R2R3-MYB transcription factor CsMYB60 controls mature fruit skin color by regulating flavonoid accumulation in cucumber.

Skin color is an important trait that determines the cosmetic appearance and quality of fruits. In cucumber, the skin color ranges from white to brown in mature fruits. However, the genetic basis for this important trait remains unclear. We conducted a genome-wide association study of natural cucumber populations, along with map-based cloning techniques, on an F2 population resulting from a cross between Pepino (with yellow-brown fruit skin) and Zaoer-N (with creamy fruit skin). We identified CsMYB60 as a candidate gene responsible for skin coloration in mature cucumber fruits. In cucumber accessions with white to pale yellow skin color, a premature stop mutation (C to T) was found in the second exon region of CsMYB60, whereas light yellow cucumber accessions exhibited splicing premature termination caused by an intronic mutator-like element insertion in CsMYB60. Transgenic CsMYB60c cucumber plants displayed a yellow-brown skin color by promoting accumulation of flavonoids, especially hyperoside, a yellow-colored flavonol. CsMYB60c encodes a nuclear protein that primarily acts as a transcriptional activator through its C-terminal activation motif. RNA sequencing and DNA affinity purification sequencing assays revealed that CsMYB60c promotes skin coloration by directly binding to the YYTACCTAMYT motif in the promoter regions of flavonoid biosynthetic genes, including CsF3'H, which encodes flavonoid 3'-hydroxylase. The findings of our study not only offer insight into the function of CsMYB60 as dominantly controlling fruit coloration, but also highlight that intronic DNA mutations can have a similar phenotypic impact as exonic mutations, which may be valuable in future cucumber breeding programs.

Daily feeding frequency affects feed intake and body weight management of growing layers.

The objective of this study was to investigate the effect of feeding behavior on feed intake and body weight in growing layers and the underlying mechanisms, thereby providing a scientific foundation for optimal feeding practices in growing layers' management. A total of 144 Hy-line brown growing layers of 10 wk old and similar body weight, were divided into 3 treatment groups with different feeding frequency and equal cumulative daily feeding amount: the once-a-day feeding group (F1) was fed at 9:00 am every day, with feeding amount of 150 g/layer; the twice-a-day feeding group (F2) were fed at 9:00 am and 13:00 pm every day, with each feeding amount of 75 g/layer; the 4 times-a-day feeding group (F4) were fed at 9:00 am, 11:00 am, 13:00 pm, and 15:00 pm every day, with each feeding amount of 37.5 g/layer. Pre-experiment lasted for 1 wk and formal experiment lasted for 8 wk. The results indicated that the daily feed intake and body weight were decreased (P < 0.05) while feed conversion ratio was not affected (P > 0.05) as daily feeding times increased. The glandular stomach proportion was significantly increased in twice-a-day feeding group, while liver proportion and ileum length were significantly increased in 4 times-feeding group (P < 0.05). Additionally, 4 times-feeding daily resulted in a significant elevation of blood glucose levels, which may have suppressed feed intake (P < 0.05). In 4 times-feeding group, the plasma triglyceride levels increased as feeding times, accompanied by a notable up-regulation in the mRNA level of appetite-suppressing gene, hypothalamic pro-opiomelanocortin (POMC) and glandular stomach ghrelin. This modulation effectively suppressed the subsequent feed intake and body weight. Therefore, 4 times feeding daily is recommended in growing layers' management, because it reduced the feed cost without affecting the feed conversion efficiency.

The association between Geriatric Nutritional Risk Index and the risk of Invasive Candidiasis in critically ill older adults.

