Perillyl alcohol attenuates Rheumatoid arthritis via regulating TLR4/NF-κB and Keap1/Nrf2 signaling pathways: A comprehensive study on in in-vitro and in-vivo experimental models

Rheumatoid arthritis is an autoimmune and chronic pathological condition characterized by an inflammatory process of the joints It is a complex and multifactorial, involving genetic, epigenetic and environmental factors and the use of experimental models is required to better understand its pathology and for drug testing. The aim of this study was to perform a systematic literature review on experimental models in rheumatoid arthritis using IRAMUTEQ, a software that analysis, qualitatively and quantitatively, text fragments, as a methodological tool. After searching for articles published in the last five years on Scopus database and applying the exclusion criteria, we ended with 84 articles. The most commonly employed experimental models was the arthritis induction by inoculation of the Complete Freund's Adjuvant (CFA), followed by the use of combined methodologies and the collagen-induced arthritis (CIA). The analyses of abstracts by the IRAMUTEQ software provided a classification according to their textual elements in four classes, which were grouped into three main themes: in vivo models (class 1), clinical practice and traditional medicine (classes 2 and 3) and in vitro models (class 4) and it was also possible to build a similarity tree of the terms present in the abstracts and a word cloud with the most cited terms. Thus, the use of the IRAMUTEQ software as a methodological tool has been satisfactory, since it was possible to identify the main experimental models used, keywords, pathological processes and molecules involved in the pathogenesis of rheumatoid arthritis free of the researchers’ bias, in addition to being a tool for visual and intuitive results.

Download Full-text

Promising Anticancer Activities of Alismatis rhizome and Its Triterpenes via p38 and PI3K/Akt/mTOR Signaling Pathways

Nutrients ◽

10.3390/nu13072455 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2455

Author(s):

Eungyeong Jang ◽

Jang-Hoon Lee

Keyword(s):

Cancer Cells ◽

Signaling Pathways ◽

Biological Activities ◽

Experimental Models ◽

Mtor Signaling ◽

Flowering Plant ◽

In Vivo Studies ◽

Anticancer Activities

The flowering plant genus Alisma, which belongs to the family Alismataceae, comprises 11 species, including Alisma orientale, Alisma canaliculatum, and Alisma plantago-aquatica. Alismatis rhizome (Ze xie in Chinese, Takusha in Japanese, and Taeksa in Korean, AR), the tubers of medicinal plants from Alisma species, have long been used to treat inflammatory diseases, hyperlipidemia, diabetes, bacterial infection, edema, oliguria, diarrhea, and dizziness. Recent evidence has demonstrated that its extract showed pharmacological activities to effectively reverse cancer-related molecular targets. In particular, triterpenes naturally isolated from AR have been found to exhibit antitumor activity. This study aimed to describe the biological activities and plausible signaling cascades of AR and its main compounds in experimental models representing cancer-related physiology and pathology. Available in vitro and in vivo studies revealed that AR extract possesses anticancer activity against various cancer cells, and the efficacy might be attributed to the cytotoxic and antimetastatic effects of its alisol compounds, such as alisol A, alisol B, and alisol B 23-acetate. Several beneficial functions of triterpenoids found in AR might be due to p38 activation and inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways. Moreover, AR and its triterpenes inhibit the proliferation of cancer cells that are resistant to chemotherapy. Thus, AR and its triterpenes may play potential roles in tumor attack, as well as a therapeutic remedy alone and in combination with other chemotherapeutic drugs.

Download Full-text

Euphorbia Factor L2 ameliorates the Progression of K/BxN Serum-Induced Arthritis by Blocking TLR7 Mediated IRAK4/IKKβ/IRF5 and NF-kB Signaling Pathways

Frontiers in Pharmacology ◽

10.3389/fphar.2021.773592 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jing Tang ◽

Xiaolan Cheng ◽

Shiyu Yi ◽

Yuanyuan Zhang ◽

Zhigang Tang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Signaling Pathways ◽

