Markers Of Damage Research Articles

Clausena harmandiana root extract ameliorates Aβ1-42 induced cognitive deficits, oxidative stress, and apoptosis in rats

BackgroundClausena harmandiana (CH), commonly known as song fa dong, was a medicinal plant traditionally used to treat illnesses and as a health tonic. CH root extract (CHRE) exhibited various bioactivities, including neuroprotective, antioxidant, antimicrobial, antifungal, anti-inflammatory, and anti-cancer effects. However, CHRE data on neuroprotective in AD-like animal models were still scarce.ObjectivesThis study aimed to investigate the effects of CHRE on Aβ1-42-induced cognitive deficits, free radical damage, and neuronal death in rats.MethodsForty-eight adult male Sprague-Dawley rats (250–300 g) were classified as sham control (SC), V+Aβ, Vit C+Aβ, CHRE125+Aβ, CHRE250+Aβ, and CHRE500+Aβ (n = 8 in each group). Animals were orally administered with 0.5% sodium carboxymethylcellulose, vitamin C (200 mg/kg BW), or CHRE (125, 250, and 500 mg/kg BW) and were untreated for 35 days. On day 21, all treated rats were injected with 1 µl of aggregated Aβ1-42 (1 µg/µl) into the lateral ventricles, bilaterally, whereas untreated rats were injected with sterilized normal saline (NS). The Morris water maze test estimated the rat’s learning and memory one week later. At the end of the treatment, all rats were sacrificed, and their brains were removed and divided into two hemispheres. On the left, morphological changes and neuronal density were observed in hippocampal CA1 and CA3 regions. While, on the right, changes in free radical damage markers (SOD, CAT, GPx, MDA, and Nrf2) and protein expression of active caspase-3 were evaluated in the hippocampus.ResultsPretreatment with CHRE at all doses could alleviate spatial learning and memory defects. CHRE also improved morphological changes and a decrease in neuronal density in CA1 and CA3 regions. Additionally, CHRE significantly increased the activities of antioxidant enzymes (SOD, CAT, GPx) and Nrf2 expression. This was coupled with significantly decreased MDA levels and active caspase-3 expression in the hippocampus of Aβ1-42-induced rats, which was similar to vitamin C exposure.ConclusionsOur findings suggested that CHRE ameliorated cognitive deficits and exhibited neuroprotective effects by reducing free radical damage and mitigating neuronal abnormality and neuronal death.

Freeze response indicators in sugarcane (Saccharum spp. hybrids)

A recent series of extreme weather events in Southern U.S. (2022 winter freeze followed by 2023 summer drought) calls for quantitative markers to expedite the release of climate resilient sugarcane varieties. A cluster analysis revealed potential markers for freeze damage including fluorescent amino acids. Of 8 cultivars investigated, tolerant variety HoCP 04–838 sustained 3–5 fold lower stalk fracture from the freeze; contained among the highest fiber; and maintained the lowest particulate juice decomposition byproducts (p<0.05). Based on those observations, fluorescence cellular markers were developed in fiber components of sugarcane to assess cold tolerance. Fluorescence microscopy visualized a cluster of markers in lignin cells around the vascular bundles of HoCP 04–838, within the far-red emission ranges attributable to lipids and other hydrophobic components. Cellular distributions of markers were made visible using fluorescent nanoparticles designed to enhance cellular uptake and imaging at wider wavelengths. Developed chemical phenotyping approaches offer advantages over post-freeze damage assessment currently used in the breeding program, as no genetic marker exists for cold tolerance of sugarcane.

