Human Breast Milk Exosomal miRNAs are Influenced by Premature Delivery and Affect Neurodevelopment.

SCOPE: This study investigates the exosomal microRNA (miRNA) profiles of term and preterm breast milk, including the most abundant and differentially expressed (DE) miRNAs, and their impact on neurodevelopment in infants. METHODS AND RESULTS: Mature milk is collected from the mothers of term and preterm infants. Using high-throughput sequencing and subsequent data analysis, exosomal miRNA profiles of term and preterm human breast milk (HBM) are acquired and it is found that the let-7 and miR-148 families are the most abundant miRNAs. Additionally, 23 upregulated and 15 downregulated miRNAs are identified. MiR-3168 is the most upregulated miRNA in preterm HBM exosome, exhibiting targeting activity toward multiple genes involved in the SMAD and MAPK signaling pathways and playing a crucial role in early neurodevelopment. Additionally, the effects of miR-3168 on neurodevelopment is confirmed and it is determined that it is an essential factor in the differentiation of neural stem cells (NSCs). CONCLUSION: This study demonstrates that miRNA expression in breast milk exosomes can be influenced by preterm delivery, thereby potentially impacting neurodevelopment in preterm infants.

Comprehensive analysis of peroxisome proliferator-activated receptors to predict the drug resistance, immune microenvironment, and prognosis in stomach adenocarcinomas.

Background: Peroxisome proliferator-activated receptors (PPARs) exert multiple functions in the initiation and progression of stomach adenocarcinomas (STAD). This study analyzed the relationship between PPARs and the immune status, molecular mutations, and drug therapy in STAD. Methods: The expression profiles of three PPAR genes (PPARA, PPARD and PPARG) were downloaded from The Cancer Genome Atlas (TCGA) dataset to analyze their expression patterns across pan-cancer. The associations between PPARs and clinicopathologic features, prognosis, tumor microenvironment, genome mutation and drug sensitivity were also explored. Co-expression between two PPAR genes was calculated using Pearson analysis. Regulatory pathways of PPARs were scored using gene set variation analysis (GSVA) package. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, Cell Counting Kit-8 (CCK-8) assay and transwell assay were conducted to analyze the expression and function of the PPAR genes in STAD cell lines (AGS and SGC7901 cells). Results: PPARA, PPARD and PPARG were more abnormally expressed in STAD samples and cell lines when compared to most of 32 type cancers in TCGA. In STAD, the expression of PPARD was higher in Grade 3+4 and male patients, while that of PPARG was higher in patient with Grade 3+4 and age > 60. Patients in high-PPARA expression group tended to have longer survival time. Co-expression analysis revealed 6 genes significantly correlated with the three PPAR genes in STAD. Single-sample GSEA (ssGSEA) showed that the three PPAR genes were enriched in 23 pathways, including MITOTIC_SPINDLE, MYC_TARGETS_V1, E2F_TARGETS and were closely correlated with immune cells, including NK_cells_resting, T_cells_CD4_memory_resting, and macrophages_M0. Immune checkpoint genes (CD274, SIGLEC15) were abnormally expressed between high-PPAR expression and low-PPAR expression groups. TTN, MUC16, FAT2 and ANK3 genes had a high mutation frequency in both high-PPARA/PPARG and low-PPARA/PPARG expression group. Fourteen and two PPARA/PPARD drugs were identified to be able to effectively treat patients in high-PPARA/PPARG and low-PPARA/PPARG expression groups, respectively. We also found that the chemotherapy drug Vinorelbine was positively correlated with the three PPAR genes, showing the potential of Vinorelbine to serve as a treatment drug for STAD. Furthermore, cell experiments demonstrated that PPARG had higher expression in AGS and SGC7901 cells, and that inhibiting PPARG suppressed the viability, migration and invasion of AGS and SGC7901 cells. Conclusions: The current results confirmed that the three PPAR genes (PPARA, PPARD and PPARG) affected STAD development through mediating immune microenvironment and genome mutation.

[Investigation on the current situation of the development of intensive care units in Inner Mongolia Autonomous Region in 2022].

