Pharmacological Activation of Piezo1 Channels Enhances Astrocyte-Neuron Communication via NMDA Receptors in the Murine Neocortex.

The Piezo1 mechanosensitive ion channel is abundant on several elements of the central nervous system including astrocytes. It has been already demonstrated that activation of these channels is able to elicit calcium waves on astrocytes, which contributes to the release of gliotransmitters. Astrocyte- and N-methyl-D-aspartate (NMDA) receptor-dependent slow inward currents (SICs) are hallmarks of astrocyte-neuron communication. These currents are triggered by glutamate released as gliotransmitter, which in turn activates neuronal NMDA receptors responsible for this inward current having slower kinetics than any synaptic events. In this project, we aimed to investigate whether Piezo1 activation and inhibition is able to alter spontaneous SIC activity of murine neocortical pyramidal neurons. When the Piezo1 opener Yoda1 was applied, the SIC frequency and the charge transfer by these events in a minute time was significantly increased. These changes were prevented by treating the preparations with the NMDA receptor inhibitor D-AP5. Furthermore, Yoda1 did not alter the spontaneous EPSC frequency and amplitude when SICs were absent. The Piezo1 inhibitor Dooku1 effectively reverted the actions of Yoda1 and decreased the rise time of SICs when applied alone. In conclusion, activation of Piezo1 channels is able to alter astrocyte-neuron communication. Via enhancement of SIC activity, astrocytic Piezo1 channels have the capacity to determine neuronal excitability.

The Effect of Preoperative Administration of Glucocorticoids on the Postoperative Complication Rate in Liver Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Glucocorticoids may grant a protective effect against postoperative complications. The evidence on their efficacy, however, has been inconclusive thus far. We investigated the effects of preoperatively administered glucocorticoids on the overall postoperative complication rate, and on liver function recovery in patients undergoing major liver surgery. Methods: We performed a systematic literature search on PubMed, Embase, and CENTRAL in October 2021, and repeated the search in April 2023. Pre-study protocol was registered on PROSPERO (ID: CRD42021284559). Studies investigating patients undergoing liver resections or transplantation who were administered glucocorticoids preoperatively and reported postoperative complications were eligible. Meta-analyses were performed using META and DMETAR packages in R with a random effects model. Risk of bias was assessed using RoB2. Results: The selection yielded 11 eligible randomized controlled trials (RCTs) with 964 patients. Data from nine RCTs (n = 837) revealed a tendency toward a lower overall complication rate with glucocorticoid administration (odds ratio: 0.71; 95% confidence interval: 0.38-1.31, p = 0.23), but it was not statistically significant. Data pooled from seven RCTs showed a significant reduction in wound infections with glucocorticoid administration [odds ratio: 0.64; 95% confidence interval: 0.45-0.92 p = 0.02]. Due to limited data availability, meta-analysis of liver function recovery parameters was not possible. Conclusions: The preoperative administration of glucocorticoids did not significantly reduce the overall postoperative complication rate. Future clinical trials should investigate homogenous patient populations with a specific focus on postoperative liver recovery.

The influence of socioeconomic deprivation on outcomes in transplant patients infected with SARS-CoV-2 in Wales.

