Paraquat and Parkinson's Disease: The Molecular Crosstalk of Upstream Signal Transduction Pathways Leading to Apoptosis.

Parkinson's disease (PD) is a heterogeneous disease involving a complex interaction between genes and the environment that affects various cellular pathways and neural networks. Several studies have suggested that environmental factors such as exposure to herbicides, pesticides, heavy metals, and other organic pollutants are significant risk factors for the development of PD. Among the herbicides, paraquat has been commonly used, although it has been banned in many countries due to its acute toxicity. Although the direct causational relationship between paraquat exposure and PD has not been established, paraquat has been demonstrated to cause the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The underlying mechanisms of the dopaminergic lesion are primarily driven by the generation of reactive oxygen species, decrease in antioxidant enzyme levels, neuroinflammation, mitochondrial dysfunction, and ER stress, leading to a cascade of molecular crosstalks that result in the initiation of apoptosis. This review critically analyses the crucial upstream molecular pathways of the apoptotic cascade involved in paraquat neurotoxicity, including mitogenactivated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT, mammalian target of rapamycin (mTOR), and Wnt/ß-catenin signaling pathways.

Exploring Team-Based Teaching of Basic Sciences and Clinical Practice: Experiences of Pharmacy Students at a Malaysian Pharmacy School.

Interdisciplinary learning combining foundational science concepts and clinical practice applications is important in many healthcare-related programmes, including pharmacy. The coherent, structured interdisciplinary curricula designed by specialists may not always be perceived as integrated by students. Team teaching, an education approach where two or more instructors share teaching responsibilities within a classroom setting, may help eliminate this perception. This study aims to explore whether team teaching can improve Asian students' experience of learning in an undergraduate pharmacy programme in Malaysia. A single 2-h interactive lecture session was delivered using a team-based approach to year 4 undergraduate pharmacy students enrolled at the School of Pharmacy, Monash University Malaysia, from 2015 to 2017. All students who attended the team-based teaching lectures were provided with an anonymous link, which requested responses on their views towards team-based teaching. Fifty out of 104 participants from three different cohorts responded to the survey of this study. Over 75% of students reported that they learnt better with the team teaching approach compared to traditional lectures delivered by one lecturer and that the team teaching approach was superior to private study. About 60% of the participants agreed that the team-based teaching approach helped develop their information-synthesising and problem-solving skills. This study provides evidence for using team teaching for design and delivery in an Asian context. The approach was well received by the participants.

Linking Diabetes to Alzheimer's Disease: Potential Roles of Glucose Metabolism and Alpha-Glucosidase.

Alzheimer's disease (AD) and type 2 diabetes mellitus (DM) are more prevalent with ageing and cause a substantial global socio-economic burden. The biology of these two conditions is well elaborated, but whether AD and type 2 DM arise from coincidental roots in ageing or are linked by pathophysiological mechanisms remains unclear. Research findings involving animal models have identified mechanisms shared by both AD and type 2 DM. Deposition of ß-amyloid peptides and formation of intracellular neurofibrillary tangles are pathological hallmarks of AD. Type 2 DM, on the other hand, is a metabolic disorder characterised by hyperglycaemia and insulin resistance. Several studies show that improving type 2 DM can delay or prevent the development of AD, and hence, prevention and control of type 2 DM may reduce the risk of AD later in life. Alpha-glucosidase is an enzyme that is commonly associated with hyperglycaemia in type 2 DM. However, it is uncertain if this enzyme may play a role in the progression of AD. This review explores the experimental evidence that depicts the relationship between dysregulation of glucose metabolism and AD. We also delineate the links between alpha-glucosidase and AD and the potential role of alpha-glucosidase inhibitors in treating AD.

Enhanced exon skipping and prolonged dystrophin restoration achieved by TfR1-targeted delivery of antisense oligonucleotide using FORCE conjugation in mdx mice.

