Design, synthesis and biological evaluation of novel tubulin inhibitors targeting colchicine sites.

Tubulin, a potential target for antitumor drug discovery, contains three main binding sites for clinical inhibitors: colchicine, vinblastine, and paclitaxel. CA-4 has been reported to be a classic tubulin inhibitor targeting the colchicine site. Herein, based on the structural modification of CA-4, 48 novel compounds were designed and synthesized by selecting structural fragments with various biological activities to replace the cis double bond of CA-4. Among these compounds, compound 8p was the most effective tubulin inhibitor (IC50 = 65 nM aganist HepG2 cells). Immunofluorescence experiment confirmed the anti-tumor effect of 8p by destroying the network structure of microtubules. Further studies showed that 8p induced tumor cell apoptosis, arrested cell cycle, inhibited tumor cell migration and invasion.

Design, synthesis, and biological activity evaluation of novel tubulin polymerization inhibitors based on pyrimidine ring skeletons.

A library of new pyrimidine analogs was designed and synthesized of these, compound K10 bearing a 1,4­benzodioxane moiety and 3,4,5­trimethoxyphenyl group, exhibiting the most potent activity, with IC50 values of 0.07-0.80 µM against four cancer cell lines. Cellular-based mechanism studies elucidated that K10 inhibited microtubule polymerization, blocked the cell cycle at the G2/M phase, and eventually induced apoptosis of HepG2 cells. Additionally, K10 inhibited the migration and invasion of HepG2 cells in a dose-dependent manner. Overall, our work indicates that the tubulin polymerization inhibitor incorporating pyrimidine and the 3,4,5­trimethoxyphenyl ring may deserve consideration for cancer therapy.

2-Methoxydiol derivatives as new tubulin and HDAC dual-targeting inhibitors, displaying antitumor and antiangiogenic response.

Multi-target drugs design has become an active research field because of their advantages in cancer treatment. In present study, HDAC inhibitors pharmacophore and 2-methoxyestradiol(2ME2) were combined into a new hybrid molecule for the first time. Forty-seven 2ME2 derivatives were synthesized and evaluated for antiproliferative activity. In particular, compound 4s exhibited a dual inhibition of tubulin polymerization and HDAC (IC50 = 0.06 µM toward HDAC2) activity, as well as the most potent cytotoxicity IC50 values of 0.37-4.84 µM against six cancer cell lines. Compound 4s remarkably disrupted microtubule networks, arrested cell cycle at G2/M phase, induced mitochondrial membrane potential collapse and eventually apoptosis in A549 cells. Notably, 4s was discovered to potently imped the tube-formation of HUVECs and prohibited the proliferation, migration, and invasion of HUVECs, as well as A549 cells. In addition, the anti-angiogenic and anti-metastasis activities were demonstrated via a zebrafish model test. All these beneficial anticancer activities together with its high selectivity toward noncancer cells, suggested 4s may deserves consideration for cancer therapy.

Role of P2X4/NLRP3 Pathway-Mediated Neuroinflammation in Perioperative Neurocognitive Disorders.

Several studies have demonstrated that neuroinflammation is the key to perioperative neurocognitive disorders (PND); however, the specific mechanism postsurgery and anesthesia has not yet been fully clarified. The present study is aimed at exploring the effects of P2X4/NLRP3 signaling pathway in neuroinflammation and cognitive impairment after surgery. 12-14-month-old male C57BL/6 mice undergoing open tibial fracture surgery by sevoflurane anesthesia were administered P2X4R inhibitor 5-BDBD or saline was intraperitoneally for 3 consecutive days after surgery. Then, the animals were subjected to Morris water maze test or sacrificed to collect the hippocampus. The level of P2X4R and NLRP3 was estimated by Western blot, the activation of microglia was detected via immunohistochemistry, and the expression of TNF-α, IL-1ß, and IL-6 was quantified by enzyme-linked immunosorbent assay. These results indicated that tibial surgery caused cognitive impairment, increased the expression of P2X4R and NLRP3, and aggravated the neuroinflammation and microglia activation. However, intraperitoneal injection of 5-BDBD attenuated these effects. In conclusion, these findings indicated that the P2X4/NLRP3 pathway might be involved in the pathophysiology of PND.

