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There are many reports that, through pre- and post-junctional mechanisms, sympathetic and parasympathetic (vagal) nerves can interact in the control of heart rate. The predominant interaction is accentuated antagonism (AA), where the bradycardia produced by vagal stimulation (VNS) is amplified when heart rate has been increased by sympathetic stimulation (SNS) or beta-adrenergic agonists. The acetylcholine-activated potassium current (I

Stress leaves a lasting impression on an organism and reshapes future responses. However, the influence of past experience and stress hormones on the activity of neural stress circuits remains unclear. Hypothalamic corticotropin-releasing hormone (CRH) neurons orchestrate behavioral and endocrine responses to stress and are themselves highly sensitive to corticosteroid (CORT) stress hormones. Here, using in vivo optical recordings, we find that CRH neurons are rapidly activated in response to stress. CRH neuron activity robustly habituates to repeated presentations of the same, but not novel stressors. CORT feedback has little effect on CRH neuron responses to acute stress, or on habituation to repeated stressors. Rather, CORT preferentially inhibits tonic CRH neuron activity in the absence of stress stimuli. These findings reveal how stress experience and stress hormones modulate distinct components of CRH neuronal activity to mediate stress-induced adaptations., Stress activates corticotropin-releasing hormone (CRH) neurons in the hypothalamus, but how their activity is regulated during and after stress is unclear. Here, the authors show that stress habituation and corticosteroid feedback tune different components of CRH neuron activity.

The sense of vision is the primary means by which we gather information from our surroundings, and vision loss, therefore, severely compromises the life of the affected individuals, their families, and society. Loss of vision becomes more frequent with age, and diabetic retinopathy, age-related macular degeneration, cataracts, and glaucoma are the major causes of vision impairment. To find active pharmacological compounds that might prevent or ameliorate the vision-threatening eye diseases, numerous studies have been performed, and some botanical compounds, including those extracted from ginseng, have been shown to possess beneficial effects in the treatment or prevention of common ocular diseases. In this review, we summarize the recent reports investigating the therapeutic effects of ginseng and ginsenosides on diverse ocular diseases and discuss their therapeutic potential. Keywords: Age-related macular degeneration, Cataract, Diabetic retinopathy, Ginseng, Glaucoma

Developments in optical imaging and optogenetics are transforming the functional investigation of neuronal networks throughout the brain. Recent studies in the neuroendocrine field have used genetic mouse models combined with a variety of light-activated optical tools as well as GCaMP calcium imaging to interrogate the neural circuitry controlling hormone secretion. The present review highlights the benefits and caveats of these approaches for undertaking both acute brain slice and functional studies in vivo. We focus on the use of channelrhodopsin and the inhibitory optogenetic tools, archaerhodopsin and halorhodopsin, in addition to GCaMP imaging of individual cells in vitro and neural populations in vivo using fiber photometry. We also address issues around the use of genetic vs viral delivery of encoded proteins to specific Cre-expressing cell populations, their quantification, and the use of conscious vs anesthetized animal models. To date, optogenetics and GCaMP imaging have proven useful in dissecting functional circuitry within the brain and are likely to become essential investigative tools for deciphering the different neural networks controlling hormone secretion.

The synthesis of a one-dimensional (1D) array of cobalt disulfide (CoS2) integrated on carbon fiber paper (CFP) was used to prepare an efficient CoS2 electrocatalyst for the hydrogen evolution reaction (HER). The combination of benefits from the unique nano-pine-tree morphology of CoS2 and interwoven carbon network in the CFP offers high electrocatalytic activity and durability, which make this newly nanostructured catalyst suitable as an alternative to platinum (Pt). We also demonstrated the generalization of this synthesis approach to various metal disulfide arrays, which make it of interest in nanoarchitecture.

