Natural Animal Model Research Articles

Neurodegenerative Diseases: What Can Be Learned from Toothed Whales?

Neurodegeneration involves a wide range of neuropathological alterations affecting the integrity, physiology, and architecture of neural cells. Many studies have demonstrated neurodegeneration in different animals. In the case of Alzheimer's disease (AD), spontaneous animal models should display two neurohistopathological hallmarks: the deposition of β-amyloid and the arrangement of neurofibrillary tangles. However, no natural animal models that fulfill these conditions have been reported and most research into AD has been performed using transgenic rodents. Recent studies have also demonstrated that toothed whales - homeothermic, long-lived, top predatory marine mammals - show neuropathological signs of AD-like pathology. The neuropathological hallmarks in these cetaceans could help to better understand their endangered health as well as neurodegenerative diseases in humans. This systematic review analyzes all the literature published to date on this trending topic and the proposed causes for neurodegeneration in these iconic marine mammals are approached in the context of One Health/Planetary Health and translational medicine.

Middle-aged dogs with low and high Aβ CSF concentrations show differences in energy and stress related metabolic profiles in CSF

BackgroundAmyloid beta (Aβ) accumulation in the brain is one of the earliest findings in Alzheimer's disease (AD). The dog is a natural animal model for amyloid processing and early brain amyloid pathology. The goal of this study is to examine which differences in metabolomic profiles in cerebrospinal fluid (CSF) could be detected in dogs with a difference in CSF Aβ concentrations before amyloid accumulation occurs. MethodMetabolic profiling was performed on CSF from 4 to 8 year old dogs with different CSF Aβ concentrations. ResultsMetabolomic profiling of CSF showed differences in brain energy metabolism. More specifically, increases in N-acetylation of amino acids and amino sugars, creatine and pentose metabolism, and a decrease in tricarboxylic acid (TCA) cycle were seen in dogs with a high CSF Aβ concentration. In addition, signs of elevated oxidative stress, higher methionine, lipid and nucleotide metabolism and increased levels of cysteine, myo-inositol and trimethylamine N-oxide were noted in these animals. ConclusionsDifferences in energy metabolism and stress mediated metabolic changes are seen in the brain of dogs with different CSF Aβ concentrations, before any amyloid deposition occurs. Similar metabolic changes, as in the high Aβ dogs, have been described in AD in humans and/or transgenic AD mice, some of them in very early phases. General significanceThe differences observed in metabolomic profiles could help in identifying potential biomarkers for an increased risk of developing amyloid pathology in the brain and open the door to the evaluation of preventive treatments for amyloid pathology in humans.

Multiple Mechanisms of Action of Sulfodyne®, a Natural Antioxidant, against Pathogenic Effects of SARS-CoV-2 Infection.

Few therapeutic options are available to treat COVID-19. The KEAP1/NRF2 pathway, the major redox-responsive pathway, has emerged as a potential therapeutic target for COVID-19 as it regulates redox homeostasis and inflammation that are altered during SARS-CoV-2 infection. Here, we characterized the effects of NRF2-agonist Sulfodyne®, a stabilized natural Sulforaphane, in cellular and animal models of SARS-CoV-2 infection. In pulmonary or colonic epithelial cell lines, Sulfodyne® elicited a more efficient inhibition of SARS-CoV-2 replication than NRF2-agonists DMF and CDDO. This antiviral activity was not dependent on NRF2 but was associated with the regulation of several metabolic pathways, including the inhibition of ER stress and mTOR signaling, which are activated during SARS-CoV-2 infection. Sulfodyne® also decreased SARS-CoV-2 mediated inflammatory responses by inhibiting the delayed induction of IFNB1 and type I IFN-stimulated genes in infected epithelial cell lines and by reducing the activation of human by-stander monocytes recruited after SARS-CoV-2 infection. In K18-hACE2 mice infected with SARS-CoV-2, Sulfodyne® treatment reduced both early lung viral load and disease severity by fine-tuning IFN-beta levels. Altogether, these results provide evidence for multiple mechanisms that underlie the antiviral and anti-inflammatory activities of Sulfodyne® and pinpoint Sulfodyne® as a potent therapeutic agent against pathogenic effects of SARS-CoV-2 infection.