Identification of novel non-toxic and anti-angiogenic α-fluorinated chalcones as potent colchicine binding site inhibitors.

α-Fluorinated chalcones were prepared and evaluated for their cell growth inhibitory properties against six human cancer cell lines. The most potent chalcone 4c demonstrated excellent selective toxicity against cancer cells versus normal human cells, with IC50 values at nanomolar concentration ranges against 5 cancer cell lines. A further study revealed that 4c could bind to the colchicine site of tubulin, disrupt the cell microtubule networks, and effectively inhibit tubulin polymerisation. Cellular-based mechanism studies elucidated that 4c arrested MGC-803 cell cycle at G2/M phase. In addition, 4c dose-dependently caused Caspase-induced apoptosis of MGC-803 cells through mitochondrial dysfunction. Notably, compound 4c was found to inhibit the HUVECs tube formation, migration, and invasion in vitro. Furthermore, our data suggested that treatment with 4c significantly reduced MGC-803 cells metastasis and proliferation in vitro. Overall, this work showed that chalcone hybrid 4c is a potent inhibitor of tubulin assembly with prominent anti-angiogenesis and anti-cancer properties.

Synthesis and biological evaluation of new 2-methoxyestradiol derivatives: Potent inhibitors of angiogenesis and tubulin polymerization.

Here, we report the structural optimization of a hit natural compound, 2-ME2 (2-methoxyestradiol), which exhibited inhibitory activity but low potency on tubulin polymerization, anti- angiogenesis, MCF-7 proliferation and metastasis in vitro and in vivo. A novel series of 3,17-modified and 17-modified analogs of 2-ME2 were synthesized and investigated for their antiproliferative activity against MCF-7 and another five different human cancer cell lines leading to the discovery of 9i. 9i bind to tubulin colchicine site tightly, inhibited tubulin polymerization and disrupted cellular microtubule networks. Cellular mechanism studies revealed that 9i could induce G2/M phase arrest by down-regulated expression of p-Cdc2, P21 and cell apoptosis by regulating apoptosis-related proteins (Parp, Caspase families) in a dose-dependent manner. Importantly, 9i significantly inhibited HUVEC tube formation, proliferation, migration and invasion. The inhibitory effect against angiogenesis in vivo was confirmed by zebrafish xenograft. Furthermore, 9i could effectively inhibit the proliferation and metastasis of MCF-7 cells in vitro and in zebrafish xenograft. The satisfactory physicochemical property and metabolic stability of 9i further indicated that it can act as a promising and potent anti-angiogenesis, inhibiting proliferation and metastasis of breast cancer agent via targeting tubulin colchicine binding site.

Modified Frailty Index Independently Predicts Postoperative Delirium and Delayed Neurocognitive Recovery After Elective Total Joint Arthroplasty.

BACKGROUND: Postoperative delirium (POD) and delayed neurocognitive recovery are 2 common subtypes of postoperative neurocognitive disorders that occur after total joint arthroplasty (TJA), associated with inferior surgical outcomes. The modified frailty index (mFI) reflects the status of physiologic decline and predicts adverse outcomes in various surgical patient cohorts. This study aims at examining the discriminatory value of the mFI to predict POD and delayed neurocognitive recovery after TJA. METHODS: The study includes 383 participants admitted for primary elective TJA under general anesthesia combined with inhalation agents over the period from January 2018 to December 2019. POD and delayed neurocognitive recovery, based on the criteria provided by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (2013), were assessed for each enrolled patient. A multivariate logistic regression analysis was performed to screen potential risk factors for POD and delayed neurocognitive recovery. RESULTS: The total incidence of POD and the delayed neurocognitive recovery of this cohort were 17.2% (66/383) and 24.8% (95/383), respectively. Our data from the multivariate logistic regression analysis indicated that a higher age (≥72 years) and a higher mFI level (≥0.18) were 2 independent risk factors for both POD and delayed neurocognitive recovery in elderly subjects after TJA. CONCLUSION: The mFI may be a promising predictor for both POD and delayed neurocognitive recovery in elderly subjects following TJA. Preoperative mFI evaluation can be used for risk stratification and offers significant potential in clinical application.

