Inhibits Tumor Necrosis Factor Research Articles

Shikonin Promotes Apoptosis and Attenuates Migration and Invasion of Human Esophageal Cancer Cells by Inhibiting Tumor Necrosis Factor Receptor-Associated Protein 1 Expression and AKT/mTOR Signaling Pathway.

The aim of this study was to investigate the anticancer effects of shikonin on esophageal cancer (EC) cells and explore the underlying molecular mechanism by identifying dysregulation in shikonin-induced tumor necrosis factor receptor-associated protein 1 (TRAP1) expression. The 3-(4, 5-dimethylthiazol-2-Yl)-2, 5-diphenyltetrazolium bromide assay and EDU assay were performed for cell viability determination. The reactive oxygen species level and mitochondrial membrane potential were evaluated using flow cytometry. The protein expression was detected using Western blot. In addition, cell migration and invasion were estimated. These results demonstrated that shikonin inhibited EC cell growth in a concentration-dependent manner and induced apoptosis through activation of the intracellular apoptotic signaling pathway. Moreover, TRAP1 downregulation promoted shikonin-induced reactive oxygen species release, whereas TRAP1 upregulation blocked it. Meanwhile, shikonin significantly promoted mitochondrial depolarization, accompanied by a large release of cytochrome C. Conversely, shikonin significantly decreased adenosine 5′-triphosphate release, demonstrating a significant intervention in the process of the glucose metabolism. In addition, not only shikonin but also short hairpin RNA (shRNA)-TRAP1 inhibited EC cell migration and invasion. shRNA-TRAP1 enhanced the inhibitory effect of shikonin on matrix metalloproteinase (MMP)2 and MMP9 expression. More interestingly, we demonstrated that shRNA-TRAP1 played a synergistic role in shikonin-mediated regulation of protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling. Collectively, shikonin promoted apoptosis and attenuated migration and invasion of EC cells by inhibiting TRAP1 expression and AKT/mTOR signaling, indicating that shikonin may be a new drug for treating EC.

Isopanduratin A Inhibits Tumor Necrosis Factor (TNF)-α-Induced Nuclear Factor κB Signaling Pathway by Promoting Extracellular Signal-Regulated Kinase-Dependent Ectodomain Shedding of TNF Receptor 1 in Human Lung Adenocarcinoma A549 Cells

Tumor necrosis factor α (TNF-α) induces the nuclear factor κB (NF-κB) signaling pathway via TNF receptor 1 (TNF-R1). We recently reported that isopanduratin A inhibited the TNF-α-induced NF-κB signaling pathway in human lung adenocarcinoma A549 cells. In the present study, we found that isopanduratin A did not inhibit the interleukin-1α-induced NF-κB signaling pathway in A549 cells. Isopanduratin A down-regulated the expression of TNF-R1 in these cells. We also revealed that isopanduratin A down-regulated the cell surface expression of TNF-R1 by promoting the cleavage of TNF-R1 into its soluble forms. TAPI-2, an inhibitor of TNF-α-converting enzyme, suppressed the inhibitory activity of isopanduratin A against the TNF-α-induced activation of NF-κB. The mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase inhibitor U0126, but not the p38 MAP kinase inhibitor SB203580, blocked the ectodomain shedding of TNF-R1 induced by isopanduratin A. Consistent with this result, isopanduratin A induced the rapid phosphorylation of ERK, but not p38 MAP kinase. Isopanduratin A also promoted the phosphorylation of eukaryotic initiation factor 2α (eIF2α). The present results indicate that isopanduratin A inhibits TNF-α-induced NF-κB signaling pathway by promoting ERK-dependent ectodomain shedding of cell surface TNF-R1, and also decreases cellular TNF-R1 levels through the phosphorylation of eIF2α in A549 cells.

