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Journal of the American Association For... Jul 2018The provision of nesting material benefits mice by reducing cold stress, improving feed conversion, increasing litter size, and improving adaptive immunity. The effects...
The provision of nesting material benefits mice by reducing cold stress, improving feed conversion, increasing litter size, and improving adaptive immunity. The effects of toxins are sensitive to environmental changes, and the introduction of novel items can alter results in some toxicologic studies. We hypothesized that nesting material would reduce stress and positively alter immunologic parameters in Crl:CD1(ICR) mice, thus changing typical results from a well-studied immunomodulating drug, cyclophosphamide. A 13-wk study assessed the following treatments in a factorial design (n = 4; 32 cages total): nesting (0 or 10 g) and drug (50 mg/kg cyclophosphamide or 10 mL/kg saline; IP weekly). Detailed examinations and body weights were recorded weekly, and nests were scored twice weekly. Fecal pellets were collected at 0, 4, 6, and 12 wk for analysis of corticosterone metabolites. At study termination, clinical pathology and immune parameters were collected, a necropsy performed, and lymphoid organs and adrenal glands were submitted for histopathology. All expected results due to cyclophosphamide were observed. Nesting reduced the proportion of mice with piloerection, and body weights were highest in saline-nested male mice. No differences in hematology, clinical chemistry, or absolute lymphocyte counts were observed. Corticosterone metabolites in all nested groups were not different from baseline levels but all nonnested groups had higher levels than baseline. Nested cyclophosphamide-treated groups had significantly lower corticosterone levels than nonnested cyclophosphamide-treated groups. This study illustrates that nesting material does not alter the results of a standard toxicology study of cyclophosphamide but alleviates study-related stress and improves mouse welfare.
Topics: Animals; Corticosterone; Cyclophosphamide; Feces; Female; Housing, Animal; Immunosuppressive Agents; Male; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Nesting Behavior; Pregnancy
PubMed: 29976274
DOI: 10.30802/AALAS-JAALAS-17-000114 -
Frontiers in Microbiology 2019The aim of this study was to evaluate the effect of a moxifloxacin-loaded organic-inorganic sol-gel with different antibiotic concentration in the biofilm development...
The aim of this study was to evaluate the effect of a moxifloxacin-loaded organic-inorganic sol-gel with different antibiotic concentration in the biofilm development and treatment against , , and , cytotoxicity and cell proliferation of MC3T3-E1 osteoblasts; and its efficacy in preventing the prosthetic joint infection (PJI) caused by clinical strains of and using an murine model. Three bacterial strains, ATCC 35984, 15981, and, ATCC 25922, were used for microbiological studies. Biofilm formation was induced using tryptic-soy supplemented with glucose for 24 h, and then, adhered and planktonic bacteria were estimated using drop plate method and absorbance, respectively. A 24-h-mature biofilm of each species growth in a 96-well plate was treated for 24 h using a MBECTM biofilm Incubator lid with pegs coated with the different types of sol-gel, after incubation, biofilm viability was estimated using alamrBlue. MC3T3-E1 cellular cytotoxicity and proliferation were evaluated using CytoTox 96 Non-Radioactive Cytotoxicity Assay and alamarBlue, respectively. The microbiological studies showed that sol-gel coatings inhibited the biofilm development and treated to a mature biofilm of three evaluated bacterial species. The cell studies showed that the sol-gel both with and without moxifloxacin were non-cytotoxic and that cell proliferation was inversely proportional to the antibiotic concentration containing by sol-gel. In the study, mice weight increased over time, except in the -infected group without coating. The most frequent symptoms associated with infection were limping and piloerection; these symptoms were more frequent in infected groups with non-coated implants than infected groups with coated implants. The response of moxifloxacin-loaded sol-gel to infection was either total or completely absent. No differences in bone mineral density were observed between groups with coated and non-coated implants and macrophage presence lightly increased in the bone grown directly in contact with the antibiotic-loaded sol-gel. In conclusion, moxifloxacin-loaded sol-gel coating is capable of preventing PJI caused by both Gram-positive and Gram-negative species.
PubMed: 32010069
DOI: 10.3389/fmicb.2019.02935 -
Biomedicine & Pharmacotherapy =... Apr 2019An extracellular polysaccharide (EPS1-1) of Rhizopus nigricans was found to enhance immunity and reduce colon cancer cell proliferation. Here, the effect of EPS1-1 on a...
