Regulation of Satiety by Bdnf-e2-Expressing Neurons through TrkB Activation in Ventromedial Hypothalamus.

The transcripts for Bdnf (brain-derived neurotrophic factor), driven by different promoters, are expressed in different brain regions to control different body functions. Specific promoter(s) that regulates energy balance remain unclear. We show that disruption of Bdnf promoters I and II but not IV and VI in mice (Bdnf-e1-/-, Bdnf-e2-/-) results in obesity. Whereas Bdnf-e1-/- exhibited impaired thermogenesis, Bdnf-e2-/- showed hyperphagia and reduced satiety before the onset of obesity. The Bdnf-e2 transcripts were primarily expressed in ventromedial hypothalamus (VMH), a nucleus known to regulate satiety. Re-expressing Bdnf-e2 transcript in VMH or chemogenetic activation of VMH neurons rescued the hyperphagia and obesity of Bdnf-e2-/- mice. Deletion of BDNF receptor TrkB in VMH neurons in wildtype mice resulted in hyperphagia and obesity, and infusion of TrkB agonistic antibody into VMH of Bdnf-e2-/- mice alleviated these phenotypes. Thus, Bdnf-e2-transcripts in VMH neurons play a key role in regulating energy intake and satiety through TrkB pathway.

Quality analysis of Rosae Radix et Rhizoma / 中国中药杂志

Rosae Radix et Rhizoma is a herbal medicine in a variety of famous Chinese patent medicines, while the quality standard for this medicine remains to be developed due to the insufficient research on the quality of Rosae Radix et Rhizoma from different sources. Therefore, this study comprehensively analyzed the components in Rosae Radix et Rhizoma of different sources from the aspects of extract, component category content, identification based on thin-lay chromatography, active component content determination, and fingerprint, so as to improve the quality control. The results showed that the content of chemical components varied in the samples of different sources, while there was little difference in the chemical composition among the samples. The content of components in the roots of Rosa laevigata was higher than that in the other two species, and the content of components in the roots was higher than that in the stems. The fingerprints of triterpenoids and non-triterpenoids were established, and the content of five main triterpenoids including multiflorin, rosamultin, myrianthic acid, rosolic acid, and tormentic acid in Rosae Radix et Rhizoma was determined. The results were consistent with those of major component categories. In conclusion, the quality of Rosae Radix et Rhizoma is associated with the plant species, producing area, and medicinal parts. The method established in this study lays a foundation for improving the quality standard of Rosae Radix et Rhizoma and provides data support for the rational use of the stem.

Research progress of tannins in traditional Chinese medicines in recent ten years / 中国中药杂志

In this paper, the newly isolated tannins were sorted after a review of the literature concerning tannins in recent 10 years, and their research progress was summarized in terms of extraction, isolation, pharmacological activity and metabolism. Hydrolysable tannins and condensed tannins are the main structural types. Modern research shows that tannins have many pharmacological effects, such as bacteriostasis, antioxidation, antitumor, antivirus and blood glucose reduction, and have broad development prospects. They are usually extracted by water, ethanol and acetone and isolated and purified by macroporous resin and gel column chromatography. The packings commonly adopted for the column chromatography mainly included Sephadex LH-20, Diaion HP-20, MCI-gel CHP-20 and Toyopearl HW-40. Modern analytical techniques such as nuclear magnetic resonance spectroscopy(NMR), fast atom bombardment mass spectrometry(FAB-MS) and circular dichroism(CD) are generally used for the structural identification of tannins. Howe-ver, their isolation, purification and structural identification are still challenging. It is necessary to use a variety of high-throughput screening methods to explore their pharmacological activities and to explore the material basis responsible for their functions through experiments in vivo.

