ABSTRACT
Herein, we report a copper-catalyzed protocol to access unsymmetrical triarylmethanes containing both indolizine and the chromone scaffolds in the same molecule via a 5-endo-dig cyclization of 2-(2-enynyl)-pyridines followed by reaction with 2-hydroxyaryl enaminones. A variety of 2-hydroxyaryl enaminones and 2-(2-enynyl)-pyridines were subjected to reaction under the optimal reaction conditions, and the respective triarylmethanes were obtained in good to excellent yields.
ABSTRACT
Herein, we report a transition-metal and base-free protocol to access a wide range of functionalized indenone derivatives through a HMPA-H2O-mediated oxygenative annulation of 2-alkynylphenyl-substituted p-quinone methides. This method worked effectively for most of the p-QMs investigated and the corresponding indenone derivatives were obtained in moderate to good yields. This methodology was further extended to the formal synthesis of one of the resveratrol based natural products, (±)-isopaucifloral F.
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BACKGROUND: Automation of surgical phase recognition is a key effort toward the development of Computer Vision (CV) algorithms, for workflow optimization and video-based assessment. CV is a form of Artificial Intelligence (AI) that allows interpretation of images through a deep learning (DL)-based algorithm. The improvements in Graphic Processing Unit (GPU) computing devices allow researchers to apply these algorithms for recognition of content in videos in real-time. Edge computing, where data is collected, analyzed, and acted upon in close proximity to the collection source, is essential meet the demands of workflow optimization by providing real-time algorithm application. We implemented a real-time phase recognition workflow and demonstrated its performance on 10 Robotic Inguinal Hernia Repairs (RIHR) to obtain phase predictions during the procedure. METHODS: Our phase recognition algorithm was developed with 211 videos of RIHR originally annotated into 14 surgical phases. Using these videos, a DL model with a ResNet-50 backbone was trained and validated to automatically recognize surgical phases. The model was deployed to a GPU, the Nvidia® Jetson Xavier™ NX edge computing device. RESULTS: This model was tested on 10 inguinal hernia repairs from four surgeons in real-time. The model was improved using post-recording processing methods such as phase merging into seven final phases (peritoneal scoring, mesh placement, preperitoneal dissection, reduction of hernia, out of body, peritoneal closure, and transitionary idle) and averaging of frames. Predictions were made once per second with a processing latency of approximately 250 ms. The accuracy of the real-time predictions ranged from 59.8 to 78.2% with an average accuracy of 68.7%. CONCLUSION: A real-time phase prediction of RIHR using a CV deep learning model was successfully implemented. This real-time CV phase segmentation system can be useful for monitoring surgical progress and be integrated into software to provide hospital workflow optimization.
Subject(s)
Artificial Intelligence , Hernia, Inguinal , Humans , Operating Rooms , Hernia, Inguinal/surgery , Algorithms , PeritoneumABSTRACT
In this article, we describe a convenient method to access 9-aryl fluorene derivatives through a TfOH-catalyzed intramolecular 1,6-conjugate arylation of 2-(aryl)-phenyl-substituted p-quinone methides (QMs) under continuous flow using the microreaction technique. This method was found to be very effective for most of the p-QMs, and the corresponding 9-aryl fluorene derivatives were obtained in moderate to excellent yields. Moreover, this protocol was further elaborated to the first total syntheses of selaginpulvilin I and isoselagintamarlin A.
Subject(s)
Indolequinones , CatalysisABSTRACT
The catalytic application of the bis(amino)cyclopropenium ion has been investigated in conjugate addition reactions. The hydrogen atom, which is attached to the cyclopropene ring of bis(amino)cyclopropenium salts, is moderately acidic and can potentially serve as a hydrogen-bond donor catalyst in some organic transformations. This hypothesis has been successfully realized in the 1,6-conjugate addition reactions of p-quinone methides with various nucleophiles such as indole, 2-naphthol, thiols, phenols, and so forth. The spectroscopic studies (NMR and UV-vis) as well as the deuterium isotope labeling studies clearly revealed that the hydrogen atom (C-H) that is present in the cyclopropene ring of the catalyst is indeed solely responsible for catalyzing these transformations. In addition, these studies also strongly indicate that the C-H hydrogen of the cyclopropene ring activates the carbonyl group of the p-quinone methide through hydrogen bonding.
