Detoxification and underlying mechanisms towards toxic alkaloids by Traditional Chinese Medicine processing: A comprehensive review.

BACKGROUND: Alkaloids have attracted enduring interest worldwide due to their remarkable therapeutic effects, including analgesic, anti-inflammatory, and anti-tumor properties, thus offering a rich source for lead compound design and new drug discovery. However, some of these alkaloids possess intrinsic toxicity. Processing (Paozhi) is a pre-treatment step before the application of herbal medicines in traditional Chinese medicine (TCM) clinics, which has been employed for centuries to mitigate the toxicity of alkaloid-rich TCMs. PURPOSE: To explore the toxicity phenotypes, chemical basis, mode of action, detoxification processing methods, and underlying mechanisms, we can gain crucial insights into the safe and rational use of these toxic alkaloid-rich herbs. Such insights have the great potential to offer new strategies for drug discovery and development, ultimately improving the quality of life for millions of people. METHODS: Literatures published or early accessed until December 31, 2023, were retrieved from databases including PubMed, Web of Science, and CNKI. The following keywords, such as "toxicity", "alkaloid", "detoxification", "processing", "traditional Chinese medicine", "medicinal plant", and "plant", were used in combination or separately for screening. RESULTS: Toxicity of alkaloids in TCM includes hepatotoxicity, nephrotoxicity, neurotoxicity, cardiotoxicity, and other forms of toxicity, primarily induced by pyrrolizidines, quinolizidines, isoquinolines, indoles, pyridines, terpenoids, and amines. Factors such as whether the toxic-alkaloid enriched part is limited or heat-sensitive, and whether toxic alkaloids are also therapeutic components, are critical for choosing appropriate detoxification processing methods. Mechanisms of alkaloid detoxification includes physical removal, chemical decomposition or transformation, as well as biological modifications. CONCLUSION: Through this exploration, we review toxic alkaloids and the mechanisms underlying their toxicity, discuss methods to reduce toxicity, and unravel the intricate mechanisms behind detoxification. These offers insights into the quality control of herbs containing toxic alkaloids, safe and rational use of alkaloid-rich TCMs in clinics, new strategies for drug discovery and development, and ultimately helping improve the quality of life for millions of people.

Corrigendum: Machine learning to construct sphingolipid metabolism genes signature to characterize the immune landscape and prognosis of patients with uveal melanoma.

[This corrects the article DOI: 10.3389/fendo.2022.1056310.].

ESM1 enhances fatty acid synthesis and vascular mimicry in ovarian cancer by utilizing the PKM2-dependent warburg effect within the hypoxic tumor microenvironment.

BACKGROUND: The hypoxic tumor microenvironment is a key factor that promotes metabolic reprogramming and vascular mimicry (VM) in ovarian cancer (OC) patients. ESM1, a secreted protein, plays an important role in promoting proliferation and angiogenesis in OC. However, the role of ESM1 in metabolic reprogramming and VM in the hypoxic microenvironment in OC patients has not been determined. METHODS: Liquid chromatography coupled with tandem MS was used to analyze CAOV3 and OV90 cells. Interactions between ESM1, PKM2, UBA2, and SUMO1 were detected by GST pull-down, Co-IP, and molecular docking. The effects of the ESM1-PKM2 axis on cell glucose metabolism were analyzed based on an ECAR experiment. The biological effects of the signaling axis on OC cells were detected by tubule formation, transwell assay, RT‒PCR, Western blot, immunofluorescence, and in vivo xenograft tumor experiments. RESULTS: Our findings demonstrated that hypoxia induces the upregulation of ESM1 expression through the transcription of HIF-1α. ESM1 serves as a crucial mediator of the interaction between PKM2 and UBA2, facilitating the SUMOylation of PKM2 and the subsequent formation of PKM2 dimers. This process promotes the Warburg effect and facilitates the nuclear translocation of PKM2, ultimately leading to the phosphorylation of STAT3. These molecular events contribute to the promotion of ovarian cancer glycolysis and vasculogenic mimicry. Furthermore, our study revealed that Shikonin effectively inhibits the molecular interaction between ESM1 and PKM2, consequently preventing the formation of PKM2 dimers and thereby inhibiting ovarian cancer glycolysis, fatty acid synthesis and vasculogenic mimicry. CONCLUSION: Our findings demonstrated that hypoxia increases ESM1 expression through the transcriptional regulation of HIF-1α to induce dimerization via PKM2 SUMOylation, which promotes the OC Warburg effect and VM.

