Coupled multiphysical model for investigation of influence factors in the application of microbially induced calcite precipitation

The study presents a comprehensive coupled thermo-bio-chemo-hydraulic(T-BCH)modeling framework for stabilizing soils using microbially induced calcite precipitation(MICP).The numerical model considers relevant multiphysics involved in MICP,such as bacterial ureolytic activities,biochemical reactions,multiphase and multicomponent transport,and alteration of the porosity and permeability.The model incorporates multiphysical coupling effects through well-established constitutive relations that connect parameters and variables from different physical fields.It was implemented in the open-source finite element code OpenGeoSys(OGS),and a semi-staggered solution strategy was designed to solve the couplings,allowing for flexible model settings.Therefore,the developed model can be easily adapted to simulate MICP applications in different scenarios.The numerical model was employed to analyze the effect of various factors,including temperature,injection strategies,and application scales.Besides,a TBCH modeling study was conducted on the laboratory-scale domain to analyze the effects of temperature on urease activity and precipitated calcium carbonate.To understand the scale dependency of MICP treatment,a large-scale heterogeneous domain was subjected to variable biochemical injection strategies.The simulations conducted at the field-scale guided the selection of an injection strategy to achieve the desired type and amount of precipitation.Additionally,the study emphasized the potential of numerical models as reliable tools for optimizing future developments in field-scale MICP treatment.The present study demonstrates the potential of this numerical framework for designing and optimizing the MICP applications in laboratory-,prototype-,and field-scale scenarios.

Treatment-induced neuroendocrine prostate cancer and de novo neuroendocrine prostate cancer:Identification,prognosis and survival,genetic and epigenetic factors

Neuroendocrine prostate cancer(NEPC)shows an aggressive behavior compared to prostate cancer(PCa),also known as prostate adenocarcinoma.Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer.NEPC may arise de novo or develop following androgen deprivation therapy(ADT).NEPC that arise following ADT has the nomenclature“treatmentemerging/induced NEPC(t-NEPC)”.t-NEPC would be anticipated in castration resistant prostate cancer(CRPC)and metastatic PCa.t-NEPC is characterized by low or absent androgen receptor(AR)expression,independence of AR signaling,and gain of neuroendocrine phenotype.t-NEPC is an aggressive metastatic tumor,develops from PCa in response to drug induced ADT,and shows very short response to conventional therapy.t-NEPC occurs in 10%-17%of patients with CRPC.De novo NEPC is rare and is accounting for less than 2%of all PCa.The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated.Sphingosine kinase 1 plays a significant role in t-NEPC development.Although neuroendocrine markers:Synaptophysin,chromogranin A,and insulinoma associated protein 1(INSM1)are expressed in t-NEPC,they are non-specific for diagnosis,prognosis,and follow-up of therapy.t-NEPC shows enriched genomic alteration in tumor protein P53(TP53)and retinoblastoma 1(RB1).There are evidences suggest that t-NEPC might develop through epigenetic evolution.There are genomic,epigenetic,and transcriptional alterations that are reported to be involved in development of t-NEPC.Knock-outs of TP53 and RB1 were found to contribute in development of t-NEPC.PCa is resistant to immunotherapy,and at present there are running trials to approach immunotherapy for PCa,CRPC,and t-NEPC.

DI-3-n-butylphthalide exerts neuroprotective effects by modulating hypoxia-inducible factor 1-alpha ubiquitination to attenuate oxidative stress-induced apoptosis

DI-3-n-butylphthalide is used to treat mild and moderate acute ischemic stroke.However,the precise underlying mechanism requires further investigation.In this study,we investigated the molecular mechanism of DI-3-n-butylphthalide action by various means.We used hydrogen peroxide to induce injury to PC12cells and RAW264.7 cells to mimic neuronal oxidative stress injury in stroke in vitro and examined the effects of DI-3-n-butylphthalide.We found that DI-3-nbutylphthalide pretreatment markedly inhibited the reduction in viability and reactive oxygen species production in PC12 cells caused by hydrogen peroxide and inhibited cell apoptosis.Furthermore,DI-3-n-butylphthalide pretreatment inhibited the expression of the pro-apoptotic genes Bax and Bnip3.DI-3-nbutylphthalide also promoted ubiquitination and degradation of hypoxia inducible factor 1α,the key transcription factor that regulates Bax and Bnip3 genes.These findings suggest that DI-3-n-butylphthalide exhibits a neuroprotective effect on stroke by promoting hypoxia inducible factor-1α ubiquitination and degradation and inhibiting cell apoptosis.

