What are cytokines?

What are cytokines?

Cytokines are small secreted proteins released by cells have a specific effect on the interactions and communications between cells. The word cytokine is derived from the Greek kytos meaning ‘hollow’ or ‘vessel’ and kinein meaning ‘to move’ and was originally used to separate a group of immuno-regulatory proteins, such as interleukins, from other chemicals, known as growth factors, that modulated the proliferation and bioactivation of nonimmune cells. Cytokines aid cell to cell communication in immune responses and stimulate the movement of cells towards sites of inflammation, infection and trauma.

Types of Cytokines

While “cytokines” is an umbrella term that includes all kinds, there are more specific names given to cytokines. The major proteins/protein families that constitute the cytokine group of regulatory molecules including Interferons (IFNs), Colony stimulation factors (CSF), Tumor necrosis factors (TNF), Neurotrophins Ciliary neurotrophic factor (CNTF), etc.

Most cytokines names are given based on cell types, biological activity and the structure. The term ‘cytokine’ was first introduced in the mid-1970s. It was applied to polypeptide growth factors controlling the differentiation and regulation of cells of the immune system. The interferons (IFNs) and interleukins (ILs) represented the major polypeptide families classified as cytokines at that time.

Interferons (IFNs) – Interferons (IFNs) are a group of signaling proteins made and released by host cells in response to the presence of several pathogens, such as viruses, bacteria, parasites, and also tumor cells.

Interleukins (ILs) – Interleukins are a group of cytokines that were first seen to be expressed by leukocytes and acting on other leukocytes.

Cytokine names on the basis of producing cell types:

  1. Lymphokines – Cytokines such as interleukin-2 (IL-2) and interferon-? (IFN-?), produced by lymphocytes
  2. Monokines – Cytokines such as tumor necrosis factor-? (TNF-?) produced by monocytes.

Cytokine names on the basis of the specific biological activity by which the cytokine was first discovered:

  1. Tumor necrosis factor (TNF) – Cytokines exhibited cytotoxic effects on some cancer cell lines2. Colony stimulating factors (CSFs) – Cytokines promoted the growth in vitro of various leukocytes in clumps or colonies.

Cytokine names on a structural basis:

  1. “?-Trefoil” cytokines – include fibroblast growth factors, interleukin-12. Chemokines – Interleukin-8, macrophage inflammatory proteins3. “Cysteine knot” cytokines- Nerve growth factor, transforming growth factors, platelet-derived growth factor4. EGF family5. Haematopoietins6. TNF family

Cytokines have important roles in chemically induced tissue damage repair, in cancer development and progression, in the control of cell replication and apoptosis, and in the modulation of immune reactions such as sensitization. Each cytokine has a matching cell-surface receptor. Subsequent cascades of intracellular signaling then alter cell functions. Cytokines are often involved in several developmental processes during embryogenesis. Cytokines are crucial for fighting off infections and in other immune responses. Cytokines constitute the single most important group of biopharmaceutical substances. As coordinators of the immune and inflammatory response, manipulation of cytokine activity can have a major influence on the body’s response to a variety of medical conditions.

About the Author

Creative Diagnostics is a leading manufacturer and supplier of antibodies, viral antigens, innovative diagnostic components and critical assay reagents.

Creative BioMart–A Leading Global Supplier of Protein Products and Protein Services

Creative BioMart is a science driven company based in the US yet radiated worldwide. Over the past decade, Creative Biomart set off from a small manufacturer of proteins and enzymes for academic institutes and bio-tech companies, and now it has become one of the most trustworthy brands in the protein market.

 

Featured Products:

Based on its own advanced protein engineering and expression platform, Creative BioMart is capable to provide a wide range of high quality protein products for research and manufacturing purposes.

 

  1. Recombinant Proteins

Creative BioMart has been dominated for its recombinant proteins for over 15 years. The company now has more than 5,000 recombinant proteins from multiple species and sources with various tags in stock. Proteins in different fragments, full length, or with various mutations could be well satisfied. The company also welcomes custom production of recombinant proteins covering most genes according to your requirements.

 

  1. Native Proteins

Native proteins provided by Creative BioMart are all obtained from proper organisms, in stable formulation and natural state, capable to retain their entire functional activities, and unaltered by outer factors such as heat, enzyme reactions, chemicals, or other denaturants. Now Creative BioMart has more than 500 native proteins available for online inquiry.