Signaling Pathway ◽

Inflammatory Cytokines ◽

Inflammatory Cells ◽

Human Pbmcs ◽

Inhibitory Effects ◽

Murine Macrophages

Toll like receptor (TLR)s have a central role in regulating innate immunity and their activation have been highlighted in the pathogenesis of rheumatoid arthritis (RA). EFL2, one of diterpenoids derived from Euphorbia seeds, is nearly unknown expect for its improving effect on acute lung injury. Our present study aimed to investigate EFL2’s pharmacokinetic features, its therapeutic effect on rheumatoid arthritis, and explored the potential anti-arthritic mechanisms. K/BxN serum transfer arthritis (STA) murine model was used to assess EFL2’s anti-arthritic effects. We also applied UPLC-MS method to measure the concentrations of EFL2 in plasma. The inhibitory effects of this compound on inflammatory cells infiltration and activation were determined by flow cytometry analysis and quantitative real-time polymerase chain reaction (qRT-PCR) in vivo, and immunochemistry staining and ELISA in murine macrophages and human PBMCs in vitro, respectively. The mechanism of EFL2 on TLRs mediated signaling pathway was evaluated by PCR array, Western blot, plasmid transfection and confocal observation. Intraperitoneal (i.p.) injection of EFL2, instead of oral administration, could effectively ameliorate arthritis severity of STA mice. The inflammatory cells migration and infiltration into ankles were also significantly blocked by EFL2, accompanied with dramatically reduction of chemokines mRNA expression and pro-inflammatory cytokines production. In vivo PCR microarray indicated that EFL2 exerted anti-arthritis bioactivity by suppressing TLR7 mediated signaling pathway. In vitro study confirmed the inhibitory effects of EFL2 on TLR7 or TLR3/7 synergistically induced inflammatory cytokines secretion in murine macrophages and human PBMCs. In terms of molecular mechanism, we further verified that EFL2 robustly downregulated TLR7 mediated IRAK4-IKKβ-IRF5 and NF-κB signaling pathways activation, and blocked IRF5 and p65 phosphorylation and translocation activity. Taken together, our data indicate EFL2’s therapeutic potential as a candidate for rheumatoid arthritis and other TLR7-dependent diseases.

Download Full-text

Neutralization of a Low Molecular Weight Heparin (LHN-1) and Conventional Heparin by Protamine Sulfate in Rats

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661675 ◽

1986 ◽

Vol 56 (03) ◽

pp. 318-322 ◽

Cited By ~ 18

Author(s):

V Diness ◽

P B Østergaard

Keyword(s):

Molecular Weight ◽

Low Molecular Weight Heparin ◽

Thrombus Formation ◽

Experimental Models ◽

Protamine Sulfate ◽

Low Molecular Weight ◽

Antithrombotic Effect ◽

Higher Doses

SummaryThe neutralization of a low molecular weight heparin (LHN-1) and conventional heparin (CH) by protamine sulfate has been studied in vitro and in vivo. In vitro, the APTT activity of CH was completely neutralized in parallel with the anti-Xa activity. The APTT activity of LHN-1 was almost completely neutralized in a way similar to the APTT activity of CH, whereas the anti-Xa activity of LHN-1 was only partially neutralized.In vivo, CH 3 mg/kg and LHN-1 7.2 mg/kg was given intravenously in rats. The APTT and anti-Xa activities, after neutralization by protamine sulfate in vivo, were similar to the results in vitro. In CH treated rats no haemorrhagic effect in the rat tail bleeding test and no antithrombotic effect in the rat stasis model was found at a protamine sulfate to heparin ratio of about 1, which neutralized APTT and anti-Xa activities. In LHN-1 treated rats the haemorrhagic effect was neutralized when APTT was close to normal whereas higher doses of protamine sulfate were required for neutralization of the antithrombotic effect. This probably reflects the fact that in most experimental models higher doses of heparin are needed to induce bleeding than to prevent thrombus formation. Our results demonstrate that even if complete neutralization of APTT and anti-Xa activities were not seen in LHN-1 treated rats, the in vivo effects of LHN-1 could be neutralized as efficiently as those of conventional heparin. The large fall in blood pressure caused by high doses of protamine sulfate alone was prevented by the prior injection of LHN-1.

Download Full-text

Antimicrobial peptides for the treatment of pulmonary tuberculosis, allies or foes?

