Increased FGF-21 Improves Ectopic Lipid Deposition in the Liver and Skeletal Muscle.

Obesity can lead to excessive lipid accumulation in non-adipose tissues, such as the liver and skeletal muscles, leading to ectopic lipid deposition and damaging target organ function through lipotoxicity. FGF-21 is a key factor in regulating lipid metabolism, so we aim to explore whether FGF-21 is involved in improving ectopic lipid deposition. We observed the characteristics of ectopic lipid deposition in the liver and skeletal muscles of obesity-resistant mice, detected the expression of FGF-21 and perilipin, and found that obesity-resistant mice showed a decrease in ectopic lipid deposition in the liver and skeletal muscles and increased expression of FGF-21. After inhibiting the expression of FGF-21, a more severe lipid deposition in liver cells and skeletal muscle cells was found. The results indicate that inhibiting FGF-21 can exacerbate ectopic lipid deposition via regulating lipid droplet synthesis and decomposition, as well as free fatty acid translocation and oxidation. In conclusion, FGF-21 is involved in improving ectopic lipid deposition caused by obesity in the liver and skeletal muscles.

Study on the flow mechanism and frequency characteristics of rales in lower respiratory tract.

The frequency characteristics of lung sounds have great significance for noninvasive diagnosis of respiratory diseases. The rales in the lower respiratory tract region that can provide rich information about symptoms of respiratory diseases are not clear. In this paper, a three-dimensional idealized bifurcated lower respiratory tract geometric model, which contains 3rd to 13th generation (G3-G13) bronchi is constructed, where Re ∼ 10 1 - 10 3 , and then the large eddy simulation and volume of fluid are used to study the fluid flow characteristics. Ffowcs Williams and Hawkings model are subsequently used to study the frequency characteristics of rale of different generations of bronchi. The results showed that bronchial blockage and sputum movement will enhance the turbulence intensity and vortex shedding intensity of flow. The dominant frequency and highest value of sound pressure level (SPL) of rhonchi/moist crackles decrease with the increase of bronchial generation. The change rates of dominant frequency of rhonchi / moist crackles in adjacent generations were 5.0 ± 0.1 ~ 9.1 ± 0.2% and 3.1 ± 0.1 ~ 11.9 ± 0.3%, respectively, which is concentrated in 290 ~ 420 Hz and 200 ~ 300 Hz, respectively. The change rates of SPL of rhonchi/moist crackles were 8.8 ± 0.1 ~ 15.7 ± 0.1% and 7.1 ± 0.1 ~ 19.5 ± 0.2%, respectively, which is concentrated in 28 ~ 50 dB and 16 ~ 32 dB, respectively. In the same generation of bronchus (e.g., G8, G9) with the same degree of initial blockage, the dominant frequency and SPL of moist crackles can be 3.7 ± 0.2% and 4.5 ± 0.3% slightly higher than that of rhonchi, respectively. This research is conducive to the establishment of a rapid and accurate noninvasive diagnosis system for respiratory diseases.

PIAS1 impedes vascular endothelial injury and atherosclerotic plaque formation in diabetes by blocking the RUNX3/TSP-1 axis.

The protein PIAS1 functions as a type of ubiquitin-protease, which is known to play an important regulatory role in various diseases, including cardiovascular diseases and cancers. Its mechanism of action primarily revolves around regulating the transcription, translation, and modification of target proteins. This study investigates role and mechanism of PIAS1 in the RUNX3/TSP-1 axis and confirms its therapeutic effects on diabetes-related complications in animal models. A diabetic vascular injury was induced in human umbilical vein endothelial cells (HUVECs) by stimulation with H2O2 and advanced glycation end product (AGE), and a streptozotocin (STZ)-induced mouse model of diabetes was constructed, followed by detection of endogenous PIAS1 expression and SUMOylation level of RUNX3. Effects of PIAS1 concerning RUNX3 and TSP-1 on the HUVEC apoptosis and inflammation were evaluated using the ectopic expression experiments. Down-regulated PIAS1 expression and SUMOylation level of RUNX3 were identified in the H2O2- and AGE-induced HUVEC model of diabetic vascular injury and STZ-induced mouse models of diabetes. PIAS1 promoted the SUMOylation of RUNX3 at the K148 site of RUNX3. PIAS1-mediated SUMOylation of RUNX3 reduced RUNX3 transactivation activity, weakened the binding of RUNX3 to the promoter region of TSP-1, and caused downregulation of TSP-1 expression. PIASI decreased the expression of TSP-1 by inhibiting H2O2- and AGE-induced RUNX3 de-SUMOylation, thereby arresting the inflammatory response and apoptosis of HUVECs. Besides, PIAS1 reduced vascular endothelial injury and atherosclerotic plaque formation in mouse models of diabetes by inhibiting the RUNX3/TSP-1 axis. Our study proved that PIAS1 suppressed vascular endothelial injury and atherosclerotic plaque formation in mouse models of diabetes via the RUNX3/TSP-1 axis.

