Effect of the configuration mixing on the polarization and angular distribution of x-ray line emissions following electron-impact excitation of Ne-like ions.

We present a systematic theoretical study on the angular distribution and linear polarization of x-ray line emissions of neon-like ions following the electron-impact excitation from the ground state to the excited levels [(2p5)1/23d3/2]J=1, [(2p5)3/23d5/2]J=1, [(2p5)3/23d3/2]J=1, and [(2p5)1/23s]J=1. The cross sections are calculated by using the flexible atomic code under configuration-interaction plus many-body perturbation theory method. The angular distribution and linear polarization are obtained based on density matrix theory. Emphasis has been placed on the effect of the configuration mixing on the angular distribution and polarization. It has been proved that the strong mixing of configuration [(2p5)3/23d3/2]J=1 with configuration [(2p5)1/23s]J=1 can result in the abrupt change of Z-dependence of angular distribution and polarization. It indicates that angular distribution and polarization can be expected to serve as a tool for investigation of configuration mixing effect.

Hydrodynamic Groundwater Modeling and Hydrochemical Conceptualization of the Closure Mining Area of the WuMa River Watershed of China.

The WuMa River (WMR) watershed is located in Renhuai City, Guizhou Province of China, which is a first-class tributary of the Chishui River. The geochemical investigation mainly included the determination of groundwater pH, total hardness, total dissolution solid, major cationic and anionic, and the geochemical groundwater modeling. The principal component analysis (PCA) and Gibbs model were used to analyze the pollution type and geochemical composition. The geochemical investigation results show that the cations of groundwater are dominated by Ca2+ and the anions are dominated by HCO3-; therefore, two main hydrochemical types in the study area are identified as Ca2+-Mg2+-HCO3- and Ca2+-Mg2+-SO42-. The chemical composition of groundwater in this area is mainly controlled by weathering of the carbonate rocks. The ion concentration of groundwater in the study area exhibited significant spatial variability between dry and wet seasons, while temporal changes of cationic and anionic concentrations exhibited irregularities. In PCA and FA analysis, PC1, PC2, and PC3 were extracted, which could explain 51.92, 26.98, and 12.61% of the total information, respectively. F1 explained 67.44% of the total variance, among which Ca2+, Mg2+, K+, SO42-, and Cl- contributed the most among the factors and were the main factors controlling the chemical composition of groundwater. The relative error between the measured water level and the simulated water level is less than 2%, which meets the requirements of simulation accuracy. During the simulation period of the model, a total recharge of 339.05 × 104 m3 was observed in the simulated area, primarily attributed to infiltration from rainfall. The total excretion amounted to 330.78 × 104 m3, primarily through evaporation, with a minor amount of lateral outflow. The migration pathway of pollutants in groundwater primarily follows the direction of groundwater flow while diffusing vertically. The migration range of the pollutant is in accordance with the direction of groundwater flow and extends along the larger hydraulic gradient, demonstrating consistency. The findings of this study serve as a reminder that the closure of coal mines can constitute a significant source of water pollution. Simultaneously, they offer empirical data and theoretical references for the simulation and prediction of groundwater contamination in enclosed coal mines.

Red blood cell distribution width improves the prediction of 28-day mortality for patients with sepsis-induced acute kidney injury: A retrospective analysis from MIMIC-IV database using propensity score matching.