 

  1. GMP Proteins

Creative BioMart provides more than 100 GMP-grade proteins for cell culture and therapeutic uses. GMP proteins by the company are strictly manufactured under related guidelines and tested by a certified ISO 9001:2008 quality system. The rigorous quality control (QC) tests include N-terminal sequence analysis, HPLC analysis, molecular weight determination by MS and SDS-PAGE, endotoxin, biological activity, and tests upon demands.

 

  1. Cell & Tissue Lysates

Creative BioMart provides an efficient collection of various lysates including cell line lysates, tissue lysates, over-expression lysates, stem cell lysates and membrane lysates. The validated lysates by the company are available in a variety of normal, tumor and disease characterized tissues, and ready for use in applications such as the controls of SDS-PAGE, IP, ELISA and Western Blot analysis.

 

  1. Assay Kits

You could find thousands of assay kits in various formats in Creative BioMart, whether it’s for enzyme activity, metabolism, cell signaling, inhibitor screening, or other detection. All the assay kits provided by the company are ready for use with full instructions, plates, necessary reagents, and analysis protocols to quickly obtain accurate results.

 

  1. Chromatography Reagents

Creative BioMart provides a variety of chromatography techniques including affinity, antibody affinity, gel filtration, hydrophobic interaction, adsorption, multimode, and other chromatography. These techniques could be applied at all scales of matrix including cross-linked cellulose, cross-linked agarose, polystyrene, methacrylic, and dextran.

 

Featured Services:

With a team of experienced scientists, Creative BioMart excels at a comprehensive range of protein services.

 

  1. Custom Protein Service

Creative BioMart features its custom protein service in a variety of protein expression platforms along with many a protein services, e.g. protein engineering, protein labeling, protein expression and purification, PEGylation, stable cell line, membrane protein and other services. Thousands of biochemical researchers benefit from these services to accelerate their scientific research or manufacturing process.

 

  1. Protein Analytical Services

Creative BioMart shows its expertise in providing efficient protein analytical services for researchers and manufacturers to produce high quality recombinant proteins and native proteins. The services include but not limited protein modification, protein interaction, protein characterization, membrane protein screening, bio-informatics, bio-safety testing, bio-analytical assay, and other services.

 

  1. Discovery and Translational Services

As a leader of protein production, Creative BioMart is professional in protein discovery and translational services including bio-marker service, cytokine and receptor analysis, epitope mapping, radioimmunoassay, transporter screening assays, GPCR screening assays, protein profiling and other assay services. With our leading technologies, Creative BioMart stands itself out in the field of protein-based lead discovery.

 

  1. Bio-pharmaceutical Solutions

To assist scientists in all stages of drug discovery and development, Creative BioMart provides a broad range of bio-pharmaceutical solutions, including downstream bio-pharmaceutical process and impurities analysis, processing development, cGMP cell-based potency assays, pharmaceutical stability analysis, pharmaceutical product release testing, quality control, drug discovery screening, and etc.

An overview of 18 kinds of amino acids and their efficacy (part II)

  1. Isoleucine(ILE)

(1). It can maintain the body balance, treat mental disorders

(2). Increase appetite and anti-anemia

(3). Present physical exhaustion, coma and other symptoms when lacking

  1. Tryptophan (TRY)

(1). Promote the synthesis of hemoglobin

(2). Prevent ecdysis

(3). Promote growth, increase appetite

(4). Its sweetness is 35 times that of sugar, which is good for the production of low-sugar foods for diabetics and obese patients.

  1. Cystine(CYS)

(1). Treatment of fatty liver and detoxification

(2). Treatment of skin damage, and effective for postpartum hair loss

  1. Lysine (LYB)

(1). Participate in the formation of connective tissue and microvascular epithelial interstitial cells and maintain normal permeability.

(2). Increase appetite, promote the secretion of pepsin, enhance immunity, improve developmental delay, prevent tooth decay, and promote child growth

(3). Improve calcium absorption and promote bone growth

(4). if it is lacking, it will reduce the sensitivity of people, for example, women will stop menstruation, anemia, dizziness, dizziness and nausea

  1. Aspartic acid(ASP)

(1). Reduce blood ammonia, have a protective effect on the liver

(2). Has a protective effect on the muscles, can treat angina pectoris, and has a preventive effect on myocardial infarction, etc.

(3). Increase umami, promote appetite

  1. Proline (VAL)

It can promote normal nervous system function.

