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Background: Means of addressing technical challenges in forming gastrojejunostomy (GJ) anastomoses and maintaining their patency are sought., Objectives: Evaluation of preclinical feasibility and healing efficacy of a novel linear magnetic compression anastomosis (MCA) device to form a patent GJ versus sutured jejunal enterotomy (JE) sites in swine., Setting: Single-center veterinary testing facility., Methods: Feasibility of 3 prototype sizes (4, 6, and 8 cm) of a metal MCA device (MCAD) to form a patent GJ was evaluated over 6 weeks. A distal magnet was laparoscopically inserted in the jejunum, a proximal magnet was placed gastroscopically in the stomach; magnets were aligned to gradually form an anastomosis, self-detached, and be expelled. At necropsy, MCAs were assessed for patency and compared with JE tissues to evaluate wound healing., Results: MCADs aligned at the GJ location without complications. In 5/6 MCAD pairs, dislodgement occurred between 7 and 26 days; expulsion 13-31 days; 1 MCAD pair was retained in the stomach. At necropsy, all pigs were healthy, gaining a mean 15.0 kg. Anastomoses were not adequately patent in 2/4 pigs receiving the 4-cm or 6-cm MCADs because their linear length was too small. But, anastomoses of both pigs receiving the 8-cm MCADs maintained full patency. Minimal inflammation and fibrosis were seen in MCA specimens versus sutured enterotomies., Conclusions: A novel linear MCA device was feasible and effectively created a patent GJ anastomosis in swine with minimal inflammation and fibrosis. The MCAD may be appropriate for clinical evaluation., (Copyright © 2024 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Diatoms (Bacillariophyta), being single-celled photosynthetic organisms, are widely distributed in aquatic ecosystems around the globe. Their exoskeletons are resistant to most environmental factors as well as chemical reagents in laboratory settings. Moreover, the ornamentation featured on exoskeletons can be used to identify individual diatomaceous species. As a result, the detection of diatoms in the internal organs, and especially rib marrow, of corpses found in water can serve as an important tool for diagnosing drowning as the cause of death as long as passive postmortem penetration of diatoms into those organs is excluded. In the environmental experiments described in this paper, diatoms were detected in rib marrow only when contamination resulted from a mechanical breach of bone integrity and structure, irrespective of the residence time of bone material in the aquatic environment. Our research suggests that the presence of diatom in the rib marrow may be the gold standard in the diagnosis of drowning in the future. Our animal model research dispels one of the doubts, such as the possibility of passive penetration of diatoms into the bone marrow, which is still under discussion in the forensic medicine community., Competing Interests: Declaration of competing interest none, (Copyright © 2024 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Background: In recent years, pragmatic metformin use in pregnancy has stretched to include prediabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus, and (most recently) preeclampsia. However, with its expanded use, concerns of unintended harm have been raised., Objective: This study developed an experimental primate model and applied ultrahigh performance liquid chromatography coupled to triple-quadrupole mass spectrometry for direct quantitation of maternal and fetal tissue metformin levels with detailed fetal biometry and histopathology., Study Design: Within 30 days of confirmed conception (defined as early pregnancy), 13 time-bred (timed-mated breeding) Rhesus dams with pregnancies designated for fetal necropsy were initiated on twice-daily human dose-equivalent 10 mg/kg metformin or vehicle control. Pregnant dams were maintained as pairs and fed either a control chow or 36% fat Western-style diet. Metformin or placebo vehicle control was delivered in various treats while the animals were separated via a slide. A cesarean delivery was performed at gestational day 145, and amniotic fluid and blood were collected, and the fetus and placenta were delivered. The fetus was immediately necropsied by trained primate center personnel. All fetal organs were dissected, measured, sectioned, and processed per clinical standards. Fluid and tissue metformin levels were assayed using validated ultrahigh performance liquid chromatography coupled to triple-quadrupole mass spectrometry in selected reaction monitoring against standard curves., Results: Among 13 pregnancies at gestational day 145 with fetal necropsy, 1 dam and its fetal tissues had detectable metformin levels despite being allocated to the vehicle control group (>1 μmol metformin/kg maternal weight or fetal or placental tissue), whereas a second fetus allocated to the vehicle control group had severe fetal growth restriction (birthweight of 248.32 g [<1%]) and was suspected of having a fetal congenital condition. After excluding these 2 fetal pregnancies from further analyses, 11 fetuses from dams initiated on either vehicle control (n=4: 3 female and 1 male fetuses) or 10 mg/kg metformin (n=7: 5 female and 2 male fetuses) were available for analyses. Among dams initiated on metformin at gestational day 30 (regardless of maternal diet), significant bioaccumulation within the fetal kidney (0.78-6.06 μmol/kg; mean of 2.48 μmol/kg), liver (0.16-0.73 μmol/kg; mean of 0.38 μmol/kg), fetal gut (0.28-1.22 μmol/kg; mean of 0.70 μmol/kg), amniotic fluid (0.43-3.33 μmol/L; mean of 1.88 μmol/L), placenta (0.16-1.00 μmol/kg; mean of 0.50 μmol/kg), fetal serum (0.00-0.66 μmol/L; mean of 0.23 μmol/L), and fetal urine (4.10-174.10 μmol/L; mean of 38.5 μmol/L) was observed, with fetal levels near biomolar equivalent to maternal levels (maternal serum: 0.18-0.86 μmol/L [mean of 0.46 μmol/L]; maternal urine: 42.60-254.00 μmol/L [mean of 149.30 μmol/L]). Western-style diet feeding neither accelerated nor reduced metformin bioaccumulations in maternal or fetal serum, urine, amniotic fluid, placenta, or fetal tissues. In these 11 animals, fetal bioaccumulation of metformin was associated with less fetal skeletal muscle (57% lower cross-sectional area of gastrocnemius) and decreased liver, heart, and retroperitoneal fat masses (P<.05), collectively driving lower delivery weight (P<.0001) without changing the crown-rump length. Sagittal sections of fetal kidneys demonstrated delayed maturation, with disorganized glomerular generations and increased cortical thickness. This renal dysmorphology was not accompanied by structural or functional changes indicative of renal insufficiency., Conclusion: Our study demonstrates fetal bioaccumulation of metformin with associated fetal growth restriction and renal dysmorphology after maternal initiation of the drug within 30 days of conception in primates. Given these results and the prevalence of metformin use during pregnancy, additional investigation of any potential immediate and enduring effects of prenatal metformin use is warranted., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Training in anastomosis is fundamental in neurosurgery due to the precision and dexterity required. Biological models, although realistic, present limitations such as availability, ethical concerns, and the risk of biological contamination. Synthetic models, on the other hand, offer durability and standardized conditions, although they sometimes lack anatomical realism. This study aims to evaluate and compare the efficiency of anastomosis training models in the intra-extracranial cerebral bypass procedure, identifying those characteristics that enhance optimal microsurgical skill development and participant experience., Methods: A neurosurgery workshop was held from March 2024 to June 2024 with 5 vascular techniques and the participation of 22 surgeons. The models tested were the human placenta, the Wistar rat, the chicken wing artery, the nasogastric feeding tube, and the UpSurgeOn Mycro simulator. The scales used to measure these models were the Main Characteristics Score and the Evaluation Score. These scores allowed us to measure, qualitatively and quantitatively, durability, anatomical similarity, variety of simulation scenarios, risk of biological contamination, ethical considerations and disadvantages with specific infrastructure., Results: The human placenta model, Wistar rat model, and UpSurgeOn model were identified as the most effective for training. The human placenta and Wistar rat models were highly regarded for anatomical realism, while the UpSurgeOn model excelled in durability and advanced simulation scenarios. Ethical and cost implications were also considered., Conclusions: The study identifies the human placenta and UpSurgeOn models as optimal for training in intra-extracranial bypass procedures, emphasizing the need for diverse and effective training models in neurosurgery., (Published by Elsevier Inc.)