OBJECTIVE: To investigate the development present situation of the department of critical care medicine in Inner Mongolia Autonomous Region (hereinafter referred to as Inner Mongolia), in order to promote the standardized and homogeneous development of critical care medicine in Inner Mongolia, and also provide a reference for discipline construction and resource allocation. METHODS: A survey study was conducted in comprehensive intensive care unit (ICU) of tertiary and secondary hospitals in Inner Mongolia by online questionnaire survey and telephone data verification. The questionnaire was based on the Guidelines for the Construction and Management of Intensive Care Units (Trial) (hereinafter referred to as the Guidelines) issued by the National Health Commission in 2009 and the development trend of the discipline. The questionnaire covered six aspects, including hospital basic information, ICU basic information, personnel allocation, medical quality management, technical skill and equipment configuration. The questionnaire was distributed in September 2022, and it was filled out by the discipline leaders or department heads of each hospital. RESULTS: As of October 24, 2022, a total of 101 questionnaires had been distributed, 85 questionnaires had been recovered, and the questionnaire recovery rate had reached 84.16%, of which 71 valid questionnaires had been collected in a total of 71 comprehensive ICU. (1) There were noticeable regional differences in the distribution of comprehensive ICU in Inner Mongolia, with a relatively weak distribution in the east and west, and the overall distribution was uneven. The development of critical care medicine in Inner Mongolia was still lacking. (2) Basic information of hospitals: the population and economy restricted the development of ICU. The average number of comprehensive ICU beds in the western region was only half of that in the central region (beds: 39.0 vs. 86.0), and the average number of ICU beds in the eastern region was in the middle (83.6 beds), which was relatively uneven. (3) Basic information of ICU: among the 71 comprehensive ICU surveyed, there were 44 tertiary hospitals and 27 secondary hospitals. The ratio of ICU beds to total beds in tertiary hospitals was significantly lower than that in secondary hospitals [(1.59±0.81)% vs. (2.11±1.07)%, P < 0.05], which were significantly lower than the requirements of the Guidelines of 2%-8%. The utilization rate of ICU in tertiary and secondary hospitals [(63.63±22.40)% and (44.65±20.66)%, P < 0.01] were both lower than the bed utilization rate required by the Guidelines (75% should be appropriate). (4) Staffing of ICU: there were 376 doctors and 1 117 nurses in tertiary hospitals, while secondary hospitals had 122 doctors and 331 nurses. There were significant differences in the composition ratio of the titles of doctors, the degree of doctors, and the titles of nurses between tertiary and secondary hospitals (all P < 0.05). Most of the doctors in tertiary hospitals had intermediate titles (attending physicians accounted for 41.49%), while most of the doctors in secondary hospitals had junior titles (resident physicians accounted for 43.44%). The education level of doctors in tertiary hospitals was generally higher than that in secondary hospitals (doctors: 2.13% vs. 0, masters: 37.24% vs. 8.20%). The proportion of nurses in tertiary hospitals was significantly lower than that in secondary hospitals (17.01% vs. 24.47%). The ratio of ICU doctors/ICU beds [(0.64±0.27)%, (0.59±0.34)%] and ICU nurses/ICU beds [(1.76±0.56)%, (1.51±0.48)%] in tertiary and secondary hospitals all failed to meet the requirements above 0.8 : 1 and 3 : 1 of the Guidelines. (5) Medical quality management of ICU: compared with secondary hospitals, the proportion of one-to-one drug-resistant bacteria care in tertiary hospitals (65.91% vs. 40.74%), multimodal analgesia and sedation (90.91% vs. 66.67%), and personal digital assistant (PDA) barcode scanning (43.18% vs. 14.81%) were significantly higher (all P < 0.05). (6) Technical skills of ICU: in terms of technical skills, the proportion of bronchoscopy, blood purification, jejunal nutrition tube placement and bedside ultrasound projects carried out in tertiary hospitals were higher than those in secondary hospitals (84.09% vs. 48.15%, 88.64% vs. 48.15%, 61.36% vs. 55.56%, 88.64% vs. 70.37%, all P < 0.05). Among them, the placement of jejunal nutrition tube, bedside ultrasound and extracorporeal membrane oxygenation were mainly completed independently in tertiary hospitals, while those in secondary hospitals tended to be completed in cooperation. (7) Equipment configuration of ICU: in terms of basic equipment, the ratio of the total number of ventilators/ICU beds in tertiary and secondary hospitals [0.77% (0.53%, 1.07%), 0.88% (0.63%, 1.38%)], and the ratio of injection pump/ICU beds [1.70% (1.00%, 2.56%), 1.25% (0.75%, 1.88%)] didn't meet the requirements of the Guidelines. The equipment ratio was insuffcient, which means that the basic needs of development had not been met yet. CONCLUSIONS: The development of comprehensive ICU in Inner Mongolia has tended to mature, but there is still a certain gap in the development scale, personnel ratio and instruments and equipment compared with the Guidelines. Moreover, the comprehensive ICU appears the characteristics of relatively weak eastern and western regions, and the overall distribution is uneven. Therefore, it is necessary to increase efforts to invest in the construction of the department of critical care medicine.