A murine model of Trypanosoma brucei-induced myocarditis and cardiac dysfunction.

Trypanosoma brucei is a protozoan parasite that causes human and animal African trypanosomiases (HAT and AAT). Cardiac symptoms are commonly reported in HAT patients, and intracardiac parasites with accompanying myocarditis have been observed in both natural hosts and animal models of T. brucei infection. Despite the importance of T. brucei as a cause of cardiac dysfunction and the dramatic socioeconomic impact of African trypanosomiases in sub-Saharan Africa, there are currently no reproducible murine models of T. brucei-associated cardiomyopathy. We present the first clinically relevant, reproducible murine model of cardiac dysfunction in chronic T. brucei infection. Similar to humans, mice showed histological evidence of myocarditis and elevation of serum NT-proBNP with electrocardiographic abnormalities. Serum NT-proBNP levels were elevated prior to the development of severe ventricular dysfunction. On flow cytometry, myocarditis was associated with an increase of most myocardial immune cell populations, including multiple T cell and macrophage subsets, corroborating the notion that T. brucei-associated cardiac damage is an immune-mediated event. This novel mouse model represents a powerful and practical tool to investigate the pathogenesis of T. brucei-mediated heart damage and supports the development of therapeutic options for T. brucei-associated cardiac disease.

Increased expression of SLC25A18 is associated with Alzheimer’s disease and is involved in Aβ42-induced mitochondrial dysfunction and apoptosis in neuronal cells

Alzheimer’s disease (AD) is currently one of the most serious public health concerns in the world. However, the best approach to treat AD has yet to be discovered, implying that we must continue to work hard to find new AD target genes. In this study, we further analysed Gene Expression Omnibus (GEO) data and discovered that the expression of the Mitochondria glutamate carrier SLC25A18 is associated with AD by screening the differentially expressed genes in different regions of the brains of Alzheimer’s disease patients. To verify the expression of SLC25A18 during Alzheimer’s disease development, we analysed animal models (5×FAD transgenic AD animal model, chemically induced AD animal model, natural ageing animal model), and the results showed that the expression of SLC25A18 was increased in animal models of AD. Further investigation of the different regions found that SLC25A18 expression was elevated in the EC, TeA, and CA3, and expressed in neurons. Next, We found that Aβ42 treatment elevated SLC25A18 expression in Neuro 2A cells. Reducing SLC25A18 expression attenuated mitochondrial dysfunction and neuronal apoptosis caused by Aβ42. Overexpression of SLC25A18 increased ATP and intracellular superoxide anions but decreased mitochondrial membrane potential. The results indicate that SLC25A18 affects mitochondrial function and neuronal apoptosis, and is related to AD, which makes it a potential target for treating brain dysfunction.

High-fat diet induces sarcopenic obesity in natural aging rats through the gut–trimethylamine N-oxide–muscle axis

