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The transverse dimensions of internasal and nasopremaxillary sutures in rats were assessed at different ages and following different dietary functional demands.Eighty‐four male Wistar rats were divided into two groups fed either a hard or a soft diet from 4 weeks of age, and sacrificed at 4 weeks (baseline: n = 12),16 weeks (n = 24), 26 weeks (n = 24), or 38 weeks (n = 24) of age. High‐resolution micro‐computed tomograms of the internasal and left nasopremaxillary sutures were obtained with 10 µm voxel size and 5 × 5 mm field of view. The endocranial and ectocranial suture widths, the mean suture width, and the suture height were measured. Linear regression analysis was used to estimate the effects of age and type of diet on suture dimensions. Internasal and nasopremaxillary suture dimensions were influenced by age, with a generally lower width and a larger height in the older animal. Regarding diet consistency, internasal suture widths were on average larger in the hard‐diet group (e.g., mean suture width 43 µm in the hard‐ versus 30 µm in the soft‐diet group at 26 weeks). In conclusion, the internasal and nasopremaxillary sutures tend to become narrower with age, while being influenced by masticatory functional demands. [ABSTRACT FROM AUTHOR]

How consciousness is lost in states such as sleep or anesthesia remains a mystery. To gain insight into this phenomenon, concurrent recordings of electrophysiology signals in the anterior cingulate cortex and whole‐brain functional magnetic resonance imaging (fMRI) are conducted in rats exposed to graded propofol, undergoing the transition from consciousness to unconsciousness. The results reveal that upon the loss of consciousness (LOC), there is a sharp increase in low‐frequency power of the electrophysiological signal. Additionally, fMRI signals exhibit a cascade of deactivation across a pathway including the hippocampus, thalamus, and medial prefrontal cortex (mPFC) surrounding the moment of LOC, followed by a broader increase in brain activity across the cortex during sustained unconsciousness. Furthermore, sliding window analysis demonstrates a temporary increase in synchrony of fMRI signals across the hippocampus‐thalamus‐mPFC pathway preceding LOC. These data suggest that LOC may be triggered by sequential activities in the hippocampus, thalamus, and mPFC, while wide‐spread activity increases in other cortical regions commonly observed during anesthesia‐induced unconsciousness may be a consequence, rather than a cause of LOC. Taken together, the study identifies a cascade of neural events unfolding as the brain transitions into unconsciousness, offering insight into the systems‐level neural mechanisms underpinning LOC. [ABSTRACT FROM AUTHOR]

Resveratrol, which is thought to have a preventive effect on the formation of different types of cancer, is abundant in grapes and other foods. Resveratrol has been shown to have anti‐cancer effects by in vitro andin vivo studies, however this is the first time its effect on atypical acinar cell foci (AACF), known as precursor forms of pancreatic carcinoma, has been experimentally investigated. Male Sprague Dawley rats, each consisting of 5 experimental groups (Cont, AzCont, AzRes10, AzRes15, and AzRes20), 10 of which were 14 days old, were used in the study. In the azaserine groups (AzCont, AzRes10, AzRes15, and AzRes20), it was investigated how the development of Atypical Cell Foci (AACF) resulting from intraperitoneal injection (i.p.) of azaserine (30 mg/kg bw) in 14‐day‐old rats was affected by dietary restoration. Male rats in the resveratrol group (AzRes10, AzRes15, and AzRes20) were fed diets containing 10%, 15%, or 20% mmol resveratrol for an 8‐month experimental period 1 week after the last azaserine injection. Pancreas preparations prepared from histological sections were examined for AACF burden and analyzed via a video image analyzer. One‐way analysis of variance (ANOVA) non‐parametric statistical analyses were performed to test whether there was a difference between the averages of the experimental and control groups. The AACF load in the azaserine group (AzCont) compared to the control group (Cont) was found to be statistically significant in all categories (p < 0.05). The calculated estimated mean AACF volume (mm3) values and the AACF ratio as a percentage of the calculated organ volume were statistically significantly lower in all resveratrol groups (AzRes10, AzRes15, and AzRes20) compared to the azaserine control group (AzCont). The calculated estimated mean AACF volume (mm3) values and the AACF ratio as a percentage of the calculated organ volume were statistically significantly lower in all resveratrol groups (AzRes10, AzRes15, and AzRes20) compared to the azaserine control group (AzCont) (p < 0.05). In addition, the calculated estimated mean AACF diameter (mm) in the AzRes10 and AzRes15 groups, in the AzRes15 group the calculated estimated mean AACF number in the whole organ and the calculated average AACF number per unit area were found to be statistically significant compared to the azaserine control group (AzCont) (p < 0.05). According to the results of our study, it has been shown that atypical acinar cell foci (AACF) formed in the exocrine pancreas of rats with azaserine can be reduced by a diet containing resveratrol. It was determined that the tumor burden decreased statistically significantly (p ≤ 0.05) in resveratrol‐treated rats. Accordingly, it is thought that the inhibitory effects of resveratrol may contribute to studies that reduce the occurrence of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Obesity stands out as one of the most significant health problems in the modern world. The prevalence of high‐calorie diets (HCDs) globally exacerbates this condition. Throughout history, plants and plant‐derived food products have been utilized for medicinal purposes, demonstrating their efficacy in the treatment and prevention of various diseases. Gundelia tournefortii (GT), a plant of interest, is known to possess beneficial properties. Hence, this study aimed to investigate the immunotoxic and neurotoxic effects of two different doses of GT plant extract on the liver, brain, and heart tissues of obese rats. For this purpose, Wistar male rats were divided into four groups: “CG,” “HCDG,” “HCDGUN1,” and “HCDGUN2” At the conclusion of the study, adenosine deaminase (ADA) and myeloperoxidase (MPO) activities, as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) biomarkers, were evaluated in the liver, heart, and brain tissues. The study results revealed a statistically significant increase in ADA and MPO activities in the HCDG group compared to the CG group, alongside a significant decrease in the HCDGUN groups compared to the HCDG group. Regarding AChE and BChE activities, a statistically significant decrease was observed in the HCDG group compared to the CG group, whereas an increase was noted in the HCDGUN groups relative to the HCDG group, with the latter approaching values similar to those of the control group. In conclusion, the intake of GT plant extract exhibited positive effects on the immunotoxic and neurotoxic effects induced by HCD in rats with an experimental obesity model, as evidenced by tissue biomarker evaluations. [ABSTRACT FROM AUTHOR]

The current study explored a free‐operant analogue of discrete‐trial procedures to study the effects of amount and delay of reinforcement on choice and response rate. Rats responded on a multiple variable‐interval (VI) 45‐s, 45‐s schedule, with interspersed choice probe trials. Comparison of relative response rates and percentage of choice revealed some discrepancies between the free‐operant analogue and discrete‐trial procedures. Amount of reward controlled choice behavior when the ratios of delays were similar. When reward delays were more discrepant, delay length controlled choice behavior. Whereas the percentage of choice was larger for the larger magnitude reward, the relative rate of response for the larger magnitude was less than.50. In contrast, when the percentage of choice generally fell to below 50% (with large amount and large delay differences between alternatives), relative response rate indicated a preference for the larger amount alternative. This study shows the feasibility and utility of a free‐operant analogue of discrete‐choice studies that could be used to develop an analysis of preference. [ABSTRACT FROM AUTHOR]

Background: After the Coronavirus Disease pandemic, depression became more present, including in adolescents. Escitalopram, a selective serotonin reuptake inhibitor, was approved in 2009 for treatment of the major depressive disorder, both in children and adolescents. The undesirable effects of antidepressants on sexual dysfunction are usually underestimated. Aims: To investigate the effects of chronic mild stress, induced from peripuberty up to adulthood, on male sexual behavior parameters, with or without the escitalopram treatment, using rats as experimental model in a translational study. Materials and methods: Forty‐four peripubertal male rats were distributed into four groups: Sham control, escitalopram, stress, and stress + escitalopram. The chronic mild stress consisted of nine different stressors randomly applied one per day, for 8 weeks (from 41 to 97 days postpartum). Escitalopram therapy by gavage (10 mg/kg) started at 70 days postpartum and lasted for 4 weeks. The male sexual behavior parameters were evaluated at 114 days postpartum. After that, euthanasia was performed for blood and testis collection. Histopathology of the testes and plasmatic testosterone level were carried out. Results: There was a reduction in sexual activity and motivation in rats exposed to the stress protocol, which were treated or not with escitalopram, as well as an increase in the total number of mounts in animals exposed to the stress and treated with escitalopram. The testosterone levels were lower in animals exposed to the stress, which were or not treated with escitalopram (stress and stress + escitalopram). The frequency of histologically normal seminiferous tubule sections was lower in animals that were exposed to the stress and/or received escitalopram (escitalopram, stress, and stress + escitalopram). Conclusion: Chronic mild stress induced from peripuberty, associated or not to escitalopram treatment, altered the testosterone levels and testicular histoarchitecture and seems to be related to the reduction in male sexual motivation. [ABSTRACT FROM AUTHOR]

