Computational insights into allosteric inhibition of focal adhesion kinase: A combined pharmacophore modeling and molecular dynamics approach.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that modulates integrin and growth factor signaling pathways and is implicated in cancer cell migration, proliferation, and survival. Over the past decade various, FAK kinase, FERM, and FAT domain inhibitors have been reported and a few kinase domain inhibitors are under clinical consideration. However, few of them were identified as multikinase inhibitors.

Functional Analysis of Membrane-Associated Scaffolding Tight Junction (TJ) Proteins in Tumorigenic Characteristics of B16-F10 Mouse Melanoma Cells.

Tight junction (TJ) proteins (Tjps), Tjp1 and Tjp2, are tight junction-associated scaffold proteins that bind to the transmembrane proteins of tight junctions and the underlying cytoskeleton. In this study, we first analyzed the tumorigenic characteristics of B16-F10 melanoma cells, including cell proliferation, migration, invasion, metastatic potential, and the expression patterns of related proteins, after the CRISPR-Cas9-mediated knockout (KO) of genes. The proliferation of and KO cells significantly increased in vitro.

Revolutionizing Drug Targeting Strategies: Integrating Artificial Intelligence and Structure-Based Methods in PROTAC Development.

PROteolysis TArgeting Chimera (PROTAC) is an emerging technology in chemical biology and drug discovery. This technique facilitates the complete removal of the target proteins that are "undruggable" or challenging to target through chemical molecules via the Ubiquitin-Proteasome System (UPS). PROTACs have been widely explored and outperformed not only in cancer but also in other diseases.

Anticancer Effects of 6-Gingerol through Downregulating Iron Transport and PD-L1 Expression in Non-Small Cell Lung Cancer Cells.

Iron homeostasis is considered a key factor in human metabolism, and abrogation in the system could create adverse effects, including cancer. Moreover, 6-gingerol is a widely used bioactive phenolic compound with anticancer activity, and studies on its exact mechanisms on non-small cell lung cancer (NSCLC) cells are still undergoing. This study aimed to find the mechanism of cell death induction by 6-gingerol in NSCLC cells.

PDZ Peptide of the ZO-1 Protein Significantly Increases UTP-Induced Anti-Inflammatory Mucin Overproduction in Human Airway Epithelial Cells.

Mucus hyperproduction and hypersecretion are observed often in respiratory diseases. MUC8 is a glycoprotein synthesized by epithelial cells and generally expressed in the respiratory track. However, the physiological mechanism by which extracellular nucleotides induce gene expression in human airway epithelial cells is unclear.

Inhibition of Urban Particulate Matter-Induced Airway Inflammation by RIPK3 through the Regulation of Tight Junction Protein Production.

Urban particulate matter (UPM) is a high-hazard cause of various diseases in humans, including in the respiratory tract, skin, heart, and even brain. Unfortunately, there is no established treatment for the damage caused by UPM in the respiratory epithelium. In addition, although RIPK3 is known to induce necroptosis, its intracellular role as a negative regulator in human lungs and bronchial epithelia remains unclear.

β-Asarone Alleviates High-Glucose-Induced Oxidative Damage via Inhibition of ROS Generation and Inactivation of the NF-κB/NLRP3 Inflammasome Pathway in Human Retinal Pigment Epithelial Cells.

Diabetic retinopathy (DR) is the leading cause of vision loss and a major complication of diabetes. Hyperglycemia-induced accumulation of reactive oxygen species (ROS) is an important risk factor for DR. β-asarone, a major component of volatile oil extracted from Rhizoma, exerts antioxidant effects; however, its efficacy in DR remains unknown.

GNAQ-Regulated ZO-1 and ZO-2 Act as Tumor Suppressors by Modulating EMT Potential and Tumor-Repressive Microenvironment in Lung Cancer.

