Subacute oral toxicology and toxicokinetics of pterostilbene, a novel Top1/Tdp1 inhibiting anti-tumor reagent.

This study evaluated the subacute toxicity and toxicokinetics of a potential anti-cancer drug candidate, pterostilbene, in rats. Animals were orally administered at two repeated doses of 200 and 500 mg/kg for 28 days. No mortality was observed during the 28 days of continuous administration of pterostilbene. Body weight and food consumption in each group increased steadily, while no significant difference was found. Liver weight in the 500 mg/kg female, but not male group increased with mild cytoplasmic vacuoles observed in histopathological study. Toxicokinetics was assessed by measuring plasma concentrations of pterostilbene on the first and 28th day of administration using UPLC-MS/MS. Toxicokinetic parameters showed that AUC0-t significantly increased in all animals, while the increase in females was greater than males. System exposure of pterostilbene appeared to be linear within the administrated dose range. In conclusion, our findings suggested a minimal subacute toxicity profile of pterostilbene, which could strongly support further development of this compound as a novel anti-cancer agent.

Varied Response of EEG Rhythm to Different tDCS Protocols and Lesion Hemispheres in Stroke Subjects with Upper Limb Dysfunction.

Transcranial direct current stimulation (tDCS) provides a way to modulate the cortical activity and promote motor rehabilitation following stroke. However, evidence indicates that the response to tDCS is highly variable. This study was aimed at exploring rhythmic response of Electroencephalography (EEG) to three tDCS protocols in stroke subjects. We hypothesize that tDCS protocols may interact with stoke characteristics, and electrode placement may affect cortical activity which could be reflected by the EEG rhythm. 32 subjects with unilateral stroke were recruited to a single-blinded, randomized, and controlled crossover experiment. All of the subjects underwent four tDCS protocols (anodal (atDCS), cathodal (ctDCS), and bilateral tDCS (bi-tDCS) and sham) with an interval of at least 1 week. Resting-state EEG was acquired before and after the stimulation. We tested the change of EEG spectral power after tDCS and the difference of change among four protocols using the paired-sample t-test and repeated measures analysis of variance. Then, we investigated the clinical factors affecting the above changes using the linear and quadratic regression model. According to the results, EEG responded to atDCS and bi-tDCS protocols on alpha and beta rhythm and subjects with a left lesion had higher response than those with the right lesion. Besides that, the change of alpha and beta power after atDCS and of beta power after bi-tDCS showed association with clinical characteristics only in subjects with the left lesion. In conclusion, the study found varied EEG response with different protocols, lesion hemispheres, and other clinical characteristics supporting the individualized cortical oscillatory effect induced by tDCS.

[Research on electroencephalogram power spectral density of stroke patients under transcranial direct current stimulation].

Transcranial direct current stimulation (tDCS) has become a new method of post-stroke rehabilitation treatment and is gradually accepted by people. However, the neurophysiological mechanism of tDCS in the treatment of stroke still needs further study. In this study, we recruited 30 stroke patients with damage to the left side of the brain and randomly divided them into a real tDCS group (15 cases) and a sham tDCS group (15 cases). The resting EEG signals of the two groups of subjects before and after stimulation were collected, then the difference of power spectral density was analyzed and compared in the band of delta, theta, alpha and beta, and the delta/alpha power ratio (DAR) was calculated. The results showed that after real tDCS, delta band energy decreased significantly in the left temporal lobes, and the difference was statistically significant ( P < 0.05); alpha band energy enhanced significantly in the occipital lobes, and the difference was statistically significant ( P < 0.05); the difference of theta and beta band energy was not statistically significant in the whole brain region ( P > 0.05). Furthermore, the difference of delta, theta, alpha and beta band energy was not statistically significant after sham tDCS ( P > 0.05). On the other hand, the DAR value of stroke patients decreased significantly after real tDCS, and the difference was statistically significant ( P < 0.05), and there was no significant difference in sham tDCS ( P > 0.05). This study reveals to a certain extent the neurophysiological mechanism of tDCS in the treatment of stroke.

The Bernoulli effect in horizontal granular flows.