The gonadotrophin-releasing hormone (GnRH) pulse generator drives pulsatile luteinizing hormone (LH) secretion essential for fertility. However, the constraints within which the pulse generator operates to drive efficient LH pulsatility remain unclear. We used optogenetic activation of the arcuate nucleus kisspeptin neurons, recently identified as the GnRH pulse generator, to assess the efficiency of different pulse generator frequencies in driving pulsatile LH secretion in intact freely behaving male mice. Activating the pulse generator at 45-minute intervals generated LH pulses similar to those observed in intact male mice while 9-minute interval stimulation generated LH profiles indistinguishable from gonadectomized (GDX) male mice. However, more frequent activation of the pulse generator resulted in disordered LH secretion. Optogenetic experiments directly activating the distal projections of the GnRH neuron gave the exact same results, indicating the pituitary to be the locus of the high frequency decoding. To evaluate the state-dependent behavior of the pulse generator, the effects of high-frequency activation of the arcuate kisspeptin neurons were compared in GDX and intact mice. The same stimulus resulted in an overall inhibition of LH release in GDX mice but stimulation in intact males. These studies demonstrate that the GnRH pulse generator is the primary determinant of LH pulse profile and that a nonlinear relationship exists between pulse generator frequency and LH pulse frequency. This may underlie the ability of stimulatory inputs to the pulse generator to have opposite effects on LH secretion in intact and GDX animals.

Breast cancer type 1 susceptibility protein (BRCA1) is a tumor suppressor gene that encodes a nuclear phosphoprotein, which is involved in homologous recombination to repair DNA double strand breaks and maintain genome stability. When BRCA1 is mutated or altered, DNA damage may not be effectively repaired, which leads to DNA replication errors and cancer growth. Accordingly, people carrying a mutation in the BRCA1 gene possess an increased risk of several types of cancer, including breast and ovarian cancer. Previous clinical studies have reported an association between BRCA1 expression level and the incidence of gastric cancer; however, to the best of our knowledge, an in vitro study has not been performed to support these clinical observations. Therefore, the present study evaluated BRCA1 expression levels in gastric cancer cell lines. In addition, the IC50 values of cisplatin and oxaliplatin in each cell line were determined to investigate a potential correlation between BRCA1 expression level and chemosensitivity to platinum agents. The present results revealed that the BRCA1 expression level in gastric cancer is variable and associated with the treatment response to platinum-based chemotherapy. This suggests that BRCA1 may serve as a therapeutic marker for platinum-based chemotherapy in gastric cancer.

A subpopulation of kisspeptin neurons located in the arcuate nucleus (ARN) operate as the GnRH pulse generator. The activity of this population of neurons can be monitored in real-time for long periods using kisspeptin neuron-selective GCaMP6 fiber photometry. Using this approach, we find that ARN kisspeptin neurons exhibit brief (∼50 seconds) periods of synchronized activity that precede pulses of LH in intact female mice. The dynamics and frequency of these synchronization episodes (SEs) are stable at approximately one event every 40 minutes throughout metestrus, diestrus, and proestrus, but slow considerably on estrus to occur approximately once every 10 hours. Evaluation of ARN kisspeptin neuron activity across the light-dark transition, including the time of onset of the proestrus LH surge, revealed no changes in SE frequency. Longer 24-hour recordings across proestrus into estrus demonstrated that an abrupt decrease in SEs occurred ∼4 to 5 hours after the onset of the LH surge to reach the low frequency of SEs observed on estrus. The frequency of SEs was stable across the 24-hour period from metestrus to diestrus. Administration of progesterone to diestrus mice resulted in the abrupt slowing of SEs. These observations show that the GnRH pulse generator exhibits an unvarying pattern of activity from metestrus through to the late evening of proestrus, at which time it slows dramatically, likely in response to postovulation progesterone secretion. The GnRH pulse generator maintains a constant frequency of activity across the time of the LH surge, demonstrating that it is not involved directly in surge generation.

In this paper, a new wavelet based image interpolation algorithm using pixel-by-pixel (PBP) cubic image interpolation and hybrid filter is proposed for images which include many mid and high frequency elements. There is much important information in frequency bands. Because conventional interpolation techniques have blurring or blocking effects, the quality of interpolated remote sensing images is not good over that of standard test images. The proposed interpolation technique uses PBP, DWT and hybrid filter to address these problems preserving thin lines and edges information. Simulation result shows that the proposed technique outperforms the conventional techniques in terms of PSNR.

