Carlo Cervellati

Cutaneous responses to environmental stressors.

Living organisms are continuously exposed to environmental pollutants. Because of its critical location, the skin is a major interface between the body and the environment and provides a biological barrier against an array of chemical and physical environmental pollutants. The skin can be defined as our first defense against the environment because of its constant exposure to oxidants, including ultraviolet (UV) radiation and other environmental pollutants such as diesel fuel exhaust, cigarette smoke (CS), halogenated hydrocarbons, heavy metals, and ozone (O3). The exposure to environmental pro‐oxidant agents leads to the formation of reactive oxygen species (ROS) and the generation of bioactive molecules that can damage skin cells. This short review provides an overview of the effects and mechanisms of action of CS, O3, and UV on cutanous tissues.

Systemic Oxidative Stress in Older Patients with Mild Cognitive Impairment or Late Onset Alzheimer's Disease.

A large body of evidences obtained in human and animal brain tissue suggest a role of oxidative stress (OxS) in the pathogenesis of late onset Alzheimers disease (LOAD); on the contrary, data on peripheral markers of OxS in LOAD are still controversial. We evaluated the serum levels of products of lipid peroxidation, hydroperoxides, advanced oxidation protein products, total and residual antioxidant power, thiols, and uric acid in a sample of 334 older individuals: 101 LOAD patients, 134 patients with mild cognitive impairment (MCI), and 99 controls. At univariate analysis, serum hydroperoxides were higher while residual antioxidant power was lower in MCI and LOAD compared with in controls. By multivariate logistic regression analysis we found that, compared with controls, high levels (over median value) of serum hydroperoxides were independently associated with an increase in the likehood of having MCI (Odd Ratio: 2.59, 95% Confidence Interval: 1.08-6.21) or LOAD (OR: 4.09, 95%CI: 1.36-11.81). Furthermore, low levels of residual antioxidant power (below the median value) were associated with increased risk of having MCI (OR: 3.97, 95% CI: 1.62-9.72), but not dementia (OR: 2.31, 95%CI: 0.83-6.63). Our study suggests that a systemic redox-imbalance leading to OxS might be associated not only with LOAD but also with MCI.

Oxidative stress, body fat composition, and endocrine status in pre- and postmenopausal women.

Objective: To evaluate the role of menopause on the regional composition and distribution of fat in women and eventual correlations with the oxidative state. Design: In this observational clinical investigation, 90 women (classified for menopause status according to Stages of Reproductive Aging Workshop criteria) were evaluated for body mass composition and fat distribution by dual-energy x-ray absorptiometry and for oxidative status by determination of serum hydroperoxide levels and residual antioxidant activity. Results: Total body fat mass increases significantly in postmenopause (P < 0.05) by 22% in comparison with premenopause, with specific increases in fat deposition at the level of trunk (abdominal and visceral) (P < 0.001) and arms (P < 0.001). Concomitantly, the antioxidant status increases significantly (P < 0.001) by 17%. When data were adjusted for age by analysis of covariance, statistical significance disappeared for the increase in fat mass, but it was retained for antioxidant status (P < 0.05). Both antioxidant status and hydroperoxide level increased with trunk fat mass, as shown by linear correlation analysis (r = 0.46, P < 0.001 and r = 0.26, P < 0.05, respectively). Conclusions: The results of our investigation demonstrate that fat content increases in the upper part of the body (trunk and arms) in postmenopause and that age is the main determinant of this increase. During the comparison of premenopausal and postmenopausal women, we also detected a significant increase in antioxidant status. Apparently this change is mainly related to menopausal endocrine and fat changes.

Bone mass density selectively correlates with serum markers of oxidative damage in post-menopausal women

Abstract Background: Post-menopausal osteoporosis (PO) affecting a large fraction of elderly women, is triggered by the decline in 17β-estradiol (E2) level. Experimental studies in animal models and cell cultures have suggested that the fall in E2 might contribute to developing oxidative stress (OS) which in turn is believed to play an important role in PO pathogenesis. The scarcity of human studies focusing on this issue prompted us to investigate the effects of the reproductive and post-reproductive phase of women’s life on OS and bone health. Methods: Serum parameters of oxidative challenge (lipid hydroperoxides and protein advanced oxidation products) and antioxidant defence (total serum antioxidants levels) along with bone mineral density (BMD) at femoral neck and lumbar spine were assessed in a sample of 191 women (98 pre- and 93 post-menopausal, of whom 30 osteoporotic). Results: Pearson’s correlation analysis unveiled that spinal BMD was negatively correlated with lipid hydroperoxides in overall postmenopausal subsample (r=–0.251, p=0.012), while no significant link between these two variables was detected in women in reproductive age (r=–0.022, p=0.833). Noteworthy, stepwise multiple regression analysis showed that the association found in post-menopausal women retained significance after adjusting for potential confounding factors (p=0.001). Conclusions: Our data showed that markers of oxidative challenge are associated with bone loss in women in post-menopausal status. We suggest that menopause-related estrogen withdrawal might contribute to make bone more vulnerable to oxidative injury thereby increasing the risk of PO development.

