Effects of alanyl-glutamine supplementation on the small intestinal mucosa barrier in weaned piglets.

OBJECTIVE: The study was to investigate the effects of alanyl-glutamine (Ala-Gln) and glutamine (Gln) supplementation on the intestinal mucosa barrier in piglets. METHODS: A total of 180 barrows with initial weight 10.01±0.03 kg were randomly allocated to three treatments, and each treatment consisted of three pens and twenty pigs per pen. The piglets of three groups were fed with control diet [0.62% alanine (Ala)], Ala-Gln diet (0.5% Ala-Gln), Gln diet (0.34% Gln and 0.21% Ala), respectively. RESULTS: The results showed that in comparison with control diet, dietary Ala-Gln supplementation increased the height of villi in duodenum and jejunum (p<0.05), Gln supplementation increased the villi height of jejunum (p<0.05), Ala-Gln supplementation up-regulated the mRNA expressions of epidermal growth factor receptor and insulin-like growth factor 1 receptor in jejunal mucosa (p<0.05), raised the mRNA expressions of Claudin-1, Occludin, zonula occludens protein-1 (ZO-1) and the protein levels of Occludin, ZO-1 in jejunal mucosa (p<0.05), Ala-Gln supplementation enlarged the number of goblet cells in duodenal and ileal epithelium (p<0.05), Gln increased the number of goblet cells in duodenal epithelium (p<0.05) and Ala-Gln supplementation improved the concentrations of secretory immunoglobulin A and immunoglobulin G in the jejunal mucosa (p<0.05). CONCLUSION: These results demonstrated that dietary Ala-Gln supplementation could maintain the integrity of small intestine and promote the functions of intestinal mucosa barriers in piglets.

Based on the Cancer Genome Atlas Database Development of a prognostic model of RNA binding protein in stomach adenocarcinoma.

The purpose of this study was to identify potential RNA binding proteins associated with the survival of gastric adenocarcinoma, as well as the corresponding biological characteristics and signaling pathways of these RNA binding proteins. RNA sequencing and clinical data were obtained from the cancer genome map (N = 32, T = 375) and the comprehensive gene expression database (GSE84437, N = 433). The samples in The Cancer Genome Atlas were randomly divided into a development group and a test group. A total of 1495 RNA binding protein related genes were extracted. Using nonparametric tests to analyze the difference of RNA binding protein related genes, 296 differential RNA binding proteins were obtained, 166 were up-regulated and 130 were down regulated. Twenty prognosis-related RNA binding proteins were screened using Cox regression, including 14 high-risk genes (hazard ratio > 1.0) and 6 low-risk genes (hazard ratio < 1.0). Seven RNA binding protein related genes were screened from the final prognostic model and used to construct a new prognostic model. Using the development group and test group, the model was verified with survival analysis, receiver operating characteristics curves and prognosis analysis curves. A prediction nomogram was finally developed and showed good prediction performance.

Narrowband organic photodetectors - towards miniaturized, spectroscopic sensing.

Omnipresent quality monitoring in food products, blood-oxygen measurement in lightweight conformal wrist bands, or data-driven automated industrial production: Innovation in many fields is being empowered by sensor technology. Specifically, organic photodetectors (OPDs) promise great advances due to their beneficial properties and low-cost production. Recent research has led to rapid improvement in all performance parameters of OPDs, which are now on-par or better than their inorganic counterparts, such as silicon or indium gallium arsenide photodetectors, in several aspects. In particular, it is possible to directly design OPDs for specific wavelengths. This makes expensive and bulky optical filters obsolete and allows for miniature detector devices. In this review, recent progress of such narrowband OPDs is systematically summarized covering all aspects from narrow-photo-absorbing materials to device architecture engineering. The recent challenges for narrowband OPDs, like achieving high responsivity, low dark current, high response speed, and good dynamic range are carefully addressed. Finally, application demonstrations covering broadband and narrowband OPDs are discussed. Importantly, several exciting research perspectives, which will stimulate further research on organic-semiconductor-based photodetectors, are pointed out at the very end of this review.

Photomultiplication-Type Organic Photodetectors for Near-Infrared Sensing with High and Bias-Independent Specific Detectivity.