Kisspeptin neurons located in the hypothalamic arcuate nucleus are thought to represent the GnRH pulse generator responsible for driving pulsatile LH secretion. The recent development of GCaMP6 fiber photometry technology has made it possible to perform long-term recordings of the population activity of the arcuate nucleus kisspeptin (ARNKISS) neurons in conscious-behaving mice. Using this approach, we show that ARNKISS neurons in intact male mice exhibit episodes of synchronized activity that last ∼2 minutes and have a mean inter-episode interval of 166 minutes, with a very wide range (43 to 347 minutes). Gonadectomy resulted in dramatic changes in the dynamics of ARNKISS neuron behavior with temporally distinct alterations in synchronization episode (SE) amplitude (sevenfold increase), inter-SE frequency (range, 2 to 58 minutes), and duration (up to 28 minutes), including the frequent appearance of seemingly unstable clusters of doublet and triplet SEs. The combination of photometry with repeated blood sampling revealed a perfect correlation between ARNKISS neuron population SEs and LH pulses in intact and short-term gonadectomized (GDX) mice. No differences were detected in SE frequency across 24 hours in either intact or GDX mice. These observations further support a role for ARNKISS neurons as the GnRH pulse generator and show that it operates in a stochastic manner without diurnal variation in both intact and GDX male mice. The removal of gonadal steroids has multiple time-dependent effects upon ARNKISS neuron synchronizations, indicating their critical role in shaping pulse generator behavior.

The pulsatile release of luteinizing hormone (LH) is critical for mammalian fertility. However, despite several decades of investigation, the identity of the neuronal network generating pulsatile reproductive hormone secretion remains unproven. We use here a variety of optogenetic approaches in freely behaving mice to evaluate the role of the arcuate nucleus kisspeptin (ARNKISS) neurons in LH pulse generation. Using GCaMP6 fiber photometry, we find that the ARNKISS neuron population exhibits brief (∼1 min) synchronized episodes of calcium activity occurring as frequently as every 9 min in gonadectomized mice. These ARNKISS population events were found to be near-perfectly correlated with pulsatile LH secretion. The selective optogenetic activation of ARNKISS neurons for 1 min generated pulses of LH in freely behaving mice, whereas inhibition with archaerhodopsin for 30 min suppressed LH pulsatility. Experiments aimed at resetting the activity of the ARNKISS neuron population with halorhodopsin were found to reset ongoing LH pulsatility. These observations indicate the ARNKISS neurons as the long-elusive hypothalamic pulse generator driving fertility.

Heart rate slowing produced by cardiac parasympathetic (vagal) stimulation is thought to be the result of modulation of the acetylcholine-activated K(+) current (IK,ACh) and the pacemaker current (If) in sinoatrial (SAN) pacemaker cells. However, the contribution of these and other ion currents to vagal slowing is controversial. Here, we examined the contributions of IK,ACh and If to vagal slowing in 15 isolated, vagal-innervated preparations of guinea-pig atria, using 300 nM tertiapin-Q (TQ) and 2 μM ZD7288 to obtain full and substantial block of these currents, respectively. Blocking IK,ACh alone reduced atrial rate responses to 10-s trains of regular vagal stimulation (supramaximal stimulation, 2-ms duration, 1-10 Hz) by ~50% (P

The popularization of smart devices and SNS as a new communication way promotes positive changes such as the user’s participation in the communication with others and the knowledge sharing. Meanwhile, it also facilitates negative social problems such as the formation of unexpected social relations, the intrusion of privacy, the cyber violence and the polarization of communication. These negative changes go toward a new viewpoint that the excessive SNS use may cause the SNS user’s fatigue. The purpose of this study is to invest how the SNS use motives and use patterns influence on the SNS user’s fatigue and ambivalent attitude. Therefore this study intended to develop a model about the SNS user’s social stress and ambivalent attitude influencing on the continual SNS use, and will empirically research this model in future studies.

In this paper, a new watermark algorithm that based on wavelet packet transform and hybrid filter is proposed for watermark of digital images, which include many high frequency components. The proposed watermark algorithm is used in the high frequency component of image and applies watermark to the overall subband that include the lowest frequency band. And the watermark is embedded on input image and hybrid filtering concept has been adopted to remove the noise that was added to the original image in watermark embedding stage. The quality of the watermarked image has been analyzed with PSNR. From the simulation results, the proposed algorithm shows better invisibility and robustness performance compare with conventional watermark methods. Especially, it demonstrates better robustness for high image compression in the remote sensing images application.

