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Yu Zhu,1,* Huiliang Cao,2,* Shichong Qiao,1,* Manle Wang,2,3 Yingxin Gu,1 Huiwen Luo,1 Fanhao Meng,2 Xuanyong Liu,2 Hongchang Lai1 1Department of Oral and Maxillofacial Implantology, Shanghai Key Laboratory of Stomatology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, 2State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 3School of Materials Engineering, Shanghai University of Engineering Science, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: A versatile strategy to endow dental implants with long-term antibacterial ability without compromising the cytocompatibility is highly desirable to combat implant-related infection. Silver nanoparticles (Ag NPs) have been utilized as a highly effective and broad-spectrum antibacterial agent for surface modification of biomedical devices. However, the high mobility and subsequent hazardous effects of the particles on mammalian cells may limit its practical applications. Thus, Ag NPs were immobilized on the surface of sand-blasted, large grit, and acid-etched (SLA) titanium by manipulating the atomic-scale heating effect of silver plasma immersion ion implantation. The silver plasma immersion ion implantation-treated SLA surface gave rise to both good antibacterial activity and excellent compatibility with mammalian cells. The antibacterial activity rendered by the immobilized Ag NPs was assessed using Fusobacterium nucleatum and Staphylococcus aureus, commonly suspected pathogens for peri-implant disease. The immobilized Ag NPs offered a good defense against multiple cycles of bacteria attack in both F. nucleatum and S. aureus, and the mechanism was independent of silver release. F. nucleatum showed a higher susceptibility to Ag NPs than S. aureus, which might be explained by the presence of different wall structures. Moreover, the immobilized Ag NPs had no apparent toxic influence on the viability, proliferation, and differentiation of rat bone marrow mesenchymal stem cells. These results demonstrated that good bactericidal activity could be obtained with very small quantities of immobilized Ag NPs, which were not detrimental to the mammalian cells involved in the osseointegration process, and promising for titanium-based dental implants with commercial SLA surfaces. Keywords: silver nanoparticles, surface modification, antibacterial effects, cytotoxicity, plasma immersion ion implantation

Background: Hepatocellular carcinoma (HCC) recurrence is highly correlated with increased mortality. Microvascular invasion (MVI) is indicative of aggressive tumor biology in HCC., Aim: To construct an artificial neural network (ANN) capable of accurately predicting MVI presence in HCC using magnetic resonance imaging., Methods: This study included 255 patients with HCC with tumors < 3 cm. Radiologists annotated the tumors on the T1-weighted plain MR images. Subsequently, a three-layer ANN was constructed using image features as inputs to predict MVI status in patients with HCC. Postoperative pathological examination is considered the gold standard for determining MVI. Receiver operating characteristic analysis was used to evaluate the effectiveness of the algorithm., Results: Using the bagging strategy to vote for 50 classifier classification results, a prediction model yielded an area under the curve (AUC) of 0.79. Moreover, correlation analysis revealed that alpha-fetoprotein values and tumor volume were not significantly correlated with the occurrence of MVI, whereas tumor sphericity was significantly correlated with MVI ( P < 0.01)., Conclusion: Analysis of variable correlations regarding MVI in tumors with diameters < 3 cm should prioritize tumor sphericity. The ANN model demonstrated strong predictive MVI for patients with HCC (AUC = 0.79)., Competing Interests: Conflict-of-interest statement: All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

In our previous study, we reported a series of N-(9,10-anthraquinone-2-carbonyl) amino acid derivatives as novel inhibitors of xanthine oxidase (XO). Recognizing the suboptimal drug-like properties associated with the anthraquinone moiety, we embarked on a nonanthraquinone medicinal chemistry exploration in the current investigation. Through systematic structure-activity relationship (SAR) studies, we identified a series of 4-(isopentyloxy)-3-nitrobenzamide derivatives exhibiting excellent in vitro potency against XO. The optimized compound, 4-isopentyloxy-N-(1H-pyrazol-3-yl)-3-nitrobenzamide (6k), demonstrated exceptional in vitro potency with an IC 50 value of 0.13 μM. Compound 6k showed favorable drug-like characteristics with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.41 and 3.73, respectively. In comparison to the initial compound 1d, 6k exhibited a substantial 24-fold improvement in IC 50 , along with a 1.6-fold enhancement in LE and a 3.7-fold increase in LLE. Molecular modeling studies provided insights into the strong interactions of 6k with critical amino acid residues within the active site. Furthermore, in vivo hypouricemic investigations convincingly demonstrated that 6k significantly reduced serum uric acid levels in rats. The MTT results revealed that compound 6k is nontoxic to healthy cells. The gastric and intestinal stability assay demonstrated that compound 6k exhibits good stability in the gastric and intestinal environments. In conclusion, compound 6k emerges as a promising lead compound, showcasing both exceptional in vitro potency and favorable drug-like characteristics, thereby warranting further exploration., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Discovering new treatments for melanoma will benefit human health. The mechanism by which deoxyhypusine synthase (DHPS) promotes melanoma development remains elucidated. Multi-omics studies have revealed that DHPS regulates m6A modification and maintains mRNA stability in melanoma cells. Mechanistically, DHPS activates the hypusination of eukaryotic translation initiation factor 5A (eIF5A) to assist METTL3 localizing on its mRNA for m6A modification, then promoting METTL3 expression. Structure-based design, synthesis, and activity screening yielded the hit compound GL-1 as a DHPS inhibitor. Notably, GL-1 directly inhibits DHPS binding to eIF5A, whereas GC-7 cannot. Based on the clarification of the mode of action of GL-1 on DHPS, it is found that GL-1 can promote the accumulation of intracellular Cu 2+ to induce apoptosis, and antibody microarray analysis shows that GL-1 inhibits the expression of several cytokines. GL-1 shows promising antitumor activity with good bioavailability in a xenograft tumor model. These findings clarify the molecular mechanisms by which DHPS regulates melanoma proliferation and demonstrate the potential of GL-1 for clinical melanoma therapy., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

A series of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors were designed and synthesized by heterocyclic-containing tail approach. The inhibitory activities against four human epidermal growth factor receptor (HER) isozymes (EGFR, HER-2, HER-3 and HER-4) of all new compounds so designed were investigated in vitro. Compound 12k was found to be the most effective and rather selective dual-target inhibitor of EGFR and HER-2 with inhibitory constant (IC 50 ) values of 6.15 and 9.78 nM, respectively, which was more potent than the clinical used agent Lapatinib (IC 50  = 8.41 and 9.41 nM). Meanwhile, almost all compounds showed excellent antiproliferative activities against four cancer cell models (A549, NCI-H1975, SK-BR-3 and MCF-7) and low damage to healthy cells. Among them, compound 12k also exhibited the most prominent antitumor activity. Moreover, the hit compound 12k could bind to EGFR and HER-2 stably in molecular docking and dynamics studies. The following wound healing assay revealed that compound 12k could inhibit the migration of SK-BR-3 cells. Further studies found that compound 12k could arrest cell cycle in the G0/G1 phase and induce SK-BR-3 cells apoptosis. Notably, compound 12k could effectively inhibit breast cancer growth with little toxicity in the SK-BR-3 cell xenograft model. Taken together, in vitro and in vivo results disclosed that compound 12k had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Thoracic spinal epidural abscess (SEA) is a rare but dangerous condition, and traditional surgical methods are accompanied by extensive trauma and approach-related complications. Here we introduce the technique of full-endoscopic transforaminal debridement and decompression and evaluate its feasibility for treating brucellar thoracic SEA., Methods: We performed thoracic full-endoscopic transforaminal decompression and debridement on two patients with neurological deficits caused by brucellar SEA, which is mainly composed of granulation tissue rather than pus. Postoperative MRI was conducted to confirm the presence of any residual abscess compressing the nerves. Frankel grading was employed to assess the recovery of neurological function, and complications were documented., Results: There were no occurrences of dural tear, postoperative hematoma, or pulmonary complications. Their neurological function had significantly improved after surgery, and postoperative MRI confirmed no residual abscess compressing the spinal cord. During the 2-year follow-up, one patient achieved complete recovery (from Frankel-C to Frankel-E), while another patient improved from Frankel-A to Frankel-D. Neither patient experienced infection recurrence, instability, nor kyphotic deformity., Conclusion: We described the novel application of transforaminal endoscopic surgery in brucellar thoracic granulomatous SEA and preliminarily indicated the feasibility of this technique as a minimally invasive alternative to open surgery., (© 2024 The Authors. Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

