Tissue Level Research Articles

Integrated Metabolomics and Proteomics of Symptomatic and Early Presymptomatic States of Colitis.

Colitis has a multifactorial pathogenesis with a strong cross-talk among microbiota, hypoxia, and tissue metabolism. Here, we aimed to characterize the molecular signature of the disease in symptomatic and presymptomatic stages of the inflammatory process at the tissue and fecal level. The study is based on two different murine models for colitis, and HR-MAS NMR on "intact" colon tissues and LC-MS/MS on colon tissue extracts were used to derive untargeted metabolomics and proteomics information, respectively. Solution NMR was used to derive metabolomic profiles of the fecal extracts. By combining metabolomic and proteomic analyses of the tissues, we found increased anaerobic glycolysis, accompanied by an altered citric acid cycle and oxidative phosphorylation in inflamed colons; these changes associate with inflammation-induced hypoxia taking place in colon tissues. Different colitis states were also characterized by significantly different metabolomic profiles of fecal extracts, attributable to both the dysbiosis characteristic of colitis as well as the dysregulated tissue metabolism. Strong and distinctive tissue and fecal metabolomic signatures can be detected before the onset of symptoms. Therefore, untargeted metabolomics of tissues and fecal extracts provides a comprehensive picture of the changes accompanying the disease onset already at preclinical stages, highlighting the diagnostic potential of global metabolomics for inflammatory diseases.

Analytical and quantitative assessment of the structural components of the adrenal glands of rats under the conditions of exposure to the venom of vipers Vipera berus berus and Vipera berus nikolskii

Snakebite envenoming is a common but neglected public health problem worldwide, especially in tropical countries. Annual mortality as a result of snakebites exceeds 138,000. It is believed that this problem is underestimated, and in many countries, individual cases of bites are not subject to proper fixation. The purpose of the study is the analytical and quantitative assessment of the structural components of the rats' adrenal glands under exposure to the venom of Vipers Vipera berus berus and Vipera berus nikolskii. Experimental studies were carried out on white, non-linear male rats. Vipera berus berus and Vipera berus nikolskii viper venom were obtained from V. N. Karazin Kharkiv National University. The freeze-dried native venom was stored at -20 °C and dissolved in saline immediately before the experiment. The animals were divided into three groups (control and 2 experimental groups) of 10 individuals each. Experimental rats were injected intraperitoneally in a physiological solution with a semi-lethal dose (LD50) (1.576 mg/g-1) of Vipera berus berus and Vipera berus nikolskii venoms. Animals of the control group were injected intraperitoneally with only a physiological solution. Rats were removed from the experiment 24 hours after exposure to the poison and anesthetised by cervical dislocation. Statistical analysis of the area of the microcirculatory channel and the nuclear-cytoplasmic index was performed using Fiji: ImageJ program and processed in Excel. Administration of the venom of the vipers Vipera berus berus and Vipera berus nikolskii to rats was accompanied by a significant increase in the area of the microcirculatory bed relative to the control group (2.9 times for Vipera berus berus and 6.5 times for Vipera berus nikolskii). Exposure to Vipera berus berus viper venom was associated with a significant decrease in the nuclear-cytoplasmic index in rats of the experimental group compared to the control group (13 % and 42 %, respectively), which is evidence of a decrease in the area of the nuclei of endocrinocytes of the adrenal cortex. This indicator in rats under the administration of Vipera berus nikolskii venom was even lower and amounted to 12 %. According to the statistical analysis of the quantitative assessment of the state of the cortical substance of the adrenal glands, it is worth noting the similar effect of the poisons of both types of snakes at the cellular level. At the same time, at the tissue level, the effect of Vipera berus nikolskii venom is more pronounced than that of Vipera berus berus - this is evidenced by the higher degree of disruption of the structure of the hemomicrocirculatory channel in the adrenal cortex of animals from the group that was affected by this venom. It led to an increase in the area of vessels due to their expansion and ruptures of their walls and haemorrhages into the surrounding parenchyma and stroma.

