Targeting α7 nicotinic acetylcholine receptors for chronic pain.

Despite rapid advances in the field of chronic pain, it remains extremely challenging in the clinic. Pain treatment strategies have not improved for decades as opioids remain the main prescribed drugs for chronic pain management. However, long-term use of opioids often leads to detrimental side effects. Therefore, uncovering the mechanisms underlying the development and maintenance of chronic pain may aid the discovery of novel therapeutics to benefit patients with chronic pain. Substantial evidence indicates downregulation of α7 nicotinic acetylcholine receptors (α7 nAChR) in the sciatic nerve, dorsal root ganglia, and spinal cord dorsal horn in rodent models of chronic pain. Moreover, our recent study and results from other laboratories demonstrate that potentiation of α7 nAChR attenuates pain behaviors in various murine models of chronic pain. This review summarized and discussed the preclinical evidence demonstrating the therapeutic potential of α7 nAChR agonists and allosteric modulators in chronic pain. This evidence indicates that potentiation of α7 nAChR is beneficial in chronic pain, mostly by alleviating neuroinflammation. Overall, α7 nAChR-based therapy for chronic pain is an area with great promise, but more research regarding its detailed mechanisms is warranted.

The Emerging Role of Quercetin in the Treatment of Chronic Pain.

Despite much research efforts being devoted to designing alternative pharmacological interventions, chronic pain remains to be an unresolved clinical problem. Quercetin, a compound that belongs to the flavonoids family, is abundantly found in fruits and vegetables. Emerging evidence indicates that quercetin possesses anti-nociceptive effects in different rodent models of chronic pain, including inflammatory pain, neuropathic pain and cancer pain. In this review, we summarize the mechanisms underlying the analgesic effect of quercetin in preclinical studies. These studies showed that quercetin exerts potent analgesic effects against chronic pain via suppressing neuroinflammation and oxidative stress as well as modulation of synaptic plasticity, GABAergic system, and opioidergic system. Considering that the safety of quercetin is well established, it has great potential for clinical use in pain treatment.

[Retracted] MicroRNA­744 inhibits tumor cell proliferation and invasion of gastric cancer via targeting brain­derived neurotrophic factor.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the cell migration assay data shown in Fig. 2D were strikingly similar to data that had appeared in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 16: 5055­5061, 2017; DOI: 10.3892/mmr.2017.7167].

Blocking the Aryl Hydrocarbon Receptor Alleviates Myocardial Ischemia/Reperfusion Injury in Rats.

OBJECTIVE: Restoring the blood perfusion of ischemic heart tissues is the main treatment for myocardial ischemia. However, the accompanying myocardial ischemia reperfusion injury (IRI) would aggravate myocardial damage. Previous studies have confirmed that aryl hydrocarbon receptor (AhR) is closely correlated to kidney and intestinal IRI. The present study aimed to explore the relationship between AhR and myocardial IRI. METHODS: An oxygen glucose deprivation/reoxygenation (OGD/R) model of H9c2 cells and an ischemia/reperfusion (I/R) model of Sprague-Dawley rat myocardium were established. OGD/R cells and myocardial IRI rats were treated with different concentrations of the AhR antagonist CH-223191 or agonist 6-formylindolo[3,2-b] carbazole (FICZ). Under the conditions of normoxia and hypoxia/reoxygenation, the activity of cardiomyocytes, lactate dehydrogenase (LDH) and cell reactive oxygen species (ROS) were detected. In rats, myocardial pathological damage and markers of myocardial injury were detected. RESULTS: According to the results of the cell viability, LDH and ROS tests in vitro, both CH-223191 and FICZ showed no myocardial protection under OGD/R conditions. However, the histological staining and analysis of myocardial injury marker LDH in vitro revealed that CH-223191 could significantly reduce the myocardial IRI. CONCLUSION: AhR exhibited a different effect on myocardial IRI in vitro and in vivo. In vivo, CH-223191 could significantly alleviate the myocardial IRI, suggesting that inhibition of AhR may play a role in myocardial protection, and AhR may serve as a potential treatment target for myocardial IRI.