Background: The predictive value of red blood cell distribution width (RDW) for mortality in patients with sepsis-induced acute kidney injury (SI-AKI) remains unclear. The present study aimed to investigate the potential association between RDW at admission and outcomes in patients with SI-AKI. Methods: The Medical Information Mart for Intensive Care (MIMIC)-IV (version 2.0) database, released in June of 2022, provides medical data of SI-AKI patients to conduct our related research. Based on propensity score matching (PSM) method, the main risk factors associated with mortality in SI-AKI were evaluated using Cox proportional hazards regression analysis to construct a predictive nomogram. The concordance index (C-index) and decision curve analysis were used to validate the predictive ability and clinical utility of this model. Patients with SI-AKI were classified into the high- and low-RDW groups according to the best cut-off value obtained by calculating the maximum value of the Youden index. Results: A total of 7574 patients with SI-AKI were identified according to the filter criteria. Compared with the low-RDW group, the high-RDW group had higher 28-day (9.49% vs. 31.40%, respectively, P <0.001) and 7-day (3.96% vs. 13.93%, respectively, P <0.001) mortality rates. Patients in the high-RDW group were more prone to AKI progression than those in the low-RDW group (20.80% vs. 13.60%, respectively, P <0.001). Based on matched patients, we developed a nomogram model that included age, white blood cells, RDW, combined hypertension and presence of a malignant tumor, treatment with vasopressor, dialysis, and invasive ventilation, sequential organ failure assessment, and AKI stages. The C-index for predicting the probability of 28-day survival was 0.799. Decision curve analysis revealed that the model with RDW offered greater net benefit than that without RDW. Conclusion: The present findings demonstrated the importance of RDW, which improved the predictive ability of the nomogram model for the probability of survival in patients with SI-AKI.

Research trends on platelet-rich plasma in the treatment of wounds during 2002-2021: A 20-year bibliometric analysis.

Platelet-rich plasma (PRP) has attracted attention because of its potential to accelerate the wound healing process. However, resources for evaluating research trends in the treatment of wounds with PRP were limited. In this study, we aimed to make a bibliometric analysis of the literature related to PRP in the treatment of wounds and explore the research status, hotspots and frontiers in this field in recent 20 years. Studies about PRP treatment for wounds from 2002 to 2021 were retrieved from the Science Citation Index Expanded (SCI-E) of Web of Science (WOS) database. Visualisation softwares such as VOSviewer and SCImago Graphica, and CiteSpace were used to analyse the research trends and features. A total of 1748 studies were identified in the SCI-Expanded from 2002 to 2021. The number of publications on PRP in the treatment of wounds has shown an increasing trend, from 6 (in 2002) to 228 (in 2021). The papers published in the United States have led in times cited (14637) and H-index (63). Though Italy was slightly lower than China in the number of publications, the H-index and average cited (47, 28.45) were higher than that of China (38, 27.01). The strongest keyword was "fibrin" (strength = 13.07), and the longest burst duration keyword was "thrombin" (began in 2002 and ended in 2014). The largest 10 co-citation clusters are as follows: endothelial cell proliferation (#0), regenerative medicine-associated treatment (#1), diabetic wound healing (#2), autologous derived (#3), platelet-rich fibrin (#4), tissue engineering (#5), regenerative potential (#6), clinical randomised trial (#7), histologic observation (#8), and wound bacteria (#9). The United States has made the most outstanding contribution in this field. Chinese researchers need to enhance the quality of publications further. Wound Repair Regen. is the most noteworthy journal. The mechanism of growth factors of PRP, combination therapy, preparation of PRP, and related clinical trials may be topics that need attention.

Breast Cancer MCF-7 Cell Spheroid Culture for Drug Discovery and Development.

In vitro 3D cancer spheroids (tumoroids) exhibit a drug resistance profile similar to that found in solid tumors. 3D spheroid culture methods recreate more physiologically relevant microenvironments for cells. Therefore, these models are more appropriate for cancer drug screening. We have recently developed a protocol for MCF-7 cell spheroid culture, and used this method to test the effects of different types of drugs on this estrogen-dependent breast cancer cell spheroid. Our results demonstrated that MCF-7 cells can grow spheroid in medium using a low attachment plate. We managed to grow one spheroid in each well, and the spheroid can grow over a month, the size of the spheroid can grow over a hundred times in volume. Our targeted drug experimental results suggest that estrogen sulfotransferase, steroid sulfatase, and G protein-coupled estrogen receptor may play critical roles in MCF-7 cell spheroid growth, while estrogen receptors α and ß may not play an essential role in MCF-7 spheroid growth. Organoids are the miniatures of in vivo tissues and reiterate the in vivo microenvironment of a specific organ, best fit for the in vitro studies of diseases and drug development. Tumoroid, developed from cancer cell lines or patients' tumor tissue, is the best in vitro model of in vivo tumors. 3D spheroid technology will be the best future method for drug development of cancers and other diseases. Our reported method can be developed clinically to develop personalized drugs when the patient's tumor tissues are used to develop a spheroid culture for drug screening.

