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Two new copper borates, namely H 6 [(μ 4 -O)Cu 4 @B 20 O 32 (OH) 8 ]⋅25 H 2 O (1) and H 6 [(μ 4 -O)Cu 4 @B 20 O 32 (OH) 8 ]⋅34 H 2 O⋅8 H 3 BO 3 (2), with 3D supramolecular framework have been made under solvothermal conditions, which built by novel cubic supramolecular cages with mesoscale cavities via the H-bondings. Interestingly, the cage is assembled by [(μ 4 -O)Cu 4 @B 20 O 32 (OH) 8 ] ({Cu 4 @B 20 }) cluster units with different point-group symmetry. Owing to extra H 3 BO 3 molecules participated in building the supramolecular framework, 2 has a larger cubic cage size and higher non-framework volume, leading to the cage size extended to mesoporous size set as a version of ''1 plus"., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Under hydrothermal conditions, replacement of the water molecules in the [Mn(III) 4 Mn(II) 2 O4 (H2 O)4 ](8+) cluster of mixed-valent Mn6 sandwiched silicotungstate [(B-α-SiW9 O34 )2 Mn(III) 4 Mn(II) 2 O4 (H2 O)4 ](12-) (1 a) with organic N ligands led to the isolation of five organic-inorganic hybrid, Mn6 -substituted polyoxometalates (POMs) 2-6. They were all structurally characterized by IR spectroscopy, elemental analysis, thermogravimetric analysis, diffuse-reflectance spectroscopy, and powder and single-crystal X-ray diffraction. Compounds 2-6 represent the first series of mixed-valent {Mn(III) 4 Mn(II) 2 O4 (H2 O)4-n (L)n } sandwiched POMs covalently functionalized by organic ligands. The preparation of 1-6 not only indicates that the double-cubane {Mn(III) 4 Mn(II) 2 O4 (H2 O)4-n (L)n } clusters are very stable fragments in both conventional aqueous solution and hydrothermal systems and that organic functionalization of the [Mn(III) 4 Mn(II) 2 O4 (H2 O)4 ](8+) cluster by substitution reactions is feasible, but also demonstrates that hydrothermal environments can promote and facilitate the occurrence of this substitution reaction. This work confirms that hydrothermal synthesis is effective for making novel mixed-valent POMs substituted with transition-metal (TM) clusters by combining lacunary Keggin precursors with TM cations and tunable organic ligands. Furthermore, magnetic measurements reveal that 3 and 6 exhibit single-molecule magnet behavior., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Two organic-inorganic hybrid pillared-layer lanthanide borates, [Ln2B8O12(bdc)3(H2O)]·H2O (Ln = Pr, 1; Nd, 2; H2bdc = 1,4-benzene dicarboxylic acid), have been made, in which inorganic layers are built by Ln-centred oxoboron ring clusters, Ln@B12O28/Ln@B12O29, while the pillars are organic bdc linkers. Interestingly, two types of linkages, Ln-O-C and B-O-C bonds, exist in the structures, showing firstly novel linking modes between inorganic polyborate and organic dicarboxylate.

Six new lanthanide (Ln) germanate cluster organic frameworks (LnGeCOFs) derived from {Ln8Ge12} cage cluster units {[Nd(pza)2(H2O)] [Nd8Ge12(μ3-O)24E12(pza)(H2O)12]}·3H2O (1), {[Dy(CH3COO)(CO3)(H2O)]2[Dy8Ge12(μ3-O)24E12(H2O)12]}·11H2O (2), {[TbGeE(HO)2O(pza) (H2O)]2[Tb8Ge12(μ3-O)24E12(H2O)6]}·18H2O (3), {[DyGeE(HO)2O(C3H5NO2)(H2O)]2[Dy8Ge12(μ3-O)24E12(H2O)8]}·8H2O (4), {[Tb(pca)2 (H2O)]3[Tb8Ge12(μ3-O)24E12(H2O)4]}·(OH)3·10H2O (5) and {[Dy(pza)2(H2O)][Dy(pza)2(H2O)2][Dy(pza)3(H2O)][Dy8Ge12(μ3-O)24E12(pza)(HCOO) (H2O)6]}·5H2O (6) have been hydrothermally synthesized and structurally characterized. Increasing the amount of the second ligands can induce not only the assembly from 1 to 5, 6 based on Ln oxides as the starting sources, but also the assembly from 2 to 3, 4 based on Ln salts as the starting sources. The successful preparation of these LnGeCOFs suggests the importance of the second ligands in the structural construction of 1-6. To our knowledge, 1 is the first example that includes right- and left-handed helical chains among LnGeCOFs based on bis(carboxyethylgermanium)sesquioxide. 2, 4 and 6 are the first dysprosium incorporated organogermanates based on bis(carboxyethylgermanium)sesquioxide. 4 and 5 display very open framework structures with a solvent-accessible volume of 34.6% for 4 and 35.0% for 5. Moreover, the solid-state photoluminescence properties of 1, 3 and 5 have been investigated at room temperature and they exhibit the characteristic emission bands derived from Ln cations.

Under hydrothermal conditions, six series of novel lanthanide (Ln) organogermanates (LnGs) [Ln8Ge12(μ3-O)24E12(H2O)16]·14H2O (Ln(3+) = Pr(3+), 1; Nd(3+), 2; Sm(3+), 3; Eu(3+), 4; Gd(3+), 5; one-dimensional (1-D) LnG cluster organic chain (LnGCOC)), {[Nd8Ge12(μ3-O)24E12(H2O)10](μ2-H2O)2[Nd8Ge12(μ3-O)24E12(H2O)16]}·18H2O (6, two-dimensional (2-D) planar LnG cluster organic layer (LnGCOL)), {[Ln2GeE(HO)2O(H2O)(CH3COO)2(CO3)]2[Ln8Ge12E12(μ3-O)24(H2O)10]}·6H2O (Ln(3+) = Pr(3+), 7; Nd(3+), 8; 2-D wave-shaped LnGCOL), [TbGeE(HO)2O(H2O)(pca)]2[Tb8Ge12E12(μ3-O)24(H2O)8]·10H2O (9, three-dimensional (3-D) LnG cluster organic framework (LnGCOF)), {([Nd(pza)2(H2O)2]2[Nd8Ge12E12(μ3-O)24(H2O)12])([Nd(pza)2]2[Nd8Ge12E12(Hpza)2(μ3-O)24(H2O)10])}·4OH·14H2O (10, 3-D LnGCOF), {[Nd8Ge12E12(μ3-O)24(H2O)10][Nd(pca)(pda)(H2O)]2}·12H2O (11, 3-D LnGCOF) and {[Nd8Ge12E12(μ3-O)24(H2O)10][Nd(pza)(pda)(H2O)]2}·12H2O (12, 3-D LnGCOF) (Hpca = 2-picolinic acid, H2pda = 2,6-pyridinedicarboxylic acid, Hpza = 2-pyrazinecarboxylic acid) were prepared by introducing the second auxiliary ligands into the organogermanate-lanthanide-oxide reaction system. The obtainment of these LnGs realized the utilization of the second auxiliary ligands inducing the assembly from 1-D LnGCOCs to 2-D LnGCOLs and 3-D LnGCOFs based on LnG cluster (LnGC) {Ln8Ge12E12(μ3-O)24(H2O)16}({Ln8Ge12}) units and Ln-organic complexes or organic ligand connectors. It should be noted that the well-organized structural constructions of 1-12 can be visualized as the gradual replacement of active water sites located at equatorial and polar positions on the hypothetical [Ln8Ge12(μ3-O)24E12(H2O)18] LnGC core with oxygen or nitrogen atoms from organic ligands. The solid-state luminescent properties of 2, 3, 4, 6, and 8-12 have been investigated at room temperature.

