Sprague-Dawley Research Articles

A comparative neuro-study of solo or accompanied low and high boric acid doses with date molasses in adult male albino rats

Boric acid (BA) is a weak acid and the simplest compound resulting from the dissolution of boron in water. There is great competition to determine whether boron is an essential or nonessential nutrient. Date molasses is a potent type of sweetener with valuable components, such as flavonoids and phenolics, and has significant health benefits. This study investigated the neuro-essentiality and neurotoxicity of boric acid boron in adult male albino rat cortex and cerebellum brain areas and the impact of date molasses treatment. Animals were grouped into the following groups: control, low and high boric acid doses, 10 and 500 mg/kg, respectively, with or without 250 mg/kg date molasses. The results revealed the ability of BAs to cross the blood–brain barrier and accumulate in the cerebellum and cortex, revealing the ability of date molasses to decrease BA accumulation at different time intervals. Additionally, the results varied between a nonsignificant increase or decrease in calcium ion content, monoamines (norepinephrine, dopamine, and serotonin), glucose, adenosine triphosphate, malondialdehyde and glutathione, depending on the BA dose. Moreover, date molasses mitigated any unwanted BA results. In conclusion, boric acid, which is within a permissible limit, could be essential and have a neuroprotective effect, whereas at a sublethal level, it could have a neurotoxic effect. Additionally, Date molasses can have neuroprotective effects and antagonize the neurotoxic effects of boric acid through its antioxidant and scavenging effects.

Salmon Nasal Cartilage-Derived Proteoglycans Alleviate Monosodium Iodoacetate-Induced Osteoarthritis in Rats

Osteoarthritis is a chronic inflammatory condition characterized by the degeneration of joint cartilage and underlying bone, resulting in pain, swelling, and reduced mobility. This study evaluates the efficacy of salmon nasal cartilage-derived proteoglycans in mitigating osteoarthritis symptoms and investigates the underlying molecular mechanisms. This study employed a rat model of osteoarthritis induced by monosodium iodoacetate (MIA) injection. The rats were orally administered salmon nasal cartilage-derived proteoglycans or ibuprofen. Key aspects of osteoarthritis pathology, including impaired exercise ability, inflammation, extracellular matrix degradation, and chondrocyte apoptosis, were assessed using histological analysis, micro-CT, treadmill testing, serum assays, and mRNA/protein expression studies. The MIA injection caused significant cartilage damage, reduced bone mineral density, and impaired exercise ability. Additionally, it elevated serum levels of prostaglandin E2 and nitric oxide, increased the mRNA and protein levels of inflammation-related factors, and activated apoptosis signaling pathways in cartilage. Treatment with salmon nasal cartilage-derived proteoglycans significantly improved cartilage morphology and mineralization, reduced inflammation, and inhibited apoptosis signaling pathways, with effects comparable to those observed with ibuprofen treatment. These findings highlight the potential of salmon nasal cartilage-derived proteoglycans as a therapeutic agent for managing osteoarthritis by effectively reducing inflammation, preventing cartilage degradation, and inhibiting chondrocyte apoptosis.

Targeted Therapy of Antibody-Induced Autoimmune Arthritis Using Peptide-Guided Nanoparticles

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints and it affects over 18 million people worldwide. Despite the availability of a variety of potent drugs for RA, over 30–40 percent of patients fail to achieve adequate remission, and many patients suffer from systemic adverse effects. Thus, there is an urgent need for a joint-targeted drug delivery system. Nanotechnology-based drug delivery methods offer a promising resource that is largely untapped for RA. Using the T cell-driven rat adjuvant-induced arthritis (AA) model of human RA, we developed a peptide-targeted liposomal drug delivery system for arthritis therapy. It was based on a novel joint-homing peptide ART-2 to guide liposomes entrapping dexamethasone (Dex) to arthritic joints of rats, and this approach was more effective in suppressing arthritis than the unpackaged (free) drug. To de-risk the translation of our innovative drug delivery technology to RA patients, we undertook the validation of ART-2-liposomal delivery in a genetically and mechanistically distinct arthritis model in mice, the collagen antibody-induced arthritis (CAIA) model. Using live imaging for tissue distribution of liposomes in vivo, immunohistochemistry of paws for cellular binding of ART-2, and liposomal Dex delivery, our results fully validated the key findings of the rat model, namely, preferential homing of peptide-functionalized liposomes to arthritic joints compared to healthy joints, and higher efficacy of liposomal Dex than free Dex. These results offer a proof-of-concept for the benefits of targeted drug delivery to the joints and its potential translation to RA patients.

