Acyclic quaternary carbon stereocenters exist widely in natural products and bioactive molecules, but their enantioselective construction remains a prominent challenge. In particular, multicomponent ...enantioselective couplings of simple precursors to acyclic all-carbon quaternary stereocenters are very rare. We describe herein an N-heterocyclic carbene (NHC)-Ni catalyzed redox-economical three-component reaction of aldehydes, alkynes, and enones that proceeds in a highly chemo-, regio-, and enantioselective manner. A wide variety of valuable acyclic α-quaternary chiral ketones were synthesized in a single step with 100% atom economy. This reaction proceeds through the formation of a transient cyclic enolate followed by an aldol reaction/ring-opening sequence. The strategy is expected to inspire new and efficient approaches to generate other acyclic quaternary stereocenters.
Display omitted
•CaCO3 capped mesoporous silica nanoparticles with surface camouflaged with cancer cell membrane.•The nanoparticles is constructed only by naturally biomaterials.•The nanoparticles ...combine biocompatibility, pH-sensitive drug release and homotypic targeting.•The nanoparticles efficiently inhibited prostate tumor growth.
Nanoparticular drug delivery system (NDDS) has great potential for enhancing the efficacy of traditional chemotherapeutic drugs. However, it is still a great challenge to fabricate a biocompatible NDDS with simple structure capable of optimizing therapeutic efficacy, such as high tumor accumulation, suitable drug release profile (e.g. no premature drug leakage in normal physiological conditions while having a rapid release in cancer cells), low immunogenicity, as well as good biocompatibility. In this work, a simple core/shell structured nanoparticle was fabricated for prostate cancer treatment, in which a mesoporous silica nanoparticle core was applied as a container to high-efficiently encapsulate drugs (doxorubicin, DOX), CaCO3 interlayer was designed to act as sheddable pH-sensitive gatekeepers for controlling drug release, and cancer cell membrane wrapped outlayer could improve the colloid stability and tumor accumulation capacity. In vitro cell experiments demonstrated that the as-prepared nanovehicles (denoted as DOX/MSN@CaCO3@CM) could be efficiently uptaken by LNCaP-AI prostate cancer cells and even exhibited a better anti-tumor efficiency than free DOX. In addition, Live/Dead cell detection and apoptosis experiment demonstrated that MSN/DOX@CaCO3@CM could effectively induce apoptosis-related death in prostate cancer cells. In vivo antitumor results demonstrated that DOX/MSN@CaCO3@CM administration could remarkably suppress the tumor growth. Compared with other tedious approaches to optimize the therapeutic efficacy, this study provides an effective drug targeting system only using naturally biomaterials for the treatment of prostate cancer, which might have great potential in clinic usage.
Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. However, how presynaptic NMDARs (PreNMDARs) in spinal nociceptor terminals control ...presynaptic plasticity and pain hypersensitivity has remained unclear. Here we report that PreNMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner. PreNMDARs depresses presynaptic transmission in basal state, while paradoxically causing presynaptic potentiation upon injury. This state-dependent modulation is dependent on Ca
influx via PreNMDARs. Small conductance Ca
-activated K
(SK) channels are responsible for PreNMDARs-mediated synaptic depression. Rather, tissue inflammation induces PreNMDARs-PKG-I-dependent BDNF secretion from spinal nociceptor terminals, leading to SK channels downregulation, which in turn converts presynaptic depression to potentiation. Our findings shed light on the state-dependent characteristics of PreNMDARs in spinal nociceptor terminals on modulating nociceptive transmission and revealed a mechanism underlying state-dependent transition. Moreover, we identify PreNMDARs in spinal nociceptor terminals as key constituents of activity-dependent pain sensitization.
