Arsenic exposure is associated with alterations to multiple red blood cell parameters among adults in rural Bangladesh.

Chronic arsenic exposures are associated with multiple hematologic disturbances, including anemia. The goal of this study was to evaluate associations between arsenic exposures and hematological parameters among men and women who are chronically exposed to elevated levels of arsenic from drinking water. Hematologic analyses were performed on blood collected from 755 participants (45% male and 54% female) in the Health Effects of Arsenic Longitudinal Study (HEALS) cohort, Bangladesh. Herein, we used linear regression models to estimate associations between red blood cell (RBC) parameters (i.e., RBC counts, hematocrit (HCT), hemoglobin (Hgb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC)) and measurements of arsenic exposure (urinary arsenic and urinary arsenic metabolites). Arsenic exposures showed trending associations with decreased RBC counts in both men and women, a positive association with MCV in males, and an inverse association with MCHC among males, but not among non-smoking females. Among men, those who smoked had stronger associations between arsenic exposures and MCHC than non-smoking males. Collectively, our results show that arsenic exposures affect multiple RBC parameters and highlight potentially important sex differences in arsenic-induced hematotoxicity.

Strain-specific clearance of seed-dependent tau aggregation by lithium-induced autophagy.

Different conformational strains of tau have been implicated in the clinicopathological heterogeneity of tauopathies. In this study, we hypothesized that distinct strains are degraded in a different manner. Lithium, a drug for bipolar disorder, had previously been reported to reduce aggregation-prone protein content by promoting autophagy. Here, we assessed the effects of lithium on tau aggregates using different tauopathy brain seeds. SH-SY5Y cells were transfected with C-terminal tau fragment Tau-CTF24 (residues 243-441), and Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) brain seeds were introduced. After 48-h lithium treatment, sarkosyl-insoluble fractions were prepared. Lithium treatment was found to reduce the amount of insoluble tau and p62, and increase LC3-II levels along with the number of autophagic vacuoles in AD-seeded cells. The effects were lower in case of CBD seeds, and comparable between PSP and AD seeds. An inhibitor of myo-inositol monophosphatase (IMPase) also demonstrated similar effects. Overall, the study suggested that aggregated tau protein is degraded by lithium-induced autophagy, influencing IMPase in a strain-specific manner.

Cartiotonic steroids affect monolayer permeability in lymphatic endothelial cells.

Edema is common in preeclampsia (preE), a hypertensive disorder of pregnancy. Cardiotonic steroids (CTSs) such as marinobufagenin (MBG) are involved in the pathogenesis of preE. To assess whether CTSs are involved in the leakage of lymphatic endothelial cell (LEC), we evaluated their effect on monolayer permeability of LECs (MPLEC) in culture. A rat mesenteric LECs were treated with DMSO (vehicle), and CTSs (MBG, CINO, OUB) at concentrations of 1, 10, and 100 nM. Some LECs were pretreated with 1 µM L-NAME (N-Nitro-L-Arginine Methyl Ester) before adding 100 nM MBG or cinobufotalin (CINO). Expression of ß-catenin and vascular endothelial (VE)-cadherin in CTS-treated LECs was measured by immunofluorescence and MPLEC was quantified using a fluorescence plate reader. Western blot was performed to measure ß-catenin and VE-cadherin protein levels and myosin light chain 20 (MLC20) phosphorylation. MBG (≥ 1 nM) and CINO (≥ 10 nM) caused an increase (p < 0.05) in the MPLEC compared to DMSO while ouabain (OUB) had no effect. Pretreatment of LECs with 1 µM L-NAME attenuated (p < 0.05) the MPLEC. The ß-catenin expression in LECs was downregulated (p < 0.05) by MBG and CINO. However, there was no effect on the LECs tight junctions for the CINO group. VE-cadherin expression was downregulated (p < 0.05) by CINO, and MLC20 phosphorylation was upregulated (p < 0.05) by MBG. We demonstrated that MBG and CINO caused an increase in the MPLEC, which were attenuated by L-NAME pretreatment. The data suggest that CTSs exert their effect via nitric-oxide-dependent signaling pathway and may be involved in vascular leak syndrome of LEC lining in preE.

A prospective cohort study on association of first-trimester serum biomarkers and risk of isolated foetal congenital heart defects.

