scholarly journals SIRT1 Modulating Compounds from High-Throughput Screening as Anti-Inflammatory and Insulin-Sensitizing Agents

2006 ◽  
Vol 11 (8) ◽  
pp. 959-967 ◽  
Author(s):  
Vasantha M. Nayagam ◽  
Xukun Wang ◽  
Yong Cheng Tan ◽  
Anders Poulsen ◽  
Kee Chuan Goh ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Metabolic Diseases ◽  
Necrosis Factor Alpha ◽  
Insulin Resistant ◽  
Ppar Γ ◽  
Inhibitory Compound ◽  
Cytokine Tumor Necrosis Factor ◽  
Anti Inflammatory ◽  
Mouse Adipocytes

The nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase SIRT1 has been linked to fatty acid metabolism via suppression of peroxysome proliferator-activated receptor gamma (PPAR-γ) and to inflammatory processes by deacetylating the transcription factor NF-κB. First, modulation of SIRT1 activity affects lipid accumulation in adipocytes, which has an impact on the etiology of a variety of human metabolic diseases such as obesity and insulin-resistant diabetes. Second, activation of SIRT1 suppresses inflammation via regulation of cytokine expression. Using high-throughput screening, the authors identified compounds with SIRT1 activating and inhibiting potential. The biological activity of these SIRT1-modulating compounds was confirmed in cell-based assays using mouse adipocytes, as well as human THP-1 monocytes. SIRT1 activators were found to be potent lipolytic agents, reducing the overall lipid content of fully differentiated NIH L1 adipocytes. In addition, the same compounds have anti-inflammatory properties, as became evident by the reduction of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α). In contrast, a SIRT1 inhibitory compound showed a stimulatory activity on the differentiation of adipocytes, a feature often linked to insulin sensitization.

scholarly journals High-Throughput Screening for CEBPD-Modulating Compounds in THP-1-Derived Reporter Macrophages Identifies Anti-Inflammatory HDAC and BET Inhibitors

2021 ◽  
Vol 22 (6) ◽  
pp. 3022
Author(s):  
Tatjana Ullmann ◽  
Sonja Luckhardt ◽  
Markus Wolf ◽  
Michael J. Parnham ◽  
Eduard Resch
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
High Throughput ◽  
Transcription Initiation ◽  
High Throughput Screening ◽  
Inflammatory Responses ◽  
Hdac Inhibitors ◽  
Screening Assay ◽  
Bet Inhibitors ◽  
Anti Inflammatory

This study aimed to identify alternative anti-inflammatory compounds that modulate the activity of a relevant transcription factor, CCAAT/enhancer binding protein delta (C/EBPδ). C/EBPδ is a master regulator of inflammatory responses in macrophages (Mϕ) and is mainly regulated at the level of CEBPD gene transcription initiation. To screen for CEBPD-modulating compounds, we generated a THP-1-derived reporter cell line stably expressing secreted alkaline phosphatase (SEAP) under control of the defined CEBPD promoter (CEBPD::SEAP). A high-throughput screening of LOPAC®1280 and ENZO®774 libraries on LPS- and IFN-γ-activated THP-1 reporter Mϕ identified four epigenetically active hits: two bromodomain and extraterminal domain (BET) inhibitors, I-BET151 and Ro 11-1464, as well as two histone deacetylase (HDAC) inhibitors, SAHA and TSA. All four hits markedly and reproducibly upregulated SEAP secretion and CEBPD::SEAP mRNA expression, confirming screening assay reliability. Whereas BET inhibitors also upregulated the mRNA expression of the endogenous CEBPD, HDAC inhibitors completely abolished it. All hits displayed anti-inflammatory activity through the suppression of IL-6 and CCL2 gene expression. However, I-BET151 and HDAC inhibitors simultaneously upregulated the mRNA expression of pro-inflammatory IL-1ß. The modulation of CEBPD gene expression shown in this study contributes to our understanding of inflammatory responses in Mϕ and may offer an approach to therapy for inflammation-driven disorders.