Highly Efficient Photocatalytic Degradation of Tetracycline by Modifying UiO-66 via Different Regulation Strategies.

Wastewater containing organic pollutants cause potential harm to the environment and human health. A series of zirconium-organic frameworks (UiO-66) and their composites were synthesized by solvothermal methods, including band gap adjustment, heterojunction construction, and metal ion doping. For the model pollutant tetracycline (TC), all of the prepared catalysts could achieve effective degradation of it. Therein, the degradation efficiency of tetracycline could reach 95% under the UV irradiation with the aid of the catalyst, in which the UiO-66-NDC was modified with P-C3N4. The free radical capture experiments demonstrated that the superoxide radical (•O2-) was the main oxidizing species for the photodegradation of tetracycline. Hence, the improvement strategy of the catalyst would provide some enlightenment for the development of more efficient photocatalysts for the degradation of organic dyes in wastewater.

Suppression of colon cancer growth by berberine mediated by the intestinal microbiota and the suppression of DNA methyltransferases (DNMTs).

The purpose of this study was to demonstrate the regulatory effect of berberine (BBR) on the intestinal microbiota and related epigenetics during the inhibition of colon cancer cell growth in vitro and in vivo. We used a nude mouse xenograft model with HT29 colon cancer cells to establish and divide into a model group and BBR group. The mice were treated for four weeks, and HT29 cells in the BBR group were cultured for 48 h. Cetuximab and the DNA transmethylase (DNMT) inhibitor 5-AZA-dC were added to HT29 cells. Tumour volume and weight were measured by hematoxylin-eosin (HE) staining for histopathological observation. Mouse faeces were collected, and the gut microbiota was analysed with 16S rDNA amplicons. The levels of cytokines in the supernatant of HT29 cells were measured by ELISA. A CCK-8 kit was used to examine the proliferation of HT29 cells, and RT‒PCR was used to measure the levels of c-Myc, DNMT1, DNMT3A, and DNMT3B. We found that BBR reduced the growth of colon cancer cells to a certain extent in vitro and in vivo, although the difference was not statistically significant compared with that in the model group. BBR significantly mediated the abundance, composition and metabolic functions of the intestinal microbial flora in mice with colon cancer. The effect of BBR on inflammatory cytokines, including IL-6, FGF, and PDGF, was not obvious, but BBR significantly downregulated IL-10 levels (P < 0.05) and reduced c-Myc, DNMT1, and DNMT3B levels (P < 0.05). Inhibiting DNMTs with 5-AZA-dC significantly suppressed the proliferation of HT29 cells, which was consistent with the effect of BBR. The inhibitory effect of berberine on colon cancer is related not only to the intestinal microbiota and its metabolic functions but also to the regulation of DNMTs.

g-C3N4-modified Zr-Fc MOFs as a novel photocatalysis-self-Fenton system toward the direct hydroxylation of benzene to phenol.

In order to explore a green, economic, and sustainable phenol production process, a heterojunction semiconductor materials g-C3N4/Zr-Fc MOF was synthesized via an in situ synthesis method. With the synergistic effect of photocatalysis and the Fenton effect, the composite could effectively catalyze the direct hydroxylation of benzene to phenol under visible light irradiation. The yield of phenol and the selectivity were 13.84% and 99.38% under the optimal conditions, respectively, and it could still maintain high photocatalytic activity after 5 photocatalytic cycles. Therefore, the designed photocatalysis-self-Fenton system has great potential in the field of the direct hydroxylation of benzene to phenol.

