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Background MicroRNAs are a type of non-coding single-stranded RNA, which is involved in the regulation of ovary insulin resistance (IR). This study aims to explore the underlying mechanisms of miR-133a-3p regulating ovary IR in obese polycystic ovary syndrome (PCOS). Methods Granulosa cells (GCs) were extracted from follicular fluids of PCOS patients (obese PCOS group and non-obese PCOS group) and healthy women (control group). The expression of miR-133a-3p in GCs was detected by qRT-PCR. The targets and pathways of miR-133a-3p were predicted by bioinformatics analyses. The protein levels of PI3K, p-AKT, GLUT4, p-GSK-3β, and p-FOXO1 were measured by Western blotting. Results MiR-133a-3p was highly expressed in GCs from PCOS patients, especially in obese PCOS patients. The protein levels of PI3K and p-AKT was downregulated in GCs from PCOS patients. There were 11 target genes of miR-133a-3p enriching in PI3K/AKT signaling pathway. miR-133a-3p mimic downregulated the expression of PI3K, p-AKT, and GLUT4, and upregulated the protein levels of p-GSK-3β and p-FOXO1. miR-133a-3p inhibitor presented the opposite effect of miR-133a-3p mimic. Conclusion MiR-133a-3p promotes ovary IR on GCs of obese PCOS patients via inhibiting PI3K/AKT signaling pathway. This study lays a foundation for further research on the mechanism of ovary IR in obese PCOS patients.

Nonviral transposon piggyBac (PB) and lentiviral (LV) vectors have been used to deliver chimeric antigen receptor (CAR) to T cells. To understand the differences in the effects of PB and LV on CAR T-cell functions, a CAR targeting CD19 was cloned into PB and LV vectors, and the resulting pbCAR and lvCAR were delivered to T cells to generate CD19pbCAR and CD19lvCAR T cells. Both CD19CAR T-cell types were strongly cytotoxic and secreted high IFN-γ levels when incubated with Raji cells. TNF-α increased in CD19pbCAR T cells, whereas IL-10 increased in CD19lvCAR T cells. CD19pbCAR and CD19lvCAR T cells showed similar strong anti-tumor activity in Raji cell-induced mouse models, slightly reducing mouse weight while enhancing mouse survival. High, but not low or moderate, concentrations of CD19pbCAR T cells significantly inhibited Raji cell-induced tumor growth in vivo. These CD19pbCAR T cells were distributed mostly in mesenteric lymph nodes, bone marrow of the femur, spleen, kidneys, and lungs, specifically accumulating at CD19-rich sites and CD19-positive tumors, with CAR copy number being increased on day 7. These results indicate that pbCAR has its specific activities and functions in pbCAR T cells, making it a valuable tool for CAR T-cell immunotherapy.

Kv7.1-Kv7.5 (KCNQ1-5) K

AIM To identify and evaluate the evidence documenting the association between neonatal morphine and later childhood neuropsychological development. METHOD We conducted a systematic literature search of eight electronic databases from inception until June 2019. We included all randomized controlled trials (RCTs) and cohort studies recruiting neonates who received morphine treatment, and measuring neuropsychological development outcomes with a minimum follow-up of 6 months. RESULTS Twelve separate reports from three RCTs and five cohort studies met our inclusion criteria. Owing to the small number of the included trials and the variable study designs, a meta-analysis was not performed. The findings from this review indicated that neonatal morphine use had no adverse effects on behaviour, cognition, motor, and executive function development at 8 to 9 years and earlier; except for the inconsistent conclusions on internalizing behavioural problems at 5 to 7 years and cognitive and motor developments at 18 months. INTERPRETATION Why a child needs morphine may have a more profound impact on later neuropsychological development than morphine itself. The small number, high heterogeneity, and limitations of the included studies limit confidence in the result of this systematic review.

