Generation of Herbicide-Resistant Soybean by Base Editing.

Weeds cause the largest yield loss in soybean production. The development of herbicide-resistant soybean germplasm is of great significance for weed control and yield improvement. In this study, we used the cytosine base editor (BE3) to develop novel herbicide-resistant soybean. We have successfully introduced base substitutions in GmAHAS3 and GmAHAS4 and obtained a heritable transgene-free soybean with homozygous P180S mutation in GmAHAS4. The GmAHAS4 P180S mutants have apparent resistance to chlorsulfuron, flucarbazone-sodium, and flumetsulam. In particular, the resistance to chlorsulfuron was more than 100 times that of with wild type TL-1. The agronomic performance of the GmAHAS4 P180S mutants showed no significant differences to TL-1 under natural growth conditions. In addition, we developed allele-specific PCR markers for the GmAHAS4 P180S mutants, which can easily discriminate homozygous, heterozygous mutants, and wild-type plants. This study demonstrates a feasible and effective way to generate herbicide-resistant soybean by using CRISPR/Cas9-mediated base editing.

Spatial patterns and associations of tree species at different developmental stages in a montane secondary temperate forest of northeastern China.

BACKGROUND: Secondary forests have become the major forest type worldwide. Research on spatial patterns and associations of tree species at different developmental stages may be informative in understanding the structure and dynamic processes of secondary forests. METHODS: In this study, we used point pattern analysis to analyze the spatial patterns and associations of tree species at seedling, sapling and adult stages in a 4ha plot in the montane secondary temperate forest of northeastern China. RESULTS: We found that species showed similar patterns at seedling, sapling and adult stages, and aggregation was the dominant pattern. The spatial patterns of tree species were mainly affected by habitat heterogeneity. In addition, the strength of positive or negative associated pattern among tree species would decrease with developmental stages, which attributed to neighborhood competition and plant size increasing. CONCLUSIONS: Our results indicated that the spatial patterns and associations of tree species at seedling and sapling stages partly reflected that at adult stage; habitat heterogeneity and neighborhood competition jointly contributed to species coexistence in this secondary forest.

Effect of kaempferol on IgE-mediated anaphylaxis in C57BL/6 mice and LAD2 cells.

BACKGROUND: Immunoglobulin E (IgE)-mediated mast cell (MC) activation is crucial in multiple allergic diseases. Parkinson disease protein 7 (DJ-1) and Lyn kinase were reported as the receptor-proximal events in IgE receptor (FcεRI) signals in human MC. Kaempferol, a natural flavonol mainly derived from the rhizome of traditional Chinese herb Kaempferia galanga L. (Zingiberaceae), has been known to inhibit allergic reactions, but it was limited to the receptor-distal signals on rat basophilic leukemia cells. A thorough investigation of the inhibitory effects of kaempferol on human MC has not been done. PURPOSE: To investigate the inhibitory effects of kaempferol on IgE-mediated anaphylaxis in vivo and in human MCs, as well as the mechanism underlying its effects, especially the receptor-proximal signals. METHODS: IgE-mediated passive cutaneous anaphylaxis and systemic anaphylaxis model were applied to elucidate the antiallergic activity of kaempferol in vivo. The degranulation assay, calcium imaging, the release of cytokines and chemokines on the laboratory of allergic disease 2 (LAD2) cells were used to evaluate the antiallergic effect of kaempferol in vitro. Western blot analysis was performed to investigate the DJ-1/Lyn signaling pathway and downstream molecules. Kinase activity assay, immunofluorescence, and molecular docking were conducted to confirm the influence of kaempferol on DJ-1/Lyn molecules. RESULTS: Kaempferol dose-dependently attenuated ovalbumin/IgE-induced mice paw swelling, primary MC activation from paw skin, as well as rehabilitated the hypothermia, and reduced the serum concentrations of histamine, tumor necrosis factor-alpha, interleukin-8, and monocyte chemo-attractant protein-1. Additionally, kaempferol suppressed IgE-mediated LAD2 cell degranulation and calcium fluctuation. Remarkably, kaempferol was found to bind with DJ-1 protein, and initially prevented DJ-1 from translocating to the plasma membrane, thereby inhibited full activation of Lyn, and eventually restrained those receptor-distal signaling molecules, involved Syk, Btk, PLCγ, IP3R, PKC, MAPKs, Akt and NF-κB. CONCLUSION: Kaempferol could be used as a DJ-1 modulator for preventing MC-mediated allergic disorders through attenuating Lyn activation.

