Bone marrow-derived IGF-1 orchestrates maintenance and regeneration of the adult skeleton.

Insulin-like growth factor I (IGF-1) is a key regulator of tissue growth and development in response to growth hormone stimulation. In the skeletal system, IGF-1 derived from osteoblasts and chondrocytes are essential for normal bone development; however, whether bone marrow (BM)-resident cells provide distinct sources of IGF-1 in the adult skeleton remains elusive. Here, we show that BM stromal cells (BMSCs) and megakaryocytes/platelets (MKs/PLTs) express the highest levels of IGF-1 in adult long bones. Deletion of Igf1 from BMSCs by Lepr-Cre leads to decreased bone formation, impaired bone regeneration, and increased BM adipogenesis. Importantly, reduction of BMSC-derived IGF-1 contributes to fasting-induced marrow fat accumulation. In contrast, deletion of Igf1 from MKs/PLTs by Pf4-Cre leads to reduced bone formation and regeneration without affecting BM adipogenesis. To our surprise, MKs/PLTs are also an important source of systemic IGF-1. Platelet-rich plasma (PRP) from Pf4-Cre; Igf1f/fmice showed compromised osteogenic potential both in vivo and in vitro, suggesting that MK/PLT-derived IGF-1 underlies the therapeutic effects of PRP. Taken together, this study identifies BMSCs and MKs/PLTs as two important sources of IGF-1 that coordinate to maintain and regenerate the adult skeleton, highlighting reciprocal regulation between the hematopoietic and skeletal systems.

Inhibition of Fap Promotes Cardiac Repair by Stabilizing BNP.

BACKGROUND: Myocardial infarction (MI) elicits cardiac fibroblast activation and extracellular matrix (ECM) deposition to maintain the structural integrity of the heart. Recent studies demonstrate that Fap (fibroblast activation protein)-a prolyl-specific serine protease-is an important marker of activated cardiac fibroblasts after MI. METHODS: Left ventricle and plasma samples from patients and healthy donors were used to analyze the expression level of FAP and its prognostic value. Echocardiography and histological analysis of heart sections were used to analyze cardiac functions, scar formation, ECM deposition and angiogenesis after MI. RNA-Sequencing, biochemical analysis, cardiac fibroblasts (CFs) and endothelial cells co-culture were used to reveal the molecular and cellular mechanisms by which Fap regulates angiogenesis. RESULTS: We found that Fap is upregulated in patient cardiac fibroblasts after cardiac injuries, while plasma Fap is downregulated and functions as a prognostic marker for cardiac repair. Genetic or pharmacological inhibition of Fap in mice significantly improved cardiac function after MI. Histological and transcriptomic analyses showed that Fap inhibition leads to increased angiogenesis in the peri-infarct zone, which promotes ECM deposition and alignment by cardiac fibroblasts and prevents their overactivation, thereby limiting scar expansion. Mechanistically, we found that BNP (brain natriuretic peptide) is a novel substrate of Fap that mediates postischemic angiogenesis. Fap degrades BNP to inhibit vascular endothelial cell migration and tube formation. Pharmacological inhibition of Fap in Nppb (encoding pre-proBNP) or Npr1 (encoding the BNP receptor)-deficient mice showed no cardioprotective effects, suggesting that BNP is a physiological substrate of Fap. CONCLUSIONS: This study identifies Fap as a negative regulator of cardiac repair and a potential drug target to treat MI. Inhibition of Fap stabilizes BNP to promote angiogenesis and cardiac repair.

Clinical efficacy and safety analysis of different treatment options for Cervical pregnancy.

