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Veterinary antibiotics in swine wastewater has drawn great public attention. The removal processes of sulfamethizole (SMZ), enrofloxacin (ENR) and chlortetracycline (CTC) were investigated in the high-rate anaerobic process. The continuous experiments demonstrated that in 3 L working volume and with the organic loading rate 5 kg/(m3·d) rised to 20 kg/(m3·d), the average removal efficiencies of the high-rate anaerobic bioreactor for SMZ, ENR and CTC were 0, 54 and 100%, respectively. By using fixed-bed adsorption models, the saturation time of SMZ, ENR and CTC were 4 hydraulic retention time (HRT) (24 h), 8 HRT (48 h) and 372 HRT (2,232 h). In the batch experiments, the adsorption and biodegradation characteristics of anaerobic granular sludge were determined. In the high-rate anaerobic bioreactor, SMZ removal process mainly relied on the adsorption but it was very weak; ENR removal process was based on the adsorption and biodegradation; CTC removal process was based to a large extent on the adsorption because of the big capacity of AnGS. These results were helpful to create a rational basis for designing more suitable treatment systems as feasible barriers to the release of antibiotics into the environment.

Neuropathic pain is chronic pain resulting from central or peripheral nerve damage that remains difficult to treat. Current evidence suggests that nobiletin, isolated from Citrus reticulata Blanco, possesses analgesic and neuroprotective effects. However, its effect on neuropathic pain has not been reported. This study evaluated the analgesic effect of nobiletin on neuropathic pain induced by chronic constriction injury (CCI) in mice. In vivo, mice were intragastrically administered with nobiletin (30, 60, 120 mg/kg) for eight consecutive days, respectively. Our study indicated that nobiletin ameliorated mechanical allodynia, cold allodynia and thermal hyperalgesia on CCI mice at doses that do not induce significant sedation. Moreover, nobiletin could ameliorate axonal and myelin injury of the sciatic nerve and further restore abnormal sciatic nerve electrical activity on CCI mice. In vitro studies indicated that nobiletin could suppress the proteins and mRNA expression of the IRF5/P2X4R/BDNF signalling pathway in fibronectin-induced BV2 cells. Overall, our results indicated that nobiletin might exert an analgesic effect on CCI-induced neuropathic pain in mice by inhibiting the IRF5/P2X4R/BDNF signalling pathway in spinal microglia. This study provided a novel potential therapeutic drug for neuropathic pain and new insights into the pharmacological action of nobiletin.

In recent years, the function of plant polyphenols to improve the intestinal barrier has been fully demonstrated. However, the exact mechanisms linking plant polyphenols with the intestinal barrier function have not yet been established. Apple polyphenols (APs) are safe and healthy nutrients, which are extracted from apples and their byproducts. Using pig and IPEC-J2 cell models, this study investigated the effects of dietary AP supplementation on intestinal antioxidant capacity and barrier function. Then, we further explored the role of the Nrf2/Keap1 signaling pathway in maintaining intestinal antioxidant capacity and barrier function. Our study found that dietary AP supplementation improved the intestinal mechanical barrier by promoting the intestinal morphology and intestinal tight junction protein expression, improved the intestinal immune barrier by increasing intestinal secretory immunoglobulin A production, and improved the intestinal biological barrier by increasing probiotics and decreasing the

Esophageal adenocarcinoma (EAC) is a leading cause of cancer deaths. Pexidartinib, a multi-gene tyrosine kinase inhibitor, through targeting colony-stimulating factor 1 (CSF-1) receptor (CSF-1R), down modulates macrophage-mediated pro-survival tumor signaling. Previously, CSF-1R inhibitors have successfully shown to enhance antitumor activity of PD-1/PD-L1 inhibitors by suppressing tumor immune evasion, in solid tumors. In this study, we investigated the antitumor activity of pexidartinib alone or in combination with blockade of PD-1 in a de novo EAC rat model. Here, we showed limited toxicity with significant tumor shrinkage in pexidartinib treated animals compared to controls, single agent and in combination with a PD-1 inhibitor, AUNP-12. Suppression of CSF-1/CSF-1R axis resulted in enhanced infiltration of CD3 + CD8 + T cells with reduced M2 macrophage polarization, in the tumor microenvironment (TME). Endpoint tissue gene expression in pexidartinib treated animals demonstrated upregulation of BAX, Cas3, TNFα, IFNγ and IL6 and downregulation of Ki67, IL13, IL10, TGFβ and Arg1 (P

This study aimed to investigate the effect and underlying mechanisms of resveratrol on porcine muscle fiber type gene expression in porcine myotubes. Here, results showed that resveratrol treatment significantly promoted slow myosin heavy chain (MyHC) and inhibited fast MyHC in porcine myotubes. The phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and the downstream factors of AMPK signaling, such as Sirtuin1 (Sirt1) and peroxlsome proliferator-activated receptor-γ coactlvator-1α (PGC-1α), were also increased by resveratrol, suggesting that resveratrol could activate the AMPK signaling pathway. Interestingly, resveratrol inhibited the expression of miR-22-3p in porcine myotubes. Furthermore, AMPK inhibitor compound C and miR-22-3p mimic effectively eliminated the effects of resveratrol on slow MyHC and fast MyHC expressions in porcine myotubes. Taken together, our findings indicate that resveratrol regulates muscle fiber type gene expression through the AMPK signaling pathway and miR-22-3p in porcine myotubes.

Epilepsy is one of the most severe neurological disorders characterized by spontaneous recurrent seizures. Although more than two-thirds of patients can be cured with anti-epileptic drugs (AEDs), the rest one-third of epilepsy patients are resistant to AEDs. A series of studies have demonstrated Rho/Rho-associated kinase (ROCK) pathway might be involved in the pathogenesis of epilepsy in the recent twenty years. Several related pathway inhibitors of Rho/ROCK have been used in the treatment of epilepsy. We searched PubMed from Jan 1, 2000 to Dec 31, 2020, using the terms "epilepsy AND Rho AND ROCK" and "seizure AND Rho AND ROCK". We selected articles that characterized Rho/ROCK in animal models of epilepsy and patients. We then chose the most relevant research studies including in-vitro, in-vivo and clinical trials. The expression of Rho/ROCK could be a potential non-invasive biomarker to apply in treatment for patients with epilepsy. RhoA and ROCK show significant upregulation in the acute and chronic stage of epilepsy. ROCK inhibitors can reduce the epilepsy, epileptic seizure-related neuronal death and comorbidities. These findings demonstrate the novel development for diagnosis and treatment for patients with epilepsy. Rho/ROCK signaling pathway inhibitors may show more promising effects in epilepsy and related neurological diseases.