Hypothalamic magnocellular neurons secrete vasopressin into the systemic circulation to maintain blood pressure by increasing renal water reabsorption and by vasoconstriction. When blood pressure rises, baroreflex activation normally inhibits vasopressin neurons via activation of GABAergic inputs. However, plasma vasopressin levels are paradoxically elevated in several models of hypertension and in some patients with essential hypertension, despite increased blood pressure. We have previously shown that vasopressin neuron activity is increased early in the development of moderate angiotensin II-dependent hypertension via blunted baroreflex inhibition of vasopressin neurons. Here, we show that antagonism of vasopressin-induced vasoconstriction slows the development of hypertension and that local administration of a GABAA receptor antagonist inhibits vasopressin neurons during, but not before, the onset of hypertension. Taken together, our data suggest that vasopressin exacerbates the increase in blood pressure evident early in the development hypertension and that blunted baroreflex inhibition of vasopressin neurons is underpinned by an excitatory shift in their response to endogenous GABA signalling. This article is protected by copyright. All rights reserved.

The purpose of this study is to examine the impact relation among the visitor satisfaction, it`s antecedents and the modification of images of Korea perceived by Chinese and Russian Tourists after their visits to Korea. According to the data analysis, the satisfaction of Russian tourists is higher than that of Chinese tourists within statistical significance. The result produced by structural equation model shows that the satisfaction of Chinese tourists is affected by destination attractiveness, public order, shopping, food and accommodations positively. Especially the public order and shopping of Korea are relative major attributes. In comparison, the satisfaction of Russian tourists is affected by only destination attractiveness, public order and food positively. Then again, the impact relation between overall satisfaction and the modification of images of Korea perceived by tourist visited Korea is affected positively within statistical significance.

The purposes of this study are (1) to examine the relationships among attitude on SNS use, subjective norm, perceived behavioral control, and SNS use, (2) to analyze effect of SNS use on bonding network and bridging network, (3) to consider moderating effect of the gender on the relationship between SNS use and Social network. We conducted a survey for 20-30`s SNS user. The results of analysis using the Structural Equation Model(SEM) represent that attitude on SNS use, subjective norm, and perceived behavioral control are significant determinants of the SNS use. SNS use affects bonding network and bridging network. An interesting result was observed that the gender had moderating effect on the relationship between SNS use and social network. Based on these results, we suggest theoretical and practical implications of this study.

Bisphenol A (BPA) is an estrogenic endocrine disrupter. However, depending on a way of treatment, the harmful effects of BPA have not been confirmed. Also, trans-generational effects of BPA on male reproduction are still controversial. Because the reabsorption of testicular fluid in the efferent ductules (ED) and initial segment (IS) is important for sperm maturation, the present study was designed to determine trans-generational effect of BPA administrated orally on expression of water transport-related molecules in the mouse ED and IS. Ethanol-dissolved BPA was diluted in water to be 100 ng (low), 10 μg (medium), and 1 mg/Ml water (high). BPA-containing water was provided for two generations. Expression of ion transporters and water channels in the ED and IS were measured by relative real-time PCR analysis. In the ED, BPA treatment caused expressional increases of carbonic anhydrase II, cystic fibrosis transmembrane regulator, Na(+)/K(+) ATPase α1 subunit, and aquaporin (AQP) 1. No change of Na(+)/H(+) exchange (NHE) 3 expression was detected. BPA treatment at medium dose resulted in an increase of AQP9 expression. In the IS, the highest expressional levels of all molecules tested were observed in medium-dose BPA treatment. Generally, high-dose BPA treatment resulted in a decrease or no change of gene expression. Fluctuation of NHE3 gene expression by BPA treatment at different concentrations was detected. These findings suggest that trans-generational exposure to BPA, even at low dose, could affect gene expression of water-transport related molecules. However, such effects of BPA would be differentially occurred in the ED and IS.

In this paper, a new edge-preserving wavelet based image interpolation algorithm using pixel-by-pixel image interpolation is proposed for images which include many high frequency elements. Because bilinear or bicubic interpolation approaches have blurring or blocking effects, the quality of interpolated remote sensing images is not good over that of standard test images in lines and edges. The proposed interpolation method uses pixel-by-pixel interpolation and DWT to address these problems preserving thin lines and edges information. The obtained result proves the superiority of the proposed technique.