Cardioprotective effect of lithium ascorbate in an in vivo model of myocardial infarction

The aim of the work was to study the cardioprotective effect of lithium ascorbate in an in vivo model of myocardial infarction. In the course of the study, we searched for compounds promising for therapy of acute myocardial infarction.Materials and methods. Myocardial infarction was modeled in Wistar rats by ligating the left coronary artery (the duration of ischemia was 45 minutes) followed by ligature loosening and 120-minute reperfusion. All manipulations were performed under alpha-chloralose anesthesia with mechanical lung ventilation and recording heart rate, blood pressure, and ECG. Lithium ascorbate was administered intravenously at a dose of 100 mg / ml before ischemia. The area at risk (the ischemia / reperfusion zone) was detected by staining the myocardium with tightened ligature with 5% potassium permanganate. After that consecutive myocardial slices were prepared, and infarct size was determined. Differentiation of the infarct size from the area at risk was performed by staining with 1% 2,3,5-triphenyl tetrazolium chloride solution for 30 minutes at 37 ºC. The infarct size and the area at risk were determined by the planimetric method. The serum concentration of myocardial damage marker creatine kinase-MB (CK-MB) was measured using ELISA kits.Results. Lithium ascorbate reduced the infarct size / area at risk ratio by 38% and decreased the serum CPKMB level in the experimental animals by 42% compared to the control group. Lithium ascorbate did not affect hemodynamics parameters during coronary artery occlusion and reperfusion.Conclusion. The cardioprotective effect of lithium ascorbate in cardiac ischemia / reperfusion in vivo was found.

Beneficial effects of CHF6467, a modified human nerve growth factor, in experimental neonatal hypoxic-ischaemic encephalopathy.

Therapeutic hypothermia (TH) has become the standard care to reduce morbidity and mortality in neonates affected by moderate-to-severe hypoxic-ischaemic encephalopathy (HIE). Despite the use of TH for HIE, the incidence of mortality and disabilities remains high. Nerve growth factor (NGF) is a potent neurotrophin, but clinical use is limited by its pain eliciting effects. CHF6467 is a recombinant modified form of human NGF devoid of algogenic activity (painless NGF). In rodent hippocampal slices exposed to oxygen and glucose deprivation, CHF6467 protected neurons from death and reverted neurotransmission impairment when combined with hypothermia. In a model of rat neonatal HIE, intranasal CHF6467 (20 μg kg-1) significantly reduced brain infarct volume versus vehicle when delivered 10min or 3h after the insult. CHF6467 (20 and 40 μg kg-1, i.n.), significantly decreased brain infarct volume to a similar extent to TH and when combined, showed a synergistic neuroprotective effect. CHF6467 (20 μg kg-1, i.n.) per se and in combination with hypothermia reversed locomotor coordination impairment (Rotarod test) and memory deficits (Y-maze and novel object recognition test) in the neonatal HIE rat model. Intranasal administration of CHF6467 resulted in meaningful concentrations in the brain, blunted HIE-induced mRNA elevation of brain neuroinflammatory markers and, when combined to TH, significantly counteracted the increase in plasma levels of neurofilament light chain, a peripheral marker of neuroaxonal damage. CHF6467 administered intranasally is a promising therapy, in combination with TH, for the treatment of HIE.

Indirect markers of muscle damage in military physical training session with neuromuscular and aerobic exercises in circuit (Cross operational): acute effects and recoverability

The Brazilian army recently developed the military physical training “Cross Operational” (CO), composed of four different difficulty levels. The moderate/high intensity character of CO can damage the muscle fibers, characterized by alterations at the cellular level, which can be evaluated indirectly by intramuscular proteins showing up in the bloodstream. In this context, the analysis of muscle damage biomarkers can be used as part of an initial injury prevention tool and in the evaluation of training progression and post-exercise recovery. This study aimed to observe the acute effect of CO on indirect markers of muscle damage in military personnel of the Brazilian army. Twenty-four male recruits aged between 18 and 26 years participated in the study. The four sessions corresponding to the CO levels were performed in cross-design, with a seven-day washout period, and blood samples were collected at rest, immediately after, 24 and 48 hours after each training session. The measured markers were creatine kinase (CK), myoglobin (Mb) and lactate dehydrogenase (LDH). In all CO levels, CK had a significant increase 24 hours after CO, whereas Mb and LDH incresead immediately after CO. Regarding recovery time, LDH returned to baseline values within 48 hours in all levels, whereas CK and Mb, after 48 hours of recovery, reduced but did not return to baseline in level 4. The serum elevations of the biomarkers studied, like those found in studies with other consolidated physical training methods, suggest that CO can contribute to the improvement of the physical training of military personnel.