IntroductionThe lack of suitable animal models for sarcopenic obesity (SO) limits in-depth research into the disease. Emerging studies have demonstrated that gut dysbiosis is involved in the development of SO. As the importance of microbial metabolites is starting to unveil, it is necessary to comprehend the specific metabolites associated with gut microbiota and SO. ObjectivesWe aimed to investigate whether high-fat diet (HFD) causes SO in natural aging animal models and specific microbial metabolites that are involved in linking HFD and SO. MethodsYoung rats received HFD or control diet for 80 weeks, and obesity-related metabolic disorders and sarcopenia were measured. 16S rRNA sequencing and non-targeted and targeted metabolomics methods were used to detect fecal gut microbiota and serum metabolites. Gut barrier function was evaluated by intestinal barrier integrity and intestinal permeability. Trimethylamine N-oxide (TMAO) treatment was further conducted for verification. ResultsHFD resulted in body weight gain, dyslipidemia, impaired glucose tolerance, insulin resistance, and systemic inflammation in natural aging rats. HFD also caused decreases in muscle mass, strength, function, and fiber cross-sectional area and increase in muscle fatty infiltration in natural aging rats. 16S rRNA sequencing and nontargeted and targeted metabolomics analysis indicated that HFD contributed to gut dysbiosis, mainly characterized by increases in deleterious bacteria and TMAO. HFD destroyed intestinal barrier integrity and increased intestinal permeability, as evaluated by reducing levels of colonic mucin-2, tight junction proteins, goblet cells and elevating serum level of fluorescein isothiocyanate-dextran 4. Correlation analysis showed a positive association between TMAO and SO. In addition, TMAO treatment aggravated the development of SO in HFD-fed aged rats through regulating the ROS-AKT/mTOR signaling pathway. ConclusionHFD leads to SO in natural aging rats, partially through the gut–microbiota–TMAO–muscle axis.

Plasticity changes in iron homeostasis in hibernating Daurian ground squirrels (Spermophilus dauricus) may counteract chronically inactive skeletal muscle atrophy.

Disuse-induced muscular atrophy is frequently accompanied by iron overload. Hibernating animals are a natural animal model for resistance to disuse muscle atrophy. In this paper, we explored changes in skeletal muscle iron content of Daurian ground squirrels (Spermophilus dauricus) during different periods of hibernation as well as the regulatory mechanisms involved. The results revealed that compared with the summer active group (SA), iron content in the soleus muscle (SOL) decreased (- 65%) in the torpor group (TOR), but returned to normal levels in the inter-bout arousal (IBA); splenic iron content increased in the TOR group (vs. SA, + 67%), decreased in the IBA group (vs. TOR, - 37%). Expression of serum hepcidin decreased in the TOR group (vs. SA, - 22%) and returned to normal levels in the IBA groups; serum ferritin increased in the TOR group (vs. SA, + 31%), then recovered in the IBA groups. Soleus muscle transferrin receptor 1 (TfR1) expression increased in the TOR group (vs. SA, + 83%), decreased in the IBA group (vs. TOR, - 30%); ferroportin 1 increased in the IBA group (vs. SA, + 55%); ferritin increased in the IBA group (vs. SA, + 42%). No significant differences in extensor digitorum longus in iron content or iron metabolism-related protein expression were observed among the groups. Significantly, all increased or decreased indicators in this study returned to normal levels after the post-hibernation group, showing remarkable plasticity. In summary, avoiding iron overload may be a potential mechanism for hibernating Daurian ground squirrels to avoid disuse induced muscular atrophy. In addition, the different skeletal muscle types exhibited unique strategies for regulating iron homeostasis.

Bearded capuchin monkeys as a model for Alzheimer's disease.

The absence of a natural animal model is one of the main challenges in Alzheimer's disease research. Despite the challenges of using nonhuman primates in studies, these animals can bridge mouse models and humans, as nonhuman primates are phylogenetically closer to humans and can spontaneously develop AD-type pathology. The capuchin monkey, a New World primate, has recently attracted attention due to its skill in creating and using instruments. We analyzed one capuchin brain using structural 7T MRI and performed a neuropathological evaluation of three animals. Alzheimer-type pathology was found in the two of the capuchins. Widespread β-amyloid pathology was observed, mainly in focal deposits with variable morphology and a high density of mature plaques. Notably, plaque-associated dystrophic neurites associated with disruption of axonal transport and early cytoskeletal alteration were frequently found. Unlike in other species of New World monkeys, cerebral arterial angiopathy was not the predominant form of β-amyloid pathology. Additionally, abnormal aggregates of hyperphosphorylated tau, resembling neurofibrillary pathology, were observed in the temporal and frontal cortex. Astrocyte hypertrophy surrounding plaques was found, suggesting a neuroinflammatory response. These findings indicate that aged capuchin monkeys can spontaneously develop Alzheimer-type pathology, indicating that they may be an advantageous animal model for research in Alzheimer's disease.