Current therapies for Duchenne muscular dystrophy (DMD) use phosphorodiamidate morpholino oligomers (PMO) to induce exon skipping in the dystrophin pre-mRNA, enabling the translation of a shortened but functional dystrophin protein. This strategy has been hampered by insufficient delivery of PMO to cardiac and skeletal muscle. To overcome these limitations, we developed the FORCETM platform consisting of an antigen-binding fragment, which binds the transferrin receptor 1, conjugated to an oligonucleotide. We demonstrate that a single dose of the mouse-specific FORCE-M23D conjugate enhances muscle delivery of exon skipping PMO (M23D) in mdx mice, achieving dose-dependent and robust exon skipping and durable dystrophin restoration. FORCE-M23D-induced dystrophin expression reached peaks of 51%, 72%, 62%, 90% and 77%, of wild-type levels in quadriceps, tibialis anterior, gastrocnemius, diaphragm, and heart, respectively, with a single 30 mg/kg PMO-equivalent dose. The shortened dystrophin localized to the sarcolemma, indicating expression of a functional protein. Conversely, a single 30 mg/kg dose of unconjugated M23D displayed poor muscle delivery resulting in marginal levels of exon skipping and dystrophin expression. Importantly, FORCE-M23D treatment resulted in improved functional outcomes compared with administration of unconjugated M23D. Our results suggest that FORCE conjugates are a potentially effective approach for the treatment of DMD.

The biggest problem confronting oligonucleotide therapeutics is a lack of compounds capable of targeting compounds to diseased tissues. This paper reports a major advance targeting the transferrin receptor to increase the delivery of morpholine oligomers to muscle cells in vivo. This work suggests the possibility for improved treatments of muscular dystrophy and other diseases.

Cellular and Molecular Events Leading to Paraquat-Induced Apoptosis: Mechanistic Insights into Parkinson's Disease Pathophysiology.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the cardinal features of tremor, bradykinesia, rigidity, and postural instability, in addition to other non-motor symptoms. Pathologically, PD is attributed to the loss of dopaminergic neurons in the substantia nigra pars compacta, with the hallmark of the presence of intracellular protein aggregates of α-synuclein in the form of Lewy bodies. The pathogenesis of PD is still yet to be fully elucidated due to the multifactorial nature of the disease. However, a myriad of studies has indicated several intracellular events in triggering apoptotic neuronal cell death in PD. These include oxidative stress, mitochondria dysfunction, endoplasmic reticulum stress, alteration in dopamine catabolism, inactivation of tyrosine hydroxylase, and decreased levels of neurotrophic factors. Laboratory studies using the herbicide paraquat in different in vitro and in vivo models have demonstrated the induction of many PD pathological features. The selective neurotoxicity induced by paraquat has brought a new dawn in our perspectives about the pathophysiology of PD. Epidemiological data have suggested an increased risk of developing PD in the human population exposed to paraquat for a long term. This model has opened new frontiers in the quest for new therapeutic targets for PD. The purpose of this review is to synthesize the relationship between the exposure of paraquat and the pathogenesis of PD in in vitro and in vivo models.

Potential Roles of α-amylase in Alzheimer's Disease: Biomarker and Drug Target.

Alzheimer's disease (AD), the most common form of dementia, is pathologically characterized by the deposition of amyloid-ß plaques and the formation of neurofibrillary tangles. In a neurodegenerative brain, glucose metabolism is also impaired and considered as one of the key features in AD patients. The impairment causes a reduction in glucose transporters and the uptake of glucose as well as alterations in the specific activity of glycolytic enzymes. Recently, it has been reported that α-amylase, a polysaccharide-degrading enzyme, is present in the human brain. The enzyme is known to be associated with various diseases such as type 2 diabetes mellitus and hyperamylasaemia. With this information at hand, we hypothesize that α-amylase could have a vital role in the demented brains of AD patients. This review aims to shed insight into the possible link between the expression levels of α-amylase and AD. Lastly, we also cover the diverse role of amylase inhibitors and how they could serve as a therapeutic agent to manage or stop AD progression.

The CNS-penetrant soluble guanylate cyclase stimulator CYR119 attenuates markers of inflammation in the central nervous system.