Regulations of expressions of rat/human sulfotransferases by anticancer drug, nolatrexed, and micronutrients.

Cancer is related to the cellular proliferative state. Increase in cell-cycle regulatory function augments cellular folate pool. This pathway is therapeutically targeted. A number of drugs influences this metabolism, that is, folic acid, folinic acid, nolatrexed, and methotrexate. Our previous study showed methotrexate influences on rat/human sulfotransferases. Present study explains the effect of nolatrexed (widely used in different cancers) and some micronutrients on the expressions of rat/human sulfotransferases. Female Sprague-Dawley rats were treated with nolatrexed (01-100 mg/kg) and rats of both sexes were treated to folic acid (100, 200, or 400 mg/kg) for 2-weeks and their aryl sulfotransferase-IV (AST-IV; ß-napthol sulfation) and sulfotransferase (STa; DHEA sulfation) activities, protein expression (western blot) and mRNA expression (RT-PCR) were tested. In human-cultured hepatocarcinoma (HepG2) cells nolatrexed (1 nM-1.2 mM) or folinic acid (10 nM-10 µM) were applied for 10 days. Folic acid (0-10 µM) was treated to HepG2 cells. PPST (phenol catalyzing), MPST (dopamine and monoamine), DHEAST (dehydroepiandrosterone and DHEA), and EST (estradiol sulfating) protein expressions (western-blot) were tested in HepG2 cells. Present results suggest that nolatrexed significantly increased sulfotransferases expressions in rat (protein, STa, F = 4.87, P < 0.05/mRNA, AST-IV, F = 6.702, P < 0.014; Student's t test, P < 0.01-0.05) and HepG2 cells. Folic acid increased sulfotransferases activity/protein in gender-dependant manner. Both folic and folinic acid increased several human sulfotransferases isoforms with varied level of significance (least or no increase at highest dose) in HepG2 cells pointing its dose-dependent multiphasic responses. The clinical importance of this study may be furthered in the verification of sulfation metabolism of several exogenous/endogenous molecules, drug-drug interaction and their influences on cancer pathophysiological processes. Further studies are necessary.

Concentration-dependent effects of chlorpyrifos oxon on peroxisome proliferator-activated receptor signaling in MCF-7 cells.

Chlorpyrifos oxon (CPO) is the active metabolite of the organophosphorus pesticide, chlorpyrifos. CPO is a potent inhibitor of acetylcholinesterase (AChE) and other serine hydrolases including fatty acid amide hydrolase (FAAH). AChE is critical in regulating cholinergic signaling while FAAH catalyzes the inactivation of fatty acid signaling lipids including the endocannabinoid (eCB) N-arachidonylethanolamine (anandamide, AEA) and eCB-like metabolites (e.g., oleoylethanolamide, OEA). AEA and OEA are both peroxisome proliferator-activated receptor (PPAR) agonists that regulate numerous genes involved in lipid metabolism and energy homeostasis. We used the MCF-7 human breast cancer cell line, which expresses AChE, FAAH and PPAR alpha and gamma subtypes, to evaluate the potential effects of CPO on PPAR-related gene expression in an in vitro human cell system. CPO elicited relatively similar concentration-dependent inhibition of both AChE and FAAH. Marked concentration- and time-dependent changes in the expression of four selected PPAR-related genes, LXRα, ACOX1, ABCG2 and AGPAT2, were noted. These findings suggest chlorpyrifos may influence lipid metabolism through blocking the degradation of eCBs or eCB-like metabolites and in turn affecting PPAR receptor activation. The results highlight the potential for non-cholinesterase actions of this common insecticide metabolite through disruption of PPAR signaling including effects on lipid metabolism, immune function and inflammation.