Highly responsive organic photodetectors allow a plethora of applications in fields like imaging, health, security monitoring, etc. Photomultiplication-type organic photodetectors (PM-OPDs) are a desirable option due to their internal amplification mechanism. However, for such devices, significant gain and low dark currents are often mutually excluded since large operation voltages often induce high shot noise. Here, a fully vacuum-processed PM-OPD is demonstrated using trap-assisted electron injection in BDP-OMe:C60 material system. By applying only -1 V, compared with the self-powered working condition, the responsivity is increased by one order of magnitude, resulting in an outstanding specific detectivity of ≈1013  Jones. Remarkably, the superior detectivity in the near-infrared region is stable and almost voltage-independent up to -10 V. Compared with two photovoltaic-type photodetectors, these PM-OPDs exhibit the great potential to be easily integrated with state-of-the-art readout electronics in terms of their high responsivity, fast response speed, and bias-independent specific detectivity. The employed vacuum fabrication process and the easy-to-adapt PM-OPD concept enable seamless upscaling of production, paving the way to a commercially relevant photodetector technology.

Biallelic mutations in spermatogenesis and centriole-associated 1 like (SPATC1L) cause acephalic spermatozoa syndrome and male infertility.

Acephalic spermatozoa syndrome is a rare type of teratozoospermia that severely impairs the reproductive ability of male patients, and genetic defects have been recognized as the main cause of acephalic spermatozoa syndrome. Spermatogenesis and centriole-associated 1 like (SPATC1L) is indispensable for maintaining the integrity of sperm head-to-tail connections in mice, but its roles in human sperm and early embryonic development remain largely unknown. Herein, we conducted whole-exome sequencing (WES) of 22 infertile men with acephalic spermatozoa syndrome. An in silico analysis of the candidate variants was conducted, and WES data analysis was performed using another cohort consisting of 34 patients with acephalic spermatozoa syndrome and 25 control subjects with proven fertility. We identified biallelic mutations in SPATC1L (c.910C>T:p.Arg304Cys and c.994G>T:p.Glu332X) from a patient whose sperm displayed complete acephalia. Both SPATC1L variants are rare and deleterious. SPATC1L is mainly expressed at the head-tail junction of elongating spermatids. Plasmids containing pathogenic variants decreased the level of SPATC1L in vitro. Moreover, none of the patient's four attempts at intracytoplasmic sperm injection (ICSI) resulted in a transplantable embryo, which suggests that SPATC1L defects might affect early embryonic development. In conclusion, this study provides the first identification of SPATC1L as a novel gene for human acephalic spermatozoa syndrome. Furthermore, WES might be applied for patients with acephalic spermatozoa syndrome who exhibit reiterative ICSI failures.

Microarray analysis of differential gene expression profile in peripheral blood cells of patients with human essential hypertension.

The polygenic nature of essential hypertension and its dependence on environmental factors pose a challenge for biomedical research. We hypothesized that the analysis of gene expression profiles from peripheral blood cells would distinguish patients with hypertension from normotensives. In order to test this, total RNA from peripheral blood cells was isolated. RNA was reversed-transcribed and labeled and gene expression analyzed using significance Analysis Microarrays (Stanford University, CA, USA). Briefly, Significance Analysis Microarrays (SAM) thresholding identified 31 up-regulated and 18 down-regulated genes with fold changes of ≥2 or ≤0.5 and q-value≤5% in expression. Statistically significantly gene ontology (GO) function and biological process differentially expressed in essential hypertension were MHC class II receptor activity and immune response respectively. Biological pathway analysis identified several related pathways which are associated with immune/inflammatory responses. Quantitative Real-Time RT-PCR results were consistent with the microarray results. The levels of C-reactive protein were higher in hypertensive patients than normotensives and inflammation-related genes were increased as well. In conclusion, genes enriched for "immune/inflammatory responses" may be associated with essential hypertension. In addition, there is a correlation between systemic inflammation and hypertension. It is anticipated that these findings may provide accurate and efficient strategies for prevention, diagnosis and control of this disorder.

Enhancing sub-bandgap external quantum efficiency by photomultiplication for narrowband organic near-infrared photodetectors.