Sustained Protraction Increases Lengthening of the Mandibular Condylar Process Whilst Changes Its Growth Direction in a Rat Model.

In Class II elastics treatment, the mandible is subject to sustained protraction. The study aimed to investigate the morphological and histological changes resulting from sustained mandibular protraction, through establishment of a novel model in rat. Forty-eight 4-week-old male Sprague-Dawley rats were randomly divided into three groups, including the 50 and 100 cN protraction groups, and the control. In the two protraction groups, NiTi coil springs were fixed between the metal bands on the maxillary incisors and mandibular molars to pull the mandible forward. CBCT scans were taken immediately before (T0), 2 weeks (T1) and 4 weeks (T2) after the traction. Histological and immunohistochemical analyses were performed at T1 and T2. Increase of the condylar process length and angular process length were significantly larger in the two protraction groups than that in the control; however, the condylar process angle (∠CPA) was significantly reduced by the protraction at T2, leading to decreased condylar height. The protraction decreased the condylar cartilage thickness at T1, which recovered to the control level at T2, with no significant changes detected in the expression of SRY-related high mobility group-box gene 9 (SOX9) and type II collagen (COL II), two chondrogenic markers. The established rat model is manoeuvrable and reliable, which exerts sustained and measurable mandibular protraction. The sustained protraction increases the lengthening of the mandibular condylar process, but alters its growth direction by causing it to turn downwards.

DESIGN, SYNTHESIS, IN SILICO STUDIES, AND PHARMACOLOGICAL EVALUATION OF 5-ARYL-4-(CHLOROACETYLAMINO)-3-MERCAPTO-1,2,4-TRIAZOLE DERIVATIVES AS ANTICONVULSANT AGENTS

Objective: In this study, we reported the synthesis of a novel series of 5-aryl-4(chloroacetylamino)-3-mercapto-1, 2,4-triazoles. Methods: These compounds were synthesized to screen for anticonvulsant effects in a Maximal Electroshock Seizure (MES) model and a Subcutaneous Pentylenetetrazole (sc‐PTZ) seizure model in rats. Furthermore, molecular docking studies with gamma-aminobutyric acid and in silico ADME prediction were carried out to determine interactions of these compounds with Benzodiazepine (BZD) receptors and their similarity with standard drugs. The rotarod test was used to evaluate neurotoxicity. Results: 08 out of 40 compounds exhibited neurotoxicity at the maximum tested dose. Most of the compounds showed anti‐MES effects without any signs of neurological deficit. All the tested compounds significantly reduced seizures induced by PTZ compared to the control group. Carbamazepine and phenytoin were used as positive controls for anticonvulsant effects. Compounds 3d, 3h (a diphenylamine derivative of 5-aryl-4(chloroacetylamino)-3-mercapto-1,2,4-triazole), and 4a (a piperidinyl derivative of 5-aryl-4(chloroacetylamino)-3-mercapto-1,2,4-triazole) exhibited greater safety than phenytoin and carbamazepine in terms of neurotoxicity. The docking scores for the identified compounds 3d, 3h and 4a was 6.5133; 6.6558 and 5.6524, respectively. Nearly all the compounds (90%) demonstrated decreased locomotor activity. Conclusion: It is gratifying that the compounds with higher hydrophobicity showed better performance in the seizure models. Many triazole derivatives holding a suitable aryl or alkyl group gave a better anticonvulsant activity in their analogs.

