更新于：2024-11-01

P4HB

更新于：2024-11-01

基本信息

别名

Cellular thyroid hormone-binding protein、DSI、ERBA2L

+ [11]

简介

This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds. At the cell surface, seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. May therefore cause structural modifications of exofacial proteins. Inside the cell, seems to form/rearrange disulfide bonds of nascent proteins. At high concentrations and following phosphorylation by FAM20C, functions as a chaperone that inhibits aggregation of misfolded proteins (PubMed:32149426). At low concentrations, facilitates aggregation (anti-chaperone activity). May be involved with other chaperones in the structural modification of the TG precursor in hormone biogenesis. Also acts as a structural subunit of various enzymes such as prolyl 4-hydroxylase and microsomal triacylglycerol transfer protein MTTP. Receptor for LGALS9; the interaction retains P4HB at the cell surface of Th2 T helper cells, increasing disulfide reductase activity at the plasma membrane, altering the plasma membrane redox state and enhancing cell migration (PubMed:21670307).

关联

项与 P4HB 相关的药物

TSN-222

靶点

P4HB x STING

作用机制

P4HB抑制剂 [+1]

在研机构

泰励生物科技(上海)有限公司

原研机构

泰励生物科技(上海)有限公司

在研适应症

晚期恶性实体瘤 [+2]

非在研适应症-

最高研发阶段临床1/2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 P4HB 相关的临床试验

CTR20231027 / Not yet recruiting临床1/2期

一项评估TSN222对晚期实体瘤或淋巴瘤受试者的安全性、耐受性、药代动力学及初步疗效评估的I/II期临床研究

评价TSN222治疗晚期实体瘤或淋巴瘤受试者的安全性和耐受性，确定最大耐受剂量（MTD）和/或II期推荐剂量RP2D(s) 评估TSN222及其代谢产物的药代动力学（PK）特征评估TSN222治疗晚期实体瘤或淋巴瘤的初步疗效

开始日期-

申办/合作机构

泰励生物科技(上海)有限公司

NCT05842785 / Recruiting临床1/2期

A Phase I/II Study to Evaluate the Safety, Tolerability, Pharmacokinetic Profile, and Preliminary Efficacy of TSN222 in Subjects With Advanced Solid Tumors or Lymphoma

The study is a first-in-human [FIH], open-label phase 1/2 study of TSN222 in subjects with advanced solid tumors or lymphomas. This study is comprised of a Phase 1 dose escalation and Phase 2 dose expansion component.

开始日期2023-07-26

申办/合作机构

泰励生物科技(上海)有限公司

100 项与 P4HB 相关的临床结果

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100 项与 P4HB 相关的转化医学

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0 项与 P4HB 相关的专利（医药）

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508

项与 P4HB 相关的文献（医药）

2024-12-01·Chemico-Biological Interactions

Inhibition of protein disulfide isomerase mitigates steroid-induced osteonecrosis of the femoral head by suppressing osteoclast activity through the reduction of cellular oxidative stress

Article

作者: Fu, Chuanyun ; Wang, Yi ; Sun, Shui ; Li, Ziqing ; Feng, Changgong ; Yuan, Tao ; Zhang, Xin ; Wang, Haojue ; Lv, YongShuang ; Lu, Qizhen

Osteonecrosis of the femoral head (ONFH) is a devastating and irreversible hip disease usually associated with increased oxidative stress due to the clinical application of high-dose or long-term glucocorticoids (GCs). Previous publications have demonstrated protein disulfide isomerase (PDI) plays a critical role in regulating cellular production of reactive oxygen species (ROS). We therefore ask whether interfering PDI could affect GCs-stimulated osteoclastogenesis. To test the hypothesis, we conducted bioinformatics and network analysis based on potential gene targets of steroid-induced osteonecrosis of the femoral head (SIONFH) in light of multiple databases and concomitantly verified the associated biological effect via the in vitro model of dexamethasone (DEX)-stimulated osteoclastogenesis. The results revealed 70 potential gene targets for SIONFH intervention, including the P4HB gene that encodes PDI. Further analysis based on network topology-based analysis techniques (NTA), protein-protein interaction (PPI) networks, and mouse cell atlas database identified the importance of PDI in regulating the cellular redox state of osteoclast during ONFH. Western blotting (WB) validations also indicated that PDI may be a positive regulator in the process of DEX-stimulated osteoclastogenesis. Hence, various PDI inhibitors were subjected to molecular docking with PDI and their performances were analyzed, including 3-Methyltoxoflavin (3M) which inhibits PDI expression, and ribostamycin sulfate (RS) which represses PDI chaperone activity. The binding energies of DEX, 3M, and RS to PDI were -5.3547, -4.2324, and -5.9917 kcal/mol, respectively. The Protein-Ligand Interaction Profiler (PLIP) analysis demonstrated that both hydrogen bonds and hydrophobic interactions were the key contributions to the DEX-PDI and 3M-PDI complexes, while only hydrogen bonds were identified as the predominant driving forces in the RS-PDI complex. Subsequent experiments showed that both 3M and RS reduced osteoclast differentiation and bone resorption activity by stifling the expression of osteoclastic markers. This reduction was primarily due to the PDI inhibitors boosting the antioxidant system, thereby reducing the production of intracellular ROS. In conclusion, our results supported PDI's involvement in SIONFH progression by regulating ROS in osteoclasts and highlighted PDI inhibitors may serve as potential options for SIONFH treatment.

