Background: Ongericimab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) levels in the phase 2 trial. A phase 3 trial was conducted to evaluate the efficacy and safety of ongericimab in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia on background lipid-lowering therapy (LLT). Methods: This was a randomized, double-blind, placebo-controlled, 52-week trial conducted in China (NCT02662569). Eligible patients receiving stable statin (±ezetimibe) therapy but not achieving LDL-C goals were enrolled. Patients were randomly assigned in a 2:1:2:1 ratio to receive either ongericimab 150 mg or placebo subcutaneously every 2 weeks (Q2W), or ongericimab 300 mg or placebo subcutaneously every 4 weeks (Q4W) for 52 weeks. The primary endpoint was percent change in LDL-C from baseline to week 24. Results: A total of 806 patients were randomized, 802 patients received at least one dose of ongericimab or placebo. The least-squares (LS) mean difference between ongericimab and placebo in LDL-C from baseline to week 24 was -67.7% (95% CI: -72.49%, -62.99%; p < 0.0001) in Q2W group and -61.2% (95% CI: -67.09%, -55.21%; p < 0.0001) in Q4W group. LDL-C reductions were maintained to Week 52. Ongericimab also favorably altered other lipid parameters (Table 1). The overall incidence of adverse events was similar between ongericimab and placebo. Conclusion: Ongericimab on stable background LLT significantly reduced LDL-C and was well tolerated in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia.
Metabolic disorders are highly prevalent in modern society. Exercise mimetics are defined as pharmacologic compounds that can produce the beneficial effects of fitness. Recently, there has been increased interest in the role of eugenol and transient receptor potential vanilloid 1 (TRPV1) in improving metabolic health. The aim of this study was to investigate whether eugenol acts as an exercise mimetic by activating TRPV1. Here, we showed that eugenol improved endurance capacity, caused the conversion of fast to slow muscle fibers, and promoted white fat browning and lipolysis in mice. Mechanistically, eugenol promoted muscle fiber type transformation by activating TRPV1-mediated CaN signaling pathway. Subsequently, we identified IL-15 as a myokine that is regulated by the CaN/Nuclear factor of activated T cells cytoplasmic 1 (NFATc1) signaling pathway. Moreover, we found that TRPV1-mediated CaN/NFATc1 signaling, activated by eugenol, controlled IL-15 levels in C2C12 myotubes. Our results suggest that eugenol may act as an exercise mimetic to improve metabolic health via activating the TRPV1-mediated CaN signaling pathway.
Abstract Background Starch is a major component of carbohydrates and a major source of energy for monogastric animals. Starch is composed of amylose and amylopectin and has different physiological functions due to its different configuration and structure. It has been shown that the energy supply efficiency of amylose is lower than that of amylopectin. However, there are few studies on the effect of starch structure on the available energy of pigs. The purpose of this study was to measure the effect of different structures of starch in the diet on the net energy (NE) of pigs using a comparative slaughter method and to establish a prediction equation to estimate the NE of starch with different structures. A total of fifty-six barrows (initial body weight 10.18 ± 0.11kg) were used, and they were housed and fed individually. Pigs were divided into 7 treatments according to their weight, with 8 replicates for each treatment and 1 pig for each replicate. One of the treatments was randomly selected as the initial slaughter group (ISG). Pigs in the remaining groups were assigned to 6 dietary treatment and slaughtered at the conclusion of the experiment. The basic diet contains corn, soybean meal, without additional starch. The other five starch experimental groups were fed semi-pure diets with amylose/amylopectin ratios (AR) of 3.09, 1.47, 0.25, 0.15 and 0.12, respectively. The diets and water were provided ad libitum for 28 d. Results Results showed that compared with the high amylose (AM) groups (AR 3.09 and 1.47), the high amylopectin (AP) group (AR 0.15) significantly increased the final BW, average daily weight gain and average daily feed intake of pigs (quadratic, P < 0.01), but the F: G of the high amylose group was lower (quadratic, P < 0.05). In addition, the high amylopectin groups (AR 0.15 and 0.12) has higher (quadratic, P < 0.001) nutrient digestibility of dry matter, crude protein, gross energy and crude ash. Meanwhile, compared with other groups AR 0.15 group has a higher NE intake and energy retention (RE), while AR 3.09 group has the lowest NE intake and RE (linear, P < 0.05). The regressive equation for predicting with starch structures was established as RE = 1235.243-48.298AM/AP ( r 2= 0.657, P = 0.05). Conclusions In conclusion, with the increase of dietary amylopectin content, NE intake and RE of pigs were increased, indicating that diets high in amylopectin were more conducive to promoting the growth of pigs in the late conservation period.
