Study on the interaction between erythrosine B and the cardiac drug amiodarone using fluorescence, scattering, and absorbance spectra and their analytical application.

In an acidic buffered solution, erythrosine B can react with amiodarone to form an association complex, which not only generates great enhancement in resonance Rayleigh scattering (RRS) spectrum of erythrosine B at 346.5 nm but also results in quenching of fluorescence spectra of erythrosine B at λemission = 550.4 nm/λexcitation = 528.5 nm. In addition, the formed erythrosine B-amiodarone complex produces a new absorbance peak at 555 nm. The spectral characteristics of the RRS, absorbance, and fluorescence spectra, as well as the optimum analytical conditions, were studied and investigated. As a result, new spectroscopic methods were developed to determine amiodarone by utilizing erythrosine B as a probe. Moreover, the ICH guidelines were used to validate the developed RRS, photometric, and fluorimetric methods. The enhancements in the absorbance and the RRS intensity and the decrease in the fluorescence intensity of the used probe were proportional to the concentration of amiodarone in ranges of 2.5-20.0, 0.2-2.5, and 0.25-1.75 µg/mL, respectively. Furthermore, limit of detection values were 0.52 ng/mL for the spectrophotometric method, 0.051 µg/mL for the RRS method, and 0.075 µg/mL for the fluorimetric method. Moreover, with good recoveries, the developed spectroscopic procedures were applied to analyze amiodarone in its commercial tablets.

Four chemometric models enhanced by Latin hypercube sampling design for quantification of anti-COVID drugs: sustainability profiling through multiple greenness, carbon footprint, blueness, and whiteness metrics.

Montelukast sodium (MLK) and Levocetirizine dihydrochloride (LCZ) are widely prescribed medications with promising therapeutic potential against COVID-19. However, existing analytical methods for their quantification are unsustainable, relying on toxic solvents and expensive instrumentation. Herein, we pioneer a green, cost-effective chemometrics approach for MLK and LCZ analysis using UV spectroscopy and intelligent multivariate calibration. Following a multilevel multifactor experimental design, UV spectral data was acquired for 25 synthetic mixtures and modeled via classical least squares (CLS), principal component regression (PCR), partial least squares (PLS), and genetic algorithm-PLS (GA-PLS) techniques. Latin hypercube sampling (LHS) strategically constructed an optimal validation set of 13 mixtures for unbiased predictive performance assessment. Following optimization of the models regarding latent variables (LVs) and wavelength region, the optimum root mean square error of cross-validation (RMSECV) was attained at 2 LVs for the 210-400 nm spectral range (191 data points). The GA-PLS model demonstrated superb accuracy, with recovery percentages (R%) from 98 to 102% for both analytes, and root mean square error of calibration (RMSEC) and prediction (RMSEP) of (0.0943, 0.1872) and (0.1926, 0.1779) for MLK and LCZ, respectively, as well bias-corrected mean square error of prediction (BCMSEP) of -0.0029 and 0.0176, relative root mean square error of prediction (RRMSEP) reaching 0.7516 and 0.6585, and limits of detection (LOD) reaching 0.0813 and 0.2273 for MLK and LCZ respectively. Practical pharmaceutical sample analysis was successfully confirmed via standard additions. We further conducted pioneering multidimensional sustainability evaluations using state-of-the-art greenness, blueness, and whiteness tools. The method demonstrated favorable environmental metrics across all assessment tools. The obtained Green National Environmental Method Index (NEMI), and Complementary Green Analytical Procedure Index (ComplexGAPI) quadrants affirmed green analytical principles. Additionally, the method had a high Analytical Greenness Metric (AGREE) score (0.90) and a low carbon footprint (0.021), indicating environmental friendliness. We also applied blueness and whiteness assessments using the high Blue Applicability Grade Index (BAGI) and Red-Green-Blue 12 (RGB 12) algorithms. The high BAGI (90) and RGB 12 (90.8) scores confirmed the method's strong applicability, cost-effectiveness, and sustainability. This work puts forward an optimal, economically viable green chemistry paradigm for pharmaceutical quality control aligned with sustainable development goals.

Direct-Acting Antiviral Drug Modulates the Mitochondrial Biogenesis in Different Tissues of Young Female Rats.

