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The peri-hematomal area (PHA) emerges as a key but puzzling interface where edematous and neuroinflammatory events co-occur after intracerebral hemorrhage (ICH), while being considered either as deleterious or protective. We aimed at unraveling the pathogeny and natural history of PHA over time after experimental ICH. Male and female rats were longitudinally followed up to day 7 using multimodal brain MRI. MRI measures were compared to neuropathological and behavioural results. While the peak of PHA volume at day 3 was predictive for spontaneous locomotor deficit without sex-effect, its drop at day 7 fitted with locomotor recovery and hematoma resorption. The PHA highest water density was observed at onset despite microvascular hypoperfusion, taken over by blood-brain barrier (BBB) leakage at day 3. Water density dropped at day 7, when vascular integrity was normalized, and the highest number of reactive astrocytes, microglial cells, and siderophages found. This study shows that the PHA with edematous component is hematoma-driven at onset and BBB-driven at day 3, but this excess neuroinflammation enabled PHA volume reduction and significant hematoma resorption as soon as day 7. Therapeutic interventions should consider this pathogeny, and be monitored by multimodal MRI in preclinical ICH models. [ABSTRACT FROM AUTHOR]

Abstract Background Cytokines, known for their pro- and anti-inflammatory roles, are also key regulators of sleep–wake cycles. Classical pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α), are associated with increased sleep, particularly slow-wave sleep (SWS), while anti-inflammatory cytokines, like interleukin-10 (IL-10), generally reduce sleep duration. Given the essential role of sleep in memory consolidation, this study aimed to investigate whether interleukin-12 (IL-12), a pro-inflammatory cytokine, could increase sleep duration following a memory acquisition task and subsequently improve memory performance. Male Swiss mice were surgically implanted with electrodes for electrocorticogram (ECoG) and electromyogram (EMG) recordings to track their sleep–wake cycles. After a recovery period, baseline sleep–wake activity was recorded. The mice were then randomly assigned to two groups and treated with either IL-12 (0.5 µg, i.p.) or a phosphate-buffered saline (PBS, i.p.) control, administered immediately before the multiple-trial inhibitory avoidance (MTIA) task, a behavioral test used to assess memory performance. Following the memory acquisition session, sleep–wake activity was immediately recorded for a continuous 24-h period. Results Mice treated with IL-12 exhibited longer latency to cross into the dark compartment during the MTIA test, indicating improved memory retention compared to the control group. Interestingly, this improved performance was associated with prolonged wakefulness, particularly in the first three hours after task acquisition. Conclusion The study shows that IL-12 can improve memory retention through prolonged wake episodes rather than increased sleep. This finding challenges the conventional understanding that sleep is the primary state for memory consolidation, suggesting that under specific conditions, wakefulness may also play a key role in supporting memory processes. Further research is needed to explore the underlying mechanisms of IL-12's cognitive effects.

Background: Cytokines, known for their pro- and anti-inflammatory roles, are also key regulators of sleep–wake cycles. Classical pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α), are associated with increased sleep, particularly slow-wave sleep (SWS), while anti-inflammatory cytokines, like interleukin-10 (IL-10), generally reduce sleep duration. Given the essential role of sleep in memory consolidation, this study aimed to investigate whether interleukin-12 (IL-12), a pro-inflammatory cytokine, could increase sleep duration following a memory acquisition task and subsequently improve memory performance. Male Swiss mice were surgically implanted with electrodes for electrocorticogram (ECoG) and electromyogram (EMG) recordings to track their sleep–wake cycles. After a recovery period, baseline sleep–wake activity was recorded. The mice were then randomly assigned to two groups and treated with either IL-12 (0.5 µg, i.p.) or a phosphate-buffered saline (PBS, i.p.) control, administered immediately before the multiple-trial inhibitory avoidance (MTIA) task, a behavioral test used to assess memory performance. Following the memory acquisition session, sleep–wake activity was immediately recorded for a continuous 24-h period. Results: Mice treated with IL-12 exhibited longer latency to cross into the dark compartment during the MTIA test, indicating improved memory retention compared to the control group. Interestingly, this improved performance was associated with prolonged wakefulness, particularly in the first three hours after task acquisition. Conclusion: The study shows that IL-12 can improve memory retention through prolonged wake episodes rather than increased sleep. This finding challenges the conventional understanding that sleep is the primary state for memory consolidation, suggesting that under specific conditions, wakefulness may also play a key role in supporting memory processes. Further research is needed to explore the underlying mechanisms of IL-12's cognitive effects. [ABSTRACT FROM AUTHOR]

Peripheral nerve repair is daily activity for several microsurgeons. Numerous nerve repair techniques are applied, including neurorrhaphy, nerve grafting and nerve transfer, depending on the nature and extent of the injury. However, these techniques become unfeasible when the distal nerve end is not preserved during the peripheral nerve injury or a segment of the muscle is transferred without the nerve supplying it. However, direct muscle neurotization (DMN) achieves muscle reinnervation by suturing the nerve directly into the muscle tissue, without requiring a distal nerve end for coaptation. Despite promising results in the literature, DMN is not widely adopted in clinical practice. Animal models may help in advancing novel therapeutic approaches, due to their anatomic and physiologic similarities to humans. This review highlights the current scientific understanding and recent advancements in DMN as well as the animal models and target muscle that have been used in the past to investigate the basic principles behind this surgical technique. The presented information should aid in establishing the clinical importance of DMN in peripheral nerve injury. [ABSTRACT FROM AUTHOR]

Objective To compare the effectiveness and safety of ventral caudal artery (VCA) versus gastroduodenal artery (GDA) approaches for hepatic artery embolization in a rat model. Methods Twenty adult male Sprague-Dawley rats underwent hepatic artery catheterization, angiography and embolization via the VCA (10) or GDA (10) approach. The catheterization success rate, technical success rate, hepatic angiography, size of embolic microspheres, procedure time and possibility of re-catheterization were evaluated. The radiation dose, radiation exposure time, responsiveness score of experimental rats, complications, and mortality rate were documented. Results The VCA group had significantly shorter average procedure time [(94±11.09) min, P<0.001] and better animal response (1.6±0.51, P=0.002) than the GDA group [(121±10.28) min, (2.60±0.52)]. Catheterization was repeatable only in the VCA group. The GDA group had significantly shorter radiation exposure [(16.00±4.85) min, P<0.001] and lower radiation dose [(19.09±4.26) mGy, P<0.001] than VCA group [(77.20±10.19) min, (62.70±9.32) mGy]. The maximum diameter of microspheres used in GDA group [(300-500) μm] was larger than that in V group [(100-300) µm]. Both groups had similar catheterization success rates, technical success rates, angiographic findings, catheterization depth, and mortality rates. Conclusion Apart from higher radiation exposure, the VCA approach of hepatic artery embolization is superior to the GDA approach in rat tolerability, procedure time and reproducibility. [ABSTRACT FROM AUTHOR]

