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This study aimed to evaluate the correlation between BMAT and bone quality, describe the long-term effects of ovariectomy on bone, and investigate BMAT's spatial distribution. Fifteen-months-old female Sprague‒Dawley rats were studied, comparing ovariectomized (OVX, n = 22) and sham-operated (SHAM, n = 11) groups at 6 months. Tibias were analyzed for bone microarchitecture, BMAT (microcomputed tomography), mineral parameters (quantitative backscattered electron imaging), and bone composition (Raman microspectroscopy). The OVX tibias showed severe trabecular bone loss (lower bone volume/total volume, p < 0.001) with increased BMAT (higher adipose volume per marrow volume, p < 0.001), decreased mineral content (lower calcium concentration, p < 0.001), and altered organic components (lower mineral/matrix ratio in new bone, p = 0.03 trabecular surface, p < 0.001 trabecular core). When the data are pooled over both groups (SHAM and OVX), the adipose volume/marrow volume ratio was negatively correlated with bone volume/total volume (r = − 0.79, p < 0.001) and mineral/matrix ratio (r = − 0.37, p = 0.04 trabecular surface; r = − 0.65, p < 0.001 trabecular core) and positively correlated with crystallinity (r = 0.55, p = 0.001 trabecular surface; r = 0.49, p = 0.006 trabecular core). The mineral/matrix ratio of trabecular surface new bone was strongly negatively correlated with the adipose compartment nearest to the bone surface. These findings suggest mechanisms underlying BMAT's role in bone resorption. [ABSTRACT FROM AUTHOR]

Background: Beyond the signature amyloid-beta plaques and neurofibrillary tangles, Alzheimer’s disease (AD) has been shown to exhibit dysregulated metabolic signaling through insulin and insulin-like growth factor (IGF) networks that crosstalk with the mechanistic target of rapamycin (mTOR). Its broad impact on brain structure and function suggests that mTOR is likely an important therapeutic target for AD. Objective: This study characterizes temporal lobe (TL) mTOR signaling abnormalities in a rat model of sporadic AD neurodegeneration. Methods: Long Evans rats were given intracerebroventricular injections of streptozotocin (ic-STZ) or saline (control), and 4 weeks later, they were administered neurobehavioral tests followed by terminal harvesting of the TLs for histopathological study and measurement of AD biomarkers, neuroinflammatory/oxidative stress markers, and total and phosphorylated insulin/IGF-1-Akt-mTOR pathway signaling molecules. Results: Rats treated with ic-STZ exhibited significantly impaired performance on Rotarod (RR) and Morris Water Maze (MWM) tests, brain atrophy, TL and hippocampal neuronal and white matter degeneration, and elevated TL pTau, AβPP, Aβ, AChE, 4-HNE, and GAPDH and reduced ubiquitin, IL-2, IL-6, and IFN-γ immunoreactivities. In addition, ic-STZ reduced TL pY1135/1136-IGF-1R, Akt, PTEN, pS380-PTEN, pS2448-mTOR, p70S6K, pT412-p70S6K, p/T-pT412-p70S6K, p/T-Rictor, and p/T-Raptor. Conclusion: Experimental ic-STZ-induced sporadic AD-type neurodegeneration with neurobehavioral dysfunctions associated with inhibition of mTOR signaling networks linked to energy metabolism, plasticity, and white matter integrity. [ABSTRACT FROM AUTHOR]

Exposure to pesticide residues during the first 1000 days of life can disrupt body homeostasis and contribute to chronic metabolic diseases. Perinatal chlorpyrifos (CPF) exposure alters gut microbiota (GM) balance, potentially affecting offspring's health. Given the GM influence on brain function, the primary aim is to determine if pesticide-induced dysbiosis (microbial imbalance) affects indirectly other organs, such as the blood–brain barrier (BBB). The secondary objective is to evaluate the prebiotics protective effects, particularly inulin in promoting microbial balance (symbiosis), in both mothers and offspring. A total of 15 or more female rats were divided in 4 groups: control, oral CPF-exposed (1 mg/kg/day), exposed to inulin (10 g/L), and co-exposed to CPF and inulin from pre-gestation until weaning of pups. Samples from intestines, spleen, liver, and brain microvessels underwent microbiological and biomolecular analyses. Bacterial culture assessed GM composition of living bacteria and their translocation to non-intestinal organs. RT qPCR and Western blotting detected gene expression and protein levels of tight junction markers in brain microvessels. CPF exposure caused gut dysbiosis in offspring, with decreased Lactobacillus and Bifidobacterium and increased Escherichia coli (p < 0.01) leading to bacterial translocation to the spleen and liver. CPF also decreased tight junction's gene expression levels (50 to 60% decrease of CLDN3, p < 0.05). In contrast, inulin partially mitigated these adverse effects and restored gene expression to control levels. Our findings demonstrate a causal link between GM alterations and BBB integrity disruptions. The protective effects of inulin suggest potential therapeutic strategies to counteract pesticide-induced dysbiosis. [ABSTRACT FROM AUTHOR]

Background/Objectives: One of the hallmarks of Alzheimer's disease (AD) is the accumulation of aggregated beta-amyloid (Aβ) protein in the form of senile plaques within brain tissue. Senile plaques contain various post-translational modifications of Aβ, including prevalent isomerization of Asp7 residue. The Asp7 isomer has been shown to exhibit increased neurotoxicity and induce amyloidogenesis in brain tissue of transgenic mice. The toxicity of Aβ peptides may be partly mediated by their structure and morphology. In this respect, in this study we analyzed the structural and aggregation characteristics of the Asp7 isoform of Aβ42 and compared them to those of synthetic Aβ42. We also investigated the effects of intracerebroventricular (i.c.v.) administration of these peptides, a method often used to induce AD-like symptoms in rodent models. Methods: Atomic force microscopy (AFM) was conducted to compare the morphological and aggregation properties of Aβ42 and Asp7 iso-Aβ42. The effects of i.c.v. stereotaxic administration of the proteins were assessed via behavioral analysis and reactive oxygen species (ROS) estimation in vivo using a scanning ion-conductance microscope with a confocal module. Results: AFM measurements revealed structural differences between the two peptides, most notably in their soluble toxic oligomeric forms. The i.c.v. administration of Asp7 iso-Aβ42 induced spatial memory deficits in rats and elevated oxidative stress levels in vivo, suggesting a potential of ROS in the pathogenic mechanism of the peptide. Conclusions: The findings support the further investigation of Asp7 iso-Aβ42 in translational research on AD and suggest its involvement in neurodegenerative processes. [ABSTRACT FROM AUTHOR]

Under inflammatory conditions, macrophage dominance affects the degree of inflammation. We assessed the effects of the active vitamin D (calcitriol) administration on inflammatory processes and macrophage dominance and aimed to determine the potential positive macroscopic and histological effects in supermicrosurgical arterial anastomosis model of rats. Forty rats were divided into five groups: control surgery (Group 1), surgery with preoperative (Group 2), post-operative (Group 3), perioperative (Group 4) systemic calcitriol and surgery with local calcitriol (Group 5). Eighty femoral artery anastomoses were planned in both legs of rats. Systemic calcitriol was administered intraperitoneally daily to the animals in the relevant groups. Preoperative vessel diameter measurements were taken before anastomosis. Three weeks post-surgery, post-operative vessel diameter measurements were taken, anastomosis patency was assessed and vascular segments were collected for histological examination, which included assessment of M1 and M2 macrophage depolarisation, leucocyte infiltration, intima–media ratio and luminal gap scoring. Systemic calcitriol administration (pre-, post- or perioperative) significantly improved the vessel diameter (p < 0.001); there was no significant difference among Groups 2–4. Histological findings revealed that Groups 3 and 4 had lower intima–media ratios (p < 0.05 and p < 0.01), higher M2-M1 macrophage ratios (p < 0.01 and p < 0.001) and lower leucocyte infiltration (p < 0.05, p < 0.01 and p < 0.001). Local calcitriol administration had no vasodilatory effects or resulted in positive histological outcomes. Although the administration of calcitriol pre- and post-operatively increased the vessel diameter, the latter appeared to have a more favourable impact on the histological analyses. [ABSTRACT FROM AUTHOR]

Background: The uncultured adipose-derived stromal vascular fraction (SVF), consisting of adipose-derived stromal cells (ADSCs), M2 macrophages (M2Φ) and others, has shown therapeutic potential against osteoarthritis (OA), however, the mechanisms underlying its therapeutic effects remain unclear. Therefore, this study investigated the effects of the SVF on OA in a human-immunodeficient rat xenotransplantation model. Methods: OA model was induced in the knees of female immunodeficient rats by destabilization of the medial meniscus. Immediately after the surgery, human SVF (1 × 105), ADSCs (1 × 104), or phosphate buffered saline as a control group were transplanted into the knees. At 4 and 8 weeks postoperatively, OA progression and synovitis were analyzed by macroscopic and histological analyses, and the expression of collagen II, SOX9, MMP-13, ADAMTS-5, F4/80, CD86 (M1), CD163 (M2), and human nuclear antigen (hNA) were evaluated immunohistochemically. In vitro, flow cytometry was performed to collect CD163-positive cells as M2Φ from the SVF. Chondrocyte pellets (1 × 105) were co-cultured with SVF (1 × 105), M2Φ (1 × 104), and ADSCs (1 × 104) or alone as a control group, and the pellet size was compared. TGF-β, IL-10 and MMP-13 concentrations in the medium were evaluated using enzyme-linked immunosorbent assay. Results: In comparison with the control and ADSC groups, the SVF group showed significantly slower OA progression and less synovitis with higher expression of collagen II and SOX9, lower expression of MMP-13 and ADAMTS-5, and lower F4/80 and M1/M2 ratio in the synovium. Only the SVF group showed partial expression of hNA-, CD163-, and F4/80-positive cells in the rat synovium. In vitro, the SVF, M2Φ, ADSC and control groups, in that order, showed larger pellet sizes, higher TGF-β and IL-10, and lower MMP-13 concentrations. Conclusions: The M2Φ in the transplanted SVF directly affected recipient tissue, enhancing the secretion of growth factors and chondrocyte-protecting cytokines, and partially improving chondrocytes and joint homeostasis. These findings indicate that the SVF is as an effective option for regenerative therapy for OA, with mechanisms different from those of ADSCs. [ABSTRACT FROM AUTHOR]