(1) Background: Hepatitis C virus (HCV) infection is endemic in Egypt, with the highest prevalence rate worldwide. Sofosbuvir (SOF) is a nucleos(t)ide analog that specifically inhibits HCV replication. This study aimed to explore the possible effects of the therapeutic dose of SOF on the mitochondrial biogenesis and functions of the liver, muscle, and ovarian tissues of young normal female rats. (2) Methods: This study was conducted on 20 female Wistar rats, classified into two groups, the control group and the exposed group; the latter was orally supplemented with 4 mg/kg/day of SOF for 3 months. (3) Results: The exposure to SOF impairs mitochondrial biogenesis via mitochondrial DNA copy number decline and suppressed mitochondrial biogenesis-regulated parameters at mRNA and protein levels. Also, SOF suppresses the DNA polymerase γ (POLG) expression, citrate synthase activity, and mitochondrial NADH dehydrogenase subunit-5 (ND5) content, which impairs mitochondrial functions. SOF increased lipid peroxidation and oxidative DNA damage markers and decreased tissue expression of nuclear factor erythroid 2-related factor 2 (Nfe2l2). (4) Conclusions: The present findings demonstrate the adverse effects of SOF on mitochondrial biogenesis and function in different tissues of young female rats, which mostly appeared in ovarian tissues.

The Intergeneration Long-Lasting Consequences of Pre-Conceptional Exposure to Sofosbuvir on the Ovarian Tissues of F1 Offspring: Experimental Study on Rats.

Sofosbuvir (SOF), a nucleos(t)ide polymerase inhibitor, has been used during the past decade for mass treatment of viral hepatitis C in endemic countries like Egypt, increasing the exposure of women at childbearing age to SOF. This study investigated the long-lasting consequences of the pre-conceptional exposure of young female rats to SOF on the ovarian tissues of F1 offspring and explored the possible molecular mechanisms of these intergenerational effects at various levels. The study was conducted on young female rats that were divided into control group and SOF-exposed group at a dose of 4 mg/kg/day for three months. After that, pregnancy was induced in both groups by mating with healthy male rats. After delivery, the female neonates were followed for 4 months, and the ovarian tissues were collected to assess the studied parameters. Pre-conceptional exposure to SOF affected the ovarian functions of F1 offspring through modulation of estrogen receptors, ovarian Kiss1 and its receptor, increased lipid peroxidation marker, DNA oxidation marker, and redox-sensitive nuclear factor kappa B, and decreased nuclear erythroid-2-related factor 2, mitochondrial function, and biogenesis. SOF affected the ovarian function of the F1 offspring by inducing oxidative stress and inflammation, leading to the modulation of mitochondrial functions and biogenesis.

The pre-conception maternal exposure to Sofosbuvir affects the mitochondrial biogenesis in prenatal fetal tissues: Experimental study on rats.

BACKGROUND: Hepatitis C virus (HCV) infection is a global public health problem and Egypt has the highest HCV prevalence worldwide. Hence, global efforts target to eliminate HCV by 2030. Sofosbuvir is a nucleotide analogue inhibitor of HCV polymerase essential for viral replication. Animal studies prove that Sofosbuvir metabolites cross the placenta and are excreted in the milk of nursing animals. We aimed to investigate the possible effects of preconception maternal exposure to Sofosbuvir on mitochondrial biogenesis in prenatal fetal liver, skeletal muscle, and placental tissues. METHODS: The study was conducted on 20 female albino rats divided into a control group receiving a placebo and an exposed group receiving 4 mg/kg orally/day for 3 months of Sofosbuvir. At the end of the treatment period, pregnancy was induced in both groups by mating with healthy male rats overnight. At gestational day 17, all pregnant female rats were sacrificed. Each fetus was dissected to obtain the fetal liver, skeletal muscle, and placental tissues. RESULTS: The results of our study indicated that the exposure of young female rats to Sofosbuvir affects pregnancy outcomes. Fetal liver and muscle showed lower mitochondrial DNA-copy number (mtDNA-CN) by about 24% and 29% respectively, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and its downstream targets; nuclear respiratory factor-1 and mitochondrial transcription factor A. While the placental tissues showed different patterns, particularly elevated in mtDNA-CN by about 43%. CONCLUSIONS: The study provides preliminary evidence of the detrimental effects of Sofosbuvir on the pregnancy outcomes of the exposed females and may impair the placental and fetal organs' development. These effects may be mediated through modulating mitochondrial homeostasis and functions.

Simultaneous Determination of Montelukast Sodium and Loratadine by Eco-Friendly Densitometry and Spectrophotometric Methods.