An efficient photocatalyst based on H5PMo10V2O40/UiO-66-NH2 for direct hydroxylation of benzene to phenol by H2O2.

To realize the direct hydroxylation of benzene to phenol by hydrogen peroxide, an efficient photoactive catalyst system was prepared by the recombination of H5PMo10V2O40 and UiO-66-NH2. The heterpolyacid was uniformly distributed on the UiO-66-NH2, and the combination was stable. The composite could effectively photocatalyze the direct hydroxylation of benzene to phenol by H2O2 in the mixture solution of acetonitrile and acetic acid. The yield and selectivity were 14.08% and 98.8% under the optimum condition, respectively. The performance of the catalyst still maintained well after 5 catalytic cycles. Hence, the investigated catalyst system might be applied in the field of hydroxylation of benzene to phenol.

High-Quality N-Doped Graphene with Controllable Nitrogen Bonding Configurations Derived from Ionic Liquids.

Controllable nitrogen doping is an effective way to regulate the electronic properties of graphene and further to facilitate its wider application. However, the synthesis of high-quality nitrogen-doped graphene (NG) with a controllable nitrogen configuration still faces considerable challenges. In this work, we present for the first time a simple method for the one-step synthesis of NG with ionic liquids (ILs) as precursors, which avoids the defects introduced by secondary doping and simplifies the process. Using 1-Ethyl-3-methylimidazolium dicyanamide (EMIM-dca) as the precursor, we obtained a high-quality NG with few defects (ID /IG is 0.83), nitrogen content (4.11 at%), and graphite-N proportion of 92% at a growth temperature of 1000 °C and field effect transistors (FETs) fabricated on SiO2 /Si substrates using the NG exhibited typical n-type semiconductor behavior in air. Our findings bring more inspiration for the controllable growth of high-quality graphitic N-doped graphene, thereby promoting its application possibilities in numerous fields.

Improvement in outpatient services using the WeChat calling system in the Shanghai Children's Hospital.

OBJECTIVES: We explored the utility of WeChat applet as part of the Outpatient Department (OPD) to provide patients with timely queuing information and compared it with the traditional calling system. METHODS: Data for the WeChat calling system was extracted for the period of May 2018 to September 2018. Data for the traditional system was extracted for the same period from the year 2017. We compared the effective patient waiting time and nurse idle time i.e. nonproductive time spent on factors outside of employees' control with the two systems. We also analyzed the relationship between the length of waiting time and conflicts between doctors and patients. RESULTS: The mean wait time for the traditional calling system was 126 minutes, while the average idle time for nurses was 96 minutes/day. On the other hand, the mean wait time for the WeChat calling system was 33 minutes, and the average idle time for nurses was 72 minutes/day. The incremental profit (cost of traditional calling system - cost of WeChat calling system) achieved from switching systems was 13,879 yuan/month. Behavioral observations showed that wait time (OR=2.745, 95%CI 1.936~3.892 P<0.0001) was a risk factor for staff-patient conflict. CONCLUSION: The cost of the WeChat calling system was significantly lower than the traditional system. Also, the traditional calling system was time-consuming. Longer waiting time was the main factor affecting OPD quality and caused conflicts between doctors and patients.

Rapid BMI Increases and Persistent Obesity in Small-for-Gestational-Age Infants.

