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Understanding charge transport in metal ion-mediated glutathione-stabilized gold nanoclusters (GSH-Au NCs) has proved difficult due to the presence of various competitive mechanisms, such as electron transfer (ET) and aggregation induction effect (AIE). In this paper, we present a dual-channel fluorescence (FL) and second-order Rayleigh scattering (SRS) sensing method for high-throughput classification of metal ions, relying on the competition between ET and AIE using GSH-Au NCs. The SRS signals show significant enhancement when Pb 2+ , Ag + , Al 3+ , Cu 2+ , Fe 3+ , and Hg 2+ are present, as a result of the aggregation of GSH-Au NCs. Notably, the fluorescence signal exhibits the opposite trend. The FL intensities of GSH-Au NCs are enhanced by Pb 2+ , Ag + , and Al 3+ through the AIE mechanism, while they are quenched by Cu 2+ , Fe 3+ , and Hg 2+ , which is dominated by the ET mechanism. By employing principal component analysis and hierarchical cluster analysis, these signals are transformed into unique fingerprints and Euclidean distances, respectively, enabling successful distinction of six metal ions and their mixtures with a low detection limit of 30 nM. This new strategy has successfully addressed interference from impurities in the testing of real water samples, demonstrating its strong ability to detect multiple metal ions. Impressively, we have achieved molecular cryptosteganography, which involves encoding, storing, and concealing information by transforming the selective response of GSH-Au NCs to binary strings. This research is anticipated to advance utilization of nanomaterials in logic sensing and information safety, bridging the gap between molecular sensors and information systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The traditional preparation method of ratiometric probes faces challenges such as cumbersome preparation and low sensitivity. Thus, there is an urgent need to provide a simple method of preparing a highly sensitive ratiometric probe. Here, Eu 3+ -doped zinc-based organic framework (Eu/Zn-MOF) was prepared through hydrothermal method for the detection of tetracycline analogs (TCs). Under the same excitation conditions, the probe can simultaneously display valuable fluorescence and second-order scattering signals. The developed probe enabled specific identification and fast detection (1 min) of TCs, including tetracycline, oxytetracycline, doxycycline, and chlortetracycline. The linear detection ranges of tetracycline, oxytetracycline, doxycycline and chlortetracycline were respectively 100 nM - 200 μM, 100 nM - 200 μM, 98 nM - 195 μM, and 97 nM - 291 μM, and the corresponding detection limits were respectively 15.79 nM, 20.83 nM, 15.31 nM, and 28.30 nM. The developed sensor was successfully applied to detect TCs in real samples, and the recovery rate was from 92.54 % to 109.69 % and the relative standard deviation was from 0.04 % to 2.97 %. Moreover, the heterometallic Eu/Zn-MOF was designed as a ratiometric neuron for Boolean logic computing and information encryption based on the specific identification of TCs. As a proof of concept, molecular steganography was successfully employed to encode, store, and conceal information by transforming the specific identification patterns of Eu/Zn-MOF into binary strings. This study is anticipated to advance the application of metal-organic frameworks in logic detection and information security, and bridging the gap between molecular sensors and the realm of information., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

β-CATENIN is an evolutionarily conserved multifunctional molecule that maintains cell adhesion as a cell junction protein to safeguard the integrity of the mammalian blood-testes barrier, and also regulates cell proliferation and apoptosis as a key signaling molecule in the WNT/β-CATENIN signaling pathway. In the crustacean Eriocheir sinensis, Es-β-CATENIN has been shown to be involved in spermatogenesis, but the testes of E. sinensis have large and well-defined structural differences from those of mammals, and the impact of Es-β-CATENIN in them is still unknown. In the present study, we found that Es-β-CATENIN, Es-α-CATENIN and Es-ZO-1 interact differently in the testes of the crab compared to mammals. In