A Systematic Review and Meta-Analysis on Multiple Cytokine Gene Polymorphisms in the Pathogenesis of Periodontitis

AimPeriodontitis is an inflammatory disease that destroys both soft and hard periodontal tissues. However, a complex periodontal cytokine network remains unclear. This systematic review explored multiple cytokine gene polymorphisms in the pathogenesis of periodontitis.Material and MethodsA systematic search was performed using the databases from previous publications, which indicated the association between cytokine polymorphisms and periodontitis pathogenesis. Meta-analysis was conducted using fixed or randomized models to calculate the significance of multiple cytokine polymorphisms. A total of 147 articles were analyzed with polymorphisms in 12 interleukins [Th1 (IL-2, IFN-γ, and TNF-α), Th2 (IL-4 and IL-13), Th17 (IL-1α, IL-1β, IL-6, and IL-17), and Treg cytokines (IL-10 and TGF-β)]. Doi plot was used to probe the occurrence of publication bias.ResultsThe polymorphisms of IL-2 and TNF-α of Th1 cytokine family may be associated with the pathogenesis or the prevention of periodontitis risk, while the polymorphism of IFN-γ is not related to periodontitis risk. The polymorphisms for IL-4 and IL-13 of Th2 cytokine family are not found to be associated with the pathogenesis of periodontitis. For the polymorphisms of the members of Th17 cytokine family, different IL-1α polymorphisms may have inverse actions in the pathogenesis of periodontitis. IL-1β is a noteworthy cytokine biomarker in periodontitis development and progression. IL-6 may have a protective function in the inflammatory responses of periodontitis, and IL-17 has a weak relationship the inflammatory responses. The polymorphisms for the members of Treg cell cytokines may have a protective function against periodontitis risk. LFK indexes show the major asymmetry due to publication bias.ConclusionIL-1β is a notable cytokine biomarker in periodontitis risk. Treg cytokines favor an anti-inflammatory and protective environment. Further data are needed to confirm the present conclusion due to publication bias.

Cytokine Gene Polymorphism and Cancer Risk: A Promising Tool for Individual Susceptibility and Prognostic Implications

Cytokines are potent molecules produced mainly by specific activated immune cells to control inflammatory responses besides other biologic processes. Although active participation of cytokines provides defense against carcinogenesis on the other hand, deregulation at the genetic level influences their activity to promote tumor development. Among many aspects, constitutional polymorphic sequence variations are key factors that derange the cytokine expression to lead an individual’s propensity to risk for different cancers. Cytokine polymorphisms are now believed to alter these critical molecules that have a dual face in carcinogenesis as, when implicated in the activation of the immune response, these molecules check the cancer development while their persistent inflammatory reaction can envisage the development of malignancy and tumor growth. We have given ample evidence of case-control studies in a range of cancers where substantial evidence, as reported in this chapter, links polymorphism of cytokine gene susceptibility with numerous cancers. Cytokine gene polymorphism is vital to be significant bimolecular genetic determinants of susceptibility and prognosis of cancer. A strong need is felt for more case-control association studies in cytokine candidate genes involved in specific pathways for particular cancer in bigger powered sample sizes involving additional variables to disclose their factual risk for cancer.

Effects of Dietary Supplementation with Mushroom or Vitamin D2-Enriched Mushroom Powders on Gastrointestinal Health Parameters in the Weaned Pig

The objective of this study was to compare the molecular, physiological and microbial effects of mushroom powder (MP), vitamin D2 enriched mushroom powder (MPD2) and zinc oxide (ZnO) in pigs post-weaning. Pigs (four pigs/pen; 12 pens/treatment) were assigned to: (1) basal diet (control), (2) basal diet + ZnO, (3) basal diet + MP (2 g/kg feed) and (4) basal diet + MPD2 (2 g/kg feed). Zinc oxide supplementation improved the feed intake (p < 0.001); increased the caecal abundance of Lactobacillus (p < 0.05); increased the villus height (p < 0.05) in the duodenum, jejunum and ileum; increased the expression of chemokine interleukin 8 (CXCL8; p < 0.05); and decreased the expression of pro-inflammatory cytokine gene interleukin 6 (IL6; p < 0.05), tumour necrosis factor (TNF; p < 0.05), nutrient transporters peptide transporter 1 (SLC15A1; p < 0.05) and fatty acid binding protein 2 (FABP2; (p < 0.05) in the duodenum. Whereas dietary supplementation with MPD2 improved the gastrointestinal morphology (p < 0.05); increased the total volatile fatty acid concentrations (p < 0.05); increased the expression of anti-inflammatory cytokine gene interleukin 10 (IL10; p < 0.05) and nutrient transporters SLC15A1 (p < 0.05), FABP2 (p < 0.05) and vitamin D receptor (VDR; p < 0.05); and reduced the expression of pro-inflammatory cytokine gene IL6 (p < 0.05), it adversely affected average daily feed intake (ADFI; p < 0.001) and average daily gain (ADG; p < 0.05). Mushroom powder supplementation had a positive impact on gastrointestinal morphology (p < 0.05) and upregulated the expression of nutrient transporters SLC15A1 (p < 0.05) and FABP2 (p < 0.05) and tight junction claudin 1 (CLDN1) (p < 0.05) compared to the controls but had no effect on the expression of inflammatory markers (p > 0.05). Furthermore, MP reduced ADFI (p < 0.01); however, this did not negatively impact the ADG (p > 0.05). In conclusion, MP and MPD2 have limited use as commercial feed additives in replacing ZnO in pig diets as feed intake was reduced post-weaning.

