bluuebunny/crossref_metadata_2025_split huggingface dataset:
Niemann–Pick disease Type C: From molecule to clinic
Authors: Tang Ying , Li He , Liu Jun‐Ping 
Published: June 2009

Summary1. Niemann–Pick Type C disease (NPC) is an incurable cholesterol‐storage disorder that stems from inherited deficiencies of lysosomal proteins involved in intracellular lipid‐trafficking proteins. The condition manifests as progressive neurological impairment and leads to death at an early age.2. To improve clinical recognization and investigate therapeutic strategies, recent studies using molecular and genetic approaches have led to significant advances in the creation of animal models of NPC, as well as in the understanding of the cellular and molecular mechanisms underlying the pathogenesis of NPC.3. Patients with NPC are divided into four groups based on age at presentation, whereas the clinical features of NPC can be divided into five categories based on the severity of the disease. Progressive neuronal loss, especially of cerebellar Purkinje cells, is a hallmark of NPC. Ballooned neurons, axonal abnormalities and astroglyosis are among the pathological changes seen. Severe demyelination is also present in the mouse model of NPC.4. Mutations in the NPC1 gene cause approximately 95% of cases of NPC, whereas mutations in the NPC2 gene account for the remainder of cases. NPC1 is a transmembrane protein and NPC2 is a soluble protein involved in lipid trafficking in lysosomes. Loss‐of‐function mutations in the NPC1 gene lead to a failure of the calcium‐mediated fusion of endosomes with lysosomes, resulting in the accumulation of cholesterol and other lipids in late endosomes and lysosomes.5. The present review updates the disorders of NPC from clinical features to animal models and molecular mechanisms.
Ets2 transcription factor, telomerase activity and breast cancer
Authors: Dwyer Julie M , Liu Jun‐Ping 
Published: June 2009

Summary1. The enzyme telomerase maintains telomeres (ends of chromosomes) by synthesizing telomeric DNA at each end of the chromosomes. Its association with telomeres has implicated telomerase in cell immortalization.2. Numerous studies have shown significant levels of telomerase activity in 85% of various types of cancer. Transcriptional control of the catalytic subunit, telomerase reverse transcriptase (TERT), dominates regulation of telomerase. Although several major factors have been identified in regulating TERT, they cannot explain all the transcriptional activity of the hTERT gene.3. The Ets transcription factor (TF) family is becoming a regular feature in tumourigenesis, particularly in breast cancer. However, the roles and mechanisms of different Ets TFs are largely unknown.4. The present minireview discusses the research that identified Ets as a regulator of telomerase required for breast cancer cell survival and proliferation, highlighting the discoveries central to understanding the molecular acts used by Ets TFs to mediate TERT gene transcription.
Allosteric networks governing regulation and catalysis of Src‐family protein tyrosine kinases: Implications for disease‐associated kinases
Authors: Cheng Heung‐Chin , Johnson Timothy M , Mills Ryan D , Chong Yuh‐Ping , Chan Khai‐Chew , Culvenor Janetta G 
Published: June 2009

Summary1. The Src‐family protein tyrosine kinases (SFKs) are multidomain oncogenic protein tyrosine kinases. Their overactivation contributes to cancer formation and progression. Thus, synthetic inhibitors of SFKs are being developed as therapeutics for cancer treatment. Understanding the regulatory and catalytic mechanisms of SFKs is necessary for the development of therapeutic SFK inhibitors.2. Although many upstream regulators and protein substrates of SFKs have been identified, both the mechanisms of activation and catalysis of SFKs are not fully understood. In particular, it is still unclear how the inactive SFKs undergo conformational transition during activation. The mechanism governing the binding of substrates and the release of products during catalysis is another area that requires investigation.3. Several recent publications indicate the presence of a ‘hydrophobic spine’ formed by four conserved interacting hydrophobic residues in the kinase domain of SFKs. In the present review, we discuss how the assembly and disassembly of the hydrophobic spine residues may govern conformational transition of SFKs during activation. In addition to regulation of kinase activity, the hydrophobic spine is implicated to be involved in catalysis. It has been postulated recently that perturbation of the hydrophobic spine residues is a key step in catalysis.4. Further investigations to decipher the roles of the hydrophobic spine residues in regulation and catalysis of SFKs will benefit the development of therapeutic SFK inhibitors for cancer treatment.
Oestrogen, telomerase, ovarian ageing and cancer
Authors: Li He , Simpson Evan R , Liu Jun‐Ping 
Published: June 2009

