Effect of Hydration Forms and Polymer Grades on Theophylline Controlled-Release Tablet: An Assessment and Evaluation.

BACKGROUND: Drug release from controlled release delivery systems is influenced by various factors, including the polymer's grade and the drug's hydration form. This study aimed to investigate the impact of these factors on the controlled release of theophylline (THN). This research compares the monohydrate form found in branded products with the anhydrous form in generic equivalents, each formulated with different polymer grades. METHODS: Quality control assessment was conducted alongside in vitro evaluation, complemented by various analytical techniques such as X-ray diffraction (XRD) and scanning electron microscopy (SEM). Additionally, thermal analyses using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were employed. RESULTS: Quality control assessments demonstrated that the generic tablets exhibited lower average weight and resistance force compared to the branded ones. In vitro tests revealed that generic tablets released contents within 120 min, compared to 720 min for the branded counterpart. Characterization using XRD and SEM identified disparities in crystallinity and particle distribution between the three samples. Additionally, the thermal analysis indicated consistent endothermic peaks across all samples, albeit with minor variations in heat flow and decomposition temperatures between the two products. CONCLUSIONS: This study demonstrated that variations in polymer grade and hydration form significantly impact THN release.

Preparation and Characterization of Theophylline Controlled Release Matrix System Incorporating Poloxamer 407, Stearyl Alcohol, and Hydroxypropyl Methylcellulose: A Novel Formulation and Development Study.

BACKGROUND: Theophylline (THN), a bronchodilator with potential applications in emerging conditions like COVID-19, requires a controlled-release delivery system due to its narrow therapeutic range and short half-life. This need is particularly crucial as some existing formulations demonstrate impaired functionality. This study aims to develop a new 12-h controlled-release matrix system (CRMS) in the form of a capsule to optimize dosing intervals. METHODS: CRMSs were developed using varying proportions of poloxamer 407 (P-407), stearyl alcohol (STA), and hydroxypropyl methylcellulose (HPMC) through the fusion technique. Their in vitro dissolution profiles were then compared with an FDA-approved THN drug across different pH media. The candidate formulation underwent characterization using X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. Additionally, a comprehensive stability study was conducted. RESULTS: In vitro studies showed that adjusting the concentrations of excipients effectively controlled drug release. Notably, the CRMS formulation 15 (CRMS-F15), which was composed of 30% P-407, 30% STA, and 10% HPMC, closely matched the 12 h controlled-release profile of an FDA-approved drug across various pH media. Characterization techniques verified the successful dispersion of the drug within the matrix. Furthermore, CRMS-F15 maintained a consistent controlled drug release and demonstrated stability under a range of storage conditions. CONCLUSIONS: The newly developed CRMS-F15 achieved a 12 h controlled release, comparable to its FDA-approved counterpart.

Pathophysiologic effects of waterpipe (shisha) smoke inhalation on liver morphology and function in mice.

AIMS: The global prevalence of waterpipe tobacco smoking is increasing. Although the cardiorespiratory, renal, and reproductive effects of waterpipe smoking (WPS) are well-documented, there is limited knowledge regarding its adverse impact on the liver. Therefore, our study aimed to assess the effects and potential mechanisms of WPS inhalation for one or four weeks on the liver. MAIN METHODS: Mice were exposed to WPS for 30 min per day, five days per week, while control mice were exposed to clean air. KEY FINDINGS: Analysis using light microscopy revealed the infiltration of immune cells (neutrophils and lymphocytes) accompanied by vacuolar hepatic degeneration upon WPS inhalation. At the four-week timepoint, electron microscopy analysis demonstrated an increased number of mitochondria with a concomitant pinching-off of hepatocyte plasma membranes. WPS exposure led to a significant rise in the activities of liver enzymes alanine aminotransferase and aspartate aminotransferase in the bloodstream. Additionally, WPS inhalation elevated lipid peroxidation and reactive oxygen species levels and disrupted the levels of the antioxidant glutathione in liver tissue homogenates. The concentration of proinflammatory cytokines, including tumor necrosis factor α, interleukin (IL)-6, and IL-1ß, was significantly increased in the WPS-exposed group. Furthermore, WPS inhalation induced DNA damage and a significant increase in the levels of cleaved caspase-3, cytochrome C and hypoxia-inducible factor 1α along with alterations in the activity of mitochondrial complexes I, II, III and IV. SIGNIFICANCE: Our findings provide evidence that WPS inhalation triggers changes in liver morphology, oxidative stress, inflammation, DNA damage, apoptosis, and alterations in mitochondrial activity.