Study on potential molecular mechanism of Mongolian medicine Bawei Sanxiang San in treatment of chronic heart failure based on network pharmacology and molecular docking / 中国中药杂志

To explore the potential molecular mechanism of Mongolian medicine Bawei Sanxiang San in the treatment of chronic heart failure(CHF) through network pharmacology and molecular docking technology. The active ingredients and potential targets of Bawei Sanxiang San were collected by applying TCMSP, BATMAN databases and literature mining. CHF-related genes were collected through TTD, GeneCards and CTD databases. After the potential common targets between Bawei Sanxiang San and CHF were disco-vered, the interaction network diagram of "compound-target-pathway" was constructed using Cytoscape. The intersecting targets were imported into the DAVID database for GO function and KEGG pathway enrichment analysis. Finally, the Autodock_vina software was used to molecularly dock the selected proteins with the active ingredients of Bawei Sanxiang San. The results showed that there were 60 active ingredients in Bawei Sanxiang San that might be used to treat CHF, involving 311 target genes and 7 signaling pathways that directly related to CHF, such as HIF-1 signaling pathway, TNF signaling pathway, adrenergic signaling in cardiomyocytes, aldosterone-regulated sodium reabsorption, calcium signaling pathway, cGMP-PKG signaling pathway, renin secretion. Additionally, molecular docking showed that the bioactive compounds had good binding activity with the protein receptors of key target genes. Bawei Sanxiang San might exert therapeutic effects on CHF by regulating cardiomyocytes, angiogenic and inflammation related targets and pathways in a multi-component, multi-target and multi-pathway manner.

Research progress on anti-atherosclerosis effect and mechanism of flavonoids compounds mediated by macrophages / 中国中药杂志

Flavonoids are important active ingredients of traditional Chinese medicine, mainly with cardiovascular, anti-liver injury, antioxidant, antispasmodic, and estrogen-like effects. These compounds have obvious effects on the cardiovascular and cerebrovascular diseases. Macrophage-derived foam cells are the key medium in the process of atherosclerosis(AS). In plaque, allserum lipids, serum lipoproteins, and various pro-or anti-inflammatory stimulating factors, chemokines, and small bioactive molecules can significantly affect the macrophage phenotype and induce stronger pro-inflammatory or anti-inflammatory properties. Studies have shown that some flavonoids can be used for macrophages through different pathways and mechanisms, playing an anti-atherosclerosis effect to different degrees, including promotion of cholesterol efflux from macrophages, anti-foaming of macrophages, inhibition of secretion of inflammatory factors, and antioxidant modified low density lipoprotein(ox-LDL)-induced apoptosis of macrophages. Related gene regulation inclu-ded ATP-binding cassette transporter A1(ABCA1), ATP-binding cassette transporter G1(ABCG1), Toll-like receptor(TLR), and scavenger receptor(SR). In this article, we would review the recent research progress of flavonoids on anti-atherosclerosis effect me-diated by macrophage. It is expected to provide new treatment strategies for AS-related cardiovascular and cerebrovascular diseases, and provide research ideas and development directions for the use of related natural medicines and design of new products.

The application of processized nutrition treatment strategy in critically ill patients / 中国中西医结合急救杂志

Objective To explore the effect of processized nutrition treatment strategy on the clinical efficacy of critically ill patients.Methods A prospective study was conducted, and 195 patients admitted to Department of Intensive Care Unit of Jiaxing Second Hospital from July 2016 to February 2017 were enrolled. From July to September 2016, 94 cases were assigned in the control group, and they were given the routine nutritional treatment program. From October to November 2016, the training of processized nutrition treatment strategy was carried out and improved according to plan-do-check-act (PDCA) cycle management plan, From December 2016 to February 2017, 101 cases were assigned in the observation group and treated by the doctor and nurse processized nutrition treatment strategy. The differences of early enteral nutrition (EEN) ratio, the time reaching standard of enteral nutrition (EN) in two group were compared, the incidence of complications related to EN, mechanical ventilation time, ICU hospitalization time, ICU expense and mortality were observed between the two groups.Results Compared with the control group, the ratio of EEN was significantly increasedin the observation group [90.1% (91/101) vs. 47.9% (45/94)], the time reaching standard of EN shortened (days: 5.18±1.43 vs. 6.47±1.95), the incidences of gastrointestinal tract related complications [0.77% (9/1173) vs. 1.67% (22/1319)] and ventilator associated pneumonia [VAP: 4.90‰(4/816) vs. 15.32‰(16/1044)] were obviously decreased, ICU hospitalization time (days:11.61±5.93 vs. 14.03±8.27), mechanical ventilation time (days: 8.08±6.16 vs. 11.11±7.87), the mortality [23.76% (24/101) vs. 31.91% (30/94)] were significantly reduced in the observation group (allP < 0.05), but the ICU hospitalization expenses had no significant difference in observation group and control group (millions: 7.26±7.23 vs. 7.07±4.60,P > 0.05).Conclusions The processized nutrition treatment strategy can improve the EEN implementation rate of critically ill patients, help to establish EN as early as possible, reduce the incidence of gastrointestinal and pulmonary infections and other complications.

