Synthesis of new bergenin derivatives as potent inhibitors of inflammatory mediators NO and TNF-α

<P>Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that eventually leads to severe cognitive impairment. Although the exact etiologies of AD still remain elusive, increasing evidence suggests that neuroinflammation cascades mediated by microglial cells are associated with AD. Piper sarmentosum Roxb. (PS) is a medicinal plant reported to possess various biological properties, including anti-inflammatory, anti-psychotic and anti-oxidant activity. However, little is known about the anti-inflammatory activity of PS roots despite their traditional use to treat inflammatory- mediated ailments. Objective: This study aimed to evaluate the anti-inflammatory and neuroprotective properties of extracts obtained from the roots of PS against beta-amyloid (Aβ)-induced microglial toxicity associated with the production of pro-inflammatory mediators. Method: BV2 microglial cells were treated with hexane (RHXN), dichloromethane (RDCM), ethyl acetate (REA) and methanol (RMEOH) extracts of the roots of PS prior to activation by Aβ. The production and mRNA expression of pro-inflammatory mediators were evaluated by Griess reagent, ELISA kits and RT-qPCR respectively. The phosphorylation status of p38α MAPK was determined via western blot assay. BV2 conditioned medium was used to treat SH-SY5Y neuroblastoma cells and the neuroprotective effect was assessed using MTT assay. Results: PS root extracts, in particular RMEOH significantly attenuated the production and mRNA expression of IL-1β, IL-6 and TNF-α in Aβ-induced BV2 microglial cells. In addition, RHXN, REA and RMEOH extracts significantly reduced nitric oxide (NO) level and the inhibition of NO production was correlated with the total phenolic content of the extracts. Further mechanistic studies suggested that PS root extracts attenuated the production of cytokines by regulating the phosphorylation of p38α MAPK in microglia. Importantly, PS root extracts have protective effects against Aβ-induced indirect neurotoxicity either by inhibiting the production of NO, IL-1β, IL-6, and TNF-α in BV2 cells or by protecting SHSY5Y cells against these inflammatory mediators. Conclusions: These findings provided evidence that PS root extracts confer neuroprotection against Aβ- induced microglial toxicity associated with the production of pro-inflammatory mediators and may be a potential therapeutic agent for inflammation-related neurological conditions including Alzheimer’s disease (AD).</P>

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Is Inflammation a Friend or Foe for Orthodontic Treatment?: Inflammation in Orthodontically Induced Inflammatory Root Resorption and Accelerating Tooth Movement

International Journal of Molecular Sciences ◽

10.3390/ijms22052388 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2388

Author(s):

Masaru Yamaguchi ◽

Shinichi Fukasawa

Keyword(s):

Inflammatory Mediators ◽

Orthodontic Treatment ◽

Alveolar Bone ◽

Tooth Movement ◽

Root Resorption ◽

Orthodontic Tooth Movement ◽

Tnf Α ◽

Orthodontic Forces ◽

Necrosis Factor

The aim of this paper is to provide a review on the role of inflammation in orthodontically induced inflammatory root resorption (OIIRR) and accelerating orthodontic tooth movement (AOTM) in orthodontic treatment. Orthodontic tooth movement (OTM) is stimulated by remodeling of the periodontal ligament (PDL) and alveolar bone. These remodeling activities and tooth displacement are involved in the occurrence of an inflammatory process in the periodontium, in response to orthodontic forces. Inflammatory mediators such as prostaglandins (PGs), interleukins (Ils; IL-1, -6, -17), the tumor necrosis factor (TNF)-α superfamily, and receptor activator of nuclear factor (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) are increased in the PDL during OTM. OIIRR is one of the accidental symptoms, and inflammatory mediators have been detected in resorbed roots, PDL, and alveolar bone exposed to heavy orthodontic force. Therefore, these inflammatory mediators are involved with the occurrence of OIIRR during orthodontic tooth movement. On the contrary, regional accelerating phenomenon (RAP) occurs after fractures and surgery such as osteotomies or bone grafting, and bone healing is accelerated by increasing osteoclasts and osteoblasts. Recently, tooth movement after surgical procedures such as corticotomy, corticision, piezocision, and micro-osteoperforation might be accelerated by RAP, which increases the bone metabolism. Therefore, inflammation may be involved in accelerated OTM (AOTM). The knowledge of inflammation during orthodontic treatment could be used in preventing OIIRR and AOTM.