Discovery of novel diarylamides as orally active diuretics targeting urea transporters.

Urea transporters (UT) play a vital role in the mechanism of urine concentration and are recognized as novel targets for the development of salt-sparing diuretics. Thus, UT inhibitors are promising for development as novel diuretics. In the present study, a novel UT inhibitor with a diarylamide scaffold was discovered by high-throughput screening. Optimization of the inhibitor led to the identification of a promising preclinical candidate, N-[4-(acetylamino)phenyl]-5-nitrofuran-2-carboxamide (1H), with excellent in vitro UT inhibitory activity at the submicromolar level. The half maximal inhibitory concentrations of 1H against UT-B in mouse, rat, and human erythrocyte were 1.60, 0.64, and 0.13 µmol/L, respectively. Further investigation suggested that 8 µmol/L 1H more powerfully inhibited UT-A1 at a rate of 86.8% than UT-B at a rate of 73.9% in MDCK cell models. Most interestingly, we found for the first time that oral administration of 1H at a dose of 100 mg/kg showed superior diuretic effect in vivo without causing electrolyte imbalance in rats. Additionally, 1H did not exhibit apparent toxicity in vivo and in vitro, and possessed favorable pharmacokinetic characteristics. 1H shows promise as a novel diuretic to treat hyponatremia accompanied with volume expansion and may cause few side effects.

Profiles of Two Glycaemia Modifying Drugs on the Expression of Rat and Human Sulfotransferases.

AIMS: To study the effects of blood glucose regulating compounds on human and rat sulfotransferases (SULTs) expressions. BACKGROUND: Phase-II enzymes, sulfotransferases catalyze the sulfuryl-group-transfer to endogenous/exogenous compounds. The alteration of expressions of SULTs may have influence on the sulfation of its substrate and other biomolecules. OBJECTIVES: The influence of the altered biotransformation might alter different biochemical events, drug-drug interactions and bioaccumulation or excretion pattern of certain drug. METHODS: In this brief study, diabetes-inducing drug streptozotocin (STZ; 10 or 50 mg/kg to male Sprague Dawley rat for 2 weeks) or hyperglycemia controlling drug tolbutamide (TLB 0.1 or 10µM to human hepato-carcinoma cells, HepG2 for 10 days) was applied and the SULTs expressions were verified. Extensive protein-protein (STa, SULT2A1/DHEAST) interactions were studied by the STRING (Search-Tool-for-the-Retrieval-of-Interacting Genes/Proteins) Bioinformatics-software. RESULTS: Present result suggests that while STZ increased the STa (in rat) (dehydroepiandrosterone catalyzing SULT; DHEAST in human HepG2), tolbutamide decreased PPST (phenol catalyzing SULT) and DHEAST activity in human HepG2 cells. Moderate decreases of MPST (monoamine catalyzing SULT) and EST (estrogen catalyzing) activities are noticed in this case. STa/DHEAST was found to be highly interactive to SHBG/- sex-hormone-binding-globulin; PPARα/lipid-metabolism-regulator; FABP1/fatty-acid-binding-protein. CONCLUSION: Streptozotocin and tolbutamide, these two glycaemia-modifying drugs demonstrated regulation of rat and human SULTs activities. The reciprocal nature of these two drugs on SULTs expression may be associated with their contrasting abilities in influencing glucose-homeostasis. Possible association of certain SULT-isoform with hepatic fat-regulations may indicate an unfocused link between calorie-metabolism and the glycemic-state of an individual. Explorations of this work may uncover the role of sulfation metabolism of specific biomolecule on cellular glycemic regulation.

Adrenomedullin Inhibits Osmotic Water Permeability in Rat Inner Medullary Collecting Ducts.