ABSTRACT
The development of novel small molecule-based catalysts for organic transformations has increased noticeably in the last two decades. A very recent addition to this particular research area is cyclopropene- and cyclopropenium-based catalysts. At one point in time, particularly in the mid-20th century, much attention was focused on the structural aspects and physical properties of cyclopropene-based compounds. However, a paradigm shift was observed in the late 20th century, and the focus shifted to the synthetic utility of these compounds. In fact, a wide range of cyclopropene derivatives have been found serving as valuable synthons for the construction of carbocycles, heterocycles and other useful organic compounds. In the last few years, the catalytic applications of cyclopropene/cyclopropenium-based compounds have been uncovered and many synthetic protocols have been developed using cyclopropene-based compounds as organocatalysts. Therefore, the main objective of this review is to highlight recent developments in the catalytic applications of cyclopropene-based small molecules in different areas of organocatalysis such as phase-transfer catalysis (PTC), Brønsted base catalysis, hydrogen-bond donor catalysis, nucleophilic carbene catalysis, and electrophotocatalysis developed within the past two decades.
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We have shown that aggregated LDL is internalized by macrophages and oxidized in lysosomes by redox-active iron. We have now investigated to determine whether the lysosomal oxidation of LDL impairs lysosomal function and whether a lysosomotropic antioxidant can prevent these alterations. LDL aggregated by SMase (SMase-LDL) caused increased lysosomal lipid peroxidation in human monocyte-derived macrophages or THP-1 macrophage-like cells, as shown by a fluorescent probe, Foam-LPO. The pH of the lysosomes was increased considerably by lysosomal LDL oxidation as shown by LysoSensor Yellow/Blue and LysoTracker Red. SMase-LDL induced senescence-like properties in the cells as shown by ß-galactosidase staining and levels of p53 and p21. Inflammation plays a key role in atherosclerosis. SMase-LDL treatment increased the lipopolysaccharide-induced secretion of TNF-α, IL-6, and MCP-1. The lysosomotropic antioxidant, cysteamine, inhibited all of the above changes. Targeting lysosomes with antioxidants, such as cysteamine, to prevent the intralysosomal oxidation of LDL might be a novel therapy for atherosclerosis.
Subject(s)
Cellular Senescence/drug effects , Cytokines/metabolism , Lipoproteins, LDL/pharmacology , Lysosomes/chemistry , Lysosomes/metabolism , Macrophages/drug effects , Macrophages/metabolism , Antioxidants/metabolism , Cell Line , Cysteamine/metabolism , Humans , Hydrogen-Ion Concentration , Inflammation/metabolism , Iron/metabolism , Lipid Peroxidation/drug effects , Macrophages/cytology , Reactive Oxygen Species/metabolismABSTRACT
Video-recorded robotic-assisted surgeries allow the use of automated computer vision and artificial intelligence/deep learning methods for quality assessment and workflow analysis in surgical phase recognition. We considered a dataset of 209 videos of robotic-assisted laparoscopic inguinal hernia repair (RALIHR) collected from 8 surgeons, defined rigorous ground-truth annotation rules, then pre-processed and annotated the videos. We deployed seven deep learning models to establish the baseline accuracy for surgical phase recognition and explored four advanced architectures. For rapid execution of the studies, we initially engaged three dozen MS-level engineering students in a competitive classroom setting, followed by focused research. We unified the data processing pipeline in a confirmatory study, and explored a number of scenarios which differ in how the DL networks were trained and evaluated. For the scenario with 21 validation videos of all surgeons, the Video Swin Transformer model achieved ~0.85 validation accuracy, and the Perceiver IO model achieved ~0.84. Our studies affirm the necessity of close collaborative research between medical experts and engineers for developing automated surgical phase recognition models deployable in clinical settings.
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Muscle contraction is driven by the molecular machinery of the sarcomere. As phosphorylation is a critical regulator of muscle function, the identification of regulatory kinases is important for understanding sarcomere biology. Pathogenic variants in alpha kinase 3 (ALPK3) cause cardiomyopathy and musculoskeletal disease, but little is known about this atypical kinase. Here we show that ALPK3 is an essential component of the M-band of the sarcomere and define the ALPK3-dependent phosphoproteome. ALPK3 deficiency impaired contractility both in human cardiac organoids and in the hearts of mice harboring a pathogenic truncating Alpk3 variant. ALPK3-dependent phosphopeptides were enriched for sarcomeric components of the M-band and the ubiquitin-binding protein sequestosome-1 (SQSTM1) (also known as p62). Analysis of the ALPK3 interactome confirmed binding to M-band proteins including SQSTM1. In human pluripotent stem cell-derived cardiomyocytes modeling cardiomyopathic ALPK3 mutations, sarcomeric organization and M-band localization of SQSTM1 were abnormal suggesting that this mechanism may underly disease pathogenesis.