Characterization of Contusive Spinal Cord Injury by Monitoring Motor-Evoked Potential

This study involves longitudinal neuro-electrophysiological analysis using motor-evoked potentials (MEP) and the Basso, Beattie, and Bresnahan behavioral examinations (BBB) to evaluate moderate mid-thoracic contusive spinal cord injury (SCI) in a rat model. Objectives/Background: The objective of the study is to characterize the onset and progression of contusive SCI over an eight-week period using a clinically applicable tool in an in vivo model. The background highlights the importance of a reliable and reproducible injury model and assessment tools for SCI. Methods: The methods section describes the experimental setup, including randomly assigned rats in three groups: Sham, Control, and Injury (undergoing a moderate contusive SCI using the NYU-Impactor). MEP monitoring and BBB examinations are conducted at baseline and weekly for eight weeks post-injury. Results: The results indicate that the relative MEP power spectral decreased to 11% and 22% in the left and right hindlimbs, respectively, during the first week post-SCI. In the second week, a slight spontaneous recovery was observed, reaching 17% in the left and 31% in the right hindlimbs. Over the following four weeks post-SCI, continuing deterioration of MEP signal power was observed with no detectable recovery. Conclusions: SCI attenuates hindlimb MEP power spectral and reduces locomotion, though the changes in MEP and locomotion exhibit distinct temporal patterns. The MEP monitoring provides valuable insights into the functional integrity of motor pathways following SCI and offer a sensitive and reliable assessment. By implementing MEP monitoring, researchers can track the progression of SCI and evaluate the efficacy of therapeutic interventions quantitatively.

Platelet-derived mitochondria regulate lipid metabolism in nonalcoholic steatohepatitis via extracellular vesicles.

Immune system activation along with lipotoxicity due to excessive lipid droplet (LD) accumulation in the liver are key drivers of non-alcoholic steatohepatitis (NASH). Extracellular vesicles (EVs) released by cells that carry biological signals to contribute intercellular communication. But the roles of immune cells-derived EVs in pathogenesis of NASH are unclear. Platelets are abundant in blood. We explored the role of platelet-derived EVs (pEVs) in LD accumulation from 30 patients with non-alcoholic fatty liver disease of different severity as well as 20 healthy subjects, a rat model, and an in vitro cell-based assay. There was increased platelet activation, accompanied by pEVs release, in NASH patients/rat model, and palmitate-treated cells. The mitochondria in the platelets and pEVs from NASH patients/rats were increased but dysfunctional, including a reduction in fatty acid β-oxidation, inactivated ACC2, and suppressed oxidative phosphorylation system complex II/III/IV activity. These damaged mitochondria could be transferred to hepatocytes via pEVs to increase the number of lipid droplet-bound mitochondria (LDM). An increase in dysfunctional LDM in hepatocytes affects lipid metabolism, resulting in excessive LD accumulation, elevated mitochondrial ROS production, and apoptosis. We offer a novel molecular mechanism that connects platelets, pEVs, and excessive LD accumulation to the development of NASH. Our results suggest that NASH progression may be alleviated by specifically inhibiting the production and release of pEVs, or by targeting pEVs components and inhibiting their uptake. Additional experiments are required to confirm this potentiality.

Discovery of SZJK-0421: A Novel Potent, Low Toxicity, Selective Second Generation of CRM1 Inhibitor for the Treatment of Both Hematological and Solid Tumors.

Nuclear export factor chromosome region maintenance 1 (CRM1) mediated the transport of various growth-regulatory proteins and was frequently overexpressed in many hematologic and solid tumors. Selinexor (KPT-330) was the only approved CRM1 inhibitor, but the severe gastrointestinal and central nervous system toxicities limited its clinical application. In this manuscript, a series of novel second-generation CRM1 inhibitors were designed, in which SZJK-0421 was a more reversible inhibitor than KPT-330. The treatment of various tumor cells with SZJK-0421 significantly inhibited the function of CRM1. SZJK-0421 displayed good liver microsome stabilities and pharmacokinetic properties. Most importantly, SZJK-0421 reduced the direct damage to the gastrointestinal mucosa, and the brain plasma distribution ratio of SZJK-0421 was very low in Sprague-Dawley (SD) rats (3%), which avoided gastrointestinal reactions such as central nausea and vomiting caused by large permeability of blood-brain barrier. In addition, SZJK-0421 exhibited strong anticancer efficacy in xenograft models of both solid and hematological tumors.