Adrenomedullin (ADM) is a vasodilator that causes natriuresis and diuresis. However, the direct effect of ADM on osmotic water permeability in the rat inner medullary collecting duct (IMCD) has not been tested. We investigated whether ADM and its ADM receptor components (CRLR, RAMP2, and 3) are expressed in rat inner medulla (IM) and whether ADM regulates osmotic water permeability in isolated perfused rat IMCDs. The mRNAs of ADM, CRLR, and RAMP2 and 3 were detected in rat IM. Abundant protein of CRLR and RAMP3 were also seen but RAMP2 protein level was extremely low. Adding ADM (100 nM) to the bath significantly decreased osmotic water permeability. ADM significantly decreased aquaporin-2 (AQP2) phosphorylation at Serine 256 (pS256) and increased it at Serine 261 (pS261). ADM significantly increased cAMP levels in IM. However, inhibition of cAMP by SQ22536 further decreased ADM-attenuated osmotic water permeability. Stimulation of cAMP by roflumilast increased ADM-attenuated osmotic water permeability. Previous studies show that ADM also stimulates phospholipase C (PLC) pathways including protein kinase C (PKC) and cGMP. We tested whether PLC pathways regulate ADM-attenuated osmotic water permeability. Blockade of either PLC by U73122 or PKC by rottlerin significantly augmented the ADM-attenuated osmotic water permeability and promoted pS256-AQP2 but did change pS261-AQP2. Inhibition of cGMP by L-NAME did not change AQP2 phosphorylation. In conclusion, ADM primarily binds to the CRLR-RAMP3 receptor to initiate signaling pathways in the IM. ADM reduced water reabsorption through a PLC-pathway involving PKC. ADM-attenuated water reabsorption may be related to decreased trafficking of AQP2 to the plasma membrane. cAMP is not involved in ADM-attenuated osmotic water permeability.

Drug-Coated Balloon for De Novo Coronary Artery Lesions: A Systematic Review and Trial Sequential Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To investigate the efficacy of drug-coated balloon (DCB) treatment for de novo coronary artery lesions in randomized controlled trials (RCTs). BACKGROUND: DCB was an effective therapy for patients with in-stent restenosis. However, the efficacy of DCB in patients with de novo coronary artery lesions is still unknown. METHODS: Eligible studies were searched on PubMed, Web of Science, EMBASE, and Cochrane Library Database. Systematic review and meta-analyses of RCTs were performed comparing DCB with non-DCB devices (such as plain old balloon angioplasty (POBA), bare-metal stents (BMS), or drug-eluting stents (DES)) for the treatment of de novo lesions. Trial sequential meta-analysis (TSA) was performed to assess the false positive and false negative errors. RESULTS: A total of 2,137 patients enrolled in 12 RCTs were analyzed. Overall, no significant difference in target lesion revascularization (TLR) was found, but there were numerically lower rates after DCB treatment at 6 to 12 months follow-up (RR: 0.69; 95% CI: 0.47 to 1.01; P = 0.06; TSA-adjusted CI: 0.41 to 1.16). TSA showed that at least 1,000 more randomized patients are needed to conclude the effect on TLR. A subgroup analysis from high bleeding risk patients revealed that DCB treatment was associated with lower rate of TLR (RR: 0.10; 95% CI: 0.01 to 0.78; P = 0.03). The systematic review illustrated that the rate of bailout stenting was lower and decreased gradually. CONCLUSIONS: DCB treatment was associated with a trend toward lower TLR when compared with controls. For patients at bleeding risk, DCB treatment was superior to BMS in TLR.

Tocopherol Moderately Induces the Expressions of Some Human Sulfotransferases, which are Activated by Oxidative Stress.