3-(3-Hydroxyphenyl)propionic acid, a microbial metabolite of quercetin, inhibits monocyte binding to endothelial cells via modulating E-selectin expression

Adhesion of monocytes to endothelial cells is an important initiating step in atherogenesis. One of the most abundant flavonoids in the diet, quercetin has been reported to inhibit monocyte adhesion to endothelial cells. However, it is poorly absorbed in the upper gastrointestinal tract during oral intake but rather is metabolized by the intestinal microbiota into various phenolic acids. Since the biological properties of the microbial metabolites of quercetin remain largely unknown, herein, we investigated how the microbial metabolite of quercetin, 3-(3-hydroxyphenyl)propionic acid (3HPPA) impact monocyte adhesion to endothelial cells. Direct treatment with 3HPPA for 24 h was not cytotoxic to human aortic endothelial cells (HAECs). Cotreatment with 3HPPA inhibited tumor necrosis factor α (TNFα)-induced adhesion of THP-1 monocytes to HAECs, and suppressed the upregulation of cell adhesion molecule E-selectin but not intercellular adhesion molecule 1 or vascular cell adhesion molecule 1. Furthermore, 3HPPA was found to inhibit TNFα-induced nuclear translocation and phosphorylation of the p65 subunit of nuclear factor κB (NF-κB). We conclude that 3HPPA mitigates the adhesion of monocytes to endothelial cells by suppressing the expression of the cell adhesion molecule E-selectin in HAECs via inhibition of the NF-κB pathway, providing additional evidence for the health benefits of dietary flavonoids and their microbial metabolites as therapeutic agents in atherosclerosis.

Transcriptional landscape associated with TNBC resistance to neoadjuvant chemotherapy revealed by single-cell RNA-seq

Triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy (NAC) represents a major clinical challenge; therefore, delineating tumor heterogeneity can provide novel insight into resistance mechanisms and potential therapeutic targets. Herein, we identified the transcriptional landscape associated with TNBC resistance to NAC at the single-cell level by analyzing publicly available transcriptome data from more than 5,000 single cells derived from four extinction (responders) and four persistence (non-responders) patients, revealing remarkable tumor heterogeneity. Employing iterative clustering and guide-gene selection (ICGS) and uniform manifold approximation and projection (UMAP), we classified TNBC single cells into several clusters based on their distinct gene signatures. The presence of clusters indicative of immune cell activation was a hallmark of the extinction group pre-NAC, while post NAC, the extinction tissue consisted mostly of breast, omental fat, and fibroblasts. The persistent gene signatures of pre-NAC resembled the gene signature of lung epithelial, mammary, and salivary glands and acute myeloid leukemia blast cells, which were associated with enhanced cellular movement and activation of FOXM1, NOTCH1, and MYC and suppression of tumor necrosis factor (TNF) and IFNG mechanistic networks. Multivariate survival analysis identified persistence-derived three-gene signature (KIF5BhighHLA-ClowIGHG2low) predictive of relapse-free survival (hazard ratio [HR]: 2.2 [1.6–3.2, p < 0.0001]) in a second cohort of 360 TNBC patients. Mechanistically, loss of function of several upregulated genes in the persistent group (BYSL, FDPS, ENO1, MED20, MRPL9, MRPL37, NDUFB11, PMVK, MYC, and GSTP1) inhibited MDA-MB-231 and BT-549 TNBC models’ colony-forming unit (CFU) potential and enhanced their sensitivity to paclitaxel. Our data unraveled the transcriptional portrait associated with NAC resistance, identified several key genes, and suggested their potential utilization as prognostic markers and therapeutic targets in TNBC.

Adiponectin associates with VO2peak after exercise in patients with cad and type 2 diabetes

Background and Aims: Introduction: Adipokines, expressed by adipose tissue, have been associated with metabolic disturbances and coronary artery disease. Adiponectin has anti-atherogenic and anti-diabetic properties, by inhibiting tumor necrosis factor (TNF)-α. Elevated levels of visfatin and TNF-α are associated with atherosclerosis. Aim: Investigate effects of long-term exercise on circulating levels and adipose tissue expression of adiponectin, visfatin and TNF-α, and explore associations between adiponectin and physical performance, assessed by VO2peak, and glucometabolic variables.