Corynoxeine, a natural active alkaloid found in Genus Uncaria, has been reported to have anti-depressant effects. In this study, a sensitive and efficient ultra-high performance liquid chromatography tandem mass spectrometry method for quantifying corynoxeine in rat plasma and tissues was established, validated and applied to investigate the pharmacokinetics and tissue distribution differences between normal rats and chronic unpredictable mild stress (CUMS)-induced depression model rats following oral administration. All bio-samples were prepared by methanol protein precipitation method with theophylline as internal standard (IS). Chromatographic separation was conducted on an Agilent ZORBAX Eclipse Plus C18 column using mobile phase A (acetonitrile) and B (0.1% formic acid in water) in gradient elution mode with a flow rate of 0.3 mL/min. Mass spectrometric detection was performed in multiple-reaction monitoring mode with positive electrospray ionization source. The transitions of m/z 383.0→160.2 for corynoxeine and m/z 181.1→124.0 for IS were chosen for quantification. The method showed good linearity, stability, accuracy, precision, recovery, and non-significant matrix effect, which were within the acceptable ranges. The pharmacokinetic results revealed that the absorption and bioavailability of corynoxeine in depression rats decreased compared to normal rats. The tissue distribution of corynoxeine trended to be mostly in the intestine and stomach and the distribution of this compound in intestine tissue of depression rats was significantly increased compared to the normal rats. The pharmacokinetics and tissue distribution profiles of corynoxeine were altered in CUMS-induced depression rats compared to normal rats and these experimental findings could provide beneficial information to the mechanism research and clinical applications of corynoxeine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

P-glycoprotein (P-gp) is an important factor leading to multidrug resistance (MDR) in cancer treatment. The co-administration of anticancer drugs and P-gp inhibitors has been a treatment strategy to overcome MDR. In recent years, tyrosine kinase inhibitor Lapatinib has been reported to reverse MDR through directly interacting with ABC transporters. In this work, a series of P-gp inhibitors (1-26) was designed and synthesized by integrating the quinazoline core of Lapatinib into the molecule framework of the third-generation P-gp inhibitor Tariquidar. Among them, compound 14 exhibited better MDR reversal activity than Tariquidar. The docking results showed compound 14 displayed the L-shaped molecular conformation. Importantly, compound 14 increased the accumulation of Adriamycin (ADM) and rhodamine 123 (Rh123) in MCF7/ADM cells. Besides, compound 14 significantly increased ADM-induced apoptosis and inhibited the proliferation, migration and invasion of MCF7/ADM cells. It was also demonstrated that compound 14 significantly inhibited the growth of MCF7/ADM xenograft tumors by increasing the sensitivity of ADM. In summary, compound 14 has the potential to overcome MDR caused by P-gp., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

The occurrence and development of the tumor are very complex biological processes. In recent years, a large number of research data shows that CD73 is closely related to tumor growth and metastasis. It has been confirmed that the cascade hydrolysis of extracellular ATP to adenosine is one of the most important immunosuppressive regulatory pathways in the tumor microenvironment. The metabolite adenosine can mediate immunosuppression by activating adenosine receptor (such as A 2A ) on effector Immune cells and enable tumor cells to achieve immune escape. Therefore, attenuating or completely removing adenosine-mediated immunosuppression in the tumor microenvironment by inhibiting CD73 is a promising approach in the treatment of solid tumors. This paper focuses on the research progress of CD73 enzyme and CD73 small molecule inhibitors, and is expected to provide some insights into the development of small-molecule antitumor drugs targeting CD73., Competing Interests: Declaration of Competing interest None of the authors have any potential conflicts of interest., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Objective: To investigate the prevalence of dyslipidemia and the level of blood lipids among Tajik people in Pamir Plateau, Xinjiang, and explore the related factors of dyslipidemia. Methods: It is a retrospective cross-sectional study. A multi-stage cluster random sampling survey was conducted among 5 635 Tajiks over 18 years old in Tashkorgan Tajik Autonomous County, Xinjiang Province from May to October 2021. Data were collected through questionnaire survey (general information, medical history, and personal history), physical examination (height, weight, waist, and blood pressure) and blood test (total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density cholesterol (HDL-C)) to analyze the dyslipidemia and its risk factors among Tajiks. Results: The age of Tajik participants was (41.9±15.0) years, including 2 726 males (48.4%). The prevalence of borderline high TC, high LDL-C and high TG levels were 17.2%, 14.7% and 8.9%, respectively. The prevalence of high TC, high LDL-C, high TG and low HDL-C were 4.1%, 4.9%, 9.4% and 32.4%, respectively, and the prevalence of dyslipidemia was 37.0%. There is a positive correlation between male,higher education level, higher body mass index (BMI) value,waist circumference, living in town, smoking and dyslipidemia. Conclusions: The low prevalence of high TC, high LDL-C, high TG and high prevalence of low HDL-C was a major characteristic of Tajik people in Pamir Plateau of Xinjiang. The lower rates of overweight and obesity may be one of the reasons for the lower prevalence of dyslipidemia among Tajik.

Breast cancer, especially the aggressive triple-negative subtype, poses a serious health threat to women. Unfortunately, effective targets are lacking, leading to a grim prognosis. Research highlights the crucial role of c-MYC overexpression in this form of cancer. Current inhibitors targeting c-MYC focus on stabilizing its G-quadruplex (G4) structure in the promoter region. They can inhibit the expression of c-MYC , which is highly expressed in triple-negative breast cancer (TNBC), and then regulate the apoptosis of breast cancer cells induced by intracellular ROS. However, the clinical prospects for the application of such inhibitors are not promising. In this research, we designed and synthesized 29 acridone derivatives. These compounds were assessed for their impact on intracellular ROS levels and cell activity, followed by comprehensive QSAR analysis and molecular docking. Compound N 8 stood out, significantly increasing ROS levels and demonstrating potent anti-tumor activity in the TNBC cell line, with excellent selectivity shown in the docking results. This study suggests that acridone derivatives could stabilize the c-MYC G4 structure. Among these compounds, the small molecule N 8 shows promising effects and deserves further investigation.