Thanks to their exceptional diversity, teeth are among the most distinctive features of vertebrates. Parameters such as tooth size, shape, number, identity, and implantation can have substantial implications for the ecology and certain social behaviors of toothed species. Despite decades of research primarily focused on mammalian dentition, particularly using the laboratory mouse model, squamate reptiles ("lizards" and snakes) offer a wide array of tooth types and dentition variations. This diversity, which includes differences in size, shape, function, and replacement capacity, provides invaluable opportunities for investigating these fundamental properties. The central bearded dragon (Pogona vitticeps), a popular pet species with well-established husbandry practices, is of particular interest. It features a broad spectrum of morphs and spontaneous mutants and exhibits a wide range of heterodont phenotypes, including variation in the size, shape, number, implantation, and renewal of teeth at both posterior and anterior positions. These characteristics position the species as a crucial model organism for developmental studies in tooth research and for gaining deeper insights into evolutionary patterns of vertebrate dentitions. In this article, we provide an overview of the current understanding of squamate dentition, its diversity, development, and replacement. Furthermore, we discuss the significant advantages offered by squamate species as model organisms for investigating the evolutionary and developmental aspects of vertebrate dentition., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Teaching methods in hypospadias repair are still traditional. Available simulators often lack authenticity in terms of haptic feedback and realistic tissue handling., Objective: Our aim was to develop a high-fidelity, easily reproducible, and affordable animal tissue model for the advanced surgical simulation of hypospadias repair with realistic haptic feedback and tissue handling., Material and Methods: A regular-sized chicken leg and a lamb tenderloin are used to assess the feasibility of simulating hypospadias correction by using the example of a Snodgrass Tubularized Incised Plate-Repair. The model preparation is incorporated into the training process., Results: A detailed description of the high-fidelity model is provided. All steps of a hypospadias repair can be trained while providing realistic anatomy, adequate size, and multilayer tissue properties. Haptic conditions highly resemble human tissue properties. Fine tissue handling corresponds to intraoperative conditions. Limitations to this surgical model apply as in other animal tissue models., Conclusion: We developed a high-fidelity, easily reproducible, and affordable hypospadias animal tissue model. Due to the multilayer animal tissue properties, this model provides realistic haptic feedback and thus an inexpensive and reproducible model for hypospadias simulation. External validation is mandatory prior to implementation into urological training., Competing Interests: Conflicts of interest None., (Copyright © 2024 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Mouse models have been instrumental in understanding mechanisms of transplant rejection and tolerance, but cross-study reproducibility and translation of experimental findings into effective clinical therapies are issues of concern. The Mouse Models in Transplantation symposium gathered scientists and physician-scientists involved in basic and clinical research in transplantation to discuss the strengths and limitations of mouse transplant models and strategies to enhance their utility. Participants recognized that increased procedure standardization, including the use of prespecified, defined endpoints, and statistical power analyses, would benefit the field. They also discussed the generation of new models that incorporate environmental and genetic variables affecting clinical outcomes as potentially important. If implemented, these strategies are expected to improve the reproducibility of mouse studies and increase their translation to clinical trials and, ideally, new Food and Drug Administration-approved drugs., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose, as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: In preclinical cardiovascular safety pharmacology studies, statistical analysis of the rate corrected QT interval (QTc) is the focus for predicting QTc interval changes in the clinic. Modeling of a concentration/QTc relationship, common clinically, is limited due to minimal pharmacokinetic (PK) data in nonclinical testing. It is possible, however, to relate the average drug plasma concentration from sparse PK samples over specific times to the mean corrected QTc. We hypothesize that averaging drug plasma concentration and the QTc-rate relationship over time provides a simple, accurate concentration-QTc relationship bridging statistical and concentration/QTc modeling., Methods: Cardiovascular telemetry studies were conducted in non-human primates (NHP; n = 48) and canines (n = 8). Pharmacokinetic samples were collected on separate study days in both species. Average plasma concentrations for specific intervals (CAverage 0-X ) were calculated for moxifloxacin in canines and NHP using times corresponding to super-intervals for the QTc data statistical analysis. The QTc effect was calculated for each super-interval using a linear regression correction incorporating QT and HR data from the whole super-interval. The concentration QTc effects were then modeled., Results: In NHP, a 10.9 ± 0.06 ms (mean ± 95% CI) change in QTc was detected at approximately 1.5× the moxifloxacin plasma concentration that causes a 10 ms QTc change in humans, based on a 0-24 h super-interval. When simulating a drug without QT effects, mock, no effect on QTc was detected at up to 3× the clinical concentration. Similarly, in canines, a 16.6 ± 0.1 ms change was detected at 1.7× critical clinical moxifloxacin concentration, and a 0.04 ± 0.1 ms change was seen for mock., Conclusions: While simultaneous PK and QTc data points are preferred, practical constraints and the need for QTc averaging did not prevent concentration-QTc analyses. Utilizing a 0-24 h super-interval method illustrates a simple and effective method to address cardiovascular questions when preclinical drug exposures exceed clinical concentrations., Competing Interests: Declaration of competing interest The authors do not report any conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Animal research continues to serve a critical role in the testing and development of medical countermeasures. The Göttingen minipig, developed for laboratory research, may provide many benefits for addressing research questions within chemical defense. Targeted development of the Göttingen minipig model could reduce reliance upon non-human primates, and improve study design, statistical power, and throughput to advance medical countermeasures for regulatory approval and fielding. In this vein, we completed foundational pharmacokinetics and physiological safety studies of intramuscularly administered atropine sulfate, pralidoxime chloride (2-PAM), and diazepam across a broad range of doses (1-6 autoinjector equivalent) using adult male Göttingen minipigs (n=11; n=4-8/study) surgically implanted with vascular access ports and telemetric devices to monitor cardiovascular, respiratory, arterial pressure, and temperature signals. Pharmacokinetic data were orderly and the concentration maximum mirrored available human data at comparably scaled doses clearly for atropine, moderately for 2-PAM, and poorly for diazepam. Time to peak concentration approximated 2, 7, and 20 min for atropine, 2-PAM, and diazepam, respectively, and the elimination half-life of these drugs approximated 2 hr (atropine), 3 hr (2-PAM), and 8 hr (diazepam). Atropine sulfate dose-dependently increased the magnitude and duration of tachycardia and decreased the PR and ST intervals (consistent with findings obtained from other species). Mild hypothermia was observed at the highest diazepam dose. Göttingen minipigs appear to provide a ready and appropriate large animal alternative to non-human primates, and further development and evaluation of novel nerve agent medical countermeasures and treatment strategies in this model are justified., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Todd M. Myers reports financial support was provided by Defense Threat Reduction Agency. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Background: Lymphaticovenous anastomosis is widely used in lymphedema management. Although its effectiveness in reducing edema in patients can be clinically observed, evaluating the long-term outcomes of this technique can be complex. This study established an animal model to assess the outcomes of lymphaticovenous anastomosis technique at 15 and 30-days post-surgery using indocyanine green lymphography, Patent Blue V dye injection, and histopathological examination., Methods: An experimental model was established in the hindlimbs of 10 rabbits using the popliteal vein and afferent lymphatic vessels in the popliteal area. The subjects were divided into two groups: the first group (n = 5) underwent patency assessment at 0 and 15 days, and the second group (n = 5) at 0 and 30-days, resulting in 20 anastomoses. Patency was verified at 0, 15, and 30-days using indocyanine green lymphography and Patent Blue V injection. Histopathological examinations were performed on the collected anastomosis samples., Results: The patency rate was 90% (19/20) initially, 60% (6/10) at 15 days post-surgery, and 80% (8/10) at 30-days. The average diameter of lymphatic vessels and veins was 1.0 mm and 0.8 mm, respectively. The median number of collateral veins was 3; the median surgical time was 65.8 min. Histopathology revealed minimal endothelial damage and inflammatory responses due to the surgical sutures, with vascular inflammation and thrombosis in a single case. Local vascular neoformations were observed., Conclusion: This study highlights the reliability and reproducibility of using rabbits as experimental models for training in lymphaticovenous anastomosis technique owing to the accessibility of the surgical site and dimensions of their popliteal vasculature., Competing Interests: Conflict of interest statement None., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Lyme carditis, a well-established manifestation of Lyme disease, has been studied in animal models to improve understanding of its pathogenesis. This review synthesizes existing literature on these models and associated disease mechanisms. Searches in MEDLINE, Embase, BIOSIS, and Web of Science yielded 53 articles (47 mice models and 6 other animal models). Key findings include: 1) Onset of carditis correlates with spirochete localization in the heart; 2) Carditis occurs within 10 days of infection, progressing to peak inflammation within 30 days; 3) Infiltrates were predominantly composed of Mac-1+ macrophages and were associated with increases in TNF-α, IL-1 and IL-12 cytokines; 4) Resolution of inflammation was primarily mediated by lymphocytes; 5) Immune system is a double-edged sword: it can play a role in the progression and severity of carditis, but can also have a protective effect. Animal models offer valuable insights into the evolution and pathophysiologic mechanisms of Lyme carditis., Competing Interests: Declaration of competing interest The authors have no financial or non-financial competing interests to declare., (Copyright © 2024. Published by Elsevier Inc.)

To better treat bacteria-infected wounds and promote healing, new wound dressings must be developed. In this study, we obtained PA@Fe by chelating iron trivalent ions (Fe 3+ ) with protocatechualdehyde (PA), which has a catechol structure. Subsequently, we reacted it with ethylene glycol chitosan (GC) via a Schiff base reaction and loaded vancomycin to obtain an antibacterial Gel@Van hydrogel with a photothermal response. The as-prepared Gel@Van hydrogel exhibited good injectability, self-healing, hemostasis, photothermal stability, biocompatibility, and antioxidant and antibacterial properties. Moreover, Gel@Van hydrogel achieved highly synergistic antibacterial efficacy through photothermal and antibiotic sterilization. In a mouse skin-damaged infection model, Gel@Van hydrogel had a strong ability to promote the healing of methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds, indicating the great potential application value of Gel@Van hydrogel in the field of treating and promoting the healing of infected wounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Metabolic dysfunction-associated steatohepatitis (MASH) is a liver disease that has gained widespread attention globally. Unfortunately, there is no approved treatment for this condition yet. However, recent research has identified Apoptosis signal-regulating kinase 1 (ASK1) and thyroid hormone receptor-β (THR-β) as potential targets for treating MASH. Although the individual effects of these two targets have been studied, their combinatory effect has not been well defined. Therefore, further research is needed to investigate the potential benefits of targeting both ASK1 and THR-β for treating MASH., Methods: We established a MASH model using the HFHFrC diet (high fat, high fructose, and cholesterol) and carbon tetrachloride (CCL4). Forty mice were evenly assigned to four groups: vehicle, GS4997 (an ASK1 inhibitor), MGL3196 (a THRβ agonist), GS4997+ MGL3196 combination (combo). The drugs were administered for 8 weeks, after which the mice were sacrificed for serum biochemical tests, liver TG and TC evaluation, liver histopathological study, and gene expression validation., Results: GS4997 and MGL3196, when used in combination, have been shown to have synergistic effects on various parameters. Firstly, they synergistically reduced body weight and liver body weight ratio. Secondly, this combination also synergistically lowered AST and TC. Thirdly, synergistic effects were also observed in liver TG and TC reduction. Fourthly, we further confirmed that GS4997 mildly improved liver inflammation, ballooning, and fibrosis, but exhibited incredible histopathological efficacy when combined with MGL3196. Finally, this combinatory effect can be interpreted by synergistically regulating lipid-related genes such as Dio1, Ctp1-α, and Cat, inflammation-related genes such as Il-6, Il-8, and Mcp-1, and fibrosis-related genes such as Tgf-β, Col1α1, and Col6α3., Conclusion: GS4997 and MGL3196, when used in combination, have been shown to have a comprehensive effect on MASH by synergistically regulating lipid, inflammation, and fibrosis-related gene expression through co-targeting ASK1 and THRβ., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Hepatitis E virus (HEV) is one of the leading causes of acute viral hepatitis worldwide. Although most of HEV infections are asymptomatic, some patients will develop the symptoms, especially pregnant women, the elderly, and patients with preexisting liver diseases, who often experience anorexia, nausea, vomiting, malaise, abdominal pain, and jaundice. HEV infection may become chronic in immunosuppressed individuals. In addition, HEV infection can also cause several extrahepatic manifestations. HEV exists in a wide range of hosts in nature and can be transmitted across species. Hence, animals susceptible to HEV can be used as models. The establishment of animal models is of great significance for studying HEV transmission, clinical symptoms, extrahepatic manifestations, and therapeutic strategies, which will help us understand the pathogenesis, prevention, and treatment of hepatitis E. This review summarized the animal models of HEV, including pigs, monkeys, rabbits, mice, rats, and other animals. For each animal species, we provided a concise summary of the HEV genotypes that they can be infected with, the cross-species transmission pathways, as well as their role in studying extrahepatic manifestations, prevention, and treatment of HEV infection. The advantages and disadvantages of these animal models were also emphasized. This review offers new perspectives to enhance the current understanding of the research landscape surrounding HEV animal models., Competing Interests: Competing interest No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article., (Copyright © 2023 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

When performing animal experimentation in Pediatric Urology studies, it is important to be aware of physiological differences between species and to understand when relevant disease models are available. Diseased animal models may be more relevant in many cases, rather than performing studies in healthy and normally developed animals. For example, they may be more appropriate for the study of congenital malformations, to investigate the secondary effects of prenatal urinary obstruction, to study the effect of prenatal exposure to endogenous or exogenous factors which may lead to disease, or in testing bioengineered structures. In this short educational article, we aim to describe some disease models that have been used to simulate human pathologies and how, if properly designed, these studies can lead to important new knowledge for human translation. In addition, we also highlight the importance of formulating a research question(s) before deciding on the animal experimental model and species to choose., (Copyright © 2023. Published by Elsevier Ltd.)