Ellagic acid (EA) is a natural polyphenolic compound, which shows various effects, such as anti-inflammatory and antioxidant effects and inhibition of platelet aggregation. In this study, we investigated the effect of EA on muscle endurance and explored its possible underlying mechanism. Our data showed that EA significantly improved muscle endurance in mice. EA increased the protein level of slow myosin heavy chain (MyHC) I and decreased the protein level of fast MyHC. We also found that the AMP-activated protein kinase (AMPK) signaling pathway was activated by EA. Finally, our data indicated that EA could increase mitochondrial biogenesis and function by increasing the content of mitochondrial DNA (mtDNA), the concentration of ATP, the activities of succinodehydrogenase (SDH) and malate dehydrogenase (MDH), and the mRNA levels of ATP synthase (

Interleukin-37b (hereafter called IL-37) was identified as fundamental inhibitor of natural and acquired immunity. The molecular mechanism and function of IL-37 in colorectal cancer (CRC) has been elusive. Here, we found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and suffered from dramatically increased tumor burdens in colon. Nevertheless, IL-37 is dispensable for intestinal mutagenesis, and CRC cell proliferation, apoptosis, and migration. Notably, IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models. CD8+ T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice, enabling tumor evasion of immune surveillance. The dysfunction led by IL-37 antagonizes IL-18–induced proliferation and effector function of CD8+ T cells, which was dependent on SIGIRR (single immunoglobulin interleukin-1 receptor-related protein). Finally, we observed that IL-37 levels were significantly increased in CRC patients, and positively correlated with serum CRC biomarker CEA levels, but negatively correlated with the CD8+ T cell infiltration in CRC patients. Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancer-immunity cycle as therapeutic targets in CRC.

This study was aimed to explore the effects of dietary plant essential oil (PEO) supplementation on growth performance and meat quality in finishing pigs. A total of eighteen Duroc × Landrace × Yorkshire finishing barrows with an average initial body weight of 79.86 ± 1.94 kg were randomly assigned to CON group (fed with a basal diet) and PEO group (fed with the basal diet containing 200 mg/kg PEO) with 9 replicates per treatment. The trial lasted for 42 days. The results showed that dietary PEO supplementation significantly increased ADG during phase I (1-21 days) and the overall experimental period (p 0.05), tended to increase ADFI in phase II (22-42 days) and the overall experimental period (p = 0.09), decreased F/G in phase I (p 0.05) and tended to decrease F/G during the overall experimental period (p = 0.08). Meanwhile, compared to the CON group, the digestibility of DM, GE and EE in the PEO group was improved remarkably (p 0.05). PEO supplementation also significantly improved T-AOC and lowered MDA content in longissimus dorsi (p 0.05), tended to increase the activity of T-SOD (p = 0.06). A higher IMF content (p = 0.09) and a lower shear force (p = 0.08) of longissimus dorsi were found in the PEO group than that in CON group (p = 0.09). Furthermore, pigs fed the PEO diet showed higher mRNA abundances of GLUT4, LPL, CPT-1, CD36, FABP and LDL-R in the liver, and GLUT4 and FAS in the longissimus dorsi (p 0.05). In conclusion, PEO fed to finishing pigs improved the growth performance and nutrient digestibility. Furthermore, PEO supplementation had the potential role to improve pork quality by increasing the antioxidant capacity and IMF content, and decreasing the shear force of longissimus dorsi to a certain extent.

In this study, eighteen healthy Duroc × Landrace × Yorkshire barrows with initial body weight of 63.89 ± 1.15 kg were randomly allotted to three treatments and fed a basal diet or a basal diet supplemented with 100 mg/kg and 200 mg/kg lycopene, respectively. Data showed that villus height to crypt depth ratio increased with 200 mg/kg lycopene (

This study aimed to investigate the effect of dietary dihydromyricetin (DHM) supplementation on lipid metabolism, antioxidant capacity and muscle fiber type transformation. Twenty-four male Kunming mice were randomly allotted to either control (basal diet) or DHM diets (supplemented with 300 mg/kg DHM). Our data showed that DHM administration decreased the triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) contents, and increased the catalase (CAT), total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px) activities in serum. In the liver, DHM decreased the TG and malondialdehyde (MDA) levels and increased the T-SOD and GSH-Px activities. For the tibialis anterior (TA) muscle, DHM increased the total antioxidant capacity (T-AOC) level and T-SOD activities. Western blotting and real-time quantitative PCR analysis showed that DHM increased the protein and mRNA levels of MyHC I and MyHC IIa and decreased the protein and mRNA levels of MyHC IIb in TA muscle, which may be achieved by activating the AMP-activated protein kinase (AMPK) signal. The mRNA levels of several regulatory factors related to mitochondrial function were up-regulated by DHM. In conclusion, dietary 300 mg/kg DHM supplementation improved lipid metabolism and antioxidant capacity and promoted the transformation of muscle fiber type from glycolysis to oxidation in mice.

Microglial activation and neuroinflammation induced by amyloid β (Aβ) play pivotal roles in Alzheimer's disease (AD) pathogenesis. Astragaloside IV (AS-IV) is one of the major active compounds of the traditional Chinese medicine Astmgali Radix. It has been reported that AS-IV could protect against Aβ-induced neuroinflammation and cognitive impairment, but the underlying mechanisms need to be further clarified. In this study, the therapeutic effects of AS-IV were investigated in an oligomeric Aβ (oAβ) induced AD mice model. The effects of AS-IV on microglial activation, neuronal damage and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression were further studied. Different doses of AS-IV were administered intragastrically once a day after intracerebroventricularly oAβ injection. Results of behavioral experiments including novel object recognition (NOR) test and Morris water maze (MWM) test revealed that AS-IV administration could significantly ameliorate oAβ-induced cognitive impairment in a dose dependent manner. Enzyme linked immunosorbent assay (ELISA) results showed that increased levels of reactive oxygen species (ROS), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and IL-6 in hippocampal tissues induced by oAβ injection were remarkably inhibited after AS-IV treatment. OAβ induced microglial activation and neuronal damage was significantly suppressed in AS-IV-treated mice brain, observed in immunohistochemistry results. Furthermore, oAβ upregulated protein expression of NADPH oxidase subunits gp91phox, p47phox, p22phox and p67phox were remarkably reduced by AS-IV in Western blotting assay. These results revealed that AS-IV could ameliorate oAβ-induced cognitive impairment, neuroinflammation and neuronal damage, which were possibly mediated by inhibition of microglial activation and down-regulation of NADPH oxidase protein expression. Our findings provide new insights of AS-IV for the treatment of neuroinflammation related diseases such as AD.

Chronic morphine administration alters gene expression in different brain regions, an effect which may contribute to plastic changes associated with addictive behavior. This change in gene expression is most possibly mediated by addictive drug-induced epigenetic remodeling of gene expression programs. Our previous studies showed that chronic morphine-induced decrease of miR-105 in the medial prefrontal cortex (mPFC) contributed to context-induced retrieval of morphine withdrawal memory. However, how chronic morphine treatment decreases miR-105 in the mPFC still remains unknown. The present study shows that chronic morphine induces addiction-related change in miR-105 in the mPFC via two kinds of transcription factors: the first transcription factor is CREB activated by mu receptors-ERK-p90RSK signaling pathway and the second transcription factor is glucocorticoid receptor (GR), which as a negative transcription factor, mediates chronic morphine-induced decrease in miR-105 in the mPFC of rats.

Major depressive disorder (MDD) is one of the most common mental disorders. We designed a fast-onset antidepressant that works by disrupting the interaction between the serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN). Chronic unpredictable mild stress (CMS) selectively increased the SERT-nNOS complex in the DRN in mice. Augmentation of SERT-nNOS interactions in the DRN caused a depression-like phenotype and accounted for the CMS-induced depressive behaviors. Disrupting the SERT-nNOS interaction produced a fast-onset antidepressant effect by enhancing serotonin signaling in forebrain circuits. We discovered a small-molecule compound, ZZL-7, that elicited an antidepressant effect 2 hours after treatment without undesirable side effects. This compound, or analogous reagents, may serve as a new, rapidly acting treatment for MDD.

