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1.
Cureus ; 16(3): e55935, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38601381

RESUMO

Although there are many forecasts regarding the impact of climate change on the aviation sector, a critical but frequently neglected dimension is the occupational safety risks faced by aviation professionals. This narrative review explores the potential impacts of the changing climate on the health and safety of aviation personnel. Furthermore, we examine the significance of resilience in helping these workers adapt and effectively manage climate-related challenges in their professional lives. Climate change poses increasing threats to the well-being of flight personnel through elevated temperatures, heightened ultraviolet radiation exposure, increased mental workload from extreme weather events, and other psychological stressors. Building resilience through workforce training, planning, and adaptation can reduce vulnerability. In future research, the iterative process of selecting measurement components to gauge the impact of climate change should balance feasibility, relevance for stakeholders, and accurately capturing exposure effects. For instance, while salivary cortisol measures stress biologically, assessments of depression or burnout may provide more nuanced insights on pilot health for industry decision-makers managing climate impacts. In conclusion, a strategic emphasis on enhancing the physical and psychological well-being of the aviation workforce is imperative for facilitating a more efficient adaptation within the sector. This is of paramount importance, considering the critical function that aviation serves in fostering human connectivity. Consequently, it is essential for regulatory bodies and policymakers to prioritize the safeguarding of employee health in the face of climate change challenges.

2.
Cureus ; 16(3): e55936, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38601380

RESUMO

INTRODUCTION: Occupational noise exposure is a major public health concern, impacting a large workforce worldwide. In this study, we sought to evaluate the serum concentrations of prestin, a cochlear protein that diminishes following noise exposure, and otolin-1, a protein secreted into the bloodstream subsequent to inner ear damage, among three diverse professional categories, each exposed to varying degrees of noise. Helicopter emergency medical service (HEMS) pilots and construction workers were considered high-risk groups due to their elevated exposure to occupational noise, whereas office workers were regarded as a low-risk group, reflecting their comparatively minimal noise exposure. METHODS: The study sample included 60 males, encompassing helicopter pilots, construction laborers, and office workers (n=20, each). Recruitment occurred during standard occupational health visits, with all participants presenting normal clinical audiograms. Serum levels of prestin and otolin-1 were measured in duplicate using commercially available immunoassays and compared across the three professional categories. RESULTS: HEMS pilots had the lowest mean serum prestin level at 211±27 pg/mL, followed by construction workers at 234±29 pg/mL, and office workers at 269±42 pg/mL (p<0.001, one-way analysis of variance), with all inter-group differences statistically significant (p<0.05, Tukey's post hoc tests). For otolin-1, HEMS pilots showed the highest mean at 216±20 pg/mL, with construction workers at 196±22 pg/mL, and office workers at 181±20 pg/mL (p<0.001, one-way analysis of variance). Statistically significant differences were found between HEMS pilots and both other groups for otolin-1 levels (p<0.05, Tukey's post hoc tests), but not between construction workers and office workers. CONCLUSIONS:  Serum concentrations of prestin and otolin-1 may differ among healthy individuals according to their occupational noise exposure and have the potential to act as indicators of subclinical inner ear injury. To substantiate these preliminary observations, incorporating exposure assessment, especially via direct measurements of noise and vibration exposure, would markedly improve the reliability of our findings.

3.
Cureus ; 16(3): e55937, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38601405

RESUMO

Chronic wounds pose a significant threat to human health, particularly for the elderly, and require extensive healthcare resources globally. Autophagy, a key molecular player in wound healing, not only offers a defense against infections but also contributes to the deposition of the extracellular matrix during the proliferative phase. Additionally, it promotes the proliferation and differentiation of endothelial cells, fibroblasts, and keratinocytes. We have recently shown that applying magnetized saline water topically can trigger autophagy in intact skin. In this case series, we document the successful management of five non-infected, difficult-to-heal wounds in elderly patients using a topical autophagy-stimulating gel containing 95% magnetized saline water. The treated wounds included pressure ulcers, venous ulcers, and trauma-related injuries that had shown minimal or no improvement with standard wound therapies over a prolonged period. Application of the autophagy-stimulating gel promoted wound healing, as indicated by reduced fibrous and necrotic tissue, granulation tissue formation, re-epithelialization, and partial or complete wound closure. These preliminary case studies suggest that a topical gel containing magnetized saline water, which promotes autophagy, may aid healing of chronic wounds in elderly patients. Further investigation is warranted to explore the potential of this novel approach, as it may offer a valuable addition to the existing arsenal of wound care treatments for the aging population, particularly in addressing difficult-to-heal wounds.