Ginger Extract Improves Cognitive Dysfunction via Modulation of Gut Microbiota-Derived Short-Chain Fatty Acids in D-Galactose/Ovariectomy-Induced Alzheimer-Like Disease.

Alzheimer's disease (AD) is the most common form of dementia with complex causes and limited treatment options. Recent research has suggested a connection between the progression of AD and the activity of gut microbiota. Ginger, a plant known for its anti-inflammatory, antioxidant, and neuroprotective properties, has gained attention as a potential treatment for alleviating AD symptoms. In this study, we induced an AD model in female rats through ovariectomy and D-galactose injection and then investigated the protective effects of oral administration of ginger ethanolic extract. We assessed changes in short-chain fatty acids (SCFAs), learning and memory abilities, neuroinflammatory markers in plasma, and the hippocampus, as well as histological changes in the intestine and hippocampus in sham-operated, diseased, and treatment groups. Oral administration of ginger ethanolic extract improved gut microbiota activity, increased SCFA levels, and enhanced the expression of tight junction proteins. Additionally, ginger extract reduced the concentrations of TNF-α and IL-1β in both plasma and the hippocampus. Furthermore, it significantly reduced cell death and amyloid plaque deposition in the hippocampal tissue. These physiological changes resulted in improved performance in learning and memory tasks in rats treated with ginger compared with the disease group. These findings provide compelling evidence for the beneficial effects of ginger on the gut-brain axis, leading to improvements in learning and memory through the reduction of neuroinflammation.

High‐resolution perfusion imaging in rodents using pCASL at 9.4 T

AbstractAdequate perfusion is critical for maintaining normal brain function and aberrations thereof are hallmarks of many diseases. Pseudo‐Continuous Arterial Spin Labeling (pCASL) MRI enables noninvasive quantitative perfusion mapping without contrast agent injection and with a higher signal‐to‐noise ratio (SNR) than alternative methods. Despite its great potential, pCASL remains challenging, unstable, and relatively low‐resolution in rodents – especially in mice – thereby limiting the investigation of perfusion properties in many transgenic or other relevant rodent models of disease. Here, we address this gap by developing a novel experimental setup for high‐resolution pCASL imaging in mice and combining it with the enhanced SNR of cryogenic probes. We show that our new experimental setup allows for optimal positioning of the carotids within the cryogenic coil, rendering labeling reproducible. With the proposed methodology, we managed to increase the spatial resolution of pCASL perfusion images by a factor of 15 in mice; a factor of 6 in rats is gained compared to the state of the art just by virtue of the cryogenic coil. We also show that the improved pCASL perfusion imaging allows much better delineation of specific brain areas, both in healthy animals as well as in rat and mouse models of stroke. Our results bode well for future high‐definition pCASL perfusion imaging in rodents.

M6A Modification of Profilin-1 in Vascular Smooth Muscle Cells Drives Phenotype Switching and Neointimal Hyperplasia via Activation of the p-ANXA2/STAT3 Pathway.