OBJECTIVE: To compare the efficacy and safety of different treatment options for cervical pregnancy (CP). MATERIALS AND METHODS: A total of 74 patients diagnosed with CP at Hunan Provincial Maternal and Child Health Care Hospital between January 2016 and September 2022 were retrospectively analyzed. Among them, 31 were treated with uterine artery embolization (UAE) followed by hysteroscopic curettage, 34 were treated with hysteroscopic curettage alone, and nine were treated with high-intensity focused ultrasound (HIFU) followed by hysteroscopic curettage. Medical records and pregnancy outcomes were analyzed. RESULTS: There were no significant differences in age, gravidity, parity, abortion, or preoperative hemoglobin levels among the patients in the three groups; however, significant differences in gestational age, gestational sac diameter, preoperative ß-hCG, and presence of cardiac pulsation were observed (p < 0.05). After treatment, there was no conversion to laparotomy, and the uterus was preserved in all patients. Significant differences in blood loss during curettage, hospitalization costs, hospital days, menstrual recovery interval, ß-hCG decline rates, retained products of conception, and intrauterine adhesions rate among the three groups were observed (p < 0.05). There were no significant differences in the placement of the uterine Foley balloon, effective curettage rate, pre-and postoperative hemoglobin decline, live birth rate, or proportion of subsequent pregnancies among the three groups. CONCLUSION: Our results showed that hysteroscopic curettage, HIFU, and UAE followed by hysteroscopic curettage are safe and effective for treating patients with CP. Compared with the UAE, HIFU has the advantages of lower hospitalization costs, shorter hospital stays, and shorter menstrual recovery intervals.

Bioinspired low-density lipoprotein co-delivery system for targeting and synergistic cancer therapy.

Epithelial-mesenchymal transition (EMT) is the culprit of tumor invasion and metastasis. As a critical transcription factor that induces EMT, snail is of great importance in tumor progression, and knocking down its expression by small interfering RNA (siRNA) may inhibit tumor metastasis. Herein, we developed a core-shelled bioinspired low-density lipoprotein (bio-LDL) in which snail siRNA-loaded calcium phosphate nanoparticles were wrapped as the core and doxorubicin was embedded in the outer phospholipids modified with a synthetic peptide of apoB100 targeting LDL receptor-abundant tumor cells. Bio-LDL exhibited pH-responsive release, lysosomal escape ability, enhanced cytotoxicity and apoptotic induction. Bio-LDL could significantly inhibit the expression of snail and regulate EMT-related proteins to reduce tumor migration and invasion in vitro. Bio-LDL also displayed favorable tumor targeting and synergistic inhibition of tumor growth and metastasis in vivo. Therefore, the multifunctional bio-LDL will be a promising co-delivery vector and holds potential value for clinical translation.

Assessment of retroperitoneal lymph node status in locally advanced cervical cancer.

BACKGROUND: The assessment of retroperitoneal lymph node status in patients with locally advanced cervical cancer is still a problem. This study aimed to explore the choice of these assessment methods. METHODS: Laparoscopic retroperitoneal lymphadenectomy was performed in 96 patients with advanced cervical cancer. The positive rates of lymph node metastasis were analyzed. The values of computed tomography lymph node minimum axial diameter (MAD) and squamous cell carcinoma antigen (SCC-Ag), and their combination in predicting retroperitoneal lymph node metastasis were compared. High-risk factors for common iliac lymph node (CILN) and/or para-aortic lymph node (PALN) metastasis were analyzed. RESULTS: The lymph node metastasis rate was 62.50% and the CILN and/or PALN metastasis rate was 31.25%. Overall, 96 patients had 172 visible lymph nodes. The positive rate of lymph node metastasis was significantly higher in the MAD ≥1.0 cm group (83.33%) than in the 0.5 cm ≤ MAD < 1.0 cm group (26.82%). The critical values of MAD and SCC-Ag in determining lymph node metastasis were 1.0 cm and 5.2 ng/mL, respectively. The accuracy, specificity, and Youden index of MAD ≥1.0 cm combined with SCC-Ag ≥ 5.2 ng/mL for evaluating lymph node metastasis were 75.71%, 100%, and 0.59, respectively, and were significantly different from the values for the MAD ≥1.0 cm (72.09%, 80.56%, and 0.47, respectively) and SCC-Ag ≥ 5.2 ng/mL (71.43%, 68.97%, and 0.42, respectively) groups. Correlation analysis showed that non-squamous cell carcinoma, pelvic lymph node (PLN) MAD ≥1.0 cm plus number ≥ 2, and 1 PLN MAD ≥1.0 cm with CILN and/or PALN MAD 0.5-1.0 cm were risk factors for CILN and/or PALN metastasis. CONCLUSION: Patients with MAD ≥1.0 cm and SCC-Ag ≥ 5.2 ng/mL, as well as high risk factors for CILN and/or PALN metastasis, should undergo resection of enlarged lymph nodes below the common iliac gland and lymphadenectomy of CILN/PALN to reduce tumor burden and to clarify lymph node metastasis status for accurate guidance in follow-up treatment. Patients with MAD < 1.0 cm and SCC-Ag < 5.2 ng/mL may be treated with chemoradiotherapy directly based on imaging, given the low lymph node metastasis rate.

