Salivary Metabolites Produced by Oral Microbes in Oral Diseases and Oral Squamous Cell Carcinoma: A Review.

In recent years, salivary metabolome studies have provided new biological information and salivary biomarkers to diagnose different diseases at early stages. The saliva in the oral cavity is influenced by many factors that are reflected in the salivary metabolite profile. Oral microbes can alter the salivary metabolite profile and may express oral inflammation or oral diseases. The released microbial metabolites in the saliva represent the altered biochemical pathways in the oral cavity. This review highlights the oral microbial profile and microbial metabolites released in saliva and its use as a diagnostic biofluid for different oral diseases. The importance of salivary metabolites produced by oral microbes as risk factors for oral diseases and their possible relationship in oral carcinogenesis is discussed.

Salivary metabolomics in patients with oral lichen planus: a preliminary study based on NMR spectroscopy.

OBJECTIVES: The present preliminary study aimed to investigate the salivary metabolic profile in patients with asymptomatic oral lichen planus (OLP) using nuclear magnetic resonance (NMR) spectroscopy. MATERIAL AND METHODS: Stimulated whole mouth saliva (SWMS) samples were collected from 15 reticular OLP female patients and 15 from age- and sex-matched controls (HCs). A total of 23 metabolites were identified and quantified. Mann-Whitney's U test was used to compare the determined concentration salivary metabolite concentrations between OLP patients and the healthy controls. RESULTS: The concentration of acetate, methylamine, and pyruvate was elevated, whereas the concentration of tyrosine was decreased in the saliva of OLP patients compared with HCs. To identify a combination of metabolites, multivariate discrimination function analysis (DFA) was conducted. DFA analysis have shown that the most powerful discrimination between the groups was achieved when methylamine and tyrosine were considered as combined biomarkers. CONCLUSIONS: Salivary tyrosine was of particular interest and a promising finding for the screening of OLP and its progression. Further longitudinal studies are required to establish it as a reliable salivary biomarker in OLP. CLINICAL RELEVANCE: The salivary metabolic profiling can describe the pathologic characteristics of OLP on non-invasive saliva samples and NMR analysis. Salivary metabolites provide details to considered early detectors and to impact oral health of OLP patients.

Microstructural changes in the irradiated and osteoradionecrotic bone: a SEM study.

Radiation exposure is a major health concern due to bone involvement including mandible, causing deleterious effects on bone metabolism, and healing with an increasing risk of infection and osteoradionecrosis. This study aims to investigate the radiotherapy-induced microstructural changes in the human mandible by scanning electron microscopy (SEM). Mandibular cortical bone biopsies were obtained from control, irradiated, and patients with osteoradionecrosis (ORN). Bone samples were prepared for light microscopy and SEM. The SEM images were analyzed for the number of osteons, number of Haversian canal (HC), diameter of osteon (D.O), the diameter of HC (D.HC), osteonal wall thickness (O.W.Th), number of osteocytes, and number of osteocytic dendrites. The number of osteons, D.O, D.HC, O.W.Th, the number of osteocytes, and osteocytic dendrites were significantly decreased in both irradiated and ORN compared to controls (p < .05). The number of HCs decreased in irradiated and ORN bone compared to the control group. However, this was statistically not significant. The deleterious effect of radiation continues gradually altering the bone quality, structure, cellularity, and vascularity in the long term (>5 years mean radiation biopsy interval). The underlying microscopic damage in bone increases its susceptibility and contributes further to radiation-induced bone changes or even ORN.

Oral Sources of Salivary Metabolites.

