PMID: 

Methods Mol Biol. 2020 ;2062:3-33. PMID: 31768969

Abstract Title: 

The RNA Exosome and Human Disease.

Abstract: 

The evolutionarily conserved RNA exosome is a multisubunit ribonuclease complex that processes and/or degrades numerous RNAs. Recently, mutations in genes encoding both structural and catalytic subunits of the RNA exosome have been linked to human disease. Mutations in the structural exosome gene EXOSC2 cause a distinct syndrome that includes retinitis pigmentosa, hearing loss, and mild intellectual disability. In contrast, mutations in the structural exosome genes EXOSC3 and EXOSC8 cause pontocerebellar hypoplasia type 1b (PCH1b) and type 1c (PCH1c), respectively, which are related autosomal recessive, neurodegenerative diseases. In addition, mutations in the structural exosome gene EXOSC9 cause a PCH-like disease with cerebellar atrophy and spinal motor neuronopathy. Finally, mutations in the catalytic exosome gene DIS3 have been linked to multiple myeloma, a neoplasm of plasma B cells. How mutations in these RNA exosome genes lead to distinct, tissue-specific diseases is not currently well understood. In this chapter, we examine the role of the RNA exosome complex in human disease and discuss the mechanisms by which mutations in different exosome subunit genes could impair RNA exosome function and give rise to diverse diseases.

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PMID: 

Nutrients. 2020 May 8 ;12(5). Epub 2020 May 8. PMID: 32397306

Abstract Title: 

L-Ascorbic Acid Inhibits Breast Cancer Growth by Inducing IRE/JNK/CHOP-Related Endoplasmic Reticulum Stress-Mediated p62/SQSTM1 Accumulation in the Nucleus.

Abstract: 

Anticancer effects of L-ascorbic acid (Vitamin C, L-AA) have been reported in various types of cancers. L-AA intake reduces breast cancer recurrence and mortality; however, the role of L-AA in the treatment of breast cancer remains poorly understood. In this study, we investigated the effect and mechanism action of L-AA on breast cancer growth. L-AA inhibited the growth of breast cancer cells by inducing apoptotic cell death at the evaluated treatment concentrations without affecting normal cells. Moreover, L-AA induces autophagosome formation via regulation of mammalian target of rapamycin (), Beclin1, and autophagy-related genes () and increased autophagic flux. Notably, we observed that L-AA increased p62/SQSTM1 (sequestosome 1) protein levels. Accumulation of p62 protein in cancer cells in response to stress has been reported, but its role in cancer regulation remains controversial. Here, we demonstrated that L-AA-induced p62 accumulation is related to L-AA-induced breast cancer growth inhibition. Furthermore, L-AA induced endoplasmic reticulum (ER) stress via the–(inositol-requiring endonuclease-c-Jun N-terminal kinase-C/EBP homologous protein) signaling pathways, which increased the nuclear levels of p62/SQSTM1. These findings provide evidence that L-AA-induced ER stress could be crucial for p62 accumulation-dependent cell death, and L-AA can be useful in breast cancer treatment.

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PMID: 

Oxid Med Cell Longev. 2020 ;2020:1504048. Epub 2020 Jan 11. PMID: 32411317

Abstract Title: 

Vitamin C versus Cancer: Ascorbic Acid Radical and Impairment of Mitochondrial Respiration?

Abstract: 

Vitamin C as a cancer therapy has a controversial history. Much of the controversy arises from the lack of predictive biomarkers for stratification of patients, as well as a clear understanding of the mechanism of action and its multiple targets underlying the anticancer effect. Our review expands the analysis of cancer vulnerabilities for high-dose vitamin C, based on several facts, illustrating the cytotoxic potential of the ascorbyl free radical (AFR) via impairment of mitochondrial respiration and the mechanisms of its elimination in mammals by the membrane-bound NADH:cytochrome b5 oxidoreductase 3 (Cyb5R3). This enzyme catalyzes rapid conversion of AFR to ascorbate, as well as reduction of other redox-active compounds, using NADH as an electron donor. We propose that vitamin C can function in"protective mode"or"destructive mode"affecting cellular homeostasis, depending on the intracellular"steady-state"concentration of AFR and differential expression/activity of Cyb5R3 in cancerous and normal cells. Thus, a specific anticancer effect can be achieved at high doses of vitamin C therapy. The review is intended for a wide audience of readers-from students to specialists in the field.

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PMID: 

J Mater Chem B. 2020 May 15. Epub 2020 May 15. PMID: 32412025

Abstract Title: 

Exogenous vitamin C triggered structural changes of redox-activated dual core-crosslinked biodegradable nanogels for boosting the antitumor efficiency.