Ex situ lung perfusion (ESLP) is used for organ reconditioning, repair, and re-evaluation prior to transplantation. Since valid preclinical animal models are required for translationally relevant studies, we developed a 17 mL low-volume ESLP for double- and single-lung application that enables cost-effective optimal compliance “reduction” of the 3R principles of animal research. In single-lung mode, ten Fischer344 and Lewis rat lungs were subjected to ESLP and static cold storage using STEEN or PerfadexPlus. Key perfusion parameters, thermal lung imaging, blood gas analysis (BGA), colloid oncotic pressure (COP), lung weight gain, histological work-up, and cytokine analysis were performed. Significant differences between perfusion solutions but not between the rat strains were detected. Most relevant perfusion parameters confirmed valid ESLP with homogeneous lung perfusion, evidenced by uniform lung surface temperature. BGA showed temperature-dependent metabolic activities with differences depending on perfusion solution composition. COP is not decisive for pulmonary oedema and associated weight gain, but possibly rather observed chemokine profile and dextran sensitivity of rats. Histological examination confirmed intact lung architecture without infarcts or hemorrhages due to optimal organ procurement and single-lung application protocol using our in-house-designed ESLP system. [ABSTRACT FROM AUTHOR]

Spinal cord ischemic-reperfusion injury (SCIRI) could occurs during surgical procedures without detection, presenting a complex course and an unfavorable prognosis. This may lead to postoperative sensory or motor dysfunction in areas innervated by the spinal cord, and in some cases, permanent paralysis. Timely detection of SCIRI and immediate waring can help surgeons implement remedial intervention to prevent irreversible spinal cord injury. Therefore, it is crucial to develop a precise and effective method for early detection of SCIRI. This study utilized rat models to simulate intraoperative SCIRI and employed somatosensory evoked potentials (SEP) for continuous monitoring during surgery. In this study, SEP signal changes were examined in six groups with varying severities of SCIRI and one normal control group. SEP signal changes were examined during operations in different groups and correlated with postoperative behavioral and histopathological data. The result demonstrated specific changes in SEP signals during SCIRI, termed as time-varying characteristics, which are associated with the duration of ischemia and subsequent reperfusion. Timevarying characteristics in SEP could potentially serve as a new biomarker for the intraoperative detection of SCIRI. This finding is significant for clinical surgeons to identify and guide early intervention of SCIRI timely. Additionally, this measurement is easily translatable to clinical application. [ABSTRACT FROM AUTHOR]

Introduction: Tongue weakness and atrophy can lead to deficits in the vital functions of breathing and swallowing in patients with motor neuron diseases (MNDs; e.g., amyotrophic lateral sclerosis (ALS) and pseudobulbar palsy), often resulting in aspiration pneumonia, respiratory failure, and death. Available treatments for patients with MNDs are largely palliative; thus, there is a critical need for therapies targeting preservation of upper airway function and suggesting a role for tongue exercise in patients with MNDs. Here, we leveraged our inducible rodent model of hypoglossal (XII) motor neuron degeneration to investigate the effects of a strength endurance tongue exercise program on upper airway structure and function. Our model was created through intralingual injection of cholera toxin B conjugated to saporin (CTB-SAP) into the genioglossus muscle of the tongue to induce targeted death of XII motor neurons. Methods: Rats in this study were allocated to 4 experimental groups that received intralingual injection of either CTB-SAP or unconjugated CTB + SAP (i.e., control) +/- tongue exercise. Following tongue exercise exposure, we evaluated the effect on respiratory function (via plethysmography), macrostructure [via magnetic resonance imaging (MRI) of the upper airway and tongue], and ultrafine structure [via ex vivo magnetic resonance spectroscopy (MRS) of the tongue] with a focus on lipid profiles. Results: Results showed that sham exercise-treated CTB-SAP rats have evidence of upper airway restriction (i.e., reduced airflow) and structural changes present in the upper airway (i.e., airway compression) when compared to CTB-SAP + exercise rats and control rats +/- tongue exercise, which was ameliorated with tongue exercise. Additionally, CTB-SAP + sham exercise rats have evidence of increased lipid expression in the tongue consistent with previously observed tongue hypertrophy when compared to CTB-SAP + exercise rats or control rats +/- tongue exercise. Conclusion: These findings provide further evidence that a strength endurance tongue exercise program may be a viable therapeutic treatment option in patients with XII motor neuron degeneration in MNDs such as ALS. Future directions will focus on investigating the underlying mechanism responsible for tongue exercise-induced plasticity in the hypoglossal-tongue axis, particularly inflammatory associated factors such as BDNF. [ABSTRACT FROM AUTHOR]

Purpose: Gait disturbances are common in human low back pain (LBP) patients, suggesting potential applicability to rodent LBP models. This study aims to assess the influence of disc-associated LBP on gait in female Sprague Dawley rats and explore the utility of the open-source Gait Analysis Instrumentation and Technology Optimized for Rodents (GAITOR) suite as a potential alternative tool for spontaneous pain assessment in a previously established LBP model. Materials and Methods: Disc degeneration was surgically induced using a one-level disc scrape injury method, and microcomputed tomography was used to assess disc volume loss. After disc injury, axial hypersensitivity was evaluated using the grip strength assay, and an open field test was used to detect spontaneous pain-like behavior. Results: Results demonstrated that injured animals exhibit a significant loss in disc volume and reduced grip strength. Open field test did not detect significant differences in distance traveled between sham and injured animals. Concurrently, animals with injured discs did not display significant gait abnormalities in stance time imbalance, temporal symmetry, spatial symmetry, step width, stride length, and duty factor compared to sham. However, comparisons with reference values of normal gait reported in prior literature reveal that injured animals exhibit mild deviations in forelimb and hindlimb stance time imbalance, forelimb temporal symmetry, and hindlimb spatial symmetry at some time points. Conclusions: This study concludes that the disc injury may have very mild effects on gait in female rats within 9 weeks post-injury and recommends future in depth dynamic gait analysis and longer studies beyond 9 weeks to potentially detect gait. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension is a group of diseases characterized by elevated pulmonary artery pressure and pulmonary vascular resistance with significant morbidity and mortality. The most prevalent type is pulmonary hypertension secondary to left heart disease (PH-LHD). The available experimental models of PH-LHD use partial pulmonary clamping by technically nontrivial open-chest surgery with lengthy recovery. We present a simple model in which the reduction of the cross-sectional area of the ascending aorta is achieved not by external clamping but by partial intravascular obstruction without opening the chest. In anesthetized rats, a blind polyethylene tubing was advanced from the right carotid artery to just above the aortic valve. The procedure is quick and easy to learn. Three weeks after the procedure, left heart pressure overload was confirmed by measuring left ventricular end-diastolic pressure by puncture (1.3 ± 0.2 vs. 0.4 ± 0.3 mmHg in controls, mean ± SD, P < 0.0001). The presence of pulmonary hypertension was documented by measuring pulmonary artery pressure by catheterization (22.3 ± 2.3 vs. 16.9 ± 2.7 mmHg, P = 0.0282) and by detecting right ventricular hypertrophy and increased muscularization of peripheral pulmonary vessels. Contributions of a precapillary vascular segment and vasoconstriction to the increased pulmonary vascular resistance were demonstrated, respectively, by arterial occlusion technique and by normalization of resistance by a vasodilator, sodium nitroprusside, in isolated lungs. These changes were comparable, but not additive, to those induced by an established pulmonary hypertension model, chronic hypoxic exposure. Intravascular partial aortic obstruction offers an easy model of pulmonary hypertension induced by left heart disease that has a vasoconstrictor and precapillary component. NEW & NOTEWORTHY: We present a new, simple model of a clinically important type of pulmonary hypertension, that induced by left heart failure. Left ventricular pressure overload is induced in rats by inserting a blinded cannula into the ascending aorta via carotid artery access. This partial intravascular aortic obstruction, which does not require opening of the chest and prolonged recovery, causes pulmonary hypertension, which has a precapillary and vasoconstrictor as well as a vascular remodeling component. [ABSTRACT FROM AUTHOR]

Chronic subdural hematoma (cSDH), a condition that develops over time, is characterized by inflammation, angiogenesis, and membrane development. As the population's average age increases, the incidence of cSDH is expected to grow. While surgery is the primary treatment technique, medicinal therapy options are being explored for high-risk patients. Currently, the most effective therapy combination is dexamethasone (Dex) and atorvastatin (Ato); however, it is associated with an increased risk of mortality. This study explored the effects of bevacizumab (Bev), a vascular endothelial growth factor antagonist, on cSDH. Ninety-five rats were divided into four groups (n = 18): sham, control hematoma, Dex-Ato, and Bev. Two separate autologous blood injections into the subdural space were used as the model. Weight was monitored for all rats to assess changes in their overall health. The control group was given i.p. saline, the Dex-Ato treatment was given by gavage, and the Bev treatment was given i.p. On seventh, 14th and 21st days six rats from each group were sacrificed and analyzed, while 23 rats were excluded from the experiment. The maximum immunological response to cSDH was observed on day 14. Hematoma volume decreased over time in all groups. Dex-Ato and Bev were both found effective, while Dex-Ato caused weight loss. Bev had similar effects to the Dex-Ato group and was well tolerated by rats. Given that cSDH is a disease of the elderly and vulnerable populations, Bev may be a viable alternative that can shed light on the disease's etiology for future research. [ABSTRACT FROM AUTHOR]