Detection of electromagnetic signals for applications such as health, product quality monitoring or astronomy requires highly responsive and wavelength selective devices. Photomultiplication-type organic photodetectors have been shown to achieve high quantum efficiencies mainly in the visible range. Much less research has been focused on realizing near-infrared narrowband devices. Here, we demonstrate fully vacuum-processed narrow- and broadband photomultiplication-type organic photodetectors. Devices are based on enhanced hole injection leading to a maximum external quantum efficiency of almost 2000% at -10 V for the broadband device. The photomultiplicative effect is also observed in the charge-transfer state absorption region. By making use of an optical cavity device architecture, we enhance the charge-transfer response and demonstrate a wavelength tunable narrowband photomultiplication-type organic photodetector with external quantum efficiencies superior to those of pin-devices. The presented concept can further improve the performance of photodetectors based on the absorption of charge-transfer states, which were so far limited by the low external quantum efficiency provided by these devices.

PIWIL1 interacting RNA piR-017061 inhibits pancreatic cancer growth via regulating EFNA5.

PIWI (P element induced wimpy testis) integrating RNAs (piRNAs) are small non-coding RNAs with the length of approximately 30 nucleotides that plays crucial roles in germ cells and adult stem cells. Recently, accumulating data have shown that piRNA and PIWI proteins are involved in tumorigenesis. However, the roles of PIWI proteins and piRNAs in pancreatic cancer are still elusive. Here, we showed that piR-017061 is significantly downregulated in pancreatic cancer patients' samples and pancreatic cancer cell lines. Furthermore, we studied the function of piR-017061 in pancreatic cancer and our data revealed that piR-017061 inhibits pancreatic cancer cell growth in vitro and in vivo. Moreover, we analyzed the genomic loci around piR-017061 and identified EFNA5 as a novel target of piR-017061. Importantly, our data further revealed a direct binding between piR-017061 and EFNA5 mRNA mediated by PIWIL1. Mechanically, piR-017061 cooperates with PIWIL1 to facilitate EFNA5 mRNA degradation and loss of piR-017061 results in accumulation of EFNA5 which facilitates pancreatic cancer development. Hence, our data provided novel insights into PIWI/piRNA-mediated gene regulation and their function in pancreatic cancer. Since PIWI proteins and piRNA predominately express in germline and cancer cells, our study provided novel therapeutic strategy for pancreatic cancer treatment.

Miniaturized VIS-NIR Spectrometers Based on Narrowband and Tunable Transmission Cavity Organic Photodetectors with Ultrahigh Specific Detectivity above 1014 Jones.

Spectroscopic photodetection plays a key role in many emerging applications such as context-aware optical sensing, wearable biometric monitoring, and biomedical imaging. Photodetectors based on organic semiconductors open many new possibilities in this field. However, ease of processing, tailorable optoelectronic properties, and sensitivity for faint light are still significant challenges. Here, the authors report a novel concept for a tunable spectral detector by combining an innovative transmission cavity structure with organic absorbers to yield narrowband organic photodetection in the wavelength range of 400-1100 nm, fabricated in a full-vacuum process. Benefiting from this strategy, one of the best performed narrowband organic photodetectors is achieved with a finely wavelength-selective photoresponse (full-width-at-half-maximum of ≈40 nm), ultrahigh specific detectivity above 1014 Jones, the maximum response speed of 555 kHz, and a large dynamic range up to 168 dB. Particularly, an array of transmission cavity organic photodetectors is monolithically integrated on a small substrate to showcase a miniaturized spectrometer application, and a true proof-of-concept transmission spectrum measurement is successfully demonstrated. The excellent performance, the simple device fabrication as well as the possibility of high integration of this new concept challenge state-of-the-art low-noise silicon photodetectors and will mature the spectroscopic photodetection into technological realities.

Organic Thin-Film Red-Light Photodiodes with Tunable Spectral Response Via Selective Exciton Activation.

Red and near-infrared light detection is vital for numerous applications, including full-color imaging, optical communication, and machine vision. However, this development is hindered by a limited choice of small band gap and narrow-bandwidth materials. Here, we report a device principle with a simple organic planar heterojunction architecture that enables a selective activation of excitons for tuning the photoresponse spectra to fabricate thin-film, filterless, red-light organic photodiodes. A sequential solution-processed active layer is formed by depositing the top layer of PC71BM onto the predeposited bottom layer of doped P3HT. By adjusting the ratio of PTB7 in P3HT, an improved responsivity and a red-shift of the photoresponse peak from 645 to 745 nm are demonstrated simultaneously. Furthermore, the responsivity of 745 nm is enhanced over 5 times with a narrow full width at half-maximum of ∼50 nm at optimized doping ratio compared to the pristine PTB7 device. As a result, a high specific detectivity in excess of 1012 Jones and broad linear dynamic range of 103 dB are achieved. This design concept shows the possibility of realizing tunable red-light selectivity even at relatively thin-film thickness, which is intriguing for the implementation of high-resolution image sensors in the near future.

