Exploring metabolic dysfunction in chronic kidney disease

Abstract Impaired kidney function and chronic kidney disease (CKD) leading to kidney failure and end-stage renal disease (ESRD) is a serious medical condition associated with increased morbidity, mortality, and in particular cardiovascular disease (CVD) risk. CKD is associated with multiple physiological and metabolic disturbances, including hypertension, dyslipidemia and the anorexia-cachexia syndrome which are linked to poor outcomes. Specific hormonal, inflammatory, and nutritional-metabolic factors may play key roles in CKD development and pathogenesis. These include raised proinflammatory cytokines, such as interleukin-1 and −6, tumor necrosis factor, altered hepatic acute phase proteins, including reduced albumin, increased C-reactive protein, and perturbations in normal anabolic hormone responses with reduced growth hormone-insulin-like growth factor-1 axis activity. Others include hyperactivation of the renin-angiotensin aldosterone system (RAAS), with angiotensin II and aldosterone implicated in hypertension and the promotion of insulin resistance, and subsequent pharmacological blockade shown to improve blood pressure, metabolic control and offer reno-protective effects. Abnormal adipocytokine levels including leptin and adiponectin may further promote the insulin resistant, and proinflammatory state in CKD. Ghrelin may be also implicated and controversial studies suggest activities may be reduced in human CKD, and may provide a rationale for administration of acyl-ghrelin. Poor vitamin D status has also been associated with patient outcome and CVD risk and may indicate a role for supplementation. Glucocorticoid activities traditionally known for their involvement in the pathogenesis of a number of disease states are increased and may be implicated in CKD-associated hypertension, insulin resistance, diabetes risk and cachexia, both directly and indirectly through effects on other systems including activation of the mineralcorticoid receptor. Insight into the multiple factors altered in CKD may provide useful information on disease pathogenesis, clinical assessment and treatment rationale such as potential pharmacological, nutritional and exercise therapies

β-Adrenergic system, a backstage manipulator regulating tumour progression and drug target in cancer therapy

Abstractβ-Adrenoceptors are broadly distributed in various tissues of the body. Stress hormones regulate a panel of important physiological functions and disease states including cancer. Nicotine and its derivatives could stimulate the release of stress hormones from cancer cells, leading to the promotion of cancer development. β-Blockers have been widely used to control hypertension for decades. Recently, these agents could have significant implications in cancer therapy through blockade of adrenoceptors in tumour tissues. In this review, we summarize recent advancements about the influence of stress hormones, nicotine and β-adrenoceptors on cancer cell proliferation, apoptosis, invasion and metastasis, and also tumour vasculature normalization. Relevant signal pathways and potential value of β-blockers in the treatment of cancer are also discussed in this review

Melatonin and human mitochondrial diseases

Mitochondrial dysfunction is one of the main causative factors in a wide variety of complications such as neurodegenerative disorders, ischemia/reperfusion, aging process, and septic shock. Decrease in respiratory complex activity, increase in free radical production, increase in mitochondrial synthase activity, increase in nitric oxide production, and impair in electron transport system and/or mitochondrial permeability are considered as the main factors responsible for mitochondrial dysfunction. Melatonin, the pineal gland hormone, is selectively taken up by mitochondria and acts as a powerful antioxidant, regulating the mitochondrial bioenergetic function. Melatonin increases the permeability of membranes and is the stimulator of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. It also acts as an inhibitor of lipoxygenase. Melatonin can cause resistance to oxidation damage by fixing the microsomal membranes. Melatonin has been shown to retard aging and inhibit neurodegenerative disorders, ischemia/reperfusion, septic shock, diabetes, cancer, and other complications related to oxidative stress. The purpose of the current study, other than introducing melatonin, was to present the recent findings on clinical effects in diseases related to mitochondrial dysfunction including diabetes, cancer, gastrointestinal diseases, and diseases related to brain function. © 2016 Journal of Research in Medical Sciences

Identifying Patient Candidates for IL-1 Inhibition: Lessons From Real-World Cases