INTRODUCTION: SARS-CoV-2 infection has had a significant impact on vulnerable individuals including transplant patients. Socioeconomic deprivation negatively affects outcomes of many health conditions. The aim of this study was to evaluate the effect of socioeconomic deprivation on the incidence and severity of SARS-CoV-2 infection among Welsh transplant patients. METHODS: This study is a retrospective, cross-sectional study on the transplant population of Wales. The Welsh Index of Multiple Deprivation (WIMD) was used to assess the influence of socioeconomic deprivation on outcomes of Welsh transplant patients who developed SARS-CoV-2 infection. Outcome measures were the incidence of SARS-CoV-2 infection, rates of hospital and ICU admission, development of acute kidney injury (AKI) and mortality. A logistic binomial regression analysis was used to correlate the various risk factors with the incidence of SARS-CoV-2 infection. RESULTS: Two hundred and sixty-six (25%) of regular follow up patients had SARS-CoV-2 infection; of these 55 (20.7%) were admitted, 15 (5.6%) to ICU, 37 (13.9%) developed AKI, and 23 (8.6%) died. In a regression analysis, patients of younger age were associated with more (p = .001) and those with SPK (simultaneous pancreas kidney) transplant less chance of infection (p = .038), whereas social deprivation was not associated with the chance of infection (p = .14). In regression analysis increased social deprivation was associated with higher chance of AKI post SARS-CoV-2 (p = .049). CONCLUSIONS: Socioeconomic deprivation did not affect the rates or severity of SARS-CoV-2 infection apart from the degree of AKI in Welsh Transplant patients. Adherence to the preventive measures for this high-risk population must continue to remain a priority.

Synergism of red blood cells and tranexamic acid in the inhibition of fibrinolysis.

BACKGROUND: Postpartum hemorrhage (PPH) is the leading cause of maternal death worldwide. The World Maternal Antifibrinolytic trial showed that antifibrinolytic tranexamic acid (TXA) reduces PPH deaths. Maternal anemia increases the risk of PPH. The World Maternal Antifibrinolytic-2 trial is now assessing whether TXA can prevent PPH in women with anemia. Low red blood cell (RBC) counts promote fibrinolysis by altering fibrin structure and plasminogen activation. OBJECTIVES: We explored interactions between RBCs and TXA in inhibiting fibrinolysis. METHODS: We used global fibrinolytic assays (ball sedimentation and viscoelasticity) to monitor the lysis of fibrin containing plasminogen and tissue-type plasminogen activator. We applied a fluorogenic kinetic assay to measure plasmin generation in fibrin clots and scanning electron microscopy to study fibrin structure. RESULTS: According to parallel-line bioassay analysis of the fibrin lysis-time data, the antifibrinolytic potency of 4-128 µM TXA was increased in the presence of 10% to 40% (v/v) RBCs. Global fibrinolysis assays showed that the joint effect of RBCs and TXA was about 15% larger than the sum of their individual effects in the inhibition of fibrinolysis. In plasminogen activation, TXA added the same increment of inhibition to the effect of RBCs at any cell count in the fibrin clot. Regarding fibrin structure, TXA thickened fibrin fibers, which impaired plasminogen activation, whereas RBCs promoted fine fibers that were more resistant to plasmin. CONCLUSIONS: The antifibrinolytic potency of TXA is enhanced in fibrin formed in the presence of RBCs through inhibition of plasminogen activation and fibrin lysis, which correlates with modifications of fibrin structures.

Outcomes of Exeter cemented total hip arthroplasty in a county hospital: survivorship of eight hundred and ninety four hips with a minimum ten-year follow up.

PURPOSE: A total of 894 hips were evaluated to describe the survivorship of Exeter cemented femoral stems and report the outcomes and complications of our 'Exeter- era', and there is no study from Central or Eastern Europe demonstrating similar results. METHODS: Between January 2000 and December 2009, a total of 894 hips were included who underwent Exeter universal and V40 femoral stems with a mean follow up of 13 years. Cemented Exeter low profile polyethylene cups were used in 889 patients (99.4%) cups. Harris hip score (HHS) was used and statistical outcome measures were calculated with revision as an endpoint for aseptic loosening of the stem, aseptic loosening of any component, all-cause revision of the stem, and all-cause revision of the hip. RESULTS: A total of 103 patients died and 129 (14.4%) operated hips were lost to follow-up before ten years. Out of the 662, ten stems (1.5%) were revised for aseptic loosening. Aseptic loosening of any component was the reason for revision in 43 cases (6.5%), consisting of 40 cup revisions and ten stem exchanges. Periprosthetic fracture occurred in 17 cases (1.9%) Periprosthetic joint infection occurred in 18 cases (2.01%). Three cups were exchanged for recurrent dislocation, and two stems had broken. CONCLUSION: Exeter hip system has provided reproducible results across different centres worldwide, as it did in our series. Thorough surgical and cementing technique is of utmost importance for achieving these results. The cup is the weak point of the system and use of a hybrid system is worth considering.