Effect of Excipients on the Quality of Drug Formulation and Immediate Release of Generic Metformin HCl Tablets.

Generic medications are bioequivalent to brand-name medications, but the quality and purity of generic medications are still debatable. The aim of this study was to compare the generic product of metformin (MET) to its branded counterpart using pure MET powder as a reference. Quality control tablet assessment and in vitro evaluation of drug release were carried out in various pH media. Additionally, several analytical methods and thermal techniques were used, namely differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier-transform infrared (FTIR), and confocal Raman microscopy. The results showed a significant difference between the two products. In terms of friability assessment, mean resistance force, and tablet disintegration, the generic MET product showed significant weight loss, higher mean resistance force, longer disintegration time, and a slower rate of drug release. In addition, DSC and TGA showed that the generic product had the lowest melting point and the least weight loss compared to the branded product and pure powder. XRD and SEM demonstrated some changes in the crystallinity structure of the molecule particles for the generic product. Additionally, FTIR and confocal Raman revealed the same peaks and band shifts in all samples, but with differences in the intensity for the generic tablet only. The observed differences could be due to the use of different excipients in the generic product. The possibility of forming a eutectic mixture between the polymeric excipient and metformin in the generic tablet was presumed, which might be attributed to alterations in the physicochemical properties of the drug molecule in the generic product. In conclusion, using different excipients might have a significant effect on the physicochemical properties of drugs in generic formulations, leading to significant changes in drug release behavior.

Enteric-coating film effect on the delayed drug release of pantoprazole gastro-resistant generic tablets.

Background: Enteric coating films in acidic labile tablets protect the drug molecule from the acidic environment of the stomach. However, variations in the excipients used in the coating formulation may affect their ability to provide adequate protection. This study is the first to investigate the potential effects of coating materials on the protective functionality of enteric coating films for pantoprazole (PNZ) generic tablets after their recall from the market. Methods: A comparative analysis was conducted between generic and branded PNZ products, using pure drug powder for identification. The in vitro release of the drug was evaluated in different pH media. The study also utilized various analytical and thermal techniques, including differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier-transform infrared (FTIR), and confocal Raman microscopy. Results: The in vitro assessment results revealed significant variations in the release profile for the generic product in acidic media at 120 min. DSC and TGA thermal profile analyses showed slight variation between the two products. XRD analysis exhibited a noticeable difference in peak intensity for the generic sample, while SEM revealed smaller particle sizes in the generic product. The obtained spectra profile for the generic product displayed significant variation in peaks and band intensity, possibly due to impurities. These findings suggest that the excipients used in the enteric coating film of the generic product may have affected its protective functionality, leading to premature drug release in acidic media. Additionally, the presence of polysorbate 80 (P-80) in the brand product might improve the properties of the enteric coating film due to its multi-functionality. Conclusions: In conclusion, the excipients used in the brand product demonstrated superior functionality in effectively protecting the drug molecule from acidic media through the enteric coating film, as compared to the generic version.

Experimental Studies Indicate That ST-2223, the Antagonist of Histamine H3 and Dopamine D2/D3 Receptors, Restores Social Deficits and Neurotransmission Dysregulation in Mouse Model of Autism.

Altered regulation of neurotransmitters may lead to many pathophysiological changes in brain disorders including autism spectrum disorder (ASD). Given the fact that there are no FDA-approved effective treatments for the social deficits in ASD, the present study determined the effects of chronic systemic treatment of the novel multiple-active H3R/D2R/D3R receptor antagonist ST-2223 on ASD-related social deficits in a male Black and Tan Brachyury (BTBR) mice. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly and dose-dependently mitigated social deficits and disturbed anxiety levels of BTBR mice (p < 0.05) in comparison to the effects of aripiprazole (1 mg/kg, i.p.). Moreover, levels of monoaminergic neurotransmitters quantified by LC-MS/MS in four brain regions including the prefrontal cortex, cerebellum, striatum, and hippocampus unveiled significant elevation of histamine (HA) in the cerebellum and striatum; dopamine (DA) in the prefrontal cortex and striatum; as well as acetylcholine (ACh) in the prefrontal cortex, striatum, and hippocampus following ST-2223 (5 mg/kg) administration (all p < 0.05). These in vivo findings demonstrate the mitigating effects of a multiple-active H3R/D2R/D3R antagonist on social deficits of assessed BTBR mice, signifying its pharmacological potential to rescue core ASD-related behaviors and altered monoaminergic neurotransmitters. Further studies on neurochemical alterations in ASD are crucial to elucidate the early neurodevelopmental variations behind the core symptoms and heterogeneity of ASD, leading to new approaches for the future therapeutic management of ASD.