Implications of Jatropha curcas L. cake feed on swine health: A microbiota-gut-brain axis perspective.

The safety of Jatropha curcas L. cake (JCC) in animal feed remains under scrutiny, despite the advent of low phorbol ester (PE) variants. This study investigates the impact of low PE JCC on swine health when used as a protein feed. Pigs were fed a 5% JCC diet with a PE concentration of 0.98 mg/kg, which surprisingly still induced toxicity. Symptoms included depression, decreased food intake, increased diarrhea, along with hypothalamus and colon lesions. The toxicity was associated with a decrease in antioxidant enzymes, an increase in inflammatory cytokines in the hypothalamus, plasma, and colon, and a rise in pro-inflammatory colon microbes and metabolites. Disturbances in neurotransmitters further suggest that this toxicity is related to disruption of the microbiota-gut-brain axis, indicating that JCC's toxic elements are not solely due to PE. The sensitivity of pigs to JCC underscores the need for thorough detoxification prior to its use as feed. These findings significantly contribute to the discourse on the safety of low PE JCC in animal feed, highlighting implications for both the feed industry and public health.

Next-generation probiotic candidates targeting intestinal health in weaned piglets: Both live and heat-killed Akkermansia muciniphila prevent pathological changes induced by enterotoxigenic Escherichia coli in the gut.

The use of next-generation probiotics (NGP) in pigs for combating diseases has been subject to limited research. Here we explored the potential of a well-known NGP candidate Akkermansia muciniphila targeting pig gut health. In the first screening experiment, we found that the abundance of A. muciniphila peaked at 14 d old but decreased at weaning (21 d old; P < 0.05), suggesting the weaning period may be an effective window for A. muciniphila intervention. Following that, 48 crossbred weaned pigs at 28 d old were randomly assigned to five groups: control (CON), high/low live A. muciniphila (HA/LA), and high/low heat-killed A. muciniphila (HIA/LIA). From 1 to 28 d old, the CON group received gastric infusion of anaerobic sterile saline every other day; the HA and LA groups were gavaged every other day with 1 × 1010 CFU/5 mL and 5 × 108 CFU/5 mL live A. muciniphila, respectively; and the HIA and LIA groups were gavaged every other day with 1 × 1010 CFU/5 mL and 5 × 108 CFU/5 mL heat-killed A. muciniphila, respectively. At d 29, pigs in the CON group were randomly and equally divided into two groups, one of which was named the enterotoxigenic Escherichia coli (ETEC) group, and all groups except CON received a 5-d ETEC challenge. The supplementation of A. muciniphila numerically reduced the diarrhea rate of weaned pigs compared to the pigs that only received the ETEC challenge (P = 0.57), but the LIA group had a higher diarrhea rate than the CON group (P < 0.05). Consistent with this, the supplementation of A. muciniphila improved the small intestinal morphology and structure, proportion of CD4+ T lymphocytes in the blood, as well as the expression of genes related to intestinal barrier and antioxidant indices of pigs with ETEC challenge, especially for the LA group (P < 0.05). Meanwhile, A. muciniphila supplementation reduced the expression of ETEC virulence factor genes in the ileum and colon of pigs challenged by ETEC (P < 0.05). Therefore, A. muciniphila may protect the intestinal health of weaned piglets from damage caused by ETEC infection, but the effect may vary depending on the concentration and activity of A. muciniphila.

Prenatal diagnosis of interrupted aortic arch using high-definition flow render mode and spatiotemporal image correlation.

OBJECTIVES: To evaluate the clinical utility of two dimensional (2D) ultrasound combined with spatiotemporal image correlation (STIC) in diagnosing interrupted aortic arch (IAA) in fetal life. METHODS: A total of 53 cases of fetal IAA were diagnosed using 2D ultrasound combined with STIC, and 53 normal fetuses of the same gestational week were selected. These cases were retrospectively analyzed to assess the utility of employing 2D ultrasound combined with STIC in the diagnosis of IAA. RESULTS: 2D ultrasound combined with STIC detected 22 cases of type A IAA, 24 cases of type B IAA, and seven cases of type C IAA. Furthermore, combining 2D ultrasound with STIC enabled dynamic visualization of the IAA, aiding in prenatal diagnosis. The diagnostic coincidence rate of IAA was found to be higher in the HD-flow combined with STIC than that in the 2D combined with HD-flow. CONCLUSION: HD-flow combined with STIC can assist in diagnosing fetal IAA, and this technique has important clinical value.