Oxidative stress is generated in biological system by several endogenous/exogenous factors like environmental-pollution/toxicity/diseases and by daily-life-stress. We previously showed that oxidative-stress impaired the activities/expressions of phase-II drug-metabolizing enzyme, sulfotransferases (SULTs). The SULT catalyzes sulfation of endogenous/exogenous compounds. Vitamin E is globally consumed by a large number of individuals for the cellular protection from oxidative stress and aging. Here, vitamin E (tocopherol; α/γ and tocotrienol; α/γ; 0, 1, 10, or 100 µM) was tested in human carcinoma cell line, HepG2 for their influences on SULTs expression/(western blotting). The effects of oxidant (glutathione-oxidized/GSSG) or reductant (glutathione-reduced/GSH, Dithiothreitol/DTT) on SULT activities were studied in rat-liver/human intestinal tissues. Results suggest, tocopherol is more inductive to monoamine-SULT (MPST) and Dehydroepiandrosterone-SULT (DHEAST) compared to that of tocotrienol (inconsistent change in PPST, phenol sulfotransferase/MPST/EST, estrogen sulfotransferase). The nuclear-factor constitutive androstane receptor (CAR) was found to be induced moderately. This study overall describes that vitamin E moderately influences SULTs expression. The induction ability of tocopherol should be judged taking into account its long-term consummation. Oxidative stress activates rat and human SULTs activities and expressions. Further studies are necessary in this regard.

SLC14A1 (UT-B) gene rearrangement in urothelial carcinoma of the bladder: a case report.

BACKGROUND: Bladder cancer (BC) is a common and deadly disease. Over the past decade, a number of genetic alterations have been reported in BC. Bladder urothelium expresses abundant urea transporter UT-B encoded by Slc14a1 gene at 18q12.3 locus, which plays an important role in preventing high concentrated urea-caused cell injury. Early genome-wide association studies (GWAS) showed that UT-B gene mutations are genetically linked to the urothelial bladder carcinoma (UBC). In this study, we examined whether Slc14a1 gene has been changed in UBC, which has never been reported. CASE PRESENTATION: A 59-year-old male was admitted to a hospital with the complaint of gross hematuria for 6 days. Ultrasonography revealed a size of 2.8 × 1.7 cm mass lesion located on the rear wall and dome of the bladder. In cystoscopic examination, papillary tumoral lesions 3.0-cm in total diameter were seen on the left wall of the bladder and 2 cm to the left ureteric orifice. Transurethral resection of bladder tumor (TURBT) was performed. Histology showed high-grade non-muscle invasive UBC. Immunostaining was negative for Syn, CK7, CK20, Villin, and positive for HER2, BRCA1, GATA3. Using a fluorescence in situ hybridization (FISH), Slc14a1 gene rearrangement was identified by a pair of break-apart DNA probes. CONCLUSIONS: We for the first time report a patient diagnosed with urothelial carcinoma accompanied with split Slc14a1 gene abnormality, a crucial gene in bladder.

The urea transporter UT-A1 plays a predominant role in a urea-dependent urine-concentrating mechanism.

Urea transporters are a family of urea-selective channel proteins expressed in multiple tissues that play an important role in the urine-concentrating mechanism of the mammalian kidney. Previous studies have shown that knockout of urea transporter (UT)-B, UT-A1/A3, or all UTs leads to urea-selective diuresis, indicating that urea transporters have important roles in urine concentration. Here, we sought to determine the role of UT-A1 in the urine-concentrating mechanism in a newly developed UT-A1-knockout mouse model. Phenotypically, daily urine output in UT-A1-knockout mice was nearly 3-fold that of WT mice and 82% of all-UT-knockout mice, and the UT-A1-knockout mice had significantly lower urine osmolality than WT mice. After 24-h water restriction, acute urea loading, or high-protein (40%) intake, UT-A1-knockout mice were unable to increase urine-concentrating ability. Compared with all-UT-knockout mice, the UT-A1-knockout mice exhibited similarly elevated daily urine output and decreased urine osmolality, indicating impaired urea-selective urine concentration. Our experimental findings reveal that UT-A1 has a predominant role in urea-dependent urine-concentrating mechanisms, suggesting that UT-A1 represents a promising diuretic target.

Dependence between estrogen sulfotransferase (SULT1E1) and nuclear transcription factor Nrf-2 regulations via oxidative stress in breast cancer.