The nature of subjective conscious experience, which accompanies us throughout our waking lives, and how it is generated, remain elusive. One of the challenges in studying subjective experience is disentangling the brain activity related to the sensory stimulus processing and stimulus-guided behavior from those associated with subjective perception. Blindsight, a phenomenon characterized by the retained visual discrimination performance but impaired visual consciousness due to damage to the primary visual cortex, becomes a special entry point to address this question. However, to fully understand the underlying neural mechanism, relying on studies involving human patients alone is insufficient. In this paper, we tried to address this issue, by first introducing the well-known cases of blindsight, especially the reports on subjective experience in both human and monkey subjects. And then we described how the impaired visual awareness of blindsight monkeys has been discovered and further studied by specifically designed tasks, as verbal reporting is not possible for these animals. Our previous studies also demonstrated that many complex visually guided cognitive processes were still retained despite the impairment of visual awareness. Further investigation needs to be conducted to explore the relationship between visually guided behavior, visual awareness and brain activity in blindsight subjects., Competing Interests: Declaration of Interests None., (Copyright © 2023 Elsevier Ltd and Japan Neuroscience Society. All rights reserved.)

Background: Because of the rise in antibiotic resistance and the control of pathogenicity, polymicrobial bacterial biofilms exacerbate wound infections. Since bacterial quorum sensing (QS) signals can dysregulate biofilm development, they are interesting therapeutic treatments. In this study, Pseudomonas Quinolone Signal (PQS) was used to treat an animal model of a wound that had both Staphylococcus aureus and Pseudomonas aeruginosa co-infection., Methods: S. aureus and P. aeruginosa mono- and co-infection models were developed in vitro on the L-929 cell line and in an animal model of wound infection. Moreover, PQS was extracted and purified using liquid chromatography. Then, the mono- and co-infection models were treated by PQS in vitro and in vivo. RT-PCR analysis was used to look into changes in biofilm, QS, tissue regeneration, and apoptosis genes after the treatment., Results: PQS significantly disrupted established biofilm up to 90% in both in vitro and in vivo models. Moreover, a 93% reduction in the viability of S. aureus and P. aeruginosa was detected during the 10 days of treatment in comparison to control groups. In addition, the biofilm-encoding and QS-regulating genes were down-regulated to 75% in both microorganisms. Also, fewer epithelial cells died when treated with PQS compared to control groups in both mono- and co-infection groups., Conclusion: According to this study, PQS may facilitate wound healing by stimulating the immune system and reducing apoptosis. It seems to be a potential medication to use in conjunction with antibiotics to treat infections that are difficult to treat., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Chronic pain is a complex and challenging medical condition that affects millions of people worldwide. Understanding the underlying mechanisms of chronic pain is a key goal of preclinical pain research so that more effective treatment strategies can be developed. In this review, we explore nociception, pain, and the multifaceted factors that lead to chronic pain by focusing on preclinical models. We provide a detailed look into inflammatory and neuropathic pain models and discuss the most used animal models for studying the mechanisms behind these conditions. Additionally, we emphasize the vital role of these preclinical models in developing new pain-relief drugs, focusing on biologics and the therapeutic potential of NMDA and cannabinoid receptor antagonists. We also discuss the challenges of TRPV1 modulation for pain treatment, the clinical failures of neurokinin (NK)- 1 receptor antagonists, and the partial success story of Ziconotide to provide valuable lessons for preclinical pain models. Finally, we highlight the overall success and limitations of current treatments for chronic pain while providing critical insights into the development of more effective therapies to alleviate the burden of chronic pain., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Subarachnoid hemorrhage (SAH) is a cerebrovascular disorder with significant mortality and morbidity. Neural injury in SAH is mediated through a variety of pathophysiological processes. Currently available treatments are either nonspecific in targeting the basic pathophysiological mechanisms that result in neural damage in SAH, or merely focus on vasospasm. Ferroptosis is a type of programmed iron dependent cell death, which has received attention due to its possible role in neural injury in SAH. Herein, we review how intracellular iron overload mediates the production of reactive free radicals and lipid peroxidation through a variety of biochemical pathways in SAH. This in turn results in induction of ferroptosis, as well as exacerbation of vasospasm. We also discuss several therapeutic agents that have been shown to inhibit ferroptosis through targeting different steps of the process. Such agents have proven effective in ameliorating vasospasm, neural damage, and neurobehavioral outcomes in animal models of SAH. Human studies to test the safety and efficacy of intrathecal or parenteral administration of the inhibitors of ferroptosis in improving outcomes of SAH patients are warranted. There are currently a few ongoing clinical trials pursuing this therapeutic concept, the results of which will be critical to determine the value of ferroptosis as a novel therapeutic target in SAH., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Wounds are a physical manifestation of injury to the skin causing it to rupture or tear. The process of wound healing naturally restores skin integrity while minimizing the extent of the damage. Hesperidin (HPN) is a natural polyphenolic flavonoid and is effective in treating wounds due to its ability to reduce inflammation and stimulate angiogenesis. However, its use is limited by its poor physicochemical attributes such as poor solubility in water. Recently, nanoparticles, particularly Cubosomes, are found to be promising candidates for advancing wound-healing therapies, owing to their unique properties. The present study was conducted to develop a hydrogel system based on Cubosomes encapsulating HPN (HPN-Cubogel), with the potential to mitigate full-thickness wounds. The therapeutic efficacy of the formulation assessed in the animal model showed that the HPN-Cubogel formulation group exhibited a wound closure rate of 98.96 ± 1.50% after 14 days post-wounding compared to 89.12 ± 2.6% in the control group suggesting superior wound contraction activity. Collagen synthesis was superior in the formulation compared to the control group, as determined through MT staining. In summary, the HPN-Cubogel formulation was found to be the most effective in enhancing full-thickness wound healing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To detect the antioxidant capacity in living organisms, an antioxidation-responsive SERS-active microneedle was fabricated by adsorbing resazurin on miniature SERS substrates, SERS-active microneedles. The SERS intensity ratio of characterized peaks of resazurin and its product, resorufin, was adopted and verified as an indicator of antioxidant capacity. The feasibility of detection of the antioxidant capacity in living organisms was proved by using the fabricated SERS-active microneedles to detect the antioxidant capacity of lipopolysaccharide-induce inflammatory animal models. The fabricated SERS-active microneedles can be inserted into target soft tissues with minimal invasion to detect their antioxidant capacity. The fabricated SERS-active microneedles would be a novel tool to bring the detection of antioxidant capacity from samplings ex vivo and cells to complex tissues to promote the researches on redox biology in living organisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Parkinson's disease is a progressive neurodegenerative condition associated with the deposition of aggregated α-synuclein. Insights into the pathogenesis of Parkinson's disease have been derived from genetics and molecular pathology. Biochemical studies, investigation of transplanted neurons in patients with Parkinson's disease, and cell and animal model studies suggest that