  1. Phenylalanine (PHE)

It transfers into tyrosine in the body and promotes the synthesis of thyroxine and adrenaline.

  1. Proline (PRO)

It has been effective for hypertension.

  1. 16. Serine(SER)

(1). Reduce blood cholesterol levels, prevent and treat high blood pressure

(2). It is a component of serine phospholipids in tissues such as the brain.

(3). It has an effect on tuberculosis bacterial disease, can treat lung disease

  1. Glutamate (GLU)

(1). Reduce blood ammonia

(2). Participate in brain protein and sugar metabolism, promote oxidation, improve central nervous activity, maintain and promote brain cell function, and promote intellectual development

(3). Have therapeutic effects for severe liver dysfunction, hepatic coma, acidosis, epilepsy schizophrenia, neurasthenia, etc.

(4). Have therapeutic effects for the treatment of gastric ulcer, lack of gastric juice, indigestion, loss of appetite

(5). Protect the skin moist, prevent dry cracks, such as the preparation of detergents, cosmetics, skin and mucous membrane stimulation, suitable for children and skin patients

  1. 18. Arginine (ARG)

(1). Reduce blood ammonia, promote urea production in the body, and treat hepatic coma, etc.

(2). Increase muscle vitality, maintain sexual function, and have a role in the treatment of sperm reduction

Supplemental amino acids are part of our healthy diets and should not be ignored.

Amino acids are used for a variety of applications in industry, but their main use is as additives to animal feed. This is necessary, since many of the bulk components of these feeds, such as soybeans, either have low levels or lack some of the essential amino acids: lysine, methionine, threonine, and tryptophan are most important in the production of these feeds. In this industry, amino acids are also used to chelate metal cations in order to improve the absorption of minerals from supplements, which may be required to improve the health or production of these animals.

The food industry is also a major consumer of amino acids, in particular, glutamic acid, which is used as a flavor enhancer, and aspartame (aspartyl-phenylalanine-1-methyl ester) as a low-calorie artificial sweetener. Similar technology to that used for animal nutrition is employed in the human nutrition industry to alleviate symptoms of mineral deficiencies, such as anemia, by improving mineral absorption and reducing negative side effects from inorganic mineral supplementation.

The chelating ability of amino acids has been used in fertilizers for agriculture to facilitate the delivery of minerals to plants in order to correct mineral deficiencies, such as iron chlorosis. These fertilizers are also used to prevent deficiencies from occurring and improving the overall health of the plants. The remaining production of amino acids is used in the synthesis of drugs and cosmetics.

Similarly, some amino acids derivatives are used in pharmaceutical industry. They include 5-HTP (5-hydroxytryptophan) used for experimental treatment of depression, L-DOPA (L-dihydroxyphenylalanine) for Parkinson’s treatment, and eflornithine drug that inhibits ornithine decarboxylase and used in the treatment of sleeping sickness.

Reference

  1. Blenis J, Resh MD (December 1993). “Subcellular localization specified by protein acylation and phosphorylation”. Current Opinion in Cell Biology. 5 (6): 984–9.
  2. Proline is an exception to this general formula. It lacks the NH2 group because of the cyclization of the side chain and is known as an imino acid; it falls under the category of special structured amino acids.
  3. Blaser HU (1992). “The chiral pool as a source of enantioselective catalysts and auxiliaries”. Chemical Reviews. 92 (5): 935–52. doi:10.1021/cr00013a009.
  4. “amino acid”. Cambridge Dictionaries Online. Cambridge University Press. 2015. Retrieved 3 July 2015.
  5. Petroff OA (December 2002). “GABA and glutamate in the human brain”. The Neuroscientist. 8 (6): 562–73. doi:10.1177/1073858402238515. PMID 12467378.

A list of Creative Biomart’s Protein Products and Protein Manufacturing Solutions

Brief Introduction

Creative Biomart is a world leader in protein and enzymes related products and technology. Founded in 2005, which is headquartered in Shirley, New York. Creative Biomart is dedicated to the offering of high quality protein products and efficient protein manufacturing techniques, including Protein Engineering Services, Protein Extraction Services, Protein Expression and Purification Services as well as Membrane Protein Services and protein labeling etc. For recent years, Creative Biomart has become a well-recognized industry leader focusing on the supply of high quality products which can be applied in various areas by the academic institutes and biotech companies. In addition, Creative Biomart is capable to provide customized service to satisfy specific requirements in order to promote the related research in drug discovery and biomedical.

