The development of innovative targeted therapeutic approaches are expected to surpass the efficacy of current forms of treatments and cause less damage to healthy cells surrounding the tumor site. ...Since the first development of targeting agents from hybridoma's, monoclonal antibodies (mAbs) have been employed to inhibit tumor growth and proliferation directly or to deliver effector molecules to tumor cells. However, the full potential of such a delivery strategy is hampered by the size of mAbs, which will obstruct the targeted delivery system to access the tumor tissue. By serendipity, a new kind of functional homodimeric antibody format was discovered in camelidae, known as heavy-chain antibodies (HCAbs). The cloning of the variable domain of HCAbs produces an attractive minimal-sized alternative for mAbs, referred to as VHH or nanobodies (Nbs). Apart from their dimensions in the single digit nanometer range, the unique characteristics of Nbs combine a high stability and solubility, low immunogenicity and excellent affinity and specificity against all possible targets including tumor markers. This stimulated the development of tumor-targeted therapeutic strategies. Some autonomous Nbs have been shown to act as antagonistic drugs, but more importantly, the targeting capacity of Nbs has been exploited to create drug delivery systems. Obviously, Nb-based targeted cancer therapy is mainly focused toward extracellular tumor markers, since the membrane barrier prevents antibodies to reach the most promising intracellular tumor markers. Potential strategies, such as lentiviral vectors and bacterial type 3 secretion system, are proposed to deliver target-specific Nbs into tumor cells and to block tumor markers intracellularly. Simultaneously, Nbs have also been employed for
molecular imaging to diagnose diseased tissues and to monitor the treatment effects. Here, we review the state of the art and focus on recent developments with Nbs as targeting moieties for drug delivery systems in cancer therapy and cancer imaging.
Traditional Chinese medicine(TCM) has played a pivotal role in maintaining the health of Chinese people and is now gaining increasing acceptance around the global scope. However, TCM is confronting ...more and more concerns with respect to its quality. The intrinsic 'multicomponent and multitarget' feature of TCM necessitates the establishment of a unique quality and bioactivity evaluation system, which is different from that of the Western medicine. However, TCM is investigated essentially as'herbal medicine' or 'natural product', and the pharmacopoeia quality monographs are actually chemicalmarkers-based, which can ensure the consistency only in the assigned chemical markers, but, to some extent, have deviated from the basic TCM theory. A concept of 'quality marker'(Q-marker), following the 'property-effect-component' theory, is proposed. The establishment of Q-marker integrates multidisciplinary technologies like natural products chemistry, analytical chemistry, bionics, chemometrics,pharmacology, systems biology, and pharmacodynamics, etc. Q-marker-based fingerprint and multicomponent determination conduce to the construction of more scientific quality control system of TCM.This review delineates the background, definition, and properties of Q-marker, and the associated technologies applied for its establishment. Strategies and approaches for establishing Q-marker-based TCM quality control system are presented and highlighted with a few TCM examples.
ABSTRACT
The physiologic properties of glucagon‐like peptide 1 (GLP‐1) make it a potent candidate drug target in the treatment of type 2 diabetes mellitus (T2DM). GLP‐1 is capable of regulating the ...blood glucose level by insulin secretion after administration of oral glucose. The advantages of GLP‐1 for the avoidance of hypoglycemia and the control of body weight are attractive despite its poor stability. The clinical efficacies of long‐acting GLP‐1 derivatives strongly support discovery pursuits aimed at identifying and developing orally active, small‐molecule GLP‐1 receptor (GLP‐1R) agonists. The purpose of this study was to identify and characterize a novel oral agonist of GLP‐1R (i.e., myricetin). The insulinotropic characterization of myricetin was performed in isolated islets and in Wistar rats. Long‐term oral administration of myricetin demonstrated glucoregulatory activity. The data in this study suggest that myricetin might be a potential drug candidate for the treatment of T2DM as a GLP‐1R agonist. Further structural modifications on myricetin might improve its pharmacology and pharmacokinetics.—Li, Y., Zheng, X., Yi, X., Liu, C., Kong, D., Zhang, J., Gong, M. Myricetin: a potent approach for the treatment of type 2 diabetes as a natural class B GPCR agonist. FASEB J. 31, 2603–2611 (2017). www.fasebj.org
Fibroblast growth factor (FGF) belongs to a large family of growth factors. FGFs use paracrine or endocrine signaling to mediate a myriad of biological and pathophysiological process, including ...angiogenesis, wound healing, embryonic development, and metabolism regulation. FGF drugs for the treatment of burn and ulcer wounds are now available. The recent discovery of the crucial roles of the endocrine-acting FGF19 subfamily in maintaining homeostasis of bile acid, glucose, and phosphate further extended the activity profile of this family. Here, the applications of recombinant FGFs for the treatment of wounds, diabetes, hypophosphatemia, the development of FGF receptor inhibitors as anti-neoplastic drugs, and the achievements of basic research and applications of FGFs in China are reviewed.
p53: A double-edged sword in tumor ferroptosis Ji, Haixia; Wang, Wenzhe; Li, Xia ...
