Dysregulation of miRISC Regulatory Network Promotes Hepatocellular Carcinoma by Targeting PI3K/Akt Signaling Pathway.

Hepatocellular carcinoma (HCC) remains the third leading malignancy worldwide, causing high mortality in adults and children. The neuropathology-associated gene AEG-1 functions as a scaffold protein to correctly assemble the RNA-induced silencing complex (RISC) and optimize or increase its activity. The overexpression of oncogenic miRNAs periodically degrades the target tumor suppressor genes. Oncogenic miR-221 plays a seminal role in the carcinogenesis of HCC. Hence, the exact molecular and biological functions of the oncogene clusters miR-221/AEG-1 axis have not yet been examined widely in HCC. Here, we explored the expression of both miR-221 and AEG-1 and their target/associate genes by qRT-PCR and western blot. In addition, the role of the miR-221/AEG-1 axis was studied in the HCC by flow cytometry analysis. The expression level of the AEG-1 did not change in the miR-221 mimic, and miR-221-transfected HCC cells, on the other hand, decreased the miR-221 expression in AEG-1 siRNA-transfected HCC cells. The miR-221/AEG-1 axis silencing induces apoptosis and G2/M phase arrest and inhibits cellular proliferation and angiogenesis by upregulating p57, p53, RB, and PTEN and downregulating LSF, LC3A, Bcl-2, OPN, MMP9, PI3K, and Akt in HCC cells.

Knockdown of human telomerase reverse transcriptase induces apoptosis in cervical cancer cell line.

Background & objectives: : Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase enzyme that maintains telomere ends by the addition of telomeric repeats to the ends of chromosomal DNA, and that may generate immortal cancer cells. Hence, the activity of telomerase is raised in cancer cells including cervical cancer. The present study aimed to validate the unique siRNA loaded chitosan coated poly-lactic-co-glycolic acid (PLGA) nanoparticle targeting hTERT mRNA to knock down the expression of hTERT in HeLa cells. Methods: : The siRNA loaded chitosan coated polylactic-co-glycolic acid (PLGA) nanoparticles were synthesized by double emulsion solvent diffusion method. The characterization of nano-formulation was done to determine efficient siRNA delivery. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot were performed to evaluate silencing efficiency of nano-formulation. Results: :Size, zeta potential and encapsulation efficiency of nanoparticles were 249.2 nm, 12.4 mV and 80.5 per cent, respectively. Sustained release of siRNA from prepared nanoparticle was studied for 72 h by ultraviolet method. Staining assays were performed to confirm senescence and apoptosis. Silencing of hTERT mRNA and protein expression were analyzed in HeLa cells by RT-PCR and Western blot. Interpretation & conclusions: : The findings showed that biodegradable chitosan coated PLGA nanoparticles possessed an ability for efficient and successful siRNA delivery. The siRNA-loaded PLGA nanoparticles induced apoptosis in HeLa cells. Further studies need to be done with animal model.

AEG-1/miR-221 Axis Cooperatively Regulates the Progression of Hepatocellular Carcinoma by Targeting PTEN/PI3K/AKT Signaling Pathway.

Hepatocellular carcinoma (HCC) is the third leading malignancy worldwide, causing mortality in children and adults. AEG-1 is functioned as a scaffold protein for the proper assembly of RNA-induced silencing complex (RISC) to optimize or increase its activity. The increased activity of oncogenic miRNAs leads to the degradation of target tumor suppressor genes. miR-221 is an oncogenic miRNA, that plays a seminal role in carcinogenesis regulation of HCC. However, the molecular mechanism and biological functions of the miR-221/AEG-1 axis have not been investigated extensively in HCC. Here, the expression of miR-221/AEG-1 and their target/associate genes was analyzed by qRT-PCR and Western blot. The role of the miR-221/AEG-1 axis in HCC was evaluated by proliferation assay, migration assay, invasion assay, and flow cytometry analysis. The expression level of miR-221 decreased in AEG-1 siRNA transfected HCC cells. On the other hand, there were no significant expression changes of AEG-1 in miR-221 mimic and miR-221 inhibitor transfected HCC cells and inhibition of miR-221/AEG-1 axis decreased cell proliferation, invasion, migration, and angiogenesis and induced apoptosis, cell cycle arrest by upregulating p57, p53, PTEN, and RB and downregulating LSF, MMP9, OPN, Bcl-2, PI3K, AKT, and LC3A in HCC cells. Furthermore, these findings suggest that the miR-221/AEG-1 axis plays a seminal oncogenic role by modulating PTEN/PI3K/AKT signaling pathway in HCC. In conclusion, the miR-221/AEG-1 axis may serve as a potential target for therapeutics, diagnostics, and prognostics of HCC.

