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1.

Background

Inflammation is a share process in atherosclerosis and stroke and is thought to be a key player in the evolution of these diseases. Ten years ago, inflammation imaging with magnetic resonance imaging (MRI) was considered very promising for both pre-clinical and clinical studies of atherosclerosis and stroke.

Contribution

We report here contributions to the field of inflammation imaging with USPIO-enhanced MRI. The goal was to investigate the life cycle of USPIOs in the body, and how the MRI signal has been impacted during their bio-interactions and bioprocessing. Those mechanisms were applied to pre-clinical longitudinal studies of inflammation in atherosclerosis and at the acute stage of ischemic stroke thus allowing the monitoring of treatment effects.

Conclusion

This review presents the contribution of the collaborative research project under the “TecSan” grant from the French Research Agency (ANR) as well as pre-clinical and clinical perspectives of USPIO's inflammation MRI in atherosclerosis and stroke.  相似文献   

2.

Background

Spontaneous intracranial hypotension (SIH) is caused by cerebrospinal fluid (CSF) leakage. Definitive diagnosis can be difficult by clinical examinations and imaging studies.

Methods

SIH was diagnosed with the following criteria: (i) evidence of CSF leakage by cranial magnetic resonance imaging (MRI) findings of intracranial hypotension and/or low CSF opening pressure; (ii) no recent history of dural puncture. We quantified CSF proteins by ELISA or Western blotting.

Results

Comparing with non-SIH patients, SIH patients showed significant increase of brain-derived CSF glycoproteins such as lipocalin-type prostaglandin D synthase (L-PGDS), soluble protein fragments generated from amyloid precursor protein (sAPP) and “brain-type” transferrin (Tf). Serum-derived proteins such as albumin, immunoglobulin G, and serum Tf were also increased. A combination of L-PGDS and brain-type Tf differentiated SIH from non-SIH with sensitivity 94.7% and specificity 72.6%.

Conclusion

L-PGDS and brain-type Tf can be biomarkers for diagnosing SIH.

General significance

L-PGDS and brain-type Tf biosynthesized in the brain appears to be markers for abnormal metabolism of CSF.  相似文献   

3.

Background

Endoglin (CD105) is overexpressed on tumor cells and tumor vasculatures, making it a potential target for diagnostic imaging and therapy of different neoplasms. Therefore, studies on nanocarrier systems designed for endoglin-directed diagnostic and drug delivery purposes would expose the feasibility of targeting endoglin with therapeutics.

Methods

Liposomes carrying high concentrations of a near-infrared fluorescent dye in the aqueous interior were prepared by the lipid film hydration and extrusion procedure, then conjugated to single chain antibody fragments either selective for murine endoglin (termed mEnd-IL) or directed towards human endoglin (termed hEnd-IL). A combination of Dynamic Light Scattering, electron microscopy, cell binding and uptake assays, confocal microscopy and in vivo fluorescence imaging of mice bearing xenografted human breast cancer and human fibrosarcoma models were implemented to elucidate the potentials of the liposomes.

Results

The mEnd-IL and hEnd-IL were highly selective for the respective murine- and human endoglin expressing cells in vitro and in vivo. Hence, the hEnd-IL bound distinctly to the tumor cells and enabled suitable fluorescence imaging of the tumors, whereas the mEnd-IL bound the tumor vasculature, but also to the liver, kidney and lung vasculature of mice.

Conclusions

The work highlights key differences between targeting vascular (murine) and neoplastic (human) endoglin in animal studies, and suggests that the hEnd-IL can serve as a delivery system that targets human endoglin overexpressed in pathological conditions.

General significance

The endoglin-targeting liposomes presented herewith represent strategic tools for the future implementation of endoglin-directed neoplastic and anti-angiogenic therapies.  相似文献   

4.
5.

Background

Intracellular pH underlies most cellular processes. There is emerging evidence of a pH-signaling role in plant cells and microorganisms. Dysregulation of pH is associated with human diseases, such as cancer and Alzheimer's disease.

Scope of review

In this review, we attempt to provide a summary of the progress that has been made in the field during the past two decades. First, we present an overview of the current state of the design and applications of fluorescent protein (FP)-based pH indicators. Then, we turn our attention to the development and applications of hybrid pH sensors that combine the capabilities of non-GFP fluorophores with the advantages of genetically encoded tags. Finally, we discuss recent advances in multicolor pH imaging and the applications of genetically encoded pH sensors in multiparameter imaging.