The study aimed to examine matrix metalloproteinase‐2 (MMP‐2) expression in a rat ligamentum flavum (LF) hypertrophy model in vivo, and the effect of elastin‐derived peptides (EDPs) on MMP‐2 and tissue inhibitors of metalloproteinases (TIMPs) in rat LF cells in vitro. Surgical destabilization was performed at the rat spinal L3/4 level to induce increased mechanical stress. Rats were killed at 6‐ and 12‐weeks postsurgery for histological staining, immunohistochemical staining, RT‐qPCR and western blot. 100 µg/mL EDPs were applied to isolated normal rat LF cells, with or without pretreatment of elastin receptor complex (ERC) inhibitors, to assess the expression of MMP‐2, TIMP‐1, and TIMP‐2. Spinal destabilization led to LF hypertrophy, observed through increased LF thickness and area, along with histological changes of chondrometaplasia and elastic fiber degradation. LF was also stained positively for Col I and Col II, where elastic fiber has broken down. MMP‐2 expression was notably elevated in the hypertrophied LF, accompanied by increased TIMP‐2 and TIMP‐3 levels. EDPs were found to suppress MMP‐2 expression and reduce TIMP‐1 and TIMP‐2 levels in rat LF cells. Interestingly, exposure to EDPs led to a significant rise in MMP‐2/TIMP‐1 and MMP‐2/TIMP‐2 ratios, dependent on the ERC. Collectively, the study suggests that increased MMP‐2 activity contributes to elastic fiber degradation in hypertrophied LF, generating EDPs that further enhance the MMP‐2/TIMPs ratio in LF cells in an ERC‐dependent manner. Further research is essential to delve into the mechanisms of EDPs in LF hypertrophy. [ABSTRACT FROM AUTHOR]

Purpose: Coronary microembolization (CME) can result in cardiac dysfunction, severe arrhythmias, and a reduced coronary flow reserve. Impairment of mitochondrial energy metabolism has been implicated in the progression and pathogenesis of CME; however, its role remains largely undetermined. This study aimed to explore alterations in mitochondria-related genes in CME. Methods: A rat model of CME was successfully established by injecting plastic microspheres into the left ventricle. The cardiac tissues of the two groups were sequenced and mitochondrial functions were assessed. Results: Using RNA-Seq, together with GO and KEGG enrichment analyses, we identified 3822 differentially expressed genes (DEGs) in CME rats compared to control rats, and 101 DEGs were mitochondria-related genes. Notably, 36 DEGs were up-regulated and 65 DEGs were down-regulated (CME vs control). In particular, the oxidative phosphorylation (OXPHOS) and mitochondrial electron transport were obviously down-regulated in the CME group. Functional analysis revealed that CME mice exhibited marked reductions in ATP and mitochondrial membrane potential (MMP), by contrast, the production of reactive oxygen species (ROS) was much higher in CME mice than in controls. Protein–protein interaction (PPI) and quantitative PCR (qPCR) validation suggested that eight hub genes including Cmpk2, Isg15, Acsl1, Etfb, Ndufa8, Adhfe1, Gabarapl1 and Acot13 were down-regulated in CME, whereas Aldh18a1 and Hspa5 were up-regulated. Conclusion: Our findings suggest that dysfunctions in mitochondrial activity and metabolism are important mechanisms for CME, and mitochondria-related DEGs may be potential therapeutic targets for CME. [ABSTRACT FROM AUTHOR]

Rheumatic heart disease (RHD) is responsible for nearly 250,000 deaths annually and poses a significant health threat in developing areas. The unclear pathogenesis of RHD makes the development of cost-effective treatments challenging, particularly as current surgical options are expensive and technologically demanding, exacerbating the economic and quality-of-life burdens for patients. Given the risks associated with direct human experimentation due to the uncertain pathogenesis, using a rat model infected with Group A Streptococcus (GAS) has become a crucial experimental strategy for RHD research. The development of an RHD rat model, refined over 23 years, now stands as a pivotal approach in studies aiming to understand the disease’s pathogenesis. This review summarizes the evolution, characteristics, advantages, and limitations of the RHD rat model, offering insights into potential areas for improvement. It aims to provide researchers with a comprehensive understanding of the model, supporting the advancement of research methodologies and the discovery of innovative treatments for RHD. [ABSTRACT FROM AUTHOR]

Background & Objective: The endometriosis treatment was critical due to complications associated with current drug delivery system. The present study was conducted with aim to compare the curative effect of Vitamin D3 (VTD3) and Omega-3 (OG3) with Diphereline during the treatment of endometriosis. Materials & Methods: In this study, endometriosis was induced in different groups containing 60 adult female rats. The rat model was categorized into 6 groups untreated and treated (Olive Oil (solvent), VTD3 (42 mcg/kg/day), OG3 (450 mg/kg/day), VTD3+OG3, Diphereline (3 mg/kg/day)). The suspension containing combination of Diphereline and supplements was injected and treated for 4 weeks to analyze the effect of supplements. The interleukin -6 (IL-6) and Tumor necrosis factor - alpha (TNFa) inflammatory responses were measured from the serum samples while endometrial implants was dissected and histopathological investigation was done. Results: At the end of four weeks, pathologic score decreased significantly with simultaneous measurement of inflammation score of endometriotic lesion, size of implant area, IL-6, TNFa response and compared with untreated female rat. No significant different was observed in groups undergoing treatment of VTD3, OG3 and Diphereline. The combined effect of VTD3+OG3 has similar responses with Diphereline treated endometrial implants. Conclusion: treatment of VTD3 deficiency and making a change in dietary habits of high-risk population for endometriosis from adolescence may also play a preventative role in adulthood. [ABSTRACT FROM AUTHOR]

Glaucoma is the second leading cause of blindness worldwide and is, in most cases, a consequence of elevated intraocular pressure (IOP), ultimately resulting in the death of retinal ganglion cells (RGCs). Current treatments are mostly focused on normalizing IOP, but we propose the additional use of neuroprotective agents, including methylene blue (MB), to block the loss of RGCs. Wistar rats were subjected to episcleral vein cauterization (EVC) in the left eye while the right eye was sham-operated. One week later, they were divided into two groups, which were injected with either 2.0 mg/kg MB or phosphate-buffered saline (PBS), twice a day, for 7 days. Fifteen days after surgery, rats were tested with scotopic electroretinography (ERG) or pattern electroretinography (PERG). After sacrifice, the number of RGCs and the thickness of the inner retina (IR) were evaluated both in the peripheral and central areas of the retina. Scotopic ERG showed a marked reduction (p < 0.0001) on the a- and b-wave amplitude and oscillatory potential (OP) complexity of the eyes subjected to EVC. These parameters were significantly (p < 0.01) restored by the application of MB. PERG indicated that EVC was responsible for a very significant decrease in N2 amplitude (p < 0.0001) and prolongation of N2 implicit time (p < 0.0001). Treatment with MB significantly restored N2 amplitude (p < 0.0001). In parallel with the ERG results, morphological analysis showed a significant loss of RGCs (p < 0.0001) and IR thickness (p < 0.0001) in both the peripheral and central retinas subjected to EVC, which was significantly prevented (p < 0.0001) by MB treatment. We have shown that MB treatment can be effective in preventing physiological and morphological hallmarks of optic neuropathy in a model of ocular hypertension, which faithfully recapitulates human open-angle glaucoma. Due to its high safety profile, this drug could therefore represent a new pharmacologic strategy to prevent vision loss in glaucoma patients. [ABSTRACT FROM AUTHOR]

Aims: The optimum type of antibiotics and their administration route for treating Gram-negative (GN) periprosthetic joint infection (PJI) remain controversial. This study aimed to determine the GN bacterial species and antibacterial resistance rates related to clinical GN-PJI, and to determine the efficacy and safety of intra-articular (IA) antibiotic injection after one-stage revision in a GN pathogen-induced PJI rat model of total knee arthroplasty. Methods: A total of 36 consecutive PJI patients who had been infected with GN bacteria between February 2015 and December 2021 were retrospectively recruited in order to analyze the GN bacterial species involvement and antibacterial resistance rates. Antibiotic susceptibility assays of the GN bacterial species were performed to screen for the most sensitive antibiotic, which was then used to treat the most common GN pathogen-induced PJI rat model. The rats were randomized either to a PJI control group or to three meropenem groups (intraperitoneal (IP), IA, and IP + IA groups). After two weeks of treatment, infection control level, the side effects, and the volume of antibiotic use were evaluated. Results: Escherichia coli was the most common pathogen in GN-PJI, and meropenem was the most sensitive antibiotic. Serum inflammatory markers, weightbearing activity, and Rissing score were significantly improved by meropenem, especially in the IA and IP + IA groups ( p < 0.05). Meropenem in the IA group eradicated E. coli from soft-tissue, bone, and prosthetic surfaces, with the same effect as in the IP + IA group. Radiological results revealed that IA and IP + IA meropenem were effective at relieving bone damage. Haematoxylin and eosin staining also showed that IA and IP + IA meropenem improved synovial inflammation and bone destruction. No pathological changes in the main organs or abnormal serum markers were observed in any of the meropenem-treated rats. The IA group required the lowest amount of meropenem, followed by the IP and IP + IA groups. Conclusion: IA-only meropenem with a two-week treatment course was effective and safe for PJI control following one-stage revision in a rat model, with less meropenem use. Cite this article: Bone Joint Res 2024;13(10):546–558.

