In situ coupling of carbon dots with zeolitic imidazolate frameworks enabling highly red emission in solid state.

In this work, an extraordinary solid red emissive phosphor was prepared based on red-emitting carbon dots (R-CDs). The synthesis was conducted under an in-situ strategy, with assistance of zeolitic imidazolate frameworks. The obtained phosphor possesses a stronger red emission located at 630 nm in solid state, with CIE coordinate of (0.63, 0.35) and quantum yield of âˆ¼ 45 %. As a consequence, not only aggregation-induced fluorescence quenching of R-CDs is avoided in solid state, but also an enhanced emission with high quantum yield is presented. Fluorescence properties were further explored in detail. The emission is found to be responsive to temperature and applied pressure. Based on the excellent emissive performance, the material has great potentials in anti-counterfeiting, latent fingerprint imaging, and temperature/pressure-sensing. This work provides a facile and promising way of preparing solid carbon-based phosphors for special applications.

Involvement of oxytocin receptor deficiency in psychiatric disorders and behavioral abnormalities.

Oxytocin and its target receptor (oxytocin receptor, OXTR) exert important roles in the regulation of complex social behaviors and cognition. The oxytocin/OXTR system in the brain could activate and transduce several intracellular signaling pathways to affect neuronal functions or responses and then mediate physiological activities. The persistence and outcome of the oxytocin activity in the brain are closely linked to the regulation, state, and expression of OXTR. Increasing evidence has shown that genetic variations, epigenetic modification states, and the expression of OXTR have been implicated in psychiatric disorders characterized by social deficits, especially in autism. Among these variations and modifications, OXTR gene methylation and polymorphism have been found in many patients with psychiatric disorders and have been considered to be associated with those psychiatric disorders, behavioral abnormalities, and individual differences in response to social stimuli or others. Given the significance of these new findings, in this review, we focus on the progress of OXTR's functions, intrinsic mechanisms, and its correlations with psychiatric disorders or deficits in behaviors. We hope that this review can provide a deep insight into the study of OXTR-involved psychiatric disorders.

Microglial Activation of GLP-1R Signaling in Neuropathic Pain Promotes Gene Expression Adaption Involved in Inflammatory Responses.

Background: Neuropathic pain is a common chronic pain, which is related to hypersensitivity to stimulus and greatly affects the quality of life of patients. Maladaptive gene changes and molecular signaling underlie the sensitization of nociceptive pathways. We previously found that the activation of microglial glucagon-like peptide 1 receptor (GLP-1R) could potently relieve formalin-, bone cancer-, peripheral nerve injury-, and diabetes-induced pain hypersensitivity. So far, little is known about how the gene profile changes upon the activation of GLP-1R signaling in the pathophysiology of neuropathic pain. Methods: Spinal nerve ligation (SNL) was performed to induce neuropathic pain in rats. Mechanical allodynia was assessed using von Frey filaments. The expression of IL-10, ß-endorphin, and µ-opioid receptor (MOR) was examined by real-time quantitative polymerase chain reaction (qPCR) and whole-cell recording. Measurements of cellular excitability of the substantia gelatinosa (SG) neurons by whole-cell recording were carried out. R packages of differential gene expression analysis based on the negative binomial distribution (DESeq2) and weighted correlation network analysis (WGCNA) were used to analyze differential gene expression and the correlated modules among GLP-1R clusters in neuropathic pain. Results: The GLP-1R agonist, exenatide, has an antiallodynic effect on neuropathic pain, which could be reversed by intrathecal injections of the microglial inhibitor minocycline. Furthermore, differential gene expression analysis (WGCNA) indicated that intrathecal injections of exenatide could reverse the abnormal expression of 591 genes in the spinal dorsal horn induced by nerve injury. WGCNA revealed 58 modules with a close relationship between the microglial GLP-1R pathway and features of nerve injuries, including pain, ligation, paw withdrawal latency (PWL), and anxiety. The brown module was identified as the highest correlated module, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that inflammatory responses were most correlated with PWL. To further unravel the changes of hyperalgesia-related neuronal electrophysiological activity mediated by microglia GLP-1 receptors, whole-cell recording identified that MOR agonism stimulated a robust outward current in the sham groups compared with the spinal nerve ligation (SNL) groups. This inhibitory effect on the SNL group was more sensitive than that of the sham group after bath application of ß-endorphin. Conclusions: Our results further confirmed that the GLP-1R pathway is involved in alleviating pain hypersensitivity mediated by spinal microglia activation, and inflammatory responses were the most correlated pathway associated with PWL changes in response to exenatide treatment. We found that the identification of gene regulation in response to GLP-1R activation is an effective strategy for identifying new therapeutic targets for neuropathic pain. Investigation for the activation of spinal microglial GLP-1R which might ameliorate inflammatory responses through gene expression and structural changes is providing a potential biomarker in pain management.