Summary1. Oestrogen plays an important role in ageing and ageing‐related development. Lack of oestrogen prompts endocrine cell ageing of the ovary, whereas oestrogen overflow impacts on epithelial cell neoplastic development.2. Recent studies indicate that oestrogen regulates cell proliferative fates by a mechanism of reprogramming the size of telomeres (ends of chromosomes) in the oestrogen target cells. This is achieved by upregulating the telomerase reverse transcriptase (TERT) gene in a temporal and spatial manner.3. Currently, the relationship between oestrogen and telomerase activity in regulating productive cell development and function remains elusive. A number of lines of evidence suggest that telomerase is a downstream target of oestrogen in oestrogen‐dependent reproductive ageing and neoplastic development.4. The present minireview discusses our current understanding of the mechanisms by which telomerase maintenance of telomere homeostasis mediates oestrogen‐induced ageing and tumourigenesis in the ovary under physiological and pathological conditions.
Glutamine attenuates hyperoxia‐induced acute lung injury in mice
Authors: Perng Wann‐Cherng , Huang Kun‐Lun , Li Min‐Hui , Hsu Ching‐Wang , Tsai Shih‐Hung , Chu Shi‐Jye , Chang Deh‐Ming 
Published: June 2009

Summary1. Glutamine is an amino acid that is used to treat various diseases. Glutamine has been reported to have protective effects in human pulmonary epithelia‐like cells exposed to hyperoxia. However, the effects of glutamine in hyperoxia‐induced lung injury have not been investigated in vivo.2. Mice treated with saline or glutamine [(750 mg/kg) intravenously] were randomly exposed to hyperoxia for 48 or 72 h. Control mice treated with saline or glutamine were exposed to room air. Cytokine levels in bronchoalveolar lavage fluid (BALF), heat shock protein (HSP) 70, the wet/dry (W/D) weight ratio, malondialdehyde (MDA) levels, myeloperoxidase (MPO) activity and pathoglogical findings in lung tissue were evaluated to determine the effects of glutamine on acute lung injury. In addition, survival was monitored.3. Lung expression of HSP70 was significantly enhanced in both the control (room air) and 48 and 72 h hyperoxic glutamine‐treated mice. The W/D ratio, BALF concentrations of tumour necrosis factor‐α and interleukin‐6, MDA levels, MPO activity, neutrophil infiltration and interstitial oedema in lung tissue were significantly lower at 48 and 72 h of hyperoxia in glutamine‐treated mice compared with saline‐treated mice.4. In a separate series of experiments evaluating survival, after 96 h continuous exposure to hyperoxia, all saline‐treated mice died. In contrast, all glutamine‐treated mice died after 108 h exposure to hyperoxia.5. The data suggest that glutamine administered to mice during hyperoxia has a protective effect against hyperoxia‐induced acute lung injury and improves survival.
Protective effects of vasonatrin peptide against hypobaric hypoxia‐induced pulmonary hypertension in rats
Authors: Yu Jun , Feng Hua‐Song , Chen Bao‐Ying , Qu Ping , Liu Li‐Bing , Chen Jian‐Kang , Tie Ru , Huang Xiao‐Jun , Zhao Yu‐Feng , Zhu Xiao‐Xing , Zhu Miao‐Zhang 
Published: June 2009

Summary1. The aim of the present study was to investigate thein vivoeffects of vasonatrin peptide (VNP) on hypoxia‐induced pulmonary hypertension (HPH).2. The HPH model was developed by subjecting rats to hypobaric hypoxia. The HPH rats were then treated with either VNP (50 μg/kg per day, i.p.) or saline (0.5 mL, i.p.) every day for 7 days. Haemodynamic indices, right ventricular hypertrophy (RVH) and remodelling of the pulmonary arteries were evaluated. In addition, plasma levels of atrial natriuretic peptide (ANP), endothelin (ET)‐1 and angiotensin II (AngII) were determined, as was natriuretic peptide receptor‐C (NPR‐C) mRNA expression in the right ventricle.3. Hypobaric hypoxia induced severe HPH compared with the normoxic control group. Treatment of HPH rats with VNP for 1 week significantly reduced mean pulmonary arterial pressure, pulmonary vascular resistance, RVH and muscularization of the pulmonary arteries, although pulmonary blood flow was increased in this group. In addition, significantly lower levels of plasma ET‐1 and AngII and cardiac NPR‐C mRNA expression were observed in VNP‐treated compared with saline‐treated HPH rats, whereas higher plasma concentrations of ANP were found in the former group. Acute intravenous administration of 50 μg/kg VNP significantly ameliorated pulmonary haemodynamics in HPH rats.4. Taken together, the date indicate that VNP has certain preventative and therapeutic effects against HPH.
Clinical and experimental evidence of sympathetic neural dysfunction during inflammatory bowel disease
Authors: Boissé Lysa , Chisholm Susan P , Lukewich Mark K , Lomax Alan E 
Published: June 2009