BACKGROUND: This study aims to assess the association between first-trimester biomarkers in foetuses with a non-chromosomal congenital heart defect (CHD) and compares it to the matched healthy foetuses. METHOD: Nuchal Translucency (NT), Pregnancy-Associated Plasma Protein-A (PAPP-A) and free beta-human Chorionic Gonadotropin (ß-hCG) were evaluated in 56 isolated foetal heart defects and 224 controls. The CHDs were further divided into Critical CHD (C-CHD) and Non-critical CHD (N-CHD) groups. RESULTS: The multiple of the median (MoM) values for PAPP-A were significantly lower (0.87 MoM vs. 0.92 MoM; p = 0.008) in the total CHD group than in controls. The median of foetal NT values was significantly higher in the total CHDs than in controls (1.16 MoM vs. 1.03 MoM; p < 0.001), especially for C-CHDs (1.28 MoM; P < 0.001). There were no significant differences in terms of PAPP-A (p = 0.779) and foetal NT values (p = 0.760) between the N-CHDs and control groups. There were no significant differences within the groups based on free ß-hCG, except for a lower ß-hCG in C-CHD group than in the control group (0.95 MoM vs. 1.11 MoM; p = 0.022). CONCLUSION: Lower PAPP-A levels and increased NT thickness were associated with an increased risk of CHDs, especially the critical type of CHDs.Clinical significanceMaternal serum PAPP-A, measured in the first trimester, is significantly lower in CHD.Foetal NT is significantly thicker in foetuses with CHD, especially those with critical CHD.Maternal serum ß-hCG was only decreased among critical CHD group.

Tribulus Terrestris may decrease muscle damage markers following a high-intensity resistance exercise: A pilot study.

The purpose of this study was to investigate the effect of two weeks of Tribulus Terrestris (TT) on the responses of Interleukin-6 (IL-6), high sensitivity C-reactive protein (hs-CRP), and enzymes creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) following a single session of resistance exercise (RE). Eighteen healthy non-athlete males (age: 22.44 ± 2.54 years, BMI: 26.15 ± 1.62 kg/m2) participated in this study and were divided randomly into two 9-person groups of supplementation or placebo. The participants consumed two 250-mg capsules of TT or placebo (maltodextrin) per day and performed six REs with the intensity 80, 85, and 90% of 1RM in three circles at the day after the end of supplementation period. Blood samples were collected before the initiation of supplementation, and before and after the RE session. Total changes of IL-6 (p<0.001) and LDH (p=0.005) were significant in both groups. Bonferroni post hoc test showed that increased values of IL-6 and CPK in both groups were significant after exercise compared with pre-exercise and baseline (p<0.001). There were no significant differences in relation to within- and between-group changes in hs-CRP (p>0.05). Moreover, differences between the groups regarding post-exercise IL-6 and CPK were not significant (p>0.05). However, post-exercise LDH in supplementation group were lower than placebo group (p=0.015). In conclusion, short-term supplementation with TT has no effect on IL-6 and hs-CRP, but may be effective on the reduction of muscle damage enzymes CPK and LDH following high-intensity circuit RE.

Potential Application of Ionic Liquids in Pharmaceutical Dosage Forms for Small Molecule Drug and Vaccine Delivery System.

Ionic liquids are salts in which the ions are poorly coordinated, which causes them to exist in liquid form below 100°C, or at room temperature. Therefore, these are also defined as room temperature ionic liquids (RTILs). In ionic liquids, at least one ion has a delocalized charge and one component is organic, which prevents the formation of a stable solid form of crystal lattice. Physical properties of ionic liquids, such as melting point, viscosity, and solubility of starting materials and other solvents, are impacted by the substituents on the organic component and by the counterions. Many ionic liquids have even been developed to address specific synthetic problems and that is the reason these are also termed as "designer solvents". Ionic liquids are considered as "green solvents" that exhibit several unique characteristics such as high ionic conductivity, high solvation power, thermal stability, low volatility, and recyclability. Although very useful with several advantages, ionic liquids have some limitations that include high cost and ease of recycling. Moreover, the toxicity and biodegradability of ionic liquids are not yet well understood. Nonetheless, ionic liquids can potentially be used in the field of pharmacy in drug design and formulation development. In drug or vaccine dosage formulation development, ionic liquids can be used as a solubility enhancer, permeability enhancer, stabilizer, targeted delivery inducer, stealth property provider or bioavailability enhancer. In this article we reviewed the physical properties of ionic liquids and potential application of ionic liquids in developing formulations for vaccines and small molecule drugs (A table has been added).