Human umbilical cord mesenchymal stem cells derivedexosomes on VEGF-A in hypoxic-induced mice retinal astrocytes and mice model of retinopathy of prematurity

AIM:To observe the effect of human umbilical cord mesenchymal stem cells(hUCMSCs)secretions on the relevant factors in mouse retinal astrocytes,and to investigate the effect of hUCMSCs on the expression of vascular endothelial growth factor-A(VEGF-A)and to observe the therapeutic effect on the mouse model of retinopathy of prematurity(ROP).METHODS:Cultured hUCMSCs and extracted exosomes from them and then retinal astrocytes were divided into control group and hypoxia group.MTT assay,flow cytometry,reverse transcription-polymerase chain reaction(RT-PCR)and Western blot were used to detect related indicators.Possible mechanisms by which hUCMSCs exosomes affect VEGF-A expression in hypoxia-induced mouse retinal astrocytes were explored.At last,the efficacy of exosomes of UCMSCs in a mouse ROP model was explored.Graphpad6 was used to comprehensively process data information.RESULTS:The secretion was successfully extracted from the culture supernatant of hUCMSCs by gradient ultracentrifugation.Reactive oxygen species(ROS)and hypoxia inducible factor-1α(HIF-1α)of mice retinal astrocytes under different hypoxia time and the expression level of VEGF-A protein and VEGF-A mRNA increased,and the ROP cell model was established after 6h of hypoxia.The secretions of medium and high concentrations of hUCMSCs can reduce ROS and HIF-1α,the expression levels of VEGF-A protein and VEGF-A mRNA are statistically significant and concentration dependent.Compared with the ROP cell model group,the expression of phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)signal pathway related factors in the hUCMSCs exocrine group is significantly decreased.The intravitreal injection of the secretions of medium and high concentrations of hUCMSCs can reduce VEGF-A and HIF-1αin ROP model tissues.HE staining shows that the number of retinal neovascularization in ROP mice decreases with the increase of the dose of hUCMSCs secretion.CONCLUSION:In a hypoxia induced mouse retinal astrocyte model,hUCMSCs exosomes are found to effectively reduce the expression of HIF-1αand VEGF-A,which are positively correlated with the concentration of hUCMSCs exosomes.HUCMSCs exosomes can effectively reduce the number of retinal neovascularization and the expression of HIF-1αand VEGF-A proteins in ROP mice,and are positively correlated with drug dosage.Besides,they can reduce the related factors on the PI3K/AKT/mTOR signaling pathway.

Integrated interpretation of dual frequency induced polarization measurement based on wavelet analysis and metal factor methods

In mineral exploration, the apparent resistivity and apparent frequency （or apparent polarizability） parameters of induced polarization method are commonly utilized to describe the induced polarization anomaly. When the target geology structure is significantly complicated, these parameters would fail to reflect the nature of the anomaly source, and wrong conclusions may be obtained. A wavelet approach and a metal factor method were used to comprehensively interpret the induced polarization anomaly of complex geologic bodies in the Adi Bladia mine. Db5 wavelet basis was used to conduct two-scale decomposition and reconstruction, which effectively suppress the noise interference of greenschist facies regional metamorphism and magma intrusion, making energy concentrated and boundary problem unobservable. On the basis of that, the ore-induced anomaly was effectively extracted by the metal factor method.

Desferoxamine preconditioning protects against cerebral ischemia in rats by inducing expressions of hypoxia inducible factor 1α and erythropoietin