Purpose: In order to compensate for the early intrauterine growth restriction, small-for-gestational age (SGA) infants have "catch-up growth" after birth. Increased caloric intake has been suggested for SGA infants conventionally. It is important to determine if the early growth rate of body mass index (BMI) is associated with risk of persistent obesity later in life. In this longitudinal cohort study, we assessed the BMI of a large cohort of children who were SGA at birth to determine their risk of persistent obesity at school age (6-7 years) due to excessive weight gain in the first 3 years of life. Methods: We collected the height and weight data of 23,871 SGA babies. A polynomial function was used to fit the BMI-for-age z-score (BAZ) values of 0-6 years old SGA children and interpolate their growth trajectory. In addition, we screened out 6,959 children from 23,871 children to further evaluate the dynamic changes of early childhood BMI. We divided the school-age children into groups as non-obese (BAZ < 2) and obese (BAZ > 2), and determined the association between changes in BMI and school-age obesity. Results: From the perspective of BMI distribution, the interpolated growth trajectory indicated that SGA children reaching overweight status or developing obesity by 3 years of age, continued to have obesity until school age (R2, 0.65; R2, 0.21). The retrospective analysis showed that children who were overweight and had obesity during school age had a high BMI from early age. By analyzing the changes in early BMI, we found that the fastest growth of SGA children occurred in the early infancy before 6 months and they continued to grow rapidly for a period of time. Interestingly, former SGA children who maintained a near overweight (1 < BAZ < 2) status before the age of 2 maintained an appropriate growth rate and usually did not develop obesity. Conclusions: A rapid increase in BMI during early infancy in former SGA newborns leads to a persistent risk of obesity. The energy intake of SGA infants should appropriately meet the infants' growth needs and early BMI changes should be closely monitored for an optimal integrated management.

Berberine inhibits epithelial-mesenchymal transition and promotes apoptosis of tumour-associated fibroblast-induced colonic epithelial cells through regulation of TGF-ß signalling.

Tumour-associated fibroblasts (TAFs) mediate the differentiation of adjacent stromal cells. Berberine (BBR), a monomer of traditional Chinese herbs, exhibits a potent therapeutic effect against cancer. However, the effects of BBR on the differentiation of normal colonic epithelial cells induced by TAFs have not been determined. In the present study, we selected the TAF-like myofibroblast cell line CCD-18Co. CCD-18Co-derived conditioned medium (CM) and co-culture induced epithelial-mesenchymal transition (EMT) changes in colonic epithelial HCoEpiC cells with decreased E-cadherin and increased vimentin and α-SMA expression. In addition, CCD-18Co stimulated the expression of ZEB1 and Snail and promoted motility. We used LY364947, a TGF-ß receptor kinase type I (TßRI) inhibitor, and BBR. Our results showed that LY364947 and BBR inhibited these phenomena. BBR decreased the expression of ZEB1 and Snail, and this effect was concentration dependent. BBR also downregulated the expression of TßRI, TßRII, Smad2/p-Smad2 and Smad3/p-Smad3. In addition, BBR induced apoptosis in EMT-like HCoEpiC cells in a concentration-dependent manner with upregulation of Bax and downregulation of Bcl-2. However, VX-702, an inhibitor of p38 MAPK, significantly suppressed the apoptosis rate. BBR promoted the expression of p38 MAPK and phosphorylated p38 MAPK. In conclusion, berberine inhibits EMT and promotes apoptosis in TAF-induced colonic epithelial cells through mediation of the Smad-dependent and SMAD-independent TGF-ß signalling pathways.

Trichostatin a inhibits phenotypic transition and induces apoptosis of the TAF-treated normal colonic epithelial cells through regulation of TGF-ß pathway.

