Intragastric Route Research Articles

4-amino-3-(phenylselanyl) benzenesulfonamide attenuates intermittent cold stress-induced fibromyalgia in mice: Targeting to the Nrf2-NFκB axis

Stress is widely recognized as the primary environmental factor associated with chronic pain conditions, including fibromyalgia. A recent study demonstrated the potential antinociceptive effects of 4-amino-3-(phenylselanyl) benzenesulfonamide (4-APSB) in acute nociceptive animal models due to its antioxidant and anti-inflammatory properties. However, the efficacy of 4-APSB in managing chronic painful conditions, such as fibromyalgia, has not been explored so far. This study investigated the pharmacological effects of 4-APSB in an experimental model of fibromyalgia induced by intermittent cold stress (ICS). Male and female mice were divided into Control, ICS, 4-APSB, and ICS + 4-APSB. After the ICS, the animals were treated with 4-APSB (1 mg kg−1) or vehicle by the intragastric route until the tenth day. The behavioral tasks were performed on days 5, 8, and 10. The findings showed a negative correlation between paw withdrawal threshold and Nrf2 or NFκB mRNA expression levels caused by ICS exposure. The 4-APSB suppressed the nociceptive signs and a depressive like-phenotype in male and female mice exposed to ICS. 4-APBS normalized the elevated levels of TBARS and the up-regulation of Nrf2 and NFκB expression in the cerebral cortex of ICS-exposed mice. This compound also modulated the oxidative stress in the spinal cord of female mice. The 4-APSB attenuated the inhibition of Na+, K+ − ATPase activity in the central nervous system (CNS) of female mice exposed to ICS. 4-APSB attenuated behavioral and redox imbalance triggered by the ICS model in male and female mice, suggesting its beneficial effects for treating fibromyalgia in both sexes.

Effects of orally exposed SiO2 nanoparticles on lipid profiles in gut-liver axis of mice.

Recently we proposed the possibility of orally exposed nanoparticles (NPs) to alter metabolite homeostasis by changing metabolism pathways, in addition to intestinal damages, but relatively few studies investigated the changes of metabolite profiles in multi-organs. This study investigated the influences of orally exposed SiO2 NPs on lipid profiles in gut-liver axis. To this end, we treated mice with 16, 160 or 1600 mg/kg bodyweight SiO2 NPs via intragastric route. After 5 days exposure (once a day), we observed that SiO2 NPs induced minimal pathological changes but increased most of the trace elements. Furthermore, lipid staining was gradually decreased in intestines and livers with the increase of NP levels. Consistently, lipidomics results showed that most of the lipid classes in mouse intestines and livers were decreased following SiO2 NP administration. We further identified the lipid classes significantly decreased in both intestines and livers, such as phosphatidylserine (PS), phosphatidylglycerol (PG), and phosphatidylethanolamine (PE). Only a few lipid classes, such as anandamide, showed opposite trends in these organs. For metabolism pathway, SiO2 NPs suppressed autophagy, showing as a significant decrease of microtubule-associated protein 1 A/1B light chain 3 (LC3) and adipose triglyceride lipase (Atgl), accompanying with an accumulation of P62, in both intestines and livers. However, lysosomal-associated membrane protein 2 (Lamp2) showed different trend, that it was significantly increased in intestines but decreased in livers. Combined, our results indicated that intragastric administration of SiO2 NPs altered trace element balance and lipid profiles, accompanying with a change of autophagic lipolysis proteins, in mouse gut-liver axis.

Vasant Kusumakar Rasa Ameliorates Diabetic Encephalopathy by Reducing Oxidative Stress and Neuroinflammation and Improving Neurotransmitter Levels in Experimental Animals.