A thermal reaction route that induces grain fracture instead of grain growth is devised and developed as a top-down approach to prepare nanostructured oxides from bulk solids. This novel synthesis approach, referred to as the sequential oxygen-nitrogen exchange (SONE) reaction, exploits the reversible anion exchange between oxygen and nitrogen in oxides that is driven by a simple two-step thermal treatment in ammonia and air. Internal stress developed by significant structural rearrangement via the formation of (oxy)nitride and the creation of oxygen vacancies and their subsequent combination into nanopores transforms bulk solid oxides into nanostructured oxides. The SONE reaction can be applicable to most transition metal oxides, and when utilized in a lithium-ion battery, the produced nanostructured materials are superior to their bulk counterparts and even comparable to those produced by conventional bottom-up approaches. Given its simplicity and scalability, this synthesis method could open a new avenue to the development of high-performance nanostructured electrode materials that can meet the industrial demand of cost-effectiveness for mass production.

1. In an isolated right atrial preparation, an increase in right atrial pressure (RAP) produces an increase in atrial rate. This rate response is larger and occurs faster when there is background vagal or muscarinic stimulation. 2. We hypothesized that in the latter situation, an increase in RAP antagonizes the effect of muscarinic stimulation through stretch inactivation of the mechanosensitive muscarinic potassium current I(K,ACh). 3. In two groups of bath-mounted right atria isolated from male Wistar rats (control n = 12; 300 nmol/L tertiapin-Q treated (to block I(K,ACh)) n = 10), we examined the change in atrial rate when RAP was raised from 2 to 8 mmHg; oxotremorine-M (oxo-M; from 10 to 500 nmol/L) was added to incrementally activate muscarinic receptors. 4. In both control and tertiapin-Q-treated groups, oxo-M reduced atrial rate, but its effect was less ( approximately 40-50%) in the latter group (P < 0.001). In control preparations, responses to an increase in RAP became progressively larger and quicker as the concentration of oxo-M was increased, whereas in tertiapin-Q treated preparations oxo-M did not affect either the amplitude or the speed of the response (P < 0.0001 for both). 5. The results support the hypothesis that atrial stretch antagonizes muscarinic slowing by its effect on I(K,ACh). We suggest that through this mechanism, parasympathetic control of heart rate may be modulated continuously by RAP.

Efficient and practical total synthesis of piceatannol via (E)-selective Wittig-Horner reaction is demonstrated with six steps in overall 40% yield from a commercially available, cheap starting material, 3,5-dihydroxybenzoic acid. Wittig-Horner reaction of diethyl phosphonate with aldehyde showed a superior (E)-selectivity compare to Wittig reaction using triphenylphosphine. We optimized the Wittig-Horner reaction condition by using NaH (6 equiv) in tetrahydrofuran (THF) at reflux 1 h to give 99% yield of single (E)-stilbene.

An efficient and practical total synthesis of benzo[b]furan natural product XH-14 is demonstrated in nine steps from vanillin. Introduction of iodide substituents in the reaction including optimization of the reaction sequences is essential for the successful synthesis of XH-14. Sonogashira coupling with iodobenzene, iodine-induced cyclization, Wittig reaction, and formylation are critical in the high-yield total synthesis of XH-14.

The present study identified the favorable conditions for isolation, enrichment and in vitro culture of highly purified, undifferentiated pig spermatogonial stem cell (SSC) lines that proliferate for long periods of time in culture. The colonies displayed morphology similar to miceSSC and were positive for markers of SSC (PGP9.5), proliferating germ cell (PigVASA), pre-meiotic germ cell (DAZL) and pluripotency (OCT4, SSEA-1, NANOG, and SOX2) based on immuno-cytochemistry and RT-PCR. The purity of these colonies was confirmed by negative expression of markers for sertoli cell (GATA4 and SOX9), peritubular myoid cell (-SMA), differentiating spermatogonial and germ cells (c-KIT). The colonies could be maintained with undifferentiated morphology for more than two months and passaged more than 8 times with doubling time between 6-7 days. Taken together, we conclude that pigSSC could be successfully isolated and cultured in vitro and they possess characteristics similar to miceSSC.

An efficient, practical and enantioselective total synthesis of (+)-decursinol, which has diverse range of biological properties including anti-cancer, anti-Helicobacter pylori, and strong antinociceptive activities, has been achieved in five steps with 41.4% overall yield from umbelliferone. The improved ring construction from coumarin to linear pyranocoumarin has been obtained through quinonemethide intermediate by using phenylboronic acid with propionic acid.