The Bernoulli effect that commonly occurs in continuous fluids is simultaneously increasing a fluid's velocity and decreasing static pressure or the fluid's gravitational potential energy. Although, the Bernoulli effect has already been extensively explored, there is a lack of research on the relationship between flow velocity and pressure in a discrete medium. In the present study, this relationship in horizontal granular flows excited by vertical vibration is experimentally studied. It was found that the random motion and horizontal directed motion of the granules restrict each other so that the total pressure remains almost constant with respect to time and height. In fact, it implies that the Bernoulli effect occurs in the granular flows. It was also found that the pressure constant of the Bernoulli effect depends on the vibrating intensity and frequency, which reflects the energy transfer in the granular flows. Our results show a dynamic property of the granular flows, which is different from continuous fluids, even though it is similar to some extent.

[Research on characteristics of brain functional network in stroke patients during convalescent period under transcranial direct current stimulation].

Transcranial direct current stimulation (tDCS) is an emerging non-invasive brain stimulation technique. However, the rehabilitation effect of tDCS on stroke disease is unclear. In this paper, based on electroencephalogram (EEG) and complex network analysis methods, the effect of tDCS on brain function network of stroke patients during rehabilitation was investigated. The resting state EEG signals of 31 stroke rehabilitation patients were collected and divided into stimulation group (16 cases) and control group (15 cases). The Pearson correlation coefficients were calculated between the channels, brain functional network of two groups were constructed before and after stimulation, and five characteristic parameters were analyzed and compared such as node degree, clustering coefficient, characteristic path length, global efficiency, and small world attribute. The results showed that node degree, clustering coefficient, global efficiency, and small world attributes of brain functional network in the tDCS group were significantly increased, characteristic path length was significantly reduced, and the difference was statistically significant ( P < 0.05). It indicates that tDCS can improve the brain function network of stroke patients in rehabilitation period, and may provide theory and experimental basis for the application of tDCS in stroke rehabilitation treatment.

Task-Demand-Dependent Neural Representation of Odor Information in the Olfactory Bulb and Posterior Piriform Cortex.

In awake rodents, the neural representation of olfactory information in the olfactory bulb is largely dependent on brain state and behavioral context. Learning-modified neural plasticity has been observed in mitral/tufted cells, the main output neurons of the olfactory bulb. Here, we propose that the odor information encoded by mitral/tufted cell responses in awake mice is highly dependent on the behavioral task demands. We used fiber photometry to record calcium signals from the mitral/tufted cell population in awake, head-fixed male mice under different task demands. We found that the mitral/tufted cell population showed similar responses to two distinct odors when the odors were presented in the context of a go/go task, in which the mice received a water reward regardless of the identity of the odor presented. However, when the same odors were presented in a go/no-go task, in which one odor was rewarded and the other was not, then the mitral cell population responded very differently to the two odors, characterized by a robust reduction in the response to the nonrewarded odor. Thus, the representation of odors in the mitral/tufted cell population depends on whether the task requires discrimination of the odors. Strikingly, downstream of the olfactory bulb, pyramidal neurons in the posterior piriform cortex also displayed a task-demand-dependent neural representation of odors, but the anterior piriform cortex did not, indicating that these two important higher olfactory centers use different strategies for neural representation.SIGNIFICANCE STATEMENT The most important task of the olfactory system is to generate a precise representation of odor information under different brain states. Whether the representation of odors by neurons in olfactory centers such as the olfactory bulb and the piriform cortex depends on task demands remains elusive. We find that odor representation in the mitral/tufted cells of the olfactory bulb depends on whether the task requires odor discrimination. A similar neural representation is found in the posterior piriform cortex but not the anterior piriform cortex, indicating that these higher olfactory centers use different representational strategies. The task-demand-dependent representational strategy is likely important for facilitating information processing in higher brain centers responsible for decision making and encoding of salience.

Electrophysiological changes in poststroke subjects with depressed mood: A quantitative EEG study.

