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Aging is associated with gender-specific hormonal changes that progressively lead to gonadal insufficiency, a condition which characterizes a minority of men and all women. Work-related factors, such as stress and pollutant exposure, affect gonadal function and can interfere with reproduction in both genders. A systematic review of the PubMed, SCOPUS and EMBASE databases was conducted, according to the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) statement to investigate the effect of occupational factors on andropause and menopause. A total of 26 studies met the inclusion and exclusion criteria: 9 studies evaluated the effects of work on andropause symptoms, 8 studies examined its effects on age at menopause onset, and 9 studies addressed its effects on menopausal symptoms. Work-related factors, such as psychological stress, physical effort, and sleep disorders, showed a significant correlation with andropause manifestations, whereas age at menopause and severity of menopausal symptoms were both influenced by factors such as pesticide exposure, high job strain, and repetitive work. Since work accompanies men and women for most of their lives, it is essential to identify and prevent the risk factors that may affect reproductive health.

Lung cancer is one of the leading causes of cancer-related deaths. It is diagnosed mostly at the locally advanced or metastatic stage. Recently, micro RNAs (miRs) and their distribution in circulation have been implicated in physiological and pathological processes. In this study, miR-126 was evaluated in serum, exosome and exosome-free serum fractions in non-small cell lung cancer (NSCLC) patients at early and advanced stages, and compared with healthy controls. Down-regulation of miR-126 was found in serum of advanced stage NSCLC patients. In healthy controls, circulating miR-126 was equally distributed between exosomes and exosome-free serum fractions. Conversely, in both early and advanced stage NSCLC patients, miR-126 was mainly present in exosomes. Different fractions of miR-126 in circulation may reflect different conditions during tumour formation. Incubation of exosomes from early and advanced NSCLC patients induced blood vessel formation and malignant transformation in human bronchial epithelial cells. On the other hand, exosome-enriched miR-126 from normal endothelial cells inhibited cell growth and induces loss of malignancy of NSCLC cells. These findings suggest a role of exo-miRs in the modulation of the NSCLC microenvironmental niche. Exosome-delivered miRs thus hold a substantial promise as a diagnostics biomarker as well as a personalized therapeutic modality.

Aging, chronic oxidative stress, and inflammation are major pathogenic factors in the development and progression of age-related macular degeneration (AMD) with the loss of retinal pigment epithelium (RPE). The human RPE contains a subpopulation of progenitors (i.e., RPE stem cells—RPESCs) whose role in the RPE homeostasis is under investigation. We evaluated the paracrine effects of mature RPE cells exposed to oxidative stress (H2O2) on RPESCs behavior through co-cultural, morphofunctional, and bioinformatic approaches. RPESCs showed a decline in proliferation, an increase of the senescence-associated β-galactosidase activity, the acquisition of a senescent-like secretory phenotype (SASP), and the reduction of their stemness and differentiation competencies. IL-6 and Superoxide Dismutase 2 (SOD2) seem to be key molecules in RPESCs response to oxidative stress. Our results get insight into stress-induced senescent-associated molecular mechanisms implicated in AMD pathogenesis. The presence of chronic oxidative stress in the microenvironment reduces the RPESCs abilities, inducing and/or maintaining a pro-inflammatory retinal milieu that in turn could affect AMD onset and progression.