Host innate immunity plays a pivotal role in the early detection and neutralization of invading pathogens. Here, we show that pseudokinase mixed lineage kinase-like protein (MLKL) is required for host defence against Streptococcus pluranimalium infection by enhancing NLRP3 inflammasome activation and extracellular trap formation. Notably, Mlkl deficiency leads to increased mortality, increased bacterial colonization, severe destruction of organ architecture, and elevated inflammatory cell infiltration in murine models of S. pluranimalium pulmonary and systemic infection. In vivo and in vitro data provided evidence that potassium efflux-dependent NLRP3 inflammasome signalling downstream of active MLKL confers host protection against S. pluranimalium infection and initiates bacterial killing and clearance. Moreover, Mlkl deficiency results in defects in extracellular trap-mediated bactericidal activity. In summary, this study revealed that MLKL mediates the host defence response to S. pluranimalium , and suggests that MLKL is a potential drug target for preventing and controlling pathogen infection.

Background: Gelsemium elegans (Gardner & Chapm.) Benth (G. elegans) has been widely used as a traditional folk medicine in China and Southeast Asia. As the most abundant alkaloid in G. elegans, Koumine (KM) has been revealed the effect of inflammatory attenuation modulating by macrophage activation and polarization., Purpose: This study aimed to explore the effect of KM on modulation of microglia polarization that led to the suppression of neuroinflammation and further improved neurodegenerative behavior., Methods: Inflammatory mediators, microglia M1 and M2 phenotype markers and Nrf2/HO-1 pathway related protein were assessed in LPS-induced BV2 cells and LPS-treated mice by RT-PCR, immunohistochemistry, immunofluorescence and Western blotting. Moreover, the learning and memory abilities of mice were evaluated by Morris water maze test, and the neuronal damage was evaluated by the Nissl staining., Results: KM attenuated LPS-induced viability and morphological changes in BV2 microglial cells. Our findings showed that KM activated the Nrf2/HO-1 signaling pathway to promote phenotypic switch from M1 to M2 phenotypes. This switch suppresses the release of inflammatory mediators in LPS-induced BV2 cells. Meanwhile, KM attenuated neuroinflammation through modulating microglia polarization and subsequently reversed the behavioral alterations in LPS-induced mice model of neuroinflammation., Conclusions: KM may alleviate neuroinflammation by regulating microglia polarization with the involvement of Nrf2/HO-1 pathway, resulting of the neuroprotective effect., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Colon adenocarcinoma (COAD) is a major cause of cancer mortality worldwide. The occurrence and development of colon cancer is regulated by complex mechanisms that require further exploration. Recently, long non-coding RNAs (lncRNAs) were found to be related to the mortality of colon cancer patients through their participation in competing endogenous RNA (ceRNA) networks. Therefore, screening the lncRNAs involved in colon cancer may contribute to clarifying the complex mechanisms., Methods: In this study, we explored the potential lncRNAs associated with colon cancer by establishing a ceRNA network using bioinformatics, followed by biological verification., Results: RP11-197K6.1 and RP11-400N13.3 were screened out owing to their involvement in the expression of CDK2NA, a gene that potentially prevents colon cancer cells from high oxygen levels., Conclusions: Our work explored the mechanisms of recurrence and metastasis in colon cancer and provided potential targets for drug development., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Niemann-Pick C1-like 1 (NPC1L1) is essential for intestinal cholesterol absorption. Together with the cholesterol-rich and Flotillin-positive membrane microdomain, NPC1L1 is internalized via clathrin-mediated endocytosis and transported to endocytic recycling compartment (ERC). When ERC cholesterol level decreases, NPC1L1 interacts with LIMA1 and moves back to plasma membrane. However, how cholesterol leaves ERC is unknown. Here, we find that, in male mice, intracellular bile acids facilitate cholesterol transport to other organelles, such as endoplasmic reticulum, in a non-micellar fashion. When cholesterol level in ERC is decreased by bile acids, the NPC1L1 carboxyl terminus that previously interacts with the cholesterol-rich membranes via the A 1272 LAL residues dissociates from membrane, exposing the Q 1277 KR motif for LIMA1 recruitment. Then NPC1L1 moves back to plasma membrane. This study demonstrates an intracellular cholesterol transport function of bile acids and explains how the substantial amount of cholesterol in NPC1L1-positive compartments is unloaded in enterocytes during cholesterol absorption., (© 2023. Springer Nature Limited.)

Based on previous work, further search for more effective and less damaging thymidylate synthase (TS) inhibitors was the focus of this study. After further optimization of the structure, in this study, a series of (E)-N-(2-benzyl hydrazine-1-carbonyl) phenyl-2,4-deoxy-1,2,3,4-tetrahydro pyrimidine-5-sulfonamide derivatives were synthesized and reported for the first time. All target compounds were screened by enzyme activity assay and cell viability inhibition assay. On the one hand, the hit compound DG1 could bind directly to TS proteins intracellularly and promote apoptosis in A549 and H1975 cells. Simultaneously, DG1 could inhibit cancer tissue proliferation more effectively than Pemetrexed (PTX) in the A549 xenograft mouse model. On the other hand, the inhibitory effect of DG1 on NSCLC angiogenesis was verified both in vivo and in vitro. In parallel, DG1 was further uncovered to inhibit the expression of CD26, ET-1, FGF-1, and EGF by angiogenic factor antibody microarray. Moreover, RNA-seq and PCR-array assays revealed that DG1 could inhibit NSCLC proliferation by affecting metabolic reprogramming. Collectively, these data demonstrated that DG1as a TS inhibitor could be promising in treating NSCLC angiogenesis, deserving further investigation., Competing Interests: Declaration of competing interest The authors declared that they have no conflicts of interest in this work. We declared that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Lower plasma levels of LDL (low-density lipoprotein) cholesterol (LDL-C) can reduce the risk of atherosclerotic cardiovascular disease. The loss-of-function mutations in PCSK9 (proprotein convertase subtilisin/kexin type 9) have been known to associate with low LDL-C in many human populations. PCSK9 genetic variants in Chinese Uyghurs who are at high risk of atherosclerotic cardiovascular disease due to their dietary habits have not been reported., Methods: The study involved the whole-exome and target sequencing of college students from Uyghur and other ethnic groups in Xinjiang, China, for the association of PCSK9 loss-of-function mutations with low plasma levels of LDL-C. The mechanisms by which the identified mutations affect the function of PCSK9 were investigated in cultured cells using biochemical and cell assays. The causal effects of the identified PCSK9 mutations on LDL-C levels were verified in mice injected with adeno-associated virus expressing different forms of PCSK9 and fed a high-cholesterol diet., Results: We identified 2 PCSK9 mutations-E144K and C378W-in Chinese Uyghurs with low plasma levels of LDL-C. The E144K and C378W mutations impaired the maturation and secretion of the PCSK9 protein, respectively. Adeno-associated virus-mediated expression of E144K and C378W mutants in Pcsk9 KO (knockout) mice fed a high-cholesterol diet also hampered PCSK9 secretion into the serum, resulting in elevated levels of LDL receptor in the liver and reduced levels of LDL-C in the serum., Conclusions: Our study shows that E144K and C378W are PCSK9 loss-of-function mutations causing low LDL-C levels in mice and probably in humans as well., Competing Interests: Disclosures None.