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A Pd-catalyzed direct method has been developed to access 1,3-disubstituted indolizines. This reaction proceeds through a regiospecific annulation of terminal alkynes with 2-pyridinyl-substituted p-quinone methides and, in most of the cases, the desired 1,3-disubstituted indolizines were obtained in moderate to good isolated yields. The control experiments suggested that the reaction does proceed through a substrate-controlled regiospecific formal [3 + 2]-annulation pathway.
Subject(s)
Alkynes , Indolizines , Catalysis , Molecular Structure , QuinonesABSTRACT
Background We have shown previously that low-density lipoprotein (LDL) can be oxidized in the lysosomes of macrophages, that this oxidation can be inhibited by cysteamine, an antioxidant that accumulates in lysosomes, and that this drug decreases atherosclerosis in LDL receptor-deficient mice fed a high-fat diet. We have now performed a regression study with cysteamine, which is of more relevance to the treatment of human disease. Methods and Results LDL receptor-deficient mice were fed a high-fat diet to induce atherosclerotic lesions. They were then reared on chow diet and drinking water containing cysteamine or plain drinking water. Aortic atherosclerosis was assessed, and samples of liver and skeletal muscle were analyzed. There was no regression of atherosclerosis in the control mice, but cysteamine caused regression of between 32% and 56% compared with the control group, depending on the site of the lesions. Cysteamine substantially increased markers of lesion stability, decreased ceroid, and greatly decreased oxidized phospholipids in the lesions. The liver lipid levels and expression of cluster of differentiation 68, acetyl-coenzyme A acetyltransferase 2, cytochromes P450 (CYP)27, and proinflammatory cytokines and chemokines were decreased by cysteamine. Skeletal muscle function and oxidative fibers were increased by cysteamine. There were no changes in the plasma total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, or triacylglycerol concentrations attributable to cysteamine. Conclusions Inhibiting the lysosomal oxidation of LDL in atherosclerotic lesions by antioxidants targeted at lysosomes causes the regression of atherosclerosis and improves liver and muscle characteristics in mice and might be a promising novel therapy for atherosclerosis in patients.
Subject(s)
Atherosclerosis , Drinking Water , Animals , Atherosclerosis/drug therapy , Atherosclerosis/genetics , Atherosclerosis/prevention & control , Cholesterol , Cysteamine/pharmacology , Humans , Lipoproteins, LDL , Liver , Mice , Muscles , Receptors, LDL/geneticsABSTRACT
A sequential two-step method for the synthesis of hetero-arylated triarylmethanes through a Ag-catalyzed sequential double cyclization-nucleophilic addition cascade is described. This methodology basically involves an initial 5-endo-dig cyclization of o-alkynyl anilines to provide 2-substituted indole derivatives, which then react with 2-(2-enynyl)-pyridines to afford indolizine-containing unsymmetrical triarylmethanes through another 5-endo-dig cyclization.
ABSTRACT
BACKGROUND AND AIMS: We have shown previously that low density lipoprotein (LDL) aggregated by vortexing is internalised by macrophages and oxidised by iron in lysosomes to form the advanced lipid/protein oxidation product ceroid. We have now used sphingomyelinase-aggregated LDL, a more pathophysiological form of aggregated LDL, to study lysosomal oxidation of LDL and its inhibition by antioxidants, including cysteamine (2-aminoethanethiol), which concentrates in lysosomes by several orders of magnitude. We have also investigated the effect of cysteamine on atherosclerosis in mice. METHODS: LDL was incubated with sphingomyelinase, which increased its average particle diameter from 26 to 170â¯nm, and was then incubated for up to 7 days with human monocyte-derived macrophages. LDL receptor-deficient mice were fed a Western diet (19-22 per group) and some given cysteamine in their drinking water at a dose equivalent to that used in cystinosis patients. The extent of atherosclerosis in the aortic root and the rest of the aorta was measured. RESULTS: Confocal microscopy revealed lipid accumulation in lysosomes in the cultured macrophages. Large amounts of ceroid were produced, which colocalised with the lysosomal marker LAMP2. The antioxidants cysteamine, butylated hydroxytoluene, amifostine and its active metabolite WR-1065, inhibited the production of ceroid. Cysteamine at concentrations well below those expected to be present in lysosomes inhibited the oxidation of LDL by iron ions at lysosomal pH (pH 4.5) for prolonged periods. Finally, we showed that the extent of atherosclerotic lesions in the aortic root and arch of mice was significantly reduced by cysteamine. CONCLUSIONS: These results support our hypothesis that lysosomal oxidation of LDL is important in atherosclerosis and hence antioxidant drugs that concentrate in lysosomes might provide a novel therapy for this disease.