BACKGROUND: Invasive candidiasis is the most common hospital-acquired fungal infection in intensive care units (ICU). The Geriatric Nutritional Risk Index (GNRI) score was developed to evaluate the nutritional status of elderly adults. We aimed to assess the association between the GNRI score and the risk of invasive candidiasis in elderly patients admitted to ICU. METHODS: Hospitalization information of elderly patients with invasive candidiasis was collected retrospectively from Medical Information Mart for Intensive Care (MIMIC) IV and MIMIC-III Clinical Database CareVue subset from 2001 to 2019. The main outcome of this study was the diagnosis of invasive candidiasis in patients. We employed a multivariable Cox regression and propensity score matching to balance the influence of confounding factors on the outcome. Furthermore, we conducted sensitivity analyses by categorizing the GNRI into classes based on thresholds of 98, 92, and 81. RESULTS: A total of 6739 patients were included in the study, among whom 134 individuals (2%) were diagnosed with invasive candidiasis. The GNRI scores of patients with invasive candidiasis upon admission to the ICU were significantly lower, measuring 88.67 [79.26-98.27], compared to the control group with a score of 99.36 [87.98-110.45] (P < 0.001). The results of the multivariable Cox regression analysis demonstrated a strong association between higher GNRI scores and a decreased risk of invasive candidiasis infection (HR: 0.98, 95% CI: 0.97-0.99, P = 0.002). Consistently, similar results were obtained when analyzing the propensity score-matched cohort (HR: 0.99, 95% CI: 0.98-1, P = 0.028). Sensitivity analyses further confirmed a significantly increased risk of invasive candidiasis infection with lower GNRI scores. Specifically, the following associations were observed: GNRI ≤ 98 (HR: 1.83, 95% CI: 1.23-2.72, P = 0.003), GNRI ≤ 92 (HR: 1.68, 95% CI: 1.17-2.4, P = 0.005), 82 ≤ GNRI ≤ 92 (HR: 1.63, 95% CI: 1.01-2.64, P = 0.046), GNRI ≤ 81 (HR: 2.31, 95% CI: 1.44-3.69, P < 0.001). CONCLUSIONS: Lower GNRI score was significantly associated with an increased risk of invasive candidiasis in elderly patients in ICU. Further research is needed to validate whether improving nutrition can prevent invasive candidiasis.

Modulation of miR-146b by N6-methyladenosine modification remodels tumor-associated macrophages and enhances anti-PD-1 therapy in colorectal cancer.

PURPOSE: MicroRNA-146b (miR-146b) alleviates experimental colitis in mice by mediating macrophage polarization and the release of inflammatory factors. Our goals were to evaluate the antitumor efficacy of miR-146b in colorectal cancer (CRC) and to investigate the underlying mechanisms. METHODS: We used murine models of CRC to evaluate whether miR-146b influenced the progression of tumors independent of tumor-associated macrophages (TAMs). RNA immunoprecipitation, N6-methyladenosine (m6A) RNA immunoprecipitation and in vitro pri-miRNA processing assays were conducted to examine whether m6A mediates the maturation of pri-miR-146b/miR-146b. In a series of in vitro and in vivo experiments, we further defined the molecular mechanisms of methyltransferase-like 3 (METTL3)/miR-146b-mediated antitumor immunity and its efficacy in combination with anti-PD-1 immunotherapy. RESULTS: We found that miR-146b deletion supported tumor progression by increasing the number of alternatively activated (M2) TAMs. Mechanistically, the m6A-related "writer" protein METTL3 and "reader" protein HNRNPA2B1 controlled miR-146b maturation by regulating the m6A modification region of pri-miR-146b. Furthermore, miR-146b deletion promoted the polarization of M2-TAMs by enhancing phosphoinositide 3-kinase (PI3K)/AKT signaling, and this effect was mediated by the class IA PI3K catalytic subunit p110ß, which reduced T cell infiltration, aggravated immunosuppression and ultimately promoted tumor progression. METTL3 knockdown or miR-146b deletion induced programmed death ligand 1 (PD-L1) production via the p110ß/PI3K/AKT pathway in TAMs and consequently augmented the antitumor activity of anti-PD-1 immunotherapy. CONCLUSIONS: The maturation of pri-miR-146b is m6A-dependent, and miR-146b deletion-mediated TAM differentiation promotes the development of CRC by activating the PI3K/AKT pathway, which induces upregulation of PD-L1 expression, inhibits T cell infiltration into the TME and enhances the antitumor activity of anti-PD-1 immunotherapy. The findings reveal that targeting miR-146b can serve as an adjuvant to anti-PD-1 immunotherapy.