4.
Cureus ; 16(1): e51650, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38318571

RESUMO

Background Insomnia and poor sleep are leading modifiable risk factors for cardiovascular disease. Given the high susceptibility of airline pilots (APs) to sleep disturbances, we sought to investigate the hypothesis that poor sleep in this professional group correlates with alterations in plasma biochemical markers that would reflect critical aspects in the pathophysiology of cardiometabolic disorders. Methods In this preliminary cross-sectional study, we examined the relation of poor sleep to fourteen plasma biomarkers reflecting multiple cardiometabolic pathways in a convenience sample of 117 male APs. The Pittsburgh Sleep Quality Index (PSQI) was used to categorize the participants into good sleepers (n = 70, 59.8%; PSQI scores from 0 to 4) and poor sleepers (n = 47, 40.2%; PSQI scores of 5 or higher). The concentrations of biomarkers were compared between the two groups using both univariable and multivariable analyses. Results Compared to good sleepers, APs identified as poor sleepers exhibited significantly different levels of four plasma cardiometabolic biochemical markers in univariable analysis. However, in multivariable-adjusted analysis, only three biomarkers, adiponectin, fibroblast growth factor (FGF)-21, and growth differentiation factor (GDF)-15, remained independently associated with poor sleep. Conclusion Poor sleep quality in APs correlates with lower plasma concentrations of adiponectin and elevated levels of FGF-21 and GDF-15. Further longitudinal studies are required to elucidate the role of these biomarkers in the link between sleep disturbances and cardiometabolic risk in this professional group.

5.
Cureus ; 16(1): e52502, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38371107

RESUMO

Background Commercial airline pilots (APs) are prone to upper gastrointestinal symptoms, such as epigastric pain and bloating. These issues are often linked to occupational risk factors like irregular diet, sleep disruption, and circadian rhythm disturbance. The use of probiotics to enhance intestinal health is well established, but their efficacy in treating upper gastrointestinal diseases is still debated. This is primarily due to the stomach's small resident microbiota and its low pH, which is inhospitable to most microbes. However, emerging research suggests that specific probiotic strains, such as Enterococcus faecium, can withstand acidic environments. Moreover, certain yeast species, including Saccharomyces boulardii, can survive at a low pH. Consequently, we conducted a preliminary, three-arm, randomized, open-label, dose-finding, four-week study to compare the effects of watchful waiting (WW) with the administration of an oral probiotic supplement containing S. boulardii and E. faecium in APs diagnosed with Helicobacter pylori-negative chronic non-atrophic gastritis (CNG). Methods The study included 39 APs with CNG who were randomized into three groups with a 1:1:1 ratio. The low-dose group (n = 13) received one capsule of the probiotic supplement twice daily, before meals, for four weeks. The high-dose group (n = 13) was administered two capsules of the supplement on the same schedule. The third group (n = 13) underwent WW and served as the control arm. Blinding was maintained for the examining physicians and laboratory staff, but not for the patients. All participants self-rated their experiences of gastric pain and bloating at the beginning and conclusion of the four-week treatment period. Additionally, serum levels of pepsinogen I (PGI) and pepsinogen II (PGII) were measured at these time points. Results Supplementation with probiotics significantly outperformed WW in reducing subjective gastric pain and bloating. This effect was consistent across both tested dosages, with no significant differences observed. However, only high-dose probiotics led to a statistically significant decrease in PGII levels and an increase in the PGI/PGII ratio after the four-week study period, a result not observed with low-dose probiotics. Conclusions Oral administration of S. boulardii and E. faecium demonstrated potential efficacy in reducing gastric pain and bloating symptoms in APs with CNG, as evidenced by statistically significant symptom improvement compared to the control group that did not receive the probiotic supplementation. Notably, high-dose probiotics resulted in a significant increase in the PGI/PGII ratio, indicating potential long-term cytoprotective effects on the gastric mucosa.