ABSTRACT Honey has a rich history of treating gastrointestinal diseases due to its diverse bioactive compounds. This study evaluated the protective effects of select Iranian honeys against cold water immersion stress (CWIS)‐induced ulcers in rats. Forty male Wistar rats (250–280 g) were randomly assigned to eight groups (n = 5): control, CWIS, and groups treated with strong (eucalyptus, Annaab, and Jangale) and weak honeys (Chand Giah, Sumaq, Gaz) + CWIS. Honey selection was based on antioxidant capacity, phenolic content, and protein concentration. Rats received 20% honey in water (1 mL/kg) orally twice daily for 14 days; controls received water. After a 24‐h fast, rats underwent 3‐h CWIS to induce ulcers. Serum samples were analyzed for malondialdehyde (MDA), total antioxidant capacity (TAC), thiol groups, tumor necrosis factor alpha (TNF‐α), and interleukin 6 (IL‐6) levels. Stomachs were assessed for ulcer severity (gastric ulcer index), gastric juice volume, and histopathological changes. Honey types were categorized as strong (eucalyptus, Annaab, and Jangale) or weak (Chand Giah, Sumaq, and Gaz) based on total phenolic content, antioxidant effects (FRAP and DPPH), and protein levels. Ulcer group showed significant increases in MDA (64%) and TNF‐α and IL‐6 levels (98.5% and 111.6%), and decreases in ferric reducing antioxidant power and 2,2‐diphenyl‐1 picrylhydrazyl (FRAP, DPPH, and thiol levels [26%, 14.39%, and 26%]) compared to controls. Strong honey groups exhibited 50% lower gastric ulcer index compared to weak honey groups. This study showed that strong honeys, due to their higher phenolic, total protein, and antioxidant content, offer greater protection against gastric damage and oxidative stress compared to weaker honeys. These results highlight the importance of bioactive compounds in honey's therapeutic properties. Therefore, high‐quality honeys with higher phenolic content can be considered as therapeutic supplements for gastrointestinal disorders, especially those caused by oxidative stress and inflammation. [ABSTRACT FROM AUTHOR]

This study aimed to determine the protective role of l‐ascorbic acid in a pregnant rat model of cadmium‐induced toxicity. Cadmium is a toxic heavy metal that can seriously harm placenta and fetus tissue in pregnant women. Forty‐two healthy female Wistar albino rats (250–300 g weight and 14–16 weeks) were randomly distributed into six equal groups (n = 7): control, cadmium 1 mg (CD1), cadmium 5 mg (CD5), ascorbic acid (AA), CD1+AA, CD5+AA. Cadmium was administered to pregnant rats by oral gavage every other day, and/or AA (200 mg) was administered every day. At the end of pregnancy (Day 21), blood, placenta, and fetuses were collected from rats. The results indicated that cadmium‐induced oxidative stress by increasing the level of MDA and by decreasing the levels of GSH, SOD, and CAT activity in the serum of maternal. However, AA administration significantly decreased MDA levels and increased GSH levels, SOD, and CAT activity (p < 0.05). Cadmium (5 mg/kg) exposure significantly increased creatinine levels compared to AA and CD1+AA groups (p < 0.05). In addition, AA (200 mg/kg) significantly attenuated cadmium‐induced histopathological alteration in the placental and fetal tissues. In conclusion, AA may prevent cadmium toxicity in maternal and fetal tissues, as it regulates oxidative imbalance in pregnant rat tissues and alleviates histopathological changes. [ABSTRACT FROM AUTHOR]

Past studies in animal models have extensively investigated the impact of early life experiences on behavioral development, yet relatively few have specifically examined the implications of peripubertal experiences on the evolution of competitive behavior across distinct stages of adulthood. In the current research, we probed potential differences in competitive behavior during emerging adulthood (3 months old) and middle adulthood (12 months old) in 81 Sprague‐Dawley male rats exposed to three different peripubertal (postnatal Days 37–60) environments: an enriched environment (EE), a chronic unpredictable mild stress (CUMS) condition, and a control condition. Anxiety‐like behavior served as a positive control in our study. Results revealed significant variations in competitive behavior among the groups during emerging adulthood. The EE group displayed the least anxiety and outperformed their peers in food‐reward‐oriented competition, whereas the CUMS group excelled in status‐driven, agonistic competition. However, these behavioral differentiations gradually attenuated by middle adulthood, at which point the control group began to show an advantage. Our findings suggest that although peripubertal experiences significantly shape competitive behavior in the emerging adulthood stage, this effect diminishes over time and is nearly non‐detectable during mid‐adulthood, underscoring the fluidity of behavioral development and demonstrating that the effects of peripubertal experiences can be modulated by subsequent life experiences. [ABSTRACT FROM AUTHOR]

Head direction (HD) neurons, signalling facing direction, generate a signal that is primarily anchored to the outside world by visual inputs. We investigated the route for visual landmark information into the HD system in rats. There are two candidates: an evolutionarily older, larger subcortical retino‐tectal pathway and a more recently evolved, smaller cortical retino‐geniculo‐striate pathway. We disrupted the cortical pathway by lesioning the dorsal lateral geniculate thalamic nuclei bilaterally, and recorded HD cells in the postsubicular cortex as rats foraged in a visual‐cue‐controlled enclosure. In lesioned rats we found the expected number of postsubicular HD cells. Although directional tuning curves were broader across a trial, this was attributable to the increased instability of otherwise normal‐width tuning curves. Tuning curves were also poorly responsive to polarizing visual landmarks and did not distinguish cues based on their visual pattern. Thus, the retino‐geniculo‐striate pathway is not crucial for the generation of an underlying, tightly tuned directional signal but does provide the main route for vision‐based anchoring of the signal to the outside world, even when visual cues are high in contrast and low in detail. Key points: Head direction (HD) cells indicate the facing direction of the head, using visual landmarks to distinguish directions.In rats, we investigated whether this visual information is routed through the thalamus to the visual cortex or arrives via the superior colliculus, which is a phylogenetically older and (in rodents) larger pathway.We lesioned the thalamic dorsal lateral geniculate nucleus (dLGN) in rats and recorded the responsiveness of cortical HD cells to visual cues.We found that cortical HD cells had normal tuning curves, but these were slightly more unstable during a trial. Most notably, HD cells in dLGN‐lesioned animals showed little ability to distinguish highly distinct cues and none to distinguish more similar cues.These results suggest that directional processing of visual landmarks in mammals requires the geniculo‐cortical pathway, which raises questions about when and how visual directional landmark processing appeared during evolution. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance This study was undertaken to test whether the postinjury plasma concentration of phosphorylated neurofilament heavy chain (pNF‐H), a marker of axonal injury, is a prognostic biomarker for the development of posttraumatic epilepsy.Tail vein plasma was sampled 48 h after traumatic brain injury (TBI) from 143 rats (10 naïve, 21 controls, 112 with lateral fluid percussion injury) to quantify pNF‐H by enzyme‐linked immunosorbent assay. During the 6th postinjury month, rats underwent 30 days of continuous video‐electroencephalographic monitoring to detect unprovoked seizures and evaluate epilepsy severity. Somatomotor (composite neuroscore) and spatial memory (Morris water maze) testing and quantitative T2 magnetic resonance imaging were performed to assess comorbidities and lesion severity.Of the 112 TBI rats, 25% (28/112) developed epilepsy (TBI+) and 75% (84/112) did not (TBI−). Plasma pNF‐H concentrations were higher in TBI+ rats than in TBI− rats (p < .05). Receiver operating characteristic curve analysis indicated that plasma pNF‐H concentration distinguished TBI+ rats from TBI− rats (area under the curve [AUC] = .647, p < .05). Differentiation was stronger when comparing TBI+ rats exhibiting severe epilepsy (≥3 seizures/month) with all other TBI rats (AUC = .732, p < .01). Plasma pNF‐H concentration on day 2 (D2) distinguished TBI+ rats with seizure clusters from other TBI rats (AUC = .732, p < .05). Higher plasma pNF‐H concentration on D2 after TBI correlated with lower neuroscores on D2 (p < .001), D6 (p < .001), and D14 (p < .01). Higher pNF‐H concentration on D2 correlated with greater T2 signal abnormality volume on D2 (p < .001) and D7 (p < .01) and larger cortical lesion area on D182 (p < .01). Plasma pNF‐H concentration on D2 did not correlate with Morris water maze performance on D37–D39.Plasma pNF‐H is a promising clinically translatable prognostic biomarker for the development of posttraumatic epilepsy with frequent seizures or seizure clusters. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the vocal fold histological characteristics during different postnatal periods in rats, especially older rats. Methods: Sprague–Dawley rats aged 4 days, 4 and 12 weeks, and 12 and 24 months were used for the experiment. Five larynges were obtained for each age and cut into 5‐μm consecutive sections. The expression of Ki‐67 was assessed using immunohistochemistry to examine cell proliferation. Elastic van Gieson staining was used to detect the collagen and elastin concentrations. The cell type was determined using multicolor immunofluorescence. Results: Ki‐67 was not expressed in the macula flava (MF) of 12‐week‐, 12‐month‐, and 24‐month‐old adults. Collagen fibers in the lamina propria (LP) increased with age. The elastic fiber concentrations in the LP decreased significantly at 24 months (p <.01) but remained stable in the MF. All posterior MF cells showed strong glial fibrillary acidic protein and vimentin‐positive reactions with weaker expressions of CD68 and α‐smooth muscle actin (α‐SMA). The myofibroblasts (α‐SMA‐positive) and macrophages (CD68‐positive) in the LP of the 24‐month‐old rats were significantly the highest (p <.01). Conclusion: The extracellular matrix in the LP increases with age, presenting as an increase in collagen with the loss of elastin, which may be due to myofibroblast proliferation. Moreover, the cellular properties or extracellular matrix components of the mature MF in rats are comparable to those in humans. [ABSTRACT FROM AUTHOR]