Analysis of radiologic and clinical outcome in acute osteoporotic vertebral compression fracture: Single-agent teriparatide vs. teriparatide with subsequent vertebroplasty.

Objectives: To analyze the difference in union and clinical outcomes between teriparatide (T) and teriparatide with vertebroplasty (V) treatment modalities in osteoporotic vertebral compression fractures (OVCFs). Methods: Patients were divided into two groups (T and V: 87 and 92 patients with 105 fractures each). Radiological features (fracture type/grade, presence of fracture gap/intravertebral vacuum cleft (IVVC)/posterior vertebral wall fracture, change in compression rate (CR)/kyphotic angle (CA), and fusion status) were assessed with 3D-CT at 3 and 6 months. The outcome was divided into success or failure based on visual analog scale (<3), absence of percussion tenderness on the spinous process, and pain during motion. Univariate and multivariate analyses were performed to identify risk factors for nonunion and failed outcomes in each group. Results: The V group showed more favorable results than the T group at 3 months (CR>10%, 58% vs. 17%; CA>5°, 36% vs. 16%; union, 66% vs. 91%; successful outcome, 77% vs. 94%). At 6 months, no significant change was detected in CR and CA. A significant difference remained in union (89% vs. 100%) and successful outcomes (79% vs. 100%). The V group with age (>75 years) and initial CR (>40%) had more benefits than the T group in the subgroup analysis. In multivariate analysis for the T group, nonunion risk factors were hypertension (P = .0054) and fracture gap (P = .0075). IVVC (P = .047) was the sole risk factor for failure. Conclusions: Teriparatide with subsequent vertebroplasty can be selected as the first-line treatment with better sequelae and outcomes in acute osteoporotic compression fractures.

Raw Lacquer Extract from Toxicodendron vernicifluum in Combination with ONC201 Enhances the Inhibitory Effects on Colorectal Cancer Cell Activity.

BACKGROUND: The purpose of the present research was to explore the therapeutic impact of raw lacquer extract from Toxicodendron vernicifluum on colorectal cancer cells and to investigate the outcome of raw lacquer extract and ONC201 co-treatment on the activity of colorectal cancer cells. METHODS: The cells of HCT116 were treated with raw lacquer extract, ONC201, or co-treatment. Subsequently, MTT, trypan blue staining, colony formation, annexin V/propidium iodide staining, wound healing, and transwell assays were performed to assess the effects of raw lacquer extract, ONC201 and the synthesis effect of co-treatment on cell activity, survival, proliferation, apoptosis, migration, and invasion in HCT116 cells. Western blotting and immunostaining assay were also performed to detect the expressions of tumor necrosis factor-related apoptosis-inducing ligand, death receptor-5, cleaved caspase-8, p-mTOR/mTOR, and p-S6K/S6K in cells. RESULTS: The results showed that ONC201 and raw lacquer extract had effective anti-cancer effects on HCT116 cells. ONC201 and raw lacquer extract treatment on colorectal cancer cells inhibited cell viability and growth, as well as induced cell apoptosis and cell death of HCT116. The migration and invasion of HCT116 cells were also inhibited. Significantly, raw lacquer extract and ONC201 cotreatment further enhanced the anti-colorectal cancer cell activity in HCT116 cells. Western blotting and immunostaining assay showed that raw lacquer extract in combination with ONC201 induced tumor necrosis factor-related apoptosis-inducing ligand/death receptor-5 expression activation, inhibited the expression of cleaved caspase-8/procaspase-8, and reduced the expression of p-mTOR/mTOR and p-S6K/S6K. CONCLUSION: These results indicated that raw lacquer extract in combination with ONC201 enhanced the inhibitory effects on colorectal cancer cell activity.