Identification of circulating apolipoprotein M as a new determinant of insulin sensitivity and relationship with adiponectin

BackgroundThe adiponectin is one of the rare adipokines down-regulated with obesity and protects against obesity-related disorders. Similarly, the apolipoprotein M (apoM) is expressed in adipocytes and its expression in adipose tissue is associated with metabolic health. We compared circulating apoM with adiponectin regarding their relationship with metabolic parameters and insulin sensitivity and examined their gene expression patterns in adipocytes and in the adipose tissue.MethodsCirculating apoM and adiponectin were examined in 169 men with overweight in a cross-sectional study, and 13 patients with obesity during a surgery-induced slimming program. Correlations with clinical parameters including the insulin resistance index (HOMA-IR) were analyzed. Multiple regression analyses were performed on HOMA-IR. The APOM and ADIPOQ gene expression were measured in the adipose tissue from 267 individuals with obesity and a human adipocyte cell line.ResultsParticipants with type 2 diabetes had lower circulating adiponectin and apoM, while apoM was higher in individuals with dyslipidemia. Similar to adiponectin, apoM showed negative associations with HOMA-IR and hs-CRP (r < −0.2), and positive correlations with HDL markers (HDL-C and apoA-I, r > 0.3). Unlike adiponectin, apoM was positively associated with LDL markers (LDL-C and apoB100, r < 0.20) and negatively correlated with insulin and age (r < −0.2). The apoM was the sole negative determinant of HOMA-IR in multiple regression models, while adiponectin not contributing significantly. After surgery, the change in HOMA-IR was negatively associated with the change in circulating apoM (r = −0.71), but not with the change in adiponectin. The APOM and ADIPOQ gene expression positively correlated in adipose tissue (r > 0.44) as well as in adipocytes (r > 0.81). In adipocytes, APOM was downregulated by inflammatory factors and upregulated by adiponectin.ConclusionsThe apoM rises as a new partner of adiponectin regarding insulin sensitivity. At the adipose tissue level, the adiponectin may be supported by apoM to promote a healthy adipose tissue.Trial registrationNCT01277068, registered 13 January 2011; NCT02332434, registered 5 January 2015; and NCT00390637, registered 20 October 2006.

The changes of chili leaf structure by Geminivirus infection

The Geminivirus in chili plants is a significant problem in chili cultivation. Symptoms of Geminivirus infection are quite easy to find in chili plants because the symptoms are quite typical: mosaic, yellowing, small leaves, leaf lamina malformation, and stunting. The visual changes in leaf morphology are due to the leaf tissue structure, such as the upper and lower epidermis and the mesophyll tissue, including the palisade and sponge. There is little information about changes in the structure of chili plants infected with the Geminivirus. Therefore, this study aims to add information about changes in the leaf tissue structure of chili plants infected with the Geminivirus. The structural changes observed were palisades. Long palisades were less preferred by whiteflies, so the incidence of geminivirus disease was lower. This information is a reference for assembling chili plants with better structural resistance. The method used was a cross-section of chili leaves, double staining, and observation with a light microscope. Observations on mild symptoms showed epidermal cells shrinking. Some parts of palisade leaves were composed of two layers with shortened cells and tend to be oval. The symptom is that the upper epidermal cells were shrunken, and the palisade also tends to shorten. Severe symptoms of the epidermis on the leaves were curly, shriveled, thinned, and even dying; the palisade is shortened and sometimes looks irregular/tight. Changes in the leaf tissue of chili plants infected with the Geminivirus cause changes at the ultra-structural, cell, or tissue level, depending on the type of virus attack and the attack level.

Proteomic Profiling of Messenger Ribonucleoproteins in Mouse Tissues Based on Formaldehyde Cross-Linking.

Messenger ribonucleoprotein particles (mRNPs) are vital for tissue-specific gene expression via mediating posttranscriptional regulations. However, proteomic profiling of proteins in mRNPs, i.e., mRNA-associated proteins (mRAPs), has been challenging at the tissue level. Herein, we report the development of formaldehyde cross-linking-based mRNA-associated protein profiling (FAXRAP), a chemical strategy that enables the identification of mRAPs in both cultured cells and intact mouse organs. Applying FAXRAP, tissue-specific mRAPs were systematically profiled in the mouse liver, kidney, heart, and brain. Furthermore, brain mRAPs in Parkinson's disease (PD) mouse model were investigated, which revealed a global decrease of mRNP assembly in the brain of mice with PD. We envision that FAXRAP will facilitate uncovering the posttranscriptional regulation networks in various biological systems.

