In In recent years, small-molecule targeted protein degraders inducing protein degradation have been developing rapidly. These molecules are attracting substantial interest from researchers since they can overcome such limitations of traditional small-molecule inhibitors as their inapplicability to ‘undruggable’ targets and tendency to induce drug resistance. Compared with other targeted protein degraders, small-molecule hydrophobic tags (HyTs) may have a smaller number of hydrogen bond donors/acceptors, smaller molecular weights, and better pharmacokinetic profiles, thus attracting extensive attention from researchers. This review focuses on the possible mechanisms and popular types of HyTs, with special attention to the potential application value of adamantane, a typical hydrophobic tag, in the fields of cancer and neurodegeneration. In general, there are still some problems like fewer types of hydrophobic tags and insufficient research on degradation mechanisms, which still need to be further explored. This review is expected to provide researchers working in the fields of small-molecule targeted protein degraders with some valuable reference.

Eight new diterpenoids, Isodons A-H (1-8), comprising seco-abietane and abietane-type structures, together with 13 known analogues (9-21), were isolated from Isodon lophanthoides (Buch.-Ham. ex D. Don) Hara. The compounds (+)-3/(-)-3, (+)-4/(-)-4, and (+)-5/(-)-5 were identified as three enantiomeric pairs. The planar structures and absolute configurations of 1-8 were determined through high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), 1D & 2D nuclear magnetic resonance (NMR) spectroscopy, electronic circular dichroism (ECD) calculations, and X-ray diffraction crystallography. A cholesterol 7α-hydroxylase (Cyp7a1) luciferase reporter assay revealed significant anti-cholestatic activities for compounds 1, (+)-4, 6, 7, 12-14, and 16. Additionally, compound 6 demonstrated anti-cholestatic effects through the farnesoid X receptor (FXR)-associated signaling pathways in vitro and in vivo. These findings suggest potential applications for I. Lophanthoides in pharmaceutical development.
Abietanes/pharmacology* ; Molecular Structure ; Animals ; Isodon/chemistry* ; Humans ; Diterpenes/pharmacology* ; Plant Extracts/chemistry*

Objective To investigate the effect of staphylococcal nuclease and tudor domain containing 1(SND1)on the biological function of osteosarcoma cells and decipher the mechanism of SND1 in regulating fer-roptosis in osteosarcoma cells via SLC7A11.Methods Human osteoblasts hFOB1.19 and osteosarcoma cell lines Saos-2,U2OS,HOS,and 143B were cultured,in which the expression level of SND1 was determined.Small in-terfering RNA was employed to knock down the expression of SND1(si-SND1)in the osteosarcoma cell line HOS and 143B.The CCK8 assay kit,colony formation assay,and Transwell assay were employed to examine the effect of SND1 expression on the biological function of osteosarcoma cells.Furthermore,we altered the expression of SND1 and SLC7A11 in osteosarcoma cells to investigate the effect of SND1 on osteosarcoma ferroptosis via SLC7A11.Results The mRNA and protein levels of SND1 in Saos-2,U2OS,HOS,and 143B cells were higher than those in hFOB1.19 cells(all P<0.01).Compared with the control group,transfection with si-SND1 down-regulated the expression level of SND1 in HOS and 143B cells(all P<0.01),decreased the viability of HOS and 143B cells,reduced the number of colony formation,and inhibited cell invasion and migration(all P<0.001).The ferroptosis inducer Erastin promoted the apoptosis of HOS and 143B cells,while the ferroptosis inhibitor Fer-rostatin-1 improved the viability of HOS and 143B cells(all P<0.001).After SND-1 knockdown,Erastin reduced the viability of HOS and 143B cells,while Ferrostatin-1 restored the cell viability(all P<0.001).After treatment with Erastin in the si-SND1 group,the levels of iron and malondialdehyde were elevated,and the level of glutathione was lowered(all P<0.001).The results of in vivo experiments showed that SND1 knockdown inhibited the mass of the transplanted tumor in 143B tumor-bearing nude mice(P<0.001).Knocking down the expression of SND1 resul-ted in down-regulated SLC7A11 expression(all P<0.001)and increased ferroptosis in HOS and 143B cells(P<0.001,P=0.020).Conclusions SND1 presents up-regulated expression in osteosarcoma cells.It may inhibit ferrop-tosis by up-regulating the expression of SLC7A11,thereby improving the viability of osteosarcoma cells.