Tumor-associated fibroblasts (TAFs) contribute to transdifferentiation of stromal cells in tumor microenvironment. Epithelial-mesenchymal transition (EMT) is a procedure of phenotypic remodeling of epithelial cells and extensively exists in local tumoral stroma. Histone deacetylase (HDAC) inhibitor Tricostatin A (TSA) and sodium butyrate (SB) are reported to play important roles in the regulation of biological behaviour of cancer cells. However, whether TSA or SB is involved in control of EMT in colon epithelial cells induced by TAFs remains unidentified. In present study, we used conditioned medium (CM) form TAF-like CCD-18Co cells to stimulate 2D- and 3D-cultured colon epithelial HCoEpiC cells for 24 h and 4 d. We found that the CCD-18Co CM triggered multiple morphological changes in HCoEpiCs including prolonged cell diameters, down-regulation of E-cadherin and up-regulation of vimentin and α-SMA. Besides, ZEB1 and Snail expression and migration were also promoted by the CM. These phenomena were abolised by 5 µg/ml LY364947, a TGF-ß receptor inhibitor. CCD-18Co induced up-regulation of HDAC1 and HDAC2 in the 2D and 3D models, while no change of HDAC4 exprerssion was found. Treatment of 2 µg/ml TSA reversed the CCD-18Co-induced morphological changes and migration of the HCoEpiCs, and suppressed the downregulation of E-cadherin and upregulation of vimentin, α-SMA, ZEB1 and Snail. However, the suppressive effect of 4 mg/ml SB on the EMT was not observed. TSA down-regulated the expressions of Smad2/3, p-Smad2/3 amd HDAC4. Besides, TSA promoted the apoptosis rate (36.84 ± 6.52%) comparing with the CCD-18Co-treated HCoEpiCs (3.52 ± 0.85%, P < 0.05), with promotion of Bax (0.5893±0.0498 in 2D and 0.8867±0.0916 in 3D) and reduction of Bcl-2 (0.0476±0.0053 in 2D and 0.0294±0.0075 in 3D). TSA stimulated expression of phosphorylated-p38 MAPK in 2D (0.3472±0.0249) and 3D (0.3188±0.0248). After pre-treatment with p38 MAPK inhibitor VX-702 (0.5 mg/ml), the apoptosis rate of TSA was decreased in 2D (10.32%) and 3D (5.26%). Our observations demonstrate that epigenetic treatment with HDAC inhibitor TSA may be a useful therapeutic tool for the reversion of TAF-induced EMT in colon epithelium through mediating canonical Smads pathway and non-canonical p38 MAPK signalling.

Difference of TGF-ß/Smads signaling pathway in epithelial-mesenchymal transition of normal colonic epithelial cells induced by tumor-associated fibroblasts and colon cancer cells.

Tumor microenvironment (TME) crucially functions in tumor initiation and progression. Stroma-tumor interactions and cellular transdifferentiation are the prerequisite for tumor formation. Transforming growth factor-ß (TGF-ß), a major cytokine secreted by tumor-associated fibroblasts (TAFs) and cancer cells, is a crucial player involving cell transdifferentiation. Therefore, we hypothesized that these TAFs and cancer cells also affect normal colon epithelium. In our study, we found for the first time that colon cancer cells HCT116 and TAF-like CCD-18Co cells induced epithelial-mesenchymal transition (EMT)-like transdifferentiation in colon epithelial cells HCoEpiCs, with enhanced migratio. Dysfunction of TGF-ß/Smads signal was also observed in the EMT-transformed HCoEpiCs. We wondered whether these phenomena were regulated by TGF-ß/Smads signaling pathway. A TGFß receptor kinase I (TßRI) inhibitor LY364947 was used. We found that the EMT induced by the HCT116- and CCD-18Co-derived CM was suppressed by the LY364947. Besides, different expression profiles for the components of TGF-ß/Smads pathway were found in the EMT-like HCoEpiCs, but high expression of p-Smad2/3 and Smad4 was the common feature. Our observations suggest that the mechanisms of phenotypic transition of colon epithelial cells are cellular environment-dependent, which maybe a basis of potential therapy targeting TME.

A mediator of phosphorylated Smad2/3, evodiamine, in the reversion of TAF-induced EMT in normal colonic epithelial cells.

Purpose Transdifferentiation exists within stromal cells in the tumour microenvironment. Transforming growth factor-ß (TGF-ß) secreted by tumour-associated fibroblasts (TAFs) affects the differentiation states of epithelial cells, including epithelial-mesenchymal transition (EMT). Evodiamine, a natural drug, can regulate differentiation. However, the specific effects and relative mechanisms of evodiamine remain unknown. Design We used four models to observe the influence of TAF-like CCD-18Co cells on the colon epithelial cell line HCoEpiC: the 3D- and 2D-mono-culture system, Transwell and direct co-culture model. Additionally, we established conditioned medium from CCD-18Co cells. The TGF-ß pathway inhibitor LY364947 and evodiamine were added. Morphological changes and classical EMT markers were observed and detected using phase contrast microscopy and immunofluorescence. Cell migration was measured by the wound-healing assay. Western blotting was performed to detect the TGF-ß/Smad signalling pathway. Results CCD-18Co cells induced EMT-like changes in the 2D- and 3D-cultured epithelial cell line HCoEpiC, accompanied by high expression of ZEB1 and Snail and the enhancement of migration. Moreover, CCD-18Co-derived conditioned medium caused dysfunction of TGF-ß/Smad signalling in EMT. Evodiamine inhibited these EMT-like HCoEpiC and their migration. Additionally, evodiamine down-regulated the expression of ZEB1/Snail and up-regulated the expression of phosphorylated Smad2/3 (pSmad2/3). Evodiamine also increased the ratios of pSmad2/Smad2 and pSmad3/Smad3. Conclusion Based on our observations, evodiamine can reverse the TAF-induced EMT-like phenotype in colon epithelial cells, which may be associated with its mediation of phosphorylated Smad2 and Smad3 expression.