Objective To investigate whether desferoxamine （DFO） preconditioning can induce tolerance against cerebral ischemia and its effect on the expression of hypoxia inducible factor 1 α （HIF- 1α） and erythropoietin （EPO） in vivo and in vitro. Methods Rat model of cerebral ischemia was established by middle cerebral artery occlusion with or without DFO administration. Infarct size was examined by TTC staining, and the neurological severity score was evaluated according to published method. Cortical neurons were cultured under ischemia stress which was mimicked by oxygen-glucose deprivation （OGD）, and the neuron damage was assessed by MTT assay. Immunofluorescent staining was employed to detect the expressions of HIF-1 and EPO. Results The protective effect induced by DFO （decreasing the infarction volume and ameliorating the neurological function） appeared at 2 d after administration ofDFO （post-DFO）, lasted until 7 d and disappeared at 14 d （P 〈 0.05）; the most effective action was observed at 3 d post-DFO. DFO induced tolerance of cultured neurons against OGD： neuronal viability was increased 23%, 34%, 40%, 48% and 56% at 8 h, 12 h, 24 h, 36 h, and 48 h, respectively, post-DFO （P 〈 0.05）. Immunofluorescent staining found that HIF-1 α and EPO were upregulated in the neurons of rat brain at 3 d and 7 d post-DFO; increase of HIF-1 α and EPO appeared in cultured cortex neurons at 36 h and 48 h post-DFO. Conclusion DFO induced tolerance against focal cerebral ischemia in rats, and exerted protective effect on OGD cultured cortical neurons. DFO significant induced the expression of HIF- 1 α and EPO both in vivo and in vitro. DFO preconditioning can protect against cerebral ischemia, which may be associated with the synthesis of HIF- 1 α and EPO.

Expression of Nerve Growth Factor and Hypoxia Inducible Factor-1α and Its Correlation with Angiogenesis in Non-Small Cell Lung Cancer

Summary： In order to investigate the expression of nerve growth factor （NGF） and hypoxia inducible factor-1α （HIF-1α） and its correlation with angiogenesis in non-small cell lung cancer （NSCLC）, paraffin-embedded tissue blocks from 20 patients with NSCLC were examined. Twenty corresponding para-cancerous lung tissue specimens were obtained to serve as a control. The expression of NGF, HIF-1α, and vascular endothelial growth factor （VEGF） in the NSCLC tissues was detected by using immunohistochemistry. The microvascular density （MVD） was determined by CD31 staining. The resuits showed that the expression levels ofNGF, HIF-1α and VEGF in the NSCLC tissues were remarkably higher than those in the para-cancerous lung tissues （P〈0.05）. There was significant difference in the MVD between the NSCLC tissues （9.19±1.43） and para-cancerous lung tissues （2.23±1.19） （P〈0.05）. There were positive correlations between NGF and VEGF, between HIF-1α and VEGF, and between NGF and HIF-1α in NSCLC tissues, with the spearman correlation coefficient being 0.588, 0.519 and 0.588, respectively. In NSCLC tissues, the MVD had a positive correlation with the three factors （P〈0.05）. Theses results suggest that NGF and HIF-1α are synergically involved in the angiogenesis of NSCLC.

Homocysteine-induced Enhanced Expression of Tissue Factor in Human Vascular Smooth Muscle Cells

The homocysteine （Hcy）-induced tissue factor （TF） expression in human vascular smooth muscle cells （VSMCs） and the effect of Hcy on the activity of nuclear factor-kappaB （NF-кB） and the expression of inducible nitric oxide synthase （iNOS） were investigated. Human umbilical artery VSMCs were cultured by tissue explanting method, identified by α-actin immunohistochemistry, and incubated with different concentrations of Hcy/PTDC （NF-кB inhibitor）. Semi-quantitative RT-PCR was performed to detect the expression of TF mRNA in VSMCs. Flow cytometry was used to assay the expression of TF protein on the surface of VSMCs and the expression of iNOS in VSMCs. Western blot was carried out to detect the expression of NF-кB protein in nuclei. The results showed that Hcy could induce VSMCs expressing TF mRNA significantly after the VSMCs were incubated with Hcy at concentrations of 10, 100, 500 μmol/L respectively. There was low expression level of TF protein on the surface of the resting VSMCs and Hcy could also induce VSMCs expressing TF pro- tein on the cell surface in different concentrations. Additionally, Hcy could rapidly induce the activation of NF-кB and this effect could be significantly inhibited by PDTC. Hcy alone could not induce the expression of iNOS in VSMCs. It was concluded that Hcy could significantly induce the expression of TF in VSMCs and enhance the activation of NF-ΚB, subsequently mediate TF gene expression and protein synthesis. NF-кB-mediated expression of TF in VSMCs might be the important mechanism of atherosclerosis and thrombosis induced by Hcy.