BACKGROUND: Inflammation in the central nervous system (CNS) is observed in many neurological disorders. Nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling plays an essential role in modulating neuroinflammation. CYR119 is a CNS-penetrant sGC stimulator that amplifies endogenous NO-sGC-cGMP signaling. We evaluated target engagement and the effects of CYR119 on markers of neuroinflammation in vitro in mouse microglial cells and in vivo in quinolinic acid (QA)-induced and high-fat diet-induced rodent neuroinflammation models. METHODS: Target engagement was verified in human embryonic kidney (HEK) cells, rat primary neurons, mouse SIM-A9 cells, and in rats by measuring changes in cGMP and downstream targets of sGC signaling [phosphorylated vasodilator-stimulated phosphoprotein (pVASP), phosphorylated cAMP-response element binding (pCREB)]. In SIM-A9 cells stimulated with lipopolysaccharides (LPS), markers of inflammation were measured when cells were treated with or without CYR119. In rats, microinjections of QA and vehicle were administered into the right and left hemispheres of striatum, respectively, and then rats were dosed daily with either CYR119 (10 mg/kg) or vehicle for 7 days. The activation of microglia [ionized calcium binding adaptor molecule 1 (Iba1)] and astrocytes [glial fibrillary acidic protein (GFAP)] was measured by immunohistochemistry. Diet-induced obese (DIO) mice were treated daily with CYR119 (10 mg/kg) for 6 weeks, after which inflammatory genetic markers were analyzed in the prefrontal cortex. RESULTS: In vitro, CYR119 synergized with exogenous NO to increase the production of cGMP in HEK cells and in primary rat neuronal cell cultures. In primary neurons, CYR119 stimulated sGC, resulting in accumulation of cGMP and phosphorylation of CREB, likely through the activation of protein kinase G (PKG). CYR119 attenuated LPS-induced elevation of interleukin 6 (IL-6) and tumor necrosis factor (TNF) in mouse microglial cells. Following oral dosing in rats, CYR119 crossed the blood-brain barrier (BBB) and stimulated an increase in cGMP levels in the cerebral spinal fluid (CSF). In addition, levels of proinflammatory markers associated with QA administration or high-fat diet feeding were lower in rodents treated with CYR119 than in those treated with vehicle. CONCLUSIONS: These data suggest that sGC stimulation could provide neuroprotective effects by attenuating inflammatory responses in nonclinical models of neuroinflammation.

The CNS-Penetrant Soluble Guanylate Cyclase Stimulator CY6463 Reveals its Therapeutic Potential in Neurodegenerative Diseases.

Effective treatments for neurodegenerative diseases remain elusive and are critically needed since the burden of these diseases increases across an aging global population. Nitric oxide (NO) is a gasotransmitter that binds to soluble guanylate cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP). Impairment of this pathway has been demonstrated in neurodegenerative diseases. Normalizing deficient NO-cGMP signaling could address multiple pathophysiological features of neurodegenerative diseases. sGC stimulators are small molecules that synergize with NO, activate sGC, and increase cGMP production. Many systemic sGC stimulators have been characterized and advanced into clinical development for a variety of non-central nervous system (CNS) pathologies. Here, we disclose the discovery of CY6463, the first brain-penetrant sGC stimulator in clinical development for the treatment of neurodegenerative diseases, and demonstrate its ability to improve neuronal activity, mediate neuroprotection, and increase cognitive performance in preclinical models. In several cellular assays, CY6463 was demonstrated to be a potent stimulator of sGC. In agreement with the known effects of sGC stimulation in the vasculature, CY6463 elicits decreases in blood pressure in both rats and mice. Relative to a non-CNS penetrant sGC stimulator, rodents treated with CY6463 had higher cGMP levels in cerebrospinal fluid (CSF), functional-magnetic-resonance-imaging-blood-oxygen-level-dependent (fMRI-BOLD) signals, and cortical electroencephalographic (EEG) gamma-band oscillatory power. Additionally, CY6463 improved cognitive performance in a model of cognitive disruption induced by the administration of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. In models of neurodegeneration, CY6463 treatment increased long-term potentiation (LTP) in hippocampal slices from a Huntington's disease mouse model and decreased the loss of dendritic spines in aged and Alzheimer's disease mouse models. In a model of diet-induced obesity, CY6463 reduced markers of inflammation in the plasma. Furthermore, CY6463 elicited an additive increase in cortical gamma-band oscillatory power when co-administered with donepezil: the standard of care in Alzheimer's disease. Together, these data support the clinical development of CY6463 as a novel treatment for neurodegenerative disorders.