Recently, the aim of analytical community is to reduce the usage of hazardous chemicals; so eco-friendly, rapid, selective and cost-effective methods were developed for simultaneous determination of montelukast sodium (MKT) and loratadine (LRT). The first method was based on chromatographic separation performed on precoated silica gel 60 GF254 plates with ethyl acetate-ethanol 9: 1 (v/v) as the mobile phase. The developed plates were scanned and quantified at 260 nm. The method gives linear correlation over concentration ranges of 0.3-3.6 µg/spot and 0.2-4.0 µg/spot for MKT and LRT, respectively. It was also successfully applied to analysis of both drugs in their pharmaceutical preparation and human plasma. The other methods are UV-spectrophotometric methods based on smart spectra manipulating to zero order spectrum of each drug. These methods are named response correlation (RC), a-centering and ratio derivative methods. RC and a-centering methods were dependent on the presence of an isosbestic point between the overlapped spectra of both drugs. While ratio derivative method based on manipulation of the ratio spectra of both drugs. The two drugs obey Beer-Lambert law over the concentration ranges of 3.0-30.0 µg/mL in the three spectrophotometric methods. Moreover, the greenness of the developed methods is assessed using suitable analytical Eco-Scale and Green Analytical Procedure Index.

The diabetogenic effects of chronic supplementation of vitamin C or E in rats: Interplay between liver and adipose tissues transcriptional machinery of lipid metabolism.

AIM: The chronic administration of vitamin C and E can differentially disrupt hepatic insulin molecular pathway in rats. Hence, this study evaluated their effects on lipogenesis in the liver and adipose tissue and investigated the possible involvement of microRNA (miR)-22/29a/27a in the induced impaired glucose tolerance. MAIN METHODS: Wistar rats were orally supplemented with vitamin C (100, 200, and 500 mg/kg) or vitamin E (50, 100, and 200 mg/kg) for eight months. KEY FINDINGS: Vitamin C or E at the highest doses significantly altered liver weight and index, serum and hepatic lipids, adiponectin, and liver enzymes; besides their reported unfavorable effect on glucose homeostasis. Vitamin C and E negatively affected peroxisome proliferator-activated receptor coactivator-1 (PGC-1α), sterol regulatory element-binding protein (SREBP)-1c/-2, miR-22/29a/27a expression, and adipose perilipin 1 to different extents, effects that were supported by the histopathological examination. SIGNIFICANCE: The current study provides a deeper insight into the findings of our previous study and highlights the detrimental effects of chronic vitamins supplementation on lipid metabolism. Overall, these findings emphasize the damage caused by the mindless use of supplements and reinforce the role of strict medical monitoring, particularly during the new COVID-19 era during which numerous commercial supplements are claiming to improve immunity.

Experimental and Molecular Modeling Studies on the Complexation of Chromium(III) with the Angiotensin-Converting Enzyme Inhibitor Captopril.

Captopril (CPT) is an inhibitor of angiotensin I converting enzyme, used as a medication for the treatment of people with high blood pressure, renal insufficiency, and cardiovascular diseases. It inhibits the angiogenesis process, vasoconstriction, and tumor metastasis. Some metal-captopril complexes exhibit antimicrobial activities. In the current work, the formation of the CrIII-CPT complex was studied spectrophotometrically and potentiometrically in aqueous solution. Kinetics of CrIII-CPT complex formation was spectrophotometrically studied over the pH range 3.20-4.20, at an ionic strength of 0.3 M at 30-50 °C. CrIII-CPT complex formation was potentiometrically studied at 25 °C, where ligand protonation constants and complexes' overall stability constants were calculated. UV-vis absorption spectra were executed to confirm the complex formation. Density functional theory and molecular dynamics simulation were performed to search the geometries of the CrIII-CPT complex. Atoms in molecules and interaction region indicator calculations are used to investigate intermolecular interactions for the formation of CrIII-CPT complex. The antimicrobial activity of the CPT ligand and CrIII-CPT complex on the prevention and control of environmental pathogenic bacteria, as tested on both Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative bacteria Escherichia coli (E. coli) via agar disc diffusion method, assess the ability to use as an antimicrobial agent. CPT had shown good antimicrobial activity against both types of bacteria, which had increased slightly the zone of inhibition in Cr-CPT that indicates the increased efficacy due to Cr(III) antimicrobial activity via its oxidative damage to the bacterial cell wall. No previous study tested the CPT antimicrobial activity against Gram-positive ones such as S. aureus.

Ameliorative effects of astaxanthin on brain tissues of alzheimer's disease-like model: cross talk between neuronal-specific microRNA-124 and related pathways.