Main Products Offered:

. Recombinant Proteins

As a leading supplier in protein related products, Creative Biomart has always been devoted to offering a wide range of off-the-shelf recombinant protein products that can be applied to support the expression of the exogenous gene, thereby achieving high-level protein expression. As different protein expression systems have different features and applications., Creative BioMart provides multiple sources of recombinant proteins to meet specific requirements. Besides, we have established a Protein Expression and Purification Platform that includes more than 20 expression systems to meet your requirements. Moreover, the 100,000+ recombinant proteins we offered covers most genes, supporting multiple species and sources, most of the products are over 90% pure by SDS-PAGE.

. Native Proteins

Creative BioMart can offer a comprehensive list of the natural proteins that are in a stable formulation, retaining their entire activity and can be used for protein functional analysis, ELISA kits, Western blotting, immunoprecipitation and more.

. Cell & Tissue Lysates

Creative BioMart now offers a diverse collection of lysates, including overexpressing lysates, tissue lysates, cell line lysates and stem cell lysates, can be applied to assess antibody quality and serve as excellent positive controls for electrophoresis, immunoblotting, immunoprecipitation, enzymatic activity analysis, protein-protein interaction analysis and tissue-specific expression identification, as well as overexpression of lysates. Our lysates are validated for a variety of normal, tumor and disease-characteristic tissues.

. Assay Kits

Thousands of assay kits in a variety of formats are available, including enzyme activity, inhibitor screening, epigenetics, apoptosis, cell damage, cell proliferation and cytotoxicity, cell signaling, metabolism and other assays. These assays are useful tools for measuring enzyme activity, monitoring signaling pathway activity, detecting and quantifying cellular processes, studying gene expression changes, and screening for small molecule inhibitors. And other test kits are ready to use and provide all the necessary reagents, instructions, plates and assays to help get accurate and repeatable results promptly.

. Chromatography Reagents

With the professional technical platform and in-house experts, Creative Biomart is able to offer all the different types of chromatography, including: cross-linked agarose, cross-linked cellulose, dextran, methacrylic acid and polystyrene.

. GMP-grade Proteins

More than 100 GMP-grade proteins are offered with high quality and consistency to meet cell culture and therapeutic needs. Our GMP grade proteins are derived from the same cloning and expression systems as the research grade proteins, in order to ensure batch-to-batch consistency and high product quality, Creative BioMart places great emphasis on the details of all aspects of the manufacturing process. Our GMP grade proteins are completely free of human and animal derived ingredients and are manufactured and tested under a certified ISO 9001:2008 quality system. Strict quality control (QC) testing ensures the highest product standards. Besides, we can support small scale and large scale GMP production, formulation and filling/finishing. The production ranges from 10L to 500L satisfy the needs of clinical research to commercial production.

. Others

We are still expanding our product portfolio to include molecular and cellular biology, diagnostics and pharmacy. These high performance reagents are strict with stringent product quality assurance requirements during manufacturing and have been validated for use in routine laboratory research as well as in the therapeutic and diagnostic industries.

. Custom Service

In order to meet the special experimental needs of some researchers, Creative Biomart also provides customized assay kits and reagents to support your research and guarantee reliable results.

The History Development and Future Challenges of Bispecific Antibodies

Bispecific antibodies (bsAbs) combine specificities of two antibodies and simultaneously address different antigens or epitopes. BsAbs with “two-target” functionality can interfere with multiple surface receptors or ligands associated.

  1. Development history of three generations of bispecific antibodies

The advent of hybridoma technology in the 1970s reminded people whether the same antibody could be used to target two different targets, namely Bispecific Antibody (bsAb).

Most of the earliest bispecific antibodies are developed by chemical coupling methods. Although the method is much simple, the resulting products are complex and heterogeneous and difficult to use in industrial production. Until the 1980s, scFv-based recombinant bispecific antibodies appeared and gradually became the focus of research with the popularization of recombinant DNA technology.

Amgen/Micromet’s BiTE (Bispecific T cell Engager) is the archetype of the first generation of bispecific antibodies, characterized by a simple structure and two scFvs connection. But it also has obvious disadvantages such as short half-life and low expression. A pump for continuous administration is clinically necessary due to the short half-life with only two hours. Fortunately, the clinical dose of BiTE is less than one tenth of the amount of common antibodies, which virtually solves the problem of mass production. The first recombinant bispecific antibody Blinatumomab (CD3-CD19 BiTE) was finally approved by the FDA in December 2014 for marketing in the United States after various difficulties.