Sialyllactose (SL), one of the most abundant oligosaccharides present in porcine breast milk, has been implicated in many biological functions, including the prebiotic and immune-modulating effects. This study was conducted to investigate the influences of dietary SL supplementation on intestinal barrier functions exposure to enterotoxigenic

Dysregulation of NLRP3 inflammasome results in uncontrolled inflammation, which participates in various chronic diseases. TWIK2 potassium channel mediates potassium efflux that has been reported to be an essential upstream mechanism for ATP-induced NLRP3 inflammasome activation. Thus, TWIK2 potassium channel could be a potential drug target for NLRP3-related inflammatory diseases. In the present study we investigated the effects of known K2P channel modulators on TWIK2 channel expressed in a heterologous system. In order to increase plasma membrane expression and thus TWIK2 currents, a mutant channel with three mutations (TWIK2(I289A/L290A/Y308A)) in the C-terminus was expressed in COS-7 cells. TWIK2 currents were assessed using whole-cell voltage-clamp recording. Among 6 known K2P channel modulators tested (DCPIB, quinine, fluoxetine, ML365, ML335, and TKDC), ML365 was the most potent TWIK2 channel blocker with an IC(50) value of 4.07 ± 1.5 μM. Furthermore, ML365 selectively inhibited TWIK2 without affecting TWIK1 or THIK1 channels. We showed that ML365 (1, 5 μM) concentration-dependently inhibited ATP-induced NLRP3 inflammasome activation in LPS-primed murine BMDMs, whereas it did not affect nigericin-induced NLRP3, or non-canonical, AIM2 and NLRC4 inflammasomes activation. Knockdown of TWIK2 significantly impaired the inhibitory effect of ML365 on ATP-induced NLRP3 inflammasome activation. Moreover, we demonstrated that pre-administration of ML365 (1, 10, 25 mg/kg, ip) dose-dependently ameliorated LPS-induced endotoxic shock in mice. In a preliminary pharmacokinetic study conducted in rats, ML365 showed good absolute oral bioavailability with F value of 22.49%. In conclusion, ML365 provides a structural reference for future design of selective TWIK2 channel inhibitors in treating related inflammatory diseases.

The avian immunosuppressive and neoplastic diseases caused by Marek’s disease virus (MDV), avian leucosis virus (ALV), and reticuloendotheliosis virus (REV) are seriously harmful to the global poultry industry. In recent years, particularly in 2020–2022, outbreaks of such diseases in chicken flocks frequently occurred in China. Herein, we collected live diseased birds from 30 poultry farms, out of 42 farms with tumour-bearing chicken flocks distributed in central China, to investigate the current epidemiology and co-infections of these viruses. The results showed that in individual diseased birds, the positive infection rates of MDV, ALV, and REV were 69.5% (203/292), 14.4% (42/292), and 4.7% (13/277), respectively, while for the flocks, the positive infection rates were 96.7% (29/30), 36.7% (11/30), and 20% (6/30), respectively. For chicken flocks, monoinfection of MDV, ALV, or REV was 53.3% (16/30), 3.3% (1/30), and 0% (0/30), respectively, but a total of 43.3% (13/30) co-infections was observed, which includes 23.3% (7/30) of MDV+ALV, 10.0% (3/30) of MDV+REV, and 10.0% (3/30) of MDV+ALV+REV co-infections. Interestingly, no ALV+REV co-infection or REV monoinfection was observed in the selected poultry farms. Our data indicate that the prevalence of virulent MDV strains, partially accompanied with ALV and/or REV co-infections, is the main reason for current outbreaks of avian neoplastic diseases in central China, providing an important reference for the future control of disease.

Porcine epidemic diarrhea virus (PEDV) infection causes watery diarrhea and vomiting in piglets. The pathogenesis of PEDV infection is related to intestinal inflammation. It is known that 1,25-dihydroxyvitamin D

This study aimed to examine the effects of apple polyphenols (APPs) on antioxidant capacity, immune and inflammatory response, and barrier function in weaning piglets. Results showed that APPs improved jejunal barrier function by increasing the villus height, villus height/crypt depth, the mRNA levels of occludin, mucin-1, and mucin-4 and up-regulating the protein expression of occluding (P 0.05). As for antioxidant capacity, APPs increased the activities of total superoxide dismutase and glutathione peroxidase and total antioxidant capacity level in jejunum (P 0.05). Besides, APPs up-regulated the protein expressions of NAD(P)H quinone dehydrogenase 1 (NQO1), heme oxygenase-1 (HO-1), and nuclear-related factor 2 (NRF2) and down-regulated the protein expression of kelch-like ECH-associated protein 1 (Keap1). As regard to immune and inflammatory response, APPs increased the immunoglobulin A content in serum and decreased the mRNA levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, toll-like receptor 4 (TLR4), nuclear factor-κB (NF-κB), and IL-8 in jejunum (P 0.05). Overall, dietary APPs supplementation improves the jejunal barrier function by enhancing antioxidant capacity and suppressing the mRNA expression related to inflammation, which may be related to the NRF2 signal and TLR4/NF-κB signal.

Increasing evidence supports the ability of eugenol to maintain intestinal barrier integrity and anti-inflammatory in vitro and in vivo; however, whether eugenol alleviates virus-mediated intestinal barrier damage and inflammation remains a mystery. Transmissible gastroenteritis virus (TGEV), a coronavirus, is one of the main causative agents of diarrhea in piglets and significantly impacts the global swine industry. Here, we found that eugenol could alleviate TGEV-induced intestinal functional impairment and inflammatory responses in piglets. Our results indicated that eugenol improved feed efficiency in TGEV-infected piglets. Eugenol not only increased serum immunoglobulin concentration (IgG) but also significantly decreased serum inflammatory cytokine concentration (TNF-α) in TGEV-infected piglets. In addition, eugenol also significantly decreased the expression of NF-κB mRNA and the phosphorylation level of NF-κB P65 protein in the jejunum mucosa of TGEV-infected piglets. Eugenol increased villus height and the ratio of villus height to crypt depth in the jejunum and ileum, and decreased serum D-lactic acid levels. Importantly, eugenol increased tight junction protein (ZO-1) and mRNA expression levels of nutrient transporter-related genes (GluT-2 and CaT-1) in the jejunum mucosa of TGEV-infected piglets. Meanwhile, compared with TGEV-infected IPEC-J2 cells, treatment with eugenol reduced the cell cytopathic effect, attenuated the inflammatory response. Interestingly, eugenol did not increase the expression of ZO-1 and Occludin in IPEC-J2 cells. However, western blot and immunofluorescence results showed that eugenol restored TGEV-induced down-regulation of ZO-1 and Occludin, while BAY11-7082 (The NF-κB specific inhibitor) enhanced the regulatory ability of eugenol. Our findings demonstrated that eugenol attenuated TGEV-induced intestinal injury by increasing the expression of ZO-1 and Occludin, which may be related to the inhibition of NF-κB signaling pathway. Eugenol may offer some therapeutic opportunities for coronavirus-related diseases.

