Focusing on cyclin-dependent kinases 5: A potential target for neurological disorders.

Cyclin-dependent kinases 5 (Cdk5) is a special member of proline-directed serine threonine kinase family. Unlike other Cdks, Cdk5 is not directly involved in cell cycle regulation but plays important roles in nervous system functions. Under physiological conditions, the activity of Cdk5 is tightly controlled by p35 or p39, which are specific activators of Cdk5 and highly expressed in post-mitotic neurons. However, they will be cleaved into the corresponding truncated forms namely p25 and p29 under pathological conditions, such as neurodegenerative diseases and neurotoxic insults. The binding to truncated co-activators results in aberrant Cdk5 activity and contributes to the initiation and progression of multiple neurological disorders through affecting the down-stream targets. Although Cdk5 kinase activity is mainly regulated through combining with co-activators, it is not the only way. Post-translational modifications of Cdk5 including phosphorylation, S-nitrosylation, sumoylation, and acetylation can also affect its kinase activity and then participate in physiological and pathological processes of nervous system. In this review, we focus on the regulatory mechanisms of Cdk5 and its roles in a series of common neurological disorders such as neurodegenerative diseases, stroke, anxiety/depression, pathological pain and epilepsy.

Focusing on Formononetin: Recent Perspectives for its Neuroprotective Potentials.

Nervous system is the most complex system of the human body, hence, the neurological diseases often lack effective treatment strategies. Natural products have the potential to yield unique molecules and produce integrative and synergic effects compared to standard therapy. Mounting evidence has shown that isoflavonoids contained in traditional medicinal plant or dietary supplementation may play a crucial role in the prevention and treatment of neurological diseases due to their pronounced biological activities correlating to nervous system. Formononetin, a non-steroidal isoflavonoid, is a bioactive constituent of numerous medicinal plants such as red clover (Trifolium pratense) and Astragalus membranaceus. Emerging evidence has shown that formononetin possesses considerable anti-inflammatory, antioxidant and anti-cancer effects. This review intends to analyze the neuropharmacological potential of formononetin on the therapy of nervous system disorders. The neuroprotective properties of formononetin are observed in multiple neurological disorders including Alzheimer's disease, dementia, cerebral ischemia, traumatic brain injury, anxiety, and depression. The beneficial effects of formononetin are achieved partially through attenuating neuroinflammation and oxidative stress via the related signaling pathway. Despite its evident effects in numerous preclinical studies, the definite role of formononetin on humans is still less known. More well-designed clinical trials are required to further confirm the neuroprotective efficacy and safety profile of formononetin before its application in clinic.

Noradrenergic innervations of the medial prefrontal cortex mediate empathy for pain in rats via the α1 and ß receptors.

Empathy involves integrated affective and cognitive processes to share the emotional state of others. This evolutionarily conserved ability has also been identified in nonhuman primates and rodents. Our previous work demonstrated that social interaction with a cagemate rat in pain induces mechanical pain hypersensitivity in cagemate observer (CO) rats. Moreover, we also demonstrated that the medial prefrontal cortex (mPFC) and the locus coeruleus-norepinephrine (LC-NE) system are involved in this process. The LC sends noradrenergic innervations throughout the brain, and its innervation of the prefrontal cortex plays important roles in working memory and attention. The present study seeks to study the roles of the LC-to-mPFC pathway in pain empathy in rats. Selective ablation of the noradrenergic innervations of the mPFC through bilateral injections of the axonally transported catecholamine immunotoxin, saporin-conjugated antiserum to dopamine-ß-hydroxylase into the mPFC diminished mechanical pain hypersensitivity in CO rats. Bilateral intra-mPFC applications of the adrenergic α1 receptor antagonist prazosin and the ß receptor antagonist propranolol, but not the adrenergic α2 antagonist yohimbine, eliminated mechanical pain hypersensitivity in CO rats. In contrast, intra-mPFC applications of prazosin, yohimbine or propranolol did not affect the mechanical pain sensitivity of rats per se. Our results indicate that noradrenergic innervations in the mPFC mediate empathy for pain in rats via the α1 and ß receptors.

Nonylphenol regulates TL1A through the AhR/HDAC2/HNF4α pathway in endothelial cells to promote the angiogenesis of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most malignant cancers worldwide. Nonylphenol (NP) is an endocrine-disruptor chemical and plays an important role in the development of cancers. However, the effects of NP on CRC remain unclear. In this study, we aimed to investigate the potential mechanisms of NP in the pathogenesis of CRC. METHODS: The levels of AhR, TL1A and HDAC2 in CRC tissues and endothelial cells were assessed by RT-qPCR or western blot. CHIP and dual luciferase reporter assays were used to confirm the interaction between AhR and HDAC2, or HNF4α and TL1A. The CCK8, would healing and tube formation assays were conducted to evaluate the proliferation, migration and angiogenesis of HUVECs. Western blot determined HNF4α protein and HNF4α acetylation levels. The secreted TL1A protein was detected by ELISA. The angiogenesis-related factor CD31 was tested by IHC. RESULTS: The expression level of AhR was significantly up-regulated in CRC tissues and endothelial cells. Moreover, NP activated the AhR pathway mediated colorectal endothelial cell angiogenesis and proliferation, while TL1A overexpression resisted these effects caused by NP. Besides, NP was found to modulate HNF4α deacetylation through AhR/HDAC2 to inhibit TL1A. Furthermore, in vivo experiments proved that NP regulated CRC growth and angiogenesis via AhR/HDAC2/HNF4α/TL1A axis. CONCLUSION: This study revealed that NP promoted CRC growth and angiogenesis through AhR/HDAC2/HNF4α/TL1A pathway and could be a new therapeutic target for CRC treatment.