A Randomized Double-Blind, Placebo Controlled, Four-Arm Parallel Study Investigating the Effect of a Broad-Spectrum Wellness Beverage on Mood State in Healthy, Moderately Stressed Adults.

OBJECTIVE: The objective of this study was to investigate the effect of a broad-spectrum wellness beverage (Zeal Wellness [ZW]) on standardized measures of mood states, including overall feelings of vitality, in healthy, moderately stressed adults. METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted among 99 eligible participants prescreened for moderate stress. Participants were randomized to one of four groups and received ZW once daily (1-dose-ZW; 14 g), ZW twice daily (2-dose-ZW; 28 g), placebo once daily (1-dose-placebo), or placebo twice daily (2-dose-placebo) for 4 weeks. A stress/vitality questionnaire assessed stress and the Profile of Moods (POMS) Questionnaire assessed vigor via mental/physical energy and global mood state. Safety was assessed by clinical chemistry, liver, kidney function, and anthropometric measures and adverse event reporting. RESULTS: Participants receiving 2-dose-ZW reported a 6.6% decrease in scores on POMS-Total Mood Disturbance (TMD; p < 0.05) and a 6.8% decrease in the anger-hostility mood state (p < 0.022) compared to the combined placebo group at day 29. The 2-dose-ZW provided a 12.8% greater improvement in POMS-TMD scores when compared to participants receiving 1-dose-ZW after 28 days of supplementation (p = 0.014). Within groups, there was a 22.4% and a 9.6% decrease in POMS-TMD scores in participants with 2-dose-ZW and 1-dose-ZW, respectively. In addition, participants receiving 2-dose-ZW showed significant improvements (p = 0.001) in the POMS t-score iceberg profile, which represented a shift to a more healthy profile. CONCLUSION: These data show that daily supplementation with 2-dose-ZW significantly decreased POMS-TMD scores and anger-hostility mood state and shifted the POMS iceberg profile to a healthy profile compared to the combined placebo, reflecting the functional benefit of rice-bran-fruit-vegetable extracts based beverage on health.

Effects of the source gap on transmission efficiency of a quadrupole mass spectrometer.

RATIONALE: Recent trends towards miniature and portable quadrupole mass spectrometry (QMS) entail challenges in instrumental sensitivity, which is influenced by 3D fringe field effects on ion transmission in the Quadrupole Mass Filter (QMF). The relationship of these effects with the gap from the ion source to the QMF entrance (source gap) is significant and little explored. We examine transmission characteristics experimentally and use the results to test the predictive accuracy of a recently developed 3D QMF simulation model. The model is then applied to directly investigate optimal transmission m/z ranges across multiple source gaps. METHODS: A portable single filter quadrupole mass spectrometer is used to analyse transmission characteristics across a range of common gases. We use an experimental approach originally proposed by Ehlert, enhanced with a novel method for absolute calibration of the transmission curve. Custom QMF simulation software employs the boundary element method (BEM) to compute accurate 3D electric fields. This is used to study the effects of the source gap on transmission efficiency. RESULTS: Experimental findings confirm a centrally peaked transmission curve; simulations correctly predict the optimal transmission location (in m/z) and percentage, and extend the experimental trend. We compare several methods for determining fringe field length, demonstrating how the size of the physical source gap influences both the length and the intensity of the fringe field at the QMF entrance. A complex relationship with ion transmission is revealed in which different source gaps promote optimal transmission at differing m/z ranges. CONCLUSIONS: The presented results map the relationship between the source gap and transmission efficiency for the given instrument, using a simulation method transferrable to other setups. This is of importance to miniature and portable quadrupole mass spectrometers design for specific applications, for the first time enabling the source gap to be tailored for optimal transmission in the desired mass range.