Background Ferulic acid (FA) is a common polyphenolic compound. The purpose of this study was to explore the effect of dietary FA supplementation on growth performance and muscle fiber type conversion in weaned piglets. In this study, eighteen 21-day-old DLY (Duroc × Landrace × Yorkshire) weaned piglets were randomly divided into control, 0.05% FA, and 0.45% FA groups. Results Our study showed that dietary FA supplementation had no effect on growth performance, but it could upregulate the expression of slow myosin heavy chain (MyHC) protein, increase the activities of succinic dehydrogenase and malate dehydrogenase, and downregulate the expression of fast MyHC protein. Dietary FA supplementation also increased the expression levels of phosphorylated AMP-activated protein kinase, sirtuin 1 (Sirt1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), myocyte enhancer factor 2C, and troponin I-SS, increased the proportion of slow-twitch fiber, and decreased the proportion of fast-twitch fiber. In addition, our results showed that dietary FA supplementation increased the messenger RNA abundance of mitochondrial nuclear transcription genes, including ATP synthase membrane subunit c locus 1, cytochrome oxidase subunit 1, nuclear respiratory factor 1, mitochondrial transcription factor A, mitochondrial transcription factor B1, and cytochrome c. Conclusion We provided the first evidence that FA could promote muscle fiber type conversion from fast-twitch to slow-twitch via the Sirt1/AMP-activated protein kinase/PGC-1α signaling pathway and could improve the mitochondrial function in weaned piglets. This means that FA can be used as a dietary supplement to improve the quality of pork. © 2021 Society of Chemical Industry.

Obesity is a metabolic disease and its relation with male subfertility has aroused a growing concern. However, it is unclear whether gene expression and post-translational modifications (PTMs), two vital molecular mechanisms regulating cellular functions, are associated with obesity-induced male reproductive dysfunction. In this study, male obesity with compromised sperm motility was induced by a high-fat diet (HFD) using a mouse model. The expression of motility related-genes, the level of histone modifications, and the global profiles of post-translational modifications (PTMs), were examined in testes of HFD and control mice by quantitative real-time PCR and western blot, respectively. Outer dense fiber protein 2, a major component of outer dense fibers in the sperm tail, is the most obviously down-regulated gene out of 11 evaluated genes, showing a reduction of about 50% RNA level in testes of obese male mice compared with that in control mice. Semi-quantitative analysis of the western blot demonstrated that ∼56% enrichment of di-methylated histone (H)3 lysine (K)36, ∼59% enrichment of 2-hydroxyisobutyrylated H4K8, ∼32% decrease of propionylated H3K23, ∼33% decrease of crotonylated H4K8, and ∼45% decrease of acetylated H3K122 and H4K8 were detected in testes of male HFD mice compared with that in control mice. In addition, male obesity up-regulated the testicular levels of ubiquitination by ∼18%, tyrosine nitration by ∼20%, lysine succinylation by ∼25%, lysine benzoylation by ∼28%, lysine malonylation by ∼32%, lysine glutarylation by ∼36%, lysine propionylation by ∼42%, lysine 2-hydroxyisobutyrylation by ∼45%, and SUMO1 modification by ∼59%, and down-regulated the testicular levels of O-GlcNAcylation by ∼12%, lysine crotonylation by ∼22%, and lysine acetylation by 35%. These findings indicate that altered gene expression and PTMs are associated with the obesity-induced male reproductive dysfunction.

A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to optimize the dosing regimen of enrofloxacin (EN) against Glaesserella parasuis in pigs. EN (2.5 mg/kg) was administered intramuscularly to eight healthy pigs and eight pigs that were experimentally infected with G. parasuis SW124. Blood samples were collected at predetermined time points. Plasma EN concentrations were determined, and the main PK parameters were estimated. The PD of EN against G. parasuis SW124 was also investigated in vitro and ex vivo. The dynamic behaviour of EN in pigs was consistent with a one-compartment model. Significant differences were observed between healthy and infected pigs in the area under the curve (AUC) (3.58 ± 0.94 and 5.39 ± 1.01 μg h/ml, respectively) and the systemic clearance (CL) (736.32 ± 171.46 and 479.36 ± 96.81 ml/h/kg, respectively), suggesting that the pathogenicity of G. parasuis SW124 to pigs might alter the PK profile of EN, and therefore should be considered in dose optimization. Both the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were 0.125 μg/ml in tryptone soya broth (TSB) medium or plasma. The mutant prevention concentration (MPC) was 0.6 μg/ml. EN inhibited or killed G. parasuis SW124 in a concentration-dependent manner. The targeted endpoints of AUC

As the demand of consumers for good meat quality is increasing, there is more interest in improving pork quality by nutritional regulation. Dihydromyricetin (DHM), a group of bioactive flavonoids, exhibits excellent biological functions and pharmacological activities. This study aimed to investigate whether dietary DHM supplementation in growing-finishing pigs could provide high-quality pork. A total of 24 healthy castrated Duroc × Landrace × Yorkshire (DLY) pigs with an average body weight of 26.95 ± 0.26 kg were randomly divided into four groups (basal diet and a basal diet supplemented with 100, 300 and 500 mg kg

Numerous long noncoding RNAs (lncRNAs) are aberrantly expressed in pancreatic cancer (PC); however, their functions and mechanisms in cancer progression are largely unknown. In this study, we identified a novel PC-associated lncRNA, RUNX1-IT1, that was significantly upregulated in PC patient samples from multiple centers and associated with poor prognosis. In vitro and in vivo, alterations in RUNX1-IT1 expression markedly affected PC proliferation, migration and invasion. RUNX1-IT1 contributed to the progression of PC by interacting with the adjacent gene RUNX1. Rescue experiments showed that RUNX1 reduced the cancer-promoting effect of RUNX1-IT1. RNA-seq analysis after silencing RUNX1-IT1 and RUNX1 highlighted alterations in the common target C-FOS. Mechanistically, we demonstrated that RUNX1-IT1 was a trans-acting factor that participated in the proliferation, migration and invasion of PC by recruiting RUNX1 to the C-FOS gene promoter. Furthermore, RUNX1-IT1 enhanced the transcription of the RUNX1 gene, indicating its potential as a cis-regulatory RNA involved in the upstream regulation of RUNX1. Overall, RUNX1-IT1 is a crucial oncogenic lncRNA that activates C-FOS expression by regulating and recruiting RUNX1 and is a potential prognostic biomarker and therapeutic target for PC.

MicroRNAs (miRNAs) are a class of conserved non-coding RNAs that are widely regarded as important regulators in a variety of biological processes. Increasing evidence has revealed that skeletal muscle fiber-type conversion is regulated by miRNAs, but the molecular mechanism is still not fully understood. In this study, we confirmed the role of miR-22-3p on skeletal muscle fiber-type conversion and investigated its potential mechanism in C2C12 myotubes. Here, we found that the miR-22-3p mimics inhibited the expressions of myosin heavy chain I (MyHC I), MyHC IIa and promoted the expression of MyHC IIb, while miR-22-3p inhibitor got inverse results. miR-22-3p mimics also downregulated phosphorylated AMPK, SIRT1 and PGC-1ɑ protein levels, which control the expression of oxidative fiber-related genes. Furthermore, Compound C (AMPK inhibitor) eliminated the effect of miR-22-3p inhibitor on MyHC I, MyHC IIa and MyHC IIb expressions. However, AICAR (AMPK activator) also abolished the effect of miR-22-3p mimics on MyHC I, MyHC IIa and MyHC IIb expressions. Collectively, our results suggest that miR-22-3p regulates skeletal muscle fiber-type conversion through inhibiting AMPK/SIRT1/PGC-1ɑ signaling pathway.

