Endoplasmic Reticulum Stress and Lipid Metabolism: Mechanisms and Therapeutic Potential

The endoplasmic reticulum (ER) plays a crucial role in protein folding, assembly, and secretion. Disruption of ER homeostasis may lead to accumulation of misfolded or unfolded proteins in the ER lumen, a condition referred to as ER stress. In response to ER stress, a signal transduction pathway known as the unfolded protein response (UPR) is activated. UPR activation allows the cell to cope with an increased protein-folding demand on the ER. Recent studies have shown that ER stress/UPR activation plays a critical role in lipid metabolism and homeostasis. ER-stress-dependent dysregulation of lipid metabolism may lead to dyslipidemia, insulin resistance, cardiovascular disease, type 2 diabetes, and obesity. In this paper, we examine recent findings illustrating the important role ER stress/UPR signalling pathways play in regulation of lipid metabolism, and how they may lead to dysregulation of lipid homeostasis

Analysis of von Willebrand factor A domain-related protein (WARP) polymorphism in temperate and tropical Plasmodium vivax field isolates

<p>Abstract</p> <p>Background</p> <p>The identification of key molecules is crucial for designing transmission-blocking vaccines (TBVs), among those ookinete micronemal proteins are candidate as a general class of malaria transmission-blocking targets. Here, the sequence analysis of an extra-cellular malaria protein expressed in ookinetes, named von Willebrand factor A domain-related protein (WARP), is reported in 91 <it>Plasmodium vivax </it>isolates circulating in different regions of Iran.</p> <p>Methods</p> <p>Clinical isolates were collected from north temperate and southern tropical regions in Iran. Primers have been designed based on <it>P. vivax </it>sequence (ctg_6991) which amplified a fragment of about 1044 bp with no size variation. Direct sequencing of PCR products was used to determine polymorphism and further bioinformatics analysis in <it>P. vivax </it>sexual stage antigen, <it>pvwarp</it>.</p> <p>Results</p> <p>Amplified <it>pvwarp </it>gene showed 886 bp in size, with no intron. BLAST analysis showed a similarity of 98–100% to <it>P. vivax </it>Sal-I strain; however, Iranian isolates had 2 bp mismatches in 247 and 531 positions that were non-synonymous substitution [T (ACT) to A (GCT) and R (AGA) to S (AGT)] in comparison with the Sal-I sequence.</p> <p>Conclusion</p> <p>This study presents the first large-scale survey on <it>pvwarp </it>polymorphism in the world, which provides baseline data for developing WARP-based TBV against both temperate and tropical <it>P. vivax </it>isolates.</p

Seasonal Abundance and Host-Feeding Patterns of Anopheline Vectors in Malaria Endemic Area of Iran

Seasonal abundance and tendency to feed on humans are important parameters to measure for effective control of malaria vectors. The objective of this study was to describe relation between feeding pattern, abundance, and resting behavior of four malaria vectors in southern Iran. This study was conducted in ten indicator villages (based on malaria incidence and entomological indices) in mountainous/hilly and plain regions situated south and southeastern Iran. Mosquito vectors were collected from indoor as well as outdoor shelters and the blood meals were examined by ELISA test. Over all 7654 female Anopheles spp. were captured, the most common species were Anopheles stephensi, An. culicifacies, An. fluviatilis, and An. d'thali. The overall human blood index was 37.50%, 19.83%, 16.4%, and 30.1% for An. fluviatilis, An. stephensi, An. culicifacies, and An. d'thali, respectively. In addition, An. fluviatilis fed on human blood during the entire year but the feeding behavior of An. stephensi and An. culicifacies varied according to seasons. Overall, the abundance of the female mosquito positive to human blood was 4.25% per human shelter versus 17.5% per animal shelter. This result indicates that the vectors had tendency to rest in animal shelters after feeding on human. Therefore, vector control measure should be planned based on such as feeding pattern, abundance, and resting behavior of these vectors in the area

Cloning, expression and transmission-blocking activity of anti-PvWARP, malaria vaccine candidate, in Anopheles stephensi mysorensis