High-Pressure Pneumoperitoneum Aggravates Surgery-Induced Neuroinflammation and Cognitive Dysfunction in Aged Mice.

Postoperative cognitive dysfunction (POCD) is a common complication after surgery, especially in aged patients. Neuroinflammation has been closely associated with the development of POCD. While the contribution of pneumoperitoneum to the systemic inflammation has been well documented, the effect of pneumoperitoneal pressure on neuroinflammation and postoperative cognitive function remains unclear. In this study, we showed that high-pressure pneumoperitoneum promoted the postoperative neuroinflammation and microglial activation in the hippocampus and aggravated the postoperative cognitive impairment in aged mice. These results support the requirement to implement interventions with lower intra-abdominal pressure, which allows for adequate exposure of the operative field rather than a routine pressure.

Flurbiprofen Axetil Enhances Analgesic Effects of Sufentanil and Attenuates Postoperative Emergence Agitation and Systemic Proinflammation in Patients Undergoing Tangential Excision Surgery.

OBJECTIVE: Our present study tested whether flurbiprofen axetil could reduce perioperative sufentanil consumption and provide postoperative analgesia with decrease in emergency agitation and systemic proinflammatory cytokines release. METHODS: Ninety patients undergoing tangential excision surgery were randomly assigned to three groups: (1) preoperative dose of 100 mg flurbiprofen axetil and a postoperative dose of 2 µg/kg sufentanil and 10 mL placebo by patient-controlled analgesia (PCA) pump, (2) preoperative dose of 100 mg flurbiprofen axetil and a postoperative dose of 2 µg/kg sufentanil and 100 mg flurbiprofen axetil by PCA pump, and (3) 10 mL placebo and a postoperative dose of 2 µg/kg sufentanil and 10 mL placebo by PCA pump. RESULTS: Preoperative administration of flurbiprofen axetil decreased postoperative tramadol consumption and the visual analog scale at 4, 6, 12, and 24 h after surgery, which were further decreased by postoperative administration of flurbiprofen axetil. Furthermore, flurbiprofen axetil attenuated emergency agitation score and Ramsay score at 0, 5, and 10 min after extubation and reduced the TNF-α and interleukin- (IL-) 6 levels at 24 and 48 h after the operation. CONCLUSION: Flurbiprofen axetil enhances analgesic effects of sufentanil and attenuates emergence agitation and systemic proinflammation in patients undergoing tangential excision surgery.

Macrophage-derived exosomes exacerbate postoperative cognitive dysfunction in mice through inflammation.

This study investigated the impact of two-hit inflammation on postoperative cognitive dysfunction (POCD) in mice and the role of macrophage-derived exosomes in regulating this process. Mice models were used to mimic the state of two-hit inflammation, and cognitive function was assessed through behavioral experiments. Proinflammatory cytokine expression levels and blood-brain barrier (BBB)-associated functional proteins were measured using ELISA and Western blot, respectively. An in vitro macrophage inflammation two-hit model was created, and the role of exosomes was examined using the previously mentioned assays. Additionally, exosomes were injected into mice to further understand their impact in the two-hit inflammation model. Mice exposed to two-hit inflammation experienced impaired cognitive function, increased BBB permeability, and elevated levels of proinflammatory cytokines. Macrophages subjected to two-hit inflammation released higher levels of proinflammatory cytokines compared to the control group and other treatment groups. Treatment with an exosome inhibitor GW4869 effectively reduced the expression levels of proinflammatory cytokines in macrophages exposed to two-hit inflammation. Moreover, injection of macrophage-released exosomes into healthy mice induced inflammation, hippocampal damage, and cognitive disorders, which were mitigated by treatment with GW4869. In mice with two-hit inflammation, macrophage-released exosomes worsened cognitive disorders by promoting inflammation in the peripheral blood and central nervous system. However, treatment with GW4869 protected cognitive function by suppressing exosome release. These findings highlight the importance of two-hit inflammation in POCD and emphasize the critical role of exosomes as regulatory factors. This research provides valuable insights into the pathogenesis of POCD and potential intervention strategies.