Insulin alleviates murine colitis through microbiome alterations and bile acid metabolism.

BACKGROUND: Insulin has been reported to exhibit anti-inflammatory activities in the context of bowel inflammation. However, the role of the interaction between insulin and the microbiota in gut health is unclear. Our goal was to investigate the mechanism of action of insulin in bowel inflammation and the relationship between insulin and the gut microbiota. METHODS: We used acute and chronic murine models of inflammatory bowel disease (IBD) to evaluate whether insulin influences the progression of colitis. Colonic tissues, the host metabolome and the gut microbiome were analyzed to investigate the relationship among insulin treatment, the microbiome, and disease. Experiments involving antibiotic (Abx) treatment and fecal microbiota transplantation (FMT) confirmed the association among the gut microbiota, insulin and IBD. In a series of experiments, we further defined the mechanisms underlying the anti-inflammatory effects of insulin. RESULTS: We found that low-dose insulin treatment alleviated intestinal inflammation but did not cause death. These effects were dependent on the gut microbiota, as confirmed by experiments involving Abx treatment and FMT. Using untargeted metabolomic profiling and 16S rRNA sequencing, we discovered that the level of the secondary bile acid lithocholic acid (LCA) was notably increased and the LCA levels were significantly associated with the abundance of Blautia, Enterorhadus and Rumi-NK4A214_group. Furthermore, LCA exerted anti-inflammatory effects by activating a G-protein-coupled bile acid receptor (TGR5), which inhibited the polarization of classically activated (M1) macrophages. CONCLUSION: Together, these data suggest that insulin alters the gut microbiota and affects LCA production, ultimately delaying the progression of IBD.

Interleukin-17 Weakens the NAFLD/NASH Process by Facilitating Intestinal Barrier Restoration Depending on the Gut Microbiota.

Interleukin-17 (IL-17) is associated with nonalcoholic fatty liver disease (NAFLD) and gut microbiota, and how IL-17 mediates the NAFLD/nonalcoholic steatohepatitis (NASH) process depending on the gut microbiota is unclear. We found that T helper 17 (TH17) cells were decreased in the small intestine in a methionine choline-deficient (MCD) diet-induced NASH model. IL-17-deficient (Il17-/-) mice showed alterations in intestinal microbiota, including the inhibition of probiotic growth and the overgrowth of certain pathogenic bacteria, and were prone to higher endotoxemia levels and more severe gastrointestinal barrier defects than wild-type (WT) mice. Furthermore, TH17 cells were responsible for restoring the intestinal barrier after administration of recombinant IL-17 to Il17-/- mice or injection of CD4+ T cells into a Rag1-/- mouse model. Additionally, transplantation of the microbiota from WT mice to Il17-/- mice restored the intestinal barrier. Notably, microbiota-depleted Il17-/- mice were resistant to MCD diet-induced intestinal barrier impairment. Fecal microbiota transplantation from Il17-/- mice to microbiota-depleted mice aggravated intestinal barrier impairment and then promoted the development of NASH. Collectively, this study showed that host IL-17 could strengthen intestinal mucosal barrier integrity and reduce dysbiosis-induced intestinal injury and secondary extraintestinal organ injury induced by a special diet. IMPORTANCE The morbidity of NASH has increased, with limited effective treatment options. IL-17 plays a protective role in the gut mucosa in high-fat-diet (HFD)-related metabolic disorders, and HFD-related microbiota dysbiosis is responsible for a decreased number of T helper 17 (TH17) cells in the lamina propria. The mechanism by which IL-17 mediates the NAFLD/NASH process depending on the gut microbiota is unclear. In our study, IL-17 originating from TH17 cells maintained intestinal barrier integrity and determined the outcomes of diet-related disease, which may be a target strategy for NAFLD/NASH.

