Tissue Distribution Research Articles

Complex-valued multi-frequency electrical impedance tomography based on deep neural networks

Abstract The utilization of multi-frequency electrical impedance tomography (mfEIT), a non-invasive imaging technique, allows for the visualization of the conductivity distribution in biological tissues across different frequencies. However, the analysis of phase angle information within complex impedance remains a challenge, as most existing deep learning-based mfEIT algorithms are limited to real number processing. To address this limitation, this study proposes a novel approach that integrates deep learning techniques with conventional reconstruction algorithms. The complex-valued conductivity distribution in the measurement region is pre-reconstructed using a sparse Bayesian learning approach. Subsequently, the pre-reconstructed results are refined using an optimized UNet network. The experimental outcomes validate the efficacy of the proposed algorithm in accurately reconstructing the complex-valued conductivity distributions of diverse biological tissues, such as potato and pig kidney, across different frequencies. Furthermore, the algorithm exhibits exceptional performance in mitigating the presence of image artifacts during the reconstruction process.

Effect of nitrogen fertilization and shading on morphogenesis, structure and leaf anatomy of Megathyrsus maximus genotypes

The use of exotic grasses of African origin for pastures in Brazil has been a major advancement in livestock production, but little is known about the responses of these grasses to nitrogen fertilizers associated with shading. In this study, the morphogenetic, structural, and leaf anatomical characteristics of Megathyrsus maximus cultivars’ Tamani and Quênia were investigated as a function of N dose and shade. Morphogenetic and structural characteristics and leaf anatomy were studied under three shading levels (0, 30, and 50 %) and four N doses (0, 100, 200, and 300 kg N ha-1) to simulate growth in a silvopastoral system. When comparing the cultivars, Quênia was more efficient in terms of phyllochron up to fertilization with 100 kg N ha-1. The leaf senescence rate of Tamani was higher than that of Quênia at the 30 and 50 % shade levels. The total area (TA) occupied by leaf tissues decreased in Quênia as a function of the increase in N fertilization, whereas the TA of Tamani did not change. The thickness of the adaxial epidermis was greater in Quênia (0.68 µm) than in Tamani (0.50 µm) when not fertilized. The area occupied by the mesophyll was greater in both cultivars when they received fertilization equivalent to 300 kg N ha-1. Quênia grass has a smaller phyllochron than Tamani grass, due to the rapid reconstruction of its photosynthetic apparatus, especially when it receives higher levels of nitrogen fertilization. However, Tamani grass has a greater distribution of plant tissues. The mesophyll area is larger in Tamani grass due to the greater presence of chloroplasts, which facilitates digestion by animals. The Tamani modified the leaf anatomical tissues more significantly in relation to shading, whereas the Quênia modified them in relation to N fertilization, which reinforces the suggestion of a more appropriate use of Tamani in silvopastoral systems.

Preparation, characterization, and liver targeting evaluation of a novel sustained-release brucine self-assembled micelle mediated by glycyrrhetinic acid.

Background: Cancer is a serious threat to human life, health and social development. In recent years, nanomicelles, as an emerging drug carrier material, have gradually entered people's field of vision because of their advantages of improving bioavailability, maintaining drug levels, reducing systemic side effects and increasing drug accumulation at target sites. Methods: In this study, B-GPSG nano-micelles were prepared by film dispersion hydration method using brucine as model drug and glycyrrhetinic acid-polyethylene glycol-3-methylene glycol-dithiodipropionic acid-glycerol monostearate polymer as nano-carrier. The preparation process, characterization, drug release in vitro, pharmacokinetics and liver targeting were investigated. Results: The results showed that the range of particle size, polydispersion index and Zeta potential were 102.7 ± 1.09nm, 0.201 ± 0.02 and -24.5 ± 0.19mV respectively. The entrapment efficiency and drug loading were 83.79 ± 2.13% and 12.56 ± 0.09%, respectively. The drug release experiments in vitro and pharmacokinetic experiments showed that it had obvious sustained release effect. For pharmacokinetics study, it shows that both the B-GPSG solution group and the B-PSG solution group changed the metabolic kinetic parameters of brucine, but the B-GPSG solution group had a better effect. Compared with the B-PSG solution group, the drug was more prolonged in rats. The half-life in the body and the retention time in the body of B-GPSG are more helpful to improve the bioavailability of the drug and play a long-term effect. The tail vein injection results of mice indicate that B-GPSG can target and accumulate brucine in the liver without affecting other key organs. Cell uptake experiments and tissue distribution experiments in vivo show that glycyrrhetinic acid modified nano-micelles can increase the accumulation of brucine in hepatocytes, has a good liver targeting effect, and can be used as a new preparation for the treatment of liver cancer. Conclusion: The B-SPSG prepared in this experiment can provide a new treatment method and research idea for the treatment of liver cancer.