Interleukin 6 (IL-6) has been shown to be an important regulator of cardiac interstitial fibrosis. In this study, we explored the role of interleukin-6 in the development of diabetic cardiomyopathy and the underlying mechanisms. Cardiac function of IL-6 knockout mice was significantly improved and interstitial fibrosis was apparently alleviated in comparison with wildtype (WT) diabetic mice induced by streptozotocin (STZ). Treatment with IL-6 significantly promoted the proliferation and collagen production of cultured cardiac fibroblasts (CFs). High glucose treatment increased collagen production, which were mitigated in CFs from IL-6 KO mice. Moreover, IL-6 knockout alleviated the up-regulation of TGFβ1 in diabetic hearts of mice and cultured CFs treated with high glucose or IL-6. Furthermore, the expression of miR-29 reduced upon IL-6 treatment, while increased in IL-6 KO hearts. Overexpression of miR-29 blocked the pro-fibrotic effects of IL-6 on cultured CFs. In summary, deletion of IL-6 is able to mitigate myocardial fibrosis and improve cardiac function of diabetic mice. The mechanism involves the regulation of IL-6 on TGFβ1 and miR-29 pathway. This study indicates the therapeutic potential of IL-6 suppression on diabetic cardiomyopathy disease associated with fibrosis.

Cardiovascular disease has become the leading cause of death and constitutes a serious public health issue in China. Faced with the burgeoning epidemic of cardiovascular disease and the huge burden and economic losses it causes, the Chinese government has attached the utmost importance to cardiovascular research, increasing funding to support basic and clinical studies, integrating resources and recruiting outstanding talent from overseas. The continued and growing support from the government has yielded substantial changes in terms of new discoveries, scientific publications and drug research and development within the last decade. In spite of the advances in cardiovascular research, China still faces significant challenges ahead in encouraging innovation, developing the prevention-oriented health policies and strengthening international collaboration., (© 2014 The British Pharmacological Society.)

Cardiovascular disease has become the most serious health threat and represents the major cause of morbidity and mortality in China, as in other industrialized nations. During the past few decades, China's economic boom has tremendously improved people's standard of living but has also changed their lifestyle, increasing the prevalence of cardiovascular disease, the so-called 'disease of modern civilization'. This new trend has attracted a significant amount of research. Many of the studies conducted by Chinese investigators are orientated towards understanding the molecular mechanisms of cardiovascular disease. At the molecular level, the long-standing consensus is that cardiovascular disease is associated with a sequence mutation (genetic anomaly) and expression deregulation (epigenetic disorder) of protein-coding genes. However, new research data have established the non-protein-coding genes microRNAs (miRNAs) as a central regulator of the pathogenesis of cardiac disease and a potential new therapeutic target for cardiovascular disease. These small non-coding RNAs have also been subjected to extensive, rigorous investigations by Chinese researchers. Over the years, a large body of studies on miRNAs in cardiovascular disease has been conducted by Chinese investigators, yielding fruitful research results and a better understanding of miRNAs as a new level of molecular mechanisms for the pathogenesis of cardiac disease. In this review, we briefly summarize the current status of research in the field of miRNAs and cardiovascular disease in China, highlighting the advances made in elucidating the role of miRNAs in various cardiac conditions, including cardiac arrhythmia, myocardial ischaemia, cardiac hypertrophy and heart failure. We have also examined the potential of miRNAs as novel diagnostic biomarkers and therapeutic targets., (© 2014 The British Pharmacological Society.)

In order to find out how parasitic Cuscuta australis influences the growth and reproduction of Solidago canadensis, the effects of the parasitism of C. australis on the morphological, growth and reproductive traits of S. canadensis were examined and the relationships between the biomass and the contents of the secondary metabolites were analyzed. The results showed that the parasitism significantly reduced the plant height, basal diameter, root length, root diameter, root biomass, stem biomass, leaf biomass, total biomass, number of inflorescences branches, axis length of inflorescence, and number of inflorescence. In particular, plant height, number of inflorescence and the stem biomass of parasitized S. canadensis were only 1/2, 1/5 and 1/8 of non-parasitized plants, respectively. There was no significant difference of plant height, root length, stem biomass and total biomass between plants parasitized with high and low intensities. But the basal diameter, root volume, leaf biomass, root biomass, the number of inflorescences branches, axis length of inflorescence and number of inflorescence of S. canadensis parasitized with high intensity were significantly lower than those of plants parasitized with low intensity. The parasitism of C. australis significantly increased the tannins content in the root and the flavonoids content in the stem of S. canadensis. The biomass of S. canadensis was significantly negatively correlated with the tannin content in the root and the flavonoids content in the stem. These results indicated that the parasitism of C. australis could inhibit the growth of S. canadensis by changing the resources allocation patterns as well as reducing the resources obtained by S. canadensis.

A series of open-framework aluminoborates (ABOs), namely, [Zn2 (en)5 ][Al2 B10 O20 ] (1), [Zn(en)(dien)][AlB5 O10 ] (2), [Zn(en)3 ][AlB7 O12 (OH)2 ] (3), [Zn(en)2 ][AlB5 O10 ] (4), K7 {AlO0.5 [BO2 (OH)]Zn@[B12 O21 (OH)3 ]}⋅H2 O (5) (en=ethylenediamine, dien=diethylenetriamine) have been made under mild solvothermal conditions and characterized by single-crystal X-ray diffraction, powder X-ray diffraction, elemental analysis, IR and UV/Vis spectroscopy, thermogravimetric analysis, and nonlinear optical determination. They were classified as two types: Compounds 1-4 contain intersecting channels and exhibit various 4-connected nets built by AlO4 tetrahedra and oxo boron clusters, zinc-amine complexes act as the templates (1-3) or directly bond to the walls of the ABO (4); compound 5 exhibits a double-layer structure made by nanosized [BO2 (OH)]Zn@[B12 O21 (OH)3 ] ({BZn@B12 }) clusters with Al2 O7 dimers, the channels are within the layer. The second harmonic generation (SHG) measurement shows that the SHG responses of 1-3 are about 2.5, 1.6, and 0.5 times that of KH2 PO4 . Compounds 1-2 are type I phase-matchable materials. UV/Vis spectroscopy indicates that compounds 1-5 are wide-band-gap semiconductors., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In China, acupuncture has been considered an effective method for treating gastrointestinal (GI) dysfunction diseases for thousands of years. In fact, acupuncture has gained progressive acceptance from both practitioners and patients worldwide. However, the therapeutic effects and underlying mechanisms in treating GI dysfunction have not yet been established due to a lack of systematic and comprehensive review articles. Therefore, the aim of this review is to discuss the efficacy of acupuncture as a treatment for GI dysfunction and the associated underlying mechanisms. A search of PubMed was conducted for articles that were published over the past 10 years using the terms "acupuncture", "gastrointestine", and other relevant keywords. In the following review, we describe the effect and underlying mechanisms of acupuncture on GI function from the perspectives of GI motility, visceral sensitivity, the GI barrier, and the brain-gut axis. The dual regulatory effects of acupuncture may manifest by promoting gastric peristalsis in subjects with low initial gastric motility, and suppressing peristalsis in subjects with active initial motility. In addition, the regulation of acupuncture on gastric motility may be intensity-dependent. Our findings suggest that further studies are needed to investigate the effects and more systematic mechanisms in treating GI dysfunction, and to promote the application of acupuncture for the treatment of GI diseases.

As an ancient therapeutic method, acupuncture has been used to treat many diseases as an adjunctive therapy. However, its clinical efficacy remains controversial and the neural mechanisms have not been well understood. Accumulating studies have revealed that fMRI has made it possible to study brain responses to acupuncture. This review aims to provide scientific evidence to support the notion and discuss how these findings contribute to the neural mechanisms of acupuncture., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Cardiovascular disease, with high morbidity and mortality, has been threatening the health of human beings. Therefore, expecting to find a more effective therapeutic method, a plenty of researchers devote themselves to the study of the cardiovascular disease all the time. Since discovered on the heart, M3 receptor of muscarinic acetylcholine receptor (mAchR, M receptor) became a new starting point of the research of the cardiovascular disease. With more and more investigation, many people found that M3 receptor could protect the heart from kinds of cardiovascular disease, which may make it a new hopeful therapeutic point. So, expecting to give support to the reference and encouragement for the study of disease related to M3 receptor in future, this review expounds M3 receptor on the heart from the main following aspects: the effect on the heart, the influence on the cardiovascular disease and the mechanism of M3 receptor involved.