Estrogen augmented visceral pain and colonic neuron modulation in a double-hit model of prenatal and adult stress.

BACKGROUND: Chronic stress during pregnancy may increase visceral hyperalgesia of offspring in a sex-dependent way. Combining adult stress in offspring will increase this sensitivity. Based on the evidence implicating estrogen in exacerbating visceral hypersensitivity in female rodents in preclinical models, we predicted that chronic prenatal stress (CPS) + chronic adult stress (CAS) will maximize visceral hyperalgesia; and that estrogen plays an important role in colonic hyperalgesia. AIM: The aim was to illuminate the role of estrogen in colonic hyperalgesia and its underlying mechanisms. METHODS: We established a CPS plus CAS rodent model in which the balloon was used to distend the colorectum. The single-fiber recording in vivo and patch clamp experiments in vitro were used to monitor the colonic neuron's activity. The reverse transcription-polymerase chain reaction, western blot, and immunofluorescence were used to study the effects of CPS and CAS on colon primary afferent sensitivity. We used ovariectomy and letrozole to reduce estrogen levels of female rats respectively in order to assess the role of estrogen in female-specific enhanced primary afferent sensitization. RESULTS: Spontaneous activity and single fiber activity were significantly greater in females than in males. The enhanced sensitization in female rats mainly came from low-threshold neurons. CPS significantly increased single-unit afferent fiber activity in L6-S2 dorsal roots in response. Activity was further enhanced by CAS. In addition, the excitability of colon-projecting dorsal root ganglion (DRG) neurons increased in CPS + CAS rats and was associated with a decrease in transient A-type K+ currents. Compared with ovariectomy, treatment with the aromatase inhibitor letrozole significantly reduced estrogen levels in female rats, confirming the gender difference. Moreover, mice treated with letrozole had decreased colonic DRG neuron excitability. The intrathecal infusion of estrogen increased brain-derived neurotrophic factor (BDNF) protein levels and contributed to the response to visceral pain. Western blotting showed that nerve growth factor protein was upregulated in CPS + CAS mice. CONCLUSION: This study adds to the evidence that estrogen-dependent sensitization of primary afferent colon neurons is involved in the development of chronic stress-induced visceral hypersensitivity in female rats.

Spinal microglial ß-endorphin signaling mediates IL-10 and exenatide-induced inhibition of synaptic plasticity in neuropathic pain.

AIM: This study aimed to investigate the regulation of pain hypersensitivity induced by the spinal synaptic transmission mechanisms underlying interleukin (IL)-10 and glucagon-like peptide 1 receptor (GLP-1R) agonist exenatide-induced pain anti-hypersensitivity in neuropathic rats through spinal nerve ligations. METHODS: Neuropathic pain model was established by spinal nerve ligation of L5/L6 and verified by electrophysiological recording and immunofluorescence staining. Microglial expression of ß-endorphin through autocrine IL-10- and exenatide-induced inhibition of glutamatergic transmission were performed by behavioral tests coupled with whole-cell recording of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) through application of endogenous and exogenous IL-10 and ß-endorphin. RESULTS: Intrathecal injections of IL-10, exenatide, and the µ-opioid receptor (MOR) agonists ß-endorphin and DAMGO inhibited thermal hyperalgesia and mechanical allodynia in neuropathic rats. Whole-cell recordings of bath application of exenatide, IL-10, and ß-endorphin showed similarly suppressed enhanced frequency and amplitude of the mEPSCs in the spinal dorsal horn neurons of laminae II, but did not reduce the frequency and amplitude of mIPSCs in neuropathic rats. The inhibitory effects of IL-10 and exenatide on pain hypersensitive behaviors and spinal synaptic plasticity were totally blocked by pretreatment of IL-10 antibody, ß-endorphin antiserum, and MOR antagonist CTAP. In addition, the microglial metabolic inhibitor minocycline blocked the inhibitory effects of IL-10 and exenatide but not ß-endorphin on spinal synaptic plasticity. CONCLUSION: This suggests that spinal microglial expression of ß-endorphin mediates IL-10- and exenatide-induced inhibition of glutamatergic transmission and pain hypersensitivity via presynaptic and postsynaptic MORs in spinal dorsal horn.

