Osteoporosis: Emerging targets on the classical signaling pathways of bone formation.

Osteoporosis is a multifaceted skeletal disorder characterized by reduced bone mass and structural deterioration, posing a significant public health challenge, particularly in the elderly population. Treatment strategies for osteoporosis primarily focus on inhibiting bone resorption and promoting bone formation. However, the effectiveness and limitations of current therapeutic approaches underscore the need for innovative methods. This review explores emerging molecular targets within crucial signaling pathways, including wingless/integrated (WNT), bone morphogenetic protein (BMP), hedgehog (HH), and Notch signaling pathway, to understand their roles in osteogenesis regulation. The identification of crosstalk targets between these pathways further enhances our comprehension of the intricate bone metabolism cycle. In summary, unraveling the molecular complexity of osteoporosis provides insights into potential therapeutic targets beyond conventional methods, offering a promising avenue for the development of new anabolic drugs.

Design and synthesis of dabigatran etexilate derivatives with inhibiting thrombin activity for hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is one of the most fatal solid malignancies worldwide. Evidence suggests that thrombin stimulates tumor progression via fibrin formation and platelet activation. Meanwhile, we also found a correlation between thrombin and HCC through bioinformatics analysis. Dabigatran is a selective, direct thrombin inhibitor that reversibly binds to thrombin. Dabigatran was used as the lead agent in this study, and 19 dabigatran derivatives were designed and synthesized based on docking mode. The thrombin-inhibitory activity of the derivative AX-2 was slightly better than that of dabigatran. BX-2, a prodrug of AX-2, showed a fairly strong inhibitory effect on thrombin-induced platelet aggregation, and effectively antagonized proliferation of HCC tumor cells induced by thrombin at the cellular level. Furthermore, BX-2 reduced tumor volume, weight, lung metastasis, and secondary tumor occurrence in nude mouse models. BX-2 combined with sorafenib increased sorafenib efficacy. This study lays the foundation for discovering new anti-HCC mechanism based on thrombin. BX-2 can be used as an anti-HCC drug lead for further research.

Structure-based virtual screening identified novel FOXM1 inhibitors as the lead compounds for ovarian cancer.

Ovarian cancer (OC) is a gynecological tumor with possibly the worst prognosis, its 5-year survival rate being only 47.4%. The first line of therapy prescribed is chemotherapy consisting of platinum and paclitaxel. The primary reason for treatment failure is drug resistance. FOXM1 protein has been found to be closely associated with drug resistance, and inhibition of FOXM1 expression sensitizes cisplatin-resistant ovarian cancer cells. Combining existing first-line chemotherapy drugs with FOXM1 prolongs the overall survival of patients, therefore, FOXM1 is considered a potential therapeutic target in ovarian cancer. Previous research conducted by our team revealed a highly credible conformation of FOXM1 which enables binding by small molecules. Based on this conformation, the current study conducted virtual screening to determine a new structural skeleton for FOXM1 inhibitors which would enhance their medicinal properties. DZY-4 showed the highest affinity towards FOXM1, and its inhibitory effect on proliferation and migration of ovarian cancer at the cellular level was better than or equal to that of cisplatin, while its efficacy was equivalent to that of cisplatin in a nude mouse model. In this study, the anti-tumor effect of DZY-4 is reported for the first time. DZY-4 shows potential as a drug that can be used for ovarian cancer treatment, as well as a drug lead for future research.

Anxiety and Depression of Nurses in a North West Province in China During the Period of Novel Coronavirus Pneumonia Outbreak.

