Tissue Organization Research Articles

Exosomes enriched by miR-429-3p derived from ITGB1 modified Telocytes alleviates hypoxia-induced pulmonary arterial hypertension through regulating Rac1 expression

BackgroundRecent studies have emphasized the critical role of Telocytes (TCs)-derived exosomes in organ tissue injury and repair. Our previous research showed a significant increase in ITGB1 within TCs. Pulmonary Arterial Hypertension (PAH) is marked by a loss of microvessel regeneration and progressive vascular remodeling. This study aims to investigate whether exosomes derived from ITGB1-modified TCs (ITGB1-Exo) could mitigate PAH.MethodsWe analyzed differentially expressed microRNAs (DEmiRs) in TCs using Affymetrix Genechip miRNA 4.0 arrays. Exosomes isolated from TC culture supernatants were verified through transmission electron microscopy and Nanoparticle Tracking Analysis. The impact of miR-429-3p-enriched exosomes (Exo-ITGB1) on hypoxia-induced pulmonary arterial smooth muscle cells (PASMCs) was evaluated using CCK-8, transwell assay, and inflammatory factor analysis. A four-week hypoxia-induced mouse model of PAH was constructed, and H&E staining, along with Immunofluorescence staining, were employed to assess PAH progression.ResultsForty-five miRNAs exhibited significant differential expression in TCs following ITGB1 knockdown. Mus-miR-429-3p, significantly upregulated in ITGB1-overexpressing TCs and in ITGB1-modified TC-derived exosomes, was selected for further investigation. Exo-ITGB1 notably inhibited the migration, proliferation, and inflammation of PASMCs by targeting Rac1. Overexpressing Rac1 partly counteracted Exo-ITGB1’s effects. In vivo administration of Exo-ITGB1 effectively reduced pulmonary vascular remodeling and inflammation.ConclusionsOur findings reveal that ITGB1-modified TC-derived exosomes exert anti-inflammatory effects and reverse vascular remodeling through the miR-429-3p/Rac1 axis. This provides potential therapeutic strategies for PAH treatment.Graphical 1. Identification of Differentially Expressed microRNAs (DEmiRs) in ITGB1 overexpressed TCs.2. Effects of Exo-ITGB1 or miR-429-3p on Hypoxia-Induced PASMCs in vitro.3. Exo-ITGB1 inhibits the hyper-proliferation and migration of PASMCs through regulating miR-429-3p/Rac1 axis in vitro.4. The therapeutic potential of Exo-ITGB1 in hypoxia-induced PAH model in vivo.

A NIR fluorescent probe with large stokes shift for sensitive detection and imaging of G4s in live cells

G4s play a very important role not only in human biological systems but are associated with tumor formation, which is considered as a novel target for the exploitation of anti-tumor drugs. Therefore, it is essential to develop near-infrared (NIR) fluorescent probes to study G4s. In this article, we designed a large stokes shift probe (AOC) which can be activated NIR fluorescent by G4s in living cells and tumor tissue. In vitro experiments shown that AOC exhibited no fluorescence emission in aqueous solution, while significantly enhanced at 768 nm in the presence of the G4s. The optimal excitation wavelength of the probe is about 640 nm, indicating that the probe AOC has a large stokes shift (128 nm). Meanwhile, AOC is dynamically responsive to the concentrations of DNA G4s (22AG, Mito-160) and exhibits high selectivity toward DNA G4s with desirable stability in the physiological pH conditions. Imaging studies of different cell lines have shown that cancer cell lines fluoresced brightly than normal cell lines, implication that the expression of G4s may be higher in tumor cell lines. We further performed fluorescence imaging of tumor tissues using AOC, which showed that tumor tissues had the brightest fluorescence intensity relative to normal organ tissues. These experimental results further suggest that the NIR fluorescent probe may have tumor diagnostic properties with great potential for application.

Biopharmaceutical distribution and pharmacodynamic evaluation of intra nasal in-situ gel of Lamotrigine for brain targeted drug delivery