A layered borate Na2B10O17·H2en (1, en = ethylenediamine) with three-dimensional microporosity within the layers has been synthesized under solvothermal conditions by using organic amines and inorganic cations as the templates. Its framework displays a unique 5-connected net constructed by B5O11 cluster and emits blue luminescence.

Three new open-framework aluminoborates (ABOs), Rb2AlB5O10·4H2O (), [C5N2H16]AlB5O10 (, C5N2H16 = N-ethyl-1,3-diaminopropane) and [H2dap][(CH3)2NH]AlB5O10 (, dap = 1,2-diaminopropane) have been made under solvothermal conditions and characterized by elemental analysis, IR, TGA, UV-vis, powder XRD, single-crystal XRD, fluorescence spectra and NLO determination, respectively. These three ABOs display two structural types: and are isostructural and crystallize in acentric space groups C2221 and P212121 respectively, showing intersecting helical channels and good NLO properties; while, crystallizes in the centrosymmetric space group Pbca and has CrB4 topology, exhibiting intersecting 8-, 11- and 14-ring channels. UV-vis spectral investigation indicates that they are wide-band-gap semiconductors.

In this trial, patients who agreed to random assignment were allocated to a randomized acupuncture group (R-acupuncture group) or control group. Those who declined randomization were assigned to a nonrandomized acupuncture group (NR-acupuncture group). Patients in the R-acupuncture group and NR-acupuncture group received up to 21 acupuncture sessions during a period of 6 weeks plus routine care, while the control group received routine care alone. Cognitive function, activities of daily living, and quality of life were assessed by mini-mental state examination (MMSE), Activities of Daily Living Scale (ADL), and dementia quality of life questionnaire (DEMQOL), respectively. All the data were collected at baseline, after 6-week treatment, and after 4-week follow-up. No significant differences of MMSE scores were observed among the three groups but pooled-acupuncture group had significant higher score than control group. Compared to control group, ADL score significantly decreased in NR-acupuncture group and pooled-acupuncture group. For DEMQOL scores, no significant differences were observed among the three groups, as well as between pooled-acupuncture group and control group. Additional acupuncture to routine care may have beneficial effects on the improvements of cognitive status and activities of daily living but have limited efficacy on health-related quality of life in VaD patients.

The morbidity of diabetes has been increasing rapidly in recent years. Delayed wound healing has become a common complication in diabetes, which seriously affects the orthobiosis of patients. Exploring and finding the molecular mechanisms of diabetic wound healing and the effective therapies to promote wound healing have important clinical significances. Stem cells transplant has become a research hotspot in accelerating diabetic wound healing. This article reviewed the present approaches concerning stem cells transplant in diabetic wound healing both at domestic and abroad, and looked forward the clinical therapy of stem cells on diabetic wound healing.

Aims: There is still no effective way to save a surviving healthy mind when there is critical organ failure in the body. The next frontier in CTA is allo-head and body reconstruction (AHBR), and just as animal models were key in the development of CTA, they will be crucial in establishing the procedures of AHBR for clinical translation., Methods and Results: Our approach, pioneered in mice, involves retaining the donor brain stem and transplanting the recipient head. Our preliminary data in mice support that this allows for retention of breathing and circulatory function. Critical aspects of the current protocol include avoiding cerebral ischemia through cross-circulation (donor to recipient) and retaining the donor brain stem. Successful clinical translation of AHBR will become a milestone of medical history and potentially could save millions of people., Conclusions: This experimental study has confirmed a method to avoid cerebral ischemia during the surgery and solved an important part of the problem of how to accomplish long-term survival after transplantation and preservation of the donor brain stem., (© 2014 John Wiley & Sons Ltd.)

The human ether-à-go-go related gene (hERG) potassium channel is an obligatory anti-target for drug development on account of its essential role in cardiac repolarization and its close association with arrhythmia. Diverse drugs have been removed from the market owing to their inhibitory activity on the hERG channel and their contribution to acquired long QT syndrome (LQTS). Moreover, mutations that cause hERG channel dysfunction may induce congenital LQTS. Recently, an increasing number of biochemical and molecular mechanisms underlying hERG-associated LQTS have been reported. In fact, numerous potential biochemical and molecular rescue strategies are hidden within the biogenesis and regulating network. So far, rescue strategies of hERG channel dysfunction and LQTS mainly include activators, blockers, and molecules that interfere with specific links and other mechanisms. The aim of this review is to discuss the rescue strategies based on hERG channel toxicology from the biochemical and molecular perspectives.

Background: Vascular cognitive impairment, no dementia (VCIND) is a condition at risk for future dementia and should be the target of preventive strategies. Preliminary evidence suggests that acupuncture may be a clinically effective intervention for people with early-stage vascular cognitive impairment. We will do a multicenter, 6-month, drug-controlled, nonblinded, randomized, parallel-group trial to determine whether acupuncture is effective for improving cognitive function and quality of life for patients with VCIND., Methods/design: A total of 216 eligible patients will be recruited and randomly assigned acupuncture for two sessions/week (n = 108) or citicoline 300 mg/day (n = 108) in a multicenter, 6-month trial. The primary endpoint is cognition (Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-cog)). Secondary endpoints include assessments of activities of daily living and behavioral symptoms (Clock Drawing Test (CDT), Activities of Daily Living (ADL) and Instrumental Activities of Daily Living scale (IADL))., Discussion: This will be the first large-scale trial specifically evaluating acupuncture therapy in VCIND. If the study confirms the effectiveness and safety of acupuncture treatment, it will be important to examine how the acupuncture approach could most effectively be integrated into the provision of routine healthcare., Trial Registration: This study is registered as an International Standard Randomised Controlled Trial on 17 January 2014, number ISRCTN 82980206.