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Effect of aerobic exercise on innate immune responses and inflammatory mediators in the spinal cord of diabetic rats

Comparative Exercise Physiology ◽

10.3920/cep190050 ◽

2020 ◽

Vol 16 (4) ◽

pp. 293-301

Author(s):

A. Kaki ◽

M. Nikbakht ◽

A.H. Habibi ◽

H.F. Moghadam

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Immune Responses ◽

Diabetic Neuropathy ◽

Aerobic Exercise ◽

Inflammatory Mediators ◽

Innate Immune ◽

Moderate Intensity ◽

Innate Immune Responses ◽

Tnf Α

Neuronal inflammation is one of the pathophysiological causes of diabetes neuropathic pain. The purpose of this research was to determine the effect of aerobic exercise on innate immune responses and inflammatory mediators in the spinal dorsal horn in rats with diabetic neuropathic pain. 40 eight-week-old male Wistar rats (weight range 220±10.2 g) were randomly divided into four groups of (1) sedentary diabetic neuropathy (SDN), (2) training diabetic neuropathy (TDN), (3) training control (TC), and (4) sedentary control (SC). Diabetes was induced by injection of streptozocin (50 mg/kg). Following confirmation of behavioural tests for diabetes neuropathy, the training groups performed 6 weeks of moderate-intensity aerobic exercise on the treadmill. The expression of Toll like receptor (TLR)4, TLR2, tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-10 genes in L4-L6 spinal cord sensory neurons was measured by Real Time PCR. Two-way ANOVA and Bonferroni’s post hoc tests were used for statistical analysis. After performing aerobic exercise protocol, the TDN compared to the SDN showed a significant decrease in the mean score of pain in the formalin test and a significant increase in the latency in Tail-Flick test was observed. The expression of TLR4, TLR2, TNF-α and IL-1β genes was significantly higher in the SDN than in the SC group (P<0.05). The expression of the above genes in the TDN was significantly lower than the SDN group (P<0.05). Also, the expression level of IL-10 gene was significantly higher in the TDN than the SDN group (P<0.05). Aerobic exercise improved sensitivity of nociceptors to pain-inducing agents in diabetic neuropathy due to inhibition of inflammatory receptors and increased levels of anti-inflammatory agents in the nervous system. Thus, aerobic exercise should be used as a non-pharmacological intervention for diabetic patients to reduce neuropathic pain.

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Expression of the Metalloproteinase ADAM8 Is Upregulated in Liver Inflammation Models and Enhances Cytokine Release In Vitro

Mediators of Inflammation ◽

10.1155/2021/6665028 ◽

2021 ◽

Vol 2021 ◽

pp. 1-17

Author(s):

Tanzeela Awan ◽

Aaron Babendreyer ◽

Justyna Wozniak ◽

Abid Mahmood Alvi ◽

Viktor Sterzer ◽

...

