Cellular signaling pathways of T cells in giant cell arteritis

Giant cell arteritis(GCA)is a commonly occurring large vacuities characterized by angiopathy of medium and large-sized vessels.GCA granulomatous formation plays an important role in the pathogenesis of GCA.Analysis of T cell lineages and signaling pathways in GCA have revealed the essential role of T cells in the pathology of GCA.T cells are the dominant population present in GCA lesions.CD4+T cell subtypes that are present include Th1,Th2,Th9,Th17,follicular helper T(Tfh)cells,and regulatory T(Treg)cells.CD8 T cells can primarily differentiate into cytotoxic CD8+T lymphocytes and Treg cells.The instrumental part of GCA is the interplay between dendritic cells,macrophages and endothelial cells,which can result in the vascular injury and the characteristics granulomatous infiltrates formation.During the inflammatory loop of GCA,several signaling pathways have been reported to play an essential role in recruiting,activating and differentiating T cells,including T-cell receptor(TCR)signaling,vascular endothelial growth factor(VEGF)-Jagged-Notch signaling and the Janus kinase and signal transducer and activator of transcription(STAT)pathway(JAK-STAT)pathway.In this review,we have focused on the role of T cells and their potential signaling mechanism(s)that are involved in the pathogenesis of GCA.A better understanding of the role of T cells mediated complicated orchestration during the homeostasis and the changes could possibly favor developments of novel treatment strategies against immunological disorders associated with GCA.

Pathological mechanisms of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system,the cause of which remains unexplained despite several years of research.Thus,the journey to understanding or treating amyotrophic lateral sclerosis is still a long one.According to current research,amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways.The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis.Here,we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis,as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis.In addition,we discuss current emerging strategies for the treatment of amyotrophic lateral sclerosis.Studying the emergence of these new therapies may help to further our understanding of the pathogenic mechanisms of the disease.

Systems biology and OMIC data integration to understand gastrointestinal cancers

Gastrointestinal(GI)cancers are a set of diverse diseases affecting many parts/organs.The five most frequent GI cancer types are esophageal,gastric cancer(GC),liver cancer,pancreatic cancer,and colorectal cancer(CRC);together,they give rise to 5 million new cases and cause the death of 3.5 million people annually.We provide information about molecular changes crucial to tumorigenesis and the behavior and prognosis.During the formation of cancer cells,the genomic changes are microsatellite instability with multiple chromosomal arrangements in GC and CRC.The genomically stable subtype is observed in GC and pancreatic cancer.Besides these genomic subtypes,CRC has epigenetic modification(hypermethylation)associated with a poor prognosis.The pathway information highlights the functions shared by GI cancers such as apoptosis;focal adhesion;and the p21-activated kinase,phosphoinositide 3-kinase/Akt,transforming growth factor beta,and Toll-like receptor signaling pathways.These pathways show survival,cell proliferation,and cell motility.In addition,the immune response and inflammation are also essential elements in the shared functions.We also retrieved information on protein-protein interaction from the STRING database,and found that proteins Akt1,catenin beta 1(CTNNB1),E1A binding protein P300,tumor protein p53(TP53),and TP53 binding protein 1(TP53BP1)are central nodes in the network.The protein expression of these genes is associated with overall survival in some GI cancers.The low TP53BP1 expression in CRC,high EP300 expression in esophageal cancer,and increased expression of Akt1/TP53 or low CTNNB1 expression in GC are associated with a poor prognosis.The Kaplan Meier plotter database also confirmed the association between expression of the five central genes and GC survival rates.In conclusion,GI cancers are very diverse at the molecular level.However,the shared mutations and protein pathways might be used to understand better and reveal diagnostic/prognostic or drug targets.