addition, defective Es-β-CATENIN resulted in increased Es-α-CATENIN protein expression levels, distorted and deformed F-ACTIN, and disturbed localization of Es-α-CATENIN and Es-ZO-1, leading to loss of hemolymph-testes barrier integrity and impaired sperm release. In addition to this, we also performed the first molecular cloning and bioinformatics analysis of Es-AXIN in the WNT/β-CATENIN pathway to exclude the effect of the WNT/β-CATENIN pathway on the cytoskeleton. In conclusion, Es-β-CATENIN participates in maintaining the hemolymph-testes barrier in the spermatogenesis of E. sinensis., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Lead (Pb) is a developmental neurotoxin that can disrupt brain development and damage the brain regions responsible for executive function, behavioral regulation and fine motor control. Sodium para-aminosalicylic acid (PAS-Na) is a non-steroidal anti-inflammatory drug that can cross the blood-brain barrier. The purpose of this study was to examine the effects of juvenile rat Pb exposure on behavioral changes and brain inflammation, and the efficacy of PAS-Na in ameliorating these effects. The results showed that Pb exposure during the juvenile period (from weaning to adult period) delayed rats' growth development and impaired their motor learning. Pb exposure not only increased Pb concentrations in several brain regions (including hippocampus, striatum and substantia nigra), but also disrupted metal-homeostasis in the brain, as higher levels of iron (Fe) and calcium (Ca) were observed in the substantia nigra. Moreover, Pb activated the MAPK pathway and increased levels of inflammatory factors such as IL-1β, TNF-α and IL-6 in the hippocampus, striatum and substantia nigra. Furthermore, Pb increased the levels of alpha-synuclein (α-syn) in these brain sites. PAS-Na improved the motor deficits and brain inflammation in the Pb-exposed rats. Moreover, the elevated Pb, Fe and Ca concentrations in the brain were significantly reduced by PAS-Na, which contains amino, carboxyl and hydroxyl functional groups, suggesting that it may act as a chelator of brain metals. In addition, PAS-Na inhibited the Pb-induced MAPK pathway activation and α-syn accumulation in the same brain regions. Taken together, our novel study suggest that PAS-Na shows efficacy in improving the Pb-induced behavioral changes in rats by inhibiting MAPK-dependent inflammatory pathways and reducing α-syn accumulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Lead (Pb) is a naturally occurring heavy metal, which can damage the brain and affect learning and memory. Sodium para-aminosalicylic acid (PAS-Na), a non-steroidal anti-inflammatory drug, can readily cross the blood-brain barrier. Our previous studies have found that PAS-Na alleviated Pb-induced hippocampal ultrastructural damage and neurodegeneration, but the mechanism has yet to be defined. Here, we investigated the molecular mechanisms that mediate Pb-induced apoptosis in hippocampal neurons, and the efficacy of PAS-Na in alleviating its effects. This work showed that juvenile developmental Pb exposure impaired rats cognitive ability by inducing apoptotic cell death in hippocampal neurons. Pb-induced neuronal apoptosis was accompanied by increased inositol 1,4,5-trisphosphate receptor (IP 3 R) expression and enhanced intracellular calcium [Ca 2+ ] i levels, which resulted in increased phosphorylation of neuronal apoptosis signal-regulating kinase 1 (ASK1) and p38. Activation of ASK1 and p38 was blocked by IP 3 R inhibitor and a Ca 2+ chelator. Importantly, PAS-Na treatment improved the Pb-induced effects on cognitive deficits in rats, concomitant with rescued neuronal apoptosis. In addition, PAS-Na reduced the expression of IP 3 R and the ensuing increase in intracellular Ca 2+ and decreased the phosphorylation of ASK1 and p38 in Pb-exposed neurons. Taken together, this study demonstrates that the IP 3 R-Ca 2+ -ASK1-p38 signaling pathway mediates Pb-induced apoptosis in hippocampal neurons, and that PAS-Na, at a specific dose-range, ameliorates these changes. Collectively, this study sheds novel light on the cellular mechanisms that mediate PAS-Na efficacy, laying the groundwork for future research to examine the treatment potential of PAS-Na upon Pb poisoning., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Many