Design, Synthesis, and Antidepressant Activity Study of Novel Aryl Piperazines Targeting Both 5-HT1A and Sigma-1 Receptors

A total of 20 novel aryl piperazine derivatives were designed and synthesized, and their structures were confirmed by mass spectrometry and nuclear magnetic resonance analyses. Their 5-HT1A and sigma-1 receptor affinities were determined, and six of them showed high affinities (K i < 20 nmol/L) to both 5-HT1A and sigma-1 targets. Then, metabolic stability (T 1/2) tests of six compounds in rat and human liver microsomes were performed. Our data indicated that compound 27 has both high affinity for 5-HT1A and sigma-1 receptors (5-HT1A: K i = 0.44 nmol/L; sigma-1: K i = 0.27 nmol/L), and good metabolic stability (T 1/2 values are 21.7 and 24.6 minutes, respectively). Interestingly, results from the forced swimming test, mouse tail suspension test, and preliminary pharmacokinetic test suggested the marked antidepressant activity, good pharmacokinetic characteristics, and low toxicity of compound 27 in the two models. In conclusion, compound 27 has great value of further study as an active molecule of antidepressant drugs.

Beating Rate Variability of Isolated Mammal Sinoatrial Node Tissue: Insight Into Its Contribution to Heart Rate Variability

BackgroundBecause of the complexity of the interaction between the internal pacemaker mechanisms, cell interconnected signals, and interaction with other body systems, study of the role of individual systems must be performed under in vivo and in situ conditions. The in situ approach is valuable when exploring the mechanisms that govern the beating rate and rhythm of the sinoatrial node (SAN), the heart’s primary pacemaker. SAN beating rate changes on a beat-to-beat basis. However, to date, there are no standard methods and tools for beating rate variability (BRV) analysis from electrograms (EGMs) collected from different mammals, and there is no centralized public database with such recordings.MethodsWe used EGM recordings obtained from control SAN tissues of rabbits (n = 9) and mice (n = 30) and from mouse SAN tissues (n = 6) that were exposed to drug intervention. The data were harnessed to develop a beat detector to derive the beat-to-beat interval time series from EGM recordings. We adapted BRV measures from heart rate variability and reported their range for rabbit and mouse.ResultsThe beat detector algorithm performed with 99% accuracy, sensitivity, and positive predictive value on the test (mouse) and validation (rabbit and mouse) sets. Differences in the frequency band cutoff were found between BRV of SAN tissue vs. heart rate variability (HRV) of in vivo recordings. A significant reduction in power spectrum density existed in the high frequency band, and a relative increase was seen in the low and very low frequency bands. In isolated SAN, the larger animal had a slower beating rate but with lower BRV, which contrasted the phenomena reported for in vivo analysis. Thus, the non-linear inverse relationship between the average HR and HRV is not maintained under in situ conditions. The beat detector, BRV measures, and databases were contributed to the open-source PhysioZoo software (available at: https://physiozoo.com/).ConclusionOur approach will enable standardization and reproducibility of BRV analysis in mammals. Different trends were found between beating rate and BRV or HRV in isolated SAN tissue vs. recordings collected under in vivo conditions, respectively, implying a complex interaction between the SAN and the autonomic nervous system in determining HRV in vivo.

Assessing Elimination of Mouse Kidney Parvovirus from Cages by Mechanical Washing

Mouse kidney parvovirus (MKPV), a newly identified parvovirus of the genus Chaphamaparvovirus, causes inclusion body nephropathy in severely immunocompromised mice and is prevalent in research mouse colonies. As nonenveloped viruses, mammalian parvoviruses are stable and generally resist thermal inactivation; however, as a novel and highly divergent parvovirus, the thermal stability of MKPV is undefined. This study aimed to evaluate the ability of cage sanitization in a mechanical washer to eliminate MKPV. Cages contaminated by MKPV-infected mice were assigned to 1 of 3 treatment groups: 1) control (bedding change only); 2) sanitization in a tunnel washer (88 °C final rinse for 20 s); or 3) sanitization in a tunnel washer followed by autoclave sterilization (121 °C for 20 min). The presence of MKPV on the cage’s interior surface was assessed by PCR of cage swab extracts collected before and after cage treatment. After treatment and swabbing, each cage housed 4 MKPV-negative CD1 mice. Each group of naive CD1 mice was assigned to one of the treatment groups and was housed in a cage from this group for two, 1 wk periods. At 12, 17, and 20 wk after the first exposure, renal tissue was collected from 1 test mouse per cage and assessed for MKPV by PCR. MKPV was detected by PCR on the surface of 63% of the pretreatment cages. All cages sanitized in a tunnel washer with or without sterilization were PCR negative after treatment. Seven of 10 mice housed in untreated cages contained a mouse positive for MKPV by 20 wk after exposure. None of the mice housed in cages sanitized in a tunnel washer with or without sterilization tested positive for MKPV at any time point. This study indicates that MKPV contaminated caging can result in MKPV infection of mice, and the use of a tunnel washer at the temperature and duration evaluated was sufficient to remove MKPV nucleic acid and prevent MKPV transmission.

Safety evaluation and antihyperlipidemia effect of aqueous extracts from fermented puerh tea

In the present paper, a safety evaluation of aqueous extracts from fermented puerh tea (EFPT) was performed, including an oral acute toxicity study in rats and mice, mutation tests, a mouse micronucleus test, mouse sperm abnormality test and a 30 day feeding study in rats.

Preliminary Toxicology Evaluation of Silymarin

Research silymarin food security through animal experiments. Acute toxicity test, mouse bone marrow micronucleus test, mice sperm abnormality test results were evaluated. Male and female mice by oral maximum tolerated dose (MTD) are more than 20.0g/kg body weight, according to the acute toxicity grading standards, which are non-toxic level. Mouse bone marrow micronucleus test, mice sperm abnormality test and genotoxicity test were negative. Showed that silymarin is a food safety component.

Investigation of biocompatibility on nitrogen-doped a-C:H film coating scaffold surface in in-vivo and in-vitro tests

ABSTRACTIn this study, in order to investigate biocompatibility of nitrogen-doped hydrogenated amorphous carbon (a-C:H:N) film coating segmented polyurethane (SPU) scaffold fiber sheet (a-C:H:N-Scaffold) in in-vitro test, mouse fibroblasts (NIH 3T3) cells were grown on the a-C:H:N-Scaffold. The cell behavior was monitored by time-lapse imaging system. Additionally, the a-C:H:N-Scaffold was implanted at partial aorta descendens of a goat for 35 days. The surface morphology, composition, and wettability of the a-C:H:N-scaffold was estimated by Scanning Electron Microscope (SEM), X-ray photoelectron spectrometer (XPS), and contact angle measurement. In in-vitro test, it was observed that a-C:H:N film coating had a facilitatory effect on cell motility and cell growth. In in-vivo test, it was observed that the a-C:H:N-Scaffold surface was uniformly covered by neointima. The a-C:H:N-Scaffold surface had no thrombus formation as an inflammatory reaction and it was shown that the a-C:H:N film coating had a good blood compatibility. These results suggest that a-C:H:N film coating has good cytocompatibility and blood compatibility and it is a promising approach for improvement of biocompatibility of biomaterial surfaces.