Exposure to extremely low-frequency magnetic fields (ELF-MF) can induce biological alterations in human cells, including peripheral blood mononuclear cells (PBMCs). However, the molecular mechanisms and key regulatory factors underlying this cellular response remain largely unknown. In this study, we analyzed the proteomic profiles of PBMCs isolated from three human subjects. PBMCs were exposed to 50 Hz, 1 mT of ELF-MF for 24 h and compared to unexposed PBMCs from the same individuals. ELF-MF exposure altered the expression levels of several PBMC proteins without affecting cell proliferation, cell viability, or cell cycle progression. A total of 51 proteins were upregulated, 36 of which were intercorrelated and associated with the Cellular Metabolic Process (GO:0044237) and Metabolic Process (GO:0008152). Among them, solute carrier family 25 member 4 (SLC25A4), which catalyzes the exchange of cytoplasmic ADP for mitochondrial ATP across the inner mitochondrial membrane, was consistently upregulated in all ELF-MF–exposed samples. Additionally, 67 proteins were downregulated, many of which are linked to T cell costimulation (GO:0031295), Cell activation (GO:0001775), and Immune system processes (GO:0002376) included ASPSCR1, PCYT1A, PCYT2, QRAS, and REPS1. In conclusion, ELF-MF exposure induces metabolic reprogramming in human PBMCs, characterized by the upregulation of mitochondrial proteins and downregulation of immune-activation-related proteins, without compromising cell viability or proliferation.

Background and objectives: Evidence shows that shift work may be correlated with insulin resistance (IR). Therefore its estimation in clinical and prevention practice is of great significance. A cross-sectional study was performed to examine the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) Index among healthcare shift workers (HCSW). Materials and Methods: A total of 272 healthcare workers (HCWs) were invited to participate in the study within an occupational surveillance framework, 137 were HCSW while 135 were healthcare non-shift workers (HCNSW). Fasting glucose, insulin, and HOMA-IR Index were evaluated in each participant and correlated with shift workers. Results: Indicators of glucose metabolism were significantly higher in HCSW p < 0.001, and logistic regression analysis confirmed a significant positive association between increased values of HOMA-IR Index and shift workers (p < 0.05). Conclusions: Shift work could be a risk factor in developing insulin resistance and metabolic syndrome.

The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2) pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune-depressed organisms) that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin) on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity.

A job-related factor is attracting a growing interest as a possible determinant of body weight gain in shift-workers. The aim of the study was to reinvestigate the issue of overweight between rotating shift workers and daytime workers, taking into consideration possible confounding covariate factors. This is a cross-sectional study, conducted by reviewing data from subjects participating in an occupational surveillance program in 2008. Participants answered a self-administered questionnaire to retrieve information about socio-demographic factors and working conditions (job schedule type, job-related physical activity, time in job), subjective health status, health care visits during the previous year, and lifestyle factors (dietary habits, leisure time physical activity, alcohol consumption). Participants underwent a medical examination for measurement of BMI, and acquisition of medical history. Compared to daytime workers (N = 229), rotating shift workers (N = 110) displayed higher BMI (mean BMI was 27.6±3.9 and 26.7±3.6 for shift workers, and daytime workers, respectively; p<0.05). Logistic regression analysis allowed to highlight the role of rotating shift-work as an independent risk factor for increased body weight (OR 1.93, 95%CI 1.01-3.71), being aged between 35 and 54 years was a major determinant of increased BMI (OR 2.39, 95%CI 1.14-5.00). In addition, family history of obesity was the strongest determinant of overweight/obesity (OR 9.79, 95%CI 1.28-74.74). Interestingly, no significant association was found between overweight and other potentially relevant factors, such as diet quality and food choices, alcohol consumption, levels of occupational and leisure-time physical activity. Present findings seem to support the notion that rotating shift work is an independent risk factor for overweight, regardless of workers' dietary habits and physical activity levels.

The DNA base excision repair pathway is the main system involved in the removal of oxidative damage to DNA such as 8-Oxoguanine (8-oxoG) primarily via the 8-Oxoguanine DNA glycosylase (OGG1). Our goal was to investigate whether the repair of 8-oxoG DNA damage follow a circadian rhythm. In a group of 15 healthy volunteers, we found a daily variation of Ogg1 expression and activity with higher levels in the morning compared to the evening hours. Consistent with this, we also found lower levels of 8-oxoG in morning hours compared to those in the evening hours. Lymphocytes exposed to oxidative damage to DNA at 8:00 AM display lower accumulation of 8-oxoG than lymphocytes exposed at 8:00 PM. Furthermore, altered levels of Ogg1 expression were also observed in a group of shift workers experiencing a deregulation of circadian clock genes compared to a control group. Moreover, BMAL1 knockdown fibroblasts with a deregulated molecular clock showed an abolishment of circadian variation of Ogg1 expression and an increase of OGG1 activity. Our results suggest that the circadian modulation of 8-oxoG DNA damage repair, according to a variation of Ogg1 expression, could render humans less susceptible to accumulate 8-oxoG DNA damage in the morning hours.