Adipocytes-Derived Exosomal microRNA-1224 Inhibits M2 Macrophage Polarization in Obesity-Induced Adipose Tissue Inflammation via MSI2-Mediated Wnt/ß-Catenin Axis.

SCOPE: Phenotypic switch of macrophage polarization in adipose tissue has been associated with obesity-induced adipose tissue inflammation (OATI). Therefore, this study aims to explore the possible mechanism of adipocytes-derived exosomes (ADEs) carrying microRNA-1224 (miR-1224) in M2 macrophage polarization of OATI. METHODS AND RESULTS: miR-1224-knockout (miR-1224-KO) mice for this study, and isolated primary adipocytes from high-fat diet (HFD) or normal diet (SD)-fed mice are developed. ADEs are extracted and cocultured with bone marrow-derived macrophages (BMDMs). The macrophagic crown-like structures (CLS) and M1 and M2 phenotype macrophages in epididymal white adipose tissue (epiWAT) are observed by immunohistochemistry and flow cytometry. The obtained data indicate that miR-1224 is highly expressed in adipose tissues and adipocytes of obese mice. miR-1224 knockout decreases CLS number and increases M2 macrophages polarization in epiWAT. In addition, miR-1224 can be transferred to BMDMs via ADEs, which targeted musashi RNA binding protein 2 (MSI2) expression and inactivated Wnt/ß-catenin pathway, inhibiting macrophage M2 polarization and promoting inflammatory factor release. CONCLUSION: Exosomal miR-1224 derived by adipocytes targets MSI2 and blocks the Wnt/ß-catenin pathway, which inhibits macrophage M2 polarization and promotes inflammatory factor release, ultimately promoting OATI.

Effects of airway deformation and alveolar pores on particle deposition in the lungs.

The distal lung (G14-G23), which are composed of alveoli and bronchi, are responsible for almost all gas exchange and micro- and nanoparticle deposition in the lungs. In the existing research using computational fluid dynamics, the geometric modeling accuracy of the bronchial bifurcation structure is given priority, and then the alveoli are attached to bronchi as discrete spherical crowns. This method ignores the correlation between alveoli. In fact, the alveoli have a tessellated distribution, and adjacent alveoli are connected by several alveolar pores. Due to the huge number of alveoli, this seemingly small difference will be greatly amplified, which may lead to a large deviation in the prediction of the overall flow. Accordingly, the objective of this study is to construct a two-dimensional distal lung model including the bronchi, acini, and alveolar pores by using the methods of regular hexagonal tessellational subdivision, fusion, and coordinate transformation. A moving boundary is introduced to simulate the process of airflow and particle deposition in the distal lung, and the effects of bronchial deformation, respiratory frequency, and alveolar pores are obtained. The results show that there are significant differences in intrapulmonary flow patterns with and without alveolar pores. Alveolar pores can establish bypass ventilation downstream of a blockage, thus providing a pathway for particles to enter the airways downstream of the blockage. Changing the respiratory frequency and the amplitude of bronchial deformation will change the relative velocity between particles and moving wall, which, in turn, will change the particle deposition efficiency in the distal lung. To summarize this study, a geometric modeling method for the distal lung with alveolar pores is established, and the important roles of detailed characteristics of the distal lung are revealed. The findings of this study provide a reasonable hydrodynamic mechanism for the prevention of related respiratory diseases.

LncRNA GAS5 Interacts with MicroRNA-10b to Inhibit Cell Proliferation and Migration and Induces Apoptosis in Colorectal Cancer.

