Chronic Low-level Inflammation Research Articles

Cellular Senescence and Inflammaging in the Skin Microenvironment.

Cellular senescence and aging result in a reduced ability to manage persistent types of inflammation. Thus, the chronic low-level inflammation associated with aging phenotype is called “inflammaging”. Inflammaging is not only related with age-associated chronic systemic diseases such as cardiovascular disease and diabetes, but also skin aging. As the largest organ of the body, skin is continuously exposed to external stressors such as UV radiation, air particulate matter, and human microbiome. In this review article, we present mechanisms for accumulation of senescence cells in different compartments of the skin based on cell types, and their association with skin resident immune cells to describe changes in cutaneous immunity during the aging process.

Adipose tissue knockdown of lysozyme reduces local inflammation and improves adipogenesis in high-fat diet-fed mice

Chronic systemic low-level inflammation in metabolic disease is known to affect adipose tissue biology. Lysozyme (LYZ) is a major innate immune protein but its role in adipose tissue has not been investigated. Here, we aimed to investigate LYZ in human and rodents fat depots, and its possible role in obesity-associated adipose tissue dysfunction. LYZ mRNA and protein were identified to be highly expressed in adipose tissue from subjects with obesity and linked to systemic chronic-low grade inflammation, adipose tissue inflammation and metabolic disturbances, including hyperglycemia, dyslipidemia and decreased markers of adipose tissue adipogenesis. These findings were confirmed in experimental models after a high-fat diet in mice and rats and also in ob/ob mice. Importantly, specific inguinal and perigonadal white adipose tissue lysozyme (Lyz2) gene knockdown in high-fat diet-fed mice resulted in improved adipose tissue inflammation in parallel to reduced lysozyme activity. Of note, Lyz2 gene knockdown restored adipogenesis and reduced weight gain in this model. In conclusion, altogether these observations point to lysozyme as a new actor in obesity-associated adipose tissue dysfunction. The therapeutic targeting of lysozyme production might contribute to improve adipose tissue metabolic homeostasis.

Improved insulin sensitivity in obese-diabetic mice via chitosan Nanomicelles mediated silencing of pro-inflammatory Adipocytokines

Obesity induced chronic low-level inflammation is strongly associated with the development of insulin resistance and progression of type-2 diabetes. Systemic treatment with anti-inflammatory therapeutics requires high doses and is associated with serious adverse effects owing to generalized suppression of the immune system. Here we study localized knockdown of pro-inflammatory adipocytokines in adipose tissue macrophages (ATMs) and adipocytes using RNA interference for the treatment of insulin resistance. Chitosan nanomicelles conjugated to ATM and adipocyte targeting ligands were used to transfect short hairpin RNA (shRNA) against tumor necrosis factor-α (TNFα) and monocyte chemoattractant protein-1 (MCP-1). Subcutaneous administration of nanomicellar/pDNA polyplexes in obese-diabetic mice resulted in decreased concentration of pro-inflammatory cytokines TNFα, MCP-1, IL-6, and IL-1β along with increased concentration of insulin-sensitizing adipokine adiponectin. Downregulation of inflammatory cytokines resulted in improved insulin sensitivity and glucose tolerance for up to six-weeks following single dose, compared to untreated obese-diabetic mice.

Post-Acute-COVID-19-Illness Neuropsychiatric Sequelae

Direct viral invasion, neurodegeneration, microvascular thrombosis, neuroinflammation, and severe systemic inflammation can be the causes of post-acute-COVID-19- illness neuropathology [1-4], supported by brain parenchyma and vessel changes of possibly driven inflammation in neurons, supportive cells, and brain vasculature in COVID-19 autopsy series [5,6]. A role in persistent brain effects of SARSCoV-2 (COVID-19) may be played by an accumulation of memory T cells, a biomarker of immunosenescence in tissue injury and aging, accompanying with the decreased ability to respond to new antigens that are demonstrated in chronic low-level brain inflammation [7].

MCC950, the NLRP3 Inhibitor, Protects against Cartilage Degradation in a Mouse Model of Osteoarthritis.

