Mediators Of Chronic Inflammation Research Articles

Targeting leptin/CCL3-CCL4 axes in NAFLD/MAFLD: A novel role for BPF in counteracting thalamic inflammation and white matter degeneration

Non-alcoholic fatty liver disease (NAFLD), redefined as Metabolic Associated Fatty Liver Disease (MAFLD), is characterized by an extensive multi-organ involvement. MAFLD-induced systemic inflammatory status and peripheral metabolic alteration lead to an impairment of cerebral function. Herein, we investigated a panel of leptin-related inflammatory mediators as predictive biomarkers of neuroinflammation and evaluated the possible role of Bergamot Polyphenolic Fraction (BPF) in counteracting this MAFLD-induced inflammatory cascade. Male DIAMOND mice were randomly assigned to fed chow diet and tap water or high fat diet with sugar water. Starting from week 16, mice were further divided and treated with vehicle or BPF (50 mg/kg/day), via gavage, until week 30. Magnetic resonance imaging was performed at the baseline and at week 30. Correlation and regression analyses were performed to discriminate the altered lipid metabolism in the onset of cerebral alterations. Steatohepatitis led to an increase in leptin levels, resulting in a higher expression of proinflammatory mediators. The inflammatory biomarkers involved in leptin/CCL3-CCL4 axes were correlated with the altered thalamus energetic metabolism and the white matter degeneration. BPF administration restored leptin level, improved glucose and lipid metabolism, and reduced chronic low-grade inflammatory mediators, resulting in a prevention of white matter degeneration, alterations of thalamus metabolism and brain atrophy. The highlighted positive effect of BPF, mediated by the downregulation of the inflammatory biomarkers involved in leptin/CCL3-CCL4 axes, affording novel elements to candidate BPF for the development of a therapeutic strategy aimed at counteracting MAFLD-related brain inflammation.

Tooth Loss in Periodontitis Patients-A Risk Factor for Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.

Periodontal disease and tooth loss have been long suggested as risk factors of mild cognitive impairment. The underlying mechanisms could be systemic chronic inflammatory mediators, direct pathologic challenge to the nervous system, malnutrition and/or loss of neurosensory stimulation input causing brain atrophy. This review aimed to examine the existing literature studies linking the effect of periodontal disease and tooth loss on the development of mild cognitive impairment. A systematic review using PEO was conducted. Three electronic databases, namely Embase, Medline and DOSS (UCLan), were searched for relevant articles published up to April 2023. Google Scholar and a hand search were also conducted to ensure no relevant studies had been missed. The Newcastle-Ottawa scale was used to assess the quality of studies. The findings showed that chronic periodontitis and tooth loss, both individually and in combination, led to an increased risk of mild cognitive decline in adults over 50 years. Within the limitations of this review, periodontitis and tooth loss both contribute to an increased risk of mild cognitive impairment and dementia, but the evidence so far is not strong. In future, more robustly designed studies investigating periodontal disease and tooth losslink with cognitive health decline are required with a longer follow-up duration.

G-Protein and G-Protein Coupled Receptors: Implications in Regulation of Immune Response

The guanine nucleotide binding proteins (G proteins) act as molecular switches of ‘on’ and ‘off’ when bound to GTP and GDP respectively while the guanine protein coupled receptors (GPCRs) are membrane bound receptors whereby extracellular substances (ligands)communicate signals from these substances to an intracellular molecule the G-proteins which in turn bind and activate or inhibit downstream effect or molecules causing cellular responses. This review is aimed at exploring the concept and mechanism of G-proteins and GPCR and their implication in immune response. The GPCR can be activated by various physiological or pathological processes cellular metabolism, hormones, neuro-transmitters, chemokines, autocrines, paracrines, endocrine and exocrine secretions which play an important role in relaying or routing signals to several intracellular pathways. The signal transduction by the extracellular activation or inhibition of the GPCR mediate metabolic enzymes, ion channels, transporters, cellular gene transcription, migration, survival, activation, differentiation and cytokine secretion of immune cells resulting in the synthesis and regulation of embryonic development, gonadal development, learning /memory organismal homeostasis, hematopoiesis and immune dynamics. Therefore, G proteins and GPCRs signaling systems are key determinants in innate and adaptive immunity. The signal transduction of G-Protein and GPCR by cytokine chemotaxis as Chronic inflammatory mediators is associated with tumorigenesis, metastasis with potential antagonism for appropriate targeted therapy.

