Hysterectomy, oophorectomy and risk of non-Hodgkin's lymphoma.

Hysterectomy is associated with an increased risk for adverse health outcomes. However, its connection to the risk of non-Hodgkin's lymphoma (NHL) remains unclear. The aims of our study were to investigate the associations between hysterectomy, oophorectomy and risk of NHL and its major subtypes (eg, diffuse large B-cell lymphoma [DLBCL]), and whether these associations were modified by exogenous hormone use. Postmenopausal women (n = 141,621) aged 50-79 years at enrollment (1993-1998) from the Women's Health Initiative were followed for an average of 17.2 years. Hysterectomy and oophorectomy were self-reported at baseline. Incident NHL cases were confirmed by central review of medical records and pathology reports. During the follow-up period, a total of 1719 women were diagnosed with NHL. Hysterectomy, regardless of oophorectomy status, was associated with an increased risk of NHL (hazard ratio [HR] = 1.23, 95% confidence interval [CI]: 1.05-1.44). Oophorectomy was not independently associated with NHL risk after adjusting for hysterectomy. When stratified by hormone use, the association between hysterectomy and NHL risk was confined to women who had never used hormone therapy (HR = 1.35, 95% CI: 1.06-1.71), especially for DLBCL subtype (P for interaction = .01), and to those who had undergone hysterectomy before the age of 55. Our large prospective study showed that hysterectomy was a risk factor of NHL. Findings varied by hormone use. Future studies incorporating detailed information on the types and indications of hysterectomy may deepen our understanding of the mechanisms underlying DLBCL development and its potential interactions with hormone use.

Canonical Rab5 GTPases are essential for pollen tube growth through style in Arabidopsis.

Pollen tubes have dynamic tubular vacuoles. Functional loss of AP-3, a regulator of one vacuolar trafficking route, reduces pollen tube growth. However, the role of canonical Rab5 GTPases that are responsible for two other vacuolar trafficking routes in Arabidopsis pollen tubes is obscure. By using genomic editing, confocal microscopy, pollen tube growth assays, and transmission electron microscopy, we demonstrate that functional loss of canonical Rab5s in Arabidopsis, RHA1 and ARA7, causes the failure of pollen tubes to grow through style and thus impairs male transmission. Functional loss of canonical Rab5s compromises vacuolar trafficking of tonoplast proteins, vacuolar biogenesis, and turgor regulation. However, rha1;ara7 pollen tubes are comparable to those of wild-type in growing through narrow passages by microfluidic assays. We demonstrate that functional loss of canonical Rab5s compromises endocytic and secretory trafficking at the plasma membrane (PM), whereas the targeting of PM-associated ATPases is largely unaffected. Despite that, rha1;ara7 pollen tubes contain a reduced cytosolic pH and disrupted actin microfilaments, correlating with the mis-targeting of vacuolar ATPases (VHA). These results imply a key role of vacuoles in maintaining cytoplasmic proton homeostasis and in pollen tube penetrative growth through style.

Body size over the adult life course and the risk of colorectal cancer among postmenopausal women.

OBJECTIVE: To assess the associations among several anthropometric measures, as well as BMI trajectories and colorectal cancer (CRC) risk in older women. DESIGN: Prospective cohort study. SETTING: Forty clinical centres in the USA. PARTICIPANTS: Totally, 79 034 postmenopausal women in the Women's Health Initiative Observational Study. RESULTS: During an average of 15·8 years of follow-up, 1514 CRC cases were ascertained. Five BMI trajectories over 18-50 years of age were identified using growth mixture model. Compared with women who had a normal BMI at age 18, women with obesity at age 18 had a higher risk of CRC (HR 1·58, 95 % CI 1·02, 2·44). Compared with women who kept relatively low normal body size during adulthood, women who progressed from normal to obesity (HR 1·29, 95 % CI 1·09, 1·53) and women who progressed from overweight to obesity (HR 1·37, 95 % CI 1·13, 1·68) had higher CRC risks. A weight gain > 15 kg from age 18 to 50 (HR 1·20, 95 % CI 1·04, 1·40) and baseline waist circumference > 88 cm (HR 1·33, 95 % CI 1·19, 1·49) were associated with higher CRC risks, compared with stable weight and waist circumference ≤ 88 cm, respectively. CONCLUSION: Women who have a normal weight in early adult life and gain substantial weight later, as well as those who are persistently heavy over adulthood, demonstrated a higher risk of developing CRC. Our study highlights the importance of maintaining a healthy body weight over the life course for reducing the risk of developing CRC in women.