Evidence for gait improvement with robotic-assisted gait training of children with cerebral palsy remains uncertain.

BACKGROUND: Cerebral palsy (CP) is a group of neuromotor diseases that develops as a result of damage to the developing central nervous system during the perinatal period. The condition is usually accompanied by musculoskeletal problems resulting in movement disorders. Gait improvement therefore, is an important part of its treatment. Roboticassisted gait training (RAGT) is a new potential rehabilitation tool for CP patients, however there is no clear evidence for the effectiveness of this method. RESEARCH QUESTION: Can robotic-assisted gait training improve walking function in children with CP? METHODS: A systematic search was performed in five databases: MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Scopus, and Web of Science. Eligible studies were randomized controlled trials (RCT) with CP patients under the age of 18. Gross motor function and kinematic gait parameters of patients were the main outcomes. Two authors determined the risk of bias of the RCTs independently using the revised Risk of Bias 2 (ROB 2) tool. Mean Differences (MDs) along with their 95% Confidence Interval (CI) were calculated when at least three studies were present for an outcome, subgroup analysis was performed based on the treatment of the control group. RESULTS: Of the 7363 screened articles, 13 papers met our inclusion criteria and among them, 7 studies could be used in our meta-analyses. The results related to RAGT suggest nonsignificant improvement in standing and walking function (Gross Motor Function Measure D, E), moreover changes in gait speed, step length, and in cadence were also only comparable to controls. SIGNIFICANCE: The results indicate that there is a trend in some gait parameters where the improvement was higher in the intervention group than in control group. The therapeutic effect of RAGT was probably not superior to physiotherapy combined with treadmill training.

Loss of Uncoupling Protein 1 Expression in the Subcutaneous Adipose Tissue Predicts Childhood Obesity.

Stimulation of thermogenesis by inducing uncoupling protein 1 (UCP1) expression in adipocytes is thought to promote weight loss by increasing energy expenditure, and it is postulated that the human newborn has thermogenic subcutaneous fat depots. However, it remains unclear whether a relevant number of UCP1-expressing (UCP1+) adipocytes exist in the early postnatal life. Here we studied the distribution of UCP1 and the expression of thermogenic genes in the subcutaneous adipose tissues of the human fetus, infant and child. We show that the deep layer of human fetal and neonatal subcutaneous fat, particularly the abdominal wall, is rich in UCP1+ adipocytes. These adipocytes develop in the late third trimester and persist throughout childhood, expressing a panel of genes linked to mitochondrial biogenesis and thermogenesis. During the early childhood adiposity rebound-a critical phase that determines obesity risk later in life-the absence of adipose tissue UCP1 expression in children with normal body mass index (BMI) correlates with an obesity-associated gene expression signature. Finally, UCP1 expression is negatively correlated with BMI z-score and adipocyte size in infants and children. Overall, our results show that the absence of UCP1 expression in adipose tissue is an early indicator of adipose tissue expansion in children.

Ancient chicken remains reveal the origins of virulence in Marek's disease virus.

The pronounced growth in livestock populations since the 1950s has altered the epidemiological and evolutionary trajectory of their associated pathogens. For example, Marek's disease virus (MDV), which causes lymphoid tumors in chickens, has experienced a marked increase in virulence over the past century. Today, MDV infections kill >90% of unvaccinated birds, and controlling it costs more than US$1 billion annually. By sequencing MDV genomes derived from archeological chickens, we demonstrate that it has been circulating for at least 1000 years. We functionally tested the Meq oncogene, one of 49 viral genes positively selected in modern strains, demonstrating that ancient MDV was likely incapable of driving tumor formation. Our results demonstrate the power of ancient DNA approaches to trace the molecular basis of virulence in economically relevant pathogens.

