Golgi Protein 73 Promotes LPS-Induced Cardiac Dysfunction via Mediating Myocardial Apoptosis and Autophagy.

ABSTRACT: Sepsis-induced cardiac dysfunction represents a major cause of high mortality in intensive care units with limited therapeutic options. Golgi protein 73 (GP73) has been implicated in various diseases. However, the role of GP73 in lipopolysaccharide (LPS)-induced cardiac dysfunction is unclear. In this study, we established a sepsis-induced cardiac dysfunction model by LPS administration in wild-type and GP73 knockout ( GP73-/- ) mice. We found that GP73 was increased in LPS-treated mouse hearts and LPS-cultured neonatal rat cardiomyocytes (NRCMs). Knockout of GP73 alleviated myocardial injury and improved cardiac dysfunction. Moreover, depletion of GP73 in NRCMs relieved LPS-induced cardiomyocyte apoptosis and activated myocardial autophagy. Therefore, GP73 is a negative regulator in LPS-induced cardiac dysfunction by promoting cardiomyocyte apoptosis and inhibiting cardiomyocyte autophagy.

Association between viral infection other than human papillomavirus and risk of esophageal carcinoma: a comprehensive meta-analysis of epidemiological studies.

BACKGROUND: Infection with viruses such as human papillomavirus (HPV) is known to induce carcinomas, including esophageal carcinoma (EC). However, the possible role of viruses other than HPV in EC carcinogenesis is unclear in many studies. Here, we aimed to explore the association between infection with viruses other than HPV and EC risk by integrating existing studies of epidemiology in a meta-analysis. METHODS: The PubMed, Web of Science, Cochrane Library and China National Knowledge Infrastructure databases were searched. The Newcastle-Ottawa scale was used to assess the quality of the included studies. Odds ratios (ORs) or relative risks (RRs) (with 95% confidence intervals [CIs]) were pooled to estimate the association between virus infection and risk of EC. RESULTS: We included 31 eligible studies involving nine different viruses. Overall, an increased risk of EC was associated with hepatitis B virus (HBV) infection (OR = 1.19, 95%CI 1.01-1.36) and hepatitis C virus (HCV) infection (OR = 1.77, 95%CI 1.17-2.36), but not human immunodeficiency virus (HIV) infection, according to the current evidence. The evidence for an association with Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), JC virus (JCV), cytomegalovirus (CMV), human T-lymphotropic virus 1 (HTLV-1) or Merkel cell polyomavirus (MCPyV) infection was insufficient. CONCLUSIONS: We confirmed the relationship between HBV and HCV infection and the risk of EC, but we found no association of EC risk with HIV and EBV infection. The roles of HSV-1, JCV, CMV, HTLV-1, and MCPyV were not clear because of the limited number of studies.

Polo-like kinase 1 promotes sepsis-induced myocardial dysfunction.

Sepsis-induced myocardial dysfunction (SIMD) is the main cause of mortality in sepsis. In this study, we identified Polo-like kinase 1 (Plk-1) is a promoter of SIMD. Plk-1 expression was increased in lipopolysaccharide (LPS)-treated mouse hearts and neonatal rat cardiomyocytes (NRCMs). Inhibition of Plk-1 either by heterozygous deletion of Plk-1 or Plk-1 inhibitor BI 6727 alleviated LPS-induced myocardial injury, inflammation, cardiac dysfunction, and thereby improved the survival of LPS-treated mice. Plk-1 was identified as a kinase of inhibitor of kappa B kinase alpha (IKKα). Plk-1 inhibition impeded NF-κB signal pathway activation in LPS-treated mouse hearts and NRCMs. Augmented Plk-1 is thus essential for the development of SIMD and is a druggable target for SIMD.