Detection and genetic characterization of chicken astrovirus and avian nephritis virus from hatchery to farm

ABSTRACT Astroviruses are an emerging hazard in hatchery management, and they are responsible for great economic losses in poultry farms worldwide. Chicken astrovirus (CAstV) and avian nephritis virus (ANV) are involved in decreased hatching rate, mainly due to embryo deaths, and pale and runted chicks too weak to hatch. Hatchery diseases occur through direct egg infection or vertical transmission. However, the specific role of astroviruses in these diseases is still largely unknown. To elucidate this a high-quality Piedmont hatchery (Italy) was selected based on farm clinical signs and the astrovirus serological positivity in the breeder farm. The viral dynamics were followed from the hatchery to the farm. The presence of both CAstV and ANV was monitored by evaluating the viral load in environmental and bird samples. Interestingly, both viruses were detected in chick yolk sacs at 18 days of incubation, and in the gut contents of 1-day chicks, whereas in the hatchery environmental samples, the eggs' external surfaces and the embryos’ intestinal contents were negative. The CAstV copy number was higher in bird tissues from the hatchery, while a greater ANV load was detected in bird tissues from the farm. Moreover, our data suggest vertical transmission of both viruses. Frequent co-infection was also observed in samples from both the hatchery and the farm. Lastly, the first Italian full-length genome and molecular characterization of ANV was obtained. RESEARCH HIGHLIGHTS Identified the role of the hatchery in astrovirus transmission. Sequenced the avian nephritis virus complete genome. Investigated tissue distribution of astrovirus from egg to chicks. Demonstrated co-infection of ANV/CAstV.

Tissue distribution and exposure risk assessment of dioxins, dioxin-like polychlorinated biphenyls and perfluoroalkyl substances in red swamp crayfish

Significant attention has been paid to the adverse effects of dioxins, dioxin-like polychlorobiphenyls (DL-PCBs) and per-and polyfluoroalkyl substances (PFAS) in environment and food on ecosystem and human health. However, limited information exists regarding the occurrence, tissue distribution and exposure risk of these pollutants in crayfish. This study investigated tissue-specific distribution characteristics, influence factors and exposure risk of dioxins, DL-PCBs and PFAS in crayfish. Dioxins, DL-PCBs, and PFAS were detected in crayfish samples, with concentrations ranging from 0.361 to 1.91 pg TEQ g−1 for sum dioxins and DL-PCBs, and 1.54–21.2 ng g−1 for sum PFAS. The highest concentrations of dioxins, DL-PCBs TEQ and total PFAS were found in crayfish viscera and accounting for over 69% of the relative body burden (RBBs) of these pollutants. The specific-tissue distribution of these pollutants linked to tissue fat and protein content and log Kow and molecular weights of homologues. The consumption of crayfish edible tissue posed no health risks from exposure to dioxins and DL-PCBs as well as sum 4 PFAS in adults. However, consumption of crayfish viscera significantly increased exposure risk. This study can provide valuable insights into the tissue-specific distribution and human exposure risks associated with dioxins, DL-PCBs and PFAS in crayfish.

The Comparison of the Clinical Efficacy and Drug Tissue Distribution of Furazolidone and Tetracycline-quadruple Therapy in Helicobacter pylori Eradication: A Randomized Controlled Trial.