Transcriptomic and physiological changes in western mosquitofish (Gambusia affinis) after exposure to norgestrel.

Norgestrel (NGT) is a synthetic progestin used in human and veterinary medicine. Adult female mosquitofish were exposed to NGT for 42 d at 377 ng L-1. The fin morphology and the liver transcriptome were assessed. NGT exposure increased ray 4:6 length ratio. As compared to the control, NGT treatment affected the expression of 11,772 annotated transcripts in female mosquitofish. Specifically, we found 5780 were repressed while 5992 were significantly induced. Gene ontology (GO) analysis showed that 53 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways and 158 GO terms were significantly over expressed. Genes showing the largest magnitude of expression changes were related to fin development, androgen biosynthesis, and lipid and fatty acid metabolisms, suggesting the involvement of these biological processes in response to NGT exposure in G. affinis. This first comprehensive study on the transcriptomic alterations by NGT in G. affinis not only provides valuable information on the development of molecular markers but also opens new avenues for studies on the molecular mechanisms of effects of NGT in particular and possibly other progestins in G. affinis.

PD-1/PD-L1 inhibitors-associated cardiac adverse events: a retrospective and real-world study based on the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors have reformed the treatment landscape for various malignancies and improved prognosis of patients. However, they also lead to events that although rare may prove to be fatal. RESEARCH DESIGN AND METHODS: Data from July 2014 to June 2022 based on FDA Adverse Event Reporting System (FAERS) were analyzed. The signal index reporting odds ratio (ROR) was used to evaluate the correlation between cardiac AEs and given medications. The indications and the median time to onset (TTO) of different PD-1/PD-L1 inhibitors were compared. RESULTS: Cardiac AEs are rare but may be fatal with particular profiles in primary tumor, onset time, and especially gender. We identified 11,538 reports that were related to cardiotoxicity of PD-1/PD-L1 inhibitors, in which 178 different preferred terms (PTs) were distinguished, and nivolumab reported the most PTs with signal. All targeted medications showed signals in myocardial disorders and pericardial disorders, which tend to occur in the first 1-2 months. Non-small cell neoplasm was the top and common indication during anti-PD-1 or anti-PD-L1 therapy with cardiotoxicity. CONCLUSIONS: This study could help early diagnosis and surveillance of ICIs-related cardiotoxicity.

High Dietary Inflammatory Index increases the risk of female infertility: An analysis of NHANES 2013-2018.

Diet-related inflammation, which can be evaluated using the dietary inflammatory index (DII), is increasingly related to female infertility. However, studies on the association between DII and infertility are limited. In this study, we aim to explore the association between DII and infertility and its dose-effect relationship among women aged 20 to 45 years through a cross-sectional analysis of the National Health and Nutrition Examination Survey 2013-2018. A total of 2613 women aged 20 to 45 years were included and analyzed. The DII was calculated using the first 24-hour dietary recall interview data and divided into quartiles. Weighted multivariable logistic regression and restricted cubic spline analysis were used to explore the relationship between DII and infertility. The odds ratio (OR) (95% confidence interval [CI]) for the association between DII and infertility was 1.06 (0.96-1.19) after multivariable adjustment. Compared with the first quartile (anti-inflammatory diet), the fourth quartile of DII (pro-inflammatory diet) was more strongly associated with an increased risk of infertility, with an OR of 1.61 (95% CI, 1.05-2.47). Restricted cubic splines showed a J-shaped nonlinear association between DII and infertility (P for nonlinear = .003), with a cutoff point of 2.45. When DII was higher than 2.45, the OR for infertility was 1.95 (95% CI, 1.49-2.54). Similar results were observed among the subgroup analyses. In conclusion, this study found high DII (pro-inflammatory diet) increases the risk of female infertility. DII had a J-shaped nonlinear relationship with female infertility, whose cut point is 2.45. Controlling the intake of pro-inflammatory food may be beneficial for female infertility.

Simultaneous removal of NO, SO2 and Hg0 with the WDRMRS.