Abstract Background Lentinan (LNT) may regulate many important physiological functions of human and animals. This study aimed to verify whether LNT administration could relieve diarrhea via improving gut immunity in rotavirus (RV)-challenged weaned pigs. Methods Twenty-eight weaned pigs were randomly fed 2 diets containing 0 or 84 mg/kg LNT product for 19 d ( n = 14). RV infection was executed on d 15. After extracting polysaccharides from LNT product, its major monosaccharides were analyzed. Then, LNT polysaccharide was used to administrate RV-infected IPEC-J2 cells. Results Dietary LNT supplementation supported normal function of piglets even when infected with RV, as reflected by reduced growth performance loss and diarrhea prevalence, and maintained gut immunity ( P < 0.05). The polysaccharide was isolated from LNT product, which molecular weight was 5303 Da, and major monosaccharides included glucose, arabinose and galactose. In RV-infected IPEC-J2 cells, this polysaccharide significantly increased cell viability ( P < 0.05), and significantly increased anti-virus immunity via regulating pattern recognition receptors and host defense peptides ( P < 0.05). Conclusion Those results suggest that LNT administration increases the piglets’ resistance to RV-induced stress, likely by supporting intestinal immunity.
This study aimed to investigate the effects of chronic exposure to low levels of dietary aflatoxin B1 (AFB1) on growth performance, apparent total tract digestibility and intestinal health in pigs. In a 102-day experiment, fourteen barrows (Duroc×Landrace×Yorkshire, initial BW = 38.21 ± 0.45 kg) were randomly divided into control (CON, basal diet) and AFB1 groups (the basal diet supplemented with 280 μg/kg AFB1). Results revealed that the AFB1 exposure decreased the final BW, ADFI and ADG in pigs (p < 0.10). AFB1 exposure also decreased the apparent total tract digestibility of dry mater and gross energy at 50 to 75 kg and 105 to 135 kg stages, and decreased the apparent total tract digestibility of ether extract at 75 to 105 kg stage (p < 0.05). Meanwhile, AFB1 exposure increased serum diamine oxidase activity and reduced the mRNA abundance of sodium-glucose cotransporter 1, solute carrier family 7 member 1 and zonula occluden-1 in the jejunal mucosa (p < 0.05). Furthermore, AFB1 exposure decreased superoxide dismutase activity (p < 0.05) and increased 8-hydroxy-2'-deoxyguanosine content (p < 0.10) in jejunal mucosa. AFB1 exposure also increased tumor necrosis factor-α, interleukin-1β and transforming growth factor-β mRNA abundance in jejunal mucosa and upregulated Escherichia coli population in colon (p < 0.05). The data indicated that chronic exposure to low levels of dietary AFB1 suppressed growth performance, reduced the apparent total tract digestibility and damaged intestinal barrier integrity in pigs, which could be associated with the decreased intestinal antioxidant capacity and the increased pro-inflammatory cytokine production.