A novel strain of cynomolgus macaque cytomegalovirus: implications for host-virus co-evolution.

BACKGROUND: Cytomegaloviruses belong to a large, ancient, genus of DNA viruses comprised of a wide array of species-specific strains that occur in diverse array of hosts. METHODS: In this study we sequenced the ~217 Kb genome of a cytomegalovirus isolated from a Mauritius cynomolgus macaque, CyCMV Mauritius, and compared it to previously sequenced cytomegaloviruses from a cynomolgus macaque of Filipino origin (CyCMV Ottawa) and two from Indian rhesus macaques (RhCMV 180.92 and RhCMV 68-1). RESULTS: Though more closely related to CyCMV Ottawa, CyCMV Mauritius is less genetically distant from both RhCMV strains than is CyCMV Ottawa. Several individual genes, including homologues of CMV genes RL11B, UL123, UL83b, UL84 and a homologue of mammalian COX-2, show a closer relationship between homologues of CyCMV Mauritius and the RhCMVs than between homologues of CyCMV Mauritius and CyCMV Ottawa. A broader phylogenetic analysis of 12 CMV strains from eight species recovers evolutionary relationships among viral strains that mirror those amongst the host species, further demonstrating co-evolution of host and virus. CONCLUSIONS: Phylogenetic analyses of rhesus and cynomolgus macaque CMV genome sequences demonstrate co-speciation of the virus and host.

Parthenolide induces apoptosis and autophagy through the suppression of PI3K/Akt signaling pathway in cervical cancer.

OBJECTIVE: To investigate the effect of parthenolide on apoptosis and autophagy and to study the role of the PI3K/Akt signaling pathway in cervical cancer. RESULTS: Parthenolide inhibits HeLa cell viability in a dose dependent-manner and was confirmed by MTT assay. Parthenolide (6 µM) induces mitochondrial-mediated apoptosis and autophagy by activation of caspase-3, upregulation of Bax, Beclin-1, ATG5, ATG3 and down-regulation of Bcl-2 and mTOR. Parthenolide also inhibits PI3K and Akt expression through activation of PTEN expression. Moreover, parthenolide induces generation of reactive oxygen species that leads to the loss of mitochondrial membrane potential. CONCLUSION: Parthenolide induces apoptosis and autophagy-mediated growth inhibition in HeLa cells by suppressing the PI3K/Akt signaling pathway and mitochondrial membrane depolarization and ROS generation. Parthenolide may be a potential therapeutic agent for the treatment of cervical cancer.

Immune response and disease resistance of carotenoids supplementation diet in Cyprinus carpio against Aeromonas hydrophila.

The effect of carotenoid-supplementation diet on immune response and disease resistance in common carp, Cyprinus carpio against Aeromonas hydrophila at weeks 1, 2, and 4 is reported. The cumulative mortality was 10% when fish were fed with 50 or 100 mg kg(-1) supplementation diets while the un-supplementation diet treated group suffered 90% mortality against the pathogen. The phagocytic activity and complement activity significantly increased with 50 and 100 mg kg(-1) diet groups from weeks 2 and 4 but not in other groups. The reactive oxygen species (ROS) production was significantly enhanced with 50 and 100 mg kg(-1) diets from weeks 1 to 4 while the production of reactive nitrogen species (RNS) enhanced on weeks 2 and 4. The lysozyme activity significantly increased when fed with 50 and 100 mg kg(-1) diets on weeks 2 and all supplementation diets on week 4. These results suggest that diet enriched with carotenoid pigment positively enhance the immune status and protects C. carpio from A. hydrophila infection.

Revisiting the Definition of 'Healthy' Participants in Substantiation of Structure/Function Claims for Dietary Supplements.