The TNFSF12/TWEAK Modulates Colonic Inflammatory Fibroblast Differentiation and Promotes Fibroblast-Monocyte Interactions.

Fibroblasts acquire a proinflammatory phenotype in inflammatory bowel disease, but the factors driving this process and how fibroblasts contribute to mucosal immune responses are incompletely understood. TNF superfamily member 12 (TNFSF12, or TNF-like weak inducer of apoptosis [TWEAK]) has gained interest as a mediator of chronic inflammation. In this study, we explore its role as a driver of inflammatory responses in fibroblasts and its contribution to fibroblast-monocyte interaction using human primary colonic fibroblasts, THP-1 and primary monocytes. Recombinant human TWEAK induced the expression of cytokines, chemokines, and immune receptors in primary colonic fibroblasts. The TWEAK upregulated transcriptome shared 29% homology with a previously published transcriptional profile of inflammatory fibroblasts from ulcerative colitis. TWEAK elevated surface expression of activated fibroblast markers and adhesion molecules (podoplanin [PDPN], ICAM-1, and VCAM-1) and secretion of IL-6, CCL2, and CXCL10. In coculture, fibroblasts induced monocyte adhesion and secretion of CXCL1 and IL-8, and they promoted a CD14high/ICAM-1high phenotype in THP-1 cells, which was enhanced when fibroblasts were prestimulated with TWEAK. Primary monocytes in coculture with TWEAK-treated fibroblasts had altered surface expression of CD16 and triggering receptor expressed on myeloid cells-1 (TREM-1) as well as increased CXCL1 and CXCL10 secretion. Conversely, inhibition of the noncanonical NF-κB pathway on colonic fibroblasts with a NF-κB-inducing kinase small molecule inhibitor impaired their ability to induce a CD14high phenotype on monocytes. Our results indicate that TWEAK promotes an inflammatory fibroblast-monocyte crosstalk that may be amenable for therapeutic intervention.

Advanced glycation end products and breast cancer: a review of the literature

Advanced glycation end products (AGEs) are mediators of chronic inflammation, which is recognized as an underlying process in carcinogenesis. The role of AGEs in cancers is the focus of recent studies. Breast cancer (BC) is the most common cancer in the world and the etiology is unknown, but some risk factors have been defined; including obesity and diabetes. Both of these disorders are linked to AGEs; thus, BC and AGEs might be associated. AGEs in the human body either derive from the glycation of proteins and lipids in the blood, or from the dietary AGEs (dAGE). AGEs are mainly associated with disease states or aging, including diabetes mellitus, cardiovascular and cerebrovascular disorders, Alzheimer, renal failure, arthritis, skin problems, viral infections, and osteoporosis. Some bioeffects of AGEs are consistent with the chain of events that occur during carcinogenesis. However, the studies about the role of AGEs in specific cancers are not conclusive, and some recent literature, especially clinical studies do not support the theory of the association between AGEs and cancers,. There does not exist a great deal of studies about the role of AGEs in BC, but the subject has been addressed recently. The present evidence is rather in favor of the association of AGEs and breast cancer; however, the direction and type of this association are unclear. In-vitro studies show that AGEs promote features of invasiveness in BC, but clinical studies show diverse findings. In this study, we present an overview of the core existing knowledge about AGEs and their relation with diseases; then provide a brief review of the results of studies that have investigated the association of AGEs and cancer, and then proceed to a concise discussion about studies on AGEs and BC.

Epigenetic changes underlie the association between diabetes mellitus and oral diseases.

Patients with diabetes mellitus (DM) suffer from oral complications related to oral infections, periodontal diseases, and endodontic lesions. Emerging evidence has revealed the contribution of the epigenetic process as the underlying mechanism of DM complications. DNA methylation, histone modifications, and non-coding RNAs are epigenetic regulators that directly affect gene expression. The present review elaborated on the role of epigenetic dysregulation in the etiology of diabetes-related periodontal and endodontic diseases. The narrative review study was prepared using databases such as PubMed, Google Scholar, Science Direct, and Scopus. The formation of glycation products as a result of hyperglycemic condition increases oxidative stress, and elevates chronic inflammatory mediators that could in turn adversely change the cellular environment and alter the epigenetic status. This process contributes to the alteration of regulatory genes expression, leading to the development of diabetes-induced bone complications and impaired odontogenic capacity of pulp. Indeed, epigenetic mechanisms mediate the interaction between gene expression and DM cellular environment. Further investigations on epigenetic factors involved in DM oral complications may provide novel therapeutic targets.