Analysis of pressure-activated Piezo1 open and subconductance states at a single channel level

Mechanically activated Piezo1 channels undergo transitions from closed to open-state in response to pressure and other mechanical stimuli. However, the molecular details of these mechanosensitive gating transitions are unknown. Here, we used cell-attached pressure-clamp recordings to acquire single channel data at steady-state conditions (where inactivation has settled down), at various pressures and voltages. Importantly, we identify and analyze subconductance states of the channel which were not reported before. Pressure-dependent activation of Piezo1 increases the occupancy of open and subconductance state at the expense of decreased occupancy of shut-states. No significant change in the mean open time of subconductance states was observed with increasing negative pipette pressure or with varying voltages (ranging from -40 to -100 mV). Using Markov-chain modeling we identified a minimal four-states kinetic scheme, which recapitulates essential characteristics of the single channel data, including that of the subconductance level. This study advances our understanding of Piezo1 gating mechanism in response to discrete stimuli (such as pressure and voltage) and paves the path to develop cellular and tissue level models to predict Piezo1 function in various cell types.

Cigarette smoke extract exacerbates progression of osteoarthritic-like changes in cartilage explant cultures.

Established risk factors for osteoarthritis (OA) include obesity, joint injury, age, race, and genetics. However, the relationship between cigarette smoking and OA has yet to be established. In the present study, we have employed the use of cigarette smoke extract (CSE), the water-soluble vapor phase of cigarette smoke, with porcine cartilage explants to investigate the effects of cigarette smoking on cartilage catabolism at the tissue level. Articular cartilage explants were first exposed to 2.5%, 5%, and 10% CSE to assess its effects on cartilage homeostasis. Following, the effects of CSE on OA-like inflammation was observed by culturing explants with a combined treatment of IL-1β and TNF-α and 10% CSE (CSE + OA). Cartilage explants were assessed for changes in viability, biochemical composition, extracellular matrix (ECM) integrity, and equilibrium mechanical properties (aggregate modulus and hydraulic permeability). CSE alone leads to both a time- and dose-dependent decrease in chondrocyte viability but does not significantly affect sGAG content, percent sGAG loss, or the ECM integrity of cartilage explants. When IL-1β and TNF-α were combined with 10% CSE, this led to a synergistic effect with more significant losses in viability, significantly more sGAG loss, and significantly higher production of ROS than OA-like inflammation only. Cartilage explant equilibrium mechanical properties were unaffected. Within the timeframe of this study, CSE alone does not cause OA but when combined with OA-like inflammation leads to worsened articular cartilage degeneration as measured by chondrocyte viability, sGAG loss, proteoglycan staining, and ROS production.

Dynamic model of tissue electroporation on the basis of biological dispersion and Joule heating

Electroporation is a complex, iterative, and nonlinear phenomenon often studied through numerical simulations. In recent years, simulations of tissue electroporation have been conducted with static models. However, the results of a static model simulation are restricted to a fixed protocol signature of the pulsed electric field. In this paper, we describe a novel dynamic model of tissue electroporation that also accounts for tissue dispersion and temperature to allow time-domain simulations. We have implemented the biological dispersion of potato tubers and thermal analysis in a commercial finite-element method software. A cell electroporation model was adapted to account for the increase in tissue conductivity. The model yielded 12 parameters divided into three dynamic states of electroporation. The thermal analysis describes the dependence of tissue conductivity on temperature. The model parameters were evaluated using experiments with vegetal tissue (Solanum tuberosum) under electrochemotherapy protocols. The proposed model can accurately predict the conductivity of tissue under electroporation from 100 to 1000 V/cm. A negligible thermal effect was observed at 1000 V/cm, with a temperature increase of 0.89 °C. We believe that the proposed model is suitable to describe the electroporation at the tissue level and provides a hint of the effects on the cell membrane.

Effects of Chronic Sleep Restriction on Transcriptional Sirtuin 1 Signaling Regulation in Male Mice White Adipose Tissue.