PD173074 blocks G1/S transition via CUL3-mediated ubiquitin protease in HepG2 and Hep3B cells.

Fibroblast growth factor receptors (FGFRs) are frequently altered in a variety of human cancer cells and are overexpressed in hepatocellular carcinoma (HCC). Several literatures have proven that they are efficacious for HCC therapy, however, the underlying mechanism remains unclear. Here, we found FGFR4 was overexpressed in HCC cell lines HepG2 and Hep3B and we used PD173074, an FGFR4 inhibitor, to explore the role of FGFR4 and its underlying mechanism in these cell lines. The results showed that PD173074 significantly arrested HepG2 and Hep3B cells in G1 phase and inhibited cell proliferation. Furthermore, Western blot analysis revealed that PD173074 decreased the levels of P-FRS2α, P-ERK, CDK2, cyclin E and NF-κB (p65) in the nucleus while it increased the levels of ubiquitin and CUL3, an E3 ubiquitin ligase which involves in cyclin E degradation. Meanwhile, the data from RT-qPCR showed that PD173074 also decreased miR-141 level. In conclusion, these results suggest that FGFR4 is involved in HCC by ERK/CUL3/cyclin E signaling pathway, and the finding may provide a potential theoretical basis for treatment by targeting FGFR4 in HCC.

Quercetin as a Lyn kinase inhibitor inhibits IgE-mediated allergic conjunctivitis.

BACKGROUND: Allergic conjunctivitis (AC) resulting from conjunctival reactive inflammation is a common ocular surface disease. Quercetin is known for its anti-allergic properties but its effects on conjunctivitis are less well understood. PURPOSE: In this study, we evaluated the anti-allergic effects of quercetin in animal models of conjunctivitis, and explored its molecular mechanism(s) of action in cultured human mast cells (MCs). KEY RESULTS: Quercetin inhibited the ovalbumin (OVA) induced expression of IgE, HA, IL-4, TNF-α and substance-P in the peripheral blood of AC mouse models. Quercetin also attenuated OVA induced MC degranulation, eosinophil number, substance P concentrations, and mRNA IL-4/TNF-α expression in the conjunctival tissue of AC models. In vitro analysis showed that quercetin reduced DNP-HSA/IgE induced calcium (Ca2+) influx, and suppressed degranulation and chemokine release in LAD2 cells (human primary mast cell). Quercetin also inhibited DNP-HSA/IgE induced Lyn/PLCγ/IP3R-Ca2+ activation, Lyn/ERK1/2 signaling, and Lyn/NF-κB activation in LAD2 cells, all of which promote inflammation. When added alone, quercetin had no effect on PLCγ1 phosphorylation or expression, but potently inhibited Lyn and phosphorylation-Lyn. Quercetin (200 µM) and Lyn inhibitors (Bafetinib, 10 µM) inhibit the activity of Lyn kinase, and quercetin can reduce the activation of Lyn kinase by Lyn agonist (Tolimidone, 10 µM). These data can be preliminarily determined that quercetin can inhibit allergic conjunctivitis as a Lyn kinase inhibitor. CONCLUSIONS AND IMPLICATIONS: This study illustrated the use of quercetin for the treatment of allergic conjunctivitis, which might act through its ability to inhibit Lyn/PLCγ/IP3R-Ca2+, Lyn/ERK1/2, and Lyn/NF-κB signaling. The inhibition of Lyn likely represents a major mechanism by which quercetin dampens the inflammatory response in AC disease models.