The role of miRNA in somatic embryogenesis.

Somatic embryogenesis (SEG) is one of the best techniques for mass production of economically important plants. It is also used for the study of morphology, anatomy, physiology, genetics and molecular mechanism of embryo development. Somatic Embryos (SE) are bipolar structures that develop from a cell other than a gamete or zygote. SEG reflects the unique developmental potential of plant somatic cells, resulting in the transition of the differentiated somatic cells to embryogenic cells to follow the zygotic embryo stages. There are several biochemical and physiological processes that transformed a single somatic cell to a whole plant. SE studies provide insight into cell mechanisms governing the totipotency process in plants. Previously, in vitro studies have suggested the role of various regulatory genes in embryogenic transition that are triggered by plant hormones in response to stress. The omic studies identify the specific genes, transcripts, and proteins required for somatic embryogenesis development. MicroRNAs (miRNAs) are small, 19-24 nucleotides (nt), non-coding small RNA regulatory molecules controlling a large number of biological processes. In addition to their role in SEG, miRNAs play vital role in plant development, secondary metabolite synthesis and metabolism of macromolecules, hormone signal transduction, and tolerance of plants to biotic and abiotic stresses. During last decade several types of miRNAs involved in SEG have been reported. Among these miRNAs, miR156, miR162, miR166a, miR167, miR168, miR171a/b, miR171c, miR393, miR397 and miR398 played very active role during various stages of SEG. In this review, we highlighted the role of these as well as other miRNAs in some economically important plants.

Overview and Future Potential of Fast Dissolving Buccal Films as Drug Delivery System for Vaccines.

Vaccination is considered one of the most successful public health interventions of the modern era. Vaccines are categorized based on the antigen used, delivery system and the route of administration. Traditional vaccines are produced from the dead, attenuated or inactivated pathogens that cause disease. However, newly developed vaccines are DNA based, liposome based, and virus like particle (VLP) based which are more effective and specific to some malignant diseases. The delivery system of vaccines has been advanced along with time as well. New delivery systems such as nanoparticles, liposomes, or cells (for DNA) has been proven to develop a more efficient vaccine. Most vaccines are administered via intramuscular (IM), subcutaneous (SQ) or oral (PO) route. However, these routes of administration have limitations and side effects. An alternative route could be oral cavity administration such as buccal or sublingual administration using film dosage form as delivery vehicle. In this article, we thoroughly reviewed the possibility of developing a quickly soluble film-based delivery system for vaccine administration. We reviewed the different types of new vaccines and vaccine formulations such as VLP based, liposome, bilosome, particulate, and summarized their suitability for use in a film dosage form. Quickly soluble film dosage form is the most optimized form of buccal administration. A film dosage form applied in the buccal cavity has several advantages: they can avoid first pass effect, they are easy to administer and prepare, and they are more cost effective. Since there is no first pass effect, only a small quantity of the vaccine is needed. Vaccines in their original form or in a nano or microparticulate form can be used in a film. The film can also be developed in multilayers to protect the vaccine from degradation by saliva or swallowing. Films are easy to prepare, administer, and can be used for systemic and local action. In addition, most of the current vaccines use mostly the parenteral route of administration, which has some major drawbacks such as poor induction of mucosal immunity, less patient compliant, less potent, high cost and cumbersome production process. Sublingual and buccal vaccine delivery can be good alternatives as they are easier to prepare and safer than parenteral administration routes. The buccal and sublingual administration have the advantage to produce both systemic and mucosal immunity.

A Novel Formulation Strategy to Deliver Combined DNA and VLP Based HPV Vaccine.