Effect of 12-Week Aerobic Exercise Training on Chemokine Ligands and Their Relative Receptors in Balb/C Mice with Breast Cancer

Background: Some chemokines like C C motif chemokine ligand (CCL) 2 and 5 and their receptors (CCR) 2 and 5 are mediators of chronic inflammation and cancer development. Moreover, physical exercise can increase the activity of antioxidant enzymes. However, its effect on cancer cells has not been reported at present. Objectives: Therefore, the present study aimed to ascertain the effect of 12-week aerobic exercise training (AET) on CCL2, CCR2, CCL5, and CCR5 in mice with breast cancer. Methods: Sixteen Balb/c mice aged 4 - 5 weeks (n = 16; approximate weight: 18 ± 2 g) were divided into two groups: AET group (AETG) and control group (CG) (n = 8 per group). The AETG performed 12-week treadmill running at 18 m/min for 40 min and five times a week. Plasma levels of CCL2 and CCL5 were measured by ELISA, and the CCR2 and CCR5 were evaluated by Western blotting. Two independent sample t-test was applied to compare the differences between AETG and CG. Results: The analysis displayed after 12 weeks showed a significant reduction in AETG compared to CG in CCL2 (3.94 ± 1.12 vs. 15.40 ± 3.29 pg/mL; P = 0.001), CCR2 (0.56 ± 0.19 vs. 1.00 ± 0.001; P = 0.002), CCL5 (138.59 ± 15.72 vs. 267.57 ± 49.06 ng/mL; P = 0.001) and CCR5 (0.36 ± 0.12 vs. 1.00 ± 0.001; P = 0.001), respectively. Conclusions: We concluded that one of the main mechanisms of a positive effect of exercise on breast cancer is reducing the inflammation via CCL2 and CCL5 and their related receptors CCR2 and CCR5, respectively. Since these molecules can be triggered off oxidative stress and tumorigenesis, these results can pave the way for further studies in this field.

Abstract 264: Neutrophil elastase (NE) inhibition enhances metastasis free survival by altering regulation of tumor intrinsic cytoskeletal and cellular adhesion pathways in murine breast cancer models

Abstract Background: Neutrophil elastase (NE), a serine protease exclusively secreted in neutrophils, is a crucial mediator of chronic inflammation and tumor progression. Studies from our group reveal that NE may be a prognostic marker of metastasis. In a cohort of 192 breast cancer patients (58% ER/PR+ve, 20%-HER-2 +ve and 22% TNBC), our results show that higher infiltration of NE-positive Tumor Associated Neutrophils (TANs), is associated with a decrease in recurrence free survival (hazard ratio=3.4, 95% CI, 1.1-5.5), regardless of breast cancer subtype Further, we observe that the genetic deletion of Elane (encoding NE) inhibits lung metastasis in in vivo models of breast cancer. Yet the precise mechanism(s) by which NE promotes tumorigenesis and metastasis of breast cancer remains to be elucidated. To address this gap in knowledge, we have identified the tumor-intrinsic and -extrinsic mechanisms by which NE promotes metastasis. Methods: The role of NE in breast cancer metastasis was assessed using Elane+/+ and Elane-/- mice in FVB/NJ genetic background, bearing PyMT tumors (orthotopic and spontaneous) respectively. These mice develop lung metastasis in 80-90% of the tumor-bearing mice within 1-3 months of primary tumor initiation. To assess metastasis-free survival (MFS), mice received orthotopic engraftment of PyMT tumors, followed by resection and subsequent monitoring for metastasis. The efficacy of the NE inhibitor AZD9668 was assessed in Elane+/+ mouse models by treating the mice with 100mg/kg B.I.D treatments. Preliminary results: Genetic ablation of NE (Elane-/-) in the PyMT models, reduced lung metastasis by ~90% (Lung metastatic index =21.8 vs. 2.7, respectively; p=0.0044). Survival studies in FVB Elane-/- showed a MFS benefit of 345 days compared to controls, which succumbed to metastasis-related death in 46 days post primary tumor resection. RNA-sequencing analysis of PyMT- Elane+/+ and Elane-/- tumors showed differential regulation of tumor intrinsic actin cytoskeleton and integrin signaling pathways between the two genetic backgrounds. These NE-regulated pathways are critical for cell-to-cell contact and tissue integrity, explaining the delay in metastasis in the Elane-/- mice. 100mg/kg daily treatment of AZD9668 reduced lung metastasis in PyMT mice by 94% compared to vehicle-treated mice (0.49+/- 0.21% vs. 0.03+/-0.01%; p=0.05) and significantly reduced instances of primary tumor recurrence. Conclusions: Collectively, our studies suggest that genetic and pharmacological ablation of NE reduces metastasis and extends MFS in in vivo models of breast cancer. Our preclinical studies presented here are likely to provide the much-needed rationale for the use of this class of NE inhibitors as a viable treatment strategy for the metastatic breast cancer. Citation Format: Amriti R. Lulla, Said Akli, Lucas D. Warma, Natalie W. Fowlkes, Kelly K. Hunt, Xiayu Rao, Jing Wang, Stephanie S. Watowich, Khandan Keyomarsi. Neutrophil elastase (NE) inhibition enhances metastasis free survival by altering regulation of tumor intrinsic cytoskeletal and cellular adhesion pathways in murine breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 264.