Effects of Acipenserid herpesvirus 2 on the outcome of a Streptococcus iniae co-infection in white sturgeon (Acipenser transmontanus)

Acipenserid herpesvirus 2 (AciHV-2) is a large double-stranded DNA virus in the family Alloherpesviridae that causes catastrophic outbreaks in young naive white sturgeon (Acipenser transmontanus) populations, with mortalities of up to 80%. Survivors of these infections are suspected to remain latently infected. The gram-positive zoonotic bacterium Streptococcus iniae is another important sturgeon pathogen that causes severe myositis and up to 50% mortality during natural outbreaks. Throughout the last decade, co-infections of AciHV-2 and S. iniae have been reported in cultured white sturgeon in California resulting in severe presentations of piscine streptococcosis. This phenomenon of herpesvirus and streptococcus co-infection appears to span multiple taxa since in humans, it is recognized that a Human herpesvirus 3 infection (VZV) is a negative prognostic indicator for pediatric Invasive Group A Streptococcal infections (IGASI). While a decrease in humoral immunity caused by VZV has been hypothesized as a potentially important factor in IGASI cases, no natural animal model exists to study this process. Moreover, no studies have investigated these reported co-infections in white sturgeon. Therefore, the goal of this study was to investigate the effects of a recent AciHV-2 infection on the outcome of a subsequent S. iniae challenge in white sturgeon fingerlings. When fish were infected with 108 colony forming units (CFU) of S. iniae intramuscularly (IM), a statistically significant decrease in survival of 41% was detected in the co-infection group compared to the S. iniae group (p-value < 0.001). This difference was not observed when fish were infected with 106 CFU of S. iniae IM. At this lower infection dose, however, a statistically significant downregulation of tnfα was observed in the spleen of fish in the co-infection group compared to the S. iniae group (p-value = 0.0098). Analysis of serum from survivors revealed a statistically significant reduction in anti-S. iniae serum IgM and serum serotransferrin in fish from the co-infection group compared to the S. iniae group (p-value = 0.0134 and p-value = 0.0183, respectively). Further studies are indicated to determine what interactions lead to the decreased production of pathogen-specific IgM, serotransferrin, and TNFα in the host.

A Novel CARMIL2 Immunodeficiency Identified in a Subset of Cavalier King Charles Spaniels with Pneumocystis and Bordetella Pneumonia.

Pet dogs are a valuable natural animal model for studying relationships between primary immunodeficiencies and susceptibility to Pneumocystis and other opportunistic respiratory pathogens. Certain breeds, such as the Cavalier King Charles Spaniel, are over-represented for Pneumocystis pneumonia (PCP), suggesting the presence of a primary immunodeficiency in the breed. Here, we report the discovery of a CARMIL2 nonsense variant in three Cavalier King Charles Spaniel dogs with either PCP (n = 2) or refractory Bordetella pneumonia (n = 1). CARMIL2 encodes a protein that plays critical roles in T-cell activation and other aspects of immune function. Deleterious CARMIL2 variants have recently been reported in human patients with PCP and other recurrent pneumonias. In addition to opportunistic respiratory infection, the affected dogs also exhibited other clinical manifestations of CARMIL2 deficiencies that have been reported in humans, including early-onset gastrointestinal disease, allergic skin disease, mucocutaneous lesions, abscesses, autoimmune disorders, and gastrointestinal parasitism. This discovery highlights the potential utility of a natural canine model in identifying and studying primary immunodeficiencies in patients affected by PCP.