The endocannabinoid system regulates synaptic transmission in nucleus accumbens by increasing DAGL-α expression following short-term morphine withdrawal.

BACKGROUND AND PURPOSE: The endocannabinoid (eCB) system is involved in pathways that regulate drug addiction and eCB-mediated synaptic plasticity has been linked with addictive behaviours. Here, we investigated the molecular mechanisms underlying the changes in eCB-dependent synaptic plasticity in the nucleus accumbens core (NAcc) following short-term withdrawal from repeated morphine treatment. EXPERIMENTAL APPROACH: Conditioned place preference (CPP) was used to evaluate the rewarding effects of morphine in rats. Evoked inhibitory postsynaptic currents of medium spiny neurons in NAcc were measured using whole-cell patch-clamp recordings. Changes in depolarization-induced suppression of inhibition (DSI) in the NAcc were assessed to determine the effect of short-term morphine withdrawal on the eCB system. To identify the potential modulation mechanism of short-term morphine withdrawal on the eCB system, the expression of diacylglycerol lipase α (DGL-α) and monoacylglycerol lipase was detected by Western blot analysis. KEY RESULTS: Repeated morphine administration for 7 days induced stable CPP. Compared with the saline group, the level of DSI in the NAcc was significantly increased in rats after short-term morphine withdrawal. Furthermore, this increase in DSI coincided with a significant increase in the expression of DGL-α. CONCLUSIONS AND IMPLICATIONS: Short-term morphine withdrawal potentiates eCB modulation of inhibitory synaptic transmission in the NAcc. We also found that DGL-α expression was elevated after short-term morphine withdrawal, suggesting that the eCB 2-arachidonyl-glycerol but not anandamide mediates the increase in DSI. These findings provide useful insights into the mechanisms underlying eCB-mediated plasticity in the NAcc during drug addiction. LINKED ARTICLES: This article is part of a themed section on Endocannabinoids. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issuetoc.

Increased expression of cannabinoid receptor 1 in the nucleus accumbens core in a rat model with morphine withdrawal.

Relapse is a major clinical problem and remains a major challenge in the treatment of drug addiction. There is strong evidence that the endocannabinoid system of the nucleus accumben core (NAcc) is involved in drug-seeking behavior, as well as in the mechanisms that underlie relapse to drug use. To reveal the mechanism that underlies this finding, we examined the expression pattern of the cannabinoid receptor 1 (CB1-R) in the NAcc of SD rats that had been undergoing morphine withdrawal (MW) for 1 day, 3 days and 3 weeks (acute, latent and chronic phases, respectively). Morphine exposure induced conditioned place preference (CPP) in rats. Significant increase of CB1-R expression in NAcc was observed in animals in the 1 day, 3 days and 3 weeks morphine withdrawal compare to the control group. Immunofluorescence labeling showed axonal fibers or terminals by fluorescence microscope observation. Immunoelectron microscopy detection showed silver-gold particles located in the presynaptic membranes that mainly give rise to symmetrical synapses. Quantitative electron microscopy showed an increase in number of CB1-R-positive terminals in the morphine withdrawal groups and the number of immunogold particles was significantly increased at these inhibitory terminals. We also confirmed that infusions of the CB1-R antagonist rimonabant into the NAcc attenuated the CPP during morphine withdrawal. Our present data have thus indicated that increasing pattern of CB1-R expression in the NAcc during above morphine withdrawal phases, which might underlie the relapse associated drug seeking behavior after morphine withdrawal.

[Distribution and composition of organochlorine pesticides in farmland top soils of Anhui Province].

By using ultrasonic method and GC/ECD, this paper analyzed the distribution and composition of 8 kinds of organochlorine pesticides (alpha-HCH, beta-HCH, gamma-HCH, delta-HCH, op'-DDE, pp'-DDD, alpha-endosulfan, and chlorothalonil) in farmland top soils (0-20 cm) in 19 districts of Anhui Province, East China. The total concentration of the pesticides in the top soils ranged from 0 to 23.75 microg x kg(-1), among which, pp'-DDD and gamma-HCH were the major pollutants, with the mean concentration being 13.83 and 13.49 microg x kg(-1), respectively. As compared with the analyses in 1990, the present mean concentration of HCH had an obvious decreasing trend, but was still higher than that in the top soils in other regions of China and in other countries. The mean concentrations of OCPs, HCHs and pp'-DDD in the test top soils were 48.58, 28.64 and 13.83 microg x kg(-1), respectively, not surpassed the first grade level (< 50 microg x kg(-1)) of the China National Soil Environmental Quality Standards (GB 15618-1995), suggesting that the farmland top soils in these districts of Anhui Province were less polluted.

[Effects of endophytic Paenibacillus polymyxa S-7 on photosynthesis, yield, and quality of sugar beet].

This study showed that inoculation of endophytic Paenibacillus polymyxa S-7 could significantly (P < 0.05) promote the photosynthesis of sugar beet. After the inoculation, the leaf net photosynthetic rate (Pn), stomatal limitation (Ls), stomatal conductance (Gs), and transpiration rate (Tr) increased by 16.11%, 23.82%, 41.91%, and 34.80%, respectively, while the stomatal intercellular CO2 concentration (Ci) decreased by 21.09%. Inoculation of endophytic P. polymyxa S-7 could also increase sugar beet yield and its quality significantly (P < 0.05), with the tuberous root biomass and its sugar content increased by 25.63% and 17.46%, respectively. It was concluded that endophytic P. polymyxa S-7 not only affected the photosynthetic parameters, but also promoted the yield and quality of sugar beet.