Background: The present research investigates the nasal delivery of Lamotrigine by incorporating it into a natural in-situ gelling system. Additionally, the retention of the drug in the nasal cavity was enhanced by employing the natural mucoadhesive polymer locust bean gum (LBG). A preliminary investigation was conducted to determine the optimal concentration of gellan gum. The dosage of the drug was calculated using the Robinson Erikson equation. The central composite design was utilized to optimize the influence of individual variables such as gellan gum and locust bean gum on various responses, including gelation time, gel viscosity, mucoadhesive strength, and the time taken for the drug to release half of its initial concentration (t50). The goal of the current study was to evaluate the in-vivo effectiveness of intra nasal in-situ gel of Lamotrigine. Methodology: The pharmacokinetic and tissue distribution studies were carried out to evaluate the brain targeting efficiency of lamotrigine. Blood samples and tissues of various vital organs like brain, liver, kidneys and heart were obtained at different time intervals, plasma and tissue concentration of Lamotrigine was estimated by reverse phase HPLC. Results: According to the pharmacokinetic analysis, Cmax and AUC0-α is found to be significantly more (P<0.05) for nasal route compared to oral route. In comparison to the oral route, Cmax and AUC0-α was 7 and 6.5 folds more for IN route. The absolute bioavailability was found to be 159.07%. with regard to the oral group, minimal drug was present in any of the other tissue samples. In the pharmacodynamic data also the formulation through nasal route showed a significant difference compared to oral route (pure drug suspension) delivery in PTZ induced study. Keywords: Lamotrigine, in-vivo study, tissue distribution, pharmacodynamics

Deep learning with diffusion MRI as in vivo microscope reveals sex-related differences in human white matter microstructure

Biological sex is a crucial variable in neuroscience studies where sex differences have been documented across cognitive functions and neuropsychiatric disorders. While gross statistical differences have been previously documented in macroscopic brain structure such as cortical thickness or region size, less is understood about sex-related cellular-level microstructural differences which could provide insight into brain health and disease. Studying these microstructural differences between men and women paves the way for understanding brain disorders and diseases that manifest differently in different sexes. Diffusion MRI is an important in vivo, non-invasive methodology that provides a window into brain tissue microstructure. Our study develops multiple end-to-end classification models that accurately estimates the sex of a subject using volumetric diffusion MRI data and uses these models to identify white matter regions that differ the most between men and women. 471 male and 560 female healthy subjects (age range, 22–37 years) from the Human Connectome Project are included. Fractional anisotropy, mean diffusivity and mean kurtosis are used to capture brain tissue microstructure characteristics. Diffusion parametric maps are registered to a standard template to reduce bias that can arise from macroscopic anatomical differences like brain size and contour. This study employ three major model architectures: 2D convolutional neural networks, 3D convolutional neural networks and Vision Transformer (with self-supervised pretraining). Our results show that all 3 models achieve high sex classification performance (test AUC 0.92–0.98) across all diffusion metrics indicating definitive differences in white matter tissue microstructure between males and females. We further use complementary model architectures to inform about the pattern of detected microstructural differences and the influence of short-range versus long-range interactions. Occlusion analysis together with Wilcoxon signed-rank test is used to determine which white matter regions contribute most to sex classification. The results indicate that sex-related differences manifest in both local features as well as global features / longer-distance interactions of tissue microstructure. Our highly consistent findings across models provides new insight supporting differences between male and female brain cellular-level tissue organization particularly in the central white matter.

Laparoscopic Versus Open Mesh Repair of Inguinal Hernia for Military Personnel

Background: An organ or fatty tissue, like the colon, might abnormally emerge through the wall of the cavity in which it normally dwells, a condition known as a hernia. Inguinal hernia repair is among the most frequently done procedures by surgeons worldwide. Treatment includes pure tissue repairs to prosthetic repairs under open or laparoscopic approach. Though so many options are available but none is superior to others. Aim of the study is to compare the effectiveness of laparoscopic hernia repair with open mesh hernia repair. Methods: The study was a comparative cross-sectional study. The study, which took place between 2016 and 2018, involved 100 cases in the General Surgery department of Combined Military Hospital (CMH), Savar (30 cases of laparoscopic hernioplasty and 70 cases of open hernioplasty). Purposive sampling technique was used to collect data. Data were collected during follow up of patients by using a semi-structured questionnaire. Data were analysed by using Statistical Package for the Social Sciences (SPSS) version 26.0. Informed written consent were obtained from the patients and ethical issues were duly addressed. Results: There were 100 patients in the study, 30 of whom were assigned to group A (the laparoscopic group) and 70 to group B (the open group). In group A, the mean operating time was 103.67±23.57 minutes, while in group B, it was 50.26±2.57 minutes. In group A, there was a decrease in pain scores, with 90% of patients reporting 1-2 (mild discomfort). Three people are in excruciating pain. Conclusion: Inguinal hernia repair is a frequently performed general surgery treatment. Because of the large socio-economic impact of inguinal hernia repair, it is the responsibility of the surgeon to consider the most advantageous approach in each given situation. For all patients needing elective hernioplasty, laparoscopic, non-randomized, pre-peritoneal mesh repair for inguinal hernias is a safe, effective method that has clear advantages over open mesh repair. Bangladesh Armed Forces Med J Vol 56 No (2) December 2023, pp 17-23