New Markers of Early Kidney Damage in Children and Adolescents with Simple Obesity

The impact of obesity on kidney injury and the development of chronic kidney disease (CKD) is well documented. Unfortunately, the early stages of CKD are asymptomatic, leading to a delayed diagnosis and a worse prognosis. There is a need for more sensitive indicators of kidney damage than those currently used. We aimed to assess the usefulness of serum t-CAF, urinary netrin-1, α-GST, π-GST, calbindin, and calprotectin as biomarkers of early kidney damage in obese children and to investigate the relationship between these indicators and the degree of obesity. A total of 125 simple obese, normoalbuminuric children and 33 non-obese children as controls were selected. Patients were divided into 2 subgroups according to SDS BMI (I: 2 ≤ 4, II: &gt;4). Serum t-CAF was significantly higher in the obese group compared to the controls, as were urinary α-GST, netrin-1, π-GST, and calprotectin. No difference was found between the two obese groups. In normoalbuminuric obese children and adolescents without significant metabolic disorders, serum t-CAF may be a new biomarker for the early detection of renal dysfunction, and urinary netrin-1, α-GST, π-GST, and calprotectin may be better indicators for the detection of early tubular damage, independent of the severity of obesity.

Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles as Natural Nanocarriers in the Treatment of Nephrotoxic Injury In Vitro.

This study investigates the delivery of miRNA-126 and anti-miRNA-126 via UC-EVs as natural nanocarriers for treating nephrotoxic injury in vitro. The umbilical cord-derived mesenchymal stem cell and UC-EVs were characterized according to specific guidelines. Rat kidney proximal tubular epithelial cells (tubular cells) were exposed to nephrotoxic injury through of gentamicin and simultaneously treated with UC-EVs carrying miRNA-126 or anti-miRNA-126. Specific molecules that manage cell cycle progression, proliferation cell assays, and newly synthesized DNA and DNA damage markers were evaluated. We observed significant increases in the expression of cell cycle markers, including PCNA, p53, and p21, indicating a positive cell cycle regulation with newly synthesized DNA via BrDU. The treatments reduced the expression of DNA damage marker, such as H2Ax, suggesting a lower rate of cellular damage. The UC-EVs, acting as natural nanocarriers of miRNA-126 and anti-miRNA-126, offer nephroprotective effects in vitro. Additionally, other components in UC-EVs, such as proteins, lipids, and various RNAs, might also contribute to these effects.

7587 The Estrogen Receptors and ARE/Nrf2 are Involved in Protecting Human Dermal Fibroblasts from Damage Caused by Mitochondrial Disfunction

Abstract Disclosure: A. Darawshe: None. A. Trachtenberg: None. Y. Sharoni: None. Skin ageing is influenced by several factors including environmental exposure and hormonal changes. Reactive oxygen species (ROS), which mediate many of the effects of these factors, can be formed by extrinsic factors, such as sun exposure, or can result from mitochondrial dysfunction as occurs during ageing. Several studies have shown the protective role of estrogens on skin health. The aim of the current study was to examine the damage to dermal fibroblasts by mitochondrially generated ROS, and to study the mechanism of the protective effects of estradiol. Rotenone, a complex I inhibitor, was used to cause mitochondrial dysfunction in human dermal fibroblasts and its effects on mitochondrial and cytosolic ROS levels, mitochondrial respiration, cell death, apoptosis, matrix metalloproteinase-1 (MMP1) and pro-collagen secretion were determined as markers of skin damage. Rotenone caused substantial reduction of respiration, followed by increased mitochondrial and cytosolic ROS which resulted in apoptotic cell death, increased MMP1 secretion and decreased collagen secretion. Pretreatment with estradiol recovered more than 50% of the respiratory activity, reduced mitochondrial and cytosolic ROS levels and MMP1 secretion and increased cell number and collagen secretion. These effects can be partially explained by a cooperative effect of estradiol and rotenone on Antioxidant Response Element (ARE/Nrf2) transcriptional activity, which leads to upregulation of antioxidant proteins such as NQO1 and Trxr1. To determine if estrogen receptors (ER) are involved in the protective effects, we used the ER inhibitor, Fulvestrant. This inhibitor, which completely inhibited ER Response Element reporter activity, partially prevented the protective effects of estradiol. The protective effects of estradiol were Similarly reduced by ML385 and Ochratoxin A, that are inhibitors of the ARE/Nrf2 transcription system. Incubating the cells with Fulvestrant and Ochratoxin A, which inhibit both pathways, completely blocked the protective effect of estradiol. These results suggest that the estrogen receptors and the ARE/Nrf2 signaling pathways are involved in the protective effects of estradiol against the damage caused by rotenone-induced mitochondria generated oxidative stress. Presentation: 6/3/2024