Multiple integrated social stress induces depressive-like behavioral and neural adaptations in female C57BL/6J mice

Despite women representing most of those affected by major depression, preclinical studies have focused almost exclusively on male subjects, partially due to a lack of ideal animal paradigms. As the persistent need regarding the sex balance of neuroscience research and female-specific pathology of mental disorders surges, the establishment of natural etiology-based and systematically validated animal paradigms for depression with female subjects becomes an urgent scientific problem. This study aims to establish, characterize, and validate a “Multiple Integrated Social Stress (MISS)” model of depression in female C57BL/6J mice by manipulating and integrating daily social stressors that females are experiencing. Female C57BL/6J mice randomly experienced social competition failure in tube test, modified vicarious social defeat stress, unescapable overcrowding stress followed by social isolation on each day, for ten consecutive days. Compared with their controls, female MISS mice exhibited a relatively decreased preference for social interaction and sucrose, along with increased immobility in the tail suspension test, which could last for at least one month. These MISS mice also exhibited increased levels of blood serum corticosterone, interleukin-6 L and 1β. In the pharmacological experiment, MISS-induced dysfunctions in social interaction, sucrose preference, and tail suspension tests were amended by systematically administrating a single dose of sub-anesthetic ketamine, a rapid-onset antidepressant. Compared with controls, MISS females exhibited decreased c-Fos activation in their anterior cingulate cortex, prefrontal cortex, nucleus accumbens and some other depression-related brain regions. Furthermore, 24 h after the last exposure to the paradigm, MISS mice demonstrated a decreased center zone time in the open field test and decreased open arm time in the elevated plus-maze test, indicating anxiety-like behavioral phenotypes. Interestingly, MISS mice developed an excessive nesting ability, suggesting a likely behavioral phenotype of obsessive-compulsive disorder. These data showed that the MISS paradigm was sufficient to generate pathological profiles in female mice to mimic core symptoms, serum biochemistry and neural adaptations of depression in clinical patients. The present study offers a multiple integrated natural etiology-based animal model tool for studying female stress susceptibility.

Bearded capuchin monkey as a model for Alzheimer’s disease (AD) research

AbstractBackgroundThe absence of a natural animal model is one of the main challenges to research in AD. AD‐type pathology has been described in chimpanzees and other primates’ brains. The bearded capuchin monkey (Sapajus libidinosus) is a New World primate that attracted attention mainly due to its skill in creating and using tools. We evaluated the brains of three captive capuchins (9, 29 and 33 years‐old) who died from natural causes at the Primate Center of University of Brasilia.MethodWhole brain was fixed in 4% buffered paraformaldehyde within 12 hours of death for three weeks. Structural 7T MRI was acquired in one case before brain slicing. Consecutive coronal sections from the fixed brain were embedded in paraffin, and 5um sections from paraffin blocks were used for staining and immunohistochemistry evaluation. All brain sections were stained with hematoxylin and eosin. Immunohistochemistry with β‐amyloid (4G8), phosphorylated tau (AT8), p62, TDP‐43, α‐synuclein (81A), 68 kDa neurofilament (2F11), GFAP and CD68 antibodies were performed in selected sections to analyze the following areas: frontal cortex, temporal cortex, parietal cortex, occipital cortex, anterior cingulate cortex, hippocampus, amygdala, basal ganglia, thalamus, mesencephalon, pons, medulla oblongata, and cerebellum.ResultMacroscopic evaluation of the brains showed considerable cortical gyrification. In addition, thick cortical ribbon was observed in the MRI. A complete neuropathological evaluation was available for two cases. Widespread β‐amyloid immunoreactivity was observed in the form of diffuse deposits, core‐space‐corona plaques, perivascular plaques, and amyloid angiopathy. A high frequency of classic neuritic plaques was observed. P‐tau antibody failed to label the dystrophic neurites. However, these lesions were revealed with p62 and neurofilament antibodies. Astrocyte hypertrophy surrounding plaques was observed without microglial activation. Very few hyperphosphorylated tau aggregates resembling neurofibrillary tangles and neuropil threads were found in the temporal and frontal cortex, and Lewy‐type and TDP‐43 pathology were not observed.ConclusionIn summary, we found β‐amyloid immunoreactivity, classic neuritic plaques surrounded by astrocyte hypertrophy, but only rare P‐tau aggregates. To our knowledge, this is the first evidence reporting brain AD‐like alterations in capuchin monkeys which suggest that this species can be considered an advantageous animal model for AD research.

