Cyclophilin inhibitors restrict Middle East respiratory syndrome coronavirus via interferon-λ in vitro and in mice

While severe coronavirus infections, including Middle East respiratory syndrome coronavirus (MERS-CoV), cause lung injury with high mortality rates, protective treatment strategies are not approved for clinical use.We elucidated the molecular mechanisms by which the cyclophilin inhibitors cyclosporin A (CsA) and alisporivir (ALV) restrict MERS-CoV to validate their suitability as readily available therapy in MERS-CoV infection.Calu-3 cells and primary human alveolar epithelial cells (hAECs) were infected with MERS-CoV and treated with CsA or ALV or inhibitors targeting cyclophilin inhibitor-regulated molecules including calcineurin, nuclear factor of activated T-cells (NFATs) or mitogen-activated protein kinases. Novel CsA-induced pathways were identified by RNA sequencing and manipulated by gene knockdown or neutralising antibodies. Viral replication was quantified by quantitative real-time PCR and 50% tissue culture infective dose. Data were validated in a murine MERS-CoV infection model.Both CsA and ALV reduced MERS-CoV titres and viral RNA replication in Calu-3 cells and hAECs, improving epithelial integrity. While neither calcineurin nor NFAT inhibition reduced MERS-CoV propagation, blockade of c-Jun N-terminal kinase diminished infectious viral particle release but not RNA accumulation. Importantly, CsA induced interferon regulatory factor 1 (IRF1), a pronounced type III interferon (IFNλ) response and expression of antiviral genes. Downregulation of IRF1 or IFNλ increased MERS-CoV propagation in the presence of CsA. Importantly, oral application of CsA reduced MERS-CoV replication in vivo, correlating with elevated lung IFNλ levels and improved outcome.We provide evidence that cyclophilin inhibitors efficiently decrease MERS-CoV replication in vitro and in vivo via upregulation of inflammatory antiviral cell responses, in particular IFNλ. CsA might therefore represent a promising candidate for treating MERS-CoV infection.

Download Full-text

Molecular mechanisms underpinning sarcomas and implications for current and future therapy

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00647-8 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Victoria Damerell ◽

Michael S. Pepper ◽

Sharon Prince

Keyword(s):

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Treatment Strategies ◽

Mesenchymal Transition ◽

Mesenchymal To Epithelial Transition ◽

Cells Of Origin ◽

Novel Treatment Strategies ◽

Future Therapy

AbstractSarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

Download Full-text

TRIM72 is required for effective repair of alveolar epithelial cell wounding

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00172.2014 ◽

2014 ◽

Vol 307 (6) ◽

pp. L449-L459 ◽

Cited By ~ 15

Author(s):

Seong Chul Kim ◽

Thomas Kellett ◽

Shaohua Wang ◽

Miyuki Nishi ◽

Nagaraja Nagre ◽

...

Keyword(s):

Epithelial Cells ◽

Molecular Mechanisms ◽

Striated Muscle ◽

Alveolar Epithelial Cell ◽

Alveolar Epithelial Cells ◽

Lung Cells ◽

Alveolar Epithelial ◽

High Tidal Volume Ventilation

The molecular mechanisms for lung cell repair are largely unknown. Previous studies identified tripartite motif protein 72 (TRIM72) from striated muscle and linked its function to tissue repair. In this study, we characterized TRIM72 expression in lung tissues and investigated the role of TRIM72 in repair of alveolar epithelial cells. In vivo injury of lung cells was introduced by high tidal volume ventilation, and repair-defective cells were labeled with postinjury administration of propidium iodide. Primary alveolar epithelial cells were isolated and membrane wounding and repair were labeled separately. Our results show that absence of TRIM72 increases susceptibility to deformation-induced lung injury whereas TRIM72 overexpression is protective. In vitro cell wounding assay revealed that TRIM72 protects alveolar epithelial cells through promoting repair rather than increasing resistance to injury. The repair function of TRIM72 in lung cells is further linked to caveolin 1. These data suggest an essential role for TRIM72 in repair of alveolar epithelial cells under plasma membrane stress failure.