Inflammation and cognitive performance in elite athletes: A cross-sectional study

Functional cognition is relevant for athletic success and interdependent with physical exercise, yet despite repeatedly demonstrated inflammatory responses to physical training, there are no studies addressing the relationship between cognition and inflammation in athletes. The aim of this study was to investigate the relationship between cognitive performance and selected inflammatory, and further physiological biomarkers in elite athletes. Data from 350 elite athletes regarding cognitive performance (processing speed, selective attention, working memory, cognitive flexibility), systemic inflammatory markers, metabolic hormones, growth factors, tissue damage markers, and micronutrients (e.g., ferritin, 25-OH-vitamin D), as well as physiological, subjective ratings of recovery and stress were analysed by correlative and multiple regression analyses. Results show that across all athletes variance in processing speed, selective attention, and working memory, could be best explained through a combination of metabolic hormones with physiological and psychological indicators of stress, and in cognitive flexibility through vitamin D levels. Only for the subgroup of athletes from closed-skill sports, the ratio TNF-α:IL-10 significantly contributed to explanation of variance in working memory and cognitive flexibility. In general, found correlations point to the importance of inflammatory balance and sufficient long-term nutrient supply for unaffected cognitive performance.

AP-2α decreases TMZ resistance of recurrent GBM by downregulating MGMT expression and improving DNA damage

AimsThe incidence of recurrent gliomas is high, exerting low survival rates and poor prognoses. Transcription factor AP-2α has been reported to regulate the progression of primary glioblastoma (GBM). However, the function of AP-2α in recurrent gliomas is largely unclear. MethodsThe expression of AP-2α and O6-methylguanine DNA-methyltransferase (MGMT) was detected in recurrent glioma tissues and cell lines by Western blots, the regulation mechanisms between AP-2α/MGMT promoter and RA/AP-2α promoter were studied by luciferase reporter assays, EMSA, and chIP assays. The effects of AP-2α and TMZ/RA treatment on cell viability in vitro and in vivo were investigated by MTT assays, γH2AX staining, comet assays and intracranial injection. Key findingsAP-2α expression negatively correlates with the expression of MGMT in glioma samples. AP-2α could directly bind with the promoter of the MGMT gene, suppresses transcriptional levels of MGMT and downregulate MGMT expression in TMZ-resistant U87MG-R and T98G cells, but TMZ treatment decreases AP-2α expression and increases MGMT expression. The extended TMZ treatment and increased TMZ concentrations reversed these effects. Moreover, AP-2α overexpression combines with TMZ to decrease cell viability, concurrently with improved DNA damage marker γH2AX. Furthermore, retinoic acid (RA) activates RAR/RXR heterodimers, which bind to RA-responsive elements (RAREs) of the AP-2α promoter, and activates AP-2α expression in recurrent glioma cells. Finally, in intracranial relapsed glioma mouse model, both RA and TMZ could retard tumor development and prolong the mouse survival. SignificanceAP-2α activation by gene overexpression or RA treatment reveals the suppressive effects on glioma relapse, providing a novel therapeutic strategy against malignant refractory gliomas.

Exploring Lysophosphatidylcholine as a Biomarker in Ischemic Stroke: The Plasma-Brain Disjunction.

