Recent Experimental Animal Studies Research Articles

Recognan (citicoline) in the correction of asthenic and anxiety-depressive disorders

The article reflects the results of a number of studies that demonstrate the therapeutic effectiveness of Recognan (citicoline) in anxiety-depressive and asthenic disorders against the background of somatic and neurological diseases, in the correction of post-stroke depression. Recent experimental animal studies prove the effect of citicoline on anxiety and depression. In the complex effect, Recognan potentiates the main pharmacological effect of antidepressants and anxiolytics. In some studies, a dose-dependent change in animal behavior has been observed in response to the analgesic and antidepressant effects of citicoline. The effectiveness of citicoline in combination with transcranial direct current stimulation in the treatment of depression has been shown. The analysis of these research materials allows us to recommend Recognan in the complex therapy of asthenic and anxiety-depressive disorders in response to such pathological conditions as anxiety, asthenia, depression.

Ingested Polystyrene Nanospheres Translocate to Placenta and Fetal Tissues in Pregnant Rats: Potential Health Implications.

Recent studies in experimental animals found that oral exposure to micro- and nano-plastics (MNPs) during pregnancy had multiple adverse effects on outcomes and progeny, although no study has yet identified the translocation of ingested MNPs to the placenta or fetal tissues, which might account for those effects. We therefore assessed the placental and fetal translocation of ingested nanoscale polystyrene MNPs in pregnant rats. Sprague Dawley rats (N = 5) were gavaged on gestational day 19 with 10 mL/kg of 250 µg/mL 25 nm carboxylated polystyrene spheres (PS25C) and sacrificed after 24 h. Hyperspectral imaging of harvested placental and fetal tissues identified abundant PS25C within the placenta and in all fetal tissues examined, including liver, kidney, heart, lung and brain, where they appeared in 10-25 µm clusters. These findings demonstrate that ingested nanoscale polystyrene MNPs can breach the intestinal barrier and subsequently the maternal-fetal barrier of the placenta to access the fetal circulation and all fetal tissues. Further studies are needed to assess the mechanisms of MNP translocation across the intestinal and placental barriers, the effects of MNP polymer, size and other physicochemical properties on translocation, as well as the potential adverse effects of MNP translocation on the developing fetus.

Early Light Sedation Increased the Duration of Mechanical Ventilation in Patients With Severe Lung Injury.

The international guidelines recommend light sedation management for patients receiving mechanical ventilation. One of the benefits of light sedation management during mechanical ventilation is the preservation of spontaneous breathing, which leads to improved gas-exchange and patient outcomes. Conversely, recent experimental animal studies have suggested that strong spontaneous breathing effort may cause worsening of lung injury, especially in severe lung injury cases. The association between depth of sedation and patient outcomes may depend on the severity of lung injury. This study aimed to describe the patients' clinical outcomes under deep or light sedation during the first 48 h of mechanical ventilation and investigate the association of light sedation on patient outcomes for each severity of lung injury. The researchers performed a retrospective observational study at a university hospital in Japan. Patients aged ≥20 years, who received mechanical ventilation for at least 48 h were enrolled. A total of 413 patient cases were analyzed. Light sedation was associated with significantly shorter 28-day ventilator-free days compared with deep sedation in patients with severe lung injury (0 [IQR 0-5] days vs. 16 [0-19] days, P = .038). In the groups of patients with moderate and mild lung injury, the sedation depth was not associated with ventilator-free days. After adjusting for the positive end-expiratory pressure and APACHE II score, it was found that light sedation decreased the number of ventilator-free days in patients with severe lung injury (-10.8 days, 95% CI -19.2 to -2.5, P = .012). Early light sedation for severe lung injury may be associated with fewer ventilator-free days.

Varicocele, Functional Foods and Nutraceuticals: From Mechanisms of Action in Animal Models to Therapeutic Application.