An extracellular polysaccharide (EPS1-1) of Rhizopus nigricans was found to enhance immunity and reduce colon cancer cell proliferation. Here, the effect of EPS1-1 on a mouse model of colitis-associated cancer (CAC) induced by azoxymethane (AOM)/dextran sodium sulfate (DSS) was investigated. Pathological symptoms, including weight loss, piloerection, hematochezia and insensitivity caused by AOM/DSS, were relieved by EPS1-1. Anatomical results showed a 100% tumor incidence, a series of neoplasms, disordered cell structure and hyperplastic glands in the model group, while the abnormal behaviors were relieved and the tumors decreased in the EPS1-1 group. Compared with the model group, the EPS1-1 group showed decreased oncogenic protein (COX-2, β-catenin, CyclinD1 and C-Myc) expression. TUNEL staining showed that EPS1-1 increased the apoptosis of colon cancer cells in mice. Furthermore, the expression of proliferative proteins (Ki-67 and PCNA) and an antiapoptotic gene transcript (Bcl-2) were significantly down regulated by EPS1-1, while apoptotic gene transcripts (p53 and Bax) were enhanced. In addition, EPS1-1 notably decreased the number of cells positive for CD68, F4/80 and NF-κB and reduced the concentrations of inflammatory factors (TNF-α and IL-6) in serum compared with those in the model group. Taken together, these results suggest that EPS1-1 may be a therapeutic option for the prevention and treatment of CAC.
Topics: Animals; Cell Proliferation; Colitis; Colon; Colorectal Neoplasms; Fungal Polysaccharides; Male; Mice; Mice, Inbred BALB C; Rhizopus; Treatment Outcome
PubMed: 30784912
DOI: 10.1016/j.biopha.2019.01.054 -
Journal of Pharmacological and... 2014The serotonin (5-HT) syndrome (SS) in man covers side effects of drugs in over dose that increase synaptic 5-HT concentration or directly activate 5-HT receptors. The SS...
INTRODUCTION
The serotonin (5-HT) syndrome (SS) in man covers side effects of drugs in over dose that increase synaptic 5-HT concentration or directly activate 5-HT receptors. The SS is characterized by mental state alterations, neuromuscular excitation, and autonomic dysregulation. In mice, a set of behavioral and autonomic responses can be induced by the same serotonergic drugs as in man. The role of the 5-HT1A receptor for the murine SS has been extensively studied and several responses have been attributed to 5-HT1A receptor activation. So far, 5-HT2A receptor activation is thought to induce head twitches and hypothermia. The aim of this study is to define the impact of the 5-HT2A and the 5-HT1A receptor for different SS-like responses.
METHODS
The effects of the full 5-HT1A receptor agonist 8-OH-DPAT, the partial 5-HT1A agonist buspirone, and the 5-HT2A receptor agonist TCB-2 were investigated in male NMRI mice. The responses were compared with the effects induced by the 5-HT precursor 5-HTP.
RESULTS
Flat body posture, hindlimb abduction, Straub tail, tremor, piloerection and decreased rearing were observed after 8-OH-DPAT treatment. A similar set of responses was seen after administration of buspirone. However, the Straub tail response did not occur, probably due to the lower efficacy of buspirone at postsynaptic 5-HT1A receptors. As expected, TCB-2 induced head twitches, but also evoked flat body posture, hindlimb abduction, and piloerection, and decreased the numbers of rearings and defecation boli.
DISCUSSION
The Straub tail response seems to be a specific sign for postsynaptic 5-HT1A receptor activation. In addition, the 5-HT2A receptor has more impact on the 5-HT syndrome than previously suggested. By inducing the broadest spectrum of signs, 5-HTP seems to be suitable as a positive control when investigating the 5-HT syndrome in mice. In summary, the murine model of the SS is a valid tool for preclinical studies to screen drugs and drug combinations for the risk to cause an SS in man.
Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Bridged Bicyclo Compounds; Buspirone; Disease Models, Animal; Male; Methylamines; Mice; Mice, Inbred Strains; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Serotonin Syndrome; Structure-Activity Relationship
PubMed: 25087754
DOI: 10.1016/j.vascn.2014.07.003 -
The Journal of Neuroscience : the... May 2019Anxiety disorders are characterized by excessive attention to threat. Several brain areas, including the orbitofrontal cortex (OFC), have been associated with threat...