Hypoxia induces cell damage via oxidative stress in retinal epithelial cells

Abstract Retinal diseases (RD), including diabetic retinopathy, are among the most important eye diseases in industrialized countries. RD is characterized by abnormal angiogenesis associated with an increase in cell proliferation and apoptosis. Hypoxia could be one of the triggers of the pathogenic mechanism of this disease. A key regulatory component of the cells hypoxia response system is hypoxia-inducible factor 1 alpha (HIF-1α). It has been demonstrated that the induction of HIF-1α expression can be also achieved in vitro by exposure with cobalt chloride (CoCl2), leading to an intracellular hypoxia-like state. In this study we have investigated the effects of CoCl2 on human retinal epithelium cells (hRPE), which are an integral part of the blood–retinal barrier, with the aim to determine the possible role of oxidative stress in chemical hypoxia-induced damage in retinal epithelial cells. Our data showed that CoCl2 treatment is able to induce HIF-1α expression, that parallels with the formation of reactive oxygen species (ROS) and the increase of lipid 8-isoprostanes and 4-hydroxynonenal (4-HNE) protein adducts levels. In addition we observed the activation of the redox-sensitive transcription factor nuclear factor-kappaB (NFkB) by CoCl2 which can explain the increased levels of vascular endothelial growth factor (VEGF). The increased number of dead cells seems to be related to an apoptotic process. Taken together these evidences suggest that oxidative stress induced by hypoxia might be involved in RD development through the stimulation of two key-events of RD such as neo-angiogenesis and apoptosis.

Oxidative Stress and Bone Resorption Interplay as a Possible Trigger for Postmenopausal Osteoporosis

The underlying mechanism in postmenopausal osteoporosis (PO) is an imbalance between bone resorption and formation. This study was conducted to investigate whether oxidative stress (OxS) might have a role in this derangement of bone homeostasis. In a sample of 167 postmenopausal women, we found that increased serum levels of a lipid peroxidation marker, hydroperoxides, were negatively and independently associated with decreased bone mineral density (BMD) in total body (r = −0.192, P < 0.05), lumbar spine (r = −0.282, P < 0.01), and total hip (r = −0.282, P < 0.05), as well as with increased bone resorption rate (r = 0.233, P < 0.05), as assessed by the serum concentration of C-terminal telopeptide of type I collagen (CTX-1). On the contrary, the OxS marker failed to be correlated with the serum levels of bone-specific alkaline phosphatase (BAP), that is, elective marker of bone formation. Importantly, multiple regression analysis revealed that hydroperoxides is a determinant factor for the statistical association between lumbar spine BMD and CTX-1 levels. Taken together, our data suggest that OxS might mediate, by enhancing bone resorption, the uncoupling of bone turnover that underlies PO development.

Systemic Oxidative Stress and Conversion to Dementia of Elderly Patients with Mild Cognitive Impairment

Mild cognitive impairment (MCI) is regarded as a prodromal phase of late onset Alzheimers disease (LOAD). It has been proposed that oxidative stress (OxS) might be implicated in the pathogenesis of LOAD. The aim of this study was to investigate whether a redox imbalance measured as serum level of hydroperoxides (i.e., by-products of lipid peroxidation) and/or serum antioxidant capacity might be predictive of the clinical progression of MCI to LOAD. The levels of these two markers were measured in 111 patients with MCI (follow-up: 2.0 ± 0.6 years), 105 patients with LOAD, and 118 nondemented healthy controls. Multivariate analysis adjusted for potential confounding factors, including age, gender, smoking, and comorbidities, showed a significant increase (P < 0.05) in baseline levels of OxS in MCI and LOAD as compared to cognitive healthy controls. No differences in either of OxS markers were found by comparing MCI patients who converted (n = 29) or not converted (n = 82) to LOAD. Overall, these results suggest that systemic OxS might be a precocious feature of MCI and LOAD. However, the role of OxS as an early prognostic marker of progression to LOAD needs further investigations.

Oxidative challenge in Alzheimer's disease: state of knowledge and future needs

A large body of experimental and postmortem findings indicate that Alzheimers disease (AD) is associated with increased oxidative stress (OxS) levels in the brain. Despite the current limitations of OxS assessment in living subjects, recent data suggest that oxidative challenge might increase early both in the central nervous system and peripheral fluids. The aim of this review was to provide an overview of the existing literature linking systemic OxS to brain OxS in AD. We firmly believe that continued research aimed at overcoming the methodological and design issues affecting the body of studies in this field is mandatory for successful development of an effective antioxidant-based treatment of AD.

Characterization of Cholylglycine Hydrolase from a Bile-Adapted Strain of Xanthomonas maltophilia and Its Application for Quantitative Hydrolysis of Conjugated Bile Salts

ABSTRACT Purified bile salt hydrolase from bile-adapted Xanthomonas maltophilia displays Michaelis-Menten kinetics on cholylglycine and cholyltaurine and hydrolyzes bile salts also in crude bovine bile. The protein is a dimer and is resistant to proteinases and to heating at 55 to 60°C for up to 60 min, in agreement with calorimetric data.

17β-estradiol levels and oxidative balance in a population of pre-, peri-, and post-menopausal women

Background. The high incidence of various diseases observed in post-menopausal women has been widely associated to the decline of 17β-estradiol (E2) occurring in correspondence of menopausal transition. One of the mechanisms suggested to explain this link takes into account the ability of E2 to counteract oxidative stress (OS) which is believed to play an important role in several pathogenic processes. Aim. To investigate whether stages of womens life characterized by different levels of E2 influence OS. Subjects and methods. We conducted a cross sectional study of OS markers in 159 women subdivided in 65 pre-menopausal, 36 peri-menopausal, and 58 post-menopausal classified according to the Staging of Reproductive Aging Workshop (STRAW) criteria. E2, follicle-stimulating hormone, and markers of OS including hydroperoxides, thiols, uric acid, total and residual antioxidant power, were assessed. Results. After adjustment for covariates, only total antioxidant power was significantly different according to menopausal status (p <0.01), with lower value in pre- with respect peri- and post-menopausal women. No significant correlations between E2 levels and OS markers were detected. Conclusions. Endogen E2, and, consequently, its decline during menopausal transition, is not a determinant factor for OS.