Berberine reversed the epithelial-mesenchymal transition of normal colonic epithelial cells induced by SW480 cells through regulating the important components in the TGF-ß pathway.

Stroma-tumor interactions within microenvironment play a crucial role in tumor development and growth. Cellular transdifferentiation in the stroma is a prerequisite for tumor formation. Targeting the interactions maybe a promising anticancer strategy. Berberine (BBR) has been confirmed to have anticancer and anti-inflammatory effects. We found for the first time that colon cancer cells SW480 induced spindle-like morphological changes and downregulation of E-cadherin and upregulation of vimentin and alpha-smooth muscle actin in colon epithelial cells HCoEpiCs by using transwell coculture system and conditioned medium from SW480. The conditioned medium also promoted the migration of HCoEpiCs. This transition was inhibited by a transforming growth factor-ß receptor inhibitor LY364947. BBR (50 and 100 µg/ml) reversed the EMT-like transition and repressed the migration in HCoEpiCs. Further results demonstrated that downregulation of TßRII, Smad2, p-Smad3, and overexpression of Smad3 participated in the SW480-induced phenotypic transition of HCoEpiCs. In addition, BBR upregulated the expressions of TßRII, Smad2, and p-Smad3. In conclusion, our findings suggest that BBR exerts the anti-EMT and antimigration effect by mediating the expression of TßRII, Smad2, and p-Smad3.

Insights into infancy weight gain patterns for term small-for-gestational-age babies.

BACKGROUND: Too fast or slow weight gain in infancy is bad for health in later life. In this study, we aim to investigate the optimal weight gain pattern during the first 2 y of life for term small-for-gestational-age (SGA) infants. METHOD: We employed data from a longitudinal, community-based cohort study on the growth and development of SGAs collected between 2004 and 2010 in Shanghai, China. Latent class growth analysis (LCGA) was applied to identify weight gain patterns among 3004 SGAs. BMI curves for each latent class from 1 mo to 5 y were produced through mixed-effects regression analysis. Multivariable regression was performed to examine the association between various classes and adverse outcomes (overweight/obesity/ malnutrition) during 2-5 y. RESULT: Five weight gain patterns aged 0-2 y of 3004 term SGAs were identified and labeled as follows--class 1: excessively rapid catch-up growth (10.7%); class 2: rapid catch-up growth (19.7%); class 3: appropriate catch-up growth (55.7%); class 4: slow catch-up growth (10.2%); class 5: almost no catch-up growth (3.7%). A decreasing age at adiposity rebound (AR) and an increasing BMI value were observed from class 5 to 1. Class 1 and 2 showed an early appearance of AR (< 4 y). SGAs in class 1 and 2 had a higher BMI in 2-5 y of life. After adjustment for potential confounding variables, class 1 and 2 were found to have an increased risk of being overweight/ obese. At the same time, we found the risk of malnutrition was especially prominent among SGAs in classes 4 and 5. CONCLUSION: Our results suggest that for term SGA infants, catch-up growth that crossing two centile levels, that is, from < 10th to the interval between 25th and 50th (ΔWAZ> 1.28) in the first several months, along with on track growth and maintenance at a median level by age 2 may be the optimal catch-up growth trajectory, minimizing risk of childhood adverse health outcomes.

Growth of infants and young children born small for gestational age: growth restriction accompanied by overweight.