Exploring the ED50 and ED95 of Remimazolam for Laryngeal Mask Airway Insertion During General Anesthesia in Pediatric Strabismus Correction Surgery.

AIM: Remimazolam, known for its rapid onset, quick metabolism, and short recovery time from sedation, offers significant advantages in clinical anesthesia. Previous studies have primarily investigated its application in adult surgical anesthesia, with less focus on its utilization in pediatric patients. Therefore, we aimed to explore the 50% effective dose (ED50) and 95% effective dose (ED95) of remimazolam for laryngeal mask airway (LMA) insertion during general anesthesia in pediatric strabismus correction surgery and investigate its dose-response relationship, thereby providing valuable reference data for safer and more rational clinical use of remimazolam. METHODS: This study included 32 patients aged 3-12 years undergoing strabismus correction surgery at Ningbo Aier Guangming Eye Hospital in 2024. The dosage of remimazolam was determined according to the Dixon 'up-and-down' sequential method: the starting induction dose was 0.2 mg/kg, with a step dose of 0.05 mg/kg. In cases of positive anesthetic effect, the subsequent patient received a reduced step dose, while in cases of negative anesthetic effect, the next subject received an increased step dose. The trial was terminated upon observing seven "positive-negative" crossover points. Furthermore, the ED50 and ED95, along with their 95% confidence intervals (95% CI) were calculated using the Probit regression analysis. Additionally, vital signs of the patients, such as peripheral oxygen (SpO2), heart rate, and blood pressure, along with the incidence of adverse events, were monitored. RESULTS: The ED50 of remimazolam for LMA insertion in pediatric strabismus correction surgery was 0.300 mg/kg (95% CI 0.276-0.323 mg/kg), and the ED95 was 0.369 mg/kg (95% CI 0.324-0.414 mg/kg). Throughout the surgery, SpO2, heart rate, and blood pressure remained stable without any significant fluctuations. CONCLUSIONS: The ED50 and ED95 of remimazolam for LMA insertion in pediatric strabismus correction surgery are 0.300 mg/kg and 0.369 mg/kg, respectively. This study demonstrates that remimazolam is both safe and effective for LMA insertion during general anesthesia in pediatric strabismus correction surgery.

Integrating Complaint Analysis into Hospital Management: A Comparative Study of Surgical and Non-Surgical Complaints.

Aims/Background: In an era where patient-centred care is paramount, effectively managing and analyzing hospital complaints is crucial for improving service quality and patient satisfaction. This study examines hospital complaints to enhance management practices by differentiating between surgery-related and non-surgery-related grievances. By identifying patterns in complaint types and outcomes, we aim to inform targeted quality improvement strategies that address specific patient concerns and boost operational efficiency. Methods: The study utilized data from an internal complaint management system over one year. Complaints were categorized as either surgery-related or non-surgery-related. Descriptive statistics and cross-tabulation analysis were employed to examine the data. The sample comprised 132 complaints, with 67 being surgery-related and 65 non-surgery-related. Results: The analysis revealed that surgery-related complaints frequently involved issues with 'Patient Communication' and 'Surgical Error', while non-surgery-related complaints were primarily about the 'Medical Treatment Process'. The Surgery Department received the highest number of complaints, indicating a critical area for intervention. Additionally, the correlation between complaint types and outcomes provided insights into potential areas for improvement. Conclusion: The findings highlight the need for targeted communication training and procedural enhancements in surgical departments. Non-surgical departments should focus on improving treatment protocols and transparency. These strategies can reduce complaints and improve patient satisfaction. Future research should develop and test interventions based on these insights to further enhance healthcare quality.