Abstract: 

Premature leakage of drugs during blood circulation and slow drug release at the tumor site are two major challenges that nanocarriers have to overcome to achieve successful cancer therapy. Herein, a dual core-crosslinked, redox-sensitive polymeric nanogel (sDL) was constructed by the self-assembly of two star-shaped amphiphilic copolymers (4sP(EG-b-LLA)-N3, 4sP(EG-b-DLA)-N3) in the presence of a redox-sensitive crosslinker (d-ss-Bu), where hydrophilic polyethylene glycol (PEG) was used as the shell and the functional hydrophobic poly(l-lactide) (PLLA) and poly(d-lactide) (PDLA) were used as the dual crosslinked core via stereocomplex formation and chemical interactions. The dual core-crosslinked structure of the nanogels allowed for almost 2-fold enhanced doxorubicin (DOX)-loading capacity, favorable structural stability to restrict the premature leakage of therapeutic drug and smaller particle size to accelerate the internalization efficiency compared to non-crosslinked nanocarriers. Furthermore, exogenous vitamin C (Vc) can trigger the breakage of redox-sensitive bonds to accelerate drug release from nanogels for improved in vitro antitumor efficacy. Notably, in vivo near-infrared imaging showed that the highly stable DOX-loaded sDL efficiently aggregated at the tumor site. Sequential administration of DOX-loaded sDL and Vc exhibited the highest tumor inhibition effect without associated systemic toxicity compared to the corresponding single injection of Vc or DOX-loaded sDL control groups for in vivo studies, indicating that exogenous administration of Vc can synergistically impact the release of DOX from sDL. Therefore, the developed nanogels proved to be promising smart carriers for achieving precise tunable-stability in response to relevant environments and the combination of Vc to activate reduction-sensitive drug delivery is a promising approach to maximize the therapeutic efficacy.

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PMID: 

Food Funct. 2020 May 18. Epub 2020 May 18. PMID: 32420559

Abstract Title: 

Therapeutic target and molecular mechanism of vitamin C-treated pneumonia: a systematic study of network pharmacology.

Abstract: 

Vitamin C (VC), a well-reported antioxidant, is found with beneficial actions of preventing and treating pneumonia. However, the detailed pharmacological target and mechanism of VC-treated pneumonia remain unclear. Thus, the present bioinformatics approach using systematic network pharmacology aimed to reveal primary predictive targets, cellular processes, and molecular pathways of VC-treated pneumonia. As shown in bioinformatics assays, the data included 90 primary presumptive targets of VC-treated pneumonia, and 5 other core targets of VC-treated pneumonia were identified as mitogen activated protein kinase 1 (MAPK1), c-c chemokine receptor type 5 (CCR5), mitogen activated protein kinase 3 (MAPK3), angiotensin II type 2 (AT-2) receptor (AGTR2), and signal transducer and activator of transcription 3 (STAT3). In addition, all biological processes (including top 20) and signaling pathways (including top 20) of VC-treated pneumonia were identified and illustrated through bioinformatics analyses. In conclusion, VC-achieved anti-pneumonia effects are mechanically implicated with the suppression of inflammation and enhancement of immunoregulation associated with functional processes and signaling pathways. More interestingly, the identified VC targets may act as biomarkers for the diagnosis and treatment of pneumonia.

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PMID: 

Viruses. 2019 May 2 ;11(5). Epub 2019 May 2. PMID: 31052499

Abstract Title: 

Extracellular Vesicles and Ebola Virus: A New Mechanism of Immune Evasion.

Abstract: 

Ebola virus (EBOV) disease can result in a range of symptoms anywhere from virtually asymptomatic to severe hemorrhagic fever during acute infection. Additionally, spans of asymptomatic persistence in recovering survivors is possible, during which transmission of the virus may occur. In acute infection, substantial cytokine storm and bystander lymphocyte apoptosis take place, resulting in uncontrolled, systemic inflammation in affected individuals. Recently, studies have demonstrated the presence of EBOV proteins VP40, glycoprotein (GP), and nucleoprotein (NP) packaged into extracellular vesicles (EVs) during infection. EVs containing EBOV proteins have been shown to induce apoptosis in recipient immune cells, as well as contain pro-inflammatory cytokines. In this manuscript, we review the current field of knowledge on EBOV EVs including the mechanisms of their biogenesis, their cargo and their effects in recipient cells. Furthermore, we discuss some of the effects that may be induced by EBOV EVs that have not yet been characterized and highlight the remaining questions and future directions.

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PMID: 

Nat Commun. 2019 06 3 ;10(1):2402. Epub 2019 Jun 3. PMID: 31160588

Abstract Title: 

Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2.