dietary NASH models require a long duration to establish (4-6 months). Chronic intermittent hypoxia (CIH), a cardinal hallmark of obstructive sleep apnea (OSA), may accelerate the progression of pediatric nonalcoholic fatty liver disease (NAFLD). However, diet-induced obese (DIO) mice exposed to CIH have not been perceived as a fast or reliable tool in NASH research. This study was designed to establish a rapid juvenile murine NASH model, and determine whether the combination of CIH and a western-style diet (hypercaloric fatty diet plus high fructose) can fully display key pathologic features of NASH., Methods: C57BL/6 N mice (3 weeks old) fed a control diet or western diet (WD) were exposed to CIH (9% nadir of inspired oxygen levels) or room air for 6 and 12 weeks., Key Findings: The Control/CIH group mainly exhibited hyperinsulinemia and insulin resistance (IR). In contrast, mice fed a WD developed weight gain after 3 weeks, microvesicular steatosis in 6 weeks, and indices of metabolic disorders at 12 weeks. Furthermore, CIH exposure accelerated WD- induced macromicrovesicular steatosis (liver triglycerides and de novo lipogenesis), liver injury (ballooned hepatocytes and liver enzymes), lobular/portal inflammation (inflammatory cytokines and macrophage recruitment), and fibrogenesis (hydroxyproline content and TGF-β protein). Notably, only the WD/CIH group exhibited elevated hepatic MDA content, protein levels of NOX4, α-SMA and collagen I, as well as reduced Nrf2 and HO-1 protein expression., Significance: WD/CIH treatment rapidly mimics the histological characteristics of pediatric NASH with metabolic dysfunction and fibrosis, representing an appropriate experimental model for NASH research., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Human Carboxylesterase 2A (hCES2A), one of the most important serine hydrolases, plays crucial roles in the hydrolysis and the metabolic activation of a wide range of esters and amides. Increasing evidence has indicated that potent inhibition on intestinal hCES2A may reduce the excessive accumulation of SN-38 (the hydrolytic metabolite of irinotecan with potent cytotoxicity) in the intestinal tract and thereby alleviate the intestinal toxicity triggered by irinotecan. In this study, more than sixty natural alkaloids have been collected and their inhibitory effects against hCES2A are assayed using a fluorescence-based biochemical assay. Following preliminary screening, seventeen alkaloids are found with strong to moderate hCES2A inhibition activity. Primary structure-activity relationships (SAR) analysis of natural isoquinoline alkaloids reveal that the benzo-1,3-dioxole group and the aromatic pyridine structure are beneficial for hCES2A inhibition. Further investigations demonstrate that a steroidal alkaloid reserpine exhibits strong hCES2A inhibition activity (IC 50  = 0.94 μM) and high selectivity over other human serine hydrolases including hCES1A, dipeptidyl peptidase IV (DPP-IV), butyrylcholinesterase (BChE) and thrombin. Inhibition kinetic analyses demonstrated that reserpine acts as a non-competitive inhibitor against hCES2A-mediated FD hydrolysis. Molecular docking simulations demonstrated that the potent inhibition of hCES2A by reserpine could partially be attributed to its strong σ-π and S-π interactions between reserpine and hCES2A. Collectively, our findings suggest that reserpine is a potent and highly selective inhibitor of hCES2A, which can be served as a promising lead compound for the development of more efficacious and selective alkaloids-type hCES2A inhibitors for biomedical applications., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Chronic intermittent hypoxia (CIH) is a consequence of obstructive sleep apnea (OSA), which increases reactive oxygen species (ROS) generation, resulting in oxidative damage and neurocognitive impairment. This study was designed to determine whether abnormal iron metabolism occurs in the brain under conditions of CIH and whether Huperzine A (HuA) could improve abnormal iron metabolism and neurological damage. The mouse model of CIH was established by reducing the percentage of inspired O 2 (FiO 2 ) from 21% to 9% 20 times/h for 8 h/day, and Huperzine A (HuA, 0.1 mg/kg, i.p.) was administered during CIH exposure for 21 days. HuA significantly