GLP-1RAs caused gastrointestinal adverse reactions of drug withdrawal: a system review and network meta-analysis

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1RAs) significantly reduce postprandial blood glucose, inhibit appetite, and delay gastrointestinal emptying. However, it is controversial that some patients are intolerant to GLP-1RAs.MethodsPubMed, Embase, Web of Science, and Cochrane Library were searched for randomized controlled trials (RCTs) using GLP-1RAs with documented withdrawal due to gastrointestinal adverse reactions (GI AEs) from their inception to September 28, 2022. After extracting the information incorporated into the studies, a random-effects network meta-analysis was performed within a frequentist framework.Results64 RCTs were finally enrolled, which included six major categories of the GLP-1RA. The sample size of the GLP-1RAs treatment group was 16,783 cases. The risk of intolerable gastrointestinal adverse reactions of Liraglutide and Semaglutide was higher than that of Dulaglutide. Meanwhile, the higher the dose of the same GLP-1RA preparation, the more likely to cause these adverse reactions. These intolerable GI AEs were not significantly related to drug homology or formulations and may be related to the degree of suppression of the appetite center.ConclusionDulaglutide caused the lowest intolerable GI AEs, while Liraglutide and Semaglutide were the highest. For Semaglutide, the higher the dose, the more likely it is to drive GI AEs. Meanwhile, the risk of these GI AEs is independent of the different formulations of the drug. All these findings can effectively guide individualized treatment.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022359346, identifier CRD42022359346

HEMATOPOIETIC STEM CELL INTEGRITY IS DEPENDENT ON ZNF143 MAINTENANCE OF CHROMOSOME STRUCTURE

Ph.DDOCTOR OF PHILOSOPHY (SOM

Synergistic Effect of Halloysite Nanotubes and Glycerol on the Physical Properties of Fish Gelatin Films

Fish gelatin (FG)/glycerol (GE)/halloysite (HT) composite films were prepared by casting method. The morphology of the composite films was observed by scanning electron microscopy (SEM). The effects of HT and GE addition on the mechanical properties, water resistance and optical properties of the composites were investigated. Results showed that with increasing GE content, the elongation at composite breaks increased significantly, but their tensile strength (TS) and water resistance decreased. SEM results showed that GE can partly promote HT dispersion in composites. TS and water resistance also increased with the addition of HTs. Well-dispersed HTs in the FG matrix decreased the moisture uptake and water solubility of the composites. All films showed a transparency higher than 80% across the visible light region (400⁻800 nm), thereby indicating that light transmittance of the resulting nanocomposites was slightly affected by GE and HTs

Genome-wide identification, phylogeny and expression analysis of the bmp gene family associated with development and skeleton deformity in cobia (Rachycentron canadum)

Bone morphogenetic proteins (BMPs) are critical for controlling skeletal development of fish, which has significant influence on external morphology, functional exercise and even survival rate in aquaculture breeding. In this study, a total of 19 bmp genes were identified in cobia (Rachycentron canadum) and these genes were divided into six sub-families according to phylogenetic analysis, including bmp1, bmp3/11/15, bmp2/4/16, bmp9/10, bmp13/14 and bmp5/6/7/8 subfamily. The identified cobia BMPs, excepting for BMP1, all possessed a similar TGF_beta domain. Phylogenetic analysis revealed that the cobia bmp genes were most closely related to those of the golden pompano (Trachinotus ovatus). The tissue distribution of these bmps in adult cobia revealed that the highest expression of most bmp genes was found in the Meckel’s cartilage; the highest expression of bmp4 was identified in the vertebrae; five other bmps were highly expressed in non-skeleton tissues including liver, heart and gill. The expression of bmp genes were also identified during the larvae and juvenile stages (1–30 dph), and most bmps revealed no certain expression pattern excepting for bmp8a, which showed significantly lower mRNA level before 15 dph and then increased to a significantly higher level. Due to the high incidence of deformity during the larvae and juvenile stages of cobia, the difference of bmp mRNA levels between deformed and normal skeletons (the Meckel’s cartilage and vertebrae) were also investigated to understand the involvement of bmp genes in skeletal deformity. The results showed that most of the bmp genes were significantly inhibited in the deformed Meckel’s cartilage excepting for bmp1, bmp5 and bmp7b; while in the deformed vertebrae, expression of most bmps were significantly increased excepting for five genes (bmp1, bmp4, bmp5, bmp7b and bmp13b)