Phytochemical Analysis and Antibacterial Property of Green Okra Fruit Extract Against Enterococcus Faecalis Bacteria Tooth Root Canals

Background: Root canal treatment aims to eliminate bacteria that cause pulp abnormalities. Enterococcus faecalis is a bacteria in the infected tooth pulp, even those that have been treated. Irrigation was carried out together with biomechanical preparation using a combination of NaOCl and EDTA. The material is antibacterial, dissolves the organic and inorganic tissue of the root canal dentin, lacks odor and irritates the soft tissue. An alternative irrigation material from Jember cultivation is green okra. The fruit contains flavonoids, tannins, steroids, terpenoids. This study aims to analyze the phytochemical and antimicrobial properties of green okra fruit extract on the growth of E. Faecalis bacteria. Method: Phytochemical analysis to see the content of alkaloids, flavonoids, tannins, saponins, steroids and terpenoids. Antimicrobial analysis included the inhibition test using disc diffusion, MIC and MBC tests using the dilution method. Samples were green okra fruit extract 100%, 50%, 25%, 12.5%, 6.25%, 3.125%, 1.563%, 2.5% NaOCl, 17% EDTA. The MIC and MBC tests were examined for Optical Density values ​​with a spectrophotometer and then subcultured to see whether there was growth of bacterial colonies. Analysis of the research data used ANOVA and LSD parametric statistical tests Result: Phytochemical content sequentially is Polyphenols, Alkaloids, Flavonoids, Saponins, Tannins, Steroids, Terpenoids. Antimicrobial properties Green okra fruit extract concentration of 6.25% had the smallest inhibition zone, the largest OD value and the highest colony count. The concentration of 100% has the largest inhibition zone, the lowest OD, there are no bacterial colonies. Antimicrobial power The concentration of 100% is close to that of 17% EDTA and 2.5% NaOCl. In the Kruskal Wallis test, there were differences in the Mann-Whitney test study group, there were significant differences between all groups Conclusion: The phytochemical content of green okra fruit extract has antimicrobial activity against E. faecalis approaching 2.5% NaOCl and 17% EDTA at 100% concentration, 6.25% MIC concentration and 12.5% ​​MBC concentration. Keywords: Phytochemical, Antibacterial, Green okra fruit extract, Enterococcus faecalis

Alterations in the Anatomy and Ultrastructure of Leaf Blade in Norway Maple (Acer platanoides L.) Growing on Mining Sludge: Prospects of Using This Tree Species for Phytoremediation.

Alterations in leaf architecture can be used as an indicator of the substrate toxicity level as well as the potential of a given plant species in the phytoremediation of polluted areas, e.g., mining sludge. In this work, we demonstrated, for the first time, the nature and scale of alterations in leaf architecture at the tissue and cellular levels occurring in Norway maple growing on mining sludge originating from a copper mine in Lubin (Poland). The substrate differs from other mine wastes, e.g., calamine or serpentine soils, due to an extremely high level of arsenic (As). Alterations in leaf anatomy predominantly included the following: (1) a significant increase in upper epidermis thickness; (2) a significant decrease in palisade parenchyma width; (3) more compact leaf tissue organization; (4) the occurrence of two to three cell layers in palisade parenchyma in contrast to one in the control; (5) a significantly smaller size of cells building palisade parenchyma. At the cellular level, the alterations included mainly the occurrence of local cell wall thickenings-predominantly in the upper and lower epidermis-and the symptoms of accelerated leaf senescence. Nevertheless, many chloroplasts showed almost intact chloroplast ultrastructure. Modifications in leaf anatomy could be a symptom of alterations in morphogenesis but may also be related to plant adaptation to water deficit stress. The occurrence of local cell wall thickenings can be considered as a symptom of a defence strategy involved in the enlargement of apoplast volume for toxic elements (TE) sequestration and the alleviation of oxidative stress. Importantly, the ultrastructure of leaf cells was not markedly disturbed. The results suggested that Norway maple may have good phytoremediation potential. However, the general shape of the plant, the significantly smaller size of leaves, and accelerated senescence indicated the high toxicity of the mining sludge used in this experiment. Hence, the phytoremediation of such a substrate, specifically including use of Norway maple, should be preceded by some amendments-which are highly recommended.

18F]AlF-NOTA-PCP2: a novel PET/CT tracer for enhanced PD-L1 heterogeneity imaging and comparative analysis with [18F]AlF-NOTA-WL12 in glioblastoma xenografts.