Discovery of the cereblon-recruiting tubulin PROTACs effective in overcoming Taxol resistance in vitro and in vivo.

Overexpression of ß3-tubulin is a common occurrence in human tumors and is associated with resistance to microtubule-targeting agents. PROTAC strategy has demonstrated significant potential in overcoming drug resistance. Herein, we report the discovery of W13 as the first PROTAC against tubulin, which was created by connecting a CRBN ligand to the widely recognized microtubule-destabilizing agent CA-4. Notably, it retains the inhibitory activity of the parental CA-4 and further exhibits substantial degradation of α/ß/ß3-tubulin in both A549 and A549/Taxol cell lines. The degradation of tubulin was subsequently verified to be mediated by the ubiquitin-proteasome system. Importantly, tumor xenograft research clearly showed W13's promising antitumor activity against human lung cancer. Taken together, the discovery of W13 demonstrated the practicality and feasibility of PROTAC targeting tubulin, hence establishing a potential therapeutic approach for treating NSCLC caused by the overexpression of ß3-tubulin.

[Efficacy of preventing postoperative nausea and vomiting after thyroid tumor surgery by TAES at neiguan (P1): a clinical observation].

OBJECTIVE: To observe the clinical efficacy of transcutaneous acupoint electrical stimulation (TAES) combined intravenous injection and/or Neiguan (P6) injection with droperidol in preventing and treating post-operative nausea and vomiting (PONV) after thyroid tumor surgery. METHODS: Recruited were 120 female patients who underwent selective thyroid tumor surgery were randomly assigned to the control group, the TAES group, the IV group (intravenous injection of droperidol), and the P6 group [Neiguan point (P6) injection of droperidol], respectively, 30 cases in each group. Thirty min before anesthesia induction, 2 mL 0.9% normal saline injection was intravenously injected to those in the control group. Patients in the TAES group received TEAS at bilateral P6 points. 2.5 mg (1 mL) droperidol added in 1 mL 0.9 normal saline was intravenously injected to those in the IV group and injected at bilateral P6 points of those in the P6 group. The occurrence and severity of PONV were observed within 0 - 6 h and within 6 - 24 h after operation in each group. RESULTS: Compared with the control group, the incidence and the severity of PONV within 0 - 6 h and within 6 - 24 h after thyroid surgery were significantly reduced in the three treatment groups (P < 0.05). There was no statistical difference in the incidence or the severity of PONV among the TAES, IV and P6 groups (P > 0.05). CONCLUSIONS: TEAS at P6 could dramatically reduce the occurrence and the severity of PONV after thyroid tumor surgery. Besides, it got equivalent effect to that by intravenous injecting droperidol or by injecting droperidol at P6.

Discovery of a novel piperlongumine analogue as a microtubule polymerization inhibitor with potent anti-angiogenic and anti-metastatic efficacy.

In an effort to discover anticancer agents with simultaneous effects on tubulin and angiogenesis, we designed and synthesized two series of piperlongumie (PL) derivatives by replacing of phenyl group with a variety of benzoheterocycle (series II) or cyclizing the C7-C8 olefin into an aromatic heterocycle (series I). Most of the new compounds showed better antiproliferative activities against six cancer cell lines than the parent drug PL. Compound II-14b had the best cytotoxic profile of these two series in cancer cells, whilst being relatively low cytotoxicity against normal human cells and high potency against drug-resistant cells. It disrupted cellular microtubule networks and inhibited tubulin assembly with an IC50 value of 5.8 µM. Further studies elucidated that II-14b showed antitumor activities through multiple mechanisms, including the pruduction of abundant ROS, the dissipation of mitochondrial membrane potential, the accumulation of DNA double-strand breaks, and the induction of cell cycle in G2/M phase. More importantly, we have observed that it possesses potential anti-angiogenesis capabilities, including suppression of HUVECs cell migration, invasion, and endothelial tube formation in vitro and in vivo. In vivo assessment indicated that II-14b inhibits the growth and metastasis of MGC-803 xenograft tumour in zebrafish. These findings show that II-14b is a high-efficacy and non-toxic antitumor agent.

