A Skin-depth Analysis of Integrins: Role of the Integrin Network in Health and Disease

Abstract

In the skin epidermis, adhesion to the underlying basement membrane is mediated through trans-membrane integrin receptors. In addition to a structural role, integrins can signal in a bi-directional manner though the membrane and thus play a crucial role in cell adhesion, migration, proliferation, and differentiation. In this review we will discuss the role of integrins and their network of partner proteins in normal skin development, and how dysregulation influences disease states such as skin blistering disorders and cancers. We also discuss major integrin-specific therapeutic advances that have been made over the past few years in treating these skin disorders as well as targeting angiogenesis, neo-vasculature, and tumorigenesis.     

Metallobiochemistry of ultratrace levels of bismuth in the rat II. Interaction of 205+206Bi3+ with tissue,intracellular and molecular components

BackgroundKnowledge on Bi metabolism in laboratory animals refers to studies at “extreme” exposures, i.e. pharmacologically relevant high-doses (mg kg⁻¹ b.w.) in relation to its medical use, or infinitesimal doses (pg kg⁻¹b.w.) concerning radiobiology protection and radiotherapeutic purposes. There are no specific studies on metabolic patterns of environmental exposure doses (ultratrace level, μg kg⁻¹ b.w.), becoming in this context Bi a “heavy metal fallen into oblivion”. We previously reported the results of the metabolic fate of ultratrace levels of Bi in the blood of rats [1]. In reference to the same study here we report the results of the retention and tissue binding of Bi with intracellular and molecular components.MethodsAnimals were intraperitoneally injected with 0.8 μg Bi kg⁻¹ b.w. as ^205+206Bi(NO)₃, alone or in combination with ⁵⁹Fe for the radiolabeling of iron proteins. The use of ^205+206Bi radiotracer allowed the determination of Bi down to pg fg⁻¹ in biological fluids, tissues, subcellular fractions, and biochemical components isolated by differential centrifugation, size exclusion chromatography, solvent extraction, precipitation, immunoprecipitation and dialysis.Main findingsAt 24 h post injection the kidney contained by far the highest Bi concentration (10 ng g⁻¹ wt.w.) followed by the thymus, spleen, liver, thyroid, trachea, femur, lung, adrenal gland, stomach, duodenum and pancreas (0.1 to 1.3 ng g⁻¹ wt.w.). Brain and testis showed smaller but consistently significant concentrations of the element (0.03 ng g⁻¹ wt.w). Urine was the predominant route of excretion. Intracellularly, liver, kidney, spleen, testis, and brain cytosols displayed the highest percentages (35%–58%) of Bi of homogenates. Liver and testis nuclei were the organelles with the highest Bi content (24 % and 27 %). However, when the recovered Bi of the liver was recorded as percent of total recovered Bi divided by percent of total recovered protein the lysosomes showed the highest relative specific activity than in other fractions. In the brain subcellular fractions Bi was incorporated by neuro-structures with the protein and not lipidic fraction of the myelin retaining 18 % of Bi of the total homogenate. After the liver intra-subcellular fractionation: (i) 65 % of the nuclear Bi was associated with the protein fraction of the nuclear membranes and 35 % with the bulk chromatin bound to non-histone and DNA fractions; (ii) about 50 % of the mitochondrial Bi was associated with inner and outer membranes being the other half recovered in the intramitochondrial matrix; (iii) in microsomes Bi showed a high affinity (close to 90 %) for the membranous components (rough and smooth membranes); (iv) In the liver cytosol three pools of Bi-binding proteins (molecular size > 300 kDa, 70 kDa and 10 kDa) were observed with ferritin and metallothionein–like protein identified as Bi-binding biomolecules. Three similar protein pools were also observed in the kidney cytosol. However, the amount of Bi, calculated in percent of the total cytosolic Bi, were significantly different compared to the corresponding pools of the liver cytosol.ConclusionsAt the best of our knowledge the present paper represents the first in vivo study, on the basis of an environmental toxicology approach, aiming at describing retention and binding of Bi in the rat at tissue, intracellular and molecular levels.     

Molecular connexin partner remodeling orchestrates connexin traffic: From physiology to pathophysiology

Connexins, through gap junctional intercellular communication, are known to regulate many physiological functions involved in developmental processes such as cell proliferation, differentiation, migration and apoptosis. Strikingly, alterations of connexin expression and trafficking are often, if not always, associated with human developmental diseases and carcinogenesis. In this respect, disrupted trafficking dynamics and aberrant intracytoplasmic localization of connexins are considered as typical features of functionality failure leading to the pathological state. Recent findings demonstrate that interactions of connexins with numerous protein partners, which take place throughout connexin trafficking, are essential for gap junction formation, membranous stabilization and degradation. In the present study, we give an overview of the physiological molecular machinery and of the specific interactions between connexins and their partners, which are involved in connexin trafficking, and we highlight their changes in pathological situations.     

Effect of genetic and environmental factors on protein biomarkers for common non-communicable disease and use of personally normalized plasma protein profiles (PNPPP)

Abstract

Objective: To study the impact of genetic and lifestyle factors on protein biomarkers and develop personally normalized plasma protein profiles (PNPPP) controlling for non-disease-related variance.