Preclinical MRI studies have been utilized for the discovery of biomarkers that predict post-traumatic epilepsy (PTE). However, these single site studies often lack statistical power due to limited and homogeneous datasets. Therefore, multisite studies, such as the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx), are developed to create large, heterogeneous datasets that can lead to more statistically significant results. EpiBioS4Rx collects preclinical data internationally across sites, including the United States, Finland, and Australia. However, in doing so, there are robust normalization and harmonization processes that are required to obtain statistically significant and generalizable results. This work describes the tools and procedures used to harmonize multisite, multimodal preclinical imaging data acquired by EpiBioS4Rx. There were four main harmonization processes that were utilized, including file format harmonization, naming convention harmonization, image coordinate system harmonization, and diffusion tensor imaging (DTI) metrics harmonization. By using Python tools and bash scripts, the file formats, file names, and image coordinate systems are harmonized across all the sites. To harmonize DTI metrics, values are estimated for each voxel in an image to generate a histogram representing the whole image. Then, the Quantitative Imaging Toolkit (QIT) modules are utilized to scale the mode to a value of one and depict the subsequent harmonized histogram. The standardization of file formats, naming conventions, coordinate systems, and DTI metrics are qualitatively assessed. The histograms of the DTI metrics were generated for all the individual rodents per site. For inter-site analysis, an average of the individual scans was calculated to create a histogram that represents each site. In order to ensure the analysis can be run at the level of individual animals, the sham and TBI cohort were analyzed separately, which depicted the same harmonization factor. The results demonstrate that these processes qualitatively standardize the file formats, naming conventions, coordinate systems, and DTI metrics of the data. This assists in the ability to share data across the study, as well as disseminate tools that can help other researchers to strengthen the statistical power of their studies and analyze data more cohesively.

Thallium (Tl) is one of the most toxic heavy metals, associated with accidental poisoning and homicide. It causes acute and chronic systemic diseases, including gastrointestinal and cardiovascular diseases and kidney failure. However, few studies have investigated the mechanism by which Tl induces acute kidney injury (AKI). This study investigated the toxic effects of Tl on the histology and function of rat kidneys using biochemical and histopathological assays after intraperitoneal thallium sulfate administration (30 mg/kg). Five days post-administration, rats exhibited severely compromised kidney function. Low-vacuum scanning electron microscopy revealed excessive calcium (Ca) deposition in the outer medulla of Tl-loaded rats, particularly in the medullary thick ascending limb (mTAL) of the loop of Henle. Tl accumulated in the mTAL, accompanied by mitochondrial dysfunction in this segment. Tl-loaded rats showed reduced expression of kidney transporters and channels responsible for Ca2+ reabsorption in the mTAL. Pre-administration of the Na–K–Cl cotransporter 2 (NKCC2) inhibitor furosemide alleviated Tl accumulation and mitochondrial abnormalities in the mTAL. These findings suggest that Tl nephrotoxicity is associated with preferential Tl reabsorption in the mTAL via NKCC2, leading to mTAL mitochondrial dysfunction and disrupted Ca2+ reabsorption, culminating in mTAL-predominant Ca crystal deposition and AKI. These findings on the mechanism of Tl nephrotoxicity may contribute to the development of novel therapeutic approaches to counter Tl poisoning. Moreover, the observation of characteristic Ca crystal deposition in the outer medulla provides new insights into diagnostic challenges in Tl intoxication. [ABSTRACT FROM AUTHOR]

Abstract Background Parkinson’s disease (PD) is a prevalent neurodegenerative disorder worldwide, diagnosed based on classic symptoms like motor dysfunction and cognitive impairments. With the development of various radioactive ligands, positron emission tomography (PET) imaging combined with specific radiolabelling probes has proven to be effective in aiding clinical PD diagnosis. Among these probes, 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl) nortropane ([18F]FECNT) has been utilized as a PET tracer to image dopamine transporter (DAT) integrity in striatal presynaptic dopaminergic terminals. However, the presence of brain-penetrant radioactive metabolites produced by [18F]FECNT may impact the accuracy of PET imaging. In previous research, we developed 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl-1,1,2,2-d4) nortropane ([18F]FECNT-d4), a deuterated derivative with enhanced stability in plasma and the striatum, along with a slower washout rate. In this study, we further investigated the potential of [18F]FECNT-d4 to detect dopaminergic neuron degeneration in Parkinson’s disease. This involved PET imaging in unilaterally-lesioned PD model rats and in vitro autoradiography conducted on postmortem brain sections. Results PET images revealed reduced specific uptake in the ipsilateral striatum of rats stereotactically injected with 6-hydroxydopamine hydrochloride (6-OHDA). Compared to the sham group, the ratio of standardized uptake value (SUV) in the ipsilateral to contralateral striatum decreased by 13%, 23%, and 63% in the mild, moderate, and severe lesioned groups, respectively. Dopaminergic denervation observed in PET imaging was further supported by behavioral assessments, immunostaining, and monoamine concentration tests. Moreover, the microPET results exhibited positive correlations with these measurements, except for the apomorphine-induced rotational behavior test, which showed a negative correlation. Additionally, [18F]FECNT-d4 uptake was approximately 40% lower in the postmortem striatal sections of a PD patient compared to a healthy subject. Furthermore, estimated human dosimetry (effective dose equivalent: 5.06 E-03 mSv/MBq), extrapolated from rat biodistribution data, remained below the current Food and Drug Administration limit for radiation exposure. Conclusion Our findings demonstrate that [18F]FECNT-d4 accurately estimates levels of dopaminergic neuron degeneration in the 6-OHDA-induced PD rat model and effectively distinguishes between PD patients and healthy individuals. This highly sensitive and safe PET probe holds promising potential for clinical application in the diagnosis and monitoring of Parkinson’s disease.

Abstract Rifaximin is FDA-approved for treatment of irritable bowel syndrome with diarrhea (IBS-D), but poor solubility may limit its efficacy against microbes in the mucus layer, e.g. Escherichia coli. Here we evaluate adding the mucolytic N-acetylcysteine (NAC) to improve rifaximin efficacy. In a resazurin checkerboard assay, combining rifaximin with NAC had significant synergistic effects in reducing E. coli levels. The optimal rifaximin + NAC combination was then tested in a validated rat model of IBS-D (induced by cytolethal distending toxin [CdtB] inoculation). Rats were inoculated with vehicle and treated with placebo (Control-PBS) or rifaximin + NAC (Control-Rif + NAC, safety), or inoculated with CdtB and treated with placebo (CdtB-PBS), rifaximin (CdtB-Rifaximin), or rifaximin + NAC (CdtB-Rif + NAC) for 10 days. CdtB-inoculated rats (CdtB-PBS) developed wide variability in stool consistency (P = 0.0014) vs. controls (Control-PBS). Stool variability normalized in rats treated with rifaximin + NAC (CdtB-Rif + NAC) but not rifaximin alone (CdtB-Rifaximin). Small bowel bacterial levels were elevated in CdtB-PBS rats but normalized in CdtB-Rif + NAC but not CdtB-Rifaximin rats. E. coli and Desulfovibrio spp levels (each associated with different IBS-D microtypes) were also elevated in CdtB-inoculated (CdtB-PBS) but normalized in CdtB-Rif + NAC rats. Cytokine levels normalized only in CdtB-Rif + NAC rats, in a manner predicted to be associated with reduced diarrhea driven by reduced E. coli. These findings suggest that combining rifaximin with NAC may improve the percentage of IBS-D patients responding to treatment.

Aims: Although low-intensity pulsed ultrasound (LIPUS) combined with disinfectants has been shown to effectively eliminate portions of biofilm in vitro, its efficacy in vivo remains uncertain. Our objective was to assess the antibiofilm potential and safety of LIPUS combined with 0.35% povidone-iodine (PI) in a rat debridement, antibiotics, and implant retention (DAIR) model of periprosthetic joint infection (PJI). Methods: A total of 56 male Sprague-Dawley rats were established in acute PJI models by intra-articular injection of bacteria. The rats were divided into four groups: a Control group, a 0.35% PI group, a LIPUS and saline group, and a LIPUS and 0.35% PI group. All rats underwent DAIR, except for Control, which underwent a sham procedure. General status, serum biochemical markers, weightbearing analysis, radiographs, micro-CT analysis, scanning electron microscopy of the prostheses, microbiological analysis, macroscope, and histopathology evaluation were performed 14 days after DAIR. Results: The group with LIPUS and 0.35% PI exhibited decreased levels of serum biochemical markers, improved weightbearing scores, reduced reactive bone changes, absence of viable bacteria, and decreased inflammation compared to the Control group. Despite the greater antibiofilm activity observed in the PI group compared to the LIPUS and saline group, none of the monotherapies were successful in preventing reactive bone changes or eliminating the infection. Conclusion: In the rat model of PJI treated with DAIR, LIPUS combined with 0.35% PI demonstrated stronger antibiofilm potential than monotherapy, without impairing any local soft-tissue. Cite this article: Bone Joint Res 2024;13(7):332–341.

Aims: To explore the efficacy of extracorporeal shockwave therapy (ESWT) in the treatment of osteochondral defect (OCD), and its effects on the levels of transforming growth factor (TGF)-β, bone morphogenetic protein (BMP)-2, -3, -4, -5, and -7 in terms of cartilage and bone regeneration. Methods: The OCD lesion was created on the trochlear groove of left articular cartilage of femur per rat (40 rats in total). The experimental groups were Sham, OCD, and ESWT (0.25 mJ/mm2, 800 impulses, 4 Hz). The animals were euthanized at 2, 4, 8, and 12 weeks post-treatment, and histopathological analysis, micro-CT scanning, and immunohistochemical staining were performed for the specimens. Results: In the histopathological analysis, the macro-morphological grading scale showed a significant increase, while the histological score and cartilage repair scale of ESWT exhibited a significant decrease compared to OCD at the 8- and 12-week timepoints. At the 12-week follow-up, ESWT exhibited a significant improvement in the volume of damaged bone compared to OCD. Furthermore, immunohistochemistry analysis revealed a significant decrease in type I collagen and a significant increase in type II collagen within the newly formed hyaline cartilage following ESWT, compared to OCD. Finally, SRY-box transcription factor 9 (SOX9), aggrecan, and TGF-β, BMP-2, -3, -4, -5, and -7 were significantly higher in ESWT than in OCD at 12 weeks. Conclusion: ESWT promoted the effect of TGF-β/BMPs, thereby modulating the production of extracellular matrix proteins and transcription factor involved in the regeneration of articular cartilage and subchondral bone in an OCD rat model. Cite this article: Bone Joint Res 2024;13(7):342–352.