Major conclusions

Genetically encoded pH sensors have proven to be indispensable noninvasive tools for selective targeting to different cellular locations. Although a variety of genetically encoded pH sensors have been designed and applied at the single cell level, there is still much room for improvements and future developments of novel powerful tools for pH imaging. Among the most pressing challenges in this area is the design of brighter redshifted sensors for tissue research and whole animal experiments.

General significance

The design of precise pH measuring instruments is one of the important goals in cell biochemistry and may give rise to the development of new powerful diagnostic tools for various diseases.  相似文献   

6.

Background

Treatment of prostate cancer using endocavitary High Intensity Focused Ultrasound (HIFU) has become more commonplace since the first treatments in the 1990s. The gold standard HIFU strategy to treat prostate cancer is the complete thermal ablation of the entire prostate gland under real-time ultrasound (US) image guidance. A more desirable treatment and the current trend, however, is towards a focal treatment but more accurate and finely tunable thermal lesions are needed along with improved US imaging guidance. In this study, Capacitive Micromachined Ultrasound Transducer (CMUT) technology is being investigated, as they have shown recent promise for US imaging and potential to be used for HIFU therapy. They offer potential advantages over current piezoelectric designs in the context of ultrasound-guided HIFU (USgHIFU) focal therapies.

Objective

The presented study evaluates the ability of a planar annular array CMUT design to achieve HIFU dynamic focusing and feasibility of generating thermal lesions in biological tissues.

Method

The proposed CMUT design consists of a 64-element annular array for HIFU delivery with a space in the center that accommodates a high-resolution 256-element linear imaging array. The pressure field simulations of the HIFU portion of the array were performed using the Rayleigh integral method. The bioheat transfer equation was then used to predict lesion formation. The HIFU performances of the proposed CMUT phased-array design were compared to those of the device currently used in the clinic. Partial CMUT prototypes, including the therapeutic part only, were fabricated and experimentally characterized (electromechanical CMUT behavior, ultrasound pressure field distribution and acoustic intensity).

Results

The planar 64-element annular CMUT design is capable of dynamically focusing a 3 MHz ultrasound beam at distances ranging from 32 to 72 mm, comparable in size and shape to the ones obtained with the clinical device. The simulated ultrasound fields correlated well to experimental measurements. Visual observation and impedance measurements of the CMUT cells allowed direct estimation of the collapse and snapback voltages of the ring-elements. The surface acoustic intensity of the CMUT ring-elements with both AC driving and DC bias voltages can achieve over 6 W/cm2, shown in simulation to be compatible with the generation of thermal lesions. The electro-acoustic efficiency of the CMUT elements increased with increasing DC bias voltages to reach 31%, and remained stable with increasing AC driving voltages. The ultrasound energy could be dynamically focused from this planar CMUT array during several dozen of minutes.

Conclusion

This work demonstrates the feasibility of utilizing a planar CMUT probe for generating dynamic HIFU focusing and lesioning compatible with the ablation of prostate tissues under endocavitary treatment approach. Future investigations will consist of validating the lesioning capability experimentally both in vitro and in vivo.  相似文献   

7.

Background

Differential Scanning Calorimetry (DSC) is a technique traditionally used to study thermally induced macromolecular transitions, and it has recently been proposed as a novel approach for diagnosis and monitoring of several diseases. We report a pilot study applying Thermal Liquid Biopsy (TLB, DSC thermograms of plasma samples) as a new clinical approach for diagnostic assessment of melanoma patients.

Methods

Multiparametric analysis of DSC thermograms of patient plasma samples collected during treatment and surveillance (63 samples from 10 patients) were compared with clinical and diagnostic imaging assessment to determine the utility of thermograms for diagnostic assessment in melanoma. Nine of the ten patients were stage 2 or 3 melanoma subjects receiving adjuvant therapy after surgical resection of their melanomas. The other patient had unresectable stage 4 melanoma and was treated with immunotherapy. Two reference groups were used: (A) 36 healthy subjects and (B) 13 samples from 8 melanoma patients who had completed successful surgical management of their disease and were determined by continued clinical assessment to have no evidence of disease.