Objective: To clarify the effect of growth and advancing age on lymphatic capillarization in rat skeletal muscles, we examined the histological and biochemical changes of lymphatic capillaries in different fiber types of skeletal muscles across juvenile, young, and middle‐aged generations. Methods: We collected the tibialis anterior (TA), extensor digitorum longus (EDL), and soleus (SOL) muscles. Immunohistochemical staining using LYVE‐1 and CD31 markers was used for lymphatic and blood capillaries, respectively. Real‐time PCR was used to analyze mRNA expression of lymphangiogenic factors. Results: The density of LYVE‐1‐positive lymphatic capillaries in the muscles peaked during the juvenile period and subsequently decreased with increasing age. In contrast to blood capillaries, fast‐twitch dominant muscles (i.e., TA and EDL) exhibited an age‐related decrease in lymphatic capillaries. Similar to blood capillaries, lymphatic capillaries were abundant in SOL, a slow‐twitch dominant muscle, which showed less susceptibility to age‐related lymphatic decline. The mRNA expression of lymphangiogenic factors was significantly upregulated in SOL and decreased in all muscles of middle‐aged rats. Conclusions: The age‐related decrease of lymphatic capillaries in fast‐twitch muscles might be associated with age‐related muscle atrophy. [ABSTRACT FROM AUTHOR]

In response to peroxynitrite (ONOO−) generation, myogenic stem satellite cell activator HGF (hepatocyte growth factor) undergoes nitration of tyrosine residues (Y198 and Y250) predominantly on fast IIa and IIx myofibers to lose its binding to the signaling receptor c‐met, thereby disturbing muscle homeostasis during aging. Here we show that rat anti‐HGF monoclonal antibody (mAb) 1H41C10, which was raised in‐house against a synthetic peptide FTSNPEVRnitroY198EV, a site well‐conserved in mammals, functions to confer resistance to nitration dysfunction on HGF. 1H41C10 was characterized by recognizing both nitrated and non‐nitrated HGF with different affinities as revealed by Western blotting, indicating that the paratope of 1H41C10 may bind to the immediate vicinity of Y198. Subsequent experiments showed that 1H41C10‐bound HGF resists peroxynitrite‐induced nitration of Y198. A companion mAb‐1H42F4 presented similar immuno‐reactivity, but did not protect Y198 nitration, and thus served as the control. Importantly, 1H41C10‐HGF also withstood Y250 nitration to retain c‐met binding and satellite cell activation functions in culture. The Fab region of 1H41C10 exerts resistivity to Y250 nitration possibly due to its localization in the immediate vicinity to Y250, as supported by an additional set of experiments showing that the 1H41C10‐Fab confers Y250‐nitration resistance which the Fc segment does not. Findings highlight the in vitro preventive impact of 1H41C10 on HGF nitration‐dysfunction that strongly impairs myogenic stem cell dynamics, potentially pioneering cogent strategies for counteracting or treating age‐related muscle atrophy with fibrosis (including sarcopenia and frailty) and the therapeutic application of investigational HGF drugs. [ABSTRACT FROM AUTHOR]

For a subset of individuals known as sign‐trackers, discrete Pavlovian cues associated with rewarding stimuli can acquire incentive properties and exert control over behaviour. Because responsiveness to cues is a feature of various neuropsychiatric conditions, rodent models of sign‐tracking may prove useful for exploring the neurobiology of individual variation in psychiatric vulnerabilities. Converging evidence points towards the involvement of dopaminergic neurotransmission in the nucleus accumbens core (NAc) in the development of sign‐tracking, yet whether this phenotype is associated with specific accumbal postsynaptic properties is unknown. Here, we examined dendritic spine structural organisation, as well as presynaptic and postsynaptic markers of activity, in the NAc core of male and female rats following a Pavlovian‐conditioned approach procedure. In contrast to our prediction that cue re‐exposure would increase spine density, experiencing the discrete lever‐cue without reward delivery resulted in lower spine density than control rats for which the lever was unpaired with reward during training; this effect was tempered in the most robust sign‐trackers. Interestingly, this same behavioural test (lever presentation without reward) resulted in increased levels of a marker of presynaptic activity (synaptophysin), and this effect was greatest in female rats. Whilst some behavioural differences were observed in females during initial Pavlovian training, final conditioning scores did not differ from males and were unaffected by the oestrous cycle. This work provides novel insights into how conditioning impacts the neuronal plasticity of the NAc core, whilst highlighting the importance of studying the behaviour and neurobiology of both male and female rats. [ABSTRACT FROM AUTHOR]

Cataracts are a disease that reduces vision due to opacity formation of the lens. Diabetic cataracts occur at young age and progress relatively quickly, so the development of effective treatment has been awaited. Several studies have shown that pyruvate inhibits oxidative stress and glycation of lens proteins, which contribute to onset of diabetic cataracts. However, detailed molecular mechanisms have not been revealed. In this study, we attempted to reduce galactose‐induced opacity by pyruvate with rat ex vivo model. Rat lenses were extracted and cultured in galactose‐containing medium to induce lens opacity. After opacity had developed, continued culturing with pyruvate in the medium resulted in a reduction of lens opacity. Subsequently, we conducted microarray analysis to investigate the genes that contribute to the therapeutic effect. We performed quantitative expression measurements using RT‐qPCR for extracted genes that were upregulated in cataract‐induced lenses and downregulated in pyruvate‐treated lenses, resulting in the identification of 34 candidate genes. Functional analysis using the STRING database suggests that metallothionein‐related factors (Mt1a, Mt1m, and Mt2A) and epithelial‐mesenchymal transition‐related factors (Acta2, Anxa1, Cd81, Mki67, Timp1, and Tyms) contribute to the therapeutic effect of cataracts. [ABSTRACT FROM AUTHOR]

Scopoletin, a coumarin class natural phytoalexin, is present in medicinal plants such as noni (Morinda citrifolia). It exhibits diverse pharmacological properties, including antioxidant, anti‐hyperuricemic, and anti‐inflammatory effects. The objective of this study was to develop a novel HPLC‐fluorescence (HPLC‐FL) method for the quantitative analysis of scopoletin in the plasma and to investigate its pharmacokinetics in rats. Sample preparation involved a methanol‐based protein precipitation method, and chromatographic separation was conducted using a C18 column with an isocratic mobile phase composed of water and acetonitrile containing 0.1% trifluoroacetic acid. The eluent was detected using an FL detector set to optimized excitation/emission wavelengths of 337/453 nm. Method validation encompassed assessments of selectivity, linearity (1–500 ng/mL), precision, accuracy, recovery, matrix effect, and stability in accordance with the prevailing Food and Drug Administration (FDA) guidelines. The developed method was successfully applied for pharmacokinetic study in rats. To the best of our knowledge, this study is the first application of a simple and sensitive HPLC‐FL method for the quantification of scopoletin in a pharmacokinetic study. This method offers a promising alternative for preclinical pharmacokinetic investigations with appropriate modifications and validations and holds potential for clinical applications. [ABSTRACT FROM AUTHOR]

The presynapse performs an essential role in brain communication via the activity‐dependent release of neurotransmitters. However, the sequence of events through which a presynapse acquires functionality is relatively poorly understood, which is surprising, since mutations in genes essential for its operation are heavily implicated in neurodevelopmental disorders. We addressed this gap in knowledge by determining the developmental trajectory of synaptic vesicle (SV) recycling pathways in primary cultures of rat hippocampal neurons. Exploiting a series of optical and morphological assays, we revealed that the majority of nerve terminals displayed activity‐dependent calcium influx from 3 days in vitro (DIV), immediately followed by functional evoked exocytosis and endocytosis, although the number of responsive nerve terminals continued to increase until the second week in vitro. However, the most intriguing discovery was that activity‐dependent bulk endocytosis (ADBE) was only observed from DIV 14 onwards. Importantly, optimal ADBE recruitment was delayed until DIV 21 in Fmr1 knockout neurons, which model Fragile X Syndrome (FXS). This implicates the delayed recruitment of ADBE as a potential contributing factor in the development of circuit dysfunction in FXS, and potentially other neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