Biomimetic PLGA/Strontium-Zinc Nano Hydroxyapatite Composite Scaffolds for Bone Regeneration.

Synthetic bone graft substitutes have attracted increasing attention in tissue engineering. This study aimed to fabricate a novel, bioactive, porous scaffold that can be used as a bone substitute. Strontium and zinc doped nano-hydroxyapatite (Sr/Zn n-HAp) were synthesized by a water-based sol-gel technique. Sr/Zn n-HAp and poly (lactide-co-glycolide) (PLGA) were used to fabricate composite scaffolds by supercritical carbon dioxide technique. FTIR, XRD, TEM, SEM, and TGA were used to characterize Sr/Zn n-HAp and the composite scaffolds. The synthesized scaffolds were adequately porous with an average pore size range between 189 to 406 µm. The scaffolds demonstrated bioactive behavior by forming crystals when immersed in the simulated body fluid. The scaffolds after immersing in Tris/HCl buffer increased the pH value of the medium, establishing their favorable biodegradable behavior. ICP-MS study for the scaffolds detected the presence of Sr, Ca, and Zn ions in the SBF within the first week, which would augment osseointegration if implanted in the body. nHAp and their composites (PLGA-nHAp) showed ultimate compressive strength ranging between 0.4-19.8 MPa. A 2.5% Sr/Zn substituted nHAp-PLGA composite showed a compressive behavior resembling that of cancellous bone indicating it as a good candidate for cancellous bone substitute.

Exacerbation of Coagulation and Cardiac Injury in Rats with Cisplatin-Induced Nephrotoxicity Following Intratracheal Instillation of Cerium Oxide Nanoparticles.

BACKGROUND/AIMS: Exposure to particulate air pollution is associated with increased cardiovascular morbidity and mortality. These effects are particularly aggravated in patients with pre-existing kidney diseases. Cerium oxide nanoparticles (CNPs), used as diesel fuel additives, are emitted in vehicle exhaust and affect humans when inhaled. However, thrombotic and cardiac injury resulting from pulmonary exposure to CNPs in experimental acute kidney injury (AKI) is not fully understood. The objective of the present study was to evaluate the thrombotic and cardiac injury effects of CNPs in a rat model of AKI. METHODS: AKI was induced in rats by a single intraperitoneal injection of cisplatin (CDDP, 6 mg/kg). Six days after injection, rats were intratracheally (i.t.) instilled with either CNPs (1 mg/kg) or saline (control), and various cardiovascular variables and markers of inflammation, oxidative stress and DNA injury were assessed by enzyme linked immunosorbent assay, colorimetric assay, single-cell gel electrophoresis assay and immunohistochemistry, the following day. RESULTS: Compared with individual CDDP or CNPs treatments, the combined CDDP + CNPs treatment elevated significantly the coagulation function, relative heart weight, and troponin I, lactate dehydrogenase, interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and total nitric oxide levels in the plasma. In heart homogenates, the combination of CDDP and CNPs induced a significant increase in IL-6, TNFα, catalase, and glutathione. Furthermore, significantly more DNA damage was observed in this group than in the CDDP or CNPs groups. Immunohistochemical analysis of the heart revealed that expression of nuclear factor erythroid-derived 2-like 2 (Nrf2) and glutathione peroxidase by cardiac myocytes and endothelial cells was increased in the CDDP + CNPs group more than in either CDDP or CNPs group. CONCLUSION: I.t. administration of CNPs in rats with AKI exacerbated systemic inflammation, oxidative stress, and coagulation events. It also aggravated cardiac inflammation, DNA damage, and Nrf2 expression.

Remote effects and biodistribution of pulmonary instilled silver nanoparticles in mice.