Summary1. Inflammatory bowel diseases (IBD) alter the function of the enteric nervous system and the sensory innervation of the gastrointestinal (GI) tract. Less is known about whether IBD also affects the sympathetic nervous system (SNS). Given the importance of the SNS in regulating GI function and possibly immune system activation, the present review examines the evidence of sympathetic dysfunction during IBD and its possible consequences.2. Sympathetic axons within the GI tract innervate several cell types, including vascular myocytes, enteric neurons and immune cells. The major neurotransmitters released from sympathetic varicosities are noradrenaline, neuropeptide Y and ATP or a related purine.3. Clinical studies of IBD patients have provided evidence of an association between IBD and axonal or demyelinating neuropathy. Assays of autonomic function suggest that ulcerative colitis and Crohn’s disease, the two major forms of IBD, have contrasting effects on sympathetic neural activity.4. Animal models of IBD have been used to examine the effects of these diseases on sympathetic neurophysiology. A decrease in the release of noradrenaline from sympathetic varicosities in inflamed and uninflamed regions of the GI tract has consistently been reported. Recent findings suggest that the decrease in neurotransmitter release may be due to inhibition of N‐type voltage‐gated Ca2+current in post‐ganglionic sympathetic neurons.5. Interest in the role of the SNS in IBD is rapidly increasing. However, much work needs to be done to enhance understanding of how SNS function is altered during IBD and what contribution, if any, these changes make to pathogenesis.
Downregulation of survival signalling pathways and increased apoptosis in the transition of pressure overload‐induced cardiac hypertrophy to heart failure
Authors: Li Xiao‐Mei , Ma Yi‐Tong , Yang Yi‐Ning , Liu Fen , Chen Bang‐Dang , Han Wei , Zhang Jian‐Fa , Gao Xiao‐Ming 
Published: June 2009

Summary1. Transition from compensated left ventricular (LV) hypertrophy to decompensated heart failure was characterized using a pressure‐overload induced model to elucidate the temporal relationship between cardiomyocyte apoptosis and survival signalling in this transition.2. Mice were subjected to transverse aortic constriction (TAC) or sham operation for 1–16 weeks and were studied by echocardiography, catheterization and histology. Relevant gene expression and phosphorylation of extracellular signal‐regulated kinase (ERK) 1/2, Akt and glycogen synthase kinase (GSK)‐3β were determined.3. Transverse aortic constriction resulted in myocyte hypertrophy and fibrosis from Week 4 and a progressive increase in left ventricular (LV) dimensions and wall thicknesses with maintained contractile function by Week 12. However, a sharp decline in contractile function and elevated LV end‐diastolic pressure from 12 to 16 weeks were observed after TAC, indicating functional decompensation.4. Following TAC, mRNA levels of atrial natriuretic peptide, B‐type natriuretic peptide, β‐myosin heavy chain (MHC) and transforming growth factor‐β1 were increased time dependently, whereas mRNA expression of α‐MHC, sarcoplasmic/endoplasmic reticulum calcium ATPase 2a and Bcl‐2 were decreased. The ratio of Bcl‐2/Bax was decreased and this was consistent with progressively increased myocyte apoptosis demonstrated by terminal deoxyribonucleotidyl transferase‐mediated dUTP–digoxigenin nick end‐labelling staining. Phosphorylation of ERK1/2 was increased by Week 4, but decreased thereafter. Levels of phosphorylated Akt declined from Week 8, whereas GSK3β phosphorylation increased from 1 to 8 weeks, then decreased from Week 12 after TAC.5. In conclusion, TAC resulted in early concentric and late eccentric hypertrophy with eventual development of LV dysfunction. This transition was temporally associated with a progressive increase in cell size, fibrosis and myocyte apoptosis. Downregulation of ERK1/2, Akt and GSK3β and enhanced cardiomyocyte apoptosis are implicated as important mechanisms in the transition from compensated hypertrophy to heart failure.
Roles for novel pharmacological blockers of aquaporins in the treatment of brain oedema and cancer
Authors: Yool Andrea J , Brown Elizabeth A , Flynn Gary A 
Published: June 2009