Role of apoptosis-inducing factor in perinatal hypoxic-ischemic brain injury

Perinatal complications,such as asphyxia,can cause brain injuries that are often associated with subsequent neurological deficits,such as cerebral palsy or mental retardation.The mechanisms of perinatal brain injury are not fully understood,but mitochondria play a prominent role not only due to their central function in metabolism but also because many proteins with apoptosis-related functions are located in the mitochondrion.Among these proteins,apoptosis-inducing factor has already been shown to be an important factor involved in neuronal cell death upon hypoxia-ischemia,but a better understanding of the mechanisms behind these processes is required for the development of more effective treatments during the early stages of perinatal brain injury.In this review,we focus on the molecular mechanisms of hypoxic-ischemic encephalopathy,specifically on the importance of apoptosis-inducing factor.The relevance of apoptosis-inducing factor is based not only because it participates in the caspase-independent apoptotic pathway but also because it plays a crucial role in mitochondrial energetic functionality,especially with regard to the maintenance of electron transport during oxidative phosphorylation and in oxidative stress,acting as a free radical scavenger.We also discuss all the different apoptosis-inducing factor isoforms discovered,focusing especially on apoptosis-inducing factor 2,which is only expressed in the brain and the functions of which are starting now to be clarified.Finally,we summarized the interaction of apoptosis-inducing factor with several proteins that are crucial for both apoptosis-inducing factor functions(prosurvival and pro-apoptotic)and that are highly important in order to develop promising therapeutic targets for improving outcomes after perinatal brain injury.

Hypoxia upregulates hypoxia inducible factor(HIF)-3α expression in lung epithelial cells: characterization and comparison with HIF-1α

The role of the hypoxia-inducible factor(HIF)subunits 1α and 2α in response to hypoxia is well established in lungepithelial cells,whereas little is known about HIF-3α with respect to transcriptional and translational regulation by hy-poxia.HIF-3α and HIF-1α are two similar but distinct basic helix-loop-helix-PAS proteins,which have been postulatedto activate hypoxia responsive genes in response to hypoxia.Here,we used quantitative real time RT-PCR and immu-noblotting to determine the activation of HIF-3α vs.HIF-1α by hypoxia.HIF-3α was strongly induced by hypoxia(1%O_2)both at the level of protein and mRNA due to an increase in protein stability and transcriptional activation,whereasHIF-1α protein and mRNA levels enhanced transiently and then decreased because of a reduction in its mRNA stabilityin A549 cells,as measured on mRNA and protein levels.Interestingly,HIF-3α and HIF-1α exhibited strikingly similarresponses to a variety of activating or inhibitory pharmacological agents.These results demonstrate that HIF-3α is ex-pressed abundantly in lung epithelial cells,and that the transcriptional induction of HIF-3α plays an important role in theresponse to hypoxia in vitro.Our findings suggest that HIF-3α,as a member of the HIF system,is complementary ratherthan redundant to HIF-1α induction in protection against hypoxic damage in alveolar epithelial cells.

Study on risk factors of extrapyramidal symptoms induced by antipsychotics and its correlation with symptoms of schizophrenia

Background Extrapyramidal symptoms (EPS) are one of the most common and neglected side effects during the treatment of schizophrenia. The risk factors of EPS in Chinese patients with schizophrenia and its relationship with psychiatric symptoms and mood symptoms of schizophrenia remain unknown. Aims The main objective of this study is to explore the risk factors of EPS caused by antipsychotics and the relationship between EPS and psychotic symptoms and mood symptoms of schizophrenia. Method This study included 679 patients with schizophrenia who have met the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition. Patients were divided into the EPS group and the non-EPS group according to the scale rating criteria and whether the anticholinergics have been used. The differences between demographic data and characters of drug intake were compared between the two groups, and the risk factors of EPS were selected between those factors. Correlation analysis was performed on the severity of schizophrenia (Positive and Negative Symptoms Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS) score) and EPS scale (Simpson-Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS) score) in 679 patients. The differences between the PANSS subscale score and the CDSS score between the EPS grong and the non-EPS group were compared. Result Compared with the non-EPS group, the EPS group patients are older, and they have a longer duration since first prescribed antipsychotics. The EPS group patients have higher frequency of atypical antipsychotics polytherapy and typical and atypical antipsychotics polytherapy or combined treatments with mood stabilisers. Logistic regression analysis shows that antipsychotics with high D2 receptor antagonistic effect and illness duration are the risk factors of EPS. The SAS score was significantly correlated with PANSS negative score, PANSS general psychopathological score and PANSS total score. The BARS scale score was significantly correlated with PANSS positive score, PANSS general psychopathological score, PANSS total score and CDSS total score. The AIMS scale score was significantly correlated with PANSS negative score. Compared with the non-EPS group, the EPS group patients have significantly higher PANSS negative score, PANSS general psychopathological score, PANSS total score and CDSS total score.