Protective potential of cerium oxide nanoparticles in diabetes mellitus.

BACKGROUND: Diabetes mellitus (DM) is a non-communicable metabolic disease which is closely related to excessive oxidative stress after constant exposure to high plasma glucose. Although the current antidiabetic medications are effective in lowering blood glucose, these medications do not prevent or reverse the disease progression. Thus, there is a crucial need to explore new therapeutic interventions that could address this shortcoming. As cerium oxide nanoparticles (CONPs) possess antioxidant property, this agent may be used as a treatment option for the management of DM. PURPOSE: This review aims to provide a critical evaluation of the pharmacological and antidiabetic effects of CONPs in cell and animal models. The roles of CONPs in attenuating DM complications are also presented in this report. METHODS: We conducted a literature search in the PubMed database using the keywords "cerium oxide", "cerous oxide", "ceria", "nanoceria", and "diabetes" from inception to December 2020. The inclusion criteria were primary source articles that investigated the role of CONPs in DM and diabetic complications. RESULTS: We identified 47 articles from the initial search. After the thorough screening, only 31 articles were included in this study. We found that CONPs can attenuate parameters that are related to DM and diabetic complications in various animals and cell culture models. CONCLUSION: CONPs could potentially be used in the treatment of those with DM and complications caused by the disease.

Protective Effects of Polydatin Against Dementia-Related Disorders.

Dementia is a collection of symptoms affecting a person's cognition. Dementia is debilitating, and therefore, finding an effective treatment is of utmost importance. Resveratrol, which exhibits neuroprotective effects, has low bioavailability. However, its glucoside polydatin is more bioavailable. Here, the evidence that supports the protective role of polydatin against dementia- related diseases such as Alzheimer's disease, vascular dementia, alcohol-related dementia, and Lewy body dementias is presented. The beneficial effects of polydatin from a mechanistic perspective are specifically emphasized in this review. Future directions in this area of research are also discussed.

Antioxidant and Anti-inflammatory Properties of Yttrium Oxide Nanoparticles: New Insights into Alleviating Diabetes.

BACKGROUND: Diabetes mellitus is a metabolic disease that requires immediate attention. Oxidative stress that leads to the generation of reactive oxygen species is a contributing factor to the disease progression. Yttrium oxide nanoparticles (Y2O3 NPs) have a profound effect on alleviating oxidative damage. METHODS: The literature related to Y2O3 NPs and oxidative stress has been thoroughly searched using PubMed and Scopus databases and relevant studies from inception until August 2020 were included in this scoping review. RESULTS: Y2O3 NPs altered oxidative stress-related biochemical parameters in different disease models including diabetes. CONCLUSION: Although Y2O3 NPs are a promising antidiabetic agent due to their antioxidant and anti- inflammatory properties, more studies are required to further elucidate the pharmacological and toxicological properties of these nanoparticles.

The potential role of nanoyttria in alleviating oxidative stress biomarkers: Implications for Alzheimer's disease therapy.

Alzheimer's disease (AD) is a fatal neurodegenerative disease that requires immediate attention. Oxidative stress that leads to the generation of reactive oxygen species is a contributing factor to the disease progression by promoting synthesis and deposition of amyloid-ß, the main hallmark protein in AD. It has been previously demonstrated that nanoyttria possesses antioxidant properties and can alleviate cellular oxidative injury in various toxicity and disease models. This review proposed that nanoyttria could be used for the treatment of AD. In this paper, the evidence on the antioxidant potential of nanoyttria is presented and its prospects on AD therapy are discussed.

The current and future perspectives of zinc oxide nanoparticles in the treatment of diabetes mellitus.

Diabetes mellitus (DM) is a multifaceted and costly disease, which requires serious attention. Finding a cheaper anti-diabetic alternative that can act on multiple disease-related targets and pathways is the ultimate treatment goal for DM. Nanotechnology has offered some exciting possibilities in biomedical and drug delivery applications. Zinc oxide nanoparticles (ZnO-NPs), a novel agent to deliver zinc, have great implications in many disease therapies including DM. This review summarizes the pharmacological mechanisms by which ZnO-NPs alleviate DM and diabetic complications. Research implications and future perspectives were also discussed.