The unsatisfactory efficacy of PD-L1 antibodies in glioblastoma (GBM) is largely due to the temporal and spatial heterogeneity of PD-L1 expression. Molecular imaging can enhance understanding of the tumor immune microenvironment and guide immunotherapy. However, highly sensitive imaging agents capable of effectively visualizing PD-L1 heterogeneity are limited. This study introduces a novel PET tracer, offering improved imaging of PD-L1 heterogeneity in GBM xenografts, with a comparative analysis to [18F]AlF-NOTA-WL12. [18F]AlF-NOTA-PCP2 was synthesized with high purity and its affinity for PD-L1 was characterized using surface plasmon resonance (SPR) and cell binding assays. Its specificity for PD-L1 was evaluated both in vitro using various cell lines and in vivo with GBM xenograft models in NOD/SCID mice. PET/CT imaging was conducted to evaluate the tracer's biodistribution, pharmacokinetics, and ability to quantify tumoral spatial heterogeneity of PD-L1 expression. A focused comparative analysis between [18F]AlF-NOTA-PCP2 and [18F]AlF-NOTA-WL12 was conducted, examining binding affinity, biodistribution, pharmacokinetics, and imaging effectiveness in GBM xenografts. Additionally, human radiation dosimetry estimates compared the safety profiles of both tracers. [18F]AlF-NOTA-PCP2 demonstrated high radiochemical purity (> 95%) and a strong affinity for PD-L1, comparable to [18F]AlF-NOTA-WL12. In vitro and in vivo studies confirmed its specificity for PD-L1, with increased uptake in PD-L1 expressing cells and tumors. Toxicological profiles indicated no significant abnormalities in serum biochemical indicators or major organ tissues. MicroPET/CT imaging showed [18F]AlF-NOTA-PCP2's effectiveness in visualizing PD-L1 expression levels and spatial heterogeneity in GBM xenografts. Comparative studies revealed [18F]AlF-NOTA-PCP2's improved pharmacokinetic properties, including higher tumor-to-blood ratios and lower nonspecific liver uptake, as well as reduced radiation exposure compared to [18F]AlF-NOTA-WL12. [18F]AlF-NOTA-PCP2 distinguishes itself as an exceptionally sensitive PET/CT tracer, adept at non-invasively and accurately quantifying PD-L1 expression and its spatial heterogeneity in tumors, especially in GBM. Its favorable pharmacokinetic properties, safety profile, and high affinity for PD-L1 highlight its potential for enhancing the precision of cancer immunotherapy and guiding individualized treatment strategies. While promising, its clinical translation, especially in brain imaging, necessitates further validation in clinical trials.

Lost in Rotation: How TiO2 and ZnO Nanoparticles Disrupt Coordinated Epithelial Cell Rotation.

Coordinated cell movement is a cardinal feature in tissue organization that highlights the importance of cells working together as a collective unit. Disruptions to this synchronization can have far-reaching pathological consequences, ranging from developmental disorders to tissue repair impairment. Herein, it is shown that metal oxide nanoparticles (NPs), even at low and non-toxic doses (1 and 10µg mL-1), can perturb the coordinated epithelial cell rotation (CECR) in micropatterned human epithelial cell clusters via distinct nanoparticle-specific mechanisms. Zinc oxide (ZnO) NPs are found to induce significant levels of intracellular reactive oxygen species (ROS) to promote mitogenic activity. Generation of a new localized force field through changes in the cytoskeleton organization and an increase in cell density leads to the arrest of CECR. Conversely, epithelial cell clusters exposed to titanium dioxide (TiO2) NPs maintain their CECR directionality but display suppressed rotational speed in an autophagy-dependent manner. Thus, these findings reveal that nanoparticles can actively hijack the nano-adaptive responses of epithelial cells to disrupt the fundamental mechanics of cooperation and communication in a collective setting.

Lung adenocarcinomas without driver genes converge to common adaptive strategies through diverse genetic, epigenetic, and niche construction evolutionary pathways

Somatic evolution selects cancer cell phenotypes that maximize survival and proliferation in dynamic environments. Although cancer cells are molecularly heterogeneous, we hypothesized convergent adaptive strategies to common host selection forces can be inferred from patterns of epigenetic and genetic evolutionary selection in similar tumors. We systematically investigated gene mutations and expression changes in lung adenocarcinomas with no common driver genes (n = 313). Although 13,461 genes were mutated in at least one sample, only 376 non-synonymous mutations evidenced positive evolutionary selection with conservation of 224 genes, while 1736 and 2430 genes exhibited ≥ two-fold increased and ≥ 50% decreased expression, respectively. Mutations under positive selection are more frequent in genes with significantly altered expression suggesting they often “hardwire” pre-existing epigenetically driven adaptations. Conserved genes averaged 16-fold higher expression in normal lung tissue compared to those with selected mutations demonstrating pathways necessary for both normal cell function and optimal cancer cell fitness. The convergent LUAD phenotype exhibits loss of differentiated functions and cell–cell interactions governing tissue organization. Conservation with increased expression is found in genes associated with cell cycle, DNA repair, p53 pathway, epigenetic modifiers, and glucose metabolism. No canonical driver gene pathways exhibit strong positive selection, but extensive down-regulation of membrane ion channels suggests decreased transmembrane potential may generate persistent proliferative signals. NCD LUADs perform niche construction generating a stiff, immunosuppressive microenvironment through selection of specific collagens and proteases. NCD LUADs evolve to a convergent phenotype through a network of interconnected genetic, epigenetic, and ecological pathways.