Effects of brassinosteroids on cancer cells: A review.

Brassinolide is a new type of steroidal hormone with strong activities, which is well known as an efficient and low-toxicity plant growth regulator for a long time. Because steroidal hormones have a wide application prospect, brassinosteroids have been gradually explored in pharmacology and animal cells in recent decades. Brassinolide could effectively reverse the resistance of human T lymphoblastoid cell line CCRF-VCR 1000 by inhibiting the effusion of drug transported by P-glycoprotein. Brassinosteroids could also accelerate wound healing by positively eliminating inflammation and stimulating reepithelialization of the reparation stage. The occurrence of cancer is a multistep process mediated by a variety of factors. Until now, cancer has always been one group of the major diseases that threaten human health. Many studies have found that brassinosteroids have attracted a great deal of potential as an anticancer agent in the treatment of cancer cells, and most of them exert anticancer activity by inducing apoptosis in cancer cells. There are few articles on the relationship between brassinosteroids and cancer so far. Accordingly, in this article, we summarized current research about the brassinosteroids and cancers. Through the review, researchers could know more about brassinosteroids which might become a new tool for the treatment of cancer in the future, and not only a plant hormone.

The methyltransferase G9a regulates HoxA9-dependent transcription in AML.

Chromatin modulators are emerging as attractive drug targets, given their widespread implication in human cancers and susceptibility to pharmacological inhibition. Here we establish the histone methyltransferase G9a/EHMT2 as a selective regulator of fast proliferating myeloid progenitors with no discernible function in hematopoietic stem cells (HSCs). In mouse models of acute myeloid leukemia (AML), loss of G9a significantly delays disease progression and reduces leukemia stem cell (LSC) frequency. We connect this function of G9a to its methyltransferase activity and its interaction with the leukemogenic transcription factor HoxA9 and provide evidence that primary human AML cells are sensitive to G9A inhibition. Our results highlight a clinical potential of G9A inhibition as a means to counteract the proliferation and self-renewal of AML cells by attenuating HoxA9-dependent transcription.

Treatment and high value utilization of glutamic acid wastewater.

Glutamate wastewater has a high yield in the world and is difficult to be treated due to its high acidity, high COD (chemical oxygen demand, reflecting the pollution degree of reduced substances in the water) and high ammonia nitrogen characteristics. In this study, Bacillus licheniformis M 2020051 was used to treat organic wastewater to ferment polyglutamic acid, which reduced the pollution of industrial wastewater and produced polyglutamic acid at a low cost. Firstly, a strain with high salt tolerance and high polyglutamic acid production was isolated from saline soil, and the mechanism of salt tolerance and polyglutamic acid production were also analyzed. Then Single-factor experiment and Response surface methodology (RSM) were used to determine the appropriate fermentation conditions to achieve maximum γ-polyglutamic acid production. After optimization, the yield of polyglutamic acid was increased to 6.91 g·L-1 by shaking fermentation, an increase of 7.13%. Finally, the agronomic experiments were carried out, and the results showed that γ-polyglutamic acid could significantly increase the germination rate of corn seeds and the growth of rapeseed. These studies will lay the foundation for reducing industrial wastewater pollution and exploring the production model of γ-polyglutamic acid.

A new activator of esterase D decreases blood cholesterol level through ESD/JAB1/ABCA1 pathway.

Excessively high cholesterol content in the blood leads to nonalcohol fatty liver disease (NAFLD) and arteriosclerosis. Although there are increasing publications and patent applications to lower blood cholesterol with small chemical molecules, limited effective drugs can be available in clinic. It is necessary to uncover new targets and drugs to alleviate high cholesterol. Esterase D (ESD) is abundant in liver and it remains unknown about its role in cholesterol metabolism. Here we reported that small chemical molecule fluorescigenic pyrazoline derivative 5 (FPD5), a new ESD activator, could effectively reverse high blood cholesterol level and prevent fatty liver and arteriosclerosis in apoE-/- mice fed the high-fat diet. We also observed that FPD5 could reduce oxidized low density lipoprotein (oxLDL)-induced formation of foam cells. To further investigate the mechanism of FPD5 action on blood cholesterol modulation, we found that ESD trigged by FPD5 was aggregated in lysosome and interacted with Jun activation domain binding protein 1 (JAB1). ESD served as a deacetylase to remove Thr89 acetylation of JAB1 and increased its activity; thus, promoting the ATP-binding cassette transporters A1 (ABCA1) to accelerate cholesterol efflux. Our findings demonstrate that FPD5 decreases blood cholesterol level to ameliorate NAFLD and arteriosclerosis through ESD/JAB1/ABCA1 pathway, and ESD functions as a novel nonclassical deacetylase that hydrolyzes serine/threonine acetyl group. Our findings not only highlight that FPD5 may be a pioneer drug for alleviating blood cholesterol but also indicate that ESD is a potential drug target that promotes cholesterol metabolism.

