Animal exercise studies in cardiovascular research:Current knowledge and optimal design--A position paper of the Committee on Cardiac Rehabilitation,Chinese Medical Doctors’Association

Growing evidence has demonstrated exercise as an effective way to promote cardiovascular health and protect against cardiovascular diseases However,the underlying mechanisms of the beneficial effects of exercise have yet to be elucidated.Animal exercise studies are widely used to investigate the key mechanisms of exercise-induced cardiovascular protection.However,standardized procedures and well-established evaluation indicators for animal exercise models are needed to guide researchers in carrying out effective,high-quality animal studies using exercise to prevent and treat cardiovascular diseases.In our review,we present the commonly used animal exercise models in cardiovascular research and propose a set of standard procedures for exercise training,emphasizing the appropriate measurements and analysis in these chronic exercise models.We also provide recommendations for optimal design of animal exercise studies in cardiovascular research,including the choice of exercise models,control of exercise protocols,exercise at different stages of disease,and other considerations,such as age,sex,and genetic background.We hope that this position paper will promote basic research on exercise-induced cardiovascular protection and pave the way for successful translation of exercise studies from bench to bedside in the prevention and treatment of cardiovascular diseases.

A Systematic Review of Animal and Clinical Studies on the Use of Scaffolds for Urethral Repair

Replacing urethral tissue with functional scaffolds has been one of the challenging problems in the field of urethra reconstruction or repair over the last several decades. Various scaffold materials have been used in animal studies, but clinical studies on use of scaffolds for urethral repair are scarce. The aim of this study was to review recent animal and clinical studies on the use of different scaffolds for urethral repair, and to evaluate these scaffolds based on the evidence from these studies. Pub Med and OVID databases were searched to identify relevant studies, in conjunction with further manual search. Studies that met the inclusion criteria were systematically evaluated. Of 555 identified studies, 38 were included for analysis. It was found that in both animal and clinical studies, scaffolds seeded with cells were used for repair of large segmental defects of the urethra, such as in tubular urethroplasty. When the defect area was small, cell-free scaffolds were more likely to be applied. A lot of pre-clinical and limited clinical evidence showed that natural or artificial materials could be used as scaffolds for urethral repair. Urinary tissue engineering is still in the immature stage, and the safety, efficacy, cost-effectiveness of the scaffolds are needed for further study.

Assessment of effectiveness of oral supplementation of isolated fiber of carrot on metabolic parameters in mature rats

This present study was conducted to evaluate the metabolic effects of isolated fi ber of carrot supplementation in rats.Physicochemical properties of fi ber were determined.The groups were as follows:animals fed a standard diet,control group;high fi ber supplementation(70 mg);low fi ber supplementation(35 mg);for 12 weeks.Blood samples were collected at the time of sacrifi ce.The weights of heart,liver,kidneys and spleen of the experimental rats with respect to body weight were recorded.Commercial kits were used to determine serum glucose concentration,lipid profi le(cholesterol,HDL-cholesterol,triglycerides),and the two main aminotransferases glutamic-oxalacetic transaminase(GOT)/glutamate-pyruvate transaminase(GPT).A histopathological assay was performed on the heart,liver,and spleen tissues of animals.Supplementation with fi ber favors weight loss in female((242.03±23.73)-(197.81±10.45)g);and male rats((262.50±32.21)-(213.96±12.56)g and induces a decrease in glucose levels in the supplemented animals.With the exception of total high-density lipoprotein cholesterol,the other lipid fractions decrease signifi cantly in rats supplemented.Fiber supplementation did not induce changes in the dissected organs of the supplemented animals.In conclusion supplementation of fiber,improves glucose control,lower plasma lipid concentrations and reduced body weight in normal rats.

Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update

Non-alcoholic fatty liver disease(NAFLD)is the predominant cause of chronic liver disease worldwide.NAFLD progresses in some cases to non-alcoholic steatohepatitis(NASH),which is characterized,in addition to liver fat deposition,by hepatocyte ballooning,inflammation and liver fibrosis,and in some cases may lead to hepatocellular carcinoma.NAFLD prevalence increases along with the rising incidence of type 2 diabetes mellitus(T2DM).Currently,lifestyle interventions and weight loss are used as the major therapeutic strategy in the vast majority of patients with NAFLD.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)are used in the management of T2DM and do not have major side effects like hypoglycemia.In patients with NAFLD,the GLP-1 receptor production is down-regulated.Recently,several animal and human studies have emphasized the role of GLP-1RAs in ameliorating liver fat accumulation,alleviating the inflammatory environment and preventing NAFLD progression to NASH.In this review,we summarize the updated literature data on the beneficial effects of GLP-1RAs in NAFLD/NASH.Finally,as GLP-1RAs seem to be an attractive therapeutic option for T2DM patients with concomitant NAFLD,we discuss whether GLP-1RAs should represent the first line pharmacotherapy for these patients.

Male-mediated developmental toxicity

Male-mediated developmental toxicity has been of concern for many years. The public became aware of male-mediated developmental toxicity in the early 1990s when it was reported that men working at Sellafield might be causing leukemia in their children. Human and animal studies have contributed to our current understanding of male-mediated effects. Animal studies in the 1980s and 1990s suggested that genetic damage after radiation and chemical exposure might be transmitted to offspring. With the increasing understanding that there is histone retention and modification, protamine incorporation into the chromatin and DNA methylation in mature sperm and that spermatozoal RNA transcripts can play important roles in the epigenetic state of sperm, heritable studies began to be viewed differently. Recent reports using molecular approaches have demonstrated that DNA damage can be transmitted to babies from smoking fathers, and expanded simple tandem repeats minisatellite mutations were found in the germline of fathers who were exposed to radiation from the Chernobyl nuclear power plant disaster. In epidemiological studies, it is possible to clarify whether damage is transmitted to the sons after exposure of the fathers. Paternally transmitted damage to the offspring is now recognized as a complex issue with genetic as well as epigenetic components.

Rac1 activates HIF-1 in laser induced choroidal neovascularization

AIM: To study the effect of Rac1 on the induction of HIF-1 alpha in choroidal neovascularization (CNV) in mice. METHODS: One hundred C57BL/6J mice were laser photocoagulated to induce CNV, fifty mice of that were selected randomly for intravitreal injection of Rac1 inhibitor NSC23766 solution (1 mu L). After laser photocoagulation, fundus fluorescein angiography (FFA) was performed to verify the growth of CNV. Immunohistochemistry and Western blot were used to detect HIF-1 alpha and Rac1 in posterior segment of eye globes. RESULTS: FFA verified that incidence of CNV was significantly reduced in the eyes with NSC23766 injection comparing with that of eyes without NSC23766 injection (P< 0.01). Immunohistochemistry detected that HIF-1 alpha and Rac1 mainly Expressed in the new fibrovascular tissue. Western blot showed that HIF-1 alpha and Rac1 was highly increased in tissue explants of retinal pigment epithelium (RPE) and choroid without NSC23766 injection. But for tissue explants of RPE and choroid with N5C23766 injection, both the expressions of HIF-1 alpha and Rac1 were inhibited. CONCLUSION: Rac1 is crucial to activate HIF-1 regulating the growth of CNV, and its inhibition may have potential therapeutic value.

Acupoint catgut embedding for simple obesity in animal studies:a systematic review and Meta-analysis