OBJECTIVE: The purpose of this study was to study the effects of the GAS5/microRNA-10b (miR-10b) axis on proliferation, migration, and apoptosis of colorectal cancer (CRC). METHODS: The expression levels of GAS5 and miR-10b in CRC tissues and cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Wound healing experiment was used to detect the effects of GAS5 and miR-10b on the migration of CRC cells. The luciferase reporter gene experiment was used to verify miRNA targets. Immunohistochemical assay was used to detect the expression of proteins related to metastasis and apoptosis in tumor tissues. RESULTS: The expression of GAS5 was downregulated in CRC tissues and cell lines. The overexpression of GAS5 can inhibit cell proliferation and progression, induce apoptosis in vitro, and inhibit the growth of CRC tumor in vivo. In contrast, the expression of miR-10b, a downstream target of GAS5, was increased in CRC tissues and cells. Suppression of the miR-10b gene can inhibit proliferation and metastasis and cause apoptosis of CRC cells. In addition, luciferase reports show that GAS5 inhibits the progression of CRC cells by binding to miR-10b. Rescue experiments showed that overexpressed miR-10b could reverse GAS5-mediated antitumor effect on CRC cells in vivo and in vitro. CONCLUSIONS: LncRNA GAS5 interacts with miR-10b to inhibit cell proliferation and migration and induces apoptosis in colorectal cancer. GAS5 and miR-10b could become potential therapeutic targets for CRC.

microRNA-15b-5p shuttled by mesenchymal stem cell-derived extracellular vesicles protects podocytes from diabetic nephropathy via downregulation of VEGF/PDK4 axis.

Diabetic nephropathy (DN) is a severe complication of diabetes lethal for end-stage renal disease, with less treatment methodologies and uncertain pathogenesis. In the current study, we determined the role of mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) containing microRNA (miR)-15b-5p in DN. After extraction and identification of MSC-derived EVs, mouse podocyte line MPC5 was selected to establish an in vitro high-glucose (HG) cell model, where expression of miR-15b-5p, pyruvate dehydrogenase kinase 4 (PDK4) and VEGFA expression in tissues and cells were determined. The loss- and gain- function assays were conducted to determine the roles of miR-15b-5p, PDK4 and VEGFA. MPC5 cells were then co-cultured with MSC-derived EVs and their biological behaviors were detected by Western blot, CCK-8 assay, and flow cytometry. The binding relationship between miR-15b-5p and PDK43 by dual luciferase reporter gene assay. The expression of miR-15b-5p was downregulated in podocytes under HG environment, but highly expressed in mouse MSCs-derived EVs. EVs-derived miR-15b-5p could protect MPC5 cell apoptosis and inflammation. miR-15b-5p inhibited the expression of PDK4 by directly bound to the 3'UTR region of PDK4 gene. miR-15b-5p inhibits VEGF expression by binding to PDK4. Inhibition of PDK4 decreased VEGFA expression and reduced apoptosis and inflammation. Collectively, miR-15b-5p shuttled by MSC-derived EV can play protective roles in HG-induced mouse podocyte injury, possibly by targeting PDK4 and decreasing the VEGFA expression.

Prdm16-Mediated Browning is Involved in Resistance to Diet-Induced and Monosodium Glutamate-Induced Obesity.

PURPOSE: To investigate resistance to diet-induced obesity (DIO) and monosodium glutamate (MSG)-induced obesity as well as the underlying mechanisms. METHODS: Newborn mice were used to construct DIO and MSG-induced obesity models. Obesity indices, such as body weight, body length, Lee index, body temperature, food intake, fat weight, and leptin level, were examined. Mice that did not exhibit obesity were defined as the obesity-resistant group. The morphological changes of white adipose tissue were observed by hematoxylin and eosin staining, and expression levels of PR domain containing 16 (Prdm16) and uncoupling protein-1 (Ucp-1) in white adipose tissue were measured by Western blot. RESULTS: Obesity-resistant mice fed a high-fat diet showed resistance beginning at week 5 along with lower weights and lengths than those in the obesity group from weeks 5 to 12. MSG-induced obesity-resistant mice showed features consistent with resistance to obesity from week 1 along with higher body lengths relative to the obesity group; however, the weight difference was not significant until week 10, when body weights decreased significantly in obesity-resistant mice. The Lee index was lower in obesity-resistant mice than in the obesity group and the normal group, further suggesting obesity resistance. Additionally, obesity-resistant mice showed higher levels of leptin, whereas obese mice induced by a high-fat diet showed leptin resistance. Furthermore, Prdm16 and Ucp-1 levels were both downregulated in the obesity group and upregulated in obesity-resistant mice, showing that white fat browning was highest in obesity-resistant mice. CONCLUSION: The phenotypes of mice with DIO and MSG-induced obesity differed. Obesity resistance might be related to Prdm16 and Ucp-1-mediated white adipocyte browning.