Concepts and definitions of 'healthy' have been evolving within clinical treatment algorithms as well as reference standards such as Body Mass Index and Dietary Reference Intakes. Consumers' perception of the word 'healthy' is also changing to reflect longer life span, need to stay active and in a good state of mental well-being while managing multiple diseases. Guidelines from the US Food and Drug Administration indicate that substantiating evidence for support of Structure/Function (S/F) claims for dietary supplements is best derived from clinical research conducted in a 'healthy' population. S/F claims cannot be represented to diagnose, treat, cure or prevent any disease. However, in this context, the term 'healthy' is non-descriptive and largely interpreted as an absence of disease. Guidelines for treatment of disease have been broadened to include biomarkers of disease risk such that the pool of 'healthy' volunteers eligible to be enrolled in clinical trials for S/F claim substantiation is greatly diminished. This perspective presents the challenges faced by the food and dietary supplement industry and by researcher efforts designed to substantiate S/F claims and suggest the phrase 'physiologically stable' or 'apparently healthy' as descriptions better suited to replace the term 'healthy.'

Exploring the cytotoxicity of dinuclear Ru(II) p-cymene complexes appended N,N'-bis(4-substituted benzoyl)hydrazines: insights into the mechanism of apoptotic cell death.

Cancer is a perilous life-threatening disease, and attempts are constantly being made to create multinuclear transition metal complexes that could lead to the development of potential anticancer medications and administration procedures. Hence, this work aims to design, synthesize, characterize, and assess the anticancer efficacy of ruthenium p-cymene complexes incorporating N,N'-bis(4-substituted benzoyl)hydrazine ligands. The formation of the new complexes (Ru2H1-Ru2H3) has been thoroughly established by elemental analysis, and FT-IR, UV-vis, NMR, and HR-MS spectral techniques. The solid-state molecular structures of the complexes Ru2H1 and Ru2H3 have been determined using the SC-XRD study, which confirms the N, O, and Cl-legged piano stool pseudo-octahedral geometry of each ruthenium(II) ion. The stability of these complexes in the solution state and their lipophilicity profile have been determined. Furthermore, the title complexes were tested for their in vitro anticancer activity against cancerous H460 (lung cancer cells), SkBr3 (breast cancer cells), HepG2 (liver cancer cells), and HeLa (cervical cancer cells) along with non-cancerous (HEK-293) cells. The IC50 results revealed that complex Ru2H3 exhibits potent activity against the proliferation of all four cancer cells and outscored the effect of the standard metallodrug cisplatin. This may be attributed to the presence of a couple of lipophilic electron-donating methoxy groups in the ligand scaffold and also the ruthenium(II) p-cymene motifs. Advantageously, all the complexes (Ru2H1-Ru2H3) displayed cytotoxic specificity only towards cancerous cells by leaving the off-target non-cancerous cells undamaged. Acridine orange/ethidium bromide (AO/EB) staining, Hoechst 33342, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) staining assays were used to investigate the apoptotic pathway and ROS levels in mitochondria. The results of western blot analysis confirmed that the complexes triggered apoptosis through an intrinsic mitochondrial pathway by upregulating Bax and downregulating Bcl-2 proteins. Finally, the extent of apoptosis triggered by the complex Ru2H3 was quantified with the aid of flow cytometry using the Annexin V-FITC/propidium iodide (PI) double-staining technique.

Deregulation of miR-375 Inhibits HOXA5 and Promotes Migration, Invasion, and Cell Proliferation in Breast Cancer.

Breast cancer (BC) is a highly aggressive tumour and one of the women's leading causes of cancer-related deaths in worldwide. MiR-375 overexpressed in BC cells, and its biological relevance is largely unknown. Here in, we explored the function of miR-375 in BC. MicroRNA-375 targets were predicted by online target prediction tools and found that HOXA5 is one of the potential targets. MTT assay was employed to assess the effect of miR-375 on cell proliferation, where migration and invasion transwell assays were applied to detect cell migratory and invasive ability. Besides, relative expression of miR-375 and HOXA5 was measured in BC and HEK-293 cells, and its downstream gene target expressions were evaluated by qRT-PCR and western blot. In this study, we found that miR-375 expression was higher in BC cell lines than in the HEK-293 cell line, whereas HOXA5 expression was significantly lower. Our study showed that exogenous inhibition of miR-375 promoted HOXA5 expression; on the contrary, miR-375 mimics down-regulated HOXA5 expression level. Knockdown of miR-375 expression in BC cells reduces cell proliferation, migration, and invasion by inverse correlation expression of HOXA5. Our findings associated that miR-375 accelerated apoptosis evasion, proliferation, migration, and invasion by targeting HOXA5. In addition, nucleolin interferes in miR-375 biogenesis while silencing of nucleolin significantly reduced miR-375 expression and increased HOXA5 expression in BC. Thus, miR-375/HOXA5 axis may represent a potential therapeutic target for BC treatment.

