Distribution In Target Organs Research Articles

PungentDB: Bridging traditional Chinese medicine of medicine food homology and modern food flavor chemistry

Merging traditional Chinese medicine's (TCM) principles of medicine-food homology with modern flavor chemistry, this research unveils PungentDB (http://www.pungentdb.org.cn/home), a database documenting 205 unique pungent flavor compounds from 231 TCMs. It provides detailed insights into their chemical attributes, biological targets (including IC50/EC50 values), and molecular structures (2D/3D), enriched with visualizations of target organ distribution and protein structures, exploring the pungent flavor space with the help of a feature-rich visual interface. This collection, derived from over 3249 sources and highlighting 9129 targets, delves into the compounds' unique pungent flavors—taste, aroma, and thermal sensations—and their interaction with taste and olfactory receptors. PungentDB bridges ancient wisdom and culinary innovation, offering a nuanced exploration of pungent flavors' role in enhancing food quality, safety, and sensory experiences. This initiative propels flavor chemistry forward, serving as a pivotal resource for food science advancement and the innovative application of pungent flavors.

Methodology for integrating MCNP6 Monte Carlo simulation into PLUNC for prostate brachytherapy planning

Brachytherapy is a well-established therapeutic technique for treating tumours involving the placement of radioactive encapsulated sources close to or in direct contact with a tumour. Considering this type of treatments, the purpose of this work is to incorporate Monte Carlo (MC) simulation into brachytherapy treatment planning. This approach allows for precise estimation of dose distribution in target organs as well as in Organs At Risk (OAR), due to the accuracy of the MC methods in describing dose deposition.To carry out this work, the medical image visualization and dose analysis tools provided by the open-source planner PlanUNC (PLUNC) were utilized. Additionally, a set of programs was developed which automatize the main steps of a treatment planning segmentation, from DICOM images, exporting geometries determining materials and seeds positions, creating an input file for the simulation code (MCNP6.2) and, finally, reading and visualization of the simulation results in the format of the used planning software. With this methodology, results of 3D dose distribution, isodoses curves, Dose-Volume Histograms (DVH), and absorbed dose in OAR were obtained. Thus, the integration of the MC simulation into PLUNC for brachytherapy treatments, has demonstrate its utility for this purpose, showing adaptability to different anatomical geometries and extensibility to various types of treatments.

Site-Specific Tritium Labeling at the Predefined Internal Position of the Chemically-Modified RNA

In nucleic acid drug discovery, it is extremely important to develop a technology to understand the distribution in target organs and to trace the degradation process in the body in order to optimize the structure and improve the efficiency of the clinical trial process. Since nucleic acid drugs are essentially metabolically degraded into numerous fragments, labeling at the internal position is preferable to that at the terminus. Due to the high molar specific activity of tritium, various approaches for tritium-labeling have been studied for nucleic acid drugs. Nevertheless, a generally-applicable method for tritium labeling of the internal position of a nucleic acid has not been established. In this study, we have demonstrated a new and efficient method for site-specific tritium labeling of the cytosine base at a predefined internal position in nucleic acid drugs. This method was developed by the chemical modification of the cytosine 4-amino group with the pyridinyl vinyl keto group by the functionality-transfer reaction using the reactive oligodeoxynucleotide (ODN), followed by reduction with NaBT4. Applicability to a variety of chemical structures, such as 5-methyl cytosine, 2'-O-methyl, 2'-fluoro ribose derivatives, Locked/Bridged nucleic acid (LNA/BNA) derivatives, as well as phosphorothioate bonds, has been evidenced using nine oligoribonucleic acid (ORN) substrates. It has been clearly demonstrated that this method is an excellent method for tritium-labeling of nucleic acid with an average conversion efficiency of 74%, an average isolated labeling yield of 60%, and an average specific activity of 61 GBq/mmol. This method is expected to contribute to the preclinical absorption, distribution, metabolism, excretion (ADME) studies of nucleic acid drug candidates.