Single-cell transcriptomic and chromatin accessibility analyses of dairy cattle peripheral blood mononuclear cells and their responses to lipopolysaccharide

BackgroundGram-negative bacteria are important pathogens in cattle, causing severe infectious diseases, including mastitis. Lipopolysaccharides (LPS) are components of the outer membrane of Gram-negative bacteria and crucial mediators of chronic inflammation in cattle. LPS modulations of bovine immune responses have been studied before. However, the single-cell transcriptomic and chromatin accessibility analyses of bovine peripheral blood mononuclear cells (PBMCs) and their responses to LPS stimulation were never reported.ResultsWe performed single-cell RNA sequencing (scRNA-seq) and single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) in bovine PBMCs before and after LPS treatment and demonstrated that seven major cell types, which included CD4 T cells, CD8 T cells, and B cells, monocytes, natural killer cells, innate lymphoid cells, and dendritic cells. Bioinformatic analyses indicated that LPS could increase PBMC cell cycle progression, cellular differentiation, and chromatin accessibility. Gene analyses further showed significant changes in differential expression, transcription factor binding site, gene ontology, and regulatory interactions during the PBMC responses to LPS. Consistent with the findings of previous studies, LPS induced activation of monocytes and dendritic cells, likely through their upregulated TLR4 receptor. NF-κB was observed to be activated by LPS and an increased transcription of an array of pro-inflammatory cytokines, in agreement that NF-κB is an LPS-responsive regulator of innate immune responses. In addition, by integrating LPS-induced differentially expressed genes (DEGs) with large-scale GWAS of 45 complex traits in Holstein, we detected trait-relevant cell types. We found that selected DEGs were significantly associated with immune-relevant health, milk production, and body conformation traits.ConclusionThis study provided the first scRNAseq and scATAC-seq data for cattle PBMCs and their responses to the LPS stimulation to the best of our knowledge. These results should also serve as valuable resources for the future study of the bovine immune system and open the door for discoveries about immune cell roles in complex traits like mastitis at single-cell resolution.