Repeated procedural pain may lead to increased secretion of cortisol and future neurobehavioral development disorders in preterm infants. Changes in the cortisol level may mediate the effect of neonatal repetitive procedural pain on altered childhood neurobehavioral development in preterm infants. However, few studies have investigated the effect of combined pharmacological, behavioral, and physical interventions over repeated painful procedures on pain response, cortisol level, and neurobehavioral development. This study examined (1) the efficacy and safety of sucrose combined with massage, music, non-nutritive sucking, and gentle human touch to treat preterm infants with repeated procedural pain; (2) the cortisol level at discharge from the neonatal intensive care unit (NICU); (3) neurobehavioral development at 40 weeks' corrected gestational age; and (4) the potential mediating effect of the cortisol level in the combined interventions on neurobehavioral development. Stable preterm infants (n = 76) were randomized to receive routine care or combined interventions across repeated painful procedures throughout their NICU stay. The Premature Infant Pain Profile scores in the early, middle, and late periods of the NICU stay were measured, as were the basal salivary cortisol level at admission and discharge, the Neonatal Behavioral Neurological Assessment score at 40 weeks' corrected gestational age, and the incidence of adverse effects during the study period. Our findings indicated that the combined interventions remained efficacious and safe for reducing repeated procedural pain, decreased the cortisol level at discharge, and promoted early neurobehavioral development in preterm infants. This effect may have been mediated through decreased cortisol levels and reduced repeated procedural pain.

Promoting angiogenesis by targeting various angiogenic regulators has emerged as a new treatment strategy for myocardial ischemia (MI). MicroRNA-126 (miR-126) has been identified as the main regulator of compensatory angiogenesis; however, its role in MI is unclear. A rat MI model and an EA. hy926 endothelial cell hypoxia model were constructed and it was found that miR-126 was highly expressed in both models. The knockdown of HIF-1α expression in EA. hy926 cells in turn downregulated VEGF and CD34 expression and consequently inhibited angiogenesis. MiR-126 inhibitor inhibited EA. hy926 cell migration and tube formation as well as downregulated VEGF and CD34 expression, and these were reversed by transfection of miR-126 mimics. Rescue tests using miR-126 and HIF-1α demonstrated that miR-126-mediated regulation of angiogenesis was dependent on HIF-1α. In summary, miR-126 regulates the occurrence and progression of angiogenesis during MI via HIF-1α and may be a potential new therapeutic target.

Objectives To identify and assess the evidence showing the efficacy of auricular acupressure alone for myopia in children and adolescents. Methods Randomized controlled trials (RCTs) that were published until March 2019 in Pubmed, Web of Science, OVID, Foreign Medical Literature Retrieval Service, China Knowledge Resource Integrated Database, The Chinese Biological Medicine Database, Wanfang Database, and Chongqing VIP Information were searched. The quality of RCTs was assessed using the Cochrane risk of bias assessment tool. Results Ten RCTs were included to be qualitatively summarized, of which 5 studies qualified for the meta-analysis of the efficacy rate in treating myopia. This review demonstrated that auricular acupressure alone was more effective than eye-drops treatment, eye exercise, and was the just as effective as needle acupuncture. Conclusions Auricular acupressure could slow the progression of myopia in children and adolescents. However, there is a need for further studies with higher methodological quality and sufficient follow-up.

The Yiqi-Huoxue granule (YQHX) is a traditional Chinese medication widely used in the therapy of the traditional Chinese medicine diagnosis “Qi deficiency” or “blood stasis” in China. Both these symptoms are related to inflammation, but the mechanisms of YQHX against inflammation are largely unknown. Thus, our present study investigated the effects of YQHX on regulating inflammatory responses induced by lipopolysaccharides (LPS) in HUVECs. Our data found that YQHX remarkably inhibits the production of prothrombotic factors, plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF), while it upregulates the protein expression of Kruppel-like factor 2 (KLF2). The increase in PAI-1 and TF was significantly attenuated through a transgenic knockdown in KLF2 with a Lenti-shKLF2 vector. YQHX also decreases the phosphorylation of nuclear factor-κB (NF-κB) p65 and IκB following LPS stimulation, and it effectively suppresses PAI-1 and TF via a NF-κB-dependent mechanism. Taken together, our results suggest that YQHX provides a notable antithrombotic activity via regulating the KLF2 expression and NF-κB signaling pathway in HUVECs. The KLF2 and NF-κB may be potential therapeutic targets for interventions of inflammation associated with atherosclerosis.