Electroacupuncture ameliorates neuroinflammation in animal models.

BACKGROUND: Neuroinflammation refers to a wide range of immune responses occurring in the brain or spinal cord. It is closely related to a variety of neurodegenerative diseases, for which it potentially represents a new direction for treatment. Electroacupuncture (EA) is one method of acupuncture treatment, which can be used as an adjuvant therapy for many diseases. This review focuses on molecular mechanisms of EA in the reduction of neuroinflammation, summarizes relevant basic research and outlines future directions for investigation. FINDINGS: A growing body of basic research has shown that EA can ameliorate neuroinflammation centrally (in animal models of ischemic stroke, Alzheimer's disease, traumatic brain injury, spinal cord injury, Parkinson's disease and vascular dementia) and peripherally (e.g. after a surgical insult or injection of lipopolysaccharide) and that its effects involve different molecular mechanisms, including activation of the α7 nicotinic acetylcholine receptor signaling pathway and P2 type purinergic receptors, inhibition of nuclear factor κB, and mitigation of damage secondary to oxidative stress and NOD-like receptor protein 3 inflammasome activation. CONCLUSIONS: EA is capable of regulating multiple cell signal transduction pathways to alleviate neuroinflammation in animal models. Although the findings of animal studies are encouraging, further prospective clinical trials are needed to verify the efficacy of EA for the treatment of neuroinflammation.

[Origin and development of HUA Tuo's acupuncturing sensation technique].

Based on HUA Tuo's personal experience, teaching experience, works as well as ancient books of similar times, this paper discusses the origin and development of HUA Tuo's acupuncturing sensation technique, and analyzes the reasons why this technology has been lost. The formation of this technique is influenced by the descriptions of "regulating qi " "arrival of qi " and "reaching qi" in Neijing (Internal Canon of Medicine) and Nanjing, and combines with the clinical summary of conduction direction and specific position of acupuncturing sensation. Due to HUA Tuo's personal experience, the inheritance characteristics of acupuncture technology and the background of his times, this technology may have been lost, but it still affects the acupuncture concept and practice of "qi reaching affected area" in later generations.

[Definition of lost acupuncture technique: based on Dictionary of Chinese Acupuncture- Moxibustion].

OBJECTIVE: By defining the inclusion criteria of the lost acupuncture technique and sorting out the content of lost acupuncture technique (possibly lost acupuncture technique), this article aimed to provide ideas and methods of the inheritance of acupuncture technique. METHODS: The whole entries of Dictionary of Chinese Acupuncture-Moxibustion were searched. The items of acupuncture technique were screened and used as the key terms to retrieve the literature from the database of CNKI, Wanfang, VIP and SinoMed. After that, the lost acupuncture technique and the possibly lost technique were selected from included items, and the terminologies of acupuncture technique were standardized. RESULTS: A total of 364 items of acupuncture technique were retrieved, including 17 items of lost acupuncture technique and 12 items of possibly lost acupuncture technique. CONCLUSION: The lost acupuncture technique is defined as the acupuncture technique recorded in ancient classics but can not be retrieved in modern literature of clinical application or expert's experience. The change of government or alternation of dynasty, the evolution of acupuncture-moxibustion theories and education are the related causes of lost acupuncture technique.

Transpeptidation-directed intramolecular bipartite tetracysteine display for sortase activity assay.

We developed a label-free method to measure sortase activity by using transpeptidation-directed intramolecular bipartite tetracysteine display. This assay is homogenous with a detection limit of 10.7 ng mL-1, and it can be applied to characterize Sortase A (SrtA)-targeted inhibitors, providing a new approach for anti-virulence drug discovery.

MicroRNA­744 inhibits tumor cell proliferation and invasion of gastric cancer via targeting brain­derived neurotrophic factor.

