Lysionotin exerts antinociceptive effects in various models of nociception induction

Background: Lysionotin, a natural flavonoid extracted from Lysionotus pauciflorus Maxim (Gesneriaceae), has several pharmacological effects including anti-bacterial, anti-hypertensive and anti-inflammatory effects. However, its analgesic effect has not been investigated. This study aimed to assess the antinociceptive activity of lysionotin using chemically and thermally induced nociception in a mouse model. Methods: The antinociceptive effects of various lysionotin doses (50, 100, 150, and 200 μg/kg) were assessed in mice using the acetic acid-induced writhing test, hot plate test, and formalin-induced paw licking assay. The effects were compared to those of mice treated with acetylsalicylic acid or morphine in the presence or absence of naloxone (an opioid receptor antagonist). Capsaicin- and glutamate-induced paw licking tests were also used to evaluate the involvement of the vanilloid and glutamatergic systems, respectively. Results: Lysionotin produced significant dose-dependent inhibition of nociceptive behavior in the acetic acid-induced writhing test, showing 60% inhibition at a dose of 200 μg/kg. Lysionotin also caused a significant increase in the latency period in response to the hot plate test (76.4% at 200 μg/kg), and significantly inhibited both the neurogenic and inflammatory phases in the formalin-induced paw licking test. Naloxone significantly reverses the effect of lysionotin in both hot plate test and formalin-induced paw licking test. Moreover, lysionotin significantly inhibited the neurogenic nociception induced by intraplantar injections of glutamate and capsaicin (57% and 67.2%, respectively at a dose of 200 μg/kg). Thus, lysionotin exhibited peripheral and central antinociception through the modulation of vanilloid receptors, opioid receptors, and the glutamatergic system. Conclusion: Lysionotin possesses antinociceptive activity on adult mice that is mediated through both central and peripheral pathways

Insights into the Molecular Mechanisms Mediating Extravasation in Brain Metastasis of Breast Cancer, Melanoma, and Lung Cancer

Brain metastasis is an incurable end-stage of systemic cancer associated with poor prognosis, and its incidence is increasing. Brain metastasis occurs through a multi-step cascade where cancer cells spread from the primary tumor site to the brain. The extravasation of tumor cells through the blood–brain barrier (BBB) is a critical step in brain metastasis. During extravasation, circulating cancer cells roll along the brain endothelium (BE), adhere to it, then induce alterations in the endothelial barrier to transmigrate through the BBB and enter the brain. Rolling and adhesion are generally mediated by selectins and adhesion molecules induced by inflammatory mediators, while alterations in the endothelial barrier are mediated by proteolytic enzymes, including matrix metalloproteinase, and the transmigration step mediated by factors, including chemokines. However, the molecular mechanisms mediating extravasation are not yet fully understood. A better understanding of these mechanisms is essential as it may serve as the basis for the development of therapeutic strategies for the prevention or treatment of brain metastases. In this review, we summarize the molecular events that occur during the extravasation of cancer cells through the blood–brain barrier in three types of cancer most likely to develop brain metastasis: breast cancer, melanoma, and lung cancer. Common molecular mechanisms driving extravasation in these different tumors are discussed

The Relationship Between Mobile Marketing and Customer Perceptions in Jordanian Commercial Banks: The Electronic Quality as A Mediator Variable

This study aims to investigate the factors influencing customer perceptions of Jordanian commercial banks, with a specific focus on the moderating role of electronic quality in mobile marketing. A comprehensive literature review was conducted, leading to the development of a research framework illustrating the research case. The theoretical foundation of this study is grounded in the concept of perceived attributes, which identifies five key factors affecting the rate of adoption. The empirical findings of this research, based on a sample of 400 respondents (N = 400), are presented. The analyses were performed using the statistical technique of Partial Least Squares Structural Equation Modeling (PLS-SEM). The reporting style adheres to the widely accepted practices in PLS-SEM analysis. The findings highlight a significant and robust relationship between mobile marketing and customer perceptions within the context of Jordanian commercial banks, particularly when electronic quality is employed as a moderator variable. Based on these results, we recommend that Jordanian commercial banks strategically integrate electronic quality into their digital marketing operations, with a specific emphasis on mobile marketing. &nbsp

Isorhamnetin Reduces Glucose Level, Inflammation, and Oxidative Stress in High-Fat Diet/Streptozotocin Diabetic Mice Model