Silver nanoparticles (AgNPs) are the most commonly used nanoparticles (NPs) owing to their anti-microbial properties, and the pulmonary system provides a major portal of entry for these NPs used in aerosolized products. AgNPs have the potential to cause pulmonary toxicity, cross the alveolar-capillary barrier, and distribute to remote organs following pulmonary exposure. The mechanism underlying the effects of AgNPs, secondary to lung exposure, on the major organs including liver, spleen, kidney and brain, however, is still not completely understood. The aim of this study was to analyze the organ toxicity and distribution of pulmonary exposure to single dose of 5 mg/kg AgNPs (10 nm) with varying coatings (polyvinylpyrrolidone and citrate), at different time points (1 and 7 days), in Balb/C mice. Silver ions (Ag+) were used as ionic control. Histological evidence of inflammation was observed in lungs for both types of AgNPs. Markers of inflammation including tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were significantly increased in lung, brain and liver in AgNPs exposed animals. Ag+ ions caused significant increase of TNF-α and IL-6 in the spleen and kidney. Significant increase of reduced glutathione, nitric oxide, and 8-isoprostane was observed in most of the organs investigated. Furthermore, AgNPs induced DNA damage and apoptosis in the lung, liver and brain. The biodistribution showed that, AgNPs were distributed mainly in the spleen, liver, lung and little in kidney and brain. Comparatively, reduced amount of Ag was detected in most organs 7 days after exposure, except for AgAc in the kidney and brain. In conclusion, pulmonary exposure to AgNPs caused oxidative stress markers, inflammation, DNA damage and biodistribution in remote organs. These findings provide a novel mechanistic insight into the pathophysiological effects and tissue distribution of lung exposure to AgNPs.

Ameliorative Effect of Gum Acacia on Hookah Smoke-Induced Testicular Impairment in Mice.

We investigated some reproductive actions of hookah smoke (HS) exposure (30 min/day, for 30 days) in male mice, and the possible mitigative effect of the prebiotic agent gum acacia (GA) thereon. Control mice were air-exposed (AE). Twenty-four hours after the last exposure, the levels of some plasma reproductive hormones, biochemical markers of inflammation, oxidative and nitrosative stress and testicular histopathology were assessed. The urinary level of cotinine, a major nicotine metabolite, was also measured. HS exposure induced significant decreases in testosterone, estradiol, luteinizing hormone, and androgen binding protein, as well as glutathione reductase activity and levels of nitrite and total nitrite. Plasma inhibin B, alkaline phosphatase, lipopolysaccharide binding protein, uric acid, lactate dehydrogenase, lipid peroxidation, 8-oxo-2'-deoxyguanosine, and cytochrome C were significantly increased following HS exposure. In testicular homogenate, nuclear factor-κB (NF-ĸB), nuclear factor erythroid 2-related factor 2 (Nrf2), interleukin- 6 (IL-6), interleukin-1ß (IL-1ß), transforming growth factor-ß1(TGF- ß1), and tumor necrosis factor-α (TNF- α) were all significantly elevated, and the steroidogenic acute regulatory protein (StAR) significantly decreased. Histopathologically, there was slight impairment and disorganization of spermatogenesis. Urinary cotinine concentration was elevated significantly in the HS-exposed group compared with the air-exposed group. GA co-administration mitigated the adverse actions of HS measured. In conclusion, daily exposure to HS at the above dose induced adverse actions on the reproductive system of male mice. GA co-administration significantly mitigated these effects by reducing the inflammation, oxidative and nitrosative stress, via a mechanism involving Nrf2, and reduction of StAR expression.

Nose-Only Water-Pipe Smoke Exposure in Mice Elicits Renal Histopathological Alterations, Inflammation, Oxidative Stress, DNA Damage, and Apoptosis.

The prevalence of water-pipe tobacco smoking is increasing worldwide, and is relatively high among youth and young adults. Exposure to water-pipe smoke (WPS) has been reported to affect various systems including the respiratory, cardiovascular and reproductive systems. However, the impact of WPS exposure on the kidney has received only scant attention. Here, we assessed the effect of nose-only WPS exposure for one or four consecutive weeks on renal histology, inflammation, oxidative stress, DNA damage, and apoptosis. The duration of the session was 30 min/day and 5 days/week. Control mice were exposed to air. Light and electron microcopy analysis revealed that the WPS exposure (especially at 4-week time point) caused degeneration of the endothelial cells of the glomerular capillaries and vacuolar degenerations of the proximal convoluted tubules. WPS exposure also significantly decreased the creatinine clearance, and significantly increased proteinuria and urinary kidney injury molecule-1 (KIM-1) concentration. Kidney lipid peroxidation, reactive oxygen species, and oxidized glutathione were significantly increased. WPS exposure also affected the concentration of reduced glutathione and the activity of catalase. Likewise, renal concentrations of interleukin (IL)-6, IL-1ß and KIM-1 were augmented by WPS exposure. Moreover, WPS caused DNA damage as evaluated by comet assay, and increased the expression of cleaved caspase-3 and cytochrome C in the kidney. We conclude that exposure of mice to WPS caused renal histopathological alterations, inflammation, oxidative stress, DNA damage, and apoptosis. If the latter findings could be substantiated by controlled human studies, it would be an additional cause for disquiet about an established public health concern.

