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.

Cancer stands as one of the predominant causes of mortality globally, necessitating ongoing efforts to develop innovative therapeutics. Historically, natural products have been foundational in the quest for anticancer agents. Bulbocodin D (BD) and Bulbocodin C (BC), two bibenzyls derived from Pleione bulbocodioides (Franch.) Rolfe, have demonstrated notable in vitro anticancer activity. In human lung cancer A549 cells, the IC_50s for BD and BC were 11.63 and 11.71 μmol·L^-1, respectively. BD triggered apoptosis, as evidenced by an upsurge in Annexin V-positive cells and elevated protein expression of cleaved-PARP in cancer cells. Furthermore, BD and BC markedly inhibited the migratory and invasive potentials of A549 cells. The altered genes identified through RNA-sequencing analysis were integrated into the CMap dataset, suggesting BD's role as a potential signal transducer and activator of transcription 3 (STAT3) inhibitor. SwissDock and MOE analyses further revealed that both BD and BC exhibited a commendable binding affinity with STAT3. Additionally, a surface plasmon resonance assay confirmed the direct binding affinity between these compounds and STAT3. Notably, treatment with either BD or BC led to a significant reduction in p-STAT3 (Tyr 705) protein levels, regardless of interleukin-6 stimulation in A549 cells. In addition, the extracellular signal-regulated kinase (ERK) was activated after BD or BC treatment. An enhancement in cancer cell mortality was observed upon combined treatment of BD and U0126, the MEK1/2 inhibitor. In conclusion, BD and BC emerge as promising novel STAT3 inhibitors with potential implications in cancer therapy.
Humans ; Lung Neoplasms/metabolism* ; STAT3 Transcription Factor/metabolism* ; Antineoplastic Agents/chemistry* ; A549 Cells ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation

Objective To investigate the relationship between lesion size of solitary bone cyst ( SBC) and pathological fracture of calcaneus, so as to provide references for the treatment of SBC. Methods The three dimensional (3D) finite element model of foot and ankle was established based on CT images. Four models with gradient spherical bone defects were constructed in the focal area to simulate different SBC lesion sizes, and the biomechanical characteristics of calcaneus in different gait phases were analyzed. Results With the increasement of SBC size, the kinematics of calcaneus did not change significantly, but the peak stress of calcaneus increased gradually. When the SBC size exceeded 75% of the calcaneal width, the stress in calcaneal sulcus and cortical bone below SBC increased by 1. 48 times and 7. 74 times, respectively. Conclusions The risk of pathological fracture increases when the SBC diameter exceeds 75% of the calcaneal width, and early surgical intervention should be recommended. The calcaneal sulcus and the cortex bone below SBC are stress concentration regions and can be used as important areas to evaluate pathological fractures.

OBJECTIVE: To investigate the biomechanical characteristics of different internal fixations for Pauwels type Ⅲ femoral neck fracture with defect, and provide reference for the treatment of femoral neck fracture. METHODS: Three-dimensional (3D) finite element models of femoral neck fractures were established based on CT images, including fracture and fracture with defects. Four internal fixations were simulated, namely, inverted cannulated screw(ICS), ICS combined with medial buttress plate, the femoral neck system (FNS) and FNS combined with medial buttress plate. The von Mises stress, model stiffness and fracture displacements of fracture models under 2 100 N axial loads were measured and compared. RESULTS: When femoral neck fracture was fixed by ICS and FNS, the peak stress was mainly concentrated on the surface of the screw near the fracture line, and the peak stress of FNS is higher than that of ICS;When the medial buttress plate was combined, the peak stress was increased and transferred to medial buttress plate, with more obvious of ICS fixation. For the same fracture model, the stiffness of FNS was higher than that of ICS. Compared with femoral neck fracture with defects, fracture model showed higher stiffness in the same internal fixation. The use of medial buttress plate increased model stiffness, but ICS increased more than FNS. The fracture displacement of ICS model exceeded that of FNS. CONCLUSION For Pauwels type Ⅲ femoral neck fracture with defects, FNS had better biomechanical properties than ICS. ICS combined with medial buttress plate can better enhance fixation stability and non-locking plate is recommended. FNS had the capability of shear resistance and needn't combine with medial buttress plate.
Humans ; Femoral Neck Fractures/surgery* ; Fracture Fixation, Internal/methods* ; Bone Screws ; Bone Plates ; Biomechanical Phenomena ; Finite Element Analysis

Animals ; Schistosoma japonicum ; Colitis, Ulcerative

This study aims to analyze the biomechanical stability of Magic screw in the treatment of acetabular posterior column fractures by finite element analysis. A three-dimensional finite element model of the pelvis was established based on the computed tomography (CT) and magnetic resonance imaging (MRI) data of a volunteer and its effectiveness was verified. Then, the posterior column fracture model of the acetabulum was generated. The biomechanical stability of the four internal fixation models was compared. The 500 N force was applied to the upper surface of the sacrum to simulate human gravity. The maximum implant stresses of retrograde screw fixation, single-plate fixation, double-plate fixation and Magic screw fixation model in standing and sitting position were as follows: 114.10, 113.40 MPa; 58.93, 55.72 MPa; 58.76, 47.47 MPa; and 24.36, 27.50 MPa, respectively. The maximum stresses at the fracture end were as follows: 72.71, 70.51 MPa; 48.18, 22.80 MPa; 52.38, 27.14 MPa; and 34.05, 30.78 MPa, respectively. The fracture end displacement of the retrograde tension screw fixation model was the largest in both states, and the Magic screw had the smallest displacement variation in the standing state, but it was significantly higher than the two plate fixations in the sitting state. Magic screw can satisfy the biomechanical stability of posterior column fracture. Compared with traditional fixations, Magic screw has the advantages of more uniform stress distribution and less stress, and should be recommended.
Biomechanical Phenomena ; Bone Plates ; Bone Screws ; Finite Element Analysis ; Fracture Fixation, Internal/methods* ; Fractures, Bone/surgery* ; Humans ; Spinal Fractures