Forsythia suspensa (Thunb.) Vahl leaves have been consumed in China as a health-promoting functional tea for centuries. Three new polyhydroxytriterpenoid glycosides named suspensanosides A-C (1-3), seven known polyhydroxytriterpenoids (4-10), and 12 known phenolics (11-22) were identified from F. suspensa leaves. Compounds 1-10, 15-17, and 22 have not been found in the Forsythia genus previously, whereas compound 14 was first reported to be isolated from the leaves of F. suspensa. All isolates were tested for their antiproliferative activities on BGC-823 and MCF-7 human tumor cell lines, whereas all phenolics were further investigated for their antioxidant activities by a DPPH assay. The results clearly demonstrate that triterpenoids, especially ursane-type triterpenoids, and the diverse phenolic components are crucial for the beneficial effects of F. suspensa leaves.

Background Preterm infants' repeated exposure to painful procedures may lead to negative consequences. Thus, non-pharmacological pain management is essential due to medication side effects. Kangaroo Mother Care, which aims at offering human care to neonates, has been established for the treatment of a single painful procedure, but the effectiveness of Kangaroo Mother Care across repeated painful procedures is unknown. Objective To test the effectiveness of repeated Kangaroo Mother Care on repeated heel-stick pain in preterm neonates. Design Randomized controlled trial. Setting Level III Neonatal Intensive Care Unit at a large teaching hospital in northeast China. Method Preterm infants (gestational age less than 37 weeks) ( n =80) were recruited and randomly assigned using a random table format to either an incubator group ( n =40) or Kangaroo Mother Care group ( n =40). Pain assessments were carried out during four routine heel stick procedures. For the first heel stick, preterm infants in each group received no intervention (routinely stayed in incubator). During the next three heel sticks, the infants in Kangaroo Mother Care group received heel sticks during Kangaroo Mother Care, while infants in the incubator group received heel sticks in incubator. The procedure of each heel stick included 3 phases: baseline, blood collection and recovery. Crying, grimacing and heart rate in response to pain were evaluated at each phase across four heel sticks by three trained independent observers who were blinded to the purpose of the study. Data were analyzed by analysis of variance (ANOVA), with repeated measures at different evaluation phases of heel stick. Results 75 preterm infants completed the protocol. Between-group comparison revealed that preterm infants' heart rate was significantly lower, and the duration of crying and facial grimacing were both significantly shorter in the Kangaroo Mother Care group ( n =38) than the incubator group ( n =37) from the blood collection phase to recovery phase during repeated heel sticks. No significant within-group difference was found in heart rate between the baseline phase and recovery phase through repeated heel sticks for Kangaroo Mother Care group. In contrast, the incubator group experienced significant within group differences in heart rate between baseline and recovery through repeated heel sticks. Conclusion The effect of repeated Kangaroo Mother Care analgesia remains stable in preterm infants over repeated painful procedures. Given the many invasive procedures that are part of clinical care in preterm infants and most mothers preferred to provide comfort for their infants during painful procedures, Kangaroo Mother Care may be a safe analgesic alternative in preterm infants in whom it is feasible.