Alzheimer's disease (AD) is a chronic, progressive, multifactorial, and the most common neurodegenerative disease which causes dementia and mental deterioration in the elderly. The available treatments for AD are not disease-modifying drugs and only provide symptomatic relief. Astaxanthin (ATX), a second-generation antioxidant, is a dark red carotenoid and exhibits the highest antioxidant capacity, anti-inflammatory, neuroprotective, and antiapoptotic effects. In this study, we investigated the therapeutic effect of different doses of ATX on the cerebral cortex and hippocampus of AD-like rats. The AD-like model was induced in rats using hydrated aluminum chloride (AlCl3.6H2O) solution that was given orally at a dose of 75 mg/kg daily for 6 weeks. Morris water maze (MWM) behavioral test was performed to confirm the cognitive dysfunction then AD-like rats were orally treated with different doses of ATX (5, 10, and 15 mg/kg) dissolved in dimethyl sulfoxide (DMSO) for six weeks. The results indicated that ATX significantly and dose-dependently improved the performance of AD-like rats treated with ATX during MWM and suppress the accumulation of amyloid ß1-42 and malondialdehyde. Also, significantly inhibit acetylcholinesterase and monoamine oxidase activities and the expression of ß-site amyloid precursor protein cleaving enzyme 1 (BACE 1). ATX also significantly elevated the content of acetylcholine, serotonin, and nuclear factor erythroid-2-related factor 2 (Nrf2) and miRNA-124 expression. The effect of ATX treatment was confirmed by histopathological observations using H&E stain and morphometric tissue analysis. From this study, we concluded that ATX may be a promising therapeutic agent for AD through targeting different pathogenic pathways.

Galantamine in rheumatoid arthritis: A cross talk of parasympathetic and sympathetic system regulates synovium-derived microRNAs and related pathogenic pathways.

The acetylcholinesterase inhibitor, galantamine, has shown therapeutic effect in rat model of rheumatoid arthritis. Hence, the current study aims at determining the mode of action of galantamine by examining different synovium-derived microRNAs (miRs) and their related pathogenic pathways. The study also focuses on how parasympathetic and sympathetic pathways in the synovial tissue could affect the mode of action and anti-arthritic effect of galantamine. Chemical sympathectomy was initiated in 12 adjuvant arthritic rats by exposure to 6-hydroxydopamine (6-OHDA; 2 × 50 mg/kg) on day 9 after adjuvant injection and again (2 × 100 mg/kg) one week later. Six rats were treated with galantamine (2.5 mg/kg/day) to explore the influence of sympathetic impairment on galantamine effect. Another twelve additional adjuvant arthritic rats were exposed to the selective α7 nicotinic acetylcholine receptor blocker methylcaconitine citrate (MLA; 5.6 mg/kg/day), 15 min before galantamine treatment. As control, six adjuvant arthritic rats were treated with galantamine alone. Treatment proceeded for 5 days, from day 14 till day 18 post-adjuvant injection. Different miRs and their related pathogenic pathways were examined. Tyrosine hydroxylase (TH) expression was also measured in joint tissue. Galantamine affected the expression of the different miRs and their related parameters. Both, 6-OHDA and MLA, interrupted the anti-inflammatory/anti-arthritic effect of galantamine to different extent. Additionally, TH expression in the synovium was affected by galantamine, suggesting a novel pathogenic target in the treatment of rheumatoid arthritis.

Effect of superparamagnetic iron oxide nanoparticles on glucose homeostasis on type 2 diabetes experimental model.

AIMS: Evaluation of the anti-diabetic effect of superparamagnetic iron oxide nanoparticles (SPIONs) on Type 2 diabetic rats and compared their effect to metformin treatment. MAIN METHODS: Diabetic rats were treated with different doses of nanoparticles one time per week for 4 weeks. Fasting blood glucose level was determined for studied groups during the experimental period (30 days). At the end of the experiment, oral glucose tolerance test was carried out, serum samples were collected for biochemical assays. Then animals were sacrificed to obtain tissues for assessment of glucose transporters, insulin receptors and insulin signaling proteins. KEY FINDING: SPIONs treatment normalized fasting blood glucose and lowering insulin level in diabetic rats compared to untreated diabetic rats. SPIONs significantly ameliorate the glucose sensing and the active components of insulin signaling pathway. The anti-diabetic effects of SPIONs may be mediated through its effect on (i) hepatic peroxisome proliferator-activated receptor gamma coactivator 1-alpha content, which induced by SPIONs treatment in a dose-dependent manner, (ii) adipocytokines as SPIONs treated diabetic rats showed significantly higher levels of adiponectin and lower retinol binding protein 4 compared to untreated diabetic rats, (iii) lipid profile as SPIONs treatment significantly corrected the lipid profile in a dose-dependent manner and to a similar extent as metformin or even better. SIGNIFICANCE: To our knowledge, this is the first study that explores the anti-diabetic effects of SPIONs on diabetic model.

Enhanced mitochondrial biogenesis is associated with the ameliorative action of creatine supplementation in rat soleus and cardiac muscles.