The nutritive arteries of bones may be injured due to fracture or surgical procedures. Therefore, there are some studies focused on the location of the nutrient foramen (NF) of bones. Rats are the most preferred animals in experimental studies. The purpose of this study is to expose the locational variations of the NF on the rat (Sprague Dawley) scapula. A total of 60 adult rat scapulae (from 16 male and 14 female rats) were used. The diameters of NFs were measured. The length, width, and distances of the NF to the proximal and cranial edges were measured. Foraminal indices were also calculated. It was determined that the average number of NF per scapula was 1.8. The location of the NFs was 52% on the medial aspect and 48% on the lateral aspect. On the medial aspect of the scapula, NFs were frequently found ventrally, on the neck region of the scapula. Laterally, 40 NFs were found in the ventral region of the infraspinatus fossa and only 12 in the ventral region of the supraspinatus fossa. Longitudinal foraminal index 95% confidence intervals were 74.25–79.18 (lateral) and 71.70–75.97 (medial). Transversal foraminal index 95% confidence intervals were 40.98–45.02 (lateral) and 42.91–46.07 (medial). Diameter of the NF 95% confidence interval was 0.21–0.39 mm. The locational knowledge of the NF can be utilized in anatomical or experimental surgery studies. The cranial and proximal edges of the rat scapula may be palpable; surgeons may palpate these regions and easily evaluate the location of the NFs. [ABSTRACT FROM AUTHOR]

Experiments should always be based on control values. This assumption fully applies to cardiovascular parameters, such as heart rate (HR) and blood pressure (BP), which are highly sensitive to various external and internal stimuli and can already be significantly altered when an experiment begins. Therefore, it is necessary to determine which values are defined as a starting point (i.e., control and baseline) or compare them with valid reference values if the goal is to evaluate the changes after experimental intervention. A generally accepted principle is a reciprocal relationship between BP and HR, in which one parameter affects the other and vice versa. BP can be measured using two methods—noninvasively (tail‐cuff) and invasively (telemetry, direct measurements of BP after introducing the sensor directly into the artery), and HR directly or by extrapolation from BP recordings. This study does not aim to evaluate the results of individual studies, but to review whether there are differences in control (baseline) BP values in normotensive and hypertensive male rats using invasive versus noninvasive methods, and to investigate whether there is a causal relationship between BP and HR in in vivo experiments with male rats. [ABSTRACT FROM AUTHOR]

Raw and cooked (autoclaved) green bananas are fed to rats for 4 weeks and their effects on cecal microbiota and biomarkers of fermentation are evaluated and compared with those of potato starch, which is rich in RS. Relative abundances of genera Lachnospiraceae_NK4A136_group and Roseburia, and species Bifidobacterium pseudolongum in rat cecum are higher in the raw green banana group with higher RS consumption than in the control group. The raw green banana group shows higher cecal acetate production and similarly high levels of cecal n‐butyrate production than that in the potato starch group. In the autoclaved green banana group, the cecal microbial composition is altered and the relative abundance of family Ruminococcaceae increased. Additionally, the molar proportion of n‐butyrate in the cecum of the autoclaved green banana group is higher than that in the control group. The levels of cecal mucin and IgA in the raw green banana and potato starch groups are found to be higher compared to those observed in the control and autoclaved green banana groups. Therefore, raw and autoclaved green bananas can alter cecal microbial composition and thus exhibit beneficial intestinal fermentation characteristics. [ABSTRACT FROM AUTHOR]

Modulation of input from primary afferent fibres has long been examined at the level of the first relays of these fibres. However, recent studies reveal that input to the spinal cord may also be modulated at the level of the very entry of afferent fibres to the spinal grey matter before action potentials in intraspinal collaterals of afferent fibres reach their target neurons. Such modulation greatly depends on the actions of GABA via extrasynaptic membrane receptors. In the reported study we hypothesized that the increase in excitability of afferent fibres following epidural polarization close to the site where collaterals of afferent fibres leave the dorsal columns is due to the release of GABA from two sources: not only GABAergic interneurons but also glial cells. We present evidence, primo, that GABA released from both these sources contributes to a long‐lasting increase in the excitability and a shortening of the refractory period of epidurally stimulated afferent fibres and, secondo, that effects of epidural polarization on the release of GABA are more critical for these changes than direct effects of DC on the stimulated fibres. The experiments were carried out in deeply anaesthetized rats in which changes in compound action potentials evoked in hindlimb peripheral nerves by dorsal column stimulation were used as a measure of the excitability of afferent fibres. The study throws new light on the modulation of input to spinal networks but also on mechanisms underlying the restoration of spinal functions. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) continues to be the most prevalent type of liver cancer worldwide. Diethylnitrosamine (DEN)‐induced HCC is an extensively used hepatic cancer model in experimental animals. Acetazolamide (AZA) is a carbonic anhydrase enzyme inhibitor. This study aimed to assess the therapeutic mechanism of AZA against DEN‐induced HCC. Thirty male Wistar albino rats were divided equally into three groups. Group I (C): control group, Group II (HCC): DEN‐induced HCC, and Group III (HCC/AZA): AZA‐treated HCC. Verification of the HCC induced by DEN was confirmed by elevated liver enzymes' activities, and increased α‐fetoprotein (AFP) levels, as well as distinct liver architecture changes. On the other hand, the AZA‐treated HCC group experienced decreases in the activities of serum liver enzymes and AFP levels, as well as, regulated liver architecture. Additionally, it downregulated p‐p38 MAPK/p‐JNK1/JNK2/p‐C‐Jun/p‐NF‐κB p65 protein expressions. Moreover, it ameliorated autophagy by controlling the expression of the p‐AMPK/p‐mTOR1/LC3 I/II proteins. Furthermore, it downregulated the relative gene expressions of carbonic anhydrase‐IX (CAIX) and hexokinase‐II (HKII). Histopathological examination of AZA‐treated HCC liver tissues supported these findings. Conclusion: AZA provides a new dimension in ameliorating experimentally induced HCC through regulation of hepatic biomarkers, antioxidant status, inflammatory markers, and autophagy, mediated by amelioration of CAIX and HKII gene expressions. [ABSTRACT FROM AUTHOR]

Background: Renal ischemia reperfusion injury (IRI) is a post‐ischemic event, which can lead to subsequent acute kidney injury (AKI), transplant failure, renal dysfunction and fibrosis via heightened oxidative stress and production of inflammatory cytokines and chemokines. Objective: This study aims to assess the effect of Modafinil, a wake‐promoting agent with previously proven anti‐inflammatory and anti‐oxidative properties, on ameliorating renal IRI. Methods: A total of 30 male Wistar rats were divided into five groups: Sham‐operated group, ischemia reperfusion (I/R) control group and Modafinil pre‐treated groups (at different doses of 50, 100 and 150 mg/kg). IRI was induced by means of bilaterally clamping the renal arteries for 45 min, followed by 24 h of reperfusion. Results: Tissue pathological assessments demonstrated a reduction of glomerular, vascular and interstitial injury at doses of 50 and 100 mg/kg of Modafinil. The biochemical studies showed a significant decrease in tissue pro‐inflammatory factors, including tumor necrosis factor alpha (TNF‐α), Interleukin‐18 (IL‐18) and lactate dehydrogenase (LDH). Moreover, an elevation was observed in levels of super oxide dismutase (SOD) and catalase, indicating the reduction of oxidative stress. Furthermore, the levels of creatinine (Cr), urea and neutrophil gelatinase‐associated lipocalin (NGAL) were declined, indicating the improvement in renal function at effective doses of Modafinil (50 and 100 mg/kg) compared to the I/R control group without Modafinil pre‐treatment. Conclusion: Our findings suggest that Modafinil holds promise as an effective therapeutic agent to address the clinical challenges associated with kidney IRI reducing the need for hospitalization and potentially alleviating related morbidities. [ABSTRACT FROM AUTHOR]

Background and Aims: The endocannabinoid (eCB) system includes ligands (anandamide and 2‐arachidonoyl glycerol, 2‐AG), receptors and catabolizing enzymes (fatty acid amide hydrolase, FAAH and monoacylglycerol lipase) expressed in both the brain and gut. We investigated whether the FAAH inhibitor, URB597, influenced visceral pain to colorectal distension (CRD) in an acute stress‐related model of visceral hypersensitivity induced by the selective corticotropin‐releasing factor receptor subtype 1 (CRF1) agonist, cortagine. Methods: Male Sprague–Dawley rats were injected subcutaneously (SC) with URB597 (3 mg/kg) or vehicle and 2 h later, intraperitoneally with cortagine (10 μg/kg) or vehicle. The visceromotor responses (VMR) were assessed to a first CRD (baseline) before injections, and to a second CRD 15 min after the last treatment. Brain, jejunum, and proximal colon were collected from treated and naïve rats for levels quantification of three fatty acid amides (FAAs) [anandamide (arachidonyl‐ethanolamide, AEA), oleoyl‐ethanolamide (OEA) and palmitoyl‐ethanolamide (PEA)], and 2‐AG. In separate animals, defecation/diarrhea were monitored after URB597 and cortagine. Key Results: URB597 inhibited cortagine‐induced increased VMR at 40 mmHg (89.0 ± 14.8% vs. 132.5 ± 15.6% for vehicle SC, p < 0.05) and 60 mmHg (107.5 ± 16.1% vs. 176.9 ± 24.4% for vehicle SC, p < 0.001) while not influencing basal VMR. In URB597 plus cortagine group, FAAs levels increased in the brain and intestinal tissue while 2‐AG did not change. URB597 did not modify cortagine‐induced defecation/diarrhea versus vehicle. Conclusions and Inferences: URB597 shows efficacy to elevate brain and intestinal FAAs and to counteract the colonic hypersensitivity induced by peripheral activation of CRF1 signaling supporting a potential strategy of FAAH inhibitors to alleviate stress‐related visceral hypersensitivity. [ABSTRACT FROM AUTHOR]