Helicobacter pylori (H. Pylori) is considered a main causative organism of gastric ulcers, gastric cancer and duodenal ulcers. The current treatment relies on a combination of antimicrobial agents and acid suppressant agents, but the eradication effect is not satisfactory. To clarify the concentration of antibiotics at the lesion site, we investigate the clinical efficacy and drug tissue distribution of the combination therapy of furazolidone and tetracycline in eradicating H. Pylori. Patients with H. pylori infection (n = 60) were randomized to either group A or B. Bismuth potassium citrate capsules 220mg, omeprazole enteric-coated capsules 20mg, amoxicillin capsules 1000mg, each twice per day, and furazolidone tablets 500mg were administered to group A. Group B was treated with bismuth potassium citrate capsules 220mg, omeprazole enteric-coated capsules 20mg, amoxicillin capsules 1000mg, and tetracycline tablets 500mg each twice per day for 2 weeks. The serum and gastric juice, gastric antrum, gastric horn, and gastric body samples were taken under a gastroscope on the 14th day. The antimicrobial concentrations in serum and tissue samples were determined by high-performance liquid chromatography. In the negative group of furazolidone, the concentrations of gastric antrum, gastric body, and gastric angle were significantly higher than those in the positive group (P = 0.017, 0.015, and 0.028). The concentrations of furazolidone in gastric fluid, gastric antrum, gastric angle, and gastric body were ∼421 times, 82 times, 17 times, and 51 times higher than those in serum, respectively. The concentrations of tetracycline in the serum and gastric angle of the tetracycline negative group were significantly higher than those in the positive group (P = 0.036 and 0.042), and the tetracycline concentrations in the gastric horn and gastric body were about 4 and 6 times higher than those in the serum, respectively. The concentration of amoxicillin in group B was higher than that in group A, especially in serum, gastric juice, gastric angle, and gastric body (P < 0.05). Furazolidone is mainly concentrated and sequentially distributed in gastric juice, gastric antrum, and gastric body tissue, and tetracycline is mainly distributed in serum, gastric angle, and gastric body, whereas amoxicillin is mainly distributed in serum, gastric juice, gastric angle, and gastric body. Improving the concentration and tissue distribution of antibacterial drugs in the human gastric mucosa is the key to ensuring the ideal eradication rate of quadruple therapy.

Unraveling Spatial Domain Characterization in Spatially Resolved Transcriptomics with Robust Graph Contrastive Clustering.

Spatial transcriptomics can quantify gene expression and its spatial distribution in tissues, thus revealing molecular mechanisms of cellular interactions underlying tissue heterogeneity, tissue regeneration, and spatially localized disease mechanisms. However, existing spatial clustering methods often fail to exploit the full potential of spatial information, resulting in inaccurate identification of spatial domains. In this paper, we develop a deep graph contrastive clustering framework, stDGCC, that accurately uncovers underlying spatial domains via explicitly modeling spatial information and gene expression profiles from spatial transcriptomics data. The stDGCC framework proposes a spatially informed graph node embedding model to preserve the topological information of spots and to learn the informative and discriminative characterization of spatial transcriptomics data through self-supervised contrastive learning. By simultaneously optimizing the contrastive learning loss, reconstruction loss, and Kullback-Leibler (KL) divergence loss, stDGCC achieves joint optimization of feature learning and topology structure preservation in an end-to-end manner. We validate the effectiveness of stDGCC on various spatial transcriptomics datasets acquired from different platforms, each with varying spatial resolutions. Our extensive experiments demonstrate the superiority of stDGCC over various state-of-the-art clustering methods in accurately identifying cellular-level biological structures. Code and data are available from https://github.com/TimE9527/stDGCC and https://figshare.com/projects/stDGCC/186525. Supplementary data are available at Bioinformatics online.

Network pharmacology and molecular dynamics study of the effect of the Astragalus-Coptis drug pair on diabetic kidney disease

