Arsenic (As) is an ubiquitous element in the environment for which the main route of human exposure is through consumption of drinking water. Reactive oxygen species generation (ROS) associated with ...As exposure is known to play a fundamental role in the induction of adverse health effects and disease (cancer, diabetes, hypertension, and cardiovascular and neurological diseases). However, the precise mechanisms of oxidative stress and damage from As exposure are not fully understood and moreover the use of non-invasive methods of measuring ROS generation and oxidative damage footprints in humans is no easy task. Although As induces adverse health effects not all exposed individuals develop degenerative chronic diseases or even manifest adverse effects or symptoms, suggesting that genetic susceptibility is an important factor involved in the human response to As exposure. This mini-review summarizes the literature describing the molecular mechanisms affected by As, as well as the most used biomarkers of oxidative stress and damage in human populations. The most reported biomarkers of oxidative DNA damage are the urinary excretion of 8-OHdG and the comet assay in lymphocytes, and more recently DNA repair mechanism markers from the base and nuclear excision repair pathways (BER and NER). Genetic heterogeneity in the oxidative stress pathways involved in As metabolism are important causative factors of disease. Thus further refinement of human exposure assessment is needed to reinforce study design to evaluate exposure–response relationships and study gene–environment interactions. The use of microarray-based gene expression analysis can provide better insights of the underlying mechanisms involved in As-induced diseases and could help to identify target genes that can be modulated to prevent disease.
Uridine diphosphate-glucuronosyltransferase 2 (UGT2)B15 and B17 enzymes conjugate dihydrotestosterone (DHT) and its metabolites androstane-3α, 17β-diol (3α-DIOL) and androsterone (ADT). The presence ...of UGT2B15/B17 in the epithelial cells of the human prostate has been clearly demonstrated, and significant 3α-DIOL glucuronide and ADT-glucuronide concentrations have been detected in this tissue. The human androgen-dependent cancer cell line, LNCaP, expresses UGT2B15 and -B17 and is also capable of conjugating androgens. To assess the impact of these two genes in the inactivation of androgens in LNCaP cells, their expression was inhibited using RNA interference. The efficient inhibitory effects of a UGT2B15/B17 small interfering RNA (siRNA) probe was established by the 70% reduction of these UGT mRNA levels, which was further confirmed at the protein levels. The glucuronidation of dihydrotestosterone (DHT), 3α-DIOL, and ADT by LNCaP cell homogenates was reduced by more than 75% in UGT2B15/B17 siRNA-transfected LNCaP cells when compared with cells transfected with a non-target probe. In UGT2B15/B17-deficient LNCaP cells, we observe a stronger response to DHT than in control cells, as determined by cell proliferation and expression of eight known androgen-sensitive genes. As expected, the amounts of DHT in cell culture media from control cells were significantly lower than that from UGT2B15/B17 siRNA-treated cells, which was caused by a higher conversion to its corresponding glucuronide derivative. Taken together these data support the idea that UGT2B15 and -B17 are critical enzymes for the local inactivation of androgens and that glucuronidation is a major determinant of androgen action in prostate cells.
Artisanal mercury mining (AMM) is an informal economic activity that employs low technology and limited protection, and poses a risk to workers and their families; due to the extraction process, ...these scenarios involve exposure to complex mixtures of pollutants that synergistically aggravate the health of miners and people living near the site. Although mercury is the predominant pollutant, there are others such as polycyclic aromatic hydrocarbons (PAHs), toluene, arsenic, and lead which have been classified as nephrotoxic pollutants. Therefore, the purpose of this research was to evaluate the association between exposure to a complex mixture of pollutants (mercury, lead, arsenic, PAHs, and toluene) and kidney damage in artisanal Hg mining workers through early kidney damage proteins (KIM-1, OPN, RBP-4, NGAL, and Cys-C). The results demonstrate the presence of OH-PAHs at concentrations of 9.21 (6.57–80.63) μg/L, hippuric acid as a biomarker of exposure to toluene, As and Pb (655. 1 (203.8–1231) mg/L, 24.05 (1.24–42.98) g/g creatinine, and 4.74 (2.71–8.14) g/dL, respectively), and urinary Hg (503.4 (177.9–878.7) g/g creatinine) in the study population. As well as biomarkers of kidney damage, NGAL and RPB-4 were found in 100% of the samples, KIM-1 and Cys-C in 44.1%, and OPN in 41% of the miners. Significant correlations were found between several of the evaluated pollutants and early kidney damage proteins. Our results demonstrate the application of the early kidney damage biomarkers for the assessment of damage caused by the exposure to mixtures of pollutants and, therefore, the urgent need for monitoring in AMM areas.