Background Sucrose combined with non-nutritive sucking provided better pain relief than sucrose or non-nutritive sucking alone in a single painful procedure. However, whether the combination of non-nutritive sucking with sucrose could obtain a significant difference in analgesic effect of the repeated procedural pain than any single intervention has not been established. Objective To compare the effect of non-nutritive sucking and sucrose alone and in combination of repeated procedural pain in preterm infants. Design Randomized controlled trial. Setting A level III neonatal intensive care unit of a university hospital in China. Method Preterm infants born before 37 weeks of gestation were randomly assigned to four groups: routine care group (routine comfort through gentle touch when infants cried; n = 21), non-nutritive sucking group (n = 22), sucrose group (0.2 ml/kg of 20%; n = 21), sucrose (0.2 ml/kg of 20%) plus non-nutritive sucking group (n = 22). Each preterm infant received three nonconsecutive routine heel sticks. Each heel stick included three phases: baseline (the last 1 min of the 30 min without stimuli), blood collection, recovery (1 min after blood collection). Three phases of 3 heel stick procedures were videotaped. Premature infant pain profile (PIPP) score, heart rate, oxygen saturation and percentage of crying time were assessed by five independent evaluators who were blinded to the purpose of the study at different phases across three heel sticks. Data were analyzed by analysis of variance, with repeated measures at different evaluation phases of heel stick. Results 86 preterm infants completed the protocol. During the blood collection and recovery phases, combination group, had lower PIPP score (4.4 ± 1.5; 3.0 ± 0.8), lower heart rate (138.6 ± 7.9; 137.4 ± 4.7), higher oxygen saturation (95.2 ± 1.6; 96.0 ± 1.2), and smaller percentage of crying time (11.5 ± 8.6; 4.6 ± 3.4), compared with the group has given non-nutritive sucking (9.3 ± 1.3, 6.8 ± 1.4; 154.2 ± 9.0, 148.0 ± 9.3; 92.9 ± 2.4, 94.1 ± 1.0; 44.2 ± 9.6, 31.2 ± 10.5; respectively) or sucrose (10.1 ± 2.0, 7.4 ± 1.6; 151.6 ± 9.6, 147.9 ± 6.9; 93.5 ± 1.7, 94.5 ± 1.2; 53.8 ± 16.7, 35.2 ± 13.9; respectively) or routine care (13.3 ± 1.6, 10.6 ± 1.9; 156.8 ± 7.2, 151.7 ± 7.9; 92.9 ± 2.1, 93.8 ± 1.6; 80.6 ± 7.6, 68.2 ± 9.9; respectively). Both non-nutritive sucking and sucrose were more effective in reducing preterm infants' PIPP score and percentage of crying time than routine care. There was no difference in PIPP score, heart rate, oxygen saturation and percentage of crying time between the non-nutritive sucking and sucrose groups. Conclusion The combination of non-nutritive sucking with sucrose provided better pain relief during repeated painful procedures than when non-nutritive sucking or sucrose was used alone. The effect of non-nutritive sucking was similar to that of sucrose on repeated procedural pain.

M-type (Kv7, KCNQ) potassium channels are proteins that control the excitability of neurons and muscle cells. Many physiological and pathological mechanisms of excitation operate via the suppression of M channel activity or expression. Conversely, pharmacological augmentation of M channel activity is a recognized strategy for the treatment of hyperexcitability disorders such as pain and epilepsy. However, physiological mechanisms resulting in M channel potentiation are rare. Here we report that intracellular free zinc directly and reversibly augments the activity of recombinant and native M channels. This effect is mechanistically distinct from the known redox-dependent KCNQ channel potentiation. Interestingly, the effect of zinc cannot be attributed to a single histidine- or cysteine-containing zinc-binding site within KCNQ channels. Instead, zinc dramatically reduces KCNQ channel dependence on its obligatory physiological activator, phosphatidylinositol 4,5-bisphosphate (PIP2). We hypothesize that zinc facilitates interactions of the lipid-facing interface of a KCNQ protein with the inner leaflet of the plasma membrane in a way similar to that promoted by PIP2. Because zinc is increasingly recognized as a ubiquitous intracellular second messenger, this discovery might represent a hitherto unknown native pathway of M channel modulation and provide a fresh strategy for the design of M channel activators for therapeutic purposes.