It is well known that menopause could worsen age-related ventricular concentric remodeling following estrogen (E2) deficiency. However the underlying mechanisms of such phenomena are not fully understood. Mitochondria, as the 'cellular power station' of hearts, play an important role in maintaining normal cardiac function and structure. Therefore, the present study aims to investigate whether mitochondrial compromise is responsible for E2 deficiency associated concentric remodeling and, if so, what is its underlying molecular mechanism. We found evident concentric remodeling pattern in both postmenopausal and ovariectomized (OVX) mice, which could be attenuated by E2 replacement. Further study showed mitochondrial structural damages and respiratory function impairment in myocardium of both postmenopausal and OVX mice and E2 supplement reversed mitochondrial dysfunction in OVX mice, suggesting that E2 deficiency could induce mitochondrial compromise in the heart. Then, peroxisome proliferator-activated receptor-γ co-activator 1-α (PGC-1α), a key mitochondrial function and biology regulator, was found significantly reduced in both postmenopausal and OVX mice. The reduction of PGC-1α protein level in OVX mice could be rescued by E2 delivery, indicating that E2 could positively regulate PGC-1α expression. Next, we found that microRNA-23a (miR-23a) could be negatively regulated by E2 in both myocardium and cultured cardiomyocytes. Moreover, miR-23a could directly downregulate PGC-1α expression in cardiomyocytes via binding to its 3'UTR which implied that miR-23a could be critical for the downregulation of PGC-1α under E2 deficiency. Overexpression of miR-23a was also found to damage mitochondria in cultured cardiomyocytes, ascribed to PGC-1α downregulation. Taken together, E2 deficiency may cause mitochondrial compromise through miR-23a-mediated PGC-1α downregulation, which may subsequently lead to the menopause-associated concentric remodeling., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A new inorganic-organic hybrid solid, [Zn(dap)2 ][AlB5 O10 ], combining the structural features of 3D open-framework inorganic solids and 2D metal-organic coordination polymers has been synthesized under solvothermal conditions. The compound displays extensive luminescence and moderate second-harmonic-generation efficiency., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Chronic shoulder pain (CSP) is the third most common type of musculoskeletal pain. It has a major impact on health-related quality of life. In Chinese medicine, CSP is considered one of the conditions most amenable to treatment with acupuncture. The purpose of this study is to evaluate the efficacy of local acupoints in combination with distal acupoints in pain relief and shoulder function improvement in CSP patients., Methods/design: This is a multicenter, single blind, factorial randomized controlled clinical trial. A total of 164 participants will be randomly allocated to four different groups: Group A will receive acupuncture at local acupoints in combination with distal acupoint. Group B will receive acupuncture at local acupoints in combination with distal non-acupoint. Group C will receive acupuncture at local non-acupoints in combination with distal acupoint. Group D will receive acupuncture at local non-acupoints in combination with distal non-acupoint. Each group will receive 12 treatments of acupuncture one to three times per week for six weeks in total. The primary outcome is shoulder pain intensity, which is graded using a 100 -mm Visual Analogue Scale. The assessment is at baseline (before treatment initiation), 6 weeks after the first acupuncture, 10 weeks after the first acupuncture and 18 weeks after the first acupuncture., Discussion: This trial will be helpful in identifying whether acupuncture at local acupoints in combination with distal acupoints may be more effective than needling points separately., Trial Registration: International Standard Randomized Controlled Trial Number Register: ISRCTN61861069 (http://www.controlled-trials.com).

Two unique organic-inorganic hybrid polyoxometalates constructed from Preyssler-type [Na(H2 O)P5 W30 O110 ](14-) ({P5 W30 }) subunits and TM/Ln-carboxylate-Ln connectors (TM=transition metal, Ln=lanthanide), KNa7 [{Sm6 Mn(μ-H2 O)2 (OCH2 COO)7 (H2 O)18 }{Na(H2 O)P5 W30 O110 }]⋅22 H2 O (1) and K4 [{Sm4 Cu2 (gly)2 (ox)(H2 O)24 }{NaP5 W30 O110 }]Cl2 ⋅25 H2 O (2; gly=glycine, ox=oxalate) have been hydrothermally synthesized and characterized by elemental analyses, IR spectra, UV/Vis-NIR spectra, thermogravimetric analyses, power X-ray diffraction, and single-crystal X-ray diffraction. Compound 1 displays one interesting 3D framework built by three types of subunits, {P5 W30 }, [Sm2 Mn(μ-H2 O)2 (OCH2 COO)2 (H2 O)5 ](4+) , and [Sm4 (OCH2 COO)5 (H2 O)13 ](2+) , whereas 2 also manifests the other intriguing 3D architecture created by three types of subunits, {P5 W30 }, [SmCu(gly)(H2 O)8 ](4+) , and [Sm2 (ox)(H2 O)8 ](4+) . To our knowledge, 1 and 2 are the first 3D frameworks that contain {P5 W30 } units and TM/Ln-carboxylate-Ln connectors. The fluorescent properties of 1 and 2 have been investigated., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Aging is associated with the gradual cognitive decline and shows the typical senile plaque formation in the brain, which results from the aggregation of beta amyloid (Aβ) peptide following the abnormal proteolytic processing of amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase. Accumulating evidence indicates that several microRNAs (miRNAs) are involved in the Alzheimer's disease (AD) by regulating the expression of APP and BACE1 proteins. However, the cognitive ability and the expression profile of the APP- and BACE1-associated miRNAs in the middle-aged population are largely unknown., Methods: The learning and memory ability in rats were determined by Morris Water Maze test. The protein levels of APP and BACE1 were detected by western blotting. The quantitative polymerase chain reaction was used to identify the miRNAs levels in forebrain cortex and the hippocampus., Results: Middle-aged rats have declined learning ability without changes in the memory ability, and increased APP and BACE1 protein expression in the forebrain cortex. Computational analysis using Targetscan and Pictar databases reveals that totally 4 predicted miRNAs have conserved binding site with APP, namely miR-106b, -17-5p, -153, -101. All of them showed decreased expression in both the forebrain cortex and hippocampus. Among the 10 predicted miRNAs targeting BACE1, different expression profiles were identified in the forebrain cortex (decreased: miR-9, -19a, -135a, -15b, -16, -195, -29c, -214; increased: miR-124; no change: miR-141) and the hippocampus (decreased: miR-9, -15b, -16, -195, -29c, -124; increased: miR-19a, -135a, -214, -141) in the middle-aged rats compared with the young rats., Conclusion: Our results provided the first evidence that middle-aged rats have begun displaying cognitive disability with abnormal expression of APP- and BACE1-related miRNAs in the hippocampus and forebrain cortex.

Three new mixed-metal borates, K4Ba2[B14O20(OH)10]·3H2O (1), LiSr2[B10O16(OH)3] (2), and LiBa[B9O15] (3), have been made under hydro(solvo)thermal conditions and characterized by means of IR, UV-vis-near-IR, thermogravimetric analysis, powder X-ray diffraction, and single-crystal X-ray diffraction, respectively. 1 is a 1D chain constructed from B14O21(OH)10(10-) cluster units, 2 is of a 2D layer with nine-membered-ring windows built up of B10O19(OH)3(9-) cluster units, while 3 exhibits a 3D framework with 12-membered-ring channels composed of B3O7 cluster units.

Neuropeptide Y (NPY), a sympathetic neurotransmitter, is highly associated with baroreflex dysfunction and multiple cardiac diseases such as diabetic myocardiopathy. In the present study, we aimed to explore the role of peripheral NPY Y1 receptor (Y1R) and Y2 receptor (Y2R), which are dominantly present in peripheral cardiovascular control, in baroreflex sensitivity (BRS) of streptozotocin (STZ)-induced diabetic rats. Peripheral Y1R and Y2R were antagonized by specific antagonists (BIBP 3226 and BIIE 0246, respectively) from subcutaneously implanted ALZET mini-osmotic pump in STZ-induced diabetic rats for 4 weeks. Then baseline systolic blood pressure, heart rate, cardiac function, BRS, plasma NPY and lipid levels were evaluated. We found that STZ led to increased plasma NPY and lipid level. And the STZ-increased lipid levels were reduced by BIBP 3226 and BIIE 0246. BIBP 3226 ameliorated the aberrant BRS, but had little effect on the impaired cardiac function of the STZ rats. BIIE 0246 alleviated sodium nitroprusside (SNP)-induced but not phenylephrine (PE)-induced aberrant baroreflex control of heart rate in the STZ rats. In addition, BIIE 0246 alleviated the bradycardia, but further impaired cardiac contractility in the STZ rats. These results suggest that peripheral Y1R and Y2R play different roles in STZ-induced impairment of BRS.

MicroRNAs (miRNAs) can efficiently regulate gene expression by targeting mRNA to cause mRNA cleavage or translational repression. Growing evidence indicates that miRNAs exist not only in cells but also in a variety of body fluids, which stimulates substantial interest in the transport mechanism and regulating process of extracellular miRNAs. This article reviews the basic biogenesis of miRNAs in detail to explore the origin of extracellular miRNAs. Different miRNA transporters have been summarized (e.g., exosomes, microvesicles, apoptosis bodies, and RNA-binding proteins). In addition, we discuss the regulators affecting miRNA transport (e.g., ATP and ceramide) and the selection mechanism for different miRNA transporters. Studies about miRNA transporters and the transport mechanism are new and developing. With the progress of the research, new functions of extracellular miRNAs may be uncovered in the future., (Copyright © 2013 Wiley Periodicals, Inc.)

