scholarly journals Design of a methotrexate-controlled chemical dimerization system and its use in bio-electronic devices

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhong Guo ◽  
Oleh Smutok ◽  
Wayne A. Johnston ◽  
Patricia Walden ◽  
Jacobus P. J. Ungerer ◽  
...  
Keyword(s):  
Critical Role ◽  
Repeated Measurements ◽  
Therapeutic Drug ◽  
Drug Induced ◽  
Signaling Systems ◽  
Chemically Induced ◽  
Entry Points ◽  
Chemically Induced Dimerization ◽  
Multiple Analytes ◽  
Protein Complex Assembly

AbstractNatural evolution produced polypeptides that selectively recognize chemical entities and their polymers, ranging from ions to proteins and nucleic acids. Such selective interactions serve as entry points to biological signaling and metabolic pathways. The ability to engineer artificial versions of such entry points is a key goal of synthetic biology, bioengineering and bioelectronics. We set out to map the optimal strategy for developing artificial small molecule:protein complexes that function as chemically induced dimerization (CID) systems. Using several starting points, we evolved CID systems controlled by a therapeutic drug methotrexate. Biophysical and structural analysis of methotrexate-controlled CID system reveals the critical role played by drug-induced conformational change in ligand-controlled protein complex assembly. We demonstrate utility of the developed CID by constructing electrochemical biosensors of methotrexate that enable quantification of methotrexate in human serum. Furthermore, using the methotrexate and functionally related biosensor of rapamycin we developed a multiplexed bioelectronic system that can perform repeated measurements of multiple analytes. The presented results open the door for construction of genetically encoded signaling systems for use in bioelectronics and diagnostics, as well as metabolic and signaling network engineering.

scholarly journals Halofuginone functions as a therapeutic drug for chronic periodontitis in a mouse model

2020 ◽  
Vol 34 ◽  
pp. 205873842097489
Author(s):  
Jiang Wang ◽  
Bo Wang ◽  
Xin Lv ◽  
Yingjie Wang
Keyword(s):  
Alveolar Bone ◽  
Immune Cell ◽  
Critical Role ◽  
Therapeutic Drug ◽  
Mice Model ◽  
T Helper 17 ◽  
Th17 Cell Differentiation ◽  
Tnf Α

Periodontitis is an inflammatory disease caused by host immune response, resulting in a loss of periodontium and alveolar bone. Immune cells, such as T cells and macrophages, play a critical role in the periodontitis onset. Halofuginone, a natural quinazolinone alkaloid, has been shown to possess anti-fibrosis, anti-cancer, and immunomodulatory properties. However, the effect of halofuginone on periodontitis has never been reported. In this study, a ligature-induced mice model of periodontitis was applied to investigate the potential beneficial effect of halofuginone on periodontitis. We demonstrated that the administration of halofuginone significantly reduced the expression levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in vivo, and markedly suppressed immune cell infiltration into the infected sites. Furthermore, we also observed that halofuginone treatment blocked the T-helper 17 (Th17) cell differentiation in vivo and in vitro. We demonstrated for the first time that halofuginone alleviated the onset of periodontitis through reducing immune responses.

A DNA-Mediated Chemically Induced Dimerization (D-CID) Nanodevice for Nongenetic Receptor Engineering To Control Cell Behavior

2018 ◽  
Vol 130 (32) ◽  
pp. 10383-10387 ◽  
Author(s):  
Hao Li ◽  
Miao Wang ◽  
Tianhui Shi ◽  
Sihui Yang ◽  
Jinghui Zhang ◽  
...  
Keyword(s):  
Control Cell ◽  
Cell Behavior ◽  
Chemically Induced ◽  
Chemically Induced Dimerization

scholarly journals Role of High-Mobility Group Box-1 in Liver Pathogenesis

2019 ◽  
Vol 20 (21) ◽  
pp. 5314 ◽  
Author(s):  
Bilon Khambu ◽  
Shengmin Yan ◽  
Nazmul Huda ◽  
Xiao-Ming Yin
Keyword(s):  
Liver Disease ◽  
Critical Role ◽  
High Mobility ◽  
High Mobility Group ◽  
Sterile Inflammation ◽  
Contributing Factors ◽  
Drug Induced ◽  
Ductular Reaction ◽  
Alcoholic Fatty Liver

High-mobility group box 1 (HMGB1) is a highly abundant DNA-binding protein that can relocate to the cytosol or undergo extracellular release during cellular stress or death. HMGB1 has a functional versatility depending on its cellular location. While intracellular HMGB1 is important for DNA structure maintenance, gene expression, and autophagy induction, extracellular HMGB1 acts as a damage-associated molecular pattern (DAMP) molecule to alert the host of damage by triggering immune responses. The biological function of HMGB1 is mediated by multiple receptors, including the receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs), which are expressed in different hepatic cells. Activation of HMGB1 and downstream signaling pathways are contributing factors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and drug-induced liver injury (DILI), each of which involves sterile inflammation, liver fibrosis, ductular reaction, and hepatic tumorigenesis. In this review, we will discuss the critical role of HMGB1 in these pathogenic contexts and propose HMGB1 as a bona fide and targetable DAMP in the setting of common liver diseases.