Dose Formulation, Biodistribution and PET Imaging Studies of a First-in-Class Fluorine-18 Organophosphorus Cholinesterase Inhibitor Tracer in Rat

Background:: To investigate dynamic live tissue organophosphorus nerve agent uptake and distribution fates resulting in acetylcholinesterase inhibition, we recently reported the first-in-class fluorine-18 [18F] radiolabeled Positron Emission Tomography (PET) imaging tracer known as [18F]O-(2-fluoroethyl)-O-(p-nitrophenyl)methylphosphonate. This tracer has been initially studied in live rats with PET imaging. Objective.: We sought to evaluate the PET tracer in vivo using a new dose formulation of saline, ethanol and L-ascorbic acid, and compare the influence of this formulation on in vivo tracer performance to previous data collected using a CH3CN:PBS formulation. Methods:: A high molar activity [18F]tracer radiosynthesis was used. Doses were formulated as saline, ethanol (≤ 1%) and L-ascorbic acid (0.1%), pH 4.0-4.5. Stability was evaluated to 6 h. Dose injection (i.v.) into male rats was followed by either ex vivo biodistribution profiling at 5, 30, 90 min, or dynamic 90 min PET imaging. Rat biodistribution and PET imaging data were compared. Results and Discussion:: An optimized radiosynthesis (8 ± 2 % RCY) resulted in stable doses for 6 h (>99%). Arterial blood included a tracer and a single metabolite. The ex vivo biodistribution and live tissue PET imaging data revealed rapid radioactivity uptake and distributed tissue levels: heart and lung, highest; liver, moderate; and brain, lowest. Conclusions:: Imaging and biodistribution data were highly correlated with expected radioactivity tissue uptake and distribution in target organs. Lower brain radioactivity levels by PET imaging were found for the new formulation (saline, 1% L-ascorbic acid, < 1% ethanol) as compared to the established CH3CN:PBS formulation. Overall, we found that the i.v. dose formulation changed the in vivo profile of an organophosphorus PET tracer that is considered an important finding for future organophosphorus PET tracer studies.

New effect of G-protein coupled receptors on blood pressure regulation

Hypertension is a clinical syndrome characterized by elevated systemic arterial blood pressure, which may be accompanied by functional or organic damage of heart, brain, kidney and other organs. The pathogenesis and development of hypertension are affected by genetic, environmental, epigenetic, intestinal microbiota and other factors. They are the result of multiple factors that promote the change of blood pressure level and vascular resistance. G protein coupled receptors(GPCRs) are the largest and most diverse superfamily of transmembrane receptors that transmit signals across cell membranes and mediate a large number of cellular responses required by human physiology. A variety of GPCRs are involved in the control of blood pressure and the maintenance of normal function of cardiovascular system. Hypertension contributes to the damages of heart, brain, kidney, intestine and other organs. Many GPCRs are expressed in various organs to regulate blood pressure. Although many GPCRs have been used as therapeutic targets for hypertension, their efficacy has not been fully studied. The purpose of this paper is to elucidate the role of GPCRs in blood pressure regulation and its distribution in target organs. The relationship between GPCRs related to intestinal microorganisms and blood pressure is emphasized. It is proposed that traditional Chinese medicine may be a new way to treat hypertension by regulating the related GPCRs via intestinal microbial metabolites.

Mechanism of Aurantii Fructus Immaturus volatile oil in treatment of slow transit constipation based on network pharmacology

