Animal Models and Experimental Medicine

Abstract Hypertension is an important global public health issue because of its high morbidity as well as the increased risk of other diseases. Recent studies have indicated that the development of hypertension is related to the dysbiosis of the gut microbiota in both animals and humans. In this review, we outline the interaction between gut microbiota and hypertension, including gut microbial changes in hypertension, the effect of microbial dysbiosis on blood pressure (BP), indicators of gut microbial dysbiosis in hypertension, and the microbial genera that affect BP at the taxonomic level. For example, increases in Lactobacillus , Roseburia , Coprococcus , Akkermansia , and Bifidobacterium are associated with reduced BP, while increases in Streptococcus , Blautia , and Prevotella are associated with elevated BP. Furthermore, we describe the potential mechanisms involved in the regulation between gut microbiota and hypertension. Finally, we summarize the commonly used treatments of hypertension that are based on gut microbes, including fecal microbiota transfer, probiotics and prebiotics, antibiotics, and dietary supplements. This review aims to find novel potential genera for improving hypertension and give a direction for future studies on gut microbiota in hypertension.

Dong Yan

Ye Sun

Xiaoyue Zhou

Wenhao Si

Jieyu Liu

Min Li

Minna Wu

Anim Models and Exp Med

Regulatory effect of gut microbes on blood pressure

肠道微生物对血压的调节作用

Abstract Circular RNAs (circRNAs) are endogenous RNAs with a covalently closed single‐stranded transcript. They are a novel class of genomic regulators that are linked to many important development and disease processes and are being pursued as clinical and therapeutic targets. Using the most powerful RNA sequencing and bioinformatics techniques, a large number of circRNAs have been identified and further functional studies have been performed. It is known that circRNAs act as potential biomarkers, sponges for microRNAs (miRNAs) and RNA‐binding proteins (RBPs), and regulators of mRNA transcription. They also participate in the translation of peptides or proteins. Many types of circRNAs are dysregulated in plasma or lung tissues, and they may be involved in regulating the proliferation and apoptosis of pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs), leading to pulmonary vascular remodeling in pulmonary hypertension (PH). One possible mechanism is that circRNAs can regulate the function of PAECs and PASMCs by acting as miRNA sponge. However, other potential mechanisms of action of circRNAs are still being actively explored in PH. This paper presents a systematic review of the biogenesis, biological characterization, relevant underlying functions, and future perspectives for studies of circRNAs in the pathogenesis of PH.

Qian Wang

Yuanyuan Sun

Qinhua Zhao

Wenhui Wu

Lan Wang

Yuqing Miao

Ping Yuan

Circular RNAs in pulmonary hypertension: Emerging biological concepts and potential mechanism

肺动脉高压中的环状RNA：新兴的生物学概念与潜在机制

Abstract Hypertriglyceridemia (HTG) often accompanies diabetes and is considered a risk factor for diabetic vascular complications. However, inducing diabetic HTG typically requires high‐fat diets in certain animal models. Leveraging our newly developed LDL receptor knockout hamster model, which exhibits features akin to human lipid metabolism, we sought to determine whether these animals would develop HTG without dietary manipulations in diabetes. Diabetes was induced via intraperitoneal injection of STZ in wild type and heterozygous LDL receptor deficient hamsters. Blood glucose, triglyceride, and cholesterol were measured over 60 days. Plasma TG clearance was determined via olive oil gavage. The effect of insulin on diabetic HTG was assessed on Day 60 post‐diabetes induction. Blood glucose increased over threefold, while plasma insulin decreased to 30% of controls after STZ injection in both wild type and heterozygous hamsters by Day 7, remaining stable for 60 days. Plasma TG in wild‐type hamsters remained unchanged at Day 7 post‐STZ injection but increased slightly thereafter. Conversely, heterozygous hamsters exhibited severe HTG by Day 7 until the end of the study. Olive oil gavage revealed much slower plasma triglyceride clearance in heterozygous hamsters compared to WT animals, despite significantly reduced lipoprotein lipase activity in post‐heparin plasma in both animals. Hyperglycemia and HTG in heterozygous hamsters were reversed to pre‐diabetic levels following intraperitoneal insulin administration. In conclusion, severe HTG in diabetic heterozygous LDL receptor deficient hamsters developed spontaneously and was insulin‐dependent. Thus, this hamster model holds promise for effectively studying the complications associated with human diabetic HTG.