Subject(s)
Antioxidants/pharmacology , Aorta/drug effects , Aortic Diseases/prevention & control , Atherosclerosis/prevention & control , Cysteamine/pharmacology , Foam Cells/drug effects , Lipoproteins, LDL/metabolism , Lysosomes/drug effects , Animals , Aorta/metabolism , Aorta/pathology , Aortic Diseases/genetics , Aortic Diseases/metabolism , Aortic Diseases/pathology , Atherosclerosis/genetics , Atherosclerosis/metabolism , Atherosclerosis/pathology , Disease Models, Animal , Female , Foam Cells/metabolism , Humans , Hydrogen-Ion Concentration , Lysosomes/metabolism , Mice, Knockout , Oxidation-Reduction , Plaque, Atherosclerotic , Receptors, LDL/deficiency , Receptors, LDL/genetics , Sphingomyelin Phosphodiesterase/metabolism , THP-1 CellsABSTRACT
Oxidised low density lipoprotein (LDL) was considered to be important in the pathogenesis of atherosclerosis, but the large clinical trials of antioxidants, including the first one using probucol (the PQRST Trial), failed to show benefit and have cast doubt on the importance of oxidised LDL. We have shown previously that LDL oxidation can be catalysed by iron in the lysosomes of macrophages. The aim of this study was therefore to investigate the effectiveness of antioxidants in preventing LDL oxidation at lysosomal pH and also establish the possible mechanism of oxidation. Probucol did not effectively inhibit the oxidation of LDL at lysosomal pH, as measured by conjugated dienes or oxidised cholesteryl esters or tryptophan residues in isolated LDL or by ceroid formation in the lysosomes of macrophage-like cells, in marked contrast to its highly effective inhibition of LDL oxidation at pH 7.4. LDL oxidation at lysosomal pH was inhibited very effectively for long periods by N,N'-diphenyl-1,4-phenylenediamine, which is more hydrophobic than probucol and has been shown by others to inhibit atherosclerosis in rabbits, and by cysteamine, which is a hydrophilic antioxidant that accumulates in lysosomes. Iron-induced LDL oxidation might be due to the formation of the superoxide radical, which protonates at lysosomal pH to form the much more reactive, hydrophobic hydroperoxyl radical, which can enter LDL and reach its core. Probucol resides mainly in the surface monolayer of LDL and would not effectively scavenge hydroperoxyl radicals in the core of LDL. This might explain why probucol failed to protect against atherosclerosis in various clinical trials. The oxidised LDL hypothesis of atherosclerosis now needs to be re-evaluated using different and more effective antioxidants that protect against the lysosomal oxidation of LDL.
Subject(s)
Antioxidants/chemistry , Lipoproteins, LDL/chemistry , Lysosomes/chemistry , Animals , Antioxidants/therapeutic use , Atherosclerosis/drug therapy , Cell Line , Ceroid/chemistry , Chromatography, High Pressure Liquid , Cysteamine/chemistry , Ferrous Compounds/chemistry , Humans , Hydrogen Peroxide/chemistry , Hydrogen-Ion Concentration , Lipoproteins, LDL/analysis , Oxidation-Reduction , Probucol/chemistry , Probucol/therapeutic use , RabbitsABSTRACT
TLRs, including TLR4, have been shown to play a crucial role in cardiovascular inflammatory-based diseases. The main goal of this study was to determine the potential of FP7, a synthetic glycolipid active as a TLR4 antagonist, to modulate haematopoietic and non-haematopoietic vascular TLR4 pro-inflammatory signalling. HUVEC, human THP-1 monocytes, THP-1-derived macrophages, mouse RAW-264.7 macrophages and Angiotensin II-infused apolipoprotein E-deficient mice were in vitro and in vivo models, respectively. Western blotting, Ab array and ELISA approaches were used to explore the effect of FP7 on TLR4 functional activity in response to bacterial LPS ( in vitro) and endogenous ligands of sterile inflammation ( in vitro and in vivo). Following activation of TLR4, in vitro and in vivo data revealed that FP7 inhibited p38 MAPK and p65 NF-kB phosphorylation associated with down-regulation of a number of TLR4-dependent pro-inflammatory proteins. In addition to inhibition of LPS-induced TLR4 signalling, FP7 negatively regulated TLR4 activation in response to ligands of sterile inflammation (hydroperoxide-rich oxidised LDL, in vitro and Angiotensin II infusion, in vivo). These results demonstrate the ability of FP7 to negatively regulate in vitro and in vivo haematopoietic and non-haematopoietic vascular TLR4 signalling both in humans and mice, suggesting the potential therapeutic use of this TLR4 antagonist for pharmacological intervention of vascular inflammatory diseases.