Involvement of Oxytocin Receptor/Erk/MAPK Signaling in the mPFC in Early Life Stress-Induced Autistic-Like Behaviors.

The neonatal or infant period is a critical stage for the development of brain neuroplasticity. Early life stresses in the neonatal period, including neonatal maternal separation (NMS), have adverse effects on an increased risk of psychiatric disorders in juveniles and adults. However, the underlying molecular mechanisms are not largely understood. Here, we found that juvenile rats subjected to 4 h daily NMS during postnatal days 1 to 20 exhibited autistic-like behavioral deficits without impairments in learning and memory functions. Molecular mechanism studies showed that oxytocin receptor (OXTR) in the medial prefrontal cortex of NMS rats was evidently downregulated when compared with control pups, especially in neurons. Erk/MAPK signaling, the downstream coupling signaling of OTXR, was also inhibited in NMS juvenile rats. Treatment with oxytocin could relieve NMS-induced social deficit behaviors and activated phosphorylation of Erk/MAPK signaling. Furthermore, medication with the inhibitor of H3K4 demethylase alleviated the abnormal behaviors in NMS rats and increased the expression of OXTR in the medial prefrontal cortex, which showed an epigenetic mechanism underlying social deficits induced by NMS. Taken together, these findings identified a molecular mechanism by which disruptions of mother-infant interactions influenced later displays of typical social behaviors and suggested the potential for NMS-driven epigenetic tuning of OXTR expression.

Efficient degradation of naproxen by persulfate activated with zero-valent iron: performance, kinetic and degradation pathways.

Degradation of naproxen (NAP) by persulfate (PS) activated with zero-valent iron (ZVI) was investigated in our study. The NAP in aqueous solution was degraded effectively by the ZVI/PS system and the degradation exhibited a pseudo-first-order kinetics pattern. Both sulfate radical (SO4 •-) and hydroxyl radical (HO•) participate in the NAP degradation. The second-order rate constants for NAP reacting with SO4 •- and HO• were (5.64 ± 0.73) × 109 M- 1 s- 1 and (9.05 ± 0.51) × 109 M- 1 s- 1, respectively. Influence of key parameters (initial pH, PS dosage, ZVI dosage, and NAP dosage) on NAP degradation were evaluated systematically. Based on the detected intermediates, the pathways of NAP degradation in ZVI/PS system was proposed. It was found that the presence of ammonia accelerated the corrosion of ZVI and thus promoted the release of Fe2+, which induced the increased generation of sulfate radicals from PS and promoted the degradation of NAP. Compared to its counterpart without ammonia, the degradation rates of NAP by ZVI/PS were increased to 3.6-17.5 folds and 1.2-2.2 folds under pH 7 and pH 9, respectively.

Bulleyaconitine A Inhibits Visceral Nociception and Spinal Synaptic Plasticity through Stimulation of Microglial Release of Dynorphin A.

Background: Visceral pain is one of the most common types of pain and particularly in the abdomen is associated with gastrointestinal diseases. Bulleyaconitine A (BAA), isolated from Aconitum bulleyanum, is prescribed in China to treat chronic pain. The present study is aimed at evaluating the mechanisms underlying BAA visceral antinociception. Methods: The rat model of chronic visceral hypersensitivity was set up by colonic perfusion of 2,4,6-trinitrobenzene sulfonic acid (TNBS) on postnatal day 10 with coapplication of heterotypic intermittent chronic stress (HeICS). Results: The rat model of chronic visceral hypersensitivity exhibited remarkable abdominal withdrawal responses and mechanical hyperalgesia in hind paws, which were dose-dependently attenuated by single subcutaneous of administration of BAA (30 and 90 µg/kg). Pretreatment with the microglial inhibitor minocycline, dynorphin A antiserum, and κ-opioid receptor antagonist totally blocked BAA-induced visceral antinociception and mechanical antihyperalgesia. Spontaneous excitatory postsynaptic currents (sEPSCs) in spinal dorsal horn lamina II neurons were recorded by using whole-cell patch clamp. Its frequency (but not amplitude) from TNBS-treated rats was remarkably higher than that from naïve rats. BAA (1 µM) significantly reduced the frequency of sEPSCs from TNBS-treated rats but not naïve rats. BAA-inhibited spinal synaptic plasticity was blocked by minocycline, the dynorphin A antiserum, and κ-opioid receptor antagonist. Dynorphin A also inhibited spinal synaptic plasticity in a κ-opioid receptor-dependent manner. Conclusions: These results suggest that BAA produces visceral antinociception by stimulating spinal microglial release of dynorphin A, which activates presynaptic κ-opioid receptors in afferent neurons and inhibits spinal synaptic plasticity, highlighting a novel interaction mode between microglia and neurons.