<p>Abstract</p> <p>Background</p> <p>Notwithstanding progress in recent years, a safe, an effective and affordable malaria vaccine is not available yet. Ookinete-secreted protein, <it>Plasmodium vivax </it>von Willebrand factor A domain-related protein (PvWARP), is a candidate for malaria transmission-blocking vaccines (TBVs).</p> <p>Methods</p> <p>The PvWARP was expressed in <it>Escherichia coli </it>BL21 using the pET-23a vector and was purified using Ni-NTA affinity chromatography from a soluble fraction. Polyclonal antibody was raised against rPvWARP and transmission blocking activity was carried out in an <it>Anopheles stephensi</it>-<it>P. vivax </it>model.</p> <p>Results</p> <p>Expression of full length of PvWARP (minus signal peptide) expression showed a 35-kDa protein. The purified protein was recognized by mouse polyclonal antibody directed against rPvWARP. Sera from the animals displayed significantly a blocking activity in the membrane feeding assay of <it>An. stephensi </it>mysorensis.</p> <p>Conclusions</p> <p>This is the first report on <it>P. vivax </it>WARP expression in <it>E. coli </it>that provides an essential base for development of the malaria TBV against <it>P. vivax</it>. This may greatly assist in malaria elimination, especially in the oriental corner of WHO Eastern Mediterranean Regional Office (WHO/EMRO) including Afghanistan, Iran and Pakistan.</p

Investigation of LAMP Technique in Diagnosis Type of Plasmodium Species in Anopheles Mosquitoes :A Fast and Practical Technique to Detect Malaria Pathogens in the Field

BACKGROUND፡ Malaria is one of the main parasitic diseases and a major health issue in some countries. This study aims to determine the rate and type of infections of Anopheles mosquitoes with malaria parasites using the molecular LAMP method in the Southeastern Iran.METHODS: In this study, 400 Anopheles mosquitoes were collected by the Zahedan Medical Insecticide Center in Nikshahr City, a high-risk area of malaria transmission in Sistan-Baluchestan Province. The mosquitoes were caught manually (by hand) in domestic (humans and animals), natural, and artificial outdoor places (Shelter pits). After DNA extraction, the LAMP method was used, which was compared with Multiplex Nested- PCR as a standard method.RESULTS: Out of 400 samples collected from Nikshahr City, 6 samples (1.5%) were infected with Plasmodium vivax. No Plasmodium falciparum or a mix (Plasmodium vivax and Plasmodium falciparum) was detected in this study.CONCLUSIONS: The results of this study indicate that in places with transmission of both species, i.e. Plasmodium vivax and Plasmodium falciparum, detection of malaria parasites by the LAMP method could be very useful in spotting infections in the field. Thus, molecular epidemiological studies could be conducted annually to monitor malaria in endemic regions. The results of this research show that contamination with mosquito malaria vectors is increasing in Nikshahr City, and it seems that more studies will be required to eliminate malaria until 2026

Bio-ecology of malaria vectors in an endemic area, Southeast of Iran

AbstractObjectiveTo determine some bio-ecological aspects of malaria vectors in Jask County, where is targeted for malaria elimination in the national program.MethodsMosquitoes were collected monthly during 2013–2014 using different collection methods. Subsequently, ELISA test was used to detect the human blood index of mosquitoes. The susceptibility status of Anopheles stephensi was evaluated against the diagnostic dosages of seven WHO recommended insecticides.ResultsA total of 3650 female and 4736 Anopheles larvae were collected including Anopheles stephensi, Anopheles culicifacies s.l., Anopheles dthali, Anopheles fluviatilis s.l., Anopheles moghulensis and Anopheles turkhodi species. Anopheles stephensi was the dominant collected species on human baits and indoors with high rate of unfed and gravid specimens in internal and external window traps. Human blood index was calculated as 14.3% for this species. It was also found to be resistant to DDT and Dieldrin.ConclusionsThe collected species had a wide range of habitats, and resting behaviors. With regarding to the presence of most important malaria vectors in Jask, control of the disease may be so complicated; as based on the weather condition it can be transmitted during the whole year, expect for cold months. With this strong potential of transmission, existing population movements in the area may lead to imported cases of malaria and local outbreak(s). So, more specific studies on malaria vectors in high risk areas of Jask County are recommended

Padimedical: Medical Image Sharing Portal with DICOM Viewer – User Experience

Digital Imaging and Communication in Medicine (DICOM) is a standard medical imaging format for medical imaging information and data. Availability to access DICOM files remotely using smartphones has shown to improve healthcare systems especially for communication between doctors fromdifferent centres. Most of DICOM files need to be viewed using conventional institutional DICOM viewer. We developed software which allows medical personnel to access DICOM images remotely from their smartphone. This newly created software platform is named Padimedical. This pilot study aims to evaluate users’ satisfaction and usability. Practising medical doctors from a radiology department in a tertiary referral centre were chosen as correspondents in this study. The survey form was sent to over 30 doctors via email. A total of 24 out of 30 respondents completed the survey. The survey showed that Padimedical DICOM viewer was easily accessible (100%), compatible with OS operating system (100%), user-friendly (87.1%), and high signal to noise ratio (100%). All respondents (100%) agreed that the image viewing was smooth and responsive. All respondents would recommend to their peers (n=24). A total of 18 respondents suggested that the quality of images was high (76%) and 23 respondents suggested that the contents in this newly created platform were easy to share (96.15%). All the participants were able to make the correct diagnosis using Padimedical. Overall, the rating of our platform is 4.3 out of 5. Conclusion: Based on this pilot survey, Padimedical software was easily accessible remotely using smartphones, compatible with OS operating system, viewing images were smooth and responsive, produce high-quality image, and easy to share DICOM contents.Keywords—DICOM, images, software

Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double‐blind, placebo‐controlled trials

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106831/1/apt12735.pd

Competency of Anopheles stephensi mysorensis strain for Plasmodium vivax and the role of inhibitory carbohydrates to block its sporogonic cycle

<p>Abstract</p> <p>Background</p> <p>Despite the abundance of studies conducted on the role of mosquitoes in malaria transmission, the biology and interaction of <it>Plasmodium </it>with its insect host still holds many mysteries. This paper provides the first study to follow the sporogonic cycle of <it>Plasmodium vivax </it>in a wild insecticide-resistant mysorensis strain of <it>Anopheles stephensi</it>, a major vector of vivax malaria in south-eastern Iran. The study subsequently demonstrates that host-parasite sugar binding interactions are critical to the development of this parasite in the salivary glands of its mosquito host. The identity of the receptors or sugars involved was revealed by a receptor "pre-saturation" strategy in which sugars fed to the mosquitoes inhibited normal host-parasite interactions.</p> <p>Methods</p> <p><it>Anopheles stephensi </it>mysorensis mosquitoes were artificially infected with <it>P. vivax </it>by feeding on the blood of gametocytaemic volunteers reporting to local malaria clinics in the Sistan-Baluchistan province of south-eastern Iran. In order to determine the inhibitory effect of carbohydrates on sporogonic development, vector mosquitoes were allowed to ingest blood meals containing both gametocytes and added carbohydrates. The carbohydrates tested were GlcNAc, GalNAc, arabinose, fucose, mannose, lactose, glucose and galactose. Sporogonic development was assessed by survival of the parasite at both the oocyst and sporozoite stages.</p> <p>Results</p> <p>Oocyst development was observed among nearly 6% of the fed control mosquitoes but the overall number of mosquitoes exhibiting sporozoite invasion of the salivary glands was 47.5% lower than the number supporting oocysts in their midgut. Of the tested carbohydrates, only arabinose and fucose slightly perturbed the development of <it>P. vivax </it>oocysts at the basal side of the mosquito midgut, and the remaining sugars caused no reductions in oocyst development. Strikingly however, sporozoites were completely absent from the salivary glands of mosquitoes treated with mannose, GalNAc, and lactose.</p> <p>Conclusion</p> <p>The study indicates that <it>An. stephensi </it>in southern Iran has the potential to survive long enough to be re-infected and transmit vivax malaria several times, based on the average adult female longevity (about 30 days) and its gonotrophic cycle (2–3 days) during the malaria transmission season. Certain sugar binding interactions are important for the development of <it>P. vivax </it>sporozoites, and this information may be instrumental for the development of transmission blocking strategies.</p

The quality control theory of aging

The quality control (QC) theory of aging is based on the concept that aging is the result of a reduction in QC of cellular systems designed to maintain lifelong homeostasis. Four QC systems associated with aging are 1) inadequate protein processing in a distressed endoplasmic reticulum (ER); 2) histone deacetylase (HDAC) processing of genomic histones and gene silencing; 3) suppressed AMPK nutrient sensing with inefficient energy utilization and excessive fat accumulation; and 4) beta-adrenergic receptor (BAR) signaling and environmental and emotional stress. Reprogramming these systems to maintain efficiency and prevent aging would be a rational strategy for increased lifespan and improved health. The QC theory can be tested with a pharmacological approach using three well-known and safe, FDA-approved drugs: 1) phenyl butyric acid, a chemical chaperone that enhances ER function and is also an HDAC inhibitor, 2) metformin, which activates AMPK and is used to treat type 2 diabetes, and 3) propranolol, a beta blocker which inhibits BAR signaling and is used to treat hypertension and anxiety. A critical aspect of the QC theory, then, is that aging is associated with multiple cellular systems that can be targeted with drug combinations more effectively than with single drugs. But more importantly, these drug combinations will effectively prevent, delay, or reverse chronic diseases of aging that impose such a tremendous health burden on our society