Research Progress in Anti-Inflammatory Bioactive Substances Derived from Marine Microorganisms, Sponges, Algae, and Corals.

Inflammation is the body's defense reaction in response to stimulations and is the basis of various physiological and pathological processes. However, chronic inflammation is undesirable and closely related to the occurrence and development of diseases. The ocean gives birth to unique and diverse bioactive substances, which have gained special attention and been a focus for anti-inflammatory drug development. So far, numerous promising bioactive substances have been obtained from various marine organisms such as marine bacteria and fungi, sponges, algae, and coral. This review covers 71 bioactive substances described during 2015-2020, including the structures (65 of which), species sources, evaluation models and anti-inflammatory activities of these substances. This review aims to provide some reference for the research progress of marine-organism-derived anti-inflammatory metabolites and give more research impetus for their conversion to novel anti-inflammatory drugs.

Effects of dietary raw or Enterococcus faecium fermented soybean meal on growth, antioxidant status, intestinal microbiota, morphology, and inflammatory responses in turbot (Scophthalmus maximus L.).

Fermentation has been reported to improve the utilization of plant ingredients including soybean meal (SBM) by fish, but the detailed mechanism is still poorly understood. This study compared the effects of partial replacement of fish meal (FM) protein with SBM or Enterococcus faecium fermented SBM (EFSM) on the growth, antioxidant status, intestinal microbiota, morphology, and inflammatory responses in turbot (Scophthalmus maximus L.). The FM-based diet was used as the control (CONT). Two experimental diets were formulated in which 45% of the FM protein was replaced with SBM or EFSM. Each diet was fed to triplicate groups of fish (7.57 ± 0.01 g) twice daily for 79 d. Inferior growth performance was observed in SBM group, however, no significant depression was observed in EFSM group compared to the CONT group. The CONT group had the highest values of lysozyme, complement component 3, total antioxidant capacity, superoxide dismutase and catalase, followed by the EFSM group, and the lowest in SBM group. The malondialdehyde content was lowest in the CONT group, followed by the EFSM group, and was highest in the SBM group. Gut morphology showed that SBM diet induced alterations typical for intestinal inflammation including decreased villus and microvillus height, and increased width and inflammatory cell infiltration of the lamina propria. However, the EFSM group alleviated such SBM-induced intestinal pathological disruption. Paralleled with the morphological symptoms, the inflammatory gene expression levels of tumor necrosis factor alpha, interleukin-1 beta and interleukin-8 were highest in the SBM group, followed by the EFSM group, and were lowest in the CONT group. Furthermore, the intestinal microbiota analysis revealed that EFSM group had an overall more similar microbiota with CONT group than SBM group. Specifically, compared with the SBM group, EFSM group significantly enhanced the probiotics Lactobacillus and anti-inflammatory bacterium Faecalibaculum, and inhibited the Vibrio. Collectively, this study indicated that Enterococcus faecium fermentation effectively counteracted the negative effects of SBM by enhancing antioxidant capacity, suppressing inflammatory responses, and modulating gut microbiota in turbot.

Administration of commensal Shewanella sp. MR-7 ameliorates lipopolysaccharide-induced intestine dysfunction in turbot (Scophthalmus maximus L.).

This study was designed to evaluate whether the administration of commensal Shewanella sp. MR-7 (MR-7) could ameliorate lipopolysaccharide (LPS)-induced intestine dysfunction in turbot. Fish (body weight: 70.00 ± 2.00 g) were randomly divided into three groups including the control group treated with dough, the LPS group treated with dough plus LPS, and the LPS+MR-7 (LMR) group treated with dough plus LPS and MR-7. These three groups with 24 fish each were force-fed with 1 g dough daily for 7 continuous days. The results revealed that MR-7 administration ameliorated LPS-induced intestinal injury, showing higher intestinal villus and microvillus height. Further results showed that MR-7 could inhibit LPS-induced activation of TLR-NF-κB signaling thus maintaining the normal expression levels of cytokines and finally ameliorate the intestinal inflammatory response in turbot. Compared with the LPS group, LMR group had less goblet cells and lower mucin-2 expression level. Moreover, MR-7 restored LPS-induced down-regulation of tight junction protein-related gene expression (zonula occluden-1, occludin, tricellulin and claudin-3). Further investigations indicated that MR-7 partially counteracted LPS-induced changes in gut microbiota composition, enhanced the beneficial bacteria Lactobacillus and reduced the Pseudomonas, thus maintaining the overall microbiota balance. Taken together, the administration of MR-7 could effectively restore LPS-induced intestine function disorder in turbot by ameliorating inflammatory response, mucosal barrier dysfunction and microbiota dysbiosis.

Improved utilization of soybean meal through fermentation with commensal Shewanella sp. MR-7 in turbot (Scophthalmus maximus L.).