The current study focused on the effect of creatine supplementation with/without exercise on the expression of genes controlling mitochondrial biogenesis in skeletal and cardiac muscles, as well as its safety profile on the liver and kidney. A total of 40 male Wister rats were included in the present study. Two unexercised groups: The control sedentary group and the sedentary creatine-treated group (n=10) were treated daily with oral creatine (0.5 g/kg per day). Two exercised groups performed swimming exercise training 5 days/week for a period of 5 weeks; The Exercise training group, and exercise training and creatine (0.5 g/kg per day) treated group. After sacrifice, blood samples, cardiac and soleus muscles were collected for assessment of mtDNA copy number, gene expression analysis and nuclear extraction for the assay of PGC-1α. The results of the current study demonstrated that, physical activity with short-term creatine supplementation increased all factors of mitochondrial biogenesis, an effect that is devoid of any kidney or liver adverse effects. Further studies are still required to explore the potential of creatine supplementation in ameliorating mitochondrial diseases, including epilepsy, skeletal and cardiac myopathies, hepatopathies and nephropathies.

Improving hepatic mitochondrial biogenesis as a postulated mechanism for the antidiabetic effect of Spirulina platensis in comparison with metformin.

Various nutritional and medicinal potencies have been accredited to metabolites from the cyanobacteria, Spirulina platensis (Arthrospira platensis) sp. Hence, our study was designed to examine whether the Spirulina supplementation would possess beneficial effects in type 2 diabetes mellitus (T2DM) in comparison with metformin. High-fat diet/low-dose streptozotocin (HFD/STZ) model was adopted and the diabetic rats were orally treated with metformin (200 mg/kg) or Spirulina (250 or 500 or 750 mg/kg) for 30 days. Spirulina ameliorated the HFD/STZ-induced elevation of fasting blood glucose, insulin, and hepatic enzymes. Moreover, Spirulina successfully rectified disrupted serum lipid profile and exhibited an anti-inflammatory effect via tumor necrosis factor-α and adiponectin modulation. On the molecular level, Spirulina reduced the expression of hepatic sterol regulatory element binding protein-1c (SREBP-1c), confirming its lipotropic effect. Furthermore, Spirulina amended compromised hepatic mitochondrial biogenesis signaling by significantly increasing peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), mitochondrial transcription factor A (Tfam), and mitochondrial DNA (mtDNA) copy number. On almost all parameters, the highest dose of Spirulina showed the best effects, which were comparable to that of metformin. To our knowledge, our study is the first to attribute the various aspects of the effect of Spirulina to the SREBP-1c and PGC-1α/Tfam/mtDNA pathways in liver. The present results clearly proved that Spirulina modulated glucose/lipid profile and exhibited prominent anti-inflammatory properties through SREBP-1c inhibition and hepatic mitochondrial biogenesis enhancement. Thus, Spirulina can be considered as an add-on to conventional antidiabetic agents and might influence the whole dynamics of the therapeutic approaches in T2DM.

Impaired peripheral glucose sensing in F1 offspring of diabetic pregnancy.

Maternal diabetes can induce permanent changes in glucose homeostasis that can occur pre- and post-natal and leads to type 2 diabetes in adulthood. This study aimed to investigate the effect of maternal diabetes on the F1 offspring peripheral glucose sensing and mitochondrial biogenesis in an attempt to clarify the mechanism of diabetogenic programming. Two groups of female Wistar rats were used (diabetic and control); diabetes was neonatally induced by STZ injection to 5-day old rats. After the pregnancy and delivery, the offspring were weaned to control diet or high-caloric (HCD) diet and followed up for 30 weeks. Every 5 weeks, OGTT was constructed, and serum and tissues were obtained for the assessment of mTFA, mtDNA, UCP2, insulin receptor (IR), phospho-insulin receptor (phospho-IR), and GLUT4. The result indicated impaired glucose tolerance (IGT) and insulin resistance in the offspring under control diet at the 15th week of age and thereafter while those offspring under HCD showed IGT at 10th week, and diabetes was evidenced at the 25th week of age. This defect in glucose metabolism was preceded by impairment in the phosphorylation of IR and decreased IR and Glut4 that cause impaired glucose sensing together with inhibited mitochondrial biogenesis in muscle and adipose tissues. This study indicated that maternal diabetes caused impaired glucose sensing and insulin resistance in the peripheral tissues and caused change in the expression of genes involved in mitochondrial biogenesis and function. Post-natal feeding with HCD may accelerate these changes. Male F1 offspring appears to be more sensitive than females for fetal programming of T2D.