Benzo[a]pyrene (B[a]P) is recognized as a neurotoxic pollutant to mammals, which could impair learning and memory function. Although there is some evidence to suggest that N-methyl-d-aspartate receptor (NMDAR), a glutamate receptor and ion channel protein in nerve cells, is involved into the B[a]P induced neurotoxicity, the exact molecular mechanisms remain to be elucidated, particularly the effects of B[a]P on the NMDAR downstream signaling transduction pathways. In the present study, we examined the neurotoxicity of sub-chronic administrated B[a]P on male Sprague-Dawley rats. Our data suggested that B[a]P exposure caused significant deficits in learning and memory function and the impairment of hippocampal LTP in rats. Further mechanistic studies indicate that B[a]P-induced learning and memory deficits are associated with the inhibition of NMDAR NR1 subunit transcription and protein phosphorylation. More importantly, the inactivation of CaMK II/PKC/PKA-ERK-CREB signaling pathways in hippocampus was detected at both the 2.5 and 6.25 mg/kg B[a]P-treated groups, indicating that multiple targets in NMDAR and downstream signaling pathways are involved in the B[a]P-induced neurotoxicity.

Early weaning-induced stress causes diarrhoea, thereby reducing the growth performance of piglets. Gut bacterial dysbiosis has emerged as a leading cause of post-weaning diarrhoea. The present study aimed to investigate the effect of capsulized faecal microbiota transplantation (FMT) on the gut bacterial community, immune response and gut barrier function of piglets. Thirty-two weaned barrows were randomly divided into two groups. The recipient group was inoculated orally with capsulized faecal microbiota of healthy Tibetan pigs during the whole period of the trial, while the control group was given an empty capsule. The feed-to-gain ratio, diarrhoea ratio, and histological damage score of recipient piglets were significantly decreased. FMT treatment significantly increased the colon length of piglets. Furthermore, the relative abundances of Firmicutes, Euryarchaeota, Tenericutes, Lactobacillus, and Methanobrevibacter in the colon of recipient piglets were increased, and the relative abundances of Campylobacter and Proteobacteria were significantly decreased compared with those in the control group. CD4+ lymphocytes and CD4+/CD8+ ratio in the peripheral blood of recipient piglets were significantly increased. FMT treatment increased the IL-4 and IL-10 levels and decreased the TNF-α and INF-γ levels in the colonic tissue of piglets. The recipient piglets’ mRNA expression of TLR2, TLR8, NF-κB, and iNOS was significantly regulated. In addition, FMT significantly enhanced the gene expression of ZO-1. Overall, treatment with capsulized FMT ameliorated diarrhoea in piglets, with significant effects on limiting colon inflammatory responses, downregulating the TLR signalling pathway and the gene expression of iNOS, and strengthening intestinal barrier function by modulating the constituents of the gut microbiota.

To explore the effect of selenium-enriched yeast (SeY) on intestinal barrier functions in weaned pigs upon oxidative stress, a 2×2 factorial design was utilized and thirty-two pigs were randomly assigned into four groups. Pigs with or without exposure to oxidative stress (diquat challenge) were fed with a basal diet or a SeY-containing diet. The trial lasted for 21 days, and result showed that SeY supplementation attenuated body-weight reduction and significantly decreased the serum concentrations of diamine oxidase (DAO) and D-lactic acid in pigs upon diquat challenge (P<0.05). Diquat challenge decreased the villus height and the ratio of villus height to crypt depth (V/C) in the jejunum and ileum (P<0.05). However, SeY supplementation not only elevated the villus height and the ratio of V/C (P<0.05) but also improved the distribution and abundance of tight-junction protein ZO-1 in the jejunum epithelium. Interestingly, SeY supplementation acutely decreased the total apoptosis rate of intestinal epithelial cells in pigs upon diquat challenge (P<0.05). Moreover, SeY elevated the content of antioxidant molecules such as glutathione peroxidase (GSH-Px) and catalase (CAT) but significantly decreased the content of malondialdehyde (MDA) in the intestinal mucosa (P<0.05). Importantly, SeY elevated the expression levels of critical functional genes such as the nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), sodium/glucose cotransporter 1 (SGLT1), and B-cell lymphoma-2 (BCL-2) in the intestinal mucosa upon diquat challenge (P<0.05). Moreover, the expression of caspase-3 was downregulated by SeY in the duodenum and jejunum mucosa (P<0.05). These results indicated that SeY attenuated oxidative stress-induced intestinal mucosa disruption, which was associated with elevated mucosal antioxidative capacity and improved intestinal barrier functions.

Ferroptosis has recently emerged as an iron-dependent form of nonapoptotic cell death, which is also a regulated necrosis process and a response to tumor suppression. However, whether ferroptosis is involved in ulcerative colitis (UC) is unknown. The aims of this study were to investigate whether the ferroptosis is involved in UC, particularly intestinal epithelial cell (IEC) death, and to analyze the effect of the nuclear factor kappa Bp65 subunit (NF-κBp65) on ferroptosis. The gene expression of ferroptosis-related proteins was assessed in intestinal mucosal samples from human UC. The experimental model of UC was induced with dextran sulfate sodium (DSS). Ferroptosis of IECs was evaluated, the effect of NF-κBp65 on ferroptosis was analyzed by using IEC-specific NF-κBp65-deleted mice (p65IEC-KO), and the ferroptosis signaling pathway was investigated in vitro and in vivo. The results showed that ferroptosis was significantly induced in the IECs from UC patients and mice with colitis, and the ferroptosis was mediated by endoplasmic reticulum (ER) stress signaling. The specific deletion of IEC NF-κBp65 clearly upregulated ferroptosis and exacerbated colitis, and the result showed that phosphorylated-NF-κBp65 significantly inhibited ER stress signaling by directly binding eukaryotic initiation factor 2α. These data indicate that ferroptosis contributes to UC via ER stress-mediated IEC cell death, and that NF-κBp65 phosphorylation suppresses ER stress-mediated IEC ferroptosis to alleviate UC. The results suggest that ferroptosis involves in IEC death in UC, NF-κBp65 play a critical role in the ferroptotic inhibition, and ferroptosis is a potential therapeutic target for UC.

Dimer procyanidin B2 [epicatechin-(4β-8)-epicatechin] (PB2) has attracted a lot of interest in nutrition and medicine because of its significant health-promoting abilities. However, the function of PB2 on different types of skeletal myofiber is still unclear. Here, we have found that PB2 significantly increased protein expression of the slow myosin heavy chain (MyHC) and decreased fast MyHC protein in C2C12 myotubes, accompanied by upregulation of mRNA expression of MyHC I, MyHC IIa, and Tnni1 and downregulation of MyHC IIx and MyHC IIb. We have also found that PB2 enhanced the activities of malate dehydrogenase and succinic dehydrogenase and reduced lactate dehydrogenase activity. PB2 promoted phosphorylation of AMPK and significantly increased mRNA expression of AMPKα1. The upstream factors of AMPK, such as phospho-LKB1, NRF1, and CaMKKβ, and the downstream factors of AMPK, including Sirt1 and PGC-1α, were also increased by PB2. Specific suppression of AMPK signaling by AMPKα1 siRNA or by AMPK inhibitor compound C significantly attenuated the PB2-induced upregulation of phospho-AMPK, PGC-1α, and slow MyHC and downregulation of fast MyHC. Our findings suggested that PB2 promotes skeletal slow-twitch myofiber gene expression through the AMPK signaling pathway in C2C12 myotubes.