BACKGROUND: Increased inclusion of plant proteins in aquafeeds has become a common practice due to the high cost and limited supply of fish meal but generally leads to inferior growth performance and health problems of fish. Effective method is needed to improve the plant proteins utilization and eliminate their negative effects on fish. This study took a unique approach to improve the utilization of soybean meal (SBM) by fish through autochthonous plant-degrading microbe isolation and subsequent fermentation. RESULTS: A strain of Shewanella sp. MR-7 was isolated and identified as the leading microbe that could utilize SBM in the intestine of turbot. It was further optimized for SBM fermentation and able to improve the protein availability and degrade multiple anti-nutritional factors of SBM. The fishmeal was able to be replaced up to 45% by Shewanella sp. MR-7 fermented SBM compared to only up to 30% by SBM in experimental diets without adverse effects on growth and feed utilization of turbot after feeding trials. Further analyses showed that Shewanella sp. MR-7 fermentation significantly counteracted the SBM-induced adverse effects by increasing digestive enzymes activities, suppressing inflammatory responses, and alleviating microbiota dysbiosis in the intestine of turbot. CONCLUSIONS: This study demonstrated that plant protein utilization by fish could be significantly improved through pre-digestion with isolated plant-degrading host microbes. Further exploitation of autochthonous bacterial activities should be valuable for better performances of plant-based diets in aquaculture.

Beneficial influences of dietary Aspergillus awamori fermented soybean meal on oxidative homoeostasis and inflammatory response in turbot (Scophthalmus maximus L.).

High levels of soybean meal (SBM) in aquafeed leads to detrimental inflammatory response and oxidative stress in fish. In the present study, fermentation with Aspergillus awamori was conducted to explore the potential effects on improving the nutritional quality of soybean meal and the health status of turbot. A 63-day feeding trial (initial weight 8.53 ±â€¯0.11 g) was carried out to evaluate the utilization of fermented soybean meal (FSM) by juvenile turbot. 0% (FM, control), 30% (S30, F30), 45% (S45, F45), and 60% (S60, F60) of fish meal were replaced with SBM or FSM, respectively. As the results showed, fermentation significantly reduced the contents of anti-nutritional factors in SBM, including raffinose (-98.8%), glycinin (-98.5%), ß-conglycinin (-97.4%), trypsin inhibitors (-80%) and stachyose (-80%). A depression of fish growth performance and activities of superoxide dismutase and lysozyme were observed in S45 and S60 groups, while these inferiorities were only observed in F60 group. Meanwhile, fermentation also improved the heights of enterocytes and microvillus significantly in the F45 and F60 groups compared with those in SBM. An induced expression of anti-inflammatory cytokine transforming growth factor-ß and depression of pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1ß in the distal intestine were observed in the F45 and F60 groups. Taken together, this study indicated that fermentation with Aspergillus awamori could improve the replacement level with soybean meal from 30% to 45% in turbot.

TCF7L1 indicates prognosis and promotes proliferation through activation of Keap1/NRF2 in gastric cancer.

Gastric cancer is one of the most common cancers worldwide and is the third leading cause of cancer-related deaths globally. Although significant progress has been made in the diagnosis and treatment for the cancer, less improvement has been made in overall survival rate. Thus, there is an urgent need for a better understanding of the biological aspects of the cancer. The transcription factor transcription factor 7-like 1 (TCF7L1) is an embryonic stem cell signature gene that is upregulated in multiple aggressive cancer types, but its role in gastric cancer has seldom been discussed. In the present study, by using the Cancer Genome Atlas dataset analysis, we demonstrated that patients with higher expression of TCF7L1 could be used to reflect prognosis. An examination of the mechanisms demonstrated that TCF7L1 could positively regulate antioxidant response in gastric cancer cells by positively regulating Keap1/NRF2 [Kelch-like ECH-associated protein 1/nuclear factor (erythroid-derived 2)-like 2] pathway. Collectively, our data demonstrated that TCF7L1 is a novel marker for predicting overall survival of gastric cancer and provided the possible underlying molecular mechanism.

Low expression of ERK signaling pathway affecting proliferation, cell cycle arrest and apoptosis of human gastric HGC-27 cells line.

This study was carried out for the first time to examine the potential role and the underlying mechanisms of Lycopene in the gastric cancer HGC-27 cells. HGC-27 cells were seeded onto heat-sterilized coverslips in six-well plates and exposed to Lycopene (5, 10, 20, 30 and 40 µmol/L) for periods of 72 h at 37 °C. Results showed that Lycopene (5, 10, 20, 30 and 40 µmol/L) dose-dependently increased NBT positive rate and decreased lactate dehydrogenase activity in HGC-27 cells. In addition, Lycopene (5, 10, 20, 30 and 40 µmol/L) inhibited proliferation and induced G0-G1 phase cell cycle arrest in HGC-27 cells. Western blot and FQRT-PCR analysis showed that Lycopene decreased pERK and extracellular signal-regulated kinase (ERK) protein and mRNA expression in a dose-dependent manner. These findings demonstrate that Lycopene inhibited gastric cancer HGC-27 cells growth and stimulated its apoptosis via the suppressing ERK signaling pathway.