7.
Nat Cancer ; 5(3): 448-462, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38267628

RESUMO

Chemotherapy often generates intratumoral senescent cancer cells that strongly modify the tumor microenvironment, favoring immunosuppression and tumor growth. We discovered, through an unbiased proteomics screen, that the immune checkpoint inhibitor programmed cell death 1 ligand 2 (PD-L2) is highly upregulated upon induction of senescence in different types of cancer cells. PD-L2 is not required for cells to undergo senescence, but it is critical for senescent cells to evade the immune system and persist intratumorally. Indeed, after chemotherapy, PD-L2-deficient senescent cancer cells are rapidly eliminated and tumors do not produce the senescence-associated chemokines CXCL1 and CXCL2. Accordingly, PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo regression driven by CD8 T cells after chemotherapy. Finally, antibody-mediated blockade of PD-L2 strongly synergizes with chemotherapy causing remission of mammary tumors in mice. The combination of chemotherapy with anti-PD-L2 provides a therapeutic strategy that exploits vulnerabilities arising from therapy-induced senescence.


Assuntos
Neoplasias Pancreáticas , Animais , Camundongos , Neoplasias Pancreáticas/metabolismo , Linfócitos T CD8-Positivos/patologia , Tolerância Imunológica , Terapia de Imunossupressão , Senescência Celular , Microambiente Tumoral
8.
Nucleic Acids Res ; 52(4): 2045-2065, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38281216

RESUMO

The genome-organizing protein p6 of Bacillus subtilis bacteriophage φ29 plays an essential role in viral development by activating the initiation of DNA replication and participating in the early-to-late transcriptional switch. These activities require the formation of a nucleoprotein complex in which the DNA adopts a right-handed superhelix wrapping around a multimeric p6 scaffold, restraining positive supercoiling and compacting the viral genome. Due to the absence of homologous structures, prior attempts to unveil p6's structural architecture failed. Here, we employed AlphaFold2 to engineer rational p6 constructs yielding crystals for three-dimensional structure determination. Our findings reveal a novel fold adopted by p6 that sheds light on its self-association mechanism and its interaction with DNA. By means of protein-DNA docking and molecular dynamic simulations, we have generated a comprehensive structural model for the nucleoprotein complex that consistently aligns with its established biochemical and thermodynamic parameters. Besides, through analytical ultracentrifugation, we have confirmed the hydrodynamic properties of the nucleocomplex, further validating in solution our proposed model. Importantly, the disclosed structure not only provides a highly accurate explanation for previously experimental data accumulated over decades, but also enhances our holistic understanding of the structural and functional attributes of protein p6 during φ29 infection.


Assuntos
Fagos Bacilares , Bacillus subtilis , Fagos Bacilares/genética , Fagos Bacilares/química , Bacillus subtilis/virologia , Replicação do DNA , DNA Viral/genética , Nucleoproteínas/metabolismo , Proteínas Virais/metabolismo
9.
Nat Commun ; 15(1): 46, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38167804

RESUMO

Addressing age-related immunological defects through therapeutic interventions is essential for healthy aging, as the immune system plays a crucial role in controlling infections, malignancies, and in supporting tissue homeostasis and repair. In our study, we show that stimulating toll-like receptor 5 (TLR5) via mucosal delivery of a flagellin-containing fusion protein effectively extends the lifespan and enhances the healthspan of mice of both sexes. This enhancement in healthspan is evidenced by diminished hair loss and ocular lens opacity, increased bone mineral density, improved stem cell activity, delayed thymic involution, heightened cognitive capacity, and the prevention of pulmonary lung fibrosis. Additionally, this fusion protein boosts intestinal mucosal integrity by augmenting the surface expression of TLR5 in a certain subset of dendritic cells and increasing interleukin-22 (IL-22) secretion. In this work, we present observations that underscore the benefits of TLR5-dependent stimulation in the mucosal compartment, suggesting a viable strategy for enhancing longevity and healthspan.