Summary1. Aquaporins (AQPs) are targets for drug discovery for basic research and medicine. Human diseases involving fluid imbalances and oedema are of major concern and involve tissues in which AQPs are expressed. The range of functional properties of AQPs is continuing to expand steadily with ongoing research in the field.2. Gating domains in AQPs are molecular sites for drug actions. Discovery of the arylsulphonamide AqB013 as an antagonist for AQP1 and AQP4 provided the first pharmacological agent with translational promise for the treatment of diseases in which AQPs have been implicated. The putative binding site for AqB013 in the internal vestibule of the AQP water pore involves amino acid residues that are located in the AQP loop D gating domain.3. Aquaporins have been proposed as novel targets in cancer and oedema and are associated with a surprising array of important processes in the brain and body, such as angiogenesis, cell migration, development and neuropathological diseases. Functions beyond their simple role as water channels are suggested by the subtype‐specific regulation of AQP expression. In both cancer and brain oedema, current therapies are limited and new pharmacological approaches focused on AQPs offer exciting potential for clinical advances.
MicroRNAs and apoptosis: implications in the molecular therapy of human disease
Authors: Yang Bao‐Feng , Lu Yan‐Jie , Wang Zhi‐Guo 
Published: June 2009

Summary1. MicroRNAs (miRNAs), the small non‐coding RNAs of approximately 22 nucleotides, are now recognized as a very large family present throughout the genomes of plants and metazoans. These small transcripts modulate protein expression by binding to complementary or partially complementary target protein‐coding mRNAs and targeting them for degradation or translational inhibition.2. The discovery of miRNAs has revolutionized our understanding of the mechanisms that regulate gene expression, with the addition of an entirely novel level of regulatory control. Considerable information on miRNAs has been accumulated in this rapidly evolving research field. We now know that miRNAs play pivotal roles in diverse processes, such as development and differentiation, control of cell proliferation and death, stress response and metabolism. Indeed, aberrant miRNA expression has been documented in human disease as well as in animal models, with evidence for a causative role in tumourigenesis.3. One of the most active fields of miRNA research is miRNA regulation of apoptosis, a programmed cell death implicated in many human diseases, such as cancer, Alzheimer’s disease, hypertrophy and heart failure. Thus far, nearly 30 of 500 human miRNAs have been validated experimentally to regulate apoptosis; this number is likely to increase with future studies.4. The present review provides a comprehensive summary and analysis of the currently available data, focusing on the transcriptional controls, target genes and signalling pathways linking the apoptosis‐regulating miRNAs and apoptotic cell death.
Interleukin‐6 enhances matrix metalloproteinase‐14 expression via the RAF–mitogen‐activated protein kinase kinase–extracellular signal‐regulated kinase 1/2–activator protein‐1 pathway
Authors: Feng Min , Cai Xiao‐Jun , Zhang Wei , Liu Xiao‐Ling , Chen Liang , Zhang Yun , Zhang Ming‐Xiang , Zhang Mei 
Published: June 2009

Summary1. Interleukin (IL)‐6 is a pivotal cytokine that regulates extracellular matrix (ECM) metabolism by increasing collagen degradation via activation of matrix metalloproteinases (MMPs), such as MMP‐14. In the present study, we investigated the role of IL‐6 in atherosclerotic plaque and signalling pathways in apolipoprotein E‐deficient (ApoE−/−) mice.2. Twenty‐five male ApoE−/− mice were fed a high‐fat diet and atherosclerotic lesions in the right common carotid artery were induced by perivascular placement of a constrictive collar. Immunohistochemical analysis detected expression of IL‐6 and MMP‐14 in atherosclerotic lesions of the right common carotid artery.3. On silencing activator protein (AP)‐1 expression with a specific small interfering RNA, 75% of the IL‐6‐induced increase in MMP‐14 expression was abolished through the RAF–mitogen‐activated protein kinase kinase–extracellular signal‐regulated kinase 1/2–AP‐1 pathway.4. These findings suggest a novel molecular pathway for inflammation‐associated ECM dysregulation, which may account for atherosclerotic plaque rupture.
Platelet aggregation in arterial hypertension: Is there a nitric oxide–urea connection?
Authors: Moss Monique B , Siqueira Mariana A , Mann Giovanni E , Brunini Tatiana MC , Mendes‐Ribeiro Antônio C 
Published: June 2009