BACKGROUND: We aimed to explore the electrophysiological changes in poststroke subjects with depressed mood. METHODS: Resting-state electroencephalogram (EEG) signals of 16 electrodes in 35 poststroke depressed, 24 poststroke nondepressed, and 35 age-matched healthy control subjects were analyzed by means of spectral power analysis, a quantitative EEG measurement of different frequency bands. The relationship among depressed mood, functional status, lesion side, and poststroke time was assessed by using variance and Spearman correlation analysis. Multiple analysis of variance was used to compare the differences among the 3 groups. Binary logistic regression analysis was used to establish a regression model to predict depressed mood in stroke subjects and to explore the association between depression and EEG band power. Receiver operating characteristic curves were used to estimate the ability of spectral power selected by binary logistic regression to indicate depressed mood in stroke subjects. RESULTS: We found that the hemisphere in which the lesion was located and the time since stroke onset had no effect on depressed mood. Only the patient's functional status was related to emotional symptoms. Quantitative EEG analysis revealed increased delta, theta, and beta2 power in stroke subjects with depressed mood, particularly in temporal regions. The theta and beta2 power in the right temporal area were shown to be highly sensitive to depressed mood, and these parameters showed good discriminatory ability for depressed subjects following stroke. CONCLUSION: Depressed mood after stroke is associated with functional status. Quantitative EEG parameters may be a useful tool in timely screening for depressed mood after stroke.

Tyrosine phosphorylation of GluK2 up-regulates kainate receptor-mediated responses and downstream signaling after brain ischemia.

Although kainate receptors play important roles in ischemic stroke, the molecular mechanisms underlying postischemic regulation of kainate receptors remain unclear. In this study we demonstrate that Src family kinases contribute to the potentiation of kainate receptor function. Brain ischemia and reperfusion induce rapid and sustained phosphorylation of the kainate receptor subunit GluK2 by Src in the rat hippocampus, implicating a critical role for Src-mediated GluK2 phosphorylation in ischemic brain injury. The NMDA and kainate receptors are involved in the tyrosine phosphorylation of GluK2. GluK2 binds to Src, and the tyrosine residue at position 590 (Y590) on GluK2 is a major site of phosphorylation by Src kinases. GluK2 phosphorylation at Y590 is responsible for increases in whole-cell currents and calcium influx in response to transient kainate stimulation. In addition, GluK2 phosphorylation at Y590 facilitates the endocytosis of GluK2 subunits, and the activation of JNK3 and its substrate c-Jun after long-term kainate treatment. Thus, Src phosphorylation of GluK2 plays an important role in the opening of kainate receptor channels and downstream proapoptosis signaling after brain ischemia. The present study reveals an additional mechanism for the regulation of GluK2-containing kainate receptors by Src family kinases, which may be of pathological significance in ischemic stroke.

Modulation of GluK2a subunit-containing kainate receptors by 14-3-3 proteins.

Kainate receptors (KARs) are one of the ionotropic glutamate receptors that mediate excitatory postsynaptic currents (EPSCs) with characteristically slow kinetics. Although mechanisms for the slow kinetics of KAR-EPSCs are not totally understood, recent evidence has implicated a regulatory role of KAR-associated proteins. Here, we report that decay kinetics of GluK2a-containing receptors is modulated by closely associated 14-3-3 proteins. 14-3-3 binding requires PKC-dependent phosphorylation of serine residues localized in the carboxyl tail of the GluK2a subunit. In transfected cells, 14-3-3 binding to GluK2a slows desensitization kinetics of both homomeric GluK2a and heteromeric GluK2a/GluK5 receptors. Moreover, KAR-EPSCs at mossy fiber-CA3 synapses decay significantly faster in the 14-3-3 functional knock-out mice. Collectively, these results demonstrate that 14-3-3 proteins are an important regulator of GluK2a-containing KARs and may contribute to the slow decay kinetics of native KAR-EPSCs.

The functional role of the visual and olfactory modalities in the development of socially transferred mechanical hypersensitivity in male C57BL/6J mice.