In sharp contrast to the numerous studies on bacteria, very little is known about the fungal community in mammalian gut. Recent studies on human and mice highlighted the importance of "mycobiota" in the metabolism and gut health of host, but our knowledge on the fungal composition and distribution in swine gut is very limited. In the current study, the fungal community in the caecal and colonic digesta from five weaned piglets was analysed based on an Illumina HiSeq 2500 platform targeting the internal transcribed spacer 1 region, and its relationship with the concentration of short-chain fatty acids was also investigated. Results revealed that the fungal profile in the caecal and colonic digesta of the piglets was distinct, and the caecal fungal diversity was significantly higher (p < .05). Basidiomycota and Ascomycota were the two predominant fungal phyla in the caecum and colon of the piglets. Comparing with that in colon, the abundance of Saccharomycopsis, Wallemia and Mrakia showed significantly higher (p < .05), and the abundance of Scheffersomyces, Aspergillus, Penicillium and Mucor was significantly lower in the caecum (p < .05). Canonical correspondence analysis showed a correlation between the fungal community and the concentration of isobutyrate, isovalerate, propionate and acetate in the digesta samples. Spearman's correlation indicated that the low-abundance genera, Fusarium, Plectosphaerella and Metarhizium, were positively correlated with of isobutyrate (p < .05), while Xeromyces were negatively correlated with acetate (p < .05), and Cornuvesica was negatively correlated with both acetate and propionate (p < .05). Results illuminated a probable interaction between the fungal composition and the bacterial degradation of protein and complex carbohydrates in the diet. These findings would be helpful to enhance our understanding of fungi in swine gut and provide a foundation for future work on the function of mycobiota in pigs.

The objective of the present study was to evaluate the effects of dietary starch structure (amylose/amylopectin ratio, AR) on intestinal health of weaned pigs by determining the intestinal morphology, barrier functions, epithelium apoptosis and digestive enzymes. A total of one hundred and eight pigs (initial body weight 7.51 ± 0.05 kg) were randomly allotted on the basis of their body weight (BW) and litters to one of the six experimental diet treatments with six replicates per treatment and three pigs per replicate. The six diets included a control (corn-soybean meal basal diet, CON) diet and five experimental diets with AR being 2.90, 1.46, 0.68, 0.31 and 0.14, respectively. The diets and water were provided ad libitum for 21 d. Results showed that pigs fed CON and AR 2.90 diets had higher (P < 0.05) villus height and ratio of villus height : crypt depth in the jejunum and ileum compared with the other four starch groups. Pigs of CON and AR 0.14 groups had greater (P < 0.05) activities of sucrase (SA) and maltase (MA) than the pigs of other groups. Additionally, compared with the high amylopectin (AR 0.31 and 0.14) groups, the total apoptotic percentage was significantly decreased in (P < 0.01) CON and high amylose (AR 2.90) groups. Ingestion of CON and high amylose diets upregulated (P < 0.05) the levels of B-cell lymphoma-2 (Bcl-2) and occludin (OCLN) gene expression in duodenum and jejunum. However, no significant differences in the level of zonula occludens 1 (ZO-1) gene expression were observed in pigs fed with different AR diets. Interestingly, CON and high amylose groups enhanced the localization of ZO-1 protein in apical intercellular region of jejunal epithelium. Together, these results suggest that diets with high amylose can influence the intestinal health of young pigs by improving their intestinal barrier functions and reducing the epithelial cell apoptosis.

Hepatocellular carcinoma (HCC) is one of the most lethal human cancers worldwide. The dietary xanthone α-mangostin (α-MGT) exhibits potent anti-tumor effects in vitro and in vivo. However, the anti-HCC effects of α-MGT and their underlying mechanisms are still vague. Aberrant activation of signal transducer and activator of transcription 3 (STAT3) is involved in the progression of HCC. We therefore investigated whether α-MGT inhibited the activation of STAT3 and thereby exhibits its anti-HCC effects. In this study, we found that α-MGT significantly suppressed cell proliferation, induced cell cycle arrest, and triggered apoptosis in HCC cells, including HepG2, SK-Hep-1, Huh7, and SMMC-7721 cells in vitro, as well as inhibiting tumor growth in nude mice bearing HepG2 or SK-Hep-1 xenografts. Furthermore, α-MGT potently inhibited the constitutive and inducible activation of STAT3 in HCC cells. In addition, α-MGT also suppressed IL-6-induced dimerization and nuclear translocation of STAT3, which led to inhibition of the expression of STAT3-regulated genes at both mRNA and protein levels. Mechanistically, α-MGT exhibited effective inhibition of the activation of STAT3’s upstream kinases, including JAK2, Src, ERK, and Akt. Importantly, α-MGT increased the protein level of Src homology region 2 domain-containing phosphatase-1 (SHP1), which is a key negative regulator of the STAT3 signaling pathway. Furthermore, α-MGT enhanced the stabilization of SHP1 by inhibiting its degradation mediated by the ubiquitin–proteasome pathway. Knockdown of SHP1 using siRNA obviously prevented the α-MGT-mediated inhibition of the activation of STAT3 and proliferation of HCC cells. In summary, α-MGT exhibited a potent anti-HCC effect by blocking the STAT3 signaling pathway via the suppression of the degradation of SHP1 induced by the ubiquitin–proteasome pathway. These findings also suggested the potential of dietary derived α-MGT in HCC therapy.

Short chain fatty acids (SCFAs) are produced when indigestible carbohydrates, such as fiber and resistant starch, undergo fermentation by specific microbiota in the hindgut. This study was designed to investigate the effects of different SCFAs on the glucolipid metabolism and appetite regulation of pigs. In a 28-day experiment, 30 barrows were divided into five groups: (1) control, (2) 0.1% sodium acetate, (3) 0.1% sodium propionate, (4) 0.1% sodium butyrate, and (5) 0.1% mixed sodium SCFAs (in the ratio of 3 : 1 : 1, respectively). Acetate administration reduced the average daily feed intake and average daily body weight gain of pigs (P < 0.05), decreased serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-c) concentrations (P < 0.05), increased serum glucagon-like peptide 1 (GLP-1), peptide YY (PYY) and leptin concentrations (P < 0.05), down-regulated fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC) and sterol regulatory element binding protein 1c (SREBP-1c) mRNA expressions in the liver (P < 0.05), enhanced silent information regulator1 (SIRT1) mRNA expression in the longissimus dorsi (P < 0.05), and up-regulated free fatty acids receptor 2 (FFAR2) and PYY mRNA expressions in the colon (P < 0.05). Propionate administration also decreased serum TG, TC, and LDL-c concentrations (P < 0.05), increased serum GLP-1, PYY and leptin concentrations (P < 0.05), down-regulated glucose-6-phosphatase (G6PC) mRNA expression in the liver (P < 0.05), enhanced PPARγ coactivator-1α (PGC-1α) mRNA expression in the liver (P < 0.05), stimulated SIRT1 mRNA expression in the longissimus dorsi (P < 0.05), and up-regulated G6PC and glucagon mRNA expressions in the colon (P < 0.05). Butyrate administration down-regulated G6PC mRNA expression in the liver (P < 0.05), enhanced PGC-1α mRNA expression in the liver (P < 0.05), and increased lipase hormone-sensitive (LIPE) and carnitine palmitoyltransferase-1α (CPT-1α) mRNA expressions in the longissimus dorsi (P < 0.05). Overall, these results suggested that SCFAs could reduce lipogenesis, and enhance lipolysis in different tissues of pigs via regulating related hormones and genes, which would further illustrate the mechanisms underlying the beneficial effects of SCFAs on appetite and body weight control.