Overexpression of E3 ubiquitin ligase Cbl attenuates endothelial dysfunction in diabetes mellitus by inhibiting the JAK2/STAT4 signaling and Runx3-mediated H3K4me3.

BACKGROUND: Diabetes mellitus (DM), a most common chronic disease, is featured with impaired endothelial function and bioavailability of nitric oxide (NO), while E3 ubiquitin ligase appears to alleviate endothelial dysfunction as a promising option for DM treatment. Herein, we aimed to determine whether E3 ubiquitin ligase casitas B-lineage lymphoma (Cbl) alleviates endothelial dysfunction in DM rats by JAK2/STAT4 pathway. METHODS: A rat model of DM was developed through intraperitoneal injection of streptozotocin, followed by collection of aortic tissues to determine the expression of Cbl, JAK2, runt-related transcription factor 3 (Runx3) and STAT4. Human umbilical vein endothelial cells (HUVECs) were cultured in high glucose (HG) condition to induce DM as an in vitro model. With gain- and loss-function method, we assessed the aberrantly expressed Cb1 on endothelial dysfunction, NO production and apoptosis of HUVECs. RESULTS: Cbl was reduced in DM rat tissues and HG-induced HUVECs, where JAK2, Runx3 and STAT4 were elevated. It was found that overexpression of Cbl alleviated endothelial dysfunction by increasing NO production and restoring vasodilation and suppressing apoptosis of HUVECs. Mechanistically, Cb1 enhanced JAK2 ubiquitination and decreased JAK2 and STAT4 expression, where STAT4 improved Runx3 expression by regulating histone H3 lysine 4 trimethylation level. Overexpression of JAK2 and STAT4, or Runx3 increased apoptosis of HUVECs, abrogating the effect of Cb1 on endothelial function. CONCLUSION: In conclusion, Cbl alleviates endothelial dysfunction by inactivation of the JAK2/STAT4 pathway and inhibition of Runx3 expression in DM. These evidence might underlie novel Cbl-based treatment against DM in the future.

Mutational Analysis of Mitochondrial tRNA Genes in 200 Patients with Type 2 Diabetes Mellitus.

OBJECTIVE: Previous studies showed that variants in mitochondrial DNA (mtDNA) are associated with type 2 diabetes mellitus (T2DM). However, the relationships between mitochondrial tRNA (mt-tRNA) variants and T2DM remain poorly understood. METHODS: In this study, we performed a mutational screening of 22 mt-tRNA genes in a cohort of 200 Han Chinese subjects with T2DM and 200 control subjects through PCR-Sanger sequencing. The identified mt-tRNA variants were assessed for their pathogenicity via the phylogenetic approach, structural and functional analysis. Furthermore, two Han Chinese pedigrees with maternally inherited diabetes and deafness (MIDD) were reported by clinical and genetic assessments. RESULTS: A total of 49 genetic variants in mt-tRNA genes were identified; among them, 31 variants (17 pathogenic/likely pathogenic) were absent in controls, located at extremely conserved nucleotides, may have potential structural and functional significance, thereby considered to be T2DM-associated variants. In addition, sequence analysis of entire mitochondrial genomes of the matrilineal relatives from two MIDD pedigrees revealed the occurrence of tRNALeu(UUR) A3243G and T3290C mutations, as well as sets of polymorphisms belonging to mitochondrial haplogroups F2 and D4. However, the lack of any functional variants in connexin 26 gene (GJB2) and tRNA 5-methylaminomethyl-2-thiouridylate (TRMU) suggested that nuclear genes may not play active roles in clinical expression of MIDD in these pedigrees. CONCLUSION: Our data indicated that mt-tRNA variants were associated with T2DM, screening for mt-tRNA pathogenic mutations was recommended for early detection and prevention of mitochondrial diabetes.