Aim: To investigate the metabolic profiles of xenograft pancreatic cancer before and after radiotherapy by high-resolution magic angle spinning proton magnetic resonance spectroscopy (HRMAS (1)H NMR) combined with principal components analysis (PCA) and evaluate the radiotherapeutic effect., Methods: The nude mouse xenograft model of human pancreatic cancer was established by injecting human pancreatic cancer cell SW1990 subcutaneously into the nude mice. When the tumors volume reached 800 mm(3), the mice received various radiation doses. Two weeks later, tumor tissue sections were prepared for running the NMR measurements. (1)H NMR and PCA were used to determine the changes in the metabolic profiles of tumor tissues after radiotherapy. Metabolic profiles of normal pancreas, pancreatic tumor tissues, and radiation- treated pancreatic tumor tissues were compared., Results: Compared with (1)H NMR spectra of the normal nude mouse pancreas, the levels of choline, taurine, alanine, isoleucine, leucine, valine, lactate, and glutamic acid of the pancreatic cancer group were increased, whereas an opposite trend for phosphocholine, glycerophosphocholine, and betaine was observed. The ratio of phosphocholine to creatine, and glycerophosphocholine to creatine showed noticeable decrease in the pancreatic cancer group. After further evaluation of the tissue metabolic profile after treatment with three different radiation doses, no significant change in metabolites was observed in the (1)H NMR spectra, while the inhibition of tumor growth was in proportion to the radiation doses. However, PCA results showed that the levels of choline and betaine were decreased with the increased radiation dose, and conversely, the level of acetic acid was dramatically increased., Conclusion: The combined methods were demonstrated to have the potential for allowing early diagnosis and assessment of pancreatic cancer response to radiotherapy.

Objective: To study the clinicopathologic characteristics of peripheral neuroblastic tumors and to evaluate the prognostic significance of these features., Methods: The clinical and pathologic findings were retrospectively reviewed in 121 cases of peripheral neuroblastic tumor. The clinical outcomes of patients were evaluated. The three-year event-free survival rate was analyzed, with respect to age of patients, Evan's staging, International Neuroblastoma Pathology Classification and mitosis-karyorrhexis index., Results: The median age at diagnosis was 2.7 years; and 96 cases (79.3%) occurred in patients younger than 5 years old. The number of cases in Evan's staging I, II, III, IV and IVs was 24, 39, 24, 29 and 5, respectively. There were 82 cases of neuroblastoma (NB) (including 2 cases of undifferentiated NB, 52 cases of poorly differentiated NB and 28 cases of differentiating NB), 9 cases of ganglioneuroblastoma, intermixed type (GNBi), 19 cases of ganglioneuroma, maturing type (GN) and 11 cases of ganglioneuroblastoma, nodular type (GNBn). Forty-nine cases were in the favorable histology subgroup and 72 cases in the unfavorable histology subgroup. The overall three-year event-free survival rate of the 121 cases was 73.0% ± 4.3%. The three-year event-free survival rates were associated with age (P = 0.002), Evan's staging (P = 0.000), histologic category (P = 0.000), mitosis-karyorrhexis index (P = 0.043), prognostic subgroup (P = 0.000)., Conclusions: Most of the peripheral neuroblastic tumors occur in the children younger than 5 years old. It is composed of NB, GNBi, GN and GNBn. The three-year event-free survival rate is approximately 70%. Significant prognostic parameters include age of patients, Evan's staging, International Neuroblastoma Pathology Classification and mitosis-karyorrhexis index.

Pseudomonas aeruginosa, a wide-spread opportunistic pathogen, often complicates clinical treatments due to its resistance to a large variety of antimicrobials, especially in immune compromised patients, occasionally leading to death. However, the resistance to antimicrobials varies greatly among the P. aeruginosa isolates, which raises a question on whether some sub-lineages of P. aeruginosa might have greater potential to develop antimicrobial resistance than others. To explore this question, we divided 160 P. aeruginosa isolates collected from cities of USA and China into distinct genotypes using I-CeuI, a special endonuclease that had previously been proven to reveal phylogenetic relationships among bacteria reliably due to the highly conserved 26-bp recognition sequence. We resolved 10 genotypes by I-CeuI analysis and further divided them into 82 sub-genotypes by endonuclease cleavage with SpeI. Eight of the 10 genotypes contained both multi-drug resistant (MDR) and less resistant isolates based on comparisons of their antimicrobial resistance profiles (ARPs). When the less resistant or susceptible isolates from different genotypes were exposed to eight individual antimicrobials, they showed similar potential to become resistant with minor exceptions. This is to our knowledge the first report to examine correlations between phylogenetic sub-lineages of P. aeruginosa and their potential to become resistant to antimicrobials. This study further alerts the importance and urgency of antimicrobial abuse control.

Previous studies have demonstrated that chronic brain hypoperfusion (CBH) causes Aβ aggregation by upregulating expression of amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1) protein, which is accompanied by cognitive impairment, but the mechanisms are not fully understood. In this study, we evaluated the effect of microRNA on memory impairment in rats induced by CBH. We show here that CBH generated by bilateral common carotid artery occlusion (2VO) significantly decreased the learning and memory ability in rats, as assessed by Morris water maze, and upregulated expression of APP and BACE1 proteins in the hippocampus and cortex of rats, as evaluated by Western blot and immunofluorescence. In reciprocal, qRT-PCR analysis showed that microRNA-195 (miR-195) was downregulated in both the hippocampus and cortex of rats following CBH, and in the plasma of dementia patients. APP and BACE1 proteins were downregulated by miR-195 overexpression, upregulated by miR-195 inhibition, and unchanged by binding-site mutation or miR-masks, indicating that APP and BACE1 are two potential targets for miR-195. Knockdown of endogenous miR-195 by lentiviral vector-mediated overexpression of its antisense molecule (lenti-pre-AMO-miR-195) elicited dementia in rats, whereas overexpression of miR-195 using lenti-pre-miR-195 reduced dementia vulnerability triggered by 2VO. Additionally, chromatin immunoprecipitation analysis showed that NFκB was bound to the promoter region of miR-195 and inhibited its expression. We conclude that miR-195 may play a key role in determining dementia susceptibility in 2VO rats by regulating APP and BACE1 expression at the post-transcriptional level, and exogenous complement of miR-195 may be a potentially valuable anti-dementia approach.

Identifying the key factor mediating pathological cardiac hypertrophy is critically important for developing the strategy to protect against heart failure. Bone morphogenetic protein-4 (BMP4) is a mechanosensitive and proinflammatory gene. In this study, we investigated the role of BMP4 in cardiac hypertrophy, apoptosis, and fibrosis in experimentally pathological cardiac hypertrophy. The in vivo pathological cardiac hypertrophy models were induced by pressure-overload and angiotensin (Ang) II constant infusion in mice, and the in vitro model was induced by Ang II exposure to cultured cardiomyocytes. The expression of BMP4 increased in pressure overload, Ang II constant infusion-induced pathological cardiac hypertrophy, but not in swimming exercise-induced physiological cardiac hypertrophy in mice. BMP4 expression also increased in Ang II-induced cardiomyocyte hypertrophy in vitro. In turn, BMP4 induced cardiomyocyte hypertrophy, apoptosis, and cardiac fibrosis, and these pathological consequences were inhibited by the treatment with BMP4 inhibitors noggin and DMH1. Moreover, Ang II-induced cardiomyocyte hypertrophy was inhibited by BMP4 inhibitors. The underlying mechanism that BMP4-induced cardiomyocyte hypertrophy and apoptosis was through increasing NADPH oxidase 4 expression and reactive oxygen species-dependent pathways. Lentivirus-mediated overexpression of BMP4 recapitulated hypertrophy and apoptosis in cultured cardiomyocytes. BMP4 inhibitor DMH1 inhibited pressure overload-induced cardiac hypertrophy in mice in vivo. The plasma BMP4 level of heart failure patients was increased compared with that of subjects without heart failure. In summary, we conclude that BMP4 is a mediator and novel therapeutic target for pathological cardiac hypertrophy.

