Tea Polyphenols Protects Tracheal Epithelial Tight Junctions in Lung during Actinobacillus pleuropneumoniae Infection via Suppressing TLR-4/MAPK/PKC-MLCK Signaling.

Actinobacillus pleuropneumoniae (APP) is the causative pathogen of porcine pleuropneumonia, a highly contagious respiratory disease in the pig industry. The increasingly severe antimicrobial resistance in APP urgently requires novel antibacterial alternatives for the treatment of APP infection. In this study, we investigated the effect of tea polyphenols (TP) against APP. MIC and MBC of TP showed significant inhibitory effects on bacteria growth and caused cellular damage to APP. Furthermore, TP decreased adherent activity of APP to the newborn pig tracheal epithelial cells (NPTr) and the destruction of the tight adherence junction proteins ß-catenin and occludin. Moreover, TP improved the survival rate of APP infected mice but also attenuated the release of the inflammation-related cytokines IL-6, IL-8, and TNF-α. TP inhibited activation of the TLR/MAPK/PKC-MLCK signaling for down-regulated TLR-2, TLR4, p-JNK, p-p38, p-PKC-α, and MLCK in cells triggered by APP. Collectively, our data suggest that TP represents a promising therapeutic agent in the treatment of APP infection.

Supplementation of n-3 PUFAs in Adulthood Attenuated Susceptibility to Pentylenetetrazol Induced Epilepsy in Mice Fed with n-3 PUFAs Deficient Diet in Early Life.

The growth and development of the fetus and newborn throughout pregnancy and lactation are directly related to the nutritional status of the mother, which has a significant impact on the health of the offspring. The purpose of this experiment was to investigate the susceptibility of n-3 polyunsaturated fatty acid deficiency in early life to seizures in adulthood. The n-3 PUFAs-deficient mice's offspring were established and then fed with α-LNA diet, DHA-enriched ethyl ester, and DHA-enriched phospholipid-containing diets for 17 days at the age of eight weeks. During this period, animals received intraperitoneal injections of 35 mg/kg of pentylenetetrazol (PTZ) every other day for eight days. The results showed that dietary n-3 PUFA-deficiency in early life could aggravate PTZ-induced epileptic seizures and brain disorders. Notably, nutritional supplementation with n-3 PUFAs in adulthood for 17 days could significantly recover the brain n-3 fatty acid and alleviate the epilepsy susceptibility as well as raise seizure threshold to different levels by mediating the neurotransmitter disturbance and mitochondria-dependent apoptosis, demyelination, and neuroinflammation status of the hippocampus. DHA-enriched phospholipid possessed a superior effect on alleviating the seizure compared to α-LNA and DHA-enriched ethyl ester. Dietary n-3 PUFA deficiency in early life increases the susceptibility to PTZ-induced epilepsy in adult offspring, and nutritional supplementation with n-3 PUFAs enhances the tolerance to the epileptic seizure.

Phosphatidylglucose alleviates atherosclerosis by increasing cholesterol alienation to bile acids and cholesterol efflux in ApoE-/- mice.

BACKGROUND: Phosphatidylcholine (PC) is considered to be the major dietary source for choline, which is associated with atherosclerosis progress. Thus, phosphatidylglucose (PG) was prepared by enzymatic modification of PC to investigate the effects on atherosclerosis in apolipoprotein E deficient (ApoE-/- ) mice, as well as to investigate its dose-response relationship. RESULTS: The results showed that dietary PG significantly decreased the atherosclerotic lesion area in a dose-dependent manner. Further studies found that intervention with a 0.8 g kg-1 and 2 g kg-1 PG diet for 4 months significantly decreased free cholesterol level and thus reduced total cholesterol levels in serum. The results of cholesterol distribution among lipoproteins showed that dietary PG significantly decreased low-density lipoprotein levels in ApoE-/- mice. In addition, only administration of high-dose PG significantly reduced total cholesterol levels in liver tissues by 31.2%. Furthermore, mice treated with high-dose PG had an expanded bile acid pool and increased the ratio of conjugated bile acids to unconjugated bile acids in the liver, serum and gallbladder by increasing hepatic gene expression of primary and conjugated bile acid synthesis. Additionally, low-dose and high-dose PG significantly increased total fecal sterols by 20.8% and 11.9%, respectively, by increasing sitosterol and ethylcoprostanol levels. CONCLUSION: These results indicate that PG alleviated atherosclerosis in a dose-dependent manner by increasing cholesterol alienation to bile acids and cholesterol efflux. © 2023 Society of Chemical Industry.