The oral cavity is very diverse, wherein saliva plays an important role in maintaining oral health. The metabolism of saliva has been used to investigate oral diseases as well as general diseases, mainly to detect diagnostic biomarkers. There are many sources of salivary metabolites in the mouth. Online English language sources and the PubMed database were searched to retrieve relevant studies on oral salivary metabolites. The physiological balance of the mouth is influenced by many factors that are reflected in the salivary metabolite profile. Similarly, the dysbiosis of microbes can alter the salivary metabolite profile, which may express oral inflammation or oral diseases. This narrative review highlights the factors to be considered when examining saliva and its use as a diagnostic biofluid for different diseases. Salivary metabolites, mainly small-molecule metabolites may enter the bloodstream and cause illness elsewhere in the body. The importance of salivary metabolites produced in the oral cavity as risk factors for general diseases and their possible relationship to the body's function are also discussed.

Salivary Metabolomics in the Diagnosis and Monitoring of Neurodegenerative Dementia.

Millions of people suffer with dementia worldwide. However, early diagnosis of neurodegenerative diseases/dementia (NDD) is difficult, and no specific biomarkers have been found. This study aims to review the applications of salivary metabolomics in diagnostics and the treatment monitoring of NDD A literature search of suitable studies was executed so that a total of 29 original research articles were included in the present review. Spectroscopic methods, mainly nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry, give us a broad view of changes in salivary metabolites in neurodegenerative diseases. The role of different salivary metabolites in brain function is discussed. Further studies with larger patient cohorts should be carried out to investigate the association between salivary metabolites and brain function and thus learn more about the complicated pathways in the human body.

Irradiation Alters the Expression of MUC1, CD44 and Hyaluronan in Oral Mucosal Epithelium.

Purpose: It is well established that cancer cells exploit aberrant synthesis of mucin 1 (MUC1) and hyaluronan (HA) synthesis along with HA's physiological cell surface receptor CD44. However, their role in irradiated oral tissue has not been reported previously. We, therefore, aimed to study MUC1, CD44 and HA immunohistochemically in irradiated oral mucosa and their role in the long-term effects after radiotherapy. Materials and Methods: Oral mucosal biopsies were obtained from healthy subjects as controls and from patients after radiotherapy for head and neck cancer (irradiated group) during dental implant surgery.The presence of MUC1, CD44, and HA in oral mucosa was studied by immunohistochemical methods. The differences in the localization and intensity in the oral epithelium between control and irradiated tissue were analyzed. Results: The staining intensity of MUC1 was confined to the superficial epithelial layer, whereas HA and CD44 were found in the cell membranes in the epithelial basal and intermediate layers of control specimens. In irradiated epithelium, MUC1 staining was distributed throughout all the layers of the oral epithelium, with significant staining in the basal and intermediate layers. Accordingly, HA and CD44 staining extended to involve the superficial cells of the irradiated epithelium. The staining pattern of MUC1 and CD44 showed significant changes in irradiated samples. Conclusions: Our results showed that the staining intensities of MUC1, CD44, and HA were significantly elevated in irradiated tissue compared to controls. MUC1, CD44, and HA are important markers and take part in long-term changes in the oral mucosa after radiotherapy.

Molecular Quantity Variations in Human-Mandibular-Bone Osteoid.

Osteoid is a layer of new-formed bone that is deposited on the bone border during the process of new bone formation. This deposition process is crucial for bone tissue, and flaws in it can lead to bone diseases. Certain bone diseases, i.e. medication related osteonecrosis, are overexpressed in mandibular bone. Because mandibular bone presents different properties than other bone types, the data concerning osteoid formation in other bones are inapplicable for human-mandibular bone. Previously, the molecular distribution of other bone types has been presented using Fourier-transform infrared (FTIR) spectroscopy. However, the spatial distribution of molecular components of healthy-human-mandibular-bone osteoid in relation to histologic landmarks has not been previously presented and needs to be studied in order to understand diseases that occur human-mandibular bone. This study presents for the first time the variation in molecular distribution inside healthy-human-mandibular-bone osteoid by juxtaposing FTIR data with its corresponding histologic image obtained by autofluorescence imaging of its same bone section. During new bone formation, bone-forming cells produce an osteoid constituted primarily of type I collagen. It was observed that in mandibular bone, the collagen type I increases from the osteoblast line with the distance from the osteoblasts, indicating progressive accumulation of collagen during osteoid formation. Only later inside the collagen matrix, the osteoid starts to mineralize. When the mineralization starts, the collagen accumulation diminishes whereas the collagen maturation still continues. This chemical-apposition process in healthy mandibular bone will be used in future as a reference to understand different pathologic conditions that occur in human-mandibular bone.