Resident macrophages in the tumor microenvironment exert a dual role in tumor progression. So far, the mechanism of intratumoral macrophage generation is still largely unknown. In the present study, the importance of macrophages in the pro-tumor role of gastric cancer-derived mesenchymal stromal cells (GC-MSCs) was observed in a mouse xenograft model with macrophage depletion. In gastric cancer tissues, high expression levels of Ym-1, Fizz-1, arginase-1, and CCR-2, as well as a low expression level of iNOS, were verified, and co-localization of GC-MSCs and tumor-associated macrophages (TAMs) was observed by dual immunofluorescence histochemistry. TAMs isolated from gastric cancer tissues predominantly displayed an M2 phenotype. In a co-culture system, the contribution of GC-MSCs to M2 polarization of macrophages was confirmed by the M2-related protein expression, M2-like immunophenotype and cytokine profile of GC-MSC-primed macrophages in vitro. Blockade of IL-6/IL-8 by neutralizing antibodies significantly attenuated the promoting effect of GC-MSCs on M2-like macrophage polarization via the JAK2/STAT3 signaling pathway. In addition, GC-MSC-primed macrophages promoted the migration and invasion of gastric cancer cells, and the process of EMT in gastric cancer cells was significantly enhanced by GC-MSC-primed macrophage treatment. Our study showed that tumor-promoting GC-MSCs contribute to M2 macrophage polarization within the gastric cancer niche through considerable secretion of IL-6 and IL-8. These GC-MSC-primed macrophages can subsequently prompt gastric cancer metastasis via EMT promotion in gastric cancer cells.

CRISPR-Cas9 is a widely-used genome editing tool, but its off-target effect and on-target complex mutations remain a concern, especially in view of future clinical applications. Non-human primates (NHPs) share close genetic and physiological similarities with humans, making them an ideal preclinical model for developing Cas9-based therapies. However, to our knowledge no comprehensive in vivo off-target and on-target assessment has been conducted in NHPs. Here, we perform whole genome trio sequencing of Cas9-treated rhesus monkeys. We only find a small number of de novo mutations that can be explained by expected spontaneous mutations, and no unexpected off-target mutations (OTMs) were detected. Furthermore, the long-read sequencing data does not detect large structural variants in the target region., The off-target effects and on-target mutations of CRISPR editing in higher non-human primates are complex. Here the authors perform whole genome trio sequencing of rhesus monkeys and see no unexpected mutations.

The aim of this study was to investigate effects of dietary supplementation of resveratrol on immunity, antioxidative capacity, intestinal barrier function in weaning piglets. Here, fifty-four 28-day-old Duroc × Landrace × Yorkshire weaning piglets were randomly divided into three dietary treatments and fed with a basal diet or a basal diet supplemented with 150 and 300 mg/kg resveratrol, respectively, for 42 days. The results indicated that resveratrol increased serum immunoglobulin G content. In serum, resveratrol increased glutathione peroxidase enzyme activity and decreased malondialdehyde (MDA) content. In liver, resveratrol not only increased T-AOC and total superoxide dismutase enzyme activities but also decreased MDA content. Meanwhile, the results showed that resveratrol had significantly increased the jejunum villus height and villus height/crypt depth, and decreased the crypt depth in jejunum. Furthermore, the mRNA expressions of

Growing evidences show a direct link between diarrhea and disorders of gut microbiota in pigs. However, whether there are microbial markers associated with post-weaning diarrhea remains unknown. In the current study, we compared the microbial community, functions and metabolites between healthy weaned piglets (group H, n=7) and piglets with post-weaning diarrhea (group D, n=7), in order to find out diarrhea associated microbial markers. Each of 7 fecal samples was collected from H and D piglets (weaned at 21 d and sampled at 26 d). The metagenomic and untargeted metabolomic analysis revealed that the microbial composition, function and metabolic profile in D pigs was considerably reshaped, including the reduced abundance and number of Bacteroides, which significantly correlated with the diarrhea status of host. The carbohydrate metabolism, biosynthesis and metabolism, lipid metabolism, amino acid metabolism, and the activity of glycan and carbohydrates digestion related enzymes showed extensively down-regulated in D pigs compared with H pigs. Diarrhea significantly changed the metabolic profiles of fecal microbiota, and most of the altered metabolites were negatively or positively correlated with the change in the abundance of Bacteroides. In conclusion, the lower abundance of Bacteroides and its associated metabolic dysfunction may be regarded as microbial markers of physiological post-weaning diarrhea in piglets.

Intestinal inflammation is a major threat to the health and growth of young animals such as piglets. As a next-generation probiotics, limited studies have shown that Akkermansia muciniphila could alleviate inflammation of intestinal epithelial cells (IECs). In this study, a TNF-α-induced inflammatory model of IPEC-J2 cells, the intestinal porcine enterocytes, was built to evaluate the effects of active or inactive A. muciniphila on the inflammation of IECs. The viability of IPEC-J2 cells was the highest when treated with active (108 copies/mL) or inactive (109 copies/mL) A. muciniphila for 7.5 h (P < 0.01). Treated with 20 ng/mL of TNF-α and followed by a treatment of A. muciniphila, the mRNA level of proinflammatory cytokines (IL-8, IL-1β, IL-6 and TNF-α) was remarkably reduced (P < 0.05) along with the increased mRNA level of tight junction proteins (ZO-1 and Occludin, P < 0.05). Flow cytometry analysis showed that active or inactive A. muciniphila significantly suppressed the rate of the early and total apoptotic of the inflammatory IPEC-J2 cells (P < 0.05). According to results of transcriptome sequencing, active and inactive A. muciniphila may decline cell apoptosis by down-regulating the expression of key genes in calcium signaling pathway, or up-regulating the expression of key genes in cell cycle signaling pathway. And the bacterium may alleviate the inflammation of IECs by down-regulating the expression of PI3K upstream receptor genes. Our results indicate that A. muciniphila may be a promising NGP targeting intestinal inflammation.

Diarrhoea caused by pathogens such as enterotoxigenic

Adequate ovarian hormones secretion is essential for pregnancy success. Oxidative damage and following inflammation can destroy the ovarian normal function in mammals. Daidzein (DAI) is a classical isoflavonic phytoestrogen with specific oestrogenic activity. This study aimed to explore the effects of daidzein supplementation on fertility and ovarian characteristics of sows through biochemical analysis and RNA-seq technology. Twelve multiparous Yorkshire × Landrace sows were randomly divided into CON and DAI groups. We found that DAI increased total number of embryos as well as P4 and E2 levels of serum. DAI not only elevated the activities of T-AOC and GSH-Px, but also tended to decrease the content of MDA and IL-6 in the serum. In ovary, RNA-Seq identified 237 differentially expressed genes (DEGs), and GO analysis showed that these DEGs were linked to functions associated with immune dysfunction. Moreover, STRING analysis demonstrated that most interacting nodes were TLR-4, LCP2, and CD86. Furthermore, DAI decreased the content of MDA, IL-1β, IL-6, and TNF-α, and increased the activities of T-AOC and CAT in ovarian tissue. Interestingly, a partial mantel correlation showed that T-AOC was the strongest correlation between the ovarian dataset and selected DEGs. Additionally, DAI supplementation not only increased the protein expressions of Nrf2, HO-1, and NQO1, but also decreased the protein expressions of TLR-4, p-NFκB, p-AKT, and p-IκBα. Altogether, our results indicated that DAI could ameliorate ovarian oxidative stress and inflammation in sows, which might be mediated by suppressing the TLR4/NF-κB signaling pathway and activating the Nrf2/HO-1 signaling pathway.