In-stent restenosis is characterized by a significant reduction in lumen diameter within the stented segment, primarily attributed to excessive proliferation of vascular smooth muscle cells (VSMCs) and neointimal hyperplasia. PFN1 (profilin-1), an actin-sequestering protein extensively studied in amyotrophic lateral sclerosis, remains less explored in neointimal hyperplasia. Utilizing single-cell RNA sequencing alongside data from in-stent restenosis patients and various experimental in-stent restenosis models (swine, rats, and mice), we investigated the role of PFN1 in promoting VSMC phenotype switching and neointimal hyperplasia. Single-cell RNA sequencing of stenotic rat carotid arteries revealed a critical role for PFN1 in neointimal hyperplasia, a finding corroborated in stented swine coronary arteries, in-stent restenosis patients, PFN1SMC-IKO (SMC-specific PFN1 knockout) mice, and PFN1 overexpressed mice. PFN1 deletion was shown to suppress VSMC phenotype switching and neointimal hyperplasia in PFN1SMC-IKO mice subjected to a wire-injured model. To elucidate the observed discordance in PFN1 mRNA and protein levels, we identified that METTL3 (N6-methyladenosine methyltransferase) and YTHDF3 (N6-methyladenosine-specific reader) enhance PFN1 translation efficiency in an N6-methyladenosine-dependent manner, confirmed through experiments involving METTL3 knockout and YTHDF3 knockout mice. Furthermore, PFN1 was mechanistically found to interact with the phosphorylation of ANXA2 (annexin A2) by recruiting Src, promoting the phosphorylation of STAT3, a typical transcription factor known to induce VSMC phenotype switching. This study unveils the significance of PFN1 N6-methyladenosine modification in VSMCs, demonstrating its role in promoting phenotype switching and neointimal hyperplasia through the activation of the p-ANXA2 (phospho-ANXA2)/STAT3 pathway.

Effects of carvacrol on hormonal, inflammatory, antioxidant changes, and ovarian reserve in polycystic ovary syndrome in Wistar rats.

The study, which explored the effects of carvacrol on female reproductive health, particularly in terms of hormonal, inflammatory, antioxidant, and ovarian reserves in polycystic ovary syndrome, could significantly influence future treatments and clinical practice. The study, conducted on thirty-five female Wistar albino rats, was designed to mimic the conditions of polycystic ovary syndrome in humans. The rats were randomly assigned into five groups: control (C), vehicle (V), polycystic ovary syndrome (PCOS), carvacrol (CAR), and polycystic ovary syndrome+ carvacrol (PCOS + CAR). The following practices were applied to the groups during the study. Normal saline was administered to the C group, DMSO to the V group, letrozole (1mg/kg/day) to the PCOS group, carvacrol (20mg/kg) to the CAR group, and letrozole and carvacrol together to the PCOS + CAR group for twenty-one days. At the end of the administration, blood, and ovarian samples were taken for hormone analysis (E2, and AMH), inflammatory (TNF-α, IL-6), oxidant-antioxidant analysis (malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GSH-Px), and catalase), and histopathological examinations. Ovary, and body weights were measured, and the ovary index was calculated. As a result, it was observed that carvacrol caused beneficial effects through inflammatory, and antioxidant mechanisms in PCOS.

DESIGN, SYNTHESIS, AND BIO PROFILING OF 2, 3-DIHYDROQUINAZOLIN-4(1H)-ONE DERIVATIVE AS TYPE II DIABETES AGENTS: A COMPREHENSIVE IN SILICO, IN VITRO, AND IN VIVO STUDY