Effect of 12-Week Aerobic Exercise Training on Chemokine Ligands and Their Relative Receptors in Balb/C Mice with Breast Cancer

Background: Some chemokines like C C motif chemokine ligand (CCL) 2 and 5 and their receptors (CCR) 2 and 5 are mediators of chronic inflammation and cancer development. Moreover, physical exercise can increase the activity of antioxidant enzymes. However, its effect on cancer cells has not been reported at present. Objectives: Therefore, the present study aimed to ascertain the effect of 12-week aerobic exercise training (AET) on CCL2, CCR2, CCL5, and CCR5 in mice with breast cancer. Methods: Sixteen Balb/c mice aged 4 - 5 weeks (n = 16; approximate weight: 18 ± 2 g) were divided into two groups: AET group (AETG) and control group (CG) (n = 8 per group). The AETG performed 12-week treadmill running at 18 m/min for 40 min and five times a week. Plasma levels of CCL2 and CCL5 were measured by ELISA, and the CCR2 and CCR5 were evaluated by Western blotting. Two independent sample t-test was applied to compare the differences between AETG and CG. Results: The analysis displayed after 12 weeks showed a significant reduction in AETG compared to CG in CCL2 (3.94 ± 1.12 vs. 15.40 ± 3.29 pg/mL; P = 0.001), CCR2 (0.56 ± 0.19 vs. 1.00 ± 0.001; P = 0.002), CCL5 (138.59 ± 15.72 vs. 267.57 ± 49.06 ng/mL; P = 0.001) and CCR5 (0.36 ± 0.12 vs. 1.00 ± 0.001; P = 0.001), respectively. Conclusions: We concluded that one of the main mechanisms of a positive effect of exercise on breast cancer is reducing the inflammation via CCL2 and CCL5 and their related receptors CCR2 and CCR5, respectively. Since these molecules can be triggered off oxidative stress and tumorigenesis, these results can pave the way for further studies in this field.

Chronic Inflammation and the Acceleration of Chronic Disease States

The chronic activation of the immune system is commonly observed in older adults, and is highly associated with multiple chronic disease states and Geriatric syndromes including physical frailty, sarcopenia and mild cognitive impairment. Chronic inflammation is multifactorial, and the individual inflammatory mediators that drive the development and propagation of disease states impact normal tissue homeostasis as well as stem cell vitality. This session will discuss age-related etiologies of chronic inflammation and specific inflammatory mediators and their measurement, including Tumor Necrosis Factor (TNF) alpha and its receptors. Inflammation-driven molecular pathways that most impact relevant chronic disease states such as the tryptophan degradation pathway, and its relationship to pathophysiological changes, will also be considered. Finally, discussion of potential treatment modalities, including several emerging from Geroscience research, will be described as will their impact on chronic disease states.

Ipilimumab, nivolumab and tocilizumab as first-line therapy for advanced melanoma.

TPS9589 Background: Interleukin 6 (IL-6) functions in the maintenance of hepatocytes, haemotopoietic progenitor cells, a variety of other tissues, and regulates the innate and adaptive immune system. IL-6 may play a role as a chronic inflammatory mediator in altering levels of acute phase proteins synthesized by the liver and circulating myeloid cells which have been shown to be associated with short survival with checkpoint inhibition and which are immune suppressive. The immunomodulatory properties of interleukin-6 may in part also be responsible for immune related adverse events, given the reversal of those toxicities observed with IL-6 receptor blockade in clinical practice. To assess if blockade of IL-6 binding is associated with a decrease in irAEs and/or an increase in efficacy defined as overall response rate (ORR) at week 24 in patients receiving ICB, we added tocilizumab to ipilimumab and nivolumab therapy. Methods: The current phase II trial is a two-stage design to assess the safety, tolerability, and grades 3-5 immune related toxicities of tocilizumab administered every 6 weeks up to week 24 in combination with ipilimumab at 1 mg/kg and nivolumab at 3 mg/kg every 3 weeks for 4 doses each during a 12 week induction period, then administered every 6 weeks with nivolumab at 240 mg flat dose every 2 weeks in maintenance for up to 24 weeks, and nivolumab alone will be given at 480 mg flat dose every 4 weeks thereafter for up to 2 years. Eligible patients include those age 18 or older with measurable and unresectable stages III/IV melanoma (cutaneous, acral, mucosal), without prior systemic treatment for metastatic disease. Adjuvant therapy (IFN-alpha, ipilimumab and/or nivolumab, or pembrolizumab) is allowed. Patients with metastatic melanoma of brain are allowed, if neurologically stable and off immunosuppressive steroids. A total of 18 patients will be treated in the first stage, and 49 additional patients in the second stage for a total of 67. The comparator data are from the N3I1 arm of Checkmate-511 trial, in which treatment-related grades 3-5 irAEs were 33.9% with a 45.6% response rate (1). Prespecified activity goal for the first stage of accrual has been met; second stage accrual began in January 2021.