Naphthoyl benzhydrazine-decorated binuclear arene Ru(II) complexes as anticancer agents targeting human breast cancer cells.

Breast cancer is the most dangerous type in women and its fatality rate has increased over the past decade. To develop more potent and target-specific breast cancer drugs, six arene ruthenium(II) complexes (1-6) containing naphthoyl benzhydrazine ligands (NL1-NL3) were synthesized and characterized by analytical and spectroscopic (infrared, UV-visible, NMR and HR-MS) methods. The SC-XRD analysis of 1 and 6 demonstrates the bis N^O bidentate binding nature of ligands to ruthenium ions and a pseudo-octahedral geometry around the Ru(II) ion. Solution stability studies using UV-Vis spectroscopy evidenced the instantaneous hydrolysis of the complexes to form monoaquated species in a solution of 1 : 9 (v/v) DMSO/phosphate buffer. All the complexes were screened for their in vitro antiproliferative activities against different human breast cancer cells, including MCF-7, SkBr3, MDA-MB-468, MDA-MB-231, and non-cancerous HEK-293 cells, by an MTT assay, and they displayed good cancer cell growth inhibitory capacity with low IC50 values. Notably, complexes 2 and 5 comprising methoxy and p-cymene groups exhibited excellent cytotoxicity towards SkBr3 cells compared to clinical drug cisplatin. AO-EB and HOECHST-33342 staining assays revealed apoptotic morphological changes in complex-treated cancer cells. Further, reactive oxygen species and mitochondrial membrane potential assays validated that the complexes induce apoptotic cell death via an intrinsic mitochondrial pathway with ROS production. In addition, the apoptotic induction and the quantification of late apoptosis were established with the aid of western blot and flow cytometry analysis, respectively.

Spectroscopic analysis of photoneutrons in intense γ-ray background.

CR-39 SSNTD is used to measure the photoneutron spectrum produced by a medical linear accelerator in an intense γ-ray background. The spectroscopic resolution and the neutron detection threshold have been improved by introducing the event selection criteria, based on the track diameter-brightness correlation. The CR-39 detector's efficiency is determined by adapting the 1H(n,el) cross section from the ENDF/B-VIII.0 evaluations. The measured spectrum was reproduced through Talys-1.96 calculations by implementing the Gogny-HFB microscopic level density model.

Association of viral kinetics, infection history, NS1 protein with plasma leakage among Indonesian dengue infected patients.

OBJECTIVES: Plasma leakage, a hallmark of disease in Dengue virus (DENV) infection, is an important clinical manifestation and is often associated with numerous factors such as viral factors. The aim of this study is to investigate the association of virus serotype, viral load kinetics, history of infection, and NS1 protein with plasma leakage. METHODS: Subjects with fever ≤ 48 hours and positive DENV infection were included. Serial laboratory tests, viral load measurements, and ultrasonography examination to assess plasma leakage were performed. RESULTS: DENV-3 was the most common serotype found in the plasma leakage group (35%). Patients with plasma leakage demonstrated a trend of higher viral load and a longer duration of viremia compared to those without. This was significantly observed on the fourth day of fever (p = 0.037). We found higher viral loads on specific days in patients with plasma leakage in both primary and secondary infections compared to those without. In addition, we also observed more rapid viral clearance in patients with secondary infection. NS1 protein, especially after 4 days of fever, was associated with higher peak viral load level, even though it was not statistically significant (p = 0.470). However, pairwise comparison demonstrated that peak viral load level in the group of patients with circulating NS1 detected for 7 days was significantly higher than the 5-day group (p = 0.037). CONCLUSION: DENV-3 was the most common serotype to cause plasma leakage. Patients with plasma leakage showed a trend of higher viral load and a longer duration of viremia. Higher level of viral load was observed significantly on day 5 in patients with primary infection and more rapid viral clearance was observed in patients with secondary infection. Longer duration of circulating NS1 protein was also seen to be positively correlated with higher peak viral load level although not statistically significant.