17,18-Epoxyeicosatetraenoic Acid Inhibits TNF-α-Induced Inflammation in Cultured Human Airway Epithelium and LPS-Induced Murine Airway Inflammation.

17,18-Epoxyeicosatetraenoic acid (17,18-EpETE), an eicosapentaenoic acid metabolite, is generated from dietary oil in the gut, and antiinflammatory activity of 17,18-EpETE was recently reported. To evaluate the inhibitory effects of 17,18-EpETE in airway inflammation, we examined in vitro and in vivo effects on mucus production, neutrophil infiltration, and cytokine/chemokine production in airway epithelium. Nasal tissue localization of G protein-coupled receptor 40 (GPR40), a receptor of 17,18-EpETE, was determined by immunohistochemical staining. Expression of GPR40 mRNA in nasal mucosa of chronic rhinosinusitis (CRS) patients and control subjects was determined by reverse transcription-polymerase chain reaction (RT-PCR). The in vitro effects on airway epithelial cells were examined using normal human bronchial epithelial cells and NCI-H292 cells. To examine the in vivo effects of 17,18-EpETE on airway inflammation, we induced goblet cell metaplasia, mucus production, and neutrophil infiltration in mouse nasal epithelium by intranasal lipopolysaccharide (LPS) instillation. GPR40 is mainly expressed in human nasal epithelial cells and submucosal gland cells. RT-PCR analysis revealed that the expression of GPR40 mRNA was increased in nasal tissues from CRS patients compared with those from control subjects. 17,18-EpETE significantly inhibited tumor necrosis factor (TNF)-α-induced production of interleukin (IL)-6 , IL-8, and mucin from cultured human airway epithelial cells dose dependently, and these antiinflammatory effects on cytokine production were abolished by GW1100, a selective GPR40 antagonist. Intraperitoneal injection or intranasal instillation of 17,18-EpETE significantly attenuated LPS-induced mucus production and neutrophil infiltration in mouse nasal epithelium. Inflammatory cytokine/chemokine production in lung tissues and bronchoalveolar lavage fluids was also inhibited. These results indicate that 17,18-EpETE plays a regulatory role in mucus hypersecretion and neutrophil infiltration in nasal inflammation. Local or systemic administration may provide a new therapeutic approach for the treatment of intractable airway disease such as CRS.

Inhibition of Lipid Accumulation and Cyclooxygenase-2 Expression in Differentiating 3T3-L1 Preadipocytes by Pazopanib, a Multikinase Inhibitor.

Pazopanib is a multikinase inhibitor with anti-tumor activity. As of now, the anti-obesity effect and mode of action of pazopanib are unknown. In this study, we investigated the effects of pazopanib on lipid accumulation, lipolysis, and expression of inflammatory cyclooxygenase (COX)-2 in differentiating and differentiated 3T3-L1 cells, a murine preadipocyte. Of note, pazopanib at 10 µM markedly decreased lipid accumulation and triglyceride (TG) content during 3T3-L1 preadipocyte differentiation with no cytotoxicity. Furthermore, pazopanib inhibited not only expression of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), and perilipin A but also phosphorylation of signal transducer and activator of transcription (STAT)-3 during 3T3-L1 preadipocyte differentiation. In addition, pazopanib treatment increased phosphorylation of cAMP-activated protein kinase (AMPK) and its downstream effector ACC during 3T3-L1 preadipocyte differentiation. However, in differentiated 3T3-L1 adipocytes, pazopanib treatment did not stimulate glycerol release and hormone-sensitive lipase (HSL) phosphorylation, hallmarks of lipolysis. Moreover, pazopanib could inhibit tumor necrosis factor (TNF)-α-induced expression of COX-2 in both 3T3-L1 preadipocytes and differentiated cells. In summary, this is the first report that pazopanib has strong anti-adipogenic and anti-inflammatory effects in 3T3-L1 cells, which are mediated through regulation of the expression and phosphorylation of C/EBP-α, PPAR-γ, STAT-3, ACC, perilipin A, AMPK, and COX-2.

