC screening. Data are from the Multiethnic Prevention and Surveillance Study (COMPASS), a longitudinal study among adults in Chicago, collected between May 2013 to March 2020. A total 2,836 African Americans completed the survey. Participants' addresses were geocoded and linked to seven community characteristics (i.e., community safety, community crime, household poverty, community unemployment, housing cost burden, housing vacancies, low food access). A structured questionnaire measured adherence to CRC screening. Weighted quantile sum (WQS) regression was used to evaluate the impact of community disadvantages on CRC screening. When analyzing all community characteristics as a mixture, overall community disadvantage was associated with less adherence to CRC screening even after controlling for individual-level factors. In the adjusted WQS model, unemployment was the most important community characteristic (37.6%), followed by community insecurity (26.1%) and severe housing cost burden (16.3%). Results from this study indicate that successful efforts to improve adherence to CRC screening rates should prioritize individuals living in communities with high rates of insecurity and low socioeconomic status.

Identification of calcium and integrin-binding protein 1 as a reprogrammed glucose metabolism mediator to restrict immune cell infiltration in the stromal compartment of pancreatic ductal adenocarcinoma.

An increasing body of evidence has suggested that reprogrammed metabolism plays a critical role in the progression of pancreatic ductal adenocarcinoma (PDAC) by affecting the tumor and stromal cellular components in the tumor microenvironment (TME). By analyzing the KRAS pathway and metabolic pathways, we found that calcium and integrin-binding protein 1 (CIB1) corresponded with upregulation of glucose metabolism pathways and was associated with poor prognosis in patients with PDAC from The Cancer Genome Atlas (TCGA). Elevated CIB1 expression combined with upregulated glycolysis, oxidative phosphorylation (Oxphos), hypoxia pathway activation, and cell cycle promoted PDAC tumor growth and increased tumor cellular com-ponents. Furthermore, we confirmed the mRNA overexpression of CIB1 and co-expression of CIB1 and KRAS mutation in cell lines from the Expression Atlas. Subsequently, immunohistochemistry staining from the Human Protein Atlas (HPA) showed that high expression of CIB1 in tumor cells was associated with an increased tumor compartment and reduced stromal cellular abundance. Furthermore, using multiplexed immunohistochemistry (mIHC), we verified that low stromal abundance was correlated with low infiltration of CD8+ PD-1- T cells which led to suppressed anti-tumor immunity. Overall, our findings identify CIB1 as a metabolic pathway-mediated factor for the restriction of immune cell infiltration in the stromal compartment of PDAC and highlight the potential value of CIB1 as a prognostic biomarker involved in metabolic reprogramming and immune modulation.

A metabolome-wide case-control study of african american breast cancer patients.

BACKGROUND: Breast cancer survivors face long-term sequelae compared to the general population, suggesting altered metabolic profiles after breast cancer. We used metabolomics approaches to investigate the metabolic differences between breast cancer patients and women in the general population, aiming to elaborate metabolic changes among breast cancer patients and identify potential targets for clinical interventions to mitigate long-term sequelae. METHODS: Serum samples were retrieved from 125 breast cancer cases recruited from the Chicago Multiethnic Epidemiologic Breast Cancer Cohort (ChiMEC), and 125 healthy controls selected from Chicago Multiethnic Prevention and Surveillance Study (COMPASS). We used liquid chromatography-high resolution mass spectrometry to obtain untargeted metabolic profiles and partial least squares discriminant analysis (PLS-DA) combined with fold change to select metabolic features associated with breast cancer. Pathway analyses were conducted using Mummichog to identify differentially enriched metabolic pathways among cancer patients. As potential confounders we included age, marital status, tobacco smoking, alcohol drinking, type 2 diabetes, and area deprivation index in our model. Random effects of residence for intercept was also included in the model. We further conducted subgroup analysis by treatment timing (chemotherapy/radiotherapy/surgery), lymph node status, and cancer stages. RESULTS: The entire study participants were African American. The average ages were 57.1 for cases and 58.0 for controls. We extracted 15,829 features in total, among which 507 features were eventually selected by our criteria. Pathway enrichment analysis of these 507 features identified three differentially enriched metabolic pathways related to prostaglandin, leukotriene, and glycerophospholipid. The three pathways demonstrated inconsistent patterns. Metabolic features in the prostaglandin and leukotriene pathways exhibited increased abundances among cancer patients. In contrast, metabolic intensity in the glycerolphospholipid pathway was deregulated among cancer patients. Subgroup analysis yielded consistent results. However, changes in these pathways were strengthened when only using cases with positive lymph nodes, and attenuated when only using cases with stage I disease. CONCLUSION: Breast cancer in African American women is associated with increase in serum metabolites involved in prostaglandin and leukotriene pathways, but with decrease in serum metabolites in glycerolphospholipid pathway. Positive lymph nodes and advanced cancer stage may strengthen changes in these pathways.

Special AT-rich sequence binding protein 1 promotes multidrug resistance in gastric cancer by regulation of Ezrin to alter subcellular localization of ATP-binding cassette transporters.