Human papillomaviruses (HPV) are small, double-stranded DNA viruses that cause cervical cancer, the second most lethal cancer among women in the world. Currently, two vaccines are on the market for preventing HPV-caused cervical cancers and warts. Both are virus-like particle (VLP)-based vaccines. However, these vaccines have limitations; they are costly, have an invasive route of administration, require trained personnel to administer, need cold chain storage to preserve them, and most of all, they are preventive vaccines that do not have curative effects. Therefore, it is necessary to develop therapeutic HPV vaccines to facilitate the control of HPV-associated malignancies and to address all these issues. Recently there are DNA vaccines under investigation to prevent HPV. In general, DNA-based vaccines are better than or an excellent alternative to traditional vaccines since they can closely mimic live infections and can induce both antibody and cell-mediated immune responses. DNA vaccines involve the delivery of plasmid DNA (pDNA) which encodes the specific antigens. DNA vaccines have potential to be effective therapeutic tools against HPV infections. Combining the VLP-based and DNA-based vaccines can be highly effective as they can complement each other. VLP vaccines are more prone to mucosal immunity whereas DNA vaccines are more towards systemic immunity. In this article, we discuss an optimal formulation that will contain both type of vaccines, preventive and therapeutic. A film dosage form can be a good option which can be administered in buccal or sublingual routes for systemic action or in the vaginal area for local action to treat cervical cancer and to protect from future infection. Multiple vaccines in native form or in particulate form can be incorporated in film dosage forms. The film dosage form of vaccines can elicit both antibody-mediated (preventative) and cell-mediated (therapeutic) mechanisms. Film dosage forms are feasible to prepare for vaccine administration in the mouth cavity, GI tract, and vagina.

Aerobic Exercise Training as a Potential Cardioprotective Strategy to Attenuate Doxorubicin-Induced Cardiotoxicity.

Doxorubicin is one of the most commonly used cytotoxic anticancer drugs against several cancers.  Although a highly effective anticancer drug, the clinical use of doxorubicin is severely limited by its cardiotoxicity which results in morbidity, poor quality of life, and premature mortality.  Only very few clinically accepted methods to minimize doxorubicin-induced cardiac injury are available today, but none of them have proven to be completely successful.  Due to limited alternative strategies, a number of potential cardioprotective therapies are currently being investigated for treating and/or preventing doxorubicin-induced cardiotoxicity.  Of these potential strategies, aerobic exercise training is the only nonpharmacologic strategy that shows a great deal of promise.  Although there are no published human clinical trials, evidence from numerous animal studies suggests that aerobic exercise training, administered prior to, during and/or following doxorubicin therapy, is protective against doxorubicin-induced cardiac injury.  Protective properties of exercise training against the cardiotoxicity of doxorubicin have been attributed to a number of potential molecular mechanisms including:  enhancing the production of endogenous antioxidant machineries; regulating proapoptotic signaling; stimulating the release, mobilization and homing of cardiac progenitor cells; limiting myocyte turnover; eliciting favorable adaptations in myocardial calcium handling and preventing calcium overload; modulating cardiac AMPK activity; downregulating cardiac autophagy/lysosomal signaling; and reducing myocardial doxorubicin accumulation.  Further preclinical and clinical research is needed to decipher and refine the molecular mechanisms underlying the cardioprotective effects of exercise training, as well as to define the nature and magnitude of the effect of exercise on doxorubicin-induced cardiotoxicity in cancer patients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Low-Dose Creatine Supplementation Lowers Plasma Guanidinoacetate, but Not Plasma Homocysteine, in a Double-Blind, Randomized, Placebo-Controlled Trial.

BACKGROUND: Creatine synthesis from guanidinoacetate consumes ~50% of s-adenosylmethionine (SAM)-derived methyl groups, accounting for an equivalent proportion of s-adenosylhomocysteine (SAH) and total homocysteine (tHcys) synthesis. Dietary creatine inhibits the synthesis of guanidinoacetate, thereby lowering plasma tHcys in rats. OBJECTIVE: We tested the hypotheses that creatine supplementation lowers plasma guanidinoacetate, increases blood SAM, lowers blood SAH, and lowers plasma tHcys. METHODS: Bangladeshi adults were randomly assigned to receive 1 of 4 treatments for 12 wk: placebo (n = 101), 3 g/d creatine (Cr; n = 101), 400 µg/d folic acid (FA; n = 153), or 3 g/d creatine plus 400 µg/d folic acid (Cr+FA; n = 103). The outcomes of plasma guanidinoacetate and tHcys, as well as whole blood SAM and SAH, were analyzed at baseline and week 12 by HPLC. Treatment effects of creatine supplementation were examined with the use of the group comparisons of Cr vs. placebo and Cr+FA vs. FA. RESULTS: Plasma guanidinoacetate declined by 10.6% (95% CI: 4.9, 15.9) in the Cr group while increasing nonsignificantly in the placebo group (3.7%; 95% CI: -0.8, 8.5) (Pgroup difference = 0.0002). Similarly, plasma guanidinoacetate declined by 9.0% (95% CI: 3.4, 14.2) in the Cr+FA group while increasing in the FA group (7.0%; 95% CI: 2.0, 12.2) (Pgroup difference < 0.0001). Plasma tHcys declined by 23.4% (95% CI: 19.5, 27.1) and 21.0% (95% CI: 16.4, 25.2) in the FA and Cr+FA groups, respectively (Pgroup difference = 0.41), with no significant changes in the placebo or Cr groups (Pgroup difference = 0.35). A decrease in guanidinoacetate over time was associated with a decrease in tHcys over time in the Cr+FA group (ß = 0.30; 95% CI: 0.17, 0.43; P < 0.0001). CONCLUSIONS: Our findings indicate that whereas creatine supplementation downregulates endogenous creatine synthesis, this may not on average lower plasma tHcys in humans. However, tHcys did decrease in those participants who experienced a decline in plasma guanidinoacetate while receiving creatine plus folic acid supplementation. This trial was registered at clinicaltrials.gov as NCT01050556.