White and other fur colourations and hybridization in golden jackals (Canis aureus) in the Carpathian basin.

The golden jackal (Canis aureus) is a reoccurring species in the centre of the Carpathian basin, in Hungary. In total, 31 golden jackal tissue samples were collected, from 8 white-coated, 2 black-coated and one mottled animal across Hungary. Sequences and fragment length polymorphisms were studied for white colour (MC1R), and for black coat colouration (CBD103). In each white animal, the most widespread mutation causing white fur colour in dogs in homozygous form was detected. Three animals were found to carry the mutation in heterozygous form. The two black golden jackals were heterozygous for the 3 bp deletion in CBD103 that mutation for black coat colouration in dogs, and one of them also carried the mutation causing white fur. None of the white animals showed signs of hybridization, but both the black and the mottled coloured individuals were found to be hybrids based on genetic testing. Kinship was found three times, twice between white animals, and once between a white animal and an agouti animal carrying the mutation of white coat. Our results confirm the findings that golden jackal-dog hybrids may occur without human intervention, and the detected mutation causing white fur colour in golden jackals could possibly be due to an early hybridization event.

Plasma Exchange versus Intravenous Immunoglobulin in Worsening Myasthenia Gravis: A Systematic Review and Meta-Analysis with Special Attention to Faster Relapse Control.

Currently used rescue interventions to prevent rapid myasthenic deterioration are plasma exchange (PLEX) and intravenous immunoglobulin (IVIG). We investigated the evidence to determine whether the two methods were interchangeable or whether one was superior to the other. This review was registered on PROSPERO (CRD42021285985). Only randomized controlled trials (RCTs) comparing the efficacy and safety of PLEX and IVIG in patients with moderate-to-severe myasthenia gravis (MG) were included. Five major databases were systematically searched (PubMed, CENTRAL, Embase, Scopus, and Web of Science). Odds ratios (OR) with 95% confidence intervals (CI) were calculated for adverse events and mean differences (MD) for changes in quantitative myasthenia gravis scores (QMG). Three RCTs met the inclusion criteria. Two investigating 114 patients in total were eligible for meta-analysis to analyze efficacy and safety. For the change in QMG score, the MD was -2.8 (95% CI: -5.614-0.113), with PLEX performing better. For adverse events, an OR of 1.04 was found (95% CI: 0.25-4.27). This study demonstrated a low risk of bias in evaluating treatment efficacy but indicated a high risk of bias in assessing procedural safety outcomes. Although the results did not show any significant difference, there was a tendency indicating faster efficacy of PLEX in the first two weeks of treatment. In such a critical clinical condition, this tendency may be clinically meaningful, but further studies should clarify this benefit.

Tuberculosis in prehistory in Eastern Central Europe (Hungary) - Chronological and geographical distribution.

Tuberculosis (TB) has long been a major scourge of humankind. Paleopathological and paleomicrobiological studies have revealed the past presence of the disease on a large spatial and temporal scale. The antiquity of the disease has extensively been studied in the Carpathian Basin, given its dynamic population and cultural changes since prehistory. These studies, however, have mainly focused on the populations living during the Common Era. The aim of this paper is to present the published and the recently discovered cases of prehistoric TB, from the Neolithic (6000-4500/4400 BCE) to the Bronze Age (2600/2500-800 BCE) Central Carpathian Basin (Hungary). We summarize 18 published cases and present new cases dating to the Neolithic period and introduce 3 newly discovered Bronze Age cases of TB. Despite extensive research, TB has not yet been identified from the Copper and Iron Ages in the Carpathian Basin. Considering the state of TB research, and supplemented by our prehistoric dataset, the spatio-temporal pattern of the disease can be further elucidated, thus advancing future molecular and paleopathological studies. Our dataset offers comprehensive spatial and temporal information on the spread of the disease in the Carpathian Basin, along with a detailed biological profile of the demonstrated cases and extensive paleopathological descriptions of the observed lesions, complemented by photographic evidence. This invaluable resource paves the way for enhanced understanding and progress in the field.