Conjunctival melanoma (CM) is a rare and fatal malignant eye tumor. In this study, we deciphered a novel anti-CM mechanism of a natural tetracyclic compound named as cucurbitacin B (CuB). We found that CuB remarkably inhibited the proliferation of CM cells including CM-AS16, CRMM1, CRMM2 and CM2005.1, without toxicity to normal cells. CuB can also induce CM cells G2/M cell cycle arrest. RNA-seq screening identified KIF20A, a key downstream effector of FOXM1 pathway, was abolished by CuB treatment. Further target identification by activity-based protein profiling chemoproteomic approach revealed that GRP78 is a potential target of CuB. Several lines of evidence demonstrated that CuB interacted with GRP78 and bound with a K _d value of 0.11 μmol/L. Furthermore, ATPase activity evaluation showed that CuB suppressed GRP78 both in human recombinant GRP78 protein and cellular lysates. Knockdown of the GRP78 gene significantly induced the downregulation of FOXM1 and related pathway proteins including KIF20A, underlying an interesting therapeutic perspective. Finally, CuB significantly inhibited tumor progression in NCG mice without causing obvious side effects in vivo. Taken together, our current work proved that GRP78-FOXM1-KIF20A as a promising pathway for CM therapy, and the traditional medicine CuB as a candidate drug to hinder this pathway.

Objective To analyze the biomechanical feasibility of two-point fixation by distal radius plate for the treatment of SandersⅢ calcaneal fractures. Methods The three-dimensional (3D) finite element musculoskeletal foot model was established based on CT and MRI images, which comprised bones, muscles, plantar fascia, ligaments and soft tissues. After validation, the SandersⅢ calcaneal fracture models fixed by distal radial plate (two-point fixation) and calcaneal plate (three-point fixation) were established, so as to compare the biomechanical characteristics of two calcaneal models. Results The maximum stress of the two-point fixation and three-point fixation model was 324.70 and 407.90 MPa, respectively. The maximum displacements of the two models were 2.498 and 2.541 mm, respectively. There was no significant difference in the posterior articular surface displacement between the two models. In both models, the Bohler’s angle and Gissane’s angle were within the normal range. Conclusions The two-point fixation by distal radial plate can satisfy the biomechanical stability of calcaneal fracture treatment. Compared with traditional steel plate, the two-point fixation shows the advantage of smaller surgical trauma, more uniform overall stress distribution, early weight-bearing rehabilitation after surgery, which is a novel treatment recommended for treating calcaneal fractures.

Acetaminophen (APAP) overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States. We investigated the role of p62/SQSTM1 (referred to as p62) in APAP-induced liver injury (AILI) in mice. We found that the hepatic protein levels of p62 dramatically increased at 24 h after APAP treatment, which was inversely correlated with the hepatic levels of APAP-adducts. APAP also activated mTOR at 24 h, which is associated with increased cell proliferation. In contrast, p62 knockout (KO) mice showed increased hepatic levels of APAP-adducts detected by a specific antibody using Western blot analysis but decreased mTOR activation and cell proliferation with aggravated liver injury at 24 h after APAP treatment. Surprisingly, p62 KO mice recovered from AILI whereas the wild-type mice still sustained liver injury at 48 h. We found increased number of infiltrated macrophages in p62 KO mice that were accompanied with decreased hepatic von Willebrand factor (VWF) and platelet aggregation, which are associated with increased cell proliferation and improved liver injury at 48 h after APAP treatment. Our data indicate that p62 inhibits the late injury phase of AILI by increasing autophagic selective removal of APAP-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.

OBJECTIVE：To prepare Imperatorin ultradeformable liposomes gel （IMP-UDLs-Gel），and to evaluate its quality. METHODS：Based on single factor test ，using 12 h accumulative penetration amount （Q12h）as evaluation index ，the proportion of carbomer 940，glycerol and propyl glycol in formulation of IMP-UDLs-Gel were investigated by orthogonal test. The optimal formulation was screened. The quality of IMP-UDLs-Gel prepared with the optimal formulation was evaluated. RESULTS ：The optimal formulation of IMP-UDLs-Gel included carbomer 940 proportion of 1％，glycerol proportion of 15％ and propyl glycol proportion of 10％. Q12 h of IMP-UDLs-Gel was （11.543±0.241）μg/cm2；the appearance was milky white and translucent ；the particle size was （93.13±1.68）nm，PDI was 0.268±0.012，Zeta potential was （－24.96±1.99）mV；pH was 7.32±0.03； viscosity was （45.37±1.27）g·s；steady flow was （0.727±0.002）μg·h/cm2，lag time was （4.358±0.175）h，apparent permeability coefficient was 1.392×10－3 cm/h，and it has good physical and optical stability. CONCLUSIONS ：The preparation method is stable and feasible ，and the prepared IMP-UDLs-Gel has good adhesion ，stability and transdermal property.