BACKGROUND Diabetic kidney disease (DKD) is the primary cause of end-stage renal disease. The Astragalus -Coptis drug pair is frequently employed in the management of DKD. However, the precise molecular mechanism underlying its therapeutic effect remains elusive. AIM To investigate the synergistic effects of multiple active ingredients in the Astragalus-Coptis drug pair on DKD through multiple targets and pathways. METHODS The ingredients of the Astragalus -Coptis drug pair were collected and screened using the TCMSP database and the SwissADME platform. The targets were predicted using the SwissTargetPrediction database, while the DKD differential gene expression analysis was obtained from the Gene Expression Omnibus database. DKD targets were acquired from the GeneCards, Online Mendelian Inheritance in Man database, and DisGeNET databases, with common targets identified through the Venny platform. The protein-protein interaction network and the “disease-active ingredient-target” network of the common targets were constructed utilizing the STRING database and Cytoscape software, followed by the analysis of the interaction relationships and further screening of key targets and core active ingredients. Gene Ontology (GO) function and Kyoto Ency-clopedia of Genes and Genomes (KEGG) pathway enrichments were performed using the DAVID database. The tissue and organ distributions of key targets were evaluated. PyMOL and AutoDock software validate the molecular docking between the core ingredients and key targets. Finally, molecular dynamics (MD) simulations were conducted to simulate the optimal complex formed by interactions between core ingredients and key target proteins. RESULTS A total of 27 active ingredients and 512 potential targets of the Astragalus -Coptis drug pair were identified. There were 273 common targets between DKD and the Astragalus -Coptis drug pair. Through protein-protein interaction network topology analysis, we identified 9 core active ingredients and 10 key targets. GO and KEGG pathway enrichment analyses revealed that Astragalus -Coptis drug pair treatment for DKD involves various biological processes, including protein phosphorylation, negative regulation of apoptosis, inflammatory response, and endoplasmic reticulum unfolded protein response. These pathways are mainly associated with the advanced glycation end products (AGE)-receptor for AGE products signaling pathway in diabetic complications, as well as the Lipid and atherosclerosis. Molecular docking and MD simulations demonstrated high affinity and stability between the core active ingredients and key targets. Notably, the quercetin-AKT serine/threonine kinase 1 (AKT1) and quercetin-tumor necrosis factor (TNF) protein complexes exhibited exceptional stability. CONCLUSION This study demonstrated that DKD treatment with the Astragalus -Coptis drug pair involves multiple ingredients, targets, and signaling pathways. We propose a novel approach for investigating the molecular mechanism underlying the therapeutic effects of the Astragalus -Coptis drug pair on DKD. Furthermore, we suggest that quercetin is the most potent active ingredient and specifically targets AKT1 and TNF, providing a theoretical foundation for further exploration of pharmacologically active ingredients and elucidating their molecular mechanisms in DKD treatment.

The challenges of assessing adiposity in a clinical setting.

To tackle the burden of obesity-induced cardiometabolic disease, the scientific community relies on accurate and reproducible adiposity measurements in the clinic. These measurements guide our understanding of underlying biological mechanisms and clinical outcomes of human trials. However, measuring adiposity and adipose tissue distribution in a clinical setting can be challenging, and different measurement methods pose important limitations. BMI is a simple and high-throughput measurement, but it is associated relatively poorly with clinical outcomes when compared with waist-to-hip and sagittal abdominal diameter measurements. Body composition measurements by dual energy X-ray absorptiometry or MRI scans would be ideal due to their high accuracy, but are not high-throughput. Another important consideration is that adiposity measurements vary between men and women, between adults and children, and between people of different ethnic backgrounds. In this Perspective article, we discuss how these critical challenges can affect our interpretation of research data in the field of obesity and the design and implementation of clinical guidelines.

Fibrostricturing Crohn's Disease Is Marked by an Increase in Active Eosinophils in the Deeper Layers.

Approximately 50% of patients with Crohn's disease (CD) develop intestinal strictures necessitating surgery. The immune cell distribution in these strictures remains uncharacterized. We aimed to identify the immune cells in intestinal strictures of patients with CD. During ileocolonic resections, transmural sections of terminal ileum were sampled from 25 patients with CD and 10 non-inflammatory bowel disease controls. Macroscopically unaffected, fibrostenotic, and inflamed ileum was collected and analyzed for immune cell distribution (flow cytometry) and protein expression. Collagen deposition was assessed through a Masson Trichrome staining. Eosinophil and fibroblast colocalization was assessed through immunohistochemistry. The Masson Trichrome staining confirmed augmented collagen deposition in both the fibrotic and the inflamed regions, though with a significant increased collagen deposition in the fibrotic compared with inflamed tissue. Distinct Th1, Th2, regulatory T cells, dendritic cells, and monocytes were identified in fibrotic and inflamed CD ileum compared with unaffected ileum of patients with CD as non-inflammatory bowel disease controls. Only minor differences were observed between fibrotic and inflamed tissue, with more active eosinophils in fibrotic deeper layers and increased eosinophil cationic protein expression in inflamed deeper layers. Last, no differences in eosinophil and fibroblast colocalization were observed between the different regions. This study characterized immune cell distribution and protein expression in fibrotic and inflamed ileal tissue of patients with CD. Immunologic, proteomic, and histological data suggest inflammation and fibrosis are intertwined, with a large overlap between both tissue types. However strikingly, we did identify an increased presence of active eosinophils only in the fibrotic deeper layers, suggesting their potential role in fibrosis development.