A sensitive and simple method using ultra‐liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) was developed and validated to determine the concentration of curcumin in rat plasma and tissue samples. Emodin was selected as the internal standard (IS), and biological samples were pretreated with simple one‐step acetonitrile precipitation. The calibration curves exhibited linearity within the range of 1–1000 ng/ml for both rat plasma and tissue samples. The accuracy and precision of intra‐day as well as inter‐day determinations ranged from 99.3% to 117.3% and from 98.2% to 105.1%, respectively. This method demonstrated excellent recovery rates ranging from 76.4% to 96.4% along with minimal matrix effect ranging from 86.5% to 99.6%. The effectiveness of this method was successfully demonstrated through its application in an in vivo pharmacokinetic and tissue distribution study after single administration via inhalation (100 mg/kg), oral gavage (100 mg/kg) and intravenous injection (2.5 mg/kg) of curcumin in rats. The results revealed that inhalation significantly improved the bioavailability of curcumin, with most of the drug being deposited in the lung. These findings highlight inhalation as an effective route for targeted delivery of drugs directly into lung tissues, thus suggesting potential future applications for treating pulmonary diseases utilizing inhaled curcumin. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) circulation plays a key role in cerebral waste clearance via the glymphatic system. Although CSF flow velocity is an essential component of CSF dynamics, it has not been sufficiently characterized, and particularly, in studies of the glymphatic system in rat. To investigate the relationship between the flow velocity of CSF in the brain aqueduct and the glymphatic waste clearance rate, using phase‐contrast MRI we performed the first measurements of CSF velocity in rats. Phase‐contrast MRI was performed using a 7 T system to map mean velocity of CSF flow in the aqueduct in rat brain. The effects of age (3 months old versus 18 months old), gender, strain (Wistar, RNU, Dark Agouti), anesthetic agents (isoflurane versus dexmedetomidine), and neurodegenerative disorder (Alzheimer' disease in Fischer TgF344‐AD rats, males and females) on CSF velocity were investigated in eight independent groups of rats (12 rats per group). Our results demonstrated that quantitative velocities of CSF flow in the aqueduct averaged 5.16 ± 0.86 mm/s in healthy young adult male Wistar rats. CSF flow velocity in the aqueduct was not altered by rat gender, strain, and the employed anesthetic agents in all rats, also age in the female rats. However, aged (18 months) Wistar male rats exhibited significantly reduced the CSF flow velocity in the aqueduct (4.31 ± 1.08 mm/s). In addition, Alzheimer's disease further reduced the CSF flow velocity in the aqueduct of male and female rats. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to investigate whether cumulative dose‐dependent isotretinoin (Roaccutane®) could affect orthodontic tooth movement (OTM) and root resorption. Materials and Methods: Ninety male Wistar Albino rats were divided into 4 groups. While, the control (SALINE), solvent (SOYBEAN) and orthodontic drug (ISOTM) groups underwent orthodontic force, the non‐orthodontic drug group (ISO) did not. The rats were administrated saline, soybean oil (SBO) and isotretinoin diluted in SBO (ISOTM, ISO) for 30 days, respectively. Six rats were euthanized in each orthodontic group. Fifty grams of orthodontic force was applied to the remaining rats' first molars using the incisors as anchorage. Six more rats in each group were euthanized on the 7th, 14th and 21st days of the force application. In the ISO group, six rats were euthanized on the 37th, 44th and 51st days of administration. Six rats that were euthanized for ISOTM on the 30th day were also used for ISO to reduce the number of rats used. Micro‐computed tomography (micro‐CT) and histological analysis were performed. Results: Independent of orthodontic force, isotretinoin caused root resorption in the apical region. However, there was no statistically significant influence of isotretinoin on OTM and orthodontically induced root resorption (OIRR). Conclusions: Despite the lack of strong evidence supporting the orthodontically induced resorptive effect of isotretinoin, this study provided findings regarding the resorptive effects of isotretinoin on non‐orthodontic root resorption. Therefore, the present results underscore the importance of close monitoring during orthodontic treatment to mitigate potential root resorption in patients who use isotretinoin because of acne complaints. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is the most widespread type of primary liver cancer. Diethylnitrosamine (DEN), a hepatotoxic hepatocarcinogenic compound, is used to induce HCC in animal models. The non‐selective β‐blocker propranolol demonstrated antiproliferative activity in many cancer types. Objective: This investigation aimed to evaluate the anticancer effect of propranolol against DEN‐induced HCC in rats. Methods: Thirty adult male rats were divided into the following groups: Group I (C, control), Group II (HCC); received DEN, 70 mg/kg body weight (b.wt.) once a week for 10 weeks, to induce HCC, and Group III (HCC/Prop); received DEN for 10 weeks for HCC induction, then received 20 mg/kg b.wt. propranolol, intraperitoneally for four successive weeks. Results: HCC was developed in rats' livers and confirmed via significant liver architecture changes, significantly elevated activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), α‐fetoprotein (AFP), total‐ and direct‐bilirubin (Bil), and a decline in albumin (ALB) level in serum. HCC group demonstrated elevated levels of malondialdehyde (MDA), nitric oxide (NO), HIF‐1α, IL‐8, NF‐κB, PGE2, TGF‐β1, VEGF, and CD8, but significant decline of GSH, and IL‐10 level, with suppression of the antioxidant enzymes' activities. In addition, the gene expression of the hepatic inducible nitric oxide synthase (iNOS), and LAG‐3 were up‐regulated. Moreover, the protein expression of p‐PKC was up‐regulated, while that of PD‐1 and PD‐L1 were down‐regulated in the liver tissues of the HCC group. However, propranolol ameliorated the investigated parameters in the HCC/Prop group. Conclusion: Propranolol exhibited an anticancer effect and thus can be considered as a promising treatment for HCC. Blocking of PD‐1/PD‐L1 and LAG‐3 signals participated in the anti‐tumor effect of propranolol on HCC. [ABSTRACT FROM AUTHOR]

The present study examined the pharmacokinetics of IMM‐H012 in rat plasma, utilizing ultra‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS). Internal standard cilostazol was employed, and plasma samples were processed using acetonitrile precipitation. A mobile phase (acetonitrile–0.1% formic acid in water) with gradient elution was used to achieve chromatographic separation using a UPLC BEH C18 column. In multiple reaction monitoring mode, electrospray ionization MS/MS was utilized in positive ionization mode. Based on findings, the lower limit of quantification was 2 ng/mL, and the linearity of IMM‐H012 in rat plasma was found to be acceptable within the range of 2–2000 ng/mL (R2 > 0.995). The intra‐day and inter‐day precision relative standard deviation was less than 14% of IMM‐H012 in rat plasma. The matrix effect was within the range of 102%–107%, and the accuracy ranged from 92% to 113%. Pharmacokinetics of IMM‐H012 in rats after oral administration were successfully studied using UPLC‐MS/MS. [ABSTRACT FROM AUTHOR]

Apical periodontitis is an inflammatory condition resulting from microbial invasion in the root canal system, causing periapical tissue destruction and bone resorption. This study investigated melatonin's effects, known for its antioxidant and anti‐inflammatory properties, on experimentally induced apical periodontitis in rats. Three groups of rats were studied: control, apical periodontitis and apical periodontitis with melatonin treatment. Proinflammatory cytokines and enzyme levels in blood serum were measured, and micro‐CT analysis assessed bone resorption. Results showed significantly elevated cytokines and enzyme levels in the apical periodontitis group compared to the control. However, in the melatonin‐treated group, these levels were significantly reduced (p < 0.01–0.001). Micro‐CT analysis indicated decreased periapical resorption cavity volume and surface area with melatonin treatment. This suggests that systemic melatonin administration can mitigate inflammation and reduce bone resorption in experimentally induced apical periodontitis in rats, potentially holding promise for human endodontic disease treatment pending further research. [ABSTRACT FROM AUTHOR]