Osteoarthritis (OA), characterized by chronic systemic low-level inflammation and cartilage degeneration, is a type of arthritis closely associated with aging. Inflammation and aging play a pivotal role in the occurrence and progression of OA. NLRP3 inflammasome is involved in many inflammatory and aging diseases, and NLRP3 inhibitor MCC950 has anti-inflammatory and antisenescence effects on some diseases such as Alzheimer's disease. In the present study, we found that NLRP3 protein was upregulated in human and mouse OA cartilage. Moreover, NLRP3 and Caspase1 expression induced by IL-1β in chondrocytes was blocked by MCC950. In addition, MCC950 inhibited the expression of inflammatory mediators, matrix-degrading enzymes, senescence marker protein P16 (INK4A), and β-galactosidase, as well as excessive production of ROS. Meanwhile, MCC950 promoted autophagy-related protein expression and autophagy flux under the inflammatory condition. However, autophagy inhibitor 3-MA reversed anti-inflammatory and anticatabolic effects of MCC950. In in vivo experiments, intra-articular administration of MCC950 further showed its protective effect on cartilage degeneration. Bioinformatic analysis and in vitro experimental results revealed that MCC950 might play a protective role in cartilage by regulating Nrf2/HO-1/NQO1, PI3k/Akt/mTOR, P38/MAPK, and JNK/MAPK pathways. In conclusion, our work demonstrated that NLRP3 inhibitor MCC950 might serve as a promising strategy for OA treatment.

Peripherally-sourced myeloid antigen presenting cells increase with advanced aging

Aging is associated with dysfunction of the gut microbiota-immune-brain axis, a major regulatory axis in both brain health and in central nervous system (CNS) diseases. Antigen presenting cells (APCs) play a major role in sensing changes in the gut microbiota and regulation of innate and adaptive immune responses. APCs have also been implicated in various chronic inflammatory conditions, including age-related neurodegenerative diseases. The increase in chronic low-level inflammation seen with aging has also been linked to behavioral decline. Despite their acknowledged importance along the gut microbiota-immune-brain axis, there is limited evidence on how APCs change with aging. In this study, we examined age-related changes in myeloid APCs in the gut, spleen, and brain as well as changes in the gut microbiota and behavioral phenotype in mice ranging in age from 2 months up to 32 months of both sexes. Our data show that the number of peripherally-sourced myeloid APCs significantly increases with advanced aging in the brain. In addition, our data showed that age-related changes in APCs are subset-specific in the gut and sexually dimorphic in the spleen. Our work highlights the importance of studying myeloid APCs in an age-, tissue-, and sex-specific manner.

Effect of aerobic and resistance exercise training on inflammation, endothelial function and ambulatory blood pressure in middle-aged hypertensive patients.

The current randomized controlled trial tested the hypothesis that both aerobic training and dynamic resistance training will improve inflammation, endothelial function and 24-h ambulatory blood pressure (ABP) in middle-aged adults with hypertension, but aerobic training would be more effective. Forty-two hypertensive patients on at least one antihypertensive medication (19 men/23 women; 30-59 years of age) were randomly assigned to 12 weeks of supervised aerobic training (n = 15), resistance training (n = 15) or a nonexercise control (n = 12) group. Inflammation, endothelial function, 24-h ABP and related measures were evaluated at pre and postintervention. We found that aerobic training and resistance training were well tolerated. Both aerobic training and resistance training reduced daytime systolic ABP (-7.2 ± 7.9 and -4.4 ± 5.8 mmHg; P < 0.05) and 24-h systolic ABP (-5.6 ± 6.2 and -3.2 ± 6.4 mmHg; P < 0.05). aerobic training and resistance training both improved brachial artery flow-mediated dilation by 1.7 ± 2.8 and 1.4 ± 2.6%, respectively (7.59 ± 3.36 vs. 9.26 ± 2.93 and 7.24 ± 3.18 vs. 8.58 ± 2.37; pre vs. post P < 0.05). However, only aerobic training decreased markers of inflammation (C-reactive protein, monocyte chemoattractant protein-1, vascular cell adhesion molecule-1 and lectin-like oxidized LDL receptor-1) and endothelin-1 and increased nitrite and nitrate levels (P < 0.05). Healthcare providers should continue to emphasize aerobic training for hypertension management given the established role of nitric oxide, endothelin-1 and chronic low-level inflammation in the pathogenesis of cardiovascular disease. However, our study demonstrates that resistance training should also be encouraged for middle-aged hypertensive patients. Our results also suggest that even if patients are on antihypertensive medications, regular aerobic training and resistance training are beneficial for blood pressure control and cardiovascular disease risk reduction.