Micro-nanobubbles can spontaneously generate hydroxyl free radicals (OH). Urea is a cheap reductant and can react with NOx species, and their products are nontoxic and harmless N2, CO2 and H2O. In this study, a Wet Direct Recycling Micro-nanobubble Flue Gas Multi-pollutants Removal System (WDRMRS) was developed for the simultaneous removal of NO, SO2 and Hg0. In this system, a micro-nanobubble generator (MNBG) was used to produce a micro-nanobubble gas-liquid dispersion system (MNBGLS) through recycling the urea solution from the reactor and the simulated flue gas composed of N2, NO, SO2 and Hg0. The MNBGLS, which has a large gas-liquid dispersion interface, was recycled continuously from the MNBG to the reactor, thus achieving cyclic absorption of various pollutants. All of the investigated parameters, including the initial pH and temperature of the absorbent as well as the concentrations of urea, NO and SO2 had significant effects on the NO removal efficiency but did not significantly affect the SO2 removal efficiency, whereas only the initial solution pH and NO concentration affected the Hg0 removal efficiency. The analysis results of the reaction mechanism showed that ·OH played a critical role in the removal of various pollutants. After the treatment by this system, the main removal products were Hg0 sediment, SO42- and NH4+ which could be easily recycled. The use of this system (MNBGLS) for the simultaneous removal of NO, SO2 and Hg0 is a new technology application and research. Recycling process based on MNBGLS succeeded in simultaneously removing NO, SO2 and Hg0. The system (MNBGLS) can provide a reference for commercial applications. The removal products are relatively simple and beneficial to recycling, which can reduce the cost of waste gas treatment.

The involvement of MALAT1-ALKBH5 signaling axis into proliferation and metastasis of human papillomavirus-positive cervical cancer.

Infection with high-risk human papillomavirus (HPV), for example, with types 16 and 18, is closely associated with cervical cancer development, which continues to threaten women's health globally. Although HPV oncogenes have been recognized as the main cause of transformation of normal cervical epithelial cells, non-coding RNA could also be involved in the initiation and promotion of cervical cancer development. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a well-documented long non-coding RNA (lncRNA), has been previously reported to exert roles in HPV-positive cervical cancer; however, the detailed underlying mechanism has yet to be investigated. In the present study, high expression levels of MALAT1 in HPV-Positive Cervical Cancer cells were confirmed, and silencing MALAT1 resulted in decreased rates of cell proliferation, migration, and invasion, both in vitro and in a zebrafish xenograft tumor model. Moreover, the results obtained showed that silencing MALAT1 led to down-regulation of the N6-methyladenosine (m6A) demethylase ALKBH5 via regulating miR-141-3p expression, which caused a decrease in the expression levels of matrix metalloproteinase 2 (MMP2) and MMP9 expression, thereby suppressing cell migration and invasion. Taken together, the results obtained have suggested that the MALAT-ALKBH5 signaling axis may be activated in HPV-positive cervical cancer cells, which could contribute to cell proliferation and metastasis through the regulation of key genes, such as MMP2 or MMP9. The findings of the present study should both help to improve our understanding of the underlying tumorigenic mechanisms of HPV-positive cervical cancer and be of further use in the development of potential therapeutic drugs.

Risk Factors for Granulocytopenia in Patients with Graves' Disease Receiving Antithyroid Drugs.

Objective: To study the risk factors for granulocytopenia caused by antithyroid drugs. Methods: Patients who were diagnosed with Graves' hyperthyroidism and regularly treated with antithyroid drugs (ATDs) from January 2010 to July 2022 at Nanjing Drum Tower Hospital, aged >18 years, were selected for general information and laboratory tests and divided into two groups according to the occurrence of granulocytopenia. Independent risk factors for the development of granulocytopenia in patients treated with ATDs were analyzed using one-way and multiway logistic regression analyses, and the predictive value of each index was evaluated using the receiver operating characteristic (ROC) curve and the area under the curve (AUC). Results: A total of 818 patients were enrolled, of which 95 developed granulocytopenia. Univariate analysis revealed that sex, white blood cell (WBC) counts, neutrophil-to-lymphocyte ratio (NLR), glutamic-pyruvic transaminase (ALT), aspartate transaminase (AST), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) before medication were risk factors for ATD-induced granulocytopenia (P < 0.05). The abovementioned indicators were taken as independent variables, and multivariate logistic regression analysis showed that female sex, higher ALT levels before medication, and lower NLR and WBC levels were independent risk factors for granulocytopenia using ATDs (P < 0.05). ROC curve analysis showed that sex, NLR, ALT, and WBC count had significant predictive values (P < 0.05), and NLR and WBC count had higher predictive values (AUC = 0.916 and 0.700, respectively). Conclusion: Sex, NLR, ALT, and WBC were the main risk factors for granulocytopenia in patients with ATD.