In this study, Lactobacillus paracasei FP02, a strain isolated from pickled Chinese cabbage, was tested for its capability to reduce uric acid in vitro, and its physiological and biochemical characteristics were characterized. Furthermore, the effect of this strain on the serum uric acid level of a hyperuricemic (HUA) rat model was explored. The in vitro results showed that L. paracasei FP02 degraded uric acid and its precursor substances, inosine and guanosine, by 29.10%, 67.09%, and 70.48%, respectively, and inhibited xanthine oxidase (XOD) activity by 64.20%. Simultaneously, this strain could ferment various sugars (alcohols) and exhibited good tolerance to gastric acid and bile salts. The 14-day continuous intragastric administration of freeze-dried L. paracasei FP02 powder reduced the serum uric acid concentration by 49.96% compared to the hyperuricemia model group (P < 0.001), which was established by intragastric administration of potassium oxonate combined with high dietary uric acid. After the treatment, the serum uric acid concentration approached the levels observed in the blank control group. Additionally, in the FP02 treatment group, uric acid excretion in the urine increased, and serum XOD activity was significantly inhibited (P < 0.001). Renal sections showed that renal injury was partially restored in the FP02 treatment group. This study will lay the foundation for the development of L. paracasei FP02 as a potential drug or functional food for preventing HUA.

Background: Parkinson's disease (PD) is a prevalent neurodegenerative disorder worldwide, diagnosed based on classic symptoms like motor dysfunction and cognitive impairments. With the development of various radioactive ligands, positron emission tomography (PET) imaging combined with specific radiolabelling probes has proven to be effective in aiding clinical PD diagnosis. Among these probes, 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl) nortropane ([18F]FECNT) has been utilized as a PET tracer to image dopamine transporter (DAT) integrity in striatal presynaptic dopaminergic terminals. However, the presence of brain-penetrant radioactive metabolites produced by [18F]FECNT may impact the accuracy of PET imaging. In previous research, we developed 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl-1,1,2,2-d4) nortropane ([18F]FECNT-d4), a deuterated derivative with enhanced stability in plasma and the striatum, along with a slower washout rate. In this study, we further investigated the potential of [18F]FECNT-d4 to detect dopaminergic neuron degeneration in Parkinson's disease. This involved PET imaging in unilaterally-lesioned PD model rats and in vitro autoradiography conducted on postmortem brain sections. Results: PET images revealed reduced specific uptake in the ipsilateral striatum of rats stereotactically injected with 6-hydroxydopamine hydrochloride (6-OHDA). Compared to the sham group, the ratio of standardized uptake value (SUV) in the ipsilateral to contralateral striatum decreased by 13%, 23%, and 63% in the mild, moderate, and severe lesioned groups, respectively. Dopaminergic denervation observed in PET imaging was further supported by behavioral assessments, immunostaining, and monoamine concentration tests. Moreover, the microPET results exhibited positive correlations with these measurements, except for the apomorphine-induced rotational behavior test, which showed a negative correlation. Additionally, [18F]FECNT-d4 uptake was approximately 40% lower in the postmortem striatal sections of a PD patient compared to a healthy subject. Furthermore, estimated human dosimetry (effective dose equivalent: 5.06 E-03 mSv/MBq), extrapolated from rat biodistribution data, remained below the current Food and Drug Administration limit for radiation exposure. Conclusion: Our findings demonstrate that [18F]FECNT-d4 accurately estimates levels of dopaminergic neuron degeneration in the 6-OHDA-induced PD rat model and effectively distinguishes between PD patients and healthy individuals. This highly sensitive and safe PET probe holds promising potential for clinical application in the diagnosis and monitoring of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a prevalent neurodegenerative disorder worldwide, diagnosed based on classic symptoms like motor dysfunction and cognitive impairments. With the development of various radioactive ligands, positron emission tomography (PET) imaging combined with specific radiolabelling probes has proven to be effective in aiding clinical PD diagnosis. Among these probes, 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl) nortropane ([18F]FECNT) has been utilized as a PET tracer to image dopamine transporter (DAT) integrity in striatal presynaptic dopaminergic terminals. However, the presence of brain-penetrant radioactive metabolites produced by [18F]FECNT may impact the accuracy of PET imaging. In previous research, we developed 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl-1,1,2,2-d4) nortropane ([18F]FECNT-d4), a deuterated derivative with enhanced stability in plasma and the striatum, along with a slower washout rate. In this study, we further investigated the potential of [18F]FECNT-d4 to detect dopaminergic neuron degeneration in Parkinson's disease. This involved PET imaging in unilaterally-lesioned PD model rats and in vitro autoradiography conducted on postmortem brain sections. Results: PET images revealed reduced specific uptake in the ipsilateral striatum of rats stereotactically injected with 6-hydroxydopamine hydrochloride (6-OHDA). Compared to the sham group, the ratio of standardized uptake value (SUV) in the ipsilateral to contralateral striatum decreased by 13%, 23%, and 63% in the mild, moderate, and severe lesioned groups, respectively. Dopaminergic denervation observed in PET imaging was further supported by behavioral assessments, immunostaining, and monoamine concentration tests. Moreover, the microPET results exhibited positive correlations with these measurements, except for the apomorphine-induced rotational behavior test, which showed a negative correlation. Additionally, [18F]FECNT-d4 uptake was approximately 40% lower in the postmortem striatal sections of a PD patient compared to a healthy subject. Furthermore, estimated human dosimetry (effective dose equivalent: 5.06 E-03 mSv/MBq), extrapolated from rat biodistribution data, remained below the current Food and Drug Administration limit for radiation exposure. Conclusion: Our findings demonstrate that [18F]FECNT-d4 accurately estimates levels of dopaminergic neuron degeneration in the 6-OHDA-induced PD rat model and effectively distinguishes between PD patients and healthy individuals. This highly sensitive and safe PET probe holds promising potential for clinical application in the diagnosis and monitoring of Parkinson's disease. [ABSTRACT FROM AUTHOR]

The irreversible pan‐HER tyrosine kinase inhibitor neratinib is approved for patients with HER2‐positive, early‐stage and metastatic breast cancer (BC). Neratinib‐associated diarrhea is the most common reason for early discontinuation. Preclinical studies identified mechanisms of neratinib‐induced diarrhea and rationale for prophylactic and preventive measures. We studied effects of neratinib on rat intestines and conducted a phase 2 study of colon pathogenesis in patients with HER2‐positive BC treated with neratinib (NCT04366713). Colon samples from female albino Wistar rats receiving neratinib or vehicle were examined for histopathological changes. Patients with HER2‐positive BC received neratinib 240 mg once daily for up to 1 year. Colonoscopy biopsies were collected at baseline and at Day 28 to identify changes consistent with rat pathologies. Rat colons were markedly altered in appearance, with similar short circuit currents (Isc) and responses to carbachol and forskolin. Mucosal barrier loss and/or significant increase in secretory propensity in neratinib‐ versus control‐treated animals were not seen. Two of four endpoint‐evaluable patients presented with mild pathological changes, largely comparable with the rat model. Preclinical evidence supports an inflammatory component of neratinib‐induced diarrhea without mucosal barrier function loss. Colonoscopy findings in patients with BC indicate mild or no pathological changes in the colon due to neratinib treatment. [ABSTRACT FROM AUTHOR]

Rifaximin is FDA-approved for treatment of irritable bowel syndrome with diarrhea (IBS-D), but poor solubility may limit its efficacy against microbes in the mucus layer, e.g. Escherichia coli. Here we evaluate adding the mucolytic N-acetylcysteine (NAC) to improve rifaximin efficacy. In a resazurin checkerboard assay, combining rifaximin with NAC had significant synergistic effects in reducing E. coli levels. The optimal rifaximin + NAC combination was then tested in a validated rat model of IBS-D (induced by cytolethal distending toxin [CdtB] inoculation). Rats were inoculated with vehicle and treated with placebo (Control-PBS) or rifaximin + NAC (Control-Rif + NAC, safety), or inoculated with CdtB and treated with placebo (CdtB-PBS), rifaximin (CdtB-Rifaximin), or rifaximin + NAC (CdtB-Rif + NAC) for 10 days. CdtB-inoculated rats (CdtB-PBS) developed wide variability in stool consistency (P = 0.0014) vs. controls (Control-PBS). Stool variability normalized in rats treated with rifaximin + NAC (CdtB-Rif + NAC) but not rifaximin alone (CdtB-Rifaximin). Small bowel bacterial levels were elevated in CdtB-PBS rats but normalized in CdtB-Rif + NAC but not CdtB-Rifaximin rats. E. coli and Desulfovibrio spp levels (each associated with different IBS-D microtypes) were also elevated in CdtB-inoculated (CdtB-PBS) but normalized in CdtB-Rif + NAC rats. Cytokine levels normalized only in CdtB-Rif + NAC rats, in a manner predicted to be associated with reduced diarrhea driven by reduced E. coli. These findings suggest that combining rifaximin with NAC may improve the percentage of IBS-D patients responding to treatment. [ABSTRACT FROM AUTHOR]