Diet-induced obesity, inflammation, and cancer

Chronic inflammation plays critical roles in tumor initiation and progression. Inflammatory tumor microenvironment populating tumor cells, inflammatory cells, fibroblasts, and adipocytes and a web of signaling molecules are crucial in the promotion and progression of tumors. Numerous studies have identified transcription factors such as nuclear factor-kappa B, hypoxia-inducible factor-1α, and signal transducer and activator of transcription 3 as key modulators in driving inflammation to cancers. Inflammatory cells increase the levels of cytokines that activate these transcription factors to stimulate diverse protumorigenic processes. Additionally, these transcription factors induce production of chemokines that attract more inflammatory cells to maintain tumor-related inflammation. Although the mechanisms by which obesity enhances tumor growth and progression are not clearly defined, population-based studies show that obesity is associated with increased cancer risk. Obesity is associated with a state of chronic low-level inflammation due to the increase in adipocyte sizes as well as resident- and recruited-macrophage activities, which alter adipokine profiles. These alterations of adipokine profiles are responsible for paracrine and endocrine crosstalk with a variety of cell types, thus enhancing tumor growth and progression.

Dietary Technologies to Optimize Healing from Injury-Induced Inflammation.

Inflammation is an acute adaptive response to injury. However, if the initial inflammatory response to an injury is not completely healed, it becomes chronic low-level inflammation that is strongly associated with many chronic disease states, including metabolic (obesity and diabetes), cardiovascular, auto-immune, and neurogenerative disorders as well as cancer. The healing process is far more complex than the initiation of inflammation. Within that complexity of healing is a sequence of events that are under profound dietary control and can be defined by specific blood markers. Those molecular events of the healing process that are under significant dietary control are termed as the Resolution Response. The purpose of this review is to describe the molecular components of the Resolution Response and how different dietary factors can either optimize or inhibit their actions. In particular, those dietary components that optimize the Resolution Response include a calorie-restricted, protein-adequate, moderate-carbohydrate, low-fat diet referred to as the Zone diet, omega-3 fatty acids, and polyphenols. The appropriate combination of these dietary interventions constitutes the foundation of Pro-Resolution Nutrition. The effect of these dietary components the actions of NF-κB, AMPK, eicosanoids, and resolvins are described in this review, as well as ranges of appropriate blood markers that indicate success in optimizing the Resolution Response by dietary interventions.

Traumatic stress history interacts with sex and chronic peripheral inflammation to alter mitochondrial function of synaptosomes