Aims: Neuropeptide substance P (SP) is produced and released by a subset of peripheral sensory neurons that respond to tissue damage (nociceptors). SP exerts excitatory effects in the central nervous system, but peripheral SP actions are still poorly understood; therefore, here, we aimed at investigating these peripheral mechanisms. Results: SP acutely inhibited T-type voltage-gated Ca2+ channels in nociceptors. The effect was mediated by neurokinin 1 (NK1) receptor-induced stimulation of intracellular release of reactive oxygen species (ROS), as it can be prevented or reversed by the reducing agent dithiothreitol and mimicked by exogenous or endogenous ROS. This redox-mediated T-type Ca2+ channel inhibition operated through the modulation of CaV3.2 channel sensitivity to ambient zinc, as it can be prevented or reversed by zinc chelation and mimicked by exogenous zinc. Elimination of the zinc-binding site in CaV3.2 rendered the channel insensitive to SP-mediated inhibition. Importantly, peripherally applied SP significantly reduced bradykinin-induced nociception in rats in vivo; knock-down of CaV3.2 significantly reduced this anti-nociceptive effect. This atypical signaling cascade shared the initial steps with the SP-mediated augmentation of M-type K+ channels described earlier. Innovation: Our study established a mechanism underlying the peripheral anti-nociceptive effect of SP whereby this neuropeptide produces ROS-dependent inhibition of pro-algesic T-type Ca2+ current and concurrent enhancement of anti-algesic M-type K+ current. These findings will lead to a better understanding of mechanisms of endogenous analgesia. Conclusion: SP modulates T-type channel activity in nociceptors by a redox-dependent tuning of channel sensitivity to zinc; this novel modulatory pathway contributes to the peripheral anti-nociceptive effect of SP. Antioxid. Redox Signal. 25, 233–251.

Background Although sucrose is most extensively examined for its analgesia effect on a single procedural pain, neonates in neonatal intensive care units can be exposed to numerous painful procedures every day requiring multiple doses of sucrose. Some experiments have been performed to examine the efficacy and safety of repeated sucrose administration for repeated procedural pain; however, a systematic review of this topic has not yet been carried out. Objective To identify and assess the evidence demonstrating the efficacy and safety of repeated sucrose for repeated procedural pain in neonates. Method A systematic review was conducted using the Cochrane methodology. Pubmed, Cochrane Library, Web of Science, CINAHL (Cumulative Index to Nursing and Allied Health Literature), CBMdisc, CNKI, VIP, and Wanfang databases were searched through December 2015. All related abstracts were reviewed and the full texts of relevant articles were studied. Randomized controlled trials (RCTs) were included. Risk of bias was assessed for RCTs using quality critical appraisal criteria recommended by Cochrane Handbook. A standardised data form was used to extract information. Results Eight RCTs met our inclusion criteria. Different study designs were used in the included RCTs, which did not allow us to carry out a meta-analysis. The findings from this review indicated that repeated sucrose was effective in reducing both behavioral pain response and composite pain scores during repeated procedural pain. However, as for physiological pain response, one trial found less variability in physiological pain response for term neonates in the sucrose group than the sterile water group, while two trials demonstrated repeated sucrose was inefficacious for preterm neonates. Regarding the clinical outcomes, no study reported adverse effects related to the repeated sucrose administration. Regarding the neurobehavioral development, two trials reported repeated sucrose for repeated procedural pain would not lead to poor neurologic development, while one trial reported that preterm infants 10 doses of sucrose per 24h in the first week of life had poorer neurologic development compared with infants who received fewer sucrose doses. What's more, no study reported the long-term neurobehavioral development outcome of neonates who repeatedly received sucrose across repeated procedural pain. Conclusion Evidence regarding the efficacy and safety of repeated sucrose across repeated procedural pain for neonates is limited. More prospective, multi-centered, large randomized controlled clinical trials with a standardised study design are required before sucrose can be recommended widely as an analgesia for repeated procedural pain in neonates.