scholarly journals Benzophenone and Benzoylphloroglucinol Derivatives from Hypericum sampsonii with Anti-Inflammatory Mechanism of Otogirinin A

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4463 ◽  
Author(s):  
Chun-Yi Huang ◽  
Tzu-Cheng Chang ◽  
Yu-Jing Wu ◽  
Yun Chen ◽  
Jih-Jung Chen
Keyword(s):  
Nitric Oxide ◽  
Inhibitory Effect ◽  
No Production ◽  
Necrosis Factor Alpha ◽  
Aerial Parts ◽  
Arginase 1 ◽  
Potent Inhibition ◽  
Ic50 Values ◽  
Cytokine Tumor Necrosis Factor ◽  
Anti Inflammatory

Three new compounds, 4-geranyloxy-2-hydroxy-6-isoprenyloxybenzophenone (1), hypericumone A (2) and hypericumone B (3), were obtained from the aerial parts of Hypericum sampsonii, along with six known compounds (4–9). The structures of these compounds were determined through spectroscopic and MS analyses. Hypericumone A (2), sampsonione J (8) and otogirinin A (9) exhibited potent inhibition (IC50 values ≤ 40.32 μM) against lipopolysaccharide (LPS)-induced nitric oxide (NO) generation. Otogirinin A (9) possessed the highest inhibitory effect on NO production with IC50 value of 32.87 ± 1.60 μM. The well-known proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α) was also inhibited by otogirinin A (9). Western blot results demonstrated that otogirinin A (9) downregulated the high expression of inducible nitric oxide synthase (iNOS). Further investigations on the mechanism showed that otogirinin A (9) blocked the phosphorylation of MAPK/JNK and IκBα, whereas it showed no effect on the phosphorylation of MAPKs/ERK and p38. In addition, otogirinin A (9) stimulated anti-inflammatory M2 phenotype by elevating the expression of arginase 1 and Krüppel-like factor 4 (KLF4). The above results suggested that otogirinin A (9) could be considered as potential compound for further development of NO production-targeted anti-inflammatory agent.

scholarly journals Bioactivity Profiling of Plant Biodiversity of Panama by High Throughput Screening

2019 ◽  
Vol 14 (1) ◽  
pp. 1934578X1901400 ◽  
Author(s):  
Anuradha Roy ◽  
Peter McDonald ◽  
Barbara N. Timmermann ◽  
Mahabir Gupta ◽  
Rathnam Chaguturu
Keyword(s):  
National Parks ◽  
High Throughput ◽  
High Throughput Screening ◽  
Cancer Cell Line ◽  
Antioxidant Response ◽  
Lung Cancer Cell Line ◽  
High Throughput Analysis ◽  
Anticancer Properties ◽  
Methanolic Extracts ◽  
Anti Inflammatory

We report relative bioactivities of extracts prepared from a large collection of plants from three national parks in Panama. Over 181 plants were collected, taxonomically identified and their detannified dichloromethane (DCM)-methanolic extracts were used for profiling selected bioactivities. Assays were performed to evaluate the antioxidant activity of the extracts for Antioxidant Response Element (ARE) induction, total non-enzymatic antioxidant potential, anti-inflammatory and anticancer properties. The high throughput analysis of 280 extracts resulted in identification of 57.5% of the extracts that could induce ARE at one or more concentrations tested, 93.5% that harbored total antioxidant capacity, and 2.1% of the extracts that showed lung cancer cell line-specific cytotoxicity. Data from our profiling experiments indicate that a large number of extracts could be a source for further isolation and chemical identification of compounds that could serve as leads for discovery of antioxidant, anticancer and anti-inflammatory agents to prevent or treat complex diseases like cancer and neurodegenerative disorders.

scholarly journals The Flavonoid Quercetin Inhibits Proinflammatory Cytokine (Tumor Necrosis Factor Alpha) Gene Expression in Normal Peripheral Blood Mononuclear Cells via Modulation of the NF-κβ System