A photoelectrochemical sensor based on In2O3/In2S3/ZnIn2S4 ternary Z-scheme heterojunction for ultrasensitive detection of dopamine in sweat.

A novel ternary heterojunction material In2O3/In2S3/ZnIn2S4 was synthesized, and a photoelectrochemical sensor was fabricated for the non-invasive test of dopamine (DA) in sweat. In2O3 multihollow microtubules were synthesized and then In2S3 was formed on their surface to construct a type-I heterojunction between In2S3 and In2O3. ZnIn2S4 was further introduced to form a Z-scheme heterojunction between In2S3/ZnIn2S4. Under photoexcitation, the photogenerated holes of In2O3 transferred to the valence band of In2S3, superimposed with the holes produced by In2S3, leads to a significantly higher photocatalytic oxidation capacity of In2O3/In2S3/ZnIn2S4 ternary composites than that of In2O3/In2S3. The Z-scheme heterojunction accelerates the transfer of photogenerated electrons accumulated on the type-I heterojunction. In the presence of DA, it is rapidly oxidized into polydopamine (PDA) by In2O3/In2S3, and the benzoquinone groups of PDA compete for the photogenerated electrons to reduce the current in the external circuit, whereby DA determination is achieved. Owing to the combination of type-I and Z-scheme heterojunction, the sensor showed extremely high sensitivity, with a detection limit of 3.94 × 10-12 mol/L. It is one of the most sensitive methods for DA detection reported and has been applied to the determination of DA in human sweat.

Advanced Nanoencapsulation-Enabled Ultrasensitive Analysis: Unraveling Tumor Extracellular Vesicle Subpopulations for Differential Diagnosis of Hepatocellular Carcinoma via DNA Cascade Reactions.

Tumor-derived extracellular vesicles (tEVs) hold immense promise as potential biomarkers for the precise diagnosis of hepatocellular carcinoma (HCC). However, their clinical translation is hampered by their inherent characteristics, such as small size and high heterogeneity and complex environment, including non-EV particles and normal cell-derived EVs, which prolong separation procedures and compromise detection accuracy. In this study, we devised a DNA cascade reaction-triggered individual EV nanoencapsulation (DCR-IEVN) strategy to achieve the ultrasensitive and specific detection of tEV subpopulations via routine flow cytometry in a one-pot, one-step fashion. DCR-IEVN enables the direct and selective packaging of multiple tEV subpopulations in clinical serum samples into flower-like particles exceeding 600 nm. This approach bypasses the need for EV isolation, effectively reducing interference from non-EV particles and nontumor EVs. Compared with conventional analytical technologies, DCR-IEVN exhibits superior efficacy in diagnosing HCC owing to its high selectivity for tEVs. Integration of machine learning algorithms with DCR-IEVN resulted in differential diagnosis accuracy of 96.7% for the training cohort (n = 120) and 93.3% for the validation cohort (n = 30), effectively distinguishing HCC, cirrhosis, and healthy donors. This strategy offers a streamlined workflow and rapid assay completion and requires only small-volume serum samples and routine clinical devices, facilitating the clinical translation of tEV-based tumor diagnosis.

Ultralow Strain-Induced Emergent Polarization Structures in a Flexible Freestanding BaTiO3 Membrane.

The engineering of ferroic orders, which involves the evolution of atomic structure and local ferroic configuration in the development of next-generation electronic devices. Until now, diverse polarization structures and topological domains are obtained in ferroelectric thin films or heterostructures, and the polarization switching and subsequent domain nucleation are found to be more conducive to building energy-efficient and multifunctional polarization structures. In this work, a continuous and periodic strain in a flexible freestanding BaTiO3 membrane to achieve a zigzag morphology is introduced. The polar head/tail boundaries and vortex/anti-vortex domains are constructed by a compressive strain as low as ≈0.5%, which is extremely lower than that used in epitaxial rigid ferroelectrics. Overall, this study c efficient polarization structures, which is of both theoretical value and practical significance for the development of next-generation flexible multifunctional devices.

Enhancing pig growth and gut health with fermented Jatropha curcas cake: Impacts on microbiota, metabolites, and neurotransmitters.