Anxiety disorders are characterized by excessive attention to threat. Several brain areas, including the orbitofrontal cortex (OFC), have been associated with threat processing, with more recent work implicating specialized roles for the medial and lateral subregions of the OFC in mediating specific symptoms of anxiety disorders. Virtually no causal work, however, has evaluated the role of these OFC subregions in regulating behavioral responses under threat. To address this gap, we compared male rhesus monkeys () with bilateral excitotoxic lesions restricted to either the lateral OFC (lOFC), targeting Walker's areas 11 and 13, or the medial OFC (mOFC), targeting Walker's area 14, to a group of unoperated controls on behavioral responses to the presentation of a fake rubber snake, fake spider, and neutral stimuli. Both lesion groups showed heightened defensive and reduced approach responses, accompanied by longer latencies to retrieve a food reward, in the presence of the threatening stimuli. Compared to unoperated controls, the mOFC lesion group also showed longer latencies to reach for rewards and a greater proportion of defensive responses (e.g., piloerection) in the presence of neutral stimuli. Thus, monkeys with mOFC lesions displayed a greater tendency to express defensive responses even in the absence of threat. Overall, our data reveal that both the mOFC and lOFC contribute to the attenuation of defensive responses. Notably, these findings, obtained following selective, excitotoxic lesions of the OFC, are diametrically opposed to the effects of aspiration lesions of OFC observed in macaques. Engaging in adaptive defensive responses under threat promotes biological fitness. The orbitofrontal cortex (OFC) has been implicated in regulating defensive responses to threat, with distinct subregions likely playing different roles. Here we tested the effects of excitotoxic damage restricted to either the lateral or medial subdivisions of the OFC in rhesus macaques. We found significantly heightened defense and reduced approach responses to threatening stimuli in both lesion groups. While lateral OFC lesions led to an increase in defense responses to the threatening stimuli, medial OFC lesions produced increases in defense responses to both threatening and neutral stimuli. Our findings provide insights into the neural regulation of defensive responses to threat and inform the etiology and treatment of anxiety disorders in humans.
Topics: Animals; Behavior, Animal; Female; Macaca mulatta; Male; Prefrontal Cortex
PubMed: 30910790
DOI: 10.1523/JNEUROSCI.2812-18.2019 -
Behavioural Brain Research Feb 2023Depression and anxiety disorders overlap in clinical populations, suggesting common mechanisms that may be further investigated in reliable animal models. We used filial...
Depression and anxiety disorders overlap in clinical populations, suggesting common mechanisms that may be further investigated in reliable animal models. We used filial 8 female Long-Evans rats bred for high (HAn; n = 19) and low anxiety (LAn)-like behavior (n = 21) to assess forced swim test mobility strategies and chronic mild stress (CMS)-induced depression-like symptoms. We measured (1) weight, (2) fur piloerection, (3) sweet food consumption, (4) grooming behavior, and (5) circulating estradiol (E2). One month after CMS terminated and following a terminal forced swim test, brains were processed for immunohistochemistry targeting c-Fos and serotonin 1 A receptor (5-HT1AR) protein in the paraventricular nucleus (PVN) of the hypothalamus. HAn female rats showed increased anxiety-like behavior (i.e., lower open to closed arm ratios, increased closed arm entries), more swimming (i.e., mobility), and less floating (i.e., immobility) behavior in the forced swim test. Overall, HAn females weighed less than their LAn counterparts. After chronic mild stress, HAn lines displayed even greater mobility and consumed fewer Froot Loops™. Fur and grooming analyses indicated no significant differences in mean counts across experimental groups. One month after CMS, cycling E2 concentrations (pg/ml) did not differ between HAn and LAn animals. Elevated c-Fos and 5-HT1AR expression were observed in the PVN, where HAn CMS rats expressed the most c-Fos and 5-HT1AR immunoreactivity. In summary, outbred HAn rats show robust anxiety-like behavior, exhibit more mobility in the forced swim test, and are more sensitive to chronic mild stress-induced grooming and decline in palatable food ingestion.
Topics: Animals; Female; Rats; Anxiety; Anxiety Disorders; Depression; Disease Models, Animal; Proto-Oncogene Proteins c-fos; Rats, Long-Evans; Stress, Psychological; Swimming; Receptor, Serotonin, 5-HT1A
PubMed: 36343695
DOI: 10.1016/j.bbr.2022.114202 -
Toxicology Reports 2017Bitter orange ( L.) extracts are widely used in dietary supplements and bitter oranges are used in various juices and food products. -Synephrine, the primary active...
Bitter orange ( L.) extracts are widely used in dietary supplements and bitter oranges are used in various juices and food products. -Synephrine, the primary active constituent, comprises approximately 90% of total protoalkaloids. This study, performed per OECD 408 guidance, examined the 90-day subchronic safety/toxicity of an extract standardized to 50% -synephrine at doses of 100, 300 and 1000 mg/kg/day to male and female rats. No adverse effects were observed with respect to any of the observed parameters of clinical signs, functional observations of sensory reactivity, grip strength and motor activity, ophthalmology, body weights, hematology, food consumption, urinalysis, organ weights, as well as gross and microscopic pathology at termination at any of the doses in either sex. Treatment at 1000 mg/kg body weight/day of the extract resulted in non-adverse effects including fully reversible signs of repetitive head burrowing in the bedding material and piloerection for short periods of time in both sexes immediately after administration, which gradually disappeared by treatment day-81. A slight and reversible elevation of BUN and urea levels in male rats, and slight to mild increase in the relative but not absolute heart weights of male and female rats was observed. Based on these results, the no-observed-effect-level (NOEL) for this bitter orange extract standardized to 50% -synephrine was 300 mg/kg, while the no-observed-adverse-effect-level (NOAEL) was 1000 mg/kg. The results indicate a high degree of safety for this bitter orange extract.