The opioid epidemic is a public health crisis affecting spine care and pain management. Medical marijuana is a potential nonopioid analgesic yet to be studied in the surgical setting since its effects on bone healing are not fully understood. Studies have demonstrated analgesic and potentially osteoinductive properties of cannabinoids with endocannabinoid receptor expression in bone tissue. We hypothesize that tetrahydrocannabinol (THC) and cannabidiol (CBD) will not decrease bone healing in spinal fusion. Seventy-eight adult Sprague-Dawley rats were used for this study. Utilizing allogenic bone grafts (6 donor rats), posterolateral inter-transverse lumbar fusion at the L4–L5 level was performed. The animals were equally divided into four treatment groups, each receiving 0.1 ml intraperitoneal injections weekly as follows: placebo (saline), 5 mg/kg THC, 5 mg/kg CBD, and a combination of 5 mg/kg THC and 5mg/kg CBD (Combo). Callus tissue was harvested 2- and 8-weeks postsurgery for qPCR assessment to quantify changes in the expression of osteogenic genes. Manual palpation was done to assess the strength of the L4–L5 arthrodesis on all rats. μCT image-based callus analysis and histology were performed. One-way ANOVA followed by post hoc comparisons was performed. μCT demonstrated no significant differences. Treatment groups had slightly increased bone volume and density compared to control. qPCR at 2 weeks indicated downregulated RANKL/OPG ratios skewing towards osteogenesis in the CBD group, with the THC and CBD+THC groups demonstrating a downward trend (p>.05). ALPL, BMP4, and SOST were significantly higher in the CBD group, with CTNNB1 and RUNX2 also showing an upregulating trend. The CBD group showed elevation in Col1A1 and MMP13. Data at eight weeks showed ALPL, RUNX2, BMP4, and SOST were downregulated for all treatment groups. In the CBD+THC group, RANK, RANKL, and OPG were downregulated. OPG downregulation reached significance for the THC and CBD+THC group compared to saline. Interestingly, the RANKL/OPG ratio showed upregulation in the CBD and CBD+THC groups. RANKL showed upregulation in the CBD group. At 2 and 8 weeks, the CBD treatment group showed superior histological progression, increasing between time points. This study demonstrates that CBD and THC have no adverse effect on bone healing and the rate of spinal fusion in rats. Osteogenic factors were upregulated in the CBD-treated groups at 2 weeks, which indicates a potential for bone regeneration. In this group, compared to control, the RANKL/OPG ratio at the early healing phase demonstrates the inhibition of osteoclast differentiation, enhancing bone formation. Interestingly, it shows promoted osteoclast differentiation at the later healing phase, enhancing bone remodeling. This aligns with the physiological expectation of a lower ratio in the early phases and a higher ratio in the later remodeling phases. CBD and THC showed no inhibitory effects on bone healing in a spinal fusion model. Moreover, histologic and gene expression analysis demonstrated that CBD may, in fact, enhance bone healing. Further research is needed to confirm the safe usage of THC and CBD in the postoperative setting following spinal fusions. [ABSTRACT FROM AUTHOR]

It is unclear of the correlation between a mild traumatic brain injury (mTBI) and repeated subconcussive (RSC) impacts with respect to injury biomechanics. Thus, the present study was designed to determine the behavioral and histological differences between a single mTBI impact and RSC impacts with subdivided cumulative kinetic energies of the single mTBI impact. Adult male Sprague-Dawley rats were randomly assigned to a single mTBI impact, RSC impact, sham, or repeated sham groups. Following a weight drop injury, anxiety-like behavior and general locomotive activity and were assessed using the open field test, while motor coordination was evaluated using a rotarod unit. Neuronal loss, astrogliosis, and microgliosis were assessed using NeuN, GFAP and Iba-1 immunohistochemistry. All assessments were undertaken at 3- and 7-days post impact. No behavioral disturbances were observed in injury groups, however, both injury groups did lead to microgliosis following 3-days post-impact. No pathophysiological differences were observed between a single mTBI impact and RSC impacts of the same energy input. Even though a cumulative injury threshold for RSC impacts was not determined, a threshold still may exist where no pathodynamic shift occurs. [ABSTRACT FROM AUTHOR]

Peri-implantitis (PI) is a current concern whose understanding and resolution are ongoing. We aimed to evaluate in vivo a new treatment with antibacterial properties, based on bacterial lysates obtained from the strains of Aggregatibacter actinomycetemcomitans, Streptococcus oralis, and Fusobacterium nucleatum. This research was conducted on 30 rats with PI which were divided into three groups and treated with antibiotic and anti-inflammatory (AAi) drugs, bacterial lysates (BLs), and saline (C), respectively. The monitoring period included the clinical and paraclinical examination where hematological, immunological, imaging, and histopathological analysis were performed. No particular clinical signs were observed, but the radiological examination showed the loss of all implants in group C, in contrast to group BL which had the highest survival rate of devices. White cells showed a decrease from the PI period, as did the immunological analysis. Only IL-6 showed an increase in the AAi and BL groups. Histopathologically, the C group presented a high degree of bone destruction, and in the BL group, many attenuated inflammatory phenomena appeared compared to the AAi animals. Bacterial lysates have similar effects to antibiotic-based therapeutic regimens for PI, and their future use may help to improve the current therapeutic management of the disease. [ABSTRACT FROM AUTHOR]

The current study uses rodent models to explore the anxiolytic properties of Hemidesmus indicus' ethanolic extract (EEHI). Hemidesmus indicus, an evergreen plant well-known for its therapeutic characteristics, has been widely used in Ayurvedic medicine to treat a variety of conditions, including anxiety. This study seeks to give scientific validation for its anxiolytic properties. The ethanolic extract was made using normal extraction processes and given to rodents in varied doses (100,200 and 400 mg/kg). The anxiolytic activity was assessed using a variety of widely recognized behavioural assays, including the Elevated Plus Maze (EPM), Open Field Test (OFT), and Light-Dark Box (LDB) test. Diazepam (2 mg/kg) served as the standard reference drug. The results revealed that EEHI significantly reduced anxiety-like behaviours in all three tests when compared to the control group. In the EPM test, EEHI-treated rodents spent more time and entered the open arms. In the OFT, ambulation, rearing and assisted rearing increased, indicating lower levels of anxiety. The LDB test supported these findings, with a significant increase in time spent in the light compartment. The study suggests that EEHI has promising anxiolytic activity and may offer a natural treatment alternative for anxiety disorders. Further research is needed to isolate specific active molecules and better understand the underlying mechanisms of action. [ABSTRACT FROM AUTHOR]

Current rodent models of anorexia nervosa (AN) often have accelerated weight loss that often do not allow for investigation of physiological ramifications of prolonged low weight status characteristic of AN. The purpose of this project was to refine a rodent model of AN to extend the duration of low weight status and allow for investigation of recovery. Eight‐week‐old female Sprague Dawley rats underwent 50%–60% food restriction for 30 days. Rats were group‐housed except during feeding, where AN rats were individually housed and given up to 2 h to consume food. Control (CON) rats were allowed to consume food ad libitum. To simulate recovery, a separate cohort of animals underwent the same food restriction protocol for 30 days, then rats (AN‐R) were allowed to consume food ad libitum to facilitate weight recovery for an additional 30 days. AN‐R rats were compared to age matched controls (CON‐R). AN rats lost ~15% bodyweight and were ~30% lighter than CON. Compared to CON, AN rats had ~35% lower fat content, ~18% lower bone mineral density, ~22% smaller plantaris muscle mass and ~52% smaller ovaries. Upon reintroduction of food, AN‐R rats achieved comparable bodyweights to CON‐R rats after ~10 days. However, after 30 days of recovery, AN‐R rats still had ~14% lower bone mineral density and ~11% smaller plantaris mass and ~21% smaller ovaries. This refinement of rodent AN results in physiological side effects of AN without reaching excessive weight loss requiring euthanasia. Moreover, some physiological consequences of simulated AN are not resolved with weight restoration. [ABSTRACT FROM AUTHOR]