Waterpipe Tobacco Smoke Inhalation Triggers Thrombogenicity, Cardiac Inflammation and Oxidative Stress in Mice: Effects of Flavouring.

The consumption of water-pipe smoking (WPS) has been promoted by the use of flavoured tobacco. However, little is known about the impact of flavouring on the cardiovascular toxicity induced by WPS inhalation. Here, we compared the cardiovascular effects and underlying mechanism of actions of plain (P) (unflavoured) versus apple-flavoured (AF) WPS (30 minutes/day, 5 days/week for 1 month) in mice. Control mice were exposed to air. Both P- and AF-WPS inhalation induced an increase in systolic blood pressure, thrombogenicity and plasma concentration of fibrinogen and von Willebrand factor. In heart homogenates, AF-WPS inhalation caused an increase of 8-isoprostane and a decrease in the levels of reduced glutathione (GSH) and superoxide dismutase (SOD). Nevertheless, P-WPS decreased only the activity of SOD. The concentrations of tumour necrosis factor α and interleukin 1ß were increased only in heart homogenates of mice exposed to AF-WPS. Although both P- and AF-WPS increased the concentration of troponin I in heart homogenates and induced DNA damage, the concentration of cleaved caspase 3 was only increased in mice exposed to AF-WPS. Immunohistochemical analysis of the hearts showed that both P- and AF- WPS inhalation decreased the expression of SOD. Moreover, the expression of nuclear factor erythroid-derived 2-like 2 at nuclear level in the heart was higher in both AF-WPS and P-WPS compared with control group, and the effect observed in AF-WPS group was more significant than that seen in P-WPS group. Likewise, the concentration of heme oxygenase-1 was significantly increased in both P-WPS and AF-WPS groups compared with control group, and the effect seen in AF-group was higher than that observed in P-WPS group. In conclusion, our findings showed that both P- and AF-WPS induce thrombogenicity and cardiac injury, and that this toxicity is potentiated by the presence of flavouring.

Comparative Study on Pulmonary Toxicity in Mice Induced by Exposure to Unflavoured and Apple- and Strawberry-Flavoured Tobacco Waterpipe Smoke.

The use of flavoured tobacco products in waterpipe smoking (WPS) has increased its attractiveness and consumption. Nonetheless, the influence of flavourings on pulmonary toxicity caused by WPS remains unclear. Here, the pulmonary toxicity induced by plain (P)-WPS, apple-flavoured (AF)-WPS, and strawberry-flavoured (SF)-WPS (30 minutes/day, 5 days/week for 1 month) was investigated in mice. Control mice were exposed to air. Exposure to P-WPS or AF-WPS or SF-WPS induced a dose-dependent increase of airway hyperreactivity to methacholine. The histological evaluation of the lungs in all the WPS groups revealed the presence focal areas of dilated alveolar spaces and foci of widening of interalveolar spaces with inflammatory cells. In the lung, the activity of neutrophil elastase and myeloperoxidase and the concentrations of tumor necrosis factor-α and glutathione were increased by the exposure to P-WPS, AF-WPS, or SF-WPS. However, the levels of interleukin-6 and catalase were only increased in the AF-WPS and SF-WPS groups, while nitric oxide activity was only increased in the SF-WPS group. DNA injury was increased in all the WPS groups, but the concentration of cleaved caspase-3 was only elevated in the SF-WPS group. The exposure to either P-WPS or AF-WPS or SF-WPS increased the expression of nuclear factor kappa-B (NF-κB) in the lung. In conclusion, the exposure to P-WPS or AF-WPS or SF-WPS induces alterations in lung function and morphology and causes oxidative stress and inflammation via mechanisms that include activation of NF-κB. Overall, the toxicity of flavoured tobacco WPS, in particular SF-WPS, was found to be greater than that of unflavoured WPS.

Aortic Oxidative Stress, Inflammation and DNA Damage Following Pulmonary Exposure to Cerium Oxide Nanoparticles in a Rat Model of Vascular Injury.