An increasing body of evidence suggests that the state of hyperalgesia could be socially transferred from one individual to another through a brief empathetic social contact. However, how the social transfer of pain develops during social contact is not well-known. Utilizing a well-established mouse model, the present study aims to study the functional role of visual and olfactory cues in the development of socially-transferred mechanical hypersensitivity. Behavioral tests demonstrated that one hour of brief social contact with a conspecific mouse injected with complete Freund's adjuvant (CFA) was both sufficient and necessary for developing socially-transferred mechanical hypersensitivity. One hour of social contact with visual deprivation could not prevent the development of socially-transferred mechanical hypersensitivity, and screen observation of a CFA cagemate was not sufficient to develop socially-transferred mechanical hypersensitivity in bystanders. Methimazole-induced olfactory deprivation, a compound with reversible toxicity on the nasal olfactory epithelium, was sufficient to prevent the development of socially-transferred mechanical hypersensitivity. Intriguingly, repeated but not acute olfactory exposure to the CFA mouse bedding induced a robust decrease in 50 % paw withdrawal thresholds (50 %PWTs) to mechanical stimuli, an effect returned to the baseline level after two days of washout with clean bedding. The findings strongly indicate that the normal olfactory function is crucial for the induction of mechanical hypersensitivity through brief empathetic contact, offering valuable insights for animal housing in future pain research.

S-nitrosylation of mixed lineage kinase 3 contributes to its activation after cerebral ischemia.

Previous studies in our laboratory have shown that mixed lineage kinase 3 (MLK3) can be activated following global ischemia. In addition, other laboratories have reported that the activation of MLK3 may be linked to the accumulation of free radicals. However, the mechanism of MLK3 activation remains incompletely understood. We report here that MLK3, overexpressed in HEK293 cells, is S-nitrosylated (forming SNO-MLK3) via a reaction with S-nitrosoglutathione, an exogenous nitric oxide (NO) donor, at one critical cysteine residue (Cys-688). We further show that the S-nitrosylation of MLK3 contributes to its dimerization and activation. We also investigated whether the activation of MLK3 is associated with S-nitrosylation following rat brain ischemia/reperfusion. Our results show that the administration of 7-nitroindazole, an inhibitor of neuronal NO synthase (nNOS), or nNOS antisense oligodeoxynucleotides diminished the S-nitrosylation of MLK3 and inhibited its activation induced by cerebral ischemia/reperfusion. In contrast, 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (an inhibitor of inducible NO synthase) or nNOS missense oligodeoxynucleotides did not affect the S-nitrosylation of MLK3. In addition, treatment with sodium nitroprusside (an exogenous NO donor) and S-nitrosoglutathione or MK801, an antagonist of the N-methyl-D-aspartate receptor, also diminished the S-nitrosylation and activation of MLK3 induced by cerebral ischemia/reperfusion. The activation of MLK3 facilitated its downstream protein kinase kinase 4/7 (MKK4/7)-JNK signaling module and both nuclear and non-nuclear apoptosis pathways. These data suggest that the activation of MLK3 during the early stages of ischemia/reperfusion is modulated by S-nitrosylation and provides a potential new approach for stroke therapy whereby the post-translational modification machinery is targeted.

Effects of Transcranial Direct Current Stimulation on EEG Power and Brain Functional Network in Stroke Patients.

Transcranial direct current stimulation (tDCS) has become a new method of rehabilitation treatment for stroke and is gradually gaining acceptance. However, the neurophysiological mechanisms of tDCS in the treatment of stroke still need to be further explored. In our research, we aimed to investigate the effects of tDCS on neural oscillation power and brain functional network (BFN) connectivity in stroke patients based on electroencephalogram (EEG). Fifteen patients with ischemic stroke attended two experimental sessions in a randomized crossover trial and received real and sham tDCS. Resting-state EEG signals were acquired before and after stimulation. First, the power of EEG delta, theta, alpha, beta, and gamma bands were analyzed before and after stimulation. Then, BFNs in different bands were constructed, and network characteristic parameters such as degree, clustering coefficient, characteristic path length, global efficiency, and small-world attribute were analyzed. The results showed that the delta power decreased significantly ( ) and the alpha power increased significantly ( ) after real tDCS, whereas the theta, beta, and gamma power did not change significantly ( ). The degree and global efficiency of the delta band BFN decreased significantly after real tDCS ( ), the characteristic path length increased significantly ( ), and the clustering coefficient and small-world attribute decreased but not statistically significant ( ). The degree, clustering coefficient, global efficiency, and small-world attribute of the alpha band BFN increased significantly after real tDCS ( ), and the characteristic path length decreased significantly ( ). The BFN characteristic parameters in theta, beta, and gamma bands did not change significantly after real tDCS ( ). There was no significant difference in sham tDCS group ( ). Our study found that the power of delta oscillations decreased and the global connectivity of delta band BFN weakened after tDCS in stroke patients, whereas the power of alpha oscillations increased and the global and local connectivity of alpha band BFN was enhanced. The findings implied that one of the neurophysiological mechanisms of tDCS treatment in stroke patients may be the modulation of the power of delta and alpha oscillations, as well as the improvement of the connectivity of delta and alpha oscillation networks.