Strategies for Developing Oral Vaccines for Human Papillomavirus (HPV) Induced Cancer using Nanoparticle mediated Delivery System.

Human Papillomaviruses (HPV) are a diverse group of small non-enveloped DNA viruses. Some HPVs are classified as low-risk as they are very rarely associated with neoplasia or cancer in the general population, and cause lenient warts. Other HPVs are considered as high-risk types because they are responsible for several important human cancers, including cervical cancer, a large proportion of other anogenital cancers, and a growing number of head and neck cancers. Transmission of HPV occurs primarily by skin-to-skin contact. The risk of contracting genital HPV infection and cervical cancer is influenced by sexual activity. Currently two prophylactic HPV vaccines, Gardasil® (Merck, USA) and Cervarix® (GlaxoSmithKline, UK), are available and recommended for mass immunization of adolescents. However, these vaccines have limitations as they are expensive and require cold chain storage and trained personnel to administer them by injection. The use of nano or micro particulate vaccines could address most of these limitations as they are stable at room temperature, inexpensive to produce and distribute to resource poor regions, and can be administered orally without the need for adjuvants in the formulation. Also it is possible to increase the efficiency of these particulate vaccines by decorating the surface of the nano or micro particulates with suitable ligands for targeted delivery. Oral vaccines, which can be delivered using particulate formulations, have the added potential to stimulate mucosa-associated lymphoid tissue located in the digestive tract and the gut-associated lymphoid tissue, both of which are important for the induction of effective mucosal response against many viruses. In addition, oral vaccines provide the opportunity to reduce production and administration costs and are very patient compliant. This review elaborately discusses different strategies that can be pursued to develop a nano or micro particulate oral vaccine for HPV induced cancers and other diseases.

Development of ß-cyclodextrin-based sustained release microparticles for oral insulin delivery.

Polymeric microparticles have been previously demonstrated to deliver various therapeutic agents efficiently to targeted regions by protecting the drug from harsh gastric milieu of the gastrointestinal tract. In this study, we investigated the hypoglycemic effect of ß-cyclodextrin polymeric insulin microparticles in diabetic rats via the oral route of administration. ß-cyclodextrin microparticles were prepared by a unique one-step spray-drying technique and stabilized by incorporating enteric retardant polymers in the formulation. The insulin-loaded microparticles had a mean size of 0.8 ± 0.25 µm with a zeta potential of 3.57 + 0.62 mV. As seen with the chromatographic analysis, the drug content in the microparticles was determined to be 94.9 ± 2.77%. RAW macrophage cells showed greater than 80% viability after 24 h of incubation with the insulin and blank microparticles. For the in vitro release study, the microparticles were able to protect the insulin in gastric fluid where no significant release was detected, followed by only 50% release in intestinal fluid for the first 8 h of the study. This was seen to correlate with the in vivo data where 50% glucose inhibition was seen after 8 h of oral administration in diabetic rats. This data suggest that the oral insulin microparticles were able to reduce glucose levels in disease conditions and would be a favorable route of administration to patients as an alternative to daily subcutaneous injections.

Spontaneous rupture of uterine varicose veins: a rare cause for obstetric shock.

Spontaneous rupture of uterine surface varicose veins is rare but may result in serious complication of pregnancy, as it is associated with high perinatal and maternal mortality. We report a 24-year-old primigravida who presented with this rare condition mimicking placenta abruption, which was successfully managed. A review of reported cases was performed.