Past and present: changes in the Odonata fauna of small lowland watercourses.

Small lowland watercourses, strongly exposed to anthropogenic activities and climate change, have received negligible odonatological attention. This study provides a revised checklist of three typical lowland small watercourses (Kállai-fofolyás, Konyári-Kálló and Ölyvös) within the Pannonian Lowland and presents the changes in their diversity over the past decades. Results revealed a significant biodiversity loss, with a 31.6% decline in Odonata fauna over the last 53 years. The upper and middle sections degraded the most, where the habitats have dried out or become intermittent. However, a diverse Odonata assemblage (1,277 individuals of 27 species) was observed at the 14 sampling sites of the three watercourses, containing protected and sensitive species (Somatochloraflavomaculata, Orthetrumbrunneum, Aeshnaisoceles, Libellulafulva). However, the low abundance of larval and exuvial forms (59 individuals of 13 species) suggests that the majority of the observed adults were developed in other watercourses. While recolonisation from nearby habitats is still possible, a parallel degradation of adjecent waterbodies could lead to an irreversible biodiversity loss.

Stimulator of Interferon Genes (STING) Triggers Adipocyte Autophagy.

Innate immune signaling in adipocytes affects systemic metabolism. Cytosolic nucleic acid sensing has been recently shown to stimulate thermogenic adipocyte differentiation and protect from obesity; however, DNA efflux from adipocyte mitochondria is a potential proinflammatory signal that causes adipose tissue dysfunction and insulin resistance. Cytosolic DNA activates the stimulator of interferon response genes (STING), a key signal transducer which triggers type I interferon (IFN-I) expression; hence, STING activation is expected to induce IFN-I response and adipocyte dysfunction. However, we show herein that mouse adipocytes had a diminished IFN-I response to STING stimulation by 2'3'-cyclic-GMP-AMP (cGAMP). We also show that cGAMP triggered autophagy in murine and human adipocytes. In turn, STING inhibition reduced autophagosome number, compromised the mitochondrial network and caused inflammation and fat accumulation in adipocytes. STING hence stimulates a process that removes damaged mitochondria, thereby protecting adipocytes from an excessive IFN-I response to mitochondrial DNA efflux. In summary, STING appears to limit inflammation in adipocytes by promoting mitophagy under non-obesogenic conditions.

DNA and histones impair the mechanical stability and lytic susceptibility of fibrin formed by staphylocoagulase.

Background: Staphylocoagulase (SCG) is a virulence factor of Staphylococcus aureus, one of the most lethal pathogens of our times. The complex of SCG with prothrombin (SCG/ProT) can clot fibrinogen, and SCG/ProT-induced fibrin and plasma clots have been described to show decreased mechanical and lytic resistance, which may contribute to septic emboli from infected cardiac vegetations. At infection sites, neutrophils can release DNA and histones, as parts of neutrophil extracellular traps (NETs), which in turn favor thrombosis, inhibit fibrinolysis and strengthen clot structure. Objectives: To characterize the combined effects of major NET-components (DNA, histone H1 and H3) on SCG/ProT-induced clot structure, mechanical and lytic stability. Methods: Recombinant SCG was used to clot purified fibrinogen and plasma. The kinetics of formation and lysis of fibrin and plasma clots containing H1 or core histones+/-DNA were followed by turbidimetry. Fibrin structure and mechanical stability were characterized with scanning electron microscopy, pressure-driven permeation, and oscillation rheometry. Results: Histones and DNA favored the formation of thicker fibrin fibers and a more heterogeneous clot structure including high porosity with H1 histone, whereas low porosity with core histones and DNA. As opposed to previous observations with thrombin-induced clots, SCG/ProT-induced fibrin was not mechanically stabilized by histones. Similarly to thrombin-induced clots, the DNA-histone complexes prolonged fibrinolysis with tissue-type plasminogen activator (up to 2-fold). The anti-fibrinolytic effect of the DNA and DNA-H3 complex was observed in plasma clots too. Heparin (low molecular weight) accelerated the lysis of SCG/ProT-clots from plasma, even if DNA and histones were also present. Conclusions: In the interplay of NETs and fibrin formed by SCG, DNA and histones promote structural heterogeneity in the clots, and fail to stabilize them against mechanical stress. The DNA-histone complexes render the SCG-fibrin more resistant to lysis and thereby less prone to embolization.