Chronic sleep restriction (CSR) is a prevalent issue in modern society that is associated with several pathological states, ranging from neuropsychiatric to metabolic diseases. Despite its known impact on metabolism, the specific effects of CSR on the molecular mechanisms involved in maintaining metabolic homeostasis at the level of white adipose tissue (WAT) remain poorly understood. Therefore, this study aimed to investigate the influence of CSR on sirtuin 1 (SIRT1) and the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway in the WAT of young male mice. Both genes interact with specific targets involved in multiple metabolic processes, including adipocyte differentiation, browning, and lipid metabolism. The quantitative PCR (qPCR) results demonstrated a significant upregulation of SIRT-1 and some of its target genes associated with the transcriptional regulation of lipid homeostasis (i.e., PPARα, PPARγ, PGC-1α, and SREBF) and adipose tissue development (i.e., leptin, adiponectin) in CSR mice. On the contrary, DNA-binding transcription factors (i.e., CEBP-β and C-myc), which play a pivotal function during the adipogenesis process, were found to be down-regulated. Our results also suggest that the induction of SIRT1-dependent molecular pathways prevents weight gain. Overall, these findings offer new, valuable insights into the molecular adaptations of WAT to CSR, in order to support increased energy demand due to sleep loss.

Molecular mechanisms in regulation of autophagy and apoptosis in view of epigenetic regulation of genes and involvement of liquid-liquid phase separation

Cellular physiology is critically regulated by multiple signaling nexuses, among which cell death mechanisms play crucial roles in controlling the homeostatic landscape at the tissue level within an organism. Apoptosis, also known as programmed cell death, can be induced by external and internal stimuli directing the cells to commit suicide in unfavourable conditions. In contrast, stress conditions like nutrient deprivation, infection and hypoxia trigger autophagy, which is lysosome-mediated processing of damaged cellular organelle for recycling of the degraded products, including amino acids. Apparently, apoptosis and autophagy both are catabolic and tumor-suppressive pathways; apoptosis is essential during development and cancer cell death, while autophagy promotes cell survival under stress. Moreover, autophagy plays dual role during cancer development and progression by facilitating the survival of cancer cells under stressed conditions and inducing death in extreme adversity. Despite having two different molecular mechanisms, both apoptosis and autophagy are interconnected by several crosslinking intermediates. Epigenetic modifications, such as DNA methylation, post-translational modification of histone tails, and miRNA play a pivotal role in regulating genes involved in both autophagy and apoptosis. Both autophagic and apoptotic genes can undergo various epigenetic modifications and promote or inhibit these processes under normal and cancerous conditions. Epigenetic modifiers are uniquely important in controlling the signaling pathways regulating autophagy and apoptosis. Therefore, these epigenetic modifiers of both autophagic and apoptotic genes can act as novel therapeutic targets against cancers. Additionally, liquid-liquid phase separation (LLPS) also modulates the aggregation of misfolded proteins and provokes autophagy in the cytosolic environment. This review deals with the molecular mechanisms of both autophagy and apoptosis including crosstalk between them; emphasizing epigenetic regulation, involvement of LLPS therein, and possible therapeutic approaches against cancers.

CADHERIN-11 regulation of myeloid phagocytes and autoimmune inflammation in murine lupus

Background and objectiveUnderstanding the regulation of efferocytosis by myeloid phagocytes is important in identifying novel targets in systemic lupus erythematosus (SLE). Cadherin-11 (CDH11), a cell adhesion molecule, is implicated in inflammatory arthritis and fibrosis and recently been shown to regulate macrophage phagocytosis. The extent and mechanism of this regulation is unknown. Our objective was to examine the extent to which CDH11 regulates myeloid phagocytes and contributes to autoimmunity and tissue inflammation. MethodsWe analyzed efferocytosis in macrophages and dendritic cells (DCs) from WT and Cdh11−/− mice and investigated the mechanisms in vitro. We investigated the role of CDH11 in disease development in vivo using the pristane induced lupus model. To translate the clinical relevance of CDH11 in human disease, we measured serum CDH11 levels in two independent pediatric SLE (pSLE) cohorts and healthy controls. ResultsUsing bone marrow derived macrophages (BMDMs) and DCs (BMDCs), we found impaired efferocytosis in phagocytes from Cdh11−/− mice, mediated by downregulated efferocytosis receptor expression and RhoGTPase activation. Specifically, loss of CDH11 downregulated Mertk expression and Rac1 activation in BMDMs, and integrin αVβ3 expression and Cdc42 activation in BMDCs, highlighting distinct pathways. In vivo, Cdh11−/− mice displayed defective efferocytosis and increased accumulation of apoptotic debris in pristane-induced lupus. Further, Cdh11−/− mice had enhanced systemic inflammation and autoimmune inflammation with increased anti-dsDNA autoantibodies, splenomegaly, type I interferons, and inflammatory cytokines. Paradoxically, at the tissue level, Cdh11−/− mice were protected against glomerulonephritis, indicating a dual role in murine lupus. Finally, SLE patients had increased serum CDH11 compared to controls. ConclusionThis study highlights a novel role of CDH11 in regulating myeloid cells and efferocytosis and its potential as a contributor to development in autoimmunity murine lupus. Despite the increase in autoimmunity, Cdh11−/− mice developed decreased tissue inflammation and damage.