Assuntos
Longevidade , Receptor 5 Toll-Like , Animais , Camundongos , Flagelina/metabolismo , Mucosa Intestinal/metabolismo , Longevidade/genética , Pulmão/metabolismo
10.
Hepatol Forum ; 5(1): 7-10, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38283276

RESUMO

Background and Aim: Airline pilots (APs) are often characterized by a sedentary lifestyle, predisposing them to adverse cardiometabolic consequences. In this cross-sectional study, we used transient elastography (TE) to investigate the prevalence of hepatic steatosis and fibrosis among apparently healthy APs. Materials and Methods: The study cohort consisted of 137 male APs of Caucasian descent who voluntarily underwent TE. To evaluate the extent and severity of hepatic steatosis and fibrosis, we employed established cutoff values for the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Results: Of the APs, 34 (24.8%) were diagnosed with TE-defined steatosis. Specifically, 25 APs (18.2%) exhibited mild steatosis, 6 (4.4%) moderate steatosis, and 3 (2.2%) severe steatosis. The majority of participants (80 APs or 58.4%) showed no signs of liver fibrosis based on LSM values. However, 49 APs (35.8%) were diagnosed with mild fibrosis (F1), 7 (5.1%) with significant fibrosis (F2), and one (0.7%) with advanced fibrosis (F3). None of the pilots had F4 (cirrhosis). In multivariable linear regression analysis, BMI was the sole independent predictor of both CAP (ß=0.34, p<0.001) and LSM (ß=0.41, p<0.001) values in our sample of male APs. Conclusion: TE is a straightforward and convenient non-invasive method for detecting hepatic steatosis and fibrosis in high-risk occupational groups such as APs.

11.
J Sci Food Agric ; 104(2): 875-882, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37690097

RESUMO

BACKGROUND: Vitamin B12 is an essential nutrient that is involved in numerous physiological processes, and its deficiency can lead to various complications, including neurological and haematological disorders. Some studies have suggested that vitamin B12 may have anti-inflammatory effects, but the mechanisms underlying this relationship are not yet fully understood. We investigated the relationship between circulating vitamin B12 and inflammatory markers interleukin (IL)-6 and C-reactive protein (CRP). The association of peripheral levels of vitamin B12 with IL-6 and CRP was assessed in 136 human samples from a high cardiovascular risk population. To corroborate the results from the human trial, the analysis was replicated in naturally aged mice. RESULTS: Individuals with higher serum levels of vitamin B12 showed lower concentrations of IL-6 and CRP after adjustment for potential confounders, and an inverse association was also found between serum IL-6 and vitamin B12 levels in naturally aged mice. CONCLUSION: Circulating vitamin B12 was inversely associated with IL-6 and CRP in humans and with IL-6 in mice, suggesting that it may exert an anti-inflammatory effect through modulation of these pro-inflammatory molecules. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.


Assuntos
Doenças Cardiovasculares , Deficiência de Vitamina B 12 , Humanos , Animais , Camundongos , Vitamina B 12 , Doenças Cardiovasculares/etiologia , Interleucina-6 , Fatores de Risco , Biomarcadores , Proteína C-Reativa/metabolismo , Fatores de Risco de Doenças Cardíacas , Anti-Inflamatórios , Ácido Fólico
12.
Nat Metab ; 5(12): 2111-2130, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38097808

RESUMO

Fibrogenesis is part of a normal protective response to tissue injury that can become irreversible and progressive, leading to fatal diseases. Senescent cells are a main driver of fibrotic diseases through their secretome, known as senescence-associated secretory phenotype (SASP). Here, we report that cellular senescence, and multiple types of fibrotic diseases in mice and humans are characterized by the accumulation of iron. We show that vascular and hemolytic injuries are efficient in triggering iron accumulation, which in turn can cause senescence and promote fibrosis. Notably, we find that senescent cells persistently accumulate iron, even when the surge of extracellular iron has subdued. Indeed, under normal conditions of extracellular iron, cells exposed to different types of senescence-inducing insults accumulate abundant ferritin-bound iron, mostly within lysosomes, and present high levels of labile iron, which fuels the generation of reactive oxygen species and the SASP. Finally, we demonstrate that detection of iron by magnetic resonance imaging might allow non-invasive assessment of fibrotic burden in the kidneys of mice and in patients with renal fibrosis. Our findings suggest that iron accumulation plays a central role in senescence and fibrosis, even when the initiating events may be independent of iron, and identify iron metabolism as a potential therapeutic target for senescence-associated diseases.