Foliar application of pyroligneous acid acts synergistically with fertilizer to improve the productivity and phytochemical properties of greenhouse-grown tomato.

Pyroligneous acid (PA) is rich in bioactive compounds and known to have the potential to improve crop productivity and phytochemical content. However, the synergistic effect of PA and fertilizer has not been thoroughly studied. In this study, we assessed the biostimulatory effect of different rates of foliar PA application (i.e., 0, 0.25, 0.5, 1, and 2% PA/ddH2O (v/v)) combined with full rate (i.e., 0.63, 0.28, 1.03 g) and half rate of nitrogen-phosphorus-potassium (NPK) fertilizer on the yield and nutritional quality of greenhouse-grown tomato (Solanum lycopersicum 'Scotia'). Plants treated with 0.25% and 0.5% PA showed a significantly (p < 0.001) higher maximum quantum efficiency of photosystem II (Fv/Fm) and increased potential photosynthetic capacity (Fv/Fo), especially when combined with the full NPK rate. Leaf chlorophyll was significantly (p < 0.001) increased by approximately 0.60 and 0.49 folds in plants treated with 2% PA and full NPK rate compared to no spray and water, respectively. Total number of fruits was significantly (p < 0.001) increased by approximately 0.56 folds with the 2% PA irrespective of the NPK rate. The combined 2% PA and full NPK rate enhanced total fruit weight and the number of marketable fruits. Similarly, fruit protein, sugar and 2,2-diphenyl-1-picrylhydrazyl (DPPH) activity were significantly (p < 0.001) enhanced by the combined 2% PA and full NPK rate. In contrast, the 0.5% PA combined with half NPK rate increased fruit carotenoid and phenolic contents while the 2% PA plus half NPK rate enhanced fruit flavonoid content. Generally, the synergistic effect of PA and NPK fertilizer increased fruit elemental composition. These showed that foliar application of 2% PA with full NPK rate is the best treatment combination that can be adopted as a novel strategy to increase the productivity and quality of tomato fruits. However, further study is required to investigate the molecular basis of PA biostimulatory effect on plants.

Development of an HPLC-PDA Method for the Simultaneous Estimation of Three Antibiotics in Pharmaceutical Formulations and Bovine Milk and Health Risk Assessment.

A simple new, rapid, sensitive, and cost-effective HPLC-PDA method was developed and validated for the determination of tetracycline (TC), oxytetracycline (OTC), and ciprofloxacin (CIP) simultaneously. Chromatographic separations were carried out using a reversed-phase Shim-pack GIS C18 column (4.60 × 250.00 mm; 5.00 µm) at 30°C. Oxalic acid (0.05 M), acetonitrile, and methanol were used as mobile phase under gradient elution conditions at the flow rate of 1.50 mL min-1. Detection wavelength was set at 330 nm. An aliquot of 20.00 µL solution was injected, and three drugs were eluted within 7.39 ± 0.05 min. As per ICH guidelines linearity, recovery, accuracy, precision, selectivity, specificity, sensitivity, stability, column efficiency, system suitability, and robustness were determined for the validation of the proposed method. Calibration curves were linear over a studied concentration range of 8.00 µg mL-1 with a correlation coefficient (r) of 0.999 for all drugs. Relative standard deviation (RSD) for intra- and interday precision was found less than 2.87% and 3.22%, respectively, indicating the method to be reproducible. The proposed method has been suitably applied for the estimation of TC, OTC, and CIP in pharmaceutical formulation and milk samples collected from local market in Bangladesh. Among 15 milk samples analyzed, most of the cases (more than 50%) TC, OTC, and CIP were detected above maximum residue levels (MRLs) though no significant toxicological effect on the health of consumers in the study area was identified.

Selection of lansoprazole from an FDA-approved drug library to inhibit the Alzheimer's disease seed-dependent formation of tau aggregates.