Gastric cancer is the fourth most common malignancy and the third leading cause of cancer­associated deaths worldwide. It has previously been demonstrated that microRNAs (miRNAs) are actively involved in the pathogenesis of gastric cancer. Therefore, miRNAs have been proposed as promising therapeutic targets in gastric cancer patients. MiR­744 is aberrantly expressed in different types of human cancer. However, the expression pattern and biological roles of miR­744 in gastric cancer remain unknown. The present study demonstrated that miR­744 expression was low in gastric cancer tissues and cell lines. Low expression levels of miR­744 was significantly correlated with lymph node metastasis, invasive depth and TNM staging in gastric cancer patients. The restoration of miR­744 expression inhibited cell proliferation and invasion in vitro. Bioinformatic prediction, luciferase reporter assay, reverse transcription­quantitative polymerase chain reaction and western blot analysis verified that brain­derived neurotrophic factor (BDNF) is a direct target of miR­744 in gastric cancer cells. Furthermore, BDNF was upregulated in gastric cancer tissues and inversely correlated with miR­744 expression. Furthermore, enforced BDNF expression reversed the tumor­suppressing effects of miR­744 on the proliferation and invasion of gastric cancer cells, indicating that BDNF is a functional mediator of miR­744 in gastric cancer. The present study suggests that miR­744 is a potential prognostic biomarker and treatment target in gastric cancer patients.

Recurrent cervicodorsal spinal intradural enterogenous cyst: case report and literature review.

This report described a recurrent enterogenous cyst of the cervicodorsal spinal canal occurred in an 8-year-old boy who experienced cervical back pain at the age of 5. He had been operated for mass lesion at the same level 3 years ago. The cervical and thoracic spine MRI showed a large intradural cyst at C7-T1. The cyst was subtotally removed via posterior approach using a laminectomy. Based on the results of immunostaining, it was identified as an enterogenous cyst. A literature review related to spinal cyst is also included.

Anesthetic management for craniotomy in a patient with massive cerebellar infarction and severe aortic stenosis: a case report.

Severe aortic stenosis combined with coronary heart disease remarkably increases the risk of perioperative morbidity and mortality during noncardiac surgery. Surgery and anesthesia often complicate the perioperative outcome if adequate monitoring and proper care are not taken. Therefore, understanding of the hemodynamic changes and anesthetic implications is an important for successful perioperative outcome. This report described the anesthetic management of a patient with a massive cerebellar infarction who was diagnosed with severe aortic stenosis combined with moderate aortic insufficiency and coronary heart disease and hypertension. He was prepared for aortic valve replacement and coronary bypass operation before massive cerebellar infarction occurred. And he received decompressive craniotomy and external ventricular drainage in the prone position under general anesthesia with endotracheal intubation.

[Alteration of apoptosis and Akt/mTOR signal pathway in hippocampal neurons of rat with post-traumatic stress].

OBJECTIVE: To observe the changes of apoptosis and protein kinase B/the mammalian target of Rapamycin (Akt/mTOR) signal pathway in hippocampal neurons of rat with post-straumatic stress disorder (PTSD), and to investigate the mechanism of PTSD. METHODS: Sixty male adult SD rats were divided into control group (n = 10) and PTSD (n = 50) model group. The PTSD animal model was established by giving the rats single-prolonged stress followed a single inescapable electric foot shock (SPS & S). The neuronal apoptosis of hiappocampus of PTSD rats at 1 d, 4 d, 7 d, 14 d and 28 d after model established was detected by flow cytometry (FCM). The expressions of phosphatase and tensin homology deleted on chromosome Ten (PTEN), phosphorylation of ARt and mTOR (p-Akt and p-mTOR) protein were detected by Western blotting. RESULTS: The apoptotic cell rate in PTSD 1 d, 4 d, 7 d and 14 d rats were higher than that in control rats (P < 0.05). The PTEN expression level was higher since PTSD 1 d than that in control group, and peaked in PTSD 4 d (P < 0.05). The p-Akt expression level was lower in PTSD 1 d than that in control group, and then increased in various time points after PTSD, but it was still lower in PTSD 28 d (P < 0.05). The p-mTOR expression level was lower than that in control group since PTSD 4 d, and then increased in various time points after PTSD 4 d, but it was still lower in PTSD 28 d (P < 0.05). CONCLUSION: The Akt/mTOR signal pathway was actived in hippocampal neurons of PTSD rats, and which was involved in neuronal apoptosis regulation.