A subgroup of patients with gouty arthritis have a chronic recurring form that is particularly difficult to treat. Such patients experience repeated flares and often have abundant tophi. Many also have underlying comorbidities, such as renal impairment, cardiovascular disease, gastrointestinal disorders, obesity, and hypertension, which contraindicate the use of standard anti-inflammatory medications. Five patients with difficult to treat gouty arthritis who were either candidates and/or treated with anti-IL therapy are described.info:eu-repo/semantics/publishedVersio

Rusty microglia: trainers of innate immunity in Alzheimer's disease

Alzheimer's disease, the most common form of dementia, is marked by progressive cognitive and functional impairment believed to reflect synaptic and neuronal loss. Recent preclinical data suggests that lipopolysaccharide (LPS)-activated microglia may contribute to the elimination of viable neurons and synapses by promoting a neurotoxic astrocytic phenotype, defined as A1. The innate immune cells, including microglia and astrocytes, can either facilitate or inhibit neuroinflammation in response to peripherally applied inflammatory stimuli, such as LPS. Depending on previous antigen encounters, these cells can assume activated (trained) or silenced (tolerized) phenotypes, augmenting or lowering inflammation. Iron, reactive oxygen species (ROS), and LPS, the cell wall component of gram-negative bacteria, are microglial activators, but only the latter can trigger immune tolerization. In Alzheimer's disease, tolerization may be impaired as elevated LPS levels, reported in this condition, fail to lower neuroinflammation. Iron is closely linked to immunity as it plays a key role in immune cells proliferation and maturation, but it is also indispensable to pathogens andmalignancies which compete for its capture. Danger signals, including LPS, induce intracellular iron sequestration in innate immune cells to withhold it from pathogens. However, excess cytosolic iron increases the risk of inflammasomes' activation, microglial training and neuroinflammation. Moreover, it was suggested that free iron can awaken the dormant central nervous system (CNS) LPS-shedding microbes, engendering prolonged neuroinflammation that may override immune tolerization, triggering autoimmunity. In this review, we focus on iron-related innate immune pathology in Alzheimer's disease and discuss potential immunotherapeutic agents for microglial de-escalation along with possible delivery vehicles for these compounds

Learning from success and failure: biologics for non-approved skin diseases

The impressive potential of biologics has been demonstrated in psoriasis, hidradenitis suppurativa, and urticaria. Numerous biologicals are entering the field for a restricted number of skin disorders. Off-label use of biologics in other recalcitrant skin diseases has increased. Mounting data point to the potential of already existing biologics acting on the IL-17/IL-23 pathway in skin disorders with epidermal hyperkeratosis (e.g., pityriasis rubra pilaris), acneiform inflammation (e.g., hidradenitis suppurativa), and loss of mucosal integrity (e.g., aphthosis). TNF-alpha blockers are also effective in the latter conditions but seem of particular value in granulomatous (e.g., granuloma annulare) and neutrophilic disorders (e.g., pyoderma gangrenosum). Failure of IL-17 blockade in skin diseases resulting from immune-mediated cell destruction (e.g., alopecia areata and vitiligo) illustrates its limited involvement in Th1-dependent skin immunology. Overall, disappointing results of TNF-alpha blockers in alopecia areata and vitiligo point to the same conclusion although promising results in toxic epidermal necrolysis suggest TNF-alpha exerts at least some in vivo Th1-related activities. Acting on both the Th1 and Th17 pathway, ustekinumab has a rather broad potential with interesting results in lupus and alopecia areata. The efficacy of omalizumab in bullous pemphigoid has revealed an IgE-mediated recruitment of eosinophils leading to bullae formation. Reconsidering reimbursement criteria for less common but severe diseases seems appropriate if substantial evidence is available (e.g., pityriasis rubra pilaris). For other disorders, investigator-and industry-initiated randomized clinical trials should be stimulated. They are likely to improve patient outcome and advance our understanding of challenging skin disorders

Cancer risk in immune-mediated inflammatory diseases (IMID).