Background/aims: Abnormal baroreceptor reflex sensitivity (BRS) and elevated plasma neuropeptide Y (NPY) are prevalent in diabetic patients. The present study was conducted to determine whether NPY Y1 receptor (Y1R) and NPY Y2 receptor (Y2R) contribute to the regulatin of BRS in diabetic rats., Methods: Diabetes mellitus (DM) rats with hyperlipidemia were developed by an emulsion diet enriched with fat, sucrose and fructose followed by streptozocin (STZ). Y1R and Y2R specific antagonists (BIBP 3226 and BIIE 0246) were administered by a mini-osmotic pump. Systolic blood pressure (SBP), heart rate (HR), BRS and heart functions, as well as the plasma NPY and lipid level were measured after treatment for 4 weeks., Results: Both BIBP 3226 and BIIE 0246 treatment reversed the elevated total cholesterol (TC) and low density lipoprotein (LDL-C) level, and reduced high density lipoprotein (HDL-C) level in DM rats. BIIE 0246 may attenuate the increased triglyceride (TG) level in DM rats. In addition, neither BIBP 3226 nor BIIE 0246 treatment produced significant effects on BRS, SBP or HR (P>0.05) in DM rats, even after PE and SNP challenge. However, BIBP 3226 and BIIE 0246 further impaired LVSP, LVEDP, +dp/dtmax and -dp/dtmax., Conclusion: This study provided us with the evidence that the inhibition of peripheral Y1R and Y2R did not affect impaired BRS but amplified the deterioration of the compromised cardiac function in STZ-induced DM rats with hyperlipidemia., (Copyright © 2013 S. Karger AG, Basel.)

Aims: The purpose of the present study was to evaluate the effects of overexpression of microRNA-1 (miR-1) on cardiac contractile function and the potential molecular mechanisms., Methods and Results: Transgenic (Tg) mice (C57BL/6) for cardiac-specific overexpression of miR-1 driven by the α-myosin heavy chain promoter were generated and identified by real-time reverse-transcription polymerase chain reaction with left ventricular samples. We found an age-dependent decrease in the heart function in Tg mice by pressure-volume loop analysis. Histological analysis and electron microscopy displayed short sarcomeres with the loss of the clear zone and H-zone as well as myofibril fragmentation and deliquescence in Tg mice. Further studies demonstrated miR-1 post-transcriptionally down-regulated the expression of calmodulin (CaM) and cardiac myosin light chain kinase (cMLCK) proteins by targeting the 3'UTRs of MYLK3, CALM1, and CALM2 genes, leading to decreased phosphorylations of myosin light chain 2v (MLC2v) and cardiac myosin binding protein-C (cMyBP-C). Knockdown of miR-1 by locked nucleic acid-modified anti-miR-1 antisense (LNA-antimiR-1) mitigated the adverse changes of cardiac function associated with overexpression of miR-1., Conclusion: miR-1 induces adverse structural remodelling to impair cardiac contractile function. Targeting cMLCK and CaM likely underlies the detrimental effects of miR-1 on structural components of muscles related to the contractile machinery. Our study provides the first evidence that miRNAs cause adverse structural remodelling of the heart.

Background: Previous studies have demonstrated that angiotensin Type I receptor blockade (ARB) reduces proteinuria, reverses glomerular injury and glomerulosclerosis in rat models of diabetic nephropathy and glomerulonephritis. However, the cellular and molecular mechanisms are unclear. To investigate the role of cells of the bone marrow (BM) in glomerular repair seen during ARB administration, we induced progressive glomerulosclerosis in enhanced green fluorescent protein BM chimeric rats by a single injection of anti-Thy 1.1 monoclonal antibody, followed by unilateral nephrectomy., Methods: Cohorts of rats received valsartan or no treatment from Week 2 to Week 8 after induction of disease. Renal function, urinary protein excretion and histological changes were examined 8 weeks after anti-Thy-1.1 monoclonal antibody injection., Results: Valsartan administration improved renal function, reduced severity of glomerulosclrosis and markedly reduced mortality. Valsartan administration promoted regeneration of the glomerular tuft, lowered proteinuria and resulted in enhanced vascular endothelial growth factor (VEGF) expression in the cortex and glomerular tuft. In addition, valsartan promoted increased recruitment of BM-derived cells (BMDCs) many of which expressed VEGF and likely contributed directly to glomerular repair. Nearly all BMDCs recruited to the glomerulus expressed the monocyte/macrophage marker CD68., Conclusions: In conclusion, the data shows that ARB by valsartan prevents glomerulosclerosis progression by enhancing glomerular capillary repair which is associated with the recruitment of VEGF producing 'reparative' monocytes and macrophages from the BM.

The synergistic effects of tamoxifen on the sensitivity of MCF-7 cells to daunorubicin have been reported. Whether the effects of daunorubicin on MCF-7/adr cells can be improved by tamoxifen in liposomes and how tamoxifen changes daunorubicin's behavior in vivo remains unclear. The aim of this study was to investigate the effects of tamoxifen on the uptake and biodistribution of daunorubicin liposomes by breast-cancer-resistant MCF-7/adr cells in vitro and in vivo. The uptake of liposomes by MCF-7/adr cells in vitro studies was measured using flow cytometry and laser confocal microscopy. The biodistributions of carriers and free drugs were evaluated by DiR dye using in vivo imaging. Tamoxifen obviously enhanced the cellular uptake of liposomes by MCF-7/adr cells in time-dependent manners. According to the results from in vivo imaging analysis, the mean fluorescence intensity of DiR liposomes with tamoxifen in the tumor regions of MCF-7/adr tumor-bearing nude mice was much stronger than that of DiR liposomes alone (16,450  ±  1,331 versus 3,666  ±  321; n = 3). Pegylated liposomes elongated the existence of daunorubicin in the circulatory system and the enhanced permeability and retention effect enhanced its concentration in local tumor tissues, which may provide the precondition for tamoxifen further promoting the uptake by MCF-7/Adr cells in vivo. Using daunorubicin liposomes and tamoxifen together generates better biodistribution profiles in tumor tissue than using daunorubicin liposomes only, which contributes to improving the therapeutic effect of breast cancer treatment.

Down-regulation of Kv4.3 K⁺ channels commonly occurs in multiple diseases, but the understanding of the regulation of Kv4.3 K⁺ channels and the role of Kv4.3 K⁺ channels in pathological conditions are limited. HEK (human embryonic kidney)-293T cells are derived from HEK-293 cells which are transformed by expression of the large T-antigen. In the present study, by comparing HEK-293 and HEK-293T cells, we find that HEK-293T cells express more Kv4.3 K⁺ channels and more transcription factor Sp1 (specificity protein 1) than HEK-293 cells. Inhibition of Sp1 with Sp1 decoy oligonucleotide reduces Kv4.3 K⁺ channel expression in HEK-293T cells. Transfection of pN3-Sp1FL vector increases Sp1 protein expression and results in increased Kv4.3 K⁺ expression in HEK-293 cells. Since the ultimate determinant of the phenotype difference between HEK-293 and HEK-293T cells is the large T-antigen, we conclude that the large T-antigen up-regulates Kv4.3 K⁺ channel expression through an increase in Sp1. In both HEK-293 and HEK-293T cells, inhibition of Kv4.3 K⁺ channels with 4-AP (4-aminopyridine) or Kv4.3 small interfering RNA induces cell apoptosis and necrosis, which are completely rescued by the specific CaMKII (calcium/calmodulin-dependent protein kinase II) inhibitor KN-93, suggesting that Kv4.3 K⁺ channels contribute to cell apoptosis and necrosis through CaMKII activation. In summary, we establish: (i) the HEK-293 and HEK-293T cell model for Kv4.3 K⁺ channel study; (ii) that large T-antigen up-regulates Kv4.3 K⁺ channels through increasing Sp1 levels; and (iii) that Kv4.3 K⁺ channels contribute to cell apoptosis and necrosis through activating CaMKII. The present study provides deep insights into the mechanism of the regulation of Kv4.3 K⁺ channels and the role of Kv4.3 K⁺ channels in cell death.