The efficacy of current treatments is still insufficient for Alzheimer's disease (AD), the most common cause of Dementia. Out of the two pathological hallmarks of AD amyloid-ß plaques and neurofibrillary tangles, comprising of tau protein, tau pathology strongly correlates with the symptoms of AD. Previously, screening for inhibitors of tau aggregation that target recombinant tau aggregates have been attempted. Since a recent cryo-EM analysis revealed distinct differences in the folding patterns of heparin-induced recombinant tau filaments and AD tau filaments, this study focused on AD seed-dependent tau aggregation in drug repositioning for AD. We screened 763 compounds from an FDA-approved drug library using an AD seed-induced tau aggregation in SH-SY5Y cell-based assay. In the first screening, 180 compounds were selected, 72 of which were excluded based on the results of lactate dehydrogenase assay. In the third screening with evaluations of soluble and insoluble tau, 38 compounds were selected. In the fourth screening with 3 different AD seeds, 4 compounds, lansoprazole, calcipotriene, desogestrel, and pentamidine isethionate, were selected. After AD seed-induced real-time quaking-induced conversion, lansoprazole was selected as the most suitable drug for repositioning. The intranasal administration of lansoprazole for 4 months to AD seed-injected mice improved locomotor activity and reduced both the amount of insoluble tau and the extent of phosphorylated tau-positive areas. Alanine replacement of the predicted binding site to an AD filament indicated the involvement of Q351, H362, and K369 in lansoprazole and C-shaped tau filaments. These results suggest the potential of lansoprazole as a candidate for drug repositioning to an inhibitor of tau aggregate formation in AD.

Elements in cultured fishes in Chittagong, Bangladesh and risk assessment.

The concentrations of manganese, iron, copper, lead, nickel, cadmium, arsenic, copper and mercury were determined in 10 cultured fish species, which were collected from local markets of Chittagong, Bangladesh, in June 2021. Measurements were performed by atomic absorption spectrophotometry, after acid digestion of the samples. In some cases, the concentration of the investigated elements was more than the maximum limit set by the WHO. Although the concentration of toxic elements in fishes was relatively high in some species, no health risk has been identified in comparison to the estimated daily intake and the maximum limit. Calculated hazard indices were below 1, which indicates the investigated fish would not cause human health risks. Carcinogenic risk indices for Cr, As, and Cu in all species were considered to be significant.

Identification of Differentially Expressed Genes and Protein-Protein Interaction in Patients With COVID-19 and Diabetes Peripheral Neuropathy: A Bioinformatics and System Biology Approach.

The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact globally, resulting in a higher death toll and persistent health issues for survivors, particularly those with pre-existing medical conditions. Numerous studies have demonstrated a strong correlation between catastrophic COVID-19 results and diabetes. To gain deeper insights, we analysed the transcriptome dataset from COVID-19 and diabetic peripheral neuropathic patients. Using the R programming language, differentially expressed genes (DEGs) were identified and classified based on up and down regulations. The overlaps of DEGs were then explored between these groups. Functional annotation of those common DEGs was performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Bio-Planet, Reactome, and Wiki pathways. A protein-protein interaction (PPI) network was created with bioinformatics tools to understand molecular interactions. Through topological analysis of the PPI network, we determined hub gene modules and explored gene regulatory networks (GRN). Furthermore, the study extended to suggesting potential drug molecules for the identified mutual DEG based on the comprehensive analysis. These approaches may contribute to understanding the molecular intricacies of COVID-19 in diabetic peripheral neuropathy patients through insights into potential therapeutic interventions.

Unravelling the link between SARS-CoV-2 mutation frequencies, patient comorbidities, and structural dynamics.

Genomic surveillance is crucial for tracking emergence and spread of novel variants of pathogens, such as SARS-CoV-2, to inform public health interventions and to enforce control measures. However, in some settings especially in low- and middle- income counties, where sequencing platforms are limited, only certain patients get to be selected for sequencing surveillance. Here, we show that patients with multiple comorbidities potentially harbour SARS-CoV-2 with higher mutation rates and thus deserve more attention for genomic surveillance. The relationship between the patient comorbidities, and type of amino acid mutations was assessed. Correlation analysis showed that there was a significant tendency for mutations to occur within the ORF1a region for patients with higher number of comorbidities. Frequency analysis of the amino acid substitution within ORF1a showed that nsp3 P822L of the PLpro protease was one of the highest occurring mutations. Using molecular dynamics, we simulated that the P822L mutation in PLpro represents a system with lower Root Mean Square Deviation (RMSD) fluctuations, and consistent Radius of gyration (Rg), Solvent Accessible Surface Area (SASA) values-indicate a much stabler protein than the wildtype. The outcome of this study will help determine the relationship between the clinical status of a patient and the mutations of the infecting SARS-CoV-2 virus.