Keyword(s):

Cell Lines ◽

Inflammatory Mediators ◽

Liver Tissue ◽

Stellate Cell ◽

Hepatoma Cell ◽

Cell Types ◽

Chronic Liver ◽

Liver Inflammation ◽

Tnf Α

Acute and chronic liver inflammation is driven by cytokine and chemokine release from various cell types in the liver. Here, we report that the induction of inflammatory mediators is associated with a yet undescribed upregulation of the metalloproteinase ADAM8 in different murine hepatitis models. We further show the importance of ADAM8 expression for the production of inflammatory mediators in cultured liver cells. As a model of acute inflammation, we investigated liver tissue from lipopolysaccharide- (LPS-) treated mice in which ADAM8 expression was markedly upregulated compared to control mice. In vitro, stimulation with LPS enhanced ADAM8 expression in murine and human endothelial and hepatoma cell lines as well as in primary murine hepatocytes. The enhanced ADAM8 expression was associated with an upregulation of TNF-α and IL-6 expression and release. Inhibition studies indicate that the cytokine response of hepatoma cells to LPS depends on the activity of ADAM8 and that signalling by TNF-α can contribute to these ADAM8-dependent effects. The role of ADAM8 was further confirmed with primary hepatocytes from ADAM8 knockout mice in which TNF-α and IL-6 induction and release were considerably attenuated. As a model of chronic liver injury, we studied liver tissue from mice undergoing high-fat diet-induced steatohepatitis and again observed upregulation of ADAM8 mRNA expression compared to healthy controls. In vitro, ADAM8 expression was upregulated in hepatoma, endothelial, and stellate cell lines by various mediators of steatohepatitis including fatty acid (linoleic-oleic acid), IL-1β, TNF-α, IFN-γ, and TGF-β. Upregulation of ADAM8 was associated with the induction and release of proinflammatory cytokines (TNF-α and IL-6) and chemokines (CX3CL1). Finally, knockdown of ADAM8 expression in all tested cell types attenuated the release of these mediators. Thus, ADAM8 is upregulated in acute and chronic liver inflammation and is able to promote inflammation by enhancing expression and release of inflammatory mediators.

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Proinflammatory responses in SARS-CoV-2 infected and soluble spike glycoprotein S1 subunit activated human macrophages

10.1101/2021.06.14.448426 ◽

2021 ◽

Author(s):

Kim Chiok ◽

Kevin Hutchison ◽

Lindsay Grace Miller ◽

Santanu Bose ◽

Tanya A Miura

Keyword(s):

Virus Infection ◽

Inflammatory Response ◽

Virus Replication ◽

Inflammatory Mediators ◽

Inflammatory Responses ◽

Activated Macrophages ◽

Human Macrophages ◽

Tnf Α ◽

Proinflammatory Responses

Critically ill COVID-19 patients infected with SARS-CoV-2 display signs of generalized hyperinflammation. Macrophages trigger inflammation to eliminate pathogens and repair tissue, but this process can also lead to hyperinflammation and resulting exaggerated disease. The role of macrophages in dysregulated inflammation during SARS-CoV-2 infection is poorly understood. We used SARS-CoV-2 infected and glycosylated soluble SARS-CoV-2 Spike S1 subunit (S1) treated THP-1 human-derived macrophage-like cell line to clarify the role of macrophages in pro-inflammatory responses. Soluble S1 upregulated TNF-α and CXCL10 mRNAs, and induced secretion of TNF-α from THP-1 macrophages. While THP-1 macrophages did not support productive SARS-CoV-2 replication, virus infection resulted in upregulation of both TNF-α and CXCL10 genes. Our study shows that S1 is a key viral component inducing inflammatory response in macrophages, independently of virus replication. Thus, virus-infected or soluble S1-activated macrophages may become sources of pro-inflammatory mediators contributing to hyperinflammation in COVID-19 patients.

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The Immuno-Modulatory Activities of Pentaherbs Formula on Ovalbumin-Induced Allergic Rhinitis Mice via the Activation of Th1 and Treg Cells and Inhibition of Th2 and Th17 Cells

Molecules ◽

10.3390/molecules27010239 ◽

2021 ◽

Vol 27 (1) ◽

pp. 239

Author(s):

Peiting Li ◽

Miranda Sin-Man Tsang ◽

Lea Ling-Yu Kan ◽

Tianheng Hou ◽

Sharon Sze-Man Hon ◽

...