Human estrogen sulfotransferase (SULT1E1) and nuclear factor erythroid 2-related factor 2 (Nrf-2) expression influences each other in advanced human breast carcinogenesis. The difference in the metabolism of estradiol (E2) in pre- and post-menopausal women remains to be connected with post-menopausal breast cancer. A synergism between ROS production and E2 generation has been demonstrated. No definite mechanism for simultaneous functions of Nrf2, oxidative stress E2 regulating enzymes (SULT1E1) has been yet clarified. Our present review demonstrates that ROS dependent regulation of Nrf-2 is one of the most important determinants of E2 regulation by altering SULT1E1 expression. This study also focuses the idea that estrogen receptor cased subtypes of cancer may have different molecular environments which has an impact on the therapeutic efficacy.

Dendrigraft poly-L-lysines delivery of DNA vaccine effectively enhances the immunogenic responses against H9N2 avian influenza virus infection in chickens.

Biodegradable nanomaterials can protect antigens from degradation, promote cellular absorption, and enhance immune responses. We constructed a eukaryotic plasmid [pCAGGS-opti441-hemagglutinin (HA)] by inserting the optimized HA gene fragment of H9N2 AIV into the pCAGGS vector. The pCAGGS-opti441-HA/DGL was developed through packaging the pCAGGS-opti441-HA with dendrigraft poly-l-lysines (DGLs). DGL not only protected the pCAGGS-opti441-HA from degradation, but also exhibited high transfection efficiency. Strong cellular immune responses were induced in chickens immunized with the pCAGGS-opti441-HA/DGL. The levels of IFN-γ and IL-2, and lymphocyte transformation rate of the vaccinated chickens increased at the third week post the immunization. For the vaccinated chickens, T lymphocytes were activated and proliferated, the numbers of CD3+CD4+ and CD4+/CD8+ increased, and the chickens were protected completely against H9N2 AIV challenge. This study provides a method for the development of novel AIV vaccines, and a theoretical basis for the development of safe and efficient gene delivery carriers.

Breast cancer pathogenesis is linked to the intra-tumoral estrogen sulfotransferase (hSULT1E1) expressions regulated by cellular redox dependent Nrf-2/NFκß interplay.

BACKGROUND: Estrogen sulfotransferase catalyzes conjugation of sulfuryl-group to estradiol/estrone and regulates E2 availability/activity via estrogen-receptor or non-receptor mediated pathways. Sulfoconjugated estrogen fails to bind estrogen-receptor (ER). High estrogen is a known carcinogen in postmenopausal women. Reports reveal a potential redox-regulation of hSULT1E1/E2-signalling. Further, oxidatively-regulated nuclear-receptor-factor 2 (Nrf2) and NFκß in relation to hSULT1E1/E2 could be therapeutic-target via cellular redox-modification. METHODS: Here, oxidative stress-regulated SULT1E1-expression was analyzed in human breast carcinoma-tissues and in rat xenografted with human breast-tumor. Tumor and its surrounding tissues were obtained from the district-hospital. Intracellular redox-environment of tumors was screened with some in vitro studies. RT-PCR and western blotting was done for SULT1E1 expression. Immunohistochemistry was performed to analyze SULT1E1/Nrf2/NFκß localization. Tissue-histoarchitecture/DNA-stability (comet assay) studies were done. RESULTS: Oxidative-stress induces SULT1E1 via Nrf2/NFκß cooperatively in tumor-pathogenesis to maintain the required proliferative-state under enriched E2-environment. Higher malondialdehyde/non-protein-soluble-thiol with increased superoxide-dismutase/glutathione-peroxidase/catalase activities was noticed. SULT1E1 expression and E2-level were increased in tumor-tissue compared to their corresponding surrounding-tissues. CONCLUSIONS: It may be concluded that tumors maintain a sustainable oxidative-stress through impaired antioxidants as compared to the surrounding. Liver-tissues from xenografted rat manifested similar E2/antioxidant dysregulations favoring pre-tumorogenic environment.

Molecular characterization of a MOSPD2 homolog in the barbel steed (Hemibarbus labeo) and its involvement in monocyte/macrophage and neutrophil migration.