Objective: Diabetes mellitus is a significant global health challenge, with Type 2 Diabetes Mellitus (T2DM) being a leading cause of mortality worldwide, demanding the need for effective interventions by developing innovative therapeutic strategies or novel antidiabetic agents. This study explores in silico, in vitro, and in vivo approaches to identify the most potent 2,3-Dihydroquinazolin-4(1H)-One derivative molecule with antidiabetic activity. Methods: Eleven new derivatives were designed, studied in silico to identify the most promising compounds, synthesized, studied spectrally to describe them, and evaluated for both in vitro and in vivo investigations. Alpha amylase and alpha-glucosidase inhibitory activities were investigated in vitro. The endogenous suppression of glucose synthesis in Hepatoblastoma cell line 2(HepG2) cells and the in vitro glucose absorption assay on cultivated L6 cell lines were conducted. To assess the ability of the newly synthesized compounds to prevent diabetes, in vivo investigations were conducted on Streptozotocin (STZ)-induced diabetic rats and the effects on various biochemical parameters were identified.Results: Leveraging computational methods, the QZ9 molecule was identified with stable interactions with key biomolecules associated with T2DM. Subsequent in vitro assays confirmed the inhibitory effects of QZ2, QZ8, and QZ9 on alpha-amylase and alpha-glucosidase activities, suggesting their potential as enzyme inhibitors. Additionally, QZ8 and QZ9 demonstrated enhanced glucose uptake and production inhibition in HepG2 cells, indicating their role in improving glucose homeostasis. In vitro, the top-ranked molecules QZ2, QZ8, and QZ9 were analyzed to validate the in silico findings and assess their potential as therapeutic agents for T2DM. The inhibition of α-amylase activity by QZ2, QZ8, and QZ9 was dose-dependent, with maximum inhibition observed at 1000 µg/ml: 57.33% for QZ2, 52.21% for QZ8, and 87.16% for QZ9. Similarly, α-glucosidase inhibition at 1000 µg/ml was 59.96% for QZ2, 53.50% for QZ8, and 81.51% for QZ9. Both QZ8 and QZ9 significantly increased glucose uptake and inhibited glucose production in HepG2 cells, with maximum glucose production inhibition at 100 µg/ml: 62.22% for QZ8 and 62.35% for QZ9. These findings suggest that QZ8 and QZ9 contribute to glucose homeostasis. QZ9 demonstrated superior enzyme inhibition compared to QZ2 and QZ8, with α-amylase and α-glucosidase inhibition up to 87.16% and 81.51%, respectively, at 1000 µg/ml. In vivo investigations in Diabetic rat models further confirmed the efficacy of these compounds by showing significant reductions in blood glucose levels. These results suggests the potentiality of QZ9 as a promising novel Antidiabetic agent.Conclusion: Combining computational predictions with experimental validations, this integrated approach highlights the promise of 2,3-Dihydroquinazolin-4(1H)-One derivative QZ9 as a novel antidiabetic agent, warranting further investigation for clinical translation.

Melanocortin-4 receptor antagonist TCMCB07 alleviates chemotherapy-induced anorexia and weight loss in rats.

Cancer patients undergoing chemotherapy often experience anorexia and weight loss that substantially deteriorates overall health, reduces treatment tolerance and quality of life, and worsens oncologic outcomes. There are currently few effective therapeutic options to mitigate these side effects. The central melanocortin system, which plays a pivotal role in regulating appetite and energy homeostasis, presents a logical target for treating anorexia and weight loss. In this preclinical study, we evaluated the efficacy of TCMCB07, a synthetic antagonist of the melanocortin-4 receptor, in mitigating anorexia and weight loss in several rat models of chemotherapy: cisplatin, 5-fluorouracil, cyclophosphamide, vincristine, doxorubicin, and a combination of irinotecan and 5-fluorouracil. Our results indicate that peripheral administration of TCMCB07 improved appetite, stabilized body weight, preserved fat and heart mass, and slightly protected lean mass after multiple cycles of chemotherapy. Furthermore, combining TCMCB07 with a growth differentiation factor 15 antibody enhanced treatment effectiveness. Similar effects from TCMCB07 treatment were observed in a rat tumor model following combination chemotherapy. No notable adverse effects nor increased chemotherapy-related toxicities were observed with TCMCB07 treatment. These findings suggest that peripheral administration of TCMCB07 holds promise as a therapeutic approach for alleviating chemotherapy-induced anorexia and weight loss, potentially benefiting numerous patients undergoing chemotherapy.

Hypoxia-Preconditioned Human Umbilical Cord Mesenchymal Stem Cells Transplantation Ameliorates Inflammation and Bone Regeneration in Peri-Implantitis Rat Model.