Despite known drawbacks, rodent models are essential tools in the research of renal development, physiology, and pathogenesis. In the past decade, rodent models have been developed and used to mimic different etiologies of acute kidney injury (AKI), AKI to chronic kidney disease (CKD) transition or progression, and AKI with comorbidities. These models have been applied for both mechanistic research and preclinical drug development. However, current rodent models have their limitations, especially since they often do not fully recapitulate the pathophysiology of AKI in human patients, and thus need further refinement. Here, we discuss the present status of these rodent models, including the pathophysiologic compatibility, clinical translational significance, key factors affecting model consistency, and their main limitations. Future efforts should focus on establishing robust models that simulate the major clinical and molecular phenotypes of human AKI and its progression. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown cardiac abnormalities in acute liver injury, suggesting a potential role in the associated high mortality. Methods: We designed an experimental study exploring the short-term effects of acute cholestasis-induced liver injury on cardiac function and structure in a rodent bile duct ligation (BDL) model to elucidate the potential interplay. Thirty-seven male Sprague-Dawley rats were subjected to BDL surgery (n = 28) or served as sham-operated (n = 9) controls. Transthoracic echocardiography, Doppler evaluation of the left anterior descending coronary artery, and myocardial contrast echocardiography were performed at rest and during adenosine and dobutamine stress 5 days after BDL. Immunohistochemical staining of myocardial tissue samples for hypoxia and inflammation as well as serum analysis were performed. Results: BDL animals exhibited acute liver injury with elevated transaminases, bilirubin, and total circulating bile acids (TBA) 5 days after BDL (TBA control: 0.81 ± 2.54 µmol/L vs. BDL: 127.52 ± 57.03 µmol/L; p < 0.001). Concurrently, cardiac function was significantly impaired, characterized by reduced cardiac output (CO) and global longitudinal strain (GLS) in the echocardiography at rest and under pharmacological stress (CO rest control: 120.6 ± 24.3 mL/min vs. BDL 102.5 ± 16.6 mL/min, p = 0.041; GLS rest control: −24.05 ± 3.8% vs. BDL: −18.5 ± 5.1%, p = 0.01). Myocardial perfusion analysis revealed a reduced myocardial blood flow at rest and a decreased coronary flow velocity reserve (CFVR) under dobutamine stress in the BDL animals (CFVR control: 2.1 ± 0.6 vs. BDL: 1.7 ± 0.5 p = 0.047). Immunofluorescence staining indicated myocardial hypoxia and increased neutrophil infiltration. Conclusions: In summary, acute cholestasis-induced liver injury can lead to impaired cardiac function mediated by coronary microvascular dysfunction, suggesting that major adverse cardiac events may contribute to the mortality of acute liver failure. This may be due to endothelial dysfunction and direct bile acid signaling. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis (CRS) is characterized by sinonasal mucosal inflammation. Staphylococcus aureus (S. aureus) is associated with severe CRS phenotypes. Different animal models have been proposed to study the association of CRS and S. aureus. However, current animal models are expensive due to the use of large animals, have high barriers to ethics approval, or require invasive surgical intervention, necessitating a need for a model that can overcome these limitations. This study aimed at establishing a reliable and efficient rat lymphoplasmacytic inflammatory model for rhinosinusitis. Sprague Dawley rats received a daily intranasal application of 20 μL of saline, S. aureus CI-182 exoprotein (250 μg/mL), or exoprotein CI-182 in combination with S. aureus clinical isolate (CI-908 or CI-913) 108 colony-forming unit (CFU)/mL. The rats' sinuses were harvested at 1 and 2 weeks post-intervention. The CFU and histopathologic examination of inflammation were evaluated. S. aureus clinical isolates CI-908 or CI-913 in combination with the exoprotein (CI-182) had higher CFUs and caused persistently higher inflammation at both the 1 and 2-week post-intervention compared to the exoprotein and saline group. The observed inflammatory cell type was lymphoplasmacytic. This study provided evidence that the combination of a S. aureus exoprotein with S. aureus induces inflammation that persists for a minimum of two weeks post-intervention. This model is the first known animal model to create the lymphoplasmacytic inflammation subtype seen in CRS patients. This offers a cost-effective, accessible, non-invasive, and easy-to-replicate model to study the causes and treatment of such inflammation. [ABSTRACT FROM AUTHOR]

Abstract In Parkinson’s disease, pathogenic factors such as the intraneuronal accumulation of the protein α-synuclein affect key metabolic processes. New approaches are required to understand how metabolic dysregulations cause degeneration of vulnerable subtypes of neurons in the brain. Here, we apply correlative electron microscopy and NanoSIMS isotopic imaging to map and quantify 13C enrichments in dopaminergic neurons at the subcellular level after pulse-chase administration of 13C-labeled glucose. To model a condition leading to neurodegeneration in Parkinson’s disease, human α-synuclein was unilaterally overexpressed in the substantia nigra of one brain hemisphere in rats. When comparing neurons overexpressing α-synuclein to those located in the control hemisphere, the carbon anabolism and turnover rates revealed metabolic anomalies in specific neuronal compartments and organelles. Overexpression of α-synuclein enhanced the overall carbon turnover in nigral neurons, despite a lower relative incorporation of carbon inside the nucleus. Furthermore, mitochondria and Golgi apparatus showed metabolic defects consistent with the effects of α-synuclein on inter-organellar communication. By revealing changes in the kinetics of carbon anabolism and turnover at the subcellular level, this approach can be used to explore how neurodegeneration unfolds in specific subpopulations of neurons.

Peri-implantitis (PI) is a current concern whose understanding and resolution are ongoing. We aimed to evaluate in vivo a new treatment with antibacterial properties, based on bacterial lysates obtained from the strains of Aggregatibacter actinomycetemcomitans, Streptococcus oralis, and Fusobacterium nucleatum. This research was conducted on 30 rats with PI which were divided into three groups and treated with antibiotic and anti-inflammatory (AAi) drugs, bacterial lysates (BLs), and saline (C), respectively. The monitoring period included the clinical and paraclinical examination where hematological, immunological, imaging, and histopathological analysis were performed. No particular clinical signs were observed, but the radiological examination showed the loss of all implants in group C, in contrast to group BL which had the highest survival rate of devices. White cells showed a decrease from the PI period, as did the immunological analysis. Only IL-6 showed an increase in the AAi and BL groups. Histopathologically, the C group presented a high degree of bone destruction, and in the BL group, many attenuated inflammatory phenomena appeared compared to the AAi animals. Bacterial lysates have similar effects to antibiotic-based therapeutic regimens for PI, and their future use may help to improve the current therapeutic management of the disease.

Arteriovenous fistulas (AVFs) have long been used as dialysis access in patients with end-stage renal disease; however, their maturation and long-term patency still fall short of clinical needs. Rodent models are irreplaceable to facilitate the study of mechanisms and provide reliable insights into clinical problems. The ideal rodent AVF model recapitulates the major features and pathology of human disease as closely as possible, and pre-induction of the uremic milieu is an important addition to AVF failure studies. Herein, we review different surgical methods used so far to create AVF in rodents, including surgical suturing, needle puncture, and the cuff technique. We also summarize commonly used evaluations after AVF placement. The aim was to provide recent advances and ideas for better selection and induction of rodent AVF models. At the same time, further improvements in the models and a deeper understanding of AVF failure mechanisms are expected.