Decompression sickness (DCS) is a systemic syndrome that can occur after an environmental pressure reduction. Previously, we showed that the plasmatic tetrameric form of transthyretin (TTR) nearly disappeared in rats suffering DCS but not in asymptomatic ones. In this pilot study, we assessed whether the resistance to DCS could be associated with polymorphism of the gene of TTR. For this study, Sanger sequencing was performed on purified PCR products from the liver of 14‐week‐old male and female standard and DCS‐resistant rats (n = 5 per group). Hepatic TTR mRNA expression was assessed by RT‐qPCR in 18–19 week‐old male and female standard and resistant rats (n = 6 per group). There is a synonymous single nucleotide polymorphism (SNP) on the third base of codon 46 (c.138 C > T). The thymine allele was present in 90% and 100% of males and females standard, respectively. However, this allele is present in only 30% of DCS‐resistant males and females (p = 0.0002301). In the liver, there is a significant effect of the resistance to DCS (p = 0.043) and sex (p = 0.047) on TTR expression. Levels of TTR mRNA were lower in DCS‐resistant animals. To conclude, DCS resistance might be associated with a SNP and a lower expression of TTR. [ABSTRACT FROM AUTHOR]

Background: Reversible loss of consciousness is the primary therapeutic endpoint of general anesthesia; however, the drug‐invariant mechanisms underlying anesthetic‐induced unconsciousness are still unclear. This study aimed to investigate the static, dynamic, topological and organizational changes in functional brain network induced by five clinically‐used general anesthetics in the rat brain. Method: Male Sprague–Dawley rats (n = 57) were randomly allocated to received propofol, isoflurane, ketamine, dexmedetomidine, or combined isoflurane plus dexmedetomidine anesthesia. Resting‐state functional magnetic resonance images were acquired under general anesthesia and analyzed for changes in dynamic functional brain networks compared to the awake state. Results: Different general anesthetics induced distinct patterns of functional connectivity inhibition within brain‐wide networks, resulting in multi‐level network reorganization primarily by impairing the functional connectivity of cortico‐subcortical networks as well as by reducing information transmission capacity, intrinsic connectivity, and network architecture stability of subcortical regions. Conversely, functional connectivity and topological properties were preserved within cortico‐cortical networks, albeit with fewer dynamic fluctuations under general anesthesia. Conclusions: Our findings highlighted the effects of different general anesthetics on functional brain network reorganization, which might shed light on the drug‐invariant mechanism of anesthetic‐induced unconsciousness. [ABSTRACT FROM AUTHOR]

This study used a marsupial Monodelphis domestica, which is born very immature and most of its development is postnatal without placental protection. RNA‐sequencing (RNA‐Seq) was used to identify the expression of influx and efflux transporters (ATP‐binding cassettes [ABCs] and solute carriers [SLCs]) and metabolizing enzymes in brains of newborn to juvenile Monodelphis. Results were compared to published data in the developing eutherian rat. To test the functionality of these transporters at similar ages, the entry of paracetamol (acetaminophen) into the brain and cerebrospinal fluid (CSF) was measured using liquid scintillation counting following a single administration of the drug along with its radiolabelled tracer [3H]. Drug permeability studies found that in Monodelphis, brain entry of paracetamol was already restricted at P5; it decreased further in the first week of life and then remained stable until the oldest age group tested (P110). Transcriptomic analysis of Monodelphis brain showed that expression of transporters and their metabolizing enzymes in early postnatal (P) pups (P0, P5, and P8) was relatively similar, but by P109, many more transcripts were identified. When transcriptomes of newborn Monodelphis brain and E19 rat brain and placenta were compared, several transporters present in the rat placenta were also found in the newborn Monodelphis brain. These were absent from E19 rat brain but were present in the adult rat brain. These data indicate that despite its extreme immaturity, the newborn Monodelphis brain may compensate for the lack of placental protection during early brain development by upregulating protective mechanisms, which in eutherian animals are instead present in the placenta. [ABSTRACT FROM AUTHOR]

Objective: There has been recent clinical interest in the use of vagus nerve stimulation (VNS) for treating gastrointestinal disorders as an alternative to drugs or gastric electrical stimulation. However, effectiveness of burst stimulation has not been demonstrated. We investigated the ability of bursting and continuous VNS to influence gastric and pyloric activity under a range of stimulation parameters and gastric pressures. The goals of this study were to determine which parameters could optimally excite or inhibit gastric activity. Materials and Methods: Data were collected from 21 Sprague–Dawley rats. Under urethane anesthesia, a rubber balloon was implanted into the stomach, connected to a pressure transducer and a saline infusion pump. A pressure catheter was inserted at the pyloric sphincter and a bipolar nerve cuff was implanted onto the left cervical vagus nerve. The balloon was filled to 15 cmH2O. Stimulation trials were conducted in a consistent order; the protocol was then repeated at 25 and 35 cmH2O. The nerve was then transected and stimulation repeated to investigate directionality of effects. Results: Bursting stimulation at the bradycardia threshold caused significant increases in gastric contraction amplitude with entrainment to the bursting frequency. Some continuous stimulation trials could also cause increased contractions but without frequency changes. Few significant changes were observed at the pylorus, except for frequency entrainment. These effects could not be uniquely attributed to afferent or efferent activity. Significance: Our findings further elucidate the effects of different VNS parameters on the stomach and pylorus and provide a basis for future studies of bursting stimulation for gastric neuromodulation. [ABSTRACT FROM AUTHOR]

Background and objectives: Maternal hypoxia disrupts neural development and subsequently leads to cerebral palsy and epilepsy in newborns. Hypoxia plays a role in neurodegeneration by increasing oxidative stress. Pistacia atlantica is known as an important antioxidant, and its anti‐inflammatory and antioxidant effects have been shown in various studies. This study aims to investigate the effects of methanolic extract of P. atlantica leaves (MEPaLs) on the oxidative parameters in the serum of rats affected by maternal hypoxia. Material and methods: In this study, eight pregnant rats were used. The newborns were divided into four groups, including the control and the hypoxia groups, which are affected by maternal hypoxia, hypoxia + MEPaL 100 mg/kg, and hypoxia + MEPaL 150 mg/kg. MEPaL was injected (i.p) for 21 days into the neonatal rats after the lactation period. Hypoxia was induced by keeping pregnant rats in a hypoxic chamber with 7% oxygen and 93% nitrogen intensity for 3 h on the 20th day of pregnancy. Behavioral changes were measured using open‐field and rotarod tests. Finally, biomarkers of oxidative stress, nitric oxide (NO), glutathione (GSH), GSSG, TAS, TOS, and oxidative stress index (OSI) were measured in the experimental groups. Results: Behavioral results showed that the anxiety behavior in the hypoxia group increased, but the motor activity (moved distance and movement speed) decreased. Moreover, the amount of time spent maintaining balance on the rotarod rod was significantly decreased in the hypoxia group. The concentration of NO in the group of hypoxia + MEPaL 100 mg/kg showed a significant decrease, and MEPaL 100, and 150 mg/kg + hypoxia also increased the concentration of GSH and decreased GSSG. In addition, MEPaL100 and 150 mg/kg caused a significant increase in the ratio of GSH to GSSG and decreased OSI and total oxidant capacity. Conclusions: Oxidative stress increased in the rats affected by maternal hypoxia and may be the main mechanism for motor activity impairment and balance disturbance, whereas MELaL improved motor performance by decreasing oxidative stress. [ABSTRACT FROM AUTHOR]

The mammalian placenta's interface with the parent is a richly vascularized tissue whose development relies upon communication between many different cell types within the uterine microenvironment. The uterine blood vessels of the interface are reshaped during pregnancy into wide‐bore, flaccid vessels that convey parental blood to the exchange region of the placenta. Invasive trophoblast as well as parental uterine macrophages and Natural Killer cells are involved in the stepwise remodeling of these vessels and their respective contributions to this crucial process are still being delineated. However, the earliest steps in arteriole remodeling are understudied as they are difficult to study in humans, and other species lack the deep trophoblast invasion that is so prominent a feature of placentation in humans. Here, we further characterize the rat, with deep hemochorial placentation akin to humans, as a model system in which to tease apart the earliest, relatively understudied events in spiral arteriole remodeling. We show that the rat uterine−placental interface increases in size and vascularity rapidly, before trophoblast invasion. The remodeling stages in the arterioles of the rat uterine–placental interface follow a sequence of anatomical changes similar to those in humans, and there are changes to the arterioles' muscular tunica media prior to the marked influx of immune cells. The rat is a tractable model in which to better understand the cell/cell interactions occurring in vivo in an intact tissue microenvironment over time. [ABSTRACT FROM AUTHOR]

Background: Measurement of rat anogenital distance (AGD) dates to at least 1912. Increased interest in endocrine disrupting chemicals and the use of AGD as a biomarker for fetal androgen effects have increased the number of studies with this endpoint in recent decades. A literature review revealed different landmarks, methods of measurement, and methods to adjust for body weight differences. AGD is often reported to hundredths of millimeters and as such, deserves precision in all these aspects. This paper presents recommendations for the measurement and analysis of rodent AGD. Methods: Literature and regulatory guidance documents that mentioned or measured rodent AGD were reviewed. Four adjustment methods were evaluated using available online data from three rat studies each with two generations of offspring. Results: Tabulation of studies reveals that species/stocks and time of data collection, but more importantly anatomical landmarks and methods of measurement have produced a variety of results which are difficult to compare. Not all studies have adjusted for test article effects on body weight (and thus size). The four adjustment methods were fairly comparable. Conclusion: Recommendations are as follows. A microscopic method should be used to measure AGD of late rodent fetuses and early postnatal pups. The caudal edge of the genital tubercle and the cranial edge of the anus are clear and identifiable landmarks. The simplest adjustment is to divide individual AGDs by the cube root of animals' body weight. These recommendations will help ensure data consistency and accuracy, and facilitate meaningful comparisons across laboratories and chemical classes. [ABSTRACT FROM AUTHOR]