Diabetic encephalopathy (DE) is one of the complications of diabetes that affects the brain. In the Ayurveda system of medicine, Vasant Kusumakar Rasa (VKR) is cited as a classical herbo-mineral formulation for diabetes. However, the role of VKR in DE is still unclear. High-fat diet and streptozotocin (35 mg/kg, i.p.) were used to induce type 2 DE in Sprague Dawley rats. VKR at doses 28 mg/kg and 56 mg/kg was given via intragastric route to diabetic rats for 16 weeks. Estimation of plasma glucose, serum insulin, glycohemoglobin, and C-reactive protein (C-RP) was analyzed. Furthermore, the Morris water maze test was performed to assess cognitive behavior. Pro-inflammatory, such as TNF-α, IL-1β, and IL-6, were measured in brain tissue homogenate. Antioxidant enzyme assays were performed to estimate the levels of malondialdehyde, reduced glutathione, superoxide dismutase, and catalase in brain tissue. Histopathology of brain sections was performed using hematoxylin and eosin (H & E) staining. Neurotransmitters (viz., serotonin (5-HT), dopamine (DA), and norepinephrine (NE)) were estimated in the brain by high-performance liquid chromatography (HPLC). The data were analyzed by using ANOVA, followed by Dunnett's multiple comparison test. VKR treatment, at a dose of 28 and 56 mg/kg, reduced the plasma glucose level significantly (236.7±17.08 and 221.8±17.50, respectively; p<0.001) when compared with diabetic control (461.7±13.03). The treatment also reduced serum insulin and glycated hemoglobin levels and improved the escape latency in VKR-treated animals as compared to diabetic animals. Brain tissue pro-inflammatory marker levels were reduced, and oxidative stress enzymes showed positive marks in diabetic rats treated with VKR. Histopathology of the brain demonstrated a reduction in neuronal damage in the VKR-treated diabetic animals. VKR treatment at doses of 28 and 56 mg/kg also improved the levels of 5-HT (1.78±0.11and 1.72±0.18, respectively)when compared with diabetic control (0.91±0.08) significantly (p<0.01). DA levels were significantly (p<0.01) increased in VKR-treated animals when compared with diabetic animals.The treatment of VKR for 16 weeks also improved the NE levels significantly when compared with diabetic control animals. The result of the study indicates that the treatment with VKR for 16 weeks has significant therapeutic potential in the management of type 2 DE.

Investigation of oral toxicity of WS2 nanosheets to mouse intestine: Pathological injury, trace element balance, lipid profile changes, and autophagy.

The success of graphene oxides has gained extensive research interests in developing novel 2D nanomaterials (NMs). WS2 nanosheets (NSs) are novel transition metal-based 2D NMs, but their toxicity is unclear. In this study, we investigated the oral toxicity of WS2 NSs to mouse intestines. Male mice were administrated with vehicles, 1, 10, or 100 mg/kg NSs via intragastric route, once a day, for 5days. The results indicate that the NSs did not induce pathological or ultrastructural changes in intestines. There were minimal changes of trace elements that the exposure did not induce W accumulation, and only Co levels were dose-dependently increased. Lipid droplets were observed in all groups of mice, but lipidomics data indicate that WS2 NSs only significantly decreased four lipid species, all belonging to phosphatidylcholine (PC). The levels of proteins regulating autophagic lipolysis, namely, LC3, lysosomal associated membrane protein 2 (LAMP2) and perilipin 2 (PLIN2), were increased, but it was only statistically significantly different for LC3. The results of this study suggest that repeated intragastric exposure to WS2 NSs only induced minimal influences on pathological injury, trace element balance, autophagy, and lipid profiles in mouse intestines, indicating relatively high biocompatibility of WS2 NSs to mouse intestine via oral route.

Evaluation of the Antioxidant and Anti-Inflammatory Activities and Acute Toxicity of Caco Seed (Chrysobalanus icaco L.) in Murine Models.

Chysobalanus icaco L. (C. icaco) is a plant that is native to tropical America and Africa. It is also found in the southeast region of Mexico, where it is used as food and to treat certain diseases. This study aimed to carry out a phytochemical analysis of an aqueous extract of C. icaco seed (AECS), including its total phenol content (TPC), total flavonoid content (TFC), and condensed tannins (CT). It also aimed to examine the antioxidant and metal-ion-reducing potential of the AECS in vitro, as well as its toxicity and anti-inflammatory effect in mice. Antioxidant and metal-ion-reducing potential was examined by inhibiting DPPH, ABTS, and FRAP. The acute toxicity test involved a single administration of different doses of the AECS (0.5, 1, and 2 g/kg body weight). Finally, a single administration at doses of 150, 300, and 600 mg/kg of the AECS was used in the carrageenan-induced model of subplantar acute edema. The results showed that the AECS contained 124.14 ± 0.32 mg GAE, 1.65 ± 0.02 mg EQ, and 0.910 ± 0.01 mg of catechin equivalents/g dried extract (mg EC/g de extract) for TPC, TFC and CT, respectively. In the antioxidant potential assays, the values of the median inhibition concentration (IC50) of the AECS were determined with DPPH (0.050 mg/mL), ABTS (0.074 mg/mL), and FRAP (0.49 mg/mL). Acute toxicity testing of the AECS revealed no lethality, with a median lethal dose (LD50) value of >2 g/kg by the intragastric route. Finally, for inhibition of acute edema, the AECS decreased inflammation by 55%, similar to indomethacin (59%, p > 0.05). These results demonstrated that C. icaco seed could be considered a source of bioactive molecules for therapeutic purposes due to its antioxidant potential and anti-inflammatory activity derived from TPC, with no lethal effect from a single intragastric administration in mice.