abnormal aggregation of α-synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson's disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson's disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson's disease. Although there are currently no disease-modifying treatments for Parkinson's disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition., Competing Interests: Declaration of interests HRM is employed by University College London, and in the past 36 months reports paid consultancy from Roche, Aprinoia, and Amylyx; lecture fees and honoraria from the British Medical Journal, Kyowa Kirin, and the Movement Disorder Society; research grants from CBD Solutions, Drake Foundation, Parkinson's UK, Cure Parkinson's Trust, PSP Association, Medical Research Council, and the Michael J Fox Foundation (MJFF); and is a coapplicant on a patent application related to C9ORF72—method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). MGS is a William Scholl Professor supported by the Scholl Foundation endowment to Cambridge University, is supported by the Wellcome Trust, is supported by the NIHR Cambridge Biomedical Research Centre Dementia (NIHR203312) and Neurodegeneration Theme (146281), and in the past 12 months has been paid lecture fees or honoraria, or both, from the Movement Disorder Society and Institute San Raffaele; is on the Scientific Advisory Board of the Tau Consortium, Qatar Biomedical Research Institute, Fondazione Don Gnocchi, Eurac, and the European Brain Research Institute; is a consultant for Astex; is in scientific collaboration with Eli Lilly and Teva; and reports research grants from Parkinson's UK, MJFF, Biotechnology and Biological Sciences Research Council, the Scholl Foundation, Fondation de la Recherche Alzheimer, Alzheimer's Research UK, Medical Research Council, Wellcome Trust, and the Bill & Melinda Gates foundation. CMS is employed by South Eastern Sydney Local Health District, Neuroscience Research Australia, and University of New South Wales; is a National Health and Medical Research Council (NHMRC) Practitioner Fellow (APP1136800); and in the past 12 months, has received research funding from the NHMRC, the Medical Research Futures Fund, MJFF, and Shake It Up Australia; and has been paid lecture fees and honoraria from the Movement Disorder Society and the Taiwan Movement Disorder Society. CHW-G is employed by the University of Cambridge, and in the past 12 months has received research funding from the Medical Research Council (MR/W029235/1), the National Institutes of Health Research (NIHR) Cambridge Biomedical Research Centre (NIHR203312), Parkinson's UK, Cure Parkinson's, the Evelyn Trust, and the Cambridge Centre for Parkinson-Plus; consultancy fees from Evidera; and speaker fees from GSK and the World Parkinson Congress., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: This systematic and meta-analysis review evaluated the transcutaneous electrical nerve stimulation (TENS)-induced action mechanisms for animal analgesia., Materials and Methods: Two independent investigators identified relevant articles published until February 2021 through a literature review, and a random-effects meta-analysis was performed to synthesize the results., Results: Of the 6984 studies found in the data base search, 53 full-text articles were selected and used in the systematic review. Most studies used Sprague Dawley rats (66.03%). High-frequency TENS was applied to at least one group in 47 studies, and most applications were performed for 20 minutes (64.15%). Mechanical hyperalgesia was analyzed as the primary outcome in 52.83% of the studies and thermal hyperalgesia in 23.07% of studies using a heated surface. More than 50% of the studies showed a low risk of bias on allocation concealment, random housing, selective outcome reporting, and acclimatization before the behavioral tests. Blinding was not performed in only one study and random outcome assessment in another study; acclimatization before the behavioral tests was not performed in just one study. Many studies had an uncertain risk of bias. Meta-analyses indicated no difference between low-frequency and high-frequency TENS with variations among the pain models., Conclusions: This systematic review and meta-analysis suggests that TENS has presented a substantial scientific foundation for its hypoalgesic effect in preclinical studies for analgesia., (Copyright © 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

This study aims to develop chitosan-bioactive glass (BG) scaffolds for diabetic wound healing, toxicity valuation, and subcutaneous implantation in animals for biocompatibility assessment. The scaffolds were prepared by lyophilization technique. In specific BG without sodium (Na), composited with chitosan for better biological activities. The equipped scaffolds were studied for their physiochemical, biological, in vitro and in vivo performances. The chitosan and chitosan-BG (Na free) scaffolds show reliable biocompatibility, cytocompatibility, anti-oxidant, and tissue regeneration. The biocompatibility, toxicity assessments, and diabetic skin wound healing experiments were examined through in vivo studies using Sprague Dawley rats. The extracted tissue samples were analyzed using hematoxylin-eosin- (H and E) and Masson's trichrome staining. Further, tissue excised after scaffold implantation declared non-toxic, non-allergic, and anti-inflammatory nature of chitosan scaffolds. Moreover, the total ribonucleic acid (RNA) expression levels were measured using reverse transcription-polymerase chain reaction (RT-PCR) for the scaffolds against vascular endothelial growth factor (VEGF), and collagen type one (Col-1) primers. Admirably, the scaffolds achieved the best level of skin wound healing via tissue regeneration by increasing epithetical cell formation and collagen deposition. Thus, the biocompatibility, non-toxicity, anti-inflammatory, and wound healing efficiency proved that the chitosan-BG (Na free) scaffold can be readily substantial for wound healing., Competing Interests: Declaration of competing interest The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Probiotic supplementation is a potential therapeutic for metabolic diseases, including obesity, metabolic syndrome (MetS), and type 2 diabetes (T2D), but most studies deliver multiple species of bacteria in addition to prebiotics or oral pharmaceuticals. This may contribute to conflicting evidence in existing meta-analyses of probiotics in these populations and warrants a systematic review of the literature to assess the contribution of a single probiotic genus to better understand the contribution of individual probiotics to modulate blood glucose. We conducted a systematic review and meta-analysis of animal studies and human randomized controlled trials (RCTs) to assess the effects of Bifidobacterium (BF) probiotic supplementation on markers of glycemia. In a meta-analysis of 6 RCTs, BF supplementation had no effect on fasting blood glucose {FBG; mean difference [MD] = -1.99 mg/dL [95% confidence interval (CI): -4.84, 0.86], P = 0.13}, and there were no subgroup differences between subjects with elevated FBG concentrations and normoglycemia. However, BF supplementation reduced FBG concentrations in a meta-analysis comprised of studies utilizing animal models of obesity, MetS, or T2D [n = 16; MD = -36.11 mg/dL (CI: -49.04, -23.18), P < 0.0001]. Translational gaps from animal to human trials include paucity of research in female animals, BF supplementation in subjects that were normoglycemic, and lack of methodologic reporting regarding probiotic viability and stability. More research is necessary to assess the effects of BF supplementation in human subjects with elevated FBG concentrations. Overall, there was consistent evidence of the efficacy of BF probiotics to reduce elevated FBG concentrations in animal models but not clinical trials, suggesting that BF alone may have minimal effects on glycemic control, may be more effective when combined with multiple probiotic species, or may be more effective in conditions of hyperglycemia rather than elevated FBG concentrations., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The complex mechanics of the gastric wall facilitates the main digestive tasks of the stomach. However, the interplay between the mechanical properties of the stomach, its microstructure, and its vital functions is not yet fully understood. Importantly, the pig animal model is widely used in biomedical research for preliminary or ethically prohibited studies of the human digestion system. Therefore, this study aims to thoroughly characterize the mechanical behavior and