After ischemic stroke, the cortex directly adjacent to the ischemic core (i.e., the peri‐infarct cortex, PIC) undergoes plastic changes that facilitate motor recovery. Dopaminergic signaling is thought to support this process. However, ischemic stroke also leads to the remote degeneration of dopaminergic midbrain neurons, possibly interfering with this beneficial effect. In this study, we assessed the reorganization of dopaminergic innervation of the PIC in a rat model of focal cortical stroke. Adult Sprague–Dawley rats either received a photothrombotic stroke (PTS) in the primary motor cortex (M1) or a sham operation. 30 days after PTS or sham procedure, the retrograde tracer Micro Ruby (MR) was injected into the PIC of stroke animals or into homotopic cortical areas of matched sham rats. Thus, dopaminergic midbrain neurons projecting into the PIC were identified based on MR signal and immunoreactivity against tyrosine hydroxylase (TH), a marker for dopaminergic neurons. The density of dopaminergic innervation within the PIC was assessed by quantification of dopaminergic boutons indicated by TH‐immunoreactivity. Regarding postsynaptic processes, expression of dopamine receptors (D1‐ and D2) and a marker of the functional signal cascade (DARPP‐32) were visualized histologically. Despite a 25% ipsilesional loss of dopaminergic midbrain neurons after PTS, the number and spatial distribution of dopaminergic neurons projecting to the PIC was not different compared to sham controls. Moreover, the density of dopaminergic innervation in the PIC was significantly higher than in homotopic cortical areas of the sham group. Within the PIC, D1‐receptors were expressed in neurons, whereas D2‐receptors were confined to astrocytes. The intensity of D1‐ and DARPP‐32 expression appeared to be higher in the PIC compared to the contralesional homotopic cortex. Our data suggest a sprouting of dopaminergic fibers into the PIC and point to a role for dopaminergic signaling in reparative mechanisms post‐stroke, potentially related to recovery. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) harms patients' health and social and economic well-being. Unfortunately, fully effective therapeutic strategies have yet to be developed to treat this disease, affecting millions worldwide. Apoptosis and autophagy are critical cell death signaling pathways after SCI that should be targeted for early therapeutic interventions to mitigate their adverse effects and promote functional recovery. Tibolone (TIB) is a selective tissue estrogen activity regulator (STEAR) with neuroprotective properties demonstrated in some experimental models. This study aimed to investigate the effect of TIB on apoptotic cell death and autophagy after SCI and verify whether TIB promotes motor function recovery. A moderate contusion SCI was produced at thoracic level 9 (T9) in male Sprague Dawley rats. Subsequently, animals received a daily dose of TIB orally and were sacrificed at 1, 3, 14 or 30 days post-injury. Tissue samples were collected for morphometric and immunofluorescence analysis to identify tissue damage and the percentage of neurons at the injury site. Autophagic (Beclin-1, LC3-I/LC3-II, p62) and apoptotic (Caspase 3) markers were also analyzed via Western blot. Finally, motor function was assessed using the BBB scale. TIB administration significantly increased the amount of preserved tissue (p < 0.05), improved the recovery of motor function (p < 0.001) and modulated the expression of autophagy markers in a time-dependent manner while consistently inhibiting apoptosis (p < 0.05). Therefore, TIB could be a therapeutic alternative for the recovery of motor function after SCI. [ABSTRACT FROM AUTHOR]

Neurostimulation carries high therapeutic potential, accompanied by an excellent safety profile. In this review, we argue that an arena in which these tools could provide breakthrough benefits is traumatic brain injury (TBI). TBI is a major health problem worldwide, with the majority of cases identified as mild TBI (mTBI). MTBI is of concern because it is a modifiable risk factor for dementia. A major challenge in studying mTBI is its inherent heterogeneity across a large feature space (e.g., etiology, age of injury, sex, treatment, initial health status, etc.). Parallel lines of research in human and rodent mTBI can be collated to take advantage of the full suite of neuroscience tools, from neuroimaging (electroencephalography: EEG; functional magnetic resonance imaging: fMRI; diffusion tensor imaging: DTI) to biochemical assays. Despite these attractive components and the need for effective treatments, there are at least two major challenges to implementation. First, there is insufficient understanding of how neurostimulation alters neural mechanisms. Second, there is insufficient understanding of how mTBI alters neural function. The goal of this review is to assemble interrelated but disparate areas of research to identify important gaps in knowledge impeding the implementation of neurostimulation. [ABSTRACT FROM AUTHOR]

In Parkinson's disease, pathogenic factors such as the intraneuronal accumulation of the protein α-synuclein affect key metabolic processes. New approaches are required to understand how metabolic dysregulations cause degeneration of vulnerable subtypes of neurons in the brain. Here, we apply correlative electron microscopy and NanoSIMS isotopic imaging to map and quantify 13C enrichments in dopaminergic neurons at the subcellular level after pulse-chase administration of 13C-labeled glucose. To model a condition leading to neurodegeneration in Parkinson's disease, human α-synuclein was unilaterally overexpressed in the substantia nigra of one brain hemisphere in rats. When comparing neurons overexpressing α-synuclein to those located in the control hemisphere, the carbon anabolism and turnover rates revealed metabolic anomalies in specific neuronal compartments and organelles. Overexpression of α-synuclein enhanced the overall carbon turnover in nigral neurons, despite a lower relative incorporation of carbon inside the nucleus. Furthermore, mitochondria and Golgi apparatus showed metabolic defects consistent with the effects of α-synuclein on inter-organellar communication. By revealing changes in the kinetics of carbon anabolism and turnover at the subcellular level, this approach can be used to explore how neurodegeneration unfolds in specific subpopulations of neurons. [ABSTRACT FROM AUTHOR]

Study Design: This is a basic science, animal research study. Objective: This study aims to explore, in rodent models, the effectiveness of systemic nonsteroidal anti-inflammatory drugs in reducing recombinant human bone morphogenetic protein-2 (rhBMP-2) induced neuroinflammation. Summary of Background Data: rhBMP-2 is increasingly used to augment fusion in lumbar interbody fusion surgeries, although it can cause complications including postoperative radiculitis. Materials and Methods: Eighteen 8-week-old Sprague-Dawley rats underwent Hargreaves testing to measure the baseline thermal withdrawal threshold before undergoing surgical intervention. The L5 nerve root was exposed and wrapped with an Absorbable Collagen Sponge containing rhBMP-2. Rats were randomized into 3 groups: (1) Low dose (LD), (2) high dose (HD) diclofenac sodium, and (3) saline, receiving daily injection treatment. Hargreaves testing was performed postoperatively on days 5 and 7. Seroma volumes were measured by aspiration and the nerve root was then harvested for hematoxylin and eosin, immunohistochemistry, Luxol Fast Blue staining, and real-time quantitative polymerase chain reaction. The Student t test was used to evaluate the statistical significance among groups. Results: The intervention groups showed reduced seroma volume, and a general reduction of inflammatory markers (MMP12, MAPK6, GFAP, CD68, and IL18) compared with controls, with the reduction in MMP12 being statistically significant (P = 0.02). Hematoxylin and eosin and immunohistochemistry of the nerve roots showed the highest macrophage density in the saline controls and the lowest in the HD group. Luxol Fast Blue staining showed the greatest extent of demyelination in the LD and saline groups. Lastly, Hargreaves testing, a functional measure of neuroinflammation, of the HD group demonstrated a minimal change in thermal withdrawal latency. In contrast, the thermal withdrawal latency of the LD and saline groups showed a statistically significant decrease of 35.2% and 28.0%, respectively (P < 0.05). Conclusion: This is the first proof-of-concept study indicating that diclofenac sodium is effective in alleviating rhBMP-2--induced neuroinflammation. This can potentially impact the clinical management of rhBMP-2--induced radiculitis. It also presents a viable rodent model for evaluating the effectiveness of analgesics in reducing rhBMP-2--induced inflammation. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) and its drainage are crucial in clearing metabolic waste and maintaining the microenvironment of the central nervous system for proper functioning. Normal-pressure hydrocephalus (NPH) is a serious neurological disorder of the elderly with obstruction of CSF flow outside the cerebral ventricles, causing ventriculomegaly. The stasis of CSF in NPH compromises brain functioning. Although treatable, often with shunt implantation for drainage, the outcome depends highly on early diagnosis, which, however, is challenging. The initial symptoms of NPH are hard to be aware of and the complete symptoms overlap with those of other neurological diseases. Ventriculomegaly is not specific to NPH as well. The lack of knowledge on the initial stages in its development and throughout its progression further deters early diagnosis. Thus, we are in dire need for an appropriate animal model for researches into a more thorough understanding of its development and pathophysiology so that we can enhance the diagnosis and therapeutic strategies to improve the prognosis of NPH following treatment. With this, we review the few currently available experimental rodent NPH models for these animals are smaller in sizes, easier in maintenance, and having a rapid life cycle. Among these, a parietal convexity subarachnoid space kaolin injection adult rat model appears promising as it shows a slow onset of ventriculomegaly in association with cognitive and motor disabilities resembling the elderly NPH in humans.

