β-Elemene is the major active ingredient of TCM anticancer drug elemene extracts. To further improve its antitumor activity and poor solubility, a polar HDACi pharmacophore was incorporated its ...scaffold. Systematic SAR studies led to the discovery of compounds 27f and 39f, which exhibited potent inhibitory activity against HDACs (HDAC1: IC
50
= 22 and 9 nM; HDAC6: 8 and 14 nM, respectively). In cellular levels, 27f and 39f significantly inhibited cell proliferation of five tumour cell lines (IC
50
: 0.79 - 4.42 µM). Preliminary mechanistic studies indicated that 27f and 39f efficiently induced cell apoptosis. Unexpectedly, compound 39f could also stimulate cell cycle arrest in G1 phase. Further in vivo study in WSU-DLCL-2 xenografted mouse model validated the antitumor activities of 27f, without significant toxicity. The results suggest the therapeutic potential of these HDACs inhibitors in lymphoma and provide valuable insight and understanding for further structural optimisation around β-elemene scaffold.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Five- and six-membered aromatic rings bearing a methyl group are important molecular fragments in drug discovery. From the medicinal chemistry standpoint, the methyl group might play a pivotal role ...in improving the biological activities and druggability due to its capability in modulating the molecular conformation as well as the physical and chemical properties (such as lipophilicity and metabolism, etc.). How to effectively install a methyl group in a designated position of an aromatic ring is a long-stand quest and a research hot spot for both medicinal chemists and synthetic organic chemists. In the past few years, significant progresses have been achieved in this field wherein the C–H bond activation and direct methylation become achievable in one step under catalytic conditions. A variety of metal catalysts reported by several research groups are capable of such transformation. The relatively mild reaction conditions and high functional group compatibility make such transformation very attractive for final step synthesis. This paper summarizes such transformation based on their reaction mechanisms, and systematically discusses the reaction conditions and their application of a variety of substrates. It provides both medicinal and synthetic organic chemists the convenience for accessing the most up-to-date methodology, and would foster the potential applications in drug discovery and organic synthesis projects.
Focusing on the site-specific direct methylation on aromatic rings, this paper discusses the recent progresses in two different categories based on the mechanisms of the C–H bond breakage: the directing group (DG) mediated method and the radical approach. It provides both medicinal chemists and synthetic organic chemists the convenience for accessing the most up-to-date methodology and would foster the potential applications in drug discovery and organic synthesis projects. Display omitted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Acute respiratory distress syndrome (ARDS) is a fatal disease characterized by excessive infiltration of inflammatory cells. MCTR1 is an endogenously pro‐resolution lipid mediator. We tested the ...hypothesis that MCTR1 accelerates inflammation resolution through resident M2 alveolar macrophage polarization. The mice received MCTR1 via intraperitoneal administration 3 days after LPS stimulation, and then, the bronchoalveolar lavage (BAL) fluid was collected 24 hours later to measure the neutrophil numbers. Flow cytometry was used to sort the resident and recruited macrophages. Post‐treatment with MCTR1 offered dramatic benefits in the resolution phase of LPS‐induced lung injury, including decreased neutrophil numbers, reduced BAL fluid protein and albumin concentrations and reduced histological injury. In addition, the expression of the M2 markers Arg1, FIZZ1, Remlα, CD206 and Dectin‐1 was increased on resident macrophages in the LPS + MCTR1 group. Resident macrophage depletion abrogated the therapeutic effects of MCTR1, and reinjection of the sorted resident macrophages into the lung decreased neutrophil numbers. Finally, treatment with MCTR1 increased STAT6 phosphorylation. The STAT6 inhibitor AS1517499 abolished the beneficial effects of MCTR1. In conclusion, MCTR1 promotes resident M2 alveolar macrophage polarization via the STAT6 pathway to accelerate resolution of LPS‐induced lung injury.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A proportion of chronic hepatitis B virus (HBV) carriers with normal alanine transaminase (ALT) present with significant liver histological changes (SLHC). To construct a noninvasive nomogram model ...to identify SLHC in chronic HBV carriers with different upper limits of normal (ULNs) for ALT. The training cohort consisted of 732 chronic HBV carriers who were stratified into four sets according to different ULNs for ALT: chronic HBV carriers I, II, III, and IV. The external validation cohort comprised 277 chronic HBV carriers. Logistic regression and least absolute shrinkage and selection operator analyses were applied to develop a nomogram model to predict SLHC. A nomogram model‐HBGP (based on hepatitis B surface antigen, gamma‐glutamyl transpeptidase, and platelet count) demonstrated good performance in diagnosing SLHC with area under the curve (AUCs) of 0.866 (95% confidence interval CI: 0.839−0.892) and 0.885 (95% CI: 0.845−0.925) in the training and validation cohorts, respectively. Furthermore, HBGP displayed high diagnostic values for SLHC with AUCs of 0.866 (95% CI: 0.839−0.892), 0.868 (95% CI: 0.838−0.898), 0.865 (95% CI: 0.828−0.901), and 0.853 (95% CI: 0.798−0.908) in chronic HBV carriers I, II, III, and IV, respectively. Additionally, HBGP showed greater ability in predicting SLHC compared with the existing predictors. HBGP has shown high predictive performance for SLHC, and thus may lead to an informed decision on the initiation of antiviral treatment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The main objective of our study was to compare the intraoperative and postoperative outcomes of direct anterior approach (DAA) with posterolateral approaches (PLA).