Expression of Wnt/β-catenin pathway in diabetic nephropathy rats and intervention effect of Chinese materia medica for dispersing blood stasis and dredging collaterals / 中草药

Objective: To investigate the expression of Wnt/β-catenin pathway in diabetic nephropathy (DN) rats and the intervention effect of Chinese materia medica (CMM) for dispersing blood stasis and dredging collateral. Methods: Ten rats were selected as control group from 60 rats, the remaining rats were established as DN models by feeding high glucose and high fat diet combined with low-dose streptozotocin ip injection. Model rats were randomly divided into model group, irbesartan treatment group, and CMM group. The rats in each group were ig administered with corresponding drug, at the end of the 20th week, the 24 h urinary total protein was detected. The expression levels of Wnt4 and β-catenin mRNA and protein in renal tissue were detected. Results: Compared with control group, the 24 h urinary total protein, expression of Wnt4, β-catenin mRNA, and protein significantly increased in the model group (P < 0.01). Compared with model group, 24 h urinary total protein, the expression of Wnt4, β-catenin mRNA, and protein decreased significantly in irbesartan group and CMM group (P < 0.01 or P < 0.05). Conclusion: CMM for dispersing blood stasis and dredging collateral might decrease proteinuria in DN rats. It can also inhibit the high expression of Wnt/β-catenin pathway in the kidney of diabetic nephropathy rats. The effect might be one of the main ways to reduce urinary protein excretion.

Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling.

Brain-derived neurotrophic factor (BDNF) regulates diverse biological functions ranging from neuronal survival and differentiation during development to synaptic plasticity and cognitive behavior in the adult. BDNF disruption in both rodents and humans is associated with neurobehavioral alterations and psychiatric disorders. A unique feature of Bdnf transcription is regulation by nine individual promoters, which drive expression of variants that encode an identical protein. It is hypothesized that this unique genomic structure may provide flexibility that allows different factors to regulate BDNF signaling in distinct cell types and circuits. This has led to the suggestion that isoforms may regulate specific BDNF-dependent functions; however, little scientific support for this idea exists. We generated four novel mutant mouse lines in which BDNF production from one of the four major promoters (I, II, IV, or VI) is selectively disrupted (Bdnf-e1, -e2, -e4, and -e6 mice) and used a comprehensive comparator approach to determine whether different Bdnf transcripts are associated with specific BDNF-dependent molecular, cellular, and behavioral phenotypes. Bdnf-e1 and -e2 mutant males displayed heightened aggression accompanied by convergent expression changes in specific genes associated with serotonin signaling. In contrast, BDNF-e4 and -e6 mutants were not aggressive but displayed impairments associated with GABAergic gene expression. Moreover, quantifications of BDNF protein in the hypothalamus, prefrontal cortex, and hippocampus revealed that individual Bdnf transcripts make differential, region-specific contributions to total BDNF levels. The results highlight the biological significance of alternative Bdnf transcripts and provide evidence that individual isoforms serve distinct molecular and behavioral functions.