Cobalt-Catalyzed Z to E Geometrical Isomerization of 1,3-Dienes.

An efficient cobalt-catalyzed geometrical isomerization of 1,3-dienes is described. In the combination of a CoCl2 precatalyst with an amido-diphosphine-oxazoline ligand, the geometrical isomerization of E/Z mixtures of 1,3-dienes proceed in a stereoconvergent manner, affording (E) isomers in high stereoselectivity. This facile transformation features a broad substrate scope with good functional group tolerance and could be scaled up to the gram scale smoothly with a catalyst loading of 1 mol %.

Parathyroid hormone-related protein prevents high-fat-diet-induced obesity, hepatic steatosis and insulin resistance in mice.

Obesity, closely related to systematic metabolic disorders, has become a major public health problem in recent decades. Here, we aimed to study the function of Parathyroid hormone-related protein (PTHrP) on high fat diet (HFD) induced murine obesity. Male C57BL/6J mice were transduced with adeno-associated virus vector encoding PTHrP (AAV-PTHrP) or adeno-associated virus control vector (AAV-Vehicle), following with HFD for 8 weeks. In addition, mice without transduction were fed on normal diet or HFD, respectively. Histological, metabolic and biochemical changes were detected. At the endpoint of experiment, body weight of mice treated with AAV-PTHrP did not increase as much as mice with AAV-Vehicle, but similar as mice with normal diet. Food efficiency ratio and weight of interscapular brown adipose tissue and epididymal white adipose tissue in mice overexpressed PTHrP were also lower than mice transducted with AAV-Vehicle. Besides, administration of AAV-PTHrP inhibited HFD-induced adipocyte hypertrophy. Protein level of PKA signaling pathway and thermogenic gene in adipose tissue exhibited a significant raise in HFD + AAV-PTHrP group, whereas transcription of inflammatory gene were decreased. Additionally, PTHrP overexpression ameliorated HFD-induced dyslipidemia, hepatic steatosis and insulin sensitivity. In HFD-induced murine obesity model, PTHrP is crucial to maintain metabolic homeostasis. PTHrP drives white adipose tissue browning and inhibits whitening of brown adipose tissue. Most importantly, PTHrP prevented HFD-induced obesity, hepatic steatosis and insulin resistance.

SUMO paralogue-specific functions revealed through systematic analysis of human knockout cell lines and gene expression data.

The small ubiquitin-related modifiers (SUMOs) regulate nearly every aspect of cellular function, from gene expression in the nucleus to ion transport at the plasma membrane. In humans, the SUMO pathway has five SUMO paralogues with sequence homologies that range from 45% to 97%. SUMO1 and SUMO2 are the most distantly related paralogues and also the best studied. To what extent SUMO1, SUMO2, and the other paralogues impart unique and nonredundant effects on cellular functions, however, has not been systematically examined and is therefore not fully understood. For instance, knockout studies in mice have revealed conflicting requirements for the paralogues during development and studies in cell culture have relied largely on transient paralogue overexpression or knockdown. To address the existing gap in understanding, we first analyzed SUMO paralogue gene expression levels in normal human tissues and found unique patterns of SUMO1-3 expression across 30 tissue types, suggesting paralogue-specific functions in adult human tissues. To systematically identify and characterize unique and nonredundant functions of the SUMO paralogues in human cells, we next used CRISPR-Cas9 to knock out SUMO1 and SUMO2 expression in osteosarcoma (U2OS) cells. Analysis of these knockout cell lines revealed essential functions for SUMO1 and SUMO2 in regulating cellular morphology, promyelocytic leukemia (PML) nuclear body structure, responses to proteotoxic and genotoxic stress, and control of gene expression. Collectively, our findings reveal nonredundant regulatory roles for SUMO1 and SUMO2 in controlling essential cellular processes and provide a basis for more precise SUMO-targeting therapies.

cfDNApipe: a comprehensive quality control and analysis pipeline for cell-free DNA high-throughput sequencing data.