To construct the active component-action target network diagram and protein-protein interaction(PPI) network diagram of Aurantii Fructus Immaturus volatile oil, so as to explore the mechanism of Aurantii Fructus Immaturus volatile oil in the treatment of slow transit constipation(STC) by analyzing the functions and pathways involved in the target. The chemical constituents of Aurantii Fructus Immaturus volatile oil were determined by gas chromatography-mass spectrometry(GC-MS). The targets of Aurantii Fructus Immaturus volatile oil were studied by PubChem, TCMSP, STITCH and Swiss Target Prediction. OMIM, Genecards-Search Resuits and TTD were used to screen out the targets of Slow Transit Constipation. The active component-action targets and PPI network diagram were constructed by Cytoscape 3.7.1. The target organ distribution was analyzed by BioGPS database. GO and KEGG pathways involved in the targets were analyzed by R language. The molecular docking between the components and the targets was verified by Discovery Studio 2.5 software. Finally, 15 volatile oil compounds from Aurantii Fructus Immaturus were detected, and 115 targets of volatile oil in the treatment of STC were predicted. GO enrichment analysis showed that the activity of Aurantii Fructus Immaturus volatile oil mainly involved blood circulation, circulation system process, response to steroid hormone, signal release and other biological processes. There were 23 KEGG enrichment pathways, among which Neuroactive ligand-receptor interaction, cAMP signaling pathway, Endocrine resistance, Calcium signaling pathway and Serotonergic synapse pathways played a significant role in STC. The results of molecular docking showed that relevant target proteins for the treatment of STC were ACHE, PTGS2, SLC6 A2 and CNR2.The multi-component, multi-target and multi-pathwaycharacteristics of Aurantii Fructus Immaturus volatile oil were revealed by network pharmacology, which provided a new therapeutic idea and method for the further study of the mechanism of Aurantii Fructus Immaturus volatile oil in the treatment of STC.

Uranium transfer and accumulation in organs of Danio rerio after waterborne exposure alone or combined with diet‐borne exposure

Uranium (U) toxicity patterns for fish have been mainly determined under laboratory-controlled waterborne exposure conditions. Because fish can take up metals from water and diet under in situ exposure conditions, a waterborne U exposure experiment (20 μg L-1 , 20 d) was conducted in the laboratory to investigate transfer efficiency and target organ distribution in zebrafish Danio rerio compared with combined waterborne exposure (20 μg L-1 ) and diet-borne exposure (10.7 μg g-1 ). 233 Uranium was used as a specific U isotope tracer for diet-borne exposure. Bioaccumulation was examined in the gills, liver, kidneys, intestine, and gonads of D. rerio. Concentrations in the organs after waterborne exposure were approximately 500 ng g-1 fresh weight, except in the intestine (> 10 μg g-1 fresh wt) and the kidneys (200 ng g-1 fresh wt). No significant difference was observed between waterborne and diet-borne conditions. Trophic U transfer in organs was found but at a low level (< 10 ng g-1 fresh wt). Surprisingly, the intestine appeared to be the main target organ after both tested exposure modalities. The gonads (57% at 20 d) and the liver (41% at 20 d) showed the highest accumulated relative U burdens. Environ Toxicol Chem 2019;38:90-98. © 2018 SETAC.

Toxicity and tissue distribution of cerium oxide nanoparticles in rats by two different routes: single intravenous injection and single oral administration

Toxicity and target organ distribution of cerium oxide nanoparticles (CeNPs) were investigated via single intravenous injection and single oral administration, respectively. Rats were sacrificed at 24h after treatment with doses of 30 and 300mg/kg, and cerium concentrations were measured in liver, kidney, spleen, lung, blood, urine and feces. Results revealed cerium levels in blood and tissues were considerably low in oral treated groups and most cerium was detected in feces, meaning CeNPs would not be absorbed in the gastro-intestinal system. Conversely, high concentrations of cerium were detected in all tissues of rats after intravenous injection. Liver and spleen were main target organs. Cerium levels in liver were 594.9 ± 95.3μg/g tissue in 30mg/kg treat group and 3741.7 ± 932.7μg/g tissue in 300mg/kg treat group. Cerium levels in spleen reached almost levels of liver. Cerium was also detected, that is relatively low compared to oral administration, in feces of rats treated via intravenous injection, that supports biliary excretion of CeNPs. Urine excretion of CeNPs was not detected in oral treatment and intravenous injection. In accordance with level of cerium distribution, toxicities based on hematology, serum biochemistry and histopathology were observed in rats treated by intravenous injection while no significance was revealed in orally treated groups.