Subject(s)
Blood Cells/drug effects , Endothelial Cells/drug effects , Glycolipids/therapeutic use , Toll-Like Receptor 4/antagonists & inhibitors , Vasculitis/drug therapy , Angiotensin II/metabolism , Animals , Blood Cells/immunology , Endothelial Cells/immunology , Glycolipids/chemical synthesis , Human Umbilical Vein Endothelial Cells , Humans , Inflammation Mediators/metabolism , Lipopolysaccharides/immunology , Lipoproteins, LDL/metabolism , Mice , Mice, Knockout, ApoE , NF-kappa B/metabolism , Phosphorylation , RAW 264.7 Cells , Signal Transduction/drug effects , THP-1 Cells , Toll-Like Receptor 4/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
OBJECTIVE: To carry out a preliminary phytochemical, acute oral toxicity and antihepatotoxic study of the roots of Paeonia officinalis (P. officinalis) L. METHODS: Preliminary phytochemical investigation was done as per standard procedures. Acute oral toxicity study was conducted as per OECD 425 guidelines. The antihepatotoxic activity of aqueous extract of root of P. officinalis was evaluated against carbon tetrachloride (CCl4) induced hepatic damage in rats. Aqueous extract of P. officinalis at the dose levels of 100 and 200 mg/kg body weight was administered daily for 14 d in experimental animals. Liver injury was induced chemically, by CCl4 administration (1 mL/kg i.p.). The hepatoprotective activity was assessed using various biochemical parameters like aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum alkaline phosphatase (SALP), total bilirubin and total protein (TP) along with histopathological studies. RESULT: Phytochemical screening revealed that the roots of P. officinalis contain alkaloids, tannins, saponins, glycosides, carbohydrates, flavonoids, terpenes, steroids and proteins. The aqueous extract did not cause any mortality up to 2â 000 mg/kg. In rats that had received the root extract at the dose of 100 and 200 mg/kg, the substantially elevated AST, ALT, SALP, total bilirubin levels were significantly lowered, respectively, in a dose dependent manner, along with CCl4 while TP levels were elevated in these groups. Histopathology revealed regeneration of the livers in extract treated groups while Silymarin treated rats were almost normal. CONCLUSIONS: The aqueous extract of P. officinalis is safe and possesses antihepatotoxic potential.
Subject(s)
Liver/drug effects , Paeonia/chemistry , Plant Extracts/pharmacology , Plant Extracts/toxicity , Plant Roots/chemistry , Animals , Carbon Tetrachloride/toxicity , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/etiology , Female , Male , Plant Extracts/chemistry , Plant Extracts/therapeutic use , Rats , Rats, WistarABSTRACT
AIMS: To establish the Quality standards of Triticum aestivum L, seeds as per WHO guidelines. To study the antioxidant and hepatoprotective profile of T. aestivum L. seeds. METHODS: Pharmacognostic studies like morphological, microscopical, physico-chemical, phytochemical evaluation, fluorescence analysis, TLC, HPTLC, phytochemical analysis etc. of various extracts of the seeds of T. aestivum were carried out as per established methods. The ethanolic extract was evaluated for antioxidant and hepatoprotective activity using rat model. RESULTS: Preliminary phytochemical analysis mainly revealed the presence of carbohydrates, phenolics, proteins, resins, lipids and flavonoids. T. aestivum at different doses, i.e. 5-45 µg/ml showed free radical scavenging activity in dose dependent manner. The amount of phenolic components was found to be 313.5 µg/mg indicating considerable antioxidant activity. The ethanolic extract of T. aestivum was administered at dose level of 100 mg/kg/day, every day for 21 days along with CCl4. Biochemical and histopathological results conclude that the seeds have hepatoprotective activity.
ABSTRACT
Hypertension (HTN) is the medical term for high blood pressure. It is dangerous because it makes the heart work too hard and contributes to atherosclerosis (hardening of arteries), besides increasing the risk of heart disease and stroke. HTN can also lead to other conditions such as congestive heart failure, kidney disease, and blindness. Conventional antihypertensives are usually associated with many side effects. About 75 to 80% of the world population use herbal medicines, mainly in developing countries, for primary health care because of their better acceptability with human body and lesser side effects. In the last three decades, a lot of concerted efforts have been channeled into researching the local plants with hypotensive and antihypertensive therapeutic values. The hypotensive and antihypertensive effects of some of these medicinal plants have been validated and others disproved. However, ayurvedic knowledge needs to be coupled with modern medicine and more scientific research needs to be done to verify the effectiveness, and elucidate the safety profile of such herbal remedies for their antihypertensive potential.