Negative valence encoding in the lateral entorhinal cortex during aversive olfactory learning.

Olfactory learning is widely regarded as a substrate for animal survival. The exact brain areas involved in olfactory learning and how they function at various stages during learning remain elusive. Here, we investigate the role of the lateral entorhinal cortex (LEC) and the posterior piriform cortex (PPC), two important olfactory areas, in aversive olfactory learning. We find that the LEC is involved in the acquisition of negative odor value during olfactory fear conditioning, whereas the PPC is involved in the memory-retrieval phase. Furthermore, inhibition of LEC CaMKIIα+ neurons affects fear encoding, fear memory recall, and PPC responses to a conditioned odor. These findings provide direct evidence for the involvement of LEC CaMKIIα+ neurons in negative valence encoding.

Phase I Metabolism of Pterostilbene, a Dietary Resveratrol Derivative: Metabolite Identification, Species Differences, Isozyme Contribution, and Further Bioactivation.

Pterostilbene (PTE), a dietary derivative of resveratrol, displayed pleiotropic health-promoting activities. This study aimed to explore the metabolic profiles and species differences of the phase I metabolism of PTE and to investigate subsequent detoxification after PTE bioactivation. PTE was found to be biotransformed to two pharmacologically active metabolites, pinostilbene and 3'-hydroxypterostilbene, in vivo and in vitro with substantial species differences. Human CYP1A2 was proved to be mainly responsible for the demethylation and 3'-hydroxylation of PTE, with its contribution to a demethylation of 94.5% and to a 3'-hydroxylation of 97.9%. An in vitro glutathione trapping experiment revealed the presence of an ortho-quinone intermediate formed by further oxidation of 3'-hydroxypterostilbene. Human glutathione S-transferase isoforms A2, T1, and A1 inactivated the ortho-quinone intermediate by catalyzing glutathione conjugation, implicating a potential protective pathway against PTE bioactivation-derived toxicity. Overall, this study provided a comprehensive view of PTE phase I metabolism and facilitated its further development as a promising nutraceutical.

S-nitrosylation of c-Src via NMDAR-nNOS module promotes c-Src activation and NR2A phosphorylation in cerebral ischemia/reperfusion.

Previous studies suggested that activated c-Src promote the tyrosine phosphorylation of NMDA receptor subunit NR2A, and thus aggravate the injury induced by transient cerebral ischemia/reperfusion (I/R) in rat hippocampus CA1 region. In this study, we examined the effect of nitric oxide (NO) on the activation of c-Src and the tyrosine phosphorylation of NMDA receptor NR2A subunit. The results show that S-nitrosylation and the phosphorylation of c-Src were induced after cerebral I/R in rats, and administration of nNOS inhibitor 7-NI, nNOS antisense oligonucleotides and exogenous NO donor sodium nitroprusside diminished the increased S-nitrosylation and phosphorylation of c-Src during cerebral I/R. The cysteine residues of c-Src modified by S-nitrosylation are Cys489, Cys498, and Cys500. On the other hand, NMDAR antagonist MK-801 could attenuate the S-nitrosylation and activation of c-Src. Taken together, the S-nitrosylation of c-Src is provoked by NO derived from endogenous nNOS, which is activated by Ca(2+) influx from NMDA receptors, and promotes the auto-phosphorylation at tyrosines and further phosphorylates NR2A. The molecular mechanism we outlined here is a novel postsynaptic NMDAR-nNOS/c-Src-mediated signaling amplification, the 'NMDAR-nNOS â†’ NO â†’ SNO-c-Src â†’ p-c-Src â†’ NMDAR-nNOS' cycle, which presents the possibility as a potential therapeutic target for stroke treatment.