KATP Opener Attenuates Diabetic-Induced Müller Gliosis and Inflammation by Modulating Kir6.1 in Microglia.

PurposeThis study aimed to determine the effect of pinacidil, a nonselective KATP channel opener, on diabetes-induced retinal gliosis and inflammation.MethodsPrimary and immortalized cell lines of retinal microglia and Müller cells were used to set up a coculture model. In the trans-well system, microglia were seeded in the upper chamber and Müller cells in the bottom chamber. Microglia were polarized into proinflammatory (M1, with lipopolysaccharide and INF-γ) with or without different pinacidil concentrations before coculturing with Müller cells. The expression of inflammatory or anti-inflammatory genes and protein in microglia, and the expression of glial fibrillary acidic protein (GFAP), Kir4.1, and AQP4 in Müller cells were examined by real-time polymerase chain reaction and Western blot. Pinacidil was injected intravitreally into streptozotocin-induced diabetic rats. Retinal gliosis and inflammation were examined by immunohistochemistry and Western blot.ResultsIntravitreal injection of pinacidil alleviated diabetes-induced Müller cell gliosis and microglial activation and reduced vascular endothelial growth factor expression. In vitro study demonstrated that pinacidil inhibited tumor necrosis factor and interleukin-1β expression in M1-type microglia and alleviated the M1 microglia-induced GFAP expression in the Müller cells. Furthermore, we found that pinacidil on its own, or in combination with IL-4, can upregulate arginase-1 (Arg-1) and Kir6.1 expression in microglial cells.ConclusionsOur results suggest that potassium channels are critically involved in diabetes-induced gliosis and microglial activation. The KATP opener, pinacidil, can reduce microglial activation by upregulating Kir6.1 expression.

Qualitative and quantitative determination of ligustilide as bioactive marker in apiaceous botanicals

Variety of bioactivities has been associated with ligustilide present in root of Angelica sinensis, and predominantly used for the treatment of irregular menstrual cycles and premenstrual syndrome. Recent pharmacological studies showed that medicinal plants containing ligustilide, have anti-inflammatory effects and contribute to the improvement of cognitive functions, alleviate brain damage, inhibit tumor necrosis factor of some cell lines, and have nephron-protective effects and neuroprotective activity. In this work, quantification of ligustilide using quantitative 1H NMR (qHNMR) in sealed tubes was performed. Four plant species were investigated: A. sinensis, Ligusticum porteri, Ligusticum striatum, andLigusticum sinense. Modified supercritical CO2 extraction of essential oil from root of four investigated species, was performed. qHNMR spectroscopy showed following percentage of ligustilide: L. porteri essential oil 3.74 (%); L. sinense essential oil 1.16 (%); L. striatum essential oil 6.61 (%) and A. sinensis essential oil 14.56 (%). The highest percentage of oil was obtained from the root of L. porteri but the highest percentage of ligustilide was obtained from A. sinensis essential oil.

Identification of a brainstem locus that inhibits tumor necrosis factor

In the brain, compact clusters of neuron cell bodies, termed nuclei, are essential for maintaining parameters of host physiology within a narrow range optimal for health. Neurons residing in the brainstem dorsal motor nucleus (DMN) project in the vagus nerve to communicate with the lungs, liver, gastrointestinal tract, and other organs. Vagus nerve-mediated reflexes also control immune system responses to infection and injury by inhibiting the production of tumor necrosis factor (TNF) and other cytokines in the spleen, although the function of DMN neurons in regulating TNF release is not known. Here, optogenetics and functional mapping reveal cholinergic neurons in the DMN, which project to the celiac-superior mesenteric ganglia, significantly increase splenic nerve activity and inhibit TNF production. Efferent vagus nerve fibers terminating in the celiac-superior mesenteric ganglia form varicose-like structures surrounding individual nerve cell bodies innervating the spleen. Selective optogenetic activation of DMN cholinergic neurons or electrical activation of the cervical vagus nerve evokes action potentials in the splenic nerve. Pharmacological blockade and surgical transection of the vagus nerve inhibit vagus nerve-evoked splenic nerve responses. These results indicate that cholinergic neurons residing in the brainstem DMN control TNF production, revealing a role for brainstem coordination of immunity.