N-3 PUFA Deficiency Aggravates Streptozotocin-Induced Pancreatic Injury in Mice but Dietary Supplementation with DHA/EPA Protects the Pancreas via Suppressing Inflammation, Oxidative Stress and Apoptosis.

It has been reported that dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) exert therapeutic potential for the preservation of functional ß-cell mass. However, the effect of dietary n-3 PUFA deficiency on pancreatic injury and whether the supplementation of n-3 PUFA could prevent the development of pancreatic injury are still not clear. In the present study, an n-3 PUFA deficiency mouse model was established by feeding them with n-3 PUFA deficiency diets for 30 days. Results showed that n-3 PUFA deficiency aggravated streptozotocin (STZ)-induced pancreas injury by reducing the insulin level by 18.21% and the HOMA ß-cell indices by 31.13% and the area of islet by 52.58% compared with the STZ group. Moreover, pre-intervention with DHA and EPA for 15 days could alleviate STZ-induced pancreas damage by increasing the insulin level by 55.26% and 44.33%, the HOMA ß-cell indices by 118.81% and 157.26% and reversed the area of islet by 196.75% and 205.57% compared to the n-3 Def group, and the effects were significant compared to γ-linolenic acid (GLA) and alpha-linolenic acid (ALA) treatment. The possible underlying mechanisms indicated that EPA and DHA significantly reduced the ration of n-6 PUFA to n-3 PUFA and then inhibited oxidative stress, inflammation and islet ß-cell apoptosis levels in pancreas tissue. The results might provide insights into the prevention and alleviation of pancreas injury by dietary intervention with PUFAs and provide a theoretical basis for their application in functional foods.

Effects of dietary chenodeoxycholic acid supplementation in a low fishmeal diet on growth performance, lipid metabolism, autophagy and intestinal health of Pacific white shrimp, Litopenaeus vannamei.

An 8-week feeding trial was conducted to evaluate the effects of chenodeoxycholic acid (CDCA) on growth performance, body composition, lipid metabolism, and intestinal health of juvenile white shrimp, Litopenaeus vannamei fed a low fishmeal diet. Four practical diets were formulated: HFM (25% fishmeal), LFM (15% fishmeal), LB1 (LFM + 0.04% CDCA), LB2 (LFM + 0.08% CDCA). Each diet was assigned to four tanks with forty shrimp (initial weight 0.33 ± 0.03 g) per tank. The results indicated that the growth performance of shrimp were similar between the four groups; the crude lipid content of shrimp fed the LB2 diet was significantly lower than those fed the HFM diet (P < 0.05). The lipase activity content in hepatopancreatic were significantly higher in the two CDCA supplemented groups than that in LFM group; the contents of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol in hemolymph were significantly lower in LFM group, LB1 group and LB2 group than that in HFM group (P < 0.05). The shrimp fed LB1 diet was significantly decreased the intestinal expression levels of tube than those fed in HFM diet; the intestinal gene expression of imd and toll were significantly lower in LB2 group than those in HFM group (P < 0.05). The results of hepatopancreas gene expression suggest that shrimp fed the LFM diet showed significantly upregulated expression levels of sterol regulatory element-binding protein (srebp), acetyl-CoA carboxylase (acc), and carnitine palmitoyltransferase 1 (cpt-1) than those fed the HFM diet; shrimp fed the LB1 diet showed significantly upregulated expression levels of srebp, acc, and AMP-activated protein kinase (ampk) than those fed the HFM diet; shrimp fed the LB2 diet had higher expression levels of srebp, acc, and cpt-1 than those fed the HFM diet (P < 0.05). In the hepatopancreas, the shrimp fed the LFM diet shown significantly up-regulated the expression levels of beclin1 compared to those fed HFM diet; the expression levels of autophagy-related protein13 (atg3), autophagy-related protein 12 (atg12) of in shrimp fed the LB1 diet were significantly higher than those fed the HFM diet; and the expression levels of autophagy-related protein13 (atg13), beclin1, atg3, atg12, autophagy-related protein 9 (atg9) of shrimp fed LB2 diet were significantly higher than those fed the HFM diet (P < 0.05). The atg3 in intestine of shrimp fed the LB2 diet were significantly higher than those fed the HFM diet (P < 0.05). Intestinal mucous fold were damaged, hepatic tubules were disorganized and B cells appeared to be swollen in LFM group. The fold height and width of shrimp fed the diets supplemented with CDCA increased significantly than those fed the LFM diet (P < 0.05), the hepatic tubules were neatly arranged, and R cells increased. In conclusion, supplementary CDCA in a low fishmeal diet promoted lipid metabolism, enhanced autophagy of shrimp, also improved the health of the intestine and hepatopancreas.