Pulmonary exposure to cerium oxide nanoparticles (CeO2 NPs) can occur either at the workplace, or due to their release in the environment. Inhaled CeO2 NPs are known to cross the alveolar-capillary barrier and reach various parts of the body, including the vasculature. The anticancer drug cisplatin (CP) causes vascular damage. However, the effects CeO2 NPs on vascular homeostasis in a rat model of CP-induced vascular injury remain unclear. Here, we assessed the impact and underlying mechanism of pulmonary exposure to CeO2 NPs on aorta in rats given a single intraperitoneal injection of cisplatin (CP, 6 mg/kg) to induce vascular damage. Six days later, the rats were intratracheally instilled with either CeO2 NPs (1 mg/kg) or saline (control), and various variables were studied 24 h thereafter in the aortic tissue. The concentration of reduced glutathione and the activity of catalase were significantly increased in the CP + CeO2 NPs group compared with both the CP + saline and the CeO2 NPs groups. The activity of superoxide dismutase was significantly decreased in the CP + CeO2 NPs group compared with both the CP + saline and CeO2 NPs groups. The expression of nuclear factor erythroid-derived 2-like 2 (Nrf2) by the nuclei of smooth muscles and endocardial cells assessed by immunohistochemistry was significantly augmented in CeO2 NPs versus saline, in CP + saline versus saline, and in CP + CeO2 NPs versus CeO2 NPs. Moreover, the concentrations of total nitric oxide, lipid peroxidation and 8-hydroxy-2-deoxyguanosine were significantly elevated in the CP + CeO2 NPs group compared with both the CP + saline and the CeO2 NPs groups. Similarly, compared with both the CP + saline and CeO2 NPs groups, the combination of CP and CeO2 NPs significantly elevated the concentrations of interleukin-6 and tumour necrosis factor-α. Additionally, aortic DNA damage assessed by Comet assay was significantly increased in CeO2 NPs compared with saline, and in CP + saline versus saline, and all these effects were significantly aggravated by the combination of CP and CeO2 NPs. We conclude that pulmonary exposure to CeO2 NPs aggravates vascular toxicity in animal model of vascular injury through mechanisms involving oxidative stress, Nrf2 expression, inflammation and DNA damage.

Testicular Toxicity of Water Pipe Smoke Exposure in Mice and the Effect of Treatment with Nootkatone Thereon.

There is a worldwide increase in the popularity of water pipe (shisha) tobacco smoking including in Europe and North America. However, little is known about the effects of water pipe smoke (WPS) exposure on male reproductivity. We have recently demonstrated that WPS exposure in mice induces testicular toxicity including inflammation and oxidative stress. Nootkatone, a sesquiterpenoid found in grapefruit, has antioxidant and anti-inflammatory effects. However, the possible protective effect of nootkatone on WPS-induced testicular toxicity has not been reported before. Here, we tested the effects of treatment of mice with nootkatone on WPS-induced testicular toxicity. Mice were exposed to normal air or WPS (30 minutes/day, for 30 days). Nootkatone (90 mg/kg) was given orally to mice by gavage, 1 h before WPS or air exposure. Nootkatone treatment significantly ameliorated the WPS-induced increase in plasma levels of inhibin, uric acid, and lactate dehydrogenase activity. Nootkatone also significantly mitigated the decrease in testosterone, androgen-binding protein, and estradiol concentrations in the plasma induced by WPS. In testicular homogenates, WPS exposure caused a decrease in the total nitric oxide level and an increase in the proinflammatory cytokine interleukin-1ß level and oxidative stress markers including malondialdehyde, cytochrome C, and 8-Oxo-2'-deoxyguanosine. All the latter effects were significantly alleviated by nootkatone treatment. Moreover, in testicular homogenate, nootkatone inhibited the expression of nuclear factor-kappaB induced by WPS. Likewise, histological examination of mouse testes showed that nootkatone treatment ameliorated the deterioration of spermatogenesis induced by WPS exposure. We conclude that nootkatone ameliorated the WPS-induced testicular inflammation and oxidative stress and hormonal and spermatogenesis alterations.

Waterpipe Smoke Exposure Triggers Lung Injury and Functional Decline in Mice: Protective Effect of Gum Arabic.