MicroRNA-133a-Dependent Inhibition of Proximal Tubule Angiotensinogen by Renal TNF (Tumor Necrosis Factor).

We showed that intrarenal suppression of TNF (tumor necrosis factor) production under low salt (LS) conditions increases renal cortical AGT (angiotensinogen) mRNA and protein expression. Intrarenal injection of murine recombinant TNF attenuated increases of AGT in mice ingesting LS. Moreover, AGT mRNA and protein expression increased ≈6-fold and 2-fold, respectively, in mice ingesting LS that also received an intrarenal injection of a lentivirus construct that specifically silenced TNF in the kidney (U6-TNF-ex4). Silencing of TNF under normal salt and high salt (HS) conditions also resulted in increased AGT expression. Since renal TNF production decreases in response to LS and increases in response to HS, the data suggest that alterations in TNF production under these conditions modulate the degree of AGT expression. We also tested the hypothesis that TNF inhibits intrarenal AGT expression by a mechanism involving miR-133a. Expression of miR-133a decreased in mice given LS and increased in response to HS for 7 days. Intrarenal silencing of TNF reversed the effects of HS on miR-133a-dependent AGT expression. In contrast, intrarenal TNF administration increased miR-133a expression in the kidney. Collectively, the data suggest that miR-133a is a salt-sensitive microRNA that inhibits AGT in the kidney and is increased by TNF. The HS-induced increase in blood pressure observed following silencing of TNF was markedly reduced upon intrarenal administration of miR-133a suggesting that intrinsic effects of TNF in the kidney to limit the blood pressure response to HS include an increase in miR-133a, which suppresses AGT expression.

PMSA prevents osteoclastogenesis and estrogen-dependent bone loss in mice.

Excessive bone resorption mediated by mature osteoclasts can cause osteoporosis, leading to fragility fractures. Therefore, an effective therapeutic strategy for anti-osteoporosis drugs is the reduction of osteoclast activity. In this study, the osteoclast inhibitory activity of a novel compound, N-phenyl-methylsulfonamido-acetamide (PMSA), was examined. PMSA treatment inhibited receptor activator of nuclear factor kappa B ligand (RNAKL)-induced osteoclast differentiation in bone marrow-derived macrophage cells (BMMs). We investigated two PMSAs, N-2-(3-acetylphenyl)-N-2-(methylsulfonyl)-N-1-[2-(phenylthio)phenyl] glycinamide (PMSA-3-Ac), and N-2-(5-chloro-2-methoxyphenyl)-N-2-(methylsulfonyl)-N-1-[2-(phenylthio)phenyl]glycinamide (PMSA-5-Cl), to determine their effects on osteoclast differentiation. PMSAs inhibited the signaling pathways at the early stage. PMSA-3-Ac inhibited tumor necrosis factor receptor-associated factor 6 (TRAF6) expression, whereas PMSA-5-Cl suppressed the mitogen-activated protein kinase (MAPK) signaling pathways. However, both PMSAs inhibited the master transcription factor, nuclear factor of activated T cell cytoplasmic-1 (NFATc1), by blocking nuclear localization. An in vivo study of PMSAs was performed in an ovariectomized (OVX) mouse model, and PMSA-5-Cl prevented bone loss in OVX mice. Therefore, our results suggested that PMSAs, specifically PMSA-5-Cl, may serve as a potential therapeutic agent for postmenopausal osteoporosis.