Regional haemodynamic variables and perfusion index in the evaluation of sciatic nerve block: a prospective observational trial.

OBJECTIVE: We determined whether regional haemodynamics and perfusion index (PI) could be reliable indicators of a successful sciatic nerve block (SNB). DESIGN: Prospective observational trial. SETTING: A tertiary teaching hospital in China from April 2020 to August 2020. PARTICIPANTS: We assessed 79 patients for eligibility to participate in this study. Nine patients were excluded for not meeting our inclusion criteria, and three patients were excluded due to missing measurements at all time points. INTERVENTIONS: The patients underwent SNB. Pulsed-wave Doppler and PI measurements were performed. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was the diagnostic power of regional haemodynamic change and PI to predict successful SNB. The secondary outcome measure was the effect of SNB on the regional haemodynamics and PI in the lower extremity. RESULTS: We assessed 79 patients in this study and 67 patients available for the final analysis. The SNB was successful in 59 patients and failed in eight patients. There were no significant differences in demographic characteristics between the patients with successful and failed SNB. Starting from 10 min after SNB, the peak systolic velocity (PSV), end-diastolic velocity, time-averaged maximum velocity and time-averaged mean velocity of the anterior tibial artery and posterior tibial artery of patients in the successful SNB group were significantly higher than those in the failed SNB group (p<0.05). The PSV percentage increase at 10 min after SNB has great potential to predict the block success. The area under the receiver operating characteristic curve (AUC) values were 0.893 (95% CI 0.7809 to 1.000) and 0.880 (95% CI 0.7901 to 0.9699). The corresponding cut-off values were 19.22 and 35.88, respectively. The PI increased during 5-45 min intervals in patients with successful SNB. The AUC for the PI percentage increases at 10 min after SNB was 0.853 (95% CI 0.7035 to 1.000), with a cut-off value of 93.09. CONCLUSION: The regional haemodynamic variables, PSV and PI in particular, can be used as alternative indicators for clinicians to evaluate the success of SNB objectively and early. TRIAL REGISTRATION NUMBER: ChiCTR2000030772.

Indazole as a Privileged Scaffold: The Derivatives and their Therapeutic Applications.

BACKGROUND: Heterocyclic compounds, also called heterocycles, are a major class of organic chemical compound that plays a vital role in the metabolism of all living cells. The heterocyclic compound, indazole, has attracted more attention in recent years and is widely present in numerous commercially available drugs. Indazole-containing derivatives, representing one of the most important heterocycles in drug molecules, are endowed with a broad range of biological properties. METHODS: A literature search was conducted in PubMed, Google Scholar and Web of Science regarding articles related to indazole and its therapeutic application. RESULTS: The mechanism and structure-activity relationship of indazole and its derivatives were described. Based on their versatile biological activities, the compounds were divided into six groups: anti-inflammatory, antibacterial, anti-HIV, antiarrhythmic, antifungal and antitumour. At least 43 indazole-based therapeutic agents were found to be used in clinical application or clinical trials. CONCLUSION: This review is a guide for pharmacologists who are in search of valid preclinical/clinical drug compounds where the progress of approved marketed drugs containing indazole scaffold is examined from 1966 to the present day. Future direction involves more diverse bioactive moieties with indazole scaffold and greater insights into its mechanism.

Design, synthesis and biological evaluation of tanshinone IIA-based analogues: Potent inhibitors of microtubule formation and angiogenesis.