Adipose Tissue Inflammation is Not Related to Adipose Insulin Resistance in Humans

The role of adipose tissue (AT) inflammation on AT function in humans is unclear. We tested whether AT macrophage (ATM) content, cytokine gene expression and senescent cell burden (markers of AT inflammation) predict AT insulin resistance measured as the insulin concentration that suppresses lipolysis by 50% (IC₅₀). We studied 86 volunteers with normal weight or obesity at baseline, and a subgroup of 25 volunteers with obesity before and after weight loss. There was a strong, positive relationship between IC₅₀and abdominal subcutaneous and femoral fat cell size (FCS). The positive, univariate relationships between IC₅₀and abdominal AT inflammatory markers: CD68, CD14, CD206 ATM/100 adipocytes, senescent cells, IL-6 and TNF-α mRNA were not significant after adjustment for FCS. A 10% weight loss significantly reduced IC₅₀, however, there was no reduction in adipose ATM content, senescent cells or cytokine gene expression. Our study suggests that commonly used markers of AT inflammation are not causally linked to AT insulin resistance, whereas FCS is a strong predictor of AT insulin resistance with respect to lipolysis.

Adipose Tissue Inflammation is Not Related to Adipose Insulin Resistance in Humans

The role of adipose tissue (AT) inflammation on AT function in humans is unclear. We tested whether AT macrophage (ATM) content, cytokine gene expression and senescent cell burden (markers of AT inflammation) predict AT insulin resistance measured as the insulin concentration that suppresses lipolysis by 50% (IC₅₀). We studied 86 volunteers with normal weight or obesity at baseline, and a subgroup of 25 volunteers with obesity before and after weight loss. There was a strong, positive relationship between IC₅₀and abdominal subcutaneous and femoral fat cell size (FCS). The positive, univariate relationships between IC₅₀and abdominal AT inflammatory markers: CD68, CD14, CD206 ATM/100 adipocytes, senescent cells, IL-6 and TNF-α mRNA were not significant after adjustment for FCS. A 10% weight loss significantly reduced IC₅₀, however, there was no reduction in adipose ATM content, senescent cells or cytokine gene expression. Our study suggests that commonly used markers of AT inflammation are not causally linked to AT insulin resistance, whereas FCS is a strong predictor of AT insulin resistance with respect to lipolysis.

Intravesical High Dose BCG Tokyo and Low Dose BCG Tokyo with GMCSF+IFN α Induce Systemic Immunity in a Murine Orthotopic Bladder Cancer Model

This study evaluates a short therapy schedule for bladder cancer using BCG Tokyo. BCG Tokyo was evaluated in vitro using bone marrow derived dendritic cells, neutrophils, RAW macrophages and the murine bladder cancer cell line, MB49PSA, and compared to other BCG strains. BCG Tokyo > BCG TICE at inducing cytokine production. In vivo, high dose (1 × 107 colony forming units (cfu)) and low dose (1 × 106 cfu) BCG Tokyo with and without cytokine genes (GMCSF + IFNα) were evaluated in C57BL/6J mice (n = 12–16 per group) with orthotopically implanted MB49PSA cells. Mice were treated with four instillations of cytokine gene therapy and BCG therapy. Both high dose BCG alone and low dose BCG combined with cytokine gene therapy were similarly effective. In the second part the responsive groups, mice (n = 27) were monitored by urinary PSA analysis for a further 7 weeks after therapy cessation. More mice were cured at day 84 than at day 42 confirming activation of the immune system. Cured mice resisted the re-challenge with subcutaneous tumors unlike naïve, age matched mice. Antigen specific T cells recognizing BCG, HY and PSA were identified. Thus, fewer intravesical instillations, with high dose BCG Tokyo or low dose BCG Tokyo with GMCSF + IFNα gene therapy, can induce effective systemic immunity.