The failure of dental implant treatments is predominantly attributed to peri-implantitis, which entails chronic inflammation within the peri-implant tissue, ultimately leading to tissue degradation. Addressing this condition, human umbilical cord mesenchymal stem cell (hUCMSC) transplantation serves as a regenerative therapy; however, concerns regarding the viability and efficacy of transplanted cells in inflamed regions persist. Hypoxic preconditioning of hUCMSCs has emerged as a potential strategy for augmenting their regenerative and immunomodulatory capacities. This study aimed to evaluate the expression of inflammatory (tumor necrosis factor [TNF]-α) and bone regenerative biomarkers (nuclear factor of activated T-cell [NFATc1], osteocalcin, collagen type I alpha 1 [COL1α1]) within peri-implantitis models subsequent to the transplantation of hypoxia-preconditioned hUCMSCs. Peri-implantitis models were established through the insertion of implants into the femur bone of 42 Wistar strain Rattus norvegicus, followed by intrasocket injection of lipopolysaccharide. The experimental animals were categorized into three groups (control, normoxia, and hypoxia) and underwent observation on days 14 and 28. The expression levels of TNF-α, NFATc1, COL1α1, and osteocalcin were evaluated using immunohistochemical staining, and the resulting data were subjected to one-way analysis of variance analysis (p < 0.05). Transplantation of hypoxia-preconditioned hUCMSCs significantly ameliorated inflammation and osteoclastogenesis, as evidenced by significant reductions in TNF-α and NFATc1 expression compared with the control group. Furthermore, hypoxic preconditioning of hUCMSCs demonstrated a significant elevation in the expression of osteocalcin and COL1α1 relative to the control group. The transplantation of hypoxia-preconditioned hUCMSCs exhibited a capacity to ameliorate inflammation and enhance bone regenerative processes in peri-implantitis rat models.

Effect of different running protocols on bone morphology and microarchitecture of the forelimbs in a male Wistar rat model.

It is accepted that the metabolic response of bone tissue depends on the intensity of the mechanical loads, but also on the type and frequency of stress applied to it. Physical exercise such as running involves stresses which, under certain conditions, have been shown to have the best osteogenic effects. However, at high intensity, it can be deleterious for bone tissue. Consequently, there is no clear consensus as to which running modality would have the best osteogenic effects. Our objective was to compare the effects of three running modalities on morphological and micro-architectural parameters on forelimb bones. Forty male Wistar rats were randomly divided into four groups: high intensity interval training (HIIT), continuous running, combined running ((alternating HIIT and continuous modalities) and sedentary (control). The morphometry, trabecular microarchitecture and cortical porosity of the ulna, radius and humerus were analyzed using micro-tomography. All three running modalities resulted in bone adaptation, with an increase in the diaphyseal diameter of all three bones. The combined running protocol had positive effects on the trabecular thickness in the distal ulna. The HIIT protocol resulted in an increase in both medio-lateral diameter and cortical bone area over total area (Ct.Ar/Tt.Ar) at the ulnar shaft compared with sedentary condition. Moreover, the HIIT protocol decreased the mean surface area of the medulla (Ma.Ar) according to sedentary condition at the ulnar shaft. This study has shown that HIIT resulted in a decrease in trabecular bone fraction in favor of cortical bone area at the ulna.

Compartment-specific small non-coding RNA changes and nucleolar defects in human mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy (mTLE) is a debilitating disease characterized by recurrent seizures originating from temporal lobe structures such as the hippocampus. The pathogenic mechanisms underlying mTLE are incompletely understood but include changes in the expression of non-coding RNAs in affected brain regions. Previous work indicates that some of these changes may be selective to specific sub-cellular compartments, but the full extent of these changes and how these sub-cellular compartments themselves are affected remains largely unknown. Here, we performed small RNA sequencing (RNA-seq) of sub-cellular fractions of hippocampal tissue from mTLE patients and controls to determine nuclear and cytoplasmic expression levels of microRNAs (miRNAs). This showed differential expression of miRNAs and isomiRs, several of which displayed enriched nuclear expression in mTLE. Subsequent analysis of miR-92b, the most strongly deregulated miRNA in the nucleus, showed accumulation of this miRNA in the nucleolus in mTLE and association with snoRNAs. This prompted us to further study the nucleolus in human mTLE which uncovered several defects, such as altered nucleolar size or shape, mis-localization of nucleolar proteins, and deregulation of snoRNAs, indicative of nucleolar stress. In a rat model of epilepsy, nucleolar phenotypes were detected in the latency period before the onset of spontaneous seizures, suggesting that nucleolar changes may contribute to the development of seizures and mTLE. Overall, these data for the first time implicate nucleolar defects in the pathogenesis of mTLE and provide a valuable framework for further defining the functional consequences of altered sub-cellular RNA profiles in this disease.