Effect of Transcranial Direct Current Stimulation on the Mismatch Negativity Features of Deviated Stimuli in Children With Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a devastating mental disorder in children. Currently, there is no effective treatment for ASD. Transcranial direct current stimulation (tDCS), which is a non-invasive brain stimulation neuromodulation technology, is a promising method for the treatment of ASD. However, the manner in which tDCS changes the electrophysiological process in the brain is still unclear. In this study, we used tDCS to stimulate the dorsolateral prefrontal cortex area of children with ASD (one group received anode tDCS, and the other received sham tDCS) and investigated the changes in evoked EEG signals and behavioral abilities before and after anode and sham stimulations. In addition to tDCS, all patients received conventional rehabilitation treatment. Results show that although conventional treatment can effectively improve the behavioral ability of children with ASD, the use of anode tDCS with conventional rehabilitation can boost this improvement, thus leading to increased treatment efficacy. By analyzing the electroencephalography pre- and post-treatment, we noticed a decrease in the mismatch negativity (MMN) latency and an increase in the MMN amplitude in both groups, these features are considered similar to MMN features from healthy children. However, no statistical difference between the two groups was observed after 4 weeks of treatment. In addition, the MMN features correlate well with the aberrant behavior checklist (ABC) scale, particularly the amplitude of MMN, thus suggesting the feasibility of using MMN features to assess the behavioral ability of children with ASD.

Alpha rhythm of electroencephalography was modulated differently by three transcranial direct current stimulation protocols in patients with ischemic stroke.

The heterogeneity of transcranial direct current stimulation (tDCS) protocols and clinical profiles may explain variable results in modulating excitability in the motor cortex after stroke. However, the cortical electrical effects induced by different tDCS protocols remain unclear. Here, we aimed to compare rhythm changes in electroencephalography (EEG) induced by three tDCS position protocols and the association between tDCS effects and clinical factors in stroke. Nineteen patients with chronic ischemic stroke underwent four experimental sessions with three tDCS protocols [anodal (atDCS), cathodal (ctDCS), and bilateral (bi-tDCS)] and a sham protocol, according to a single-blind randomized crossover design. Resting-state EEG was acquired before and after each protocol. First, a paired-sample t-test was used to examine the difference in spectral power between pre- and post-stimulation. Then, linear and quadratic regression models were used separately to describe the association between the clinical factors of stroke and changes in spectral power which was significantly different between pre- and post-tDCS. Finally, repeated measures analysis of variance with lesion hemisphere, stimulation protocol, and the location was performed to investigate the effects of tDCS over time. The induced effect of tDCS was mainly reflected in the alpha rhythms. The alpha power was increased by atDCS, especially low-alpha (8-10 Hz), in localized areas of the central and distant areas of the frontal and parietal lobes. Bi-tDCS also affected alpha power but in a smaller area that mainly focused on high-alpha rhythms (10-13 Hz). However, ctDCS and sham had no significant effects on any EEG rhythm. The clinical factors of time since stroke and motor impairment level were related to the change in high-alpha induced by atDCS and bi-tDCS following quadratic regression models. The above-mentioned modulation effect lasted for 20 min without attenuation. In conclusion, our findings provide evidence that the alpha rhythm of EEG is modulated differently by different tDCS protocols and that high alpha is affected by clinical characteristics such as post-stroke time and motor deficits, which is of great significance for understanding the modulation effect of different tDCS protocols on stroke and the guidance of protocols to promote motor recovery following stroke.

Effect of Pterostilbene, a Natural Derivative of Resveratrol, in the Treatment of Colorectal Cancer through Top1/Tdp1-Mediated DNA Repair Pathway.

