PMID: 

Mol Nutr Food Res. 2020 Feb 12:e1900876. Epub 2020 Feb 12. PMID: 32050056

Abstract Title: 

Dietary Supplementation of Black Rice Anthocyanin Extract Regulates Cholesterol Metabolism and Improves Gut Microbiota Dysbiosis in C57BL/6J Mice Fed a High-Fat and Cholesterol Diet.

Abstract: 

SCOPE: This study explored the beneficial effects of dietary supplementation of black rice anthocyanin extract (BRAE) on cholesterol metabolism and gut dysbiosis.METHODS AND RESULTS: C57BL/6J mice were grouped into the normal chow diet group (NCD), the high-fat and cholesterol diet group (HCD), and three treatment groups feeding HCD supplemented with various dosage of BRAE (BAL, BAM, BAH) for 12 weeks. Results revealed that BRAE alleviated the increased body weight, serum triglyceride (TG), total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C) levels, and increased fecal sterols excretion and caecal short-chain fatty acids (SCFAs) concentration in HCD-induced hypercholesterolemic mice. Moreover, BRAE decreased hepatic TC content through elevated hepatic AMPKα, LXRα, CYP7A1 and decreased FXR, SHP, HMGCOA-R mRNA levels. Meanwhile, BRAE depressed NPC1L1, ACAT2, MTTP, and preserved CYP7A1, ABCG5/8 mRNA expression, and the relative abundance of gut microbiota. Additionally, the antibiotic treatment experiment indicated that the beneficial effects of BRAEin reducing hypocholesterolemia risk largely depended on the gut microbiota homeostasis (e.g., Bifidobacterium, Lactobacillus).CONCLUSION: BRAE supplement could be a beneficial treatment option for preventing HCD-induced hypocholesterolemia and related metabolic syndromes. This article is protected by copyright. All rights reserved.

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PMID: 

Sci Rep. 2019 Aug 22 ;9(1):12277. Epub 2019 Aug 22. PMID: 31439870

Abstract Title: 

Inhibition of NLRP3 inflammasome in tumor microenvironment leads to suppression of metastatic potential of cancer cells.

Abstract: 

Tumor microenvironment favors tumor cells to promote their growth and metastasis such as migration, invasion, and angiogenesis. IL-1β, one of the inflammatory cytokines released from myeloid cells in tumor microenvironment, plays an important role in development and progress of tumor. The activation of inflammasome is a critical step to secrete mature IL-1β through stepwise reactions to activate capspase-1. Therefore, we investigated whether the inhibition of NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome in macrophages regulated the metastatic potential of tumor cells. NLRP3 inflammasome was activated by ATP in bone marrow-derived primary mouse macrophages. The metastatic potential of mouse melanoma cell line (B16F10) was determined by migration and invasion assays with transwell system. ATP-treated wild-type macrophages increased the migration and invasion of melanoma cells. However, NLRP3- or caspase-1-knockout macrophages exhibited greatly diminished ability to promote the migration and invasion of melanoma cells. In addition, treatment with celastrol, an inhibitor of NLRP3 inflammasome, reduced the potency of macrophages to stimulate migration and invasion of melanoma cells. The results demonstrate that inhibition of the NLRP3 inflammasome in macrophages by genetic deficiency or a pharmacological inhibitor is linked to suppression of the metastatic potential of tumor cells. The results would provide a novel anti-cancer strategy to modulate tumor microenvironment by suppressing NLRP3 inflammasome and consequently reducing IL-1β production.

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PMID: 

Int J Clin Exp Pathol. 2019 ;12(2):576-583. Epub 2019 Feb 1. PMID: 31933862

Abstract Title: 

Protective effect of celastrol for burn-induced acute lung injury in rats.

Abstract: 

Celastrol (CEL) was shown to display anti-inflammatory properties, and played an important role in anti-apoptosis. There were inflammation mediated by cytokines and apoptosis distinctly in the progression of acute lung injury (ALI) burn-induced. This study was conducted to explore the role of CEL in ALI induced by burns. In order to induce burn injury, rats were exposed to a 92°C water bath for 18 seconds. After burn experiment, the Burn + Celastrol group received CEL, and vehicle (DMSO) was used to treat the rats from Burn + Vehicle group. And the Sham + Burn group received no treatment. Vascular protein leakage was detected by Evans blue (EB) concentration to evaluatethe lung microvascular permeability. Then wet-to-dry lung weight ratio (W/D), and hematoxylin and eosin staining (H&E) were measured respectively to investigate interstitial edema, neutrophil recruitment, and histopathological changes in lung tissues burn-induced ALI. To explore the mechanism of action of CEL, we assessed levels of inflammatory cytokines by ELISA assay, TUNEL staining and western blotting. Then we detected apoptosis-related factors, including the amount of apoptotic cells, caspase-3 activity, and Bax or Bcl-xl, respectively. The pulmonary microvascular hyperpermeability, histopathological characteristics, and a high W/D were attenuated by CEL for burn-injury rats. The concentration of cytokines burn-induced ALI from tissues and serum were decreased by CEL. Furthermore, after CEL treatment, TUNEL-positive cells, the protein level of Bax and caspase-3 activity reduced, and the level of Bcl-xl in protein increased. In conclusion, in lung injury burn-induced, CEL has a positive effect on anti-inflammation and anti-apoptosis. Thus, CEL could be as a latent for the cure of ALI burn-induced.

