Oral health in relation to all-cause mortality: the IPC cohort study

We evaluated the association between oral health and mortality. The study population comprised 76,188 subjects aged 16–89 years at recruitment. The mean follow-up time was 3.4 ± 2.4 years. Subjects with a personal medical history of cancer or cardiovascular disease and death by casualty were excluded from the analysis. A full-mouth clinical examination was performed in order to assess dental plaque, dental calculus and gingival inflammation. The number of teeth and functional masticatory units 10 missing teeth and functional masticatory units 10 missing teeth (HR = 2.31, [95% CI: 1.40–3.82]) and functional masticatory units <5 (HR = 2.40 [95% CI 1.55–3.73]). Moreover, when ≥3 oral diseases were cumulated in the model, the risk increased for all-cause mortality (HR = 3.39, [95% CI: 2.51–5.42]), all-cancer mortality (HR = 3.59, [95% CI: 1.23–10.05]) and non-cardiovascular and non-cancer mortality (HR = 4.71, [95% CI: 1.74–12.7]). The present study indicates a postive linear association between oral health and mortality

The Reg3alpha (HIP/PAP) Lectin Suppresses Extracellular Oxidative Stress in a Murine Model of Acute Liver Failure

BACKGROUND AND AIMS: Acute liver failure (ALF) is a rapidly progressive heterogeneous illness with high mortality rate and no widely accessible cure. A promising drug candidate according to previous preclinical studies is the Reg3alpha (or HIP/PAP) lectin, which alleviates ALF through its free-radical scavenging activity. Here we study the therapeutic targets of Reg3alpha in order to gain information on the nature of the oxidative stress associated with ALF. METHODS: Primary hepatocytes stressed with the reactive oxygen species (ROS) inducers TNFalpha and H2O2 were incubated with a recombinant Reg3alpha protein. ALF was induced in C57BL/6J mice by an anti-CD95 antibody. Livers and primary hepatocytes were harvested for deoxycholate separation of cellular and extracellular fractions, immunostaining, immunoprecipitation and malondialdehyde assays. Fibrin deposition was studied by immunofluorescence in frozen liver explants from patients with ALF. RESULTS: Fibrin deposition occurs during experimental and clinical acute liver injuries. Reg3alpha bound the resulting transient fibrin network, accumulated in the inflammatory extracellular matrix (ECM), greatly reduced extracellular ROS levels, and improved cell viability. Hepatocyte treatment with ligands of death receptors, e.g. TNFalpha and Fas, resulted in a twofold increase of malondialdehyde (MDA) level in the deoxycholate-insoluble fractions. Reg3alpha treatment maintained MDA at a level similar to control cells and thereby increased hepatocyte survival by 35%. No antioxidant effect of Reg3alpha was noted in the deoxycholate-soluble fractions. Preventing fibrin network formation with heparin suppressed the prosurvival effect of Reg3alpha. CONCLUSIONS: Reg3alpha is an ECM-targeted ROS scavenger that binds the fibrin scaffold resulting from hepatocyte death during ALF. ECM alteration is an important pathogenic factor of ALF and a relevant target for pharmacotherapy

Epigenetics and developmental programming of welfare and production traits in farm animals

The concept that postnatal health and development can be influenced by events that occur in utero originated from epidemiological studies in humans supported by numerous mechanistic (including epigenetic) studies in a variety of model species. Referred to as the ‘developmental origins of health and disease’ or ‘DOHaD’ hypothesis, the primary focus of large-animal studies until quite recently had been biomedical. Attention has since turned towards traits of commercial importance in farm animals. Herein we review the evidence that prenatal risk factors, including suboptimal parental nutrition, gestational stress, exposure to environmental chemicals and advanced breeding technologies, can determine traits such as postnatal growth, feed efficiency, milk yield, carcass composition, animal welfare and reproductive potential. We consider the role of epigenetic and cytoplasmic mechanisms of inheritance, and discuss implications for livestock production and future research endeavours. We conclude that although the concept is proven for several traits, issues relating to effect size, and hence commercial importance, remain. Studies have also invariably been conducted under controlled experimental conditions, frequently assessing single risk factors, thereby limiting their translational value for livestock production. We propose concerted international research efforts that consider multiple, concurrent stressors to better represent effects of contemporary animal production systems