Vertical organic permeable dual-base transistors for logic circuits.

The main advantage of organic transistors with dual gates/bases is that the threshold voltages can be set as a function of the applied second gate/base bias, which is crucial for the application in logic gates and integrated circuits. However, incorporating a dual gate/base structure into an ultra-short channel vertical architecture represents a substantial challenge. Here, we realize a device concept of vertical organic permeable dual-base transistors, where the dual base electrodes can be used to tune the threshold voltages and change the on-currents. The detailed operation mechanisms are investigated by calibrated TCAD simulations. Finally, power-efficient logic circuits, e.g. inverter, NAND/AND computation functions are demonstrated with one single device operating at supply voltages of <2.0 V. We believe that this work offers a compact and technologically simple hardware platform with excellent application potential for vertical-channel organic transistors in complex logic circuits.

Identification of a novel deletion mutation in DPY19L2 from an infertile patient with globozoospermia: a case report.

BACKGROUND: Male infertility is an increasing medical concern worldwide. In most cases, genetic factors are considered as the main cause of the disease. Globozoospermia (MIM102530) (also known as round-headed sperm) is a rare and severe malformed spermatospermia caused by acrosome deficiency or severe malformation. A subset of genetic mutations, such as DNAH6, SPATA16, DPY19L2, PICK1, and CCIN related to globozoospermia, have been reported in the past few years. The DPY19L2 mutation is commonly found in patients with globozoospermia. Herein, a 180-kbp homozygote deletion at 12q14.2 (g.63950001-64130000) was identified by copy number variation sequencing (CNVseq) in a patient with a globozoospermia, including the complete deletion of DPY19L2. CASE PRESENTATION: A 27-year-old patient at the First Affiliated Hospital of Xiamen University was diagnosed with infertility because, despite normal sexual activity for 4 years, his wife did not conceive. The patient was in good health with no obvious discomfort, no history of adverse chemical exposure, and no vices, such as smoking and drinking. The physical examination revealed normal genital development. However, semen tests showed a normal sperm count of 0% and the morphology was the round head. Sperm cytology showed that acrosomal enzyme was lower than normal. Reproductive hormones were in the normal range. B ultrasound did not show any abnormal seminal vesicle, prostate, bilateral testis, epididymis, and spermatic veins. The karyotype was normal, 46, XY, and no microdeletion of Y chromosome was detected. However, a homozygous deletion mutation was found in DPY19L2, which was further diagnosed as globozoospermia. CONCLUSIONS: The present study reported a male infertility patient who was diagnosed with globozoospermia. The analysis of gene mutations revealed that DPY19L2 had a homozygous mutation, which was the primary cause of globozoospermia.

Chromatin configurations in the germinal vesicle of mammalian oocytes.

In all the studied mammalian species, chromatin in the germinal vesicle (GV) is initially decondensed with the nucleolus not surrounded by heterochromatin (the NSN configuration). During oocyte growth, the GV chromatin condenses into perinucleolar rings (the SN configuration) or other corresponding configurations with or without the perinucleolar rings, depending on species. During oocyte maturation, the GV chromatin is synchronized in a less condensed state before germinal vesicle breakdown (GVBD) in species that has been minutely studied. Oocytes may also take on a SN/corresponding configuration during early atresia, but they undergo GVBD at the advanced stage of atresia. As not all the species show the SN configuration while in all the species, gene transcription always stops at the late stage of oocyte growth, it is suggested that not the formation of perinucleolar rings but a thorough condensation of GV chromatin is essential for transcriptional repression. The GV chromatin configuration is highly correlated with oocyte competence; oocytes must end the NSN configuration before they gain the full meiotic competence, and they must take on the SN/corresponding configurations and stop gene transcription before they acquire the competence for early embryonic development. While factors inhibiting follicle atresia tend to synchronize oocytes in a chromatin configuration toward maturation, factors inducing follicle atresia tend to synchronize oocytes in a chromatin configuration reminiscent of early atresia. Furthermore, although condensation of GV chromatin is associated with transcriptional repression, both processes may not be associated with histone deacetylation during oocyte growth.