Optimized QRT-PCR Approach for the Measurable Impact of Adjuvant Cholecalciferol Therapy in Ameliorating Cytokine Gene Expression

The endemic Vitamin D deficiency in Pakistan and the current COVID-19 epidemic have converged into a double whammy scenario in Pakistan [1]. Nutritional epigenomic studies have highlighted Vitamin D as a master Vitamin influencing various genomic expressions through its active metabolite 1α,25-dihydroxyvitamin D3 [2]. The objective of this study was to evaluate the measurable impact of adjuvant Cholecalciferol therapy in the Cytokine gene expression of COVID-19 patients by quantitative Real-Time Polymerase Chain Reaction analysis. The trial was a randomized control prospective open label interventional trial done on moderate to severe COVID-19 patients with deranged inflammatory and coagulation biomarkers. SunnyD STAT (Vitamin D3 200000 IU) softgels were given at Day 1, Day 3 and Day 5 of the treatment. Optimized quantitative Real-Time Polymerase Chain Reaction analysis showed decreased genetic expressions of Interleukin 6 (IL-6), Interleukin 2RA (IL-2RA) and Tumor Necrosis Factor (TNF-a) in the interventional group against the age and co-morbidities matched controls, providing molecular and genetic level evidence for the purported mechanism of amelioration of Cytokines induced pathogenic inflammation. However, inherent limitations of the design restrict the generalizability of the results and warrants caution for extrapolation. We recommend randomized placebo-controlled trials with larger sampling and genome wide profiling to infer more definite interpretations.

EXAMINING LOCALLY EXPRESSED mRNA OF INFLAMMATORY MEDIATOR GENES IN A MODEL OF RETINAL PIGMENT EPITHELIUM ATROPHY AND RETINAL DEGENERATION INDUCED BY SUBRETINAL SALINE INJECTION IN RABBITS

Degenerative-dystrophic retinal diseases, particularly age-related macular degeneration (AMD), are now considered to be the lead cause of blindness and low vision in developed countries, with a steadily increasing trend. Recent publications provide evidence for the involvement of inflammatory mechanisms in TMD development and progression unveiled due to advances in innate and adaptive immunity research. However, the immunopathogenesis of atrophic AMD form, “geographic atrophy” (GA) remains largely unstudied. Objective: to investigate local mRNA expression of inflammatory cytokines IL-1β, IL-18, CCL2/MCP-1 in a model of RPE atrophy induced after subretinal injection of 0.9% sodium chloride solution in experimental rabbits. The investigation was carried out in tissue complex retina-RPE-choroid (TC) samples isolated from eyes of 23 albino New Zealand rabbits after modeling RPE atrophy by subretinal injection of 0.9% sodium chloride solution and 5 healthy rabbits lacking eye lesions. Animals in the experimental group (one week before surgical intervention, in the early period, and in the period of sustained RPE atrophy formation) and controls were subjected to optical coherence tomography (OCT) and ocular fundus autofluorescence (FAF). Evaluation of proinflammatory cytokine gene expression levels in TC was performed by RT-PCR. Results. Subretinal injection of 0.01 ml of 0.9% sodium chloride solution induced experimental RPE atrophy development in rabbits vs. control that was associated with multidirectional changes of IL-1β, IL-18, MCP-1/CCL2 gene mRNA expression. Three types of response in the TC, formed during development of atrophic changes and determined by the value of local cytokine gene expression were characterized: 1) hypo/ no response – decreased/no expression; 2) normal response – moderate increase; 3) hyper response – overexpression. 69.6% of animals with persistent atrophy had a moderate to hypertrophic increase in locally expressed mRNA MCP-1/CCL2, whereas 30% cases had significantly increased IL-1β mRNA expression – factors damaging the blood-retinal barrier and contributing to posterior segment immune privilege. It should be taken into account while developing new strategies for treatment of ophthalmic pathology, in particular the currently actively studied and tested options for RPE stem cell transplantation into subretinal space. The data obtained may be useful to investigate various types of RPE atrophy and develop new strategies of ophthalmopathology treatment in preclinical studies.