Effects of nitrogen levels on gene expression and amino acid metabolism in Welsh onion.

BACKGROUND: Welsh onion constitutes an important crop due to its benefits in traditional medicine. Nitrogen is an important nutrient for plant growth and yield; however, little is known about its influence on the mechanisms of Welsh onion regulation genes. In this study, we introduced a gene expression and amino acid analysis of Welsh onion treated with different concentrations of nitrogen (N0, N1, and N2 at 0 kg/ha, 130 kg/ha, and 260 kg/ha, respectively). RESULTS: Approximately 1,665 genes were differentially regulated with different concentrations of nitrogen. Gene ontology enrichment analysis revealed that the genes involved in metabolic processes, protein biosynthesis, and transportation of amino acids were highly represented. KEGG analysis indicated that the pathways were related to amino acid metabolism, cysteine, beta-alanine, arginine, proline, and glutathione. Differential gene expression in response to varying nitrogen concentrations resulted in different amino acid content. A close relationship between gene expression and the content of amino acids was observed. CONCLUSIONS: This work examined the effects of nitrogen on gene expression and amino acid synthesis and provides important evidence on the efficient use of nitrogen in Welsh onion.

Prediction of Unbound Ceftriaxone Concentration in Children: Simple Bioanalysis Method and Basic Mathematical Equation.

The pharmacological activity of ceftriaxone depends on the unbound concentration. However, direct measurement of unbound concentrations is obstructive, and high individual variability of the unbound fraction of ceftriaxone was shown in children. We aim to evaluate and validate a method to predict unbound ceftriaxone concentrations in pediatric patients. Ninety-five pairs of concentrations (total and unbound) from 92 patients were measured by the bioanalysis method that we developed. The predictive performance of the three equations (empirical in vivo equation, disease-adapted equation, and multiple linear regression equation) was assessed by the mean absolute prediction error (MAPE), the mean prediction error (MPE), the proportions of the prediction error within ±30% (P30) and ±50% (P50), and linear regression of predicted versus actual unbound levels (R2). The average total and unbound ceftriaxone concentrations were 126.18 ± 81.46 µg/ml and 18.82 ± 21.75 µg/ml, and the unbound fraction varied greatly from 4.75% to 39.97%. The MPE, MAPE, P30, P50, and R2 of the empirical in vivo equation, disease equation, and multiple linear equation were 0.17 versus 0.00 versus 0.06, 0.24 versus 0.15 versus 0.27, 63.2% versus 89.5% versus 74.7%, 96.8% versus 97.9% versus 86.3%, and 0.8730 versus 0.9342 versus 0.9315, respectively. The disease-adapted equation showed the best predictive performance. We have developed and validated a bioanalysis method with one-step extraction pretreatment for the determination of total ceftriaxone concentrations, and a prediction equation of the unbound concentration is recommended. The proposed method can facilitate clinical practice and research on unbound ceftriaxone in children. (This study has been registered at ClinicalTrials.gov under identifier NCT03113344.).

Discovery of a fluorescigenic pyrazoline derivative targeting ubiquitin.

Despite significant process in ubiquitin modification by using traditional genetic methods, chemical small molecules that directly target and modify ubiquitin are little reported. Here, we find that a fluorescigenic pyrazoline derivative (FPD5) could do so effectively. Molecule docking revealed that lysine 11 of ubiquitin was the key contact residue. FPD5, with stronger fluorescence, elevated the ubiquitination of beclin 1 (BECN1) and promoted autophagy. This study highlights that targeting ubiquitin by chemical small molecules enables us to modulate ubiquitination and the downstream signaling in the ubiquitin system.

Developmental population pharmacokinetics-pharmacodynamics and dosing optimization of cefoperazone in children.

