Amlodipine inhibits the proliferation and migration of esophageal carcinoma cells through the induction of endoplasmic reticulum stress

BACKGROUND L-type calcium channels are the only protein channels sensitive to calcium channel blockers,and are expressed in various cancer types.The Cancer Genome Atlas database shows that the mRNA levels of multiple L-type calcium channel subunits in esophageal squamous cell carcinoma tumor tissue are significantly higher than those in normal esophageal epithelial tissue.Therefore,we hypothesized that amlodipine,a long-acting dihydropyridine L-type calcium channel blocker,may inhibit the occurrence and development of esophageal cancer(EC).AIM To investigate the inhibitory effects of amlodipine on EC through endoplasmic reticulum(ER)stress.METHODS Cav1.3 protein expression levels in 50 pairs of EC tissues and corresponding paracancerous tissues were examined.Subsequently,the inhibitory effects of amlodipine on proliferation and migration of EC cells in vitro were detected using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide and Transwell assays.In vivo experiments were performed using murine xenograft model.To elucidate the underlying mechanisms,in vitro cell studies were performed to confirm that ER stress plays a role in inhibition proliferation and migration of EC cells treated with amlodipine.RESULTS The expression level of Cav1.3 in esophageal carcinoma was 1.6 times higher than that in paracancerous tissues.Amlodipine treatment decreased the viability of esophageal carcinoma cells in a dose-and time-dependent manner.In vivo animal experiments also clearly indicated that amlodipine inhibited the growth of EC tumors in mice.Additionally,amlodipine reduces the migration of tumor cells by inhibiting epithelial-mesenchymal transition(EMT).Mechanistic studies have demonstrated that amlodipine induces ER stress-mediated apoptosis and suppresses EMT.Moreover,amlodipine-induced autophagy was characterized by an increase in autophagy lysosomes and the accumulation of light chain 3B protein.The combination of amlodipine with the ER stress inhibitor 4-phenylbutyric acid further confirmed the role of the ER stress response in amlodipine-induced apoptosis,EMT,and autophagy.Furthermore,blocking autophagy increases the ratio of apoptosis and migration.CONCLUSION Collectively,we demonstrate for the first time that amlodipine promotes apoptosis,induces autophagy,and inhibits migration through ER stress,thereby exerting anti-tumor effects in EC.

Environmental Indicators Related to Native Plants to Assess the Quality of Life in the Degraded Desert Area

In Kuwait, the scarcity and irregularity of rainfall, the availability of areas of sand supply and the prevalence of strong north westerly winds significantly influence the stability of the fragile ecosystem. Naturally, grown native shrubs and trees can provide potential shelter to soil surface in desert areas. To study the environmental indicators provided by native plant and their ability to improve quality of life, the morphological properties of the vegetated nabkhas within different areas in Kuwait desert and within protected area were assessed. The vegetated dunes can trap maximum mobile sediments from 10.5 to 0.45 ton thus cost saving per plant estimated to be from 5.5 to 0.24 USD. The arrangements of the native plant from highest efficiency in absorbing carbon dioxides to the least were as follows: Nitraria retusa, Haloxylon salicornicum, Citrullus colocynthis, Tamarix aucheriana, Lycium shawii, Convolvolus oxyphyllus, Rhanterium epapposum, Panicum turgidum, Calligonum polygonoides, Astragalus spinosus, Cyperus conglomerates. The cost saving of CO_(2) per year estimated to be from 0.95 to 1,542.1 USD. The revegetation enhanced physical and chemical quality of soil and created microenvironments for the flora and fauna. The aim of this paper is to identify the environmental indicators related to native plants for the assessment of quality of life.