Nutritional muscular dystrophy in broiler thigh muscles: pathological analysis of a problem in the field

Objective. This study aims to use histopathologic method to investigate nutritional muscular dystrophy in broilers due to vitamin E deficiency. Materials and methods. Tissue samples taken from 20 dead chicks and total 28 blood samples sent by taking from diseased also eight chicks were analyzed. The amount of vitamin E determined in feed analysis was found to be 5% less than the amount declared to be present in the feed ration. Results. The average amount of α-tocopherol in blood serums was measured as 0.285 µg/g. Plasma calcium and phosphorus levels were found to be high, whereas sodium, potassium, and magnesium levels were found to be normal levels. Histopathologically, nutritional muscular dystrophy was defined in 18 of 20 chicks (90%). In the histopathologic examination of muscular sections, varying degrees of hyaline degenerations, necrosis, mineralization, lipidosis, and mononuclear cell infiltrations were observed. Conclusions. It was determined that when the fat content of the ration was increased, vitamin and mineral levels, particularly vitamin E, changed within the ration content, and the health of the chicks deteriorated, resulting in histopathologic damages in different organ tissues. The study concludes that the poultry farming industry should attach importance to feed management systems for chick’s the proper and healthy feeding.

CLINICAL CASE, RESECTION OF BONE METASTASIS IN THE OLECRANON, AFTER EXCISION OF RENAL CARCINOMA OF PRIMARY ORIGIN

Introduction: Bone is a common site of metastasis, after cancer has spread to the bone, it can rarely be cured, however it can often be treated to stop its proliferation. Bone metastasis is much more common than primary bone cancers, particularly in adults. Objective: to describe the present clinical case objectively and to make an analysis of the subject. Methodology: an objective description of the clinical case and a review with analysis of a total of 17 articles, including review and original articles, as well as clinical cases, of which 12 bibliographies were used because the other articles were not relevant for this study. The sources of information were PubMed, Google Scholar and Cochrane; the terms used to search for information in Spanish, Portuguese and English were: bone metastasis, bone tumor, oncologic surgery, renal carcinoma. Results: renal cell carcinoma represents about 2-3% of malignant neoplasms in adult individuals. Most of the cases occur between 50-70 years of age. One third of the tumors metastasize (synchronous metastases) and another third manifest themselves in the future (metachronous metastases), even up to 20 years after nephrectomy. In order of manifestation, the most common findings in renal cell carcinoma are: hematuria (59%), pain (41%), fever (7%), anemia (21%) and weight loss (33%). In order of involvement, renal cell carcinoma metastasizes to the lung (60%), bone (20%), liver (8%), adrenal glands and brain (5%), and other organs can also be affected. Conclusions: Bone is a common site of metastasis, being called metastasis the capacity of a tumor cell to move from the primary tumor and adhere to tissues of a distant organ by hematogenous, lymphatic or contiguous route. After the cancer has spread to the bones, it can rarely be cured, although it can often be treated to stop its proliferation. Bone metastases are now much more common than primary bone cancers, particularly in adults. The clinical management of metastatic bone disease in renal cell carcinoma deserves more attention than it has been given so far. A multidisciplinary approach is required for the management of affected individuals with bone metastases, and each patients case must be individualized, since not all affected individuals can undergo the same surgical procedure or treatment. Key words: metastasis, cancer, bone, tumor, renal carcinoma.

Reproducibility of freehand vs. foam cast as well as the intrarater reliability of foam cast ultrasound scans assessing the muscle architecture and tissue organization of the gastrocnemius medialis and vastus lateralis muscles.