Zinc Finger Protein ZBTB20 protects against cardiac remodelling post-myocardial infarction via ROS-TNFα/ASK1/JNK pathway regulation.

This study aims to determine the efficacy of Zinc finger protein ZBTB20 in treatment of post‐infarction cardiac remodelling. For this purpose, left anterior descending (LAD) ligation was operated on mice to induce myocardial infarction (MI) with sham control group as contrast and adeno‐associated virus (AAV9) system was used to deliver ZBTB20 to mouse heart by myocardial injection with vehicle‐injected control group as contrast two weeks before MI surgery. Then four weeks after MI, vehicle‐treated mice with left ventricular (LV) remodelling underwent deterioration of cardiac function, with symptoms of hypertrophy, interstitial fibrosis, inflammation and apoptosis. The vehicle‐injected mice also showed increase of infarct size and decrease of survival rate. Meanwhile, the ZBTB20‐overexpressed mice displayed improvement after MI. Moreover, the anti‐apoptosis effect of ZBTB20 was further confirmed in H9c2 cells subjected to hypoxia in vitro. Further study suggested that ZBTB20 exerts cardioprotection by inhibiting tumour necrosis factor α/apoptosis signal‐regulating kinase 1 (ASK1)/c‐Jun N‐terminal kinase 1/2 (JNK1/2) signalling, which was confirmed by shRNA‐JNK adenoviruses transfection or a JNK activator in vitro as well as ASK1 overexpression in vivo. In summary, our data suggest that ZBTB20 could alleviate cardiac remodelling post‐MI. Thus, administration of ZBTB20 can be considered as a promising treatment strategy for heart failure post‐MI.Significance Statement: ZBTB20 could alleviate cardiac remodelling post‐MI via inhibition of ASK1/JNK1/2 signalling.

Ulinastatin attenuates protamine-induced cardiotoxicity in rats by inhibiting tumor necrosis factor alpha.

Protamine causes cardiac depression, which may be mediated by tumor necrosis factor alpha (TNF-α). Ulinastatin, a human urinary protease inhibitor, inhibits TNF-α. Here, we aimed to investigate whether ulinastatin prevented protamine-induced myocardial depression by inhibiting TNF-α. Rat hearts were perfused using a Langendorff system, and three protocols were followed. Protocol 1: The hearts were divided into saline, ulinastatin-low, and ulinastatin-high groups. Protamine was administered to each group, and myocardial contractility was the primary outcome. Protocol 2: The hearts were allotted to saline or ulinastatin group. Protamine was administered to each group. TNF-α expression in the coronary effluent and myocardial tissue was measured. Protocol 3: The hearts were allotted to saline and ulinastatin groups. Recombinant rat-TNF-α was administered to each group. Protamine alone reduced the maximum left ventricular pressure derivative (LV dP/dt max) by 45 ± 4%. In contrast, the reduction in LV dP/dt max was 4 ± 3% in the ulinastatin-high group. Compared with that in the saline group, the increase in TNF-α in the coronary effluent was attenuated in the ulinastatin group. Recombinant TNF-α alone reduced LV dP/dt max (- 21 ± 14%). In contrast, when TNF-α was added in the presence of ulinastatin, the decrease in LV dP/dt max was prevented significantly (- 3 ± 8%). We showed, for the first time, that ulinastatin protected against protamine-induced myocardial damage, both by inhibiting TNF-α synthesis and by directly preventing the cardiodepressant action of TNF-α.

Quercetin inhibits TNF-α induced HUVECs apoptosis and inflammation via downregulating NF-kB and AP-1 signaling pathway in vitro.