Transcriptional factor RUNX1:A potential therapeutic target for fibrotic pulmonary disease

Runt-related transcription factor-1(RUNX1),also known as the core-binding factor alpha 2 subunit,is closely related to human leukemia.The functions of RUNX1 in modulating cell proliferation,differentiation,and survival in multiple systems have been gradually discovered with the emergence of transgenic mice.RUNX1 is a powerful transcription factor implicated in diverse signaling pathways and cellular mechanisms that participate in lung development and pulmonary diseases.RUNX1 has recently been identified as a target regulator of fibrotic remodeling diseases,particularly in the kidney.However,the role of RUNX1 in pulmonary fibrosis is unclear.Pulmonary fibrosis is characterized by obscure nosogenesis,limited therapy,and poor prognosis.Moreover,the population of patients with pulmonary fibrosis is gradually increasing.Thus,there is an unmet need for therapeutic targets.In this review,we retrospectively discuss the alteration in RUNX1 mRNA expression in the RNA sequencing data of human fibrotic lungs and the protein levels in mouse pulmonary fibrosis.Subsequently,we focused on the interaction between RUNX1 and several signaling pathways involved in pulmonary fibrosis.Finally,this review highlights the therapeutic potential of RUNX1 as a target for slowing the progression of fibrotic lung disease.

The Effect of Frat-1, Idax and Axam toward the Wnt Signaling Pathway

This paper describes the effect of Frat-1, Idax and Axam toward the Wnt signaling pathway. The Wnt pathway is an important intracellular signaling pathway that plays a crucial role in the cell cycle process at several levels of development. Understanding this pathway thoroughly will enable identification of new drug targets and thereby open avenues to more effective therapies for a range of Wnt pathway related diseases such as cancer, osteoporosis, and mesothelioma. Dishevelled （Dsh） is one of the multi-module proteins working m the Wnt pathway. The function of Dsh depends on the regulators which bind to it, components it interacts with and most importantly the Wnt signal. It is important to note that positive regulators are those factors that induce gene transcription. Conversely, the negative regulators induce β-Catenin degradation. The positive regulator such as Frat- 1 would promote the Wnt signaling pathway and downstream gene transcription. Meanwhile the negative regulator such as Idax and Axam would inhibit the signaling pathway and promotes β-Catenin degradation which will thereby prevent aberrant gene transcription.

Leptin signaling and leptin resistance

With the prevalence of obesity and associated comorbidities,studies aimed at revealing mechanisms that regulate energy homeostasis have gained increasing interest.In 1994,the cloning of leptin was a milestone in metabolic research.As an adipocytokine,leptin governs food intake and energy homeostasis through leptin receptors(LepR)in the brain.The failure of increased leptin levels to suppress feeding and elevate energy expenditure is referred to as leptin resistance,which encompasses complex pathophysiological processes.Within the brain,LepR-expressing neurons are distributed in hypothalamus and other brain areas,and each population of the LepR-expressing neurons may mediate particular aspects of leptin effects.In LepR-expressing neurons,the binding of leptin to LepR initiates multiple signaling cascades including janus kinase(JAK)–signal transducers and activators of transcription(STAT)phosphatidylinositol 3-kinase(PI3K)-protein kinase B(AKT),extracellular regulated protein kinase(ERK),and AMP-activated protein kinase(AMPK)signaling,etc.,mediating leptin actions.These findings place leptin at the intersection of metabolic and neuroendocrine regulations,and render leptin a key target for treating obesity and associated comorbidities.This review highlights the main discoveries that shaped the field of leptin for better understanding of the mechanism governing metabolic homeostasis,and guides the development of safe and effective interventions to treat obesity and associated diseases.