improved cognitive impairment and neuronal damage in the hippocampus of CIH mice via increasing the ratio of Bcl-2/Bax and inhibiting caspase-3 cleavage. HuA considerably decreased ROS levels by downregulating the high levels of NADPH oxidase (NOX 2, NOX 4) mediated by CIH. There was an overload of iron, which was characterized by high levels of ferritin (FTL and FTH) and transferrin receptor 1 (TfR1) and low levels of ferroportin 1 (FPN1) in the hippocampus of CIH mice. Decreased levels of TfR1 and FTL proteins observed in HuA treated CIH group, could reduce iron overload in hippocampus. HuA increased PSD 95 protein expression, CREB activation and BDNF protein expression to protect against synaptic plasticity impairment induced by CIH. HuA acts as an effective iron chelator to attenuate apoptosis, oxidative stress and synaptic plasticity mediated by CIH., Competing Interests: Declaration of competing interest The authors declare no conflict of financial interest or benefit., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Menstrual disorders are common diseases among reproductive-aged women with increasing concerns. Until now, there have been limited studies about the association between menstrual disorders and air pollution. This study aimed to investigate the association between short-term (concurrent day and within 1 week prior) ambient air pollution exposure and menstrual disorder outpatient visits in Xi'an, a metropolis in northwestern China. Daily baseline outpatient data of menstrual disorders from January 1, 2010 to February 18, 2016 (2239 days) were obtained. An over-dispersed Poisson generalized additive model was applied to discover the relationship between short-term air pollution exposure and the number of menstrual disorder outpatient visits by adjusting the day of the week and weather conditions. A total of 51,893 outpatient visits for menstrual disorders were recorded. A 10 μg/m 3 increase of PM 10 and NO 2 concentrations corresponded to 0.236% (95% Cl: 0.075%, 0.397%) and 2.173% (95% Cl: 0.990%, 3.357%) elevations in outpatient-visits for menstrual disorders at lag 7 and lag 01 (concurrent day and previous 1 day), respectively. The association was more significant in young females (18-29 years) and there was no obvious association observed between SO 2 and menstrual disorder outpatient visits. This is the first evidence that short-term exposure to ambient air pollution can be associated with an increased risk of menstrual disorder attacks. The results of our study may help to establish more comprehensive understanding of the health effects of ambient air pollution on menstrual disorders and other reproductive diseases., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The prominent feature of obstructive sleep apnea (OSA) is chronic intermittent hypoxia (CIH). Given the strong antioxidant ability of resveratrol against oxidative stress, we evaluated the potential protective effects of resveratrol on myocardial injury induced by CIH. Twenty-four rats were divided into normal control group, CIH group, CIH plus resveratrol treated (CIH + Res) group, and resveratrol treated control (Res) group. We proved that CIH impaired cardiac structure and function with an increase in oxidative stress, endoplasmic reticulum (ER) stress and NOD-like receptors (NLRP3) inflammasome induction in heart, which was attenuated after resveratrol administration. NLRP3 inflammasome blockade by resveratrol appeared to be mediated by activating AMP-activated Protein Kinase (AMPK), which could restrain mTOR/TTP/NLRP3 mRNA signalling. Furthermore, resveratrol attenuated CIH-induced oxidative stress through elevation antioxidant molecules expression via NF-E2-related factor-2 (Nrf2). Moreover, AMPK may play a role in Nrf2/HO-1 signalling by resveratrol. These results expand our understanding of the myocardial protective mechanism of resveratrol during CIH and suggest that resveratrol treatment may be useful to counteract OSA-associated cardiac injury., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: Resveratrol is a polyphenolic compound that has received much attention for its use in ameliorating various systemic pathological conditions. The present study was performed to investigate whether the resveratrol alleviated cardiac hypertrophy and functional