Download Full-text

Fucoidan Prevents RANKL-Stimulated Osteoclastogenesis and LPS-Induced Inflammatory Bone Loss via Regulation of Akt/GSK3β/PTEN/NFATc1 Signaling Pathway and Calcineurin Activity

Marine Drugs ◽

10.3390/md17060345 ◽

2019 ◽

Vol 17 (6) ◽

pp. 345 ◽

Cited By ~ 5

Author(s):

Sheng-Hua Lu ◽

Yi-Jan Hsia ◽

Kuang-Chung Shih ◽

Tz-Chong Chou

Keyword(s):

Bone Loss ◽

Molecular Mechanisms ◽

Bone Erosion ◽

Osteoclast Differentiation ◽

Bone Diseases ◽

Nuclear Factor ◽

Activated T Cells ◽

Calcineurin Activity

Excessive osteoclast differentiation and/or function plays a pivotal role in the pathogenesis of bone diseases such as osteoporosis and rheumatoid arthritis. Here, we examined whether fucoidan, a sulfated polysaccharide present in brown algae, attenuates receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclastogenesis in vitro and lipopolysaccharide (LPS)-induced bone resorption in vivo, and investigated the molecular mechanisms involved. Our results indicated that fucoidan significantly inhibited osteoclast differentiation in RANKL-stimulated macrophages and the bone resorbing activity of osteoclasts. The effects of fucoidan may be mediated by regulation of Akt/GSK3β/PTEN signaling and suppression of the increase in intracellular Ca2+ level and calcineurin activity, thereby inhibiting the translocation of nuclear factor-activated T cells c1 (NFATc1) into the nucleus. However, fucoidan-mediated NFATc1 inactivation was greatly reversed by kenpaullone, a GSK3β inhibitor. In addition, using microcomputer tomography (micro-CT) scanning and bone histomorphometry, we found that fucoidan treatment markedly prevented LPS-induced bone erosion in mice. Collectively, we demonstrated that fucoidan was capable of inhibiting osteoclast differentiation and inflammatory bone loss, which may be modulated by regulation of Akt/GSK3β/PTEN/NFATc1 and Ca2+/calcineurin signaling cascades. These findings suggest that fucoidan may be a potential agent for the treatment of osteoclast-related bone diseases.

Download Full-text

Therapeutic Effects of Curcumin—From Traditional Past to Present and Future Clinical Applications

International Journal of Molecular Sciences ◽

10.3390/ijms20153757 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3757 ◽

Cited By ~ 6

Author(s):

Beatrice Bachmeier ◽

Dieter Melchart

Keyword(s):

Molecular Mechanisms ◽

Malignant Tumors ◽

Scientific Evidence ◽

Treatment Strategies ◽

Therapeutic Effects ◽

Microbial Infection ◽

Therapeutic Benefits ◽

Novel Treatment Strategies

The efficacy of the plant-derived polyphenol curcumin, in various aspects of health and wellbeing, is matter of public interest. An internet search of the term “Curcumin” displays about 12 million hits. Among the multitudinous information presented on partly doubtful websites, there are reports attracting the reader with promises ranging from eternal youth to cures for incurable diseases. Unfortunately, many of these reports are not based on scientific evidence, but they feed the desideratum of the reader for a “miracle cure”. This circumstance makes it very difficult for researchers, who work in a scientifically sound and evidence-based manner on the therapeutic benefits (or side effects) of curcumin, to demarcate their results from sensational reports that circulate in the web and in other media. This is only one of many obstacles making it difficult to pave curcumin’s way into clinical application; others are its nonpatentability and low economic usability. A further impediment comes from scientists who never worked with curcumin or any other natural plant-derived compound in their own labs. They have never tested these compounds in any scientific assay, neither in vitro nor in vivo; however, they claim, in a sometimes polemic manner, that everything that has so far been published on curcumin’s molecular effects is based on artefacts. The here presented Special Issue comprises a collection of five scientifically sound articles and nine reviews reporting on the therapeutic benefits and the molecular mechanisms of curcumin or of chemically modified curcumin in various diseases ranging from malignant tumors to chronic diseases, microbial infection, and even neurodegenerative diseases. The excellent results of the scientific projects that underlie the five original papers give reason to hope that curcumin will be part of novel treatment strategies in the near future—either as monotherapy or in combination with other drugs or therapeutic applications.