BackgroundRepeated exposures to chronic stress can lead to long lasting negative behavioral and metabolic outcomes. Here, we aim to determine the impact of chronic stress and chronic low-level inflammation on behavior and synaptosomal metabolism. MethodsMale (n = 31) and female (n = 32) C57Bl/6 mice underwent chronic repeated predation stress or daily handling for two rounds of 15 consecutive days of exposure during the adolescent and early adult timeframes. Subsequently, mice were exposed to repeated lipopolysaccharide (LPS; 7.5 × 105 EU/kg) or saline injections every third day for eight weeks. Exploratory and social behaviors were assessed in the open field and social interaction tests prior to examination of learning and memory with the Barnes Maze. Mitochondrial function and morphology were assessed in synaptosomes post-mortem using the Cell Mito Stress test and Seahorse XFe24 analyzer, TEM, and western analysis, respectively. In addition, expression of TNF-α, IL-1ß, and ROMO1 were examined in the hippocampus and prefrontal cortex with Taqman qPCR. Circulating pro- and anti-inflammatory cytokines in the periphery were assessed using the MSD V-plex Proinflammatory Panel 1 following the first and last LPS injection as well as at the time of tissue collection. Circulating ROMO1 was assessed in terminal samples via ELISA. ResultsExposure to repeated predatory stress increased time spent in the corners of the open field, suggestive of anxiety-like behavior, in both males and females. There were no significant group differences in the social interaction test and minimal effects were evident in the Barnes maze. A history of chronic stress interacted with chronic LPS in male mice to lead to a deficit in synaptosomal respiration. Female mice were more sensitive to both chronic stress and chronic LPS such that either a history of chronic stress or chronic LPS exposure was sufficient to disrupt synaptosomal respiration in females. Both stress and chronic LPS were sufficient to increase inflammation and reactive oxygen in males centrally and peripherally. Females had increased markers of peripheral inflammation following acute LPS but no evidence of peripheral or central increases in inflammatory factors or reactive oxygen following chronic exposures. ConclusionCollectively, these data suggest that while metrics of inflammation and reactive oxygen are disrupted in males following chronic stress and chronic LPS, only the combined condition is sufficient to alter synaptosomal respiration. Conversely, although evidence of chronic inflammation or chronic elevation in reactive oxygen is absent, females demonstrate profound shifts in synaptosomal mitochondrial function with either a history of chronic stress or a history of chronic inflammation. These data highlight that different mechanisms are likely in play between the sexes and that sex differences in neural outcomes may be precipitated by sex-specific effects of life experiences on mitochondrial function in the synapse.

Intestinal microbial metabolite stercobilin involvement in the chronic inflammation of ob/ob mice

It is crucial that the host and intestinal microflora interact and influence each other to maintain homeostasis and trigger pathological processes. Recent studies have shown that transplantation of the murine intestinal content to recipient germ-free mice enables transmission of the donor’s phenotypes, such as low level chronic inflammation associated with lifestyle-related diseases. These findings indicate that intestinal bacteria produce some molecules to trigger pathological signals. However, fecal microbial metabolites that induce obesity and the type II diabetic phenotype have not been fully clarified. Here, we showed that the intestinal bacterial metabolite stercobilin, a pigment of feces, induced proinflammatory activities including TNF-α and IL-1β induction in mouse macrophage RAW264 cells. Proinflammatory stercobilin levels were significantly higher in ob/ob mice feces than in the feces of control C57BL/6 J mice. Moreover, in this study, we detected stercobilin in mice plasma for the first time, and the levels were higher in ob/ob mice than that of C57BL/6 J mice. Therefore, stercobilin is potentially reabsorbed, circulated through the blood system, and contributes to low level chronic inflammation in ob/ob mice. Since, stercobilin is a bioactive metabolite, it could be a potentially promising biomarker for diagnosis. Further analyses to elucidate the metabolic rate and the reabsorption mechanism of stercobilin may provide possible therapeutic and preventive targets.

Elevated levels of proinflammatory volatile metabolites in feces of high fat diet fed KK-Ay mice.

When the microfloral composition deteriorates, it triggers low-level chronic inflammation associated with several lifestyle-related diseases including obesity and diabetic mellitus. Fecal volatile organic compounds (VOCs) have been found to differ in gastrointestinal diseases as well as intestinal infection. In this study, to evaluate a potential association between the pathogenesis of lifestyle-related diseases and VOCs in the intestinal tract, fecal VOCs from obese/diabetic KK-Ay mice (KK) or controls (C57BL/6J mice; BL) fed a normal or high fat diet (NFD or HFD) were investigated using headspace sampler-GC-EI-MS. Principal component analysis (PCA) of fecal VOC profiles clearly separated the experimental groups depending on the mouse lineage (KK vs BL) and the diet type (NFD vs HFD). 16 s rRNA sequencing revealed that the PCA distribution of VOCs was in parallel with the microfloral composition. We identified that some volatile metabolites including n-alkanals (nonanal and octanal), acetone and phenol were significantly increased in the HFD and/or KK groups. Additionally, these volatile metabolites induced proinflammatory activity in the RAW264 murine macrophage cell line indicating these bioactive metabolites might trigger low-level chronic inflammation. These results suggest that proinflammatory VOCs detected in HFD-fed and/or diabetic model mice might be novel noninvasive diagnosis biomarkers for diabetes.