Bulleyaconitine A Exerts Antianxiety and Antivisceral Hypersensitivity Effects.

Visceral pain is one of the leading causes for abdominal pain in gastroenterological diseases and is still hard to treat effectively. Bulleyaconitine A (BAA) is an aconitine analog and has been used for the treatment of pain. Our previous work suggested that BAA exerted analgesic effects on neuropathic pain through stimulating the expression of dynorphin A in spinal microglia. Here, we investigated the inhibitory effect of BAA on visceral pain and examined whether the expression of dynorphin A in spinal microglia was responsible for its effects. We found that BAA produced significant antivisceral pain effect induced by acetic acid through stimulating dynorphin A expression in spinal microglia. In addition, anxiety and chronic visceral pain are highly prevalent comorbid conditions in clinical research, which is still a problem to be solved. We also aimed to evaluate the effects of BAA on anxiety. A comorbidity model with characteristics of both chronic visceral pain and anxiety was developed by colorectal injection of 2,4,6-trinitrobenzene sulfonic acid and the induction of heterotypic intermittent chronic stress protocol. In comorbid animals, BAA exerted great antianxiety effects. Meanwhile, the antianxiety mechanism of BAA was different with the antivisceral pain mechanism of BAA. In conclusion, our study demonstrated, for the first time, that BAA exerted marked antivisceral pain and antianxiety effects, which expands the analgesic spectrum and clinical application of BAA. Furthermore, it also it provides a better guidance for the clinical use of BAA.

Effects of regulating intestinal microbiota on anxiety symptoms: A systematic review.

BACKGROUND: Anxiety symptoms are common in mental diseases and a variety of physical disorders, especially in disorders related to stress. More and more basic studies have indicated that gut microbiota can regulate brain function through the gut-brain axis, and dysbiosis of intestinal microbiota was related to anxiety. However, there is no specific evidence to support treatment of anxiety by regulating intestinal microbiota. AIMS: To find evidence supporting improvement of anxiety symptoms by regulation of intestinal microbiota. METHODS: This systematic review of randomised controlled trials was searched based on the following databases: PubMed, EMBASE, the Cochrane Library, OVID, Web of Knowledge, China National Knowledge Infrastructure (CNKI), Wanfang Data, VIP databases and SinoMed. The retrieval time dated back to 25 July 2018. Then we screened research literatures based on established inclusion and exclusion criteria. Quality evaluation for each included study was done using the Cochrane risk of bias and the Jadad scale. RESULTS: A total of 3334 articles were retrieved and 21 studies were included which contained 1503 subjects. In the 21 studies, 15 chose probiotics as interventions to regulate intestinal microbiota and six chose non-probiotic ways such as adjusting daily diets. Probiotic supplements in seven studies contained only one kind of probiotic, two studies used a product that contained two kinds of probiotics and the supplements used in the other five studies included at least three kinds of probiotics. In the studies that used treatment as usual plus interventions regulating intestinal flora (IRIF) as interventions (five studies), only non-probiotic ways were effective (two studies), which means 40% of studies were effective; in the studies that used IRIF alone (16 studies, 11 studies used probiotic ways and 5 studies used non-probiotic ways), 56% of studies could improve anxiety symptoms, and 80% of studies that conducted the non-probiotic interventions were effective, while 45% of studies that used probiotic supplementations had positive effects on anxiety symptoms. Overall, 11 studies showed a positive effect on anxiety symptoms by regulating intestinal microbiota, which indicated 52% of the 21 studies were effective, and there were five studies that used probiotic supplements as interventions and six used non-probiotic interventions. In addition, it should be noted that six of seven studies showed that regulation of intestinal microbiota could treat anxiety symptoms, the rate of efficacy was 86%. CONCLUSIONS: We find that more than half of the studies included showed it was positive to treat anxiety symptoms by regulation of intestinal microbiota. There are two kinds of interventions (probiotic and non-probiotic interventions) to regulate intestinal microbiota, and it should be highlighted that the non-probiotic interventions were more effective than the probiotic interventions. More studies are needed to clarify this conclusion since we still cannot run meta-analysis so far.