Background: Isorhamnetin is a flavonoid that is found in medical plants. Several studies showed that isorhamnetin has anti-inflammatory and anti-obesity effects. This study aims to investigate the anti-diabetic effects of isorhamnetin in a high-fat diet and Streptozotocin-(HFD/STZ)-induced mice model of type 2 diabetes. Materials and Methods: Mice were fed with HFD followed by two consecutive low doses of STZ (40 mg/kg). HFD/STZ diabetic mice were treated orally with isorhamnetin (10 mg/kg) or (200 mg/kg) metformin for 10 days before sacrificing the mice and collecting plasma and soleus muscle for further analysis. Results: Isorhamnetin reduced the elevated levels of serum glucose compared to the vehicle control group (p p p p > 0.01). LDL, triglyceride, and cholesterol were reduced in diabetic mice treated with isorhamnetin compared to vehicle control (p p p p < 0.05) in diabetic mice compared to vehicle control. Conclusions: Isorhamnetin ameliorates insulin resistance, oxidative stress, and inflammation. Isorhamnetin could represent a promising therapeutic agent to treat T2D

Tumor Derived Mutations of Protein Tyrosine Phosphatase Receptor Type K Affect Its Function and Alter Sensitivity to Chemotherapeutics in Glioma

<div><p>Poor prognosis and resistance to therapy in malignant gliomas is mainly due to the highly dispersive nature of glioma cells. This dispersive characteristic results from genetic alterations in key regulators of cell migration and diffusion. A better understanding of these regulatory signals holds promise to improve overall survival and response to therapy. Using mapping arrays to screen for genomic alterations in gliomas, we recently identified alterations of the protein tyrosine phosphatase receptor type kappa gene (PTPRK) that correlate to patient outcomes. These PTPRK alterations are very relevant to glioma biology as PTPRK can directly sense cell–cell contact and is a dephosphorylation regulator of tyrosine phosphorylation signaling, which is a major driving force behind tumor development and progression. Subsequent sequencing of the full length PTPRK transcripts revealed novel PTPRK gene deletion and missense mutations in numerous glioma biopsies. PTPRK mutations were cloned and expressed in PTPRK-null malignant glioma cells. The effect of these mutations on PTPRK anti-oncogenic function and their association with response to anti-glioma therapeutics, such as temozolomide and tyrosine kinase inhibitors, was subsequently analyzed using <i>in vitro</i> cell-based assays. These genetic variations altered PTPRK activity and its post-translational processing. Reconstitution of wild-type PTPRK in malignant glioma cell lines suppressed cell growth and migration by inhibiting EGFR and β-catenin signaling and improved the effect of conventional therapies for glioma. However, PTPRK mutations abrogated tumor suppressive effects of wild-type PTPRK and altered sensitivity of glioma cells to chemotherapy.</p></div

NOTCH3 Is a Prognostic Factor That Promotes Glioma Cell Proliferation, Migration and Invasion via Activation of CCND1 and EGFR

<div><p>Using a GWA analysis of a comprehensive glioma specimen population, we identified whole gain of chromosome 19 as one of the major chromosomal aberrations that correlates to patients’ outcomes. Our analysis of significant loci revealed for the first time NOTCH3 as one of the most significant amplification. NOTCH3 amplification is associated with worse outcome compared to tumors with non-amplified locus. NOTCH receptors (NOTCH1-4) are key positive regulators of cell-cell interactions, angiogenesis, cell adhesion and stem cell niche development which have been shown to play critical roles in several human cancers. Our objective is to determine the molecular roles of NOTCH3 in glioma pathogenesis and aggressiveness. Here we show for the first time that NOTCH3 plays a major role in glioma cell proliferation, cell migration, invasion and apoptosis. Therefore, our study uncovers the prognostic value and the oncogenic function of NOTCH3 in gliomagenesis and supports NOTCH3 as a promising target of therapy in high grade glioma. Our studies allowed the identification of a subset of population that may benefit from GSI- or anti-NOTCH3- based therapies. This may lead to the design of novel strategies to improve therapeutic outcome of patients with glioma by establishing medical and scientific basis for personalized chemotherapies.</p></div

Evaluation of Two Simultaneous Metabolomic and Proteomic Extraction Protocols Assessed by Ultra-High-Performance Liquid Chromatography Tandem Mass Spectrometry