Comparison of cerebral oxygen extraction fraction using ASE and TRUST methods in patients with sickle cell disease and healthy controls

Abnormal oxygen extraction fraction (OEF), a putative biomarker of cerebral metabolic stress, may indicate compromised oxygen delivery and ischemic vulnerability in patients with sickle cell disease (SCD). Elevated OEF was observed at the tissue level across the brain using an asymmetric spin echo (ASE) MR method, while variable global OEFs were found from the superior sagittal sinus (SSS) using a T2-relaxation-under-spin-tagging (TRUST) MRI method with different calibration models. In this study, we aimed to compare the average ASE-OEF in the SSS drainage territory and TRUST-OEF in the SSS from the same SCD patients and healthy controls. 74 participants (SCD: N = 49; controls: N = 25) underwent brain MRI. TRUST-OEF was quantified using the Lu-bovine, Bush-HbA and Li-Bush-HbS models. ASE-OEF and TRUST-OEF were significantly associated in healthy controls after controlling for hematocrit using the Lu-bovine or the Bush-HbA model. However, no association was found between ASE-OEF and TRUST-OEF in patients with SCD using either the Bush-HbA or the Li-Bush-HbS model. Plausible explanations include a discordance between spatially volume-averaged oxygenation brain tissue and flow-weighted volume-averaged oxygenation in SSS or sub-optimal calibration in SCD. Further work is needed to refine and validate non-invasive MR OEF measurements in SCD.

Spatiotemporal metabolic responses to water deficit stress in distinct leaf cell-types of poplar.

The impact of water-deficit (WD) stress on plant metabolism has been predominantly studied at the whole tissue level. However, plant tissues are made of several distinct cell types with unique and differentiated functions, which limits whole tissue 'omics'-based studies to determine only an averaged molecular signature arising from multiple cell types. Advancements in spatial omics technologies provide an opportunity to understand the molecular mechanisms underlying plant responses to WD stress at distinct cell-type levels. Here, we studied the spatiotemporal metabolic responses of two poplar (Populus tremula× P. alba) leaf cell types -palisade and vascular cells- to WD stress using matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI). We identified unique WD stress-mediated metabolic shifts in each leaf cell type when exposed to early and prolonged WD stresses and recovery from stress. During water-limited conditions, flavonoids and phenolic metabolites were exclusively accumulated in leaf palisade cells. However, vascular cells mainly accumulated sugars and fatty acids during stress and recovery conditions, respectively, highlighting the functional divergence of leaf cell types in response to WD stress. By comparing our MALDI-MSI metabolic data with whole leaf tissue gas chromatography-mass spectrometry (GC-MS)-based metabolic profile, we identified only a few metabolites including monosaccharides, hexose phosphates, and palmitic acid that showed a similar accumulation trend at both cell-type and whole leaf tissue levels. Overall, this work highlights the potential of the MSI approach to complement the whole tissue-based metabolomics techniques and provides a novel spatiotemporal understanding of plant metabolic responses to WD stress. This will help engineer specific metabolic pathways at a cellular level in strategic perennial trees like poplars to help withstand future aberrations in environmental conditions and to increase bioenergy sustainability.

Strong YKL-40 expression in the invasive tumor front of colorectal cancer–A pilot study

Тhe poor prognosis of patients initially diagnosed at an advanced stage of colorectal cancer (CRC) and the heterogeneity within the same tumor stage define the need for additional predictive biomarkers. Tumor buds are proposed as a poor prognostic factor for CRC, however, they are still not implemented into routine pathology reporting. In turn, the chitinase-3-like protein 1 (CHI3L1) also known as YKL-40, is regarded as a candidate circulating biomarker and therapeutic target in CRC. The aim of our study was to investigate tissue YKL-40 localization and tumor budding in CRC. Thirty-one CRC patients and normal colonic tissues were examined. The correlation between YKL-40 levels, tumor budding and clinocopathological parameters was evaluated by polychoric correlation analysis. The immunohistochemical assessment revealed high YKL-40 expression in CRC in contrast to normal mucosa. Specifically, intense YKL-40 staining was detected in the front of tumor invasion compared with tumor parenchyma and noncancerous tissue. We present novel data for increased YKL-40 expression in tumor buds within the front of tumor invasion. We assume that the combination of this morphological parameter with the tissue level of the pleotropic YKL-40 glycoprotein could serve as a future prognostic biomarker for CRC stratification and treatment.