Molecular Cloning and Characterization of Scavenger Receptor Class B Type 1 in Grass Carp (Ctenopharyngodon idellus) and Its Expression Profile following Grass Carp Reovirus Challenge

As a member of the pattern recognition receptor (PRR) class, scavenger receptor class B type 1 (SRB1) plays a key role in innate immunity. Grass carp (Ctenopharyngodon idellus) ranks among the most extensively cultivated freshwater aquaculture species in China. However, little is known about the function of SRB1 in C. idellus. In this research study, a SRB1 gene was identified in C. idellus, named CiSRB1. The full-length cDNA of CiSRB1 is 2486 bp long, with an open reading frame (ORF) of 2486 bp encoding a 497 amino acid (aa) protein containing a conserved CD36 domain. The identified genomic DNA length of CiSRB1 is 20,042 bp, including 12 exons and 11 introns. The predictive analysis of protein interactions revealed that CiSRB1 could interact with the outer capsid proteins of typical GCRV strains. The tissue distribution of CiSRB1 exhibited age-dependent characteristics. CiSRB1 displayed the highest expression in the intestines and moderate levels in muscle, spleen, liver, and brain of one-year-old grass carp while maintaining relatively low levels in three-year-old grass carp. Following grass carp reovirus (GCRV) infection, notable upregulation of CiSRB1 transcripts was observed in major immune tissues (gills, intestines, spleen, and liver). Furthermore, significant differences were found between one-year-old and three-year-old grass carp, with lower CiSRB1 expression levels being detected in the older group. Additionally, a distinct response to GCRV infection was observed in one-year-old and three-year-old grass carp. It was found that one-year-old individuals had a mortality rate of up to 84% 6 days post-infection (dpi), whereas all three-year-old counterparts survived after GCRV infection. The analysis of GCRV copy numbers across tissues revealed substantially higher levels in one-year-old grass carp compared with their older counterparts, confirming the existence of age-dependent susceptibility to GCRV infection in grass carp. Combined with these results, it was speculated that the decline in cell-surface CiSRB1 expression with age may impede reovirus binding to host cells, potentially explaining why older grass carp demonstrated enhanced resistance to GCRV infection. This observation accentuates the importance of CiSRB1 in the context of GCRV infection and provides insights into age-dependent susceptibility to reovirus.

The usefulness of determining plasma and tissue concentrations of phosphorodiamidate morpholino oligonucleotides to estimate their efficacy in Duchenne muscular dystrophy patients.

Currently four kinds of phosphorodiamidate morpholino oligomers (PMOs) such as viltolarsen have been approved for the treatment of Duchenne muscular dystrophy (DMD); however, it is unclear whether human efficacy can be estimated using plasma concentrations. This study summarizes the tissue distribution of viltolarsen in mice and cynomolgus monkeys and evaluates the relationship between exposure and efficacy based on exon skipping. In the tissue distribution studies, all muscles in DMD model mice showed higher concentrations of viltolarsen than those in wild-type mice and cynomolgus monkeys, and the concentrations in skeletal muscle were correlated with the exon-skipping efficiency in mice and cynomolgus monkeys. In addition, a highly sensitive bioanalytical method using liquid chromatography with tandem mass spectrometry shows promise for determining plasma concentrations up to a later time point, and the tissue (muscle)/plasma concentration ratio (Kp) in DMD model mice was shown to be useful for predicting changes in pharmacodynamic (PD) markers in humans. Our results suggest that pharmacokinetic (PK)/PD analysis can be conducted by using the human PK profile or Kp values and skipping efficiency in DMD model mice. This information will be useful for the efficient and effective development of PMOs as therapeutic agents. Significance Statement We compare that plasma and tissue concentrations with the efficiency of exon skipping for viltolarsen as an example phosphorodiamidate morpholino oligomers in skeletal and cardiac muscle of mice and cynomolgus monkeys for pharmacokinetics/pharmacodynamics (PK/PD) analysis. Our results suggest that PK/PD analysis can be conducted by using the human PK profile or Kp values and skipping efficiency in DMD model mice.