Normal reproductive functioning in mammals depends upon gonadotropin-releasing hormone (GnRH) neurons generating a pulsatile pattern of gonadotropin secretion. The neural mechanism underlying the episodic release of GnRH is not known, although recent studies have suggested that the kisspeptin neurons located in the arcuate nucleus (ARN) may be involved. In the present experiments we expressed channelrhodopsin (ChR2) in the ARN kisspeptin population to test directly whether synchronous activation of these neurons would generate pulsatile luteinizing hormone (LH) secretion in vivo. Characterization studies showed that this strategy targeted ChR2 to 70% of all ARN kisspeptin neurons and that, in vitro, these neurons were activated by 473-nm blue light with high fidelity up to 30 Hz. In vivo, the optogenetic activation of ARN kisspeptin neurons at 10 and 20 Hz evoked high amplitude, pulse-like increments in LH secretion in anesthetized male mice. Stimulation at 10 Hz for 2 min was sufficient to generate repetitive LH pulses. In diestrous female mice, only 20-Hz activation generated significant increments in LH secretion. In ovariectomized mice, 5-, 10-, and 20-Hz activation of ARN kisspeptin neurons were all found to evoke LH pulses. Part of the sex difference, but not the gonadal steroid dependence, resulted from differential pituitary sensitivity to GnRH. Experiments in kisspeptin receptor-null mice, showed that kisspeptin was the critical neuropeptide underlying the ability of ARN kisspeptin neurons to generate LH pulses. Together these data demonstrate that synchronized activation of the ARN kisspeptin neuronal population generates pulses of LH.

Popularized social network service and the routinized using SNS have recently increased positive change communication, participation with others and share of knowledge. Otherwise, it has promoted negative social. These negative social changes are seen in a new way that is due to overuse of SNS, causing fatigue. The purpose of this study is to investigate that how SNS use motivation and use pattern have effect on SNS fatigue and attitude ambivalence. So in this study, it develops user's social fatigue is affected SNS continuance intention and model of attitude ambivalence. It will be an empirical study in next study.

In this paper, a new digital image watermark algorithm using wavelet packet transform and hybrid filter is proposed for right protection. The proposed watermark algorithm applies watermark to the overall subband that include the lowest frequency band and uses hybrid filter to remove the noise that was added to the watermarked image. The hybrid filter consists of median filter and wiener filter. Simulation analyzes PSNR and similarity of the watermarked image to test the quality and robustness of the watermarked images. From the simulation results, the proposed algorithm shows better invisibility and robustness performance compare with conventional wavelet transform based watermarking methods.

Vasopressin secretion from the posterior pituitary gland is determined by action potential discharge of hypothalamic magnocellular neurosecretory cells. Vasopressin is a potent vasoconstrictor, but vasopressin levels are paradoxically elevated in some patients with established hypertension. To determine whether vasopressin neurons are excited in hypertension, extracellular single-unit recordings of vasopressin neurons from urethane-anaesthetized Cyp1a1-Ren2 rats with inducible angiotensin-dependent hypertension were made. The basal firing rate of vasopressin neurons was higher in hypertensive Cyp1a1-Ren2 rats than in non-hypertensive Cyp1a1-Ren2 rats. The increase in firing rate was specific to vasopressin neurons because oxytocin neuron firing rate was unaffected by the induction of hypertension. Intravenous injection of the α1-adrenoreceptor agonist, phenylephrine (2.5 μg/kg), transiently increased mean arterial blood pressure to cause a baroreflex-induced inhibition of heart rate and vasopressin neuron firing rate (by 52 ± 9%) in non-hypertensive rats. By contrast, intravenous phenylephrine did not inhibit vasopressin neurons in hypertensive rats, despite a similar increase in mean arterial blood pressure and inhibition of heart rate. Circulating angiotensin II can excite vasopressin neurons via activation of afferent inputs from the subfornical organ. However, the increase in vasopressin neuron firing rate and the loss of inhibition by intravenous phenylephrine were not blocked by intra-subfornical organ infusion of the angiotensin AT1 receptor antagonist, losartan. It can be concluded that increased vasopressin neuron activity at the onset of hypertension is driven, at least in part, by reduced baroreflex inhibition of vasopressin neurons and that this might exacerbate the increase in blood pressure at the onset of hypertension.

LPC analogues including natural and unnatural LPC, 3-L-2-PC, acetylated LPC and ethylene glycol derivative are prepared from D-mannitol using in convenient procedures by only changing the synthetic sequences, and their protective activities against cecal ligation and puncture (CLP)-induced severe sepsis are compared. The chirality at C2 position in LPC is found to be required as (S)-configuration for sepsis inhibition, comparing from the protection activity between LPC 6 and unnatural LPC 8. The hydroxyl functionality is also very important and required at C2 or C3 position as shown in the protection activities of ethylene glycol analogue 11 and 3-L-2-PC 9.