Given the escalating global crisis in feed protein availability, Jatropha curcas L. cake has attracted significant interest as a viable alternative protein source in animal feed. This experiment was conducted to investigate the effects of fermented Jatropha curcas L. cake (FJCC) as a protein feed in the diet of pigs. A total of 96 growing pigs with an average weight of 27.60 ± 1.59 kg were divided into three dietary groups with varying FJCC inclusion levels (0, 2.5, and 5%) for a 28 d trial. Results showed that the diet with 5% FJCC (FJCC5) demonstrated significant improvements in average daily gain (p = 0.009), feed-to-gain ratio (p = 0.036), nutrient digestibility, and intestinal morphology. Furthermore, the FJCC5 diet resulted in a decrease in pH values in different gut sections (jejunum p = 0.045, cecum p = 0.001, colon p = 0.012), and favorably altered the profile of short-chain fatty acids (SCFAs) with increased butyric acid content (p = 0.005) and total SCFAs (p = 0.019). Additionally, this diet notably decreased IL-6 levels in the jejunum (p = 0.008) and colon (=0.047), significantly reduced IL-1 levels in the hypothalamus (p < 0.001), and lowered IL-1, IL-6, and IL-10 levels in plasma (p < 0.05). Microbiota and metabolite profile analysis revealed an elevated abundance of beneficial microbes (p < 0.05) and key metabolites such as 4-aminobutyric acid (GABA) (p = 0.003) and serotonin (5-HT) (p = 0.022), linked to neuroactive ligand-receptor interaction. Moreover, FJCC5 significantly boosted circulating neurotransmitter levels of 5-HT (p = 0.006) and GABA (p = 0.002) in plasma and hypothalamus, with corresponding increases in precursor amino acids (p < 0.05). These findings suggest that FJCC, particularly at a 5% inclusion rate, can be an effective substitute for traditional protein sources like soybean meal, offering benefits beyond growth enhancement to gut health and potentially impacting the gut-brain axis. This research underscores FJCC's potential as a valuable component in sustainable animal nutrition strategies.

Right ventricular volume and function by three-dimensional echocardiography: results of the echocardiographic measurements in normal Chinese adults (EMINCA) II.

Three-dimensional (3D) echocardiography is an emerging technique for assessing right ventricular (RV) volume and function, but 3D-RV normal values from a large Chinese population are still lacking. The aim of the present study was to establish normal values of 3D-RV volume and function in healthy Chinese volunteers. A total of 1117 Han Chinese volunteers from 28 laboratories in 20 provinces of China were enrolled, and 3D-RV images of 747 volunteers with optimal image quality were ultimately analyzed by a core laboratory. Both vendor-dependent and vendor-independent software platforms were used to analyze the 3D-RV images. We found that men had larger RV volumes than women did in the whole population, even after indexing to body surface area, and older individuals had smaller RV volumes. The normal RV volume was significantly smaller than that recommended by the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines in both sexes. There were significant differences in 3D-RV measurements between the two vendor ultrasound systems and the different software platforms. The echocardiographic measurements in normal Chinese adults II study revealed normal 3D-RV volume and function in a large Chinese population, and there were significant differences between the sexes, ages, races, and vendor groups. Thus, normal 3D-RV values should be stratified by sex, age, race, and vendor.

Investigation into the impact of CeO2 morphology regulation on the oxidation process of dichloromethane.

Four distinct CeO2 catalysts featuring varied morphologies (nanorods, nanocubes, nanoparticles, and nano spindle-shaped) were synthesized through a hydrothermal process and subsequently employed in the oxidation of dichloromethane (DCM). The findings revealed that the nano spindle-shaped CeO2 exhibited exposure of crystal faces (111), demonstrating superior catalytic oxidation performance for DCM with a T90 of 337 °C and notably excellent low-temperature catalytic activity (T50 = 192 °C). The primary reaction products were identified as HCl and CO2. Through obvious characterizations, it showed that the excellent catalytic activity presented by CeO2-s catalyst might be related to the higher oxygen vacancy concentration, surface active oxygen content, and superior redox performance caused by specific exposed crystal planes. Meanwhile, CeO2-s catalyst owned outstanding stability, reusability, and water inactivation regeneration, which had tremendous potential in practical treatment.

Influence of Gadoxetate disodium to the hepatic proton density fat fraction quantified with the Dixon sequences in a rabbit model.