Introduction Material and Methods Results Conclusions Uterus transplantation has revolutionized reproductive medicine for women with absolute uterine factor infertility, resulting in more than 40 reported successful live births worldwide to date. Small animal models are pivotal to refine this surgical and immunological challenging procedure aiming to enhance safety for both the mother and the child.We established a syngeneic bicornuate uterus transplantation model in young female Lewis rats. All surgical procedures were conducted by an experienced and skilled microsurgeon who organized the learning process into multiple structured steps. Animals underwent meticulous preoperative preparation and postoperative care. Transplant success was monitored by sequential biopsies, monitoring graft viability and documenting histological changes long‐term.Bicornuate uterus transplantation were successfully established achieving an over 70% graft survival rate with the passage of time. The bicornuate model demonstrated safety and feasibility, yielding outcomes comparable to the unicornuate model in terms of ischemia times and complications. Longitudinal biopsies were well‐tolerated, enabling comprehensive monitoring throughout the study.Our novel bicornuate rat uterus transplantation model provides a distinctive opportunity for sequential biopsies at various intervals after transplantation and, therefore, comprehensive monitoring of graft health, viability, and identification of potential signs of rejection. Furthermore, this model allows for different interventions in each horn for comparative studies without interobserver differences contrary to the established unicornuate model. By closely replicating the clinical setting, this model stands as a valuable tool for ongoing research in the field of uterus transplantation, promoting further innovation and deeper insights into the intricacies of the uterus transplant procedure. [ABSTRACT FROM AUTHOR]

Spatial memory encoding depends in part on cholinergic modulation. How acetylcholine supports spatial memory encoding is not well understood. Prior studies indicate that acetylcholine release is correlated with exploration, including epochs of rearing onto hind legs. Here, to test whether elevated cholinergic tone increases the probability of rearing, we tracked rearing frequency and duration while optogenetically modulating the activity of choline acetyltransferase containing (i.e., acetylcholine producing) neurons of the medial septum in rats performing a spatial working memory task (n = 17 rats). The cholinergic neurons were optogenetically inhibited using halorhodopsin for the duration that rats occupied two of the four open arms during the study phase of an 8‐arm radial arm maze win‐shift task. Comparing rats' behaviour in the two arm types showed that rearing frequency was not changed, but the average duration of rearing epochs became significantly longer. This effect on rearing was observed during optogenetic inhibition but not during sham inhibition or in rats that received infusions of a fluorescent reporter virus (i.e., without halorhodopsin; n = 6 rats). Optogenetic inhibition of cholinergic neurons during the pretrial waiting phase had no significant effect on rearing, indicating a context‐specificity of the observed effects. These results are significant in that they indicate that cholinergic neuron activity in the medial septum is correlated with rearing not because it motivates an exploratory state but because it contributes to the processing of information acquired while rearing. [ABSTRACT FROM AUTHOR]

Discrimination performance in perceptual choice tasks is known to reflect both sensory discriminability and nonsensory response bias. In the framework of signal detection theory, these aspects of discrimination performance are quantified through separate measures, sensitivity (d′) for sensory discriminability and decision criterion (c) for response bias. However, it is unknown how response bias (i.e., criterion) changes at the single‐trial level as a consequence of reinforcement history. We subjected rats to a two‐stimulus two‐response conditional discrimination task with auditory stimuli and induced response bias through unequal reinforcement probabilities for the two responses. We compared three signal‐detection‐theory‐based criterion learning models with respect to their ability to fit experimentally observed fluctuations of response bias on a trial‐by‐trial level. These models shift the criterion by a fixed step (1) after each reinforced response or (2) after each nonreinforced response or (3) after both. We find that all three models fail to capture essential aspects of the data. Prompted by the observation that steady‐state criterion values conformed well to a behavioral model of signal detection based on the generalized matching law, we constructed a trial‐based version of this model and find that it provides a superior account of response bias fluctuations under changing reinforcement contingencies. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to evaluate whether exogenous melatonin (MEL) mitigates the deleterious effects of high‐dose caffeine (CAF) administration in pregnant rats upon the fetal hippocampus. Materials and methods: A total of 32 adult Wistar albino female rats were divided into four groups after conception (n = 8). At 9–20 days of pregnancy, intraperitoneal (i.p.) MEL was administered at a dose of 10 mg/kg/day in the MEL group, while i.p. CAF was administered at a dose of 60 mg/kg/day in the CAF group. In the CAF plus MEL group, i.p. CAF and MEL were administered at a dose of 60 and 10 mg/kg/day, respectively, at the same period. Following extraction of the brains of the fetuses sacrificed on the 21st day of pregnancy, their hippocampal regions were analyzed by hematoxylin and eosin and Cresyl Echt Violet, anti‐GFAP, and antisynaptophysin staining methods. Results: While there was a decrease in fetal and brain weights in the CAF group, it was found that the CAF plus MEL group had a closer weight average to that of the control group. Histologically, it was observed that the pyramidal cell layer consisted of 8–10 layers of cells due to the delay in migration in hippocampal neurons in the CAF group, while the MEL group showed similar characteristics with the control group. It was found that these findings decreased in the CAF plus MEL group. Conclusion: It is concluded that high‐dose CAF administration causes a delay in neurogenesis of the fetal hippocampus, and exogenous MEL is able to mitigate its deleterious effects. [ABSTRACT FROM AUTHOR]

Studies on the effects of glyphosate (GlyP) and glyphosate‐based herbicides (GBHs) on cerebellar development are extremely limited. This study examined the effects of maternal exposure to GlyP and GBH on rat cerebellar development in male offspring. From day 6 of gestation until day 21 postpartum at weaning, dams were given GlyP at 1.5% or 3.0% in diet or GBH at 1.0% in drinking water (corresponding to 0.36% GlyP). At weaning, GBH exposure was linked to increased numbers of DCX+ migrating granule cells in the cortex and TUNEL+ apoptotic cells in the internal granular layer (IGL), suggesting the disappearance of mismigrated granule cells via apoptosis. GBH also upregulated Nr4a3 and downregulated Cdk5 in the cerebellar vermis, suggesting a causal relation with the impaired granule cell development at this time. GlyP (3.0%) tended to increase in the number of DCX+ migrating granule cells in the IGL and upregulated Nr4a3 at weaning. Both compounds also upregulated genes related to granule cell migration (Astn1, Astn2, Nfia, and/or Nfix) at weaning and in adulthood, which might be an ameliorative response to delayed granule cell migration. Moreover, GBH induced Purkinje cell misalignment at weaning, which could be the result of delayed granule cell migration. In adulthood, GBH was associated with upregulation of the reelin signaling‐related genes Reln, Dab1, and Efnb1, suggesting a compensatory response to Purkinje cell misalignment. GlyP induced the same gene expression changes. These results suggest that GBH reversibly disrupts cerebellar development, primarily by targeting granule cell migration and differentiation, whereas GlyP exhibited similar toxic potential as GBH. [ABSTRACT FROM AUTHOR]

The effects of exercise training (ET) on the heart of aortic stenosis (AS) rats are controversial and the mechanisms involved in alterations induced by ET have been poorly clarified. In this study, we analyzed the myocardial proteome to identify proteins modulated by moderate‐intensity aerobic ET in rats with chronic supravalvular AS. Wistar rats were divided into four groups: sedentary control (C‐Sed), exercised control (C‐Ex), sedentary aortic stenosis (AS‐Sed), and exercised AS (AS‐Ex). ET consisted of five treadmill running sessions per week for 16 weeks. Statistical analysis was performed by ANOVA or Kruskal–Wallis and Goodman tests. Results were discussed at a significance level of 5%. At the end of the experiment, AS‐Ex rats had higher functional capacity, lower blood lactate concentration, and better cardiac structural and left ventricular (LV) functional parameters than the AS‐Sed. Myocardial proteome analysis showed that AS‐Sed had higher relative protein abundance related to the glycolytic pathway, oxidative stress, and inflammation, and lower relative protein abundance related to beta‐oxidation than C‐Sed. AS‐Ex had higher abundance of one protein related to mitochondrial biogenesis and lower relative protein abundance associated with oxidative stress and inflammation than AS‐Sed. Proteomic data were validated for proteins related to lipid and glycolytic metabolism. Chronic pressure overload changes the abundance of myocardial proteins that are mainly involved in lipid and glycolytic energy metabolism in rats. Moderate‐intensity aerobic training attenuates changes in proteins related to oxidative stress and inflammation and increases the COX4I1 protein, related to mitochondrial biogenesis. Protein changes are combined with improved functional capacity, cardiac remodeling, and LV function in AS rats. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a widespread neurodevelopmental disorder with unknown etiology. Dysfunction of several brain areas including the prefrontal cortex (PFC), hippocampus, and cerebellum is involved in cognitive and behavioral deficits associated with ASD. Several studies have reported a reduction in the number of parvalbumin‐immunoreactive (PV+) neurons in brain areas of ASD patients and animal models such as a shank mutant mouse model and rodents receiving fetal valproic acid (VPA) administration. Developing therapeutic interventions that restore PV interneurons can be the future therapeutic approach to ASD. The present study examined the possible effect of agmatine (AG), an endogenous NMDA antagonist, on the number of PV+ neurons in a VPA animal model of autism. The therapeutic effects of AG in ameliorating ASD‐like behaviors were previously reported in VPA rats. AG was gavaged at dosages of 0.001, 0.01, and 0.1 mg/kg from gestational day (GD) 6.5 to 18.5, and the number of PV interneurons was analyzed by immunohistochemistry in the 1‐month‐old rats. Prenatal VPA (GD 12.5) or AG led to a decrease of PV neurons in the PFC, Cornu ammonia (CA1), and molecular layers (MLs) of the cerebellum. However, exposure to AG restored the PV population induced by VPA. AG may modify underlying neuronal mechanisms resulting in the increased survival or restoration of the PV population. [ABSTRACT FROM AUTHOR]