We searched Cochrane library, Web ...of Science, and PubMed for literatures comparing DAA with PLA. On the basis of inclusion and exclusion criteria, relevant literatures were selected. Two members independently screened qualified literatures, evaluated the literature quality, and extracted data information.
Eighteen randomized controlled trials (RCTs) and non-RCTs totaling 34,873 patients (DAA = 9636, PLA = 25237) were contained in this systematic review and meta-analysis. The results showed that DAA were reduced in terms of length of hospital stay (weighted mean difference (WMD) = -0.43, 95% confidence interval (CI) -0.78 to -0.09, P = 0.01), LLD (WMD = -2.00, 95% CI -2.75 to -1.25, P < 0.00001), PE/DVT (WMD = 0.36, 95% CI 0.15 to 0.85, P = 0.02), dislocation (WMD = 0.42, 95% CI 0.30 to 0.59, P < 0.00001) and visual analog scale (VAS) (WMD = -0.57, 95% CI -0.91 to -0.23, P = 0.0009) compared with PLA; however, DAA compared with the PLA was increasing in terms of operative time (WMD = 14.81, 95% CI 7.18 to 22.44, P = 0.0001), intraoperative blood loss (WMD = 105.13, 95% CI 25.35 to 184.90, P = 0.01), fracture (WMD = 1.46, 95% CI 1.00 to 2.11, P = 0.05), and Harris hip score (HHS) (WMD = 1.19, 95% CI 0.77 to 1.61, P < 0.00001).
DAA was preferable effectiveness to PLA in early pain relief and functional recovery; however, PLA has a shorter operation time, intraoperative less blood loss and fracture.
Registration ID, CRD42020151208.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Ataxia telangiectasia and RAD3-related kinase (ATR) is one of the key phosphatidylinositol 3-kinase-related kinase family members important for DNA damage response and repair pathways. Targeting ATR ...kinase for potential cancer therapy has attracted a great deal of attention to both pharmaceutical industries and academic community.
This article surveys the patents published since 2014 aiming to analyze the structural features of scaffolds and the patent space. It also discusses the recent clinical developments and provides perspectives on the challenges and the future directions.
ATR kinase appears to be a viable drug target for anticancer therapy. Similar to DNA-PK inhibitors, the clinical investigation of an ATRi employs both monotherapy and combination strategy. In the combination strategy, an ATRi is typically combined with a radiation or a targeted drug such as chemotherapy agent poly (ADP-ribose) polymerase (PARP) inhibitor, etc. Diverse structures comprising different scaffolds from mono-heteroaryl to bicyclic heteroaryl to tricyclic heteroaryl to macrocycle are capable of achieving good ATR inhibitory activity and good ATR selectivity over other closely related enzymes. There are eight ATR inhibitors currently being evaluated in clinics, with the hope to get approval in the near future.
Background
White matter hyperintensity (WMH) is widely observed in aging brain and is associated with various diseases. A pragmatic and handy method in the clinic to assess and follow up white matter ...disease is strongly in need.
Purpose
To develop and validate a radiomics nomogram for the prediction of WMH progression.
Study Type
Retrospective.
Population
Brain images of 193 WMH patients from the Picture Archiving and Communication Systems (PACS) database in the A Medical Center (Zhejiang Provincial People's Hospital). MRI data of 127 WMH patients from the PACS database in the B Medical Center (Zhejiang Lishui People's Hospital) were included for external validation. All of the patients were at least 60 years old.