OBJECTIVE: To study the impact of Gx on quantification of hepatic fat contents under metabolic dysfunction-associated steatotic liver disease (MASLD) imaged on VIBE Dixon in hepatobiliary specific phase. METHODS: Forty-two rabbits were randomly divided into control group (n = 10) and high-fat diet group (n = 32). Imaging was performed before enhancement (Pre-Gx) and at the 13th (Post-Gx13) and 17th (Post-Gx17) min after Gx enhancement with 2E- and 6E-VIBE Dixon to determine hepatic proton density fat fractions (PDFF). PDFFs were compared with vacuole percentage (VP) measured under histopathology. RESULTS: 33 animals were evaluated and including control group (n = 11) and MASLD group (n = 22). Pre-Gx, Post-Gx13, Post-Gx17 PDFFs under 6E-VIBE Dixon had strong correlations with VPs (r2 = 0.8208-0.8536). PDFFs under 2E-VIBE Dixon were reduced significantly (P < 0.001) after enhancement (r2 = 0.7991/0.8014) compared with that before enhancement (r2 = 0.7643). There was no significant difference between PDFFs of Post-Gx13 and Post-Gx17 (P = 0.123) for which the highest consistency being found with 6E-VIBE Dixon before enhancement (r2 = 0.8536). The signal intensity of the precontrast compared with the postcontrast, water image under 2E-VIBE Dixon increased significantly (P < 0.001), fat image showed no significant difference (P = 0.754). CONCLUSION: 2E- and 6E-VIBE Dixon can obtain accurate PDFFs in the hepatobiliary specific phase from 13 to 17th min after Gx enhancement. On 2E-VIBE Dixon (FA = 10°), effective minimization of T1 Bias by the Gx administration markedly improved the accuracy of the hepatic PDFF quantification.

Post-secondary classroom teaching quality evaluation using small object detection model.

The classroom video has a complex background and dense targets. This study utilizes small object detection technology to analyze and evaluate students' behavior in the classroom, aiming to objectively and accurately assess classroom quality. Firstly, noise is removed from the images using a median filter, and the contrast of the images is enhanced through histogram equalization. Label smoothing is applied to reduce the model's sensitivity to labels. Then, features are extracted from the preprocessed images, and multi-scale feature fusion is employed to enhance semantic expression across multiple scales. Finally, a combination loss function is utilized to improve the accuracy of multi-object recognition tasks. Real-time detection of students' behaviors in the classroom is performed based on the small object detection model. The average head-up rate in the classroom is calculated, and the quality of teaching is evaluated and analyzed. This study explores the methods and applications of small object detection technology based on actual teaching cases and analyzes and evaluates its effectiveness in evaluating the quality of higher education classroom teaching. The research findings demonstrate the significant importance of small object detection technology in effectively evaluating students' learning conditions in higher education classrooms, leading to improved teaching quality and personalized education.

Dietary ethylenediamine dihydroiodide mitigated Escherichia coli O78-induced immune and intestinal damage of ducks via suppression of NF-κB signal.

This study investigated the effect of Ethylenediamine dihydroiodide (EDDI) on growth performance, immune function and intestinal health of meat ducks challenged with Avian pathogenic Escherichia coli (APEC). A total of 360 one-day-old Cherry Valley ducks with similar body weight were randomly allocated to 6 treatments (6 floor cages, 10 birds/cage). A 3 × 2 factor design was used with 3 dietary iodine levels (0, 8, 16 mg/kg in the form EDDI and whether APEC was challenged or not at 7-day-old ducks. The feeding period lasted for 20 d. The results showed that the addition of EDDI reduced APEC-induced decrease of the 20-d weight loss of meat ducks (P < 0.05), and alleviated the inflammatory response of liver tissue induced by APEC challenge in meat ducks. In terms of immune function, EDDI supplementation reduced the immune organ index and increased the immune cell count of meat ducks, reduced the level of endotoxins in the serum of meat ducks (P < 0.05), as well as inhibited the expression levels of liver and spleen inflammatory factors and TLR signaling pathway related genes induced by APEC (P < 0.05). In terms of intestinal health, EDDI inhibited APEC-induced decreases in ZO-3 genes expression and increases in IL-1ß and TNF-α expression, increased relative abundance of beneficial bacteria in the cecum and content of metabolites. Pearson correlation analysis showed that there was a significant correlation between liver inflammatory factors and TLR4 signaling pathway genes, and there might be a significant correlation between intestinal microbial flora and other physiological indexes of meat ducks, which indicated that EDDI could reduce the damage to immune function and intestinal health caused by APEC challenge through regulating the structure of intestinal flora. Collectively, our findings suggest that the EDDI can promote growth performance, improve immune function and the intestinal barrier in APEC-challenged meat ducks, which may be related to the suppression of NF-κB signal.

