ABSTRACT
Proteolysis targeting chimera (PROTAC) refers to heterobifunctional small molecules that can simultaneously bind an E3 ubiquitin ligase and a target protein, enabling specific degradation of the target protein with the aid of the ubiquitin proteasome system. At present, most PROTAC drugs are in the clinical trial stage, and the ligands are mainly non-covalent compounds. PROTAC drugs have the advantage of overcoming drug resistance and degrading "undruggable" target proteins, but non-covalent ligands could lead to the hook effect that undermines drug efficacy. With its own advantages, covalent ligands can avoid the occurrence of this phenomenon, which is of great help to the development of PROTAC. This review summarizes the progress in preclinical and clinical research and application of PROTAC molecules targeting three different classes of protein targets, including intranuclear, transmembrane, and cytosolic proteins. We also offer perspective discussions to provide research ideas and references for the future development of PROTAC.
Subject(s)
Proteolysis , Proteolysis Targeting Chimera , Proteasome Endopeptidase Complex/metabolism , Ubiquitin-Protein Ligases/metabolism , Proteins/metabolism , LigandsABSTRACT
A retrospective study was conducted on one patient with postmenopausal hyperandrogenism. The postmenopausal female patient was found with significant hyperandrogenism ( total testosterone 6. 4 nmol/ L) and hirsutism, with normal adrenal androgen ( dehydroepiandrosterone-sulfate ) level. Computed tomography and ultrasound did not detect any ovarian and adrenal mass. Positron emission tomography revealed without high metabolic region, either. Ovarian and adrenal vein catheterization did not reveal any positive result. Obviously, ovary-derived hyperandrogenism was highly suspected, but the patient still refused any surgical exploration. After a trial of a single dose of gonadotropin releasing hormone analogue(GnRHa) triptorelin, increased testosterone level returned to normal along with decreasing level of gonadotropin. Multiple doses were needed for maintenance of testosterone at normal level with the intervals of 2 ～ 12 months. This response to the treatment was consistent with that of gonadotropin dependent hyperandrogenism.
ABSTRACT
Cushing's syndrome in pediatrics is very rare. In most child patients, the onset of Cushing's syndrome is insidious. The most common presenting symptom is growth retardationin inconsistant with the weight gain. The most common cause of Cushing's syndrome in children is exogenous administration of glucocorticoids and Cushing' s disease. Here we present a case of pediatric Cushing' s syndrome; the diagnosis and treatment are discussed.
ABSTRACT
Cushing's syndrome in pediatrics is very rare. In most child patients, the onset of Cushing's syndrome is insidious. The most common presenting symptom is growth retardationin inconsistant with the weight gain. The most common cause of Cushing's syndrome in children is exogenous administration of glucocorticoids and Cushing' s disease. Here we present a case of pediatric Cushing' s syndrome; the diagnosis and treatment are discussed.
ABSTRACT
[Summary] Eighteen patients with idiopathic hypogonadotropic hypogonadism( IHH) receiving aromatase-inhibitor( AI) letrozole for at least 3 months were recruited.After 3 months′treatment, LH levels were increased from (2.1 ±1.5) IU/L to (3.6 ±3.7) IU/L(P=0.029), and FSH levels from (2.6 ±1.8) IU/L to (4.3 ±3.4) IU/L (P=0.003).Total testosterol was increased from (87 ±42) ng/dl to (166 ±200) ng/dl(P=0.082), and estradiol wasdecreasedfrom(22.7±18.7) pg/ml to (13.4±10.6) pg/ml(P=0.020).The average testis volume was increased[(14.3 ±3.9 vs 11.2 ±4.9) ml, P<0.01].Sperms were detected in 8 out of 9 patients who did seminal fluid test.The result of general linear model showed that LH(60 min) was significantly related with total testosterol increment( P=0.045) .
ABSTRACT
[Summary] Hypogonadotropic hypogonadism (HH) in women is characterized by failure of ovarian function secondary to deficient gonadotropin secretion,resulting from either a hypothalamic or pituitary defect.Estrogenprogestin therapy can induce and maintain secondary sex characteristic and artificial menstrual evcle.If the patient requires fertility,ovulation and even pregnancy can be induced either with exogenous gonadotropins or with pulsatile gonadotropin releasing hormone therapy.In the present article,different ovulation induction therapies of female HH were reviewed.
ABSTRACT
<p><b>OBJECTIVE</b>To evaluate the effect of pretreatment with erythropoietin (EPO) on disordered pro- and anti- inflammatory balance in rats with severe acute pancreatitis (SAP) and explore the underlying mechanisms.</p><p><b>METHODS</b>Ninety healthy male SD rats were randomized equally into sham-operated group, SAP group and EPO pretreatment group. SAP model was induced in the latter two groups by retrograde injection of 1 ml/kg 3.5% sodium traurocholate into the biliopancreatic duct. In EPO group, 3000 U/kg EPO (1000 U/ml) was administered intravenously 1 h before SAP, and normal saline was administered in the other two groups. Serum amylase activity, interleukin-10 (IL-10)and IL-18 levels were measured at different time points after the operation. The translocation and activation of nuclear factor-κB (NF-κB) in the pancreatic tissue was detected using immunofluorescence staining, and pancreatic pathologies were evaluated.</p><p><b>RESULTS</b>Compared with SAP group, EPO group showed a markedly decreased activation rate of NF-κB after SAP except for 12 h (P<0.05), significantly decreased serum amylase activity at 3, 6, and 12 h (P<0.05) and decreased serum IL-18 levels at 3, 6, 24 h (P<0.05), whereas serum IL-10 underwent no significant changes. The rats in EPO group showed an obviously milder pancreatic pathology than those in SAP group at 6, 12, and 24 h (P<0.05).</p><p><b>CONCLUSION</b>EPO can effectively inhibit NF-κB activation by regulating the inflammatory mediators and restoring the pro-and anti-inflammatory balance to alleviate SAP in rats.</p>