Download Full-text

Matrine inhibits the development and progression of ovarian cancer by repressing cancer associated phosphorylation signaling pathways

Cell Death and Disease ◽

10.1038/s41419-019-2013-3 ◽

2019 ◽

Vol 10 (10) ◽

Cited By ~ 3

Author(s):

Xi Zhang ◽

Guoqing Hou ◽

Andong Liu ◽

Hui Xu ◽

Yang Guan ◽

...

Keyword(s):

Ovarian Cancer ◽

Side Effects ◽

Cancer Cells ◽

Signaling Pathways ◽

Molecular Mechanisms ◽

Chemotherapy Resistance ◽

Treatment Strategies ◽

Ovarian Cancer Cells

Abstract Ovarian cancer remains the most lethal gynecologic malignancy with late detection and acquired chemoresistance. Advanced understanding of the pathophysiology and novel treatment strategies are urgently required. A growing body of proteomic investigations suggest that phosphorylation has a pivotal role in the regulation of ovarian cancer associated signaling pathways. Matrine has been extensively studied for its potent anti-tumor activities. However, its effect on ovarian cancer cells and underlying molecular mechanisms remain unclear. Herein we showed that matrine treatment inhibited the development and progression of ovarian cancer cells by regulating proliferation, apoptosis, autophagy, invasion and angiogenesis. Matrine treatment retarded the cancer associated signaling transduction by decreasing the phosphorylation levels of ERK1/2, MEK1/2, PI3K, Akt, mTOR, FAK, RhoA, VEGFR2, and Tie2 in vitro and in vivo. Moreover, matrine showed excellent antitumor effect on chemoresistant ovarian cancer cells. No obvious toxic side effects were observed in matrine-administrated mice. As the natural agent, matrine has the potential to be the targeting drug against ovarian cancer cells with the advantages of overcoming the chemotherapy resistance and decreasing the toxic side effects.

Download Full-text

Epigenetic roles of PIWI proteins and piRNAs in lung cancer

Cell & Bioscience ◽

10.1186/s13578-019-0368-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Hadis Fathizadeh ◽

Zatollah Asemi

Keyword(s):

Lung Cancer ◽

Molecular Mechanisms ◽

Treatment Strategies ◽

High Mobility ◽

P Element ◽

In Vivo Studies ◽

Cancer Pathogenesis ◽

Non Coding Rnas

AbstractLung cancer is one of very important malignancies which are related to high mobility and mortality in the world. Despite several efforts for improving diagnosis and treatment strategies of lung cancer, finding and developing new and effective therapeutic and diagnostic are needed. A variety of internal and external factors could be involved in lung cancer pathogenesis. Among internal factors, epigenetic mechanisms have been emerged as very important players in the lung cancer. Non-coding RNAs is known as one of epigenetic regulators which exert their effects on a sequence of cellular and molecular mechanisms. P-element induced wimpy testis (PIWI)-interacting RNAs (piRNAs or piR) is one of small non-coding RNAs that the deregulation of these molecules is associated with initiation and progression of different cancers such as lung cancer. Several activities are related to PIWI/piRNA pathway such as suppression of transposons and mobile genetic elements. In vitro and in vivo studies demonstrated the upregulation or downregulation of PIWI proteins and piRNAs could lead to the increasing of cell proliferation, apoptosis reduction and promoting tumor growth in the lung cancer. Hence, PIWI proteins and piRNA could be introduced as new diagnostic and therapeutic biomarkers in the lung cancer therapy. Herein, we have focused on PIWI proteins and piRNA functions and their impact on the progression of lung cancer.