The mother's thyroid hormone status during gestation and the first few months after delivery can play a crucial role in maturation during the brain development of the child. Transient abnormalities in thyroid function at birth indicate developmental and cognitive disorders in adulthood. Choline supplementation during gestation and the perinatal period in rats causes long‐lasting memory improvement in the offspring. However, it remains unclear whether choline is able to restore the deficits in rats with maternal hypothyroidism. The aim of this study was to evaluate the effects of choline supplementation on the alteration of cognitive‐behavioral function, long‐term potentiation (LTP), and morphological changes as well as apoptosis in pre‐pubertal offspring rats. To induce hypothyroidism, 6‐propyl‐2‐thiouracil was added to the drinking water from the 6th day of gestation to the 21st postnatal day (PND). Choline treatment was started twice a day on the first day of the gestation until PND 21 via gavage. LTP recording and Morris water maze (MWM) test were conducted at PND 28. Then, the rats were sacrificed to assess their brains. The results revealed that developmental thyroid hormone deficiency impaired spatial learning and memory and reduced LTP (both: P < 0.001). Choline treatment alleviated LTP (P < 0.001), as well as learning and memory deficits (P < 0.01) in both male and female hypothyroid rats. However, no significant changes were observed in the number of caspase‐3 stained cells in choline‐receiving hypothyroid groups. The results revealed that developmental thyroid hormone deficiency impaired spatial learning and memory and reduced LTP. Choline treatment alleviated LTP, as well as learning and memory deficits in both male and female hypothyroid rats. [ABSTRACT FROM AUTHOR]

The cerebellum is involved in higher order cognitive function and is susceptible to agerelated atrophy. However, limited evidence has directly examined the cerebellum's role in cognitive aging. To interrogate potential substrates of the relationship between cerebellar structure and memory in aging, here we target the Purkinje cells (PCs). The sole output neurons of the cerebellum, PC loss and/or degeneration underlie a variety of behavioral abnormalities. Using a rat model of normal cognitive aging, we immunostained sections through the cerebellum for the PC-specific protein, calbindin-D28k. Although morphometric quantification revealed no significant difference in total PC number as a function of age or cognitive status, regional cell number was a more robust correlate of memory performance in the young cerebellum than in aged animals. Parallel biochemical analysis of PC-specific protein levels in whole cerebellum additionally revealed that calbindin-D28k and Purkinje cell protein-2 (pcp-2) levels were lower selectively in aged rats with spatial memory impairment compared to both young animals and aged rats with intact memory. These results suggest that cognitive aging is associated with cerebellum vulnerability, potentially reflecting disruption of the cerebellum--medial temporal lobe network. [ABSTRACT FROM AUTHOR]

In this study, molybdenum(IV) sulfide (MoS2) nanoparticles (97 ± 32 nm) and microparticles (1.92 ± 0.64 μm) stabilized with poly (vinylpolypyrrolidone) (PVP) were administered intratracheally to male and female rats (dose of 1.5 or 5 mg/kg bw), every 14 days for 90 days (seven administrations in total). Blood parameters were assessed during and at the end of the study (hematology, biochemistry including glucose, albumins, uric acid, urea, high density lipoprotein HDL, total cholesterol, triglycerides, aspartate transaminase, and alanine transaminase ALT). Bronchoalveolar lavage fluid (BALF) analyses included cell viability, biochemistry (total protein concentration, lactate dehydrogenase, and glutathione peroxidase activity), and cytokine levels (tumor necrosis factor α, TNF‐α, macrophage inflammatory protein 2‐alpha, MIP‐2, and cytokine‐induced neutrophil chemoattractant‐2, CINC‐2). Tissues were subjected to routine histopathological and electron microscopy (STEM) examinations. No overt signs of chronic toxicity were observed. Differential cell counts in BALF revealed no significant differences between the animal groups. An increase in MIP‐2 and a decrease in TNF‐α were observed in BALF in the exposed males. The histopathological changes in the lung evaluated according to a developed classification system (based on severity of inflammation, range 0–4, with 4 indicating the most severe changes) showed average histopathological score of 1.33 for animals exposed to nanoparticles and microparticles at the lower dose, 1.72 after exposure to nanoparticles at the higher dose, and 2.83 for animals exposed to microparticles at the higher dose. In summary, it was shown that nanosized and microsized MoS2 can trigger dose‐dependent inflammatory reactions in the lungs of rats after multiple intratracheal instillation irrespective of the animal sex. Some evidence indicates a higher lung pro‐inflammatory potential of the microform. Molybdenum(IV) sulfide (MoS2) nanoparticles and microparticles administered intratracheally to rats (1.5 or 5 mg/kg bw), every 14 days for 90 days, induced no overt signs of systemic chronic toxicity. An increase in MIP‐2 and a decrease in TNF‐α were observed in BALF in the exposed males. Based on histopathological examination, nanosized and microsized MoS2 can trigger dose‐dependent inflammatory reactions in the lungs of rats after multiple intratracheal instillations, with a slightly higher lung pro‐inflammatory potential of the microform. [ABSTRACT FROM AUTHOR]

The current manuscript had been conducted to evaluate the effect of ageing on the brains of albino rats on the macro‐morphometric level and to assess the different parameters of brain and brain structures affected by ageing. Fifty apparently healthy rats of both sexes (27 males and 23 females) were used in the study, in addition to three rats for MRI. The animals were divided into four groups according to their age. Magnetic resonance imaging and cross sections of the brain were performed to document dimensions of various brain structures such as the hippocampus, surface area of lateral ventricle as well as dorsal and piriform cortices. Ageing would result into a negative impact on some brain structures. However, some others had not been affected as much. Furthermore, sex of the animal presented an important role as a variant where male rats of each age group demonstrated different results than their analogous female rats. In addition, MRI examination of the rat brain allowed recognition of the major cerebral structures. Findings of this work might be considered as a trial to provide a proof of changes resulted from normal ageing in both male and female rats and which sex is more affected than the other. [ABSTRACT FROM AUTHOR]

Solute carriers (SLCs) regulate transfer of a wide range of molecules across cell membranes using facilitative or secondary active transport. In pregnancy, these transporters, expressed at the placental barrier, are important for delivery of nutrients to the fetus, whilst also limiting entry of potentially harmful substances, such as drugs. In the present study, RNA‐sequencing analysis was used to investigate expression of SLCs in the fetal (embryonic day 19) rat brain, choroid plexus and placenta in untreated control animals and following maternal paracetamol treatment. In the treated group, paracetamol (15 mg/kg) was administered to dams twice daily for 5 days (from embryonic day 15 to 19). In untreated animals, overall expression of SLCs was highest in the placenta. In the paracetamol treatment group, expression of several SLCs was significantly different compared with control animals, with ion, amino acid, neurotransmitter and sugar transporters most affected. The number of SLC transcripts that changed significantly following treatment was the highest in the choroid plexus and lowest in the brain. All SLC transcripts that changed in the placenta following paracetamol treatment were downregulated. These results suggest that administration of paracetamol during pregnancy could potentially disrupt fetal nutrient homeostasis and affect brain development, resulting in major consequences for the neonate and extending into childhood. What is the central question of this study?How does maternal paracetamol treatment affect expression of solute carrier (SLC) transporters in the fetal (embryonic day 19) rat brain, choroid plexus and placenta?What is the main finding and its importance?Paracetamol administered to dams at embryonic days 15–19 resulted in changed expression of a large number of SLC transporters in the placenta and the fetal brain and choroid plexus. In the placenta, all SLC transporters that changed expression were downregulated. In the fetal brain and choroid plexus, expression of SLC transporters was both up‐ and downregulated. These findings might have implications for development of fetuses and offspring of mothers who have taken paracetamol during pregnancy. [ABSTRACT FROM AUTHOR]