The cellular and molecular processes associated with scopolamine-induced memory deficit: A model of Alzheimer's biomarkers.

Alzheimer's disease (AD) is neurodegenerative disorder that is associated with memory and cognitive decline in the older adults. Scopolamine is commonly used as a behavioral model in studying cognitive disorders including AD. Many studies have also concurrently examined the neurochemical mechanisms underlying the behavioral modifications by scopolamine treatment. Nonetheless, the scopolamine model has not become a standard tool in the early assessment of drugs. Furthermore, the use of scopolamine as a pharmacological model to study AD remains debatable. This report reviews the scopolamine-induced cellular and molecular changes and discusses how these changes relate to AD pathogenesis.

The protective mechanisms of polydatin in cerebral ischemia.

The prevalence of stroke is high in both developing and developed nations. It causes a heavy social and financial burden to the sufferers and their caregivers. Thrombolytic therapy is the only pharmacological treatment available for stroke. However, thrombolytic agents do not provide substantial improvement on long term motor and cognitive disabilities. Thus, there is a need to explore for new compounds that can halt or reverse the deterioration of neurons in the stroke patients' brain. Polydatin, a precursor of resveratrol, is a natural stilbene commonly found in food. This review article describes how different parameters were altered with ischemic injury and polydatin treatment, why it is important and how it could be beneficial or useful in future studies. Our review of polydatin provides convincing evidence regarding the potential of polydatin to be developed into preventive or therapeutic products for ischemic stroke. Nevertheless, additional studies are necessary in order to properly elucidate the biological mechanisms of polydatin, especially its molecular mechanisms of protection and target proteins, in cerebral ischemia.

Cligosiban, A Novel Brain-Penetrant, Selective Oxytocin Receptor Antagonist, Inhibits Ejaculatory Physiology in Rodents.

INTRODUCTION: Few treatments are available for men with premature ejaculation (PE); oxytocin (OT) receptor antagonism in the central nervous system (CNS) is a potential new approach. AIM: To determine if cligosiban selectively inhibits human OT receptors, penetrates the CNS, shows pharmacology in the CNS, and effects ejaculatory physiology in pre-clinical systems. METHODS: Experiments complied with United Kingdom legislation and were subject to local ethical review. In vitro potency and selectivity of cligosiban was assessed using recombinant and native OT receptor systems including both neuronal and non-neuronal cell types. Selectivity was determined over neighboring V1A, V1B, and V2 vasopressin receptors using a combination of recombinant and native vasopressin receptor assay systems. To determine an effect on central OT receptors and on ejaculation, cligosiban was evaluated in 2 anesthetized rat models-the electromyography model of ejaculatory physiology and a model of OT-mediated CNS neuronal firing. The CNS penetration of cligosiban was also determined by measuring cerebrospinal fluid and plasma drug concentrations following an intravenous (IV) infusion in rats. MAIN OUTCOME MEASURE: These were functional measures of pharmacology in vitro, in cell lines and tissues, and in vivo in rats. RESULTS: Cligosiban is a potent OT receptor antagonist, with a base dissociation constant of 5.7 nmol/L against native human uterine smooth muscle cell OT receptors. Cligosiban displays similar antagonistic potency against human recombinant and rat native OT receptors, including neuronal OT receptors. Cligosiban demonstrates >100-fold selectivity over human V1A, V1B, and V2 vasopressin receptors. In the electromyography model, cligosiban (0.9 mg/kg, IV bolus) reduced the bulbospongiosum burst pattern and contraction amplitude associated with ejaculation. In the anesthetized CNS neuronal firing model, the same dosing regimen of cligosiban (0.9 mg/kg IV bolus) modulated the OT-mediated response in the nucleus tractus solitarius. After systemic dosing to rats, cligosiban showed good CNS penetration. CLINICAL IMPLICATIONS: As the first highly selective and centrally penetrant OT receptor antagonist, cligosiban represents a promising compound to test the clinical hypothesis that antagonism of central OT receptors may be of therapeutic benefit in the treatment of PE. STRENGTH & LIMITATIONS: The pharmacology and selectivity of cligosiban is determined using functional assays in recombinant cell lines, native cell lines, and tissue. Functional outcomes in in vivo systems are linked to CNS measures of pharmacology. The translation of the animal models of ejaculation to PE in man is unproven. CONCLUSION: Cligosiban, a potent, selective OT receptor antagonist, demonstrated CNS penetration and pharmacology and, using the same dosing regimen, inhibited apomorphine-induced ejaculation in rats. Cligosiban is a promising compound to test the clinical hypothesis that antagonism of central OT receptors may be of therapeutic benefit in the treatment of PE. Wayman C, Russell R, Tang K, et al. Cligosiban, A Novel Brain Penetrant Selective Oxytocin Receptor Antagonist, Inhibits Ejaculatory Physiology in Rodents. J Sex Med 2018;15:1698-1706.