Pharmacological research,
March 2022, 2022-03-00, 20220301, 2022-03-01, Letnik:
177
Journal Article
Recenzirano
Odprti dostop
Ferroptosis is a type of lipid peroxidation-induced cell death that can be regulated in various ways, from changing the activity of antioxidant enzymes to the levels of transcription factors. The p53 ...tumor suppressor gene is the "guardian of the genome" and is involved in controlling cell survival and division under various pressures. In addition to its effects on apoptosis, autophagy, and cell cycle, p53, through the way of transcription dependent or independent two-way, also regulates the biological processes of tumor cell sensitivity to ferroptosis, including the metabolism of amino acids, nicotinamide adenine dinucleotide phosphate, and lipid peroxidation, as well as the biosynthesis of glutathione, phospholipids, NADPH and coenzyme Q10. As reviewed here, we summarized the metabolic network of p53 and its signaling pathway in regulating ferroptosis and elucidated possible factors and potential clinical application of p53 regulating ferroptosis. This review will provide a basis for further understanding the role of p53 in tumor ferroptosis and new strategies for cancer therapeutic avenues.
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Quality control of Chinese medicine (CM) is an effective measure to ensure the safety and efficacy of CM in clinical practice, which is also a key factor to restrict the modernization process of CM. ...Various chemical components exist in CM and the determination of several chemical components is the main approach for quality control of vast majority of CM in the present. However, many components determined lack not only specificity, but also biological activities. This is bound to greatly reduce the actual value of quality standard of CM.
Professor Changxiao Liu proposed the “quality marker” (Q-marker) concept to ensure the standardization and rationalization for the quality control of CM. As we all know, CMs are taken orally in most cases and could be extensively metabolized in vivo. Both prototype components and the metabolites could be the actual therapeutic material basis. Pharmacokinetic studies could benefit the elucidation of actual therapeutic material basis which is closely related to the identification of Q-markers. Therefore, a new strategy about Q-marker was proposed based on the pharmacokinetic analysis of CM, hoping to provide some ideas for the discovery and identification of Q-marker.
The relationship between pharmacokinetic studies and the identification of Q-markers was demonstrated in this review and a new strategy was proposed. Starting from the pharmacokinetic analysis, reverse tracing of the prototype active components and the potential prodrugs in CM were conducted first and the therapeutic material basis were identified as Q-markers. Then, modern analytical techniques and methods were applied to obtain comprehensive quality control for these constituents. Several CMs including gingko biloba, ginseng, Periplocae Cortex, Mori Cortex, Bupleuri Radix and Scutellariae Radix were listed as examples to clarify how the new strategy could be applied.
Pharmacokinetic studies play an important role for the elucidation of therapeutic material basis of CM and the identification of Q-markers and it should be taken into account during the process of the investigation of Q-marker.
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Panax notoginseng (Sanqi) is a cardiovascular herb containing ginsenosides that are believed to be responsible for the therapeutic effects of Sanqi. The aim of this study was to evaluate rat exposure ...to ginsenosides after oral administration of Sanqi extract and to identify the key factors affecting their absorption and disposition. Ginsenosides were administered to rats, either in the form of Sanqi extract or as pure chemicals. The ginsenosides Ra(3), Rb(1), Rd, Re, Rg(1), and notoginsenoside R(1) were the major saponins present in the herbal extract. Systemic exposure to ginsenosides Ra(3), Rb(1), and Rd after oral administration of the extract was significantly greater than that to the other compounds. Considerable colonic deglycosylation of the ginsenosides occurred, but the plasma levels of deglycosylated metabolites were low in rats. Poor membrane permeability and active biliary excretion are the two primary factors limiting systemic exposure to most ginsenosides and their deglycosylated metabolites. In contrast with other ginsenosides, biliary excretion of ginsenosides Ra(3) and Rb(1) was passive. Meanwhile, the active biliary excretion of ginsenoside Rd was significantly slower than that of other saponins. Slow biliary excretion, inefficient metabolism, and slow renal excretion resulted in long-circulating and thus relatively high exposure levels for these three ginsenosides. For these reasons, plasma ginsenosides Ra(3), Rb(1), and Rd were identified as pharmacokinetic markers for indicating rat systemic exposure to Sanqi extract. This is a systematic investigation of the absorption and disposition of ginsenosides from an herb, the information gained from which is important for linking Sanqi administration to its medicinal effects.
The abnormal metabolism of uric acid results in many disease such as chronic kidney disease, hyperuricemia, nephrolithiasis, gout, hypertension, vascular disease and so on. Serum uric acid levels are ...maintained by the balance between production and elimination. There are many factors that maintain the balance of serum uric acid. One of them is transporters which are responsible for the debouchment of uric acid within blood. The transport and excretion of uric acid is a complicated procedure which is related with various transporters such as OAT1, OAT3, OAT4, URAT1, GLUT9, BCRP, MRP4, NPT1, NTP4, and so on. In recent years, a large number of genome-wide association studies have shown that the single nucleotide polymorphisms of uric acid transporters were closely related to serum uric acid level. What’s more, some mutations on these gene locus may also break the balance of serum uric acid. Here, the polymorphisms of uric acid transporters closely related with the serum uric acid balance were reviewed and discussed because of their important significance in clinical therapy for a precision medicine. The mechanism of metabolic diseases with gene variation may provide new strategy for the design and development of innovative drug to treat diseases with uric acid metabolic disturbance.
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