Lipids and their bioactive metabolites, notably lysophosphatidylcholine (LPC), are increasingly important in ischemic stroke research. Reduced plasma LPC levels have been linked to stroke occurrence and poor outcomes, positioning LPC as a potential prognostic or diagnostic marker. Nonetheless, the connection between plasma LPC levels and stroke severity remains unclear. This study aimed to elucidate this relationship by examining plasma LPC levels in conjunction with brain LPC levels to provide a deeper understanding of the underlying mechanisms. Adult male Sprague-Dawley rats underwent transient middle cerebral artery occlusion and were randomly assigned to different groups (sham-operated, vehicle, LPC supplementation, or LPC inhibition). We measured multiple LPC species in the plasma and brain, alongside assessing sensorimotor dysfunction, cerebral perfusion, lesion volume, and markers of BBB damage, inflammation, apoptosis, and oxidative stress. Among five LPC species, plasma LPC(16:0) and LPC(18:1) showed strong correlations with sensorimotor dysfunction, lesion severity, and mechanistic biomarkers in the rat stroke model. Despite notable discrepancies between plasma and brain LPC levels, both were strongly linked to functional outcomes and mechanistic biomarkers, suggesting that LPC's prognostic value is retained extracranially. This study advances the understanding of LPC as a blood marker in ischemic stroke and highlights directions for future research to further elucidate its association with stroke severity, particularly through investigations in more clinically representative models.

Evidence That Long-Term Treatment Prevents Tissue Oxidative Damage in Patients With Inherited Disorders of the Propionate Pathway.

Propionic and methylmalonic acidemias (PAcidemia and MMAcidemia, respectively) are genetic disorders clinically characterized by metabolic decompensation associated with life-threatening encephalopathic episodes in the neonatal period. Adequate and rapid therapeutic management is essential for patients' survival and prognosis. In this study, a restricted protein diet associated with L-carnitine (LC) supplementation was shown to decrease mortality and morbidity in patients affected by these disorders probably by decreasing the accumulation of the major metabolites and therefore their toxicity. Since oxidative stress was proposed as a contributing mechanism of tissue damage in PAcidemia and MMAcidemia and LC has potent antioxidant properties, our objective in this work was to investigate the effects of a long-term therapy consisting of reduced protein intake associated with LC supplementation on oxidative damage markers in patients affected by these diseases. We measured urinary isoprostanes, di-tyrosine, and oxidized guanine species, which reflect oxidative damage to lipids, proteins, and DNA/RNA, respectively, as well as the concentrations of NO products (nitrate plus nitrite) in patients untreated or submitted to short-term or a long-term treatment. Results revealed significant increases of isoprostanes, di-tyrosine, and oxidized guanine species, as well as a moderate nonsignificant increase of NO levels in the untreated patients, relatively to controls. Furthermore, these altered markers were attenuated after short-term treatment and normalized after prolonged treatment. In conclusion, data from this work show for the first time that long-standing treatment of patients with disorders of the propionate pathway can protect against oxidative damage. However, it remains to be elucidated whether oxidative stress identified in this study directly correlates with the clinical conditions of the affected patients.

B-222 Receptor-donor CYP3A5 and CYP3A4 genotype testing in liver transplant patients and its influence in tacrolimus blood levels: a retrospective study

Abstract Background Optimal immunosupression is crucial for transplant success. In orthohepatic transplants, blood target levels of tacrolimus, when coadministred with corticoids and mycophenolic acid, are between 6 and 10 ng/mL during the first three months post-transplant. Notwithstanding, achieving tacrolimus concentrations into this range may be tough because of factors such as liver function status, age, sex, drug-drug interactions, etc. In this way, pharmacogenetic testing of CYP3A5 and CYP3A4 genes have demonstrated to be useful in tacrolimus dosing optimization. Nonetheless, there is no evidence enough for pharmacogenetic based adjusting in liver transplant, specially if receptor and graft’s genotypes differ in these loci. The aim of the present study is to find out how the receptor and donor genotypes in CYP3A5 and CYP3A4 genes affect tacrolimus pharmacokinetics. Methods Genotypic profiling of 108 receptor-donor's pairs biopsies gathered from patients who were underwent hepatic transplant from 2012 to 2019 were carried out using Taqman® OpenArray™ PGx Express 120 panel (ThermoFisher™). We focused on CYP3A5*3, *6 and *7; and CYP3A4*1B, *3 and *22 alleles. Next to pharmacogenetic testing, each patient was classified as very poor, poor, intermediate, rapid or ultrarapid metabolizer according to their own genotype, graft’s genotype or both of them. Patient’s initial dose, at seven days after treatment start and after discharge of tacrolimus and their trough concentrations (C0) were collected from their electronic health records. Tacrolimus levels were measured by affinity chrome-mediated immunoassay. C0 was normalized by weight-adjusted dosage (C/D ratio); then, median C/D ratios between different metabolic profiles were compared through Kruskal-Wallis test. Results When patients were classified based on donor’s genotype isolated or combined with receptor’s genotype, lower C/D ratios were found as metabolizer ability increases (p=0.045 for donors and p=0.027 for combined genotypes, respectively). No statistically differences were found for C/D ratios at seven days and discharge, though that differences were almost significant for donor’s genotypes (p=0.06 in both cases). Conclusions These results show that previous information about both patient’s and specially donor’s CYP genes genotype may improve initial immunosupression and avoid tacrolimus induced toxicity. Pharmacogenetics has been currently proposed as a guide for tacrolimus treatment of some solid organ transplants as kidney transplanted patients. Better understanding of how receptor and donor’s CYP genotype affects its pharmacokinetics, along with liver’s damage markers and other genetic polymorphisms will allow clinicians, in the era of personalized medicine, to improve immunosupressive management.