Keyword(s):

Allergic Rhinitis ◽

T Cell ◽

Inflammatory Mediators ◽

Th17 Cells ◽

Lavage Fluid ◽

Nasal Lavage ◽

Nasal Epithelium ◽

Tnf Α ◽

Nasal Lavage Fluid ◽

Sinonasal Mucosa

Allergic rhinitis (AR) is a highly prevalent allergic disease induced by immunoglobulin (Ig) E-mediated hypersensitivity reaction at the nasal epithelium against inhaled allergens. Previous studies have demonstrated that Pentaherbs formula (PHF), a modified herbal formula comprising five herbal medicines (Flos Lonicerae, Herba Menthae, Cortex Phellodendri, Cortex Moutan and Rhizoma Atractylodis), could suppress various immune effector cells to exert anti-inflammatory and anti-allergic effects in allergic asthma and atopic dermatitis. The present study aimed to further determine the anti-inflammatory activities of PHF in an ovalbumin (OVA)-induced AR BALB/c mouse model. Nasal symptoms such as sneezing and nose rubbing were recorded and the serum total IgE and OVA-specific IgG1, as well as interleukin (IL)-4, IL-5, IL-10, IL-13, chemokines CXCL9 CXCL10, and tumor necrosis factor (TNF)-α concentrations in nasal lavage fluid (NALF) were measured during different treatments. Effects of PHF on the expression of inflammatory mediators in the sinonasal mucosa were quantified using real-time QPCR. PHF was found to suppress allergic symptoms, infiltration of inflammatory cells, and hyperplasia of goblet cells in the nasal epithelium of the OVA-induced AR mice. PHF could reduce OVA-specific IgG1 level in serum, and TNF-α and IL-10 in nasal lavage fluid (NALF), significantly up-regulate the splenic regulatory T (Treg) cell level, increase the Type 1 helper T cell (Th1)/Type 2 helper T cell (Th2) ratio, and reduce the Th17 cells (all p < 0.05). PHF could also alleviate in situ inflammation in sinonasal mucosa of OVA-induced AR mice. In conclusion, oral treatment of PHF showed immuno-modulatory activities in the OVA-induced AR mice by regulating the splenic T cell population to suppress the nasal allergy symptoms and modulating inflammatory mediators, implicating that PHF could be a therapeutic strategy for allergic rhinitis.

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Cytokine and Eicosanoid Production by Cultured Human Monocytes Exposed to Titanium Particulate Debris

Microscopy and Microanalysis ◽

10.1017/s1431927699000173 ◽

1999 ◽

Vol 5 (5) ◽

pp. 344-351 ◽

Cited By ~ 2

Author(s):

Timothy M. Robinson ◽

Paul A. Manley ◽

Paul A. Sims ◽

Ralph Albrecht ◽

Benjamin J. Darien

Keyword(s):

Titanium Alloy ◽

Inflammatory Mediators ◽

Wear Debris ◽

In Vitro Models ◽

Sem Analysis ◽

Blood Monocytes ◽

Healthy Human ◽

Premature Failure ◽

Tnf Α

Phagocytosis of particulate wear debris from arthroplasties by macrophages induces an inflammatory response that has been linked to implant loosening and premature failure of artificial joints. Inflammatory mediators released by phagocytic macrophages such as tumor necrosis factor-a (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) are believed to play a central role in the pathogenesis of aseptic loosening. The objective of this study was to characterize titanium alloy particulates that closely match wear debris found around joint arthroplasties and to study their effects on the biosynthesis of inflammatory mediators by cultured monocytes. Peripheral blood monocytes were isolated from healthy human volunteers. Monocytes were cultured in 96-well plates for 24 h, washed, and exposed to three concentrations of titanium particulates and controls from 18Ð24 h. Supernatants were assayed for TNF-α, IL-1β, IL-6, and PGE2 activity. Energy dispersive X-ray spectroscopy (EDX) verified the titanium alloy to be Ti6A14V. Scanning electron microscopy (SEM) analysis showed significant titanium particulate heterogeneity with approximately 95% of the particles <1 micrometer in diameter. SEM and EDX technology was useful in the characterization of the titanium particulates utilized for in vitro models of titanium-induced cytokine release by monocytes. Incubation of titanium particulates (in concentrations similar to those found around loosened prosthetic joints) with cultured monocytes significantly increased their production of TNF-α, IL-1β, and PGE2.