Aim: In-Stent Restenosis (ISR) is the major reason for recurrent ischemia and amputation after endovascular treatment of Peripheral Artery Disease (PAD). Our previous study demonstrated that ...miR-140-3p is significantly down-regulated in PAD arteries. However, expression and function of miR-140-3p in ISR of human PAD are currently unclear.The aim of this study is to determine the miR-140-3p expression and its regulative role in ISR of PAD.Methods: The RNA level was determined by quantitative real-time polymerase chain Reaction (qRT-PCR) and in situ hybridization. Primary cultured ASMCs were isolated from human femoral arterial of the healthy donors or ISR patients. Cell proliferation was determined by Edu incorporation and CCK-8 assay. Apoptosis was determined by Annexin-Ⅴ/PI Double-Staining assay and TUNEL assay. A rat carotid artery balloon angioplasty model was used to investigate the effect of miR-140-3p on restenosis.Results: MiR-140-3p was significantly down-regulated in PAD and ISR arteries than normal arteries. Primary cultured ISR ASMCs exhibited elevated proliferation and down-regulated miR-140-3p than normal ASMCs. Transfection of miR-140-3p mimic attenuated PDGF-BB-induced proliferation in cultured ASMCs and induced apoptosis. Luciferase reporter assay indicated that miR-140-3p transfection significantly down-regulated C-Myb and BCL-2 in ISR ASMCs by targeting to their 3'-UTRs. MiR-140-3p transfection induced anti-proliferation and apoptosis in ASMCs, which were ameliorated by over-expression of C-Myb or BCL-2. Moreover, the animal study showed that miR-140-3p can reduce restenosis following angioplasty via targeting C-Myb and BCL-2.Conclusions: The result suggests that miR-140-3p regulates ASMC function via targeting C-Myb and BCL-2 in the process of ISR in PAD. The novel findings may offer a hopeful therapeutic target for human PAD.
Purpose
In cohort studies on liver cancer, there are often immortal time bias and interference of competing risk events. This study proposes to explore the role of internal and external radiotherapy ...for hepatocellular carcinoma using SEER data, using a competing risk model and controlling immortal time bias.
Methods
Data of SEER from 2004 till 2015 was included. To analyze whether there was a difference in survival between HCC (hepatocellular carcinoma) patients receiving external radiation and internal radiation, we used a competing risk analysis after excluding immortal time bias, and created a nomogram to assess the risk of cancer-specific death (CSD) in hepatocellular carcinoma patients receiving radiotherapy.
Results
Potential confounding factors adjusted, there was no significant difference in CSD between external and internal radiation therapy HR and its 95% CI = 1.098 (0.874–1.380). The constructed nomogram performed better than the traditional AJCC model. The AUC and calibration curve results showed that this well-calibrated nomogram could be used to make clinical decisions regarding the prognosis and personalized treatment of hepatocellular carcinoma treated. There was no difference in the cumulative risk of death between patients with liver cancer treated with external radiation therapy and internal radiation therapy.
Conclusion
There is no difference in the cumulative risk of death between patients with liver cancer treated with external radiation therapy and internal radiation therapy. The nomogram predicts the results more accurately. These results can be used to guide the choice of treatment options for patients with HCC and to predict their survival prognosis.
Immune suppression contributes to nosocomial infections (NIs) and poor prognosis in sepsis. Recent studies revealed that CD71
erythroid cells had unappreciated immunosuppressive functions. This study ...aimed to investigate the values of CD71
erythroid cells (CECs) in predicting NIs and prognosis among adult septic patients. The potential factors associated with the expansion of CECs were also explored.
In total, 112 septic patients and 32 critically ill controls were enrolled. The frequencies of CD71
cells, CD71
CD235a
cells, and CD45
CECs were measured by flow cytometry. The associations between CECs and NIs and 30-day mortality were assessed by ROC curve analysis and Cox and competing-risk regression models. Factors associated with the frequency of CECs were identified by linear regression analysis.
The percentage of CD71
cells, CECs, and CD45
CECs were higher in septic patients than critically ill controls. In septic patients, the percentages of CD71
cells, CECs, and CD45
CECs were associated with NI development, while CD71
cells and CECs were independently associated with 30-day mortality. Linear regression analysis showed that the levels of interleukin (IL)-6 and interferon (IFN)-γ were positively associated with the frequencies of CD71
cells, CECs, and CD45
CECs, while IL-10 was negatively associated with them. Additionally, the levels of red blood cells (RBCs) were negatively associated with the percentage of CD45
CECs.