Effect of smoking on MUC1 expression in oral epithelial dysplasia, oral cancer, and irradiated oral epithelium.

OBJECTIVES: The aim of this study was to assess the MUC1 expression in the oral epithelium of normal, oral epithelial dysplasia (OED), oral squamous cell carcinoma (OSCC), and irradiated oral epithelium (IROE) and its association with smoking habits in non-smokers and smokers. DESIGN: Oral mucosal biopsies from controls, OED, OSCC, and IROE groups were obtained and categorized based on the smoking history as non-smokers, smoker I (25 pack-years), and smoker II (>25 pack-years). Immunohistochemical staining of MUC1 using human milk fat globule 1 (HMFG 1) antibody was performed, and the MUC1 score was calculated. The relation between MUC1 expression and clinicopathological findings was examined. RESULTS: MUC1 staining of superficial oral epithelial cells with mild MUC1 score was detected in all control samples. The MUC1 staining extended from superficial to basal cell layer of oral epithelium with the increase in MUC1 score from moderate to strong in OED, OSCC, and IROE, and the difference was significant (p < 0.004, p < 0.002 and p < 0.004, respectively) compared to controls. A positive association between smoking and MUC1 score was observed within groups (p < 0.05). CONCLUSION: The depolarization of MUC1 protein expression is associated with smoking habits in OED and OSCC. In the IROE, the radiation causes subcellular and molecular changes, observed as altered MUC1 expression and accelerated by smoking, furthermore, complicating the oral mucosal adaptation and progress to radiation-induced lesions as a delayed effect.

Irradiation Induced Biochemical Changes in Human Mandibular Bone: A Raman Spectroscopic Study.

Understanding the biochemical changes in irradiated human mandible after radiotherapy of cancer patients is critical for oral rehabilitation. The underlying mechanism for radiation-associated changes in the bone at the molecular level could lead to implant failure and osteoradionecrosis. The study aimed to assess the chemical composition and bone quality in irradiated human mandibular bone using Raman spectroscopy. A total of 33 bone biopsies from 16 control and 17 irradiated patients were included to quantify different biochemical parameters from the Raman spectra. The differences in bone mineral and matrix band intensities between control and irradiated groups were analyzed using unpaired Student's t-test with statistical significance at p < 0.05. Findings suggest that the intensity of the phosphate band is significantly decreased and the carbonate band is significantly increased in the irradiated group. Further, the mineral crystallinity and carbonate to phosphate ratio are increased. The mineral to matrix ratio is decreased in the irradiated group. Principal component analysis (PCA) based on the local radiation dose and biopsy time interval of irradiated samples did not show any specific classification between irradiation sub-groups. Irradiation disrupted the interaction and bonding between the organic matrix and hydroxyapatite minerals affecting the bone biochemical properties. However, the normal clinical appearance of irradiated bone would have been accompanied by underlying biochemical and microscopical changes which might result in radiation-induced delayed complications.

Osteocyte Apoptosis, Bone Marrow Adiposity, and Fibrosis in the Irradiated Human Mandible.