Three-Phase Morphology Evolution in Sequentially Solution-Processed Polymer Photodetector: Toward Low Dark Current and High Photodetectivity.

Sequentially solution-processed polymer photodetectors (SSP PPDs) based on poly(3-hexylthiophene-2,5-diyl) (P3HT)/[6,6]-phenyl C71-butyric acid methyl ester (PC71BM) are fabricated by depositing the top layers of PC71BM from an appropriate cosolvent of 2-chlorophenol (2-CP)/o-dichlorobenzene (ODCB) onto the predeposited bottom layers of P3HT. By adjusting the ratio of 2-CP/ODCB in the top PC71BM layers, the resulting SSP PPD shows a decreased dark current and an increased photocurrent, leading to a maximum detectivity of 1.23 × 1012 Jones at a wavelength of 550 nm. This value is 5.3-fold higher than that of the conventional bulk heterojunction PPD. Morphology studies reveal that the PC71BM partially penetrates the predeposited P3HT layer during the spin-coating process, resulting in an optimal three-phase morphology with one well-mixed interdiffusion P3HT/PC71BM phase in the middle of the bulk and two pure phases of P3HT and PC71BM at the two electrode sides. We show that the pure phases form high Schottky barriers (>2.0 eV) at the active layer/electrodes interface and efficiently block unfavorable reverse charge carrier injection by significantly decreasing the dark current. The interdiffussion phase enlarges the donor-acceptor interfacial area leading to a large photocurrent. We also reveal that the improved performance of SSP PPDs is also due to the enhanced optical absorption, improved P3HT crystallinity, increased charge carrier mobilities, and suppressed bimolecular recombination.

Effects of cysteamine supplementation on the intestinal expression of amino acid and peptide transporters and intestinal health in finishing pigs.

This study aimed to evaluate the effects of cysteamine supplementation on the expression of jejunal amino acid and peptide transporters and intestinal health in finishing pigs. Sixty barrows were allocated into two experimental diets consisting of a basal control diet supplemented with 0 or 142 mg/kg cysteamine. After 41 days, 10 pigs per treatment were slaughtered. The results showed that cysteamine supplementation increased the apparent digestibility of crude protein (CP) (P < 0.05) and the trypsin activity in jejunal digesta (P < 0.01). Cysteamine supplementation also increased the messenger RNA abundance of SLC7A7, SLC7A9 and SLC15A1, occludin, claudin-1 and zonula occludens protein-1 (P < 0.001) in the jejunum mucosa. Increased glutathione content (P < 0.01) and glutathione peroxidase activity (P < 0.05) and decreased malondialdehyde content (P < 0.01) were observed in pigs receiving cysteamine. Additionally, cysteamine supplementation increased the concentrations of secretory immunoglobulin A (IgA) (P < 0.05), IgM (P < 0.001) and IgG (P < 0.001) in the jejunal mucosa. It is concluded that cysteamine supplementation could influence protein digestion and absorption via increasing trypsin activity, enhancing the digestibility of CP, and promoting the expression of jejunal amino acid and peptide transporters. Moreover, cysteamine improved intestinal integrity, antioxidant capacity and immune function in the jejunum, which were beneficial for intestinal health.

Effects of Dietary Crude Protein Levels and Cysteamine Supplementation on Protein Synthetic and Degradative Signaling in Skeletal Muscle of Finishing Pigs.

