Yu Li Yan Wenming Abstract: Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes mellitus, occurring at the earliest, with an incidence ranging from 25% to 90% as reported in the literature.DPN can involve sensory, motor and autonomic nerves, but sensory nerves are the most common [1]. It not only causes increased mortality and disability in diabetic patients, but also brings complex care and medical problems, and is the main cause of repeated hospitalizations in diabetic patients. Its pathogenesis is not fully understood, but it is known that it is not due to a single factor [2]. Recent clinical and experimental studies of diabetic complications have shown that metabolic disorders, vascular damage, and immune factors play a role, among which nerve growth factor has always occupied an important position [3]. Yan Wenming, Department of Radiotherapy, Affiliated Hospital of Inner Mongolia Medical University Topic: nerve growth factor; diabetic peripheral neuropathy 1. Introduction Nerve growth factor (NGF) and ciliary neurotrophic factor (CNTF), glial cell derived neurotrophic factor (GDNF) together NGF [4] is the first neurotrophic factor discovered by Levi Montalcini R in mouse sarcoma cells in the early 1950s, which contains three subunits α, β, γ, with a relative molecular mass of 13 000 000 u, commonly known as 7 sNGF. The biological activity of NGF is mainly to maintain the function of sympathetic and sensory nerves. It induces the synthesis of neurotransmitters, protein phosphorylation, methylation and synthesis of enzymes required for the expression of ras a protein-like genes, and selectively nourishes sympathetic ganglion neurons and small fiber sensory neurons of the peripheral nervous system [5]. The mature protein of nerve growth factor is basic. It is cleaved from the corresponding precursors and has about 120 amino acids, of which about 50% are homologous and all have six absolutely conserved cysteine residues. NGF was discovered in 1952, and the amino acid sequence of NGF was analyzed and derived in 1973. lP21, P22, l. Gene structural features: a large precursor, a signal peptide of about 18 amino acids after the start codon, and a signal peptide of about 18 amino acids in the precursor structure. The last four amino acids in the precursor structure have an “Arg-X a basic amino acid residue an Arg” structure, which is a typical protease cleavage site; the mature protein is preceded by an N-glycosylation site at residues 8-9, the gene family. The gene family is selected to produce a variety of transcriptional regulators. These transcriptional regulators in turn regulate the expression of other genes, causing an increase in protein synthesis, cell volume, proliferation of mesenchymal cells, cell differentiation, etc., thus exerting the role of growth factors. 3. The Ras-MAPK receptor tyrosine protein kinase signaling mode is used to transmit information from the cell membrane to the nucleus and cause cellular response effects. The first step in the biological effect of NTEs is to bind to the effector cell membrane-specific receptor. The expression levels of NGF in brain and peripheral tissues do not differ significantly between sites, but are higher in the submandibular gland of male mice. Nerve growth factor acts by binding to receptors on the cell surface of responding neurons and is important in regulating biological functions. Nerve growth factor (NGF) is the prototype protein of NTs and can be classified into high-affinity neurotrophin receptor (HANR) and low-affinity receptor (10w-8mnity neurotrophin receptor, LANR) according to the magnitude of the affinity of the nerve growth factor receptor (NGFR) to NGF [6]. The two types of receptors differ mainly in affinity, stability, distribution and biological functions.3.1 High-affinity receptors are tyrosine protein kinases encoded by tyrosine kinase pro-oncogene (prototrk), single transmembrane glycoproteins with molecular weights of 120-160 kD, called trk receptor. The equilibrium binding constant (Kd) of the high-affinity receptor. Trks include TrkA, TrkB and TrkC, trkA type, TrkA is the NGF receptor, NGFR is produced in the dorsal root ganglion (DRG) and transported to axon terminals to bind to NGF. trkA-type decreased NGFR leads to decreased uptake of NGF axon terminals and axon transport, causing decreased neurotrophic support and resulting in ineffective axon regeneration, independent of p75NGFR. trkA-type extracellular membrane structures include a unique IgG -TrkA is found in sensory and sympathetic neurons, striatum and cholinergic neurons at the base of the rat