Effect of Chinese herbs for stasis removing and collaterals dredging upon angiotensin-converting enzyme 2-angiotensin-(1-7)-mas axis in the renal cortex of diabetic nephropathy rats / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe the effect of Chinese herbs for stasis removing and collaterals dredging (CHSRCD) upon angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas axis in the renal cortex of diabetic nephropathy rats.</p><p><b>METHODS</b>Totally 89 male Sprague-Dawley rats were randomly divided into the blank control group (C group, n=22), the high-glucose high-fat control group (H group, n=10), and the streptozotocin (STZ)-injecting group (n=57). The diabetes rat model (n=50) was induced by feeding high-glucose high-fat diet in combination with intraperitoneal injection of STZ, which were further divided into the model group (M group, n=24), the irbesartan group (I group, n=13), and the CHSRCD (Z group, n=13). Rats in I and Z groups were intragastrically fed with suspension of irbesartan and CHSRCD, once daily for 16 weeks. Equal volume of drinking water was administrated to rats in the rest groups. Blood glucose and 24 h urine protein quantitation were tested at four time points. And the mRNA expression of ACE2 and Mas at various time points was detected by Real-time PCR, immunohistochemical assay, and Western blot. Quantitative analyses of ACE2 and Mas protein expression were performed at the end of week 16.</p><p><b>RESULTS</b>Compared with the C group, blood glucose increased in the H and M groups (P < 0.01). It was higher in the H group (P < 0. 01). 24 h urine protein quantitation at different time points increased in the M group, and it was higher than that in the H group (P < 0.05). Compared with the M group, 24 h urine protein quantitation decreased at the end of week 8 in the I group, and at the end of week 8 and 16 in the Z group (P < 0.05). It was lower in the Z group than in the I group at the end of week 16 (P < 0.05). Compared with the C and H groups, the expression of ACE2 mRNA in the renal cortex was lower in the M group at the end of week 16 (P < 0.01). Compared with the M group, it was higher in the Z group (P < 0. 01). There was no statistical difference in the expressions of Mas mRNA at the end of week 16 between the C group and the M group (P > 0.05). It was lower in the M group than in the H group (P < 0.05). It was higher in the Z group than in the M group (P < 0.05), and higher than in the I group (P < 0.05). The expression of ACE2 and Mas protein in the M group decreased as time went by. The expression quantitation of ACE2 and Mas protein at the end of week 16 was lower in the M group than in the C group (P < 0.05). Compared with the M group, ACE2 expression of the Z group and Mas of the I and Z groups increased more significantly (P < 0. 05).</p><p><b>CONCLUSION</b>CHSRCD could play a role in renal protection for diabetic nephropathy rats by up-regulating the mRNA and protein expression of ACE2 and Mas, promoting the ACE2-Ang-(1-7)-Mas axis, and lowering urinary protein.</p>

Forebrain glutamatergic neurons mediate leptin action on depression-like behaviors and synaptic depression.

The glutamatergic system has been implicated in the pathophysiology of depression and the mechanism of action of antidepressants. Leptin, an adipocyte-derived hormone, has antidepressant-like properties. However, the functional role of leptin receptor (Lepr) signaling in glutamatergic neurons remains to be elucidated. In this study, we generated conditional knockout mice in which the long form of Lepr was ablated selectively in glutamatergic neurons located in the forebrain structures, including the hippocampus and prefrontal cortex (Lepr cKO). Lepr cKO mice exhibit normal growth and body weight. Behavioral characterization of Lepr cKO mice reveals depression-like behavioral deficits, including anhedonia, behavioral despair, enhanced learned helplessness and social withdrawal, with no evident signs of anxiety. In addition, loss of Lepr in forebrain glutamatergic neurons facilitates NMDA-induced hippocampal long-term synaptic depression (LTD), whereas conventional LTD or long-term potentiation (LTP) was not affected. The facilitated LTD induction requires activation of the GluN2B subunit as it was completely blocked by a selective GluN2B antagonist. Moreover, Lepr cKO mice are highly sensitive to the antidepressant-like behavioral effects of the GluN2B antagonist but resistant to leptin. These results support important roles for Lepr signaling in glutamatergic neurons in regulating depression-related behaviors and modulating excitatory synaptic strength, suggesting a possible association between synaptic depression and behavioral manifestations of depression.

SNP and mRNA expression for glutathione peroxidase 4 in Kashin-Beck disease.