OBJECTIVE:To assess the efficacy of acupoint catgut embedding(ACE)for simple obesity in preclinical animal experiments.METHODS:We searched the following 14 electronic databases:PubM ed,Cochrane Library,EMBASE,Oriental Medicine Advanced Searching Integrated System,KoreaMed,Korean Studies Information Service System,Science-on,Research Information Sharing Service,Korea Citation Index,Korea Traditional Knowledge Portal,China Network Knowledge Infrastructure Database,Wanfang Database,Chinese Science and Technology Journal Database,and Chinese Biology Medicine Database,from inception to November 2021 without language limitation.The assessment was performed according to the guidelines of Animal Research:Reporting of in vivo experiments;and Metaanalysis was performed using Reviewer Manager 5.4.1 software.RESULTS:Twenty-four studies involving 813 animals were selected.Meta-analysis showed that ACE was beneficial for weight control[n=40,MD=-50.63,95%CI(-57.59,-43.67),P<0.00001,I 2=0%]and reduced the Lee index[n=40,MD=-18.79,95%CI(-20.01,-17.57),P<0.00001,I 2=0%].However,when efficacy of ACE was compared with that of manual acupuncture,electroacupuncture,or oilistat therapy,statistical difference was not observed between the two groups.CONCLUSIONS:This systematic review suggests that ACE may be efficacious in treating obesity.Moreover,the analyses highlighted the necessity to perform welldesigned,higher-quality experiments.

Glyphosate-Residues in Roundup-Ready Soybean Impair Daphnia magna Life-Cycle

Herbicide tolerant plants such as Roundup-Ready soybean contain residues of glyphosate herbicide. These residues are considered safe and previous animal-feeding-studies have failed to find negative effects related to such chemical residues. The present study tests 8 experimental soy- meal diets as feed in groups (each containing 20 individuals) of test-animals (D. magna). The diets have different levels of glyphosate residues and we show that animal growth, reproductive maturity and number of offspring are correlated with these chemicals. The tested soybeans are from ordinary agriculture in Iowa USA and the residues are below the regulatory limits. Despite this, clear negative effects are seen in life-long feeding. The work enhances the need for including analysis of herbicide residues in future assessment of GMO.

Genomics-driven derivatization of the bioactive fungal sesterterpenoid variecolin:Creation of an unnatural analogue with improved anticancer properties

A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin(1)and variecolactone(2)was identified in Aspergillus aculeatus ATCC 16872.Heterologous production of 1 and 2 was achieved in Aspergillus oryzae by expressing the sesterterpene synthase VrcA and the cytochrome P450 VrcB.Intriguingly,the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues(5-7).Analysis of the compounds’anticancer activity in vitro and in vivo revealed that although 5 and 1 had comparable activities,5 was associated with significantly reduced toxic side effects in cancer-bearing mice,indicating its potentially broader therapeutic window.Our study describes the first tests of variecolin and its analogues in animals and demonstrates the utility of synthetic biology for creating molecules with improved biological activities.

Regulatory considerations for animal studies of biomaterial products

Animal studies play a vital role in validating the concept,feasibility,safety,performance and efficacy of biomaterials products during their bench-to-clinic translation.This article aims to share regulatory considerations for animal studies of biomaterial products.After briefly emphasizing the importance of animal studies,issues of animal studies during biomaterial products’translation are discussed.Animal studies with unclear purposes,flawed design and poor reporting quality could significantly reduce the translation efficiency and create regulatory challenges.Regulatory perspectives on the purpose,principle,quality and regulatory science of animal studies are also presented.Animal studies should have clear purposes,follow principles of 3R+DQ(replacement,reduction,refinement,design and quality)and execute under an efficiently operating quality management system.With the advancement of regulatory science,National Medical Products Administration of China has been developing a series of standards and guidance documents on animal studies of medical devices.Case studies of making decisions on whether to conduct animal studies are provided in the end with drug-eluting stents as examples.In summary,animal studies of biomaterial products should pay close attention to the rationale,design and quality in order to achieve their purposes.

Anti-inflammatory effects of acupuncture in the treatment of chronic obstructive pulmonary disease