Stroke remains a major burden on patients, families, and healthcare professionals, despite major advances in prevention, acute treatment, and rehabilitation. Preclinical basic research can help to better define mechanisms contributing to stroke pathology, and identify therapeutic interventions that can decrease ischemic injury and improve outcomes. Animal models play an essential role in this process, and mouse models are particularly well-suited due to their genetic accessibility and relatively low cost. Here, we review the focal cerebral ischemia models with an emphasis on the middle cerebral artery occlusion technique, a "gold standard" in surgical ischemic stroke models. Also, we highlight several histologic, genetic, and in vivo imaging approaches, including mouse stroke MRI techniques, that have the potential to enhance the rigor of preclinical stroke evaluation. Together, these efforts will pave the way for clinical interventions that can mitigate the negative impact of this devastating disease. [ABSTRACT FROM AUTHOR]

Transplantation of human induced pluripotent stem cell-derived dopaminergic (iPSC-DA) neurons is a promising therapeutic strategy for Parkinson's disease (PD). To assess optimal cell characteristics and reproducibility, we evaluated the efficacy of iPSC-DA neuron precursors from two individuals with sporadic PD by transplantation into a hemiparkinsonian rat model after differentiation for either 18 (d18) or 25 days (d25). We found similar graft size and dopamine (DA) neuron content in both groups, but only the d18 cells resulted in recovery of motor impairments. In contrast, we report that d25 grafts survived equally as well and produced grafts rich in tyrosine hydroxylase-positive neurons, but were incapable of alleviating any motor deficits. We identified the mechanism of action as the extent of neurite outgrowth into the host brain, with d18 grafts supporting significantly more neurite outgrowth than nonfunctional d25 grafts. RNAseq analysis of the cell preparation suggests that graft efficacy may be enhanced by repression of differentiation-associated genes by REST, defining the optimal predifferentiation state for transplantation. This study demonstrates for the first time that DA neuron grafts can survive well in vivo while completely lacking the capacity to induce recovery from motor dysfunction. In contrast to other recent studies, we demonstrate that neurite outgrowth is the key factor determining graft efficacy and our gene expression profiling revealed characteristics of the cells that may predict their efficacy. These data have implication for the generation of DA neuron grafts for clinical application. [ABSTRACT FROM AUTHOR]

Hepatitis B infection caused by the hepatitis B virus is a life-threatening cause of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Researchers have produced multiple in vivo models for hepatitis B virus (HBV) and, currently, there are no specific laboratory animal models available to study HBV pathogenesis or immune response; nonetheless, their limitations prevent them from being used to study HBV pathogenesis, immune response, or therapeutic methods because HBV can only infect humans and chimpanzees. The current study is the first of its kind to identify a suitable chemically induced liver cirrhosis/HCC model that parallels HBV pathophysiology. Initially, data from the peer-reviewed literature and the GeneCards database were compiled to identify the genes that HBV and seven drugs (acetaminophen, isoniazid, alcohol, D-galactosamine, lipopolysaccharide, thioacetamide, and rifampicin) regulate. Functional enrichment analysis was performed in the STRING server. The network HBV/Chemical, genes, and pathways were constructed by Cytoscape 3.6.1. About 1546 genes were modulated by HBV, of which 25.2% and 17.6% of the genes were common for alcohol and lipopolysaccharide-induced hepatitis. In accordance with the enrichment analysis, HBV activates the signaling pathways for apoptosis, cell cycle, PI3K-Akt, TNF, JAK-STAT, MAPK, chemokines, NF-kappa B, and TGF-beta. In addition, alcohol and lipopolysaccharide significantly activated these pathways more than other chemicals, with higher gene counts and lower FDR scores. In conclusion, alcohol-induced hepatitis could be a suitable model to study chronic HBV infection and lipopolysaccharide-induced hepatitis for an acute inflammatory response to HBV. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown cardiac abnormalities in acute liver injury, suggesting a potential role in the associated high mortality. Methods: We designed an experimental study exploring the short-term effects of acute cholestasis-induced liver injury on cardiac function and structure in a rodent bile duct ligation (BDL) model to elucidate the potential interplay. Thirty-seven male Sprague-Dawley rats were subjected to BDL surgery (n = 28) or served as sham-operated (n = 9) controls. Transthoracic echocardiography, Doppler evaluation of the left anterior descending coronary artery, and myocardial contrast echocardiography were performed at rest and during adenosine and dobutamine stress 5 days after BDL. Immunohistochemical staining of myocardial tissue samples for hypoxia and inflammation as well as serum analysis were performed. Results: BDL animals exhibited acute liver injury with elevated transaminases, bilirubin, and total circulating bile acids (TBA) 5 days after BDL (TBA control: 0.81 ± 2.54 µmol/L vs. BDL: 127.52 ± 57.03 µmol/L; p < 0.001). Concurrently, cardiac function was significantly impaired, characterized by reduced cardiac output (CO) and global longitudinal strain (GLS) in the echocardiography at rest and under pharmacological stress (CO rest control: 120.6 ± 24.3 mL/min vs. BDL 102.5 ± 16.6 mL/min, p = 0.041; GLS rest control: −24.05 ± 3.8% vs. BDL: −18.5 ± 5.1%, p = 0.01). Myocardial perfusion analysis revealed a reduced myocardial blood flow at rest and a decreased coronary flow velocity reserve (CFVR) under dobutamine stress in the BDL animals (CFVR control: 2.1 ± 0.6 vs. BDL: 1.7 ± 0.5 p = 0.047). Immunofluorescence staining indicated myocardial hypoxia and increased neutrophil infiltration. Conclusions: In summary, acute cholestasis-induced liver injury can lead to impaired cardiac function mediated by coronary microvascular dysfunction, suggesting that major adverse cardiac events may contribute to the mortality of acute liver failure. This may be due to endothelial dysfunction and direct bile acid signaling.

Stroke remains a major burden on patients, families, and healthcare professionals, despite major advances in prevention, acute treatment, and rehabilitation. Preclinical basic research can help to better define mechanisms contributing to stroke pathology, and identify therapeutic interventions that can decrease ischemic injury and improve outcomes. Animal models play an essential role in this process, and mouse models are particularly well-suited due to their genetic accessibility and relatively low cost. Here, we review the focal cerebral ischemia models with an emphasis on the middle cerebral artery occlusion technique, a “gold standard” in surgical ischemic stroke models. Also, we highlight several histologic, genetic, and in vivo imaging approaches, including mouse stroke MRI techniques, that have the potential to enhance the rigor of preclinical stroke evaluation. Together, these efforts will pave the way for clinical interventions that can mitigate the negative impact of this devastating disease.