Ya‐Hong Ma

Yuhui Wang

George Liu

Development of a hamster model of spontaneous hypertriglyceridemia in diabetes

糖尿病自发高甘油三酯血症仓鼠模型的开发

Abstract Background Besides seizures, a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy, which further debilitates their quality of life. This study provides an in‐depth characterization of the impact of brivaracetam and rufinamide individually and in combination at 10 and 20 mg/kg doses, respectively, on corneal kindling‐induced generalized seizures and behavioral alterations. Furthermore, observed convulsive frequency and behavioral changes were correlated to post‐kindling‐induced changes in the activity of markers of oxidative stress. Methods Adult C57BL/6 mice were kindled via twice‐daily transcorneal 50‐Hz electrical stimulations (3 mA) for 3 s for 12 days until animals reached a fully kindled state. After the kindling procedure, animals were tested using a set of behavioral tests, and neurochemical alterations were assessed. Results Corneal‐kindled animals exhibited intense generalized convulsions, altered behavioral phenotypes typified by positive symptoms (hyperlocomotion), negative symptoms (anxiety and anhedonia), and deficits in semantic and working memory. BRV 10 + RFM 20 dual regime increased convulsive threshold and propensity toward the start of stage 4–5 seizures and improved phenotypical deficits, that is, anxiety, depression, and memory impairments. Moreover, this combination therapy mitigated kindling‐induced redox impairments as evidenced by reduced malondialdehyde and acetylcholinesterase levels and increased glutathione antioxidant activity in the brain of animals subjected to repetitive brain insult. Conclusion Based on our outcomes, this dual therapy provides supporting evidence in alleviating epilepsy‐induced neurobehavioral comorbidities and changes in redox homeostasis.

Awais Sattar

Zohabia Rehman

Hammad Murtaza

Waseem Ashraf

Tanveer Ahmad

Faleh Alqahtani

Imran Imran

Brivaracetam and rufinamide combination increased seizure threshold and improved neurobehavioral deficits in corneal kindling model of epilepsy

布瓦西坦和鲁非酰胺联合用药提高了癫痫角膜点燃模型的发作阈值并改善了神经行为缺陷

Abstract Background In view of the ever‐increasing representation of Staphylococcus spp. strains resistant to various antibiotics, the development of in vivo models for evaluation of novel antimicrobials is of utmost importance. Methods In this article, we describe the development of a fully immunocompetent porcine model of extensive skin and soft tissue damage suitable for testing topical antimicrobial agents that matches the real clinical situation. The model was developed in three consecutive stages with protocols for each stage amended based on the results of the previous one. Results In the final model, 10 excisions of the skin and underlying soft tissue were created in each pig under general anesthesia, with additional incisions to the fascia performed at the base of the defects and immediately inoculated with Staphylococcus aureus suspension. One pig was not inoculated and used as the negative control. Subsequently, the bandages were changed on Days 4, 8, 11, and 15. At these time points, a filter paper imprint technique (FPIT) was made from each wound for semi‐quantitative microbiological evaluation. Tissue samples from the base of the wound together with the adjacent intact tissue of three randomly selected defects of each pig were taken for microbiological, histopathological, and molecular‐biological examination. The infection with the inoculated S. aureus strains was sufficient during the whole experiment as confirmed by both FPIT and from tissue samples. The dynamics of the inflammatory markers and clinical signs of infection are also described. Conclusions A successfully developed porcine model is suitable for in vivo testing of novel short‐acting topical antimicrobial agents.