Genentech’s Paul Carter team invented the knob-into-holes bispecific antibody in the 1990s as the second-generation bispecific antibodies, with a structure and stability similar to that of natural IgG. Roche/Chugai’s Emicizumab (factor IX and factor X bsAb) using the knob-into-hole technology was approved by the FDA in November 2017 as the second bispecific antibody marketed in the United States.

There are currently about 120 bispecific antibodies in different clinical development stages around the world, including third generation bispecific antibodies. If taking T cell-targeted therapy as an example, Roche’s CEA-TCB (CD3-CEA bispecific antibody) is a typical representative of third-generation bispecific antibodies, which utilizes the knob-into-hole technology of second-generation bispecific antibodies, and Roche engineers invented CrossMab technology shortly after the acquisition of Genentech and successfully solved the bottleneck of knob-into-hole in common light chain. In addition, CEA-TCB achieves bivalent binding of tumor antigens and monovalent binding of CD3, enabling the bispecific antibody to produce avidity effects when combined with tumor antigens while reducing CD3 antibody binding toxicity. At present, CEA-TCB has completed Phase 1 clinical trials and achieved satisfactory results.

  1. 2.The challenges for bispecific antibodies development

Since 1986, the first antibody drug, Muromonab (OKT3), has been approved for marketing, the FDA has approved the listing of 73 antibody drugs by the end of 2017, and there are only two bispecific antibodies listed above. The development of bispecific antibodies lags significantly behind therapeutic monoclonal antibodies, which mainly results from the following reasons: Early bispecific antibody has a difficult expression and poor stability, as well as a complicated production process; The early development cost of bispecific antibodies is significantly higher than that of monoclonal antibodies; Bispecific antibody project involves target biology, structural biology, antibody engineering, and screening strategies.

In 2017, the market capacity of antibody drugs broke through the $100 billion mark for the first time. Antibody drugs have become one of the fastest growing areas in the pharmaceutical industry. Bispecific antibodies at the forefront of antibody drug development have long been the development direction of major pharmaceutical companies around the world. It is believed that bispecific antibody will have a considerable market share in the field of solid tumor treatment. Compared with CAR-T, bispecific antibody drugs have the advantages of dose controllable and flexible drug administration period. At the same time, bispecific antibody drugs can also target other immune cells, such as NK, Macrophage, etc.

Author Bio

Creative Biolabs was established in 2004 by scientists who are dedicated to conquering of cancer. Over the past 10 years, Creative Biolabs has grown into a recognized world leader in antibody (rAb) discovery, engineering, production, and analysis. Standing on the shoulder of a giant, the bispecific antibody (BsAb) team has a collective of experienced scientists committed to providing high-quality services to customers all over the world. Now, with the cutting-edge platforms and methods (quadroma development, chemical conjugation, and genetic engineering), a comprehensive list of bispecific antibody products is available to customers in academia and industry fields.

Guide For Short Tandem Repeats And Its Implementation Importance

Brief Introduction to Short Tandem Repeats

Microsatellite DNA, also known as short tandem repeats (STR) or simple repeat sequences (SRS or SSR), is widely found in prokaryotic and eukaryotic genomes, consisting of a unit of two to thirteen nucleotides repeated hundreds of times in a row on the DNA strand which is about 5% of the eukaryotic genome, the basic unit (core sequence) is 1-6bp. The most common of these is (CA) n and (TG) n, and the human genome has about 5 × 104 ~ 1 × 105 (CA) n repeats which take 10% of the genome. Each microsatellite DNA has the same core sequence structure, the number of repeating units is about 10 to 60 times, and its length is generally not more than 300bp, mostly located in the non-coding region of the gene, intron or untranslated region. which may be present in the Alu sequence or Satellite sequence, but in the coding sequence and exon also can find the presence of microsatellite DNA.

 

The high polymorphism of microsatellite DNA is mainly due to the difference in the number of tandem numbers. There is a big difference in the distribution for microsatellite DNA in different races and populations due to the number of repeat units and repetition, which constituted STR genetic polymorphism. And the number of repetitions between different individuals at a homologous STR site is also different so that STR loci analysis can identify individuals that are similar to fingerprint recognition. It is possible to create a personal gene file by identifying a specific sequence of genomes at particular loci. Currently, there are more than 10,000 STR loci are available. STR analysis has become an important analytical method for individual identification and paternity testing in the field of forensic science. It can be applied to judicial case investigation, that is, genetic fingerprint analysis.