Pharmacological Characterization of IW-1973, a Novel Soluble Guanylate Cyclase Stimulator with Extensive Tissue Distribution, Antihypertensive, Anti-Inflammatory, and Antifibrotic Effects in Preclinical Models of Disease.

Soluble guanylate cyclase (sGC), a key signal-transduction enzyme, increases the conversion of guanosine-5'-triphosphate to cGMP upon binding of nitric oxide (NO). Endothelial dysfunction and/or reduced NO signaling have been implicated in cardiovascular disease pathogenesis and complications of diabetes and have been associated with other disease states and aging. Soluble guanylate cyclase (sGC) stimulators are small-molecule drugs that bind sGC and enhance NO-mediated cGMP signaling. The pharmacological characterization of IW-1973 [1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl) pyrimidin-4-yl)amino)methyl)propan-2-ol], a novel clinical-stage sGC stimulator under clinical investigation for treatment of heart failure with preserved ejection fraction and diabetic nephropathy, is described. In the presence of NO, IW-1973 stimulated sGC in a human purified enzyme assay and a HEK-293 whole cell assay. sGC stimulation by IW-1973 in cells was associated with increased phosphorylation of vasodilator-stimulated phosphoprotein. IW-1973, at doses of 1-10 mg/kg, significantly lowered blood pressure in normotensive and spontaneously hypertensive rats. In a Dahl salt-sensitive hypertension model, IW-1973 significantly reduced blood pressure, inflammatory cytokine levels, and renal disease markers, including proteinuria and renal fibrotic gene expression. The results were affirmed in mouse lipopolysaccharide-induced inflammation and rat unilateral ureteral obstruction renal fibrosis models. A quantitative whole-body autoradiography study of IW-1973 revealed extensive tissue distribution and pharmacokinetic studies showed a large volume of distribution and a profile consistent with predicted once-a-day dosing in humans. In summary, IW-1973 is a potent, orally available sGC stimulator that exhibits renoprotective, anti-inflammatory, and antifibrotic effects in nonclinical models.

Expression of Plasma hsa-miR122 in HBV-Related Hepatocellular Carcinoma (HCC) in Vietnamese Patients.

BACKGROUND: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death in the world and considered as one of the most susceptible cancers in humans. The microRNA molecule, hsa-miR122, considered as a potential biological marker linked with the injury of hepatocellular tissue, is the most common microRNA in human liver cancer. Understanding the expression profile of hsa-miR122 plays an important role in the diagnosis of HCC. OBJECTIVE: Identification and comparison of cut-off values of plasma hsa-miR122 expression were conducted in blood samples of healthy control, HBV infected and HBV-related HCC Vietnamese patients. METHODS AND RESULT: Fifty-two blood samples of healthy control and HBV-related HCC cases, collected between 2015 and 2017 were obtained from Ho Chi Minh City Oncology Hospital, Vietnam. Written informed consent was attained from all patients and the Human Research Ethics Committee, Oncology Hospital (#08/BVUB-HDDD) approved the research protocol. Total RNA was isolated from blood samples with TrizolTM Reagent (Thermo Fisher Scientific, USA). To analyze the expression level of hsa-miR122, miRNA specific reverse transcription was performed using Sensi- FASTTM cDNA Synthesis Kit (Bioline, UK) as described by the manufacturer, followed by running RT-qPCR with SensiFASTTMSYBR No-ROX Kit (Bioline, UK). The housekeeping gene, GAPDH (glyceraldehyde-3-phosphate dehydrogenase) was used for normalization. The presence of hsamiR122 and HBV-DNA was identified in human blood using RT-PCR and LAMP techniques. Downregulation of plasma hsa-miR122 was observed in HBV-related HCC patients with a .Ct value of 7.9 ± 2.1 which was significantly lower than found in healthy control (p<0.01). The loss of hsa-miR122 expression was observed in HBV infected patients. We also identified the difference of diagnostic values of this microRNA in different populations and provided a high diagnostic accuracy of HCC (AUC = 0.984 with sensitivity and specificity of 96% and 94%, respectively). CONCLUSION: hsa-miR122 was downregulated in HBV-related HCC patients and found to be lower by approximately 10 fold than in healthy control, resulting in a potential biomarker for microRNA based diagnosis of HCC in human blood.