The Study on the Relationship between Serum Vascular Endothelial Growth Factor and Proteinuria in Adriamycin induced Nephrotic Rats

To study the relationship between serum vascular endothelial growth factor (VEGF) and proteinuria in adriamycin induced nephrotic rats, a rat model of adriamycin induced nephrotitis was developed by injection of adriamycin into a tail vein in a rat. At different time points, 24 h urinary protein excretion was measured by using Coomassie brilliant blue method and the serum VEGF levels detected by using ELISA assay. The interventional effect of VEGF on this model was observed. The results showed that: (1) The adriamycin induced nephrotic syndrome rat model was developed successfully; (2) Serum VEGF levels and proteinuria were significantly increased at 7th day after intravenous injection of adriamycin. There was a positive correlation between serum VEGF levels and 24 h urinary protein excretion ( r=0.67, P <0.05). (3) The 24 h urinary protein excretion was significantly increased in the rats receiving administration of VEGF ( P <0.05). It was concluded that VEGF might play an important role in the pathogenesis of proteinuria in adriamycin induced nephrotic rats.

Nerve growth factor and inducible nitric oxide synthase expression in the mesencephalon and diencephalon, as well as visual-and auditory-related nervous tissues, in a macaque model of type 2 diabetes

The present study detected distribution and expression of nerve growth factor and inducible nitric oxide synthase in the mesencephalon and diencephalon, as well as visual- and auditory-related nervous tissues, in a macaque model of type 2 diabetes using immunohistochemistry. Results showed that nerve growth factor expression decreased, but inducible nitric oxide synthase expression increased, in the mesencephalon and diencephalon, as well as visual- and auditory- related nervous tissues. These results suggested that nerve growth factor and inducible nitric oxide synthase play an important role in regulating the development of diabetic visual- and auditory-related diseases.

Antisense Oligonucleotide of Hypoxia-inducible Factor-1alpha Suppresses Growth and Tumorigenicity of Lung Cancer Cells A549

Summary： To study the role and mechanisms of hypoxia-inducible factor-lalpha （HIF-1α on the growth and tumorigenicity of lung cancer cells A549, the antisense oligonucleotide of HIF-1α was transfected to A549 cells. The effect of the antisense oligonucleotide on tumor growth in vitro and in vivo was evaluated by the growth rate suppression of A549 cells and subcutaneous implanted tumor in nude mice, and the effect on tumorigenicity was evaluated by the expression inhibition of angiogenic factors, the microvessel density （MVD）and vascular endothelial growth factor （VEGF） protein expression which were detected by immohistochemistry and western blot respectively. This study revealed that in vitro the growth rate of antisense oligonucleotide group was significantly decreased as compared with that of control group, sense oligonucleotide group and false-sense oligonucleotide group; in vivo the weight of implanted tumors in nude mice of antisense oligonucleotide group was 1.51±0.40 g, which was significantly lower than that of control group （2.79±0.33 g）, sense oligonucleotide group （2.81±0.45g） and false-sense oligonucleotide group （2.89±0.39 g） and the inhibitory rate was 47 %. Both MVD and VEGF protein expression were significantly inhibited in antisense oligonucleotide group compared with those in other groups. These results indicated that antisense oligonucleotide of HIF-1α could inhibit lung cancer cells A549 growth in vitro and in vivo, and the mechanism may be due to the inhibition of vascular growth and VEGF protein expression.

Expression of caspase-3 and hypoxia inducible factor 1αin hepatocellular carcinoma complicated by hemorrhage and necrosis