Several cell-signaling mechanisms are activated by visible light radiation in human keratinocytes, but the key regulatory proteins involved in this specific cellular response have not yet been identified. Human keratinocytes (HaCaT cells) were exposed to blue or red light at low or high irradiance for 3 days in cycles of 12 h of light and 12 h of dark. The cell viability, apoptotic rate and cell cycle progression were analyzed in all experimental conditions. The proteomic profile, oxidative stress and mitochondrial morphology were additionally evaluated in the HaCaT cells following exposure to high-irradiance blue or red light. Low-irradiance blue or red light exposure did not show an alteration in the cell viability, cell death or cell cycle progression. High-irradiance blue or red light reduced the cell viability, induced cell death and cell cycle G2/M arrest, increased the reactive oxygen species (ROS) and altered the mitochondrial density and morphology. The proteomic profile revealed a pivotal role of Cytoplasmic thioredoxin reductase 1 (TXNRD1) and Aldo-keto reductase family 1 member C3 (AKR1C3) in the response of the HaCaT cells to high-irradiance blue or red light exposure. Blue or red light exposure affected the viability of keratinocytes, activating a specific oxidative stress response and inducing mitochondrial dysfunction. Our results can help to address the targets for the therapeutic use of light and to develop adequate preventive strategies for skin damage. This in vitro study supports further in vivo investigations of the biological effects of light on human keratinocytes.

Objective Impairment of clock gene expression and changes in melatonin and 17-ß-estradiol levels may constitute biological alterations underlying the increased risk of breast cancer among shift workers. The aim of this study was to compare levels of selected core clock gene expression, 6-sulfatoxymelatonin (aMT6s), and 17-ß-estradiol between rotational shift work (SW) and daytime (DT) workers after a day off. Methods The cross-sectional study comprised 60 nurses with>2 years of SW and 56 permanent DT nurses. Transcript levels of circadian genes BMAL1, CLOCK, NPAS2, CRY1, CRY2, PERI, PER2, PER3, and REVERBa were determined by quantitative real-time polymerase chain reaction (PCR) in lymphocytes. All participants were tested in the early follicular phase of the menstrual cycle. Samples were collected at the beginning of the morning-shift after a regular night's sleep on a day off. Chronotype and sociodemographic characteristics were also evaluated. Results We found a significantly higher expression of BMAL1, CLOCK, NPAS2, PERI, PER2, and REVERBa and a lower expression of PER3, CRY1 and CRY2 among SW compared to DT nurses. SW participants did not demonstrate a significant difference in aMT6s levels, but they did show significantly higher 17-ß-estradiol levels compared to DT nurses. Multiple linear regression analysis confirmed the role of SW on expression of BMAL1 (ß0.21, P=0.040), CLOCK(ß0.35, P=0.008), NPAS2 (ß0.30, P=0.012), PERI (ß0.33, P=0.008), PER2 (ß0.19, P=0.047), PER3 (ß-0.27, P=0.012), CRY1 (ß-0.33, P=0.002), CRY2 (ß-0.31, P=0.005), REVERBa (ß0.19, P=0.045), and on 17-ß-estradiol levels (ß0.32, P=0.003). The analysis also confirmed the role of chronotype as an independent factor for PERI (ß0.48, P=0.001) and PER2 (ß-0.22, P=0.022) expression, and 17-ß-estradiol levels (ß0.26, P=0.011). Conclusions Rotating SW nurses show alterations in peripheral clock gene expression and 17-ß-estradiol levels at the beginning of the morning shift after a day off.