Lower adaptive immunity in invasive Egyptian geese compared to sympatric native waterfowls

Successful invasive species increase their spreading success by trading-off nutritional and metabolic resources allocated to reproduction and range expansion with other costly body functions. One proposed mechanism for the reallocation of resources is a trade-off with the immune function and the regulation of oxidative status. Relying on a panel of blood-based markers of immune function and oxidative status quantified in an invasive species (Egyptian goose) and two native competing species (mallard and mute swan) in Germany, we tested the hypothesis that the invasive species would have (i) lower investment in immune function, (ii) lower levels of oxidative damage, and (iii) no higher antioxidant defences compared to the native species. We found lower levels of adaptive immune markers (lymphocytes and immunoglobulin Y), in the invasive species compared to the two native species. Innate immune profile was generally similar between Egyptian geese and mallards. By contrast, mute swans showed higher levels of heterophils and lysozymes, and lower levels of bacteria killing ability compared to both Egyptian geese and mallards. Mute swans also showed higher levels of haemolysis and haemagglutination, but lower levels of monocytes and haematocrit compared to Egyptian geese. Reactive oxygen metabolites, a marker of oxidative damage, were higher in mallards and lower in Egyptian geese compared to the other waterfowl species, while levels of antioxidants were generally similar among the three species. Our results point to a reduced investment in adaptive immune function in the invasive species as a possible resources-saving immunological strategy due to the loss of co-evolved parasites in the new colonised habitats, as observed in a previous study. A lower investment in immune function may benefit other energy-demanding activities, such as reproduction, dispersal, and territoriality, while maintaining relatively higher innate immunity is beneficial since invasive species mainly encounter novel pathogens. Results pointed out also other important species-specific differences in baseline immune status, supporting previous findings on the relationship between species' body mass and immune profile.

Persistent hypertension induces atrial remodeling and atrial fibrillation through DNA damage and ATM/CHK2/p53 signaling pathway

Atrial fibrillation (AF) is the most prevalent arrhythmia in clinical practice, with hypertension emerging as an independent risk factor. Previous literature has established associations between DNA damage response (DDR) and autophagy in relation to the pathogenesis of AF. The aim of this study was to evaluate the effect of atrial DNA damage response in persistent hypertension-induced atrial electrical and structural remodeling, and to further explore the potential therapeutic targets. Patient samples, spontaneous hypertensive rats (SHR) and angiotensin II (Ang II)-challenged HL-1 cells were employed to elucidate the detailed mechanisms. Bioinformatics analysis and investigation on human atrial samples revealed a critical role of DDR in the pathogenesis of AF. The markers of atrial DNA damage, DDR, autophagy, inflammation and fibrosis were detected by western blot, immunofluorescence, monodansyl cadaverine (MDC) assay and transmission electron microscopy. Compared with the control group, SHR exhibited significant atrial electrical and structural remodeling, abnormal increase of autophagy, inflammation, and fibrosis, which was accompanied by excessive activation of DDR mediated by the ATM/CHK2/p53 pathway. These detrimental changes were validated by in vitro experiments. Ang II-challenged HL-1 cells also exhibited significantly elevated γH2AX expression, and markers related to autophagy, inflammation as well as structural remodeling. Additionally, inhibition of ATM with KU55933 (a specific ATM inhibitor) significantly reversed these effects. Collectively, these data demonstrate that DNA damage and the subsequently overactivated ATM/CHK2/p53 pathway play critical roles in hypertension-induced atrial remodeling and the susceptibility to AF. Targeting ATM/CHK2/p53 signaling may serve as a potential therapeutic strategy against AF.