Calcium and Phosphorus Contents, and Microstructure of Vertebrae in Rainbow Trout (Oncorhynchus mykiss) at Different Developmental Stages

The skeletal system of fish consists of the axial skeleton (skull, vertebral column, ribs, and intermuscular bones) and the appendicular skeleton, which are essential for behavioral and physiological functions such as locomotion, feeding, predator avoidance, and load-bearing. As for the vertebral column of teleosts, it is composed of many vertebrae connected from the head to the caudal base. The morphological characteristics of the vertebrae (such as the number and structure) vary among different fish species. These characters (especially the vertebrae number) provide an important basis for species identification. For instance, the number of vertebrae in Salmo salar is 57–60 (30 trunk vertebrae, 27–30 caudal vertebrae), while rainbow trout (Oncorhynchus mykiss) has a total of 63 vertebrae (including 33 trunk vertebrae and 30 caudal vertebrae), which can be used for species identification. Fish with a similar number of vertebrae require further skeletal morphological features to distinguish them. For instance, the three-dimensional structure of the same vertebra segment from 32 different teleost species (belonging to 10 different orders) were compared and analyzed using Micro-computed tomography (Micro-CT) scanning technology. The results showed that the lamellar trabeculae and its internal cavity structure on the spine differed between the species, suggesting that these structural characteristics can serve as additional evidence to classify and identify fish species. In addition, calcium (Ca) and phosphorus (P) are the most important mineral elements in a fish skeleton, and their contents vary among different fish. Therefore, there is potential to use the skeletal Ca and P contents in classifying and identifying fish and their life history characteristics.To examine the vertebrae number in O. mykiss, specimens of juvenile O. mykiss of body weight (1.27±0.21) g were cleaned and double-stained to obtain the whole skeletal image. A total of 63 vertebrae were identified, and all were completely ossified at this developmental stage. X-ray scanner technology scanned and photographed the entire skeletal structure of adult O. mykiss. The adult results were similar to the juvenile results of 63 vertebrae with both ends connected with the head or tail, and the ribs were attached to the trunk vertebrae. The ventral sides of the 1–33 trunk vertebrae were arranged in an arc, which was downward and separate. No intermuscular spine was evident. On the dorsal side of the vertebrae, the neural arches surrounding the neural canal were fused with the neural spines. Unlike the ribs, the caudal vertebrae had vascular arches, which formed passages for blood vessels and nerves and were fused with the vascular spines on the ventral side.The calcium and phosphorus content, and microstructure of the vertebrae in O. mykiss at different developmental stages were assessed. Vertebrae samples were collected at four developmental stages (young stage Ⅰ, young stage Ⅱ, adult stage Ⅰ, and adult stage Ⅱ; with an average body weight of 4, 35, 644 and 2 129 g, respectively). The calcium and phosphorus contents in the 1–6th vertebrae were assessed by inductively coupled plasma mass spectrometry (ICP-MS). The 4–6th vertebrae were scanned using Micro-CT technology. The results revealed the calcium and phosphorus contents of the vertebrae initially increased and then decreased during development. The highest levels of calcium and phosphorus in the vertebrae was at young stage Ⅱ, (4 711.121±567.948) and (3 649.488±446.961) μmol/g, respectively. The Ca/P molar mass ratio increased significantly with the growth of O. mykiss (P < 0.05). These results indicated that the degree of mineralization in the vertebrae increased with growth and development. Micro-CT scanning results indicated that the bone volume and surface of the vertebrae increased significantly with the growth of O. mykiss. The vertebrae segments became more obvious, and the structure became more complete. The vertebral microstructure indexes in O. mykiss at the different developmental stages suggested the trabecular number (Tb.N) significantly decreased with the growth of O. mykiss (P < 0.05). The highest levels occurred at young stage Ⅰ with (19.915±0.758) ind./mm, the lowest levels occurred at adult stage Ⅱ with (1.960±0.043) ind./mm. The trabecular thickness (Tb.Th) and trabecular separation/spacing (Tb.Sp), both significantly increased with O. mykiss growth (P < 0.05). Tb.Th and Tb.Sp of the vertebrae in O. mykiss were the lowest, (0.060±0.001) mm and (0.068±0.004) mm, respectively at young stage Ⅰ, and the highest levels, (0.718±0.026) mm and (0.402±0.029) mm, respectively) were at adult stage Ⅱ. In addition, the bone volume fraction (BV/TV), tissue mineral density (TMD), and bone mineral density (BMD) showed a trend of initially decreasing and then increasing. The lowest levels were at adult stage Ⅰ, (62.620±13.223)%, (460.300±102.825) mg/mL and (678.052± 4.417) mg/mL, respectively, and the highest BV/TV and TMD, (86.473±1.029)% and (654.797± 7.031) mg/mL were at adult stage Ⅱ. Conversely, the highest BMD, (820.527±5.003) mg/mL, was at young stage Ⅰ. The evaluation indexes of the bone spatial morphological structures (such as TV, BV, BV/TV, BS, Tb.Th, and Tb.Sp) increased significantly during the growth and development of rainbow trout, while Tb.N decreased significantly. The bone strength evaluation index, BMD initially decreased and then increased. The significant variation in the vertebra microstructure at the different developmental stages might be closely related to its function. These results indicate that the microstructure and element contents of vertebrae in O. mykiss changes significantly during development and the relative results could provide more reliable data for age, group, and taxonomic identification of fish