Značaj određivanja C-reaktivnog proteina kod obolelih sa metaboličkim sindromom

Objecive. Previous research has shown that CRP is elevated in patients with metabolic syndrome (MS) and that low-intensity inflammation is a characteristic of MS. The aim of this study was to determine the concentration of CRP and to examine the significance of elevated CRP in MS patients. Methods. The study included 149 outpatients, 67 patients with MS (68.9 ± 8.7 years) and 82 subjects who were in the control group of the appropriate age (68.9 ± 8.6 years) (p> 0.05). CRP was determined by turbidimetry and the reference range was up to 5.0 mg / L. Results. The average CRP concentration for MS patients was 5.33 ± 3.60 mg / L, while in the control group the CRP concentration value was 4.60 ± 2.03 mg / L (p <0.001). There was no significant difference in CRP concentrations between men (6.02 ± 4.88 mg / L) and women with MS (4.97 ± 2.87 mg / L) (p> 0.05). Almost a third of patients (29.8%) and only 6.1% of subjects in the control group had a CRP concentration greater than 5 mg / L (p <0.01). Conclusion. A significantly higher frequency of elevated serum CRP concentrations in individuals with MS, compared to those without MS, indicates both the importance of inflammation in the pathogenesis of MS and CRP being biomarkers and mediators of chronic inflammation.

Inhibitors of cytoskeletal dynamics in malignant mesothelioma.

Malignant mesotheliomas (MMs) are highly aggressive mesenchymal tumors that originate from mesothelial cells lining serosal cavities; i.e., the pleura, peritoneum, and pericardium. Classically, there is a well-established link between asbestos exposure, oxidative stress, release of reactive oxygen species, and chronic inflammatory mediators that leads to progression of MMs. MMs have an intermediate phenotype, with co-expression of mesenchymal and epithelial markers and dysregulated communication between the mesothelium and the microenvironment. We have previously shown that the organization and function of key cytoskeletal components can distinguish highly invasive cell lines from those more indolent. Here, we used these tools to study three different types of small-molecule inhibitors, where their common feature is their influence on production of reactive oxygen species. One of these, imipramine blue, was particularly effective in counteracting some key malignant properties of highly invasive MM cells. This opens a new possibility for targeted inhibition of MMs based on well-established molecular mechanisms.

Targeting Mediators Of Chronic Inflammation: A Promising Alternative Therapeutic Use Of Plant-Derived Remedies With Potent Bioactivity And Lower Cytotoxicity

Abstract Introduction/Objective Medicinal plants have a long history of use and has been exploited for basic health care needs for many centuries. The various parts of plants are rich sources of a plethora of pharmacologically active remedies that has remained largely unexplored for their therapeutic capabilities. Grewia mollis is one of the medicinal plants that are used to treat painful inflammatory conditions including rheumatism and associated fever. The inhibition of enzymes involved in prostaglandin (PG) synthesis are of great interest in combating chronic inflammation. Cyclooxygenases (COX) and Lipoxygenases (LOX), in particular COX-2 and 5-LOX utilize different pathways for PG synthesis and are important drivers of chronic inflammation. However, the use of conventional anti-inflammatory drugs and specific enzyme inhibitors against them are associated with severe adverse side-effects and organ toxicities. Therefore, attention has shifted to the search for potent and safer alternative strategies to treat chronic inflammation involving these mediators Methods The leaf part of G. mollis was extracted with solvents of varying polarities. The extracts were tested in vitro against COX-1, 2 and 5-LOX. In addition, the cytotoxicity and selectivity index of the plant extracts were evaluated using vero monkey kidney cells Results The hexane fraction of G. mollis leaf extracts had better inhibition against COX-1 (0,97±1,9 µg/mL) and COX-2 (1,13±0,2 µg/mL) when compared with the indomethacin control (1,30±0,6 µg/mL) and (1,52±0,2 µg/mL) respectively. Also, the butanol fraction inhibited 5-LOX (12,48±2,9 µg/mL) better than quercetin positive control (61,82±5,5 µg/mL). Overall, the extracts and fractions indicated reduced cytotoxicity (30,56-689,39 µg/mL) relative to the doxorubicin control (2,59 µg/mL). Conclusion The results indicated that extracts of G. mollis contained bioactive molecules capable of inhibiting the activities of C0X and 5-LOX with lower cytotoxicity. Pharmacologically active molecules with safety profile could be used, at least as a part of the template for remedies against mediators of chronic inflammation