Dietary gamma-aminobutyric acid ameliorates growth impairment and intestinal dysfunction in turbot (Scophthalmus maximus L.) fed a high soybean meal diet.

Over-substitution of fishmeal with soybean meal (SBM) commonly induces inferior growth and intestinal dysfunction in fish. This study aims to evaluate whether dietary gamma-aminobutyric acid (GABA) could ameliorate the adverse effects in turbot fed a high-SBM diet (HSD). Two hundred and seventy turbots were randomly divided into three treatment groups including turbots fed on a control diet (CNT, containing 60% fishmeal), an HSD (with 45% fishmeal protein replaced by SBM), and an HSD supplemented with GABA (160 mg kg-1) for 53 days. The growth and feed utilization parameters were calculated and the intestinal antioxidant status, inflammation, apoptosis, and microbiota were evaluated using assay kits, histological analysis, qRT-PCR, high throughput sequencing, and bioinformatics analysis. The results showed that GABA ameliorated HSD-induced growth impairment and enhanced feed intake of turbot. GABA ameliorated HSD-induced intestinal oxidative stress and apoptosis by restoring the MDA content, CAT and T-AOC activities, and apoptosis-related gene (Bcl-2, Bax, Bid, and Caspase-3) expressions to similar levels to those in the CNT group. GABA also alleviated HSD-induced intestinal inflammation through down-regulating the expressions of TNF-α, IL-1ß, and NF-κB p65 and up-regulating the expression of TGF-ß1. Furthermore, GABA reversed HSD-induced microbiota dysbiosis through regulating the overall bacterial richness and dominative bacterial population. Spearman's correlation analysis indicated that the altered microbiota was closely associated with growth and intestinal function. Collectively, GABA could ameliorate HSD-induced intestinal dysfunction via relieving oxidative stress, inflammation, apoptosis and microbiota dysbiosis, and these findings would contribute to a better understanding of the function of GABA in the fish intestine.

AAED1 modulates proliferation and glycolysis in gastric cancer.

Gastric cancer is one of the most common and lethal malignancies globally, especially in East Asia. Although significant progress has been made in the diagnosis and treatment of the disease, the overall survival rate remains unchanged at 20­25%. Thus, there is an urgent need for a better understanding of the disease. Recent years have witnessed the critical roles of aberrant cancer cell metabolism in the maintenance of malignant properties of cancer cells, and targeting cancer cell metabolism has been regarded as a novel aspect in the development of treatments against cancer. In the present study, we identified a novel gene, AAED1 (AhpC/TSA antioxidant enzyme domain containing 1), which is upregulated in gastric cancer cells. By using lentivirus mediated transfection method, we silenced AAED1 expression and silencing of AAED1 inhibited cancer cell proliferation in vitro in gastric cancer cell lines, as demonstrated by cell viability and colony formation assay. Furthermore, we uncovered novel functions of AAED1 in regulating hypoxia inducible factor 1α (HIF1α) and the resultant aerobic glycolysis, which was measured by extracellular flux analysis. Collectively, the results of the present study uncovered novel markers that could identify the possible molecular mechanisms involved in gastric cancer.

Swing mesh versus Modified Kugel mesh for primary inguinal hernia repair. A prospective randomized clinical trial.

PURPOSE: To evaluate the safety and efficacy of a new mesh in the pre-peritoneal repair of inguinal hernia. METHODS: We randomly divided 120 patients undergoing pre-peritoneal repair into 2 groups between March 2012 and December 2013. The patients were randomized to receive the Swing mesh (n=60; study group) or the Modified Kugel mesh (n=60; control group). The primary end point of this study was to compare postoperative groin pain of the two groups. Complications, recurrence and analgesic use were also recorded. RESULTS: There were no recurrent cases in either group throughout the study period. There was no significant difference between the groups with respect to postoperative complications. The VAS of early postoperative pain was 1.32±1.69 in study group and 1.52±1.93 in control group, with the difference being not statistically significant (p = 0.547). Concerning chronic pain, no remarkable statistically significant difference was observed between the two groups at 3-month, 6-month, 12- and 18-month follow-up period. CONCLUSION: Swing mesh can be safely and effectively used in inguinal hernia repair with the same advantage compared to the Modified Kugel mesh.

Bortezomib inhibits gastric carcinoma HGC-27 cells through the phospho-Jun N-terminal kinase (p-JNK) pathway in vitro.