Numerous randomised controlled trials have suggested the positive effects of acupuncture on chronic obstructive pulmonary disease(COPD).However,the underlying therapeutic mechanisms of acupuncture for COPD have not been clearly summarized yet.Inflammation is central to the development of COPD.In this review,we elucidate the effects and underlying mechanisms of acupuncture from an antiinflammatory perspective based on animal studies.Cigarette smoke combined with lipopolysaccharide is often used to establish animal models of COPD.Electroacupuncture can be an effective intervention to improve inflammation in COPD,and Feishu(BL13)and Zusanli(ST36)can be used as basic acupoints in COPD animal models.Different acupuncture types can regulate different types of inflammatory cytokines;meanwhile,different acupuncture types and acupoint options have similar effects on modulating the level of inflammatory cytokines.In particular,acupuncture exerts anti-inflammatory effects by inhibiting the release of inflammatory cells,inflammasomes and inflammatory cytokines.The main underlying mechanism through which acupuncture improves inflammation in COPD is the modulation of relevant signalling pathways:nuclear factor-κB(NF-κB)(e.g.,myeloid differentiation primary response 88/NF-κB,toll-like receptor-4/NF-κB,silent information regulator transcript-1/NF-κB),mitogen-activated protein kinase signalling pathways(extracellular signal-regulated kinase 1/2,p38 and c-Jun NH2-terminal kinase),cholinergic anti-inflammatory pathway,and dopamine D2 receptor pathway.The current synthesis will be beneficial for further research on the effect of acupuncture on COPD inflammation.

Role of gut microbiota in ischemic stroke:A narrative review of human and animal studies

The high incidence,mortality,and disability associated with ischemic stroke pose a significant threat to human health.The intestinal microbiota significantly influences the onset,progression,and prognosis of ischemic stroke.Gut flora plays a pivotal role in brain-gut interactions.The reflection of changes in the gut and brain caused by gut microbes faciltates the investigation of early warning biomarkers and potential therapeutic targets for ischemic stroke.In this narrative review of the relationship between gut microbiota and ischemic stroke,we primarily discuss three topics,grounded in real-world human and animal studies.First,we examined the relationship between ischemic stroke and intestinal microbiota and its metabolites,delineate the overall characteristics of intestinal microbiota dysregulation in ischemic stroke,and assess the potential clinical value,prevailing research controversies,and unique phenomena of intestinal microbiota metabolites such as trimethylamine N-oxide and short-chain fatty acids in ischemic stroke.Second,we explored the potential communication pathways between intestinal flora and ischemic stroke based on the brain-gut axis,encompassing metabolic pathways,immune pathways,and neural pathways.Finally,we encapsulated the factors influencing the severity of ischemic stroke via intestinal flora,the pharmacological and nonpharmacological interventions that modulate intestinal flora in treating ischemic stroke,and the current research landscape of intestinal flora in the context of ischemic stroke sequelae.

Swine model of arterial bifurcation aneurysm

Objective To create an arterial bifurcation aneurysm model in swine and evaluate it with digital subtraction angiography (DSA).Methods Ten swine were used for constructing the arterial bifurcation aneurysm models. Seven pigs underwent subsequent intraarterial DSA. Both surgical procedure and transarterial angiography were carried out under anesthesia with mechanical ventilation after tracheal intubation.Results Bifurcation aneurysms were surgically created in ten animals. After surgical procedure, 2 pigs died from aneurysmal rupture and one died of anesthetic overdose. DSA was performed in all other 7 animals and it demonstrated 6 patent aneurysms and one occluded. Three of the 6 patent bifurcation aneurysms were wide necked and 3 were narrow necked.Conclusion Arterial bifurcation aneurysm model can be successfully constructed in swine. It will provide us with an in vivo model to observe and develop therapeutic devices, teach endovascular techniques, and study aneurysmal hemodynamics.

Brain Mechanisms Underlying Panic Attack and Panic Disorder

Panic disorder is a psychiatric disorder characterized by recurrent panic attacks,with a prevalence of~4%in the general population,causing heavy personal and socioeconomic burdens.The similarities of animal defense responses to clinical panic attack symptoms in humans make it possible to translate neuroanatomical pathways identified in animal studies to panic disorder in humans.Therefore,in this review we first present a basic overview of panic disorder in humans including the main subtypes,models commonly used to trigger panic attacks,related hypotheses,the neurotransmitter systems that may be involved,and the current clinical treatments to give the reader a comprehensive understanding of panic disorder.The animal section introduces the models that trigger panic-like behavior in animals and the brain regions that may be involved,providing insights for future elucidation of the neural circuit mechanisms behind panic attacks.