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.

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).

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.

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.

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.

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.

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.

Comparison of clinical outcomes and biochemical markers in normal and preeclamptic pregnancies: a prospective cohort study.

Background: Preeclampsia (PreE), the de novo onset of hypertension and proteinuria at 20 weeks of gestation, is a leading cause of maternal and fetal morbidity and mortality. This study compared inflammatory biomarkers in PreE and normal pregnancies using paired samples of mothers and neonates. Methods: Twenty normal pregnant and 27 PreE patients were monitored for biomarkers, neonatal outcomes, and placental morphologies. Fetal and maternal serum levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble endoglin (sENG), and soluble fms-like tyrosine kinase-1 (sFLT-1) were measured by enzyme-linked immunosorbent assay. Results: Placental thickness was 25 mm in early PreE subjects compared to 32 mm in late PreE subjects (P < 0.05). Placental volume was 296 cm3 in early PreE compared to 393 cm3 in late PreE (P < 0.05). The average hospital stay for PreE babies was longer (20 ± 5 days) compared to babies from normal pregnancies (2 ± 1 days; P < 0.05). PreE babies had a lower Ponderal index (2.28 ± 0.3) than those from normal pregnancies (2.95 ± 0.2; P < 0.05). sENG and sFLT-1 had cord values like the maternal values, while VEGF and PlGF did not. Conclusion: PreE alters the intrauterine environment by activating chemical mediators that result in maternal and fetal complications.

New prenylated isoflavonoids as protein tyrosine phosphatase 1B (PTP1B) inhibitors from Erythrina addisoniae.

Bioassay-guided fractionation of the EtOAc extract of the root of Erythrina addisoniae (Leguminosae) resulted in the isolation of four new (1-4), along with 2 known prenylated isoflavonoids (5-6). The structures of the isolates were assigned on the basis of spectroscopic data analysis, focusing on interpretation of 1D and 2D NMR, and MS data. All the isolates were evaluated for their inhibitory effects on protein tyrosine phosphatase 1B (PTP1B), as well as their growth inhibition on MCF7, adriamycin-resistant MCF7 (MCF7/ADR), and MDA-MB-231 breast cancer cell lines. Compounds which exhibited PTP1B inhibitory activity (IC(50) values ranging from 4.6 ± 0.3 to 24.2 ± 2.1 µM) showed potential cytotoxic activity (IC(50) values ranging from 3.97 ± 0.17 to 11.4 ± 1.9 µM). Taken together, our data suggest that prenylated isoflavonoids, especially the isoflavone-type skeleton could be considered as new lead compounds against breast cancer via PTP1B inhibition.

Modulation of the sublingual microenvironment and pH-dependent transport pathways to enhance atropine sulfate permeability for the treatment of organophosphates poisoning.

Atropine sulfate (AS) auto-injectors are the only approved antidote for out-of-hospital emergency treatment of organophosphates (OP) toxicity. However, they are only available for military use and require the administration of multiple auto-injectors. Therefore, an alternative, patient-friendly and more affordable fast-disintegrating sublingual tablets (FDSTs) of AS were previously developed. In this article, the effect of modifying the microenvironment's pH and/or using penetration enhancers on AS sublingual transport pathways were evaluated in an attempt to further enhance AS sublingual permeability. Ten different AS FDST formulations with or without the incorporation of alkalizer and various penetration enhancers were manufactured and characterized. AS permeability was investigated through excised porcine sublingual membrane using Franz cells. Results showed that the incorporation of either a transcellular enhancer or alkalizer achieved a significantly higher AS permeability enhancement (twofold). Combining sodium bicarbonate (Na Bicarb) 2% as alkalizer with sodium dodecyl sulfate (SDS) 1% as a transcellular enhancer resulted in the greatest synergistic enhancement in AS sublingual permeability (up to twelvefold). In conclusion, the modified AS FDST developed in this work has the potential to improve the pharmacokinetic parameters of AS following sublingual administration for the first-aid treatment of OP toxicity in future animal bioequivalency studies.