remodelling by regulating autophagy., Materials and Methods: Male rats were exposed to CIH 8 h/day for five weeks and/or intragastric administration of resveratrol daily. The morphological and echocardiography were used to evaluate the cardiac protective effects. The apoptosis was detected by TUNEL staining. The biochemical assessments were used to evaluate oxidative stress. Further, the effect of resveratrol on autophagy and PI3K/AKT/mTOR pathway was investigated., Key Findings: The CIH group exhibited increased heart weight/body weight and left ventricle weight/body weight ratios, which was accompanied by left ventricular remodelling. Echocardiography analysis showed that CIH-treated rats had significantly higher left ventricular posterior wall thickness, ejection fraction and fractional shortening than those of controls. In addition, the apoptosis index and oxidative markers were significantly elevated in the CIH group versus the control. The autophagy marker Beclin-1 was elevated, while p62 was decreased by CIH treatment. Resveratrol treatment significantly improved cardiac function and alleviated cardiac hypertrophy, oxidative stress, and apoptosis in CIH rats. Further results indicated that PI3K/AKT pathway-mediated inhibition of the mammalian target of rapamycin (mTOR) pathway played a role in the activation of autophagy by resveratrol after CIH stimulation., Significance: In conclusion, resveratrol supplementation during CIH upregulates autophagy by targeting the PI3K/AKT/mTOR pathway, which appears to be beneficial for resisting cardiac hypertrophy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: Hydrogen gas (H 2 ) has a diversity of effects such as anti-apoptotic, anti-inflammatory and anti-oxidative properties. However, molecular mechanism underlying the potential effect of H 2 on chronic intermittent hypoxia (CIH) induced renal injury remains obscure., Materials and Methods: In the present study, adult male Sprague-Dawley rats were randomly allocated into four groups: control (CON) group, CIH group, CIH with H 2 treatment (CIH + H 2 ) group, and control with H 2 treatment (CON + H 2 ) group. Oxidative stress, autophagy and endoplasmic reticulum (ER) stress were detected to determine how H 2 affected the renal function of CIH exposed rats., Key Findings: We demonstrated that rats who inhale hydrogen gas showed improved renal function, alleviated pathological damage, oxidative stress and apoptosis in CIH rats. Meanwhile, CIH-induced endoplasmic reticulum stress was decreased by H 2 as the expressions of CHOP, caspase-12, and GRP78 were down-regulated. Furthermore, relative higher levels of LC3-II/I ratio and Beclin-1, with decreased expression of p62, were found after H 2 administrated. Inhibition of mTOR may be involved in the upregulation of autophagy by H 2 . Finally, increased phosphorylation of p38 and JNK was involved in the CIH-induced pathological process. H 2 could inhibit the activation of p38 and JNK, suggesting H 2 played an active part in resisting renal injury via MAPK., Significance: Taken together, our study reveals that H 2 can ameliorate CIH-induced kidney injury by decreasing endoplasmic reticulum stress and activating autophagy through inhibiting oxidative stress-dependent p38 and JNK MAPK activation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Lumbar disc herniation is a common cause of radicular pain, but the mechanism remains ambiguous and the treatment stays unsatisfied. Many studies revealed a traditional Chinese medicine puerarin may moderate chronic pain from diabetes and nerve injury. Thus far, the role and mechanism of puerarin in radicular pain is still unknown. In this study, by using a rat model of lumbar disc herniation, which was induced by autologous nucleus pulposus (NP) implantation, the analgesic effect of puerarin on radicular pain was tested. Puerarin was delivered intraperitoneally form 1 h before surgery, and once daily for 7 days. The results demonstrated that NP implantation induced long-lasting pain, characterized by decrease of paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in ipsilateral hindpaws, as long as day 20 after surgery. Spinal phosphorylated extracellular signal-regulated kinase (p-ERK) was up-regulated from day 5 to day 20 after surgery in ipsilateral but not contralateral