Current Pharmaceutical Design ◽

10.2174/1381612824666180327162357 ◽

2018 ◽

Vol 24 (10) ◽

pp. 1138-1147

Author(s):

Bruno Rivas-Santiago ◽

Flor Torres-Juarez

Keyword(s):

Pulmonary Tuberculosis ◽

Antimicrobial Peptides ◽

Experimental Models ◽

New Drugs ◽

World Health ◽

Public Health Issue ◽

Health Organization ◽

Drug Resistant Strains

Tuberculosis is an ancient disease that has become a serious public health issue in recent years, although increasing incidence has been controlled, deaths caused by Mycobacterium tuberculosis have been accentuated due to the emerging of multi-drug resistant strains and the comorbidity with diabetes mellitus and HIV. This situation is threatening the goals of World Health Organization (WHO) to eradicate tuberculosis in 2035. WHO has called for the creation of new drugs as an alternative for the treatment of pulmonary tuberculosis, among the plausible molecules that can be used are the Antimicrobial Peptides (AMPs). These peptides have demonstrated remarkable efficacy to kill mycobacteria in vitro and in vivo in experimental models, nevertheless, these peptides not only have antimicrobial activity but also have a wide variety of functions such as angiogenesis, wound healing, immunomodulation and other well-described roles into the human physiology. Therapeutic strategies for tuberculosis using AMPs must be well thought prior to their clinical use; evaluating comorbidities, family history and risk factors to other diseases, since the wide function of AMPs, they could lead to collateral undesirable effects.

Download Full-text

Epithelial Organotypic Cultures: A Viable Model to Address Mechanisms of Carcinogenesis by Epitheliotropic Viruses

Current Topics in Medicinal Chemistry ◽

10.2174/1568026618666180410125850 ◽

2018 ◽

Vol 18 (4) ◽

pp. 246-255 ◽

Cited By ~ 1

Author(s):

Lara Termini ◽

Enrique Boccardo

Keyword(s):

Three Dimensional ◽

Cell Types ◽

Experimental Models ◽

Biological Research ◽

Specific Gene ◽

Specific Cell ◽

Organotypic Cultures ◽

Skin Physiology

In vitro culture of primary or established cell lines is one of the leading techniques in many areas of basic biological research. The use of pure or highly enriched cultures of specific cell types obtained from different tissues and genetics backgrounds has greatly contributed to our current understanding of normal and pathological cellular processes. Cells in culture are easily propagated generating an almost endless source of material for experimentation. Besides, they can be manipulated to achieve gene silencing, gene overexpression and genome editing turning possible the dissection of specific gene functions and signaling pathways. However, monolayer and suspension cultures of cells do not reproduce the cell type diversity, cell-cell contacts, cell-matrix interactions and differentiation pathways typical of the three-dimensional environment of tissues and organs from where they were originated. Therefore, different experimental animal models have been developed and applied to address these and other complex issues in vivo. However, these systems are costly and time consuming. Most importantly the use of animals in scientific research poses moral and ethical concerns facing a steadily increasing opposition from different sectors of the society. Therefore, there is an urgent need for the development of alternative in vitro experimental models that accurately reproduce the events observed in vivo to reduce the use of animals. Organotypic cultures combine the flexibility of traditional culture systems with the possibility of culturing different cell types in a 3D environment that reproduces both the structure and the physiology of the parental organ. Here we present a summarized description of the use of epithelial organotypic for the study of skin physiology, human papillomavirus biology and associated tumorigenesis.

Download Full-text

Comparison of In Vitro and In Vivo Effects of Infliximab on Cytokine Production in Proliferating CD4+ T Cells in Patients with Rheumatoid Arthritis

Clinical Anti-Inflammatory & Anti-Allergy Drugs ◽

10.2174/2212703802666150127001412 ◽

2015 ◽

Vol 1 (2) ◽

pp. 122-128

Author(s):

Syuichi Koarada ◽

Yuri Sadanaga ◽

Natsumi Nagao ◽

Satoko Tashiro ◽

Rie Suematsu ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Cd4 T Cells ◽

Cytokine Production

Download Full-text

Mechanism of CK2.3, a Novel Mimetic Peptide of Bone Morphogenetic Protein Receptor Type IA, Mediated Osteogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms20102500 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2500 ◽

Cited By ~ 3

Author(s):

Vrathasha Vrathasha ◽

Hilary Weidner ◽

Anja Nohe

Keyword(s):