Acute 2-phenyl-3-(phenylselanyl)benzofuran treatment reverses the neurobehavioral alterations induced by sleep deprivation in mice

Sleep is a fundamental state for maintaining the organism homeostasis. Disruptions in sleep patterns predispose to the appearance of memory impairments and mental disorders, including depression. Recent pre-clinical studies have highlighted the antidepressant-like properties of the synthetic compound 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1). To further investigate the neuromodulatory effects of SeBZF1, this study aimed to assess its therapeutic efficacy in ameliorating neurobehavioral impairments induced by sleep deprivation (SD) in mice. For this purpose, a method known as multiple platforms over water was used to induce rapid eye movement (REM) SD. Two hours after acute SD (24 h), male Swiss mice received a single treatment of SeBZF1 (5 mg/kg, intragastric route) or fluoxetine (a positive control, 20 mg/kg, intraperitoneal route). Subsequently, behavioral tests were conducted to assess spontaneous motor function (open-field test), depressive-like behavior (tail suspension test), and memory deficits (Y-maze test). Brain structures were utilized to evaluate oxidative stress markers, monoamine oxidase (MAO) and acetylcholinesterase (AChE) activities. Our findings revealed that SD animals displayed depressive-like behavior and memory impairments, which were reverted by SeBZF1 and fluoxetine treatments. SeBZF1 also reverted the increase in lipoperoxidation levels and glutathione peroxidase activity in the pre-frontal cortex in mice exposed to SD. Besides, the increase in hippocampal AChE activity induced by SD was overturned by SeBZF1. Lastly, cortical MAO-B activity was reestablished by SeBZF1 in mice that underwent SD. Based on the main findings of this study, it can be inferred that the compound SeBZF1 reverses the neurobehavioral alterations induced by sleep deprivation in male Swiss mice.

A REVIEW ON FAST DISSOLVING FILM

Orally fast dissolving films (OFDFs) have been introduced in the market recently as they provide convenience and ease of use over other dosage forms such as orally disintegrating tablets. This technology evolved over the past few years from the confection and oral care markets in the form of breath strips and became a novel and widely accepted form by consumers, so OFDFs are gaining the interest of large number of pharmaceutical industries. Orally fast dissolving film is the type of drug delivery system which when placed in the oral cavity, disintegrate or dissolve within few seconds without the intake of water. OFDFs are very similar to postage stamp in their shape, size and thickness. These films have a potential to deliver the drug systemically through intragastric, sublingual or buccal route of administration and also has been used for local action. This type of technology offer a convenient way of dosing medication, not to special population groups like pediatric, geriatric, bedridden patients, mentally ill patients, but also to the general population. The present review provides an account of various formulation considerations, method of preparation and quality control of the OFDFs.

Mucosal Immunization with Spore-Based Vaccines against Mannheimia haemolytica Enhances Antigen-Specific Immunity.

Mannheimia haemolytica is a bovine respiratory pathogen commonly associated with bacterial bronchopneumonia. Current vaccine strategies have shown variable efficacy in feedlot cattle, and therefore novel vaccines are needed. Bacillus subtilis spores have been investigated as a mucosal vaccine platform, due to their ability to bind and present antigens to the mucosa and act as an adjuvant. The aim of this study was to develop two spore-based mucosal vaccines targeting M. haemolytica and evaluate their immunogenicity in mice. Two antigen constructs composed of cholera toxin B subunit, M. haemolytica leukotoxin, and either the M. haemolytica outer membrane protein PlpE (MhCP1) or GS60 (MhCP2) were synthesized, purified and then bound to spores as vaccines. In two separate mice trials, the spore-bound vaccines (Spore-MhCP1 and Spore-MhCP2) were administered to mice through intranasal and intragastric routes, while free antigens were administered intranasally and intramuscularly. Unbound spores were also evaluated intranasally. Antigen-specific serum IgG and mucosal IgA from bronchoalveolar lavage, feces, and saliva were measured after vaccination. Mice sera from all treatment groups were assessed for their bactericidal activity against M. haemolytica. In both mice experiments, intramuscular immunization induced the strongest serum IgG antibody response. However, the intranasal administration of Spore-MhCP1 and Spore-MhCP2 elicited the greatest secretory IgA-specific response against leukotoxin, PlpE, and GS60 in bronchoalveolar lavage, saliva, and feces (p < 0.05). Compared to the intranasal administration of free antigen, spore-bound antigen groups showed greater bactericidal activity against M. haemolytica (p < 0.05). Since intranasally delivered Spore-MhCP1 and Spore-MhCP2 elicited both systemic and mucosal immune responses in mice, these vaccines may have potential to mitigate lung infection in cattle by restricting M. haemolytica colonization and proliferation in the respiratory tract. The efficacy of these mucosal spore-based vaccines merits further assessment against M. haemolytica in cattle.