Epithelial-to-mesenchymal transition (EMT) plays a critical role in the development and progression of lung cancer by promoting its invasiveness and metastasis. Using integrative analyses of the public lung cancer database, we found that the expression levels of the tight junction proteins, zonula occluden (ZO)-1 and ZO-2, were lower in lung cancer tissues, including both lung adenocarcinoma and lung squamous cell carcinoma than in normal lung tissues analyzed using The Cancer Genome Atlas (TCGA). Although the ectopic expression or knockdown of ZO-1 and ZO-2 did not affect the growth of lung cancer cells, they significantly regulated cell migration and invasion.

Nrf2-mediated activation of HO-1 is required in the blocking effect of compound K, a ginseng saponin metabolite, against oxidative stress damage in ARPE-19 human retinal pigment epithelial cells.

Background: The beneficial effects of compound K (CK) on different chronic diseases have been shown to be at least related to antioxidant action. Nevertheless, since its antioxidant activity in human retinal pigment epithelial (RPE) cells is still unknown, here we investigated whether CK alleviates oxidative stress-stimulated damage in RPE ARPE-19 cells.

Methods: The cytoprotective consequence of CK in hydrogen peroxide (HO)-treated cells was evaluated by cell viability, DNA damage, and apoptosis assays.

Inhibition of Pseudomonas aeruginosa LPS-Induced airway inflammation by RIPK3 in human airway.

Although the physiological function of receptor-interacting protein kinase (RIPK) 3 has emerged as a critical mediator of programmed necrosis/necroptosis, the intracellular role it plays as an attenuator in human lungs and human bronchial epithelia remains unclear. Here, we show that the expression of RIPK3 dramatically decreased in the inflamed tissues of human lungs, and moved from the nucleus to the cytoplasm. The overexpression of RIPK3 dramatically increased F-actin formation and decreased the expression of genes for pro-inflammatory cytokines (IL-6 and IL-1β), but not siRNA-RIPK3.

Induction of apoptosis through inactivation of ROS-dependent PI3K/Akt signaling pathway by platycodin D in human bladder urothelial carcinoma cells.

Platycodin D (PD) is a triterpenoid saponin, a major bioactive constituent of the roots of Platycodon grandiflorum, which is well known for possessing various pharmacological properties. However, the anti-cancer mechanism of PD in bladder cancer cells remains poorly understood. In the current study, we investigated the effect of PD on the growth of human bladder urothelial carcinoma cells.

Protection against Oxidative Stress-Induced Apoptosis by Fermented Sea Tangle ( Aresch) in Osteoblastic MC3T3-E1 Cells through Activation of Nrf2 Signaling Pathway.

The purpose of the present study was to explore the efficacy of fermented extract of sea tangle ( Aresch, FST) with on DNA damage and apoptosis in hydrogen peroxide (HO)-stimulated osteoblastic MC3T3-E1 cells and clarify related signaling pathways. Our results showed that exposure to FST significantly improved cell viability, inhibited apoptosis, and suppressed the generation of reactive oxygen species (ROS) in HO-stimulated cells. In addition, HO triggered DNA damage in MC3T3-E1 cells was markedly attenuated by FST pretreatment.

Expression profiles of human endogenous retrovirus (HERV)-K and HERV-R Env proteins in various cancers.

The vertebrate genome contains an endogenous retrovirus that has been inherited from the past millions of years. Although approximately 8% of human chromosomal DNA consists of sequences derived from human endogenous retrovirus (HERV) fragments, most of the HERVs are currently inactive and noninfectious due to recombination, deletions, and mutations after insertion into the host genome. Several studies suggested that Human endogenous retroviruses (HERVs) factors are significantly related to certain cancers.

The PDZ motif peptide of ZO-1 attenuates Pseudomonas aeruginosa LPS-induced airway inflammation.

Pseudomonas aeruginosa is known to play a role in many human diseases. Therefore, examining the negative control mechanisms of tight junction protein ZO-1 on the exotoxin LPS of P. aeruginosa-induced diseases could be critical in the development of novel therapeutics.

Down-regulation of diesel particulate matter-induced airway inflammation by the PDZ motif peptide of ZO-1.