microstructure of the porcine stomach. For this purpose, multiple quasi-static mechanical tests were carried out with three different loading modes, i.e., planar biaxial extension, radial compression, and simple shear. Stress-relaxation tests complemented the quasi-static experiments to evaluate the deformation and strain-dependent viscoelastic properties. Each experiment was conducted on specimens of the complete stomach wall and two separate layers, mucosa and muscularis, from each of the three gastric regions, i.e., fundus, body, and antrum. The significant preconditioning effects and the considerable regional and layer-specific differences in the tissue response were analyzed. Furthermore, the mechanical experiments were complemented with histology to examine the influence of the microstructural composition on the macrostructural mechanical response and vice versa. Importantly, the shear tests showed lower stresses in the complete wall compared to the single layers which the loose network of submucosal collagen might explain. Also, the stratum arrangement of the muscularis might explain mechanical anisotropy during tensile tests. This study shows that gastric tissue is characterized by a highly heterogeneous microstructure with regional variations in layer composition reflecting not only functional differences but also diverse mechanical behavior. STATEMENT OF SIGNIFICANCE: Unfortunately, only few experimental data on gastric tissue are available for an adequate material parameter and model estimation. The present study therefore combines layer- and region-specific stomach wall mechanics obtained under multiple loading conditions with histological insights into the heterogeneous microstructure. On the one hand, the extensive data sets of this study expand our understanding of the interplay between gastric mechanics, motility and functionality, which could help to identify and treat associated pathologies. On the other hand, such data sets are of high relevance for the constitutive modeling of stomach tissue, and its application in the field of medical engineering, e.g., in the development of surgical staplers and the improvement of bariatric surgical interventions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Acid mine drainage (AMD) is widely acknowledged as a substantial threat to the biodiversity of aquatic ecosystems. The present study aimed to study the toxicological effects of Cu-rich AMD from the Sulitjelma mine in zebrafish larvae. The AMD from this mine was found to contain elevated levels of dissolved metals including Mg (46.7 mg/L), Al (20.2 mg/L), Cu (18.3 mg/L), Fe (19.8 mg/L) and Zn (10.6 mg/L). To investigate the toxicological effects, the study commenced by exposing zebrafish embryos to various concentrations of AMD (ranging from 0.75% to 9%) to determine the median lethal concentration (LC 50 ). Results showed that 96 h LC 50 for zebrafish larvae following AMD exposure was 2.86% (95% CI: 2.32-3.52%). Based on acute toxicity results, zebrafish embryos (<2 hpf) were exposed to 0.1% AMD (Cu: 21.7 µg/L) and 0.45% AMD (Cu: 85.7 µg/L) for 96 h to assess development, swimming behaviour, heart rate, respiration and transcriptional responses at 116 hpf. Light microscopy results showed that both 0.1% and 0.45% AMD reduced the body length, eye size and swim bladder area of zebrafish larvae and caused phenotypic abnormalities. Swimming behaviour results showed that 0.45% AMD significantly decreased the locomotion of zebrafish larvae. Heart rate was not affected by AMD exposure. Furthermore, exposure caused a significant increase in oxygen consumption indicating vascular stress in developing larvae. Taken altogether, the study shows that even heavily diluted AMD with environmentally relevant levels of Cu caused toxicity in zebrafish larvae., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Hyaluronan (HA) has been recently identified as a key component of the densification of thoracolumbar fascia (TLF), a potential contributor to non-specific lower back pain (LBP) currently treated with manual therapy and systemic or local delivery of anti-inflammatory drugs. The aim of this study was to establish a novel animal model suitable for studying ultrasound-guided intrafascial injection prepared from HA with low and high Mw. Effects of these preparations on the profibrotic switch and mechanical properties of TLF were measured by qPCR and rheology, respectively, while their lubricating properties were evaluated by tribology. Rabbit proved to be a suitable model of TLF physiology due to its manageable size enabling both TLF extraction and in situ intrafascial injection. Surprisingly, the tribology showed that low Mw HA was a better lubricant than the high Mw HA. It was also better suited for intrafascial injection due to its lower injection force and ability to freely spread between TLF layers. No profibrotic effects of either HA preparation in the TLF were observed. The intrafascial application of HA with lower MW into the TLF appears to be a promising way how to increase the gliding of the fascial layers and target the myofascial LBP., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Robert Schleip reports a relationship with Contipro a.s. that includes: consulting or advisory and paid expert testimony. Vladimir Velebny reports a relationship with Contipro a.s. that includes: board membership and equity or stocks., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Glioblastoma multiforme (GBM) is the most common and devastating primary brain tumor among adults. It is highly lethal disease, as only 25% of patients survive longer than 1 year and only 5% more than 5 years from the diagnosis. To search for the new, more effective methods of treatment, the understanding of mechanisms underlying the process of tumorigenesis is needed. The new light on this problem may be shed by the analysis of biochemical anomalies of tissues affected by tumor growth. Therefore, in the present work, we applied the Fourier transform infrared (FTIR) and Raman microspectroscopy to evaluate changes in the distribution and structure of biomolecules appearing in the rat brain as a result of glioblastoma development. In turn, synchrotron X-ray fluorescence microscopy was utilized to determine the elemental anomalies appearing in the nervous tissue. To achieve the assumed goals of the study animal models of GBM were used. The rats were subjected to the intracranial implantation of glioma cells with different degree of invasiveness. For spectroscopic investigation brain slices taken from the area of cancer cells administration were used. The obtained results revealed, among others, the decrease content of lipids and compounds containing carbonyl groups, compositional and structural changes of proteins as well as abnormalities in the distribution of low atomic number elements within the region of tumor., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: The flavonoid-rich fraction of Rosa damascena (FRFRD) contains antioxidant and active compounds. Therefore, this study aimed to investigate the role of FRFRD, rich in quercetin and kaempferol, in liver fibrosis induced by CCl4., Materials and Methods: The FRFRD fraction was separated and standardized by High-Performance Liquid Chromatography (HPLC) based on the levels of quercetin and kaempferol. Liver fibrosis was induced over CCl4 over 12 weeks in 30 male Wistar rats, and three concentrations of FRFRD were administered to them during the last four weeks. Subsequently, after evaluation of liver serum markers and fibrotic parameters, the relative expression of transforming growth factor-beta-1 (TGF-β 1 ), platelet-derived growth factor (PDGF), and lysyl oxidase homolog 2 (Loxl2) genes were assessed, along with the measurement of lysyl oxidase activity and oxidative markers., Results: Fibrotic markers demonstrated progressive recovery of liver damage in the treated group compared to the non-treatment group (p < 0.01). These results were accompanied by a significant decrease in the expression of TGF-β 1 , PDGF, and Loxl2 genes, as well as, a reduction in lysyl oxidase activity (p < 0.001). The antioxidant effects of the treatment were observed through a significant decrease in malondialdehyde (MDA) levels and an increase in catalase enzyme (CAT) and glutathione peroxidase (GPx) activity in the treatment group compared to the fibrotic group (p < 0.01)., Conclusion: The flavonoid-rich fraction of Rosa damascena ameliorates liver damage by affecting collagen cross-linking and lowering oxidative and inflammatory levels., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest, (Copyright © 2023. Published by Elsevier Inc.)