forebrain, etc. The lgG-C2 region of Trks is the binding site for NT and is a crystalline structure, and its amino acid The order of its amino acid arrangement determines the specificity of different trk receptors and their different affinities with different growth factors; the biological effects of nerve growth factors are mainly mediated by high-affinity receptors, making their expression distinctly stage-specific and tissue-specific. Its cytoplasmic tyrosine kinase active region is the insulin receptor tyrosine kinase. When the growth factor binds to its specific receptor, the receptor can be induced to recruit and form a multimer, and the receptor tyrosine kinase is activated to catalyze the phosphorylation of tyrosine residues in the specific sequence of the receptor itself. The phosphorylated tyrosine residues and the short sequences at both ends of the receptor can then be specifically recognized and bound to cytoplasmic messaging molecules with Sre homology domains, linking a wide range of signaling components and activating different messaging pathways. 3.2 The low-affinity p75 NGFR, produced in Schwann cells (SC), is a 75 kD molecular weight glycoprotein to which members of the nerve growth factor family can bind. The Kd of the p75 receptor is 10.0-9.0 mol/L. The dissociation rate is fast (T1/2 about 10 s). The p75 receptor is more susceptible to trypsin destruction, soluble in tritonX100, and distributed in both effector and non-neuronal cells, probably related to the uptake of certain amino acids, stimulation of mast cell degranulation and release of histamine. Its extracellular structural region is identical to that of the tumor necrosis factor receptor, and the cytoplasmic structural region has a IImr structure, which is the death signal region (Figure 2). P “m has been shown to promote apoptosis in the absence of trk receptors: in the presence of trk receptors, P “m is evenly involved in the formation of high-affinity sites and enhances the specificity of trk receptors for members of the nerve growth factor family.4. Nerve growth factor signaling pathways [7] NGF can activate two NGF activation of these two receptors can initiate many complex signaling pathways. 4.2 Signaling of Trk Trk mediates neuronal survival via the Ras pathway. In NGF-mediated survival, the first signal transduction protein to be activated is the small GTP-binding protein Ras. NGF has a significant pro-survival effect on sympathetic and sensory neurons at developmental stages and in culture, and their survival is dependent on the continued presence of a certain concentration of NGF. Inhibition of Ras activity prevents most sympathetic neurons from surviving. In the absence of NTs, removal of the Ras-regulated inhibitory factor NF-1 (neurofibromatosis.1) enabled the survival of cultured peripheral neurons. Ras does not act directly in NGF-dependent neuronal survival, but rather translates and mediates multiple signaling pathways initiated by NTs, mainly PI.3K/PKB and MEK/MAPK.8 Ras/PI.3K/PKB inhibits the production and activity of apoptotic proteins; MEK/MAPK activates anti-apoptotic proteins to promote survival.4.3 p75NTa Signal transduction p75NTR was the first NTs receptor to be isolated and is a member of the p75NTR/Fas/TNFRl family. but the understanding of its physiological function and signaling pathways is not well It has been found that when p75NTR binds to NTs to form p75NTR homodimers, it can connect to a variety of signal transduction proteins, including TRAF2/4, TRAF6, NRAGE, SC I1, NRIF and RhoA, which can regulate cell survival, cell cycle and axonal growth. p75NTR is in most cases a ligand-activated apoptotic receptor that can The p75NTR enhances Trk activity by activating NF-KB (Figure 2). p75NTR inhibits JNK via Ras and PI-3K/PKB in the JNK-p53-Bax pathway, or inhibits The death protein Forkhead. p75NTR inhibits Trk-mediated survival and growth through ceramide inhibition of PKB and Raf activity. The interaction between Trk and p75NTR has an important role in determining the development of the nervous system and post-injury repair. p75NTR’s major biological effects include (i) regulation of neuronal growth. (ii) promotion of neuronal survival. (iii) Induction of neuronal apoptosis.5 NGF biosynthesis and action NGF is a class of protein factors capable of promoting neuronal cell survival, growth, and differentiation. it is released from the target tissue of sensitive neurons, binds to specific receptors and enters the cell body via reverse axonal transport, and has physiological characteristics such as causing morphological differences