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PMID: 

Cancer Chemother Pharmacol. 2020 Feb ;85(2):331-343. Epub 2020 Jan 27. PMID: 31989218

Abstract Title: 

Novel complementary antitumour effects of celastrol and metformin by targeting IκBκB, apoptosis and NLRP3 inflammasome activation in diethylnitrosamine-induced murine hepatocarcinogenesis.

Abstract: 

One promising strategy for minimizing chemotherapeutic resistance in hepatocellular carcinoma (HCC) is the use of effective chemosensitizers. We studied the complementary multi-targeted molecular mechanisms of metformin and celastrol in mice with diethylnitrosamine-induced HCC to investigate whether metformin could augment the sensitivity of HCC tissue to the effect of celastrol. Simultaneous administration of celastrol (2 mg/kg) and metformin (200 mg/kg) improved liver function, enhanced the histological picture and prolonged survival. Additionally, combination therapy exerted anti-inflammatory activity, as indicated by the decreased levels of TNF-α and IL-6. This protective role could be attributed to inhibitionof inflammasome activation. Herein, our data revealed downregulated NLRP3 gene expression, suppressed caspase-1 activity and reduced levels of the active forms of IL-1β and IL-18. Under this condition, pyroptotic activity was suppressed. In contrast, in the celastrol and celastrol + metformingroups, the apoptotic potential was amplified, as revealed by the increase in the caspase-9 and caspase-3 levels and Bax:BCL-2 ratio. In addition to their repressive effect on the gene expression of NFκBp65, TNFR and TLR4, metformin and celastrol inhibited phosphorylation-induced activation of IκBκB and NFκBp65 and decreased IκBα degradation. Combination therapy with metformin and celastrol repressed markers of angiogenesis, metastasis and tumour proliferation, as revealed by the decreased hepatic levels of VEGF, MMP-2/9 and cyclin D1 mRNA, respectively. In conclusion, by inhibiting NLRP3 inflammasome and its prerequisite NFκB signalling, simultaneous administration of metformin and celastrol appears to have additive benefits in the treatment of HCC compared to cela monotherapy. This effect warrants further clinical investigation.

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PMID: 

Int J Mol Sci. 2020 Feb 6 ;21(3). Epub 2020 Feb 6. PMID: 32041250

Abstract Title: 

Celastrol Alleviates Gamma Irradiation-Induced Damage by Modulating Diverse Inflammatory Mediators.

Abstract: 

The present study aimed to explore the possible radioprotective effects of celastrol and relevant molecular mechanisms in an in vitro cell and in vivo mouse models exposed to gamma radiation. Human keratinocytes (HaCaT) and foreskin fibroblast (BJ) cells were exposed to gamma radiation of 20Gy, followed by treatment with celastrol for 24 h. Cell viability, reactive oxygen species (ROS), nitric oxide (NO) and glutathione (GSH) production, lipid peroxidation, DNA damage, inflammatory cytokine levels, and NF-κB pathway activation were examined. The survival rate, levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in blood, and p65 and phospho-p65 expression were also evaluated in mice after exposure to gamma radiation and celastrol treatment. The gamma irradiation of HaCaT cells induced decreased cell viability, but treatment with celastrol significantly blocked this cytotoxicity. Gamma irradiation also increased free radical production (e.g., ROS and NO), decreased the level of GSH, and enhanced oxidative DNA damage and lipid peroxidation in cells, which were effectively reversed by celastrol treatment. Moreover, inflammatory responses induced by gamma irradiation, as demonstrated by increased levels of IL-6, TNF-α, and IL-1β, were also blocked by celastrol. The increased activity of NF-κB DNA binding following gamma radiation was significantly attenuated after celastrol treatment. In the irradiated mice, treatment with celastrol significantly improved overall survival rate, reduced the excessive inflammatory responses, and decreased NF-κB activity. As a NF-κB pathway blocker and antioxidant, celastrol may represent a promising pharmacological agent with protective effects against gamma irradiation-induced injury.

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Science is not about good and bad, it is about proven and not proven

PMID: 

Mar Drugs. 2019 Feb 2 ;17(2). Epub 2019 Feb 2. PMID: 30717366

Abstract Title: 

Neorogioltriol and Related Diterpenes from the Red AlgaInhibit Inflammatory Bowel Disease in Mice by Suppressing M1 and Promoting M2-Like Macrophage Responses.