Objective: Radiation necrosis (RN) is a long-term side effect of Gamma Knife stereotactic radiosurgery that may require surgical intervention. Pentoxifylline and vitamin E have previously been shown to be effective in the treatment of RN in the published literature, but there are no data on the prophylactic use of these molecules or, more importantly, whether prophylaxis is required., Methods: The iatrogenic RN model included 50 Sprague-Dawley rats of both sexes. There were 7 treatment subgroups established. Gamma-Plan 8.32 was used to plan after magnetic resonance scans were performed in a specially designed frame. The injection doses used in the treatment groups were vitamin E (30 mg/kg/day in a single dose) and pentoxifylline (50 mg/kg/day in 2 doses). Control magnetic resonance scans were performed at the end of a 16-week treatment, and the subjects were decapitated for pathological evaluations., Results: The intensity of hypoxia - inducible factor 1α immunoreactivity is statistically significantly lower in the therapeutic vitamin E, prophylactic pentoxifylline and vitamin E, and therapeutic pentoxifylline and vitamin E groups than in the other groups. Similarly, the intensity of vascular endothelial growth factor immunoreactivity was reduced in the therapeutic vitamin E and prophylactic pentoxifylline and vitamin E treatment modality groups. When compared with other groups, the therapeutic pentoxifylline group had significantly fewer vascular endothelial growth factor-immunoreactive cells in the perinecrotic area, with an accompanying decreased contrast enhancement pattern., Conclusions: Both vitamin E and pentoxifylline are effective for the treatment and/or restriction of RN, either alone or in combination. The use of these molecules as a preventive measure did not outperform the therapeutic treatment., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The importance of nicotinamide adenine dinucleotide (NAD + ) in human physiology is well recognized. As the NAD + concentration in human skin, blood, liver, muscle, and brain are thought to decrease with age, finding ways to increase NAD + status could possibly influence the aging process and associated metabolic sequelae. Nicotinamide mononucleotide (NMN) is a precursor for NAD + biosynthesis, and in vitro/in vivo studies have demonstrated that NMN supplementation increases NAD + concentration and could mitigate aging-related disorders such as oxidative stress, DNA damage, neurodegeneration, and inflammatory responses. The promotion of NMN as an antiaging health supplement has gained popularity due to such findings; however, since most studies evaluating the effects of NMN have been conducted in cell or animal models, a concern remains regarding the safety and physiological effects of NMN supplementation in the human population. Nonetheless, a dozen human clinical trials with NMN supplementation are currently underway. This review summarizes the current progress of these trials and NMN/NAD + biology to clarify the potential effects of NMN supplementation and to shed light on future study directions., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Obesity is a global health difficulty characterized by an excessive accumulation of fat that increases body weight. Obesity has been studied in multiple animal models, of which those in which it is induced by diet stand out. Due to the increase in this condition, other mechanisms have been addressed that are triggered by states of overweight or obesity, such as the appearance of oxidative stress. These models aim to relate obesity caused by diet and how it influences the development of oxidative stress. In this study, a systematic review of the literature of 39 articles that studied obesity due to the consumption of hypercaloric diets and the appearance of oxidative stress in different animal models was carried out. This review identified the models with the most excellent use and the characteristics of the most appropriate diets to characterize states of oxidative stress due to obesity. In addition, the advantages and disadvantages of each model used are provided, as well as the techniques used for the assessment of obesity, and oxidative stress, providing the information in such a way that there is a general overview of the existing models of the parameters that allow to adequately establish both variables studied, providing information that allows the researcher to choose the appropriate model and factors according to the interest and objectives of the present research., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Multi-parametric MRI (mpMRI) technology enables non-invasive and quantitative assessments of the structural, molecular, and functional characteristics of various neurological diseases. Despite the recognized importance of studying spinal cord pathology, mpMRI applications in spinal cord research have been somewhat limited, partly due to technical challenges associated with spine imaging. However, advances in imaging techniques and improved image quality now allow longitudinal investigations of a comprehensive range of spinal cord pathological features by exploiting different endogenous MRI contrasts. This review summarizes the use of mpMRI techniques including blood oxygenation level-dependent (BOLD) functional MRI (fMRI), diffusion tensor imaging (DTI), quantitative magnetization transfer (qMT), and chemical exchange saturation transfer (CEST) MRI in monitoring different aspects of spinal cord pathology. These aspects include cyst formation and axonal disruption, demyelination and remyelination, changes in the excitability of spinal grey matter and the integrity of intrinsic functional circuits, and non-specific molecular changes associated with secondary injury and neuroinflammation. These approaches are illustrated with reference to a nonhuman primate (NHP) model of traumatic cervical spinal cord injuries (SCI). We highlight the benefits of using NHP SCI models to guide future studies of human spinal cord pathology, and demonstrate how mpMRI can capture distinctive features of spinal cord pathology that were previously inaccessible. Furthermore, the development of mechanism-based MRI biomarkers from mpMRI studies can provide clinically useful imaging indices for understanding the mechanisms by which injured spinal cords progress and repair. These biomarkers can assist in the diagnosis, prognosis, and evaluation of therapies for SCI patients, potentially leading to improved outcomes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Parkinson's disease (PD) is one of the most common neurodegenerative diseases in the elderly. Cognitive dysfunction represents a common and challenging non-motor symptom for people with Parkinson's disease. The number of neurotrophic proteins in the brain is critical in neurodegenerative diseases such as Parkinson's. This research aims to compare the effects of two types of exercise, forced and voluntary, on spatial memory and learning and neurochemical factors (CDNF and BDNF)., Methods: In this research, 60 male rats were randomly divided into six groups (n = 10): the control (CTL) group without exercise, the Parkinson's groups without and with forced (FE) and voluntary (VE) exercises, and the sham groups (with voluntary and forced exercise). The animals in the forced exercise group were placed on the treadmill for four weeks (five days a week). At the same time, voluntary exercise training groups were placed in a special cage equipped with a rotating wheel. At the end of 4 weeks, learning and spatial memory were evaluated with the Morris water maze test. BDNF and CDNF protein levels in the hippocampus were measured by the ELISA method., Results: The results showed that although the PD group without exercise was at a significantly lower level than other groups in terms of cognitive function and neurochemical factors, both types of exercise, could improve these problems., Conclusion: According to our results, 4 weeks of voluntary and forced exercises were all found to reverse the cognitive impairments of PD rats., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Chemical exchange saturated transfer (CEST) MRI has biomarker potential to assess tissue microenvironment in brain tumors. Multi-pool Lorentzian or spinlock models provides useful insights into the CEST contrast mechanism. However, T 1 contribution to the complex overlapping effects of brain tumors is difficult under the non-equilibrium state. Therefore, this study evaluated T 1 contributions on multi-pool parameters with quasi-steady-state (QUASS) algorithm reconstructed equilibrium data. MRI scans were performed in rat brain tumor models, including relaxation, diffusion, and CEST imaging. A pixel-wise seven-pool spinlock-model was employed to fit QUASS reconstructed CEST Z-spectra and evaluated the magnetization transfer (MT), amide, amine, guanidyl, and nuclear-overhauled effect (NOE) signals in tumor and normal tissues. In addition, T 1 was estimated from the spinlock-model fitting and compared with measured T 1 . We observed tumor had a statistically significant increase in the amide signal (p < 0.001) and decreases in the MT and NOE signals (p < 0.001). On the other hand, the differences in amine and guanidyl between the tumor and contralateral normal regions were not statistically significant. The differences between measured and estimated T 1 values were 8% in the normal tissue and 4% in the tumor. Furthermore, the isolated MT signal strongly correlated with R 1 (r = 0.96, P < 0.001). In summary, we successfully unraveled multi-factorial effects in the CEST signal using spinlock-model fitting and QUASS method and demonstrated the effect of T 1 relaxation on MT and NOE., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Cerebral