PURPOSE: To investigate the anxiety and depression levels of frontline clinical nurses working in 14 hospitals in Gansu Province, China, during this period. DESIGN: A cross-sectional survey was conducted online between February 7 and 10, 2020, with a convenience sample of 22,034 nurses working in 14 prefecture and city hospitals in Gansu Province, located in northwest China. METHODS: A self-reported questionnaire with four parts (demographic characteristics, general questions related to novel coronavirus-infected pneumonia, self-rating anxiety scale, and self-rating depression scale) was administered. Descriptive statistics including frequencies, means, and SDs were computed. The associations between anxiety and depression with sociodemographic characteristics, work-related concerns, and impacts were analyzed, followed by multiple stepwise linear regression to identify factors that best predicted the nurses' anxiety and depression levels. FINDINGS: A total of 21,199 questionnaires were checked to be valid, with an effective recovery rate of 96.21%. The mean ± SD age of the respondents was 31.89 ± 7.084 years, and the mean ± SD length of service was 9.40 ± 7.638 years. The majority of the respondents were female (98.6%) and married (73.1%). Some demographic characteristics, related concerns, and impacts of COVID-19 were found to be significantly associated with both anxiety (p < .001) and depression (p < .001). Nurses who needed to take care of children or elderly relatives, took leave from work because they were worried about COVID-19, avoided contact with family and friends, and wanted to obtain more COVID-19-related knowledge had higher levels of both anxiety and depression. CONCLUSIONS: Results show that nurses faced with the COVID-19 outbreak are at risk for experiencing anxiety and depression. Demographic background, psychosocial factors, and work-related factors predicted the psychological responses. The family responsibilities and burdens of women may explain the higher levels of anxiety and depression among nurses with these obligations as compared to those without. On the other hand, nurses who chose not to take leave from work or who did not avoid going to work during this period were less anxious and depressed. CLINICAL RELEVANCE: Professional commitment might be a protective factor for adverse psychological responses. It is pertinent to provide emotional support for nurses and recognize their professional commitment in providing service to people in need.

Structure and Sense Organs of Ovipositors of an Endoparasitoid Aprostocetus causalis and an Ectoparasitoid Quadrastichus mendeli in Leptocybe spp.

Little is known of the olfactory mechanisms of host detection in the ovipositors of endoparasitoids and ectoparasitoids. An endoparasitoid Aprostocetus causalis La Salle & Wu (Hymenoptera: Eulophidae) and an ectoparasitoid Quadrastichus mendeli Kim & La Salle (Hymenoptera: Eulophidae: Tetrastichinae) are the two parasitoids of the eucalyptus gall wasp Leptocybe spp. Structures and sense organs of ovipositors of A. causalis and Q. mendeli were studied using scanning and transmission electron microscopy, which provided essential information for exploring the mechanism of host detection by endoparasitoid and ectoparasitoid. The ovipositors of two parasitoids consisted of the first and second valvulae and ended in a pointed tip. There were three types of microtrichia, two types of sensilla chaetica, and one type of sensilla campaniformia on the ovipositors of A. causalis and Q. mendeli. However, Q. mendeli has the fourth type of microtrichia on the ovipositor. The morphology, types, distribution, length, and width of these sensilla and microtrichia were described, and their possible functions are discussed in conjunction with the stinging, oviposition, and the host selection process.

Assessment of neovascularization within carotid plaques in patients with ischemic stroke.

AIM: To assess neovascularization within human carotid atherosclerotic soft plaques in patients with ischemic stroke. METHODS: Eighty-one patients with ischemic stroke and 95 patients without stroke who had soft atherosclerotic plaques in the internal carotid artery were studied. The thickest soft plaque in each patient was examined using contrast-enhanced ultrasound. Time-intensity curves were collected from 5 s to 3 min after contrast injection. The neovascularization within the plaques in the internal carotid artery was evaluated using the ACQ software built into the scanner by 2 of the experienced investigators who were blinded to the clinical history of the patients. RESULTS: Ischemic stroke was present in 7 of 33 patients (21%) with grade I plaque, in 14 of 51 patients (28%) with grade II plaque, in 26 of 43 patients (61%) with grade III plaque, and in 34 of 49 patients (69%) with grade IV plaque (P < 0.001 comparing grade IV plaque with grade I plaque and with grade II plaque and P = 0.001 comparing grade III plaque with grade I plaque and with grade II plaque). Analysis of the time intensity curves revealed that patients with ischemic stroke had a significantly higher intensity of enhancement (IE) than those without ischemic stroke (P < 0.01). The wash-in time (WT) of plaque was significantly shorter in stroke patients (P < 0.05). The sensitivity and specificity for IE in the plaque were 82% and 80%, respectively, and for WT were 68% and 74%, respectively. There was no significant difference in the peak intensity or time to peak between the 2 groups. CONCLUSION: This study shows that the higher the grade of plaque enhancement, the higher the risk of ischemic stroke. The data suggest that the presence of neovascularization is a marker for unstable plaque.