Antibacterial Effects of Ramulus mori Oligosaccharides against Streptococcus mutans.

Ramulus mori has been widely used in traditional Chinese medicine because of its physiological activities, including antibacterial, anti-inflammatory, and antioxidant activities. Antimicrobial properties of Ramulus mori extract have been well described. However, no information is available regarding on Ramulus mori oligosaccharides (RMOS). The aim of this study was to investigate the effects of RMOS on the growth and virulence properties of the cariogenic bacterium Streptococcus mutans. The effects of RMOS on the biofilm structure and virulence gene expression of S. mutans were also evaluated, and the results were compared with the effects of commercial prebiotic galactooligosaccharides. RMOS were found to have an antibacterial effect against S. mutans, resulting in significant reductions in acid production, lactate dehydrogenase activity, adhesion, insoluble extracellular polysaccharide production, glucosyltransferase activity, and biofilm formation in a dose-dependent manner. Moreover, the biofilm structure was visibly damaged. A quantitative real-time PCR assay revealed downregulation of virulence gene-regulated acid production, polysaccharide production, adhesion, biofilm formation, and quorum sensing. These findings suggest that RMOS may be a promising natural product for the prevention of dental caries.

Novel evaluation indicators of MOG35∼55 induced experimental autoimmune encephalomyelitis in C57BL/6J mice.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by demyelinating neuropathy. Despite a long period of research on the immune mechanisms involved in CNS diseases, the etiology of MS remains unknown. MS may present with different clinical and pathological manifestations due to the involvement of different pathogenic processes, including balance and mobility disorders, psychiatric abnormalities, and intestinal dysfunction. We used an animal model of MS, experimental autoimmune encephalomyelitis (EAE), to assess clinical symptoms of MS with the aim of creating new indicators for the assessment of EAE. Our results show that EAE mice develop severe bone loss, anxiety-like moods, and intestinal inflammation in addition to clinical phenomena such as inflammatory infiltration and demyelination of the spinal cord. Our new indicators aim to provide a more comprehensive assessment of MS to avoid the pitfalls of a single intervention and also to provide a more systematic assessment of the effectiveness of drugs used to treat MS.

Inhibition of fibroblast activation protein ameliorates cartilage matrix degradation and osteoarthritis progression.

Fibroblast activation protein (Fap) is a serine protease that degrades denatured type I collagen, α2-antiplasmin and FGF21. Fap is highly expressed in bone marrow stromal cells and functions as an osteogenic suppressor and can be inhibited by the bone growth factor Osteolectin (Oln). Fap is also expressed in synovial fibroblasts and positively correlated with the severity of rheumatoid arthritis (RA). However, whether Fap plays a critical role in osteoarthritis (OA) remains poorly understood. Here, we found that Fap is significantly elevated in osteoarthritic synovium, while the genetic deletion or pharmacological inhibition of Fap significantly ameliorated posttraumatic OA in mice. Mechanistically, we found that Fap degrades denatured type II collagen (Col II) and Mmp13-cleaved native Col II. Intra-articular injection of rFap significantly accelerated Col II degradation and OA progression. In contrast, Oln is expressed in the superficial layer of articular cartilage and is significantly downregulated in OA. Genetic deletion of Oln significantly exacerbated OA progression, which was partially rescued by Fap deletion or inhibition. Intra-articular injection of rOln significantly ameliorated OA progression. Taken together, these findings identify Fap as a critical pathogenic factor in OA that could be targeted by both synthetic and endogenous inhibitors to ameliorate articular cartilage degradation.

N-trimethyl chitosan nanoparticle-encapsulated lactosyl-norcantharidin for liver cancer therapy with high targeting efficacy.