Effects of TNF‐Alpha on TGF‐Beta Expression in Human Skeletal Muscle Cells: A Cell Model for Inflammation

Approximately 25.3 million adults suffer from chronic pain, often caused by chronic inflammatory conditions. We hypothesize that chronic inflammation negatively alters myofascial tissue structure and function. To better understand this process and test our hypothesis, we are developing a cell model to examine chronic inflammation in myofascial tissue. The goal of this investigation is to determine if chronic inflammation changes cell signaling of the myofascial tissue and lead to fibrosis. Human skeletal muscle (HSkM) cells and human fibroblasts make up the myofascial tissue. Therefore, we will first examine the relationship between the chronic inflammatory mediator, TNF‐alpha, and HSkM cell expression of TGF‐beta. We find that TNF‐alpha increases expression of TGF‐beta in HSkM cells changing the cell phenotype to a fibrotic state.

Middle-Aged Indians with Type 2 Diabetes Are at Higher Risk of Biological Ageing with Special Reference to Serum CDKN2A.

Sedentary lifestyle and high visceral adiposity have elevated the risk of type 2 diabetes (T2DM) among Indians at younger age. In this study, we aimed to investigate the association of oxidative stress and chronic inflammatory mediators with ageing with special reference to the biological ageing marker cyclin-dependent kinase inhibitor 2A (CDKN2A) among middle-aged (31-50 years) Indian healthy and T2DM subjects. Malondialdehyde (MDA), oxidized LDL (oxLDL), interleukin-6 (IL-6), interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and CDKN2A were measured in T2DM patients (n = 80) and controls (n = 80) aged 31-50 years, further grouped into G1: 31-40 years and G2: 41-50 years. IL-6, TNF-α, MCP-1, and CDKN2A showed a significant association with ageing among both T2DM patients and controls. But the strength of the association of MCP-1 and CKDN2A with ageing was significantly stronger in T2DM patients than the controls. All the oxidative stress and proinflammatory mediators showed nonsignificant associations with CDKN2A in the controls. However, IL-6, TNF-α, and MCP-1 showed a strong association with CDKN2A in T2DM patients. An increased risk of high levels of CDKN2A was found in G1 T2DM patients (OR: 3.484 (95% CI: 1.246-9.747) p = 0.017) and G2 T2DM patients (OR: 5.000 (95% CI: 1.914-13.061), p = 0.001) with reference to the respective control groups. Our study reveals that the middle-aged Indians with T2DM are at higher risk of biological ageing. The development of T2DM is more common among middle-aged Indians. T2DM may exacerbate the ageing process and may subsequently predispose Indians to various age-related complications at a much early age.

IL-6 produced by prostate epithelial cells stimulated with Trichomonas vaginalispromotes proliferation of prostate cancer cells by inducing M2 polarization of THP-1-derived macrophages.

Trichomonas vaginalis (Tv), a protozoan parasite causing sexually-transmitted disease, has been detected in tissue of prostatitis, benign prostatic hyperplasia (BPH) and prostate cancer (PCa). IL-6, a mediator of chronic inflammation, induces the progression of prostate cancer, and influences the polarization of M2 macrophages, which are the main tumor-associated macrophages. We investigated whether IL-6 produced by human prostate epithelial cells stimulated with Tv induces the M2 polarization of THP-1-derived macrophages, which in turn promotes the progression of PCa. Conditioned medium was prepared from Tv-infected (TCM) and uninfected (CM) prostate epithelial cells (RWPE-1). Thereafter conditioned medium was prepared from macrophages after incubation with CM (M-CM) or TCM (M-TCM). RWPE-1 cells infected with Tv produced IL-6 and chemokines such as CCL2 and CXCL8. When human macrophages were treated with conditioned medium of RWPE-1 cells co-cultured with Tv (TCM), they became polarized to M2-like macrophages as indicated by the production of IL-10 and TGF-β, and the expression of CD36 and arginase-1, which are M2 macrophage markers. Moreover, proliferation of the M2-like macrophages was also increased by TCM. Blockade of IL-6 signaling with IL-6 receptor antibody and JAK inhibitor (Ruxolitinib) inhibited M2 polarization of THP-1-derived macrophages and proliferation of the macrophages. To assess the effect of crosstalk between macrophages and prostate epithelial cells inflamed by Tv infection on the growth of prostate cancer (PCa) cells, PC3, DU145 and LNCaP cells were treated with conditioned medium from THP-1-derived macrophages stimulated with TCM (M-TCM). Proliferation and migration of the PCa cells were significantly increased by the M-TCM. Our findings suggest that IL-6 produced in response to Tv infection of the prostate has an important effect on the tumor microenvironment by promoting progression of PCa cells following induction of M2 macrophage polarization.