OBJECTIVES: To evaluate the population pharmacokinetics of cefoperazone in children and establish an evidence-based dosing regimen using a developmental pharmacokinetic-pharmacodynamic approach in order to optimize cefoperazone treatment. METHODS: A model-based, open-label, opportunistic-sampling pharmacokinetic study was conducted in China. Blood samples from 99 cefoperazone-treated children were collected and quantified by HPLC/MS. NONMEM software was used for population pharmacokinetic-pharmacodynamic analysis. This study was registered at ClinicalTrials.gov (NCT03113344). RESULTS: A two-compartment model with first-order elimination agreed well with the experimental data. Covariate analysis showed that current body weight had a significant effect on the pharmacokinetics of cefoperazone. Monte Carlo simulation showed that for bacteria for which cefoperazone has an MIC of 0.5 mg/L, 78.1% of hypothetical children treated with '40 mg/kg/day, q8h, IV drip 3 h' would reach the pharmacodynamic target. For bacteria for which cefoperazone has an MIC of 8 mg/L, 88.4% of hypothetical children treated with 80 mg/kg/day (continuous infusion) would reach the treatment goal. A 160 mg/kg/day (continuous infusion) regimen can cover bacteria for which cefoperazone has an MIC of 16 mg/L. Nevertheless, even if using the maximum reported dose of 160 mg/kg/day (continuous infusion), the ratio of hypothetical children reaching the treatment target was only 9.9% for bacteria for which cefoperazone has an MIC of 32 mg/L. CONCLUSIONS: For cefoperazone, population pharmacokinetics were evaluated in children and an appropriate dosing regimen was developed based on developmental pharmacokinetics-pharmacodynamics. The dose indicated in the instructions (20-160 mg/kg/day) can basically cover the clinically common bacteria for which cefoperazone has an MIC of ≤16 mg/L. However, for bacteria for which the MIC is >16 mg/L, cefoperazone is not a preferred choice.

Off-label use of tacrolimus in children with glomerular disease: Effectiveness, safety and pharmacokinetics.

Glomerular diseases are leading causes of end-stage renal disease in children. Tacrolimus is frequently used off-label in the treatment of glomerular diseases. The effectiveness, safety and pharmacokinetic data of tacrolimus in the treatment of glomerular diseases in children are reviewed in this paper to provide evidence to support its rational use in clinical practice. The remission rates in previously published studies were different. In 19 clinical trials on children with nephrotic syndrome, the overall remission rate was 52.6-97.6%. In four clinical trials on children with lupus nephritis, the overall remission rate was 81.8-89.5%. In a pilot study with paediatric Henoch-Schönlein purpura nephritis patients, the overall remission rate was 100.0%. Infection, nephrotoxicity, gastrointestinal symptoms and hypertension are the most common adverse events. Body weight, age, CYP3A5 genotype, cystatin-C and daily dose of tacrolimus may have significant effects on the pharmacokinetics of tacrolimus in children with glomerular disease. More prospective controlled trials with long follow-up are needed to demonstrate definitely the effectiveness, safety and pharmacokinetics of tacrolimus in children with glomerular diseases.

The novel HOCl fluorescent probe CAN induced A549 apoptosis by inhibiting chlorination activity of MPO.

Hypochlorous acid (HOCl) is an important signaling molecule for cell survival. However, it has been reported that excessive HOCl contributes to a variety of diseases such as cancers. And in cancer cells, the level of HOCl is much higher than that in normal cells. Here a coumarin-based fluorescent probe 7-Diethylamino-3-(2,3-dihydro-1H-perimidin-2-yl)-chromen-2-one (CAN) was successfully developed for HOCl detection. The probe could be oxidized by HOCl to induce significant change in its fluorescence profile, which made it feasible for ratiometric detecting HOCl. CAN (below 1 µM) did not affect cell viability and had good capacity in ratiometric detection of HOCl in RAW 264.7 cells. CAN induced A549 apoptosis and inhibited tumor growth in vitro and in vivo. And CAN could decrease the chlorination activity of myeloperoxidase (MPO) in A549. These findings suggested that CAN (below 1 µM) would develop into a HOCl probe. High activity of MPO and level of HOCl might be helpful for A549 survival. A549 could be induced apoptosis by reducing the HOCl level by CAN. It implies a new anticancer strategy by targeting HOCl.