Materials and methods: Proximity extension assays were used to measure 145 proteins in 632 controls and 344 cases with non-communicable diseases.

Results: Genetic and lifestyle factors explained 20–88% of the variation in healthy controls. Adjusting for these factors reduced the number of candidate biomarkers by 63%.

Conclusion: PNPPP efficiently controls for non-disease-related variance, allowing both for efficient discovery of novel biomarkers and for covariate-independent linear cut-offs suitable for clinical use.     

Relationship between urinary heavy metals with metabolic syndrome and its components in population from Hoveyzeh cohort study: A case-control study in Iran

BackgroundThe incidence of Metabolic Syndrome (MetS) has been growing rapidly and is rising to pandemic proportions. Although obesity is a primary risk factor for the enhancement of these conditions, not all obese individuals develop metabolic syndrome, indicating that the risk for developing MetS is impacted by other genetic and/or environmental factors such as heavy metals. Therefore, the present study focused on the association between exposures to heavy metal and MetS.MethodsUrine samples were collected from 150 participants (75 patients with MetS and 75 healthy participants), which were used from Hoveyzeh Cohort center. To make a quantitative comparison between the two groups, Man-Whitney nonparametric test was used. The logistic regression was performed adjusted for age, demographic, lifestyle factor, physical activity, occupational history and urine creatinine.ResultsThe results of logistic regression showed that OR and 95 % CI for Cd, Pb, Sr, As and Fe concentration were still significant after adjusting for urine creatinine. Moreover, there was a relationship between Cd and Pb levels and waist circumstance (WC). After adjusting for urine creatinine, age, sex, occupation, smoking status, education and place of residence, only Pb concentration was showed a significant association with systolic blood pressure (SBP). The subjects with high urine level of Cd had the high odds (OR: 6.273; 95 % Cl: 1.783–22.070) of MetS and low high-density lipoprotein (HDL-C). The relationship between As concentration and high fasting blood sugars confirmed the previous evidence suggesting that high As level can cause diabetes.ConclusionThese results indicated that outbreak of MetS and its component are associated with heavy metal concentrations in urine.     

Biochemical and molecular identification of Xanthomonas translucens pv. undulosa causing bacterial leaf streak of wheat in Punjab,Pakistan

Xanthomonas translucens pv. undulosa, (Xtu.), causal agent of Bacterial leaf streak (BLS) of wheat, was characterised through pathogencity, hypersensitivity, biochemical and molecular assays. Fifty symptomatic leaves of wheat were collected from eight agro-ecological zones of Punjab out of which 25 were isolated and purified. Maximum incidence and severity in Faisalabad were followed by Multan and Rahim Yar Khan. The pathogen isolated from diseased leaves was identified on the basis of colonies pattern, colour, biochemical and pathogencity test as X. translucens pv. undulosa and confirmed its pathogencity through pathogencity test. For molecular characterization, the bacterial 16S–23S rDNA spacer fragments were amplified by PCR with conserved primers (C1 and C2) and then in combination with specific primers (T1 & T2). 300?bp product amplified by C1 and C2 primer pair confirmed the presence of Xanthomonas, while specific primers T1 and T2 amplified a product of 200?bp, confirmed the presence of X. translucens pv. undulosa. This work will be quite helpful for wheat pathologist and breeders for future management strategy for this disease.     

Iron as a target of chemoprevention for longevity in humans

Abstract

Iron is universally abundant and no life can exist without it. However, iron levels should be maintained within a narrow range. Iron deficiency causes anaemia, whereas excessive iron increases cancer risk, presumably by free radical generation. Several pathological conditions such as genetic haemochromatosis, chronic viral hepatitis B and C, conditions related to asbestos fibre exposure and ovarian endometriosis have been recognized as iron overload-associated conditions that also increase human cancer risks. Iron's carcinogenicity has been documented in animal experiments. Surprisingly, these studies have revealed that the homozygous deletion of CDKN2A/2B is a major hallmark of iron-induced carcinogenesis. Recently, the hormonal regulation of iron metabolism has been elucidated. A commonly hypothesized mechanism may be the lack of any iron disposal pathway other than for bleeding and a mechanism of iron re-uptake as catechol chelate has been discovered. Iron overload in neurons via the ferroportin block may play a role in Alzheimer's disease. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy was associated with decreased cancer risks in a general population. Given that the required amounts of iron decrease during ageing, the fine control of body iron stores would be a wise strategy for chemoprevention of several diseases.     

The Clinical and Laboratory Studies of Superoxide Dismutase Activity in the Human Whole Blood with Early Gastric Cancer

In this study, we tried to evaluate the usefulness of Superoxide Dismutase (SOD) activity in detecting gastric cancer. SOD was determined according to M. Minami and H. Yoshikawa. a simple and inexpensive assay method. For II fibrognstroscopy and pathological proved gastric cancer cases, the average levels of SOD activity was found significantly lower than 30 patients with gastric diseases, 8 patients with atypical hyperplasia and 32 controls.