Natural hosts and animal models for Rift Valley fever phlebovirus.

Rift Valley fever phlebovirus (RVFV) is a zoonotic mosquito-transmitted arbovirus, presenting a serious threat to humans and animals. Susceptible hosts are of great significance for the prevention of RVFV. Appropriate animal models are helpful to better understand the onset and development of diseases, as well as the control measures and vaccine research. This review focuses on the role of animal hosts in the maintenance of the virus, and summarizes the host range of RVFV. We list some common animal models in the process of RVFV research, which would provide some important insights into the prevention and treatment of RVFV, as well as the study of Rift Valley fever (RVF) pathogenesis and vaccines.

Plasticity changes in neuromuscular junction morphology and related regulatory proteins in the hibernating ground squirrel.

Skeletal muscle disuse atrophy can cause degenerative changes in neuromuscular junction morphology. Although Daurian ground squirrels (Spermophilus dauricus) are a natural anti-disuse animal model for studying muscle atrophy during hibernation, little is known about the morphological and regulatory mechanisms of their neuromuscular junctions. Here, we found that morphological indices of the soleus muscle were significantly lower during hibernation (torpor and interbout arousal) compared to pre-hibernation but recovered during post-hibernation. In the extensor digitorum longus muscle, neuromuscular junction morphology did not change significantly during hibernation. Agrin-Lrp4-MuSK is a key pathway for the formation and maintenance of the neuromuscular junction. Our results showed that low-density lipoprotein receptor-associated protein 4 (Lrp4) expression in the soleus (slow muscle) decreased by 46.2% in the interbout arousal group compared with the pre-hibernation group (p = 0.019), with recovery in the post-hibernation group. Compared to the pre-hibernation group, agrin expression in the extensor digitorum longus (fast muscle) increased by 67.0% in the interbout arousal group (p = 0.016). In conclusion, periodic up-regulation in agrin expression during interbout arousal may be involved in the maintenance of neuromuscular junction morphology in the extensor digitorum longus muscle during hibernation. The degenerative changes in neuromuscular junction morphology and the periodic decrease in Lrp4 protein expression in the soleus during hibernation, these changes recovered to the pre-hibernation levels in the post-hibernation group, also exhibiting significant plasticity. This plasticity may be an important mechanism for resisting disuse atrophy in hibernating animals.

Metallothionein I/II Expression and Metal Ion Levels in Correlation with Amyloid Beta Deposits in the Aged Feline Brain.

Brain aging has been correlated with high metallothionein I-II (MT-I/II) expression, iron and zinc dyshomeostasis, and Aβ deposition in humans and experimental animals. In the present study, iron and zinc accumulation, the expression of MT-I/II and Aβ42, and their potential association with aging in the feline brain were assessed. Tissue sections from the temporal and frontal grey (GM) and white (WM) matter, hippocampus, thalamus, striatum, cerebellum, and dentate nucleus were examined histochemically for the presence of age-related histopathological lesions and iron deposits and distribution. We found, using a modified Perl's/DAB method, two types of iron plaques that showed age-dependent accumulation in the temporal GM and WM and the thalamus, along with the age-dependent increment in cerebellar-myelin-associated iron. We also demonstrated an age-dependent increase in MT-I/II immunoreactivity in the feline brain. In cats over 7 years old, Aβ immunoreactivity was detected in vessel walls and neuronal somata; extracellular Aβ deposits were also evident. Interestingly, Aβ-positive astrocytes were also observed in certain cases. ICP-MS analysis of brain content regarding iron and zinc concentrations showed no statistically significant association with age, but a mild increase in iron with age was noticed, while zinc levels were found to be higher in the Mature and Senior groups. Our findings reinforce the suggestion that cats could serve as a dependable natural animal model for brain aging and neurodegeneration; thus, they should be further investigated on the basis of metal ion concentration changes and their effects on aging.