Effects of Ninjurin 2 polymorphisms on susceptibility to coronary heart disease.

OBJECTIVE: The aim of this study was to explore the effects of Ninjurin 2 (NINJ2) polymorphisms on susceptibility to coronary heart disease (CHD). METHODS: We conducted a case-control study with 499 CHD cases and 505 age and gender-matched controls. Five single nucleotide polymorphisms (SNPs) in NINJ2 (rs118050317, rs75750647, rs7307242, rs10849390, and rs11610368) were genotyped by the Agena MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression analysis to assess the association of NINJ2 polymorphisms and CHD risk-adjusted for age and gender. What's more, risk genes and molecular functions were screened via protein-protein interaction (PPI) network and functional enrichment analysis. RESULTS: Rs118050317 in NINJ2 significantly increased CHD risk in people aged more than 60 years and women. Rs118050317 and rs7307242 had strong relationships with hypertension risk in CHD patients. Additionally, rs75750647 exceedingly raised diabetes risk in cases under multiple models, whereas rs10849390 could protect CHD patients from diabetes in allele, homozygote, and additive models. We also observed two blocks in NINJ2. Further interaction network and enrichment analysis showed that NINJ2 played a greater role in the pathogenesis and progression of CHD. CONCLUSION: Our results suggest that NINJ2 polymorphisms are associated with CHD risk.

Dynamic changes and clinical value of Sirt6 in acute coronary syndrome (ACS) patients.

This study aimed to investigate the role of Sirt6 and inflammatory cytokines in blood samples of patients with ACS. This is a retrospective randomized controlled clinical trial, a total of 30 patients from our hospital are included and divided into following two groups: control group and experimental group, and experimental group consists of 15 patients with ACS and control group consists of 15 patients with non-acute coronary syndrome. Sirt6 protein is detected by western blotting and Sirt6 mRNA is detected by real-time PCR, then inflammatory cytokines such as IL-1ß, IL-18, TnI, and CK-MB are measured by ELISA and cytokines NT-proBNP are monitored by immunofluorescence. Our outcomes show that Sirt6 protein and Sirt6 mRNA in experimental group are remarkably lower than those in control group, and IL-1ß, IL-18, TnI, CK-MB, and NT-proBNP in the experimental group are remarkably higher than those in control group. We can conclude that Sirt6 can prevent or inhibit the development of ACS and IL-1ß, IL-18, TnI, CK-MB, and NT-proBNP can accelerate the development of ACS.

Betaine addition to the diet alleviates intestinal injury in growing rabbits during the summer heat through the AAT/mTOR pathway.

BACKGROUND: The aim of this experiment was to investigate the effect of different levels of betaine (Bet) inclusion in the diet on the intestinal health of growing rabbits under summer heat. A total of 100 weaned Qixing meat rabbits aged 35 d with body weight of 748.61 ± 38.59 g were randomly divided into 5 treatment groups: control group (basal diet) and Bet groups (basal diet + 0.75, 1.0, 1.5 or 2.0 g/kg Bet). The average daily temperature in the rabbitry during the experiment was 30.48 °C and the relative humidity was 69.44%. RESULTS: Dietary addition of Bet had no significant effect on growth performance and health status of growing rabbits (P > 0.05), but it increased ileal secretory immunoglobulin A content compared to the control under summer heat (P < 0.05). Addition of 0.75 g/kg Bet up-regulated jejunal IL-4, down-regulated ileal TNF-α expression (P < 0.05). The addition of 1.0 g/kg Bet increased the villi height (VH) in the jejunum (P < 0.05). Serum glucose levels were reduced, and the expression of SLC6A20 was up-regulated in jejunum and ileum of rabbits fed with 1.5 g/kg Bet (P < 0.05). When added at 2.0 g/kg, Bet reduced serum HSP70 content, increased jejunal VH, and up-regulated duodenal SLC7A6, SLC38A2, mTOR and 4EBP-2 expression (P < 0.05). Correlation analysis revealed that intestinal mTOR expression was significantly and positively correlated with SLC7A6, SLC38A2, SLC36A1 and IL-4 expression (P < 0.05). CONCLUSIONS: Dietary addition of Bet can up-regulate the expression of anti-inflammatory factors through the AAT/mTOR pathway, improve the intestinal immune function, alleviate intestinal damage in growing rabbits caused by summer heat, and improve intestinal health.

