Discovery of a Highly Potent Lysine Methyltransferases G9a/NSD2 Dual Inhibitor to Treat Solid Tumors.

Both G9a and NSD2 have been recognized as promising therapeutic targets for cancer treatment. However, G9a inhibitors only showed moderate inhibitory activity against solid tumors and NSD2 inhibitors were limited to the treatment of hematological malignancies. Inspired by the advantages of dual-target inhibitors that show great potential in enhancing efficiency, we developed a series of highly potent G9a/NSD2 dual inhibitors to treat solid tumors. The candidate 16 demonstrated much enhanced antiproliferative activity compared to the selective G9a inhibitor 3 and NSD2 inhibitor 15. In addition, it exhibited superior potency in inhibiting colony formation, inducing cell apoptosis, and blocking cancer cell metastasis. Furthermore, it effectively inhibited the catalytic functions of both G9a and NSD2 in cells and exhibited significant antitumor efficacy in the PANC-1 xenograft model with good safety. Therefore, compound 16 as a highly potent G9a/NSD2 dual inhibitor presents an attractive anticancer drug candidate for the treatment of solid tumors.

NG2-Glia Cause Diabetic Blood-Brain Barrier Disruption by Secreting MMP-9.

Background: Disorders of the blood-brain barrier (BBB) arising from diabetes mellitus are closely related to diabetic encephalopathy. Previous research has suggested that neuron-glia antigen 2 (NG2)-glia plays a key role in maintaining the integrity of the BBB. However, the mechanism by which NG2-glia regulates the diabetic BBB remains unclear. Methods: Type 2 diabetes mellitus (T2DM) db/db mice and db/m mice were used. Evans-Blue BBB permeability tests and transmission electron microscopy techniques were applied. Tight junction proteins were assessed by immunofluorescence and transmission electron microscopy. NG2-glia number and signaling pathways were evaluated by immunofluorescence. Detection of matrix metalloproteinase-9 (MMP-9) in serum was performed using enzyme-linked immunosorbent assay (ELISA). Results: In T2DM db/db mice, BBB permeability in the hippocampus significantly increased from 16 weeks of age, and the structure of tight junction proteins changed. The number of NG2-glia in the hippocampus of db/db mice increased around microvessels from 12 weeks of age. Concurrently, the expression of MMP-9 increased in the hippocampus with no change in serum. Sixteen- week-old db/db mice showed activation of the Wnt/ß-catenin signaling in hippocampal NG2-glia. Treatment with XAV-939 improved structural and functional changes in the hippocampal BBB and reduced MMP-9 secretion by hippocampal NG2-glia in db/db mice. It was also found that the upregulation of ß-catenin protein in NG2-glia in the hippocampus of 16-week-old db/db mice was significantly alleviated by treatment with XAV-939. Conclusion: The results indicate that NG2-glia can lead to structural and functional disruption of the diabetic BBB by activating Wnt/ß-catenin signaling, upregulating MMP-9, and degrading tight junction proteins.

Targeted Quantification of Glutathione/Arginine Redox Metabolism Based on a Novel Paired Mass Spectrometry Probe Approach for the Functional Assessment of Redox Status.

Glutathione (GSH) redox control and arginine metabolism are critical in regulating the physiological response to injury and oxidative stress. Quantification assessment of the GSH/arginine redox metabolism supports monitoring metabolic pathway shifts during pathological processes and their linkages to redox regulation. However, assessing the redox status of organisms with complex matrices is challenging, and single redox molecule analysis may not be accurate for interrogating the redox status in cells and in vivo. Herein, guided by a paired derivatization strategy, we present a new ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based approach for the functional assessment of biological redox status. Two structurally analogous probes, 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) and newly synthesized 2-methyl-6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (MeAQC), were set for paired derivatization. The developed approach was successfully applied to LPS-stimulated RAW 264.7 cells and HDM-induced asthma mice to obtain quantitative information on GSH/arginine redox metabolism. The results suggest that the redox status was remarkably altered upon LPS and HDM stimulation. We expect that this approach will be of good use in a clinical biomarker assay and potential drug screening associated with redox metabolism, oxidative damage, and redox signaling.