Coaxial nanofibrous aerogel featuring porous network-structured channels for ovarian cancer treatment by sustained release of chitosan oligosaccharide

Ovarian cancer, the deadliest gynecological malignancy, primarily treated with chemotherapy. However, systemic chemotherapy often leads to severe toxic side effects and chemoresistance. Drug-loaded aerogels have emerged as a promising method for drug delivery, as they can improve drug solubility and bioavailability, control drug release, and reduce drug distribution in non-targeted tissues, thereby minimizing side effects. In this research, chitosan oligosaccharide (COS)-loaded nanofibers composite chitosan (CS) aerogels (COS-NFs/CS) with a porous network structure were created using nanofiber recombination and freeze-drying techniques. The core layer of the aerogel has a COS loading rate of 60 %, enabling the COS-NFs/CS aerogel to significantly inhibit the migration and proliferation of ovarian cancer cells (resulting in a decrease in the survival rate of ovarian cancer cells to 33.70 % after 48 h). The coaxial fiber's unique shell-core structure and the aerogel's porous network structure enable the COS-NFs/CS aerogels to release COS steadily and slowly over 30 days, effectively reducing the initial burst release of COS. Additionally, the COS-NFs/CS aerogels exhibit good biocompatibility, degradability (only retaining 18.52 % of their weight after 6 weeks of implantation), and promote angiogenesis, thus promoting wound healing post-oophorectomy. In conclusion, COS-NFs/CS aerogels show great potential for application in the treatment of ovarian cancer.

Development of Peptide Paratope Mimics Derived from the Anti-ROR1 Antibody and Long-Acting Peptide-Drug Conjugates for Targeted Cancer Therapy.

Antibody-based targeted therapy in cancer faces a challenge due to uneven antibody distribution in solid tumors, hindering effective drug delivery. We addressed this by developing peptide mimetics with nanomolar-range affinity for Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) using computational methods. These peptides showed both specific targeting and deep penetration in vitro and in vivo. Additionally, we created peptide-drug conjugates (PDCs) by linking targeting peptides to toxin drugs via various linkers and enhancing their in vivo half-life with fatty side chains for albumin binding. The antitumor candidate II-3 displayed exceptional affinity (KD = 1.72 × 10-9 M), internalization efficiency, anticancer potency (IC50 = 0.015 ± 0.002 μM), and pharmacokinetics (t1/2 = 2.6 h), showcasing a rational approach for designing PDCs with favorable tissue distribution and strong tumor penetration.

Adipose Tissue Sex Steroids in Postmenopausal Women with and without Menopausal Hormone Therapy.

The decrease in serum estrogens after menopause is associated with a shift from a gynoid to an android adipose tissue (AT) distribution. Menopausal hormone therapy (HT) mitigates this change and accompanying metabolic dysfunction, but its effects on AT sex steroid metabolism have not been characterized. We studied effects of HT on subcutaneous and visceral AT estrogen and androgen concentrations and metabolism in postmenopausal women. Serum and subcutaneous and visceral AT from 63 postmenopausal women with (n=50) and without (n=13) per oral HT were analyzed for estrone, estradiol, progesterone, testosterone, androstenedione, dehydroepiandrosterone, and serum estrone sulfate using liquid chromatography-tandem mass spectrometry. Steroid sulfatase activity was measured using radiolabeled precursors. mRNA expression of genes encoding sex steroid-metabolizing enzymes and receptors was performed using real-time reverse transcription quantitative polymerase chain reaction. HT users had 4- to 7-fold higher concentrations of estrone and estradiol in subcutaneous and visceral AT, and 30% lower testosterone in visceral AT compared to non-users. Estrogen-to-androgen ratios were 4- to 12-fold higher in AT of users compared to non-users of HT. In visceral AT, estrogen-to-androgen ratios increased with HT estradiol dose. AT to serum ratios of estrone and estradiol remained high in HT users. Higher local estrogen to androgen ratios and high AT to serum ratios of estrogen concentrations in HT users suggest that HT may significantly influence intracrine sex steroid metabolism in AT, and these local changes could be involved in the preventive effect of HT on menopause-associated abdominal adiposity.