Background:Quercetin, a major flavonol, wildly exists in plantage, which has been reported to have an anti-apoptosis and anti-inflammation effects on vascular endothelial cells, but its underlying molecular mechanisms remain unclear.Objective:The aim of this study was to investigate the mechanisms of how quercetin inhibits tumor necrosis factor alpha (TNF-α) induced human umbilical vein endothelial cells (HUVECs) apoptosis and inflammation.Methods and Results:HUVECs were preconditioned with quercetin for 18 hours, and subsequently treated with TNF-α for 6 hours to induce apoptosis. The expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin, β-actin mRNA was then detected by RT-PCR. Flow cytometry was used to estimate the apoptosis rates, and the expression of activator protein 1 (AP-1) and nuclear factor kappa B (NF-κB) was measured by Western blot. TNF-α induced elevated apoptosis rates and upregulation of VCAM-1, ICAM-1, and E-selectin were meaningfully reduced in HUVECs by pretreatment with quercetin. In addition, quercetin also inhibited the activation of AP-1and NF-κB.Conclusion:Results indicate that quercetin could suppress TNF-α induced apoptosis and inflammation by blocking NF-κB and AP-1 signaling pathway in HUVECs, which might be one of the underlying mechanisms in treatment of coronary heart disease.

Structure-Activity relationship of Quercetin and its Tumor Necrosis Factor Alpha inhibition activity by computational and machine learning methods

The Tumor Necrosis Factor Alpha is a pro inflammatory cytokine responsible for mediating inflammation. Tumor Necrosis Factor alpha inhibitors can be used to treat arthritis and inflammatory neurological disorders. The Tumor Necrosis Factor alpha inhibitory ability of Quercetin and its Structure-Activity relationship study was carried out using computational and machine learning based methods. The ability of Quercetin to inhibit Tumor Necrosis Factor alpha was modelled In Silico using molecular dynamics simulation and the protein–ligand complex formation was studied. The binding affinity of protein and ligand was estimated using AutoDock. The likeliness of Quercetin being orally active drug in humans was estimated using the Lipinski’s rule. The charge transfer interactions responsible for the bio-activeness of Quercetin were studies through NBO calculations. The reactive sites of Quercetin were studied through MEP and ELF calculations. The Quantitative Structure Activity relationship studies were carried out using machine learning QSAR python package, PyQSAR. From the Quantitative Structure-Activity Relationship it can be understood that chemical potential should be more positive and Electrophilicity index be more negative for better Tumor Necrosis Factor-Alpha inhibitory activity for Quercetin and it’s structurally alike flavonoids.

Synthesis and Biological Activity of New 7-Amino-oxazolo[5,4-d]Pyrimidine Derivatives.

The synthesis of a series of novel 7-aminooxazolo[5,4-d]pyrimidines 5, transformations during their synthesis and their physicochemical characteristics have been described. Complete detailed spectral analysis of the intermediates 2–4, the N′-cyanooxazolylacetamidine by-products 7 and final compounds 5 has been carried out using MS, IR, 1D and 2D NMR spectroscopy. Theoretical research was carried out to explain the privileged formation of 7-aminooxazolo[5,4-d]pyrimidines in relation to the possibility of their isomer formation and the related thermodynamic aspects. Additionally, the single-crystal X-ray diffraction analysis for 5h was reported. Ten 7-aminooxazolo[5,4-d]pyrimidines 5 (SCM1–10) were biologically tested in vitro to preliminarily evaluate their immunological, antiviral and anticancer activity. Compounds SCM5 and SCM9 showed the best immunoregulatory profile. The compounds displayed low-toxicity and strongly inhibited phytohemagglutinin A-induced proliferation of human peripheral blood lymphocytes and lipopolysaccharide-induced proliferation of mouse splenocytes. Compound SCM9 caused also a moderate suppression of tumor necrosis factor α (TNF-α) production in a human whole blood culture. Of note, the compounds also inhibited the growth of selected tumor cell lines and inhibited replication of human herpes virus type-1 (HHV-1) virus in A-549 cell line. Molecular investigations showed that the compounds exerted differential changes in expression of signaling proteins in Jurkat and WEHI-231 cell lines. The activity of SCM5 is likely associated with elicitation of cell signaling pathways leading to cell apoptosis. The compounds may be of interest in terms of therapeutic utility as inhibitors of autoimmune disorders, virus replication and antitumor agents.