Introduction: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world, currently affecting over 350 billion people globally. For the most prevalent late-stage form of this disease, atrophic AMD, there are no available prevention strategies or treatments, in part due to inherent difficulties in early-stage diagnosis. Photo-oxidative damage is a well-established model for studying inflammatory and cell death features that occur in late-stage atrophic AMD, however to date has not been investigated as a potential model for studying early features of disease onset. Therefore, in this study we aimed to determine if short exposure to photo-oxidative damage could be used to induce early retinal molecular changes and advance this as a potential model for studying early-stage AMD. Methods: C57BL/6J mice were exposed to 1, 3, 6, 12, or 24h photo-oxidative damage (PD) using 100k lux bright white light. Mice were compared to dimreared (DR) healthy controls as well as mice which had undergone long periods of photo-oxidative damage (3d and 5d-PD) as known timepoints for inducing late-stage retinal degeneration pathologies. Cell death and retinal inflammation were measured using immunohistochemistry and qRT-PCR. To identify retinal molecular changes, retinal lysates were sent for RNA sequencing, following which bioinformatics analyses including differential expression and pathway analyses were performed. Finally, to investigate modulations in gene regulation as a consequence of degeneration, microRNA (miRNA) expression patterns were quantified using qRT-PCR and visualized using in situ hybridization. Results: Short exposure to photo-oxidative damage (1-24h-PD) induced early molecular changes in the retina, with progressive downregulation of homeostatic pathways including metabolism, transport and phototransduction observed across this time-course. Inflammatory pathway upregulation was observed from 3h-PD, preceding observable levels of microglia/macrophage activation which was noted from 6h-PD, as well as significant photoreceptor row loss from 24h-PD. Further rapid and dynamic movement of inflammatory regulator miRNA, miR-124-3p and miR-155-5p, was visualized in the retina in response to degeneration. Conclusion: These results support the use of short exposure to photo-oxidative damage as a model of early AMD and suggest that early inflammatory changes in the retina may contribute to pathological features of AMD progression including immune cell activation and photoreceptor cell death. We suggest that early intervention of these inflammatory pathways by targeting miRNA such as miR124-3p and miR-155-5p or their target genes may prevent progression into latestage pathology. [ABSTRACT FROM AUTHOR]

Cirrhotic patients often suffer from cirrhotic cardiomyopathy (CCM). Previous animal models of CCM were inconsistent concerning the time and mechanism of injury; thus, the temporal dynamics and cardiac vulnerability were studied in more detail. Rats underwent bile duct ligation (BDL) and a second surgery 28 days later. Cardiac function was assessed by conductance catheter and echocardiography. Histology, gene expression, and serum parameters were analyzed. A chronotropic incompetence (Pd31 < 0.001) and impaired contractility at rest and a reduced contractile reserve (Pd31 = 0.03, Pdob-d31 < 0.001) were seen 31 days after BDL with increased creatine (Pd35, Pd42, and Pd56 < 0.05) and transaminases (Pd31 < 0.001). A total of 56 days after BDL, myocardial fibrosis was seen (Pd56 < 0.001) accompanied by macrophage infiltration (CD68: Pgroup < 0.001) and systemic inflammation (TNFα: Pgroup < 0.001, white blood cell count: Pgroup < 0.001). Myocardial expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) was increased after 31 (Pd31 < 0.001) and decreased after 42 (Pd42 < 0.001) and 56 days (Pd56 < 0.001). Caspase-3 expression was increased 31 and 56 days after BDL (Pd31 = 0.005; Pd56 = 0.005). Structural changes in the myocardium were seen after 8 weeks. After the second surgery (second hit), transient myocardial insufficiency with secondary organ dysfunction was seen, characterized by reduced contractility and contractile reserve. [ABSTRACT FROM AUTHOR]

With the rising worldwide obesity rates, bariatric surgeries are increasing. Although the surgery offers an effective treatment option for weight loss, the procedure causes dramatic physiological and metabolic changes. Animal models in rodents provide a valuable tool for studying the systemic effects of the surgery. Since the surgery may significantly influence the pharmacokinetic properties of medications, animal studies should provide essential insight into mechanisms underlying changes in how the body handles the drug. This review summarizes research work in rodents regarding the impact of standard bariatric procedures on pharmacokinetics. A qualitative literature search was conducted via PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE. Studies that examined bariatric surgery's effects on drug pharmacokinetics in rodent models were included. Clinical studies and studies not involving drug interventions were excluded. A total of 15 studies were identified and assessed in this review. These studies demonstrate the possible impact of bariatric surgery on drug absorption, distribution, metabolism, excretion, and potential mechanisms. Pharmacokinetic changes exhibited in the limited pre-clinical studies highlight a need for further investigation to fully understand the impact and mechanism of bariatric surgery on drug responses. [ABSTRACT FROM AUTHOR]

Appropriate treatment options are lacking for hepatitis E virus (HEV)-infected pregnant women and immunocompromised individuals. Thus, we aimed to identify efficient anti-HEV drugs through high-throughput screening, validate them in vitro and in vivo (in a preclinical animal study), and elucidate their underlying antiviral mechanism of action. Using appropriate cellular and rodent HEV infection models, we studied a critical pathway for host-HEV interactions and performed a preclinical study of the corresponding antivirals, which target proteostasis of the HEV replicase. We found 17 inhibitors that target HEV-HSP90 interactions by unbiased compound library screening on human hepatocytes harboring an HEV replicon. Inhibitors of HSP90 (iHSP90) markedly suppressed HEV replication with efficacy exceeding that of conventional antivirals (IFNα and ribavirin) in vitro. Mechanistically, iHSP90 treatment released the viral replicase ORF1 protein from the ORF1-HSP90 complex and triggered rapid ubiquitin/proteasome-mediated degradation of ORF1, resulting in abrogated HEV replication. Furthermore, a preclinical trial in a Mongolian gerbil HEV infection model showed this novel anti-HEV strategy to be safe, efficient, and able to prevent HEV-induced liver damage. In this study, we uncover a proteostatic pathway that is critical for host-HEV interactions and we provide a foundation from which to translate this new understanding of the HEV life cycle into clinically promising antivirals. Appropriate treatment options for hepatitis E virus (HEV)-infected pregnant women and immunocompromised patients are lacking; hence, there is an urgent need for safe and effective HEV-specific therapies. This study identified new antivirals (inhibitors of HSP90) that significantly limit HEV infection by targeting the viral replicase for degradation. Moreover, these anti-HEV drugs were validated in an HEV rodent model and were found to be safe and efficient for prevention of HEV-induced liver injury in preclinical experiments. Our findings substantially promote the understanding of HEV pathobiology and pave the way for antiviral development. [Display omitted] • We identified 17 HSP90 inhibitors via high-throughput screening of anti-HEV compounds using replicon models. • Inhibiting the HEV replicase-HSP90 interaction releases ORF1 for K48-linked ubiquitination and proteasomal degradation. • Cytosolic ORF1-HSP90 aggregates are critical for HEV replication. • Preclinical studies demonstrate that targeting HSP90 prevents sustained HEV infection and liver injury in rodents. [ABSTRACT FROM AUTHOR]

Purpose: Sleeve gastrectomy with transit bipartition (SG-TB) could be an attractive alternative to Roux-en-Y gastric bypass (RYGB) on weight loss and improvement of comorbidities in patients with obesity. However, there is little long-term data. Translational research on a rat model could allow long-term projection to assess efficacy and safety of SG-TB. The aim of this research was to evaluate the long-term efficacy and safety of SG-TB compared to RYGB and SHAM in rat model. Materials and Methods: Ninety-four male obese Wistar rats were distributed into 3 groups: SG-TB (n = 34), RYGB (n = 32), and SHAM (control group, n = 28). The percentage of total weight loss (%TWL), coprocalorimetry, glucose and insulin tolerance test, insulin, GLP-1, PYY, and GIP before and after surgery were assessed. The animals were followed over 6 months (equivalent to 16 years in humans). Results: At 6 months, %TWL was significantly greater(p = 0.025) in the SG-TB group compared to the RYGB group. There was no difference between the groups (p = 0.86) in malabsorption 15 and 120 days postoperatively. Glucose tolerance was significantly improved (p = 0.03) in the SG-TB and RYGB groups compared to the preoperative state. Insulin secretion, at 3 months, was significantly more important in the SG-TB group (p = 0.0003), compared to the RYGB and SHAM groups. GLP-1 secretion was significantly increased in the SG-TB and RYGB groups compared to the preoperative state (p = 0.001) but similar between SG-TB and RYGB animals (p = 0.72). Conclusion: In a rat model, at long term compared to RYGB, SG-TB provides greater and better-maintained weight loss and an increased insulin secretion without impairing nutritional status. [ABSTRACT FROM AUTHOR]