 

The Causes of STR

The replication slip caused by mismatches between DNA strands during the mitotic process is considered to be the most common cause of the occurrence of STR, and in general, there will be an average of one-thousandths of microsatellite DNA will undergo replication slippage. The study showed that the rate of tandem duplication at repeat sequences was higher than the probability of point mutations occurring elsewhere in the genome. Most of the replication slides only cause a change in the repeat unit, and the probability of replication slip is different due to the size of the different copy units and different species.

 

STR Detection Method

STR analysis is one of the most useful methods in molecular biology which is used to compare specific loci on DNA from two or more samples. There are two common methods for STR detection: capillary electrophoresis (CE) and gel electrophoresis, which can be used to determine the specific amount of microbes Satellite sequence and draw the STR map. Typically, each allele is shared by about 5-20% of people. And the advantages of STR analysis will be reflected in the simultaneous identification of multiple STR loci. Each individual can be identified accurately by the resulting STR map. In theory, if there were 16 STR loci being used in combination, the recognition rate will be 0.999999999998.

 

The Importance of STR Analysis

It is still common for cell lines to be misidentified and cross-contamination, although scientists use a variety of traditional methods to identify cells, there are still dozens of cross-contamination happened. And even some researchers found that cell lines were misidentified or cross-contamination while cell identification reports for the higher score study articles publication, resulting in erroneous conclusions. All of which will lead to the waste of research funding and time, and resulting in a large number of invalid or erroneous data that will mislead other researchers. Based on the statistics data, around 20% of the cell lines were misidentified and cross-contamination in the labs so that it is a serious concern for researchers to provide accurate cell line identification and prevent cell lines from cross-contamination. Currently, several STR loci have been developed to analyze cross-contamination and cell types at the same time, that can detect up to 0.1 ng of DNA (about 15 Diploid genomes) with high sensitivity for the trace pollution.

All the mentioned above is the complete guide for the Short Tandem Repeat and its importance!

The Introduction of Fibroblast Growth Factor Receptors

Some antibodies:

  1. R1MAB1(FGFR1 antibody)

An anti-fibroblast growth factor receptor-1 (FGFR1) antibody is a human antibody which can be potentially used for the treatment of diabetes.

  1. CBL539 (FGFR2 antibody)

This antibody is a rat monoclonal antibody that binds specifically to mouse FGFR2, and it can neutralize the bioactivity of mouse FGFR2.

  1. R3Mab (FGFR3 antibody)

Recombinant Human Antibody (R3Mab) is capable of binding FGFR3 expressed in HEK 293 cells as the combination of a heavy chain (HC) containing VH from anti-FGFR3 mAb and CH1-3 region of human IgG1 and a light chain (LC) encoding VL from anti-FGFR3 proteins mAb and CL of human kappa light chain. Exists as a disulfide linked dimer of the HC and LC hetero-dimer under non-reducing condition. This antibody inhibit not only WT FGFR3, but also various mutants of the receptor.

  1. U4-3(FGFR4 antibody)

The antibody is used to bind the FGFR4 and the medical use thereof, in particular for the diagnosis prevention or treatment of diseases associated with FGFR expression, over-expression or hyperactivity.

What is FGFR?

 

Figure1. FGFR2b

Fibroblast growth factor receptors (FGFRs) are members of the immunoglobulin gene superfamily, whose extracellular segments have three or two immunoglobulin-like functional regions. FGFRs are also a family of proteins. Four kinds of independent gene-coded FGFRs have been found that are FGFR1, FGFR2, FGFR3 and FGFR4 which widely distribute on the surface of target cells of fibroblast growth factor (FGF), such as vascular endothelial cells, fibroblasts, T and B lymphocytes. The biological activity of FGF is achieved by acting on FGFRs. It is known that the FGF gene family has many biological activities, such as stimulating angiogenesis, promoting embryonic tissue development and differentiation, participating in wound healing and tissue regeneration, neurotrophic and endocrine regulation.