Hepatic stellate cells:central modulators of hepatic carcinogenesis

Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related death worldwide, and is increasing in incidence. Currently, our therapeutic repertoire for the treatment of HCC is severely limited, and therefore effective new therapies are urgently required. Recently, there has been increasing interest focusing on the cellular and molecular interactions between cancer cells and their microenvironment. HCC represents a unique opportunity to study the relationship between a diseased stroma and promotion of carcinogenesis, as 90 % of HCCs arise in a cirrhotic liver. Hepatic stellate cells (HSC) are the major source of extracellular proteins during fibrogenesis, and may directly, or via secreted products, contribute to tumour initiation and progression. In this review we explore the complex cellular and molecular interplay between HSC biology and hepatocarcinogenesis. We focus on the molecular mechanisms by which HSC modulate HCC growth, immune cell evasion and angiogenesis. This is followed by a discussion of recent progress in the field in understanding the mechanistic crosstalk between HSC and HCC, and the pathways that are potentially amenable to therapeutic intervention. Furthermore, we summarise the exciting recent developments in strategies to target HSC specifically, and novel techniques to deliver pharmaceutical agents directly to HSC, potentially allowing tailored, cell-specific therapy for HCC

Association between periodontitis and pulse wave velocity: a systematic review and meta-analysis

Objectives: Severe periodontitis has been associated with endothelial dysfunction and arterial stiffness. The present study aimed to provide a critical appraisal and a meta-analysis of the literature investigating pulse wave velocity (PWV) in patients with and without severe periodontitis and to assess whether treatments influence PWV. Materials and methods: English literature was searched on multiple databases up to April 2020 by two independent reviewers. Studies comparing PWV between patients with and without severe periodontitis or assessing the impact of periodontal treatments on PWV were searched and retrieved. Pool data analyses with random effect models were performed. The risk of bias was assessed using Newcastle–Ottawa Scale and RoB2 tools. Results: Seventeen studies were selected. Of these, 10 were used for the meta-analysis. Twelve were cross-sectional studies and 5 interventional studies, including 3176 patients, of whom 1894 had severe periodontitis and 1282 were considered as the controls (without severe periodontitis). Based on carotid–femoral PWV measurement, patients with severe periodontitis (n = 309) have a significantly higher PVW than patients with non-severe periodontitis (n = 213), with a mean difference of 0.84&nbsp;m/s (95% CI 0.50–1.18; p &lt; 0.0001; I2&nbsp;= 5%). Similarly, carotid–radial or brachial–ankle PWV values were significantly higher in patients with severe periodontitis. Results concerning the effect of non-surgical periodontal therapy were not conclusive. Overall, 9 studies (53%) were classified at a low risk of bias. Conclusions: The present study demonstrates that patients with severe periodontitis have higher PWV compared to patients with non-severe periodontitis. Clinical significance: Severe periodontitis is associated with arterial stiffness, supporting the mutual involvement of dentists and physicians

A steroid modulatory domain on NR2B controls N-methyl-d-aspartate receptor proton sensitivity

N-methyl-d-aspartate (NMDA) receptor function is modulated by several endogenous molecules, including zinc, polyamines, protons, and sulfated neurosteroids. Zinc, polyamines, and phenylethanolamines exert their respective modulatory effects by exacerbating or relieving tonic proton inhibition. Here, we report that pregnenolone sulfate (PS) uses a unique mechanism for enhancement of NMDA receptor function that is independent of the proton sensor. We identify a steroid modulatory domain, SMD1, on the NMDA receptor NR2B subunit that is critical for both PS enhancement and proton sensitivity. This domain includes the J/K helices in the S2 region of the glutamate recognition site and the fourth membrane transmembrane region (M4). A molecular model based on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor structure suggests that steroid modulatory domain 1 contributes residues to a hydrophobic pocket that is capable of accommodating PS. The results demonstrate that the J/K helices and the fourth membrane transmembrane region participate in transducing allosteric interactions induced by steroid and proton binding to their respective sites