N-Trimethyl chitosan (TMC) was synthesized and used to prepare lactosyl-norcantharidin TMC nanoparticles (Lac-NCTD-TMC-NPs) using an ionic cross-linkage process. Lac-NCTD-TMC-NPs with an average particle size of 120.6 ± 1.7 nm were obtained, with an entrapment efficiency of 69.29% ± 0.76%, and a drug-loading amount of 9.1% ± 0.07%. The release of Lac-NCTD-TMC-NPs in vitro was investigated through a dialysis method, and its sustained effect was evident. In the human liver cancer cell line HepG2, the half-maximum inhibiting concentration (IC(50)) of TMC-encapsulated Lac-NCTD (Lac-NCTD-TMC-NPs) was only 24.2% that of free Lac-NCTD at 24 hours. Lac-NCTD induced HepG2 cell death by triggering apoptosis. In vitro cellular uptake and in vivo NIR fluorescence real-time imaging both indicated a high targeting efficacy. In comparison with Lac-NCTD and Lac-NCTD chitosan NPs (Lac-NCTD-CS-NPs ), Lac-NCTD-TMC-NPs had the strongest antitumor activity on the murine hepatocarcinoma 22 subcutaneous model. FROM THE CLINICAL EDITOR: In this article the preparation of N-trimethyl chitosan-encapsulated lactosyl-norcantharidin nanoparticles is described that displayed efficient targeting and sustained release in a hepatocarcinoma SC murine model.

Skeletal stem cells: a game changer of skeletal biology and regenerative medicine?

Skeletal stem cells (SSCs) were originally discovered in the bone marrow stroma. They are capable of self-renewal and multilineage differentiation into osteoblasts, chondrocytes, adipocytes, and stromal cells. Importantly, these bone marrow SSCs localize in the perivascular region and highly express hematopoietic growth factors to create the hematopoietic stem cell (HSC) niche. Thus, bone marrow SSCs play pivotal roles in orchestrating osteogenesis and hematopoiesis. Besides the bone marrow, recent studies have uncovered diverse SSC populations in the growth plate, perichondrium, periosteum, and calvarial suture at different developmental stages, which exhibit distinct differentiation potential under homeostatic and stress conditions. Therefore, the current consensus is that a panel of region-specific SSCs collaborate to regulate skeletal development, maintenance, and regeneration. Here, we will summarize recent advances of SSCs in long bones and calvaria, with a special emphasis on the evolving concept and methodology in the field. We will also look into the future of this fascinating research area that may ultimately lead to effective treatment of skeletal disorders.

Analysis of Lactobacillus rhamnosus GG in Mulberry Galacto-Oligosaccharide Medium by Comparative Transcriptomics and Metabolomics.

Lactobacillus rhamnosus GG (LGG) has strong acid resistance and can survive passing through the stomach to colonize the intestines, where it promotes the growth of beneficial bacteria. Prebiotics such as mulberry galacto-oligosaccharide (MGO), mulberry polysaccharide solution (MPS), and galactooligosaccharides (GOS) promote LGG proliferation, and MGO has the greatest effect. After culturing LGG with prebiotics, changes in gene expression were studied at the transcriptomic and metabolomic levels. The results showed that, in the stable 24-h growth period of cultivation, ~63 and 132% more differential genes were found after MPS and MGO were added to the MRS medium, respectively, than after GOS was added, and the numbers of up-regulated genes were about 18 and 66% higher with MPS and MGO, respectively, than GOS. Analysis using the KEGG database revealed that, when LGG was cultured with MGO, 120 genes that were up-regulated as the growth rate increased were mainly enriched in pathways such as membrane transport, amino acid metabolism, and carbohydrate metabolism. The genes gatB and gatC were up-regulated for galactose metabolism, and bglA was up-regulated in the glycolysis/gluconeogenesis pathway. The qRT-RCR results, which were in agreement with the RNA-seq, indicated the genes involved in the proliferation effect of LGG were up-regulated. UDP-glucose may be a key metabolite for MGO to promote LGG proliferation.

Relationship between fat mass and obesity-associated gene expression and type 2 diabetes mellitus severity.