Haplotype-resolved and chromosome-scale genomes provide insights into co-adaptation between the Amur tiger and Amur leopard

DEAR EDITOR,Big cats,such as Amur tigers(Panthera tigris altaica)and Amur leopards(P.pardus orientalis),are apex predator and have evolved specialized traits for hunting and carnivory(Moya et al.,2022),thus playing a crucial role in maintaining biodiversity and ecosystem integrity by regulating prey-predator dynamics.However,human-induced pressures,habitat fragmentation,and environmental alterations have restricted these species in small and isolated populations.Currently,all extant big cats are categorized as endangered or threatened according to their conservation status.Amur tigers and Amur leopards share overlapping geographic ranges,habitats,and certain prey species in the forests of Northeast Asia(Jiang et al.,2015).To reduce interspecies conflict,these carnivores exhibit differentiated dietary and temporal niches.Amur tigers predominantly prey on large ungulates,while Amur leopards hunt small to medium-sized animals(Sugimoto et al.,2016).Additionally,they occupy different temporal niches,with tigers being active at night and leopards more active during the day.Despite spatial and temporal niche partitioning,interspecific competition between these two species is inevitable.Tigers,benefiting from their greater size,have a competitive advantage over leopards,which can manifest in occasional leopard predation by tigers and declines in leopard populations with increasing tiger density(Jiang et al.,2015).Tigers also displace leopards from marginal habitats in nature reserves where they coexist.

高压NMR在蛋白质结构和动力学研究中的应用

与温度一样,压力是基本的热力学变量.蛋白质在溶液中是多种构象的热力学平衡体.在不同的温度和压力等条件下,蛋白质包括折叠构象、变性构象以及各种中间体在内的不同构象的存在频率各不相同.当用压力作为扰动时,由于这些构象的偏摩尔体积不同,它们的存在频率便会因而发生变化,加压可将平衡向具有较小偏摩尔体积的方向移动.因此,利用高压核磁共振(NMR)技术,不仅可以研究高压对蛋白质结构和动力学的影响,还可以通过改变压力,在更为广泛的构象空间研究蛋白质结构和动力学.例如,利用平衡体系在加压时向体积小的构象方向移动这一特性,能够对在常压下因其存在频率低而难于检测、但在高压下因其体积小而存在频率增加了的构象进行深入研究,而这些构象往往与蛋白质的功能密切相关.该篇综述首先介绍了高压在蛋白质科学研究中的历史、有关概念和高压NMR技术;其次,结合实例,阐述高压NMR技术在蛋白质结构、折叠以及动力学研究中的应用;最后,对高压NMR技术在蛋白质研究中的应用前景进行展望.

Regulation of the cell cycle gene, BTG2, by miR-21 in human laryngeal carcinoma

MicroRNAs are short regulatory RNAs that negatively modulate gene expression at the post-transcriptional level, and are deeply involved in the pathogenesis of several types of cancers. To investigate whether specific miRNAs and their target genes participate in the molecular pathogenesis of laryngeal carcinoma, oligonucleotide microarrays were used to assess the differential expression profiles of microRNAs and mRNAs in laryngeal carcinoma tissues compared with normal tissues. The oncogeuic miRNA, microRNA-21 （miR-21）, was found to he npregulated in laryngeal carcinoma tissues. Knockdown of miR-21 by specific antisense oligonucleotides inhibited the proliferation potential of HEp-2 cells, whereas overexpression of miR-21 elevated growth activity of the cells, as detected by the colony formation assay. The cell number reduction caused by miR-21 inhibition was due to the loss of control of the G1-S phase transition, instead of a noticeable increase in apoptosis. Subsequently, a new target gene of miR- 21, BTG2, was found to be downregulated in laryngeal carcinoma tissues. BTG2 is known to act as a pan-cell cycle regulator and tumor suppressor. These findings indicate that aberrant expression of miR-21 may contribute to the malignant phenotype of laryngeal carcinoma by maintaining a low level of BTG2. The identification of the oneogenic miR-21 and its target gene, BTG2, in laryngeal carcinoma is potentially valuable for cancer diagnosis and therapy.

SHEsis,a powerful software platform for analyses of linkage disequilibrium,haplotype construction,and genetic association at polymorphism loci

In multiloci-based genetic association studies of complex diseases, a powerful and high efficient tool for analyses oflinkage disequilibrium (LD) between markers, haplotype distributions and many chi-square/p values with a large numberof samples has been sought for long. In order to achieve the goal of obtaining meaningful results directly from raw data,we developed a robust and user-friendly software platform with a series of tools for analysis in association study withhigh efficiency. The platform has been well evaluated by several sets of real data.