Differentially Expressed miRNAs and mRNAs in Regenerated Scales of Rainbow Trout (<i>Oncorhynchus mykiss</i>) under Salinity Acclimation

In order to explore the potential effects of salinity acclimation on bone metabolism of rainbow trout (Oncorhynchus mykiss), transcriptional information of regenerated scales under salinity acclimation (sea water, SW) was compared to those of fish under fresh water (FW) environments. According to the high-throughput sequencing results, a total of 2620 significantly differentially expressed genes (DEGs) were identified in the data of SW vs. FW. Compared with the FW group, six significantly downregulated and 44 significantly upregulated miRNAs were identified in the SW scales (p < 0.05). Furthermore, a total of 994 significantly differentially expressed target genes (DETGs) were identified from the 50 significantly differentially expressed miRNAs (DE miRNAs). Gene ontology analysis of the aforementioned DETGs was similar to the results of the differentially expressed genes (DEGs) obtained from mRNA-seq data, these genes were mainly related to ion metabolism. KEGG enrichment analysis of the DEGs and DETGs suggested that many significantly enriched pathways were related to the energy metabolism pathway

Different Responses of Microbiota across Intestinal Tract to Enterococcus faecium HDRsEf1 and Their Correlation with Inflammation in Weaned Piglets

Enterococcus faecium HDRsEf1 (HDRsEf1) was identified to reduce the incidence of diarrhea in weaned piglets, but the mechanism has not been elucidated yet. Based on the fact that gut microbiota plays a crucial role in regulating inflammatory responses, the effects of HDRsEf1 on microbiota across the intestinal tract in weaned piglets were investigated. Microbiota from the luminal contents and the mucosa of the ileum, cecum, and colon of HDRsEf1-treated piglets were explored by 16S rRNA sequencing and qPCR. It was demonstrated that microbiota in different gut niches responded specifically to HDRsEf1, with major alterations occurring in the ileum and cecum. The total bacterial load of microbiota in ileal luminal contents and the relative abundance of Escherichia-Shigella in the ileal mucosa was significantly down-regulated by HDRsEf1 administration, while the relative abundance of butyrate-producing bacteria (including Clostridiaceae-1, Rumencoccidae, and Erysipelotrichaceae) in cecal luminal contents was significantly up-regulated. Moreover, the utilization of HDRsEf1 improved intestinal morphological development and reduced the inflammatory response, which were negatively correlated with the relative abundance of Escherichia-Shigella in the ileal mucosa and butyrate-producing bacteria in cecal luminal contents, respectively. Collectively, this study suggests that the administration of HDRsEf1 alters gut microbiota, thereby alleviating inflammation and improving intestinal morphological development in weaned piglets