The targeting effect of H_7K(R_2)_2-modified pH-sensitive liposomes on U87-MG cells

The present study aimed to investigate the targeting effect of H7K（R2）2-modified pH -sensitive liposomes on U87-MG cells. Using coumarin-6 as a fluorescence probe, we prepared H7K（R2）2-modified p H-sensitive liposomes（designated as coumarin-6-PSL-H7K（R2）2）. The flow cytometry assay was used to evaluate the effect of H7K（R2）2 proportions on the cellular uptake and endocytosis pathways of coumarin--6--PSL--H7K（R2）2 on U87-MG cells. The circular dichroism（CD） spectroscopy assay was used to investigate the secondary structures of H7K（R2）2 peptide at pH 7.4 and H 6.8, respectively. Our results indicated that the 2.5% proportion of H7K（R2）2 in the coumarin-6--PSL-H7K（R2）2 was superior to those of 1% and 3.5% of H7K（R2）2. The uptake of coumarin--6-PSL--H7K（R2）2 on U87--MG cells was not inhibited by filipin, M-β--CD or chlorpromazine. The secondary structure of H7K（R2）2 at pH 6.8 was mostly presented as β--turn. In conclusion, we suggested that the appropriate proportion of H7K（R2）2 in the H7K（R2）2--modified pH--sensitive liposomes could be set at 2.5%. The cellular uptake pathway for H7K（R2）2-modified pH--sensitive liposomes was via the cell penetrating capacity of H7K（R2）2 which responded to acidic condition. The secondary structure of H7K（R2）2 at pH 6.8, which was presented as the shape of hairpin, might be mainly responsible for its targeting and cell penetrating effect.

Low-intensity pulsed ultrasound stimulates proliferation of stem/progenitor cells: what we need to know to translate basic science research into clinical applications

Low-intensity pulsed ultrasound (LIPUS) is a promising therapy that has been increasingly explored in basic research and clinical applications. LIPUS is an appealing therapeutic option as it is a noninvasive treatment that has many advantages, including no risk of infection or tissue damage and no known adverse reactions. LIPUS has been shown to have many benefits including promotion of tissue healing, angiogenesis, and tissue regeneration;inhibition of inflammation and pain relief;and stimulation of cell proliferation and differentiation. The biophysical mechanisms of LIPUS remain unclear and the studies are ongoing. In recent years, more and more research has focused on the relationship between LIPUS and stem/progenitor cells. A comprehensive search of the PubMed and Embase databases to July 2020 was performed. LIPUS has many effects on stem cells. Studies show that LIPUS can stimulate stem cells in vitro;promote stem cell proliferation, differentiation, and migration;maintain stem cell activity;alleviate the problems of insufficient seed cell source, differentiation, and maturation;and circumvent the low efficiency of stem cell transplantation. The mechanisms involved in the effects of LIPUS are not fully understood, but the effects demonstrated in studies thus far have been favorable. Much additional research is needed before LIPUS can progress from basic science research to large-scale clinical dissemination and application.

Structure-based design and biological evaluation of novel mTOR inhibitors as potential anti-cervical agents

The mammalian target of rapamycin(mTOR) is a critical component of the PI3K-AKT signaling pathway. It is highly activated in cervical cancer, which continues to pose an important clinical challenge with an urgent need for new and improved therapeutic approaches. Herein, we describe the structure-based drug discovery and biological evaluation of a series of m TOR kinase inhibitors as potential anti-cervical cancer agents. The results of enzymatic activity assays supported C3 as a potential m TOR inhibitor, which exhibited high inhibitory activity with an IC50 of 1.57 μM. Molecular docking and dynamics simulation were conducted to predict the binding patterns, suggesting relationships between structure and activity. The anti-proliferative assay against diverse cancer cell lines was displayed subsequently, revealing that C3 exhibited significant proliferation inhibition against cervical cancer cell He La(IC50=0.38μM) compared with other cell lines. Moreover, C3 could effectively reduce the expression of phospho-ribosomal S6 protein(p-S6) in He La cells in a dose-dependent manner. Noteworthily, m TOR signaling and other cellular pathways might contribute to the significant effect of C3 against cervical cancer simultaneously. These data indicated that C3 represented a good lead molecule for further development as a therapeutic agent for cervical cancer treatment.