Assuntos
Senescência Celular , Fenótipo Secretor Associado à Senescência , Humanos , Ferro , Rim , Fibrose
13.
Int J Mol Sci ; 24(24)2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38139202

RESUMO

The presence of antiphospholipid antibodies (aPLs) is associated with antiphospholipid syndrome (APS), characterized by thrombosis and obstetric morbidity. aPLs included in APS classification criteria are lupus anticoagulant, anti-cardiolipin and anti-beta-2-glycoprotein-I of IgG or IgM isotypes. Enzyme-linked immunosorbent assay is the most used diagnostic technique to determine aPLs. Recently, new automated technologies mainly based in antigen-coated beads have been developed. The aim is to compare a fluorescence enzyme immunoassay (M1) and an antigen-coated bead assay (M2) in obstetric and thrombotic APS patients. All samples from the first 1020 patients received in the Immune Service Laboratory (Hospital 12 de Octubre) during the recruitment period, without exclusions, were analysed for aPLs. The weighted kappa for both methods in all the patients was 0.39 (0.30-0.47). Agreement increased to 0.56 (0.38-0.73) in patients with autoimmune disease. Sensitivity and specificity obtained for M1 were 17.1% and 89.3%, respectively, and 12.7% and 91.4% for M2. The sensibility and specificity of IgG isotypes were higher than the IgM ones. Regarding obstetric patients, M1 obtained significant diagnostic performance and had more sensitivity 23.75 (14.95-34.58) compared to M2 12.50 (6.16-21.79). In conclusion, clinical suspicion-based method selection for aPLs should be considered. To identify obstetric APS patients, solid phase methods remain more preferable.


Assuntos
Síndrome Antifosfolipídica , Trombose , Feminino , Gravidez , Humanos , Anticorpos Antifosfolipídeos , Inibidor de Coagulação do Lúpus , Imunoglobulina G , Imunoglobulina M
14.
Cureus ; 15(11): e49180, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38130575

RESUMO

Background Water exposed to a magnetic field exhibits several changes in its properties, such as increased electrical conductivity, reduced density, and low surface tension. Additionally, it has reduced dissolved oxygen levels and becomes more alkaline. Previous experimental studies have demonstrated that exposure to saline alkaline water leads to a dose-dependent increase in the expression of autophagy-related genes. Here, we hypothesize that the topical application of magnetized alkaline water to the skin can activate autophagy and improve cutaneous biophysical parameters, making it a promising strategy for enhancing skin aesthetics. Methods Two distinct substudies were undertaken. Firstly, a 12-week, uncontrolled, open-label investigation was conducted with 20 females who desired to enhance the appearance of their facial and neck skin. Secondly, a molecular study was carried out on a subset of 10 females to investigate the serum's impact on two autophagy markers (Beclin-1 and mammalian/mechanistic target of rapamycin {mTOR}) in skin biopsies taken from the posterior neck area below the hair attachment line. Results After a period of 12 weeks, the application of the serum resulted in significant improvements in skin hydration within the stratum corneum (56 ± 14 arbitrary units {a.u.}) compared to the baseline measurement (47 ± 12 a.u.; p < 0.001). Moreover, the transepidermal water loss (TEWL) decreased from 14 ± 2 g/m2/hour to 11 ± 3 g/m2/hour (p < 0.001). The results also revealed a notable reduction in sebum content from 38 ± 7 µg/cm2 to 30 ± 4 µg/cm2 after the 12-week period of serum application (<0.001). Additionally, the melanin index (p < 0.01) and erythema index (p < 0.001) were both significantly lower at 12 weeks compared to baseline. The molecular study showed a 38% increase in Beclin-1 levels after 12 weeks of serum application on the posterior neck area, as measured from skin biopsies. In contrast, mTOR levels decreased by 24% from baseline to 12 weeks. Conclusion The application of magnetized saline water topically, within a serum formulation, shows potential in improving skin biophysical parameters for females seeking to enhance the appearance of their facial and neck skin. These beneficial effects are achieved through the activation of cutaneous autophagy, as evidenced by an increase in Beclin-1 expression and a decrease in mTOR content in the skin.