Purpose: To assess the effect of radiation therapy on osteocyte apoptosis, osteocyte death, and bone marrow adipocytes in the human mandible and its contribution to the pathophysiology of radiation damage to the mandibular bone. Methods and Materials: Mandibular cancellous bone biopsies were taken from irradiated patients and nonirradiated controls. Immunohistochemical detection of cleaved caspase-3 was performed to visualize apoptotic osteocytes. The number of apoptotic osteocytes per bone area and per total amount of osteocytes, osteocytes per bone area, and empty lacunae per bone area were counted manually. The percentage fibrotic tissue and adipose tissue per bone marrow area, the percentage bone marrow of total area, and the mean adipocyte diameter (µm) was determined digitally from adjacent Goldner stained sections. Results: Biopsies of 15 irradiated patients (12 men and 3 women) and 7 nonirradiated controls (5 men and 2 women) were assessed. In the study group a significant increase was seen in the number of empty lacunae, the percentage of adipose tissue of bone marrow area, and the adipocyte diameter. There was no significant difference in bone marrow fibrosis nor apoptotic osteocytes between the irradiated group and the controls. Conclusions: Irradiation alone does not seem to induce excessive bone marrow fibrosis. The damage to bone mesenchymal stem cells leads to increased marrow adipogenesis and decreased osteoblastogenic potential. Early osteocyte death resulting in avital persisting bone matrix with severely impaired regenerative potential may contribute to the vulnerability of irradiated bone to infection and necrosis.

Irradiation affects the structural, cellular and molecular components of jawbones.

PURPOSE: Emerging evidence shows that changes in the bone and its microenvironment following radiotherapy are associated with either an inhibition or a state of low bone formation. Ionizing radiation is damaging to the jawbone as it increases the complication rate due to the development of hypovascular, hypocellular, and hypoxic tissue. This review summarizes and correlates the current knowledge on the effects of irradiation on the bone with an emphasis on jawbone, as these have been a less extensively studied area. CONCLUSIONS: The stringent regulation of bone formation and bone resorption can be influenced by radiation, causing detrimental effects at structural, cellular, vascular, and molecular levels. It is also associated with a high risk of damage to surrounding healthy tissues and an increased risk of fracture. Technological advances and research on animal models as well as a few human bone tissue studies have provided novel insights into the ways in which bone can be affected by high, low and sublethal dose of radiation. The influence of radiation on bone metabolism, cellular properties, vascularity, collagen, and other factors like inflammation, reactive oxygen species are discussed.

Salivary Metabolomics for Diagnosis and Monitoring Diseases: Challenges and Possibilities.

Saliva is a useful biological fluid and a valuable source of biological information. Saliva contains many of the same components that can be found in blood or serum, but the components of interest tend to be at a lower concentration in saliva, and their analysis demands more sensitive techniques. Metabolomics is starting to emerge as a viable method for assessing the salivary metabolites which are generated by the biochemical processes in elucidating the pathways underlying different oral and systemic diseases. In oral diseases, salivary metabolomics has concentrated on periodontitis and oral cancer. Salivary metabolites of systemic diseases have been investigated mostly in the early diagnosis of different cancer, but also neurodegenerative diseases. This mini-review article aims to highlight the challenges and possibilities of salivary metabolomics from a clinical viewpoint. Furthermore, applications of the salivary metabolic profile in diagnosis and prognosis, monitoring the treatment success, and planning of personalized treatment of oral and systemic diseases are discussed.

Low-Dose Doxycycline Treatment Normalizes Levels of Some Salivary Metabolites Associated with Oral Microbiota in Patients with Primary Sjögren's Syndrome.