CECs were expanded in sepsis and can serve as independent predictors of the development of NI and 30-day mortality. Low levels of RBCs and high levels of IL-6 and IFN-γ may contribute to the expansion of CECs in sepsis.
ChiCTR, ChiCTR1900024887. Registered 2 August 2019, http://www.chictr.org.cn/showproj.aspx?proj=38645.
BACKGROUND:Patients with locally advanced rectal cancer could be managed by a watch-and-wait approach if they achieve clinical complete response after preoperative chemoradiotherapy. Mucosal ...integrity, endorectal ultrasound, and rectal MRI are used to evaluate clinical complete response; however, the accuracy remains questionable. Clinical practice based on those assessment methods needs more data and discussion.
OBJECTIVE:The aim of this prospective study was to evaluate the accuracy of mucosal integrity, endorectal ultrasound, and rectal MRI to predict clinical complete response after chemoradiotherapy.
DESIGN:Endorectal ultrasound and rectal MRI were undertaken 6 to 7 weeks after preoperative chemoradiation therapy. Patients then received radical surgery based on the principles of total mesorectal excision. Preoperative tumor staging achieved by endorectal ultrasound and rectal MRI was compared with postoperative staging by pathologic examination. Sensitivity, specificity, and accuracy of each evaluation method were calculated.
SETTINGS:The study was conducted at a single tertiary care center.
PATIENTS:Patients diagnosed with mid-low rectal cancer by biopsy between May 2014 and December 2016 were enrolled in this study.
RESULTS:A total of 124 patients were enrolled in this study, and postoperative pathology revealed that 20 patients (16.13%) achieved complete response (ypT0N0). The sensitivity of mucosal integrity, endorectal ultrasound, and MRI to predict clinical complete response was 25%. The specificity of mucosal integrity, endorectal ultrasound, and MRI was 94.23%, 93.90%, and 93.27%. The combination of each 2 or all 3 methods did not improve accuracy. Regression analysis showed that none of these methods could predict postoperative ypT0.
LIMITATIONS:The sample size is small, and we did not focus on the follow-up data and cannot compare prognosis data with previous research studies.
CONCLUSIONS:Both single-method and combined mucosal integrity, endorectal ultrasound, and rectal MRI have poor correlation with postoperative pathologic examination. A watch-and-wait approach based on these methods might not be a proper strategy compared with radical surgery after neoadjuvant therapy. See Video Abstract at http://links.lww.com/DCR/A693.
ABSTRACT
Aim
The aim of the present study was to screen and verify downstream genes involved in the epithelial mesenchymal transition (EMT) induced by paired box 2 (PAX2) in NRK‐52E cells.
Methods
...NRK‐52E cells were transfected with lentivirus carrying PAX2 gene or no‐load virus respectively. Total RNA was isolated 72 h after transfection from PAX2‐overexpressing cells and control cells. Isolated RNA was then hybridized with the Rat OneArray Plus expression profile chip. The chips were examined by Agilent 0.1 XDR to screen for differentially expressed genes, which were further analyzed to investigate complement‐related genes as genes of interest.
Results
In NRK‐52E cells, PAX2 overexpression promoted EMT followed by upregulation of 298 genes and downregulation of 293 genes. KEGG analysis indicated the differential expression of genes related to cytokines and their receptors, extracellular matrix (ECM), MAPKs, local adhesion, cancer, the complement cascade, and coagulation. Gene oncology analysis screened out genes related to molecular functions (e.g., hydrolase activity, phospholipase activity, components of the ECM) and biological processes (e.g., cell development, signal transduction, phylogeny), and cell components (e.g., cytoplasm, cell membrane, and ECM). Analysis of the complement system revealed upregulation of C3 and downregulation of CD55 and complement regulator factor H (CFH).
Conclusion
PAX2 overexpression upregulates EMT in vitro and may regulate C3, CD55, and CFH.