The relationship between structure and function of FGFRs

FGFRs are transmembrane proteins belonging to receptor tyrosine kinases, which are composed of three main components: extracellular, transmembrane and intracellular segments. The extracellular segment of FGFRs is generally made up of three immunoglobulin-like functional regions, signal peptide structure and acid box. There are two tyrosine kinase active regions in the intracellular segment of FGFRs. When the extracellular segment of FGFRs binds to ligands, the receptors form dimers, which activate the tyrosine kinase in the intracellular segment, catalyze the phosphorylation of their own tyrosine residues, and also phosphorylate the tyrosine residues in the target protein of FGFRs. The activity of receptor tyrosine kinase is very crucial for the signal transduction pathways required for mitosis, transformation and differentiation of cells. It is the signal transduction pathways initiated by tyrosine phosphorylation that lead to changes in gene transcription in the nucleus and ultimately to biological reactions.

FGFRs have three unique characteristics:

  • Overlapping recognition and multi-specificity. That is, one receptor can bind to several kinds of FGFin similar affinity, and one kind of FGF can bind to several kinds of FGFRs in similar forms;
  • The binding of FGFand its receptor depends on heparin sulfate proteoglycan on the cell surface;
  • Many kinds of cell-binding and secretory receptors can be produced from the same gene.
  1. Structure and function of FGFR1

Various types of FGFR1 can be formed due to different forms of splicing of the precursor of mRNA. Receptor cross-linking test showed that FGFR1 with two or three immunoglobulin-like functional regions in the extracellular segment was the main type of FGFR1. The affinity of the two types of FGFR1 was similar to that of aFGF and bFGF. The first immunoglobulin-like functional region (Ig1) can be deleted, and the affinity of Ig1-deleted FGFR1 with aFGF and bFGF is not affected.

  1. Structure and function of FGFR2

FGFR2 with two or three immunoglobulin-like functional regions is the main type of FGFR2. These two types have similar affinity to aFGF and bFGF. Another truncated FGFR2 was found in the study of keratinocyte growth factor (KGF) receptors. Its first immunoglobulin-like functional region and acid box were simultaneously deleted. This is the first FGFR without acid box. Two kinds of FGFR2 with different carboxyl end were found in human cancer cDNA library by DNA sequencing analysis. In most cells, there are 27 amino acids at the carboxyl end of FGFR2 and only 12 amino acids at the carboxyl end of variant FGFR2. Although its function is still unclear, previous studies have shown that mutations in the carboxyl end of receptor tyrosine can increase the potential of protein transformation.

  1. Structure and FGFR3 and FGFR4

Up to now, the cloned FGFR3 and FGFR4 belong to receptors containing three immunoglobulin-like functional regions.

FGFRs and cell signaling

Intercellular communication is an important link in the genesis, development and survival of cells and multicellular organs. Most cell signals are mediated by polypeptides secreted by cells. These polypeptides regulate cell growth, differentiation and maintain the stability of the metabolic environment. Studies have found that polypeptide growth factors and cytokines function significantly in regulating cell growth and differentiation, and they play their biological functions through receptors on the cell surface. FGFRs are the basis for FGF to exert its biological activity. The tyrosine kinase activity of FGFRs is the key link in the signal transduction pathway required for cell mitosis, transformation and differentiation. When FGF binds to FGFR, tyrosine kinase in the cell segment of fibroblast growth factor receptors is activated, and tyrosine residues of receptors themselves are phosphorylated and can be subjected to it. Tyrosine residues on body target proteins are converted to phosphorylation, which initiates signaling cascades.

After the binding of growth factors and receptors, almost all of them form receptor dimers, which may vary because they’r induced by different growth factors.

Regulation of the expression of FGFRs

Some studies have shown that tissue-specific splicing of FGFR and tissue-specific expression of different FGFR genes can make different tissue cells express different FGFRs, which can selectively respond to different members of the fibroblast family, so as to regulate cell growth and differentiation.

The relationship between FGFRs and diseases

The changes of gene and expression of FGFRs realtes to the occurrence of many diseases.

  1. FGFRs and breast cancer

Researchers have detected the expression of FGFR1 in normal breast epithelial cells and breast cancer cells, and found that the expression of FGFR1 in breast cancer cells is much higher than that in normal breast cells. It was found that breast epithelial cells could express four kinds of FGFRs, namely, FGFR1, FGFR2, FGFR3 and FGFR4, but the expression levels of FGFR2 and FGFR4 were high. In this cell, a variant FGFR3 located in the nucleus was found. The FGFR3 consisted of only intracellular tyrosine kinase regions.