Liensinine and neferine, a kind of isoquinoline alkaloid, can antagonize the ventricular arrhythmias. The human ether-a-go-go-related gene (hERG) is involved in repolarization of cardiac action potential. We investigated the effects of liensinine and neferine on the biophysical properties of hERG channel and the underlying structure-activity relationships. The effects of liensinine and neferine were examined on the hERG channels in the stable transfected HEK293 cells using a whole-cell patch clamp technique, western blot analysis and immunofluorescence experiment. The pharmacokinetics and tissue distribution determination of liensinine and neferine in rats were determined by a validated RP-HPLC method. Liensinine and neferine induced decrease of current amplitude in dose-dependent. Liensinine reduced hERG tail current from 70.3±6.3 pA/pF in control group to 56.7±2.8 pA/pF in the 1 μM group, 53.0±2.3 pA/pF (3 μM) and 17.8±0.7 pA/pF (30 μM); the corresponding current densities of neferine-treated cells were 41.9±3.1 pA/pF, 32.3±3.1 pA/pF and 16.2±0.6 pA/pF, respectively. Neferine had binding affinity for the open and inactivated state of hERG channel, liensinine only bound to the open state. The inhibitory effects of liensinine and neferine on hERG current were attenuated in the F656V or Y652A mutant channels. Neferine distributed more quickly than liensinine in rats, which was found to be in higher concentration than liensinine. Both liensinine and neferine had no effect on the generation and expression of hERG channels. In conclusion, neferine is a more potent blocker of hERG channels than liensinine at low concentration (<10 μM), which may be due to higher hydrophobic nature of neferine compared with liensinine. Neferine may be safety even for long-term treatment as an antiarrhythmic drug., (Copyright © 2012 S. Karger AG, Basel.)

This review provides systematic coverage of examples in the field of in-capillary electrophorecially mediated microanalysis (EMMA). The recent developments and applications in the time period up to mid 2011 have been described, as well as relevant older papers. The basic principles and modes of in-capillary assays have been demonstrated. An overview is also given of the various injection, separation and detection modes implemented in combination with EMMA. The review is presented in two parts mainly dealing with (i) enzymatic and (ii) derivatization or chemical reactions. Finally, the future trends of CE in performing and monitoring reactions have been drawn., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: A recent genome-wide association study has identified a new susceptibility locus, kinesin family member 1B gene (KIF1B), strongly associated with progression from chronic hepatitis B (CHB) to hepatitis B virus-related hepatocellular carcinoma (HCC) in Chinese population, this study was carried out to explore the role of the genetic variants in KIF1B in the development of chronic hepatitis B., Methodology/principal Findings: Three KIF1B polymorphisms (rs8019, rs17401924, and rs17401966) were selected and genotyped in 473 CHB patients and 580 controls with no history of CHB. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression model. None of these three SNPs showed association with CHBs after adjusting for age and gender. Equivalence-based method analysis confirmed the absence of association. In the further haplotype analysis, three common haplotypes were observed in this study population, but no significant effect was also found for haplotypes in the progression to CHB., Conclusions/significance: This study showed the new locus identified for HCC, KIF1B, was not associated with progression to CHB, implying distinct genetic susceptibility factor contributes to the progression from hepatitis B virus infection to HCC. Nevertheless, further comprehensive analyses are warranted to dissect the mechanism.

HIV-infected patients have a high prevalence of long QT syndrome (LQTs). hERG K(+) channel encoded by human ether-a-go-go related gene contributes to IKr K(+) currents responsible for the repolarization of cardiomyocytes. Inhibition of hERG K(+) channels leads to LQTs. HIV Tat protein, the virus transactivator protein, plays a pivotal role in AIDS. The aim of the present study is to examine the effects of HIV Tat protein on hERG K(+) channels stably expressed in HEK293 cells. The hERG K(+) currents were recorded by whole-cell patch-clamp technique and the hERG channel expression was measured by real-time PCR and Western blot techniques. HIV Tat protein at 200 ng/ml concentration showed no acute effect on hERG currents, but HIV Tat protein (200 ng/ml) incubation for 24 h significantly inhibited hERG currents. In HIV Tat incubated cells, the inactivation and the recovery time from inactivation of hERG channels were significantly changed. HIV Tat protein incubation (200 ng/ml) for 24h had no effect on the hERG mRNA expression, but dose-dependently inhibited hERG protein expression. The MTT assay showed that HIV Tat protein at 50 ng/ml and 200 ng/ml had no effect on the cell viability. HIV Tat protein increased reactive oxygen species (ROS) generation and the inhibition of hERG channel protein expression by HIV Tat protein was prevented by antioxidant tempol. HIV Tat protein in vivo treatment reduced IKr currents and prolonged action potential duration of guinea pig cardiomyocytes. We conclude that HIV Tat protein inhibits hERG K(+) currents through the inhibition of hERG protein expression, which might be the potential mechanism of HIV infection induced LQTs., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Hirschsprung's disease is the congenital absence of generating the peristaltic contractions transmitting from the proximal colon to rectum. We previously have found that tetraethylammonium (TEA), the nonselective Ca(2+)-activated K(+) channel blocker, increases the maximal contractile force and the amplitude of the contraction in rat duodenum. The present study is to test the effect of TEA on motility of colon and rectum from rats and Hirschsprung's disease patients in vitro, in order to find an alternative method to improve the syndrome of Hirschsprung's disease. The rectal and colonic motility was recorded by a tension transducer connected to a biology function experiment system. Histology was analyzed with standard hematoxylin and eosin staining. TEA (1, 3, and 5 mM) significantly increased the amplitude and frequency of contractility of colon and rectum from rats in longitudinal and circular direction. TEA at 5 and 15 mM concentrations showed no effect on histology of colon and rectum from rats that were administered locally with TEA into colon lumen from anus for 10 days. TEA at 15 mM increased the amplitude and frequency of contractions of the colon and rectum from Hirschsprung's disease patients. Our data showed that TEA increased the contractility of colon and rectum from rats and Hirschsprung's disease patients in vitro, suggesting that local administration of TEA in colon or rectum lumen might be an alternative method to ameliorate the syndrome of Hirschsprung's disease patients who are not cured completely by surgery or not suitable for surgery.

Aim: To prepare the monoclonal antibodies associated with hepatocellular carcinoma (HCC) for diagnosis., Methods: 3 BALB/c mice were immunized with high metastasis characteristic HCC cells (HCCLM-6). The splenocytes from the immunized mice were fused with murine myeloma cells (Sp2/0). The hybridoma cells were screened by ELISA after coating with the total protein and the culture supernatant of HCCLM-6 cells. The mAbs were characterized by immunohistochemical staining in the HCC tissues, and by indirect immunofIuorescent staining in different cell lines. The antigen and epitope recognized by the mAbs were identified by the screening premade Uni-ZAP human liver cDNA expression library., Results: Twenty-eight hybridoma cells secreting mAbs were established. One clone of the hybridomas, QGA062, secreted specific mAb associated with HCC. The antigen recognized by the mAb QGA062 was identified as fibronectin (FN), and the epitope was localized among the peptide YTVSLVAIKGNQESPK., Conclusion: The mAb against a HCC-associated epitope in FN is established and characterized, will be a very useful reagent for diagnosis of HCC.