Effect of 2-Week Naringin Supplementation on Neurogenesis and BDNF Levels in Ischemia–Reperfusion Model of Rats

Background: Ischemic stroke is the leading cause of mortality and disability worldwide with more than half of survivors living with serious neurological sequelae; thus, it has recently attracted a lot of attention in the field of medical study. Purpose: The aim of this study was to determine the effect of naringin supplementation on neurogenesis and brain-derived neurotrophic factor (BDNF) levels in the brain in experimental brain ischemia–reperfusion. Study design: The research was carried out on 40 male Wistar-type rats (10–12 weeks old) obtained from the Experimental Animals Research and Application Center of Selçuk University. Experimental groups were as follows: (1) Control group, (2) Sham group, (3) Brain ischemia–reperfusion group, (4) Brain ischemia–reperfusion + vehicle group (administered for 14 days), and (5) Brain ischemia–reperfusion + Naringin group (100 mg/kg/day administered for 14 days). Methods: In the ischemia–reperfusion groups, global ischemia was performed in the brain by ligation of the right and left carotid arteries for 30 min. Naringin was administered to experimental animals by intragastric route for 14 days following reperfusion. The training phase of the rotarod test was started 4 days before ischemia–reperfusion, and the test phase together with neurological scoring was performed the day before and 1, 7, and 14 days after the operation. At the end of the experiment, animals were sacrificed, and then hippocampus and frontal cortex tissues were taken from the brain. Double cortin marker (DCX), neuronal nuclear antigen marker (NeuN), and BDNF were evaluated in hippocampus and frontal cortex tissues by Real-Time qPCR analysis and immunohistochemistry methods. Results: While ischemia–reperfusion increased the neurological score values, DCX, NeuN, and BDNF levels decreased significantly after ischemia in the hippocampus and frontal cortex tissues. However, naringin supplementation restored the deterioration to a certain extent. Conclusion: The results of the study show that 2 weeks of naringin supplementation may have protective effects on impaired neurogenesis and BDNF levels after brain ischemia and reperfusion in rats.

Curculigoside, a traditional Chinese medicine monomer, ameliorates oxidative stress in Alzheimer's disease mouse model via suppressing ferroptosis.

Alzheimer's disease (AD) is a neurodegenerative disorder where oxidative stress, induced by ferroptosis, has been linked to neuronal damage and cognitive deficits. The objective of this study is to investigate if the potential therapeutic agent, Curculigoside (CUR), could ameliorate AD by inhibiting ferroptosis. The potential therapeutic targets, such as GPX4 and SLC7A11, were identified using weighted gene co-expression network analysis (WGCNA). Concurrently, CUR was also screened against these potential targets using various analytical methods. For the in vivo studies, intragastric administration of CUR significantly ameliorated cognitive impairment in AD model mice induced by scopolamine and okadaic acid (OA). In vitro, CUR protected neuronal cells by altering the levels of ferroptosis-related specific markers in OA and scopolamine-induced neurotoxicity. The administration of CUR through intragastric route significantly reduced the levels of AD-promoting factors (such as Aβ1-42, p-tau) and ferroptosis-promoting factors in the hippocampus and cortex of AD mice. Furthermore, CUR up-regulated the expression of GPX4 and decreased the expression of SLC7A11 in the ferroptosis signaling pathway, thereby increasing the ratio of glutathione (GSH)/oxidized glutathione (GSSG) in vivo and vitro. In conclusion, the cumulative results suggest that the natural compound CUR may serve as a promising therapeutic agent to ameliorate AD by inhibiting ferroptosis.

Soybean Isoflavones Ameliorates Lactation Performance in Postpartum Mice by Alleviating Oxidative Stress and Regulating Gut Microflora.

Postpartum dysgalactiae syndrome (PPDS) is one of the key issues affecting breastfeeding, usually occurring as breast swelling, a low milk yield, and at length a stop of breast milk secretion. Therefore, there is a need to investigate the effectiveness of Traditional Chinese Medicine (TCM) diet therapy in treating or preventing PPDS. This study aims to analyze the effect of soybean isoflavone (SIF), a natural estrogen found in plants, on postpartum lactation performance in mice and to evaluate its potential as a treatment for PPDS. Adult female BALB/c mice at 8 weeks of age (25 ± 3g) are randomly divided into four groups fed with different levels of SIF and a normal diet for 14 days. SIF (0, 50, 100, 200mg kg-1 BW) is provided via intra-gastric route to the experimental mice. Using a high-throughput sequencing of microbial diversity and mammary gland metabolites, it is found that SIF-treated mice potentially show an improved milk performance via enhanced antioxidant capacity and altered gut microbiota. SIF from plant sources at a high dosage promotes the lactation in normal postpartum mice.