[Transvaginal endoscopic resection of rectal tumor: a report of 2 cases].

Two female patients with rectal tumor undergoing proctectomy via vagina, namely natural orifice transluminal endoscopic surgery (NOTES), are reported. The operations were performed on June 8 and August 10, 2010, respectively. No Trocar was used in the abdomen except for the transumbilical incision. There were no visible scars in the abdomen. Tubulovillous adenoma and moderately differentiated adenocarcinoma were diagnosed respectively through postoperative pathological examination. Both patients resumed normal work and life at the most recent follow up. Sexual life was satisfactory.

Rhein lysinate inhibits cell growth by modulating various mitogen-activated protein kinases in cervical cancer cells.

In previous studies, we found that rhein lysinate (RHL; the salt of rhein and lysine, easily dissolved in water) inhibited the growth of tumor cells in breast and ovarian cancer and hepatocellular carcinoma. This study aimed to investigate the effect of RHL on the growth of human cervical carcinoma HeLa cells and any underlying mechanisms. RHL inhibited the growth of HeLa cells in a dose- and time-dependent manner. It was also noted that RHL induced apoptosis in HeLa cells in a dose-dependent manner. Mechanistically, RHL triggered HeLa cell apoptosis by increasing the levels of cleaved poly ADP-ribose polymerase (PARP) and caspase-3/7. In addition, the activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) was a critical mediator in RHL-induced growth inhibition. Inhibition of the expression of p38 MAPK and JNK by pharmacological inhibitors reversed RHL-induced growth inhibition by decreasing the level of cleaved PARP and caspase-3/7. Phosphorylation of the extracellular signal-related kinase (ERK) was increased by RHL; conversely, the MEK inhibitor which inhibits ERK activity, synergistically enhanced RHL-induced growth inhibition in HeLa cells. The results showed that RHL inhibits Hela cell growth through the activation of p38 MAPK and JNK, and is a potential chemotherapeutic agent for cervical cancer.

Regulation of spinal neuroimmune responses by prolonged morphine treatment in a rat model of cancer induced bone pain.

Cancer induced bone pain (CIBP) is a major clinical problem. Although opioids remain the principal axis in drug therapies for CIBP, their sustained application is known to induce cellular and molecular adaptations including enhanced neuroimmune reactivity. This is generally characterized by glial activation and proinflammatory cytokine production which frequently results in pharmacological tolerance. This research was performed to investigate spinal neuroimmune responses after prolonged systemic morphine treatment in a rat model of CIBP. The model was established using a unilateral intra-tibia injection of Walker 256 mammary gland carcinoma cells. Subcutaneous morphine was repeatedly administered from postoperative days 14 to 19. Mechanical allodynia to von Frey filaments and ambulatory pain scores were recorded to investigate changes of nociceptive behaviors. Spinal glial activation was detected by immunohistochemistry and real-time PCR; the production of proinflammatory cytokines (IL-1beta and TNF-alpha) was examined through real-time PCR and ELISA. Results showed that chronic morphine use failed to elicit analgesic tolerance in the rat CIBP model. Moreover, the treatment had no significant influence on the activated spinal glia morphology, cell density and expression of special cytomembrane markers, whereas it significantly down-regulated the local proinflammatory cytokine production at the mRNA and protein level. Collectively, these data suggest that chronic morphine treatment in CIBP is not concomitant with pharmacological tolerance, at least partially because the treatment fails to amplify spinal neuroimmune responses.

Evaluation of side effects through selective ablation of the mu opioid receptor expressing descending nociceptive facilitatory neurons in the rostral ventromedial medulla with dermorphin-saporin.