Heme oxygenase-1 (HO-1) shows multiple beneficial effects on cardiovascular diseases. However, the effect of HO-1 on the injury of artery has never been identified. In the present study, we established systemic HO-1 overexpression transgenic mice and investigated the effect of HO-1 on the injury of artery induced by electric stimulation and pressure-overload in transgenic mice. Artery injury was induced by electric stimulation and pressure overload. The contractive function, endothelium-dependent and -independent relaxation of arteries were measured through an isometric force transducer connected to a multichannel acquisition and analysis system. Western blot results showed that HO-1 protein level in transgenic mice arteries was significantly higher than that in wild type mice arteries, while no difference of HO-2 protein level in the arteries of transgenic and wild type mice. Arterial reendothelialization after electric injury was accelerated in transgenic mice. No significant difference in contractive function, endothelium-dependent and -independent relaxation of arteries was observed between wild type and transgenic mice at day 7 after electric injury and 4 weeks after pressure overload. We concluded that HO-1 overexpression accelerated the reendothelialization, but did not prevent the functional impairment of injured artery in mice., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Arsenic trioxide (As(2)O(3)) has been widely used to treat patients with acute promyelocytic leukemia and has also been shown to exhibit therapeutic effects on various types of solid tumors, including gastric cancer and lung carcinoma. Breast cancer is a type of solid tumor whose incidence has been increasing for many years. The present study was designed to investigate the effects of As(2)O(3) on the human breast cancer cell line MCF-7, and to explore its potential mechanisms. The MTT assay demonstrated that As(2)O(3) decreased the cellular viability of MCF-7 cells in a concentration-dependent manner. Morphological observation, the TUNEL assay and flow cytometric analysis revealed that apoptosis was involved in the process. An assay for caspase-3 activity suggested that the apoptosis was mediated through caspase-3 activation. Further investigation indicated that protein levels of the human ether-a-go-go-related gene (HERG) were markedly downregulated by As(2)O(3). Taken together, the results indicate that arsenic trioxide induces the apoptosis of human breast cancer MCF-7 cells at least in part through the activation of caspase-3 and the decrease in HERG expression.

Aim: To investigate whether fluvastatin is able to ameliorate the impaired cardiac function or baroreflex sensitivity (BRS) in rats with type 1 diabetes., Methods: Type 1 diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ) and then administered fluvastatin (1.5, 3.0, and 6.0 mg·kg(-1)·d(-1)) for 30 d. Food and drink intake was recorded every day. Fasting blood glucose (FBG) level, blood lipid level, cardiac function and BRS were measured in diabetic rats after fluvastatin treatment for 30 d., Results: The polydipsia, polyphagia and abnormal biochemical indexes of blood were significantly ameliorated by the the 3.0- and 6.0-mg doses of fluvastatin in STZ-induced diabetic rats. FBG was decreased in diabetic rats after fluvastatin treatment for 30 d. The left ventricular systolic pressure (LVSP) and the maximum rate of change of left ventricular pressure in the isovolumic contraction and relaxation period (±dp/dt(max)) were elevated, and left ventricular diastolic pressure (LVEDP) was decreased by fluvastatin. The attenuated heart rate responses to arterial blood pressure (ABP) increase induced by phenylephrine (PE) and ABP decrease induced by sodium nitroprusside (SNP) were reversed by the 3.0-mg dose of fluvastatin., Conclusion: Fluvastatin regulates blood lipid levels and decreases the FBG level in diabetic rats. These responses can protect the diabetic heart from complications by improving cardiac function and BRS.

Activation of the calcium-sensing receptor (CaSR) leads to an increase of intracellular calcium concentration and alteration of cellular activities. High level of intracellular calcium is involved in hypoxia-induced proliferation of pulmonary arterial smooth muscle cells (PASMCs). However, whether the CaSR is expressed in PAMSCs and is related to the hypoxia-induced proliferation of PASMCs is unclear. In this study, the expression and distribution of CaSRs were detected by RT-PCR, western blotting and immunofluorescence; the intracellular concentration of free calcium ([Ca(2+) ](i) ) was determined by confocal laser scanning microscopy; cell proliferation was tested using an MTT and BrdU incorporation assay; cell cycle analysis was carried out using a flow cytometric assay; and the expression of proliferating cell nuclear antigen (PCNA), extracellular signal-regulated protein kinase 1,2 (ERK1,2) and AKT were analysed by western blotting. We observed that both CaSR mRNA and protein were expressed in rat PASMCs. Lowering of oxygen from 21% to 2.5% led to increased [Ca(2+) ](i) and CaSR expression. This condition of hypoxia also stimulated PASMCs proliferation accompanying with increased phosphorylation of ERK1,2 and AKT. GdCl(3) (an agonist of CaSR) or NPS2390 (an antagonist of CaSR) amplified or weakened the effect of hypoxia, respectively. PD98059 (a MEK1 inhibitor) or LY294002 (a PI3K inhibitors) decreased the up-regulation of PCNA expression and the increase of the cell proliferation index induced by hypoxia and GdCl(3) in PASMCs. Our results suggest that CaSR is expressed in rat PASMCs, and that CaSR activation through MEK1/ERK1,2 and PI3 kinase pathways is involved in hypoxia-induced proliferation of PASMCs., (© 2010 The Authors. Basic & Clinical Pharmacology & Toxicology © 2010 Nordic Pharmacological Society.)

Background: Myocardial ischemia/reperfusion injury is the major cause of morbidity and mortality for cardiovascular diseases. Dopamine D2 receptors are expressed in cardiac tissues. However, the roles of dopamine D2 receptors in myocardial ischemia/reperfusion injury and cardiomyocyte apoptosis are unclear. Here we investigated the effects of both dopamine D2 receptors agonist (bromocriptine) and antagonist (haloperidol) on apoptosis of cultured neonatal rat ventricular myocytes induced by ischemia/reperfusion injury., Methods: Myocardial ischemia/reperfusion injury was simulated by incubating primarily cultured neonatal rat cardiomyocytes in ischemic (hypoxic) buffer solution for 2 h. Thereafter, these cells were incubated for 24 h in normal culture medium., Results: Treatment of the cardiomyocytes with 10 μM bromocriptine significantly decreased lactate dehydrogenase activity, increased superoxide dismutase activity, and decreased malondialdehyde content in the culture medium. Bromocriptine significantly inhibited the release of cytochrome c, accumulation of [Ca2+]i, and apoptosis induced by ischemia/reperfusion injury. Bromocriptine also down-regulated the expression of caspase-3 and -9, Fas and Fas ligand, and up-regulated Bcl-2 expression. In contrast, haloperidol (10 μM) had no significant effects on the apoptosis of cultured cardiomyocytes under the aforementioned conditions., Conclusions: These data suggest that activation of dopamine D2 receptors can inhibit apoptosis of cardiomyocytes encountered during ischemia/reperfusion damage through various pathways.

Background: The extracellular calcium-sensing receptor (CaSR) belongs to family C of the G protein coupled receptors. Whether the CaSR is expressed in the pulmonary artery (PA) is unknown., Methods: The expression and distribution of CaSR were detected by RT-PCR, Western blotting and immunofluorescence. PA tension was detected by the pulmonary arterial ring technique, and the intracellular calcium concentration ([Ca2+]i) was detected by a laser-scanning confocal microscope., Results: The expressions of CaSR mRNA and protein were found in both rat pulmonary artery smooth muscle cells (PASMCs) and PAs. Increased levels of [Ca2+]o (extracellular calcium concentration) or Gd3+ (an agonist of CaSR) induced an increase of [Ca2+]i and PAs constriction in a concentration-dependent manner. In addition, the above-mentioned effects of Ca2+ and Gd3+ were inhibited by U73122 (specific inhibitor of PLC), 2-APB (specific antagonist of IP3 receptor), and thapsigargin (blocker of sarcoplasmic reticulum calcium ATPase)., Conclusions: CaSR is expressed in rat PASMCs, and is involved in regulation of PA tension by increasing [Ca2+]i through G-PLC-IP3 pathway.