vasospasm is one of the most fatal complications after spontaneous aneurysmal subarachnoid hemorrhage. Although various treatments have been tried for the treatment of cerebral vasospasm so far, the effect is insignificant or temporary except for oral nimodipine. Phosphodiesterase isozyme type 5 inhibitor, which is used to treat erection dysfunction, recently has been known to have a cerebrovascular vasodilation. It is thought that this will be effective in cerebral vasospasm, and the effect will be compared and analyzed with oral nimodipine through an animal model of cerebral vasospasm., Material and Methods: A total of 40 rabbits were used to make subarachnoid hemorrhage model and were divided into three groups - a control group, nimodipine group, and tadalafil group. The cerebral vessels were angiographically measured before and on the third day of subarachnoid hemorrhage. Then vertebrobasilar arteries were harvested and evaluated. Under the microscope, lumen area and media area were measured for each group and were compared., Results: Angiographically, tadalafil group showed significant vasodilation compared with the control group (p < 0.01). Histologically, tadalafil showed a similar effect on lumen and on media area to that of nimodipine group compared with the control group., Conclusions: Cerebral vasospasm could leave neurologic deficit or sequelae even after proper treatment. Therefore, prevention is important. Tadalafil showed preventive effect against cerebral vasospasm and vasodilative effect similar to that of nimodipine. Therefore, tadalafil could be considered an alternative preventive treatment of cerebral vasospasm., Competing Interests: Declaration of Competing Interest None of the authors has any relevant financial or non-financial interests to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The experience of prolonged stress changes how individuals interact with their environment and process interoceptive cues, with the end goal of optimizing survival and well-being in the face of a now-hostile world. The chronic stress response includes numerous changes consistent with limiting further damage to the organism, including development of passive or active behavioral strategies and metabolic adjustments to alter energy mobilization. These changes are consistent with symptoms of pathology in humans, and as a result, chronic stress has been used as a translational model for diseases such as depression. While it is of heuristic value to understand symptoms of pathology, we argue that the chronic stress response represents a defense mechanism that is, at its core, adaptive in nature. Transition to pathology occurs only after the adaptive capacity of an organism is exhausted. We offer this perspective as a means of framing interpretations of chronic stress studies in animal models and how these data relate to adaptation as opposed to pathology., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Pathological cardiac hypertrophy occurs in response to numerous increased afterload stimuli and precedes irreversible heart failure (HF). Therefore, therapies that ameliorate pathological cardiac hypertrophy are urgently required. Sirtuin 3 (Sirt3) is a main member of histone deacetylase class III and is a crucial anti-oxidative stress agent. Therapeutically enhancing the Sirt3 transfection efficiency in the heart would broaden the potential clinical application of Sirt3. Ultrasound-targeted microbubble destruction (UTMD) is a prospective, noninvasive, repeatable, and targeted gene delivery technique. In the present study, we explored the potential and safety of UTMD as a delivery tool for Sirt3 in hypertrophic heart tissues using adult male Bama miniature pigs. Pigs were subjected to ear vein delivery of human Sirt3 together with UTMD of cationic microbubbles (CMBs). Fluorescence imaging, western blotting, and quantitative real-time PCR revealed that the targeted destruction of ultrasonic CMBs in cardiac tissues greatly boosted Sirt3 delivery. Overexpression of Sirt3 ameliorated oxidative stress and partially improved the diastolic function and prevented the apoptosis and profibrotic response. Lastly, our data revealed that Sirt3 may regulate the potential transcription of catalase and MnSOD through Foxo3a. Combining the advantages of ultrasound CMBs with preclinical hypertrophy large animal models for gene delivery, we established a classical hypertrophy model as well as a strategy for the targeted delivery of genes to hypertrophic heart tissues. Since oxidative stress, fibrosis and apoptosis are indispensable in the evolution of cardiac hypertrophy and heart failure, our findings suggest that Sirt3 is a promising therapeutic option for these diseases. STATEMENT OF SIGNIFICANCE: Pathological cardiac hypertrophy is a central prepathology of heart failure and is seen to eventually precede it. Feasible targets that may prevent or reverse disease progression are scarce and urgently needed. In this study, we developed surface-filled lipid octafluoropropane gas core cationic microbubbles that could target the release of human Sirt3 reactivating the endogenous Sirt3 in hypertrophic hearts and protect against oxidative stress in a pig model of cardiac hypertrophy induced by aortic banding. Sirt3-CMBs may enhance cardiac diastolic function and ameliorate fibrosis and apoptosis. Our work provides a classical cationic lipid-based, UTMD-mediated Sirt3 delivery system for the treatment of Sirt3 in patients with established cardiac hypertrophy, as well as a promising therapeutic target to combat pathological cardiac hypertrophy., Competing Interests: Declaration of Competing Interest All authors declare no known competing financial interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The time since death is an important aspect of forensic medicine; however, there is not an accurate single method to determine this data. Therefore, this research aimed to evaluate parameters and procedures based on the morphological analysis of cells and tissues to determine the time since death, using animal models. Pigs were chosen in this research because of their similarities with human anatomy, physiology, and pathophysiology. We identified the cells and tissue alterations in the viscera of pig cadavers according to the time since death, also describing the changes in the temperature of the organs and the bodies. The environmental temperature during the sample collection was also registered. The viscera analysis was performed for 24 h, with a 2-h variation period. After the sample collection, microscope slides were prepared for optical microscopy analysis. Through this 24-h analysis, we observed that the pancreas, small intestine, and large intestine presented more cellular alterations than the other organs. The alterations observed in the other viscera have significance when analyzed in combination. The meninges presented higher stability and few changes in 24 h, which could be relevant in an investigation of the time since death in a period greater than 24 h. Our results showed that histological evaluation is an excellent method to determine the time since death., Competing Interests: Declaration of competing interest I, Eduardo Novakoski, principal investigator of this research, communicate on behalf of all collaborators that we have no commercial, financial, personal, academic, or another conflict of interest in the submission, approval, or refusal of this project., (Copyright © 2023 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Bioluminescence imaging is a highly sensitive technique commonly used for various in vivo applications. Recent efforts to expand the utility of this modality have led to the development of a suite of activity-based sensing (ABS) probes for bioluminescence imaging by 'caging' of luciferin and its structural analogs. The ability to selectively detect a given biomarker has presented researchers with many exciting opportunities to study both health and disease states in animal models. Here, we highlight recent (2021-2023) bioluminescence-based ABS probes with an emphasis on probe design and in vivo validation experiments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Spheroids can allow three-dimensional (3D) cell culture without scaffolds, potentially promoting the production of growth factors from adipose-derived stem cells (ADSCs). We hypothesized that ADSC spheroids exert more favourable effects on osteochondral defects than ADSCs in two-dimensional (2D) cultures. The purpose of this study was to compare the therapeutic effects of 2D and 3D cultures of ADSCs on osteochondral defects using animal models., Methods: Rat femoral osteochondral defects were created. When creating osteochondral defects, phosphate-buffered saline, 2D ADSCs, or ADSC spheroids as a 3D culture were administered on to the lesion. At 2, 4, 6, 8, 10 and 12 weeks post-surgery, knee tissues were harvested and evaluated via histological examination. The expression of genes related to growth factors and apoptosis were compared between 2D and 3D ADSCs., Results: Histologically, the repair of osteochondral defects was significantly enhanced in 3D ADSCs than in 2D ADSCs in terms of the Wakitani score and cartilage repair rate. In 3D ADSCs, TGF-β1, VEGF, HGF and BMP-2 were significantly upregulated, while apoptosis was suppressed in the early phase., Conclusion: The therapeutic effects of 3D ADSC spheroids on osteochondral defects were more potent than those of 2D ADSCs. The upregulated expression of growth factors and suppression of apoptosis could contribute to promoting these therapeutic effects. Overall, ADSC spheroids can help treat osteochondral defects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)