Gut dysbiosis and heart failure: navigating the universe within.

Alternations in gut microbial composition (i.e. loss of microbial diversity or 'gut dysbiosis') have been associated with heart failure with reduced ejection fraction (HFrEF). It has also been suggested that increased chronic low-level inflammation and immune system dysregulation seen in patients with HFrEF could be related to gut dysbiosis and increased intestinal permeability. Hence, the concept of modulating gut microbial composition with the goal of reducing systemic inflammation and controlling HFrEF progression has generated a substantial interest in the scientific community. However, several challenges to the gut dysbiosis theory remain as the exact gut microbial composition in HFrEF patients in these studies is not the same and a common microbiome linked to HFrEF is not yet established. With the advances in culture independent sequencing techniques it has also become evident that the gut microbiome may be much more diverse than previously believed. Further, various 'omic' technologies have enabled us to appreciate the potential role of gut microbial metabolites in various physiological processes in the host. Hence, identification of specific gut microbial metabolites may offer an alternative approach at solving this gut microbiome-HFrEF puzzle. In the current review, we evaluate the concept of gut symbiosis, the potential role of gut dysbiosis in systemic inflammation and HFrEF, and finally highlight the challenges faced by the gut dysbiosis theory in HFrEF and provide a framework for the possible solutions.

TNF Receptor-Associated Factor 6 Mediates TNFα-Induced Skeletal Muscle Atrophy in Mice During Aging.

During aging, muscle mass decreases, leading to sarcopenia, associated with low-level chronic inflammation (inflammaging), which induces sarcopenia by promoting proteolysis of muscle fibers and inhibiting their regeneration. Patients with a variety of pathologic conditions associated with sarcopenia, including rheumatoid arthritis (RA), have systemically elevated TNFα serum levels, and transgenic mice with TNFα overexpression (TNF-Tg mice, a model of RA) develop sarcopenia between adolescence and adulthood before they age. However, if and how TNFα contributes to the pathogenesis of sarcopenia during the normal aging process and in RA remains largely unknown. We report that TNFα levels are increased in skeletal muscles of aged WT mice, associated with muscle atrophy and decreased numbers of satellite cells and Type IIA myofibers, a phenotype that we also observed in adult TNF-Tg mice. Aged WT mice also have increased numbers of myeloid lineage cells in their skeletal muscles, including macrophages and granulocytes. These cells have increased TNFα expression, which impairs myogenic cell differentiation. Expression levels of TNF receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, which mediates signaling by some TNF receptor (TNFR) family members, are elevated in skeletal muscles of both aged WT mice and adult TNF-Tg mice. TRAF6 binds to TNFR2 in C2C12 myoblasts and mediates TNFα-induced muscle atrophy through NF-κB-induced transcription of the muscle-specific E3 ligases, Atrogen1 and Murf1, which promote myosin heavy-chain degradation. Haplo-deficiency of TRAF6 prevents muscle atrophy and the decrease in numbers of satellite cells, Type IIA myofibers, and myogenic regeneration in TRAF6+/- ;TNF-Tg mice. Our findings suggest that pharmacologic inhibition of TRAF6 signaling in skeletal muscles during aging could treat/prevent age- and RA-related sarcopenia by preventing TNFα-induced proteolysis and inhibition of muscle fiber regeneration. © 2020 American Society for Bone and Mineral Research.

Association of Hypomorphic P2X7 Receptor Genotype With Age.