The prevalence of waterpipe (shisha) tobacco smoking has recently seen a substantial increase worldwide and is becoming a public health problem. Both human and animal studies have established that waterpipe smoke (WPS) increases airway reactivity and inflammation. Gum Arabic (GA) is a prebiotic agent that possesses antioxidant and anti-inflammatory properties. However, its effects on lung toxicity induced by WPS exposure are unknown. Thus, the aim of this study was to investigate the possible salutary effects and underlying mechanisms of GA on WPS-induced pulmonary pathophysiologic effects. C57BL/6 mice were exposed to air or WPS (30 minutes/day for one month) with or without GA treatment in drinking water (15%, w/v). Exposure to WPS induced an influx of neutrophil polymorphs in the peribronchiolar and interstitial spaces and an increase of tumor necrosis factor-α and 8-isoprostane, a marker of lipid peroxidation, concentrations in lung homogenates. The latter effects were significantly mitigated by GA treatment. Likewise, the lung DNA damage induced by WPS exposure was prevented by GA administration. Western blot analysis of the lung showed that GA inhibited nuclear factor kappa-B (NF-κB) expression caused by WPS and augmented that of nuclear factor erythroid 2-related factor 2 (Nrf2). Similarly, immunohistochemical analysis of bronchial epithelial cells and alveolar cells showed a parallel and significant increase in the nuclear expression of Nrf2 and cytoplasmic expression of glutathione in mice treated with GA and exposed to WPS. Moreover, GA administration has significantly prevented airway hyperreactivity to methacholine induced by WPS. We conclude that GA administration significantly declined the physiological, histological, biochemical, and molecular indices of lung toxicity caused by WPS exposure, indicating its beneficial respiratory impact. Considering that GA is a safe agent with health benefits in humans, our data suggest its potential usage in waterpipe smokers.

Impact of Pulmonary Exposure to Cerium Oxide Nanoparticles on Experimental Acute Kidney Injury.

BACKGROUND/AIMS: Cerium oxide nanoparticles (CeO2 NPs) are released from diesel engines that use cerium compounds as a catalytic agent to decrease the diesel exhaust particles, leading to human exposure by inhalation to CeO2 NPs. We have recently demonstrated that pulmonary exposure to CeO2 NPs induces lung inflammation, thrombosis, and oxidative stress in various organs including kidneys. It is well known that particulate air pollution effects are greater in patients with renal diseases. The aim of this study is to investigate the effects of pulmonary exposure to CeO2 NPs in a rat model of acute kidney injury (AKI). METHODS: AKI was induced in rats by a single intraperitoneal injection of cisplatin (CP, 6 mg/kg). Six days later, the rats were intratracheally (i.t.) instilled with either CeO2 NPs (1 mg/kg) or saline (control), and various renal and pulmonary endpoints were assessed 24 h afterward using histological, colorimetric assay, enzyme-linked immunosorbent assay and Comet assay techniques. RESULTS: CP alone decreased body weight, and increased water intake, urine volume and relative kidney weight. CP also increased the plasma concentrations urea and creatinine, and decreased creatinine clearance. In the kidneys, CP significantly increased renal injury molecule-1, interleukin-6 (IL-6), tumor necrosis factor α (TNFα) and glutathione concentrations, and caused renal tubular necrosis, and DNA injury assessed by Comet assay. All these actions were significantly aggravated in rats given both CP and CeO2 NPs. Histopathological changes in lungs of CeO2 NPs-treated rats included marked interstitial cell infiltration and congestion. These were aggravated by the combination of CP + CeO2 NPs. Moreover, this combination exacerbated the increase in the concentrations of TNFα and IL-6, and the decrease in the activity of pulmonary catalase and total nitric oxide concentration, and lung DNA damage. CONCLUSION: We conclude that the presence of CeO2 NPs in the lung exacerbated the renal and lung effects of CP-induced AKI.

Gum Arabic Ameliorates Impaired Coagulation and Cardiotoxicity Induced by Water-Pipe Smoke Exposure in Mice.

Water-pipe smoking (WPS) is prevalent in the East and elsewhere. WPS exposure is known to induce thrombosis and cardiovascular toxicity involving inflammation and oxidative stress. Here, we have investigated the effect of Gum Arabic (GA), a prebiotic with anti-oxidant, anti-inflammatory and cytoprotective properties, on WPS exposure (30 min/day for 1 month) on coagulation and cardiac homeostasis, and their possible underlying mechanisms in mice. Animals received either GA in drinking water (15%, w/v) or water only for the entire duration of study. GA significantly mitigated thrombosis in pial microvessels in vivo, platelet aggregation in vitro, and the shortening of prothrombin time induced by WPS exposure. The increase in plasma concentrations of fibrinogen, plasminogen activator inhibitor-1 and markers of lipid peroxidation, 8-isoprostane and malondialdehyde, induced by WPS were significantly reduced by GA administration. Moreover, WPS exposure induced a significant increase in systolic blood pressure and the concentrations of the pro-inflammatory cytokines tumor necrosis factor-α and interleukin 1ß in heart homogenates. GA significantly alleviated these effects, and prevented the decrease of reduced glutathione, catalase and total nitric oxide levels in heart homogenates. Immunohistochemical analysis of the hearts showed that WPS exposure increased nuclear factor erythroid-derived 2-like 2 (Nrf2) expressions by cardiac myocytes and endothelial cells, and these effects were potentiated by the combination of GA and WPS. WPS also increased DNA damage and cleaved caspase 3, and GA administration prevented these effects. Our data, obtained in experimental murine model of WPS exposure, show that GA ameliorates WPS-induced coagulation and cardiovascular inflammation, oxidative stress, DNA damage and apoptosis, through a mechanism involving Nrf2 activation.