Alterations in histology of the aging salivary gland and correlation with the glandular inflammatory microenvironment

Aging-related salivary dysfunction typically causes reduced saliva volumes, which leads to debilitating consequences, even affecting patient quality of life. Understanding the respective clinicopathological characteristics and molecular mechanisms underlying salivary gland functioning during aging is vital for therapeutic purposes. Here, we provide a detailed atlas of the salivary gland microenvironment during aging, and we identified several phenotypes characteristic of aging salivary glands, including acini atrophy, increased inflammatory cells, altered immune responses, and accumulation of lysosomes and autophagosomes in aging cells, which may reflect progressive degeneration of salivary gland function. Furthermore, our analyses suggested significant enrichment of metabolic pathways in aging glands. Our results revealed complex cellular cross-talk among aging acinar cells, inflammatory factors, and immune responses. A natural aging animal model was established to verify these findings. This study provides mechanistic insights into age-related clinicopathogenesis, important implications for early diagnosis, and identification of new targets for improving salivary gland dysfunction.

Integrated metabolomics and phosphoproteomics reveal the protective role of exosomes from human umbilical cord mesenchymal stem cells in naturally aging mouse livers

BackgroundAging is characterized by a general decline in cellular function, which ultimately affects whole body homeostasis. This study aimed to investigate the effects and underlying mechanisms of exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSC-exos) on the livers of naturally aging mice. MethodTwenty-two-month-old C57BL6 mice were used as a natural aging animal model, divided into a saline-treated wild‐type aged control group (WT-AC) and a hUCMSC-exo-treated group (WT-AEX), and then detected by morphology, metabolomics and phosphoproteomics. ResultsMorphological analysis showed that hUCMSC-exos ameliorated structural disorder and decreased markers of senescence and genome instability in aging livers. Metabolomics showed that hUCMSC-exos decreased the contents of saturated glycerophospholipids, palmitoyl-glycerols and eicosanoid derivatives associated with lipotoxicity and inflammation, consistent with the decreased phosphorylation of metabolic enzymes, such as propionate-CoA ligase (Acss2), at S267 detected by phosphoproteomics. Moreover, phosphoproteomics indicated that hUCMSC-exos reduced the phosphorylation of proteins participating in nuclear transport and cancer signaling, such as heat shock protein HSP90-beta (Hsp90ab1) at S226 and nucleoprotein TPR (Tpr) at S453 and S379, while increasing those involved in intracellular communication, such as calnexin (Canx) at S563 and PDZ domain-containing protein 8 (Pdzd8). Finally, phosphorylated HSP90β and Tpr were verified predominantly in hepatocytes. ConclusionHUCMSC-exos improved metabolic reprogramming and genome stability mainly associated with phosphorylated HSP90β in hepatocytes in natural aging livers. This work provides a comprehensive resource of biological data by omics to support future investigations of hUCMSC-exos in aging.

Bank Voles Show More Impulsivity in IntelliCage Learning Tasks than Wood Mice

Impulsivity is a personality trait of healthy individuals, but in extreme forms common in mental disorders. Previous behavioral testing of wild-caught bank voles and wood mice suggested impulsiveness in bank voles. Here, we compared behavioral performance of bank voles and wood mice in tests for response control in the IntelliCage. In the reaction time task, a test similar to the five-choice serial-reaction time task (5CSRTT), bank voles made more premature responses. Impulsivity in the reaction time task was associated with smaller medial habenular nucleus in bank voles. Additional tests revealed reduced behavioral flexibility in the self-paced flexibility task in bank voles, but equal spatial and reversal learning in the chaining/reversal task in both species. Expression of immediate early gene Arc after behavioral testing was low in medial prefrontal cortex, but high in hypothalamic supraoptic and paraventricular nucleus in bank voles. Wood mice showed the opposite pattern. Numbers of Arc-positive cells in the dorsal hippocampus were higher in bank voles than wood mice. Due to continuous behavioral testing (24/7), associations between behavioral performance and Arc were rare. Corticosterone measurements at the end of experiments suggested that IntelliCage testing did not elicit a stress response in these wild rodents. In summary, habenular size differences and altered activation of brain areas after testing might indicate differently balanced activations of cortico-limbic and cortico-hypothalamic circuits in bank voles compared to wood mice. Behavioral performance of bank voles suggest that these rodents could be a natural animal model for investigating impulsive and perseverative behaviors.