One of the main risk factors for brain diseases is aging. Recent studies have shown that aging is a progressive degenerative process associated with chronic low-level inflammation. The ATP-gated P2X7 receptor (P2X7R) plays an important role in inflammation and has been associated with different brain (e.g., Alzheimer’s and Parkinson’s) or other age-related (osteoporosis, arthritis, cancer) diseases. Several single nucleotide polymorphisms (SNPs) in the P2RX7 gene have been identified, including the loss-of-function 1513A>C and 1405A>G SNPs, and the gain-of-function 489C>T and 1068G>A SNPs. We carried out a literature analysis to verify an association between P2RX7 SNPs’ frequency and age. In 34 worldwide eligible studies (11.858 subjects) no correlation between 1513CC genotype frequency and age emerged. On the contrary, analysis of European Caucasian cohorts (7.241 subjects) showed a significant increase in 1513CC frequency with age (P = 0.027). In agreement with these findings, analysis of two publicly available datasets, including USA Caucasian cohorts, unveiled an increased frequency of 1513CC and 489CC genotypes with age (P = 0.0055 and P = 0.0019, respectively). Thus, hypomorphic P2RX7 genotypes may be positively selected with age in European and North American Caucasian populations. We hypothesize that Caucasian individuals bearing an anti-inflammatory P2X7R phenotype and living in high-income countries may have a longer life expectancy.

Renibacterium salmoninarum and Mycobacterium spp.: two bacterial pathogens present at low levels in wild brown trout (Salmo trutta fario) populations in Austrian rivers

BackgroundRenibacterium salmoninarum and Mycobacterium sp. are important bacterial pathogens of fish. R. salmoninarum is the causative agent of bacterial kidney disease, a Gram-positive bacterium mostly known for causing chronic infections in salmonid fish, while multiple species belonging to the Mycobacterium genus have been associated with mycobacteriosis in fish as well as in human. The objective of this study was to determine the prevalence of these two bacterial pathogens in populations of wild brown trout (Salmo trutta fario) in four rivers (Kamp, Wulka, Traun and Ybbs) in Austria.ResultsA total of 457 kidney samples were examined for both bacterial agents using nested and conventional PCR as well as bacterial cultivation on KDM-2, histological examination and immunohistochemistry. Molecular evidence showed an estimated prevalence level of 0.94% for R. salmoninarum in 2017 while the bacterium could not be detected in 2018 and histology showed signs consistent with a low-level chronic inflammation in the kidney of infected fish. Similarly, no fish were found positive for Mycobacterium in 2017 but in 2018, the prevalence was found to be 37.03% in the Kamp river (4.08% across all rivers). The sequencing data confirmed that these fish carried Mycobacterium sp. although the precise species of Mycobacterium could not be ascertained.ConclusionsThis survey constitutes the first insight into the prevalence rate of R. salmoninarum and Mycobacterium sp. in wild brown trout (Salmo trutta fario) populations in Austria. Both of these pathogens were only detected in the summer months (June and July), which might suggest that the stress linked to increased water temperature could act as stressor factor and contribute to the outbreak of these diseases. The age of the fish might also play a role, especially in the case of Mycobacterium sp. as all the infected fish were in their first summer (June).

Targeted metabolomic analysis of serum phospholipid and acylcarnitine in the adult Fontan patient with a dominant left ventricle.

Background:Patients with a Fontan circulation have altered cholesterol and lipoprotein values. We analysed small organic molecules in extended phopsholipid and acylcarnitine metabolic pathways (‘metabolomes’) in adult Fontan patients with a dominant left ventricle, seeking differences between profiles in baseline and Fontan circulations.Methods:In an observational matched cross-sectional study, we compared phosphatidylcholine (PC), sphingomyelin (SM), and acylcarnitine metabolomes (105 analytes; AbsoluteIDQ® p180 kit (Biocrates Life Sciences AG, Innsbruck, Austria) in 20 adult Fontan patients having a dominant left ventricle with those in 20 age- and sex-matched healthy controls.Results:Serum levels of total PC (q-value 0.01), total SM (q-value 0.0002) were significantly lower, and total acylcarnitines (q-value 0.02) were significantly higher in patients than in controls. After normalisation of data, serum levels of 12 PC and 1 SM Fontan patients were significantly lower (q-values <0.05), and concentrations of 3 acylcarnitines were significantly higher than those in controls (q-values <0.05).Conclusion:Metabolomic profiling can use small specimens to identify biomarker patterns that track derangement in multiple metabolic pathways. The striking alterations in the phospholipid and acylcarnitine metabolome that we found in Fontan patients may reflect altered cell signalling and metabolism as found in heart failure in biventricular patients, chronic low-level inflammation, and alteration of functional or structural properties of lymphatic or blood vessels.Trial registration number:ClinicalTrials.gov Identifier NCT03886935