Multidrug resistance is a primary factor in the poor response to chemotherapy and subsequent death in gastric cancer patients. However, the molecular mechanisms involved remain unclear. In this study, the high expression of special AT-rich sequence binding protein 1 (SATB1) in gastric cancer was found to be associated with reduced sensitivity to various chemotherapy drugs. Our results demonstrate that SATB1 can promote chemotherapy resistance in gastric cancer in vitro and in vivo. SATB1 exerts its effect by enhancing the activity of multiple ATP-binding cassette (ABC) transporters (P-glycoprotein, multidrug resistance-associated protein, and breast cancer resistance protein) in gastric cancer cell lines. We also found that SATB1 affects ABC transporters by altering the subcellular localization of the ABC transporter rather than its expression. Subsequently, we confirmed that Ezrin binds to various ABC transporters and affects their subcellular localization. In addition, we found that SATB1 can also bind to the Ezrin promoter and regulate its expression. In the present study, we elucidate the mechanism of SATB1-mediated multidrug resistance in gastric cancer, providing a basis for SATB1 as a potential target for reversal of resistance.

Biosynthetic Silver Nanoparticles Inhibit the Malignant Behavior of Gastric Cancer Cells and Enhance the Therapeutic Effect of 5-Fluorouracil by Promoting Intracellular ROS Generation and Apoptosis.

(1) Background: Gastric cancer (GC) is the fourth leading cause of cancer death worldwide. Silver nanoparticles (Ag-NPs) have been increasingly used in the diagnosis and treatment of cancer due to their physicochemical properties. This study investigated the role of a kind of biosynthetic silver nanoparticle (b-Ag) in the development of GC, the enhancement of 5-fluorouracil (5F), and its mechanism. (2) Methods: X-ray, transmission electron microscopy (TEM), and UV absorbance were used to detect the characterizations of AgNPs. CCK8, Colony formation and a Transwell assay were performed to confirm the malignant behaviors of GC. DCFH-DA and DHE were used to detect intracellular reactive oxygen species (ROS). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression of apoptosis-related genes. (3) Results: Compared with the chemosynthetic silver nanoparticles (c-Ag), b-Ag had a stronger cytokilling effect, and it had a better inhibition on the malignant phenotype of GC when combined with 5F. The b-Ag increased the expression of Bax and P53 while decreasing the expression of Bcl2. It also promoted the generation of intracellular ROS. (4) Conclusions: By promoting cell apoptosis and increasing intracellular ROS, b-Ag inhibited the development of GC and enhanced the inhibition of 5F on GC.

LncRNA HOXC-AS1 Sponges miR-99a-3p and Upregulates MMP8, Ultimately Promoting Gastric Cancer.

Gastric cancer (GC) is among the most lethal tumors worldwide. Long noncoding RNAs (lncRNAs) are reported to be critical during the occurrence and progression of malignancies. The HOXC cluster antisense RNA 1 (HOXC-AS1) has been suggested to participate in the genesis and development of GC. Therefore, we examined GC cells and tissues for the expression of HOXC-AS1 and correlated the expression levels with the disease specific survival of the patients, finding that HOXC-AS1 was overexpressed and probably had a tendency of leading to a poor prognosis. The Cell Counting Kit-8 assay and colony formation assay were then performed under knockdown of HOXC-AS1, revealing that cell proliferation of GC was distinctly decreased. Afterwards, miR-99a-3p was predicted to bind with HOXC-AS1 by DIANA tools. We carried out dual-luciferase reporter gene assays to identify the interaction between them. After knockdown of HOXC-AS1, miR-99a-3p was clearly overexpressed in GC cells. In addition, matrix metalloproteinase 8 (MMP8) was shown to be combined with miR-99a-3p using TargetScan. Similar experiments, along with western blot, were conducted to validate the correlation between miR-99a-3p and MMP8. Finally, rescue experiments for CCK-8 were completed, disclosing that HOXC-AS1 promoted cell progression of GC through sponging miR-99a-3p followed by subsequent upregulation of MMP8.

Alpha-Lipoic Acid Promotes Intestinal Epithelial Injury Repair by Regulating MAPK Signaling Pathways.

Intestinal epithelial cells are an essential barrier in human gastrointestinal tract, and healing of epithelial wound is a key process in many intestinal diseases. α-Lipoic acid (ALA) was shown to have antioxidative and anti-inflammatory effects, which could be helpful in intestinal epithelial injury repair. The effects of ALA in human colonic epithelial cells NCM460 and human colorectal adenocarcinoma cells Caco-2 were studied. ALA significantly promoted NCM460 and Caco-2 migration, increased mucosal tight junction factors ZO-1 and OCLN expression, and ALA accelerated cell injury repair of both cells in wound healing assay. Western blot analysis indicated that ALA inhibited a variety of mitogen-activated protein kinase (MAPK) signaling pathways in the epithelial cells. In conclusion, ALA was beneficial to repair of intestinal epithelial injury by regulating MAPK signaling pathways.

Design, Synthesis, and Biological Evaluations of DOT1L Peptide Mimetics Targeting the Protein-Protein Interactions between DOT1L and MLL-AF9/MLL-ENL.

On the basis of a previously identified DOT1L peptide mimetic (compound 3), a series of novel peptide mimetics were designed and synthesized. These compounds can potently bind to AF9 and ENL either in cell-free binding assays or in leukemia cells, and selectively inhibit the growth of leukemia cells containing mixed lineage leukemia (MLL) fusion proteins. The most potent compound 12 exhibited comparable anticancer cellular activities to those of EPZ5676, a clinical stage enzymatic inhibitor of DOT1L in several leukemia cell lines containing MLL fusion proteins. Mechanism studies for compound 12 indicated that it did not affect the global methylation of H3K79 catalyzed by DOT1L but could effectively suppress the methylation of H3K79 at MLL fusion proteins targeted genes and inhibit the expressions of these genes. Our studies thus demonstrated that inhibiting the protein-protein interactions between DOT1L and MLL fusion proteins is a potentially effective strategy for the treatment of MLL rearranged leukemias.