Varicocele is one of the main causes of infertility in men, thus representing an important clinical problem worldwide. Inflammation contributes mainly to its pathogenesis, even if the exact pathophysiological mechanisms that correlate varicocele and infertility are still unknown. In addition, oxidative stress, apoptosis, hypoxia, and scrotal hyperthermia seem to play important roles. So far, the treatment of varicocele and the care of the fertility-associated problems still represent an area of interest for researchers, although many advances have occurred over the past few years. Recent experimental animal studies, as well as the current epidemiological evidence in humans, demonstrated that many functional foods of natural origin and nutraceuticals that are particularly abundant in the Mediterranean diet showed anti-inflammatory effects in varicocele. The aim of the present narrative review is to mainly evaluate recent experimental animal studies regarding the molecular mechanisms of varicocele and the state of the art about possible therapeutic approaches. As the current literature demonstrates convincing associations between diet, food components and fertility, the rational intake of nutraceuticals, which are particularly abundant in foods typical of plant-based eating patterns, may be a reliable therapeutic supportive care against varicocele and, consequently, could be very useful in the cure of fertility-associated problems in patients.

Induced Human Regulatory T Cells Express the Glucagon-like Peptide-1 Receptor.

The glucagon-like peptide-1 receptor (GLP-1R) plays a key role in metabolism and is an important therapeutic target in diabetes and obesity. Recent studies in experimental animals have shown that certain subsets of T cells express functional GLP-1R, indicating an immune regulatory role of GLP-1. In contrast, less is known about the expression and function of the GLP-1R in human T cells. Here, we provide evidence that activated human T cells express GLP-1R. The expressed GLP-1R was functional, as stimulation with a GLP-1R agonist triggered an increase in intracellular cAMP, which was abrogated by a GLP-1R antagonist. Analysis of CD4+ T cells activated under T helper (Th) 1, Th2, Th17 and regulatory T (Treg) cell differentiation conditions indicated that GLP-1R expression was most pronounced in induced Treg (iTreg) cells. Through multimodal single-cell CITE- and TCR-sequencing, we detected GLP-1R expression in 29–34% of the FoxP3+CD25+CD127- iTreg cells. GLP-1R+ cells showed no difference in their TCR-gene usage nor CDR3 lengths. Finally, we demonstrated the presence of GLP-1R+CD4+ T cells in skin from patients with allergic contact dermatitis. Taken together, the present data demonstrate that T cell activation triggers the expression of functional GLP-1R in human CD4+ T cells. Given the high induction of GLP-1R in human iTreg cells, we hypothesize that GLP-1R+ iTreg cells play a key role in the anti-inflammatory effects ascribed to GLP-1R agonists in humans.

Novel Insight into the Mechanisms of the Bidirectional Relationship between Diabetes and Periodontitis.

Periodontitis and diabetes are two major global health problems despite their prevalence being significantly underreported and underestimated. Both epidemiological and intervention studies show a bidirectional relationship between periodontitis and diabetes. The hypothesis of a potential causal link between the two diseases is corroborated by recent studies in experimental animals that identified mechanisms whereby periodontitis and diabetes can adversely affect each other. Herein, we will review clinical data on the existence of a two-way relationship between periodontitis and diabetes and discuss possible mechanistic interactions in both directions, focusing in particular on new data highlighting the importance of the host response. Moreover, we will address the hypothesis that trained immunity may represent the unifying mechanism explaining the intertwined association between diabetes and periodontitis. Achieving a better mechanistic insight on clustering of infectious, inflammatory, and metabolic diseases may provide new therapeutic options to reduce the risk of diabetes and diabetes-associated comorbidities.

Endothelial progenitor cell-derived small extracellular vesicles for Myocardial angiogenesis and revascularization

Endothelial progenitor cells (EPCs) have been well-studied for their differentiation potential and paracrine activity in vitro and in experimental animal studies. EPCs are the precursors of endothelial cells (ECs) and a rich source of pro-angiogenic factors, and hence, possess enormous potential to treat ischemic heart through myocardial angiogenesis. Their proven safety and efficacy observed during the pre-clinical and clinical studies have portrayed them as a near ideal cell type for cell-based therapy of ischemic heart disease.In response to the chemical cues from the ischemic heart, EPCs from the bone marrow and peripheral circulation home-in to the ischemic myocardium and participate in the intrinsic repair process at the molecular and cellular levels through paracrine activity and EC differentiation. EPCs also release small extracellular vesicles (sEVs) loaded with bioactive molecules as part of their paracrine activity for intercellular communication to participate in the reparative process in the heart. This literature review is based on the published data regarding the characteristic features of EPC-derived sEVs and their proteomic and genomic payload, besides facilitating safe and effective repair of the ischemic myocardium. In light of the encouraging published data, translational and clinical assessment of EPC-derived sEVs is warranted. We report the recent experimental animal studies and their findings using EPC-derived sEVs on cardiac angiogenesis and preservation of cardiac function. With the promising results from pre-clinical studies, clinical trials should be conducted to assess the clinical utility of EPC-derived sEVs in the treatment of the ischemic myocardium.