  1. FGFRsand Achondroplasia

Researchers have found that the etiology of Achondroplasia (ACH) is related to the point mutation of FGFR3 gene. In 19 patients, G mutation at position 1138 of the transmembrane region of FGFR3 accounted for L5 cases of A mutation and 4 cases of G mutation to C mutation. The ACH caused by the point mutation of this receptor gene can be inherited.

  1. FGFRs and ophthalmic diseases

Biological effects mediated by the binding of FGF and its receptors have been paid more and more attention in ophthalmic diseases. Eye is the most widely originated organ of embryonic tissue. FGF can be produced by various cells, such as corneal endothelial cells, lens epithelial cells, melanocytes, glial cells, pigment epithelial cells and retinal cells. Moreover, soluble high affinity FGFR1 exists in the vitreous humor of the eyes. It is speculated that regulating the biological effects of FGF binding to membrane receptors is important. Many ophthalmic diseases are caused by disorders in the regulation of growth factors and their receptors. It has been reported that proliferative vitreoretinopathy is a complication of ocular trauma, rhegmatogenous retinal detachment and vitreoretinal surgery. Fibroblasts, glial cells and retinal pigment epithelial cells that form proliferative vitreoretinopathy have the expression of FGFR.

In addition, FGFRs play an important role in the occurrence of fibrotic diseases and angiogenesis of tumors.

With the further study of FGFRs, the pathogenesis of some diseases will be revealed. Therapeutic methods and drugs related to FGFRs will emerge as the times require.

CDH17 is a New Diagnostic Marker for Digestive System Adenocarcinoma

CDH17, also known as liver-cadherin or liver-intestine cadherin, belongs to 7D-cadherin family. Its coding gene is located on human chromosome 8 q22.1. Cadherin-17 is a protein that in humans is encoded by the CDH17 gene.This quality is an individual from the cadherin superfamily, qualities encoding calcium-subordinate, layer related glycoproteins. The encoded protein is cadherin-like, comprising of an extracellular locale, containing 7 cadherin spaces, and a transmembrane district yet deficient with regards to the monitored cytoplasmic area. The protein is a segment of the gastrointestinal tract and pancreatic channels, going about as an intestinal proton-subordinate peptide transporter in the initial phase in oral ingestion of numerous medicinally significant peptide-based medications.

 

Tissue distribution in the human cd34 antibody under normal conditions: expressed in the epithelial cells of the liver and gastrointestinal tract during human embryo development; expressed in the small intestine and colorectal epithelial cells of adults, and expressed statically in the liver and stomach.

Expression of CDH17 antibody in normal colon

 

Cadherin:

It is a type of transmembrane protein that is an important protein that binds between cells and cells, between cells and tissues. They play an important role in cell adhesion, cell recognition, cell migration, and embryonic cell morphogenesis. They must function in the presence of calcium ions.

 

CDH17 and tumor:

The occurrence and development of tumor is a gradual process of interaction between intrinsic genetic factors and external environmental factors. The change of intercellular adhesion ability and the imbalance of cell motility are one of the important mechanisms of tumor invasion and metastasis. CDH17 is a new member of the cadherin family that is calcium-dependently mediated by intercellular junctions and plays an important role in cell adhesion, cell recognition, tissue organ development, and structural integrity maintenance. Studies have shown that its structural abnormalities and dysfunction lead to decreased adhesion between tumor cells, loose tissue cells, easy to fall off or deform, so that tumor cells gain stronger invasiveness and promote tumor invasion and metastasis.

 

Application of CDH17 in digestive system adenocarcinoma:

Specificity and sensitivity of CDH17 in digestive system adenocarcinoma:

A large number of clinical studies by Nelson G. Ordónez in 2014 found that the vast majority of primary gastrointestinal adenocarcinomas showed CDH17 positive (99% colon adenocarcinoma, 44% gastric adenocarcinoma, 75% esophageal adenocarcinoma), in metastatic The positive rate in colon adenocarcinoma was 100%; while in other systemic adenocarcinomas, CDH17 was essentially absent. A large amount of data shows that the sensitivity of CDH17 is significantly higher than that of CDX2 (the most widely used one for diagnosing whether the source of an unknown cancer is a marker of the digestive system)

 

A large number of data show that CDH17 is significantly more sensitive than CDX2 in colorectal adenocarcinoma, esophageal adenocarcinoma, and pancreatic cancer.

 

Summary of the application of CDH17 in digestive system adenocarcinoma:

Studies have shown that CDH17 is only expressed in digestive system adenocarcinoma and can be used to distinguish between digestive system adenocarcinoma and other tumors.