side, and p-ERK was mainly co-localized with microglia. Puerarin decreased p-ERK expression from day 7 to day 20 after surgery. Puerarin or ERK inhibitor PD98059 alleviated pain behaviors, decreased expression of microglia marker ionized calcium-binding adaptor molecule 1 (Iba-1) in rats with NP implantation. The results suggested puerarin may alleviate radicular pain by inhibiting ERK-dependent or accompanied spinal microglia activation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Epidemiological and experimental studies have correlated hyperhomocysteinemia to a range of neurodegenerative conditions, including Alzheimer's disease, stroke, and Parkinson's disease. Although homocysteine-induced apoptosis in neurons has been extensively studied, little information is available regarding the effect of homocysteine on microglia. In this report, we demonstrated that homocysteine promoted proliferation and up-regulated the expression of CD11b (a marker of microglial activation). Consistent with our in vitro results, a significant increase in the number of CD11b-positive microglia was also observed in brain sections of mice with hyperhomocysteinemia. Homocysteine promoted the activity of NAD(P)H oxidases, resulting in the generation of reactive oxygen species. Up-regulation of NAD(P)H oxidase activity by homocysteine appears to be due to its ability to induce the phosphorylation of p47phox through the p38 MAPK pathway. Furthermore, inhibition of reactive oxygen species significantly blocked cellular proliferation and activation in microglia. Since microglial proliferation and activation play an important role in the development of several neurodegenerative disorders, our results reveal a novel role of homocysteine in the pathogenesis of neurodegenerative diseases., (Copyright © 2008 Elsevier Inc. All rights reserved.)

Elevated homocysteine levels are defined as hyperhomocysteinemia (HHcy), a disorder that is associated with cardiovascular and neurodegenerative diseases as well as with hepatic fibrosis. Recent studies have shown that HHcy promotes hepatic injury by increasing oxidative stress. Although homocysteine induces cell cycle arrest in a variety of different cell types, it is not known whether HHcy has a definitive role in hepatocyte proliferation during liver regeneration. In this report, we investigated the effect of homocysteine on liver regeneration. Our results demonstrated that mice with HHcy exhibited an impairment in liver regeneration after partial hepatectomy, as measured by immunohistochemical staining of proliferation cell nuclear antigen and bromodeoxyuridine incorporation. Impaired proliferation was also correlated with reduced cyclin D1 induction and elevated expression levels of both p53 and p21Cip1. In addition, the phosphorylation of Akt, which plays an essential role in normal regeneration responses, was attenuated during the early phases of liver regeneration in HHcy mice. Our results also indicated that the cAMP/protein kinase A pathway mediated the inhibitory effect of homocysteine on liver regeneration. These findings provide evidence that impairment of liver regeneration by HHcy may result in delayed recovery from liver injury induced by homocysteine itself.

This paper deals with the influencing factors on removal of chlorobenzene from unsaturated soils by soil vapor extraction (SVE) method. A series of one-dimensional column experiments were conducted to study the influencing factors for SVE method, the factors included extracted vapor flow rate, soil grain size, extraction mode, soil organic matter content and water content. The results indicated that: (1) the increase of vapor flow rate led to higher contaminant removal efficiency, but the increment of removal was not significant at higher flow rate levels; (2) soil grain sizes had a great impact on chlorobenzene removal efficiency, the coarser the sand, the higher the removal rate; (3) pulsed vapor extraction and continuous vapor extraction almost had the same contaminant removal effects in the sand column; (4) the higher organic content in the soil could decrease the removal efficiency; (5) water content in the soil had different impact on the contaminant removal efficiency which related with the organic content in the soil., (2009 Elsevier B.V. All rights reserved.)