Ketamine-Induced Alteration of Working Memory Utility during Oculomotor Foraging Task in Monkeys.

Impairments of working memory (WM) are commonly observed in a variety of neurodegenerative disorders but they are difficult to quantitatively assess in clinical cases. Recent studies in experimental animals have used low-dose ketamine (an NMDA receptor antagonist) to disrupt WM, partly mimicking the pathophysiology of schizophrenia. Here, we developed a novel behavioral paradigm to assess multiple components of WM and applied it to monkeys with and without ketamine administration. In an oculomotor foraging task, the animals were presented with 15 identical objects on the screen. One of the objects was associated with a liquid reward, and monkeys were trained to search for the target by generating sequential saccades under a time constraint. We assumed that the occurrence of recursive movements to the same object might reflect WM dysfunction. We constructed a “foraging model” that incorporated (1) memory capacity, (2) memory decay, and (3) utility rate; this model was able to explain more than 92% of the variations in behavioral data obtained from three monkeys. Following systemic administration of low dosages of ketamine, the memory capacity and utility rate were dramatically reduced by 15% and 57%, respectively, while memory decay remained largely unchanged. These results suggested that the behavioral deficits during the blockade of NMDA receptors were mostly due to the decreased usage of short-term memory. Our oculomotor paradigm and foraging model appear to be useful for quantifying multiple components of WM and could be applicable to clinical cases in future studies.

Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities.

Periodontitis, a major inflammatory disease of the oral mucosa, is epidemiologically associated with other chronic inflammation-driven disorders, including cardio-metabolic, neurodegenerative and autoimmune diseases and cancer. Emerging evidence from interventional studies indicates that local treatment of periodontitis ameliorates surrogate markers of comorbid conditions. The potential causal link between periodontitis and its comorbidities is further strengthened by recent experimental animal studies establishing biologically plausible and clinically consistent mechanisms whereby periodontitis could initiate or aggravate a comorbid condition. This multi-faceted ‘mechanistic causality’ aspect of the link between periodontitis and comorbidities is the focus of this Review. Understanding how certain extra-oral pathologies are affected by disseminated periodontal pathogens and periodontitis-associated systemic inflammation, including adaptation of bone marrow haematopoietic progenitors, may provide new therapeutic options to reduce the risk of periodontitis-associated comorbidities.

The learned placebo response in the immune system

The learned placebo response of the immune system is based on the mutual interaction between the brain and the immune system; both systems continually exchange information via humoral and neural communication pathways. This communication network enables the modification, i.e. suppression or stimulation, of peripheral immune functions by classical or Pavlov's conditioning. The present article provides an overview of the results of recent experimental animal studies, which also document the potential clinical relevance of learned immune responses. Learned immunological responses mediated by classical conditioning have also been demonstrated in humans. The knowledge gained from experimental data and clinical observations paves the way for apotential implementation of learned immune responses as supportive measures to standard immunopharmacological treatment strategies to reduce drug dosage as well as adverse side effects while simultaneously maximizing the therapeutic effect.

Altered Expression of Adrenomedullin 2 and its Receptor in the Adipose Tissue of Obese Patients.