MOTIVATION: Cell-free DNA (cfDNA) is gaining substantial attention from both biological and clinical fields as a promising marker for liquid biopsy. Many aspects of disease-related features have been discovered from cfDNA high-throughput sequencing (HTS) data. However, there is still a lack of integrative and systematic tools for cfDNA HTS data analysis and quality control (QC). RESULTS: Here, we propose cfDNApipe, an easy-to-use and systematic python package for cfDNA whole-genome sequencing (WGS) and whole-genome bisulfite sequencing (WGBS) data analysis. It covers the entire analysis pipeline for the cfDNA data, including raw sequencing data processing, QC and sophisticated statistical analysis such as detecting copy number variations (CNVs), differentially methylated regions and DNA fragment size alterations. cfDNApipe provides one-command-line-execution pipelines and flexible application programming interfaces for customized analysis. AVAILABILITY AND IMPLEMENTATION: https://xwanglabthu.github.io/cfDNApipe/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A novel histone deacetylase inhibitor LT-548-133-1 induces apoptosis by inhibiting HDAC and interfering with microtubule assembly in MCF-7 cells.

Many studies have indicated that histone deacetylase inhibitors (HDACis) have a significant antitumor effect in cancer. Here we report a compound named LT-548-133-1 that not only acts as an HDAC inhibitor but also interferes with microtubule assembly to inhibit MCF-7 cell proliferation and induce apoptosis. Consistent with Chidamide, LT-548-133-1 inhibited HDAC activity and increased histone H3 acetylation. But the difference is that it significantly induced cell cycle G2/M arrest while Chidamide caused G0/G1 arrest in MCF-7 cells. By Western blotting, we found the accumulation of CyclinB1 and phosphorylated histone H3 in LT-548-133-1 treated cells. Immunofluorescence based microtubule-repolymerization experiments and immunofluorescence staining of cell microtubules and nuclei showed that LT-548-133-1inhibited microtubule-repolymerization and induced mitotic abnormalities. The decreased expression of Bcl-2 and the increased expression of Bax, p53, p21, and cleaved-Caspase3 indicated the occurrence of apoptosis. Flow cytometry results also showed an increase in the proportion of apoptotic cells after administration of LT-548-133-1 or Chidamide. Therefore, we demonstrated that LT-548-133-1 could act as an HDAC inhibitor while inhibiting microtubule-repolymerization, causing mitosis to be arrested in G2/M. These two effects ultimately lead to proliferation inhibition and apoptosis of MCF-7 cells.

Review: Inhibitory potential of low molecular weight Heparin in cell adhesion; emphasis on tumor metastasis.

Low molecular weight heparin is a Heparin derivative, produced from commercial-grade Heparin through Chemical or enzymatic depolymerization. LMWH has remained a favored regimen for anticoagulation in cancer patients. Evidence from several studies has suggested that LMWHs possess antitumor and antimetastatic activity aside from their anticoagulant activity. Cancer metastasis is the foremost reason for cancer-related motility rate. Studies have pointed out that adhesion molecules play a decisive role in enhancing recurrent, invasive, and distant metastasis. Therefore, it is hypothesized that Cell adhesion molecules can be determined as a potential therapeutic target group, as antibodies or small-molecule inhibitors could easily access their extracellular domains. Furthermore, data from several investigations have reported LWMH potential effects as antimetastatic agents through influencing cell adhesion molecules. This review's objective is to emphasize the evidence available for the effects of the LMWHs in cell adhesion to inhibit tumor metastasis.

Parathyroid hormone-related protein activates HSCs via hedgehog signalling during liver fibrosis development.

