ABSTRACT
Chemotherapy-induced complications, particularly lethal cardiovascular diseases, pose significant challenges for cancer survivors. The intertwined adverse effects, brought by cancer and its complication, further complicate anticancer therapy and lead to diminished clinical outcomes. Simple supplementation of cardioprotective agents falls short in addressing these challenges. Developing bi-functional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously. Drug repurposing was naturally endowed with co-therapeutic potential of two indications, implying a unique chance in the development of bi-functional agents. Herein, we further proposed a novel "trilogy of drug repurposing" strategy that comprises function-based, target-focused, and scaffold-driven repurposing approaches, aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent. Through function-based repurposing, a cardioprotective agent, carvedilol (CAR), was identified as a potential neddylation inhibitor to suppress lung cancer growth. Employing target-focused SAR studies and scaffold-driven drug design, we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection. Remarkably, optimal derivative 43 displayed promising bi-functional effects, especially in various self-established heart failure mice models with and without tumor-bearing. Collectively, the present study validated the practicability of the "trilogy of drug repurposing" strategy in the development of bi-functional co-therapy agents.
ABSTRACT
Ubiquitin (Ub) and ubiquitin-like (Ubl) pathways are critical post-translational modifications that determine whether functional proteins are degraded or activated/inactivated. To date, >600 associated enzymes have been reported that comprise a hierarchical task network (e.g., E1-E2-E3 cascade enzymatic reaction and deubiquitination) to modulate substrates, including enormous oncoproteins and tumor-suppressive proteins. Several strategies, such as classical biochemical approaches, multiomics, and clinical sample analysis, were combined to elucidate the functional relations between these enzymes and tumors. In this regard, the fundamental advances and follow-on drug discoveries have been crucial in providing vital information concerning contemporary translational efforts to tailor individualized treatment by targeting Ub and Ubl pathways. Correspondingly, emphasizing the current progress of Ub-related pathways as therapeutic targets in cancer is deemed essential. In the present review, we summarize and discuss the functions, clinical significance, and regulatory mechanisms of Ub and Ubl pathways in tumorigenesis as well as the current progress of small-molecular drug discovery. In particular, multiomics analyses were integrated to delineate the complexity of Ub and Ubl modifications for cancer therapy. The present review will provide a focused and up-to-date overview for the researchers to pursue further studies regarding the Ub and Ubl pathways targeted anticancer strategies.
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ObjectiveTo perform a predictive analysis of the quality marker（Q-Marker） for the anticoagulant activity of Kunning granules. MethodThe chemical components of Kunning granules were analyzed by ultra high performance liquid chromatography-quadrupole-time of flight tandem mass spectrometry（UHPLC-Q-TOF-MS/MS） on a Waters ACQUITY UPLC HSS T3 column（2.1 mm×100 mm， 1.8 μm） with the mobile phase of acetonitrile（A）-25 mmol∙L-1 ammonium acetate aqueous solution（B） for gradient elution （0-5 min， 5%-22%A； 5-10 min， 22%-30%A； 10-15 min， 30%-95%A； 15-20 min， 95%-5%A； 20-30 min， 5%A）， flow rate of 0.2 mL∙min-1， column temperature at 30 ℃， injection volume of 1 μL， electrospray ionization（ESI）， positive and negative ion detection modes. Interaction analysis between the targets of chemical components and the targets of abnormal uterine bleeding（AUB） was performed by network pharmacology， and the key components were screened through network topology analysis. The fingerprints of 10 batches of Kunning granules were established by high performance liquid chromatography（HPLC）， the anticoagulant activity of the granules was determined by blood coagulation method and fibrinogen plate method， and the spectrum-effective relationship was established. The components co-occurring in the topological analysis and spectrum-effective relationship were selected as Q-Markers， and their anticoagulant activities were verified and confirmed. ResultA total of 475 chemical components were identified from Kunning Granule， of which 22 key components such as salvianolic acid B， paeoniflorin， naringin and neohesperidin， were the potential material basis for the treatment of AUB. The spectrum-effective analysis showed that peaks 7（paeoniflorin）， 9（naringin）， 10（neohesperidin） and 11（salvianolic acid B） were the optimal principal components， and in vitro activity test showed that these four components could better characterize their anticoagulant activity. ConclusionSalvianolic acid B， paeoniflorin， neohesperidin and naringin may be Q-Markers for the anticoagulant activity of Kunning granules.