Efficacy of tanshinone IIA in rat models with myocardial ischemia-reperfusion injury: a systematic mini-review and meta-analysis.

Myocardial ischemia-reperfusion injury (MIRI) refers to severe damage to the ischemic myocardium following the restoration of blood flow, and it is a major complication of reperfusion therapy for myocardial infarction. Notably, drugs such as metoprolol have been utilized to reduce ischemia-reperfusion injury. Tanshinone IIA is a major constituent extracted from Salvia miltiorrhiza Bunge. Recently, tanshinone IIA has been studied extensively in animal models for controlling MIRI. Therefore, we conducted a meta-analysis on the application of tanshinone IIA in rat models with MIRI to evaluate the therapeutic effects of tanshinone IIA. A comprehensive search was conducted across PubMed, Web of Science, Embase, the Cochrane Library, the China National Knowledge Infrastructure database, the Wanfang database, and the Chinese Scientific Journal Database to gather studies on tanshinone IIA intervention in rat models with MIRI.We employed SYRCLE's risk of bias tool to assess study quality. The primary outcome indicators were superoxide dismutase (SOD) and malondialdehyde (MDA). Myocardial infarction area was a secondary outcome indicator. This study was registered at PROSPERO (registration number CRD 42022344447). According to the inclusion and exclusion criteria, 15 eligible studies were selected from 295 initially identified studies. In rat models with MIRI, tanshinone IIA significantly increased SOD levels while reducing MDA levels and myocardial infarction area. Moreover, the duration of myocardial ischemia influenced the effectiveness of tanshinone IIA. However, additional high-quality research studies are needed to establish the efficacy and definitive guidelines for the use of tanshinone IIA. Animal studies demonstrated that tanshinone IIA exerted a significant therapeutic effect when the ischemia duration was less than 40 minutes. Tanshinone IIA was found to be more effective when administered via intravenous, intraperitoneal, and intragastric routes at doses above 5 mg/kg. Additionally, treatment with tanshinone IIA at all stages-prior to myocardial ischemia, after ischemia but before reperfusion, prior to ischemia and after reperfusion, and after reperfusion-showed satisfactory results. Tanshinone IIA enhanced SOD activity and reduced MDA levels, thereby ameliorating oxidative stress damage during MIRI. Additionally, it reduced the myocardial infarction area, indicating its effectiveness in mitigating MIRI-induced damage in rats and demonstrating a myocardial protective effect. These findings contribute valuable insights for developing MIRI treatment strategies.

Экспериментальное изучение хронической токсичности пегилированного интерферона лямбда-1

Introduction. Lambda interferons (IFN-λ), known as type III interferons (type III IFN), demonstrate significant prospects in the field of antivirus defense. IFN-λ are similar in their antiviral activity to type I IFN, but have unique mechanisms of induction and functioning because of the specific location of their receptors. Type I receptors are expressed in most nucleated cells, IFN-λ receptors (IFN-λR1 or IL-28Rα) are mainly found in epithelial cells. IFN-λ are considered as the first line of defense against microbial attacks, therefore, the development of IFN-λ-based drugs seems very promising. A prototype of an IFN-λ-based drug for enteral administration, PEGylated (polyethylene glycol) using electron beam synthesis technology, has already been developed. Aim. To study the common toxic properties of the intragastrically administered IFN-λ1-based drug in experiments in vivo. Materials and methods. The IFN-λ1-based drug was administered daily intragastrically at doses of 2.6, 13.0 and 26.0 µg/kg (1 therapeutic dose (TD), 5 TD and 10 TD, respectively) to rats and 2.6 and 13.0 µg/kg (1 TD and 5 TD) to rabbits once a day for 180 days. The doses of the drug were calculated for each animal individually, based on body weight. Rabbits were followed-up during the drug administration (180 days), and rats – additionally for 30 days after the end of administration (210 days). In animals, vital signs, behavioral reactions, laboratory parameters of cellular and biochemical composition of blood, electrocardiography data, hematopoiesis parameters, pathomorphological signs were assessed. Results. No deaths were observed during the study. The animals showed a stable state of health, the absence of visible changes in an appetite, appearance, and behavior. During a pathomorphological examination, no abnormalities were found that could indicate a negative effect of the substance. A significant decrease in the mass and mass coefficient of the thymus and spleen was revealed in rats receiving the drug at a dose of 26.0 µg/kg after 180 days of administration compared with the corresponding control. The thymus and spleen mass and the mass coefficient of the thymus and spleen normalized 30 days after drug withdrawal in all groups, where abnormalities were observed. A microscopic examination of the internal organs of rats receiving the highest dose of the IFN-λ1-based drug (26.0 µg/kg) for 180 days revealed specific changes in the thymus and spleen, while analysis of the thymus and spleen in rats receiving a lower dose of the drug (13.0 µg/kg) did not reveal similar pathological changes.This indicates the possibility of dose-dependent toxic effect of the drug. 30 days after the IFN-λ1-based drug withdrawal, the mass and mass coefficient of the thymus and spleen of rats receiving the highest dose of the drug returned to the reference values and did not differ from the corresponding control. Both in rats and rabbits, the indicators of body weight gain, peripheral blood and bone marrow, biochemical parameters of the blood serum in both males and females in the experimental and control groups did not differ significantly throughout the study. The pathomorphological examination found no changes in such crucial organs as the brain, heart, lungs, liver, etc., which indicates the absence of negative effect of the drug on the health and condition of the tissues of rabbits. Conclusion. Based on in vivo experiments to study the common toxic properties of IFN-λ1-based drug in the intragastric route of administration, it can be argued that the drug belongs to the 4th hazard class (GOST 12.1.007-76).