Recently, we showed that parathyroid hormone-like hormone (PTHLH), a cytokine-like polyprotein, is critical for extracellular matrix (ECM) deposition through the activation of hepatic stellate cells (HSCs). Here, we show that N-terminal PTHLH is secreted into the supernatant of injured hepatocytes, its expression is positively correlated with liver fibrosis severity based on mice liver biopsies, and it is primarily expressed in the cytoplasm of hepatocytes along the fibrous septa of fibrotic livers. PTHLH overexpression in mice was achieved through adeno-associated virus-mediated gene delivery (AAV9-PTHLH), and liver fibrosis was induced with carbon tetrachloride (CCl4). We observed that AAV9-PTHLH induced spontaneous development of liver fibrosis and increased sensitivity to CCl4. PTHLH increased Hedgehog (Hh) pathway activation in a PTH1R-dependent manner, and the effect of PTHLH was primarily mediated by protein kinase C (PKC) θ. PTHLH-mediated PTH1R-PKC θ pathway activation is a key event in the profibrotic Hh-dependent activation of HSCs.

A Molecular Targeted Immunotherapeutic Strategy for Ulcerative Colitis via Dual-targeting Nanoparticles Delivering miR-146b to Intestinal Macrophages.

BACKGROUND AND AIMS: Macrophages are a promising therapeutic target for intestinal mucosal repair. MiR-146b appears to control macrophage activation and cell proliferation. METHODS: By loading miR-146b mimic on mannose-modified trimethyl chitosan [MTC]-conjugated nanoparticles [NPs] [MTC-miR146b], a molecular targeted immunotherapeutic approach was developed to selectively target intestinal macrophages for mucosal regeneration and tumourigenesis in mouse models. RESULTS: We first confirmed that miR-146b expression was significantly enhanced during mucosal regeneration in a murine colitis model. Moreover， after mucosal damage, MTC-miR146b mimic-treated wild-type mice had dramatically restored body weight and mucosal barrier function compared with MTC-NC treated mice. Strikingly, MTC-miR146b mimic oral administration protected miR-146b-deficient mice from dextran sodium sulphate [DSS] injury and the colitis-associated cancer process. Mechanistically, miR-146b strongly inhibited M1 macrophage activation by suppressing the Toll-like receptor 4 [TLR4] signalling pathway, resulting in the repression of the induction of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1ß. More importantly, miR-146b overexpression in bone marrow-derived macrophages [BMDMs] in M1 differentiation conditions induced a phenotype similar to M2 macrophages and improved the proliferation of co-cultured colonic epithelial cells via STAT3-dependent IL-10 production. CONCLUSIONS: MTC-miR146b should be regarded as an effective candidate for oral delivery and could improve the efficacy of immunotherapies for ulcerative colitis and colitis-associated cancer.

Low-Molecular-Weight Heparins: Reduced Size Particulate Systems for Improved Therapeutic Outcomes.

A wide range of diseases have been treated using low-molecular-weight heparins (LMWHs), the drug of choice for anticoagulation. Owing to their better pharmacokinetic features compared to those of unfractionated heparin (uFH), several systems incorporating LMWHs have been investigated to deliver and improve their therapeutic outcomes, especially through development of their micro- and nano-particles. This review article describes current perspectives on the fabrication, characterization, and application of LMWHs-loaded micro- and nano-particles to achieve ameliorated bioavailability. The valuable applications of LMWH will continue to encourage researchers to identify efficient delivery systems that have specific release characteristics and ameliorated bioavailability, overcoming the challenges presented by biological obstructions and the physicochemical properties of LMWHs.

Parathyroid Hormone-Like Hormone Induces Epithelial-to-Mesenchymal Transition of Intestinal Epithelial Cells by Activating the Runt-Related Transcription Factor 2.