Challenging refractory type B lactic acidosis in gastric adenocarcinoma-a successfully managed case.

Type B lactic acidosis is a rare complication of gastric adenocarcinoma and is associated with poor prognosis. Very few cases have been reported in the literature. A 48-year-old female presented with recurrent episodes of vomiting, loss of appetite and loss of weight for 1 month duration. Endoscopy and subsequent biopsy revealed poorly differentiated adenocarcinoma at the pyloric antrum causing gastric outflow obstruction. Contrast enhanced computed tomography scan of the chest, abdomen and pelvis revealed a malignant neoplasm of the pylorus with no distant metastasis. She developed refractory lactic acidosis not responding to medical treatment. Distal gastrectomy with limited lymph node clearance was done and lactic acidosis improved. Pathophysiology of type B lactic acidosis in solid organ malignancies can be due to the rapid turnover of cells inducing anaerobic glycolysis, thiamine deficiency and extensive hepatic metastasis. This patient did not have hepatic metastasis. This is a successful, surgically managed case of type B lactic acidosis in a patient with gastric adenocarcinoma so far reported in the region. Type B lactic acidosis is very rare in gastric cancer. Patients with refractory lactic acidosis should bring about high suspicion of solid organ malignancies and good clinical outcomes can be obtained by the reduction of tumour burden.

Triphenylphosphonium conjugated gold nanotriangles impact Pi3K/AKT pathway in breast cancer cells: a photodynamic therapy approach.

Although gold nanoparticles based photodynamic therapy (PDT) were reported to improve efficacy and specificity, the impact of surface charge in targeting cancer is still a challenge. Herein, we report gold nanotriangles (AuNTs) tuned with anionic and cationic surface charge conjugating triphenylphosphonium (TPP) targeting breast cancer cells with 5-aminoleuvinic acid (5-ALA) based PDT, in vitro. Optimized surface charge of AuNTs with and without TPP kill breast cancer cells. By combining, 5-ALA and PDT, the surface charge augmented AuNTs deliver improved cellular toxicity as revealed by MTT, fluorescent probes and flow cytometry. Further, the 5-ALA and PDT treatment in the presence of AuNTs impairs cell survival Pi3K/AKT signaling pathway causing mitochondrial dependent apoptosis. The cumulative findings demonstrate that, cationic AuNTs with TPP excel selective targeting of breast cancer cells in the presence of 5-ALA and PDT.

Impact of Surface Charge-Tailored Gold Nanorods for Selective Targeting of Mitochondria in Breast Cancer Cells Using Photodynamic Therapy.

Herein, the impact of surface charge tailored of gold nanorods (GNRs) on breast cancer cells (MCF-7 and MDA-MB-231) upon conjugation with triphenylphosphonium (TPP) for improved photodynamic therapy (PDT) targeting mitochondria was studied. The salient features of the study are as follows: (i) positive (CTAB@GNRs) and negative (PSS-CTAB@GNRs) surface-charged gold nanorods were developed and characterized; (ii) the mitochondrial targeting efficiency of gold nanorods was improved by conjugating TPP molecules; (iii) the conjugated nanoprobes (TPP-CTAB@GNRs and TPP-PSS-CTAB@GNRs) were evaluated for PDT in the presence of photosensitizer (PS), 5-aminolevulinic acid (5-ALA) in breast cancer cells; (iv) both nanoprobes (TPP-CTAB@GNRs and TPP-PSS-CTAB@GNRs) induce apoptosis, damage DNA, generate reactive oxygen species, and decrease mitochondrial membrane potential upon 5-ALA-based PDT; and (v) 5-ALA-PDT of two nanoprobes (TPP-CTAB@GNRs and TPP-PSS-CTAB@GNRs) impact cell signaling (PI3K/AKT) pathway by upregulating proapoptotic genes and proteins. Based on the results, we confirm that the positively charged (rapid) nanoprobes are more advantageous than their negatively (slow) charged nanoprobes. However, depending on the kind and degree of cancer, both nanoprobes can serve as efficient agents for delivering anticancer therapy.

Human endogenous retroviruses and multiple sclerosis: innocent bystanders or disease determinants?