Activation of LXR signaling ameliorates apoptosis of alveolar epithelial cells in Bronchopulmonary dysplasia

Background and purposesLiver X receptors (LXRs) are specialized nuclear receptors essential for maintaining cholesterol homeostasis, modulating LXR activity could have therapeutic potential in lung diseases. Bronchopulmonary dysplasia (BPD) is a chronic lung disease characterized by impaired alveolar development, in which apoptosis of alveolar epithelial cells is a key contributing factor. The current research focuses on exploring the potential mechanism by which the LXR pathway regulating alveolar epithelial type II cell apoptosis in response to hyperoxia exposure.MethodsBPD infants and non-BPD preterm infants were enrolled to measure serum total cholesterol (TC) levels. To further investigate the role of cholesterol metabolism in BPD, a neonatal rat model of BPD was established, and in vitro studies were conducted using mouse lung epithelial cells (MLE12). These experiments aimed to explore the impact of hyperoxia on cholesterol metabolism and assess the effects of LXR agonist intervention.ResultsElevated serum TC levels in BPD infants were observed, accompanied by lung cholesterol overload in BPD rats. Hyperoxia exposure also led to intracellular cholesterol accumulation in MLE12 cells, which may be attributed to the downregulated LXR signaling pathway. Activation of the LXR pathway prevented apoptosis and mitochondrial dysfunction in MLE12 cell. In BPD rats, intervention with the LXR agonist restored alveolar architecture and reduced alveolar epithelial type II cell apoptosis, which was associated with decreased oxidative stress and lung cholesterol accumulation.ConclusionsDisrupted cholesterol metabolism and impaired homeostasis in premature infants may contribute to the development of BPD. Targeting LXR signaling may provide potential therapeutic targets in BPD.Clinical trial numberNot applicable.

Banxia-Yiyiren alleviates insomnia and anxiety by regulating the gut microbiota and metabolites of PCPA-induced insomnia model rats

Banxia-Yiyiren alleviates insomnia and anxiety by regulating the gut microbiota and metabolites of PCPA-induced insomnia model rats

Nanoparticle ultrasonication: a promising approach for reducing bacterial biofilm in total joint infection-an in vivo rat model investigation.

While the benefits of sonication for improving periprosthetic joint infection (PJI) are well-documented, its potential therapeutic effect against bacterial biofilm remains unstudied. This study aimed to investigate the safety and efficacy of a novel nanoparticle ultrasonication process on methicillin-resistant Staphylococcus aureus (MRSA) bacterial biofilm formation in a PJI rat model. This novel ultrasonication process was designed to remove attached bacterial biofilm from implant and peri-articular tissues, without damaging native tissues or compromising implant integrity. Twenty-five adult Sprague-Dawley rats underwent a surgical procedure and were colonized with intra-articular MRSA, followed by the insertion of a titanium screw. Three weeks after the index surgery, the animals received a second procedure during which the screws were explanted, and soft tissue was sampled. The intraoperative use of the nanoparticle sonication treatment was employed to assess the device's safety, while ex vivo treatment on the retrieved tissue and implants was used to evaluate its efficacy. Clinical and histological assessments did not indicate any macro- or micro-damage to the host tissue. Sonication of the retrieved tissues demonstrated an average bacterial removal of 2 × 103CFU/mL and 1 × 104CFU/gram of tissue. Compared to the standard-of-care group (n = 10), implants treated with sonication (n = 15) had significantly lower remaining bacteria, as indicated by crystal violet absorbance measurements (P = 0.012). This study suggests that nanoparticle sonication technology can successfully remove attached bacterial biofilms from explanted orthopedic hardware and the joint capsule, without negatively affecting native tissue. The study provides initial results supporting the potential of nanoparticle sonication as an adjuvant treatment option during a DAIR (debridement, antibiotics, and implant retention) procedure for PJI, paving the way for future clinical trials.