2024-12-01·Molecular Biology Reports

Exome sequencing identified mutations in the WNT1 and COL1A2 genes in osteogenesis imperfecta cases

Article

作者: Gupta, Sushil ; Rajender, Singh ; Mehta, Poonam ; Chattopadhyay, Naibedya ; Vishvkarma, Rahul

BACKGROUNDOsteogenesis imperfecta (OI) is a heritable connective tissue disorder characterized by bone deformities, fractures and reduced bone mass. OI can be inherited as a dominant, recessive, or X-linked disorder. The mutational spectrum has shown that autosomal dominant mutations in the type I collagen-encoding genes are responsible for OI in 85% of the cases. Apart from collagen genes, mutations in more than 20 other genes, such as CRTAP, CREB3L1, MBTPS2, P4HB, SEC24D, SPARC, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, WNT1, BMP1, TMEM38B, and IFITM5 have been reported in OI.METHODS AND RESULTSTo understand the genetic cause of OI in four cases, we conducted whole exome sequencing, followed by Sanger sequencing. In case #1, we identified a novel c.506delG homozygous mutation in the WNT1 gene, resulting in a frameshift and early truncation of the protein at the 197th amino acid. In cases #2, 3 and 4, we identified a heterozygous c.838G > A mutation in the COL1A2 gene, resulting in a p.Gly280Ser substitution. The clinvar frequency of this mutation is 0.000008 (GnomAD-exomes). This mutation has been identified by other studies as well and appears to be a mutational hot spot. These pathogenic mutations were found to be absent in 96 control samples analyzed for these sites. The presence of these mutations in the cases, their absence in controls, their absence or very low frequency in general population, and their evaluation using various in silico prediction tools suggested their pathogenic nature.CONCLUSIONSMutations in the WNT1 and COL1A2 genes explain these cases of osteogenesis imperfecta.

2024-11-01·Carbohydrate Polymers

Creation of fully degradable and mechanically robust poly(4-hydroxybutyrate) films by filling modified starch

作者: Ding, Yitong ; Kan, Ze ; Li, Mingjiao ; Wu, Hao ; Li, Zhibo ; Chen, Xinyi

Chem. synthesized poly(4-hydroxybutyrate) (P4HB) is a new generation of biomass-derived and degradable semi-crystalline polymer with good comprehensive properties, but high costs limit its application.Starch, as an inexpensive natural polymer, can reduce the cost of P4HB products.However, starch lacks thermoplastic behavior and has poor compatibility with P4HB, thus its extensive use will inevitably impair the mech. properties of P4HB.In this study, the ball-milling starch grafting process is adopted, which can simultaneously solve the two major deficiencies of starch, and the prepared ball-milling starch-g-polycaprolactone (BSt-g-PCL) has thermoplasticity and better compatibility with P4HB.BSt-g-PCL can melt near 55°C, and the interweaving of its mol. chains with P4HB reduces the binding energy (Einteraction) of both, making the phase interface blurred or even disappear.Therefore, the elongation at break retention (REB) of P4HB/BSt-g-PCL can increase from 37.1% to 74.3% compared to P4HB/starch at the same filling (70 Phr).Addnl., BSt-g-PCL can exert the effect of accelerating P4HB degradation and still make it maintain excellent anti-aging ability.The ball-milling starch graft process provides a simple and effective method for the preparation of inexpensive fully biodegradable P4HB composite films with excellent mech. properties.