Synthesis and Biological Evaluation of 4ß-N-Acetylamino Substituted Podophyllotoxin Derivatives as Novel Anticancer Agents.

A series of novel podophyllotoxin derivatives obtained by 4ß-N-acetylamino substitution at C-4 position was designed, synthesized, and evaluated for in vitro cytotoxicity against four human cancer cell lines (EC-9706, HeLA, T-24 and H460) and a normal human epidermal cell line (HaCaT). The cytotoxicity test indicated that most of the derivatives displayed potent anticancer activities. In particular, compound 12h showed high activity with IC50 values ranging from 1.2 to 22.8 µM, with much better cytotoxic activity than the control drug etoposide (IC50: 8.4 to 78.2 µM). Compound 12j exhibited a promising cytotoxicity and selectivity profile against T24 and HaCaT cell lines with IC50 values of 2.7 and 49.1 µM, respectively. Compound 12g displayed potent cytotoxicity against HeLA and T24 cells with low activity against HaCaT cells. According to the results of fluorescence-activated cell sorting (FACS) analysis, 12g induced cell cycle arrest in the G2/M phase accompanied by apoptosis in T24 and HeLA cells. Furthermore, the docking studies showed possible interactions between human DNA topoisomerase IIα and 12g. These results suggest that 12g merits further optimization and development as a new podophyllotoxin-derived lead compound.

Glucuronidation: driving factors and their impact on glucuronide disposition.

Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the secondary metabolic pathway for a compound preceded by phase I hydroxylation, glucuronidation alone could serve as the dominant metabolic pathway for many compounds, including some with high aqueous solubility. Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases (UGTs) into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Therefore, elimination of parent compound via glucuronidation in a metabolic active cell is controlled by two driving forces: the formation of glucuronides by UGT enzymes and the (polarized) excretion of these glucuronides by efflux transporters located on the cell surfaces in various drug disposition organs. Contrary to the common assumption that the glucuronides reaching the systemic circulation were destined for urinary excretion, recent evidences suggest that hepatocytes are capable of highly efficient biliary clearance of the gut-generated glucuronides. Furthermore, the biliary- and enteric-eliminated glucuronides participate into recycling schemes involving intestinal microbes, which often prolong their local and systemic exposure, albeit at low systemic concentrations. Taken together, these recent research advances indicate that although UGT determines the rate and extent of glucuronide generation, the efflux and uptake transporters determine the distribution of these glucuronides into blood and then to various organs for elimination. Recycling schemes impact the apparent plasma half-life of parent compounds and their glucuronides that reach intestinal lumen, in addition to prolonging their gut and colon exposure.

Design, synthesis and biological evaluation of enzymatically cleavable NSAIDs prodrugs derived from self-immolative dendritic scaffolds for the treatment of inflammatory diseases.

It has been reported that delivery systems based on dendritic prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) improved the properties of drug molecules and reduced the side effects and irritation on the gastric mucosa. To find a more effective way in NSAIDs dendritic prodrugs, in this paper, three different dendritic scaffolds of enzymatically cleavable naproxen conjugates have been synthesized in a convergent approach and well characterized by NMR and MS techniques. These self-immolative dendritic NISADs prodrugs programmed to release multiple molecules of the potent naproxen after a single enzymatic activation step, and in 50% human plasma, the drug released from the compound T3 reaching 47.3% after 24h in vitro assay. Moreover, all prodrugs were also found to maintain more significant anti-inflammatory activity, no significant cytotoxicity against HEK293 cells and less degree of ulcerogenic potential in vivo than their monomeric counterpart naproxen. These results provided an effective entry to the development of new dendritic NSAIDs prodrugs.