Association of ambient air pollution with cognitive functioning and markers of structural brain damage: The Maastricht study

IntroductionGiven the absence of curative interventions and the rising global incidence of dementia, research is increasingly focusing on lifestyle factors for prevention. However, identifying shared environmental risk for dementia, next to individual factors, is crucial for optimal risk reduction strategies. Therefore, in the present study we investigated the association between air pollution, cognitive functioning, and markers of structural brain damage. MethodsWe used cross-sectional data from 4,002 participants of The Maastricht Study on volumetric markers of brain integrity (white and grey matter volume, cerebrospinal fluid volume, white matter hyperintensities volume, presence of cerebral small vessel disease) and cognitive functioning (memory, executive functioning and attention, processing speed, overall cognition). Individuals were matched by postal code of residence to nationwide data on air pollution exposure (particulate matter < 2.5 μm (PM2.5), particulate matter <10 μm (PM10), nitrogen dioxide (NO2), soot). Potentia linear and non-linear associations were investigated with linear, logistic, and restricted cubic splines regression. All analyses were adjusted for demographic characteristics and a compound score of modifiable dementia risk and protective factors. ResultsExposure to air pollutants was not related to cognitive functioning and most brain markers. We found curvilinear relationships between high PM2.5 exposures and grey matter and cerebrospinal fluid volume. Participants in the low and high range of exposure had lower grey matter volume. Higher cerebrospinal fluid volumes were only associated with high range of exposure, independent of demographic and individual modifiable dementia risk factors. After additional post hoc analyses, controlling for urbanicity, the associations for grey matter volume became non-significant. In men only, higher exposure to all air pollutants was associated with lower white matter volumes. No significant associations with white matter hyperintensities volume or cerebral small vessel disease were observed. DiscussionOur findings suggest that higher PM2.5 exposure is associated with more brain atrophy.

Protective effects of nordalbergin against LPS-induced endotoxemia through inhibiting MAPK/NF-κB signaling pathway, NLRP3 inflammasome activation, and ROS production.

Nordalbergin is a coumarin extracted from Dalbergia sissoo DC. To date, the biological effects of nordalbergin have not been well investigated. To investigate the anti-inflammatory responses and the anti-oxidant abilities of nordalbergin using lipopolysaccharide (LPS)-activated macrophages and LPS-induced sepsis mouse model. Production of nitrite oxide (NO), prostaglandin E2 (PGE2), pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β), reactive oxygen species (ROS), tissue damage and serum inflammatory markers, and the activation of the NLRP3 inflammasome were examined. Our results indicated that nordalbergin reduced the production of NO and pro-inflammatory cytokines in vitro and ex vivo. Nordalbergin also suppressed iNOS and cyclooxygenase-2 expressions, decreased NF-κB activity, and attenuated MAPKs signaling pathway activation by decreasing JNK and p38 phosphorylation by LPS-activated J774A.1 macrophages. Notably, nordalbergin diminished NLRP3 inflammasome activation via repressing the maturation of IL-1β and caspase-1 and suppressing ROS production by LPS/ATP- and LPS/nigericin-activated J774A.1 macrophages. Furthermore, nordalbergin exhibited protective effects against the infiltration of inflammatory cells and also inhibited the levels of organ damage markers (AST, ALT, BUN) by LPS-challenged mice. Nordalbergin possesses anti-inflammatory effects in macrophage-mediated innate immune responses, alleviates ROS production, decreases NLRP3 activation, and exhibits protective effects against LPS-induced tissue damage in mice.