Oxidative stress, mitochondrial damage and neurodegenerative diseases

Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Oxidative stress is characterized by the overproduction of reactive oxygen species, which can induce mitochondrial DNA mutations, damage the mitochondrial respiratory chain, alter membrane permeability, and influence Ca2＋ homeostasis and mitochondrial defense systems. All these changes are implicated in the development of these neurodegenerative diseases, mediating or amplifying neuronal dysfunction and triggering neurodegeneration. This paper summarizes the contribution of oxidative stress and mitochondrial damage to the onset of neurodegenerative diseases and discusses strategies to modify mitochondrial dysfunction that may be attractive therapeutic interventions for the treatment of various neurodegenerative diseases.

Regional gray matter abnormality in hepatic myelopathy patients after transjugular intrahepatic portosystemic shunt: a voxel-based morphometry study

Hepatic myelopathy is a complication seen in patients with chronic liver failure with physiologic or iatrogenic portosystemic shunting. The main symptom is progressive lower limb dyskinesia. The role of the brain motor control center in hepatic myelopathy is unknown. This study aimed to investigate the gray matter changes in patients with hepatic myelopathy secondary to transjugular intrahepatic portosystemic shunt and to examine their clinical relevance. This was a cross-sectional study. Twenty-three liver failure patients with hepatic myelopathy(hepatic myelopathy group), 23 liver failure patients without hepatic myelopathy(non-hepatic myelopathy group) after transjugular intrahepatic portosystemic shunt, and 23 demographically matched healthy volunteers were enrolled from March 2014 to November 2016 at Xijing Hospital, Air Force Military Medical University(Fourth Military Medical University), China. High-resolution magnetization-prepared rapid gradient-echo brain imaging was acquired. Group differences in regional gray matter were assessed using voxel-based morphometry analysis. The relationship between aberrant gray matter and motor characteristics was investigated. Results demonstrated that compared with the non-hepatic myelopathy group, gray matter volume abnormalities were asymmetric, with decreased volume in the left insula(P = 0.003), left thalamus(P = 0.029), left superior frontal gyrus(P = 0.006), and right middle cingulate cortex(P = 0.021), and increased volume in the right caudate nucleus(P = 0.017), corrected with open-source software. The volume of the right caudate nucleus in the hepatic myelopathy group negatively correlated with the lower limb clinical rating of the Fugl-Meyer Assessment(r = –0.53, P = 0.01). Compared with healthy controls, patients with and without hepatic myelopathy exhibited overall increased gray matter volume in both thalami, and decreased gray matter volume in both putamen, as well as in the globus pallidus, cerebellum, and vermis. The gray matter abnormalities we found predominantly involved motor-related regions, and may be associated with motor dysfunction. An enlarged right caudate nucleus might help to predict weak lower limb motor performance in patients with preclinical hepatic myelopathy after transjugular intrahepatic portosystemic shunt. This study was approved by the Ethics Committee of Xijing Hospital, Air Force Military Medical University(Fourth Military Medical University), China(approval No. 20140227-6) on February 27, 2014.

Complex interactions between microRNAs and hepatitis B/C viruses

MicroRNAs(miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate the expression of many target genes via mRNA degradation or translation inhibition. Many studies have shown that miRNAs are involved in the modulation of gene expression and replication of hepatitis B virus(HBV) and hepatitis C virus(HCV) and play a pivotal role in host-virus interactions. Increasing evidence also demonstrates that viral infection leads to alteration of the miRNA expression profile in hepatic tissues or circulation. The deregulated miRNAs participate in hepatocellular carcinoma(HCC)initiation and progression by functioning as oncogenes or tumor suppressor genes by targeting various genes involved in cancer-related signaling pathways. The distinct expression pattern of miRNAs may be a useful marker for the diagnosis and prognosis of virus-related diseases considering the limitation of currently used biomarkers. Moreover, the role of deregulated miRNA in host-virus interactions and HCC development suggested that miRNAs may serve as therapeutic targets or astools. In this review, we summarize the recent findings about the deregulation and the role of miRNAs during HBV/HCV infection and HCC development, and we discuss the possible mechanism of action of miRNAs in the pathogenesis of virus-related diseases. Furthermore, we discuss the potential of using miRNAs as markers for diagnosis and prognosis as well as therapeutic targets and drugs.