Combination of curcumin with N-n-butyl haloperidol iodide inhibits hepatocellular carcinoma malignant proliferation by downregulating enhancer of zeste homolog 2 (EZH2) - lncRNA H19 to silence Wnt/ß-catenin signaling.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cause of cancer-related death worldwide. Curcumin (C) has been extensively investigated in different types of malignancies, including hepatocellular carcinoma, but its physicochemical properties have significantly influenced its clinical use. Several approaches are being explored to enhance curcumin's therapeutic response, including its combination with various drugs. PURPOSE: This study aimed to evaluate the anti-tumor effect of curcumin (C) in combination with F2 (N-n-butyl haloperidol iodide) on hepatocellular carcinoma and its potential underlying mechanism in vitro and in vivo. METHODS: Cell proliferation was evaluated by CCK-8 and colony formation assays, and apoptosis was measured by flow cytometry. The migratory and invasive abilities of Hep3B and SMMC-7721 cells were measured by wound-healing and matrigel transwell assays. In order to investigate the molecular pathways, various experiments such as western blotting, qPCR, RNA-seq, immunostaining and transfection were performed. To evaluate the anti-HCC effects in vivo, a xenograft tumor model was used. RESULTS: Our findings showed that the combination of curcumin (C) & F2 (F2C) strongly inhibited malignant proliferation and migration in SMMC-7721 and Hep3B cells. The F2C treatment downregulates enhancer of zeste homolog 2 (EZH2) transcription and protein expression, which is key epigenetic regulator responsible for HCC development. Moreover, the inhibition of EZH2 by F2C led to Wnt/ß-catenin signaling inhibition by decreasing tri-methylation of histone H3 at lysine 27 (H3K27me3) and long non-coding RNA H19 expression. The inhibition of F2C was associated with the suppression of tumorigenicity in xenograft HCC models. CONCLUSION: These findings suggested that, F2C inhibited HCC formation, migration and its modulatory mechanism seemed to be associated with downregulation of EZH2, silencing Wnt/ß-catenin signaling by interacting with H19, suggesting that F2C may be a promising drug in the clinical treatment of HCC.

PXR: a center of transcriptional regulation in cancer.

Pregnane X receptor (PXR, NR1I2) is a prototypical member of the nuclear receptor superfamily. PXR can be activated by both endobiotics and xenobiotics. As a key xenobiotic receptor, the cellular function of PXR is mostly exerted by its binding to the regulatory gene sequences in a ligand-dependent manner. Classical downstream target genes of PXR participate in xenobiotic responses, such as detoxification, metabolism and inflammation. Emerging evidence also implicates PXR signaling in the processes of apoptosis, cell cycle arrest, proliferation, angiogenesis and oxidative stress, which are closely related to cancer. Here, we discussed, in addition to the characterization of PXR per se, the biological function and regulatory mechanism of PXR signaling in cancer, and its potential for the targeted prevention and therapeutics.

Intrinsic tannins affect ensiling characteristics and proteolysis of Neolamarckia cadamba leaf silage by largely altering bacterial community.

The mechanism that tannins alter microbial community to inhibit proteolysis and enhance silage quality is unclear. Neolamarckia cadamba leaf (NCL; rich in tannins) were ensiled alone or with addition of polyethylene glycol (PEG, tannins inactivator), and then fermentation quality, proteolysis activity and bacterial community were investigated during ensiling (Day 3, 7, 14 and 30). As a result, PEG addition increased lactic acid (1.09% vs 2.03%, on dry matter basis) and nonprotein-N (13.65% vs 17.59%, on crude protein basis) contents but decreased ammonia-N content (9.21% vs 2.29%, on crude protein basis) in NCL silage. Meanwhile, the dominant microbiome shifted from Cyanobacteria (60.92%-81.50%) to Firmicutes (48.96%-88.67%), where the unclassified genus (80.95%-85.71%) was substituted by Leuconstoc (42.03%-55.55%) and subsequently Lactobacillus (65.98%-82.43%). This study suggests that the intrinsic tannins inhibit lactic acid fermentation and protein degradation in NCL silage.

Improving the quality of rice straw silage with Moringa oleifera leaves and propionic acid: Fermentation, nutrition, aerobic stability and microbial communities.