Saliva is a complex oral fluid, and plays a major role in oral health. Primary Sjögren's syndrome (pSS), as an autoimmune disease that typically causes hyposalivation. In the present study, salivary metabolites were studied from stimulated saliva samples (n = 15) of female patients with pSS in a group treated with low-dose doxycycline (LDD), saliva samples (n = 10) of non-treated female patients with pSS, and saliva samples (n = 14) of healthy age-matched females as controls. Saliva samples were analyzed with liquid chromatography mass spectrometry (LC-MS) based on the non-targeted metabolomics method. The saliva metabolite profile differed between pSS patients and the healthy control (HC). In the pSS patients, the LDD treatment normalized saliva levels of several metabolites, including tyrosine glutamine dipeptide, phenylalanine isoleucine dipeptide, valine leucine dipeptide, phenylalanine, pantothenic acid (vitamin B5), urocanic acid, and salivary lipid cholesteryl palmitic acid (CE 16:0), to levels seen in the saliva samples of the HC. In conclusion, the data showed that pSS is associated with an altered saliva metabolite profile compared to the HC and that the LLD treatment normalized levels of several metabolites associated with dysbiosis of oral microbiota in pSS patients. The role of the saliva metabolome in pSS pathology needs to be further studied to clarify if saliva metabolite levels can be used to predict or monitor the progress and treatment of pSS.

Effects of irradiation in the mandibular bone loaded with dental implants. An experimental study with a canine model.

Radiation therapy may compromise the quality of bone around dental implants, and its ability to regenerate, remodel, and revascularize. This study aimed to describe the irradiation effect on the bone microstructure of the mandible using dental implants in a canine model. Five beagle dogs were exposed to 40 Gy fractionated radiation. In total, 20 dental implants were inserted, two in the irradiated and two in the non-irradiated side. The mandible bone blocks were subjected to 3D micro-computed tomography (µCT) imaging, later evaluated histomorphometrically by light microscopy and scanning electron microscopy. Alterations in irradiated bone were observed under µCT imaging showing an increased anisotropy, porosity, and pore volume. Bone surface-to-bone volume decreased. The bone to implant contact index was significantly reduced in the irradiated bone (75.6% ± 5.8%) as compared to the non-irradiated bone (85.1% ± 6.8%). In the irradiated mandible, osteocytes with their filopodial processes, the bone beneath the periosteum, and subperiosteal veins showed structural differences but were not significant, whereas the diameter of Haversian canals were smaller statistical significant as compared to the control side. The study highlights that radiation dosage of fractioned 40 Gy causes alterations in the alveolar bone microstructure with compatible osseointegration and clinically stable dental implants.

Compensatory IgM to the Rescue: Patients with Selective IgA Deficiency Have Increased Natural IgM Antibodies to MAA-LDL and No Changes in Oral Microbiota.

IgA is the most abundant Ab in the human body. However, most patients with selective IgA deficiency (SIgAD) are asymptomatic. IgM, and to lesser extent IgG Abs, are generally presumed to compensate for the lack of IgA in SIgAD by multiplying and adopting functions of IgA. We used data from the Northern Finland Birth Cohort 1966 to investigate whether SIgAD patients have differences in levels of natural Abs to oxidized epitopes compared with 20 randomly selected healthy controls. First, we screened the saliva and serum samples from the Northern Finland Birth Cohort 1966 cohort (n = 1610) for IgA concentration. We detected five IgA-deficient subjects, yielding a prevalence of 0.3%, which is consistent with the general prevalence of 0.25% in the Finnish population. To detect natural Abs, we used malondialdehyde acetaldehyde-low-density lipoprotein (MAA-LDL), an Ag known to bind natural Abs. In this study, we show that natural secretory IgM and IgG Abs to MAA-DL were significantly increased in subjects with SIgAD. Given that secretory IgA is an important part of mucosal immune defense and that, in the gut microbiota, dysbiosis with SIgAD patients has been observed, we characterized the oral bacterial microbiota of the subjects with and without SIgAD using high-throughput 16S rRNA gene sequencing. We found no significant alterations in diversity and composition of the oral microbiota in subjects with SIgAD. Our data suggest that increased levels of secretory natural Abs in patients with SIgAD could be a compensatory mechanism, providing alternative first-line defense against infections and adjusting mucosal milieu to maintain a healthy oral microbiota.

Prevalence of oral mucosal normal variations and lesions in a middle-aged population: a Northern Finland Birth Cohort 1966 study.