2006 ◽  
Vol 13 (3) ◽  
pp. 319-328 ◽  
Author(s):  
Madhavan P. Nair ◽  
Supriya Mahajan ◽  
Jessica L. Reynolds ◽  
Ravikumar Aalinkeel ◽  
Harikrishnan Nair ◽  
...  
Keyword(s):  
Gene Expression ◽  
Proinflammatory Cytokine ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor

ABSTRACT The flavonoids comprise a large class of low-molecular-weight plant metabolites ubiquitously distributed in food plants. These dietary antioxidants exert significant antitumor, antiallergic, and anti-inflammatory effects. The molecular mechanisms of their biological effects remain to be clearly understood. We investigated the anti-inflammatory potentials of a safe, common dietary flavonoid component, quercetin, for its ability to modulate the production and gene expression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) by human peripheral blood mononuclear cells (PBMC). Our results showed that quercetin significantly inhibited TNF-α production and gene expression in a dose-dependent manner. Our results provide direct evidence of the anti-inflammatory effects of quercetin by PBMC, which are mediated by the inhibition of the proinflammatory cytokine TNF-α via modulation of NF-κβ1 and Iκβ.

High-Throughput Screening for Small-Molecule Adiponectin Secretion Modulators

2011 ◽  
Vol 16 (6) ◽  
pp. 628-636 ◽  
Author(s):  
Kyosuke Hino ◽  
Hidetaka Nagata ◽  
Manabu Shimonishi ◽  
Motoharu Ido
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Drug Candidates ◽  
Insulin Resistant ◽  
Therapeutic Benefits ◽  
Pparγ Agonists ◽  
Agonistic Activity

Adiponectin is an adipokine secreted by adipocytes and plays a role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. Several studies have shown that upregulation of adiponectin has a number of therapeutic benefits. Although peroxisome proliferator-activated receptor γ (PPARγ) agonists are known to increase adiponectin secretion both in cultured adipocytes and humans, they have several side effects, such as weight gain, congestive heart failure, and edema. Therefore, adiponectin secretion modulators that do not possess PPARγ agonistic activity seem to promising for a number of conditions. Here, the authors report on the development of a reporter-based high-throughput screening (HTS) assay using insulin-resistant-mimic 3T3-L1 adipocytes for discovery of adiponectin secretion modulators. They screened a library of approximately 100 000 small-molecule compounds using this model, performed several follow-up screens, and identified six hit compounds that increase adiponectin secretion without having PPARγ agonistic activity. These compounds may be useful drug candidates for diabetes, obesity, atherosclerosis, and other metabolic syndromes. This HTS assay might be applicable to screening for other adipokine modulators that can be useful for the treatment of other conditions.

scholarly journals Kaempferia parviflora Extract as a Potential Anti-Acne Agent with Anti-Inflammatory, Sebostatic and Anti-Propionibacterium acnes Activity

2018 ◽  
Vol 19 (11) ◽  
pp. 3457 ◽  
Author(s):  
Solee Jin ◽  
Mi-Young Lee
Keyword(s):  
Propionibacterium Acnes ◽  
Nuclear Translocation ◽  
Raw 264.7 Cells ◽  
Signal Molecules ◽  
Kaempferia Parviflora ◽  
Necrosis Factor Alpha ◽  
Ppar Γ ◽  
Anti Inflammatory ◽  
Main Component ◽  
Α Level

Kaempferia parviflora, referred to as black ginger, has traditionally been used as a health-promoting alternative medicine. In this study, we examined the anti-inflammatory, sebostatic, and anti-Propionibacterium acnes activities of K. parviflora extract. The extract significantly down-regulated the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) level. Moreover, the phosphorylation of IĸBα and nuclear factor-kappa B (NF-κB), and the enhanced nuclear translocation of NF-κB p65 in lipopolysaccharide-stimulated murine macrophage-like cell line (RAW 264.7) cells were markedly decreased by the extract. Notably, the main component of K. parviflora, 5,7-dimethoxyflavone, also modulated the expression of iNOS and NF-κB signal molecules in P. acnes-stimulated human keratinocyte (HaCaT) cells. Additionally, K. parviflora extract inhibited the lipogenesis of sebocytes, as evidenced by a reduced level of triglyceride and lipid accumulation in the sebocytes. The sebostatic effect was also confirmed by a reduced expression of peroxisome proliferation-activating receptors (PPAR-γ) and oil-red O staining in sebocytes. Taken together, this study suggests for the first time that K. parviflora extract could be developed as a potential natural anti-acne agent with anti-inflammatory, sebostatic, and anti-P. acnes activity.