Adrenomedullin 2 (AM2) plays protective roles in the renal and cardiovascular systems. Recent studies in experimental animals demonstrated that AM2 is an adipokine with beneficial effects on energy metabolism. However, there is little information regarding AM2 expression in human adipose tissue. To investigate the pattern and regulation of the expression of AM2 and its receptor component in human adipose tissue, in the context of obesity and type 2 diabetes. We measured metabolic parameters, serum AM2, and expression of ADM2 and its receptor component genes in abdominal subcutaneous and visceral adipose tissue in obese (with or without type 2 diabetes) and normal-weight women. Serum AM2 was assessed before and 6 to 9 months after bariatric surgery. Expression/secretion of AM2 and its receptor were assessed in human adipocytes. ADM2 mRNA in both fat depots was higher in obese patients, whether diabetic or not. Although serum AM2 was significantly lower in obese patients, it was not changed after bariatric surgery. AM2 and its receptor complex were predominantly expressed by adipocytes, and the expression of CALCRL, encoding a component of the AM2 receptor complex, was lower in both fat depots of obese patients. Incubating adipocytes with substances mimicking the microenvironment of obese adipose tissue increased ADM2 mRNA but reduced both AM2 secretion into culture media and CALCRL mRNA expression. Our data indicate that AM2 signaling is suppressed in adipose tissue in obesity, involving lower receptor expression and ligand availability, likely contributing to insulin resistance and other aspects of the pathophysiology associated with obesity.

Effects of Estrogen in Gender-dependent Fetal Programming of Adult Cardiovascular Dysfunction.

Epidemiological studies and experimental studies have demonstrated that intrauterine adverse environment increases the risk of Cardiovascular Disease (CVD) in adulthood. However, whether an individual develops a cardiovascular dysfunctional phenotype may depend on genetic background, age, and sex. In this review, we summarize some of the recent experimental animal studies in the developmental programming of adult CVD with an emphasis on sex differences and the potential role of estrogen in mediating sexual dimorphism. Few epidemiological studies report the effect of sex on the developmental programming of CVD. However, numerous experimental animal studies have shown a sex difference in fetal programming of adult cardiovascular dysfunction. Most of the animal studies indicate that male offspring develop cardiovascular dysfunction and CVD in adulthood, whereas adult females appear to be protected. Estrogen is one of the key factors that contributes to the sex difference of adult CVD. Estrogen/its Receptor (ER) may interact with the RAS system by changes of DNA methylation patterns at the target gene promoter, serve as an antioxidant to counteract the prenatal insults-induced heightened ROS, and function as an eNOS activator to increase vasodilation, resulting in the protection of female offspring from the development of hypertension and other CVDs. These studies suggest that estrogen/ER may contribute to sex differences in cardiovascular response to an adverse intrauterine environment and play a significant role in modulating the cardiovascular response in adulthood.

Long-term persistence of human donor alveolar macrophages in lung transplant recipients

BackgroundAlveolar macrophages (AMFs) are critical regulators of lung function, and may participate in graft rejection following lung transplantation. Recent studies in experimental animals suggest that most AMFs are self-maintaining cells...

Newborn Brain Function Is Affected by Fetal Exposure to Maternal Serotonin Reuptake Inhibitors.

Recent experimental animal studies have shown that fetal exposure to serotonin reuptake inhibitors (SRIs) affects brain development. Modern recording methods and advanced computational analyses of scalp electroencephalography (EEG) have opened a possibility to study if comparable changes are also observed in the human neonatal brain. We recruited mothers using SRI during pregnancy (n = 22) and controls (n = 62). Mood and anxiety of mothers, newborn neurology, and newborn cortical function (EEG) were assessed. The EEG parameters were compared between newborns exposed to drugs versus controls, followed by comparisons of newborn EEG features with maternal psychiatric assessments. Neurological assessment showed subtle abnormalities in the SRI-exposed newborns. The computational EEG analyses disclosed a reduced interhemispheric connectivity, lower cross-frequency integration, as well as reduced frontal activity at low-frequency oscillations. These effects were not related to maternal depression or anxiety. Our results suggest that antenatal serotonergic treatment might change newborn brain function in a manner compatible with the recent experimental studies. The present EEG findings suggest links at the level of neuronal activity between human studies and animal experiments. These links will also enable bidirectional translation in future studies on the neuronal mechanisms and long-term neurodevelopmental effects of early SRI exposure.