Diabetes mellitus and metformin in hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the leading cause of cancer-related death worldwide. Diabetes mellitus, a risk factor for cancer, is also globally endemic. The clinical link between these two diseases has been the subject of investigation for a century, and diabetes mellitus has been established as a risk factor for HCC. Accordingly, metformin, a first-line oral anti-diabetic, was first proposed as a candidate anti-cancer agent in 2005 in a cohort study in Scotland. Several subsequent large cohort studies and randomized controlled trials have not demonstrated significant efficacy for metformin in suppressing HCC incidence and mortality in diabetic patients; however, two recent randomized controlled trials have reported positive data for the tumor-preventive potential of metformin in non-diabetic subjects. The search for biological links between cancer and diabetes has revealed intracellular pathways that are shared by cancer and diabetes. The signal transduction mechanisms by which metformin suppresses carcinogenesis in cell lines or xenograft tissues and improves chemoresistance in cancer stem cells have also been elucidated. This review addresses the clinical and biological links between HCC and diabetes mellitus and the anti-cancer activity of metformin in clinical studies and basic experiments.

Changes of resting cerebral activities in subacute ischemic stroke patients

This study aimed to detect the difference in resting cerebral activities between ischemic stroke pa- tients and healthy participants, define the abnormal site, and provide new evidence for pathological mechanisms, clinical diagnosis, prognosis prediction and efficacy evaluation of ischemic stroke. At present, the majority of functional magnetic resonance imaging studies focus on the motor dysfunc- tion and the acute stage of ischemic stroke. This study recruited 15 right-handed ischemic stroke patients at subacute stage （15 days to 11.5 weeks） and 15 age-matched healthy participants. A rest- ing-state functional magnetic resonance imaging scan was performed on each subject to detect cerebral activity. Regional homogeneity analysis was used to investigate the difference in cerebral activities between ischemic stroke patients and healthy participants. The results showed that the ischemic stroke patients had lower regional homogeneity in anterior cingulate and left cerebrum and higher regional homogeneity in cerebellum, left precuneus and left frontal lobe, compared with healthy participants. The experimental findings demonstrate that the areas in which regional homogeneity was different between ischemic stroke patients and healthy participants are in the cerebellum, left precuneus, left triangle inferior frontal gyrus, left inferior temporal gyrus and anterior cingulate. These locations, related to the motor, sensory and emotion areas, are likely po- tential targets for the neural regeneration of subacute ischemic stroke patients.

Upregulation of kazrin F by miR-186 suppresses apoptosis but promotes epithelial-mesenchymal transition to contribute to malignancy in human cervical cancer cells

Objective：Previous studies have identified that kazrin is a constituent of desmosome and influences intercellular adhesion,growing development and morphology.We previously cloned another new isoform,kazrin F and found that it has anti-apoptotic effects on human glioma cell line.To further explore whether kazrin F is involved in tumorigenesis,we investigated its expression and role in cervical cancer（CC） cells.Methods：The role of kazrin F and miR-186 in CC was determined by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide（MTT） assay,colony formation,transwell,and apoptosis assays.Using enhanced green fluorescent protein（EGFP） reporter assays,reverse transcription-quantitative polymerase chain reaction（RT-qPCR） and western blot analysis,we identified kazrin F post-transcriptional regulation by miR-186.Results：We demonstrate that kazrin F is highly expressed in CC tissues compared with the adjacent noncancerous tissues and promotes cell proliferation,colony formation,migration and invasion in HeLa and C33 A cells by suppressing apoptosis and facilitating epithelial-to-mesenchymal transition（EMT）.Furthermore,miR-186 was confirmed as a regulator of kazrin F dysregulation.An EGFP reporter assay proved that miR-186 directly targets the 3＇-untranslated region（3＇UTR） of kazrin F and downregulates its expression,and miR-186 expression showed an inverse correlation with kazrin F levels in CC tissues.In addition,overexpression of miR-186 suppressed the malignant behaviors of CC cells.The ectopic expression of kazrin F rescued the inhibitory effects of miR-186.Conclusions：Our findings indicate that the upregulation of kazrin F due to downregulated miR-186 levels contributes to malignancy,and highlight the significance of kazrin F in CC tumorigenesis.