Abstract 350: Visualizing alectinib distribution in mice brain by using MALDI mass spectrometry imaging technique

Abstract [Introduction] In the development of anticancer drug, measurement of drug concentration in target tissue has been thought to be crucial for predicting its efficacy and safety. However, measuring homogenized tissue by using quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) completely loss the spatial information of the compound in a target tissue. Mass spectrometry imaging (MSI) has been recently applied as innovative tools to detect pharmaceutical distributions in heterogeneous targets; however, it still needs to be improved in quantitative capability or reproducibility. [Purpose] We propose quantitative approach for MSI (qMSI) that administere matrix-assisted laser desorption ionization (MALDI)-MSI, concurrently with LC-MS/MS by using serial sections. We applied qMSI for visualizing spatial distribution of alectinib, novel ALK inhibitor, in mouse brain and examined the effect of MDR1 (p-glycoprotein) on the pharmacokinetic profiles in FVB and Mdr1a/b knockout mice. [Method] Pharmacokinetic study of alectinib was conducted in FVB and Mdr1a/b KO mice. Plasma, cerebrospinal fluid (CSF) and brain tissue were collected at 1, 1.5, 2, and 4 hours after a single oral administration dose of 4 and 20 mg/kg. The concentration of alectinib in plasma, CSF and brain tissue sections was measured by LC-MS/MS. The distribution of alectinib in mice brain tissue section was visualized by qMSI that we established. [Results] Developing qMSI showed the brain distribution of alectinib in the range from 1.2 to 952.6 pg/mm2 per each section, and the results made with qMSI were in excellent agreement with the complementary measurements by using laser-micro dissection to verify the exposure level. While plasma alectinib concentrations had no difference between both mice, the diffuse alectinib distributions in brain were observed in Mdr1a/b knockout compared with that in FVB mice. The dominant localization of alectinib in choroid plexus and brain blood vessels of FVB mice was observed by 20 μm resolution MSI analysis. [Conclusion] Our qMSI technique is expected to contribute to the development of anticancer drugs and translational research by visualizing drug distribution in target organs and tumors. Citation Format: Hiroaki Aikawa, Mitsuhiro Hayashi, Shoraku Ryu, Makiko Yamashita, Naoto Ohtsuka, Masanobu Nishidate, Akinobu Hamada. Visualizing alectinib distribution in mice brain by using MALDI mass spectrometry imaging technique. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 350.

STUDY THE RELATION BETWEEN SELENIUM AND GLUTATHIONE PEROXIDASE ACTIVITY IN IRON DEFICIENT GUINEA PIG.

Little information is available on the relationship of Selenium deposit in target organs and Glutathione peroxidase (GPx) activity in iron deficiency anemia ( IDA). As red blood cells (RBCs) play a crucial role on Se metabolism during Fe deficiency anemia a lower count of RBCs is featured, we aimed to investigate the influence of this pathology on Se bioavailability and the relationship with antioxidant status. 20 male guinea pig were randomly divided into two groups, a control group receiving 100 g diet with normal Fe content (45 mg/kg diet) and the Fe-deficient group receiving 100 g diet with low Fe content (5 mg/kg diet) for 60 days. Both diets were prepared with an adequate Se content (0.180 mg/kg diet). The digestive and metabolic utilization of Se, the distribution in target organ, the GPx activity and thiobarbituric acid-reactive substances (TBARS) production were measured after receiving the diets. Se retention increased (P ≤ 0.001) in the anemic group, fact that contributes to keep the enzymatic antioxidant activity of GPx in normal levels and the tendency observed is that stored Se increased in the organs, especially in kidney (P ≤ 0.01) . The lower count of RBCs featured in this pathology (P ≤ 0.001) causes an increase in kidney deposit is a consequence of the lower urinary losses (P ≤ 0.001

Mercury distribution in target organs and biochemical responses after subchronic and trophic exposure to Neotropical fish Hoplias malabaricus