Descending facilitation from the rostral ventromedial medulla (RVM) contributes to some pathological pain states. The intra-RVM microinjection with dermorphin-saporin could specifically abolish this facilitation in rodent models by selectively ablating the RVM neurons expressing mu opioid receptors. Thus, this targeted lesion may be an alternative mechanism-based approach for intractable pain. This research was performed to investigate potential side effects after a single intra-RVM application of dermorphin-saporin in rats. Results showed though some acute cardiovascular signs were observed with dermorphin-saporin, the treatment exhibited no long-lasting significant influence on some physiological functions for up to 3-month observation period, including normal sensory function, locomotor activity, ingestive behaviors, body weight, rectal temperature, respiratory rate, heart rate, systolic blood pressure, cardiac structure and function. Moreover, there were only mild microglial responses on day 7 post-microinjection, while no significant increase in the immunostaining of astrocytes and no noticeable up-regulation in the production of proinflammatory cytokines were detected in the RVM treated with dermorphin-saporin. Taken together, these data would suggest that this selective ablation of mu opioid receptor bearing descending facilitatory neurons in the RVM with dermorphin-saporin did not elicit the long-standing evident adverse toxicity in terms of some physiological parameters and neurochemical alterations we determined, plausibly providing us a safe and reliable approach to treat some intractable pain.

[Construction of rat constitutively active recombinant caspase-3 and investigation of its pro-apoptotic effect in vitro].

OBJECTIVE: To investigate the apoptosis induction effect by the rat recombinant caspase-3. METHODS: Reversed rat caspase-3 gene was gained by settling the small subunit prior to the large one through recombinant PCR, and cloned into the expression vector to transfect human 293T cells and rat immortalized neural progenitor cells. The expression and pro-apoptotic effect of recombinant caspase-3 was observed by the changes of morphology of the transfected cells through immunofluorescence and analyzed by Annexin V-FITC staining, Flowcytometry and MTT assay. RESULTS: The transfected cells presented obvious apoptosis as detected by immunofluorescence. MTT assay showed that the proliferation of recombinant caspase-3 transfected cells was significantly inhibited [(48.35 +/- 0.16)%, (44.61 +/- 0.15)%] (P < 0.05). Annexin V-FITC staining revealed that the percentage of apoptotic cells in the transfectants of recombinant caspase-3 gene was [(30.7 +/- 1.5)%, (16.0 +/- 1.0)%] (P < 0.05), which was much higher than that of control cells. CONCLUSIONS: Rat recombinant caspase-3 can be expressed and induce apoptosis effectively, and used safely both in vitro and in vivo. It can also cause neural cells to death.

Effects of intrathecal NMDA and AMPA receptors agonists or antagonists on antinociception of propofol.

AIM: To study the effects of intrathecal (it) agonists and antagonists of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors and NMDAR1 antisense oligodeoxynucleotides (AS ODN) on the antinociception of propofol. METHODS: Hot-plate test (HPPT) and acetic acid-induced writhing test were used to measure the nociceptive thresholds in mice. The effects of intrathecal NMDA, AMPA, MK-801, NBQX, or NMDAR1 AS ODN on the antinociception of propofol were observed. RESULTS: Propofol (25, 50 mg/kg, ip) displayed an appreciable antinociceptive effect in hot-plate test and acetic acid-induced writhing test. NMDA (12.5, 25 ng, it) or AMPA (1.25, 2.5 ng, it) exhibited no effects on the behavior but decreased HPPT significantly compared with basal HPPT and aCSF group (P<0.05, P<0.01). No effects on behavior and HPPT were obtained in NMDA (6.25 ng, it) or AMPA (0.625 ng, it) groups. NMDA (6.25, 12.5, and 25 ng, it) dose-dependently decreased the HPPT in propofol-treated group. AMPA (1.25, 2.5 ng, it) also decreased HPPT significantly. MK-801 (0.25, 0.5 microg, it) or NBQX (0.25, 0.5 microg, it) groups had no behavioral changes, two antagonists 0.5 microg but not 0.25 microg increased HPPT in conscious or propofol-treated mice. AS ODN (5, 10, and 20 microg, it) groups exhibited dose-dependent increased in HPPT in propofol-treated groups compared with aCSF group (P<0.05, P<0.01). CONCLUSION: Both agonists NMDA and AMPA reversed the antinociception of propofol. MK-801, NBQX, and NMDAR1 AS ODN potentiated the antinociceptive effects of propofol. Propofol produced antinociception through an interaction with spinal NMDA and AMPA receptors in mice.