Endometriosis, a heterogeneous, inflammatory, and estrogen-dependent gynecological disease defined by the presence and growth of endometrial tissues outside the lining of the uterus, affects approximately 5-10% of reproductive-age women, causing chronic pelvic pain and reduced fertility. Although the etiology of endometriosis is still elusive, emerging evidence supports the idea that immune dysregulation can promote the survival and growth of retrograde endometrial debris. Peritoneal macrophages and natural killer (NK) cells exhibit deficient cytotoxicity in the endometriotic microenvironment, leading to inefficient eradication of refluxed endometrial fragments. In addition, the imbalance of T-cell subtypes results in aberrant cytokine production and chronic inflammation, which contribute to endometriosis development. Although it remains uncertain whether immune dysregulation represents an initial cause or merely a secondary enhancer of endometriosis, therapies targeting altered immune pathways exhibit satisfactory effects in preventing disease onset and progression. Here, we summarize the phenotypic and functional alterations of immune cells in the endometriotic microenvironment, focusing on their interactions with microbiota and endocrine and nervous systems, and how these interactions contribute to the etiology and symptomology of endometriosis.
Female ; Humans ; Endometriosis/metabolism* ; Killer Cells, Natural/metabolism* ; T-Lymphocytes/metabolism* ; Estrogens ; Endometrium/metabolism*

Objective To screen potential metabolites and significantly altered metabolic pathways of liver lesions by central carbon pathway metabolites. Methods 32 healthy volunteers (HC), 23 patients with biliary cysts (CYST), 19 patients with biliary stones (Stone), 45 patients with hepatocellular carcinoma (HCC), and 50 patients with hilarcholangiocarcinoma (HCCA) were recruited. Their serum samples were collected for UPLC-QQQ-MS analysis and further MPP statistical analysis. Pattern recognition was further used to discovery the differences in metabolome between groups, and to explore the significantly altered metabolic pathway and possible pathogenic mechanism of liver diseases. Results A total of 15, 7, 7, and 3 metabolites and a total of 8, 4, 4, and 1 metabolic pathway that were significantly different in serum between CYST, Stone, HCC, HCCA and healthy controls were identified and enriched through serum metabolomics analysis, respectively. Conclusion According to the above identified differential metabolites and enriched metabolic pathway results, it is shown that liver lesions mainly involved in the energy metabolism and amino acid metabolism & transport, in addition, inositol phosphate metabolism were significantly changed both in CYST, Stone, HCC and HCCA.

Objective:To investigate the expression of PDLIM3 in the ectopic and orthotopic endometrium of endometriosis(EMT)patients,as well as in healthy endometrium,and to explore its relationship with clinical signifi-cance.Methods:Bioinformatics analysis based on the Gene Expression Omnibus(GEO)database was conduc-ted,and a prospective cohort study was undertaken,involving 58 EMT patients treated at West China Second Hospital of Sichuan University and 27 patients with other benign gynecological diseases as the control group from December 2019 to July 2020.Ectopic and orthotopic endometrium samples were obtained from EMT patients,and normal control samples were obtained from patients with other benign gynecological diseases.Real-time quantita-tive polymerase chain reaction(qPCR),western blot,and immunohistochemistry were utilized to investigate PD-LIM3 expression in various tissue samples.Clinical parameters were analyzed to determine the correlation be-tween PDLIM3 and clinical features.Results:Compared to orthotopic endometrial tissues of EMT patients and normal endometrial tissues of control subjects,the mRNA(F =46.05,P<0.05)and protein(F =238.6,P<0.05)expression levels of PDLIM3 in ectopic endometrial lesions were significantly upregulated.The average optical density(AOD)of PDLIM3 protein obtained through immunohistochemical experiments in ectopic endometrial le-sions showed a positive correlation with the degree of dysmenorrhea(r =0.86,P<0.05)and CA 125 level(r = 0.41,P<0.05)in EMT patients.But no obvious correlation was found between the expression level of PDLIM3 and disease stage,menstrual volume,and CA199 level(P>0.05).Conclusions:The expression level of PDLIM3 in endometriosis lesions was significantly upregulated and correlated with the degree of dysmenorrhea and serum CA125 level.These findings suggest that PDLIM3 may play a significant role in the development and progression of endometriosis and could serve as a potential therapeutic target.