Should All Men with Type 2 Diabetes Be Routinely Prescribed a Phosphodiesterase Type 5 Inhibitor?

Important health problems in men such as type 2 diabetes (T2DM), insulin resistance, erectile dysfunction, benign prostatic hyperplasia and depression have been shown to have to share common pathological processes, such as endothelial dysfunction and inflammation. This paper discusses the role of phosphodiesterase type 5 (PDE5) inhibitors, through beneficial effects on endothelial function and mediators of chronic inflammation and the possibility to treat or preventing these common conditions. We explore possible barriers to this approach, namely the lack of multiple product licences to treat each of these conditions and how these can be overcome by involving the patient in personalised decisions. We also discuss how opportunities are lost by patients with multiple medical conditions being referred to specialists, primarily interested in one specific problem, with little motivation to treat or prevent conditions outside their remit. We explore how these problems might be related to time and financial restraints or simply a lack of awareness of evidence published in journals related to other specialities. As specialists, we often pride ourselves on providing “personalised” or “patient centred” care, but we can only truly be doing so if we assess the specific needs of the patient across a range of conditions. As part of personalised care in T2DM, we routinely prescribe statins, angiotensin converting enzyme inhibitors and metformin, often with poor compliance. In this paper we explore whether the licensed daily PDE5 inhibitor tadalafil should be added routinely to this list as it will potentially improve and prevent bothersome symptoms and improve compliance with other medications.

Elevated plasma and synovial fluid interleukin-8 and interleukin-18 may be associated with the pathogenesis of knee osteoarthritis

PurposeOsteoarthritis (OA) of the knee is a multifactorial degenerative disease typically defined as the ‘wear and tear’ of articular joint cartilage. However, recent studies suggest that OA is a disease arising from chronic low-grade inflammation. We conducted a study to investigate the relationship between chronic inflammatory mediators present in both the systemic peripheral blood system and localised inflammation in synovial fluid (SF) of OA and non-OA knees; and subsequently made direct comparative analyses to understand the mechanisms that may underpin the processes involved in OA. Methods20-Plex proteins were quantified using Human Magnetic Luminex® assay (R&D Systems, USA) from plasma and SF of OA (n = 14) and non-OA (n = 14) patients. Ingenuity Pathway Analysis (IPA) software was used to predict the relationship and possible interaction of molecules pertaining to OA. ResultsThere were significant differences in plasma level for matrix metalloproteinase (MMP)-3, interleukin (IL)-27, IL-8, IL-4, tumour necrosis factor-alpha, MMP-1, IL-15, IL-21, IL-10, and IL-1 beta between the groups, as well as significant differences in SF level for IL-15, IL-8, vascular endothelial growth factor (VEGF), MMP-1, and IL-18. Our predictive OA model demonstrated that toll-like receptor (TLR) 2, macrophage migration inhibitory factor (MIF), TLR4 and IL-1 were the main regulators of IL-1B, IL-4, IL-8, IL-10, IL-15, IL-21, IL-27, MMP-1 and MMP-3 in the plasma system; whilst IL-1B, TLR4, IL-1, and basigin (BSG) were the regulators of IL-4, IL-8, IL-10, IL-15, IL-18, IL-21, IL-27, MMP-1, and MMP-3 in the SF system. ConclusionThe elevated plasma IL-8 and SF IL-18 may be associated with the pathogenesis of OA via the activation of MMP-3.