The development of a rapid and accurate model for determining the genotoxicity and carcinogenicity of chemicals is crucial for effective cancer risk assessment. This study aims to develop a 1-day, single-dose model for identifying genotoxic hepatocarcinogens (GHCs) in rats. Microarray gene expression data from the livers of rats administered a single dose of 58 compounds, including 5 GHCs, was obtained from the Open TG-GATEs database and used for the identification of marker genes and the construction of a predictive classifier to identify GHCs in rats. We identified 10 gene markers commonly responsive to all 5 GHCs and used them to construct a support vector machine-based predictive classifier. In the silico validation using the expression data of the Open TG-GATEs database indicates that this classifier distinguishes GHCs from other compounds with high accuracy. To further assess the model's effectiveness and reliability, we conducted multi-institutional 1-day single oral administration studies on rats. These studies examined 64 compounds, including 23 GHCs, with gene expression data of the marker genes obtained via quantitative PCR 24 h after a single oral administration. Our results demonstrate that qPCR analysis is an effective alternative to microarray analysis. The GHC predictive model showed high accuracy and reliability, achieving a sensitivity of 91% (21/23) and a specificity of 93% (38/41) across multiple validation studies in three institutions. In conclusion, the present 1-day single oral administration model proves to be a reliable and highly sensitive tool for identifying GHCs and is anticipated to be a valuable tool in identifying and screening potential GHCs. [ABSTRACT FROM AUTHOR]

Implant surface nanofiber (NF) coatings represent an alternative way to prevent/treat periprosthetic joint infection (PJI) via local drug release. We developed and characterized a coaxial erythromycin (EM)-doped PLGA/PCL-PVA NF coating. The purpose of this study was to determine the efficacy of EM-NF coatings (EM0, no EM, EM100 (100 mg/mL), and EM1000 (1000 mg/mL) wt/wt) in a rat PJI model. A strong bond of the EM-NF coating to the surface of titanium (Ti) pins was confirmed by in vitro mechanical testing. Micro-computed tomography (mCT) analysis showed that both EM100 and EM1000 NF effectively reduced periprosthetic osteolysis compared to EM0 at 8 and 16 weeks after implantation. Histology showed that EM100 and EM1000 coatings effectively controlled infection and enhanced periprosthetic new bone formation. The bone implant contact (BIC) of EM100 (35.08%) was higher than negative controls and EM0 (3.43% and 0%, respectively). The bone area fraction occupancy (BAFO) of EM100 (0.63 mm2) was greater than controls and EM0 (0.390 mm2 and 0.0 mm2, respectively). The BAFO of EM100 was higher than that of EM1000 (0.3 mm2). These findings may provide a basis for a new implant surface fabrication strategy aimed at reducing the risks of defective osseointegration and PJI. [ABSTRACT FROM AUTHOR]

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Ageratum conyzoides, an annual herbaceous plant that inhabits tropical and subtropical regions, has been traditionally used in Asia, Africa, and South America for phytotherapy to treat infectious and inflammatory conditions. However, the pharmacological effects of standardized ethanolic extract of Ageratum conyzoides (ACE) on benign prostatic hyperplasia (BPH) remain unexplored. The objective of this research is to examine the potential physiological impacts of ACE, a traditionally utilized remedy for inflammatory ailments, in a rat model with BPH induced by testosterone propionate (TP). Rats were subcutaneously administered TP (3 mg/kg) to induce BPH and concurrently orally administered ACE (20, 50, and 100 mg/kg) daily for 42 days. ACE markedly improved BPH characteristics, including prostate weight, prostate index, and epithelial thickness, while also suppressing androgens and related hormones. The findings were supported by a decrease in androgen receptor and downstream signals associated with BPH in the prostate tissues of the ACE groups. Furthermore, increased apoptotic signals were observed in the prostate tissue of the ACE groups, along with heightened detection of the apoptotic nucleus compared to the BPH alone group. These changes seen in the group that received finasteride were similar to those observed in this group. These findings suggest that ACE shows promise as an alternative phytotherapeutic agent for treating BPH. [ABSTRACT FROM AUTHOR]

AbstractThe aim of this work was to identify the regulatory function of hsa_circ_0004776 in the progression of diabetic retinopathy (DR). The direct interactions between hsa_circ_0004776 and hsa-miR-382-5p and between hsa-miR-382-5p and BDNF, were confirmed via dual-luciferase reporter assays. Quantitative Real-Time PCR analysis indicated that hsa_circ_0004776 was highly expressed in aqueous humour samples of DR patients and human retinal microvascular epithelial cells (hRECs) under a high-glucose environment, whereas hsa-miR-382-5p showed the opposite trend. Overexpressed hsa_circ_0004776 significantly enhanced DNA synthesis, proliferation, migration, and tube formation in hRECs in hyperglycaemia, while hsa-miR-382-5p mimics reversed these changes. Additionally, in a streptozotocin-induced Sprague-Dawley rat model of DR, vitreous microinjection of rno-miR-382-5p agomir reversed the pathologic features in the progression of DR, including retinal vascular leakage, capillary decellularization, loss of pericytes, fibrosis, and gliosis. Our results indicated that under hyperglycaemic conditions, hsa_circ_0004776 influences the progression of DR via hsa-miR-382-5p and thus represents a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Aim/Background: Alcohol-induced liver necrosis requires effective treatment. This study tests Polyherbal Extract's hepatoprotective effects on alcohol-induced liver necrosis in rats. The extract's impact on inflammatory pathways, serum liver enzymes (AST, ALT and ALP), bilirubin and histopathological changes are examined to determine mechanisms. Materials and Methods: We tested Polyherbal Extract's hepatoprotective effect in rats with ethanol-induced liver injury, which mimics human liver necrosis. To assess liver health, multiple Polyherbal Extract dosage groups were carefully established. In conventional and untreated groups, liver damage progression was monitored. Polyherbal Extract's liver and immune effects were assessed by inflammatory pathways. Bilirubin, AST, ALT and ALP showed hepatoprotection. The entire histology showed liver architecture changes. This integrated experimental design examines Polyherbal Extract's potential hepatoprotective mechanisms in alcohol-induced liver necrosis using ethanol-induced liver damage, diverse treatment groups, phytochemical analysis, toxicity assessment and parameter measurements. Results: This study found Polyherbal Extract's hepatoprotective effects promising. Its therapeutic potential was confirmed by phytochemical analysis. The acute toxicity study confirmed the extract's safety at specified dosages, supporting its therapeutic use. In liver function, Polyherbal Extract was effective. Compared to toxins, treated groups had significantly lower AST, ALT and ALP levels. Bilirubin levels decreased dose-dependently, indicating the extract's liver health benefits. Histopathological findings were useful at higher extract doses. Hepatocellular necrosis and inflammatory cell infiltration decreased in treated groups, suggesting the extract may reduce liver tissue structural damage. Conclusion: The Polyherbal Extract demonstrated promising hepatoprotective effects against alcohol-induced liver necrosis in the rat model. The reduction in liver enzymes, bilirubin levels and histopathological improvements, along with its safety profile, suggest its potential as an effective hepatoprotective agent. Further investigations into its mechanisms and clinical applications are warranted. [ABSTRACT FROM AUTHOR]

Background: Adolescent brains are highly vulnerable to heavy alcohol exposure. Increased understanding of how alcohol adversely impacts brain maturation may improve treatment outcomes. Objectives: This study characterizes short-term versus long-term effects of ethanol feeding on behavior, frontal lobe glial proteins, and mTOR signaling. Methods: Adolescent rats (8/group) were fed liquid diets containing 26% or 0% ethanol for 2 or 9 weeks, then subjected to novel object recognition (NOR) and open field (OF) tests. Frontal lobes were used for molecular assays. Results: Significant ethanol effects on OF performance occurred in the 2-week model (p <.0001). Further shifts in OF and NOR performance were unrelated to ethanol exposure in the 9-week models (p <.05 to p <.0001). Ethanol inhibited MAG1 (p <.01) and MBP (p <.0001) after 2 but not 9 weeks. However, both control and ethanol 9-week models had significantly reduced MAG1 (p <.001–0.0001), MBP (p <.0001), PDGFRA (p <.05–0.01), and PLP (p <.001–0.0001) relative to the 2-week models. GFAP was the only glial protein significantly inhibited by ethanol in both 2- (p <.01) and 9-week (p <.05) models. Concerning the mTOR pathway, ethanol reduced IRS-1 (p <.05) and globally inhibited mTOR (p <.01 or p <.001) in the 9- but not the 2-week model. Conclusions: Short-term versus long-term ethanol exposures differentially alter neurobehavioral function, glial protein expression, and signaling through IRS-1 and mTOR, which have known roles in myelination during adolescence. These findings suggest that strategies to prevent chronic alcohol-related brain pathology should consider the increased maturation-related vulnerability of adolescent brains. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is an acute inflammatory reaction of the pancreatic tissue, which involves auto-digestion, edema, hemorrhage, and necrosis. AP can be categorized into mild, moderately severe, and severe AP, with severe pancreatitis also referred to as acute necrotizing pancreatitis (ANP). ANP is characterized by the accumulation of necrotic material in the peritoneal cavity. This can result in intestinal injury. However, the mechanism of ANP-associated intestinal injury remains unclear. We established an ANP-associated intestinal injury rat model (ANP-IR model) by injecting pancreatitis-associated ascites fluid (PAAF) and necrotic pancreatic tissue at various proportions into the triangular area formed by the left renal artery and ureter. The feasibility of the ANP-IR model was verified by comparing the similar changes in indicators of intestinal inflammation and barrier function between the two rat models. In addition, we detected changes in apoptosis levels and YAP protein expression in the ileal tissues of rats in each group and validated them in vitro in rat epithelial crypt cells (IEC-6) to further explore the potential injury mechanisms of ANP-associated intestinal injury. We also collected clinical data from patients with ANP to validate the effects of PAAF and pancreatic necrosis on intestinal injury. Our findings offer a theoretical basis for restricting the buildup of peritoneal necrosis in individuals with ANP, thus promoting the restoration of intestinal function and enhancing treatment efficacy. The use of the ANP-IR model in further studies can help us better understand the mechanism and treatment of ANP-associated intestinal injury. NEW & NOTEWORTHY: We constructed a rat model of acute necrotizing pancreatitis-associated intestinal injury and verified its feasibility. In addition, we identified the mechanism by which necrotic pancreatic tissue and pancreatitis-associated ascites fluid (PAAF) cause intestinal injury through the HIPPO signaling pathway. [ABSTRACT FROM AUTHOR]