Results

Plasma thermogram analysis applied to melanoma patients generally agrees with clinical evaluation determined by physical assessment or diagnostic imaging (~80% agreement). No false negatives were obtained from DSC thermograms. Importantly, this methodology was able to detect changes in disease status before it was identified clinically.

Conclusions

Thermal Liquid Biopsy could be used in combination with current clinical assessment for the earlier detection of melanoma recurrence and metastasis.

General significance

TLB offers advantages over current diagnostic techniques (PET/CT imaging), limited in frequency by radiation burden and expense, in providing a minimally-invasive, low-risk, low-cost clinical test for more frequent personalized patient monitoring to assess recurrence and facilitate clinical decision-making.  相似文献   

8.
J. Wischhusen  F. Padilla 《IRBM》2019,40(1):10-15

Background

Ultrasound-targeted microbubble destruction (UTMD) is a type of ultrasound therapy, in which low frequency moderate power ultrasound is combined with microbubbles to trigger cavitation. Cavitation is the process of oscillation of gas bubbles causing biophysical effects such as pushing and pulling or shock waves that permeabilize biological barriers. In vivo, cavitation results in tissue permeabilization and is used to enable local delivery of nanomedicine. While cavitation can occur in biological liquids when high pressure ultrasound is applied, the use of microbubbles as cavitation nuclei in UTMD largely facilitates the induction of cavitation. UTMD is intensively studied for drug delivery into tumor tissue, but also for the activation of anti-tumor immune responses. The first clinical studies of UTMD-mediated chemotherapy delivery confirmed safety and efficacy of this approach.

Aim

The present review summarizes ultrasound settings, cavitation approaches, biophysical mechanisms of drug delivery, drug carriers, and pre-clinical and clinical applications of UTMD for drug delivery into tumors.  相似文献   

9.
V. Sharma  K.C. Juglan 《IRBM》2018,39(5):313-323

Background

Fatty Liver Disease (FLD) is one of the most critical diseases that should be detected and cured at the earlier stage in order to decrease the mortality rate. To identify the FLD, ultrasound images have been widely used by the radiologists. However, due to poor quality of ultrasound images, they found difficulties in recognizing FLD. To resolve this problem, many researchers have developed various Computer Aided Diagnosis (CAD) systems for the classification of fatty and normal liver ultrasound images. However, the performance of existing CAD systems is not good in terms of sensitivity while classifying the FLD.

Methods

In this paper, an attempt has been made to present a CAD system for the classification of liver ultrasound images. For this purpose, texture features are extracted by using seven different texture models to represent the texture of Region of Interest (ROI). Highly discriminating features are selected by using Mutual Information (MI) feature selection method.

Results

Extensive experiments have been carried out with four different classifiers, and for carrying out this study, 90 liver ultrasound images have been taken. From the experimental results, it has been found that the proposed CAD system is able to give 95.55% accuracy and sensitivity of 97.77% with the 20 best features selected by the MI feature selection technique.

Conclusion

The experimental results show that the proposed system can be used for the classification of fatty and normal liver ultrasound images with higher accuracy.  相似文献   

10.

Background

Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, typically presenting with metastasis at the time of diagnosis and exhibiting profound resistance to existing therapies. The development of molecular markers and imaging probes for incipient PDAC would enable earlier detection and guide the development of interventive therapies. Here we sought to identify novel molecular markers and to test their potential as targeted imaging agents.

Methods and Findings

Here, a phage display approach was used in a mouse model of PDAC to screen for peptides that specifically bind to cell surface antigens on PDAC cells. These screens yielded a motif that distinguishes PDAC cells from normal pancreatic duct cells in vitro, which, upon proteomics analysis, identified plectin-1 as a novel biomarker of PDAC. To assess their utility for in vivo imaging, the plectin-1 targeted peptides (PTP) were conjugated to magnetofluorescent nanoparticles. In conjunction with intravital confocal microscopy and MRI, these nanoparticles enabled detection of small PDAC and precursor lesions in engineered mouse models.

Conclusions

Our approach exploited a well-defined model of PDAC, enabling rapid identification and validation of PTP. The developed specific imaging probe, along with the discovery of plectin-1 as a novel biomarker, may have clinical utility in the diagnosis and management of PDAC in humans.  相似文献   

11.