This study sought to investigate any correlation between fat mass and obesity-associated gene (FTO) expression and the severity of type 2 diabetes mellitus (T2DM). In total 110 patients newly diagnosed with T2DM in the outpatient department of Yantai Yuhuangding Hospital between September 2016 and March 2017 were selected as study subjects and were divided into severe (58 cases) and mild groups (52 cases) according to T2DM severity. Patients in the severe group were followed up for 12 weeks. An additional 60 healthy individuals were selected to serve as the normal control group. Fasting plasma glucose (FPG), fasting insulin (FINs), fasting C-peptide (FCP), glycosylated hemoglobin (HbA1c) and homeostasis model assessment of insulin resistance (HOMA-IR) were examined for every patient in the study. Real-time polymerase chain reaction (RT-PCR) was used to detect FTO messenger ribonucleic acid (mRNA) expression levels in patient peripheral blood lymphocytes. Western blotting was used to detect serum FTO protein expression levels, upon which the correlation between FTO protein levels and all other indices were analyzed. Compared with the normal control group, both T2DM groups showed significantly increased waist circumferences, hip circumferences, body mass indexes (BMIs), blood glucose indexes (FPG, FCP, HbA1c, FINs, HOMA-IR) and FTO mRNA/protein levels (p<0.05). Additionally, the increases presented by the severe T2DM group were significantly greater than those presented by the mild T2DM group (p<0.05). After 12 weeks of treatment, the severe T2DM group showed decreased BMI, blood glucose index and FTO protein expression (p<0.05). FTO protein expression in T2DM patients was higher than in healthy controls, with severe patients showing greater expression levels than mild group patients. FTO expression was positively correlated with BMI, waist circumference, chest circumference, FPG, FCP, HbA1c, FINs and HOMA-IR. Therefore, FTO expression can serve as a marker for the clinical diagnosis and treatment of T2DM.

Statin use and endometrial cancer risk: a meta-analysis.

Several studies have evaluated the association between statin use and endometrial cancer risk. We carried out a meta-analysis of randomized controlled trials (RCTs) and non-randomized studies to evaluate the effect of statins on endometrial cancer risk. A comprehensive search of electronic databases, conference abstracts and clinical trial registers was conducted for published and unpublished results. Studies that evaluated exposure to statins and endometrial cancer risk were considered. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using either a fixed-effects or a random-effects model. Two RCTs and eleven non-randomized studies (four cohort and seven case-control studies) involving 9,517 cases of endometrial cancer were included in the analysis. There was no evidence of an association between statin use and endometrial cancer risk either among RCTs (RR, 0.72; 95% CI, 0.19 to 2.67) or among non-randomized studies (RR, 0.94; 95% CI, 0.82 to 1.07). Combined analysis of all included studies also showed that statin use did not significantly affect endometrial cancer risk (RR, 0.94; 95% CI, 0.82 to 1.07). The sensitivity analysis confirmed the stability of our results. Our findings do not support a protective effect of statins against endometrial cancer at the population level.

Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor.

Multidrug resistance (MDR) is a major obstacle for the clinical therapy of malignant human cancers. The discovery of RNA interference provides efficient gene silencing within tumor cells for reversing MDR. In this study, a new "binary polymer" low-density lipoprotein-N-succinyl chitosan-cystamine-urocanic acid (LDL-NSC-SS-UA) with dual pH/redox sensitivity and targeting effect was synthesized for the co-delivery of breast cancer resistance protein small interfering RNA (siRNA) and paclitaxel (PTX). In vivo, the co-delivering micelles can accumulate in tumor tissue via the enhanced permeability and retention effect and the specific recognition and combination of LDL and LDL receptor, which is overexpressed on the surface of tumor cell membranes. The siRNA-PTX-loaded micelles inhibited gene and drug release under physiological conditions while promoting fast release in an acid microenvironment or in the presence of glutathione. The micelles escaped from the lysosome through the proton sponge effect. Additionally, the micelles exhibited superior antitumor activity and downregulated the protein and mRNA expression levels of breast cancer resistance protein in MCF-7/Taxol cells. The biodistribution and antitumor studies proved that the siRNA-PTX-loaded micelles possessed prolonged circulation time with a remarkable tumor-targeting effect and effectively inhibited tumor growth. Therefore, the novel dual pH/redox-sensitive polymers co-delivering siRNA and PTX with excellent biocompatibility and effective reversal of MDR demonstrate a considerable potential in cancer therapy.