Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers

Anti-inflammatory effects of luteolin: A review of in vitro, in vivo, and in silico studies

The lack of therapy and the failure of existing therapy has been a challenge for clinicians in treating various cancers. Doxorubicin, 5-fluorouracil, cisplatin, and paclitaxel are the first-line therapy in various cancers; however, toxicity, resistance, and treatment failure limit their clinical use. Their status leads us to discover and investigate more targeted therapy with more efficacy. In this article, we dissect literature from the patient perspective, the tumor biology perspective, therapy-induced metastasis, and cell data generated in the laboratory.

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Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis

Cancer is the second cause of death worldwide. Chemotherapy and radiotherapy are the most common modalities for the treatment of cancer. Experimental studies have shown that inflammation plays a central role in tumor resistance and the incidence of several side effects following both chemotherapy and radiotherapy. Inflammation resulting from radiotherapy and chemotherapy is responsible for adverse events such as dermatitis, mucositis, pneumonitis, fibrosis, and bone marrow toxicity. Chronic inflammation may also lead to the development of second cancer during years after treatment. A number of anti-inflammatory drugs such as nonsteroidal anti-inflammatory agents have been proposed to alleviate chronic inflammatory reactions after radiotherapy or chemotherapy. Curcumin is a well-documented herbal anti-inflammatory agents. Studies have proposed that curcumin can help management of inflammation during and after radiotherapy and chemotherapy. Curcumin targets various inflammatory mediators such as cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor κB (NF-κB), thereby attenuating the release of proinflammatory and profibrotic cytokines, and suppressing chronic production of free radicals, which culminates in the amelioration of tissue toxicity. Through modulation of NF-κB and its downstream signaling cascade, curcumin can also reduce angiogenesis, tumor growth, and metastasis. Low toxicity of curcumin is linked to its cytoprotective effects in normal tissues. This protective action along with the capacity of this phytochemical to sensitize tumor cells to radiotherapy and chemotherapy makes it a potential candidate for use as an adjuvant in cancer therapy. There is also evidence from clinical trials suggesting the potential utility of curcumin for acute inflammatory reactions during radiotherapy such as dermatitis and mucositis.

Curcumin as an anti-inflammatory agent: Implications to radiotherapy and chemotherapy.

The diagnosis of Lyme disease often depends on the measurement of serum antibodies to Borrelia burgdorferi, the spirochete that causes this disorder. Although prompt treatment with antibiotics may abrogate the antibody response to the infection, symptoms persist in some patients. We studied 17 patients who had presented with acute Lyme disease and received prompt treatment with oral antibiotics, but in whom chronic Lyme disease subsequently developed. Although these patients had clinically active disease, none had diagnostic levels of antibodies to B. burgdorferi on either a standard enzyme-linked immunosorbent assay or immunofluorescence assay. On Western blot analysis, the level of immunoglobulin reactivity against B. burgdorferi in serum from these patients was no greater than that in serum from normal controls. The patients had a vigorous T-cell proliferative response to whole B. burgdorferi, with a mean ( +/- SEM) stimulation index of 17.8 +/- 3.3, similar to that (15.8 +/- 3.2) in 18 patients with chronic Lyme disease who had detectable antibodies. The T-cell response of both groups was greater than that of a control group of healthy subjects (3.1 +/- 0.5; P less than 0.001). We conclude that the presence of chronic Lyme disease cannot be excluded by the absence of antibodies against B. burgdorferi and that a specific T-cell blastogenic response to B. burgdorferi is evidence of infection in seronegative patients with clinical indications of chronic Lyme disease.

Seronegative lyme disease: dissociation of specific t and b lymphocyte responses to borrelia burgdorferi

Luteolin ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of platinum accumulation, inflammation and apoptosis in the kidney.