High density gas state at water/graphite interface studied by molecular dynamics simulation

In this paper molecular dynamics simulations are performed to study the accumulation behaviour of N2 and H2 at water/graphite interface under ambient temperature and pressure. It finds that both N2 and H2 molecules can accumulate at the interface and form one of two states according to the ratio of gas molecules number to square of graphite surface from our simulation results： gas films （pancake-like） for a larger ratio and nanobubbles for a smaller ratio. In addition, we discuss the stabilities of nanobubbles at different environment temperatures. Surprisingly, it is found that the density of both kinds of gas states can be greatly increased, even comparable with that of the liquid N2 and liquid H2. The present results are expected to be helpful for the understanding of the stable existence of gas film （pancake-like） and nanobubbles.

Transient receptor potential vanilloid 4-dependent calcium influx and ATP release in mouse and rat gastric epithelia

AIM: To explore the expression of transient receptor potential vanilloid 4(TRPV4) and its physiological meaning in mouse and rat gastric epithelia. METHODS: RT-PCR and immunochemistry were used to detect TRPV4 m RNA and protein expression in mouse stomach and a rat normal gastric epithelial cell line(RGE1-01), while Ca2+-imaging and electrophysiology were used to evaluate TRPV4 channel activity. ATP release was measured by a luciferin-luciferase assay. Gastric emptying was also compared between WT and TRPV4 knockout mice. RESULTS: TRPV4 m RNA and protein were detected in mouse tissues and RGE1-01 cells. A TRPV4-specific agonist(GSK1016790A) increased intracellular Ca2+ concentrations and/or evoked TRPV4-like current activities in WT mouse gastric epithelial cells andRGE1-01 cells, but not TRPV4 KO cells. GSK1016790 A or mechanical stimuli induced ATP release from RGE1-01 cells while TRPV4 knockout mice displayed delayed gastric emptying in vivo. CONCLUSION: TRPV4 is expressed in mouse and rat gastric epithelium and contributes to ATP release and gastric emptying.

A central analgesic mechanism of acupuncture for migraine An ongoing functional MRI study

Shaoyang acupoints are the most frequently used in migraine treatment. However, the central anal- gesic mechanism remains poorly understood. Studies have demonstrated that single stimulus of the verum acupuncture in healthy subjects can induce significant connectivity or activity changes in pain- related central networks compared with sham acupuncture. However, these findings are not indicative of the central analgesic mechanism of acupuncture at Shaoyang acupoints. Thus, we recruited 100 migraine sufferers and randomly assigned them into five groups： Shaoyang uncommon acupoint, Shaoyang common acupoint, Yangming uncommon acupoint, non-acupoint control, and blank control groups. Subjects were subjected to evaluation of curative effects and functional MRI prior to and after 10 and 20 acupuncture treatments. All subjects were diagnosed by physicians and enrolled following clinical physical examination. Subjects were observed during 1-4 weeks after inclusion. At the fifth week, the first clinical evaluation and resting functional MRI were conducted. The Shaoyang uncom- mon acupoint, Shaoyang common acupoint, Yangming uncommon acupoint, and non-acupoint control grousp then were treated with acupuncture, five times per week, 20 times in total over 4 weeks. The second and third clinical evaluations and resting functional MRI screenings were conducted following 10 and 20 acupuncture treatments. The blank control group was observed during the 5 to 8 week pe- riod, followed by clinical evaluation and resting functional MRI. The aim of this study was to examine changes in brain functional activity and central networks in subjects with migraine undergoing acu- puncture at Shaoyang uncommon acupoints. This study provides a further explanation of the central analgesic mechanism by which acupuncture at Shaoyang acupoints treats migraine,

Effect of temperature on the morphology of nanobubbles at mica/water interface

The great implication of nanobubbles at a solid/water interface has drawn wide attention of the scientific community and industries. However, the fundamental properties of nanobubbles remain unknown as yet. In this paper, the temperature effects on the morphology of nanobubbles at the mica/water interface are explored through the combination of AFM direct image with the temperature control. The results demonstrate that the apparent height of nanobubbles in AFM images is kept almost constant with the increase of temperature, whilst the lateral size of nanobubbles changes significantly. As the temperature increases from 28℃ to 42℃, the lateral size of nanobubbles increases, reaching a maximum at about 37℃, and then decreases at a higher temperature. The possible explanation for the size change of nanobubbles with temperature is suggested.