Background

Besides its influence on survival, growth, proliferation, invasion and metastasis, cancer cell metabolism also greatly influences the cellular responses to molecular-targeted therapies.

Scope of the review

To review the recent advances in elucidating the metabolic effects of BRAF and MEK inhibitors (clinical inhibitors of the MAPK/ERK pathway) in melanoma and discuss the underlying mechanisms involved in the way metabolism can influence melanoma cell death and resistance to BRAF and MEK inhibitors. We also underlined the therapeutic perspectives in terms of innovative drug combinations.

Major conclusion

BRAF and MEK inhibitors inhibit aerobic glycolysis and induce high levels of metabolic stress leading to effective cell death by apoptosis in BRAF-mutated cancer cells. An increase in mitochondrial metabolism is required to survive to MAPK/ERK pathway inhibitors and the sub-population of cells that survives to these inhibitors are characterized by mitochondrial OXPHOS phenotype. Consequently, mitochondrial inhibition could be combined with oncogenic “drivers” inhibitors of the MAPK/ERK pathway for improving the efficacy of molecular-targeted therapy.

General significance

Metabolism is a key component of the melanoma response to BRAF and/or MEK inhibitors. Mitochondrial targeting may offer novel therapeutic approaches to overwhelm the mitochondrial addiction that limits the efficacy of BRAF and/or MEK inhibitors. These therapeutic approaches might be quickly applicable to the clinical situation.  相似文献   

12.

Background

Kinase inhibitor sorafenib is the most widely used drug for advanced HCC clinical treatment nowadays. However, sorafenib administration is only effective for a small portion of HCC patients, and the majority develop sorafenib-resistance during treatment. Thus, it is urgent to discover the endogenous mechanism and identify new pharmaceutical targets of sorafenib-resistance.

Methods

Pregnane X receptor (PXR) was detected by immunohistochemistry and quantitative PCR. GST-pull down and LC-MS/MS was used to detect the interaction of PXR and Sorafenib. To test the properties of HCC tumor growth and metastasis, in vivo tumor explant model, FACS, trans-well assay, cell-survival inhibitory assay and Western blot were performed. In terms of mechanistic study, additional assays such as ChIP and luciferase reporter gene assay were applied.

Results

In the present work, we found high PXR level in clinical specimens is related to the poor prognosis of Sorafenib treated patients. By the mechanistic studies, we show that sorafenib binds to PXR and activates PXR pathway, and by which HCC cells develop sorafenib-resistance via activating. Moreover, PXR overexpression helps HCC cells to persist to sorafenib treatment.

Conclusion

This study reports the endogenous sorafenib-resistance mechanism in HCC cells, which offers an opportunity to design new therapeutic approaches for HCC treatment.

General significance

PXR mediates sorafenib-resistance in HCC cells and targeting PXR can be a useful approach to facilitate HCC treatment.  相似文献   

13.

Background and aims

KLOTHO is an anti-ageing circulating hormone involved in insulin signaling, inflammation and vascular homeostasis through its protective effects on the endothelium and antioxidant actions. The common functional “KL-VS” variant of the KLOTHO gene is reproducibly associated with longevity in humans. Large number of studies have evaluated close relationship between KLOTHO protein and diabetes but the association between KL-VS variant and retinopathy in type 1 diabetes mellitus (T1D) is unknown. Therefore, in the present study we examined the association between the KL-VS polymorphism and the risk of diabetic retinopathy (DR) in patients with T1D.

Methods

We examined 400 patients with T1D and 350 healthy age-matched controls. The analysis concerned KL-VS polymorphism along with the levels of serum inflammatory (CRP, TNF-α) and anti-inflammatory (IL-10) markers, pro-angiogenic (angiogenin) and anti-angiogenic interferon gamma-induced protein 10 (IP-10) factors as well as adhesion molecules (ICAM-1, ICAM-3).

Results

We did not find significant association between T1D and KL-VS alleles. However, we observed that the incidence of KL-VS genotype is lower in a group with retinopathy in comparison to diabetic patients without this complication. Moreover, we established that KL-VS carriers had the lowest levels of inflammatory markers, pro-angiogenic factors and adhesion molecules. Simultaneously, the KL-VS carriers had increased serum levels of anti-inflammatory and anti-angiogenic cytokines than holders bearing wild type genotype.