Objectives To compare growth profiles of children born small for gestational age (SGA) with those born the appropriate size for gestational age (AGA), and examine expected growth patterns for SGA in early childhood. Methods A survey on 23,871 SGA children was conducted in Shanghai. Data were collected at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, and 60 months of age (+30 days). A check-up included assessments of weight, height, and head circumference. Results At 5 years old, weight, height, and head circumference were lower in SGA children compared with AGA children. The proportions of overweight and obesity of SGA children at 4 to 18 months after birth were significantly higher than those in AGA children, with higher proportions in boys than in girls. There was no correlation between overweight at 5 years old and overweight before 2 years old in SGA children. Conclusions Children born SGA remain shorter and lighter, with a smaller head circumference at 5 years old compared with AGA children. At 4 to 18 months after birth, there is a high incidence of overweight and obesity in SGA children. Overweight and obesity in SGA boys are more serious than those in SGA girls.

CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer's Disease.

Protein phosphatase 2A (PP2A) inhibition causes hyperphosphorylation of tau and APP in Alzheimer's disease (AD). However, the mechanisms underlying the downregulation of PP2A activity in AD brain remain unclear. We demonstrate that Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is overexpressed in AD brain. CIP2A-mediated PP2A inhibition drives tau/APP hyperphosphorylation and increases APP ß-cleavage and Aß production. Increase in CIP2A expression also leads to tau mislocalization to dendrites and spines and synaptic degeneration. In mice, injection of AAV-CIP2A to hippocampus induced AD-like cognitive deficits and impairments in long-term potentiation (LTP) and exacerbated AD pathologies in neurons. Indicative of disease exacerbating the feedback loop, we found that increased CIP2A expression and PP2A inhibition in AD brains result from increased Aß production. In summary, we show that CIP2A overexpression causes PP2A inhibition and AD-related cellular pathology and cognitive deficits, pointing to CIP2A as a potential target for AD therapy.

Extrasynaptic NMDA receptor-induced tau overexpression mediates neuronal death through suppressing survival signaling ERK phosphorylation.

Intracellular accumulation of the hyperphosphorylated tau is a pathological hallmark in the brain of Alzheimer disease. Activation of extrasynaptic NMDA receptors (E-NMDARs) induces excitatory toxicity that is involved in Alzheimer's neurodegeneration. However, the intrinsic link between E-NMDARs and the tau-induced neuronal damage remains elusive. In the present study, we showed in cultured primary cortical neurons that activation of E-NMDA receptors but not synaptic NMDA receptors dramatically increased tau mRNA and protein levels, with a simultaneous neuronal degeneration and decreased neuronal survival. Memantine, a selective antagonist of E-NMDARs, reversed E-NMDARs-induced tau overexpression. Activation of E-NMDARs in wild-type mouse brains resulted in neuron loss in hippocampus, whereas tau deletion in neuronal cultures and in the mouse brains rescued the E-NMDARs-induced neuronal death and degeneration. The E-NMDARs-induced tau overexpression was correlated with a reduced ERK phosphorylation, whereas the increased MEK activity, decreased binding and activity of ERK phosphatase to ERK, and increased ERK phosphorylation were observed in tau knockout mice. On the contrary, addition of tau proteins promoted ERK dephosphorylation in vitro. Taking together, these results indicate that tau overexpression mediates the excitatory toxicity induced by E-NMDAR activation through inhibiting ERK phosphorylation.

Zinc binds to and directly inhibits protein phosphatase 2A in vitro.

Zinc induces protein phosphatase 2A (PP2A) inactivation and tau hyperphosphorylation through PP2A (tyrosine 307) phosphorylation in cells and the brain, but whether Zn(2+) has a direct inhibitory effect on PP2A is not clear. Here we explored the effect of Zn(2+) on PP2A and their direct interaction in vitro. The results showed that Zn(2+) mimicked the inhibitory effect of okadaic acid on protein phosphatase and prevented tau dephosphorylation in N2a cell lysates. PP2A activity assays indicated that a low concentration (10 µmol/L) of Zn(2+) inhibited PP2A directly. Further Zn(2+)-IDA-agarose affinity binding assays showed that Zn(2+) bound to and inhibited PP2Ac(51-270) but not PP2Ac(1-50) or PP2Ac(271-309). Taken together, Zn(2+) inhibits PP2A directly through binding to PP2Ac(51-270) in vitro.