A DNA-Mediated Chemically Induced Dimerization (D-CID) Nanodevice for Nongenetic Receptor Engineering To Control Cell Behavior

2018 ◽  
Vol 57 (32) ◽  
pp. 10226-10230 ◽  
Author(s):  
Hao Li ◽  
Miao Wang ◽  
Tianhui Shi ◽  
Sihui Yang ◽  
Jinghui Zhang ◽  
...  
Keyword(s):  
Control Cell ◽  
Cell Behavior ◽  
Chemically Induced ◽  
Chemically Induced Dimerization

Drug-Induced Metabolic Disorders and Parenteral Nutrition in the Intensive Care Unit: A Pharmaceutical and Metabolic Perspective

DICP ◽  
1989 ◽  
Vol 23 (5) ◽  
pp. 363-371 ◽  
Author(s):  
Joseph F. Dasta ◽  
David F. Driscoll
Keyword(s):  
Critical Care ◽  
Parenteral Nutrition ◽  
Metabolic Disorders ◽  
Care Setting ◽  
Critical Role ◽  
Critical Care Setting ◽  
Nutrition Support ◽  
Sensitive Period ◽  
Electrolyte Balance ◽  
Drug Induced

Since its inception, the field of parenteral nutrition has continued to evolve requiring the expertise of several health care disciplines. This feature has made nutrition support unique among clinical subspecialties. As a member of this team, the pharmacist plays a critical role in the provision of sterile admixtures, compatible nutritional formulations, and cost-effective, therapeutically equivalent strategies. The pharmacist has become more involved in the clinical care of the patient, with particular emphasis on the development of drug-induced metabolic disorders. The multitude of drugs prescribed to hospitalized patients increases the potential for serious metabolic disturbances. This is especially true in the critical care setting where sudden changes in metabolism (e.g., acid-base homeostasis, fluid and electrolyte balance) may result in profoundly negative effects. The critical care setting also represents the most sensitive period of hospitalization where even subtle changes in metabolic homeostasis may assume major clinical significance. Early recognition of offending agents and the institution of appropriate intervention may avert serious iatrogenic diseases. The nutrition support team is in a unique position to address many such disorders through selective manipulation of the various components in the parenteral nutrient admixture. The ability of the pharmacist to recognize the development of drug-induced metabolic disorders lends further support for clinical pharmacy in nutrition support services.

scholarly journals Uridine Metabolism and Its Role in Glucose, Lipid, and Amino Acid Homeostasis

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Yumei Zhang ◽  
Songge Guo ◽  
Chunyan Xie ◽  
Jun Fang
Keyword(s):  
Amino Acid ◽  
Acid Metabolism ◽  
De Novo ◽  
Feeding Habits ◽  
Critical Role ◽  
Atp Depletion ◽  
Cellular Functions ◽  
Drug Induced ◽  
Three Stages ◽  
Amino Acid Homeostasis

Pyrimidine nucleoside uridine plays a critical role in maintaining cellular function and energy metabolism. In addition to its role in nucleoside synthesis, uridine and its derivatives contribute to reduction of cytotoxicity and suppression of drug-induced hepatic steatosis. Uridine is mostly present in blood and cerebrospinal fluid, where it contributes to the maintenance of basic cellular functions affected by UPase enzyme activity, feeding habits, and ATP depletion. Uridine metabolism depends on three stages: de novo synthesis, salvage synthesis pathway and catabolism, and homeostasis, which is tightly relating to glucose homeostasis and lipid and amino acid metabolism. This review is devoted to uridine metabolism and its role in glucose, lipid, and amino acid homeostasis.

scholarly journals Noninvasive wearable electroactive pharmaceutical monitoring for personalized therapeutics

2020 ◽  
Vol 117 (32) ◽  
pp. 19017-19025 ◽  
Author(s):  
Shuyu Lin ◽  
Wenzhuo Yu ◽  
Bo Wang ◽  
Yichao Zhao ◽  
Ke En ◽  
...  
Keyword(s):  
Development Strategy ◽  
Large Scale ◽  
Critical Role ◽  
Analytical Framework ◽  
Therapeutic Drug ◽  
Boron Doped Diamond ◽  
Redox Peak ◽  
Boron Doped ◽  
The Right ◽  
Surface Modified