This study compares the reproducibility of freehand (FH) vs. foam cast (FC) scans and investigates the intrarater reliability of the ultrasound FC muscle architecture and tissue organization measurements of the gastrocnemius medialis (GM) and vastus lateralis (VL) muscles with fixed and repositioning FC scans. Thirteen young adults (22 ± 3 years) underwent repeated sagittal B-mode ultrasound measurements of GM and VL. FH, FC, and repositioned FC scans were conducted. Muscle architecture measurements included muscle thickness (MT), pennation angle (PA), and fascicle length (FL). Spatial frequency analysis assessed muscle tissue organization. MT decreased from 2.1 to 1.8 cm in GM and from 2.4 to 2.2 cm in VL with the FC compared with the FH. Reproducibility between the FH and the FC showed poor to good intraclass correlation coefficients (ICCs) for MT (0.46-0.77) and PA (0.09-0.86) as well as poor to moderate ICCs for FL (0.41), with very low to moderate test-retest variability (TRV) (4%-18%). Tissue organization indicated low to good ICCs (0.21-0.80) with low to moderate TRV (4%-19.5%). The re-scanning results of fixed FC indicated excellent ICCs for MT (0.95-0.996), good for PA (0.77-0.90), and moderate for FL (0.73-0.76), with low TRV (5%-10%) for both muscles. Tissue organization displayed moderate to good ICCs (0.61-0.87) with very low to low TRV (4%-9%). For repositioned FC scans in GM and VL, MT showed good to excellent ICCs (0.86-0.98) with very low to low TRV (2%-8%). PA and FL demonstrated moderate to good ICCs (0.57-0.75), with very low to moderate TRV (2%-13%). Tissue organization revealed ICCs ranging from poor to good (0.13-0.87) for both muscles, with low to moderate TRV (5%-18%). The FC systematically reduced MT by 2-3 mm. Furthermore, reproducibility revealed low ICCs and high data variability for several muscle architecture and tissue organization parameters. Thus, switching methods within a single study is not recommended. Nevertheless, FC ultrasound scans demonstrated excellent intrarater reliability for assessing MT. In the case of fixed FC scans particularly, moderate to excellent ICCs were observed for all muscle architecture and tissue organization parameters, accompanied by very low to low variability. Therefore, FC scans are recommended for investigating acute effects on muscle architecture and tissue organization when the FC remains on the leg throughout the period of measurements.

Time-restricted Eating to Improve Metabolic Health: Investigating the Mechanisms Underlying Glycolytic and Lipolytic actions

Time-restricted eating (TRE) is a behavioral intervention approach motivated by the emerging role of circadian rhythms in physiology and metabolism. In this approach, all caloric intake is restricted within a regular interval of less than 12 hours, with no overt attempt to reduce calories. We present a whole-body computational model of TRE that incorporates enzyme and substrate reactions as well as hormonal actions during fasting and postprandial states. The model is divided into seven compartments: brain, heart, skeletal muscle, gastrointestinal tract, liver, adipose tissue, and other tissues. We conducted simulations to test the hypothesis that TRE modulates whole-body glucose balance by improving postprandial hyperglycemia and hypertriglyceridemia, keeping these excursions to a minimum. We simulated different TRE schedules with meals varying in fat and carbohydrate content. Our results highlight the importance of chrono-pharmacological considerations in glycemic control: TRE modulates the interplay between glycogenolysis in the liver, lipolysis in adipose tissue and fatty acid oxidation in other organs to improve glucose control. The alternation of eating and fasting, in particular, could be manipulated to balance blood sugar levels. TRE simulations have also shown beneficial effects on the lipid front, such as lower triglyceride levels and improved lipolytic effciency, meaning the body is better able to use fat stores for fuel. This work was supported by the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery award. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Ectonucleotidase Activity in Smooth Muscle Tissues of Rats with a Valproate Model of Autism.

Ectonucleotidases play an important role in regulating the level of extracellular nucleotides and nucleosides and are an important part of the regulation of the effects of adenosine and ATP on adenosine and P2 receptors, respectively. We have previously established the ambiguous effect of P2 receptor agonists on the contractile activity of smooth muscle tissue in rats with the valproate model of autism. In this work, HPLC was used to evaluate the activity of ectonucleotidases in the smooth muscle tissues of the internal organs of rats with a valproate model of autism. The activity of ectonucleotidases was significantly higher in the smooth muscle tissues of the duodenum, vas deferens, and bladder, but lower in the ileum and uterus. The results obtained make it possible to compare the activity of ectonucleotidases identified here with changes in P2 receptor-mediated contractility of smooth muscle tissues revealed in our previous experiments.