Exposure to inorganic fluoride (F) has been implicated in cardiovascular and kidney dysfunction mainly in adult populations. However, limited epidemiological information from susceptible populations, ...such as children, is available. In this study we evaluated the relationship of F exposure with some vascular and kidney injury biomarkers in children. A cross-sectional study was conducted in 374 Mexican schoolchildren. Dental fluorosis and F concentrations in the water and urine were evaluated. The glomerular filtration rate (eGFR) and the urinary concentrations of kidney injury molecule 1 (KIM-1) and cystatin-C (uCys-C) were examined to assess kidney injury. The carotid intima media thickness (cIMT) and serum concentrations of vascular adhesion molecule 1 (VCAM-1), intracellular adhesion molecule 1 (ICAM-1), endothelin 1(ET-1) and cystatin-C (sCys-C) were measured to assess vascular alterations. High proportions of children exposed to F were observed (79.7% above 1.2 ppm F in urine) even in the low water F exposure regions, which suggested additional sources of F exposure. In robust multiple linear regression models, urinary F was positively associated with eGFR (β = 1.3, p = 0.015), uCys-C (β = −8.5, p = 0.043), VCAM-1 (β = 111.1, p = 0.019), ICAM-1 (β = 57, p = 0.032) and cIMT (β = 0.01, p = 0.032). An inverse association was observed with uCys-C (β = −8.5, p = 0.043) and sCys-C (β = −9.6, p = 0.021), and no significant associations with ET-1 (β = 0.069, p = 0.074) and KIM-1 (β = 29.1, p = 0.212) were found. Our findings revealed inconclusive results regarding F exposure and kidney injury. However, these results suggest that F exposure is related to early vascular alterations, which may increase the susceptibility of cardiovascular diseases in adult life.
•The relationship of child F exposure with vascular and kidney injury was assessed.•The F exposure in children was partially explained by water F levels.•Overall, the results were unable to elucidate kidney damage by F exposure.•Childhood F exposure was associated with atherosclerotic biomarkers.•Decreased serum and urine Cystatin-C levels were related with F exposure.
Heavy metals such as cadmium (Cd), mercury (Hg), lead (Pb), chromium (Cr) and platinum (Pt) are a major environmental and occupational hazard. Unfortunately, these non-essential elements are toxic at ...very low doses and non-biodegradable with a very long biological half-life. Thus, exposure to heavy metals is potentially harmful. Because of its ability to reabsorb and accumulate divalent metals, the kidney is the first target organ of heavy metal toxicity. The extent of renal damage by heavy metals depends on the nature, the dose, route and duration of exposure. Both acute and chronic intoxication have been demonstrated to cause nephropathies, with various levels of severity ranging from tubular dysfunctions like acquired Fanconi syndrome to severe renal failure leading occasionally to death. Very varied pathways are involved in uptake of heavy metals by the epithelium, depending on the form (free or bound) of the metal and the segment of the nephron where reabsorption occurs (proximal tubule, loop of Henle, distal tubule and terminal segments). In this review, we address the putative uptake pathways involved along the nephron, the mechanisms of intracellular sequestration and detoxification and the nephropathies caused by heavy metals. We also tackle the question of the possible therapeutic means of decreasing the toxic effect of heavy metals by increasing their urinary excretion without affecting the renal uptake of essential trace elements. We have chosen to focus mainly on Cd, Hg and Pb and on in vivo studies.