Macrophorins H and L, two new HMG-conjugate macrophorins from rihzospheric Penicillium sp. NX-05-G-3.

Macrophorins H (4) and L (5), two rare HMG-conjugate macrophorins along with three known macrophorins (1-3), three DMOA-derived meroterpenoids (6-8) and two ergosterol derivates (9-10) were isolated from sterilized rice medium cultured Penicillium sp. NX-05-G-3. Their structures were elucidated by 1D and 2D NMR. The cytotoxicities of all compounds were evaluated, and compounds 1 and 2 showed extensive cytotoxicity against human cancer cell lines Hela, SCC15, MDA-MB-453 and A549, with IC50 values ranging from 17.6 to 32.8 µM.

Tandem Vinylogous Aldol and Intramolecular [2 + 2] Cycloaddition toward Benzocyclobutenes by UV Light Photocatalysis.

A facile and efficient radical tandem vinylogous aldol and intramolecular [2 + 2] cycloaddition reaction for direct synthesis of cyclobutane-containing benzocyclobutenes (BCBs) under extremely mild conditions without using any photocatalysts is reported. This approach exhibited definite compatibility with functional groups and afforded new BCBs with excellent regioselectivity and high yields. Moreover, detailed mechanism studies were carried out both experimentally and theoretically. The readily accessible, low-cost, and ecofriendly nature of the developed strategy will endow it with attractive applications in organic and medicinal chemistry.

Unveiling the Intricacies of the Inner Ear Anatomy: Novel 3D-Printed Model for Detailed Visualization and Functional Demonstrations.

OBJECTIVES: This research aimed to print realistically detailed and magnified three-dimensional models of the inner ear, specifically focusing on visualising its complex labyrinth structure and functioning simulation. METHODS: Temporal bone computed-tomography data were imported into Mimics software to construct an initial three-dimensional inner-ear model. Subsequently, the model was amplified and printed with precision using a three-dimensional printer. Five senior attending physicians evaluated the printed model using a Likert scale to gauge its morphological accuracy, clinical applicability and anatomical teaching value. RESULTS: The printed inner-ear model effectively demonstrated the intricate internal structure. All five physicians agreed that the model closely resembled the real inner ear in shape and structure, and simulated certain inner-ear functions. The model was considered highly valuable for understanding anatomical structure and disorders. CONCLUSION: The three-dimensionally printed inner-ear model is highly simulated and provides a valuable visual tool for studying inner-ear anatomy and clinical teaching, benefiting otologists.

Copper-catalyzed C2-selective alkynylation of chromones via 1,4-conjugate addition.

Copper-catalyzed selective alkynylation with N-propargyl carboxamides as nucleophiles has been successfully developed for the synthesis of C2-functionalized chromanones. Under optimized reaction conditions, 21 examples were obtained in one-pot procedure through 1,4-conjugate addition. This protocol features readily available feedstocks, easy operations, and moderate to good yields, which provides viable access to pharmacologically active C2-functionalized chromanones.

In Silico Studies, Anti-oxidant Properties, Antisorbitol Dehydrogenase, Anti-alpha Amylase and Anti-gastrointestinal Cancer Potential of Violanthin as a Natural Compound.

