scholarly journals In Vivo Metabolic Response upon Exposure to Gold Nanorod Core/Silver Shell Nanostructures: Modulation of Inflammation and Upregulation of Dopamine

2020 ◽  
Vol 21 (2) ◽  
pp. 384 ◽  
Author(s):  
Haiyun Li ◽  
Tao Wen ◽  
Tao Wang ◽  
Yinglu Ji ◽  
Yaoyi Shen ◽  
...  
Keyword(s):  
Rational Design ◽  
Molecular Mechanisms ◽  
Metabolic Response ◽  
Dopamine Metabolism ◽  
Gold Nanorod ◽  
Ag Nps ◽  
Shell Nanostructures ◽  
Antioxidant Defense Systems ◽  
Silver Shell

With the increasing applications of silver nanoparticles (Ag NPs), the concerns of widespread human exposure as well as subsequent health risks have been continuously growing. The acute and chronic toxicities of Ag NPs in cellular tests and animal tests have been widely investigated. Accumulating evidence shows that Ag NPs can induce inflammation, yet the overall mechanism is incomplete. Herein, using gold nanorod core/silver shell nanostructures (Au@Ag NRs) as a model system, we studied the influence on mice liver and lungs from the viewpoint of metabolism. In agreement with previous studies, Au@Ag NRs’ intravenous exposure caused inflammatory reaction, accompanying with metabolic alterations, including energy metabolism, membrane/choline metabolism, redox metabolism, and purine metabolism, the disturbances of which contribute to inflammation. At the same time, dopamine metabolism in liver was also changed. This is the first time to observe the production of dopamine in non-neural tissue after treatment with Ag NPs. As the upregulation of dopamine resists inflammation, it indicates the activation of antioxidant defense systems against oxidative stress induced by Au@Ag NRs. In the end, our findings deepened the understanding of molecular mechanisms of Ag NPs-induced inflammation and provide assistance in the rational design of their biomedical applications.

Interference of Steroidogenesis by Gold Nanorod Core/Silver Shell Nanostructures: Implications for Reproductive Toxicity of Silver Nanomaterials

Small ◽  
2016 ◽  
Vol 13 (10) ◽  
pp. 1602855 ◽  
Author(s):  
Xiumei Jiang ◽  
Liming Wang ◽  
Yinglu Ji ◽  
Jinglong Tang ◽  
Xin Tian ◽  
...  
Keyword(s):  
Reproductive Toxicity ◽  
Gold Nanorod ◽  
Shell Nanostructures ◽  
Silver Nanomaterials ◽  
Silver Shell

Single-Dosed Genotoxicity Study of Gold Nanorod Core/Silver Shell Nanostructures by Pig-a, Micronucleus, and Comet Assays

2018 ◽  
Vol 14 (11) ◽  
pp. 1953-1964 ◽  
Author(s):  
Dan Wang ◽  
Mo Dan ◽  
Yinglu Ji ◽  
Xiaochun Wu ◽  
Liming Xu ◽  
...  
Keyword(s):  
Gold Nanorod ◽  
Shell Nanostructures ◽  
Silver Shell

scholarly journals Potent germline-like monoclonal antibodies: Rapid identification of promising candidates for antibody-based antiviral therapy

2021 ◽  
Author(s):  
Xiaoyi Zhu ◽  
Fei Yu ◽  
Yanling Wu ◽  
Tianlei Ying
Keyword(s):  
Monoclonal Antibodies ◽  
Rational Design ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
Human Mabs

Abstract Recent years, fully human monoclonal antibodies (mAbs) are making up an increasing share of the pharmaceutical market. However, to improve affinity and efficacy of antibodies, many somatic hypermutation could be introduced during affinity maturation, which cause several issues including safety and efficacy and limit their application in clinic. Here, we propose a special class of human mAbs with limited level of somatic mutations, referred to as germline-like mAbs. Remarkably, germline-like mAbs could have high affinity and potent neutralizing activity in vitro and in various animal models, despite lacking of extensive affinity maturation. Furthermore, the germline nature of these mAbs implies that they exhibit lower immunogenicity and can be elicited relatively fast in vivo compared with highly somatically mutated antibodies. In this review, we summarize germline-like mAbs with strong therapeutic and protection activity against various viruses that caused large-scale outbreaks in the last decade, including influenza virus H7N9, Zika virus (ZIKV), Dengue virus (DENV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We also illustrate underlying molecular mechanisms of these germline-like antibodies against viral infections from the structural and genetic perspective, thus providing insight into further development as therapeutic agents for treatment of infectious diseases and implication for rational design of effective vaccines.

scholarly journals Towards Polypharmacokinetics: Pharmacokinetics of Multicomponent Drugs and Herbal Medicines Using a Metabolomics Approach

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Ke Lan ◽  
Guoxiang Xie ◽  
Wei Jia
Keyword(s):  
Molecular Mechanisms ◽  
Metabolic Response ◽  
Herbal Medicines ◽  
Multivariate Statistical ◽  
Vast Number ◽  
Wide Range ◽  
Viable Approach