In the present study, we investigated the mercury distribution, mercury bioaccumulation, and oxidative parameters in the Neotropical fish Hoplias malabaricus after trophic exposure. Forty-three individuals were distributed into three groups (two exposed and one control) and trophically exposed to fourteen doses of methylmercury each 5 days, totalizing the doses of 1.05 μg g⁻¹ (M1.05) and 10.5 μg g⁻¹ (M10.5 group). Autometallography technique revealed the presence of mercury in the intestinal epithelia, hepatocytes, and renal tubule cells. Mercury distribution was dose-dependent in the three organs: intestine, liver, and kidney. Reduced glutathione concentration, glutathione peroxidase, catalase, and glutathione S-transferase significantly decreased in the liver of M1.05, but glutathione reductase increased and lipid peroxidation levels were not altered. In the M10.5, most biomarkers were not altered; only catalase activity decreased. Hepatic and muscle mercury bioaccumulation was dose-dependent, but was not influenced by fish sex. The mercury localization and bioaccumulation corroborates some histopathological findings in this fish species (previously verified by Mela et al. in Ecotoxicol Environ Saf 68:426-435, 2007). However, the results of redox biomarkers did not explain histopathological findings previously reported in M10.5. Thus, fish accommodation to the stressor may reestablish antioxidant status at the highest dose, but not avoid cell injury.

Se bioavailability and glutathione peroxidase activity in iron deficient rats

Little information is available on the relationship of Se deposit in target organs and GPx activity in iron deficiency anemia. As red blood cells (RBCs) play a crucial role on Se metabolism and during Fe deficiency anemia a lower count of RBCs is featured, we aimed to investigate the influence of this pathology on Se bioavailability and the relationship with antioxidant status. 20 male Wistar rats were randomly divided into two groups, a control group receiving AIN-93G diet with normal Fe content (45 mg/kg diet) and the Fe-deficient group receiving AIN-93G diet with low Fe content (5 mg/kg diet) for 40 days. Both diets were prepared with an adequate Se content (0.180 mg/kg diet). The digestive and metabolic utilization of Se, the distribution in target organ, the GPx activity and TBARS production were measured after receiving the diets. Se retention increased ( P < 0.001) in the anemic group, fact that contributes to keep the enzymatic antioxidant activity of GPx in normal levels and the tendency observed is that stored Se increased in the organs, especially in kidney ( P < 0.01), however, a lower Se deposit was found in sternum of anemic rats ( P < 0.001). The lower count of RBCs featured in this pathology ( P < 0.001) causes a decrease of Se concentration in sternum meanwhile the increase in kidney deposit is a consequence of the lower urinary losses ( P < 0.001).

Bacterial lipopolysaccharide enhances deposition of immune complexes and exacerbates nephritis in BXSB lupus-prone mice

Systemic autoimmune disease is influenced by genetic, immunological, hormonal, and environmental factors. Although environmental factors are major agents that induce or exacerbate autoimmune diseases, the mechanism(s) and the molecular events by which they operate remain poorly understood. Here we used the lupus-prone BXSB mouse as an animal model of systemic autoimmune disease, and we used a bacterial lipopolysaccharide (LPS) as a surrogate infectious agent to gain some insight into the mechanism(s) by which infectious agents exacerbate autoimmune diseases. Our experimental protocol was designed to address three questions: (i) whether spontaneous polyclonal B cell activation (PBA) that occurs in BXSB mice could be further enhanced by bacterial LPS; (ii) whether repeated exposure to LPS would exacerbate autoimmune disease, as reflected by enhanced deposits of immune complexes (ICs) in kidneys and exacerbated nephritis; and (iii) whether the mechanism by which LPS exacerbates nephritis might involve interference with blood cell carrier function, mononuclear phagocyte function, or both. BXSB mice were injected with LPS (25 micrograms) twice a week for 5 weeks; control autoimmune BXSB mice and immunologically normal (C57BL/6) mice were injected with vehicle only. The three groups of mice were then challenged with soluble ICs to assess the kinetics of their disappearance from the circulation, their uptake by the mononuclear phagocyte system (liver, spleen), their distribution in target organ (kidney), and blood cell carrier function. The results indicate that: (i) spontaneous PBA can be enhanced further by LPS; (ii) exposure to LPS results in increased deposits of endogenous ICs in kidneys and exacerbated nephritis; and (iii) defective handling of ICs by the mononuclear phagocyte system and impaired blood cell carrier function are contributory factors to exacerbated nephritis, but that mechanisms in addition to passive localization of ICs may also be operative.