Finding the mechanism of esterase D activation by a small molecule.

People with reduced esterase D (ESD) activity are susceptible to many diseases. However, how to activate ESD is still unknown. To address the question, we identified that 4-chloro-2-(5-phenyl-1-(pyridin-2-yl)-4, 5-dihydro-1H-pyrazol-3-yl) phenol (FPD5) could be a good candidate activator for ESD activity. We found that FPD5 could increase ESD activity in a dose-dependent way. FPD5 bound directly to ESD at Lys180 rather than its ubiquitination site Lys213. Site-directed mutagenesis at the binding site or the ubiquitination site inhibited FPD5 action. FPD5 increased the level of ESD mono-ubiquitination and mutESD K213A completely inhibited this action. Our findings highlighted the activation mechanism of ESD via promoting the mono-ubiquitination of ESD.

Cefotiam Treatment in Children: Evidence of Subtherapeutic Levels.

BACKGROUND: Cefotiam, a second-generation cephalosporin, is a broad-spectrum antibiotic with good antibacterial action against both gram-negative and gram-positive bacteria. It is used widely in clinical practice, although bacterial drug resistance makes its clinical use problematic. The authors hypothesized that subtherapeutic concentrations of cefotiam leads to bacterial resistance. The present study was conducted to evaluate whether the standard cefotiam dosing regimen resulted in a subtherapeutic concentrations in children. METHOD: Data were prospectively collected from pediatric patients with suspected or confirmed community-acquired pneumonia who were receiving cefotiam at the standard dosing regimen (40-80 mg/kg, 2 or 3 times daily). A blood sample was collected after 70%-100% of the dosing interval, and plasma concentrations were determined by high-performance liquid chromatography using an ultraviolet detector. RESULTS: The data from 88 patients (age, 3.0 ± 2.8 years; weight, 15.4 ± 8.3 kg) were used for analysis. The average of cefotiam concentrations was 0.06 mcg/mL (range: <0.05-0.79 mcg/mL). Most patients (n = 72, 81.8%) had concentrations below 0.1 mcg/mL; only 2 patients had concentrations higher than 0.4 mcg/mL. CONCLUSIONS: The standard dosing regimen for cefotiam resulted in extremely low plasma concentrations in children; such low concentrations may lead to antimicrobial drug resistance. Thus, an increase in cefotiam dosage in children to 80 mg/kg 4 times daily is recommended (maximum dose on the label).

First dose in neonates: pharmacokinetic bridging study from juvenile mice to neonates for drugs metabolized by CYP3A.

First dose prediction is challenging in neonates. Our objective in this proof-of-concept study was to perform a pharmacokinetic (PK) bridging study from juvenile mice to neonates for drugs metabolized by CYP3A. We selected midazolam and clindamycin as model drugs. We developed juvenile mice population PK models using NONMEM. The PK parameters of these two drugs in juvenile mice were used to bridge PK parameters in neonates using different correction methods. The bridging results were evaluated by the fold-error of 0.5- to 1.5-fold. Simple allometry with and without a correction factor for maximum lifespan potential could be used for a bridging of clearance (CL) and volume of distribution (Vd), respectively, from juvenile mice to neonates. Simulation results demonstrated that for midazolam, 100% of clinical studies for which both the predictive CL and Vd were within 0.5- to 1.5-fold of the observed. For clindamycin, 75% and 100% of clinical studies for which the predictive CL and Vd were within 0.5- to 1.5-fold of the observed. A PK bridging of drugs metabolized by CYP3A is feasible from juvenile mice to neonates. It could be a complement to the ADE and PBPK models to support the first dose in neonates.

The Impact of a Gluten-Free Diet on Celiac Disease: A Comprehensive Evaluation of Two Cases Using NIH Patient Reported Outcome Measures (PROMIS, NTCB, and Neuro-QoL).

The aim of this study is to demonstrate the effectiveness of the gluten-free diet (GFD) for celiac disease (CD) in a multidisciplinary outpatient Gastroenterology clinic with two adult cases using the innovative, paradigm-shifting measurement systems: The NIH Patient reported outcome measures (PROs). CD results in gastrointestinal (GI) dysfunction, but is also associated with other inflammatory responses, psychosocial impairment, and cognitive deficits such as "brain fog." Adherence to the GFD for 6 months was associated with improvement in specific GI symptoms in one case (PROMIS-GI; Case 2) and improvement in cognitive functioning (NIH Toolbox Cognitive Battery) and psychosocial functioning (Neuro-QOL) in both cases. Notably, improvement in cognitive flexibility occurred in both younger and an older adult patient. This suggests that cognitive decline and the psychosocial deficits associated with CD are reversible with GFD. The NIH PROs were found to be effective, sensitive to change, and minimally disruptive to clinic operations.