High-Throughput Screening Platform for the Discovery of New Immunomodulator Molecules from Natural Product Extract Libraries

2016 ◽  
Vol 21 (6) ◽  
pp. 567-578 ◽  
Author(s):  
José Pérez del Palacio ◽  
Caridad Díaz ◽  
Mercedes de la Cruz ◽  
Frederick Annang ◽  
Jesús Martín ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Natural Product ◽  
High Throughput ◽  
High Throughput Screening ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Immunomodulatory Activity ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

It is widely accepted that central nervous system inflammation and systemic inflammation play a significant role in the progression of chronic neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, neurotropic viral infections, stroke, paraneoplastic disorders, traumatic brain injury, and multiple sclerosis. Therefore, it seems reasonable to propose that the use of anti-inflammatory drugs might diminish the cumulative effects of inflammation. Indeed, some epidemiological studies suggest that sustained use of anti-inflammatory drugs may prevent or slow down the progression of neurodegenerative diseases. However, the anti-inflammatory drugs and biologics used clinically have the disadvantage of causing side effects and a high cost of treatment. Alternatively, natural products offer great potential for the identification and development of bioactive lead compounds into drugs for treating inflammatory diseases with an improved safety profile. In this work, we present a validated high-throughput screening approach in 96-well plate format for the discovery of new molecules with anti-inflammatory/immunomodulatory activity. The in vitro models are based on the quantitation of nitrite levels in RAW264.7 murine macrophages and interleukin-8 in Caco-2 cells. We have used this platform in a pilot project to screen a subset of 5976 noncytotoxic crude microbial extracts from the MEDINA microbial natural product collection. To our knowledge, this is the first report on an high-throughput screening of microbial natural product extracts for the discovery of immunomodulators.

scholarly journals Parallel comparison of fibroblast-like synoviocytes from the surgically removed hyperplastic synovial tissues of rheumatoid arthritis and osteoarthritis patients

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Wei Huang ◽  
Linlin Zhang ◽  
Chao Cheng ◽  
Wenshan Shan ◽  
Ruixiang Ma ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Cytokine ◽  
Cellular Functions ◽  
Cell Surface Antigens ◽  
Necrosis Factor Alpha ◽  
Inflammatory Status ◽  
Cytokine Tumor Necrosis Factor ◽  
Anti Inflammatory ◽  
Synovial Tissues ◽  
Fibroblast Like Synoviocytes

Abstract Background Fibroblast-like synoviocytes (FLS) are essential cellular components in inflammatory joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). Despite the growing use of FLS isolated from OA and RA patients, a detailed functional and parallel comparison of FLS from these two types of arthritis has not been performed. Methods In the present study, FLS were isolated from surgically removed synovial tissues from twenty-two patients with OA and RA to evaluate their basic cellular functions. Results Pure populations of FLS were isolated by a sorting strategy based on stringent marker expression (CD45−CD31−CD146−CD235a−CD90+PDPN+). OA FLS and RA FLS at the same passage (P2-P4) exhibited uniform fibroblast morphology. OA FLS and RA FLS expressed a similar profile of cell surface antigens, including the fibroblast markers VCAM1 and ICAM1. RA FLS showed a more sensitive inflammatory status than OA FLS with regard to proliferation, migration, apoptosis, inflammatory gene expression and pro-inflammatory cytokine secretion. In addition, the responses of OA FLS and RA FLS to both the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and the anti-inflammatory drug methotrexate (MTX) were also evaluated here. Conclusion The parallel comparison of OA FLS and RA FLS lays a foundation in preparation for when FLS are considered a potential therapeutic anti-inflammatory target for OA and RA.

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