Epithelial-to-mesenchymal transition (EMT) is a key contributor to fibroblast activation in fibrosis of multiple organs, including the intestine. Parathyroid hormone-like hormone (PTHLH) is an important factor in renal fibrosis and regulates several processes, including EMT. Herein, we investigated the role of PTHLH-induced EMT in intestinal fibrosis associated with Crohn disease. The expression levels of the EMT-related proteins, PTHLH, and parathyroid hormone receptor 1 (PTH1R) in intestinal tissues were determined by immunohistochemistry, and our results revealed that PTHLH and PTH1R were significantly elevated and associated with EMT marker expression. Moreover, neutralizing PTH1R and antagonizing PTHLH bioactivity prevented transforming growth factor-ß1-induced EMT. PTH1R can propagate the protein kinase A (PKA) signal and activate downstream nuclear transcription factors, including runt-related transcription factor 2 (Runx2). In addition, lentiviral vector-PTHLH-treated mice were highly sensitive to 2,4,6-trinitrobenzene sulfonic acid, and analysis of the PTHLH-PTH1R axis revealed the involvement of PKA-Runx2 in PTHLH-induced EMT. Our results indicate that PTHLH triggered EMT in intestinal epithelial cells through the PKA-Runx2 pathway, which might serve as a therapeutic target for intestinal fibrosis in Crohn disease.

Targeted delivery of microRNA 146b mimic to hepatocytes by lactosylated PDMAEMA nanoparticles for the treatment of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, and precision therapeutic will be a benefit for the NAFLD regression. In this study, we observed low microRNA 146 b (miR-146 b) expression in NAFLD mice model induced by methionine-choline-deficient diet (MCD) compared with control group. Furthermore, miR-146b-/- mice induced MCD exhibited severe liver steatosis and hepatitis. A bio-distribution study showed that novel Lactosylated PDMAEMA nanoparticles effectively targeted hepatocytes Lac-PDMAEMA. We coupled miR-146b mimic with Lac-PDMAEMA and then were administrated to NAFLD mice model, which could obviously alleviate the hepatic steatosis. Lac-PDMAEMA effectively delivered miR-146b mimic to hepatocytes with a ∼8-fold upregulation of miR-146b mimic targeting MyD88 and IRAK1, and in turn suppressed the expression of PPARγ. Meanwhile, TNF-α and IL-6 mRNA levels were decreased after administration of Lac-PDMAEMA/miR-146b mimic. So, we made a conclusion that targeted delivering miR-146b mimic to the hepatocytes by, coupling Lac-PDMAEMA nanoparticles could effectively alleviate the hepatic steatosis in NAFLD mice, which maybe bring a new and effective way to intervene and therapy the NAFLD.

The rs1024611 in the CCL2 gene and risk of gynecological cancer in Asians: a meta-analysis.

BACKGROUND: The -2518A/G (rs1024611) polymorphism of the CCL2 (C-C motif chemokine ligand 2), also known as MCP-1 (monocyte chemotactic protein-1) gene, has been reported to be associated with increased gynecological cancer risk, but the results are conflicting. METHODS: In this analysis, 1089 cases and 1553 controls from six publications were used to investigate the association between CCL2-2518A/G (rs1024611) polymorphism and the risk of gynecological cancer with a meta-analytic approach. Studies published on EBSCO, EMBASE, Web of Science, PubMed, SpringerLink, ScienceDirect, Weipu, and CNKI databases were identified (last update was on November 3, 2015). Six articles focused on the association between CCL2-2518A/G (rs1024611) polymorphism, and gynecological cancer risk was selected and data were extracted. The cancer type included endometrial cancer (n = 1), breast cancer (n = 2), ovarian cancer (n = 2), and cervical cancer (n = 1). All statistical analyses were performed using the STATA version 12.0 software. RESULTS: The meta-analysis showed that CCL2-2518A/G (rs1024611) polymorphism is associated with risk of gynecological cancer (GG vs AG + AA, OR = 1.55, 95%CI = 1.07-2.24, P < 0.05; AA vs GG, OR = 0.59 95%CI = 0.38-0.92, P < 0.05). Notably, the subgroup analysis demonstrated that the genotype AA is associated with a reduced gynecological cancer risk in Asians, but an increased risk when compared to AG in Europeans. CONCLUSIONS: Our data demonstrated the CCL2-2518A/G (rs1024611) polymorphism is significantly associated with risk of gynecological cancer, and the association differs by ethnicity.