Many studies have shown that natural dietary agents, in combination with chemical agents, can improve the therapeutic response of cancers to chemotherapy and reduce the associated side-effects. In the present study, we investigated the therapeutic potential and mechanisms of anticancer effects for the combination of 5-fluorouracil (5-FU) and resveratrol (Res). In these studies, we employed the cancer cell lines TE-1 and A431 and an animal model of skin cancer. The presented results provide the first evidence that Res can enhance the anti-tumor potency of 5-FU by inducing S-phase arrest. The combination of Res and 5-FU demonstrates synergistic efficacy, causing tumor regression in a two-stage model of mouse skin carcinogenesis induced by DMBA and TPA. There was clear evidence of Res augmenting the growth inhibitory effect of 5-FU on the TE-1 and A431 cancer cells in vitro. In the in vivo studies, the tumor regression rate in the combination group increased significantly after four weeks of treatment ( P

In a previous study, we showed that membrane depolarization induced elevation of membrane phosphatidylinositol 4,5-bisphosphates (PtdIns(4,5)P(2), also known as PIP(2)) and subsequently increased the KCNQ2/Q3 currents expressed in Xenopus oocytes through increased PI4 kinase activity. In this study, the underlying mechanism for this depolarization-induced enhancement of PIP(2) synthesis was further investigated. Our results indicate that activation of protein kinase C (PKC) isozyme βII was responsible for the enhanced PIP(2) synthesis. We found that phorbol-12-myristate, 13-acetate (PMA), an activator of PKC, mimicked the effects of the membrane depolarization by increasing KCNQ2/Q3 activity, elevating membrane PIP(2) levels and increasing activity of PI4 kinase β. Furthermore, membrane depolarization enhanced PKC activity. The effects of both depolarization and PMA were blocked by a PKC inhibitor or PI4 kinase β RNA interference. Further results demonstrate that the depolarization selectively activated the PKC βII isoform and enhanced its interaction with PI4 kinase β. These results reveal that the depolarization-induced elevation of membrane PIP(2) is through activation of PKC and the subsequent increased activity of PI4 kinase β.

The Ca(2+) activated Cl(-) channels (CaCCs) play a multitude of important physiological functions. A number of candidate proteins have been proposed to form CaCC, but only two families, the bestrophins and the TMEM16 proteins, recapitulate the properties of native CaCC in expression systems. Studies of endogenous CaCCs are hindered by the lack of specific pharmacology as most Cl(-) channel modulators lack selectivity and a systematic comparison of the effects of these modulators on TMEM16A and bestrophin is missing. In the present study, we studied seven Cl(-) channel inhibitors: niflumic acid (NFA), NPPB, flufenamic acid (FFA), DIDS, tannic acid, CaCCinh-A01 and T16Ainh-A01 for their effects on TMEM16A and bestrophin-1 (Best1) stably expressed in CHO (Chinese hamster ovary) cells using patch clamp technique. Among seven inhibitors studied, NFA showed highest selectivity for TMEM16A (IC50 of 7.40 ± 0.95 μM) over Best1 (IC50 of 102.19 ± 15.05 μM). In contrast, DIDS displayed a reverse selectivity inhibiting Best1 with IC50 of 3.93 ± 0.73 μM and TMEM16A with IC50 of 548.86 ± 25.57 μM. CaCCinh-A01 was the most efficacious blocker for both TMEM16A and Best1 channels. T16Ainh-A01 partially inhibited TMEM16A currents but had no effect on Best1 currents. Tannic acid, NPPB and FFA had variable intermediate effects. Potentiation of channel activity by some of these modulators and the effects on TMEM16A deactivation kinetics were also described. Characterization of Cl(-) channel modulators for their effects on TMEM16A and Best1 will facilitate future studies of native CaCCs.