Clostridium perfringens is a major cause of infectious foodborne disease, frequently associated with the consumption of raw and undercooked food. Despite intensive studies on clarifying C. perfringens pathogenesis, the molecular mechanisms of host-pathogen interactions remain poorly understood. In soft tissue and mucosal infection models, Gpr120 - / - mice, G protein-coupled receptor 120 (GPR120), are more susceptible to C. perfringens infection. Gpr120 deficiency leads to a low survival rate (30 and 10%, p < 0.01), more bacterial loads in the muscle (2.26 × 10 8 ± 2.08 × 10 8 CFUs/g, p < 0.01), duodenum (2.80 × 10 7 ± 1.61 × 10 7 CFUs/g, p < 0.01), cecum (2.50 × 10 8 ± 2.05 × 10 8 CFUs/g, p < 0.01), and MLN (1.23 × 10 6 ± 8.06 × 10 5 CFUs/g, p < 0.01), less IL-18 production in the muscle (8.54 × 10 3 ± 1.20 × 10 3 pg/g, p < 0.01), duodenum (3.34 × 10 3 ± 2.46 × 10 2 pg/g, p < 0.01), and cecum (3.81 × 10 3 ± 5.29 × 10 2 pg/g, p < 0.01), and severe organ injury. Obviously, GPR120 facilitates IL-18 production and pathogen control via potassium efflux-dependent NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling. Mechanistically, GPR120 interaction with NLRP3 potentiates the NLRP3 inflammasome assembly. Thus, this study uncovers a novel role of GPR120 in host protection and reveals that GPR120 may be a potential therapeutic target for limiting pathogen infection.

Our previous studies suggested that N-phenyl aromatic amides are a class of promising xanthine oxidase (XO) inhibitor chemotypes. In this effort, several series of N-phenyl aromatic amide derivatives (4a-h, 5-9, 12i-w, 13n, 13o, 13r, 13s, 13t and 13u) were designed and synthesized to carry out an extensive structure-activity relationship (SAR). The investigation provided some valuable SAR information and identified N-(3-(1H-imidazol-1-yl)-4-((2-methylbenzyl)oxy)phenyl)-1H-imidazole-4-carboxamide (12r, IC 50  = 0.028 µM) as the most potent XO inhibitor with close in vitro potency to that of topiroxostat (IC 50  = 0.017 µM). Molecular docking and molecular dynamics simulation rationalized the binding affinity through a series of strong interactions with the residues Glu1261, Asn768, Thr1010, Arg880, Glu802, etc. In vivo hypouricemic studies also suggested that the uric acid lowering effect of compound 12r was improved compared with the lead g25 (30.61 % vs 22.4 % reduction in uric acid levels at 1 h; 25.91 % vs 21.7 % reduction in AUC of uric acid) . Pharmacokinetic studies revealed that compound 12r presented a short t 1/2 of 0.25 h after oral administration. In addition, 12r has non-cytotoxicity against normal cell HK-2. This work may provide some insights for further development of novel amide-based XO inhibitors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Percutaneous pedicle screw placement (PPSP) is a minimally invasive procedure highly dependent on fluoroscopic guidance, which results in increased radiation exposure and prolonged operative time. Ultrasound can image the lumbar paravertebral anatomy and the needle trajectory in real time, which may help reduce the use of fluoroscopy and radiation dose in PPSP. We will conduct a parallel randomised controlled trial to mainly investigate the effect of ultrasound guidance in radiation reduction during PPSP., Methods and Analysis: A total of 42 patients will be recruited and randomly assigned to the intervention group and the control group at a 1:1 ratio. In the intervention group, we will use ultrasound in combination with fluoroscopy to guide the insertion of the Jamshidi needles. In the control group, PPSP will be performed under conventional fluoroscopic guidance. The primary outcomes are the cumulative fluoroscopy time (s), radiation dose (mGy) and exposure times of screw placement. The secondary outcomes are insertion time of guidewire, rate of pedicle perforation, rate of facet joint violation, visual analogue scale for back pain, Oswestry Disability Index and complications. The participants, outcome assessors and data analysts will be blinded to allocation., Ethics and Dissemination: The trial was approved by the research ethics committee of Shengjing Hospital, China Medical University. The results will be presented at academic seminars and submitted for publication in peer-reviewed journals.This study involves human participants and was approved by Research Ethics Committee of Shengjing Hospital, China Medical University reference number：2022PS704K. Participants gave informed consent to participate in the study before taking part., Trial Registration Number: ChiCTR2200057131., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Our previous work firstly reported that (E)-2-styrylanthracene-9,10-dione is a novel fluorescent core (EK01) with the ability of specific mitochondria imaging. In this effort, we mainly focused our attention on the structure-photophysical property relationship and application in cells imaging of this new fluorescent chemotype. A series of the structural derivatives (TZ series) were designed and synthesized by introducing some substituents onto the 2-styryl moiety. The structure-photophysical property relationship analysis suggested that TZ03 is an excellent fluorescent molecular building block with the property of fluorescent "turn-on" effect after the modification of acylation, and TZ07 is an excellent fluorescent dye with a series of advantages such as high fluorescence intensity (F max  = 4049.0 in CH 2 Cl 2 , 25.80 μM), moderate molar extinction coefficients (3.77 × 10 3 -5.93 × 10 3  mol -1 ∙L∙cm -1 ), strong fluorescence quantum yield (Φ max  = 0.739 in CH 2 Cl 2 ), large Stokes shift (99.0 nm-161.8 nm) and well biological tolerance. As a classical D-π-A structure, the ICT characteristic of TZ07 was analyzed through spectroscopy verification and DFT calculations. Furthermore, optimized compound TZ07 was successfully applied in the living cells imaging with the excellent selectivity to mitochondria in a green fluorescent form. It was also suggested that the mechanism of TZ07 targeting mitochondria is independent of mitochondrial membrane potential, but probably related to the mitochondrial complex I. These findings may provide some insights into the development of novel mitochondria-targeted fluorescent probes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Advanced platelet-rich fibrin extract (APRFE) contains a high concentration of various cytokines that are helpful for improving stem cells repair function., Objective: However, the underlying mechanism of APRFE improving stem cell repairing is not clear., Methods: We produced APRFE by centrifuging fresh peripheral blood samples and isolated and identified human adipose-derived mesenchymal stem cells (ADMSCs). The abundance of cytokines contained in APRFE was detected by the Enzyme-linked immunosorbent assay (ELISA). The ADMSCs treated with or without APRFE were collected for transcriptome sequencing., Results: Based on the sequencing data, the expression profiles were contracted. The differentially expressed genes and lncRNA (DEGs and DElncRNAs) were obtained using for the differential expression analysis. The lncRNA-miRNA-mRNA network was constructed based on the miRNet database. The further enrichment analysis results showed that the biological functions were mainly related to proliferation, differentiation, and cell-cell function. To explore the role of APRFE, the protein-protein interaction network was constructed among the cytokines included in APRFE and DEGs. Furthermore, we constructed the global regulatory network based on the RNAInter and TRRUST database. The pathways in the global regulatory network were considered as the core pathways. We found that the DEGs in the core pathways were associated with stemness scores., Conclusion: In summary, we predicted that APRFE activated three pathways (tryptophan metabolism, mTOR signaling pathway, and adipocytokine signaling) to promote the proliferation and differentiation of ADMSCs. The finding may be helpful for guiding the application of ADMSCs in the clinic., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Xanthine oxidase (XO) inhibitors are widely used in the control of serum uric acid levels in the clinical management of gout. Our continuous efforts in searching novel amide-based XO inhibitors culminated in the identification of N-(4-((3-cyanobenzyl)oxy)-3-(1H-tetrazol-1-yl)phenyl)isonicotinamide (TS10), which exhibited comparable in vitro inhibition to that of topiroxostat (TS10, IC 50  = 0.031 μM; topiroxostat, IC 50  = 0.020 μM). According to the molecular modeling, we speculated that, as well as topiroxostat, TS10 would be biotransformed by XO to yield TS10-2-OH. In this work, TS10-2-OH was successfully identified in XO targeted metabolism study, demonstrated that TS10 underwent a covalent binding with XO via a TS10-O-Mo intermediate after anchoring in the XO molybdenum cofactor pocket. Furthermore, TS10-2-OH is a weak active metabolite, and its potency was explained by the molecular docking. In metabolites identification, TS10 could be oxidized by CYP2C9, CYP3A4 and CYP3A5 to generate two mono-hydroxylated metabolites (not TS10-2-OH); and could occur degradation in plasma to mainly generate a hydrolytic metabolite (TS10-hydrolysate). In pharmacokinetic assessment, the low oral system exposure was observed (C max  = 14.73 ± 2.66 ng/mL and AUC last  = 9.17 ± 1.42 h⋅ng/mL), which could be explained by the poor oral absorption property found in excretion studies. Nonetheless, in pharmacodynamic evaluation, TS10 exhibited significant uric acid-lowering effect after oral administration in a dose-dependent manner. Briefly, in addition to allopurinol and topiroxostat, TS10 is possibly another explicitly mechanism-based XO inhibitor with powerful covalent inhibition., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Xanthine oxidase (XO) is a flavoprotein that exists in various organisms and can catalyze the uric acid formation in the human body. Based on the amide framework of N-(4-((3-cyanobenzyl)oxy)-3-(1H-tetrazol-1-yl)phenyl)isonicotinamide (compound 1) reported in our previous work, a series of N-(4-alkoxy-3-(1H-tetrazol-1-yl)phenyl) heterocyclic aromatic amide derivatives were designed, synthesized and evaluated as novel amide-based XO inhibitors. Structure-activity relationship campaign identified the most promising compound g25 (IC 50  = 0.022 μM), which possesses a special 1H-imidazole-5-carboxamide scaffold and presented comparable XO inhibitory potency to topiroxostat (IC 50  = 0.017 μM). Enzyme kinetic studies revealed that compound g25 acted as a mixed-type XO inhibitor. Molecular docking and molecular dynamics indicated that imidazole NH of g25 formed two stable hydrogen bonds with Glu1261 residue of XO that provided a vital contribution for the binding affinity. In addition, in vivo activity evaluation demonstrated that compound g25 exhibited obviously hypouricemic effect on a potassium oxonate induced hyperuricemic rat model., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Sorghum [ Sorghum bicolor (L.) Moench] is an important crop for food security in semiarid and arid regions due to its high tolerance to abiotic and biotic stresses and its good performance in marginal lands with relatively low fertility. To deeply understand the interrelationship among sorghum genotype, environment, sowing dates, and densities in the spring sowing early maturing (SSEM) areas of China, and to provide a basis for specifying scientific and reasonable cultural practices, a two-year field experiment was conducted with six popular varieties at six locations. Combined ANOVA showed that the yield difference between years was significant ( P<0.05 ); the yield differences among locations, varieties, sowing dates, and densities were all highly significant ( P<0.01 ). The variety effect was mainly influenced by location, year, sowing dates and their interactions. The sowing effect was mainly influenced by the location, year, variety and their interactions The plant density effect was significantly influenced by location and location-year interaction. Of the contributions of various test factors to yield variance, the location was the largest one (38.18%), followed by variety (12.31%), sowing date (1.53%), density (0.54%), and year (0.09%), with all these single factors accounting for 52.65%. The total contribution of all two-factor interactions accounted for 14.24%, among which the greatest contributor was location-hybrid interaction (8.07%). The total contribution of all three-factor interactions accounted for 14.58%, of which year-location-hybrid interaction was the largest contributor (9.02%). Sowing dates significantly affected model of sorghum growth and development, especially during the late period. The key climatic factors affecting yield were different among the six locations. Weather factors during the grain filling stages contributed much more than those during the early stage to grain yield. Mid-maturing varieties are recommended other than early maturing varieties for the SSEM areas even when late sowing occurs. Sowing as early as possible is recommended for areas with very short frost-free period (Harbin, Tongliao, and Datong). Proper delayed sowing is recommended for areas with a relative long frost-free period (Gongzhuling, Baicheng and Zhangjiakou). This research will provide a conducive reference for sorghum production in similar areas., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gao, Yan, Gao, Huang, Li, Song, Ren, Li, Jiang, Tang, Wang, Liu, Fan, Wang, Guo, Meng, Han, Jiao and Li.)