Mixed ensiling is believed an effective way to improve nutrient preservation and utilization. The effect of mixing Moringa oleifera leaves (MOL) on silage quality, aerobic stability and microbial communities of rice straw ensiled with/without propionic acid were investigated after 140 days fermentation. The results showed that mixing MOL decreased the pH (4.69 vs 3.85), butyric acid (17.4 g/kg DM vs not detected), ammonia-N (3.36 vs 2.17 g/kg DM) and fiber contents (626 vs 462 g/kg DM) but increased protein content (88.4 vs 125 g/kg DM) of rice straw silages. It also increased the relative abundance of Lactobacillus (12.96% vs 50.82%) at unsealing and Issatchenkia (2.02% vs 36.03%) after exposure to air, and might improve aerobic stability of silages. The addition of propionic acid could inhibit deaminization activity during ensiling and exposure to air. It is suggested mixing MOL could improve the fermentation quality and nutrition of rice straw silage.

Ensiling characteristics, proteolysis and bacterial community of high-moisture corn stalk and stylo silage prepared with Bauhinia variegate flower.

Bauhinia variegate flower (BVF) was supposed to improve silage fermentation due to its abundant active components. Thus, corn stalk and stylo were ensiled with addition of 0, 5% or 10% BVF, and then ensiling characteristics, protein fraction and bacterial community were analyzed after 60-day fermentation. The contents of butyric acid (2.9 vs not detected, 13.2 vs 3.0 g/kg DM in corn stalk and stylo silage, respectively), ammonia-N (100.2 vs 83.2, 110.8 vs 61.9 g/kg total N) and free amino acid (35.6 vs 16.5, 35.0 vs 16.4 g/kg total N) were decreased in 10% BVF treated silages. The bacterial diversity was increased, where the relative abundance of Enterobacter or Clostridium decreased and that of lactic acid producing bacteria such as Lactobacillus, Weissella or Enterococcus increased. It is suggested that BVF could be used to improve fermentation quality and nutrient preservation of high-moisture corn stalk and stylo silage.

Effects of citric acid on fermentation characteristics and bacterial diversity of Amomum villosum silage.

To study the effects of citric acid on fermentation process of Amomum villosum silage, A. villosum was ensiled without or with 1%, 2% citric acid and fermentation parameters and bacterial diversity were analyzed after 3, 7, 14, 30 days ensiling, respectively. Citric acid treated silages had lower dry matter loss (1.83% vs 2.23%), pH (3.84 vs 6.02), ammonia-N (0.33 vs 1.79 g/kg DM) and coliform bacteria number (<2.00 vs 7.27 log10 CFU/g FM) than the control after 30 days ensiling. The relative abundance of lactic acid bacteria, Pediococcus and Lactobacillus increased, whereas undesirable microorganisms like Enterobacter, Escherichia-Shigella and Pantoea decreased in citric acid treated A. villosum silage. These results indicated that quality A. villosum silage could be obtained by citric acid addition.

The nutrients in Moringa oleifera leaf contribute to the improvement of stylo and alfalfa silage: Fermentation, nutrition and bacterial community.

Moringa oleifera leaf (MOL) has been proved to improve silage fermentation but the exact reason is unclear yet. Fermentation quality, protein preservation, antioxidant activity and bacterial community of stylo and alfalfa ensiled with 5%, 10% dry MOL, stylo or alfalfa were investigated. The present results showed that mixing MOL led to the decrease of pH (5.15 vs 4.76, 5.71 vs 4.57 for stylo and alfalfa, respectively), butyric acid (15.1, 28.3 g/kg DM vs not detected), ammonia-N (111 vs 50.7, 351 vs 100 g/kg total N) contents, and the increase of lactic acid content (8.70 vs 13.0, 0.23 vs 14.0 g/kg DM) and antioxidant activity relative to the control. The relative abundance of Clostridium was lowered (55.4% to 1.69%, 8.34% to 0.57%), whereas Lactobacillus was increased (14.9% to 63.2%, 11.7% to 23.5%). In conclusion, nutrients in MOL help to improve protein preservation and nutritional value of high-moisture stylo and alfalfa silage.

Fermentation quality and microbial community of alfalfa and stylo silage mixed with Moringa oleifera leaves.