PubMed: 29214145
DOI: 10.1016/j.toxrep.2017.11.002 -
Marine Drugs Nov 2022The frequent occurrence of marine dinoflagellates producing palytoxin (PLTX) or okadaic acid (OA) raises concern for the possible co-presence of these toxins in seafood,...
The frequent occurrence of marine dinoflagellates producing palytoxin (PLTX) or okadaic acid (OA) raises concern for the possible co-presence of these toxins in seafood, leading to additive or synergistic adverse effects in consumers. Thus, the acute oral toxicity of PLTX and OA association was evaluated in mice: groups of eight female CD-1 mice were administered by gavage with combined doses of PLTX (30, 90 or 270 μg/kg) and OA (370 μg/kg), or with each individual toxin, recording signs up to 24 h (five mice) and 14 days (three mice). Lethal effects occurred only after PLTX (90 or 270 μg/kg) exposure, alone or combined with OA, also during the 14-day recovery. PLTX induced scratching, piloerection, abdominal swelling, muscle spasms, paralysis and dyspnea, which increased in frequency or duration when co-administered with OA. The latter induced only diarrhea. At 24 h, PLTX (90 or 270 μg/kg) and OA caused wall redness in the small intestine or pale fluid accumulation in its lumen, respectively. These effects co-occurred in mice co-exposed to PLTX (90 or 270 μg/kg) and OA, and were associated with slight ulcers and inflammation at forestomach. PLTX (270 μg/kg alone or 90 μg/kg associated with OA) also decreased the liver/body weight ratio, reducing hepatocyte glycogen (270 μg/kg, alone or combined with OA). No alterations were recorded in surviving mice after 14 days. Overall, the study suggests additive effects of PLTX and OA that should be considered for their risk assessment as seafood contaminants.
Topics: Mice; Animals; Female; Okadaic Acid; Cnidarian Venoms; Acrylamides; Liver
PubMed: 36547882
DOI: 10.3390/md20120735 -
Seizure May 2022Ictal piloerection (IP) is a rare manifestation of focal epilepsy. Autoimmune limbic encephalitis (LE) and malignant brain tumours are the most frequent recognized... (Review)
Review
BACKGROUND
Ictal piloerection (IP) is a rare manifestation of focal epilepsy. Autoimmune limbic encephalitis (LE) and malignant brain tumours are the most frequent recognized aetiologies.
METHODS
We selected all patients diagnosed with LE in our Institute from 2004 to 2020 and manifesting with IP. We performed a literature review on LE patients presenting IP.
RESULTS
Of 15 patients diagnosed with LE (13.3%), two manifested IP as prominent ictal feature. One of them also had stiff-limb syndrome. Video-EEG documented ictal discharges from the right temporal regions with concomitant sympathetic skin response (SSR) recording. Antibody testing showed elevated serum and CSF titres of GAD65 antibodies (Ab), in both cases. Despite a combination of several anti-seizure medications and first- and second-line immunotherapy, they showed a poor clinical outcome after 2 and 9 years of follow-up, respectively. The literature review yielded 13 papers reporting 26 LE cases with IP. LGI1 Ab were the most frequently associated (73.1%) followed by VGKC-complex (7.7%), GAD65 (7.7%), NMDAr (3.8%), Ma2 (3.8%) and Hu (3.8%) Ab. Cases with LGI1 Ab showed a good response to immunotherapy.
DISCUSSION AND CONCLUSION
The prevalence of IP in our LE cohort was of 13.3%, higher than expected. According to the literature review, most cases were associated with LGI1 Ab and showed a good response to immunotherapy. With the contribution of our cases, GAD65 emerged as the second most frequently detected Ab, showing a poor outcome. Our findings widen the spectrum of IP-associated Ab, with the respective prognostic implications.
Topics: Autoantibodies; Autoimmune Diseases; Electroencephalography; Humans; Limbic Encephalitis
PubMed: 35427850
DOI: 10.1016/j.seizure.2022.03.025 -
Journal of the American Academy of... Jun 2024
PubMed: 38871084
DOI: 10.1016/j.jaad.2024.05.082