Despite intense research in understanding Clostridium perfringens ( C. perfringens ) pathogenesis, the mechanisms by which it is cleared from the host are largely unclarified. In C. perfringens gas gangrene and enterocolitis model, Mlkl -/- mice, lacking mixed lineage kinase-like protein (MLKL), are more susceptible to C. perfringens infection. Mlkl deficiency results in a defect in inflammasome activation, and IL-18 and IL-1β releases. Exogenous administration of recombinant IL-18 is able to rescue the susceptibility of Mlkl -/- mice. Notably, K + efflux-dependent NLRP3 inflammasome signaling downstream of active MLKL promotes bacterial killing and clearance. Interestingly, the defect of bactericidal activity is also mediated by decreased classical extracellular trap formation in the absence of Mlkl . Our results demonstrate that MLKL mediates extracellular trap formation in a NLRP3 inflammasome-dependent manner. These findings highlight the requirement of MLKL for host defense against C. perfringens infection through enhancing NLRP3 inflammasome-extracellular traps axis., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

This study aimed to build a home use deep learning segmentation model to identify the scope of caries lesions. A total of 494 caries photographs of molars and premolars collected via endoscopy were selected. Subsequently, these photographs were labeled by physicians and underwent segmentation training by using DeepLabv3+, and then verification and evaluation were performed. The mean accuracy was 0.993, the sensitivity was 0.661, the specificity was 0.997, the Dice coefficient was 0.685, and the intersection over union (IoU) was 0.529. Therefore, the present deep learning segmentation model can identify and segment the scope of caries.

Human epidermal growth factor receptor 2 (HER-2) is an essential member of the receptor tyrosine kinase (RTK) superfamily and has been reported as a critical method for treating HER-2 positive breast cancer. Here, we retained (E)-4-methyl-2-(4-(trifluoromethyl)styryl)oxazole, a fragment of HER-2 inhibitor Mubritinib, and synthesized 32 novel compounds from it. We screened out the most potential compound Q7j with HER-2 positive breast cancer cells through MTT assays, which possessed low toxicity on normal cells (MCF7-10A). Subsequently, wound healing, transwell, western blotting, and immunofluorescence experiments were performed, and it was found that compound Q7j could suppress cell migration by inhibiting the phosphorylation of HER-2 and affecting the expression of EMT-related proteins. Moreover, the SKBR3 orthotopic xenograft model confirmed that compound Q7j was more effective than Mubritinib in inhibiting the proliferation of cancer cells. In general, compound Q7j was a potential HER-2 inhibitor in treating breast cancer, which may be of great significance for developing and improving HER-2 small molecule inhibitors., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