BACKGROUND: In this cross-sectional study we investigated the oral mucosal changes in a middle-aged Finnish population. We analyzed the prevalence of potentially malignant disorders and the influence of smoking, snuff and alcohol use on the mucosal changes. METHODS: Of the 12,068 members of the NFBC 1966, a total of 1961 participants (16.2%) constituted the study population. Mucosal changes were diagnosed and photographed by seven general dentists, and two specialists re-analyzed all the diagnoses based on the documentation Cross-tabulation with Chi-square tests and logistic regression analysis were used to analyze the data. RESULTS: Of the participants, 10.5% had some mucosal changes, of which 81.8% were diagnosed as oral mucosal lesions (OML) and 18.2% as normal variations. Of the normal variations, the most common were Fordyce granules (1.2%), fissured tongue (1.1%) and geographic tongue (0.9%). The most common OMLs were white lesions (6.5%), of which oral lichen planus (OLP) and lichenoid reactions (OLR), grouped as oral lichenoid diseases, were present in 3.5%, males more often (3.8% vs. 3.1%). OLP was found in 1.5% of all participants, females more often (1.8% vs. 1.2%), while OLR was more common in males (2.7% vs. 1.3%). Leukoplakia was identified in 0.5% of the population; twice more often in males (0.6% vs. 0.3%). Erythroplakia was not found. Current smokers had higher risk for oral mucosal changes than former or non-smokers (OR 3.0, 95% CI 2.11-4.28), and snuff, used occasionally or regularly, also raised the risk (OR 2.6, 95% CI 1.48-4.70). CONCLUSIONS: In the middle-aged northern Finland population, 4% of OMLs were potentially malignant disorders, including OLR (2%), OLP (1.5%) and leukoplakia (0.5%). In particular, smoking and snuff use increased the risk for having any oral mucosa changes.

Variability of salivary metabolite levels in patients with Sjögren's syndrome.

PURPOSE: To investigate inter- and intra-individual variation in the levels and outputs (concentration multiplied by salivary flow rate) of salivary metabolites in patients with primary Sjögren's syndrome (pSS). METHODS: A total of 56 samples of stimulated saliva were collected from 14 female pSS patients during four laboratory visits within 20 weeks and analyzed using proton nuclear magnetic resonance spectroscopy. Single saliva samples from each of 15 controls were also analyzed. RESULTS: Among 21 quantified metabolites, choline was significantly elevated in the pSS patients at each time point (P ≤ 0.015), taurine at the last three time points (P ≤ 0.013), alanine at the last two time points (P ≤ 0.007) and glycine at the last time point (P = 0.005). Inter-individual variation in metabolite concentrations was generally larger among the patients than among the controls, and significantly large variations were observed for glycine (P ≤ 0.007, all time points), choline (P ≤ 0.033, three last time points) and alanine (P = 0.028, baseline). Metabolite output analysis showed that choline had the lowest intra-patient variation. CONCLUSION: In spite of considerable intra- and inter-individual variation, levels and outputs of specific metabolites in patients with pSS differ from those in controls, and may be potentially applicable as new biological markers for monitoring of the response to treatment.

Metabolome of canine and human saliva: a non-targeted metabolomics study.