Abstract Background Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with severe social communication, interaction, and sensory processing impairments. Efforts to understand its etiology and pathophysiology are crucial for improving treatment and prevention measures. Preclinical models of ASD are essential for investigating the biological mechanisms and should present translatability potential. We aim to evaluate the consistency of the most commonly used rodent models of ASD in displaying autistic-like behavior through a systematic review and meta-analysis. Methods This review will focus on the most frequently used autism models, surveying studies of six genetic (Ube3a, Pten, Nlgn3, Shank3, Mecp2, and Fmr1), three chemically induced (valproic acid (VPA), lipopolysaccharide (LPS), and polyinosinic:polycytidylic acid (poly(I:C))), and one inbred model (BTBR T+ Itpr3tf/J mouse strain). Two independent reviewers will screen the records. Data extraction of behavioral outcomes and risk of bias evaluation will be performed. We will conduct a meta-analysis whenever at least five studies investigate the same model and behavioral outcome. We will also explore the heterogeneity and publication bias. Network meta-analyses are planned to compare different models. Discussion By shortening the gap between animal behavior and human endophenotypes or specific clinical symptoms, we expect to help researchers on which rodent models are adequate for research of specific behavioral manifestations of autism, which potentially require a combination of them depending on the research interest. Systematic review registration PROSPERO CRD42021226299 .

Abstract Background Hashimoto’s thyroiditis (HT) is an autoimmune illness that renders individuals vulnerable to neuropsychopathology even in the euthyroid state, the mechanisms involved remain unclear. We hypothesized that activated microglia might disrupt synapses, resulting in cognitive disturbance in the context of euthyroid HT, and designed the present study to test this hypothesis. Methods Experimental HT model was induced by immunizing NOD mice with thyroglobulin and adjuvant twice. Morris Water Maze was measured to determine mice spatial learning and memory. The synaptic parameters such as the synaptic density, synaptic ultrastructure and synaptic-markers (SYN and PSD95) as well as the interactions of microglia with synapses were also determined. Results HT mice had poorer performance in Morris Water Maze than controls. Concurrently, HT resulted in a significant reduction in synapse density and ultrastructure damage, along with decreased synaptic puncta visualized by immunostaining with synaptophysin and PSD-95. In parallel, frontal activated microglia in euthyroid HT mice showed increased engulfment of PSD95 and EM revealed that the synaptic structures were visible within the microglia. These functional alterations in microglia corresponded to structural increases in their attachment to neuronal perikarya and a reduction in presynaptic terminals covering the neurons. Conclusion Our results provide initial evidence that HT can induce synaptic loss in the euthyroid state with deficits might be attributable to activated microglia, which may underlie the deleterious effects of HT on spatial learning and memory.

With the rising worldwide obesity rates, bariatric surgeries are increasing. Although the surgery offers an effective treatment option for weight loss, the procedure causes dramatic physiological and metabolic changes. Animal models in rodents provide a valuable tool for studying the systemic effects of the surgery. Since the surgery may significantly influence the pharmacokinetic properties of medications, animal studies should provide essential insight into mechanisms underlying changes in how the body handles the drug. This review summarizes research work in rodents regarding the impact of standard bariatric procedures on pharmacokinetics. A qualitative literature search was conducted via PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE. Studies that examined bariatric surgery’s effects on drug pharmacokinetics in rodent models were included. Clinical studies and studies not involving drug interventions were excluded. A total of 15 studies were identified and assessed in this review. These studies demonstrate the possible impact of bariatric surgery on drug absorption, distribution, metabolism, excretion, and potential mechanisms. Pharmacokinetic changes exhibited in the limited pre-clinical studies highlight a need for further investigation to fully understand the impact and mechanism of bariatric surgery on drug responses.

IntroductionAge-related macular degeneration (AMD) is the leading cause of blindness in the developed world, currently affecting over 350 billion people globally. For the most prevalent late-stage form of this disease, atrophic AMD, there are no available prevention strategies or treatments, in part due to inherent difficulties in early-stage diagnosis. Photo-oxidative damage is a well-established model for studying inflammatory and cell death features that occur in late-stage atrophic AMD, however to date has not been investigated as a potential model for studying early features of disease onset. Therefore, in this study we aimed to determine if short exposure to photo-oxidative damage could be used to induce early retinal molecular changes and advance this as a potential model for studying early-stage AMD.MethodsC57BL/6J mice were exposed to 1, 3, 6, 12, or 24h photo-oxidative damage (PD) using 100k lux bright white light. Mice were compared to dim-reared (DR) healthy controls as well as mice which had undergone long periods of photo-oxidative damage (3d and 5d-PD) as known timepoints for inducing late-stage retinal degeneration pathologies. Cell death and retinal inflammation were measured using immunohistochemistry and qRT-PCR. To identify retinal molecular changes, retinal lysates were sent for RNA sequencing, following which bioinformatics analyses including differential expression and pathway analyses were performed. Finally, to investigate modulations in gene regulation as a consequence of degeneration, microRNA (miRNA) expression patterns were quantified using qRT-PCR and visualized using in situ hybridization.ResultsShort exposure to photo-oxidative damage (1-24h-PD) induced early molecular changes in the retina, with progressive downregulation of homeostatic pathways including metabolism, transport and phototransduction observed across this time-course. Inflammatory pathway upregulation was observed from 3h-PD, preceding observable levels of microglia/macrophage activation which was noted from 6h-PD, as well as significant photoreceptor row loss from 24h-PD. Further rapid and dynamic movement of inflammatory regulator miRNA, miR-124-3p and miR-155-5p, was visualized in the retina in response to degeneration.ConclusionThese results support the use of short exposure to photo-oxidative damage as a model of early AMD and suggest that early inflammatory changes in the retina may contribute to pathological features of AMD progression including immune cell activation and photoreceptor cell death. We suggest that early intervention of these inflammatory pathways by targeting miRNA such as miR-124-3p and miR-155-5p or their target genes may prevent progression into late-stage pathology.