Antiproliferative and pro­apoptotic effects of Cyclocarya paliurus polysaccharide and X­ray irradiation combination on SW480 colorectal cancer cells.

The anti­hyperglycemic effects of Cyclocarya paliurus polysaccharide (CPP) have attracted increasing attention; however, limited research has been conducted on the potential effects of CPP on inhibiting tumor growth. The present study aimed to investigate the functions of CPP in combination with X­ray irradiation on colorectal cancer cells and the underlying mechanisms. SW480 cells were treated with various concentrations of CPP for 24, 48 and 72 h to determine cell viability using a Cell Counting Kit­8 assay. Then, the cells were divided into four groups as follows: Control, CPP (100 µmol/l), 8 Gy and CPP + 8 Gy. The proliferation and apoptosis, and colony formation of cells were detected using flow cytometry and plate clone formation assays, respectively. Reverse transcription­quantitative PCR and western blot analyses were conducted to determine the expression of proliferation and apoptosis­associated, and PI3K/Akt signaling­associated genes. Treatment with 75 µmol/l CPP for 48 h significantly decreased cell viability compared with untreated cells. CPP in combination with 8 Gy X­ray treatment significantly promoted the induction of apoptosis, and suppressed cell proliferation and clone formation compared with the control, CPP and 8 Gy groups. The detection of mRNA and protein expression levels by reverse transcription­PCR and western blotting demonstrated that CPP in combination with 8 Gy not only significantly decreased the expression of proliferation marker protein Ki­67, p53 and Bcl­2, but also upregulated the expression of cleaved caspase­3 and Bax, compared with the control. In addition, CPP and 8 Gy combined significantly attenuated the phosphorylation of PI3K and Akt. The present study demonstrated that the combination of CPP with X­ray irradiation suppressed SW480 cell proliferation and promoted cell apoptosis compared with the control, CPP and 8 Gy groups. The underlying mechanisms may involve inhibition of PI3K/Akt signaling.

Mouse trefoil factor 3 ameliorated high-fat-diet-induced hepatic steatosis via increasing peroxisome proliferator-activated receptor-α-mediated fatty acid oxidation.

Hepatic trefoil factor 3 (Tff3) was identified as a potential protein for the treatment of diabetes, yet the effect of Tff3 on nonalcoholic fatty liver disease (NAFLD) has never been explored. Here, we found that the expression of hepatic Tff3 was significantly decreased in NAFLD mice models, suggesting that Tff3 was a potential marker gene for NAFLD. Restoring the expression of Tff3 in the liver of NAFLD mice, including diabetic (db), obese (ob/ob), and diet-induced obese mice, with adenovirus-mediated Tff3 (Ad-Tff3) apparently attenuates the fatty liver phenotype. In contrast, adenovirus-mediated knockdown of Tff3 (Ad-shTff3) in C57BL/6J mice results in an obvious fatty liver phenotype. Furthermore, our molecular experiments indicated that hepatic Tff3 could alleviate hepatic steatosis via upregulating the expression of peroxisome proliferator-activated receptor-α (PPARα) directly, thereby enhancing the fatty acid oxidation process in the liver. Notably, we found that Tff3 attenuates the fatty liver phenotype independent of modulation of lipogenesis and improves the capacity of anti-inflammation. Overall, our results suggested that hepatic Tff3 could be effectively used as a potential therapy target for the treatment of NAFLD.

Human placenta mesenchymal stem cells suppress airway inflammation in asthmatic rats by modulating Notch signaling.