Molecular dynamics simulation studies on some topics of water molecules on hydrophobic surfaces

Molecular dynamics simulations have been used to study two topics of water molecules on hydrophobic surfaces. Some properties of the nanobubbles with different ingredients and behavior of single water chains in sin- gle-walled carbon nanochannels are exploited. Molecular simulations show that the density of the N2 and H2 are quite high, which is critical for the stability of the nanobubbles and may have potential applications, such as hydrogen storage, incorporated with recent experimental method to controllably produce hydrogen nanobubbles. The water molecules inside the nanochannel show an unexpected directed motion with long time period, which is indispensable in the future study of the dynamics of biological channels.

Regional brain structural abnormality in ischemic stroke patients:a voxel-based morphometry study

Our previous study used regional homogeneity analysis and found that activity in some brain areas of patients with ischemic stroke changed significantly. In the current study, we examined structural changes in these brain regions by taking structural magnetic resonance imaging scans of 11 ischemic stroke patients and 15 healthy participants, and analyzing the data using voxel-based morphometry. Compared with healthy participants, patients exhibited higher gray matter density in the left inferior occipital gyrus and right anterior white matter tract. In contrast, gray matter density in the right cerebellum, left precentral gyrus, right middle frontal gyrus, and left middle temporal gyrus was less in ischemic stroke patients. The changes of gray matter density in the middle frontal gyrus were negatively associated with the clin- ical rating scales of the Fugl-Meyer Motor Assessment （r = -0.609, P = 0.047） and the left middle temporal gyrus was negatively correlated with the clinical rating scales of the nervous functional deficiency scale （r = -0.737, P = 0.010）. Our findings call objectively identify the functional abnormality in some brain regions of ischemic stroke patients.

Construction and Expression of Methionine-rich and Lysine-rich Fusion Gene in Bacillus natto

Methionine and lysine are restrictive essential amino acids of livestock, they are also the most attentive indexes in the feed production to carry out the quality control and quality evaluation. Their contents in feed directly affect livestock protein synthesis. Bacillus natto has excellent probiotic properties. In this experiment, we used the genetic engineering method, fusion PCR technique, to connect methionine-rich gene （zein） from maize endosperm protein with lysine-rich gene （Cflr） from the pepper anther, then the fusion gene was inserted into the expression vector pHT43, and the recombinant plasmid pHT43/zein-Cflr was constructed. The recombinant plasmid was transferred into Bacillus natto, and induced by IPTG for the expression of the fusion gene. We found an apparent band at 40 ku site for the recombinant strain by SDS-PAGE. The contents of methionine and lysine were individually detected with HPLC, the quantities of methionine and lysine in the recombinant strain increased by 18.37% and 24.68% than the wild one, respectively. We also verified the stability of the recombinant bacterium during passaging, and found the stability was 100%. This study provided research-basis for the application of the recombined Bacillus natto as feed additive.

MATHEMATICAL FOUNDATION OF A NEW COMPLEXITY MEASURE

For many continuous bio-medieal signals with both strong nonlinearity and non-stationarity, two criterions were proposed for their complexity estimation ： （1） Only a short data set is enough for robust estimation; （2） No over-coarse graining preproeessing, such as transferring the original signal into a binary time series, is needed. Co complexity measure proposed by us previously is one of such measures. However, it lacks the solid mathematical foundation and thus its use is limited. A modified version of this measure is proposed, and some important properties are proved rigorously. According to these properties, this measure can be considered as an index of randomness of time series in some senses, and thus also a quantitative index of complexity under the meaning of randomness finding complexity. Compared with other similar measures, this measure seems more suitable for estimating a large quantity of complexity measures for a given task, such as studying the dynamic variation of such measures in sliding windows of a long process, owing to its fast speed for estimation.