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BackgroundInsomnia disorder has become a common disease in the current society. Cognitive Behavior Therapy for Insomnia （CBTI） is one of the non-drug treatment methods for insomnia disorder， but relevant studies of its effect on sleep quality and cognitive function of patients with insomnia disorder are limited. ObjectiveTo explore the effects of CBTI on sleep quality and cognitive function in patients with insomnia disorder， so as to provide references for non-drug treatment of insomnia disorder. MethodsA total of 47 patients with insomnia disorder were recruited as the study subjects. They all met the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders， fifth edition （DSM-5） and have visited Sichuan Mental Health Center from January 2021 to October 2022. The patients underwent CBTI for 6 weeks. Before the treatment， depression and anxiety symptoms were assessed using Hamilton Depression Scale-24 item （HAMD-24） and Hamilton Anxiety Scale （HAMA）. Sleep status and cognitive function were assessed using Pittsburgh Sleep Quality Index （PSQI） and Montreal Cognitive Assessment （MoCA） before and 6 weeks after the treatment. Spearman correlation analysis was used to examine the correlation between the reduction of PSQI score and the increase of MoCA score after treatment. ResultsAfter the 6-week treatment， the factor scores and total score of PSQI across 6 subscales （the sleep quality， sleep onset time， sleep time， sleep efficiency， sleep disorder and daytime dysfunction） were lower than those before the treatment， and the score differences were of statistical significance （t=5.569~15.290， P<0.01）. Both factor and total scores of MoCA across 6 items （visuospatial and executive， naming， attention， language， abstraction and memory） were significantly higher than those before the treatment with score differences reaching statistical significance （t=-11.273~-4.277， P<0.01）. Spearman correlation analysis demonstrated that there was a positive correlation between the decrease in PSQI total score and the increase in MoCA total score after the 6-week CBTI treatment （r=0.323， P=0.027）. ConclusionCBTI may help improve sleep quality and cognitive function in patients with insomnia disorders. The improvement of sleep quality after CBTI intervention may be related to the improvement of cognitive function. ［Funded by Scientific Research Project of Sichuan Provincial Health Commission （number， 19PJ216）］
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This paper aims to analyze the clinical efficacy of cognitive behavioral therapy for insomnia （CBTI） in chronic insomnia treatment， with a view to providing a theoretical basis for promoting the clinical use of CBTI and providing a reference for the non-pharmacological treatment of chronic insomnia patients in China. Chronic insomnia is a common disorder， and CBTI has emerged as the first approach to treating chronic insomnia， so this review focuses on the current status， clinical efficacy， adverse effects， existed problems and management strategies of CBTI for chronic insomnia treatment from the perspectives of physiological mechanisms and neuroimaging.
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Streptococcus dysgalactiae subspecies equisimilis (SDSE) belongs to group C or group G β-hemolytic Streptococcus, SDSE infection cases are mostly related with the consumption of contaminated dairy or meat products, the major symptom is upper respiratory tract infection, and is easily to be misdiagnosed.In June 2014, an outbreak of acute upper respiratory tract infection due to SDSE occurred in a kindergarten in Xi'an City.All cases were followed up, the initial case developed as latent nephritis, the main cause for the development of latent nephritis was not performing diagnosis and treatment timely.In order to enhance the understanding of the epidemiological and clinical features of SDSE infection, strengthen prevention and control ability, and reduce the occurrence of adverse sequelae, investigation of the case and epidemic situation should be reported.
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Objective To observe the clinical effect of headless compression Screw (HCS)under arthroscope in the treat-ment of patella fracture.Methods Nineteen patients of patella transverse fractures were selected,all of them were treated with HCS fixation under arthroscope,reviewed and followed-up after surgery.Results X-ray examination after surgery of 3 -5 weeks found that the fracture lines blurred or disappeared,and the patella articular surface was smooth without displacement.The healing time of fracture was 8 weeks on average after operation;There was no statistical difference in the range of the knee joint in the af-fected side in (135.42±5.82)°and the contralateral side in (139.38±6.55)°(P >0.05);The knee Lysholm score of the last follow-up was 86-100 points[(93.7±4.14)points],which was significantly higher than the preoperative score of 65.7 (P <0.05);There was no fracture displacement in the period of followed-up,drop of internal fixator,fracture and other complications.Conclusion HCS fixation under arthroscope in treatment of patella fracture is effective.The joint function recovered quickly with less complica-tion.It could be one of the effective methods for the treatment of patella transverse fracture.