15.
Cureus ; 15(11): e49565, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38156152

RESUMO

Introduction Water is essential for life and is vital for almost all functions of the human body. Recent studies have shown that treating water with magnets can alter its physicochemical properties, including intracluster bonds and water-ion interactions. Magnetized water also undergoes modifications in its physicochemical characteristics, such as pH, salinity, and dissolved oxygen. While there is a significant amount of literature on the use of magnetized water in agricultural settings, research on its potential biomedical applications is still limited. Based on previous findings indicating a potential relationship between autophagy activation and hair loss reversal, a pilot study was designed to explore the effects of topically applied magnetized saline water in patients with androgenetic alopecia. The hypothesis was that the process of water magnetization, which promotes the creation of hydroxyl ions, could potentially induce hair growth through the induction of alkali-induced autophagy in the scalp. Methods We recruited 20 Caucasian men with mild-to-moderate androgenetic alopecia (Norwood-Hamilton stages II-III). Initially, we conducted a 12-week open-label study to evaluate the potential of a topical lotion containing 95% magnetized saline water (2 mL applied once daily) to increase hair count and hair mass index (HMI). Subsequently, we investigated the effect of the lotion on two autophagy markers (Beclin-1 and LC3B) in scalp biopsies from a subgroup of 10 men. Results Hair count significantly increased after 12 weeks of topical treatment with magnetized saline water (from 20.6 ± 9.8 at baseline to 32.5 ± 12.4 at 12 weeks, P < 0.001). Similarly, the mean HMI increased from 37.8 ± 11.4 at baseline to 45.1 ± 13.6 at 12 weeks (P < 0.01). At the molecular level, the topical lotion effectively increased Beclin-1 levels in scalp biopsies by 44% at 12 weeks as compared to the baseline. Similarly, LC3B levels increased by 36% from baseline to 12 weeks, indicating that the lotion effectively activated autophagy in the scalp. Conclusions After 12 weeks of topical treatment, a lotion containing magnetized saline water activated scalp autophagy and significantly increased hair count and HMI in men with mild-to-moderate androgenetic alopecia.

16.
Res Sq ; 2023 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-37986947

RESUMO

Biomarkers of biological age that predict the risk of disease and expected lifespan better than chronological age are key to efficient and cost-effective healthcare1-3. To advance a personalized approach to healthcare, such biomarkers must reliably and accurately capture individual biology, predict biological age, and provide scalable and cost-effective measurements. We developed a novel approach - image-based chromatin and epigenetic age (ImAge) that captures intrinsic progressions of biological age, which readily emerge as principal changes in the spatial organization of chromatin and epigenetic marks in single nuclei without regression on chronological age. ImAge captured the expected acceleration or deceleration of biological age in mice treated with chemotherapy or following a caloric restriction regimen, respectively. ImAge from chronologically identical mice inversely correlated with their locomotor activity (greater activity for younger ImAge), consistent with the widely accepted role of locomotion as an aging biomarker across species. Finally, we demonstrated that ImAge is reduced following transient expression of OSKM cassette in the liver and skeletal muscles and reveals heterogeneity of in vivo reprogramming. We propose that ImAge represents the first-in-class imaging-based biomarker of aging with single-cell resolution.

17.
Nat Cell Biol ; 25(12): 1804-1820, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38012402

RESUMO

Drugs that selectively kill senescent cells (senolytics) improve the outcomes of cancer, fibrosis and age-related diseases. Despite their potential, our knowledge of the molecular pathways that affect the survival of senescent cells is limited. To discover senolytic targets, we performed RNAi screens and identified coatomer complex I (COPI) vesicle formation as a liability of senescent cells. Genetic or pharmacological inhibition of COPI results in Golgi dispersal, dysfunctional autophagy, and unfolded protein response-dependent apoptosis of senescent cells, and knockdown of COPI subunits improves the outcomes of cancer and fibrosis in mouse models. Drugs targeting COPI have poor pharmacological properties, but we find that N-myristoyltransferase inhibitors (NMTi) phenocopy COPI inhibition and are potent senolytics. NMTi selectively eliminated senescent cells and improved outcomes in models of cancer and non-alcoholic steatohepatitis. Our results suggest that senescent cells rely on a hyperactive secretory apparatus and that inhibiting trafficking kills senescent cells with the potential to treat various senescence-associated diseases.