A series of 4-(phenoxymethyl)-1H-1,2,3-triazole derivatives were designed, synthesized, and evaluated for their xanthine oxidase (XO) inhibitory activities. Among these compounds, 9m emerged as the most effective XO inhibitor with an IC 50 value of 0.70 μM, which was approximately 14-fold more potent than allopurinol. Additionally, compound 9m displayed favorable drug-like properties with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.33 and 3.41, respectively. We further explored the binding mode of 9m in complex with XO by molecular docking and molecular dynamics studies. In vivo hypouricemic studies also suggested that 9m could effectively lower the serum uric acid levels of rat. In summary, compound 9m could be a promising lead for further development of XO inhibitors., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Organophosphorus nerve agents (OPNAs) covalently bind to tyrosine 411 of human serum albumin (HSA) and the formed adducts are stable biomarkers of OPNA exposure. The detection of these adducts has been limited to mass spectrometry techniques combined with protein digestion. Here, we developed indirect competitive ELISA (icELISA) methods to verify OPNA exposure by the detection of OPNA-phosphonylated adducts at tyrosine 411 residue (OPNA-HSA adducts), in which monoclonal antibodies (mAbs) against phosphonylation sites at tyrosine 411 were introduced. The two mAbs were prepared by the fourth generation of rabbit mAb technology using the phosphonylated peptides of LVRY (GD or VX) TKKVPQC as the haptens. These mAbs were screened using our developed competitive ELISA method and then selected based on their individual affinity and selectivity. As a result, we obtained two mAbs that recognized the HSA Tyr 411 adduct of GD (mAb-5G2) or VX (mAb-12B9), respectively. They shared the highest affinity exhibiting a Kd value of about 10 -6  mol/L of the OPNA exposure concentration. They also had remarkable selectivity, which could especially recognize their individual OPNA-HSA adducts in a native state but did not recognize other OPNA-HSAs and unadducted HSAs. Especially for mAb-12B9, it could clearly distinguish VX-HSA and GB-HSA between which there was only one alkyl difference in their phosphonyl portion of the adducted sites. The two mAbs were then used to build the icELISA method for analysis of the serum samples exposed to OPNA. It was found that the detectable lowest GD- and VX-exposed concentrations in serum samples were respectively 1.0 × 10 -6  mol/L and 10.0 × 10 -6  mol/L. This study provides one novel approach and strategy for the retrospective detection of OPNA exposure, and the two mAbs have great potential to be extended for point-of-care testing of OPNA intoxication., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

Targeting EGFR and HER-2 is an essential direction for cancer treatment. Here, a series of N-(1,3,4-thiadiazol-2-yl)benzamide derivatives containing a 6,7-methoxyquinoline structure was designed and synthesized to serve as EGFR/HER-2 dual-target inhibitors. The kinase assays verified that target compounds could inhibit the kinase activity of EGFR and HER-2 selectively. The results of CCK-8 and 3D cell viability assays confirmed that target compounds had excellent anti-proliferation ability against breast cancer cells (MCF-7 and SK-BR-3) and lung cancer cells (A549 and H1975), particularly against SK-BR-3 cells, while the inhibitory effect on healthy breast cells (MCF-10A) and lung cells (Beas-2B) was weak. Among them, the hit compound YH-9 binded to EGFR and HER-2 stably in molecular dynamics studies. Further studies found thatYH-9could induce the release of cytochrome c and inhibit proliferation by promoting ROS expression in SK-BR-3 cells. Moreover,YH-9could diminish the secretion of VEGF and bFGF factors in SK-BR-3 cells, then inhibited tube formation and angiogenesis. Notably,YH-9could effectively inhibit breast cancer growth and angiogenesis with little toxicity in the SK-BR-3 cell xenograft model. Taken together,in vitroandin vivoresults revealed that YH-9 had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth and angiogenesis., (Copyright © 2021. Published by Elsevier Inc.)

CDK4/6 were attractive chemotherapeutic targets for the treatment of malignant tumors, CDK4/6 selective inhibitors have made outstanding contributions in the treatment of breast cancer. However, these inhibitors share a single skeleton of N-(pyridin-2-yl) pyrimidin-2-amine which cannot overcome the side effects in clinical application. In our previous study, an N'- acetylpyrrolidine-1-carbohydrazide was hit as the initial fragment by analyzing the active site characteristics of CDK6. Two series of N-(pyridin-3-yl) proline were obtained by fragment growth method. The QSAR study was carried out according to the in vitro activities data against CDK4/6, and two compounds 7c and 7p with potent inhibitory activities were found to interact with CDK4 in different binding conformation. They showed potential inhibition of cell proliferation against the breast cancer cell, and 7c exhibited promised anti-breast cancer effect in vivo., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Our previous work identified a promising isonicotinamide based xanthine oxidase (XO) inhibitor, N-(3-cyano-4-((2-cyanobenzyl)oxy)phenyl)isonicotinamide (1), and concluded that amide is an effective linker in exploring the XO inhibitor chemical space that is completely different from the five-membered ring framework of febuxostat and topiroxostat. Indole, an endogenous bioactive substance and a popular drug construction fragment, was involved in the structural optimization campaign of the present effort. After the installation of some functional groups, N-(1-alkyl-3-cyano-1H-indol-5-yl) was generated and employed to mend the missing H-bond interaction between the 3'-cyano of 1 and Asn768 residue of XO by shortening their distance. In this context, eight kinds of heterocyclic aromatic amide chemotypes were rationally designed and synthesized to investigate the structure-activity relationship (SAR) of amide-based XO inhibitors. The optimized compound a6 (IC 50  = 0.018 μM) exhibits 17.2-fold improved potency than the initial compound 1 (IC 50  = 0.31 μM). Its potency is comparable to that of topiroxostat (IC 50  = 0.013 μM). Molecular docking and molecular dynamics studies proved the existence of the stable H-bond between the cyano group and the Asn768 residue. Moreover, oral administration of a6 (11.8 mg/kg) could effectively reduce serum uric acid levels in an acute hyperuricemia rat model. Liver microsomal stability assay illustrated that compound a6 possesses well metabolic stability in rat liver microsomes. However, the in vivo potency of a6 was much lower than that of topiroxostat, which may be explained by the poor absorption found in the parallel artificial membrane permeability assay (PAMPA). In addition, 6a has non-cytotoxicity against normal cell lines MCF10A and 16HBE. Taken together, this work culminated in the identification of compound 6a as an excellent lead for further exploration of amide-based XO inhibitors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Our previous work demonstrated that amide is an efficient linker to explore chemical space of xanthine oxidase (XO) inhibitors that are entirely different from febuxostat and topiroxostat. In this effort, with 3-cyano-1H-indol-5-yl as a key moiety, two series of amide-based XO inhibitors, N-(3-cyano-1H-indol-5-yl)isonicotinamides (2a-w) and N-(3-cyano-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamides (3a-i), were designed and synthesized. The structure-activity relationship investigation identified N-(3-cyano-1-cyclopentyl-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (3i, IC 50  = 0.62 μM) as the most promising compound, with 14.4-fold higher in vitro inhibitory potency than allopurinol (IC 50  = 8.91 μM). Molecular simulations provided reasonable interaction modes for the representative compounds. Furthermore, in vivo activity evaluation demonstrated that compound 3i (oral dose of 12.8 mg/kg) has obviously hypouricemic effect on a potassium oxonate induced hyperuricemic rat model. Cytotoxicity assay and ADME prediction also supported that 3i is an excellent lead for further exploration of amide-based XO inhibitors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Based on the novel allosteric site of deoxyhypusine synthase (DHPS), two series of 30 novel 5-(2-methoxyphenoxy)-2-phenylpyrimidin-4-amine derivatives as DHPS inhibitors were designed and synthesized. Among them, compound 8m , with the best DHPS inhibitory potency (IC 50 = 0.014 μM), exhibited excellent inhibition against melanoma cells, which was superior to that of GC7. Besides, molecular docking and molecular dynamics (MD) simulations further proved that compound 8m was tightly bound to the allosteric site of DHPS. Flow cytometric analysis and enzyme-linked immunosorbent assay (ELISA) showed that compound 8m could inhibit the intracellular reactive oxygen species (ROS) level. Furthermore, by western blot analysis, compound 8m effectively activated caspase 3 and decreased the expressions of GP-100, tyrosinase, eIF5A2, MMP2, and MMP9. Moreover, both Transwell analysis and wound healing analysis showed that compound 8m could inhibit the invasion and migration of melanoma cells. In the in vivo study, the tumor xenograft model showed that compound 8m effectively inhibited melanoma development with low toxicity.