Abstract: 

Platelet-leukocyte interactions amplify inflammatory reactions, but the underlying mechanism is still unclear. CLEC5A and CLEC2 are spleen tyrosine kinase (Syk)-coupled C-type lectin receptors, abundantly expressed by leukocytes and platelets, respectively. Whereas CLEC5A is a pattern recognition receptor (PRR) to flaviviruses and bacteria, CLEC2 is the receptor for platelet-activating snake venom aggretin. Here we show that dengue virus (DV) activates platelets via CLEC2 to release extracellular vesicles (EVs), including exosomes (EXOs) and microvesicles (MVs). DV-induced EXOs (DV-EXOs) and MVs (DV-MVs) further activate CLEC5A and TLR2 on neutrophils and macrophages, thereby induce neutrophil extracellular trap (NET) formation and proinflammatory cytokine release. Compared to  stat1mice, simultaneous blockade of CLEC5A and TLR2 effectively attenuates DV-induced inflammatory response and increases survival rate from 30 to 90%. The identification of critical roles of CLEC2 and CLEC5A/TLR2 in platelet-leukocyte interactions will support the development of novel strategies to treat acute viral infection in the future.

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PMID: 

Viruses. 2019 Jun 6 ;11(6). Epub 2019 Jun 6. PMID: 31174402

Abstract Title: 

Exosomes Carry microRNAs into Neighboring Cells to Promote Diffusive Infection of Newcastle Disease Virus.

Abstract: 

Newcastle disease virus (NDV), an avian paramyxovirus, was shown to prefer to replicate in tumor cells instead of normal cells; however, this mechanism has not been fully elucidated. Exosomes play a crucial role in intercellular communication due to the bioactive substances they carry. Several studies have shown that exosomes are involved in virus infections. However, the effect that exosomes have on NDV-infected tumor cells is not known. In this study, we focus on the role of exosomes secreted by NDV-infected HeLa cells in promoting NDV replication. Three miRNA candidates (miR-1273f, miR-1184, and miR-198) embraced by exosomes were associated with enhancing NDV-induced cytopathic effects on HeLa cells. Furthermore, luciferase assays, RT-qPCR, and enzyme-linked immunosorbent assay (ELISA) all demonstrated that these miRNAs could suppress interferon (IFN)-β gene expression. Enhanced NDV replication in HeLa cells was identified by Western blot and plaque assays. Based on these results, we speculate that NDV employed exosomes entry into neighboring cells, which carry miRNAs, resulting in inhibition of the IFN pathway and promotion of viral infection.To our knowledge, this is the first report on the involvement of NDV-employed exosomes in tumor cells, and as such, it provides new insights into the development of anti-tumor therapies.

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PMID: 

Sci Rep. 2020 May 14 ;10(1):7939. Epub 2020 May 14. PMID: 32409751

Abstract Title: 

Complexity and ultrastructure of infectious extracellular vesicles from cells infected by non-enveloped virus.

Abstract: 

Enteroviruses support cell-to-cell viral transmission prior to their canonical lytic spread of virus. Poliovirus (PV), a prototype for human pathogenic positive-sense RNA enteroviruses, and picornaviruses in general, transport multiple virions en bloc via infectious extracellular vesicles, 100~1000 nm in diameter, secreted from host cells. Using biochemical and biophysical methods we identify multiple components in secreted microvesicles, including mature PV virions; positive-sense genomic and negative-sense replicative, template viral RNA; essential viral replication proteins; and cellular proteins. Using cryo-electron tomography, we visualize the near-native three-dimensional architecture of secreted infectious microvesicles containing both virions and a unique morphological component that we describe as a mat-like structure. While the composition of these mat-like structures is not yet known, based on our biochemical data they are expected to be comprised of unencapsidated RNA and proteins. In addition to infectious microvesicles, CD9-positive exosomes released from PV-infected cells are also infectious and transport virions. Thus, our data show that, prior to cell lysis, non-enveloped viruses are secreted within infectious vesicles that also transport viral unencapsidated RNAs, viral and host proteins. Understanding the structure and function of these infectious particles helps elucidate the mechanism by which extracellular vesicles contribute to the spread of non-enveloped virus infection.

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States are increasingly mandating the use of face masks in public places, but evidence suggests face coverings do little to reduce risk of illness and, in some cases, may even increase your likelihood of contamination.

As recently as February 29, 2020, U.S. Surgeon General Jerome Adams tweeted, “Seriously people — STOP BUYING MASKS! They are NOT effective in preventing general public from catching coronavirus … ”[i]

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