In vitro studies have shown flavonoids to be effective antioxidants. Flavonoid C-glycosides have antioxidant properties, but there are very few data on their cellular antioxidant activity. The chemical activities of violanthin against alpha amylase and sorbitol dehydrogenase were investigated utilizing the molecular docking study. The anti-cancer activities of the compounds were evaluated against MKN45, AGS, and KATO III cell lines. The chemical activities of violanthin against some of the expressed surface receptor proteins (estrogen receptor, folate receptor, and CD44) in the mentioned cell lines were estimated using molecular docking calculations. 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) analyzes were performed to determine the effects of compound on cell viability levels. The results showed the possible interactions and their features at an atomic level. The docking scores indicated that violanthin has a significant binding affinity to the enzymes and proteins. IC50 values of violanthin for gastric cell lines (MKN45, AGS, KATO III) were 31.95±3.95, 53.06±6.02, 47.98±5.16 µM, respectively. For α-amylase and sorbitol dehydrogenase enzymes, IC50 values were 25.03 and 1.47 µM. Moreover, this compound formed strong contact with the enzymes and receptors. Therefore, violanthin could be a potential inhibitor for these enzymes and cancer cells. Several secondary problems of diabetes mellitus have been discovered to be prevented or treated with sorbitol dehydrogenase inhibitors.

Metal-Free Catalyzed Oxidation/Decarboxylative [3+2] Cycloaddition Sequences of 3-Formylchromones to Access Pyrroles with Anti-Cancer Activity.

An efficient and direct approach to pyrroles was successfully developed by employing 3-formylchromones as decarboxylative coupling partners, and facilitated by microwave irradiation. The protocol utilizes easily accessible feedstocks, a catalytic amount of DBU without any metals, resulting in high efficiency and regioselectivity. Notably, all synthesized products were evaluated against five different cancer cell lines and compound 3l selectively inhibited the proliferation of HCT116 cells with an IC50 value of 10.65 µM.

Visible-Light-Mediated Catalyst-Free [2+2] Cycloaddition Reaction for Dihydrocyclobuta[b]naphthalene-3,8-diones Synthesis under Mild Conditions.

A facile and efficient visible-light-mediated method for directly converting 1,4-naphthoquinones into dihydrocyclo-buta[b]naphthalene-3,8-diones (DHCBNDOs) under mild and clean conditions without using any photocatalysts is reported. This approach exhibited favorable compatibility with functional groups and afforded a series of DHCBNDOs with excellent regioselectivity and high yields. Moreover, detailed mechanism studies were carried out both experimentally and theoretically. The readily accessible, low-cost and ecofriendly nature of the developed strategy will endow it with attractive applications in organic and medicinal chemistry.

NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance.

Glucose metabolism is known to orchestrate oncogenesis. Whether glucose serves as a signaling molecule directly regulating oncoprotein activity for tumorigenesis remains elusive. Here, we report that glucose is a cofactor binding to methyltransferase NSUN2 at amino acid 1-28 to promote NSUN2 oligomerization and activation. NSUN2 activation maintains global m5C RNA methylation, including TREX2, and stabilizes TREX2 to restrict cytosolic dsDNA accumulation and cGAS/STING activation for promoting tumorigenesis and anti-PD-L1 immunotherapy resistance. An NSUN2 mutant defective in glucose binding or disrupting glucose/NSUN2 interaction abolishes NSUN2 activity and TREX2 induction leading to cGAS/STING activation for oncogenic suppression. Strikingly, genetic deletion of the glucose/NSUN2/TREX2 axis suppresses tumorigenesis and overcomes anti-PD-L1 immunotherapy resistance in those cold tumors through cGAS/STING activation to facilitate apoptosis and CD8+ T cell infiltration. Our study identifies NSUN2 as a direct glucose sensor whose activation by glucose drives tumorigenesis and immunotherapy resistance by maintaining TREX2 expression for cGAS/STING inactivation.

Silver-Catalyzed Decarboxylative Acylation of Isocyanides Accesses to α-Ketoamides with Air as a Sole Oxidant.