Abstract: 

Macrophages are central mediators of inflammation, orchestrating the inflammatory response through the production of cytokines and nitric oxide. Macrophages obtain pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, which can be modulated by soluble factors, including natural products. Despite the crucial protective role of inflammation, chronic or deregulated inflammation can lead to pathological states, such as autoimmune diseases, metabolic disorders, cardiovascular diseases, and cancer. In this case, we studied the anti-inflammatory activity of neorogioltriol () in depth and identified two structurally related diterpenes, neorogioldiol (), and,15-cyclo-14-bromo-14,15-dihydrorogiol-3,11-diol (), with equally potent activity. We investigated the mechanism of action of metabolites⁻and found that all three suppressed macrophage activation and promoted an M2-like anti-inflammatory phenotype by inducing expression of Arginase1, MRC1, IRAK-M, the transcription factor C/EBPβ, and the miRNA miR-146a. In addition, they suppressed iNOS induction and nitric oxide production. Importantly, treatment of mice withorsuppressed DSS-induced colitis by reducing tissue damage and pro-inflammatory cytokine production. Thus, all these three diterpenes are promising lead molecules for the development of anti-inflammatory agents targeting macrophage polarization mechanisms.

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PMID: 

Biochem Biophys Res Commun. 2018 06 12 ;500(4):944-951. Epub 2018 May 2. PMID: 29705698

Abstract Title: 

Red alga polysaccharides attenuate angiotensin II-induced inflammation in coronary endothelial cells.

Abstract: 

The pro-inflammatory vasoconstrictor Angiotensin II can cause endothelial dysfunction and is considered to be one of the mediators of atherosclerosis. Our former results demonstrated that polysaccharides derived from the red alga Porphyridium sp. attenuate inflammatory processes by interfering with tumor necrosis factor-alpha-induced inflammation, in human coronary artery endothelial cells. However, the anti-inflammatory effect of these polysaccharides on inflammation processes occurring under Angiotensin II stimulation is yet unknown. Herein, we studied the polysaccharide's anti-inflammatory effect by quantification of inflammatory markers in Angiotensin II- stimulated Human Coronary Artery Endothelial Cells following pre-treatment with polysaccharides. Inflammatory atherosclerotic pathways up-regulated by Angiotensin II, including adhesion molecule expression and nuclear factor kappa-light-chain-enhancer of activated B cells translocation, were significantly attenuated or diminished in cells pre-treated with the polysaccharides. In addition, the polysaccharides increased the antioxidant response elements activity through the nuclear factor-E2-related factor 2- antioxidant protection system. These polysaccharide's promising abilities may be considered as a basis for future use as a therapeutic agent aimed at improving vascular health by attenuation of the inflammatory atherosclerotic process.

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PMID: 

Molecules. 2019 Jan 29 ;24(3). Epub 2019 Jan 29. PMID: 30699968

Abstract Title: 

Rare Acetogenins with Anti-Inflammatory Effect from the Red Alga.

Abstract: 

Three new rare Cacetogenins (enyne derivatives⁻) were isolated from the organic extract obtained from the red alga, collected from the Red Sea. The chemical structures of the isolated compounds were established by spectroscopical data analyses. Potent anti-inflammatory effect of the isolated metabolites was evidenced by inhibition of the release of inflammatory mediators (e.g., TNF-α, IL-1β and IL-6) by employing Human Peripheral Blood Mononuclear Cells (PBMC).

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PMID: 

Phytomedicine. 2019 Sep ;62:152939. Epub 2019 Apr 23. PMID: 31100678

Abstract Title: 

Inhibitory effects of collismycin C and pyrisulfoxin A on particulate matter-induced pulmonary injury.

Abstract: 

BACKGROUND: Inhalation of fine particulate matter (PM) is associated with elevated pulmonary injury caused by the loss of vascular barrier integrity. Marine microbial natural products isolated from microbial culture broths were screened for pulmonary protective effects against PM. Two 2,2'-bipyridine compounds isolated from a red alga-associated Streptomyces sp. MC025-collismycin C (2) and pyrisulfoxin A (5)-were found to inhibit PM-mediated vascular barrier disruption.PURPOSE: To confirm the inhibitory effects of collismycin C and pyrisulfoxin A on PM-induced pulmonary injury STUDY DESIGN: In this study, we investigated the beneficial effects of collismycin C and pyrisulfoxin A on PM-induced lung endothelial cell (EC) barrier disruption and pulmonary inflammation.METHODS: Permeability, leukocyte migration, proinflammatory protein activation, reactive oxygen species (ROS) generation, and histology were evaluated in PM-treated ECs and mice.RESULTS: Collismycin C and pyrisulfoxin A significantly scavenged PM-induced ROS and inhibited the ROS-induced activation of p38 mitogen-activated protein kinase as well as activated Akt, which helped in maintaining endothelial integrity, in purified pulmonary endothelial cells. Furthermore, collismycin C and pyrisulfoxin A reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in the bronchoalveolar lavage fluid of PM-treated mice.CONCLUSION: These data suggested that collismycin C and pyrisulfoxin A might exert protective effects on PM-induced inflammatory lung injury and vascular hyperpermeability.

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