Spinal cord injury (SCI) often has devastating consequences for the patient's physical, mental and occupational health. At present, there is no effective treatment for SCI, and appropriate animal models are very important for studying the pathological manifestations, injury mechanisms, and corresponding treatment. However, the pathological changes in each injury model are different, which creates difficulties in selecting appropriate models for different research purposes. In this article, we analyze various SCI models and introduce their pathological features, including inflammation, glial scar formation, axon regeneration, ischemia–reperfusion injury, and oxidative stress, and evaluate the advantages and disadvantages of each model, which is convenient for selecting suitable models for different injury mechanisms to study therapeutic methods. [ABSTRACT FROM AUTHOR]

Although bariatric surgery is known to change the metabolome, it is unclear if this is specific for the intervention or a consequence of the induced bodyweight loss. As the weight loss after Roux-en-Y Gastric Bypass (RYGB) can hardly be mimicked with an evenly effective diet in humans, translational research efforts might be helpful. A group of 188 plasma metabolites of 46 patients from the randomized controlled Würzburg Adipositas Study (WAS) and from RYGB-treated rats (n = 6) as well as body-weight-matched controls (n = 7) were measured using liquid chromatography tandem mass spectrometry. WAS participants were randomized into intensive lifestyle modification (LS, n = 24) or RYGB (OP, n = 22). In patients in the WAS cohort, only bariatric surgery achieved a sustained weight loss (BMI −34.3% (OP) vs. −1.2% (LS), p ≤ 0.01). An explicit shift in the metabolomic profile was found in 57 metabolites in the human cohort and in 62 metabolites in the rodent model. Significantly higher levels of sphingolipids and lecithins were detected in both surgical groups but not in the conservatively treated human and animal groups. RYGB leads to a characteristic metabolomic profile, which differs distinctly from that following non-surgical intervention. Analysis of the human and rat data revealed that RYGB induces specific changes in the metabolome independent of weight loss. [ABSTRACT FROM AUTHOR]

Aldosterone, an effector molecule of the renin–angiotensin–aldosterone system (RAAS), has been receiving more attention in the field of ophthalmology because of its possible role in the pathogenesis of various eye diseases or abnormalities; it may even become a target for their treatment. Primary aldosteronism, a typical model of a systemic aldosterone excess, may cause vision loss due to various ocular diseases, such as retinal vein occlusion, central serous chorioretinopathy, and, possibly glaucoma. RAAS components are present in various parts and types of cells present in the eye. Investigations of the local RAAS in various animal models of diabetic macular edema, retinal vein occlusion, retinopathy of prematurity, central serous chorioretinopathy, and glaucoma have found evidence that aldosterone or mineralocorticoid receptors may exacerbate the pathology of these disorders. Further studies are needed to elucidate whether the modulation of aldosterone or mineralocorticoid receptors is an effective treatment for preventing vision loss in patients with eye diseases. [ABSTRACT FROM AUTHOR]

The Cohen Diabetic rat is a model of type 2 diabetes mellitus that consists of the susceptible (CDs/y) and resistant (CDr/y) strains. Diabetes develops in CDs/y provided diabetogenic diet (DD) but not when fed regular diet (RD) nor in CDr/y given either diet. We recently identified in CDs/y a deletion in Sdf2l1, a gene that has been attributed a role in the unfolded protein response (UPR) and in the prevention of endoplasmic reticulum (ER) stress. We hypothesized that this deletion prevents expression of SDF2L1 and contributes to the pathophysiology of diabetes in CDs/y by impairing UPR, enhancing ER stress, and preventing CDs/y from secreting sufficient insulin upon demand. We studied SDF2L1 expression in CDs/y and CDr/y. We evaluated UPR by examining expression of key proteins involved in both strains fed either RD or DD. We assessed the ability of all groups of animals to secrete insulin during an oral glucose tolerance test (OGTT) over 4 weeks, and after overnight feeding (postprandial) over 4 months. We found that SDF2L1 was expressed in CDr/y but not in CDs/y. The pattern of expression of proteins involved in UPR, namely the PERK (EIF2α, ATF4 and CHOP) and IRE1 (XBP-1) pathways, was different in CDs/y DD from all other groups, with consistently lower levels of expression at 4 weeks after initiation of DD and coinciding with the development of diabetes. In CDs/y RD, insulin secretion was mildly impaired, whereas in CDs/y DD, the ability to secrete insulin decreased over time, leading to the development of the diabetic phenotype. We conclude that in CDs/y DD, UPR participating proteins were dysregulated and under-expressed at the time point when the diabetic phenotype became overt. In parallel, insulin secretion in CDs/y DD became markedly impaired. Our findings suggest that under conditions of metabolic load with DD and increased demand for insulin secretion, the lack of SDF2L1 expression in CDs/y is associated with UPR dysregulation and ER stress which, combined with oxidative stress previously attributed to the concurrent Ndufa4 mutation, are highly likely to contribute to the pathophysiology of diabetes in this model. [ABSTRACT FROM AUTHOR]

Infection associated with biomedical implants remains the main cause of failure, leading to reoperation after orthopedic surgery. Orthopedic infections are characterized by microbial biofilm formation on the implant surface, which makes it challenging to diagnose and treat. One potential method to prevent and treat such complications is to deliver a sufficient dose of antibiotics at the onset of infection. This strategy can be realized by coating the implant with thermoregulatory polymers and triggering the release of antibiotics during the acute phase of infection. We developed a multi-layered temperature-responsive polymer brush (MLTRPB) coating that can release antibiotics once the temperature reaches a lower critical solution temperature (LCST). The coating system was developed using copolymers composed of diethylene glycol methyl ether methacrylate and 2-hydroxyethyl methacrylate by alternatively fabricating monomers layer by layer on the titanium surface. LCST was set to the temperature of 38–40 °C, a local temperature that can be reached during infection. The antibiotic elution characteristics were investigated, and the antimicrobial efficacy was tested against S. aureus species (Xen29 ATCC 29 213) using one to four layers of MLTRPB. Both in vitro and in vivo assessments demonstrated preventive effects when more than four layers of the coating were applied, ensuring promising antibacterial effects of the MLTRPB coating. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) and its drainage are crucial in clearing metabolic waste and maintaining the microenvironment of the central nervous system for proper functioning. Normal-pressure hydrocephalus (NPH) is a serious neurological disorder of the elderly with obstruction of CSF flow outside the cerebral ventricles, causing ventriculomegaly. The stasis of CSF in NPH compromises brain functioning. Although treatable, often with shunt implantation for drainage, the outcome depends highly on early diagnosis, which, however, is challenging. The initial symptoms of NPH are hard to be aware of and the complete symptoms overlap with those of other neurological diseases. Ventriculomegaly is not specific to NPH as well. The lack of knowledge on the initial stages in its development and throughout its progression further deters early diagnosis. Thus, we are in dire need for an appropriate animal model for researches into a more thorough understanding of its development and pathophysiology so that we can enhance the diagnosis and therapeutic strategies to improve the prognosis of NPH following treatment. With this, we review the few currently available experimental rodent NPH models for these animals are smaller in sizes, easier in maintenance, and having a rapid life cycle. Among these, a parietal convexity subarachnoid space kaolin injection adult rat model appears promising as it shows a slow onset of ventriculomegaly in association with cognitive and motor disabilities resembling the elderly NPH in humans. [ABSTRACT FROM AUTHOR]

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism with poor clinical outcomes. Therapeutic approaches to prevention of fibrotic remodeling of the pulmonary vascular bed in CTEPH are limited. In this work, we tested the hypothesis that Janus kinase 1/2 (JAK1/2) inhibition with ruxolitinib might prevent and attenuate CTEPH in a rat model. CTEPH was induced by repeated embolization of the pulmonary artery with partially biodegradable 180 ± 30 μm alginate microspheres. Two weeks after the last injection of microspheres, ruxolitinib was administered orally at doses of 0.86, 2.58, and 4.28 mg/kg per day for 4 weeks. Prednisolone (1.475 mg/kg, i.m.) was used as a reference drug. Ruxolitinib in all doses as well as prednisolone reduced pulmonary vascular wall hypertrophy. Ruxolitinib at a dose of 2.58 mg/kg and prednisolone reduced vascular wall fibrosis. Prednisolone treatment resulted in decreased right ventricular systolic pressure. Pulmonary vascular resistance was lower in the prednisolone and ruxolitinib (4.28 mg/kg) groups in comparison with the placebo group. The plasma level of brain natriuretic peptide was lower in groups receiving ruxolitinib at doses of 2.58 and 4.28 mg/kg versus placebo. This study demonstrated that JAK1/2 inhibitor ruxolitinib dose-dependently reduced pulmonary vascular remodeling, thereby preventing CTEPH formation in rats. [ABSTRACT FROM AUTHOR]