Effect of gigantol on the proliferation of hepatocellular carcinoma cells tested by a network-based pharmacological approach and experiments.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common clinical malignant disease and the second leading cause of cancer-related death worldwide. Dendrobium is a commonly applied nourishing drug in traditional Chinese medicine. Gigantol is a phenolic compound extracted from Dendrobium. The compound has attracted attention for its anticancer effects. However, the mechanism of gigantol in HCC has not been extensively explored. METHODS: Potential targets of gigantol were predicted by SwissTargetPrediction. HCC-related genes were obtained from the GeneCards, Online Mendelian Inheritance in Man (OMIM), Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB), Therapeutic Target Database (TTD) and DrugBank databases. The "gigantol-target-disease" network was constructed using Cytoscape software. Protein interaction network analysis was performed using STRING software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were executed utilizing the R package to explore the possible regulatory mechanisms of gigantol in HCC. To authenticate the role of gigantol in HCC, Cell Counting Kit-8 (CCK-8) assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, wound healing assay, Matrigel invasion assay and Western blot were performed. RESULTS: Three core genes were screened from 32 closely linked genes. Pathway analysis yielded many signaling pathways associated with cancer. The CCK-8 assay and EdU assay indicated that gigantol suppressed the growth of HCC cells. The wound healing assay and Matrigel invasion assay showed the inhibition of migration and metastasis of HCC cells by gigantol. We verified from molecular docking and protein level that gigantol can exert regulatory effects through three targets, ESR1, XIAP and HSP90AA1. Furthermore, Western blot results tentatively revealed that gigantol may inhibit HCC progression through the HSP90/Akt/CDK1 pathway. CONCLUSIONS: Our results confirms anti-HCC proliferation activity of gigantol through PI3K pathway described in existing literature by different experimental approaches. Furthermore, it has discovered other proteins regulated by the drug that was not previously reported in the literature.These findings provide potential molecular and cellular evidence that gigantol may be a promising antitumor agent.

Analysis of Antidepressant Activity of Huang-Lian Jie-Du Decoction Through Network Pharmacology and Metabolomics.

Depressive disorder is a common mental disorder characterized by depressed mood and loss of interest or pleasure. As the Herbal medicines are mainly used as complementary and alternative therapy for depression. This study aimed at exploring antidepressant activity of Huang-lian Jie-du Decoction (HLJDD), and evaluating active components and potential depression-associated targets. HLJDD was administered on chronic unpredictable mild stress-induced (CUMS) depressive mice. Behavior evaluation was performed through force swimming test (FST), novelty-suppressed feeding test (NSF), and open field test (OFT). Active components of HLJDD, potential targets, and metabolic pathways involved in depression were explored through systemic biology-based network pharmacology assay, molecular docking and metabonomics. FST assay showed that CUMS mice administered with HLJDD had significantly shorter immobility time compared with control mice. Further, HLJDD alleviated feeding latency of CUMS mice in NSFand increased moving distance and duration in OFT. In the following network pharmacology assay, thirty-eight active compounds in HLJDD were identified based on drug-like characteristics, and pharmacokinetics and pharmacodynamics profiles. Moreover, forty-eight molecular targets and ten biochemical pathways were uncovered through molecular docking and metabonomics. GRIN2B, DRD, PRKCA, HTR, MAOA, SLC6A4, GRIN2A, and CACNA1A are implicated in inhibition of depressive symptoms through modulating tryptophan metabolism, serotonergic and dopaminergic synaptic activities, cAMP signaling pathway, and calcium signaling pathway. Further network pharmacology-based analysis showed a correlation between HLJDD and tryptophan metabolism. A total of thirty-seven active compounds, seventy-six targets, and sixteen biochemical pathways were involved in tryptophan metabolism. These findings show that HLJDD acts on potential targets such as SLC6A4, HTR, INS, MAO, CAT, and FoxO, PI3K/Akt, calcium, HIF-1, and mTOR signaling pathways, and modulates serotoninergic and dopaminergic synaptic functions. In addition, metabonomics showed that tryptophan metabolism is the primary target for HLJDD in CUMS mice. The findings of the study show that HLJDD exhibited antidepressant effects. SLC6A4 and MAOA in tryptophan metabolism were modulated by berberine, baicalein, tetrahydroberberine, candicine and may be the main antidepressant targets for HLJDD.