Osteochondral lesions of the talar dome Barbier, Olivier
Orthopaedics & traumatology, surgery & research,
February 2023, 2023-Feb, 2023-02-00, 20230201, Letnik:
109, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Ankle pain and/or instability is a frequent, non-specific reason for consultation, and may reveal an osteochondral lesion of the talar dome (OLTD).
There are 2 types of OLTD: (1) posteromedial, ...usually idiopathic, wide and deep, featuring isolated pain with severe functional impact; (2) anterolateral, often implicating trauma and associated in 30% of cases with lateral ligament involvement, in a clinical presentation associating pain and instability.
The aim of the present study was to review the issue of OLTD, with 5 questions:
There are no specific clinical signs. A diagnosis of OLTD should be considered in all cases of painful and/or unstable ankle and especially in case of history of sprain. The clinical work-up screens systematically for laxity or associated hindfoot malalignment. CT-arthrography is the gold-standard, enabling morphologic analysis of OLTD.
CT-arthrography determines length, depth and any cartilage dissection, classifying OLTD in 3 grades. Grade 1 is a lesion<10mm in length and<5mm in depth. Grade 2 is>10mm in length and/or>5mm in depth with intact cartilage around the lesion. Grade 3 is the same as grade 2 but with overlying cartilage dissection.
After failure of 6 months’ well-conducted medical treatment (sports rest, analgesics, physiotherapy), surgical options in France today comprise microfracture in grade 1 OLTD, raising the fragment, freshening the floor of the lesion and fixing the fragment (known as “lift, drill, fill, fix” (LDFF)) in grade 2, and mosaicplasty in grade 3.
Treatments are progressing and improving. Ideal treatment should restore hyaline cartilage to prevent secondary osteoarthritis. Matrix and cell culture techniques need to be validated.
Management according to grade secures AOFAS scores≥80/100 in 80% of cases, whatever the grade. Return to sport is feasible in 80% of case, at a mean 6 months. Progression is satisfactory after treatment adapted to the lesion.
V, expert opinion.
Particulate matter (PM) adverse effects on health include lung and heart damage. The renin-angiotensin-aldosterone (RAAS) and kallikrein-kinin (KKS) endocrine systems are involved in the ...pathophysiology of cardiovascular diseases and have been found to impact lung diseases. The aim of the present study was to evaluate whether PM exposure regulates elements of RAAS and KKS.
Sprague-Dawley rats were acutely (3 days) and subchronically (8 weeks) exposed to coarse (CP), fine (FP) or ultrafine (UFP) particulates using a particulate concentrator, and a control group exposed to filtered air (FA). We evaluated the mRNA of the RAAS components At1, At2r and Ace, and of the KKS components B1r, B2r and Klk-1 by RT-PCR in the lungs and heart. The ACE and AT1R protein were evaluated by Western blot, as were HO-1 and γGCSc as indicators of the antioxidant response and IL-6 levels as an inflammation marker. We performed a binding assay to determinate AT1R density in the lung, also the subcellular AT1R distribution in the lungs was evaluated. Finally, we performed a histological analysis of intramyocardial coronary arteries and the expression of markers of heart gene reprogramming (Acta1 and Col3a1).
The PM fractions induced the expression of RAAS and KKS elements in the lungs and heart in a time-dependent manner. CP exposure induced Ace mRNA expression and regulated its protein in the lungs. Acute and subchronic exposure to FP and UFP induced the expression of At1r in the lungs and heart. All PM fractions increased the AT1R protein in a size-dependent manner in the lungs and heart after subchronic exposure. The AT1R lung protein showed a time-dependent change in subcellular distribution. In addition, the presence of AT1R in the heart was accompanied by a decrease in HO-1, which was concomitant with the induction of Acta1 and Col3a1 and the increment of IL-6. Moreover, exposure to all PM fractions increased coronary artery wall thickness.