Field Strength/Sequence
T1‐fluid attenuated inversion recovery images were acquired using a 3T scanner.
Assessment
WMH was evaluated utilizing the Fazekas scale based on MRI. WMH progression was assessed with a follow‐up MRI using a visual rating scale. Three neuroradiologists, who were blinded to the clinical data, assessed the images independently. Moreover, interobserver and intraobserver reproducibility were performed for the regions of interest for segmentation and feature extraction.
Statistical Tests
A receiver operating characteristic (ROC) curve, the area under the curve (AUC) of the ROC was calculated, along with sensitivity and specificity. Also, a Hosmer–Lemeshow test was performed.
Results
The AUC of radiomics signature in the primary, internal validation cohort, external validation cohort were 0.886, 0.816, and 0.787, respectively; the specificity were 71.79%, 72.22%, and 81%, respectively; the sensitivity were 92.68%, 87.94% and 78.3%, respectively. The radiomics nomogram in the primary cohort (AUC = 0.899) and the internal validation cohort (AUC = 0.84). The Hosmer–Lemeshow test showed no significant difference between the primary cohort and the internal validation cohort (P > 0.05). The AUC of the radiomics nomogram, radiomics signature, and hyperlipidemia in all patients from the primary and internal validation cohort was 0.878, 0.848, and 0.626, respectively.
Data Conclusion
This multicenter study demonstrated the use of a radiomics nomogram in predicting the progression of WMH with elderly adults (an age of at least 60 years) based on conventional MRI.
Level of Evidence: 3
Technical Efficacy: Stage 2
J. Magn. Reson. Imaging 2020;51:535–546.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Touch sensation is essential for behaviours ranging from environmental exploration to social interaction; however, the underlying mechanisms are largely unknown. In Drosophila larvae, two types of ...sensory neurons, class III and class IV dendritic arborization neurons, tile the body wall. The mechanotransduction channel PIEZO in class IV neurons is essential for sensing noxious mechanical stimuli but is not involved in gentle touch. On the basis of electrophysiological-recording, calcium-imaging and behavioural studies, here we report that class III dendritic arborization neurons are touch sensitive and contribute to gentle-touch sensation. We further identify NOMPC (No mechanoreceptor potential C), a member of the transient receptor potential (TRP) family of ion channels, as a mechanotransduction channel for gentle touch. NOMPC is highly expressed in class III neurons and is required for their mechanotransduction. Moreover, ectopic NOMPC expression confers touch sensitivity to the normally touch-insensitive class IV neurons. In addition to the critical role of NOMPC in eliciting gentle-touch-mediated behavioural responses, expression of this protein in the Drosophila S2 cell line also gives rise to mechanosensitive channels in which ion selectivity can be altered by NOMPC mutation, indicating that NOMPC is a pore-forming subunit of a mechanotransduction channel. Our study establishes NOMPC as a bona fide mechanotransduction channel that satisfies all four criteria proposed for a channel to qualify as a transducer of mechanical stimuli and mediates gentle-touch sensation. Our study also suggests that different mechanosensitive channels may be used to sense gentle touch versus noxious mechanical stimuli.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Protein arginine methyltransferases (PRMTs), enzymes catalyzing the methylation of target proteins, play an essential role in maintaining functional homeostasis in normal physiology. Aberrant ...expressions and enhanced enzymatic activities of PRMTs have been closely associated with pathological states such as cancer, inflammatory, immune, metabolic, and neurodegenerative diseases. Therefore, the development of inhibitors targeting PRMTs has attracted a great deal of attention in both pharmaceutical industries and academic community. This review focuses on the small-molecule inhibitors targeting PRMTs in cancer therapy in the patents published since 2019. The recent clinical development is also discussed here. In recent years, the discovery of small-molecule PRMT inhibitors, especially PRMT5 inhibitors has become a rapidly expanding research area for cancer therapy. Although a number of potent PRMT inhibitors with different chemical scaffolds have been developed and nine of them have entered into clinical trials, their scaffolds are relatively less diverse. Sub-type selectivity should be considered in drug discovery as nonselective inhibition of PRMTs may cause undesirable pharmacological effects. Hence, the development of new effective inhibitors with isoform-specific and tumor-biased distributions remains an important area for further studies.
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