BACKGROUND Hepatocellular carcinoma(HCC)is a malignant tumor that occurs in the liver.Its onset is latent,and it shows high heterogeneity and can readily experience intrahepatic metastasis or systemic metastasis,which seriously affects patients’quality of life.Numerous studies have shown that hypoxia inducible factor1α(HIF-1α)plays a significant role in the occurrence and development of tumors,as it promotes the formation of intratumoral vessels and plays a key role in their metastasis and invasion.Some studies have reported that caspase-3,which is induced by various factors,is involved in the apoptosis of tumor cells.AIM To investigate the expression of caspase-3 and HIF-1αand their relationship to the prognosis of patients with primary HCC complicated by pathological changes of hemorrhage and necrosis.METHODS A total of 88 patients with HCC complicated by pathological changes of hemorrhage and necrosis who were treated at our hospital from January 2017 to December 2019 were selected.The expression of caspase-3 and HIF-1αin HCC and paracancerous tissues from these patients was assessed.RESULTS The positive expression rate of caspase-3 in HCC tissues was 27.27%,which was significantly lower than that in the paracancerous tissues(P<0.05),while the positive expression rate of HIF-1αwas 72.73%,which was significantly higher than that in the paracancerous tissues(P<0.05).The positive expression rates for caspase-3 in tumor node metastasis(TNM)stage III and lymph node metastasis tissues were 2.78%and 2.50%,respectively,which were significantly lower than those in TNM stage I-II and non-lymph node metastasis tissues(P<0.05).The positive expression rates of HIF-1αin TNM stage III,lymph node metastasis,and portal vein tumor thrombus tissues were 86.11%,87.50%,and 88.00%,respectively,and these values were significantly higher than those in TNM stage I-II,non-lymph node metastasis,and portal vein tumor thrombus tissues(P<0.05).The expression of caspase-3 and HIF-1αin HCC tissues were negatively correlated(rs=−0.426,P<0.05).The median overall survival time of HCC patients was 18.90 mo(95%CI:17.20–19.91).The results of the Cox proportional risk regression model analysis showed that TNM stage,portal vein tumor thrombus,lymph node metastasis,caspase-3 expression,and HIF-1αexpression were the factors influencing patient prognosis(P<0.05).CONCLUSION The expression of caspase-3 decreases and HIF-1αincreases in HCC tissues complicated by pathological changes of hemorrhage and necrosis,and these are related to clinicopathological features and prognosis.

The Regulation and Interactions of the Hypoxia Inducible Factor Pathway in Carcinogenesis and Potential Cancer Therapeutic Strategies

The Hypoxia Inducible factor (HIF) pathway is known to be constitutionally active in various cancers and is the dominant pathway in some cancers such as VHL mutant clear cell Renal cell carcinoma. HIF-1α and HIF-2α overexpression is known to be important for tumor cell proliferation, maintenance of stemness and angiogenesis. There has been growing interest in therapeutic strategies targeting the HIF pathway over the last decade. We review in this section the role of hypoxia inducible factor pathway in carcinogenesis, its crosstalk with other pathways and potential cancer therapeutic strategies targeting the HIF pathway, its upstream regulators and downstream signaling.

Hypoxia inducible factor in hepatocellular carcinoma:A therapeutic target

Hepatocellular carcinoma(HCC) is one of the most commonly diagnosed and deadly cancers worldwide; its incidence has been rising in the United States due to the increase in hepatitis C associated cirrhosis and the growing epidemic of obesity. There have been no effective therapeutic options in the advanced disease setting beyond sorafenib, a multi-targeted tyrosine kinase inhibitor that showed significant survival benefit. Because of this, there is an urgent need to search for novel pathways in sorafenib experienced patients. This review will focus on the role of hypoxia and hypoxiainducible factor alpha(HIF-1α) in cancer development, specifically in HCC. We will discuss the biology of HIF-1α, the pathways with which it interacts, and the function of HIF-1α in HCC. Furthermore, we will review studies highlighting the relevance of HIF-1α in the clinical setting, as well as the pre-clinical data supporting its further investigation. Finally, we will conclude with a discussion of the potential role of a HIF-1α m RNA antagonist for the treatment of HCC, and hypothesize the ways in which such an inhibitor may be best utilized in the management of advanced HCC. Hypoxia plays a significant role in the development of HCC. HIF-1α is a key transcription factor involved in the hypoxic response of cancer cells. It activates transcription of genes responsible for angiogenesis, glucose metabolism, proliferation, invasion and metastasis in HCC. Its involvement in multiple, essential tumor pathways makes it an attractive potential therapeutic target in HCC.