Neurogenic locus notch homolog protein (Notch) signaling mediates intracellular communication and may regulate cell fate decisions, including cell proliferation, differentiation, and apoptosis. Mesenchymal stem cells (MSCs) possess immunomodulatory properties and the potential for use in stem cell replacement treatments. The aim of the present study was to evaluate the therapeutic effects of human placenta­deviated MSCs (hPMSCs) in asthma and to investigate the mechanisms of Notch signaling mediated by transplanted MSCs. A Sprague­Dawley rat ovalbumin (OVA)­sensitized acute asthma model was established and challenged. MSCs derived from human placenta (hPMSCs) were transplanted into the asthmatic rats. Transplantation resulted in reduced Notch­1, Notch­2 and jagged­1, and increased Notch­3, Notch­4 and delta­like ligand (delta)­4 expression in lung, blood, and lymph samples. Notch­1, Notch­2, and jagged­1 expression in OVA­treated rats was significantly decreased compared with controls and hPMSC­treated rats; however, Notch­3, Notch­4 and delta­4 expression was significantly increased. Serum interferon­Î³ significantly increased after hPMSCs transplantation, whereas interleukin­4 and immunoglobulin E decreased. In OVA­treated rats, Notch­1, Notch­2 and jagged­1 levels were increased in the lymph compared with the blood, although Notch­4 and delta­4 levels were decreased. Peribronchial infiltration of cells and goblet cell hyperplasia were markedly decreased in the OVA + hPMSCs group compared with those in the OVA­treated and control groups. Alterations in Notch signaling pathway expression were accompanied by decreased inflammatory cell infiltration, goblet cell hyperplasia and mucus production in lung tissues. The results of the present study are consistent with hPMSC suppression of asthma symptoms and inflammation by regulating the Notch signaling pathway in the rat asthma model.

Effect of a 12-Week Aerobic Exercise Training on Serum Fetuin-A and Adipocytokine Levels in Type 2 Diabetes.

OBJECTIVE: We aimed to evaluate the effect of 12-week aerobic exercise training on fetuin-A levels in type 2 diabetes mellitus and examine the relationships between fetuin-A and adipocytokine levels and cardiovascular risk factors. METHODS: The study included 32 patients with type 2 diabetes mellitus who were assigned to an exercise or a control group. The exercise group underwent 12 weeks of exercise (consisting of a 5-min warm-up, 60-min aerobic bicycle training performed at 70% of the maximal heart rate, a cool-down period, 5 times/week). Adiponectin, resistin, and fetuin-A serum levels were measured using enzyme-linked immunosorbent assay. Leptin serum levels were measured by a radioimmunoassay. RESULTS: Exercise for 12 weeks significantly reduced serum fetuin-A (643.1±109.4 to 448.7±92.5 µg/mL, P<0.05), leptin (11.9±7.2 to 8.6±5.7 ng/dL, P<0.05), and resistin (3.2±1.5 to 2.2±1.4 ng/mL, P<0.05) levels, but increased adiponectin (6.9±1.9 to 8.1±1.7 µg/mL, P<0.05) levels. In the exercise group, Δfetuin-A positively correlated with differences in weight (r=0.654, P=0.046), body mass index (r=0.725, P=0.002), waist circumference (r=0.898, P=0.013), and adiponectin levels (r=0.662, P=0.035). CONCLUSIONS: Aerobic exercise significantly decreased serum fetuin-A levels in type 2 diabetes mellitus, which can be attributed to weight loss and related to increased adiponectin levels.

mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity.

We here tested the anti-colorectal cancer (CRC) activity by a first-in-class small molecule TRAIL inducer ONC201. The potential effect of mTOR on ONC201's actions was also examined. ONC201 induced moderate cytotoxicity against CRC cell lines (HT-29, HCT-116 and DLD-1) and primary human CRC cells. Significantly, AZD-8055, a mTOR kinase inhibitor, sensitized ONC201-induced cytotoxicity in CRC cells. Meanwhile, ONC201-induced TRAIL/death receptor-5 (DR-5) expression, caspase-8 activation and CRC cell apoptosis were also potentiated with AZD-8055 co-treatment. Reversely, TRAIL sequestering antibody RIK-2 or the caspase-8 specific inhibitor z-IETD-fmk attenuated AZD-8055 plus ONC201-induced CRC cell death. Further, mTOR kinase-dead mutation (Asp-2338-Ala) or shRNA knockdown significantly sensitized ONC201's activity in CRC cells, leading to profound cell death and apoptosis. On the other hand, expression of a constitutively-active S6K1 (T389E) attenuated ONC201-induced CRC cell apoptosis. For the mechanism study, we showed that ONC201 blocked Akt, but only slightly inhibited mTOR in CRC cells. Co-treatment with AZD-8055 also concurrently blocked mTOR activation. These results suggest that mTOR could be a primary resistance factor of ONC201 in CRC cells.