α-Ketoamide moieties, as privileged units, may represent a valuable option to develop compounds with favorable biological activities, such as low toxicity, promising PK and drug-like properties. An efficient silver-catalyzed decarboxylative acylation of α-oxocarboxylic acids with isocyanides was developed to derivatize the α-ketoamide functional group via a multicomponent reaction (MCR) cascade sequence in one pot. A series of α-ketoamides was synthesized with three components of isocyanides, aromatic α-oxocarboxylic acid analogues and water in moderate yields. Based on the research, the silver-catalyzed decarboxylative acylation confirmed that an oxygen atom of the amide moiety was derived from the water and air as a sole oxidant for the whole process.

Unexpected Cascade Sequence Forming the C(sp3)-N/C(sp2)-C(sp2) Bond: Direct Access to γ-Lactam-Fused Pyridones with Anticancer Activity.

An unexpected Ugi cascade reaction was developed for the facile construction of γ-lactam-fused pyridone derivatives with high tolerance of substrates. A C(sp3)-N bond and a C(sp2)-C(sp2) bond were formed together, accompanied by a chromone ring-opening in Ugi adducts, under the basic conditions without any metal catalyst for the whole process. Screening data of several difficult-to-inhibit cancer cell lines demonstrated that 7l displayed a high cytotoxicity against HCT116 cells (IC50 = 5.59 ± 0.78 µM). Taken together, our findings revealed new insights into the molecular mechanisms underlying compound 7l and provided potential usage of this scaffold for cancer therapeutics.

Highly potent Platinum(IV) complexes with multiple-bond ligands targeting mitochondria to overcome cisplatin resistance.

The efficacy and resistance of cisplatin-based compounds are very intractable problems at present. This study reports a series of platinum(IV) compounds containing multiple-bond ligands, which exhibited better tumor cell inhibitory activity and antiproliferative and anti-metastasis activities than cisplatin. The meta-substituted compounds 2 and 5 were particularly excellent. Further research showed that compounds 2 and 5 possessed appropriate reduction potential and performed significantly better than cisplatin in cellular uptake, reactive oxygen species response, the up-regulation of apoptosis and DNA lesion-related genes, and drug-resistant cell activity. The title compounds exhibited better antitumor potential and fewer side effects than cisplatin in vivo. Multiple-bond ligands were introduced into cisplatin to form the title compounds in this study, which not only enhanced their absorption and overcame drug resistance but also demonstrated the potential to target mitochondria and inhibit the detoxification of tumor cells.

Correction: An intramolecular hydrogen bond-promoted "green" Ugi cascade reaction for the synthesis of 2,5-diketopiperazines with anticancer activity.

[This corrects the article DOI: 10.1039/D2RA04958A.].

Acid-Promoted Direct C-H Carbamoylation at the C-3 Position of Quinoxalin-2(1H)-ones with Isocyanide in Water.

Described herein is a concise and practical direct amidation at the C-3 position of quinoxalin-2(1H)-ones through an acid-promoted carbamoylation with isocyanide in water. In this conversion, environmentally friendly water and commercial inexpensive isocyanide were used as a solvent and carbamoylation reagent, respectively. This study not only provides a green and efficient strategy for the construction of 3-carbamoylquinoxalin-2(1H)-one derivatives that can be applied to the synthesis of druglike structures but also expands the application of isocyanide in organic chemistry.

Assessment of the local blood supply when femoral neck fracture occurs:advances in the anatomy research and its clinical application / 中国骨伤

The stability of internal fixation of femoral neck fractures can be obtained through surgical techniques, the configuration of screws and bone grafting, etc. However, the blood supply injury caused by fractures could not be completely reversed by the current medical management. Hence, the comprehensive evaluation of the residual blood supply of the femoral neck, to perioperatively avoid further iatrogenic injury, has become a hotspot. The anatomy of the extraosseous blood supply of the femoral neck has been widely reported, while its clinical application mostly involved the assessment of the medial circumflex femoral artery and retinacular arteries. However, further studies are needed to explore the prognosis of patients with these artery injuries, with different degrees, caused by femoral neck fractures. Direct observations of nutrient foramina in vivo are not possible with current clinical technologies, but it is possible to make reasonable preoperative planning to avoid subsequent femoral head necrosis based on the distribution features of nutrient foramina. The anatomy and clinical application studies of the intraosseous blood supply focused on the junction area of the femoral head and neck to probe the mechanism of femoral head necrosis. Thus, the intraosseous blood supply of other regions in the femoral neck remains to be further investigated. In addition, a blood supply evaluation system based on a three-level structure, extraosseous blood vessels, nutrient foramina, and intraosseous vascular network, could be explored to assist in the treatment of femoral neck fractures.