Excessive screen viewing time by adolescents and body fatness in a developing country: Vietnam.

BACKGROUND AND OBJECTIVES: Screen time among youth has been increasingly recognized as a public health problem because of its link with obesity. This has been demonstrated in many studies conducted in developed countries but few studies have addressed the problem in developing countries, despite an increase literature about the emergence of obesity and a greater access to screen devices in a country like Vietnam. Our study aimed at assessing screen time and its relationship with BMI in adolescents of Ho Chi Minh City (HCMC), Vietnam. METHODS AND STUDY DESIGN: In a cross-sectional study of 2024 junior high school students aged 11-14 of HCMC, students were measured for BMI and questioned on time spent watching television/Video/DVD or using computer for fun. High users were defined as time >=2 h/d. International Obesity Task Force BMI cutoffs were used to define overweight and obesity. RESULTS: Adolescents spent 2.2 h/d in screen time, with higher values for boys than girls (p<0.001). 53.8% of the respondents were high users. Time spent using computers for fun increased with age, and with the household wealthy index. The overall prevalence of overweight and obesity was 21.1%. Using multiple logistic regression, overweight and obesity was higher in boys (adjusted OR=2.66, 95% CI: [2.06; 3.44], p<0.001) and in children aged 11-12 who had a screen time >=2 h/d (adjusted OR=1.48, 95% CI: [1.09; 1.99], p<0.02). CONCLUSIONS: In HCMC, a majority of adolescents spent >=2 h/d on screen time. High screen time is associated with an increased prevalence of overweight and obesity in young adolescents. Public health intervention programs are needed to reduce screen time among youth.

Discovery and Characterization of a Potent Interleukin-6 Binding Peptide with Neutralizing Activity In Vivo.

Interleukin-6 (IL-6) is an important member of the cytokine superfamily, exerting pleiotropic actions on many physiological processes. Over-production of IL-6 is a hallmark of immune-mediated inflammatory diseases such as Castleman's Disease (CD) and rheumatoid arthritis (RA). Antagonism of the interleukin IL-6/IL-6 receptor (IL-6R)/gp130 signaling complex continues to show promise as a therapeutic target. Monoclonal antibodies (mAbs) directed against components of this complex have been approved as therapeutics for both CD and RA. To potentially provide an additional modality to antagonize IL-6 induced pathophysiology, a peptide-based antagonist approach was undertaken. Using a combination of molecular design, phage-display, and medicinal chemistry, disulfide-rich peptides (DRPs) directed against IL-6 were developed with low nanomolar potency in inhibiting IL-6-induced pSTAT3 in U937 monocytic cells. Targeted PEGylation of IL-6 binding peptides resulted in molecules that retained their potency against IL-6 and had a prolongation of their pharmacokinetic (PK) profiles in rodents and monkeys. One such peptide, PN-2921, contained a 40 kDa polyethylene glycol (PEG) moiety and inhibited IL-6-induced pSTAT3 in U937 cells with sub-nM potency and possessed 23, 36, and 59 h PK half-life values in mice, rats, and cynomolgus monkeys, respectively. Parenteral administration of PN-2921 to mice and cynomolgus monkeys potently inhibited IL-6-induced biomarker responses, with significant reductions in the acute inflammatory phase proteins, serum amyloid A (SAA) and C-reactive protein (CRP). This potent, PEGylated IL-6 binding peptide offers a new approach to antagonize IL-6-induced signaling and associated pathophysiology.