Background: In recent years, a new technology, mixed reality (MR), has emerged and surpassed the limitations of augmented reality (AR) with its inability to interact with hologram. This study aimed to investigate the feasibility of the application of MR in mandible reconstruction with fibula flap., Methods: Computed tomography (CT) examination was performed for one cadaveric mandible and ten fibula bones. Using professional software Proplan CMF 3.0 (Materialize, Leuven, Belgium), we created a defected mandibular model and simulated the reconstruction design with these 10 fibula bones. The surgical plans were transferred to the HoloLens. We used HoloLens to guide the osteotomy and shaping of the fibular bone. After fixing the fibular segments using the Ti template, all segments underwent a CT examination. Before and after objects were compared for measurements of the location of fibular osteotomies, angular deviation of fibular segments, and intergonial angle distances., Results: The mean location of the fibular osteotomies, angular deviation of the fibular segments, and intergonial angle distances were 2.11 ± 1.31 mm, 2.85°± 1.97°, and 7.24 ± 3.42 mm, respectively., Conclusion: The experimental results revealed that slight deviations remained in the accuracy of fibular osteotomy. With the further development of technology, it has the potential to improve the efficiency and precision of the reconstructive surgery., (Copyright © 2021. Published by Elsevier Masson SAS.)

Introduction: Resection of head and neck malignancy usually causes facial defects and esthetic deformities. Among the wide range of free flaps available for reconstruction, a novel chimeric free flap-the femur-vastus intermedius muscle-anterolateral thigh osteomyocutaneous free flap (FVATLO flap)-has been demonstrated for clinical use. In this study, we illustrate the anatomy and harvest of the FVATLO flap., Methods: Eighteen fresh cadavers without damage to either thigh were recruited for dissection. Blood supply to the vastus intermedius muscle and femur were traced and recorded. The diameter, circumference of the middle part of the femur, and thickness of the femoral cortex were measured., Results: The major blood supply to the vastus intermedius muscle showed two patterns of origin. The first arising from the descending branch of the lateral circumflex femoral artery (LCFA-db) accounts for 78% of the cases (28/36), and the second arising from the transverse branch of the lateral circumflex femoral artery (LCFA-tb) accounts for 22% (8/36). Blood supply to the femur consists of two major sources: one from branches penetrating through the nutrient foramen on the posteromedial surface of the femur to the medullary cavity, and the other from the periosteum branches spreading over on the femoral surface. No visible branch from the vastus intermedius muscle to the underlying periosteum was found. The mean diameter, femoral circumference, and mean cortical thickness were 26.30 mm, 85.58 mm, and 6.85 mm, respectively., Conclusion: Considering that there is only one injured donor site, the FVALTO flap is an alternative chimeric flap for cases with a large amount of soft tissue loss together with small bony defects., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest regarding the publication of this paper. All authors contributed to dissection, data collection, manuscript writing, and reviewing the manuscript., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

To further explore the research of novel PARP-1 inhibitors, we designed and synthesized a series of novel amide PARP-1 inhibitors based on our previous research. Most compounds displayed certain antitumor activities against four tumor cell lines (A549, HepG2, HCT-116, and MCF-7). Specifically, the candidate compound R8e possessed strong anti-proliferative potency toward A549 cells with the IC 50 value of 2.01 μM. Compound R8e had low toxicity to lung cancer cell line. And the in vitro enzyme inhibitory activity of compound R8e was better than rucaparib. Molecular docking studies provided a rational binding model of compound R8e in complex with rucaparib. The following cell cycle and apoptosis assays revealed that compound R8e could arrest cell cycle in the S phase and induce cell apoptosis. Western blot analysis further showed that compound R8e could effectively inhibit the PAR's biosynthesis and was more effective than rucaparib. Overall, based on the biological activity evaluation, compound R8e could be a potential lead compound for further developing novel amide PARP-1 inhibitors., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: The authors explore the role of DNASE1L2 in breast cancer (BC) and its affect on the cell phenotype. Methods: Breast invasive ductal carcinoma RNA-Seq data set was downloaded from The Cancer Genome Atlas database for analyzing DNASE1L2 levels. Overall survival curve was plotted by Kaplan-Meier methods. The correlations between DNASE1L2 expression and clinical characteristics were analyzed by chi-square tests. Cox regression models were implemented for analyzing the potential prognosticators of BC. Small interference RNA-DNASE1L2 and pcDNA3.1-DNASE1L2 were transfected into BC cells to silence and overexpress DNASE1L2, respectively. Relative mRNA and protein levels were determined by quantitative real-time PCR (qRT-PCR) and Western blot, respectively. Cell counting Kit-8, clone formation, and Transwell assays were employed to measure the proliferative, invasive, and migratory abilities. Results: Bioinformatics analysis showed that the levels of DNASE1L2 were found to be elevated in BC tissues, which was further proved by qRT-PCR tests. Besides, high expression of DNASE1L2 was dramatically led to a poor overall survival. Furthermore, DNASE1L2 expression was remarkably associated with age and pathologic-stage. Silencing DNASE1L2 showed an inhibitory effect on the proliferation, invasion, and migration of MCF7 cells, whereas overexpression of DNASE1L2 in BT549 cells presented the opposite results. Mechanistically, downregulation of DNASE1L2 could significantly enhance the levels of E-cadherin, as well as suppress the levels of Vimentin, N-cadherin and Snail, whereas upregulation of DNASE1L2 showed the reverse outcomes. Conclusion: This study for the first time demonstrated that DNASE1L2 was upregulated in BC cells, and acted as an oncogene to affect the phenotype of BC cells by modulating the epithelial-mesenchymal transition process, which suggested that DNASE1L2 might be considered as a useful biomarker for BC therapeutics.

In the past five years, our team had been committed to click chemistry research, exploring the biological activity of 1,2,3-triazole by synthesizing different target inhibitors. In this study, a series of novel indole-2-one derivatives based on 1,2,3-triazole scaffolds were synthesized for the first time, and their inhibitory activity on vascular endothelial growth factor receptor-2 (VEGFR-2) was tested. Most of the compounds had shown promising activity in the VEGFR-2 kinase assay and had low toxicity to human umbilical vein endothelial cells (HUVECs). The compound 13d (IC 50  = 26.38 nM) had better kinase activity inhibition ability than sunitinib (IC 50  = 83.20 nM) and was less toxic to HUVECs. Moreover, it had an excellent inhibitory effect on HT-29 and MKN-45 cells. On the one hand, by tube formation assay, transwell, and Western blot analysis, compound 13d could inhibit VEGFR-2 protein phosphorylate on HUVECs, thereby inhibiting HUVECs migration and tube formation. In vivo study, the zebrafish model with VEGFR-2 labeling also verified that compound 13d had more anti-angiogenesis ability than sunitinib. On the other hand, molecular docking and molecular dynamics (MD) simulation results showed that compound 13d could stably bind to the active site of VEGFR-2. Based on the above findings, compound 13d could be considered an effective anti-angiogenesis drug and has more development value than sunitinib., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The molecular chaperone heat shock protein 90 (Hsp90) is a promising target for cancer therapy. Natural product aconitine is a potential Hsp90 inhibitor reported in our previous work. In this study, we designed and synthesized a series of 2-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives as potent Hsp90 inhibitors by simplifying and modifying aconitine scaffold. Among these compounds, 14t exhibited an excellent antiproliferative activity against LoVo cells with an IC 50 value of 0.02 μM and a significant Hsp90α inhibitory activity with an IC 50 value of 0.71 nM. Molecular docking studies provided a rational binding model of 14t in complex with Hsp90α. The following cell cycle and apoptosis assays revealed that compound 14t could arrest cell cycle at G1/S phase and induce cell apoptosis via up-regulation of bax and cleaved-caspase 3 protein expressions while inhibiting the expressions of bcl-2. Moreover, 14t could inhibit cell migration in LoVo and SW620 cell lines. Consistent with in vitro results, 14t significantly repressed tumor growth in the SW620 xenograft mouse model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