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Pro-inflammatory Mediators and Oxidative Stress: Therapeutic Markers for Recurrent Angina Pectoris after Coronary Artery Stenting in Elderly Patients

Current Vascular Pharmacology ◽

10.2174/1570161119666210129142707 ◽

2021 ◽

Vol 19 ◽

Author(s):

Xia Li ◽

Dianxuan Guo ◽

Hualan Zhou ◽

Youdong Hu ◽

Xiang Fang ◽

...

Keyword(s):

Oxidative Stress ◽

Coronary Artery ◽

Angina Pectoris ◽

Elderly Patients ◽

Inflammatory Mediators ◽

The Elderly ◽

Recurrent Angina ◽

Coronary Artery Stenting ◽

Tnf Α ◽

And Oxidative Stress

Background: Pro-inflammatory mediators and oxidative stress are related to severity of angina pectoris in patients with coronary heart disease. Objective: We evaluated the effects of pro-inflammatory mediators and oxidative stress on recurrent angina pectoris after coronary artery stenting in elderly patients. Methods: We determined the expression levels of malondialdehyde (MDA), acrolein (ACR), tumour necrosis factor-α (TNF-α), toll-like receptor 4 (TLR4), superoxide dismutase 3 (SOD3), paraoxonase-1 (PON-1), stromal cell-derived factor-1α (SDF-1α) and endothelial progenitor cells (EPCs) in elderly patients with recurrent angina pectoris after coronary artery stenting. Results: Levels of MDA, ACR, TNF-α and TLR4 were significantly increased (p<0.001), and levels of SOD3, PON-1, SDF-1α and EPCs were significantly decreased (p<0.001) in the elderly patients with recurrent angina pectoris after coronary artery stenting. MDA, ACR, TNF-α and TLR4 as markers of oxidative stress and pro-inflammatory mediators may have suppressed SOD3, PON-1, SDF-1α and EPCs as markers of anti-oxidative stress/anti-inflammatory responses. Oxidative stress and pro-inflammatory mediators were important factors involved in recurrent angina pectoris of elderly patients after coronary artery stenting. Conclusion: Oxidative stress and pro-inflammatory mediators could be considered as potential non-invasive prognostic, predictive and therapeutic biomarkers for stable recurrent angina and recurrent unstable angina in the elderly patients after coronary artery stenting.

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Endoplasmic Reticulum Stress Contributes to Nociception via Neuroinflammation in a Murine Bone Cancer Pain Model

Anesthesiology ◽

10.1097/aln.0000000000003078 ◽

2020 ◽

Vol 132 (2) ◽

pp. 357-372 ◽

Cited By ~ 2

Author(s):