A Novel Synthetic Compound (E)-5-((4-oxo-4H-chromen-3-yl)methyleneamino)-1-phenyl-1H-pyrazole-4-carbonitrile Inhibits TNFα-Induced MMP9 Expression via EGR-1 Downregulation in MDA-MB-231 Human Breast Cancer Cells.

Breast cancer is a common malignancy among women worldwide. Gelatinases such as matrix metallopeptidase 2 (MMP2) and MMP9 play crucial roles in cancer cell migration, invasion, and metastasis. To develop a novel platform compound, we synthesized a flavonoid derivative, (E)-5-((4-oxo-4H-chromen-3-yl)methyleneamino)-1-phenyl-1H-pyrazole-4-carbonitrile (named DK4023) and characterized its inhibitory effects on the motility and MMP2 and MMP9 expression of highly metastatic MDA-MB-231 breast cancer cells. We found that DK4023 inhibited tumor necrosis factor alpha (TNFα)-induced motility and F-actin formation of MDA-MB-231 cells. DK4023 also suppressed the TNFα-induced mRNA expression of MMP9 through the downregulation of the TNFα-extracellular signal-regulated kinase (ERK)/early growth response 1 (EGR-1) signaling axis. These results suggest that DK4023 could serve as a potential platform compound for the development of novel chemopreventive/chemotherapeutic agents against invasive breast cancer.

CE: The Effects of Smoking on Bone Health and Healing.

The number of orthopedic surgeries performed in the United States has increased substantially over the past several years. The most recent data available from the Agency for Healthcare Research and Quality indicate that five of the 10 operative procedures most commonly performed during inpatient stays involve the musculoskeletal system. Cigarette smoking is one of the most prevalent and preventable risk factors for musculoskeletal disorders and orthopedic surgery complications. This article discusses the effects of smoking on bone health, the importance of smoking cessation among patients scheduled for or recovering from orthopedic surgery, and the vital role nurses play in supporting patient efforts to lead a tobacco-free life.

Transcutaneous Stimulation of Auricular Branch of the Vagus Nerve Attenuates the Acute Inflammatory Response After Lung Lobectomy.

Systemic inflammation is a potentially debilitating complication of thoracic surgeries with significant physical and economic morbidity. There is compelling evidence for the role of thecentral nervous system inregulating inflammatory processes through humoral mechanisms. Activation of theafferent vagus nerve by cytokines triggers anti-inflammatory responses. Peripheral electrical stimulation of the vagus nerve in vivo during lethal endotoxemia in rats inhibited tumor necrosis factor synthesis and prevented shock development. However, the vagal regulatory role of systemic inflammation after lung lobectomy is unknown. One hundred patients who underwent lobectomy via thoracotomy were recruited and equally randomized to treated group or controls. Intermittent stimulation of the auricular branch of vagus nerve in the triangular fossa was applied in the treated group using neurostimulator V (Ducest®, Germany), starting 24h preoperatively and continued till the 4th postoperative day (POD). Inflammatory interleukins (IL) were analyzed using ELISA preoperatively, on the 1st and 4th POD. On the 1st POD, patients who underwent neurostimulation had reduced serum concentrations of CRP (p = 0.01), IL6 (p = 0.02) but elevated IL10 (p = 0.03) versus controls. On the 4th POD, serum concentrations of CRP, IL6 and IL10 were similar in both groups. Moreover, the treated group was associated with lower incidence of pneumonia (p = 0.04) and shorter hospitalization time (p = 0.04) versus controls. Modulations in the brain stem caused by noninvasive transcutaneous stimulation of the vagus nerve after lung lobectomy attenuate the acute postsurgical inflammatory response by the regulation of IL6 and IL10, resultingin reduced incidence of postoperative pneumonia and short hospitalization time. NCT03204968.