The silage quality of alfalfa and stylo without or with 25%, 50% Moringa oleifera leaves (MOL) was investigated, and microbial community after ensiling was analysed. Results showed that the silage samples with MOL have lower butyric acid (0.50 vs 1.20, 0.60 vs 14.5 g/kg dry matter (DM) in alfalfa and stylo silage, respectively), ammonia-N (152 vs 262, 109 vs 180 g/kg total N) content and DM loss (7.71% vs 14.6%, 6.49% vs 18.9%). The addition of MOL also influenced the bacterial community distribution. The relative abundance of Enterobacter decreased from 58.6% to 30.5%, 17.4% to 9.1% in alfalfa and stylo silage when 50% MOL was added. Clostridium decreased from 23.5% to 0.2% in stylo silage, whereas Lactobacillus abundance increased from 30.4% to 49.9%, 41.8% to 86.0% in alfalfa and stylo silage, respectively. In conclusion, mixing with MOL could be a feasible way to improve the quality of alfalfa and stylo silage.

Effects of mixing Neolamarckia cadamba leaves on fermentation quality, microbial community of high moisture alfalfa and stylo silage.

Neolamarckia cadamba is not only a fodder of high nutritional value, but also a source of natural antimicrobial agent. The silage quality of high moisture alfalfa and stylo with or without N. cadamba leaves (NCL) was investigated, and microbial community after ensiling was analysed. Results showed that the silage samples with NCL have lower pH (4.32 versus 4.88, 4.26 versus 4.71 in alfalfa and stylo silage, respectively), ammonia-N content (67.5 versus 146, 42.2 versus 95.1 g kg-1 total N) and higher lactic acid (13.3 versus 10.4, 17.3 versus 13.6 g kg-1 dry matter), true protein N (592 versus 287, 815 versus 589 g kg-1 total N). The addition of NCL also influenced the bacterial community distribution. The relative abundance of Clostridium and Enterobacter decreased, whereas Lactobacillus abundance increased when NCL was added. In conclusion, NCL could inhibit undesirable microorganisms in high moisture alfalfa and stylo silage. Mixing with NCL could be a feasible way to improve the quality of silage.

Bacterial diversity and fermentation quality of Moringa oleifera leaves silage prepared with lactic acid bacteria inoculants and stored at different temperatures.

Four lactic acid bacteria strains (LP, LF, LL, W), isolated and selected from Moringa oleifera leaves (MOL) silage, were identified as Lactobacillus plantarum, L. farciminis, Lactococcus lactis, Weissella thailandensis, respectively. Fermentation quality and bacterial community of MOL ensiled without or with the four strains at 15 °C and 30 °C were investigated. Results showed that all the LAB strains decreased (P < 0.05) the pH and ammonia-N content of MOL silage. Silage stored at 30 °C showed higher (P < 0.05) DM loss, acetic acid and ammonia-N content, and lower LAB count than 15 °C. The environmental temperature also made a great influence on bacterial community of MOL silage. Bacterial diversity was lower and the abundance of Lactobacillus was higher in silages stored at 15 °C. In conclusion, LAB inoculants and a relatively low environmental temperature could be effective to improve the quality of MOL silage.

Dynamics of Bacterial Community and Fermentation Quality during Ensiling of Wilted and Unwilted Moringa oleifera Leaf Silage with or without Lactic Acid Bacterial Inoculants.