Determination of pharmacokinetics (PKs) of multicomponent pharmaceuticals and/or nutraceuticals (polypharmacokinetics, poly-PKs) is difficult due to the vast number of compounds present in natural products, their various concentrations across a wide range, complexity of their interactions, as well as their complex degradation dynamicsin vivo. Metabolomics coupled with multivariate statistical tools that focus on the comprehensive analysis of small molecules in biofluids is a viable approach to address the challenges of poly-PK. This paper discusses recent advances in the characterization of poly-PK and the metabolism of multicomponent xenobiotic agents, such as compound drugs, dietary supplements, and herbal medicines, using metabolomics strategy. We propose a research framework that integrates the dynamic concentration profile of bioavailable xenobiotic molecules that result fromin vivoabsorption and hepatic and gut bacterial metabolism, as well as the human metabolic response profile. This framework will address the bottleneck problem in the pharmacological evaluation of multicomponent pharmaceuticals and nutraceuticals, leading to the direct elucidation of the pharmacological and molecular mechanisms of these compounds.

scholarly journals Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis

2019 ◽  
Author(s):  
E. P. Kusnadi ◽  
A. S. Trigos ◽  
C. Cullinane ◽  
D. L. Goode ◽  
O. Larsson ◽  
...  
Keyword(s):  
Ribosome Biogenesis ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Single Agent ◽  
Acquired Resistance ◽  
Cellular Metabolism ◽  
Mrna Translation ◽  
Pol I ◽  
Polymerase I

AbstractElevated ribosome biogenesis in oncogene-driven cancers is commonly targeted by DNA-damaging cytotoxic drugs. Our first-in-human trial of CX-5461, a novel, less genotoxic agent that specifically inhibits ribosome biogenesis via suppression of RNA Polymerase I (Pol I) transcription, revealed single agent efficacy in refractory blood cancers. Despite this clinical response, patients were not cured. In parallel, we demonstrated a marked improvement in the in vivo efficacy of CX-5461 in combination with PI3K/AKT/mTORC1 pathway inhibitors. Here we show that this improved efficacy is associated with specific suppression of translation of mRNAs encoding regulators of cellular metabolism. Importantly, acquired resistance to this co-treatment is driven by translational re-wiring that results in dysregulated cellular metabolism and induction of a cAMP-dependent pathway critical for the survival of blood cancers including lymphoma and acute myeloid leukemia. Our studies identify the molecular mechanisms underpinning the response of blood cancers to selective ribosome biogenesis inhibitors and identify metabolic vulnerabilities that will facilitate the rational design of more effective regimens for Pol I-directed therapies.

Initiation of protective autophagy in hepatocytes by gold nanorod core/silver shell nanostructures

Nanoscale ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 6429-6437 ◽  
Author(s):  
Haiyun Li ◽  
Jiaqi Chen ◽  
Huizhen Fan ◽  
Rui Cai ◽  
Xinshuang Gao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Human Hepatocytes ◽  
Gold Nanorod ◽  
Shell Nanostructures ◽  
Lethal Doses ◽  
Silver Shell

At sub-lethal doses, Au@Ag NRs induce oxidative stress that activates the protective autophagy of human hepatocytes.

scholarly journals Hydroxylation of Steroids by a Microbial Substrate-Promiscuous P450 Cytochrome (CYP105D7): Key Arginine Residues for Rational Design

2019 ◽  
Vol 85 (23) ◽  
Author(s):  
Bingbing Ma ◽  
Qianwen Wang ◽  
Haruo Ikeda ◽  
Chunfang Zhang ◽  
Lian-Hua Xu
Keyword(s):  
Active Site ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Fold Increase ◽  
Site Directed Mutagenesis ◽  
Cytochrome P450 Monooxygenases ◽  
Content Type ◽  
Conversion Rates ◽  
Arginine Residues

ABSTRACT Our previous study showed that CYP105D7, a substrate-promiscuous P450, catalyzes the hydroxylation of 1-deoxypentalenic acid, diclofenac, naringenin, and compactin. In this study, 14 steroid compounds were screened using recombinant Escherichia coli cells harboring genes encoding CYP105D7 and redox partners (Pdx/Pdr, RhFRED, and FdxH/FprD), and the screening identified steroid A-ring 2β- and D-ring 16β-hydroxylation activity. Wild-type CYP105D7 was able to catalyze the hydroxylation of five steroids (testosterone, progesterone, 4-androstene-3,17-dione, adrenosterone, and cortisone) with low (<10%) conversion rates. Structure-guided site-directed mutagenesis of arginine residues around the substrate entrance and active site showed that the R70A and R190A single mutants and an R70A/R190A double mutant exhibited greatly enhanced conversion rates for steroid hydroxylation. For the conversion of testosterone in particular, the R70A/R190A mutant's kcat/Km values increased 1.35-fold and the in vivo conversion rates increased significantly by almost 9-fold with high regio- and stereoselectivity. Molecular docking analysis revealed that when Arg70 and Arg190 were replaced with alanine, the volume of the substrate access and binding pocket increased 1.08-fold, which might facilitate improvement of the hydroxylation efficiency of steroids. IMPORTANCE Cytochrome P450 monooxygenases (P450s) are able to introduce oxygen atoms into nonreactive hydrocarbon compounds under mild conditions, thereby offering significant advantages compared to chemical catalysts. Promiscuous P450s with broad substrate specificity and reaction diversity have significant potential for applications in various fields, including synthetic biology. The study of the function, molecular mechanisms, and rational engineering of substrate-promiscuous P450s from microbial sources is important to fulfill this potential. Here, we present a microbial substrate-promiscuous P450, CYP105D7, which can catalyze hydroxylation of steroids. The loss of the bulky side chains of Arg70 and Arg190 in the active site and substrate entrance resulted in an up to 9-fold increase in the substrate conversion rate. These findings will support future rational and semirational engineering of P450s for applications as biocatalysts.