INTRODUCTION: Saliva metabolites are suggested to reflect the health status of an individual in humans. The same could be true with the dog (Canis lupus familiaris), an important animal model of human disease, but its saliva metabolome is unknown. As a non-invasive sample, canine saliva could offer a new alternative material for research to reveal molecular mechanisms of different (patho)physiological stages, and for veterinary medicine to monitor dogs' health trajectories. OBJECTIVES: To investigate and characterize the metabolite composition of dog and human saliva in a non-targeted manner. METHODS: Stimulated saliva was collected from 13 privately-owned dogs and from 14 human individuals. We used a non-targeted ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-qTOF-MS) method to measure metabolite profiles from saliva samples. RESULTS: We identified and classified a total of 211 endogenous and exogenous salivary metabolites. The compounds included amino acids, amino acid derivatives, biogenic amines, nucleic acid subunits, lipids, organic acids, small peptides as well as other metabolites, like metabolic waste molecules and other chemicals. Our results reveal a distinct metabolite profile of dog and human saliva as 25 lipid compounds were identified only in canine saliva and eight dipeptides only in human saliva. In addition, we observed large variation in ion abundance within and between the identified saliva metabolites in dog and human. CONCLUSION: The results suggest that non-targeted metabolomics approach utilizing UHPLC-qTOF-MS can detect a wide range of small compounds in dog and human saliva with partially overlapping metabolite composition. The identified metabolites indicate that canine saliva is potentially a versatile material for the discovery of biomarkers for dog welfare. However, this profile is not complete, and dog saliva needs to be investigated in the future with other analytical platforms to characterize the whole canine saliva metabolome. Furthermore, the detailed comparison of human and dog saliva composition needs to be conducted with harmonized study design.

Regulation of mucin 1 expression and its relationship with oral diseases.

OBJECTIVE: The aim of this study is to describe the polymorphic mucin 1 (MUC1), and to provide an overview of the known complex and multiple functions of MUC1 in normal oral mucosa and oral mucosal lesions in compromised situations as well as exploring the challenges associated with the heterogeneous nature of MUC1. We will review the current knowledge and provide insights into the future management possibilities of using MUC1 as a therapeutic agent. METHODS: A literature search of the electronic databases included MEDLINE (1966 -December 2019) and hand searches of cross-references were undertaken using terms related to mucins, MUC1. RESULTS: MUC1 is a large transmembrane glycoprotein expressed on the apical surface of most of epithelial cell surfaces. Not only is it involved in lubrication, cell surface hydration, and protection against degrading enzymes, MUC1 also promotes abnormal cellular signalling, angiogenesis, anti-adhesion and tumorigenesis. Aberrant glycosylation, overexpression, loss of apical constraint are characteristics of the transformation of a normal cell to a cancerous cell. This review summarizes studies of MUC1 expression and function with a special emphasis on oral epithelial cells in normal and abnormal conditions. In addition, current knowledge of MUC1 and unexplored areas of MUC1 are presented. CONCLUSION: MUC1 is an archetypical transmembrane protein, the presence of MUC1 in ectopic regions may lead to dysregulation of certain enzymes and activation of various pathways, favouring the development of inflammatory responses and tumour formation. This review examines the potential of MUC1 in the development of future therapeutics.

1H NMR Based Metabolomics in Human Sepsis and Healthy Serum.

Early diagnosis is essential but challenging in severe sepsis. Quantifying and comparing metabolite concentrations in serum has been suggested as a new diagnostic tool. Here we used proton nuclear magnetic resonance spectroscopy (1H NMR) based metabolomics to analyze the possible differences in metabolite concentrations between sera taken from septic patients and healthy controls, as well as between sera of surviving and non-surviving sepsis patients. We took serum samples from 44 sepsis patients when the first sepsis induced organ dysfunction was found. Serum samples were also collected from 14 age and gender matched healthy controls. The samples were analyzed by quantitative 1H NMR spectroscopy for non-lipid metabolites. We found that the serum levels of glucose, glycine, 3-hydroxybutyrate, creatinine and glycoprotein acetyls (mostly alpha-1-acid glycoprotein, AGP) were significantly (p < 0.05) higher in sepsis compared to healthy sera, whereas citrate and histidine were significantly (p < 0.05) lower in sepsis patients compared to healthy controls. We found statistically significantly higher serum lactate and citrate concentrations in non-survivors compared to 30-day survivors. According to our study, 3-hydroxybutyrate, citrate, glycine, histidine, and AGP are candidates for further studies to enable identification of phenotype association in the early stages of sepsis.