Titanium (IV) complexes of some tetra-dentate symmetrical bis-Schiff bases of 1,6-hexanediamine: Synthesis, characterization, and in silico prediction of potential inhibitor against coronavirus (SARS-CoV-2).

Symmetrical bis-Schiff bases (LH 2) have been synthesized by the condensation of 1,6-hexanediamine (hn) and carbonyl or dicarbonyl. One of the synthesized Schiff bases has been subjected to the molecular docking for the prediction of their potentiality against coronavirus (SARS-CoV-2). Molecular docking revealed that tested Schiff base possessed high binding affinity with the receptor protein of SARS CoV-2 compared with hydroxychloroquine (HCQ). The ADMET analysis showed that ligand is non-carcinogenic and less toxic than standard HCQ. Schiff bases acting as dibasic tetra-dentate ligands formed titanium (IV) complexes of the type [TiL(H2O)2Cl2] or [TiL(H2O)2]Cl2 being coordinated through ONNO donor atoms. Ligands and complexes were characterized by the elemental analysis and physicochemical and spectroscopic data including FTIR, 1H NMR, mass spectra, UV-Visible spectra, molar conductance, and magnetic measurement. Optimized structures obtained from quantum chemical calculations supported the formation of complexes. Antibacterial, antifungal, and anti-oxidant activity assessments have been studied for synthesized ligands and complexes.

Alterations in the renin-angiotensin system in a rat model of human preeclampsia.

BACKGROUND/AIMS: Preeclampsia is a hypertensive disorder unique to pregnancy in which elevated levels of marinobufagenin (MBG) have been reported. The renin-angiotensin system (RAS) may also play a role in the pathogenesis of preeclampsia. The aim of our study was to evaluate the status of the RAS in a rat model of preeclampsia characterized by hypertension, proteinuria, excessive weight gain and intrauterine growth restriction. METHODS: We evaluated the components of the RAS in 5 groups of animals: nonpregnant control; normal pregnant (NP); pregnant rats which received injections of desoxycorticosterone acetate and 0.9% saline as their drinking water (PDS); normal pregnant rats injected with MBG (NPM), and PDS rats to which resibufogenin (RBG) had been administered (PDSR). RBG is an antagonist of MBG differing in structure from MBG only in the absence of a hydroxyl group in the beta-5 position. RESULTS: Plasma levels of active renin, renin and Ang II were significantly lower in PDS and NPM compared to NP and PDSR rats (p < 0.05). However, placental levels of these components were increased significantly in PDS and NPM compared to NP and PDSR rats (p < 0.05). Placental AT(1) receptor expression was significantly higher in PDS and NPM compared to NP and PDSR rats (p < 0.05). CONCLUSIONS: (1) The peripheral RAS is downregulated, and the uteroplacental RAS is upregulated in this rat model of preeclampsia; (2) MBG is involved in the causation of these alterations, and (3) RBG prevents these changes.

The Role of Oxidative Stress and Its Counteractive Utility in Colorectal Cancer (CRC).

An altered redox status accompanied by an elevated generation of reactive oxygen/nitrogen species (ROS/RNS) has been implicated in a number of diseases including colorectal cancer (CRC). CRC, being one of the most common cancers worldwide, has been reported to be associated with multiple environmental and lifestyle factors (e.g., dietary habits, obesity, and physical inactivity) and harboring heightened oxidative stress that results in genomic instability. Although under normal condition ROS regulate many signal transduction pathways including cell proliferation and survival, overwhelming of the antioxidant capacity due to metabolic abnormalities and oncogenic signaling leads to a redox adaptation response that imparts drug resistance. Nevertheless, excessive reliance on elevated production of ROS makes the tumor cells increasingly vulnerable to further ROS insults, and the abolition of such drug resistance through redox perturbation could be instrumental to preferentially eliminate them. The goal of this review is to demonstrate the evidence that links redox stress to the development of CRC and assimilate the most up-to-date information that would facilitate future investigation on CRC-associated redox biology. Concomitantly, we argue that the exploitation of this distinct biochemical property of CRC cells might offer a fresh avenue to effectively eradicate these cells.