Preparation of betaine injection and its therapeutic effect in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by elevated pulmonary pressure, right ventricular failure (RVF) and ultimately death. Aggressive treatment of RVF is considered an important therapeutic strategy to treat PAH. Previous studies have indicated that betaine may be may a promising therapeutic approach for PAH-induced RVF. Therefore, in this study, betaine solution for injection was prepared and characterised using various techniques. The therapeutic efficacy of three different methods of administration (intragastric, nebulised inhalation and intravenous injection) were comprehensively evaluated in terms of pharmacokinetics, tissue distribution and pharmacodynamics. The pharmacokinetic results demonstrated that betaine injection administered via nebulised inhalation significantly prolonged betaine's half-life and increased its internal circulation time compared to the intragastric and intravenous routes. Biodistribution experiments verified that the betaine formulation accumulated in the lung tissue when administered via inhalation. The results of the pharmacodynamic analysis further confirmed that right ventricular systolic pressure, mean pulmonary artery pressure and right ventricular hypertrophy index increased in the model group and that inhaled betaine suppressed these pathological changes to a level comparable to those observed in the control group. Taken together, these results indicate that betaine administered by inhalation is a promising strategy for the treatment of PAH-induced RVF.

Pharmacokinetics of collagen dipeptides (Gly-Pro and Pro-Hyp) and tripeptides (Gly-Pro-Hyp) in rats.

Although systemic exposure to peptides, such as Gly-Pro-Hyp, Pro-Hyp, and Gly-Pro, has been reported following administration of collagen hydrolysates from fish scale and porcine skin in vivo, the individual peptide pharmacokinetics remain unknown. We administered the three peptides individually to rats via the intravenous (5mg/kg) and intragastric (100mg/kg) routes and then monitored systemic exposure and urinary excretion. The peptides in biological samples were analyzed via liquid chromatography/tandem mass spectrometry. Gly-Pro-Hyp tended to exhibit higher first-pass metabolism than Pro-Hyp; the absolute oral bioavailabilities of Gly-Pro-Hyp and Pro-Hyp were 4.4% and 19.3%, respectively. Gly-Pro levels were very low in the systemic circulation. Pro-Hyp biotransformed from Gly-Pro-Hyp behaved similarly to Pro-Hyp alone when administered orally. Flip-flop kinetics (elimination rate ≫ absorption rate) were evident, probably reflecting transporter-mediated slow absorption. A double-peak phenomenon was observed for Gly-Pro-Hyp and Pro-Hyp when administered orally, and 5.9%±2.6% and 1.9%±0.3% of each dose were excreted in urine after intravenous administration, respectively. Urinary recovery of Gly-Pro was limited to 0.4%±0.5% of the intravenous dose. This work represents the first individual pharmacokinetics of Gly-Pro-Hyp, Pro-Hyp, and Gly-Pro in vivo.