To investigate the effects of wilting and lactic acid bacterial inoculants on the fermentation quality and bacterial community of Moringa oleifera leaf silage, fresh and wilted M. oleifera leaves were ensiled with or without Lactobacillus farciminis LF or Lactococcus lactis LL for 1, 7, 14, 30, and 60 days. The results showed that wilting, inoculants, and their interaction exerted significant (P < 0.05) effects on the fermentation characteristics covering dry matter loss, pH value, lactic acid bacterial number, the ratio of lactic acid to acetic acid, and the relative abundances of bacteria, like for species of Lactobacillus, Lactococcus, Pediococcus, Enterococcus, Leuconostoc, and Enterobacter Both LF and LL improved the fermentation quality of wilted and unwilted M. oleifera leaf silage by accelerating lactic acid production and pH decline, decreasing dry matter loss, and inhibiting yeast and coliform bacterial growth through the whole fermentation process. During ensiling, the abundances of Lactococcus, Enterococcus, and Leuconostoc spp. increased from day 1 to day 7 and then declined sharply from day 7 to day 14. Members of these genera and Enterobacter were inhibited, whereas Lactobacillus spp. were enhanced by these two lactic acid bacterial inoculants. The relative abundances of Enterobacter, Enterococcus, and Pediococcus spp. in inoculated silages were relatively low during the whole ensiling process. A lower abundance of Enterobacter spp. was observed in wilted silages than in unwilted silages. In summary, wilting and lactic acid bacterial inoculants had an influence on bacterial community and the fermentation process; LF and LL improved the fermentation quality of wilted and unwilted M. oleifera leaf silage.IMPORTANCEMoringa oleifera leaf is a high-quality feed source for livestock and is increasingly used all over the world. Ensiling might be an effective method for preservation of the leaves. In the practice of silage making, lactic acid bacterial inoculants and wilting are commonly used to improve nutrition preservation. Monitoring the changes in a bacterial community during fermentation gives an insight into understanding and improving the ensiling process. Our results suggest that wilting and lactic acid bacterial inoculants had an influence on the bacterial community and fermentation process of M. oleifera leaf silage. Wilting showed positive effects on silage fermentation by decreasing the abundance of Enterobacter spp., while LF and LL improved the fermentation quality by inhibiting Enterobacter spp. and enhancing Lactobacillus spp. Both LF and LL accelerated the ensiling process from cocci (like Lactococcus, Enterococcus, and Leuconostoc spp.) to lactobacilli.

Dynamics of proteolysis, protease activity and bacterial community of Neolamarckia cadamba leaves silage and the effects of formic acid and Lactobacillus farciminis.

To investigate the reason for well preservation of protein in Neolamarckia cadamba leaves (NCL) during ensiling, fresh NCL were ensiled with or without addition of 2.0 mL/kg formic acid (FA) or 1.0 × 109CFU/kg Lactobacillus farciminis (LF), and the dynamics of protease activity and microbial community were analyzed. Nonprotein-N, free amino acid, ammonia-N, the activities of carboxypeptidase and aminopeptidase, and bacterial diversity were low during NCL ensiling. Exiguobacterium dominated in NCL silage and its relative abundance increased while Enterobacter abundance decreased during ensiling. FA lowered (P < 0.05) pH and coliform bacteria number, while LF increased (P < 0.05) lactic acid bacteria number, lactic acid content and Lactobacillus abundance at the early stage of fermentation. In summary, protein in NCL can be well preserved during ensiling likely due to its low protease and bacterial activity, and FA and LF improve the quality of NCL silage in different ways.

The regulation of FOXO1 and its role in disease progression.

Cell proliferation, apoptosis, autophagy, oxidative stress and metabolic dysregulation are the basis of many diseases. Forkhead box transcription factor O1 (FOXO1) changes in response to cellular stimulation and maintains tissue homeostasis during the above-mentioned physiological and pathological processes. Substantial evidences indicate that FOXO1's function depends on the modulation of downstream targets such as apoptosis- and autophagy-associated genes, anti-oxidative stress enzymes, cell cycle arrest genes, and metabolic and immune regulators. In addition, oxidative stress, high glucose and other stimulations induce the regulation of FOXO1 activity via PI3k-Akt, JNK, CBP, Sirtuins, ubiquitin E3 ligases, etc., which mediate multiple signalling pathways. Subsequent post-transcriptional modifications, including phosphorylation, ubiquitination, acetylation, deacetylation, arginine methylation and O-GlcNAcylation, activate or inhibit FOXO1. The regulation of FOXO1 and its role might provide a significant avenue for the prevention and treatment of diseases. However, the subtle mechanisms of the post-transcriptional modifications and the effect of FOXO1 remain elusive and even conflicting in the development of many diseases. The determination of these questions potentially has implications for further research regarding FOXO1 signalling and the identification of targeted drugs.