Assuntos
Neoplasias , Senoterapia , Camundongos , Animais , Complexo de Golgi/metabolismo , Senescência Celular , Neoplasias/metabolismo , Fibrose
18.
Nat Metab ; 5(11): 1911-1930, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37973897

RESUMO

Transient reprogramming by the expression of OCT4, SOX2, KLF4 and MYC (OSKM) is a therapeutic strategy for tissue regeneration and rejuvenation, but little is known about its metabolic requirements. Here we show that OSKM reprogramming in mice causes a global depletion of vitamin B12 and molecular hallmarks of methionine starvation. Supplementation with vitamin B12 increases the efficiency of reprogramming both in mice and in cultured cells, the latter indicating a cell-intrinsic effect. We show that the epigenetic mark H3K36me3, which prevents illegitimate initiation of transcription outside promoters (cryptic transcription), is sensitive to vitamin B12 levels, providing evidence for a link between B12 levels, H3K36 methylation, transcriptional fidelity and efficient reprogramming. Vitamin B12 supplementation also accelerates tissue repair in a model of ulcerative colitis. We conclude that vitamin B12, through its key role in one-carbon metabolism and epigenetic dynamics, improves the efficiency of in vivo reprogramming and tissue repair.


Assuntos
Plasticidade Celular , Reprogramação Celular , Animais , Camundongos , Vitamina B 12 , Cicatrização , Vitaminas
19.
Cureus ; 15(9): e45335, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37849603

RESUMO

BACKGROUND: The possible associations between occupational factors and autophagy - a catabolic process that is evolutionarily conserved and serves as a vital cornerstone in maintaining cellular balance - remain largely unexplored. OBJECTIVES: We assessed serum levels of beclin-1, a principal effector of autophagy, and the mammalian/mechanistic target of rapamycin (mTOR), a protein recognized for its part in suppressing autophagy, within a group of healthy individuals hailing from three different professional fields, each characterized by its unique working conditions. METHODS: A total of 60 men were recruited from three distinct occupational categories: airline pilots, construction laborers, and fitness trainers. Each group consisted of 20 subjects who were selected during routine occupational health appointments. Serum levels of beclin-1 and mTOR were measured using commercially available immunoassays and compared among the three categories. RESULTS: Fitness instructors had the highest concentration of beclin-1 (3.1 ± 0.9 ng/mL). Construction workers followed with a mean of 2.4 ± 0.4 ng/mL, while airline pilots had the lowest levels at 1.9 ± 0.5 ng/mL (one-way analysis of variance, P < 0.001). In terms of mTOR levels, construction workers had the highest concentration (5.9 ± 1.9 ng/mL), followed by airline pilots (4.4 ± 1.7 ng/mL). Fitness instructors, on the other hand, had the lowest mTOR levels (3.5 ± 1.2 ng/mL; one-way analysis of variance, P < 0.001). CONCLUSIONS: Serum levels of autophagy biomarkers can vary among healthy individuals based on their professional roles. Considering the crucial function autophagy serves in both health and disease, further investigations are crucial to deepen our comprehension of the potential implications of autophagy in the field of occupational medicine.

20.
Neuro Endocrinol Lett ; 44(7): 439-443, 2023 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-37874553

RESUMO

BACKGROUND: Neurotrophins (NTs) encompass a group of closely associated proteins regulating various aspects of neuronal growth and survival. The potential association between work-related factors and the levels of circulating NTs has not been extensively examined. In this preliminary investigation, we evaluated plasma concentrations of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in a cohort of healthy individuals from three distinct professional categories, each with unique work environments and lifestyle factors. METHODS: The study involved 60 men from three professional fields: airline pilots, construction laborers, and fitness trainers (20 participants per category) recruited during routine occupational health appointments. Plasma levels of NTs were measured using commercially available immunoassays and compared in the three professional groups. RESULTS: Among the professions studied, fitness instructors displayed the highest concentrations of BDNF and NGF, with airline pilots ranking second, and construction workers showing the lowest levels. Significantly decreased NT-3 levels were observed in airline pilots compared to fitness instructors and construction workers, but no differences were found between the latter two occupations. NT-4 levels were similar across all three occupational groups. CONCLUSIONS: Our pilot results suggest that plasma concentrations of NTs, which are involved in various aspects of neuronal and cognitive functioning, may display significant differences among healthy individuals depending on their occupation. These observations warrant additional research to explore potential implications for the field of occupational medicine.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Indústria da Construção , Masculino , Humanos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator de Crescimento Neural/metabolismo , Neurotrofina 3 , Neurônios/metabolismo , Ocupações
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