Cytomegaloviruses (CMVs), members of the herpesvirus family, have evolved a variety of mechanisms to evade the immune response to survive in infected hosts and to establish latent infection. They effectively hide infected cells from the effector mechanisms of adaptive immunity by eliminating cellular proteins (major histocompatibility Class I and Class II molecules) from the cell surface that display viral antigens to CD8 and CD4 T lymphocytes. CMVs also successfully escape recognition and elimination of infected cells by natural killer (NK) cells, effector cells of innate immunity, either by mimicking NK cell inhibitory ligands or by downregulating NK cell-activating ligands. To accomplish these immunoevasion functions, CMVs encode several proteins that function in the biosynthetic pathway by inhibiting the assembly and trafficking of cellular proteins that participate in immune recognition and thereby, block their appearance at the cell surface. However, elimination of these proteins from the cell surface can also be achieved by perturbation of their endosomal route and subsequent relocation from the cell surface into intracellular compartments. Namely, the physiological route of every cellular protein, including immune recognition molecules, is characterized by specific features that determine its residence time at the cell surface. In this review, we summarize the current understanding of endocytic trafficking of immune recognition molecules and perturbations of the endosomal system during infection with CMVs and other members of the herpesvirus family that contribute to their immune evasion mechanisms.

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Cytomegalovirus immune evasion by perturbation of endosomal trafficking

Major histocompatibility class I (MHC-I) molecules are present at the cell surface both as fully conformed trimolecular complexes composed of heavy chain (HC), beta-2-microglobulin (β2m) and peptide, and various open forms, devoid of peptide and/or β2m (open MHC-I conformers). Fully conformed MHC-I complexes and open MHC-I conformers can be distinguished by well characterized monoclonal antibody reagents that recognize their conformational difference in the extracellular domain. In the present study, we used these tools in order to test whether conformational difference in the extracellular domain determines endocytic and endosomal route of plasma membrane (PM) proteins. We analyzed PM localization, internalization, endosomal trafficking, and recycling of human and murine MHC-I proteins on various cell lines. We have shown that fully conformed MHC-I and open MHC-I conformers segregate at the PM and during endosomal trafficking resulting in the exclusion of open MHC-I conformers from the recycling route. This segregation is associated with their partitioning into the membranes of different compositions. As a result, the open MHC-I conformers internalized with higher rate than fully conformed counterparts. Thus, our data suggest the existence of conformation-based protein sorting mechanism in the endosomal system.

Early endosomal rerouting of major histocompatibility class I conformers.

Landmarks of endosomal remodeling in the early phase of cytomegalovirus infection.

Cytomegaloviruses (CMV) reorganize membranous system of the cell in order to develop
 a virion assembly compartment (VAC). The development starts in the early (E) phase of
 infection with the reorganization of the endosomal system and the Golgi and proceeds
 to the late phase until newly formed virions are assembled and released. The events in
 the E phase involve reorganization of the endosomal recycling compartment (ERC) in
 a series of cellular alterations that are mostly unknown. In this minireview, we discuss
 the effect of murine CMV infection on Rab proteins, master regulators of membrane
 trafficking pathways, which in the cascades with their GEFs and GAPs organize the flow
 of membranes through the ERC. Immunofluorescence analyzes of murine CMV infected
 cells suggest perturbations of Rab cascades that operate at the ERC. Analysis of cellular
 transcriptome in the course of both murine and human CMV infection demonstrates
 the alteration in expression of cellular genes whose products are known to build Rab
 cascades. These alterations, however, cannot explain perturbations of the ERC. Cellular
 proteome data available for human CMV infected cells suggests the potential role of
 RabGAP downregulation at the end of the E phase. However, the very early onset of
 the ERC alterations in the course of MCMV infection indicates that CMVs exploit Rab
 cascades to reorganize the ERC, which represents the earliest step in the sequential
 establishment of the cVAC.

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Gordana Blagojević Zagorac

Papers

Luteolin ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of platinum accumulation, inflammation and apoptosis in the kidney.

Cytomegalovirus immune evasion by perturbation of endosomal trafficking

Early endosomal rerouting of major histocompatibility class I conformers.

Landmarks of endosomal remodeling in the early phase of cytomegalovirus infection.

Cytomegaloviruses Exploit Recycling Rab Proteins in the Sequential Establishment of the Assembly Compartment