The rice striped stem borer (SSB, Chilo suppressalis) is one of the most destructive pests of rice plants. Si-mediated rice defense against various pests has been widely reported, and sodium silicate (SS) has been used as an effective source of silicon for application to plants. However, there is quite limited information about the direct effects of Si application on herbivorous insects. SSB larval performance and their insecticide tolerance were examined after they had been reared either on rice plants cultivated in nutrient solution containing 0.5 and 2.0 mM SS or on artificial diets with 0.1% and 0.5% SS. SS amendment in either rice culture medium or artificial diets significantly suppressed the enzymatic activities of acetylcholinesterase, glutathione S-transferases, and levels of cytochrome P450 protein in the midgut of C. suppressalis larvae. Larvae fed on diets containing SS showed lower insecticide tolerance. Additionally, RNA-seq analysis showed that SS-mediated larval insecticide tolerance was closely associated with fatty acid biosynthesis and pyruvate metabolism pathways. Our results suggest that Si not only enhances plant resistance against insect herbivore, but also impairs the insect's capacity to detoxify the insecticides. This should be considered as another important aspect in Si-mediated plant-insect interaction and may provide a novel approach of pest management.
The gastrointestinal microbiota plays a pivotal role in maintaining animal health, immunity and reproductive performances. However, literature about the relationship between microbiota and reproductive performance is limited. The aim of the present study was to determine differences in the intestinal microbiota of broiler breeders with different egg laying rate. A total of 200 AA+ parent broiler breeders (41-week-old) were separated into two groups according to their different egg laying rate [average egg laying rate group (AR: 78.57 ± 0.20%) and high egg laying rate group (HR: 90.79 ± 0.43%). Feed conversion ratio (FCR), ovary cell apoptosis rate (ApoCR) and relative abdominal fat weight were lower ( p = 0.01), while the hatchability rate of qualified egg was higher ( p = 0.04) in HR group than that in AR group. Phascolarctobacterium abundance were lower ( p = 0.012) in ileum of HR birds. Romboutsia (genus) in ileum was negatively related to the feed efficiency ( r = −0.58, p < 0.05), Firmicutes (phylum) and Lactobacillus (genus) abundances in cecum were positively related to the egg laying rate (ELR) ( r = 0.35 and 0.48, p < 0.05), feed efficiency ( r = 0.42 and 0.43, p < 0.05), while Spirochaetes (phylum) and Sphaerochaeta (genus) abundances in cecum were negatively related to the ELR ( r = −0.43 and −0.70, p < 0.05), feed efficiency ( r = 0.54 and 0.48, p < 0.05), and positively related to ApoCR ( r = 0.46 and 0.47, p < 0.05). Our results suggested that microbiota, such as Firmicutes (phylum) and Lactobacillus (genus) have positive relationship, while Spirochaetes (phylum) and Romboutsia (genus) abundances exert negative relationship with broiler breeders' reproductive performances.
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Purpose. β-Defensin 118 (DEFB118) is a novel host defense peptide (HDP) identified in humans. To evaluate its potentials for future utilization, the DEFB118 gene was expressed in Escherichia coli (E. coli) and the recombinant protein was fully characterized. Methods. The DEFB118 protein was obtained by heterologous expression using E. coli Rosetta (DE3). Antibacterial activity of DEFB118 was determined by using various bacterial strains. IPEC-J cells challenged by E. coli K88 were used to determine its influences on inflammatory responses. Results. The E. coli transformants yielded more than 250 μg/mL DEFB118 protein after 4 h induction by 1.0 mM IPTG. The DEFB118 was estimated by SDS-PAGE to be 30 kDa, and MALDI-TOF analysis verified that it is a human β-defensin 118. Importantly, the DEFB118 showed antimicrobial activities against both Gram-negative bacteria (E. coli K88 and E. coli DH5α) and Gram-positive bacteria (S. aureus and B. subtilis), with a minimum inhibitory concentration (MIC) of 4 μg/mL. Hemolytic assays showed that DEFB118 had no detrimental impact on cell viability. Additionally, DEFB118 was found to elevate the viability of IPEC-J2 cells upon E. coli K88 challenge. Moreover, DEFB118 significantly decreased cell apoptosis in the late apoptosis phase and downregulated the expression of inflammatory cytokines such as IL-1β and TNF-α in IPEC-J2 cell exposure to E. coli K88. Conclusions. These results suggested a novel function of the mammalian defensins, and the antibacterial and anti-inflammatory properties of DEFB118 may allow it as a potential substitute for conventionally used antibiotics or drugs.
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