Sex Differences in Kidney Damage in BUF/MnaMcwi Rats

Kidney disease is commonly found in the BUF (Buffalo) strain of rats. It has been observed that male BUF rats show signs of focal glomerulosclerosis (FSGS). They are known to have proteinuria, hypoalbuminemia, and hyperlipidemia as they age. This is preceded by renal macrophage activation and Th2 lymphocyte polarization. There is no prior literature that explores kidney disease in female BUF rats.We previously observed that kidneys in female BUF rats appeared more damaged than their male mates, leading to the hypothesize that the female BUF/MnaMcwi (BUF) breeder rats have greater kidney damage features than male mates. To determine the relationship between sex and function, we collected urine samples using metabolic cages (at 12, 17, and 23 weeks of age), harvested organ tissue (heart left, ventricle, spleen, thymus, and kidneys), and used histopathological examination of formalin-fixed paraffn-embedded kidney samples to determine cortex tubule damage and glomerular area. We expected to see sex differences in relative sizes (mg/g BW) of the thymus, heart left ventricle, kidneys, and spleen. We found that the male BUF rats had larger absolute body weight (g), as expected. We also found that there were no significant sex differences in relative sizes (mg/g BW) of the thymus, heart left ventricle, and spleen. There was a significant sex difference in relative total kidney size (mg/g BW), with the females having larger kidney sizes compared to their body weight. In addition, there was increased microalbumin in the female BUF overnight urine collection that was significantly higher than the male BUF rats. There was no significant sex difference in the microalbumin: creatinine ratio. Finally, we found no significant sex difference in cortex tubular damage between the age-matched BUF rats, but there was a significant difference in glomeruler area (mm 2), with male glomeruler areas being significantly larger. Future studies will be done to replicate the findings and determine if virgin females show the same results. ASPIRE Program (R25HL 168782) Medical College of Wisconsin. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The relationship between sarcomerogenesis and the development of tissue organization of the myocardium in embryonic chicken cardiogenesis

Background. The general basis for understanding how the limited range of sarcomere contraction ensures cardiac output during systole is the analysis of the ontogenetic formation and local features of the development of the myofibrillar structure of cardiomyocytes by comparing the phase states of the myocardium. The purpose of the research is to determine phase and topological features and quantitative ultrastructural characteristics of sarcomerogenesis in cardiomyocytes of chicken embryos. Methods. Embryos of Cobb500 crossbred chickens were studied from the beginning of the 6th day to the 21st day of incubation. Ultrastructural features of contractile cardiomyocytes in different areas of ventricular and atrial myocardium in systole and diastole were studied using transmission electron microscopy. Results. At the 29th stage of development of chicken embryos in diastole, immature sarcomeres had different lengths. The average length of sarcomeres was 1.86±0.09 μm in the left ventricle and 1.91±0.21 μm in the right ventricle. At the 36th stage in the state of diastole, a significant increase in the length of sarcomeres was observed in the compact myocardium of the left ventricle and left atrium, while in the right parts of the heart, the increase in Z-Z distance was less active. In the right units of the heart, sarcomeres with unequal lengths were more often found in the compact myocardium and in the trabeculae. In different areas of the myolamella and trabeculae, the degree of relaxation of sarcomeres during simulation of maximum diastole was not the same. Incomplete relaxation of sarcomeres was noted in the initial and final sections of the muscle plates. In the middle part of the trabeculae, the length of the sarcomeres was significantly longer (1.82±0.04 μm), and in the intermediate (main) part of the muscle plates of the compact ventricular myocardium, the sarcomeres were 10.4% (p<0.05) longer, than in their basis. Conclusion. By the end of prenatal cardiogenesis, the tangential orientation of the Z-discs of myofibrils and the shape of cardiomyocytes in systole was formed and strengthened due to the mutual displacement of neighboring myolamella during the counter-directional rotation of the basal and apical parts of the left ventricle during the shortening of sarcomeres to 1.83±0.04 μm. In the right ventricle and atrial myocardium, systolic contraction did not change the orthogonal orientation of telophragms and intercalated discs when sarcomeres were shortened to 1.79-1.84 μm. In the state of diastole, the orthogonal orientation of Z-discs is characteristic of contractile cardiomyocytes of all chambers when the length of sarcomeres reaches 2.17±0.07 μm in the intermediate part of the myolamella of both ventricles, 2.12±0.13 μm in the middle part of atrial and ventricular trabeculae, 2.02±0.10 μm at the base of trabeculae of all chambers and muscle plates of both ventricles.

Impact of sub-chronic polystyrene nanoplastics exposure on hematology, histology, and endoplasmic reticulum stress-related protein expression in Nile tilapia (Oreochromis niloticus)