Topoisomerase 1 (Top1) inhibitor is an effective anticancer drug, but several factors limit its clinical application such as drug inactivation, tyrosyl-DNA phosphodiesterase 1 (Tdp1)-mediated tumor drug resistance, and its toxicity. Our previous study identified pterostilbene (PTE) and resveratrol (RE) to suppress these two proteins by binding to their active center. PTE and RE could inhibit the proliferation of various colorectal cancer cells, induce cell apoptosis, and make cell cycle stay in G2/M phase in vitro. PTE and RE could decrease Top1 and Tdp1 contents and mRNA expression in wild-type, constructed Tdp1 overexpressing CL187, Top1- or Tdp1- silenced CL187 cell lines. PTE exhibited excellent antitumor activity in subcutaneous CL187 transplantation model (TGI = 79.14 ± 2.85%, 200 mg/kg, i.p.) and orthotopic transplantation model (TGI = 76.57 ± 6.34%, 100 mg/kg, i.p.; TGI = 72.79 ± 4.06%, 500 mg/kg, i.g.) without significant toxicity. PTE had no significant inhibitory effect on non-tumor cell proliferation in vitro and would not induce damage to liver, kidney, and other major organs. Overall, PTE and RE can inhibit the activity of Top1 enzyme and inhibit the DNA damage repair pathway mediated by Top1/Tdp1, and can effectively inhibit colorectal cancer development with low toxicity, thus they have great potential to be developed into a new generation of anti-tumor drugs.

Oxytocin modulates neural processing of mitral/tufted cells in the olfactory bulb.

AIM: Oxytocin plays an important role in social recognition in rodents, which is mediated predominantly by the olfactory system. Although oxytocin modulates neural activity in the olfactory bulb, the underlying mechanism is largely unknown. Here, we studied how direct infusion of oxytocin into the olfactory bulb affect social interactions in mice and modulate the neural activity of mitral/tufted cells in the olfactory bulb. METHODS: A three-chamber social interaction test was used in the behavioural test. For in vivo studies, single unit recordings, local field potential recordings and fibre photometry recordings were used to record the neural activity of olfactory bulb. For in vitro studies, we performed patch clamp recordings in the slice of the olfactory bulb. RESULTS: Behaviourally, direct oxytocin infusion in olfactory bulb increased performance in a social interaction task. Moreover, odour-evoked responses of mitral/tufted cells and neural discrimination of odours were both enhanced by oxytocin, whereas the spontaneous firing rate of mitral/tufted cells was reduced. At the neural network level, oxytocin decreased the amplitude of odour-evoked high gamma responses. At the cell population level, oxytocin decreased odour-evoked calcium responses (reflecting neural activity) specifically in granule cells. Moreover, in vitro slice recordings revealed that the inhibitory effect of oxytocin on mitral cell activity is mediated mainly by modulation of ATP-sensitive potassium channels and involves the oxytocin receptor-Gq-PLC-IP3 signalling pathway. CONCLUSION: Oxytocin modulates social interaction, likely by increasing the signal-to-noise ratio of odour responses in mitral cells which is partly through ATP-sensitive potassium channel.

Partial depletion of dopaminergic neurons in the substantia nigra impairs olfaction and alters neural activity in the olfactory bulb.

Olfactory dysfunction is a major non-motor symptom that appears during the early stages of Parkinson's Disease (PD), a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra (SN). Depletion of SN dopaminergic neurons by 6-hydroxydopamine (6-OHDA) is widely used as a model for PD and ultimately results in motor deficits. However, it is largely unknown whether olfactory behavior and, more importantly, neural activity in the olfactory bulb (OB) are impaired prior to the appearance of motor deficits. We partially depleted the SN dopaminergic population in mice by injection of 6-OHDA. Seven days after injection of 6-OHDA, motor ability was unchanged but olfactory-driven behaviors were significantly impaired. Injection of 6-OHDA into the SN significantly increased the power of the ongoing local field potential in the OB for all frequency bands, and decreased odor-evoked excitatory beta responses and inhibitory high-gamma responses. Moreover, 6-OHDA treatment led to increased odor-evoked calcium responses in the mitral cells in the OB of awake mice. These data suggest that the olfactory deficits caused by depletion of the SN dopaminergic population are likely due to abnormal hyperactivity of the mitral cells in the OB.