Filip Raška

Břetislav Lipový

Šárka Kobzová

Lukáš Vacek

Rea Jarošová

Dominika Kleknerová

Katarína Matiašková

Peter Makovický

Monika Vícenová

Edita Jeklová

Roman Pantůček

Martin Faldyna

Lubomír Janda

Development of a porcine model of skin and soft‐tissue infection caused by <i>Staphylococcus aureus</i>, including methicillin‐resistant strains suitable for testing topical antimicrobial agents

开发一种由金黄色葡萄球菌（包括耐甲氧西林菌株）引起的猪皮肤和软组织感染模型，适用于测试局部抗菌药物

Abstract Background Esophageal strictures following esophageal atresia repair are a source of significant morbidity. To test new therapeutic approaches, we designed a piglet model of esophageal stricture by resecting variable lengths of esophagus with subsequent re‐anastomosis. This study describes the model and validates its physiologic impact by blinded analysis of the weight gains of the piglets. Methods A total of 24 two‐week old Pietrain piglets had esophageal resections performed, ranging from 0 to 5 cm, with the goal of inducing postoperative esophageal strictures. Postoperative body‐weights were evaluated by repeated analysis of variance followed by pairwise group‐comparisons based on estimated marginal means. In addition, body weight was modeled by linear‐mixed model regression. Different resection lengths were compared. The esophagi were evaluated postmortem for stricture. Results Of 24 operated piglets, 23 reached the endpoint, and 90% developed an esophageal stricture that was radiologically visible in a contrast study, as well as appreciable macroscopically in the necropsy. We found differences in pre‐ and postoperative body weights for all piglets ( F (1, 18) = 298.54, p &lt; 0.001), but no differences between resection lengths ( F (4, 18) = 0.36, p = 0.837). Conclusion Our model of postoperative esophageal stricture offers the opportunity to investigate potential treatments for strictures associated with esophageal atresia, since it reliably induces strictures and results in minimal loss of animals. The similar body weight gain in all groups indicates that stricture is mainly the result of esophageal resection and re‐anastomosis, regardless of the length of the resected segment.

Christina Oetzmann von Sochaczewski

Ann‐Kristin Riedesel

Andreas Lindner

Axel Heimann

Arne Schröder

Oliver J. Muensterer

A novel piglet model of esophageal stricture following variable segmental esophageal resection and re‐anastomosis

一种新型猪仔食管狭窄模型：变段食管切除与再吻合术

Abstract Background Over the past few decades, a threefold increase in obesity and type 2 diabetes (T2D) has placed a heavy burden on the health‐care system and society. Previous studies have shown correlations between obesity, T2D, and neurodegenerative diseases, including dementia. It is imperative to further understand the relationship between obesity, T2D, and cognitive deficits. Methods This investigation tested and evaluated the cognitive impact of obesity and T2D induced by high‐fat diet (HFD) and the effect of the host genetic background on the severity of cognitive decline caused by obesity and T2D in collaborative cross (CC) mice. The CC mice are a genetically diverse panel derived from eight inbred strains. Results Our findings demonstrated significant variations in the recorded phenotypes across different CC lines compared to the reference mouse line, C57BL/6J. CC037 line exhibited a substantial increase in body weight on HFD, whereas line CC005 exhibited differing responses based on sex. Glucose tolerance tests revealed significant variations, with some lines like CC005 showing a marked increase in area under the curve (AUC) values on HFD. Organ weights, including brain, spleen, liver, and kidney, varied significantly among the lines and sexes in response to HFD. Behavioral tests using the Morris water maze indicated that cognitive performance was differentially affected by diet and genetic background. Conclusions Our study establishes a foundation for future quantitative trait loci mapping using CC lines and identifying genes underlying the comorbidity of Alzheimer's disease (AD), caused by obesity and T2D. The genetic components may offer new tools for early prediction and prevention.