STUDIES ON ACHILLES TENDINOSIS: BILATERAL RECOVERY AFTER UNILATERAL SURGERY, AND SIMILAR HISTOPATHOLOGICAL APPEARANCES BILATERALLY

It is frequently observed that midportion Achilles tendinopathy/tendinosis occurs bilaterally. With this as a background, the outcome of unilateral operations was evaluated in 13 patients (seven males and six females)...

Insulin-like growth factor 1 and 2 (IGF1, IGF2) expression in human microglia: differential regulation by inflammatory mediators

BackgroundRecent studies in experimental animals show that insulin-like growth factor 1 (IGF1) plays a trophic role during development and tissue injury and that microglia are important sources of IGF1. However, little information is available regarding the expression, regulation, and function of IGF1 and related proteins in human brain cells. In the current study, we examined the expression of IGF1 and IGF2 in human microglia in vivo and in vitro.MethodsExpression of IGF1 and IGF2 was examined by immunohistochemistry in post-mortem human brain sections derived from HIV+ and HIV− brains. In primary cultures of human fetal microglia, IGF1 and IGF2 mRNA and protein expression was examined by Q-PCR, ELISA, and Western blot analysis. Additionally, the role of IGF1 and IGF2 in neuroprotection was examined in primary human neuronal glial cultures.ResultsImmunohistochemistry of human brain tissues showed that nonparenchymal cells (vessels and meninges), as well as parenchymal microglia and macrophages were positive for IGF1, in both HIV encephalitis and control brains, while IGF2 was undetectable. Cultured microglia expressed IGF1 mRNA and produced pg/ml levels of IGF1 protein; this was significantly suppressed by proinflammatory mediators, such as lipopolysaccharide (LPS), poly(I:C), and IFNγ. The Th2 cytokines IL-4 and IL-13 had no significant effect, but the cAMP analog (dibutyryl cAMP) significantly increased IGF1 production. In contrast, microglial IGF2 mRNA and protein (determined by Western blot) were upregulated by LPS. IGF1 receptor (IGF1R) immunoreactivity was predominantly expressed by neurons, and both IGF1 and IGF2 significantly protected neurons from cytokine (IL-1/IFNγ) induced death.ConclusionsOur study in human brain tissues and cells indicates that microglia are important sources of neurotrophic growth factors IGF1 and IGF2, and that microglial activation phenotypes can influence the growth factor expression. Importantly, our results suggest that chronic neuroinflammation and upregulation of proinflammatory cytokines could lead to neurodegeneration by suppressing the production of microglia-derived neuronal growth factors, such as IGF1.

Association of CLOCK gene variants with semen quality in idiopathic infertile Han-Chinese males

Recent experimental animal studies suggested that the circadian locomotor output cycles kaput protein gene (CLOCK) may play an important role in male reproduction. So far, such data for humans are not available. This study used single-nucleotide polymorphisms (SNP) to examine the association between CLOCK and semen quality in a human population with idiopathic infertility. Three-variant genotyping of CLOCK and semen analysis were performed in 478 men with idiopathic infertility by SNP genotyping assays and computer-aided sperm analysis. Subjects carrying a C allele at rs3749474 (CC and TC) presented significantly lower semen volume (P=<0.001 and 0.001, respectively) compared with the TT genotype. Subjects carrying the rs3749474 CC genotype had significantly lower sperm number per ejaculate (P=0.026) and sperm motility (P=0.021) than TT genotype carriers. rs1801260 TC genotype carriers had significantly lower sperm motility compared with the TT genotype (P=0.028). For the rs3817444 genotypes, CA and AA genotype carriers presented significantly lower semen volume compared with the CC genotype (P=0.022 and 0.001, respectively). The findings suggest, as far as is known for the first time, an association between CLOCK genetic variants and altered semen quality in a human population with idiopathic infertility.The gene encoding the circadian locomotor output cycles kaput protein (CLOCK) functions as an important positive enhancer of the circadian system. The observations reported in recent experimental animal studies suggested that CLOCK may play an important role in male reproduction. So far, such data for humans are not available. In this study, single-nucleotide polymorphisms (SNP) were used to examine the association between CLOCK and semen quality in human population with idiopathic infertility. Three-variant genotyping of CLOCK and semen analysis were performed in 478 males with idiopathic infertility by SNP genotyping assays and computer-assisted semen analysis. The results showed that the subjects carrying a C allele at rs3749474 (CC and TC) presented significantly lower semen volume compared with the TT genotype. For subjects carrying the CC genotype, sperm number per ejaculate and sperm motility were significantly lower compared with TT genotype carriers. The rs1801260 TC genotype carriers also had significantly lower sperm motility compared with the TT genotype. For the rs3817444 genotypes, the CA and AA genotype carriers presented significantly lower semen volume compared with the CC genotype. The findings suggested, as far as is known for the first time, an association between CLOCK genetic variants and altered semen quality in a human population with idiopathic infertility.