Reduced Expression of Septin7 Hinders Skeletal Muscle Regeneration.

Septins are considered the fourth component of the cytoskeleton with the septin7 isoform playing a critical role in the formation of diffusion barriers in phospholipid bilayers and intra- and extracellular scaffolds. While its importance has already been confirmed in different intracellular processes, very little is known about its role in skeletal muscle. Muscle regeneration was studied in a Sept7 conditional knock-down mouse model to prove the possible role of septin7 in this process. Sterile inflammation in skeletal muscle was induced which was followed by regeneration resulting in the upregulation of septin7 expression. Partial knock-down of Sept7 resulted in an increased number of inflammatory cells and myofibers containing central nuclei. Taken together, our data suggest that partial knock-down of Sept7 hinders the kinetics of muscle regeneration, indicating its crucial role in skeletal muscle functions.

Biobased chitosan-derived self-nitrogen-doped porous carbon nanofibers containing nitrogen-doped zeolites for efficient removal of uremic toxins during hemodialysis.

Highly efficient adsorbents are needed to remove uremic toxins and reduce the economic and societal burden of the current dialysis treatments in resource-limited environments. In this study, nanostructured porous carbon nanofibers with nitrogen-doped zeolites (NZ-PCNF) were prepared, by electrospinning zeolites with chitosan-poly(ethylene oxide) blends, followed by a one-step carbonization process, without further activation steps or aggressive chemical additives for N-doping. The results showed that N-zeolites were successfully integrated into an ultrafine carbon nanofiber network, with a uniform nanofiber diameter of approximately 25 nm, hierarchical porous structure (micro- and mesopores), and high specific surface area (639.29 m2/g), facilitating uremic toxin diffusion and adsorption. The self-N-doped structure in the NZ-PCNF removed more creatinine (∼1.8 times) than the porous carbon nanofibers when using the same weight of precursor materials. Cytotoxicity and hemolysis tests were performed to verify the safety of NZ-PCNF. This study provides a novel strategy for transforming chitosan-based materials into state-of-the-art porous carbon nanofiber/zeolite self-N-doped composites, affording an efficient bioderived adsorbent for the removal of uremic toxins in patients with chronic kidney disease.

Migration of Myogenic Cells Is Highly Influenced by Cytoskeletal Septin7.

Septin7 as a unique member of the GTP binding protein family, is widely expressed in the eukaryotic cells and considered to be essential in the formation of hetero-oligomeric septin complexes. As a cytoskeletal component, Septin7 is involved in many important cellular processes. However, its contribution in striated muscle physiology is poorly described. In skeletal muscle, a highly orchestrated process of migration is crucial in the development of functional fibers and in regeneration. Here, we describe the pronounced appearance of Septin7 filaments and a continuous change of Septin7 protein architecture during the migration of myogenic cells. In Septin7 knockdown C2C12 cultures, the basic parameters of migration are significantly different, and the intracellular calcium concentration change in migrating cells are lower compared to that of scrambled cultures. Using a plant cytokinin, forchlorfenuron, to dampen septin dynamics, the altered behavior of the migrating cells is described, where Septin7-depleted cells are more resistant to the treatment. These results indicate the functional relevance of Septin7 in the migration of myoblasts, implying its contribution to muscle myogenesis and regeneration.