Signaling Pathways ◽

Treatment Options ◽

Time Frame ◽

Bmp Signaling ◽

C2c12 Cells ◽

Molecular Sequence ◽

Sequence Of Events ◽

Protein Receptor

Background: Osteoporosis is a degenerative skeletal disease with a limited number of treatment options. CK2.3, a novel peptide, may be a potential therapeutic. It induces osteogenesis and bone formation in vitro and in vivo by acting downstream of BMPRIA through releasing CK2 from the receptor. However, the detailed signaling pathways, the time frame of signaling, and genes activated remain largely unknown. Methods: Using a newly developed fluorescent CK2.3 analog, specific inhibitors for the BMP signaling pathways, Western blot, and RT-qPCR, we determined the mechanism of CK2.3 in C2C12 cells. We then confirmed the results in primary BMSCs. Results: Using these methods, we showed that CK2.3 stimulation activated OSX, ALP, and OCN. CK2.3 stimulation induced time dependent release of CK2β from BMPRIA and concurrently CK2.3 colocalized with CK2α. Furthermore, CK2.3 induced BMP signaling depends on ERK1/2 and Smad1/5/8 signaling pathways. Conclusion: CK2.3 is a novel peptide that drives osteogenesis, and we detailed the molecular sequence of events that are triggered from the stimulation of CK2.3 until the induction of mineralization. This knowledge can be applied in the development of future therapeutics for osteoporosis.

Download Full-text

Schistosoma mansoni eggs induce Wnt/β-catenin signaling and activate the protooncogene c-Jun in human and hamster colon

Scientific Reports ◽

10.1038/s41598-020-79450-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Jakob Weglage ◽

Friederike Wolters ◽

Laura Hehr ◽

Jakob Lichtenberger ◽

Celina Wulz ◽

...

Keyword(s):

Signaling Pathways ◽

Colorectal Carcinogenesis ◽

Sub Saharan Africa ◽

Interleukin 4 ◽

Health Burden ◽

Sub Saharan ◽

Considerable Morbidity ◽

First Time

AbstractSchistosomiasis (bilharzia) is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, with considerable morbidity in parts of the Middle East, South America, Southeast Asia, in sub-Saharan Africa, and particularly also in Europe. The WHO describes an increasing global health burden with more than 290 million people threatened by the disease and a potential to spread into regions with temperate climates like Corsica, France. The aim of our study was to investigate the influence of S. mansoni infection on colorectal carcinogenic signaling pathways in vivo and in vitro. S. mansoni infection, soluble egg antigens (SEA) and the Interleukin-4-inducing principle from S. mansoni eggs induce Wnt/β-catenin signaling and the protooncogene c-Jun as well as downstream factor Cyclin D1 and markers for DNA-damage, such as Parp1 and γH2a.x in enterocytes. The presence of these characteristic hallmarks of colorectal carcinogenesis was confirmed in colon biopsies from S. mansoni-infected patients demonstrating the clinical relevance of our findings. For the first time it was shown that S. mansoni SEA may be involved in the induction of colorectal carcinoma-associated signaling pathways.

Download Full-text

The Radiation-Induced Regenerative Response of Adult Tissue-Specific Stem Cells: Models and Signaling Pathways

Cancers ◽

10.3390/cancers13040855 ◽

2021 ◽

Vol 13 (4) ◽

pp. 855

Author(s):

Paola Serrano Martinez ◽

Lorena Giuranno ◽

Marc Vooijs ◽

Robert P. Coppes

Keyword(s):

Signaling Pathways ◽

Progenitor Cells ◽

Tissue Regeneration ◽

Normal Tissue ◽

Cellular Response ◽

Adult Tissue ◽

Tissue Specific ◽

Radiation Induced

Radiotherapy is involved in the treatment of many cancers, but damage induced to the surrounding normal tissue is often inevitable. Evidence suggests that the maintenance of homeostasis and regeneration of the normal tissue is driven by specific adult tissue stem/progenitor cells. These tasks involve the input from several signaling pathways. Irradiation also targets these stem/progenitor cells, triggering a cellular response aimed at achieving tissue regeneration. Here we discuss the currently used in vitro and in vivo models and the involved specific tissue stem/progenitor cell signaling pathways to study the response to irradiation. The combination of the use of complex in vitro models that offer high in vivo resemblance and lineage tracing models, which address organ complexity constitute potential tools for the study of the stem/progenitor cellular response post-irradiation. The Notch, Wnt, Hippo, Hedgehog, and autophagy signaling pathways have been found as crucial for driving stem/progenitor radiation-induced tissue regeneration. We review how these signaling pathways drive the response of solid tissue-specific stem/progenitor cells to radiotherapy and the used models to address this.

Download Full-text