Adipose Tissue Sex Steroids in Postmenopausal Women with and without Menopausal Hormone Therapy.

The decrease in serum estrogens after menopause is associated with a shift from a gynoid to an android adipose tissue (AT) distribution. Menopausal hormone therapy (HT) mitigates this change and accompanying metabolic dysfunction, but its effects on AT sex steroid metabolism have not been characterized. We studied effects of HT on subcutaneous and visceral AT estrogen and androgen concentrations and metabolism in postmenopausal women. Serum and subcutaneous and visceral AT from 63 postmenopausal women with (n=50) and without (n=13) per oral HT were analyzed for estrone, estradiol, progesterone, testosterone, androstenedione, dehydroepiandrosterone, and serum estrone sulfate using liquid chromatography-tandem mass spectrometry. Steroid sulfatase activity was measured using radiolabeled precursors. mRNA expression of genes encoding sex steroid-metabolizing enzymes and receptors was performed using real-time reverse transcription quantitative polymerase chain reaction. HT users had 4- to 7-fold higher concentrations of estrone and estradiol in subcutaneous and visceral AT, and 30% lower testosterone in visceral AT compared to non-users. Estrogen-to-androgen ratios were 4- to 12-fold higher in AT of users compared to non-users of HT. In visceral AT, estrogen-to-androgen ratios increased with HT estradiol dose. AT to serum ratios of estrone and estradiol remained high in HT users. Higher local estrogen to androgen ratios and high AT to serum ratios of estrogen concentrations in HT users suggest that HT may significantly influence intracrine sex steroid metabolism in AT, and these local changes could be involved in the preventive effect of HT on menopause-associated abdominal adiposity.

Getting Nosy: olfactory rosette morphology and lamellar microstructure of two chondrichthyan species.

To smell, fish rely on passive water flow into their olfactory chambers and through their olfactory rosettes to detect chemical signals in their aquatic environment. The olfactory rosette is made up of secondarily folded tissues called olfactory lamellae. The olfactory morphology of cartilaginous fishes varies widely in both rosette gross morphology and lamellar microstructure. Previous research has shown differences in lamellar sensory morphology depending on the position along the rosette in hammerheads (family Sphyrnidae). Here, we investigate if this pattern continues in members of two other chondrichthyan families: Squalidae and Chimaeridae. Using contrast- enhanced microCT and scanning electron microscopy, we investigated patterns in lamellar morphology based on lamellar position along the olfactory rosette in Pacific spiny dogfish (Squalus suckleyi) and spotted ratfish (Hydrolagus colliei). We describe the gross olfactory rosette anatomy and lamellar microstructure of both species. We also put forth a new method, combining 3D morphological microCT data with 2D SEM microstructure data to better approximate lamellar sensory surface area. We found that in both species, lamellae in the center of the rosette were larger with more secondary folds. However, we found no significant differences in lamellar sensory surface area among lamellar positions. Previously, differences in lamellar sensory morphology have been tied to the internal fluid dynamics of the olfactory chamber. It is possible that the internal flow dynamics of these species are like other chondrichthyan models, where water flow patterns differ in the lateral versus the medial part of the organ, and the consistent distribution of sensory tissue does not correspond to this flow. Alternatively, the olfactory morphology of these species may result in uniform flow patterns throughout the olfactory chamber, correlating with the consistent distribution of sensory tissue throughout the organ. This study emphasizes that further investigations into chondrichthyan fluid dynamics is paramount to any future studies on the correlations between distribution of sensory tissues and water flow.

Biodistribution and Biotoxicity Assessment of Fluorescent Conjugated Polymer Dots.

Conjugated polymer dots (Pdots) have shown potential in the biomedical fields due to their optical properties and customizable design. However, the limited research on the biotoxicity of Pdots hinders their further application and translation. Lipophilic Pdots are prone to adsorbing specific proteins, leading to targeted tissue accumulation. Therefore, lipophilic fluorescent Pdots (Bare-Pdots) are synthesized using the conjugated polymer poly[2-methoxy-5-(2'-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV) to systematically evaluate their biodistribution and biotoxicity in stem cells, zebrafish embryos, and mice. It is observed that Bare-Pdots are readily internalized by cells and adhered to the embryonic chorion. Additionally, Bare-Pdots exhibit a distinct distribution in brown adipose tissue and heart, closely associated with phagocytosis of capillary endothelial cells involved in lipid metabolism. Notably, injection of Bare-Pdots at 5mgkg-1results in dysfunction of brown adipose tissue and an increased risk of obesity 90days post-injection. Furthermore, hydrophilic COOH-Pdots and NH2-Pdots with reduced lipophilicity are synthesized using amphiphilic ligands. NH2-Pdots show similar distribution but lower biotoxicity compared to Bare-Pdots. Nevertheless, injection of COOH-Pdots at 5mgkg-1 causes a decrease in white blood cells and renal tubular damage. These findings provide valuable insights for optimizing dosage to ensure the safe use of Pdots in preclinical applications.