We report the structural optimization of tanshinone IIA, a natural product which possesses anti-tumor properties but low water-solubility, weak antiproliferative activity and poor PK properties. A new series of ring A/C/D modified tanshinone analogues were synthesized and studied for their antiproliferative capacities against six human cancer cell lines. SAR study revealed that ring A cleavage of tanshinone IIA led to improved anti-cancer activity. Introduction of a methoxy group to the phenyl ring could enhance the anti-cancer activity even further. Compound 2f with methoxy group at C-8 position was selected as an early lead with IC50 values of 0.28-3.16 µM against six tested cell lines. 2f could bind to tubulin colchicine site, inhibit tubulin assembly and disrupt the normal formation of microtubule networks. Cellular mechanistic studies revealed that 2f induced apoptotic cell death of A549 cells in a dose-dependent manner. In vitro investigations showed that 2f impeded the tubule-formation of HUVECs and potently inhibited the proliferation, migration and invasion of A549 cells as well as HUVECs. Furthermore, the in vivo anti-angiogenic effect of 2f was confirmed via a zebrafish model test. The satisfactory physicochemical property and metabolic stability of 2f, as well as improved water-solubility, further suggested that 2f could serve as a promising tubulin inhibitor and anti-angiogenic agent.

Discovery of novel tubulin/HDAC dual-targeting inhibitors with strong antitumor and antiangiogenic potency.

A novel series of cis-diphenylethene and benzophenone derivatives as tubulin/HDAC dual-targeting inhibitors were designed and synthesized. Among them, compound 28g exhibited the most potent antiproliferative activities against six different human cancer cell lines, 28g could not only inhibited tubulin polymerization, disrupted cellular microtubule networks but also selectively inhibited class IIa HDACs, especially HDAC7 activity. Further molecular docking demonstrated 28g could occupy the binding pockets of tubulin and HDAC7 meanwhile. Cellular mechanism studies revealed that 28g could induce G2/M phase arrest by down-regulated expression of p-cdc2 and cell apoptosis by regulating mitochondrial membrane potential, reactive oxygen species (ROS) levels and apoptosis-related proteins (PARP, Caspase families) in a dose-dependent manner. Importantly, 28g significantly inhibited HUVEC tube formation, proliferation, migration and invasion. The inhibitory effect against angiogenesis in vivo was confirmed by zebrafish xenograft. Furthermore, 28g could effectively suppress the proliferation and metastasis of MGC-803 cells in vitro and in zebrafish xenograft. All above results indicated that 28g can act as a promising antitumor and antiangiogenic agent via targeting tubulin and class IIa HDACs.

The Investigation of Hippocampus-Dependent Cognitive Decline Induced by Anesthesia/Surgery in Mice Through Integrated Behavioral Z-Scoring.

OBJECTIVE: Patients undergoing major surgeries may experience certain cognitive decline, which is known as postoperative delirium (POD) or postoperative cognitive dysfunction (POCD). We employed integrated behavioral Z-scoring introduced by Guilloux et al. (2011) to investigate the effects of fracture fixation under anesthesia on hippocampus-dependent memory in mice. METHODS: ICR mice (12-14 months) underwent stabilized tibial fracture operation under sevoflurane anesthesia. They were subjected to a battery of successive hippocampus-dependent tests following surgery, including open field test (OF), novel object recognition (NOR), fear conditioning test (FC), and Morris water maze (MWM). The integrated behavioral Z-scoring was applied to assess the hippocampus-dependent memory after anesthesia/surgery, and the association between the integrated behavioral Z-scores and hippocampal pro-inflammatory cytokines was explored. RESULTS: Mice after anesthesia/surgery were found to have impaired hippocampus-dependent memory in NOR, FC, and MWM but with different degrees in these aspects as represented by P-value and effect size. The integrated memory Z-scores based on principal parameters of the above three tests can reduced the variability and increase the comprehensiveness of behavioral results. However, we found no statistic associations between hippocampal pro-inflammatory cytokines and the integrated Z-scores, as the elevated cytokines quickly return to normal on postoperative day 3 and/or day 7. CONCLUSION: The integrated Z-score methodology could facilitate the interpretation of the anesthesia/surgery induced cognitive decline in mice and robustly quantify the behavioral phenotyping of hippocampus-dependent memory.