Motile sperm domain containing 2 (MOSPD2) is a single-pass membrane protein to which until recently little function had been ascribed. Although its mammalian homologs have been identified, the status of the mospd2 gene in lower vertebrates is still unknown. In the present study, cDNA of the mospd2 gene of barbel steed (Hemibarbus labeo) was cloned and sequenced to characterize its potential involvement in the innate immune system of this fish. Sequence analysis revealed that the predicted barbel steed MOSPD2 protein contained an N-terminal extracellular portion composed of a CRAL-TRIO domain, a motile sperm domain, and a transmembrane domain, as well as a short C-terminal intracellular domain. Phylogenetic tree analysis indicated that barbel steed MOSPD2 is closely related to that of zebrafish. Barbel steed mospd2 transcripts were detected in a wide range of tissues, with the highest level being found in the gill. In response to lipopolysaccharide (LPS) treatment or Aeromonas hydrophila infection, mospd2 gene expression was significantly altered in the head kidney, spleen, and mid-intestine. The expression of mospd2 gene was detected in monocytes/macrophages (MO/MФ), neutrophils, and lymphocytes, and was found to be mainly expressed in MO/MФ. At the same time, using flow cytometry, we also confirmed that MOSPD2 protein is located on MO/MФ, neutrophil, and lymphocyte membranes. Following treatment with LPS or A. hydrophila, MOSPD2 protein expression was induced in these immune cells. The migration of MO/MФ and neutrophils decreased significantly upon MOSPD2 blockade with anti-MOSPD2 IgG in a dose-dependent manner, whereas this treatment had no significant effect on lymphocytes migration. To the best of our knowledge, our study, for the first time, provides evidence that MOSPD2 mediates the migration of MO/MФ and neutrophils in a fish species.

High glucose reduces expression of podocin in cultured human podocytes by stimulating TRPC6.

The transient receptor potential canonical 6 (TRPC6) channel and podocin are colocalized in the glomerular slit diaphragm as an important complex to maintain podocyte function. Gain of TRPC6 function and loss of podocin function induce podocyte injury. We have previously shown that high glucose induces apoptosis of podocytes by activating TRPC6; however, whether the activated TRPC6 can alter podocin expression remains unknown. Western blot analysis and confocal microscopy were used to examine both expression levels of TRPC6, podocin, and nephrin and morphological changes of podocytes in response to high glucose. High glucose increased the expression of TRPC6 but reduced the expression of podocin and nephrin, in both cultured human podocytes and type 1 diabetic rat kidneys. The decreased podocin was diminished in TRPC6 knockdown podocytes. High glucose elevated intracellular Ca2+ in control podocytes but not in TRPC6 knockdown podocytes. High glucose also elevated the expression of a tight junction protein, zonula occludens-1, and induced the redistribution of zonula occludens-1 and loss of podocyte processes. These data together suggest that high glucose reduces protein levels of podocin by activating TRPC6 and induces morphological changes of cultured podocytes.

Tretinoin enhances minoxidil response in androgenetic alopecia patients by upregulating follicular sulfotransferase enzymes.

Minoxidil sulfate is the active metabolite required to exert the vasodilatory and hair growing effects of minoxidil. For hair growth, sulfotransferase enzymes expressed in outer root sheath of the hair follicle sulfonate minoxidil. The large intra-subject variability in follicular sulfotransferase was found to predict minoxidil response and thus explain the low response rate to topical minoxidil in the treatment of androgenetic alopecia. A method to increase minoxidil response would be of significant clinical utility. Retinoids have been reported to increase minoxidil response. The purported mechanism of action was retinoid modulation of skin permeation to minoxidil; however, evidence to the contrary supports retinoids increase dermal thickness. In order to elucidate the effect of topical retinoids on minoxidil response, we studied the effect of topical tretinoin on follicular sulfotransferase. In this study, we demonstrate that topical tretinoin application influences the expression of follicular sulfotransferase. Of clinical significance, in our cohort, 43% of subjects initially predicted to be nonresponders to minoxidil were converted to responders following 5 days of topical tretinoin application. To the best of our knowledge, this is the first study to elucidate the interaction mechanism between topical minoxidil and retinoids and thus provides a pathway for the development of future androgenetic alopecia treatments.