Level of high sensitivity troponin I and its correlation with hemodialysis vintage – A pilot study

Background: Renal replacement therapy (RRT) is advised in end-stage renal disease, the last stage of chronic kidney disease (CKD). RRT includes maintenance hemodialysis (MHD)/peritoneal dialysis/renal transplant. The requirement for MHD is annually escalating in India. It is important to note that over 80% of patients receiving MHD have at least one cardiac disease at the time of dialysis initiation, such as ischemic heart disease, congestive cardiac failure, and arrhythmias. Aims and Objectives: The present study aimed to study high-sensitivity cardiac troponin I (hs-cTnI) serum level as a marker of cardiovascular injury in patients receiving MHD. It was an attempt to envisage a correlation between serum hs-cTnI and hemodialysis (HD) vintage (duration since initiation of dialysis till date). Materials and Methods: We enrolled 40 patients. Group 1 included those who had received MHD for ≤24 months, and Group 2 included those who had received MHD for more than 24 months. Results: We found no significant difference between the two groups’ clinical characteristics and demographic features. The pre-and post-HD serum hs-cTnI values of all patients were recorded. The serum hs-cTnI levels were found to be elevated in 34 out of 40 patients’ post-dialysis, and the result was statistically significant (P=0.0001). Conclusion: The present study has encouraging results, with values of hs-cTnI raised in post-dialysis samples; however, the levels did not correlate with HD vintage. Further studies with larger sample sizes and longer follow-ups would provide more detailed information on hs-cTnI’s role as a marker for HD-induced cardiac damage.

Biomarkers of Acute Brain Injury

Introduction: Acute brain injury is one of the most important causes of morbidity, mortality and disability worldwide. Time is the most important aspect of acute brain injury management. In this context, biomarkers could mitigate the limitations of neuroimaging. Neuro-biomarkers could be used both to diagnose intracranial pathology and to predict the effectiveness of treatment applications. Aim: The aim of this review is to describe the role of various and specific markers of brain damage with particular emphasis on acute brain injury and stroke. Results/discussion: The diagnostic and prognostic value of modern biomarkers remains relatively questionable, although grouping biomarkers into panels is improving their usefulness. The groups of biomarkers that will be analyzed include astrocytic, axonal, neuronal as well as extracellular biomarkers. Conclusion: Future studies will demonstrate the utility of neuro-biomarkers in the diagnosis, prognosis and therapeutic monitoring of patients with acute brain injury in the intensive care unit.

Polycystic Ovary Syndrome Accompanied by Hyperandrogenemia or Metabolic Syndrome Triggers Glomerular Podocyte Injury.

Objective: To determine whether the urinary excretion of podocyte degradation products varies according to PCOS phenotype and metabolic syndrome (MetS). Methods: The concentrations of podocalyxin (PDX) and nephrin, chronic markers of podocyte damage, and neutrophil gelatinase-associated lipocalin (NGAL), a marker of acute glomerular damage, were analyzed in the morning urine samples of 50 PCOS patients and 50 healthy controls matched by age and BMI. Albuminuria was assessed by calculating the urine albumin-creatinine ratio (uACR). Results: The PDX, nephrin and NGAL concentrations of PCOS participants were significantly higher than those of the control group. While PDX, nephrin and NGAL levels of classic phenotypes were similar, they were higher than ovulatory and non-hyperandrogenic phenotypes. Significant increases in urinary levels of each podocyte protein were detected in PCOS patients with MetS compared to patients without MetS. A positive significant correlation between podocyte proteins and BMI, systolic blood pressure, testosterone, glucose, HOMA-IR and uACR. After adjusting for age and BMI, podocyte proteins were an independent risk factor for microalbuminuria. The incidence of microalbuminuria in PCOS increased 6-fold compared to controls. The frequency of microalbuminuria was higher in classical phenotypes than in ovulatory phenotype. The frequency of microalbuminuria in PCOS patients with MetS was 6.5 times higher than in PCOS patients without MetS. Conclusions: In PCOS accompanied by hyperandrogenemia or metabolic syndrome, leakage of acute and chronic podocyte breakdown products into the urine becomes more pronounced.