Paeoniflorin ameliorates schistosomiasis liver fibrosis through regulating IL-13 and its signalling molecules in mice.

Treatment of liver fibrosis associated with Schistosoma japonicum ova-induced granulomas remains a challenging proposition. Paeoniflorin (PAE, C23H28O11) has anti-inflammatory, anti-allergic, and immunoregulatory effects and it is commonly used in Chinese Herbal prescriptions to treat hepatic disorders. The present study was carried out to investigate the effects of PAE on hepatic fibrosis of mice infected with S. japonicum and to explore its possible mechanism. Upon pathological examination of PAE-treated mice, the size of egg granuloma, fibrosis scores, the concentration of IL-13 and hydroxyproline in liver were significantly reduced compared with the model mice. In the primary culture of hepatic stellate cells (HSCs), PAE inhibited IL-13-induced collagen synthesis. These results suggested that PAE might alleviate the hepatic granulomas and fibrosis caused by S. japonicum and the inhibitory effect of PAE on hepatic fibrosis might be associated with its ability to decrease the level of IL-13 and to interfere with the IL-13 signalling molecule in HSCs.

[Inhibitory effect of anluohuaxianwan on experimental hepatic fibrosis in rats].

OBJECTIVE: To investigate the effects of anluohuaqianwan on experimental hepatic fibrosis induced by dimethyl nitrosamine (DMN) in rats. METHODS: 36 male SD rats were randomly dividied into three groups: model group, normal group, anluohuaqianwan group. The rats in the three groups were treated with DMN daily for 4 weeks. The liver function was detected using auto biochemistry analyzer, the serum HA, LN, IV-C, PIIIP were detected by immunoradiometry, the histopathology was observed in the left liver lobe after HE staining, the expression of matrix metalloproteinase-2 (MMP-2) in liver tissue were detected by immunohistochemistry. RESULTS: The serum levels of ALT, AST, ALP, TP, ALB and the contents of HA, LN, IV-C in model group were significantly increased compared to these in the normal group (P less than 0.01). The serum levels of ALT, AST and the contents of HA in anluohuaqianwan group were significantly lower than those in the model group (P less than 0.01). The liver MMP-2 in the model group was significantly increased compared to that in the normal group (P less than 0.05). The expression of MMP-2 in liver tissue of model group was lower than that in the anluohuaqianwan group (P less than 0.05). CONCLUSION: Anluohuaqianwan can inhibit liver fibrosis in rats induced by DMN.

Paeoniflorin: a monomer from traditional Chinese medical herb ameliorates Schistosoma japonicum egg-induced hepatic fibrosis in mice.

Treatment of liver fibrosis associated with Schistosoma japonicum ova-induced granulomas remains a challenging proposition. There is a close relationship between high levels of interleukin-13 (IL-13) and the development of severe schistosome fibrosis. In contrast, IL-13 receptor (R) α2 has an effective role in attenuation of profibrosis. Several Chinese herbs have significant beneficial effects in liver disease. Accordingly, the purpose of the present study was to investigate the therapeutic effect of Paeoniflorin (PAE) on liver fibrosis. A mouse model for liver fibrosis was established, using infection with S. japonicum cercariae via the skin. Liver tissue was used to examine the effect of PAE on hydroxyproline, collagen I and III, and IL-13 and IL-13Rα2. The results showed that PAE has significant suppressive effect on the increase of both hepatic hydroxyproline and collagen I and III, which are the main components of extracellular matrix (ECM). Meanwhile, PAE not only inhibits IL-13 production, it also elevates IL-13Rα2 in PAE-pretreated groups compared with controls. These results suggested that PAE can improve liver fibrosis due to S. japonicum infection. The effect of PAE appears to depend on a decrease of IL-13 and an increase of IL-13Rα2.