Kashin-Beck disease (KBD) is a chronic endemic osteoarthropathy, which mainly occurs in West and Northeast China. Epidemiological studies suggest that Se deficiency is an important environmental factor for the incidence of KBD. Glutathione peroxidase 4 (GPx4) belongs to the glutathione peroxidase family, which is crucial for optimal antioxidant defences. Our purpose is to investigate the putative association between GPx4 polymorphisms and the risk of KBD. Restriction fragment length polymorphism-PCR was used to detect two SNP (rs713041, rs4807542) in 219 cases and 194 controls in Han Chinese subjects, and quantitative analysis for the GPx4 mRNA level was performed by the real-time PCR method. The results revealed that linkage disequilibrium existed in the two SNP. A significant difference was observed in the haplotype A-T (P = 0·0066) of GPx4, which was obviously lower in the KBD cases (0·006 v. 0·032 %). Correlation analysis based on a single locus showed no association between each SNP and KBD risk. Furthermore, the GPx4 mRNA level was dramatically lower in the blood of KBD patients. Overall, our finding indicated GPx4 polymorphisms and decreased mRNA level may be related to the development of KBD in the Chinese population, suggesting GPx4 as a possible candidate susceptibility gene for KBD.

Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning.

Despite its increasing use in experimental and clinical settings, the cellular and molecular mechanisms underlying transcranial direct current stimulation (tDCS) remain unknown. Anodal tDCS applied to the human motor cortex (M1) improves motor skill learning. Here, we demonstrate in mouse M1 slices that DCS induces a long-lasting synaptic potentiation (DCS-LTP), which is polarity specific, NMDA receptor dependent, and requires coupling of DCS with repetitive low-frequency synaptic activation (LFS). Combined DCS and LFS enhance BDNF-secretion and TrkB activation, and DCS-LTP is absent in BDNF and TrkB mutant mice, suggesting that BDNF is a key mediator of this phenomenon. Moreover, the BDNF val66met polymorphism known to partially affect activity-dependent BDNF secretion impairs motor skill acquisition in humans and mice. Motor learning is enhanced by anodal tDCS, as long as activity-dependent BDNF secretion is in place. We propose that tDCS may improve motor skill learning through augmentation of synaptic plasticity that requires BDNF secretion and TrkB activation within M1.

Effect of changing grain and selenium supplementation on control of children's Kaschin-Beck disease in Qinghai province / 中国地方病学杂志

Objective To observe the effect of changing grain and selenium supplementation for 1-year on control of children's Kaschin-Beck disease in Qinghai province. Methods Epidemiology, clinical and right-hand X-ray examination were carried out on children aged 7 - 12 years in 2008. Patients were diagnosed and divided into 3 groups by village, control group from Xinjianping village in Guide county, changing grain group from Xiemalang village in Guide county and supplying salt with selenium and iodine group from Shanglujuan and Xialujuan villages in Xinghai county. One year before and after the treatment, right-hand X-ray photograph (including carpal bones)was taken and child hair samples were collected, selenium was detected by 2,3-diaminonaphthalene fluorescence spectrophotometry. Results After 1 year prevention and control, the detectable rate of X-ray in control group was raised from 4.88%(2/41) to 12.20%(5/41) , the detection rate in changing grain group was declined from 17.54%(10/57) to 5.26%(3/57), and from 13.51%(10/74) to 5.41%(4/74) in supplying salt with selenium and iodine group. In changing grain group, there were 10 patients, 7 cases were cured, 2 patients stable, 1 case progressed,no new case;in supplying salt with selenium and iodine group of 10 patients, 7 were cured, 3 patients stable, 1 new diagnosed case;in control group, 2 patients stable, 2 new diagnosed metaphysis cases, 1 new diagnosed metaphyseal case. Compared with control group, the difference was statistically significant between changing grain group and supplying salt with selenium and iodine group(x2 = 5.49,4.14, all P ＜ 0.05). After 1 year control and prevention,hair selenium contents in control group and changing grain group were increased from (107.15 ± 42.30), (125.30 ±40.30)μg/kg to (108.32 ± 35.67), (135.38 ± 65.24)μg/kg, the difference was statistically insignificant(t = 0.01,0.68, all P ＞ 0.05), and selenium contents in supplying salt with selenium and iodine group were obviously increased from (95.62 ± 43.42)μg/kg to (197.64 ± 97.08)μg/kg (t = 5.41, P ＜ 0.05). Conclusion Changing grain and supplying selenium can prevent and control children's Kaschin-Beck disease.