Mechanisms underlying the therapeutic effects of Gang Huo Qing wen granules in the treatment of influenza based on network pharmacology, molecular docking and molecular dynamics

Influenza (Flu) is a severe health, medical, and economic problem, but no medication that has excellent outcomes and lowers the occurrence of these problems is now available. GanghuoQingwenGranules (GHQWG) is a common Chinese herbal formula for the treatment of influenza (flu). However, its methods of action remain unknown. We used network pharmacology, molecular docking, and molecular dynamics simulation techniques to investigate the pharmacological mechanism of GHQWG in flu. TCMSP and various types of literature were used to obtain active molecules and targets of GHQWG. Flu-related targets were found in the Online Mendelian Inheritance in Man (OMIM) database, the DisFeNET database, the Therapeutic Target Database (TTD), and the DrugBank database. To screen the key targets, a protein–protein interaction (PPI) network was constructed. DAVID was used to analyze GO and KEGG pathway enrichment. Target tissue and organ distribution was assessed. Molecular docking was used to evaluate interactions between possible targets and active molecules. For the ideal core protein–compound complexes obtained using molecular docking, a molecular dynamics simulation was performed. In total, 90 active molecules and 312 GHQWG targets were discovered. The PPI network's topology highlighted six key targets. GHQWG's effects are mediated via genes involved in inflammation, apoptosis, and oxidative stress, as well as the TNF and IL-17 signaling pathways, according to GO and KEGG pathway enrichment analysis. Molecular docking and molecular dynamics simulations demonstrated that the active compounds and tested targets had strong binding capabilities. This analysis accurately predicts the effective components, possible targets, and pathways involved in GHQWG flu treatment. We proposed a novel study strategy for future studies on the molecular processes of GHQWG in flu treatment. Furthermore, the possible active components provide a dependable source for flu drug screening.

Kidney targeting and modulating macrophage polarization through AMPK signaling: Therapeutic mechanism of berberine in uric acid nephropathy

Uric acid nephropathy (UAN), caused by a common metabolic disorder resulting from hyperuricemia (HUA), has an increasing incidence. Previous studies have shown that berberine (BBR) has clear urate-lowering and anti-inflammatory effects in UAN mice, but its mechanism needs to be further clarified. Therefore, Potassium Oxonate (PO) combined with hypoxanthine (HX) induced UAN mice model and MSU induced THP-1 cells polarization model were adopted to investigate the mechanism of BBR on UAN in terms of tissue distribution and molecular pharmacology. Study unveiled that BBR was first found to bind to red blood cells (RBCs), which were recognized and phagocytosed by monocytes, then recruited by the injured kidney. Subsequently, BBR was enriched and functional in damaged kidney. The results of in vivo experiments revealed that, BBR reduced UA, BUN, CRE levels as well as the release of TNF-α, IL-1β, IL-18 and IL-6, and alleviated renal injury in UAN mice, as consistent with previous studies. Additionally, BBR decreased MCP-1 expression, while diminishing macrophage infiltration and decreasing M1 proportion as determined by RT-qPCR. In vitro experiments, demonstrated that MSU promoted inflammatory polarization of THP-1 cells, while BBR reduced synthesis of inflammatory factors and inhibited MSU-induced inflammatory polarization. These effects of BBR were dependent on AMPK activation along with indirect inhibition of NF-κB signaling pathway mediated. However, the anti-inflammatory and macrophage polarization regulation effects of BBR were completely reversed upon administration of Compound C, an AMPK inhibitor. Therefore, BBR ameliorated kidney injury via regulating macrophage polarization through AMPK, which has therapeutic potential for UAN patients.