The cardioprotective effects of metformin

In patients with type 2 diabetes mellitus, treatment with metformin is associated with a lower cardiovascular morbidity and mortality, compared with alternative glucose-lowering drugs. It has been suggested that metformin might exert direct protective effects on the heart. This review appraises recent experimental animal studies on the effect of metformin on myocardial ischaemia-reperfusion injury and remodeling. In murine models of myocardial infarction, the administration of metformin potently limits infarct size. Activation of adenosine monophosphate-activated protein kinase, increased formation of adenosine, and the prevention of opening of the mitochondrial permeability transition pore at reperfusion all contribute to this cardioprotective effect. In addition, metformin therapy attenuates postinfarction cardiac remodeling. There is evidence that activation of adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase, and a reduced collagen expression are crucial for this effect. The finding that metformin limits myocardial infarct size and remodeling in animal models of myocardial infarction suggests that patients suffering from myocardial ischaemia could benefit from treatment with metformin, even when these patients do not have diabetes. Currently, several clinical trials are being performed to test this hypothesis.

Molecular Analysis of Patterning of Conduction Tissues in the Developing Human Heart

Recent studies in experimental animals have revealed some molecular mechanisms underlying the differentiation of the myocardium making up the conduction system. To date, lack of gene expression data for the developing human conduction system has precluded valid extrapolations from experimental studies to the human situation. We performed immunohistochemical analyses of the expression of key transcription factors, such as ISL1, TBX3, TBX18, and NKX2-5, ion channel HCN4, and connexins in the human embryonic heart. We supplemented our molecular analyses with 3-dimensional reconstructions of myocardial TBX3 expression. TBX3 is expressed in the developing conduction system and in the right venous valve, atrioventricular ring bundles, and retro-aortic nodal region. TBX3-positive myocardium, with exception of the top of the ventricular septum, is devoid of fast-conducting connexin40 and connexin43 and hence identifies slowly conducting pathways. In the early embryonic heart, we found wide expression of the pacemaker channel HCN4 at the venous pole, including the atrial chambers. HCN4 expression becomes confined during later developmental stages to the components of the conduction system. Patterns of expression of transcription factors, known from experimental studies to regulate the development of the sinus node and atrioventricular conduction system, are similar in the human and mouse developing hearts. Our findings point to the comparability of mechanisms governing the development of the cardiac conduction patterning in human and mouse, which provide a molecular basis for understanding the functioning of the human developing heart before formation of a discrete conduction system.

Zastosowanie wysokich dawek tokoferolu w prewencji i potencjalizacji działania dioksyn w doświadczalnym zapaleniu

Emission of toxic and persistent organochlorine compounds into the environment is known to have been recently a very important environmental and health problem. One of the major groups of these compounds is the polychlorinated dibenzodioxins (PCDDs), commonly named dioxins, including 75 compounds composed of benzene rings with bound chlorine atoms in different positions and quantities. Polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs) are known to have a similar structure and properties. The biological effects of dioxins in food chains have been widely studied in the literature on the subject for the last four years. The major pathways of their impact on the organism are suspected to stimulate the cascade of inflammatory cytokines and the induction of oxidative stress. An effective way to prevent poisoning may, therefore, be expected to be administration of antioxidants and anti-inflammatory agents. Recent studies in experimental animals have confirmed the protective action of high doses of tocopherol and mentioned substances against dioxins.