To achieve the mission of personalized medicine, centering on delivering the right drug to the right patient at the right dose, therapeutic drug monitoring solutions are necessary. In that regard, wearable biosensing technologies, capable of tracking drug pharmacokinetics in noninvasively retrievable biofluids (e.g., sweat), play a critical role, because they can be deployed at a large scale to monitor the individuals’ drug transcourse profiles (semi)continuously and longitudinally. To this end, voltammetry-based sensing modalities are suitable, as in principle they can detect and quantify electroactive drugs on the basis of the target’s redox signature. However, the target’s redox signature in complex biofluid matrices can be confounded by the immediate biofouling effects and distorted/buried by the interfering voltammetric responses of endogenous electroactive species. Here, we devise a wearable voltammetric sensor development strategy—centering on engineering the molecule–surface interactions—to simultaneously mitigate biofouling and create an “undistorted potential window” within which the target drug’s voltammetric response is dominant and interference is eliminated. To inform its clinical utility, our strategy was adopted to track the temporal profile of circulating acetaminophen (a widely used analgesic and antipyretic) in saliva and sweat, using a surface-modified boron-doped diamond sensing interface (cross-validated with laboratory-based assays,R2∼ 0.94). Through integration of the engineered sensing interface within a custom-developed smartwatch, and augmentation with a dedicated analytical framework (for redox peak extraction), we realized a wearable solution to seamlessly render drug readouts with minute-level temporal resolution. Leveraging this solution, we demonstrated the pharmacokinetic correlation and significance of sweat readings.

scholarly journals Brain tumors in neurofibromatosis type 1

2019 ◽  
Vol 2 (Supplement_1) ◽  
pp. i85-i97
Author(s):  
Amanda De Andrade Costa ◽  
David H Gutmann
Keyword(s):  
Tumor Growth ◽  
Neurofibromatosis Type 1 ◽  
Vision Loss ◽  
Critical Role ◽  
Neurofibromatosis Type ◽  
Therapeutic Drug ◽  
Low Grade ◽  
Increased Risk ◽  
Genetically Engineered Mice

Abstract AbstractAs a cancer predisposition syndrome, individuals with neurofibromatosis type 1 (NF1) are at increased risk for the development of both benign and malignant tumors. One of the most common locations for these cancers is the central nervous system, where low-grade gliomas predominate in children. During early childhood, gliomas affecting the optic pathway are most frequently encountered, whereas gliomas of the brainstem and other locations are observed in slightly older children. In contrast, the majority of gliomas arising in adults with NF1 are malignant cancers, typically glioblastoma, involving the cerebral hemispheres. Our understanding of the pathogenesis of NF1-associated gliomas has been significantly advanced through the use of genetically engineered mice, yielding new targets for therapeutic drug design and evaluation. In addition, Nf1 murine glioma models have served as instructive platforms for defining the cell of origin of these tumors, elucidating the critical role of the tumor microenvironment in determining tumor growth and vision loss, and determining how cancer risk factors (sex, germline NF1 mutation) impact on glioma formation and progression. Moreover, these preclinical models have permitted early phase analysis of promising drugs that reduce tumor growth and attenuate vision loss, as an initial step prior to translation to human clinical trials.

scholarly journals Computational toxicology

2015 ◽  
Vol 34 (12) ◽  
pp. 1304-1309 ◽  
Author(s):  
RT Naven ◽  
S Louise-May
Keyword(s):  
Critical Role ◽  
Pharmaceutical Research ◽  
In Vitro Models ◽  
New Drugs ◽  
Data Sets ◽  
Predictive Toxicology ◽  
Drug Induced ◽  
Chemical Toxicology

Predictive toxicology plays a critical role in reducing the failure rate of new drugs in pharmaceutical research and development. Despite recent gains in our understanding of drug-induced toxicity, however, it is urgent that the utility and limitations of our current predictive tools be determined in order to identify gaps in our understanding of mechanistic and chemical toxicology. Using recently published computational regression analyses of in vitro and in vivo toxicology data, it will be demonstrated that significant gaps remain in early safety screening paradigms. More strategic analyses of these data sets will allow for a better understanding of their domain of applicability and help identify those compounds that cause significant in vivo toxicity but which are currently mis-predicted by in silico and in vitro models. These ‘outliers’ and falsely predicted compounds are metaphorical lighthouses that shine light on existing toxicological knowledge gaps, and it is essential that these compounds are investigated if attrition is to be reduced significantly in the future. As such, the modern computational toxicologist is more productively engaged in understanding these gaps and driving investigative toxicology towards addressing them.

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