Inflammation and cancer have a profound yet ambiguous relationship. Inflammation - especially chronic inflammation - has protumorigenic effects, but inflammatory cells also mediate an immune response against the tumor and immunosuppression is known to increase the risk for certain tumors.This article reviews current literature on the role of inflammation in cancer and the cancer risk in immune-mediated inflammatory diseases (IMIDs). We discuss the effect on cancer risk of different drug classes used in the treatment of IMIDs treatment, including biologicals such as tumor necrosis factor (TNF) inhibitors.Overall cancer incidence and mortality risk are similar to the general population in inflammatory bowel disease (IBD), and slightly increased for rheumatoid arthritis and psoriasis, with risk profiles differing for different tumor types. Increased risk for non-melanoma skin cancer is associated with thiopurine treatment in IBD, with the combination of anti-TNF and methotrexate in rheumatoid arthritis and with PUVA, cyclosporine and anti-TNF treatment in psoriasis. Data on the safety of using biologic or immunosuppressant therapy in IMID patients with a history of cancer are scarce.This review provides clinicians with a solid background to help them in making decisions about treatment of immune-mediated diseases in patients with a tumor history.This article is related to another review article in Molecular Cancer: http://www.molecular-cancer.com/content/12/1/86.Peer reviewe

Identification of Single Nucleotide Polymorphisms Predicting Susceptibility of Ankylosing Spondylitis and the Response to Anti-TNFα Therapy

INTRODUCTION: Different genetic features may result in different incidences of diseases, treatment response and adverse events following medical therapy. The studies included in this thesis collectively aim to identify polymorphisms associated with ankylosing spondylitis (AS) and those can predict therapeutic efficacy and adverse events of anti-tumor necrosis factor-α (TNFα) treatment in Chinese Han patients.METHODS: We performed a case-control study including 149 Chinese Han ankylosing spondylitis patients ethnicity- and gender-matched to 106 healthy controls, and genotyped 14genes encompassing 28 short nucleotide polymorphisms (SNPs) by using the Matrix-assisted Laser Desorption/ionization-time of Flight Mass Spectrometry technique in order to evaluate which genes and SNPs are associated with AS. Furthermore, we performed genotyping on 106 Chinese an patients with AS, who received infliximab or a recombinant human TNFα receptor II–IgG Fc fusion protein (rhTNFR–Fc) therapy, for evaluating associations between drug response and polymorphisms of TNFα gene -238, -308, -857, and -1031. We also conducted a meta-analysis on the same set of SNPs in 211 spondyloarthritis (SpA) patients and 392 inflammatory bowel disease (IBD) to validate their capability in predicting response toward anti-TNFα therapy. Finally, 402 Chinese AS patients with anti-TNFα monotherapy were monitored for short-term adverse events within two hours. Additionally, long-term adverse effects of anti-TNF therapy were profiled for 172 patients at 8, 12, 52, and 104 weeks, and their incidences were analyzed for the frequency of the aforementioned SNPs of TNFα gene.RESULTS: We demonstrated that SNPs in TNFα-857 (rs1799724, p=0.0002), TNFα-308 (rs1800629, p=0.0484), tumor necrosis factor receptor super-family 1A (TNFRSF1A) (rs4149577, p=0.0087), human leukocyte antigen B27tagged (HLA-B27tagged) (rs4349859, p=0.0004), and interleukin 23 receptor (IL-23R) (rs1004819, p=0.0131), have close associations with AS. Regarding the pharmacogenomics of infliximab and rhTNFR–Fc therapy, we revealed that TNFα -857 C/C and -1031 T/T genotypes were significant predictors of treatment response. The results from meta-analysis showed that TNFα genotypes -308 G/G (p = 0.0020) and -857 C/C (p = 0.0100) responded better to anti-TNFα therapy. By analyzing the side effects of TNF inhibitors (TNFi), we found elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) as well as the duration of disease are highly associated with increased risk for short-term and long-term adverse events (p < 0.05). Additionally, rhTNFR-Fc therapy was associated with less adverse events than Infliximab during long-term treatment (p < 0.01). However, when we correlated the SNP frequencies in TNFα genes to the occurrence of adverse events, none of them was found to be an effective predictor of side effects in AS patients treated with TNF blockers. CONCLUSION: Collectively, these studies outline AS-related SNPs in Chinese Han patients. In particular, SNPs at promoter regions of TNFαare closely associated with the predisposition of SpA and IBD, and responsiveness to anti-TNFα therapy. The prevalence of short- and long-term adverse events of TNFi monotherapy were profiled and were not associated with SNPs at TNFα promoter. Future studies are expected to confirm these findings in larger cohorts and perhaps establish these SNPs as reliable biomarkers at clinics