Review of closed reduction techniques for femoral neck fracture / 中国骨伤

For patients with femoral neck fractures who plan to undergo internal fixation, satisfied alignment of fracture ends is an important prerequisite for internal fixation stability and fracture healing. There are many reports on the reduction methods of displaced femoral neck fractures, which can be summarized into three categories:First, the solely longitudinal traction of lower limbs, supplemented by other manipulations such as rotation and compression; Second, the resultant force formed by the longitudinal traction of lower limbs and the lateral traction;the third is accomplished by vertical traction in the axis of femur with hip joint flexed. Each reduction method has its own advantages, but no single method can be applied to all fracture displacement. In this paper, some classical reduction techniques in the literatures are briefly reviewed. It is hoped that clinicians will not be limited to a certain reduction method, they should analyze the injury mechanism and fracture displacement process according to the morphology features and flexibly select targeted reduction methods to improve the success rate of closed reduction of femoral neck fracture.

Comparison of effect between internal fixation and total hip replacement in the treatment of displaced femoral neck fracture in middle age patients / 中国骨伤

OBJECTIVE@#To analyze and compare the clinical efficacy of internal fixation and total hip replacement in the treatment of displaced femoral neck fracture from 55 to 65 years.@*METHODS@#From September 2016 to August 2020, 86 patients with Garden type Ⅲ or Ⅳ femoral neck fracture were divided into two groups according to different surgical methods. Among them, 38 patients were treated with lag screws for internal fixation, there were 26 males and 12 females, aged 55 to 64 years old with an average of(60.2±3.1) years;the other 48 patients were treated with total hip replacement, including 28 males and 20 females, aged from 57 to 65 years old with an average of(61.3±3.8) years. The time from injury to operation ranged from 1 to 3 days. The reoperation rate, incidence of deep infection, Harris score of hip joint function, visual analogue scale(VAS) of pain and patients reported outcome scores(European five-dimensional Health Questionnaire, EQ-5D) were compared between two groups.@*RESULTS@#All patients were followed up for 24 to 54 months with an average of (35.8±10.3) months. There was significant difference in reoperation rate between two groups (P<0.05). There was no significant difference on the incidence of deep infection, hip Harris score and VAS between two groups(P>0.05) . The postoperative EQ-5D score of patients with internal fixation was lower than that of total hip replacement, and the difference was statistically significant(P<0.05).@*CONCLUSION@#Both the surgery of internal fixation and total hip replacement have similar effect in short-and medium term among the patients aged 55 to 65 years old. However, for the reoperation rate, the group of internal fixation was higher than that of total hip replacement. For the subjective functional score of patients, the group of internal fixation was lower than that of total hip replacement.

Ugi Cascade Sequence for the Construction of 3-Pyrrolin-2-one Scaffolds: Anti-proliferation in Prostate Cancer Cells.

Herein, a small series of 3-pyrrolin-2-ones was efficiently synthesized through a three-step Ugi cascade sequence. This method features readily available substrates, simple aqueous workup procedures and good yields, dramatically improving generality of reaction. Importantly, the newly product N-benzyl-2-(3-(4-chlorophenyl)-4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)-2-phen-ylacetamide exhibited potent anti-proliferation in prostate cancer cell line through G1/S cell cycle arrest and targeted in PI3K/AKT/TSC2 signal pathway.