scholarly journals Real-time in vivo imaging of size-dependent transport and toxicity of gold nanoparticles in zebrafish embryos using single nanoparticle plasmonic spectroscopy

2013 ◽  
Vol 3 (3) ◽  
pp. 20120098 ◽  
Author(s):  
Lauren M. Browning ◽  
Tao Huang ◽  
Xiao-Hong Nancy Xu
Keyword(s):  
Embryonic Development ◽  
Real Time ◽  
Rational Design ◽  
Dark Field ◽  
Molecular Probes ◽  
Noble Metal Nanoparticles ◽  
Zebrafish Embryos ◽  
Ag Nps ◽  
Au Nps

Noble metal nanoparticles (NPs) show distinctive plasmonic optical properties and superior photostability, enabling them to serve as photostable multi-coloured optical molecular probes and sensors for real-time in vivo imaging. To effectively study biological functions in vivo , it is essential that the NP probes are biocompatible and can be delivered into living organisms non-invasively. In this study, we have synthesized, purified and characterized stable (non-aggregated) gold (Au) NPs (86.2 ± 10.8 nm). We have developed dark-field single NP plasmonic microscopy and spectroscopy to study their transport into early developing zebrafish embryos (cleavage stage) and their effects on embryonic development in real-time at single NP resolution. We found that single Au NPs (75–97 nm) passively diffused into the embryos via their chorionic pore canals, and stayed inside the embryos throughout their entire development (120 h). The majority of embryos (96 ± 3%) that were chronically incubated with the Au NPs (0–20 pM) for 120 h developed to normal zebrafish, while an insignificant percentage of embryos developed to deformed zebrafish (1 ± 1)% or dead (3 ± 3)%. Interestingly, we did not observe dose-dependent effects of the Au NPs (0–20 pM) on embryonic development. By comparing with our previous studies of smaller Au NPs (11.6 ± 0.9 nm) and similar-sized Ag NPs (95.4 ± 16.0 nm), we found that the larger Au NPs are more biocompatible than the smaller Au NPs, while the similar-sized Ag NPs are much more toxic than Au NPs. This study offers in vivo assays and single NP microscopy and spectroscopy to characterize the biocompatibility and toxicity of single NPs, and new insights into the rational design of more biocompatible plasmonic NP imaging probes.

scholarly journals Emerging Highly Virulent Porcine Epidemic Diarrhea Virus: Molecular Mechanisms of Attenuation and Rational Design of Live Attenuated Vaccines

2019 ◽  
Vol 20 (21) ◽  
pp. 5478 ◽  
Author(s):  
Yixuan Hou ◽  
Qiuhong Wang
Keyword(s):  
Porcine Epidemic Diarrhea Virus ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Economic Losses ◽  
Live Attenuated Vaccines ◽  
Diarrhea Virus ◽  
Porcine Epidemic Diarrhea ◽  
Highly Virulent

The highly virulent porcine epidemic diarrhea virus (PEDV) emerged in China in 2010. It infects pigs of all ages, and causes severe diarrhea and high mortality rates in newborn pigs, leading to devastating economic losses in the pork industry worldwide. Effective and safe vaccines against highly virulent PEDV strains are still unavailable, hampering the further prevention, control and eradication of the disease in herds. Vaccination of pregnant sows with live attenuated vaccines (LAVs) is the most effective strategy to induce lactogenic immunity in the sows, which provides A passive protection of suckling piglets against PEDV via the colostrum (beestings, or first milk) and milk. Several LAV candidates have been developed via serially passaging the highly virulent PEDV isolates in non-porcine Vero cells. However, their efficacies in the induction of sufficient protection against virulent PEDV challenge vary in vivo. In this review, we summarize the current knowledge of the virulence-related mutations of PEDV and their potential roles in PEDV attenuation in vivo. With the successful development of reverse genetics systems for PEDV, we also discuss how to use them to generate promising LAV candidates that are safe, effective and genetically stable. This article provides timely insight into the rational design of effective and safe PEDV LAV candidates.

Sign in / Sign up

Export Citation Format

Share Document