Download Full-text

Treatment of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19): a systematic review of in vitro, in vivo, and clinical trials

Theranostics ◽

10.7150/thno.48342 ◽

2021 ◽

Vol 11 (3) ◽

pp. 1207-1231

Author(s):

Young Joo Han ◽

Keum Hwa Lee ◽

Sojung Yoon ◽

Seoung Wan Nam ◽

Seohyun Ryu ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Middle East ◽

Severe Acute Respiratory Syndrome ◽

Middle East Respiratory Syndrome

Download Full-text

Immunotherapeutic Efficacy of IgY Antibodies Targeting the Full-Length Spike Protein in an Animal Model of Middle East Respiratory Syndrome Coronavirus Infection

Pharmaceuticals ◽

10.3390/ph14060511 ◽

2021 ◽

Vol 14 (6) ◽

pp. 511

Author(s):

Sherif A. El-Kafrawy ◽

Aymn T. Abbas ◽

Sayed S. Sohrab ◽

Ashraf A. Tabll ◽

Ahmed M. Hassan ◽

...

Keyword(s):

Middle East ◽

Specific Binding ◽

High Titer ◽

Egg Yolk ◽

Middle East Respiratory Syndrome ◽

Therapeutic Interventions ◽

Dot Blot ◽

S Protein

Identified in 2012, the Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe and often fatal acute respiratory illness in humans. No approved prophylactic or therapeutic interventions are currently available. In this study, we developed chicken egg yolk antibodies (IgY Abs) specific to the MERS-CoV spike (S) protein and evaluated their neutralizing efficiency against MERS-CoV infection. S-specific IgY Abs were produced by injecting chickens with the purified recombinant S protein of MERS-CoV at a high titer (4.4 mg/mL per egg yolk) at week 7 post immunization. Western blotting and immune-dot blot assays demonstrated specific binding to the MERS-CoV S protein. In vitro neutralization of the generated IgY Abs against MERS-CoV was evaluated and showed a 50% neutralizing concentration of 51.42 μg/mL. In vivo testing using a human-transgenic mouse model showed a reduction of viral antigen positive cells in treated mice, compared to the adjuvant-only controls. Moreover, the lung cells of the treated mice showed significantly reduced inflammation, compared to the controls. Our results show efficient neutralization of MERS-CoV infection both in vitro and in vivo using S-specific IgY Abs. Clinical trials are needed to evaluate the efficiency of the IgY Abs in camels and humans.

Download Full-text

C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism

Oncogene ◽

10.1038/s41388-020-01593-5 ◽

2020 ◽

Author(s):

Yu Zhang ◽

Qian Yan ◽

Lanqi Gong ◽

Hang Xu ◽

Beilei Liu ◽

...

Keyword(s):

Glucose Metabolism ◽

Molecular Mechanisms ◽

Critical Role ◽

Genetic Alterations ◽

Metabolic Reprogramming ◽

Mice Model ◽

Activated T Cells ◽

Chronic Hepatitis B Virus

AbstractChronic hepatitis B virus (HBV) infection is strongly associated with the initiation and development of hepatocellular carcinoma (HCC). However, the genetic alterations and pathogenesis mechanisms remain significantly unexplored, especially for HBV-induced metabolic reprogramming. Analysis of integration breakpoints in HBV-positive HCC samples revealed the preferential clustering pattern within the 3′-end of X gene in the HBV genome, leading to the production of C-terminal truncated X protein (Ct-HBx). In this study, we not only characterized the oncogenic role of two Ct-HBx (HBx-120 and HBx-134) via in vitro and in vivo functional assays but also deciphered their underlying molecular mechanisms. Gene expression profiling by transcriptome sequencing identified potential targets of Ct-HBx and novel malignant hallmarks such as glycolysis, cell cycle, and m-TORC1 signaling in Ct-HBx-expressing cells. TXNIP, a well-established regulator of glucose metabolism, was shown to be downregulated by Ct-HBx and play a pivotal role in Ct-HBx-mediated HCC progression. Suppression of TXNIP is frequently observed in HCC patients with Ct-HBx expression and significantly (P = 0.015) correlated to a poorer prognosis. Re-introduction of TXNIP attenuated the metabolic reprogramming induced by the Ct-HBx and inhibited the tumor growth in the mice model. Further study suggested that Ct-HBx could downregulate TXNIP via a transcriptional repressor nuclear factor of activated T cells 2 (NFACT2). Collectively, our findings indicate that TXNIP plays a critical role in Ct-HBx-mediated hepatocarcinogenesis, serving as a novel therapeutic strategy in HCC treatment.

Download Full-text