in neurons, enhancing neural regeneration, and stimulating neurotransmitter expression [8]. Neurotrophic factors not only reduce neurodegeneration to stop the disease process, but also have the function of stimulating axonal growth and promoting regeneration. Neurotrophic factors are most likely to become an important tool for the treatment of nerve injury and neurological diseases in the future [9]. Isolated experiments have demonstrated that nerve growth factor supports survival and promotes the growth of protrusions in all dorsal root ganglia of neural crest origin, which has also been confirmed by Liu Jingsheng et al{10}, a domestic scholar, in their studies on peripheral nerve regeneration. NGF also has a significant protective effect on peripheral nerves and a good neurotrophic effect on sensory neurons.Dyck et al{11} showed that the application of NGF can prevent, stabilize or improve deficits and symptoms caused by smaller fiber neuropathy and can lower thermal and pain thresholds.NGF, as a member of the peptide growth factor network, has a significant role in inflammatory response, tissue injury repair, promotion of wound healing and acute delayed hypersensitivity reactions. In diabetes, the lack or reduction of NGF reduces the reverse transport of nerve growth factors to neurons and damages the neurons sensitive to them. Therefore, it has been recently suggested that nerve repair is an energy-consuming process and that, in addition to ischemia, nerve growth factor deficiency is also an important factor affecting its repair [12]. Supplementation with nerve growth factors can promote nerve regeneration and improve nerve conduction velocity. The impaired synthesis, secretion and metabolism of these factors is one of the causes of diabetic neuropathy. In recent years, nerve growth factors have received much attention in the development and treatment of diabetic neuropathy. Adult Schwann cells have also been shown to produce nerve growth factor and to express growth factor receptors during neuronal development. Hyperglycemia-sorbitol-related damage to Schwann cells decreases NGF synthesis, affects regulation of gene expression, and decreases synthesis of neurofilaments and microtubule mRNA levels, leading to impaired nerve axon dystrophy, impaired regeneration, and in severe cases, fiber atrophy and loss.13 Nerve growth factor levels decreased progressively with disease progression and progressively decreased in different tissues as diabetes progressed, particularly in the calf muscle and sciatic nerve, which showed reduced nerve mRNA levels early in the course of diabetes. The levels of nerve growth factor in streptozotocin-diabetic rats were found to be increased in the target tissues and decreased in the sciatic and sympathetic ganglia, suggesting that the reverse axonal transport of nerve growth factor is impaired, which is detrimental to nerve regeneration. Apfel et al. found that streptozotocin decreased substance P and calcitonin-related gene peptide levels in the dorsal root ganglion of diabetic rats by approximately 30%, consistent with the findings of Femyhough et al. in the sciatic nerve, where peptide levels increased after administration of nerve growth factor. The above reports suggest that nerve growth factor is implicated in the mechanism of diabetic peripheral neuropathy. Recombinant human nerve growth factor is the only neurotrophic factor that has been used in clinical trials for the treatment of diabetic peripheral neuropathy, and its phase 1 clinical trial has been completed with encouraging results [15]. Both neurons and glial cells can produce NGF, which has an important trophic function for basal forebrain cholinergic neurons, and NGF exerts its protective function on neurons mainly by regulating calcium ion homeostasis and fighting against free radicals.NGF has a significant protective effect on peripheral nerves, and also has a good neurotrophic effect on sensory neurons.Dyck et al. showed that by the application of NGF was able to prevent, stabilize, or improve deficits and symptoms caused by smaller fiber neuropathies and to lower thermal and pain thresholds [16].NGF, as a member of the peptide growth factor network, plays a role in inflammatory responses, tissue injury repair, promotion of wound healing, and acute delayed hypersensitivity reactions [171, [18].7 Outlook With the elucidation of the mechanism of action of NGF and its source, formulation, administration NGF has shown a promising future as a drug for the treatment of clinical diseases [19]. 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