Search

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. [ABSTRACT FROM AUTHOR]

Overexpression of β3-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/β/β3-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 β3-tubulin. [Display omitted] • A series of CRBN-based PROTACs have been firstly synthesized as tubulin degrader. • W13 induces α/β/β3-tubulin in A549S and A549T cells via UPS-dependent manners. • The RI values of W13 on drug-resistant cancer cells was superior to that of Taxol. • The tumor growth inhibition values of W13 were 65.8% on A549T xenograft tumor model. [ABSTRACT FROM AUTHOR]

Phosphorus fertilisation and increasing litter input are widely employed to restore the degraded grasslands. Despite the key roles of nitrogen-cycling microbes in determining the soil nitrogen dynamics and development of grassland degradation, little is known about their responses to these restoration efforts. Here, a microcosm experiment, with soils collected from a degraded Tibetan alpine meadow, was conducted to investigate the responses of nitrogen-cycling microbes to litter and phosphorus amendments, and their links with the changes in soil properties. Copies of the corresponding nitrogen-cycling genes ( nifH , amoA , narG , nirK , and nirS genes) and their mRNAs were determined using real-time PCR. The results showed that the litter amendment significantly stimulated the transcription of nifH and nirS genes, but reduced the copies of amoA gene and bacterial amoA mRNA. It also significantly increased soil dissolved organic carbon, available phosphorus, ammonium nitrogen, and microbial biomass concentrations, but decreased soil inorganic and nitrate nitrogen concentrations. The phosphorus amendment exerted little effects on soil properties and nitrogen-cycling microbes, while the litter-phosphorus interactions significantly offset the individual negative effects of the litter and phosphorus amendments on the denitrifier abundance. The soil nitrate and inorganic nitrogen concentrations were positively correlated with the amoA genes and bacterial amoA mRNA copies, but negatively correlated with nirS mRNA copies. These results indicate that litter addition may decrease soil nitrate and inorganic nitrogen concentrations by suppressing nitrifiers and stimulating nirS gene expression, highlighting the vital roles of nitrogen-cycling microbes in determining the soil nitrogen dynamics during the restoration of degraded grasslands. [ABSTRACT FROM AUTHOR]

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 IC 50 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. [Display omitted] • A total of fifty novel piperlongumine analogues were prepared as microtubule polymerization inhibitors. • II-14b exhibited higher selectivity than normal human cells, with an IC 50 value of 0.458 ± 0.01 μM against MGC-803 cell line. • II-14b effectively attenuated the migration and invasion of MGC-803 cells by blocking the FAK, MMP9 and ERK/EMT pathway. • II-14b exhibited potent anti-angiogenesis effect through theVEGFR2/PI3K/AKT/MAPK pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel inhibitors of microtubule protein polymerization targeting the colchicine site were designed and synthesized. • K10 exhibited nanomolar anti-proliferative efficacies with IC 50 values of 0.07–0.80 μM against four cancer cell lines. • K10 caused cycle arrest and apoptosis and inhibit tubulin polymerization by binding to the colchicine site. • K10 inhibited the migration and invasion of HepG2 cells in a dose-dependent manner. A library of new pyrimidine analogs was designed and synthesized of these, compound K10 bearing a 1,4‑benzodioxane moiety and 3,4,5‑trimethoxyphenyl group, exhibiting the most potent activity, with IC 50 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 3,4,5‑trimethoxyphenyl ring may deserve consideration for cancer therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] 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 (IC 50 = 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. [ABSTRACT FROM AUTHOR]

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 2 8g 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. [Display omitted] • 28 g can obviously inhibit the polymerization of tubulin and has a high selectivity to HDAC-7, with an IC50 value of 0.05 μM. • 28 g showed strong potency to decrease angiogenesis in vitro and in vivo. • 28 g suppressed migration and invasion of stomach cancer in vitro and in vivo. [ABSTRACT FROM AUTHOR]

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 IC 50 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. [Display omitted] • Ring A modification of tanshinone IIA potently improved its anti-cancer activities. • 2f acted as a novel colchicine site tubulin polymerization inhibitor. • 2f showed potent anti-angiogenetic and anti-metastasis activities. [ABSTRACT FROM AUTHOR]