An investigation of the endoplasmic reticulum stress in obesity exposure in the prenatal period

ObjectivesExposure to maternal obesity has been shown to make offspring more prone to cognitive and metabolic disorders later in life. Although the underlying mechanisms are unclear, the role of endoplasmic reticulum (ER) stress in the fetal programming process is remarkable. ER stress can be activated by many chronic diseases, including obesity and diabetes. Therefore, our study aimed to investigate the role of ER stress caused by maternal diet-induced obesity in the offspring hippocampus. We also evaluated the protective effect of N-acetylcysteine (NAC) against ER stress. MethodsA rat obesity model was created by providing a high-fat (60 % kcal) diet. N-acetylcysteine (NAC) was administered at a dosage of 150 mg/kg via the intragastric route. The animals were mated at the age of 12 weeks. The same diet was maintained during pregnancy and lactation. The experiment was terminated on the postnatal 28th day, and the offspring's brain tissues were examined. Immunohistochemical staining for ER stress markers was performed on sections taken from tissues after routine histological procedures. ResultsThe results revealed increased GRP78, PERK, and eIF2α immunoreactivities in the hippocampal dentate gyrus (DG) and cornu ammonis 1 (CA1) regions in the obese group offspring, while the expression of those markers in those regions normalized with NAC supplementation (p < 0.01). Statistical analysis of XBP1 immunoreactivity H-scores revealed no difference between the study groups (p > 0.05). DiscussionThese results suggest that exposure to obesity during the prenatal period may cause increased ER stress in hippocampal neurons, which have an important role in the regulation of learning, memory and behavior, and this may contribute to decreased cognitive performance. On the other hand, NAC stands out as an effective agent that can counteract hippocampal ER stress.

Chiranthodendron pentadactylon Larreat (Sterculiaceae), a Potential Nephroprotector against Oxidative Damage Provoked by STZ-Induced Hyperglycemia in Rats.

Chiranthodendron pentadactylon, known in Mexico as the "tree of the little hands", flower's infusion is used to treat kidney failure associated with diseases such as diabetes. The aim of this work is to evaluate the antioxidant effect of the methanolic extract of its flowers on oxidative damage in kidneys caused by streptozotocin in rats. The extract phytochemical profile was performed with HPLC. Antioxidant potential in vitro was determined with DPPH and total phenolic tests; antioxidant evaluation in vivo was performed in diabetic rats administered daily via the intragastric route (100 and 200 mg/kg) for 6 weeks; serum glucose/creatinine, food/water consumption, and urinary volume were measured. Relative weight, protein/DNA ratios and oxidative stress were measured in renal tissue. The extract showed 20.53% of total phenolic content and IC50 of 18.05 µg/mL in DPPH, and this was associated with ferulic acid, phloretin and α-amyrin. Both doses showed a moderate decrease in the protein/DNA ratio in renal tissue, and the same behavior was observed for total urinary protein loss and serum creatinine, while the best antioxidant effect was exerted by a lower dose, which increased catalase activity and decreased lipid peroxidation in the kidneys. Results demonstrated that C. pentadactylon methanolic flower's extract improves renal function through antioxidant mechanisms during experimental diabetes.

Fenugreek Seed Ethanolic Extract Improves Alveolar Bone Parameters by Attenuating Inflammation in Ovariectomized Rats.

Alveolar bone residual ridge resorption remains a major challenge for dental implant placement in patients with edentulism. Fenugreek seed extracts have been reported to have potential roles in bone metabolism. This study aimed to evaluate the effects of fenugreek seed ethanolic extract (FSEE) on bone cells, inflammation, hormones, and angiogenesis parameters of alveolar bone tissue following teeth extraction in an ovariectomized (OVX) model. A total of 30 adults female Wistar rats were assigned into two major groups. Each group consisted of control, OVX, OVX+FSEE 100 mg/kg BW, OVX+FSEE 200 mg/kg BW, and OVX+FSEE 400 mg/kg BW. The FSEE treatment was applied through the intragastric route for 7 days in the first group and for 30 days in the second group of animals. The first molar tooth of the right maxilla was extracted before the FSEE treatment. The level of 17β-estradiol was measured by the ELISA method. The dissected maxilla alveolar bone processus was sectioned for histological evaluation by hematoxylin-eosin staining and an immunohistochemistry assay. This study found that FSEE reduced the blood estrogen level and increased estrogen receptor-α (ER-α) expression. FSEE administration modified the number of bone cells, angiogenesis, vascular endothelial growth factor (VEGF), sclerostin, and the osteoprotegerin/receptor activator of nuclear factor kappa-β ligand (OPG/RANKL) ratio. Alterations were seen in the inflammatory markers interleukin-6 (IL-6), transforming growth factor-β1 (TGF-β1), and the macrophage-1/macrophage-2 (M1/M2) ratio. In this study, inflammation was found to be attenuated by reductions in IL-6 and sclerostin, and an increase in TGF-β1. The maturation of bone osteocytes increased along with the increase in ER-α expression and ratio of OPG/RANKL.