Alda-1, an aldehyde dehydrogenase-2 agonist, causes deterioration in renal functions following ischemia-reperfusion injury due to crystalline nephropathy.

Renal ischemia-reperfusion injury (IRI) induces the production of aldehydes which are detoxified by aldehyde dehydrogenases (ALDHs). Alda-1 is a selective ALDH2 agonist and its protective effect was demonstrated in several conditions. The effect of Alda-1 on the kidney or on renal IRI was not investigated. We investigated the effect of Alda-1 on the renal dysfunction following IRI. Wistar rats underwent left IRI for 40 min. Group-Alda (n = 11) received Alda-1 starting 24 h before IRI and continued for 7 days thereafter when renal functions were measured. Group-Vx (n = 11) underwent similar protocol but received the dissolvent. Alda-1 did not affect renal blood flow or glomerular filtration rate in the left ischemic kidney in Group-Alda compared to Group-Vx (3.05 ± 0.50 vs. 3.53 ± 0.70, and 0.40 ± 0.06 vs. 0.51 ± 0.08, respectively, p > .05 for both). However, left renal fractional sodium excretion was higher in Group-Alda (2.80 ± 0.43 vs. 1.37 ± 0.36, p = .02). Alda-1 also adversely affected the gene expressions of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin (217 ± 38 vs. 99 ± 13 and 49 ± 13 vs. 20 ± 5, respectively, p < .05 for both) and the alterations in tumor necrosis factor-α, transforming growth factor-ß1, plasminogen activator inhibitor-1, fibronectin 1 and p53 (4.4 ± 0.9 vs. 2.1 ± 0.3, 1.5 ± 0.1 vs. 1.1 ± 0.1, 30.0 ± 2.7 vs. 11.7 ± 2.3, 3.6 ± 0.4 vs. 2.1 ± 0.2 and 1.3 ± 0.1 vs. 0.9 ± 0.07, respectively, p ≤ .05 for all). This was associated with intratubular crystal deposition suggestive of crystalline nephropathy. Alda-1 exacerbated the IRI-induced renal tubular dysfunction and alterations in markers of acute kidney injury, biomarkers of inflammation, fibrosis and apoptosis and this was associated with intratubular crystal deposition suggestive of crystalline nephropathy.

Exercise Training Mitigates Water Pipe Smoke Exposure-Induced Pulmonary Impairment via Inhibiting NF-κB and Activating Nrf2 Signalling Pathways.

Water pipe smoking is a tobacco smoking method commonly used in Eastern countries and is gaining popularity in Europe and North America, in particular among adolescents and young adults. Several clinical and experimental studies have reported that exposure to water pipe smoke (WPS) induces lung inflammation and impairment of pulmonary function. However, the mechanisms of such effects are not understood, as are data on the possible palliative effect of exercise training. The present study evaluated the effects of regular aerobic exercise training (treadmill: 5 days/week, 40 min/day) on subchronic exposure to WPS (30 minutes/day, 5 days/week for 2 months). C57BL/6 mice were exposed to air or WPS with or without exercise training. Airway resistance measured using forced oscillation technique was significantly and dose-dependently increased in the WPS-exposed group when compared with the air-exposed one. Exercise training significantly prevented the effect of WPS on airway resistance. Histologically, the lungs of WPS-exposed mice had focal moderate interstitial inflammatory cell infiltration consisting of neutrophil polymorphs, plasma cells, and lymphocytes. There was a mild increase in intra-alveolar macrophages and a focal damage to alveolar septae in some foci. Exercise training significantly alleviated these effects and also decreased the WPS-induced increase of tumor necrosis factor α and interleukin 6 concentrations and attenuated the increase of 8-isoprostane in lung homogenates. Likewise, the lung DNA damage induced by WPS was significantly inhibited by exercise training. Moreover, exercise training inhibited nuclear factor kappa-B (NF-κB) expression induced by WPS and increased that of nuclear factor erythroid 2-related factor 2 (Nrf2). Our findings suggest that exercise training significantly mitigated WPS-induced increase in airway resistance, inflammation, oxidative stress, and DNA damage via mechanisms that include inhibiting NF-κB and activating Nrf2 signalling pathways.