Dogs as a Natural Animal Model of Epilepsy.

Epilepsy is a common neurological disease in both humans and domestic dogs, making dogs an ideal translational model of epilepsy. In both species, epilepsy is a complex brain disease characterized by an enduring predisposition to generate spontaneous recurrent epileptic seizures. Furthermore, as in humans, status epilepticus is one of the more common neurological emergencies in dogs with epilepsy. In both species, epilepsy is not a single disease but a group of disorders characterized by a broad array of clinical signs, age of onset, and underlying causes. Brain imaging suggests that the limbic system, including the hippocampus and cingulate gyrus, is often affected in canine epilepsy, which could explain the high incidence of comorbid behavioral problems such as anxiety and cognitive alterations. Resistance to antiseizure medications is a significant problem in both canine and human epilepsy, so dogs can be used to study mechanisms of drug resistance and develop novel therapeutic strategies to benefit both species. Importantly, dogs are large enough to accommodate intracranial EEG and responsive neurostimulation devices designed for humans. Studies in epileptic dogs with such devices have reported ictal and interictal events that are remarkably similar to those occurring in human epilepsy. Continuous (24/7) EEG recordings in a select group of epileptic dogs for >1 year have provided a rich dataset of unprecedented length for studying seizure periodicities and developing new methods for seizure forecasting. The data presented in this review substantiate that canine epilepsy is an excellent translational model for several facets of epilepsy research. Furthermore, several techniques of inducing seizures in laboratory dogs are discussed as related to therapeutic advances. Importantly, the development of vagus nerve stimulation as a novel therapy for drug-resistant epilepsy in people was based on a series of studies in dogs with induced seizures. Dogs with naturally occurring or induced seizures provide excellent large-animal models to bridge the translational gap between rodents and humans in the development of novel therapies. Furthermore, because the dog is not only a preclinical species for human medicine but also a potential patient and pet, research on this species serves both veterinary and human medicine.

A Comparative Assessment of the Diagnosis of Swallowing Impairment and Gastroesophageal Reflux in Canines and Humans.

Swallowing impairment is a highly prevalent and clinically significant problem affecting people and dogs. There are myriad causes of swallowing impairment of which gastroesophageal reflux is the most common in both species. Similarities in anatomy and physiology between humans and canines results in analogous swallowing disorders including cricopharyngeus muscle achalasia, esophageal achalasia, hiatal herniation, and gastroesophageal reflux with secondary esophagitis and esophageal dysmotility. Accordingly, the diagnostic approach to human and canine patients with swallowing impairment is similar. Diagnostic procedures such as swallowing fluoroscopy, high-resolution manometry, pH/impedance monitoring, and endolumenal functional luminal imaging probe can be performed in both species; however, nasofacial conformation, increased esophageal length, and the difficulty of completing several of these procedures in awake dogs are inherent challenges that need to be considered. Human patients can convey their symptoms and respond to verbal cues, whereas veterinarians must rely on clinical histories narrated by pet owners followed by comprehensive physical examination and observation of the animal eating different food consistencies and drinking water. Dogs may also be unwilling to drink or eat in the hospital setting and may be resistant to physical restraint during diagnostic procedures. Despite the species differences and diagnostic challenges, dogs are a natural animal model for many oropharyngeal and esophageal disorders affecting people, which presents a tremendous opportunity for shared learnings. This manuscript reviews the comparative aspects of esophageal anatomy and physiology between humans and canines, summarizes the diagnostic assessment of swallowing impairment in both species, and discusses future considerations for collaborative medicine and translational research.