Molecular glues can specifically induce aggregation between two or more proteins to modulate biological functions. In recent years, molecular glues have been widely used as protein degraders. In addition, however, molecular glues play a variety of vital roles, such as complex stabilization, interactome modulation and transporter inhibition, enabling challenging therapeutic targets to be druggable and offering an exciting novel approach for drug discovery. Since most molecular glues are identified serendipitously, exploration of their systematic discovery and rational design are important. In this review, representative examples of molecular glues with various physiological functions are divided into those mediating homo-dimerization, homo-polymerization and hetero-dimerization according to their aggregation modes, and we attempt to elucidate their mechanisms of action. In particular, we aim to highlight some biochemical techniques typically exploited within these representative studies and classify them in terms of three stages of molecular glue development: starting point, optimization and identification.

Objective:To investigate the clinical application effect of latissimus dorsi muscle flap in reconstruction of muscle strength around shoulder after electric burns.Methods:From March 2014 to September 2020, 13 patients with electric burns and severe injury around shoulder were admitted to the First Affiliated Hospital of Air Force Medical University, including 11 males and 2 females, aged 19-55 years. A retrospective observational study was conducted. The left upper limbs were injured in 8 cases, and the right upper limbs were injured in 5 cases, all with eschar wounds of Ⅲ-Ⅳ degree. Among which, there were biceps defects in 6 cases, deltoid defects in 3 cases, triceps defects in 2 cases, and composite defects of multiple muscles around shoulder in 2 cases. The surgery was carried out in two stages. In stage Ⅰ, debridement and exploration of electric burn wounds around shoulders were conducted to preserve local tissue and save the limb as much as possible on the premise of guaranteeing the stability of the body condition. After the last debridement, the wound area was from 10 cm×6 cm to 40 cm×15 cm, the muscle defect area was from 8 cm×4 cm to 19 cm×12 cm, and the humerus was exposed in 7 patients. In stage Ⅱ, according to the residual limb defect degree, muscle reconstruction around shoulder was conducted with the latissimus dorsi muscle flap, and area of the latissimus dorsi muscle flap was 15 cm×6 cm to 20 cm×18 cm. The residual wounds were repaired with autologous split-thickness skin grafts of head, and the donor sites of muscle flaps were sutured directly. The survivals of the muscle flaps and wounds closure post operation, and the appearances of the donor sites and recipient sites during follow-up were observed. At the last follow-up, the shoulder joint function was evaluated using the trial standard for the evaluation of the functions of the upper limbs of the Hand Surgery Society of the Chinese Medical Association, and the satisfaction degrees of patients for appearance and function recoveries of shoulder were investigated by self-made questionnaire with reference to the concise test scoring system of shoulder joint.Results:All of the 13 muscle flaps around shoulder survived after surgery. Two patients had residual wounds in the skin grafting area, the wound in one of the patients was healed after dressing change, and the wound in the other 1 patient was healed with the second autologous split-thickness skin grafting on head after dressing change. During follow-up of 6 to 18 months for all the patients, the muscle flaps of patients were full in appearance and not bloated, and atrophic scar in the repaired area was soft in texture and closed with normal skin around. Linear suture scars were left in the donor sites of muscle flaps, which did not affect the overall appearance. At the last follow-up, the active abduction range of the shoulder joint was 60-90°, upward lift on 120-180°, muscle strength recovered to level Ⅳ and above in 8 cases and to level Ⅲ in 5 cases, and the shoulder joint function was evaluated as excellent in 8 cases and good in 5 cases; 10 patients were very satisfied and 3 patients were satisfied with the appearance and function recovery of the shoulders.Conclusions:The application of latissimus dorsi muscle flap provides a better choice for the muscle strength reconstruction around shoulder after electric burns, with good appearance of the operative areas and ideal prognosis of upper limb function.