Yanting Mao ◽

Chenchen Wang ◽

Xinyu Tian ◽

Yulin Huang ◽

Ying Zhang ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Cancer Pain ◽

Inflammatory Mediators ◽

Bone Cancer ◽

Intrathecal Administration ◽

Bone Cancer Pain ◽

Stress Markers ◽

Mechanical Threshold ◽

Tnf Α

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Prolonged endoplasmic reticulum stress has been identified in various diseases. Inflammatory mediators, which have been shown to induce endoplasmic reticulum stress in several studies, have been suggested to serve as the important modulators in pain development. In this study, the authors hypothesized that the endoplasmic reticulum stress triggered by inflammatory mediators contributed to pain development. Methods The authors used a male mouse model of bone cancer pain. The control mice were intrathecally injected with tumor necrosis factor-α (TNF-α) and lipopolysaccharide, the bone cancer pain mice were intrathecally injected with the endoplasmic reticulum stress inhibitors 4-PBA and GSK2606414. The nociceptive behaviors, endoplasmic reticulum stress markers, and inflammatory mediators were assessed. Results Increased expression of the p-RNA-dependent protein kinase-like endoplasmic reticulum kinase and p-eukaryotic initiation factor 2α were found in the spinal neurons during bone cancer pain, along with upregulation of inflammatory mediators (TNF-α, interleukin 1β, and interleukin 6). Intrathecal administration of TNF-α or lipopolysaccharide increased the expression of endoplasmic reticulum stress markers in control mice. Inhibition of endoplasmic reticulum stress by intrathecal administration of 4-PBA (baseline vs. 3 h: 0.34 ± 0.16 g vs. 1.65 ± 0.40 g in paw withdrawal mechanical threshold, 8.00 ± 1.20 times per 2 min vs. 0.88 ± 0.64 times per 2 min in number of spontaneous flinches, P < 0.001, n = 8) or GSK2606414 (baseline vs. 3 h: 0.37 ± 0.08 g vs. 1.38 ± 0.11 g in paw withdrawal mechanical threshold, 8.00 ± 0.93 times per 2 min vs. 3.25 ± 1.04 times per 2 min in number of spontaneous flinches, P < 0.001, n = 8) showed time- and dose-dependent antinociception. Meanwhile, decreased expression of inflammatory mediators (TNF-α, interleukin 1β, and interleukin 6), as well as decreased activation of astrocytes in the spinal cord, were found after 4-PBA or GSK2606414 treatment. Conclusions Inhibition of inflammatory mediator–triggered endoplasmic reticulum stress in spinal neurons attenuates bone cancer pain via modulation of neuroinflammation, which suggests new approaches to pain relief.

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Effects of Caffeoylquinic Acid Derivatives and C-Flavonoid from Lychnophora ericoides on in vitro Inflammatory Mediator Production

Natural Product Communications ◽

10.1177/1934578x1000500512 ◽

2010 ◽

Vol 5 (5) ◽

pp. 1934578X1000500 ◽

Cited By ~ 6

Author(s):

Michel David dos Santos ◽

Guanjie Chen ◽

Maria Camila Almeida ◽

Denis Melo Soares ◽

Glória Emília Petto de Souza ◽

...

Keyword(s):

Inflammatory Mediators ◽

Cultured Cells ◽

Dependent Manner ◽

Caffeoylquinic Acid ◽

Inflammatory Mediator Production ◽

Dicaffeoylquinic Acid ◽

Tnf Α ◽

Dose Dependent Fashion ◽

Dose Dependent

In this study we aimed at evaluating the effect of the major polar constituents of the medicinal plant Lychnophora ericoides on the production of inflammatory mediators produced by LPS-stimulated U-937 cells. The 6,8-di- C-β-glucosylapigenin (vicenin-2) presented no effect on tumor necrosis factor (TNF)-α production, but inhibited, in a dose-dependent manner, the production of prostaglandin (PG) E2 without altering the expression of cyclooxygenase (COX) -2 protein. 3,5-Dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid, at lower concentrations, had small but significant effects on reducing PGE2 levels; at higher doses these compounds stimulated PGE2 and also TNF-α production by the cells. All the caffeoylquinic acid derivatives, in a dose-dependent fashion, were able to inhibit monocyte chemoattractant protein-3 synthesis/release, with 4,5-DCQ being the most potent at the highest tested concentration. These results add important information on the effects of plant natural polyphenols, namely vicenin-2 and caffeoylquinic acid derivatives, on the production of inflammatory mediators by cultured cells.

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