Dietary protein levels and cysteamine (CS) supplementation can affect growth performance and protein metabolism of pigs. However, the influence of dietary protein intake on the growth response of CS-treated pigs is unclear, and the mechanisms involved in protein metabolism remain unknown. Hence, we investigated the interactions between dietary protein levels and CS supplementation and the effects of dietary crude protein levels and CS supplementation on protein synthetic and degradative signaling in skeletal muscle of finishing pigs. One hundred twenty barrows (65.84 ± 0.61 kg) were allocated to a 2 × 2 factorial arrangement with five replicates of six pigs each. The primary variations were dietary crude protein (CP) levels (14% or 10%) and CS supplemental levels (0 or 700 mg/kg). The low-protein (LP) diets (10% CP) were supplemented with enough essential amino acids (EAA) to meet the NRC AA requirements of pigs and maintain the balanced supply of eight EAA including lysine, methionine, threonine, tryptophan, valine, phenylalanine, isoleucine, and leucine. After 41 days, 10 pigs per treatment were slaughtered. We found that LP diets supplemented with EAA resulted in decreased concentrations of plasma somatostatin (SS) (P<0.01) and plasma urea nitrogen (PUN) (P<0.001), while dietary protein levels did not affect other traits. However, CS supplementation increased the average daily gain (P<0.001) and lean percentage (P<0.05), and decreased the feed conversion ratio (P<0.05) and back fat (P<0.05). CS supplementation also increased the concentrations of plasma insulin-like growth factor 1 (IGF-1) (P<0.001), and reduced the concentrations of leptin, SS, and PUN (P<0.001). Increased mRNA abundance of Akt1 and IGF-1 signaling (P<0.001) and decreased mRNA abundance of Forkhead Box O (FOXO) 4 (P<0.01) and muscle atrophy F-box (P<0.001) were observed in pigs receiving CS. Additionally, CS supplementation increased the protein levels for the phosphorylated mammalian target of rapamycin (mTOR), eIF-4E binding protein 1, and ribosomal protein S6 kinase 1 (P<0.001). There were no interactions between dietary protein levels and CS supplementation for all traits. In conclusion, dietary protein levels and CS supplementation influenced growth and protein metabolism through independent mechanisms in pigs. In addition, LP diets supplemented with EAA did not affect growth performance and other traits except the concentrations of SS and PUN probably through maintenance of protein synthesis and degradation signaling. Moreover, CS supplementation improved growth performance by increasing plasma IGF-1 concentrations possibly through alterations of mTOR and Akt/FOXO signaling pathways in skeletal muscle of finishing pigs.

Regulation of skeletal muscle protein synthetic and degradative signaling by alanyl-glutamine in piglets challenged with Escherichia coli lipopolysaccharide.

OBJECTIVE: The aim of this study was to investigate the effects of alanyl-glutamine (Ala-Gln) on skeletal muscle protein synthetic and degradative signaling in piglets challenged with Escherichia coli lipopolysaccharide (LPS). METHODS: Piglets were arranged in a 2 × 2 factorial design and the main effects were LPS challenge (0 or 100 units) and diets (0.62% Ala or 0.5% Ala-Gln). After treatment with either Ala or Ala-Gln for 10 d, piglets were injected twice with either saline or LPS on days 11 and 15. RESULTS: During days 11 to 15 (postchallenge), LPS challenge affected the growth performance of piglets. Ala-Gln supplementation tended to alleviate the reduction of the average daily weight gain (P = 0.071) and the average daily feed intake (P = 0.087) of the LPS-challenged piglets. LPS challenge increased the concentrations of cytokines in plasma (P < 0.05), however, Ala-Gln supplementation prevented the elevation of cortisol induced by LPS challenge (P < 0.05). Moreover, Ala-Gln supplementation increased the mRNA expressions of insulin-like growth factor-1 signaling and Akt (P < 0.05). Ala-Gln supplementation also increased the phosphorylation abundance of the mammalian target of rapamycin, eIF-4 E binding protein 1 and ribosomal protein S6 kinase 1 (P < 0.05). Additionally, Ala-Gln supplementation down-regulated the mRNA abundances of toll-like receptor 4 (TLR4), muscle atrophy F-box, and muscle RING finger 1, which are associated with protein degradation induced by LPS challenge. CONCLUSION: Ala-Gln supplementation had beneficial effects in improving protein synthesis signaling of skeletal muscle, and reversed the deleterious changes of signaling molecules in muscle atrophy mainly through down-regulation of Akt/FOXO and TLR4 signaling pathways induced by LPS challenge.

Effects and mechanisms of auricular vagus nerve stimulation on high-fat-diet--induced obese rats.