The effect of quercetin, a flavonoid, on lung injury caused by sepsis

Background/Aim: Lung injury is frequently observed in cases with sepsis, which can lead to conditions that progress to acute respiratory distress syndrome (ARDS) causing mortality. There is no specific treatment for sepsis or sepsis-induced lung injury. Antioxidant therapy has been one of the most prominent options for treatment, according to pathophysiological studies. The aim of this study was to investigate the effects of quercetin, a powerful antioxidant, on sepsis and sepsis-related lung injury. Methods: Thirty-two adult male Sprague Dawley rats were divided into five groups. The control group (CNRL) received 1.5 ml saline via the intragastric route. The quercetin group (QUER [n=5]) underwent no sepsis procedure and received 20 mg/kg quercetin via the intragastric route starting 15 days before the procedure. The sham group (SHAM [n=6]) underwent a surgical incision and received 1.5 ml intragastric olive oil (quercetin dissolves in oil). The sepsis group (SEPS [n=7]) underwent the sepsis procedure. The sepsis and quercetin group (SEPS+QUER [n=7]) underwent the sepsis procedure and received 20 mg/kg quercetin via the intragastric route for 15 days before the procedure. Cecal ligation and puncture methods were used to induce sepsis. While ALT, AST, LDH, GGT and CRP values were analyzed from rat blood, MDA and GSH levels were analyzed from lung tissue. Results: The results showed that quercetin reduced neutrophil infiltration (TLIS 3.5 [0.26] in the SEPS group vs TLIS 2.75 [0.29] in the SEPS+QUER group [P=0.01]), intra-alveolar macrophage count (SEPS vs SEPS+QUER [P=0.01]) and cell proliferation (SEPS vs SEPS+QUER [P=0.01]), and that it helped to preserve lung anatomy during sepsis. It was observed that MDA levels in the lung tissue decreased with the treatment of quercetin to septic rats (SEPS vs SEPS+QUER [P=0.046]). Conclusion: These findings suggest that quercetin may be a potential treatment option for sepsis. However, more studies are needed to determine whether quercetin is a viable option as a therapeutic strategy in patients.

Both C57BL/KsJ (H2d haplotype) and CB10-H2 (H2b haplotype) mice are highly susceptible to congenital toxoplasmosis

Congenital toxoplasmosis may cause abortion, neonatal death, or foetal abnormalities. Despite little information from human studies, a genetic influence over congenital disease was demonstrated and, host genome have been implicated to resistance/susceptibility to Toxoplasma gondii infection in both human and mice. It was previously shown that BALB/c mice (H2d) were more resistant to congenital toxoplasmosis than C57BL/6 mice (H2b). However, it is unclear whether these differences are attributable to the MHC haplotype or to other components of the mouse's genetic background. Therefore, in this work, we intend to address this question by investigating the pregnancy outcome in H2d -congenic C57BL/6 mice (C57BL/KsJ-H2d) and H2b-congenic BALB/c mice (CB10-H2-H2b). For this, animals were infected by intragastric route on the first day of pregnancy and examined on days 8 (8dP/8dI) or 18 (18dP/18dI) of gestation and infection. The pregnancy outcome, parasite burden, systemic cytokine profile and antibody response to infection were evaluated. Infected mice showed adverse pregnancy outcomes, in parallel low parasite detection in the uterus/placenta, being that the C57BL/KsJ showed the worst results in relation to CB10-H2 mice. Both mouse lineages showed an increase in IFN-γ and TNF levels systemically on 8dP/8dI and on 18dP/18dI, and C57BL/KsJ showed an increase in IL-6 levels in both gestation/infection periods. Additionally, C57BL/KsJ showed 7- and 7-fold increase in IL-6, 4- and 2.5-fold increase in IFN-γ and, 6- and 4-fold increase in TNF production on 8dP/8dI and 18dP/18dI, respectively in association with 1.5-fold decrease in TGF-β levels on 8dP/8dI compared to CB10-H2 mice. In conclusion, the high IFN-γ and TNF serum levels observed in C57BL/KsJ (H2d) and CB10-H2 (H2b) mice were involved in the poor pregnancy outcomes in congenital toxoplasmosis. In addition, the higher IFN‐γ, IL‐6 and TNF levels detected in C57BL/KsJ in relation to CB10‐H2 mice on 8dP/8dI seem to be related to the genetic background of C57BL/6J mice that may have contributed to the worse pregnancy outcome in this mouse lineage.