Medium-Term Results of Staged Laparoscopic Traction Orchiopexy for Intra-abdominal Testes: A Multicenter Analysis.

BACKGROUND: Staged laparoscopic traction orchiopexy (SLTO) is a novel technique for the intra-abdominal testis (IAT) based on elongation of the testicular vessels without separating them. This multicenter study evaluated the medium-term results of this technique. METHODS: Data of SLTO performed in three pediatric surgical centers between 2013 and 2020 were analyzed retrospectively. In 2021, physical and Doppler ultrasound examinations were performed to determine the position and viability of testes. Success was defined as an intra-scrotal testicle without atrophy. RESULTS: SLTO was performed on 48 cases (55 testes, 7 bilateral). Mean age at first stage was 2.9 (0.8-12.6) years. High intra-abdominal testes were found in 16.4% and in 60% morphological abnormalities were observed. To fix the testes to the abdominal wall monofilament suture was used in 67.3%, braided in 29.1%. Mean time between the two stages was 16.4 weeks; three testes required redo traction. Perioperative complications occurred in 21 patients (38.2%) including insufficient fixation (11), testicular atrophy (4), wound complications (4), adhesion of the spermatic cords (1) and hydrocele (1). In case of insufficient fixation monofilament sutures were used in 90.9%. In 2021 38 patients (43 testes) had physical and 36 patients (41 testes) had ultrasound examinations. Mean follow-up was 2.7 (0.34-7.9) years. Altogether five atrophies were identified, and three testicular ascents (7.0%) occurred. The overall success rate was 82.2%. CONCLUSIONS: SLTO may be a feasible alternative to conventional treatments of IATs. Additionally, braided suture seems to be a better option to fix the testicle to the abdominal wall. LEVEL OF EVIDENCE: LEVEL IV.

The Role of the Piezo1 Mechanosensitive Channel in the Musculoskeletal System.

Since the recent discovery of the mechanosensitive Piezo1 channels, many studies have addressed the role of the channel in various physiological or even pathological processes of different organs. Although the number of studies on their effects on the musculoskeletal system is constantly increasing, we are still far from a precise understanding. In this review, the knowledge available so far regarding the musculoskeletal system is summarized, reviewing the results achieved in the field of skeletal muscles, bones, joints and cartilage, tendons and ligaments, as well as intervertebral discs.

Fruit Extract, Rich in Polyphenols and Flavonoids, Modifies the Expression of DNMT and HDAC Genes Involved in Epigenetic Processes.

Recently, the field of epigenetics has been intensively studied in relation to nutrition. In our study, the gene expression patterns of histone deacetylases (HDACs), which regulate the stability of histone proteins, and DNA methyltransferases (DNMTs), which regulate DNA methylation, were determined in mice. The animals were fed a human-equivalent dose of the aqueous extract of fruit seeds and peels, which is rich in flavonoids and polyphenols, for 28 days and then exposed to the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). The concentrations of trans-resveratrol and trans-piceid were determined in the consumed extract by HPLC and were 1.74 mg/L (SD 0.13 mg/L) and 2.37 mg/L (SD 0.32 mg/L), respectively, which corresponds to the consumption of 0.2-1 L of red wine, the main dietary source of resveratrol, in humans daily. Subsequently, 24 h after DMBA exposure, the expression patterns of the HDAC and DNMT genes in the liver and kidneys were determined by qRT-PCR. The DMBA-induced expression of the tested genes HDAC1, HDAC2, DNMT1, DNMT3A and DNMT3B was reduced in most cases by the extract. It has already been shown that inhibition of the DNMT and HDAC genes may delay cancer development and tumour progression. We hypothesise that the extract studied may exert chemopreventive effects.