Untargeted multi-omics analysis of plasma is an emerging tool for the identification of novel biomarkers for evaluating disease prognosis, and for developing a better understanding of molecular mechanisms underlying human disease. The successful application of metabolomic and proteomic approaches relies on reproducibly quantifying a wide range of metabolites and proteins. Herein, we report the results of untargeted metabolomic and proteomic analyses from blood plasma samples following analyte extraction by two frequently-used solvent systems: chloroform/methanol and methanol-only. Whole blood samples were collected from participants (n = 6) at University Hospital Sharjah (UHS) hospital, then plasma was separated and extracted by two methods: (i) methanol precipitation and (ii) 4:3 methanol:chloroform extraction. The coverage and reproducibility of the two methods were assessed by ultra-high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS). The study revealed that metabolite extraction by methanol-only showed greater reproducibility for both metabolomic and proteomic quantifications than did methanol/chloroform, while yielding similar peptide coverage. However, coverage of extracted metabolites was higher with the methanol/chloroform precipitation

Skin Cancer Metabolic Profile Assessed by Different Analytical Platforms

Skin cancer, including malignant melanoma (MM) and keratinocyte carcinoma (KC), historically named non-melanoma skin cancers (NMSC), represents the most common type of cancer among the white skin population. Despite decades of clinical research, the incidence rate of melanoma is increasing globally. Therefore, a better understanding of disease pathogenesis and resistance mechanisms is considered vital to accomplish early diagnosis and satisfactory control. The “Omics” field has recently gained attention, as it can help in identifying and exploring metabolites and metabolic pathways that assist cancer cells in proliferation, which can be further utilized to improve the diagnosis and treatment of skin cancer. Although skin tissues contain diverse metabolic enzymes, it remains challenging to fully characterize these metabolites. Metabolomics is a powerful omics technique that allows us to measure and compare a vast array of metabolites in a biological sample. This technology enables us to study the dermal metabolic effects and get a clear explanation of the pathogenesis of skin diseases. The purpose of this literature review is to illustrate how metabolomics technology can be used to evaluate the metabolic profile of human skin cancer, using a variety of analytical platforms including gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), and nuclear magnetic resonance (NMR). Data collection has not been based on any analytical method

Preclinical and Clinical Applications of Metabolomics and Proteomics in Glioblastoma Research

Glioblastoma (GB) is a primary malignancy of the central nervous system that is classified by the WHO as a grade IV astrocytoma. Despite decades of research, several aspects about the biology of GB are still unclear. Its pathogenesis and resistance mechanisms are poorly understood, and methods to optimize patient diagnosis and prognosis remain a bottle neck owing to the heterogeneity of the malignancy. The field of omics has recently gained traction, as it can aid in understanding the dynamic spatiotemporal regulatory network of enzymes and metabolites that allows cancer cells to adjust to their surroundings to promote tumor development. In combination with other omics techniques, proteomic and metabolomic investigations, which are a potent means for examining a variety of metabolic enzymes as well as intermediate metabolites, might offer crucial information in this area. Therefore, this review intends to stress the major contribution these tools have made in GB clinical and preclinical research and highlights the crucial impacts made by the integrative “omics” approach in reducing some of the therapeutic challenges associated with GB research and treatment. Thus, our study can purvey the use of these powerful tools in research by serving as a hub that particularly summarizes studies employing metabolomics and proteomics in the realm of GB diagnosis, treatment, and prognosis

COVID-19 Vaccines, Effectiveness, and Immune Responses

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has captivated the globe’s attention since its emergence in 2019. This highly infectious, spreadable, and dangerous pathogen has caused health, social, and economic crises. Therefore, a worldwide collaborative effort was made to find an efficient strategy to overcome and develop vaccines. The new vaccines provide an effective immune response that safeguards the community from the virus’ severity. WHO has approved nine vaccines for emergency use based on safety and efficacy data collected from various conducted clinical trials. Herein, we review the safety and effectiveness of the WHO-approved COVID-19 vaccines and associated immune responses, and their impact on improving the public’s health. Several immunological studies have demonstrated that vaccination dramatically enhances the immune response and reduces the likelihood of future infections in previously infected individuals. However, the type of vaccination and individual health status can significantly affect immune responses. Exposure of healthy individuals to adenovirus vectors or mRNA vaccines causes the early production of antibodies from B and T cells. On the other hand, unhealthy individuals were more likely to experience harmful events due to relapses in their existing conditions. Taken together, aligning with the proper vaccination to a patient’s case can result in better outcomes