In this study, a combination of network pharmacology, bioinformatics analysis, molecular docking and transcriptomics was used to investigate the active ingredient and potential target of Gelsemium elegans in the treatment of colorectal cancer. Koumine was screened as the active component by targeting PDK1 through network pharmacology and reverse docking. RNA-Seq, enrichment analysis and validation experiment were then further employed to reveal koumine might function in inhibiting Akt/mTOR/HK2 pathway to regulate cell glycolysis and detachment of HK2 from mitochondria and VDAC-1 to activate cell apoptosis both in vitro and in vivo . In the present study, we provide a systematical approach for the identification of effective ingredient and potential target of herbal medicine. Our results have important implication for the intensive study of koumine as novel anticancer agents for colorectal cancer and could be supportive in its further structural modification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2020 Wang, Xu, Liang, Ding and Meng.)

Cyclin-dependent kinase 2 (CDK2) is the family of Ser/Thr protein kinases that has emerged as a highly selective with low toxic cancer therapy target. A multistage virtual screening method combined by SVM, protein-ligand interaction fingerprints (PLIF) pharmacophore and docking was utilised for screening the CDK2 inhibitors. The evaluation of the validation set indicated that this method can be used to screen large chemical databases because it has a high hit-rate and enrichment factor (80.1% and 332.83 respectively). Six compounds were screened out from NCI, Enamine and Pubchem database. After molecular dynamics and binding free energy calculation, two compounds had great potential as novel CDK2 inhibitors and they also showed selective inhibition against CDK2 in the kinase activity assay.

C-Met plays a crucial role in the development and progression of neoplastic disease. Type II c-Met inhibitors recognise the inactive DFG-out conformation of the kinase, result in better anti-tumour effects due to synergistic effect against the other kinases. According to our previous works, an (E)-N'- benzylidene group was selected as the initial fragment. Two series of ( E )- N' -benzylidene hydrazides were designed by fragment growth method. The inhibitory activities were in vitro investigated against c-Met and VEGFR-2. Compound 10b exhibited the most potent inhibitory activity against the c-Met inhibitor (IC 50 = 0.37 nM). Compound 11b exhibited multi-target c-Met kinase inhibitory activity as a potential type II c-Met inhibitor (IC 50 = 3.41 nM against c-Met; 25.34 nM against VEGFR-2). The two compounds also demonstrate the feasibility of fragment-based virtual screening method for drug discovery.

A series of novel (E)-N-phenyl-4-(pyridine-acylhydrazone) benzamide derivatives were designed, synthesized, and evaluated for their anti-proliferative activity against two different human cancer cell lines and one human normal cell line. Compound 8b had the best anti-proliferative activity (IC 50  = 0.12 ± 0.09 μM, RPMI8226 cells) than the other compounds. And compound 8b had lower toxicity than imatinib. Flow cytometry analysis showed that compound 8b could arrest the cell cycle at the G0/G1 phase, and induce apoptosis of RPMI8226 cells by promoting mitochondrial ROS release, thereby effectively inhibiting cell proliferation. Our findings provided a promising lead compound 8b for further structural optimization and will be instructive for the discovery of more potent antitumor drugs with high selectivity and low toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Src plays a crucial role in many signaling pathways and contributes to a variety of cancers. Therefore, Src has long been considered an attractive drug target in oncology. However, the development of Src inhibitors with selectivity and novelty has been challenging. In the present study, pharmacophore-based virtual screening and molecular docking were carried out to identify potential Src inhibitors. A total of 891 molecules were obtained after pharmacophore-based virtual screening, and 10 molecules with high docking scores and strong interactions were selected as potential active molecules for further study. Absorption, distribution, metabolism, elimination and toxicity (ADMET) property evaluation was used to ascertain the drug-like properties of the obtained molecules. The proposed inhibitor-protein complexes were further subjected to molecular dynamics (MD) simulations involving root-mean-square deviation and root-mean-square fluctuation to explore the binding mode stability inside active pockets. Finally, two molecules (ZINC3214460 and ZINC1380384) were obtained as potential lead compounds against Src kinase. All these analyses provide a reference for the further development of novel Src inhibitors.

Background: The casein kinase 2-interacting protein-1 (CKIP-1) is important in the development of osteoblasts and cardiomyocytes. However, the effects of CKIP-1 on osteoblast precursor mesenchymal stem cells (MSCs) remain unclear. This study aimed to determine whether CKIP-1 affects osteogenic differentiation in MSCs and explore the relationship of CKIP-1 and inflammation., Methods: Bone marrow MSCs of CKIP-1 wild type (WT) and knockout (KO) mice were cultivated in vitro. Cell phenotype was analyzed by flow cytometry, colony formation was detected to study the proliferative ability. Osteogenic and adipogenic induction were performed. The osteogenic ability was explored by alizarin red staining, alkaline phosphatase (ALP) staining and ALP activity detection. Quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to determine the mRNA expression levels of osteoblast marker genes. The adipogenic ability was detected by oil red O staining. Content of the bone was analyzed to observe the differences of bone imaging parameters including trabecular bone volume/tissue volume (BV/TV), bone surface area fraction/trabecular BV, trabecular number (Tb.N), and trabecular spacing (Tb.sp). Interleukin (IL)-1β was injected on WT mice of 2 months old and 18 months old, respectively. Difference in CKIP-1 expression was detected by RT-PCR and western blot. The relationship between CKIP-1 and inflammation was explored by RT-PCR and western blot., Results: ALP assays, alizarin red staining, and qRT-PCR showed that MSCs derived from CKIP-1 KO mice exhibited a stronger capability for osteogenesis. Micro-computed tomography detection showed that among 18-month-old mice, CKIP-1 KO mice presented significantly higher bone mass compared with WT mice (P = 0.02). No significant difference was observed in 2-month-old mice. In vivo data showed that expression of CKIP-1 was higher in the bone marrow of aging mice than in young mice (4.3-fold increase at the mRNA level, P = 0.04). Finally, the expression levels of CKIP-1 in bone marrow (3.2-fold increase at the mRNA level, P = 0.03) and cultured MSCs were up-regulated on chronic inflammatory stimulation by IL-1β., Conclusions: CKIP-1 is responsible for negative regulation of MSC osteogenesis with age-dependent effects. Increasing levels of inflammation with aging may be the primary factor responsible for higher expression levels of CKIP-1 but may not necessarily affect MSC aging.