Hаematologic indices in clinically healthy outdoor dogs exposed to vector-borne pathogens

Haematologic abnormalities possibly associated with exposure to vector-borne pathogens are rarely reported in clinically healthy outdoor dogs. Therefore, we analysed changes in the complete blood count (CBC) of clinically healthy outdoor dogs seroreactive to Anaplasma spp. and Babesia spp., with or without microfilariosis. Stray, shelter and hunting dogs, 81 in total, that were polymerase chain reaction negative for Anaplasma spp. and Babesia spp. were divided into groups according to their seroreactive status and results of a modified Knott?s test: seronegative to both Anaplasma spp. and Babesia spp. SN (N=26); seroreactive to A. phagocythophilum SR-A (N=12); seroreactive to B. canis, B. gibsoni and/or B. vogeli SR-B (N=25); and seroreactive to both of the pathogens SR-AB (N=8). These four groups were negative to microfilariosis, unlike the fifth group, seroreactive to either or to both of the pathogens and with microfilariosis SR-M (N=10). The frequencies of CBC alterations among all analysed dogs were: 0.35 ? leucocytosis, 0.44 ? granulocytosis, 0.28 ? anaemia, 0.74 ? microcytosis, 0.37 ? increased mean cell haemoglobin concentration (MCHC) and 0.33 ? thrombocytopenia. The frequency of alterations did not differ across the groups. An exception was the SR-M group wherein increased MCHC peaked with a frequency of 0.80, while in the other four groups, the frequency ranged between 0.10 and 0.50. Clinically healthy outdoor dogs have multiple CBC abnormalities, consistent with stress and low-level chronic inflammation, but not associated with a previous exposure to Anaplasma spp. or Babesia spp. The presence of microfilaria increases haemolysis in vitro.

Viral Hepatitides, Inflammation and Tumour Microenvironment.

In this chapter, we discuss the role of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in the establishment of hepatocellular carcinoma (HCC), highlighting the key role of the multiple, non-mutually exclusive, pathways involved in the modulation of immune responses and in the orchestration of a chronic low-level inflammation state favouring HCC development. In particular, we discuss (i) HCC as a classical paradigm of inflammation-linked cancer; (ii)the role of the most relevant inflammatory cytokines involved (i.e. IL-6, TNF-α, IL-18, IL-1β, TGF-β IL-10); (iii) the role of T cell exhaustion by immune checkpoints; (iv) the role of the Wnt3a/β-catenin signalling pathway and (v) the role of different subsets of suppressor cells.

Mechanisms of Calorie Restriction: A Review of Genes Required for the Life-Extending and Tumor-Inhibiting Effects of Calorie Restriction

This review focuses on mechanisms of calorie restriction (CR), particularly the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis as an evolutionary conserved signal that regulates aging and lifespan, underlying the effects of CR in mammals. Topics include (1) the relation of the GH-IGF-1 signal with chronic low-level inflammation as one of the possible causative factors of aging, that is, inflammaging, (2) the isoform specificity of the forkhead box protein O (FoxO) transcription factors in CR-mediated regulation of cancer and lifespan, (3) the role for FoxO1 in the tumor-inhibiting effect of CR, (4) pleiotropic roles for FoxO1 in the regulation of disorders, and (5) sirtuin (Sirt) as a molecule upstream of FoxO. From the evolutionary view, the necessity of neuropeptide Y (Npy) for the effects of CR and the pleiotropic roles for Npy in life stages are also emphasized. Genes for mediating the effects of CR and regulating aging are context-dependent, particularly depending on nutritional states.