Background: The major concern in patients who have suffered from cardiac arrest (CA) and undergone successful extracorporeal cardiopulmonary resuscitation (E‐CPR) is poor neurological outcomes. In this study, we aimed to introduce a rat model of selective brain perfusion (SBP) during E‐CPR to improve the neurological outcome after CA. Methods: The rats underwent 7 min of untreated asphyxial CA and then were resuscitated with E‐CPR for 30 min. The right external jugular vein and right femoral artery were separately cannulated to the E‐CPR outflow and inflow. The right common carotid artery was cannulated from the proximal to the distal side for SBP. Subsequently, rats were removed from E‐CPR, wounds were closed, and 90 min of intensive care were provided. Neurological deficit scores were tested after 4 h of recovery when the rats were mechanical ventilation‐free. S100 calcium‐binding protein B (S100B) and glial fibrillary acidic protein (GFAP) were detected through immunohistochemistry (IHC) of brain tissue. Results: The rats that received SBP while resuscitated by E‐CPR showed markedly better neurological performances after 4‐h recovery than those resuscitated by E‐CPR only. The IHC staining of GFAP and S100B in the hippocampus was low in the rats receiving SBP during E‐CPR, but only GFAP showed significant differences. Conclusions: We successfully developed a novel and reproducible rat model of SBP while resuscitated by E‐CPR to ameliorate the neurological performances after CA. This achievement might have opportunities for studying how to improve the neurological outcome in the clinical condition. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate potential osteoarthritic alterations within the ankle using a surgically-induced chronic lateral ankle instability (CLAI) model. Twelve rats were assigned randomly to either the control (n = 4) or CLAI group (n = 8). Surgery was performed on the right ankle. Osteoarthritis was assessed through in-vivo micro-CT at 8 weeks and a clinical analysis. Macroscopic analysis, high-resolution ex-vivo micro-CT and histological examination were conducted after euthanasia at 12 weeks. Three subgroups (SG) were analyzed. SG1 comprised the operated ankles of the CLAI group (n = 8). SG2 consisted of the non-operated ankles of the CLAI group (n = 8). SG3 included both sides of the control group (n = 8). In-vivo micro-CT revealed no significant differences among the three subgroups when analyzed together (p = 0.42), and when comparing SG1 with SG2 (p = 0.23) and SG3 (p = 0.43) individually. No noticeable clinical differences were observed. After euthanasia, macroscopic analysis employing OARSI score, did not demonstrate significant differences, except between the medial tibia of SG1 and SG3 (p = 0.03), and in the total score comparison between these two subgroups (p = 0.015). Ex-vivo micro-CT did not reveal any differences between the three subgroups regarding bony irregularities and BV/TV measurements (SG1 vs. SG2 vs. SG3: p = 0.72; SG1 vs. SG2: p = 0.80; SG1 vs. SG3: p = 0.72). Finally, there was no difference between the three subgroups regarding OARSI histologic score (p = 0.27). These findings indicate that the current model failed to induce significant osteoarthritis. However, they lay the groundwork for improving the model's effectiveness and expanding its use in CLAI research, aiming to enhance understanding of this pathology and reduce unnecessary animal sacrifice. [ABSTRACT FROM AUTHOR]

Emesis, a multifaceted physiological response, presents significant challenges in clinical scenarios such as chemotherapy-induced nausea and vomiting. Novel antiemetic interventions are imperative to enhance patient care and well-being. This study investigated the antiemetic potential of Syzygium aromaticum (clove) extract using a comprehensive approach involving phytochemical analysis and animal models of emesis. Using chick model of emesis, male chicks aged 4 days were assigned to groups receiving different treatments, including copper sulfate, clove extract and metoclopramide. The effectiveness of treatments were assessed by monitoring retching frequency and changes in feed intake. Similarly, albino Wistar rats were used modelling emesis in rat and were categorized into groups receiving cisplatin, clove extract and metoclopramide as a standard control. Emetic responses were evaluated through pica behaviour assessment. In the chick model, a single dose of the following drugs was administered, either orally (p.o) or intra-peritoneally (i.p) as following: Copper sulfate at 50mg/kg p.o., Clove extract at 50mg/kg p.o, and Metoclopramide at 100mg/kg i.p. For the rat animal model, a once-daily dosage of cisplatin at 3 mg/kg i.p, metoclopramide at 2.5 mg/kg i.p., and clove extract at 100 mg/kg p.o. for three consecutive days were administered. Phytochemical analysis unveiled the intricate composition of clove extract, with eugenol standing out as a prominent constituent (71.56%). In the chick model, clove extract reduced copper sulfate-induced retching, displaying an impressive 84.63% inhibition rate. Similarly, in the rat model, the extract significantly alleviated cisplatin-induced pica behavior, with a statistically significant reduction in retching instances (P < 0.05). Clove extract's multifaceted antiemetic effects, attributed to eugenol and other bioactive components, provide promising insights for managing emesis. The study's findings hold translational significance, suggesting clove extract's potential as a complementary antiemetic therapy alongside conventional treatments. The identification of eugenol as a key contributor warrants further investigation into molecular mechanisms, offering hope for effectively managing chemotherapy-induced nausea and vomiting. [ABSTRACT FROM AUTHOR]

Aims Adequate animal models are necessary to understand human conditions, such as takotsubo syndrome (TS) characterized by the heart's transient regional wall motion abnormalities. This study aims to develop a reproducible, low-mortality TS model that closely mimics the human condition and addresses the limitations of existing models. Methods and results We conducted six experiments using 309 Sprague Dawley rats, each approximately 300 g and aged 7–8 weeks. Initially, we replicated an established model using intraperitoneal isoprenaline injections. Subsequent experiments varied the doses and infusion durations of intravenous isoprenaline and assessed the effects of sex, strain, and breeder on the development of reversible akinetic segments. High-resolution echocardiography monitored the regional wall motion over 30 days to correlate with histological changes. Increasing the isoprenaline dose and the infusion time significantly enhanced akinesia (P < 0.01), resulting in pronounced apical ballooning observed in three-dimensional imaging. Akinesia peaked at 6 h post-infusion, with recovery observed at 24 h; most rats recovered from akinetic segments within 48–72 h. Optimizing the mode of administration, dose, and duration achieved a TS-like phenotype in 90% of cases, with a 16.7% mortality rate. Histological examinations confirmed that myocardial injury occurred, independent of apical ballooning. Conclusion This study presents a refined TS model that reliably replicates the syndrome's key features, including morphological and electrocardiographic changes, demonstrating its transient nature with high fidelity and reduced mortality. The model's reproducibility, evidenced by consistent results across trials, suggests its potential for broader application pending further validation. [ABSTRACT FROM AUTHOR]

The use of paclitaxel as a chemotherapeutic drug is limited by the development of dose-dependent paclitaxel-induced neuropathic pain (PINP). Recently, we observed that the combination of indomethacin plus minocycline (IPM) attenuates PINP in a mouse model in a cannabinoid (CB) receptor-dependent manner. Indomethacin inhibits cyclooxygenase (COX) activity, and minocycline inhibits 5-lipoxygenase (5-LOX) activity. Male Sprague Dawley rats with paclitaxel-induced mechanical allodynia were treated with indomethacin, minocycline, IPM combination, licofelone (a dual COX/LOX inhibitor), or their vehicles. AM251, a CB1 receptor antagonist, and AM630, a CB2 receptor antagonist, were administered before the IPM combination or licofelone. Mechanical allodynia was measured using a dynamic plantar aesthesiometer. Molecular docking was performed using CB-Dock2. Licofelone and IPM combination had antiallodynic effects, which were significantly higher than either indomethacin or minocycline alone. AM251 and AM630 blocked the antiallodynic effects of IPM combination and licofelone. Molecular docking showed that licofelone binds to both CB1 and CB2 receptors with a high affinity similar to the phytocannabinoid 1-trans-delta-9-tetrahydrocannabinol and the synthetic cannabinoid WIN 55,212-2. Licofelone inhibits COX and LOX and/or directly interacts with CB receptors to produce antiallodynic effects in a rat model of PINP. The findings further suggest that licofelone could be a therapeutic agent for managing PINP. [ABSTRACT FROM AUTHOR]

Animal experiments are important in trauma-related studies because they simulate in vivo effects. Rodents are a good choice for preparing trauma models; however, contractile healing in rodents results in a healing pattern that differs considerably from that in humans. Therefore, this study developed a new rodent model that avoids contractile healing of the skin around the wound using an anticontraction ring, and the skin in the wound's center remains intact and acts as a source for epithelialized diffusion healing. Cell proliferation, migration, revascularization, and collagen secretion did not differ between the novel and conventional full-skin defect trauma models. However, the healing rate at various stages significantly differed between the 2 groups owing to differences in the healing patterns. And without effective treatment, the experimental group cannot heal. The stabilities of the novel and conventional methods were good regardless of operator or batch. In summary, this new animal trauma model provides a stable experimental environment similar to that in humans, which may promote trauma-related research. [ABSTRACT FROM AUTHOR]

Hormone receptor-positive (HR+) breast cancer (BC) is the most common type of breast cancer among women worldwide, accounting for 70–80% of all invasive cases. Patients with HR+ BC are commonly treated with endocrine therapy, but intrinsic or acquired resistance is a frequent problem, making HR+ BC a focal point of intense research. Despite this, the malignancy still lacks adequate in vitro and in vivo models for the study of its initiation and progression as well as response and resistance to endocrine therapy. No mouse models that fully mimic the human disease are available, however rat mammary tumor models pose a promising alternative to overcome this limitation. Compared to mice, rats are more similar to humans in terms of mammary gland architecture, ductal origin of neoplastic lesions and hormone dependency status. Moreover, rats can develop spontaneous or induced mammary tumors that resemble human HR+ BC. To date, six different types of rat models of HR+ BC have been established. These include the spontaneous, carcinogen-induced, transplantation, hormone-induced, radiation-induced and genetically engineered rat mammary tumor models. Each model has distinct advantages, disadvantages and utility for studying HR+ BC. This review provides a comprehensive overview of all published models to date. [ABSTRACT FROM AUTHOR]