Conclusions

In conclusion, the findings of our studies suggest that the functional KL-VS variant of the KLOTHO gene protects against the development of retinopathy in patients with T1D.  相似文献   

14.
15.

Background

The glycan moieties sialyl-Lewis-X and/or -A (sLeX/A) are the primary ligands for E-selectin, regulating subsequent tumor cell extravasation into distant organs. However, the nature of the glycoprotein scaffolds displaying these glycans in breast cancer remains unclear and constitutes the focus of the present investigation.

Methods

We isolated glycoproteins that bind E-selectin from the CF1_T breast cancer cell line, derived from a patient with ductal carcinoma. Proteins were identified using bottom-up proteomics approach by nanoLC-orbitrap LTQ-MS/MS. Data were curated using bioinformatics tools to highlight clinically relevant glycoproteins, which were validated by flow cytometry, Western blot, immunohistochemistry and in-situ proximity ligation assays in clinical samples.

Results

We observed that the CF1_T cell line expressed sLeX, but not sLeA and the E-selectin reactivity was mainly on N-glycans. MS and bioinformatics analysis of the targeted glycoproteins, when narrowed down to the most clinically relevant species in breast cancer, identified CD44 glycoprotein (HCELL) and CD13 as key E-selectin ligands. Additionally, the co-expression of sLeX-CD44 and sLeX-CD13 was confirmed in clinical breast cancer tissue samples.

Conclusions

Both CD44 and CD13 glycoforms display sLeX in breast cancer and bind E-selectin, suggesting a key role in metastasis development. Such observations provide a novel molecular rationale for developing targeted therapeutics.

General significance

While HCELL expression in breast cancer has been previously reported, this is the first study indicating that CD13 functions as an E-selectin ligand in breast cancer. This observation supports previous associations of CD13 with metastasis and draws attention to this glycoprotein as an anti-cancer target.  相似文献   

16.

Background

ABC transporters have attracted considerable attention for their function as drug transporters in a broad range of tumours and are therefore considered as major players in cancer chemoresistance. However, less attention has been focused on their potential role as active players in cancer development and progression.

Scope of review

This review presents the evidence suggesting that ABC transporters might have a more active role in cancer other than the well known involvement in multidrug resistance and discusses the potential strategies to target each ABC transporter for a specific tumour setting.

Major conclusions

Emerging evidence suggests that ABC transporters are able to transport bioactive molecules capable of playing key roles in tumour development. Characterization of the effects of these transporters in specific cancer settings opens the possibility for the development of personalized treatments.

General significance

A more targeted approach of ABC transporters should be implemented that considers which specific transporter is playing a major role in a particular tumour setting in order to achieve a more successful outcome for ABC transporters inhibitors in cancer therapy.  相似文献   

17.

Background

Selenium is an essential element with a rich and varied chemistry in living organisms. It plays a variety of important roles ranging from being essential in enzymes that are critical for redox homeostasis to acting as a deterrent for herbivory in hyperaccumulating plants. Despite its importance there are many open questions, especially related to its chemistry in situ within living organisms.

Scope of review

This review discusses X-ray spectroscopy and imaging of selenium in biological samples, with an emphasis on the methods, and in particular the techniques of X-ray absorption spectroscopy (XAS) and X-ray fluorescence imaging (XFI). We discuss the experimental methods and capabilities of XAS and XFI, and review their advantages and their limitations. A perspective on future possibilities and next-generation of experiments is also provided.

Major conclusions

XAS and XFI provide powerful probes of selenium chemistry, together with unique in situ capabilities. The opportunities and capabilities of the next generation of advanced X-ray spectroscopy experiments are particularly exciting.

General significance

XAS and XFI provide versatile tools that are generally applicable to any element with a convenient X-ray absorption edge, suitable for investigating complex systems essentially without pre-treatment.  相似文献   

18.

Background

Adoptive transfer of donor-derived T cells can be applied to improve immune reconstitution in immune-compromised patients after allogeneic stem cell transplantation. The separation of beneficial T cells from potentially harmful T cells can be achieved by using the major histocompatibility complex (MHC) I-Streptamer isolation technology, which has proven its feasibility for the fast and pure isolation of T-cell populations with a single specificity. We have analyzed the feasibility of the simultaneous isolation of multiple antigen-specific T-cell populations in one procedure by combining different MHC I-Streptamers.