Epigenetic silencing of tumor-suppressor genes by promoter hypermethylation contributes considerably to the initiation and progression of cancer. Nucleoside analogs, the most widely used DNA methylation inhibitors, have the drawbacks of inducing repetitive sequence hypomethylation. Here, we aimed to specifically reverse tumor-suppressor gene (TSG) promoter hypermethylation with bovine oocyte extract. H460 human lung cancer cells were reversibly permeabilized and incubated with bovine oocyte extract for 3.5 h. The extract treatment led to significant demethylation of the hypermethylated promoters of the TSGs RUNX3, CDH1, RASSF1A and WIF1; however, the methylation levels of repetitive sequences were not affected. The promoter demethylation induced by bovine oocyte extract substantially upregulated the expression of RUNX3, CDH1, RASSF1A and WIF1, and significantly inhibited the anchorage-independent proliferation, migration and invasion of H460 cells. This study demonstrates that bovine oocyte extract can reverse the malignant phenotype by serving as an efficient and safe DNA demethylator. The active demethylation activity of bovine oocyte extract is valuable for dissecting the epigenetic alterations in cancer cells and developing novel safe anticancer drugs based on epigenetic mechanisms.

BACKGROUND AND PURPOSE: Celecoxib (CXB) is a widely prescribed COX-2 inhibitor used clinically to treat pain and inflammation. Recently, COX-2 independent mechanisms have been described to be the targets of CXB. For instance, ion channels such as the voltage-gated sodium channel, L-type calcium channel, Kv2.1, Kv1.5, Kv4.3 and HERG potassium channel were all reported to be inhibited by CXB. Our recent study revealed that CXB is a potent activator of Kv7/M channels. M currents expressed in dorsal root ganglia play an important role in nociception. Our study was aimed at establishing the role of COX-2 independent M current activation in the analgesic action of CXB. METHODS AND RESULTS: We compared the effects of CXB and its two structural analogues, unmethylated CXB (UMC) and 2,5-dimethyl-CXB (DMC), on Kv7/M currents and pain behavior in animal models. UMC is a more potent inhibitor of COX-2 than CXB while DMC has no COX-2 inhibiting activity. We found that CXB, UMC and DMC concentration-dependently activated Kv7.2/7.3 channels expressed in HEK293 cells and the M-type current in dorsal root ganglia neurons, negatively shifted I-V curve of Kv7.2/7.3 channels, with a potency and efficiency inverse to their COX-2 inhibitory potential. Furthermore, CXB, UMC and DMC greatly reduced inflammatory pain behavior induced by bradykinin, mechanical pain behavior induced by stimulation with von Frey filaments and thermal pain behavior in the Hargreaves test. CXB and DMC also significantly attenuated hyperalgesia in chronic constriction injury neuropathic pain. CONCLUSION: CXB, DMC and UMC are openers of Kv7/M K(+) channels with effects independent of COX-2 inhibition. The analgesic effects of CXBs on pain behaviors, especially those of DMC, suggest that activation of Kv7/M K(+) channels may play an important role in the analgesic action of CXB. This study strengthens the notion that Kv7/M K(+) channels are a potential target for pain treatment.

Ion channels involved in the migration of tumor cells that is required for their invasion and metastasis. In this paper, we describe the interaction of TRPM7 channel and epidermal growth factor (EGF), an important player in cancer development in the migration of lung cancer cells. The TRPM7 currents in A549 cells were first characterized by means of electrophysiology, pharmacology and RNA interference. Removing Ca2+ from the extracellular solution not only potentiated a large inward current, but also abolished the outward rectification. 200 μM 2-APB inhibited the outward and the inward TRPM7 currents and at the same time restored the property of outward rectification. EGF greatly enhanced the migration of A549 cells, and also markedly up-regulated the membrane protein expression of TRPM7 and the amplitude of TRPM7 currents. Depressing the function of TRPM7 with RNA interference or pharmacological agents not only reversed the EGF-enhanced migration of A549 cells but also inhibited the basal migration of A549 cells in the absence of EGF. Thus it seems that TRPM7 plays a pivotal role in the migration of A549 cells induced by EGF and thus could be a potential therapeutic target in lung cancers.