Curcumin abrogates cobalt-induced neuroinflammation by suppressing proinflammatory cytokines release, inhibiting microgliosis and modulation of ERK/MAPK signaling pathway

Curcumin, a bioactive polyphenol derived from turmeric, has been reported to have anti-inflammatory properties. The current study investigated the anti-inflammatory effect of curcumin in the hippocampal subfields (CA1 and CA3) after exposure to cobalt (Co) and the impact of ERK protein. Twenty-eight albino Wistar rats were divided into four groups, each with seven randomly selected rats as follows: Control (distilled water), Cobalt (Co) only (40 mg/kg), 120 mg/kg or 240 mg/kg curcumin + Co (40 mg/kg). Treatment was via oral gavage for 28 days. We performed a biochemical investigation to determine the levels of proinflammatory cytokines (TNFα and IL-1β). Furthermore, we conducted an immunohistochemical evaluation to assess the expression of IBA1 by microglial cells and the immunoexpression of ERK protein in the hippocampus. Results revealed a significant (p<0.05) elevation in the tissue level of TNFα and IL-1β, an increase in the number of IBA1-positive microglia, and upregulation of ERK protein in the hippocampal subfields of the rats after exposure to cobalt-only. Nevertheless, pretreatment with curcumin restored these parameters to levels comparable to control. In conclusion, our results showed that curcumin abrogated the Co-induced neuroinflammation by suppressing the release of proinflammatory biomarkers, reducing microgliosis, and modulating the ERK/MAPK pathway.

Variables Influencing Bone Formation After Transcrestal Sinus Floor Elevation: Radiographic and Tomographic Evaluations.

To evaluate the influence of initial implant protrusion within the subantral space on hard tissue gain for implants placed simultaneously with transcrestal sinus floor elevation (TSFE) with a biomaterial. A total of 50 implants were placed after TSFE in 44 patients using either a human demineralized bone matrix or a deproteinized bone mineral matrix. Intraoral radiographs were obtained before and immediately after surgery. CBCT scans were obtained at the last follow-up (mean: 6.6 years). The initial bone crest height was 4.6 ± 1.4 mm, and the initial protrusion of the implants above the sinus floor was 3.5 ± 1.4 mm. At the follow-up assessments, the hard tissue mean gain was 2.5 ± 1.5 mm, resulting in a mean residual protrusion of 1.1 ± 1.3 mm. Only 10 implants did not protrude above the apical level of hard tissue. Positive correlations were found between hard tissue gain and initial protrusion (r = 0.55; 95% CI: 0.32 to 0.72; P = .0001), between the initial and final protrusions (r = 0.38; 95% CI: 0.10 to 0.60; P = .007), and between the follow-up period and final protrusion (r = 0.35; 95% CI: 0.07 to 0.58; P = .012). The higher the initial protrusion was, the higher were the hard tissue gain and the final protrusion of the implant above the apical level of the hard tissue.

NAT10-mediated mRNA N4-acetylcytidine modification of MDR1 and BCRP promotes breast cancer progression.