Methods

First, the effect of combining different amounts of MHC I-Streptamers used in the isolation procedure on the isolation efficacy of target antigen-specific T cells and on the number of off-target co-isolated contaminating cells was assessed. The feasibility of this approach was demonstrated in large-scale validation procedures targeting both high and low frequent T-cell populations using the Good Manufacturing Practice (GMP)-compliant CliniMACS Plus device.

Results

T-cell products targeting up to 24 different T-cell populations could be isolated in one, simultaneous MHC I-Streptamer procedure, by adjusting the amount of MHC I- Streptamers per target antigen-specific T-cell population. Concurrently, the co-isolation of potentially harmful contaminating T cells remained below our safety limit. This technology allows the reproducible isolation of high and low frequent T-cell populations. However, the expected therapeutic relevance of direct clinical application without in vitro expansion of these low frequent T-cell populations is questionable.

Discussion

This study provides a feasible, fast and safe method for the generation of highly personalized MHC I-Streptamer isolated T-cell products for adoptive immunotherapy.  相似文献   

19.
L. Torrisi  N. Restuccia 《IRBM》2018,39(5):307-312

Background

The present study it is part of the study of the applications of biocompatible nanoparticles in a biological environment. Nowadays, in fact, nanoparticles are making it possible to reach surprising results in the field of biomaterials, drug delivery and their transport in the blood flux, as the use of the contrast medium for medical imaging and to be injected in tumors before to apply radio and thermal therapy. Nanoparticles modify the chemical and physical properties of solids, liquids, and gases and in particular of physiological liquids, soft and hard biological tissues.

Methods

The present article focalizes on the role of Au nanoparticles for biological and medical applications in which their insertion in cells, tissues, and organs may improve the diagnostic imaging contrast with traditional X-ray imaging and the absorbed doses due to radio- and thermal-therapies. Their injection in the tissue, in fact, increases the effective atomic number of the tissue, thus the increment of the electron density of the medium causes higher radiation LET (linear energy transfer) with the increment of released dose and major effects of radiotherapy expositions.

Main findings

The present paper shows the possibility to generate spherical gold nanoparticles with an average diameter of about 5 nm, pure and not agglomerated, biocompatible, stable and without the addition of chemical agents, by laser ablation of gold material in water. The solution can be directly injected in the extracellular liquid of cell cultures or directly in the blood flux of mice to be transported inside the complex living system. Here it is accumulated in specific organs in which the up-take and decay can be measured using suitable images of fluorescence of the organs of the mouse.

Conclusions

The aim of this research is to transport the nanoparticles in places where tissue disease exists and reduce their concentration in healthy tissues. This permit a better observation of the diseased tissues and their preparation as targeting for radio- and thermal-therapy to be applied to damage tumor cells saving healthy tissues.  相似文献   

20.

Background

The 1,4-dihydropyridines (DHPs) are one of the most frequently prescribed classes of antihypertensive monotherapeutic agents worldwide. In addition to treating hypertension, DHPs also exert other beneficial effects, including hepatoprotective effects. However, the mechanism underlying the hepatoprotection remains unclear.

Methods

Biochemical AlphaScreen and cell-based reporter assays were employed to detect the activities of DHPs towards FXR. A crystallographic analysis was adopted to study the binding modes of four DHPs in complex with FXR. Acetaminophen (APAP)-treated wild-type and FXR knockout mice were used to investigate the functional dependence of the effects of the selected DHPs on FXR.

Results

A series of DHPs were uncovered as FXR ligands with different activities for FXR, suggesting FXR might serve as an alternative drug target for DHPs. The structural analysis illustrated the specific three-blade propeller binding modes of four DHPs to FXR and explained the detailed mechanisms by which DHPs bind to and are recognized by FXR. The results in mice demonstrated that cilnidipine protected the liver from APAP-induced injury in an FXR-dependent manner.

Conclusions

This study reports the crystal structures of FXR in complex with four DHPs, and confirms that DHPs exert hepatoprotection by targeting FXR.

General significance

Our research not only reveals valuable insight for the design and development of next-generation Ca2+ blocker drugs to provide safer and more effective treatments for cardiovascular disorders but also provides a novel and safe structural template for the development of drugs targeting FXR. Moreover, DHPs might be potentially repurposed to treat FXR-mediated diseases other than hypertension.  相似文献   

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