All-trans retinoic acid alleviates transmissible gastroenteritis virus-induced intestinal inflammation and barrier dysfunction in weaned piglets.

BACKGROUND: Transmissible gastroenteritis virus (TGEV) is one of the main pathogens causing severe diarrhea of piglets. The pathogenesis of TGEV is closely related to intestinal inflammation. All-trans retinoic acid (ATRA) is the main active metabolite of vitamin A, which has immunomodulatory and anti-inflammatory properties. However, it is unclear whether ATRA can alleviate TGEV-induced intestinal inflammation and barrier dysfunction in piglets. This study aimed to investigate the effects of ATRA on growth performance, diarrhea, intestinal inflammation and intestinal barrier integrity of TGEV-challenged piglets. METHODS: In a 19-d study, 32 weaned piglets were randomly divided into 4 treatments: Control group (basal diet), TGEV group (basal diet + TGEV challenge), TGEV + ATRA5 group (basal diet + 5 mg/d ATRA + TGEV challenge) and TGEV + ATRA15 group (basal diet + 15 mg/d ATRA + TGEV challenge). On d 14, piglets were orally administered TGEV or the sterile medium. RESULTS: Feeding piglets with 5 and 15 mg/d ATRA alleviated the growth inhibition and diarrhea induced by TGEV (P < 0.05). Feeding piglets with 5 and 15 mg/d ATRA also inhibited the increase of serum diamine oxidase (DAO) activity and the decrease of occludin and claudin-1 protein levels in jejunal mucosa induced by TGEV, and maintained intestinal barrier integrity (P < 0.05). Meanwhile, 5 mg/d ATRA feeding increased the sucrase activity and the expressions of nutrient transporter related genes (GLUT2 and SLC7A1) in jejunal mucosa of TGEV-challenged piglets (P < 0.05). Furthermore, 5 mg/d ATRA feeding attenuated TGEV-induced intestinal inflammatory response by inhibiting the release of interleukin (IL)-1ß, IL-8 and tumor necrosis factor-α (TNF-α), and promoting the secretion of IL-10 and secretory immunoglobulin A (sIgA) (P < 0.05). Feeding 5 mg/d ATRA also down-regulated the expressions of Toll-like receptors and RIG-I like receptors signaling pathway related genes (TLR3, TLR4, RIG-I, MyD88, TRIF and MAVS) and the phosphorylation level of nuclear factor-κB-p65 (NF-κB p65), and up-regulated the inhibitor kappa B alpha (IκBα) protein level in jejunal mucosa of TGEV-challenged piglets (P < 0.05). CONCLUSIONS: ATRA alleviated TGEV-induced intestinal barrier damage by inhibiting inflammatory response, thus improving the growth performance and inhibiting diarrhea of piglets. The mechanism was associated with the inhibition of NF-κB signaling pathway mediated by TLR3, TLR4 and RIG-I.

Targeting iron-metabolism:a potential therapeutic strategy for pulmonary fibrosis.

Iron homeostasisis is integral to normal physiological and biochemical processes of lungs. The maintenance of iron homeostasis involves the process of intake, storage and output, dependening on iron-regulated protein/iron response element system to operate tightly metabolism-related genes, including TFR1, DMT1, Fth, and FPN. Dysregulation of iron can lead to iron overload, which increases the virulence of microbial colonisers and the occurrence of oxidative stress, causing alveolar epithelial cells to undergo necrosis and apoptosis, and form extracellular matrix. Accumulated iron drive iron-dependent ferroptosis to exacerbated pulmonary fibrosis. Notably, the iron chelator deferoxamine and the lipophilic antioxidant ferritin-1 have been shown to attenuate ferroptosis and inhibit lipid peroxidation in pulmonary fibrosis. The paper summarises the regulatory mechanisms of dysregulated iron metabolism and ferroptosis in the development of pulmonary fibrosis. Targeting iron metabolism may be a potential therapeutic strategy for the prevention and treatment of pulmonary fibrosis.