Although diesel airborne particulate matter (PM2.5) has been known to play a role in many human diseases, there is no direct evidence that therapeutic drugs or proteins can diminish PM2.5-induced diseases.

Diesel particulate matter2.5 promotes epithelial-mesenchymal transition of human retinal pigment epithelial cells via generation of reactive oxygen species.

Although several studies have linked PM (particulate matter with a diameter less than 2.5 μm) to ocular surface diseases such as keratitis and conjunctivitis, very few studies have previously addressed its effect on the retina. Therefore, the aim of this study was to evaluate the effect of PM on epithelial-mesenchymal transition (EMT), a process involved in disorders of the retinal pigment epithelial (RPE) on APRE-19 cells.

Specific bacteriophage of Bordetella bronchiseptica regulates B. bronchiseptica-induced microRNA expression profiles to decrease inflammation in swine nasal turbinate cells.

Background: Respiratory diseases in pigs are the main health concerns for swine producers. Similar to the diseases in human and other animals, respiratory diseases are primary related to morbidity and are the result of infection with bacteria, viruses, or both. B.

Pasteurella multocida specific bacteriophage suppresses P. multocida-induced inflammation: identification of genes related to bacteriophage signaling by Pasteurella multocida-infected swine nasal turbinate cells.

Background: Although Pasteurella multocida is highly prevalent pathogen in animals and plays an important role in swine respiratory diseases, only a few studies on the use of bacteriophages specific to Pasteurella multocida disease have been reported.

Objective: The object of this study was to investigate the therapeutic effect of specific P. multocida bacteriophages and to identify genes related to bacteriophage signaling utilizing RNA microarrays in swine nasal turbinate cells.

Exercise training reduces the risk of opportunistic infections after acute exercise and improves cytokine antigen recognition.

In general, acute exercise is thought to inhibit immune function and increase the risk of opportunistic infections, but there is some opposition to this due to a lack of quantitative evaluation. Therefore, we quantified the effect of exercise on immune function and observed the interaction between antigens and cytokines using an intramuscular infection with Trichinella spiralis (T. spiralis), a common parasitic infection model.

Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice.

Background/aims: Malaria is the most deadly parasitic infection in the world, resulting in damage to various organs, including the liver, of the infected organism; however, the mechanism causing this damage in the liver remains unclear. Liver fibrosis, a major characteristic of liver diseases, occurs in response to liver injury and is regulated by a complex network of signaling pathways. Hedgehog (Hh) signaling orchestrates a number of hepatic responses including hepatic fibrogenesis.

Bordetella bronchiseptica bateriophage suppresses B. bronchiseptica-induced inflammation in swine nasal turbinate cells.

The development of therapeutic bacteriophages will provide several benefits based on an understanding the basic physiological dynamics of phage and bacteria interactions for therapeutic use in light of the results of antibiotic abuse. However, studies on bacteriophage therapeutics against microbes are very limited, because of lack of phage stability and an incomplete understanding of the physiological intracellular mechanisms of phage. The major objective of this investigation was to provide opportunity for development of a novel therapeutic treatment to control respiratory diseases in swine.

Cordycepin inhibits lipopolysaccharide-induced cell migration and invasion in human colorectal carcinoma HCT-116 cells through down-regulation of prostaglandin E2 receptor EP4.

Prostaglandin E2 (PGE2), a major product of cyclooxygenase-2 (COX-2), plays an important role in the carcinogenesis of many solid tumors, including colorectal cancer. Because PGE2 functions by signaling through PGE2 receptors (EPs), which regulate tumor cell growth, invasion, and migration, there has been a growing amount of interest in the therapeutic potential of targeting EPs. In the present study, we investigated the role of EP4 on the effectiveness of cordycepin in inhibiting the migration and invasion of HCT116 human colorectal carcinoma cells.

Effect of MUC8 on Airway Inflammation: A Friend or a Foe?

In this review, we compile identifying molecular mechanisms of gene expression and studies characterizing the physiological functions of in the airway and analyzing how altered gene expression in the lung is affected by negative regulators.