N-acetyltransferase 10 (NAT10) serves as a critical enzyme in mediating the N4-acetylcytidine (ac4C) that ensures RNA stability and effective translation processes. The role of NAT10 in driving the advancement of breast cancer remains uninvestigated. We observed an increase in NAT10 expression, both at mRNA level through the analysis of the Cancer Genome Atlas (TCGA) database and at the protein level of tumor tissues from breast cancer patients. We determined that a heightened expression of NAT10 served as a predictor of an unfavorable clinical outcome. By screening the Cancer Cell Line Encyclopedia (CCLE) cell bank, this expression pattern of NAT10 was consistency found across almost all the classic breast cancer cell lines. Functionally, interference of NAT10 expression exerts an inhibitory effect on proliferation and invasion of breast cancer cells. By using ac4C RNA immunoprecipitation (ac4c-RIP) and acRIP-qPCR assays, we identified a reduction of ac4C enrichment within the ATP binding cassette (ABC) transporters, multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), consequent to NAT10 suppression. Expressions of MDR1 and BCRP exhibited a positive correlation with NAT10 expression in tumor tissues, and the inhibition of NAT10 in breast cancer cells resulted in a decrease of MDR1 and BCRP expression. Therefore, the overexpressing of MDR1 and BCRP could partially rescue the adverse consequences of NAT10 depletion. In addition, we found that, remodelin, a NAT10 inhibitor, reinstated the susceptibility of capecitabine-resistant breast cancer cells to the chemotherapy, both in vitro and in vivo. The results of our study demonstrated the essential role of NAT10-mediated ac4c-modification in breast cancer progression and provide a novel strategy for overcoming chemoresistance challenges.

Correlation of serum ferritin and thyroid hormone levels: A matched case–control study

Introduction: Hypothyroidism is a common disorder of the endocrine system caused by insufficient biologically active hormones at the tissue level or the inability of the tissue to utilize thyroid hormones. Iron plays a crucial role in the synthesis and metabolism of thyroid hormones, and it is stored in the body as ferritin. We aimed to evaluate the correlation between serum ferritin (SF) levels and thyroid hormone panel levels in both hypothyroid and euthyroid subjects. Methods: In 2022, a matched case–control study was conducted. The study involved participants with hypothyroidism and a control group (n = 53). The levels of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), and SF were measured using the chemiluminescence immunoassay on a Mindray Cl 900-i analyzer (Shenzhen Mindray Bio-Medical Electronics Co., China). Results: The hypothyroid group had TSH levels that were significantly higher (10.76 [8.54-18.76] vs. 1.76 [1.26-2.58]; p &lt; 0.001) and SF concentrations that were significantly lower (39.08 [21.15-45.70] vs. 54.09 [41.41-71.82]; p &lt; 0.001) compared to the control group. In both male and female subjects of the hypothyroid group, a strong negative correlation was found between SF concentration and TSH levels ([Rho = −0.855,p &lt; 0.01]; [Rho = −0.747; p &lt; 0.01]). In female subjects of the hypothyroid group, a weak positive correlation was found between SF concentration and fT3 (Rho = 0.488; p &lt; 0.05). In the euthyroid group, a correlation of the same strength and direction was found for fT4 (Rho = 0.366; p &lt; 0.05). Conclusion: Research results indicate a correlation between lower SF concentrations and hypothyroidism, which is of particular importance for understanding the etiopathogenesis, diagnosis, monitoring, and treatment modalities of patients with hypothyroidism.

Implications of Heat Stress-induced Metabolic Alterations for Endurance Training.

Inducing a heat-acclimated phenotype via repeated heat stress improves exercise capacity and reduces athletes̓ risk of hyperthermia and heat illness. Given the increased number of international sporting events hosted in countries with warmer climates, heat acclimation strategies are increasingly popular among endurance athletes to optimize performance in hot environments. At the tissue level, completing endurance exercise under heat stress may augment endurance training adaptation, including mitochondrial and cardiovascular remodeling due to increased perturbations to cellular homeostasis as a consequence of metabolic and cardiovascular load, and this may improve endurance training adaptation and subsequent performance. This review provides an up-to-date overview of the metabolic impact of heat stress during endurance exercise, including proposed underlying mechanisms of altered substrate utilization. Against this metabolic backdrop, the current literature highlighting the role of heat stress in augmenting training adaptation and subsequent endurance performance will be presented with practical implications and opportunities for future research.

Advantages of Tissue Level Implants in Case of Alveolar Ridge and Mucosal Atrophy

In the modern market, there is a great variety of dental implants, which differ from each other in design, geometry, connection type, surface treatment technology, etc. However, the most fundamental and main differentiating component between implants is how the implants are inserted into the bone and how it is positioned concerning the soft tissues. Accordingly, they are divided into sunken, i.e., bone level implants and non-sunken, i.e., tissue level implants, in which case the implant-abutment connection, or interface, is located at the gum level. This study shows advantages of tissue level - implants in atrophy of the alveolar ridge, also studies comparison of bone loss in case of bone - level implants and tissue level implants.