The study is designed to explore the anticancer mechanism of Bortezomib. The effects of Bortezomib on the proliferation of human gastric cancer cells HGC-27 and expression levels of the phospho-Jun N-terminal kinase (p-JNK) pathway-related proteins in vitro were investigated. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that the Bortezomib significantly decreased the viability of HGC-27 cells and induced apoptosis. Western blot showed that the Bortezomib strongly increased the levels of p-JNK, caspase-3, PARP, and bax proteins while it increased the level of bcl-2. However, SP600125 can significantly decrease antitumour effects of Bortezomib in HGC-27 cells. It can be concluded that Bortezomib has significant inhibitory effects on the growth of HGC-27 cells. The effect may be achieved partly via upregulating JNK pathway and its down-stream apoptosis-related proteins. Therefore, Bortezomib may be beneficial in gastric carcinoma treatment.

Swing mesh versus Modified Kugel mesh for primary inguinal hernia repair. A prospective randomized clinical trial

ABSTRACT PURPOSE To evaluate the safety and efficacy of a new mesh in the pre-peritoneal repair of inguinal hernia. METHODS We randomly divided 120 patients undergoing pre-peritoneal repair into 2 groups between March 2012 and December 2013. The patients were randomized to receive the Swing mesh (n=60; study group) or the Modified Kugel mesh (n=60; control group). The primary end point of this study was to compare postoperative groin pain of the two groups. Complications, recurrence and analgesic use were also recorded. RESULTS There were no recurrent cases in either group throughout the study period. There was no significant difference between the groups with respect to postoperative complications. The VAS of early postoperative pain was 1.32±1.69 in study group and 1.52±1.93 in control group, with the difference being not statistically significant (p = 0.547). Concerning chronic pain, no remarkable statistically significant difference was observed between the two groups at 3-month, 6-month, 12- and 18-month follow-up period. CONCLUSION Swing mesh can be safely and effectively used in inguinal hernia repair with the same advantage compared to the Modified Kugel mesh.

New insights into sexual dimorphism during progression of heart failure and rhythm disorders.

Neurohormonal imbalance is a key determinant of the progression of heart failure (HF), which results in an elevated risk of mortality. A better understanding of mechanisms involved may influence treatment strategies. The incidence and prevalence of HF are lower in women. We explored sexual dimorphism in the progression of HF using a mice model of neurohormonal-dependent HF. Male and female mice overexpressing the human beta2-adrenergic receptor (TG4 strain) develop HF. We compared TG4 animals with age-matched wild-type controls. Cardiac function was studied in vivo by echocardiography and electrocardiography. Histological studies were performed. Conduction parameters were assessed by intracardiac electrophysiological exploration, as was the occurrence of spontaneous and inducible arrhythmias. The patch-clamp technique was used to determine the cellular electrophysiological profile. The role of hormonal status in HF progression was investigated by surgical gonadectomy. High mortality rate was observed in TG4 mice with a dramatic difference between males and females. Male TG4 mice exhibited intraventricular conduction abnormalities, as measured by infrahisian interval and QRS durations potentially determining reentrant circuits and increasing susceptibility to arrhythmia. The severity of HF was correlated with the degree of fibrosis, which was modulated by the gonadal hormones. Action potentials recorded from male and female left ventricular cardiomyocytes were indistinguishable, although both sexes exhibited delayed repolarization when compared with their wild-type counterparts. In conclusion, female TG4 mice were better protected than males against cardiac remodeling and rhythm disorders. A link between fibrosis, conduction time, and mortality was established in relation with sex hormones.

Analysis of the role of the SA gene in blood pressure regulation by gene targeting.

The SA gene is expressed in the proximal tubule of the kidney and may be involved in blood pressure (BP) regulation. However, direct evidence for this is lacking. We constructed and analyzed an SA-null mouse in which exons 2 and 3 of the SA gene (including the start codon) had been deleted by homologous recombination. Basal BP and BP changes in response to increased salt and to treatment with losartan were compared between mice homozygous for the targeted SA allele (SA-/- mice) and littermates carrying the wild-type allele (SA+/+ mice). Molecular and biochemical analysis confirmed the lack of SA gene product in SA-/- mice. SA-/- mice grew normally, were fertile, and had no overt phenotype. With both indirect and direct techniques, basal BP was similar in SA-/- and SA+/+ mice. A high salt diet for 4 weeks caused a significant increase in BP in SA-/- and SA+/+, mice but there was no difference between the 2 strains. Losartan caused a significant decrease in BP, but again the response was similar between SA-/- and SA+/+ mice, as were their kidney renin mRNA levels. SA is not involved in the regulation of either basal or salt related BP, and the lack of differential effect in SA-/- mice is not a consequence of compensatory activation of the renin-angiotensin system.