Background: We determined if endogenous cortisol 6 beta-hydroxylation clearance [CL(m(6 beta))] could be used as a reliable index for in vivo CYP3A phenotyping (including both hepatic and intestinal CYP3A activities)., Methods: In this study, 16 healthy volunteers received a single 7.5 mg oral dose of midazolam (MDZ). Blood samples were drawn up to 24 h after dosing. Urine samples were collected at various time periods after dosing. MDZ, 1-hydroxymidazolam (1-OHMDZ), cortisol (F) and 6 beta-hydroxycortisol (6 beta-OHF) in plasma or urine were determined by high-performance liquid chromatography with ultraviolet absorbance detection (HPLC-UV)., Results: CL(m(6 beta)) was poorly correlated (P>0.2) with MDZ oral clearance [CL(oral(MDZ))] and the ratio of AUC(0-infinity(1-OHMDZ)) versus AUC(0-infinity(MDZ)) [MR((AUC))]. However, when examining the data obtained from male volunteers exclusively, strong correlations were observed between CL(m(6 beta)) and CL(oral(MDZ)). Larger interindividual and intraindividual variabilities were observed in urinary ratio of 6 beta-OHF/F compared with CL(m(6 beta))., Conclusion: CL(m(6 beta)) cannot reflect the overall CYP3A activity accurately and quantitatively in the population.

Background: Embryonic stem (ES) cell-derived cardiomyocytes transplantation and tissue engineering together represent a promising approach for the treatment of myocardial infarction, despite the limited supply of cardiac myocytes. This study examines whether functional cardiomyocytes can be efficiently enriched from mouse embryonic stem (mES) cells., Methods: mES cells were induced by ascorbic acid to differentiate into cardiomyocytes. Beating cells were observed after 1 week and increased in number with time while under differentiation conditions. Furthermore, the differentiated cultures could be dissociated and enriched by Percoll gradient density centrifugation., Results: The beating cells expressed markers characteristic of cardiomyocytes, such as cardiac troponin T (cTnT). The enriched population contained 88.7% cardiomyocytes and showed expression of cardiomyocyte markers of troponin T and cardiac genes, including alpha-MHC, beta-MHC, ANF and Nkx2.5. However, Oct-4, a marker of early-stage ES cells, was not expressed in the mES cell-derived cardiac cell clusters. Moreover, the mES cell-derived and Percoll-enriched cardiomyocytes responded appropriately to cardioactive drugs, as did normal neonatal rat cardiomyocytes., Conclusions: mES cell-derived functional cardiomyocytes can be enriched by the method of discontinuous Percoll gradient centrifugation. The ability to differentiate and enrich for functional mouse cardiomyocytes makes it possible for further development of these cells as a model of myocardial repair through cell transplantation or tissue engineering.

We describe the synthesis of 3-oxo-4-aza-5alpha-androst-1-ene-17beta-(N-tert-butylcarboxamide) (finasteride) from 4-androstene-3,17-dione (AD) in seven steps in an overall yield of 18.6% via oxidation, ammoniumation, dehydration, and dehydrogenation.

Background: Cardiac tissue engineering aims to construct cardiac tissue with characteristics similar to those of the native tissue. Engineered cardiac tissues (ECTs) can be constructed using synthetic scaffold or liquid collagen. We report an initial study using our own newly designed cardiac muscle device to construct heart tissue. We investigated the effects of cell seeding density and collagen quantity on the formation of liquid collagen-based cardiac muscle., Methods: We obtained cardiac myocytes from neonatal rats mixed with collagen type I and matrix factors cast in circular molds to form circular strands. Cell densities (0.1 x 10(7) to 6 x 10(7)) and collagen quantity (0.3 to 1.0 ml/ECT) were tested. Cell gross morphology, cell orientation, spatial distribution and ultrastructure were evaluated using histologic analyses, confocal laser scanning microscopy and transmission electron microscopy., Results: Histologic analyses of ECTs revealed that cardiac cells reconstituted longitudinally oriented, cardiac bundles with morphologic features characteristic of the native tissue. Confocal and electron microscopy demonstrated that, using optimized cell density and collagen quantity, we made ECTs with characteristic features similar to those of native differentiated myocardium., Conclusions: ECTs comparable to native cardiac tissue can be engineered under optimized conditions. This construct is a first step in the development of cardiac tissue engineered in vitro, and may be used as a basis for studies of cardiac development, drug testing and tissue replacement therapy.