Objective To observe and analyze the pathological changes in BALB/c mice infected with herpes simplex virus typeⅡ (HSV-2) through nasal and genital inoculation. Methods Six-week old female BALB/c mice were divided into two groups, experimental and control groups. In the experimental group, the mice were infected with HSV-2 (104 CCID50/20μl per mouse) through nasal and genital tract in-oculation. Accordingly, the mice in the control group were injected with equal volume of PBS. Tissue speci-mens were collected from lung, nervous system and reproductive system for pathological analysis and viral load detection at different time points after infection. Lat gene expression in mouse trigeminal and sacral gan-glia was detected through in situ hybridization. In addition, the proliferation of viruses isolated form trigemi-nal and sacral ganglia of the infected mice was observed in vitro. Results Weight loss and histopathological lesions were observed in the mice of the experimental group 6 d after infection. Major pathological changes in the HSV-2-infected mice through nasal tract inoculation involved the lung and central nervous system( CNS) , including alveolar wall congestion, cerebrovascular cuff response and lymphocyte infiltration. How-ever, the major lesions in the infected mice through genital tract inoculation were found in the reproductive ducts, such as sacral ganglion necrosis, eosinophilia in the vagina and uterus, and ovarian congestion. Re-sults of the viral load detection in tissues and organs of the infected mice were consistent with the pathological changes. The mice infected through nasal tract inoculation had significantly higher viral loads in the nerves and lungs than those by genital tract inoculation, but lower viral loads in the genital tracts and sacral ganglia. Positive expression of lat gene at mRNA level was detected in the trigeminal and sacral ganglia of mice with HSV-2 latency 28 d after infection. In addition, both of the tissue fragments from trigeminal and sacral ganglia had cytopathic effects ( CPEs) on Vero cells. Enhanced expression of lat gene at mRNA level and much severer CPEs were induced by genital tract inoculation than by nasal tract inoculation. Conclu-sions HSV-2 could infect and cause histopathological damages in BALB/c mice through both nasal and genital tracts. In addition, the locations of the pathological lesions were closely related to the mode of infection.

Objective To investigate the characteristics and the risk factors of pulmonary function in patients with chronic obstructive pulmonary disease (COPD) for a 3 year follow-up.Methods Subjects diagnosed as COPD were followed up for 3 years in the Management Center of Chronic Respiratory Disease at XINQIAO Hospital from September 2009 to June 2012.This was a retrospective study.Parameters related to respiratory function mainly first second forced expiratory volume (FEV1),COPD assessment test (CAT),6 minutes walking distance (6MWD) and acute exacerbation were recorded during follow-up.Results Although the majority of patients were treated with drugs such as inhaled corticosteroid combined with longterm bronchial dilatation during the three years,FEV1 decreased progressively.The average annual decline of FEV1 was(31.80 ± 61.99) ml,translating into a mean annual decline of(3.74 ± 6.18) ％.However,there were significant differences in changes of FEV1.Approximately,FEV1 in 78.3％ (47/60) patients decreased,only 21.7％ (13/60) patients kept stable FEV1.There was a correlation between decrease of FEV1,FEV1 ％ predicted and the exacerbation (r =0.298,0.361,0.273;P ＜ 0.05).Logistic regression showed that the positive bronchodilator reversibility and the initial FEV1 were the independent factors associated with significant changes in FEV1 (respectively,OR =5.54,95％ CI 1.55-19.73;OR =8.28,95％ CI 1.42-48.32).Conclusion The changes of pulmonary function in patients with COPD are heterogeneous,although most patients are treated in a standard way.Nearly 80％ patients still represent deterioration of pulmonary function.Decline of FEV1 is closely related to the initial pulmonary function and bronchodilator reversibility.