Nanoplastics (NPs) are one of the most hazardous marine litters, having the potential to cause far-reaching impacts on the environment and humankind. The effect of NPs on fish health has been studied, but their impact on the subcellular organelles remains unexplored. The present investigation studied the possible implications of polystyrene-nanoplastics (PS-NPs) on the hematology, tissue organization, and endoplasmic reticulum (ER) stress-related proteins in Nile tilapia (Oreochromis niloticus). Fish were exposed to ∼100 nm PS-NPs at environmentally relevant (0.1 mg/L), and sublethal (1, 10 mg/L) concentrations for 14 days through water exposure. The growth performance and hematological parameters such as erythrocytes, hemoglobin, hematocrit, and leucocytes decreased, while thrombocytes increased with PS-NPs dose-dependently. The gills, liver, kidney, and heart tissues displayed increasing degrees of pathology with increased concentrations of PS-NPs. The gills showed severe epithelial hyperplasia and lamellar fusion. The liver had an abstruse cellular framework, membrane breakage, and vacuolation. While glomerular and tubular atrophy was the most prominent pathology in the kidney tissue, the heart displayed extensive myofibrillar loss and disorderly arranged cardiac cells. The ER-stress-related genes such as bip, atf6, ire1, xbp1, pkr, and apoptotic genes such as casp3a, and bax were over-expressed, while, the anti-apoptotic bcl2 was under-expressed with increasing concentrations of PS-NPs. Immunohistochemistry and blotting results of GRP78, CHOP, EIF2S, and ATF6 in gills, liver, kidney, and heart tissues affirmed the translation to ER stress proteins. The results revealed the sub-lethal adverse effects and the activation of the ER-stress pathway in fish with sub-chronic exposure to PS-NPs.

Design, synthesis, in-silico studies and apoptotic activity of novel amide enriched 2-(1H)- quinazolinone derivatives

Cancer is a broad classification of diseases that can affect any organ or body tissue due to aberrant cellular proliferation for unknown reasons. Many present chemotherapeutic drugs are highly toxic and have little selectivity. Additionally, they lead to the development of medication resistance. Therefore, developing tailored chemotherapeutic drugs with minimal side effects and good selectivity is crucial for cancer treatment. 2-(1H)-Quinazolinone is one of the vital scaffold and anticancer activity is one of the prominent biological activities of this class. Here we report the novel set of amide-enriched 2-(1H)-quinazolinone derivatives (7a-j) and their apoptotic activity with the help of MTT assay method against four human cancer cell lines: PC3 (prostate cancer), DU-145 (prostate cancer), A549 (lung cancer), and MCF7 (breast cancer). When compared to etoposide, every synthetic test compound (7a-j) exhibited moderate to excellent activity. The IC50 values of the new amide derivatives (7a-j) varied from 0.07 ± 0.0061 μM to 10.8 ± 0.69 μM. While the positive control, etoposide, exhibited 1.97 ± 0.45 μM to 3.08 ± 0.135 μM range. Among the novel amide derivatives (7a-j), in particular, 7i and 7j showed strong apoptotic activity against MCF7; 7h showed against PC3, and 7g showed against DU-145. Molecular docking studies of test compounds (7a-j) with the EGFR tyrosine kinase domain (PDB ID: 1M17) protein provided the significant docking scores for each test compound (7a-j) (−9.00 to −9.67 kcal/mol). Additionally, DFT investigations and MD simulations validated the predictions of molecular docking. According to the findings of the ADME analysis, oral absorption by humans is anticipated to be higher than 85 % for all test compounds.

Laparoscopic transabdominal-sacrococcygeal approach for resection of Altman type III sacrococcygeal teratoma in adult women: A case report.

Adult sacrococcygeal teratoma (SCT) is a rare disease that is not easily detected or easily missed, and its treatment is based on surgery, including transabdominal, transsacral, or a combination of both, but there are no clear guidelines for diagnosis and treatment. We share a case of Altman type III SCT in order to provide more reference protocols for the diagnosis and treatment of adult SCT, and more importantly to increase our understanding of different types of SCT cases in adults. Our patient was a 31-year-old adult woman who underwent complete surgical resection of a cystic mature teratoma of the right ovary 8 years ago and is currently 13 months postpartum without menstruation, usually with a feeling of anal bulge, with symptoms such as constipation. We diagnosed SCT by vaginal ultrasonography, computed tomography and magnetic resonance imaging (MRI); benign tumors were considered in the results of serum tumor markers. We chose the surgical approach of laparoscopic transabdominal-sacrococcygeal approach to completely remove the patient SCT and coccyx. The location of SCT is concealed and the clinical symptoms are not obvious. Vaginal ultrasonography, CT and MRI can not only improve the diagnostic rate of SCT, but also understand the size and mass of SCT, providing an exact basis for clinicians to select the laparoscopic transabdominal-sacrococcygeal approach. Our sharing increases the reports of rare cases of teratoma with the same histological findings in different organ tissues of the same patient at different times, whether this occurs incidentally requires more case reports and further basic research; in addition, the laparoscopic transabdominal-sacrococcygeal approach is a safe and effective surgical approach for the treatment of Altman type III SCT in adults; finally, this case reminds us that SCT may not affect pregnancy and pregnancy outcomes and provides a reference for the selection of interventions for SCT with pregnancy.