OBJECTIVE: Obesity is a major public health problem. Regulating food intake and promoting metabolism of fat are two important options for treating obesity. Auricular vagus nerve stimulation (AVNS) is considered as an alternative approach to vagal nerve stimulation. The aim of this study was to investigate the effects of AVNS and its mechanisms on obesity in obese rats. METHODS: Male Sprague-Dawley rats were fed either a high-fat diet (HFD) or a normal diet for 8 wk. Qualified HFD rats were randomly divided into three groups: the HFD group, the AVNS group, and the sham group for 6 wk treatment. Body weight and daily energy intake were recorded weekly. The rats were sacrificed for measurement of weight of bilateral perirenal, epididymal white adipose tissue (WAT), dorsal brown adipose tissue (BAT), and gastric emptying. Serum cholecystokinin (CCK), peptide YY3 to 36 (PYY3-36) and norepinephrine (NE) were assayed by enzyme-linked immunosorbent assay. Real-time quantitative polymerase chain reaction was used to assess the mRNA expressions of CCK subtype receptor a (CCKa) in the antrum, PYY3-36 receptor in the distal ileum, ß3-adrenoceptor, and uncoupling protein gene 1 (UCP1) in the BAT. RESULTS: Compared with HFD group, AVNS significantly reduced body weight and epididymal WAT and increased BAT weight, serum NE, mRNA expressions of ß3-adrenoceptors, and UCP1 of the BAT, but had no effect on daily energy intake, perirenal WAT weight, gastric emptying, serum levels of CCK and PYY, or mRNA expressions of CCKa receptor and PYY3-36 receptor in the relevant tissues. The sham group, as a comparison group for AVNS, saw less effect in any of the indexes compared with the HFD group. AVNS had more effect on weight loss, reduction of perirenal WAT, and increase of NE, ß3-adrenoceptor, and UCP1 than sham. CONCLUSIONS: AVNS was more effective in reducing body weight and causing visceral fat loss. Biochemical tests found more NE released in the serum and more ß3-adrenoceptor and UCP1 expression in the BAT. All of these features suggested that energy expenditure might play an important role in obesity management by AVNS.

Dimethyloxalylglycine prevents bone loss in ovariectomized C57BL/6J mice through enhanced angiogenesis and osteogenesis.

Hypoxia-inducible factor 1-α (HIF-1α) plays a critical role in angiogenesis-osteogenesis coupling during bone development and bone regeneration. Previous studies have shown that 17ß-estradiol activates the HIF-1α signaling pathway and that mice with conditional activation of the HIF-1α signaling pathway in osteoblasts are protected from ovariectomy (OVX)-induced bone loss. In addition, it has been shown that hypoxia facilitates the osteogenic differentiation of mesenchymal stem cells (MSCs) and modulates Wnt/ß-catenin signaling. Therefore, we hypothesized that activation of the HIF-1α signaling pathway by hypoxia-mimicking agents would prevent bone loss due to estrogen deficiency. In this study, we confirmed the effect of dimethyloxalylglycine (DMOG), a hypoxia-mimicking agent, on the HIF-1α signaling pathway and investigated the effect of DMOG on MSC osteogenic differentiation and the Wnt/ß-catenin signaling pathway. We then investigated the effect of DMOG treatment on OVX-induced bone loss. Female C57BL/6J mice were divided into sham, OVX, OVX+L-DMOG (5 mg/kg/day), and OVX+H-DMOG (20 mg/kg/day) groups. At sacrifice, static and dynamic bone histomorphometry were performed with micro computed tomography (micro-CT) and undecalcified sections, respectively. Bone strength was assessed with the three-point bending test, and femur vessels were reconstructed and analyzed by micro-CT. Serum vascular endothelial growth factor (VEGF), osteocalcin, and C-terminal telopeptides of collagen type(CTX) were measured by ELISA. Tartrate-resistant acid phosphatase staining was used to assess osteoclast formation. Alterations in the HIF-1α and Wnt/ß-catenin signaling pathways in the bone were detected by western blot. Our results showed that DMOG activated the HIF-1α signaling pathway, which further activated the Wnt/ß-catenin signaling pathway and enhanced MSC osteogenic differentiation. The micro-CT results showed that DMOG treatment improved trabecular bone density and restored the bone microarchitecture and blood vessels in OVX mice. Bone strength was also partly restored in DMOG-treated OVX mice. Dynamic bone histomorphometric analysis of the femur metaphysic revealed that DMOG increased the mineralizing surface, mineral apposition rate, and bone formation rate. The serum levels of VEGF and osteocalcin were higher in DMOG-treated OVX mice. However, there were no significant differences in serum CTX or in the number of tartrate-resistant acid phosphatase-stained cells between DMOG-treated OVX mice and OVX mice. Western blot results showed that DMOG administration partly rescued the decrease in HIF-1α and ß-catenin expression following ovariectomy. Collectively, these results indicate that DMOG prevents bone loss due to ovariectomy in C57BL/6J mice by enhancing angiogenesis and osteogenesis, which are associated with activated HIF-1α and Wnt/ß-catenin signaling pathways.