During development, melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) become light sensitive much earlier than rods and cones. IpRGCs project to many subcortical areas, whereas physiological functions of these projections are yet to be fully elucidated. Here, we found that ipRGC-mediated light sensation promotes synaptogenesis of pyramidal neurons in various cortices and the hippocampus. This phenomenon depends on activation of ipRGCs and is mediated by the release of oxytocin from the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) into cerebral-spinal fluid. We further characterized a direct connection between ipRGCs and oxytocin neurons in the SON and mutual projections between oxytocin neurons in the SON and PVN. Moreover, we showed that the lack of ipRGC-mediated, light-promoted early cortical synaptogenesis compromised learning ability in adult mice. Our results highlight the importance of light sensation early in life on the development of learning ability and therefore call attention to suitable light environment for infant care.

RPA is a master regulator of DNA metabolism and RPA availability acts as a rate-limiting factor. While numerous studies focused on the post-translational regulations of RPA for its functions, little is known regarding how RPA availability is controlled. Here we identify a novel lncRNA Discn as the guardian of RPA availability in stem cells. Discn is induced upon genotoxic stress and binds to neucleolin (NCL) in the nucleolus. This prevents NCL from translocation into nucleoplasm and avoids undesirable NCL-mediated RPA sequestration. Thus, Discn-NCL-RPA pathway preserves a sufficient RPA pool for DNA replication stress response and repair. Discn loss causes massive genome instability in mouse embryonic stem cells and neural stem/progenigor cells. Mice depleted of Discn display newborn death and brain dysfunctions due to DNA damage accumulation and associated inflammatory reactions. Our findings uncover a key regulator of DNA metabolism and provide new clue to understand the chemoresistance in cancer treatment., Various lncRNAs functions have been associated to replication stress and DNA double strand breaks in ESC. Here the authors reveal the lncRNA Discn-NCL-RPA axis pathway, which can regulate the availability of RPA pool for DNA replication stress response and repair.

Endoplasmic reticulum stress (ERS) and apoptosis are widely considered as essential factors associated with intestinal disorders, whereas nutritional therapeutic approaches targeting ERS may control disease activity. Thus, we focus on the potential benefit of chitosan oligosaccharide (COS) on repressing ERS and ERS-induced apoptosis. In this study, we used the ERS model with tunicamycin (TM)-induced IPEC-J2 cells

Porcine NK-Lysine (PNKL) is a new antimicrobial peptide (AMP) identified in the small intestine. In this study, PNKL protein was obtained through heterologous expression in Escherichia coli and was estimated by SDS-PAGE at 33 kDa. The antibacterial activities of PNKL were determined using various bacterial strains and showed broad-spectrum antimicrobial activity against Gram-negative and Gram-positive bacteria. Furthermore, E. coli K88-challenged IPEC-J2 cells were used to determine PNKL influences on inflammatory responses. Hemolytic assays showed that PNKL had no detrimental impact on cell viability. Interestingly, PNKL elevated the viability of IPEC-J2 cells exposure to E. coli K88. PNKL significantly decreased the cell apoptosis rate, and improved the distribution and abundance of tight junction protein ZO-1 in IPEC-J2 cells upon E. coli K88-challenge. Importantly, PNKL not only down regulated the expressions of inflammatory cytokines such as the IL-6 and TNF-α, but also down regulated the expressions of NF-κB, Caspase3, and Caspase9 in the E. coli K88-challenged cells. These results suggest a novel function of natural killer (NK)-lysin, and the anti-bacterial and anti-inflammatory properties of PNKL may allow it a potential substitute for conventionally used antibiotics or drugs.

L-leucine (Leu), as one of the effective amino acids to activate the mTOR signaling pathway, can alleviate transmissible gastroenteritis virus (TGEV) infection. However, the underlying mechanism by which Leu alleviates the virus infection has not been fully characterized. In particular, how Leu impacts TGEV replication through mTOR signaling has yet to be elucidated. In the present study, we found that TGEV proliferated efficiently in intestinal porcine epithelial cells (IPEC-J2 cells) as evidenced by the increase in viral contents by flow cytometry, the inhibition of cell proliferation by CCK-8 assay as well as the reduction of PCNA level by western blot. Besides, western blot analysis showed that STAT1 expression was markedly reduced in TGEV-infected cells. The results of ELISA revealed the inhibition of ISGs (ISG56, MxA, and PKR) expressions by TGEV infection. TGEV-induced mTOR and its downstream p70 S6K and 4E-BP1, STAT1 and ISGs downregulation were blocked by an mTOR activator-MHY1485 but not by an mTOR inhibitor-RAPA. Concurrently, mTOR activation by MHY1485 reduced the contents of TGEV and vice versa. Furthermore, Leu reversed the inhibition of STAT1 and ISGs by activating mTOR and its downstream p70 S6K and 4E-BP1 in TEGV-infected cells. Our findings demonstrated that Leu promoted the expressions of STAT1 and ISGs via activating mTOR signaling in IPEC-J2 cells, aiming to prevent TGEV infection.

Ellagic acid (EA), because of its remarkable health-promoting ability, has aroused widespread interest in the fields of nutrition and medicine. However, no reports showed that EA regulates mitochondrial biogenesis as well as muscle fiber-type composition in pigs. Our study found that dietary 75 and 150 mg/kg EA obviously augmented the slow myosin heavy chain (MyHC) protein level, the number of slow-twitch muscle fibers, and the activity of malate dehydrogenase (MDH) in the longissimus thoracis (LT) muscle of growing-finishing pigs. In contrast, dietary 75 and 150 mg/kg EA decreased the fast MyHC level, the number of fast-twitch muscle fibers, and the activity of lactate dehydrogenase (LDH) in the LT muscle. In addition, our further study found that dietary 75 and 150 mg/kg EA promoted the mitochondrial DNA (mtDNA) content, the mRNA expressions of ATP synthase (

During mammalian embryogenesis, spatial regulation of gene expression and cell signaling are functionally coupled with lineage specification, patterning of tissue progenitors, and germ layer morphogenesis. While the mouse model has been instrumental for understanding mammalian development, comparatively little is known about human and non-human primate gastrulation due to the restriction of both technical and ethical issues. Here, we present a spatial and temporal survey of the molecular dynamics of cell types populating the non-human primate embryos during gastrulation. We reconstructed three-dimensional digital models from serial sections of cynomolgus monkey (Macaca fascicularis) gastrulating embryos at 1-day temporal resolution from E17 to E21. Spatial transcriptomics identifies gene expression profiles unique to the germ layers. Cross-species comparison reveals a developmental coordinate of germ layer segregation between mouse and primates, and species-specific transcription programs during gastrulation. These findings offer insights into evolutionarily conserved and divergent processes during mammalian gastrulation.