Avia Paz

Kareem Midlej

Osayd Zohud

Iqbal M. Lone

Fuad A. Iraqi

The collaborative cross mouse for studying the effect of host genetic background on memory impairments due to obesity and diabetes

合作交叉小鼠研究肥胖和糖尿病对宿主遗传背景影响记忆障碍的作用

Abstract Background Metabolic abnormalities are considered to play a key regulatory role in vascular remodeling of pulmonary arterial hypertension. However, to date, there is a paucity of research documenting the changes in metabolome profiles within the supernatants of pulmonary artery smooth muscle cells (PASMC) during their transition from a contractile to a synthetic phenotype. Methods CCK‐8 and Edu staining assays were used to evaluate the cell viability and proliferation of human PASMCs. IncuCyte ZOOM imaging system was used to continuously and automatically detect the migration of the PASMCs. A targeted metabolomics profiling was performed to quantitatively analyze 121 metabolites in the supernatant. Orthogonal partial least squares discriminant analysis was used to discriminate between PDGF‐BB‐induced PASMCs and controls. Metabolite set enrichment analysis was adapted to exploit the most disturbed metabolic pathways. Results Human PASMCs exhibited a transformation from contractile phenotype to synthetic phenotype after PDGF‐BB induction, along with a significant increase in cell viability, proliferation, and migration. Metabolites in the supernatants of PASMCs treated with or without PDGF‐BB were well profiled. Eleven metabolites were found to be significantly upregulated, whereas seven metabolites were downregulated in the supernatants of PASMCs induced by PDGF‐BB compared to the vehicle‐treated cells. Fourteen pathways were involved, and pyruvate metabolism pathway was ranked first with the highest enrichment impact followed by glycolysis/gluconeogenesis and pyrimidine metabolism. Conclusions Significant and extensive metabolic abnormalities occurred during the phenotypic transformation of PASMCs. Disturbance of pyruvate metabolism pathway might contribute to pulmonary vascular remodeling.

Meng‐Jie Zhang

Jie‐Jian Kou

Hong‐Da Zhang

Xin‐Mei Xie

Yun‐Feng Zhou

Xiao‐Bin Pang

Lu‐Ling Zhao

Jing Qiu

Yang‐Yang He

Metabolic alterations in human pulmonary artery smooth muscle cells treated with <scp>PDGF</scp>‐<scp>BB</scp>

<scp>PDGF</scp>‐<scp>BB</scp>处理的人肺动脉平滑肌细胞的代谢改变

短名	Anim Models and Exp Med
Journal Impact	3.67
国际分区	MEDICINE, RESEARCH & EXPERIMENTAL(Q2)
期刊索引	中科院 3 区中国科学引文数据库

ISSN	2096-5451, 2576-2095
h-index	25
国内分区	医学(3区)医学生化与分子生物学(3区)医学医学研究与实验(3区)

出版信息	出版商: John Wiley and Sons Inc，出版周期: ，期刊类型: journal，开源期刊: 否
基本数据	创刊年份: 2018，原创研究文献占比: ，自引率:， Gold OA占比:

Animal Models and Experimental Medicine

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Regulatory effect of gut microbes on blood pressure

Circular RNAs in pulmonary hypertension: Emerging biological concepts and potential mechanism

Development of a hamster model of spontaneous hypertriglyceridemia in diabetes

Brivaracetam and rufinamide combination increased seizure threshold and improved neurobehavioral deficits in corneal kindling model of epilepsy

Development of a porcine model of skin and soft‐tissue infection caused by Staphylococcus aureus, including methicillin‐resistant strains suitable for testing topical antimicrobial agents

Development of a hamster model of spontaneous hypertriglyceridemia in diabetes

A novel piglet model of esophageal stricture following variable segmental esophageal resection and re‐anastomosis

Development of a porcine model of skin and soft‐tissue infection caused by Staphylococcus aureus, including methicillin‐resistant strains suitable for testing topical antimicrobial agents

The collaborative cross mouse for studying the effect of host genetic background on memory impairments due to obesity and diabetes

Metabolic alterations in human pulmonary artery smooth muscle cells treated with PDGF‐BB