A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia.

Organized neuronal firing is crucial for cortical processing and is disrupted in schizophrenia. Using rapid amplification of 5' complementary DNA ends in human brain, we identified a primate-specific isoform (3.1) of the ether-a-go-go-related K(+) channel KCNH2 that modulates neuronal firing. KCNH2-3.1 messenger RNA levels are comparable to full-length KCNH2 (1A) levels in brain but three orders of magnitude lower in heart. In hippocampus from individuals with schizophrenia, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A expression. A meta-analysis of five clinical data sets (367 families, 1,158 unrelated cases and 1,704 controls) shows association of single nucleotide polymorphisms in KCNH2 with schizophrenia. Risk-associated alleles predict lower intelligence quotient scores and speed of cognitive processing, altered memory-linked functional magnetic resonance imaging signals and increased KCNH2-3.1 mRNA levels in postmortem hippocampus. KCNH2-3.1 lacks a domain that is crucial for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K(+) current and a high-frequency, nonadapting firing pattern. These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target.

[Advances in studies on potential toxicity of flavonoids].

Flavonoids, including flavones, flavonols, anthocyanins, flavanones, chalcones, flavan, proanthocyanidins, isoflavonoids and biflavonoids, etc, are natural components in our diet and plants. Several beneficial properties have been attributed to these compounds, including antioxidant, anti-inflammatory and anticarcinogenic effects, etc. Flavonoid preparations are marketed as herbal medicines or dietary supplements for a variety of alleged nontoxic therapeutic effects. However, they have yet to pass controlled clinical trials for efficacy, and their potential for toxicity is an understudied field of research. This review summarizes the current studies on the toxicity induced by flavonoids and gives some advices for ingesting flavonoids.

The yin and yang of neurotrophin action.

Neurotrophins have diverse functions in the CNS. Initially synthesized as precursors (proneurotrophins), they are cleaved to produce mature proteins, which promote neuronal survival and enhance synaptic plasticity by activating Trk receptor tyrosine kinases. Recent studies indicate that proneurotrophins serve as signalling molecules by interacting with the p75 neurotrophin receptor (p75NTR). Interestingly, proneurotrophins often have biological effects that oppose those of mature neurotrophins. Therefore, the proteolytic cleavage of proneurotrophins represents a mechanism that controls the direction of action of neurotrophins. New insights into the 'yin and yang' of neurotrophin activity have profound implications for our understanding of the role of neurotrophins in a wide range of cellular processes.

Studies on analogues of huperzine A for treatment of senile dementia. VI. Asymmetric total synthesis of 14-nor-huperzine A and its inhibitory activity of acetylcholinesterase / 药学学报

<p><b>AIM</b>To study asymmetric total synthesis of 14-nor-huperzine A 2 and its inhibitory activity on acetylcholinesterase.</p><p><b>METHODS</b>Highly enantioselective synthesis of compound 5 from beta-keto-ester 3 and 2-methylene-1,3-propanediol diacetate 4 by palladium-catalyzed bicycloannulation was carried out using new chiral ferrocenylphosphine ligands, such as 10, 11, followed by regioselective double-bond migration to produce compound 6. Optically pure 6 was obtained after enantio-enrichment recrystallization. Then, according to similar procedures of huperzine A synthesis, the target compound 14-nor-huperzine A 2 was prepared. The inhibitory activity was tested with rat erythrocyte membrame acetylcholinesterase.</p><p><b>RESULTS</b>The inhibitory activity of synthetic (-)-14-nor-huperzine A was 8 fold less potent than that of (-)-huperzine A.</p><p><b>CONCLUSION</b>A hydrogen-bond between 14-methyl group of (-) huperzine A and the main-chain oxygen of His 440 is necessary for the highly acetylcholinesterase inhibitory activity of huperzine A.</p>