Loss of HMBOX1 promotes LPS-induced apoptosis and inhibits LPS-induced autophagy of vascular endothelial cells in mouse.

Our previous study revealed that Homeobox containing 1 (HMBOX1), essential for the survival of vascular endothelial cells (VECs), was involved in the progression of atherosclerosis. Knockdown of HMBOX1 promoted apoptosis and inhibited autophagy through regulating intracellular free zinc level in cultured VECs. In current study, in order to investigate the roles of HMBOX1 in vivo and in endothelium, we generated a knockout (KO) mouse for HMBOX1 by using transcription activator-like effector nucleases (TALENs) technology. Herein, we reported that the protein level of HMBOX1 was gradually increased during mouse development. The HMBOX1 KO mouse was viable and fertile. There existed no differences in apoptosis and autophagy of aortic endothelial cells between wild type and KO mouse. Whereas, loss of HMBOX1 promoted apoptosis and inhibited autophagy of aortic endothelial cells under lipopolysaccharide (LPS) stimulation in mouse. We also demonstrated that HMBOX1 deletion had no influence on the secretion of inflammatory cytokines TNF-α and IL-6. Moreover, overexpression or knockdown of HMBOX1 failed to regulate multiple pro-apoptotic genes expression in vitro. In conclusion, HMBOX1 participated in the functional maintenance of mouse aortic endothelial cells, the aortic endothelial cells of HMBOX1 KO mouse showed increased apoptosis and decreased autophagy with LPS treatment.

Effects of annexin A7 inhibitor-ABO on the expression and distribution of long noncoding RNA-CERNA1 in vascular endothelial cells apoptosis.

More and more studies reported that diverse biological roles of long noncoding RNAs were usually dependent on their subcellular location. In our previous study, long noncoding RNA CERNA1 was identified both located in cytoplasm and nucleus of vascular endothelial cells (VECs). And CERNA1 in cytoplasm, which functioned as competitive endogenous RNA (ceRNA), alleviated the apoptosis of VECs. However, the function of CERNA1 in nucleus was still unclear. In this study, we found that nuclear CERNA1 positively regulated BCL2L10, which accelerated the serum and FGF-2 starvation-induced apoptosis of VECs, by enhancing the histone modification level of H3K9ac and H3K4me3 in BCL2L10 promoter region. Furthermore, due to the paradoxical function, we investigated the variation of CERNA1 subcellular location in VECs. The results showed that, as the change of apoptosis status, CERNA1 altered the cellular distribution in VECs. And the annexin A7 inhibitor, ABO (6-amino-2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine), not only increased the expression of CERNA1 by TIA-1, but also specifically improved its cytoplasm distribution proportion so as to inhibit the apoptosis of VECs. This evidence suggested that the subcellular location of CERNA1 played an important role in the VECs apoptosis and ABO might be a potential chemical molecule for therapy of VECs apoptosis related cardiovascular diseases.

Low-concentration HCP1 inhibits apoptosis in vascular endothelial cells.

Vascular endothelial cell (VEC) apoptosis takes part in the development of various cardiovascular diseases. Heat shock protein 90 (HSP90) regulates apoptosis through various apoptosis associated client proteins. In previous study, we identified a novel HSP90 inhibitor HCP1 induced apoptosis in A549 human lung cancer cells. Here, we found that low-concentration HCP1 (1 µM, 2 µM) suppressed VEC apoptosis caused by serum and fibroblast growth factor 2 (FGF-2) deprivation. HCP1 directly bound to glucose-regulated protein 94 (Grp94), an isoform of HSP90 located in endoplasmic reticulum, and HCP1 selectively inhibited Grp94 activity via binding to site 3. Overexpression of Grp94 inhibited the anti-apoptotic effect of HCP1 in human umbilical vein endothelial cells. Therefore, we provided HCP1 as a new VEC apoptosis inhibitor which might be a potential compound in the treatment of VEC apoptosis related vascular diseases. And we provided new pieces of evidence to understand the role of Grp94 in VEC apoptosis.