The pelvic plexus: innervation of pelvic and extrapelvic visceral tissues.

The pelvic plexus is an association of neurons that govern visceral tissues involved in eliminative and reproductive functions. It is the singular site in the autonomic nervous system where sympathetic and parasympathetic neurons occur in the same ganglia. Within the plexus, ganglia are not randomly positioned; sympathetic neurons tend to occur more ventrally while parasympathetic neurons are located more dorsally, both in accordance with the location of their target tissues and the entry point of their corresponding preganglionic nerve tracts. For example, the vas deferens and seminal vesicle are ventral in position and thus are innervated by more ventrally located pelvic neurons. Neurochemical studies of pelvic ganglia indicate that there are some characteristic associations of putative neurotransmitters which are based on target organ distribution and in part, dictated by the variety of target tissues within each organ. Penile neurons comprise a uniform population in that they are cholinergic and also may release vasoactive intestinal polypeptide (VIP) and nitric oxide. In contrast, target tissues of the internal genitalia are more diverse, requiring adrenergic and nonadrenergic innervation and a complementary neuropeptide. Preganglionic innervation may also be coded and although sympathetic and parasympathetic fibers are cholinergic, they may differ in respect to neuropeptides and nitric oxide. Sensory neuron collaterals may also influence principal neurons as do intrinsic neurons such as small intensely fluorescent cells. Transmission through pelvic ganglia may be simple as is apparent in penile innervation, or shows a greater integrative capacity, as exemplified by the innervation of the urinary bladder. The extent of interaction of sympathetic and parasympathetic pathways at the level of the pelvic plexus remains largely unknown.

A common viral infection can change nickel target organ distribution

The autoradiographic distribution of the toxic heavy metal nickel (Ni) was studied at 4 and 7 days post-coxsackievirus B3 (CB3) infection in Balb c mice. The distribution of the iv injected 63Ni was studied 10 min, 4 hr, and 24 hr after administration. Results clearly show that the site of 63Ni accumulation is greatly changed during this viral infection. This newly discovered distribution was mainly visible as a greatly increased accumulation in the pancreas and the wall of the ventricular myocardium. Healthy animals showed almost no 63Ni accumulation in these tissues. These results for the first time show that an invading microorganism can change the distribution of an environmental pollutant.

DNA-binding studies with 6BT and 5I: implications for DNA-binding/carcinogenicity and DNA-binding/mutagenicity correlations

The divergent activities of a reported carcinogen/noncarcinogen pair of monoazo dyes related to the hepatocarcinogen Butter Yellow (DAB) are currently under investigation in our laboratories. As part of these studies we have determined (a) target organ distribution after oral dosing to rats and (b) covalent binding of 14C-labelled compound to DNA. In DNA-binding studies, 3 rat liver-metabolising systems were employed: in vivo (whole liver), isolated intact hepatocytes, and liver subcellular fractions. Distribution studies revealed that comparable levels of both compounds were detected in the liver at similar times after dosing, and these in vivo tissue concentrations were used for in vitro DNA-binding studies. At this ‘in vivo equivalent dose’, the carcinogen was consistently bound to DNA more effectively, and the difference (ratio of DNA binding) between the 2 compounds was far greater in vivo. In subsequent studies, covalent DNA binding to bacterial (Salmonella) DNA was assessed at the in vivo equivalent dose. In contrast to the afore-mentioned findings in mammalian systems, the carcinogen was bound less effectively to DNA, and give fewer revertant counts/plate when the 2 compounds were the 2 compounds were bound to an equivalent extent. These data are discussed in view of their implications for DNA-binding/carcinogenicity correlations, and with respect to the relationship between DNA binding and mutageneity in the Salmonella assay.