Summary1. Systemic arterial hypertension (SAH) is a major independent risk factor for cardiovascular disease. The physiopathology of SAH is multifactorial, complex and remains to be elucidated. Nitric oxide (NO) is an important regulator of vascular and haemostatic functions. The cationic amino acid l‐arginine serves as the substrate for NO synthases (NOS) and arginase, an enzyme of the urea cycle. We have previously reported inhibition of l‐arginine transport in erythrocytes and platelets in hypertension.2. The aim of the present study was to investigate the l‐arginine–NO pathway and urea cycle in platelets and their role in platelet function and systemic inflammatory responses in SAH patients. The expression and activity of NOS and arginase in platelets, platelet aggregation and plasma levels of C‐reactive protein (CRP) were evaluated in 20 SAH patients and 18 age‐matched healthy volunteers.3. There was a reduction of NOS activity in hypertensive patients that was associated with activation of platelet aggregability induced by collagen, but not by ADP. Platelets from SAH patients exhibited compensatory overexpression of inducible NOS, but not endothelial NOS. Intraplatelet arginase activity in SAH patients was not affected, but systemic concentrations of CRP were increased compared with controls.4. It is likely that diminished NO bioavailability in SAH contributes to cardiovascular complications. Our findings may provide the basis for developing new therapeutic approaches for the treatment of hypertension.
Post‐inflammatory modification of colonic afferent mechanosensitivity
Authors: Hughes PA , Brierley SM , Blackshaw LA 
Published: June 2009

Summary1. The present review discusses interactions between the immune and nervous systems in post‐infectious irritable bowel syndrome (PI‐IBS).2. Visceral pain is the single symptom that most affects the quality of life of patients with irritable bowel syndrome (IBS), yet it is the least successfully managed. An underlying hypersensitivity of colonic afferents to mechanical stimuli has long been implicated in visceral pain in IBS, but little more is known of the physiological aetiology.3. The PI‐IBS patients are a cohort of IBS patients who attribute their symptoms to a preceding gastrointestinal infection by pathogens such as Campylobacter or Salmonella. Current evidence suggests that the immune system remains activated in these patients and contributes to their visceral hypersensitivity. This is characterized by a shift in the phenotype of circulating immune cells towards a Type 1 (Th1 predominating) state. Products from these immune cells sensitize colonic afferents to mechanical stimuli.4. Rectal instillation of trinitrobenzene sulphonic acid induces a Th1‐mediated inflammatory response, consistent with clinical observations in PI‐IBS. The visceral hypersensitivity observed in this model is biphasic, with an initial onset characterized by visceral hypersensitivity correlating with histological damage followed by a delayed phase that occurs after histological recovery. Interestingly, this chronic visceral hypersensitivity is mediated by afferents in closest apposition to blood vessels, but furthest from the initial site of damage.5. Both clinical and experimental evidence indicates that chronic dysregulation of the immune system induces visceral afferent hypersensitivity and, therefore, may be the central mechanism underlying PI‐IBS.
Significance of endogenous sulphur‐containing gases in the cardiovascular system
Authors: Wang Xin‐Bao , Jin Hong‐Fang , Tang Chao‐Shu , Du Jun‐Bao 
Published: June 2009

Summary1. The sulphur‐containing gases hydrogen sulphide and sulphur dioxide can be generated endogenously in mammalian tissues and exert significant biological effects in the cardiovascular system. Hydrogen sulphide is considered to be the third novel gasotransmitter in addition to nitric oxide and carbon monoxide. The present review describes the effects of hydrogen sulphide on the cardiovascular system and its possible mechanisms under physiological conditions. We also discuss the pathophysiological effects of hydrogen sulphide on cardiovascular diseases. The therapeutic potential of hydrogen sulphide is summarized.2. We recently discovered that sulphur dioxide, another endogenous sulphur‐containing gas, has important physiological and pathophysiological roles in the cardiovascular system. To some extent, the effect of sulphur dioxide is similar to that of the other gasotransmitters nitric oxide, carbon monoxide and hydrogen sulphide. Sulphur dioxide may also be a novel gas mediator in the cardiovascular system.