We demonstrate that exposure to PM induces the expression of RAAS and KKS elements, including AT1R, which was the main target in the lungs and the heart.
Polycyclic aromatic hydrocarbons (PAHs) are environmental persistent chemicals, produced by the incomplete combustion of solid fuels, found in smoke. PAHs are considered carcinogenic, teratogenic, ...and genotoxic. Children are susceptible to environmental pollutants, particularly those living in high-exposure settings. Therefore, the main objective of this study was to evaluate the exposure to PAHs through hydroxylated metabolites of PAHs (OH-PAHs), 1-hydroxynaphtalene (1-OH-NAP), and 2-hydroxynaphtalene (2-OH-NAP); 2-,3-, and 9-hydroxyfluorene (2-OH-FLU, 3-OH-FLU, 9-OH-FLU); 1-,2-,3-, and 4-hydroxyphenanthrene (1-OH-PHE, 2-OH-PHE, 3-OH-PHE, 4-OH-PHE); and 1-hydroxypyrene (1-OH-PYR), as well as kidney health through biomarkers of early kidney damage (osteopontin (OPN), neutrophil gelatinase-associated lipocalin (NGAL), α1-microglobulin (α1-MG), and cystatin C (Cys-C)) in children from an indigenous community dedicated to footwear manufacturing and pottery in Ticul, Yucatán, Mexico. The results show a high exposure to PAHs from the found concentrations of OH-PAHs in urine in 80.5% of the children in median concentrations of 18.4 (5.1-71.0) μg/L of total OH-PAHs, as well as concentrations of kidney damage proteins in 100% of the study population in concentrations of 4.8 (3-12.2) and 7.9 (6.5-13.7) μg/g creatinine of NGAL and Cys-C respectively, and 97.5% of the population with concentrations of OPN and α1-MG at mean concentrations of 207.3 (119.8-399.8) and 92.2 (68.5-165.5) μg/g creatinine. The information provided should be considered and addressed by the health authorities to establish continuous biomonitoring and programs to reduce para-occupational exposure in the vulnerable population, particularly children, based on their fundamental human right to health.
Complex Regional Pain Syndrome (CRPS) is characterized by pain, motor and inflammatory symptoms usually affecting one limb. Cognitive difficulties have been reported to affect patients' ability to ...represent, perceive and use their affected limb. It is debated whether these difficulties result from deficits in controlling goal-directed movements in space or from a learned strategy to protect the affected limb. In order to dissociate the two hypotheses, patients with upper-limb CRPS were asked to move with their unaffected hand towards visual targets projected at different positions on a horizontal semi-reflexive mirror. By means of a robotic handle placed below the screen, they were asked to move a cursor, to reach and cross lines at their estimated midpoint. In some of the stimulation series, the affected hand was placed below the mirror so that some lines appeared projected onto that hand. Vision of the hands and the robotic handle was preserved or prevented by opening or closing a shutter below the mirror. Lines were displayed on the mirror according to which part of the body was affected (ispi- vs. contralateral) and the actual position of the affected hand (inside vs. outside the workspace). Comparatively to control participants, CRPS patients generally biased their estimation by bisecting the lines towards their left side, irrelative of which part of the body was affected and the position of the affected hand, both in ipsi- and contralateral space, with only a few exceptions. Our results are in line with previous studies having described a visuospatial deficit in CRPS patients and discard the explanation of observed symptoms in terms of learned nonuse strategies, as only the unaffected hand was used to perform the task. It is suggested that CRPS patients can display difficulties to perform tasks requesting visuo-motor coordination, reflecting the complex cortical reorganization occurring in CRPS.
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