Human endogenous retroviruses (HERVs) constitute 5-8% of human genomic DNA and are replication incompetent despite expression of individual HERV genes from different chromosomal loci depending on the specific tissue. Several HERV genes have been detected as transcripts and proteins in the central nervous system, frequently in the context of neuroinflammation. The HERV-W family has received substantial attention in large part because of associations with diverse syndromes including multiple sclerosis (MS) and several psychiatric disorders. A HERV-W-related retroelement, multiple sclerosis retrovirus (MSRV), has been reported in MS patients to be both a biomarker as well as an effector of aberrant immune responses. HERV-H and HERV-K have also been implicated in MS and other neurological diseases but await delineation of their contributions to disease. The HERV-W envelope-encoded glycosylated protein, syncytin-1, is encoded by chromosome 7q21 and exhibits increased glial expression within MS lesions. Overexpression of syncytin-1 in glia induces endoplasmic reticulum stress leading to neuroinflammation and the induction of free radicals, which damage proximate cells. Syncytin-1's receptor, ASCT1 is a neutral amino acid transporter expressed on glia and is suppressed in white matter of MS patients. Of interest, antioxidants ameliorate syncytin-1's neuropathogenic effects raising the possibility of using these agents as therapeutics for neuroinflammatory diseases. Given the multiple insertion sites of HERV genes as complete and incomplete open reading frames, together with their differing capacity to be expressed and the complexities of individual HERVs as both disease markers and bioactive effectors, HERV biology is a compelling area for understanding neuropathogenic mechanisms and developing new therapeutic strategies.

Breaking new frontiers: Assessment and re-evaluation of clinical trial design for nutraceuticals.

Despite sophisticated study designs and measurement tools, we have yet to create an innovative space for diet and dietary supplements in the health care system. The path is challenging due to current hierarchies of scientific evidence and regulatory affairs. The role of the randomized, double-blind, placebo-controlled clinical trial (RCT) as a research approach functions well to characterize the benefits and risks of drugs but lacks the sensitivity to capture the efficacy and safety of nutraceuticals. While some facets of RCTs can be relevant and useful when applied to nutraceuticals, other aspects are limiting and potentially misleading when taken in their entirety. A differentiation between guidelines for evidence-based medicine and the evidence required for nutrition spotlight the need to reconceptualize constituents of the RCT and their applicability with relevance to health promotion. This perspective identifies the limitations of the traditional RCT to capture the complexities of nutraceuticals and proposes the N-of-1 as Level 1 evidence better suited for the proof of efficacy of nutraceuticals.

The absence of cellular glucose triggers oncogene AEG-1 that instigates VEGFC in HCC: A possible genetic root cause of angiogenesis.

BACKGROUND AND OBJECTIVE: Astrocyte Elevated Gene-1 (AEG-1) is the master and multi-regulator of the various transcriptional factor primarily regulating chemoresistance, angiogenesis, metastasis, and invasion under the pathological condition, including liver cancer. This study was focused on investigating the process of tumor angiogenesis in liver carcinoma by studying the role of AEG-1 under GD/2DG conditions. METHOD AND RESULTS: The PCR and western blot analysis revealed that glucose depletion (GD) induces the overexpression of AEG-1. Further, it leads to the constant expression of VEGFC through the activation of HIF-1α/CCR7 via the stimulations of PI3K/Akt signaling pathways. GLUT2 is the major transporter of a glucose molecule that is highly participating under GD through the expression of AEG-1 and constantly expresses glucokinase (GCK). The obtained data suggest that AEG-1 act as an angiogenesis and glycolysis regulator by modulating the expression of GCK through HIF-1α and GLUT2. 2-deoxy-D-glucose (2DG) is a glycolysis inhibitor that induces impaired glycolysis and cellular apoptosis by cellular oxidative stress. The administration of 2DG has led to the chemoresistance of AEG-1. CONCLUSION: The total findings of the study judged that disruption of cellular energy metabolism induced by the absence of glucose or the presence of mutant glucose moiety (2DG) promotes the overexpression of AEG-1. The GD/2DG activates the VEGFC by inducing the HIF-1α and CCR7. Moreover, AEG-1 induces the expression of OPN, which regulates metastasis, angiogenesis, and actively participates in protective autophagy by promoting LC3 a/b.