Evaluation of hypoxia inducible factor targeting pharmacological drugs as antileishmanial agents

Objective:To evaluate whether hypoxia inducible factor(HIF-1α) targeting pharmacological drugs,echinomycin,resveratrol and CdCl_2 which inhibit HIF-1α stimulation,and mimosine,which enhances the stability of HIF-1α present antileishmanial properties.Methods:The leishmanicidal effect of drugs was evaluated in mouse macrophages and Balb/c mouse model for cutaneous leishmaniosis.Results:Resveratrol and CdCl_2 reduced the parasite load [IC50,(27.3±2.25) μM and(24.8±0.95) μM,respectively].The IC50 value of echinomycin was(22.7±7.36) nM and mimosine did not alter the parasite load in primary macrophages.The macrophage viability IC50 values for resveratrol,echinomycin and CdCl_2 and mimosine were >40 μM,>100 nM,> 200 μM and>2 000 μM,respectively.In vivo no differences between cutaneous lesions from control,resveratrol-and echinomycin-treated Balb/c mice were detected.Conclusions:Resveratrol,echinomycin and CdCl_2 reduce parasite survival in vitro.The HIF-1α targeting pharmacological drugs require further study to more fully determine their anti-Leishmania potential and their role in therapeutic strategies.

Transcriptional Factor Snail Mediates Epithelial-Mesenchymal Transition in Human Bronchial Epithelial Cells Induced by Silica

Epithelial-mesenchymal transition （EMT） plays an important role in fibrotic diseases. We have previously showed that silica induces EMT in human bronchial epithelial cells （BECs）; however, the underlying mechanism of silica-induced EMT is poorly understood. In the present study, we investigated the role of Snail in silica-induced EMT in human BECs in vitro. Human BECs were treated with silica at various concentrations and incubation times. Then MTr assay, western blot, electrophoretic mobility shift assay （EMSA）, and small interfering RNA （siRNA） transfection were performed. We found that silica increased the expression and DNA binding activity of Snail in human BECs. SNAI silica-induced expression siRNA upregulated the siRNA inhibited the of Snail. Moreover, SNAI expression of epithelial marker E-cadherin, but attenuated the expression of mesenchymal marker a-smooth muscle actin and vimentin in silica-stimulated cells. These results suggest that Snail mediates the silica-induced EMT in human BECs.

Sirtuin1 attenuates acute liver failure by reducing reactive oxygen species via hypoxia inducible factor 1α

BACKGROUND The occurrence and development of acute liver failure(ALF)is closely related to a series of inflammatory reactions,such as the production of reactive oxygen species(ROS).Hypoxia inducible factor 1α(HIF-1α)is a key factor that regulates oxygen homeostasis and redox,and the stability of HIF-1αis related to the ROS level regulated by Sirtuin(Sirt)family.The activation of Sirt1 will lead to a powerful antioxidant defense system and therapeutic effects in liver disease.However,little is known about the relationship between HIF-1αand Sirt1 in the process of ALF and the molecular mechanism.AIM To investigate whether HIF-1αmay be a target of Sirt1 deacetylation and what the effects on ALF are.METHODS Mice were administrated lipopolysaccharide(LPS)/D-gal and exposed to hypoxic conditions as animal model,and resveratrol was used as an activator of Sirt1.The cellular model was established with L02 cells stimulated by LPS.N-acetyl-Lcysteine was used to remove ROS,and the expression of Sirt1 was inhibited by nicotinamide.Western blotting was used to detect Sirt1 and HIF-1αactivity and related protein expression.The possible signaling pathways involved were analyzed by immunofluorescent staining,co-immunoprecipitation,dihydroethidium staining,and Western blotting.RESULTS Compared with mice stimulated with LPS alone,the expression of Sirt1 decreased,the level of HIF-1αacetylation increased in hypoxic mice,and the levels of carbonic anhydrase 9 and Bcl-2-adenovirus E1B interacting protein 3 increased significantly,which was regulated by HIF-1α,indicating an increase of HIF-1αactivity.Under hypoxia,the down-regulation of Sirt1 activated and acetylated HIF-1αin L02 cells.The inhibition of Sirt1 significantly aggravated this effect and the massive production of ROS.The regulation of ROS was partly through peroxisome proliferatoractivated receptor alpha or AMP-activated protein kinase.Resveratrol,a Sirt1 activator,effectively relieved ALF aggravated by hypoxia,the production of ROS,and cell apoptosis.It also induced the deacetylation of HIF-1αand inhibited the activity of HIF-1α.CONCLUSION Sirt1 may have a protective effect on ALF by inducing HIF-1α deacetylation to reduce ROS.