Hydroxylated (E)-stilbene natural products are widely present in nature and show a variety of biological activities including anti-inflamatory, antioxidative, lipid-lowering, radical scavenging, neuroprotection, anticarcinogenic and antiviral activities. (E)-3,3',4,5'-tetrahydroxystilbene (piceatannol, 1, Figure 1) was isolated from Rheum undulatum which has been widely used in China and Korea for the treatment of blood platelet aggregation. It was reported that 0.3 g of pure piceatannol was isolated from 1 kg of dry root of Rheum undulatum. The limited supply of piceatannol from nature has prevented the diverse characterization of its biological activities. Several syntheses of (E)-stilbene have been reported by using Wittig-Horner, Heck and Suzuki coupling reactions. However, the polyhydroxy (E)-stilbenes are difficult to prepare due to oxidizing sensitivity of the polyphenolic groups, and due to inherent difficulties of controlling trans-selectivity. We report herein the new total synthesis of piceatannol (1) in 6 steps from vanillin by using Sonogashira coupling reaction. Vanillin (2) in acetone at reflux with benzyl bromide and potassium carbonate produced 95% yield of benzylated vanillin 3 which was then reacted with trimethylsilyl diazomethane and n-buthyllithium in THF at −78 C to give ethynylbenzene 4 in 99% yield by Colvin rearrangement (Scheme 1). Sonogashira coupling of 4 with 1-iodo-3,5dimethoxybenzene by using PdCl2(PPh3)2/CuI/Et3N in DMF yielded 5 in 97% yield. Direct reduction of 5 to give (E)stilbene produced no reaction (entries 1-6) or afforded only (Z)-stilbene 7b in 80% yield by using Zn/HCl in acetonitrile (entry 7) as shown in Table 1. In order to produce (E)stilbene, 5 was reacted with bromine at −78 C and gave only the desired (E)-dibromostilbene 6 in 80% yield through the cyclic bromoniun intermediate (Scheme 2). Reductive debromination of 6 with Zn/KI/HCl in ethanol (entry 3) yielded 80% of (E)-stilbene 7a as shown in Table 2. However, LAH and n-BuLi (entries 4 and 6) in reductive debromination reaction produced only the acethylene 5 back, and t-BuLi (entry 5) gave the 1:1 mixture of 5 and 7a. Finally, dealkylation of 7a by BBr3 in methylene chloride gave piceatannol (1) in 50% yield. Polymethoxy aryl ether has been known to difficult for demethylation by using BBr3 or other reagents probably due to susceptibility for oxidation of polyphenolic substances.

Despite advances in our understanding concerning the pathology of hypertension, the mechanisms that underpin the origin of hypertension remain to be fully elucidated. This enigma is, at least in part, due to inherent limitations of various animal models of hypertension. Here, we show the genetically modified Cyp1a1-Ren2 rat model, in which the onset and severity of angiotensin II-dependent hypertension can be tightly controlled, as an effective model for investigating increased sympathetic drive for the onset of hypertension. Cyp1a1-Ren2 rats were surgically prepared with radiotelemetric transmitters for the continuous measurement of arterial blood pressure (ABP). ABP was recorded in freely moving rats that were fed with either normal rat chow or a diet containing indole-3-carbinol (0.225% w/w) for 7 days to induce hypertension. Structural morphology of and endothelial NO synthase (eNOS) protein expression in heart and/or vascular tissue were analyzed. Sympathetic tone was estimated using spectral analysis of heart rate variability. The progressive induction of hypertension over 7 days was matched with a parallel increase in sympathetic tone. By day 7 of hypertension, eNOS expression in the mesenteric artery was elevated. However, the elevated ABP, sympathetic tone, and eNOS had not elicited gross morphological remodeling of the heart or vasculature. Importantly, both the increase in sympathetic tone and overexpression of eNOS within the vasculature were reversed when ABP was returned to normal. We conclude that the Cyp1a1-Ren2 rat provides an effective model for investigating specific adverse and transient changes in central sympathetic modulation of arterial blood pressure during the early onset of angiotensin-dependent hypertension.