Summary at a Glance
This molecular analysis examines the effect of overexpressing paired box 2 (PAX2) in a tubule epithelial cell line. Results establish a link between pax2 and both epithelial‐mesenchymal transition (EMT) and the complement pathway.
Purpose: Quercetin is a potent chemotherapeutic drug. Clinical trials exploring different schedules of administration of quercetin
have been hampered by its extreme water insolubility. To overcome ...this limitation, this study is aimed to develop liposomal
quercetin and investigate its distribution in vivo and antitumor efficacy in vivo and in vitro .
Experimental Design: Quercetin was encapsulated in polyethylene glycol 4000 liposomes. Biodistribution of liposomal quercetin i.v. at 50 mg/kg
in tumor-bearing mice was detected by high-performance liquid chromatography. Induction of apoptosis by liposomal quercetin
in vitro was tested. The antitumor activity of liposomal quercetin was evaluated in the immunocompetent C57BL/6N mice bearing LL/2
Lewis lung cancer and in BALB/c mice bearing CT26 colon adenocarcinoma and H22 hepatoma. Tumor volume and survival time were
observed. The mechanisms underlying the antitumor effect of quercetin in vivo was investigated by detecting the microvessel density, apoptosis, and heat shock protein 70 expression in tumor tissues.
Results: Liposomal quercetin could be dissolved in i.v. injection and effectively accumulate in tumor tissues. The half-time of liposomal
quercetin was 2 hours in plasma. The liposomal quercetin induced apoptosis in vitro and significantly inhibited tumor growth in vivo in a dose-dependent manner. The optimal dose of liposomal quercetin resulted in a 40-day survival rate of 40%. Quantitative
real-time PCR showed that liposomal quercetin down-regulated the expression of heat shock protein 70 in tumor tissues. Immunohistochemistry
analysis showed that liposomal quercetin inhibited tumor angiogenesis as assessed by CD31 and induced tumor cell apoptosis.
Conclusions: Our data indicated that pegylated liposomal quercetin can significantly improve the solubility and bioavailability of quercetin
and can be a potential application in the treatment of tumor.
Diosgenin is a well-known steroid saponin possessing neuroprotective activities. However, it is unknown whether diosgenin could alleviate depression-like symptoms.
The antidepressant-like effect of ...diosgenin was investigated in mice induced by chronic restraint stress. The effects of diosgenin on behaviors, inflammation, neuroendocrine, neurotrophic function, and gut microbiota were evaluated.
The results showed that diosgenin alleviated the depressive-like behaviors in mice. In addition, diosgenin was found to reduce serum concentrations of proinflammatory cytokines and the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Besides, diosgenin could activate hippocampal brain-derived neurotrophic factor (BDNF)/TrkB/ERK/CREB signaling pathway and improve the expression of postsynaptic protein PSD95. Meanwhile, the neurogenesis which was inhibited by chronic restraint stress, was totally reversed by diosgenin. Moreover, diosgenin increased the abundance of phylum Firmicutes and the genus Lactobacillus in stressed mice. The results further showed that diosgenin caused a strong correlation between gut microbiota composition and inflammation, the HPA axis activity, or hippocampus neurotrophic function.
Only male mice were used for evaluation in the present study, which limits the understanding of effects of diosgenin on the both sexes. In addition, the results only indicate microbiota at the phylum or genus mediate the regulation of neuroinflammation, neuroendocrine, and neurotrophic function, but does not elucidate how microbiota modulate the systems via their primary or secondary metabolites.
The present study shows that diosgenin exerts the antidepressant activity, which is associated with the enhancement of neurotrophic function and the inhibition of inflammatory and neuroendocrine activities via the regulation of gut microbiota.
Display omitted
•Diosgenin possessed the antidepressant-like effect in CRS-induced mice.•Diosgenin inhibited inflammatory activity in both serum and hippocampus.•Diosgenin suppressed the hyperactivation of the HPA axis.•Diosgenin promoted hippocampal neurotrophic function.•Diosgenin reshaped the gut microbiota compositions.
PDF