PGC-1α may associated with the anti-obesity effect of taurine on rats induced by arcuate nucleus lesion.

OBJECTIVE: To observe the effect of taurine treatment in rats with monosodium glutamate (MSG)-induced obesity. METHODS: Rats with MSG-induced obesity were administered taurine for five weeks. The Lee's index, food intake, blood pressure, body temperature, body mass index (BMI), fat weight, and triglyceride (TG), low density lipoprotein (LDL), and high density lipoprotein (HDL) levels were compared. The PGC-1α expression levels in white and brown adipose were measured using reverse transcription polymerase chain reaction and western blotting, and pathological changes in the arcuate nucleus and liver were examined. RESULTS: Compared with the model group, BMI, TG, and LDL in the high and low taurine dose groups were significantly lower, while HDL was higher. Body temperature in the taurine treatment groups was higher, and blood pressure was lower. The weight of brown fat in the taurine treatment groups was significantly higher than in the model group, while the white fat weight was significantly lower. Compared with the control group, the PGC-1α levels in white and brown adipose were higher in the taurine treatment groups and more significantly up-regulated in brown adipose. DISCUSSION: This study suggests that taurine prevents obesity in MSG-treated rats and may be closely associated with energy metabolism.

Association between resistin +299A/A genotype and nonalcoholic fatty liver disease in Chinese patients with type 2 diabetes mellitus.

OBJECTIVE: To investigate the relationship between the resistin intronic +299G/A polymorphism and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). METHODS: We selected 738 T2DM patients, including 395 with NAFLD and 343 without fatty liver disease, as well as 279 healthy control individuals, and analyzed their resistin +299G/A polymorphism genotype by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Plasma resistin levels in T2DM patients with NAFLD were at the highest (P<0.05). The frequency of AA genotype at the +299 site of the resistin gene in patients with concurrent T2DM combined with NAFLD was significantly different from that in the control (P<0.05). The AA genotype was found to be associated with a 1.80-fold increased risk for T2DM combined with NAFLD, 2.05-fold increased risk for obesity and 2.37-fold increased risk for obesity of abdominal type compared to the GG (P<0.05, respectively). The multivariate non-conditional logistic regression model analysis further shows that the AA genotype is a risk factor for the development of NAFLD in T2DM patients (OR, 2.32; 95% CI, 1.05-4.68; P<0.05). CONCLUSION: The resistin +299AA genotype may be associated with increases in the risk of the NAFLD development in T2DM patients.

[Association between the serum TSH concentration and thyroid cancer incidence].

OBJECTIVE: To investigate the association between serum TSH concentration and thyroid cancer incidence. METHODS: Three hundred and thirty patients with thyroid tumors who underwent surgical treatment were included in this study (99 cases of malignancy and 231 cases of benign tumors). The data of their serum TSH level, gender, age, tumor type, and number of tumors detected by ultrasonic inspection were retrospectively analyzed, and their association with thyroid cancer incidence was explored. RESULTS: The proportion of thyroid cancer in the groups of younger than twenty years and older than seventy years were 63.0% and 58.3%, respectively, significantly higher than that in the group of age between 60 and 69 years (23.3%, P < 0.05). The incidence of thyroid cancer of the 81 male patients was 43.2%, significantly higher than that in the 249 female patients (25.7%, P = 0.003). The incidence of thyroid cancer in the 112 patients with single nodule was 42.0%, significantly higher than that in the 218 patients with multiple nodules (23.9%, P < 0.001). In the groups with TSH level lower than 0.28 mIU/L and higher than 4.20 mIU/L, the incidence of thyroid cancer were 54.6% and 50.0%, respectively, significantly higher than that in the group with TSH level between 0.28 and 1.44 mIU/L (16.1%, P < 0.05). The proportion of patients with thyroid cancer was also increased with the increasing serum TSH level in the normal range (P < 0.001). High serum TSH level (OR = 1.465, P = 0.014), male (OR = 1.964, P = 0.016) and a single thyroid nodule (OR = 2.090, P = 0.006) are independent risk factors of thyroid cancer. CONCLUSION: The high serum TSH level, male, single thyroid nodule are factors leading to a high incidence of thyroid cancer.