Introduction: Phe508del is the most common cystic fibrosis transmembrane conductance regulator (CFTR) gene variant that results in the recessive genetic disorder cystic fibrosis (CF). The recent development of highly effective CFTR modulator therapies has led to significant health improvements in individuals with this mutation. While numerous animal models of CF exist, few have a CFTR mutation that is amenable to the triple combination therapy elexacaftor-tezacaftor-ivacaftor (ETI). Methods: To determine the responsiveness of Phe508del rats to ETI, a baseline nasal potential difference wasmeasured. Subsequently, they received ETI daily for 14 days, after which post-treatment nasal potential difference, lung mechanics (via flexiVent) and lung ventilation (via X-ray Velocimetry) were assessed. Results: Chloride ion transport in nasal airways was restored in Phe508del rats treatedwith ETI, but neither lungmechanics nor ventilationwere significantly altered. Discussion: These findings validate the usefulness of this rat model for future investigations of modulator therapy in CF. [ABSTRACT FROM AUTHOR]

Obesity is a global health problem and is increasing in prevalence in most countries. Although obesity affects all age groups, children are the most vulnerable sector. Functional foods are novel formulated foods containing substances (i.e., nutrients, phytochemicals, probiotics, etc.) that have potential health-enhancing or disease-preventing value. The research objective was to study the possible beneficial effects of providing a functional food made with amaranth flour, chia seed, and curcumin extract on the metabolism and behavior of a rat model of childhood obesity. Male Wistar rat pups from two litters of different sizes, a normal litter (NL) (10 pups) and a small litter (SL) (4 pups), were used. After weaning, the rats were fed a hypercaloric diet (HD) or an HD supplemented with the functional food mixture. Body weight and energy intake were measured for seven weeks, and locomotor activity, learning, and memory tests were also performed. At the end of the experiment, glucose and lipid metabolism parameters were determined. The results showed that in this model of obesity produced by early overfeeding and the consumption of a hypercaloric diet, anxiety-like behaviors and metabolic alterations occurred in the rat offspring; however, the provision of the functional food failed to reduce or prevent these alterations, and an exacerbation was even observed in some metabolic indicators. Interestingly, in the NL rats, the provision of the functional food produced some of the expected improvements in health, such as significant decreases in body weight gain and liver cholesterol and non-significant decreases in adipose tissue and leptin and insulin serum levels. [ABSTRACT FROM AUTHOR]

This study aimed to examine the anti-inflammatory properties of boric acid (BA) in treating knee osteoarthritis (KOA) in rats, evaluating its biochemical and histopathological therapeutic effects. A KOA rat model was induced by injecting monosodium iodoacetate into the knee joint. Random assignment was performed for the experimental groups as follows: group-1(control), group-2(KOA control), group-3 (BA:4 mg/kg, orally), group-4(BA:10 mg/kg, orally), group-5(BA:4 mg/kg, intra-articularly), and group-6(BA:10 mg/kg, intra-articularly). The rats received 100 µL of BA intra-articularly on days 1, 7, 14, and 21 or 1 mL orally once a day (5 days/week) for 4 weeks. Serum levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and activity of matrix metalloproteinase-13 (MMP-13) were measured. Histopathological and immunohistochemical analyses were performed on knee joint samples using specific antibodies for IL-1β, TNF-α, MMP-13, and nitric oxide synthase-2 (NOS-2). Group-2 exhibited higher serum IL-1β and TNF-α levels and MMP-13 activity than group-1 (P < 0.05). However, IL-1β and TNF-α levels and MMP-13 activity were lower in all treatment groups than in group-2, with statistically significant reductions observed in groups-4, 5, and 6. Histopathologically, group-2 displayed joint space narrowing, cartilage degeneration, and deep fissures. Groups-5 and 6 demonstrated significant joint space enlargement, articular cartilage tissue regeneration, and immunostaining patterns similar to those in group-1. Immunohistochemically, group-2 showed significant increases in IL-1β, TNF-α, MMP-13, and NOS-2 expression. However, all treatment groups exhibited reductions in these expression levels compared to group-2, with statistically significant decreases observed in groups-5 and 6 (P < 0.01). BA shows potential efficacy in reducing inflammation in experimental KOA model in rats. It may be a promising therapeutic agent for KOA, warranting further clinical studies for validation. [ABSTRACT FROM AUTHOR]

Objective: We aimed to evaluate the potential of Ampiang-Dadih (AD), a combination of Indonesian traditional fermented buffalo milk (Dadih) and black glutinous rice flakes (Ampiang) as an anti-hypercholesterolemic agent and to prevent liver-cell degeneration using a rat model. Materials and Methods: A mixture of black glutinous rice powder (0.3 gm/gm feed) and fermented buffalo milk (3.74/200 gm BW) was prepared to obtain AD. Fifteen adult male Sprague Dawley rats were divided into three groups of five animals each: (A) negative control group (distilled water; 5 weeks), (B) hypercholesterolemia group (1% cholesterol per feed; 5 weeks), and (C) preventive AD group (1% cholesterol and AD; 5 weeks). The blood lipid profiles were measured at weeks 2, 4, and 5. The liver enzyme activity, cholesterol level, and histology were observed at the end of week 5. Results: AD administration simultaneously with cholesterol in Group C significantly prevented an increase in total plasma cholesterol and low-density lipoprotein levels compared to Group B. Alanine transaminase and aspartate transaminase were maintained at normal levels in Group C. Furthermore, the levels of liver cholesterol and liver cell degeneration in Group C were also maintained because of AD administration compared to that in Group B. Conclusion: This study demonstrated that AD has the potential to be developed as a functional food for hypercholesterolemia prevention. [ABSTRACT FROM AUTHOR]

Repetitive motion or exercise is associated with oxidative stress and muscle inflammation, which can lead to declining grip strength and muscle damage. Oleanolic acid and ursolic acid have anti-inflammatory and antioxidant properties and can be extracted from Chaenomeles speciosa through ultrasonic sonication. We investigated the association between grip strength declines and muscle damage induced by lambda carrageenan (LC) injection and exercise exposure in rats. We also assessed the reparative effects of transdermal pretreatment and post-treatment with C. speciosa extracts (CSEs) by using a supersonic atomizer. The half-maximal inhibitory concentration (IC50) of CSEs for cells was 10.5 mg/mL. CSEs significantly reduced the generation of reactive oxygen species and inflammatory factors (interleukin [IL]-6 and IL-1β) in in vitro cell tests. Rats subjected to LC injection and 6 weeks of exercise exhibited significantly increased inflammatory cytokine levels (IL-1β, TNF-α, and IL-6). Hematoxylin and eosin staining revealed inflammatory cell infiltration and evident muscle damage in the gastrocnemius muscle, which exhibited splitting and the appearance of the endomysium and perimysium. The treated rats' grip strength significantly declined. Following treatment with CSEs, the damaged muscles exhibited decreased IL-1β, TNF-α, and IL-6 levels and normal morphologies. Moreover, grip strength significantly recovered. Pretreatment with CSEs yielded an immediate and significant increase in grip strength, with an increase of 180% and 165% occurring in the rats exposed to LC injection and exercise within the initial 12 h period, respectively, compared with the control group. Pretreatment with CSEs delivered transdermally using a supersonic atomizer may have applications in sports medicine and training or competitions. [ABSTRACT FROM AUTHOR]

ABSTRACT Yersinia pestis, one of the deadliest bacterial pathogens ever known, is responsible for three plague pandemics and several epidemics, with over 200 million deaths during recorded history. Due to high genomic plasticity, Y. pestis is amenable to genetic mutations as well as genetic engineering that can lead to the emergence or intentional development of pan-drug-resistant strains. Indeed, antibiotic-resistant strains (e.g., strains carrying multidrug-resistant or MDR plasmids) have been isolated in various countries and endemic areas. Thus, there is an urgent need to develop novel, safe, and effective treatment approaches for managing Y. pestis infections. This includes infections by antigenically distinct strains for which vaccines (none FDA approved yet) may not be effective and those that cannot be managed by currently available antibiotics. Lytic bacteriophages provide one such alternative approach. In this study, we examined post-exposure efficacy of a bacteriophage cocktail, YPP-401, to combat pneumonic plague caused by Y. pestis CO92. YPP-401 is a four-phage preparation effective against a panel of at least 68 genetically diverse Y. pestis strains. Using a pneumonic plague aerosol challenge model in gender-balanced Brown Norway rats, YPP-401 demonstrated ~88% protection when delivered 18 h post-exposure for each of two administration routes (i.e., intraperitoneal and intranasal) in a dose-dependent manner. Our studies provide proof-of-concept that YPP-401 could be an innovative, safe, and effective approach for managing Y. pestis infections, including those caused by naturally occurring or intentionally developed multidrug-resistant strains.IMPORTANCECurrently, there are no FDA-approved plague vaccines. Since antibiotic-resistant strains of Y. pestis have emerged or are being intentionally developed to be used as a biothreat agent, new treatment modalities are direly needed. Phage therapy provides a viable option against potentially antibiotic-resistant strains. Additionally, phages are nontoxic and have been approved by the FDA for use in the food industry. Our study provides the first evidence of the protective effect of a cocktail of four phages against pneumonic plague, the most severe form of disease. When treatment was initiated 18 h post infection by either the intranasal or intraperitoneal route in Brown Norway rats, up to 87.5% protection was observed. The phage cocktail had a minimal impact on a representative human microbiome panel, unlike antibiotics. This study provides strong proof-of-concept data for the further development of phage-based therapy to treat plague.