Magnolin inhibits IgE/Ag-induced allergy in vivo and in vitro.

Mast cells (MCs) play critical roles in allergic reactions and modulating the activation of MCs could be an effective strategy to treat allergic diseases, which cause a rapidly increasing threat to the public health. Herein, we described that Magnolin, a major component from Flos magnoliae could inhibit IgE-dependent MCs activation. We found Magnolin inhibited IgE/Ag-induced calcium mobilization, degranulation, and cytokines release in LAD2 cells. Magnolin was also found to attenuate IgE/Ag-induced mice paw swelling in a dose-dependent manner. Further mechanistic studies suggested a possible anti-allergic and anti-inflammatory effects of Magnolin in IgE/Ag-induced anaphylactic reactions. Thereby, Magnolin could be a potential therapeutic agent for preventing mast cell-related immediate and delayed allergic diseases.

A Mast Cell-Specific Receptor Is Critical for Granuloma Induced by Intrathecal Morphine Infusion.

Intrathecal morphine infusion is often applied to treat chronic pain related to cancer and other conditions. However, persistent pain can be caused by nerve compression because of granuloma formation. In this study, a mouse model of morphine-induced granuloma formation by intrathecal catheterization morphine infusion into the atlanto-occipital membrane of the foramen magnum was established in wild-type mice, MrgprB2 mutant (MrgprB2-/-) mice, and in mast cell-deficient W-sash c-kit mutant (KitW-sh/W-sh) mice. Heat-related pain after surgery was performed to investigate the antipain effect of morphine. H&E staining and immunofluorescence staining of the spinal cord were applied to analyze the mechanism of granuloma formation. Morphine-induced mast cell degranulation was assessed by measuring the Ca2+ influx and mediator release. Anaphylactoid reactions were measured after s.c. morphine infusion to the paws. Chemokine release by mast cells was determined by Human XL Cytokine Array. Experiments with wild-type, MrgprB2 mutant, and mast cell-deficient W-sash c-kit mutant mice demonstrated that morphine activated mast cells and inflammatory cell aggregation through MrgprB2 in intrathecal infusion sites. The chemokine production of human mast cells demonstrated that granuloma formation is correlated with chemokines release. In addition, morphine activated mouse primary mast cells and de novo chemokine synthesis via the MRGPRX2 in human LAD2 cells. We concluded that granuloma formation during intrathecal morphine infusion was associated with MrgprB2/X2. Reducing MRGPRX2 potentially blocks morphine-induced side effects, including granuloma formation.

Neohesperidin suppresses IgE-mediated anaphylactic reactions and mast cell activation via Lyn-PLC-Ca2+ pathway.

Mast cells play an essential role in IgE-FcεR1-mediated allergic diseases. Citrus aurantium is a prolific source of flavonoids with various biological activities, including anti-inflammatory, antioxidant, and anti-tumor efficacies. Neohesperidin is a novel flavonoid isolated from the leaves of C. aurantium. In this study, the anti-allergic and anti-inflammatory potentials of neohesperidin were investigated along with its molecular mechanism. The anti-anaphylactic activity of neohesperidin was evaluated through hind paw extravasation study in mice. Calcium imaging was used to assess intracellular Ca2+ mobilization. The levels of cytokines and chemokines were measured using enzyme immunoassay kits. Western blotting was used to explore the related molecular signaling pathways. Neohesperidin suppressed IgE-induced mast cell activations, including degranulation and secretion of cytokines and eicosanoids through inhibiting phosphorylation of Lyn kinase. Neohesperidin inhibited the release of histamine and other proinflammatory cytokines through a mast cell-dependent passive cutaneous anaphylaxis animal model. Histological studies demonstrated that neohesperidin substantially inhibited IgE-induced cellular infiltration and attenuated mast cell activation in skin tissue. In conclusion, our study revealed that neohesperidin could inhibit allergic responses in vivo and in vitro, and the molecule may be regarded as a novel agent for preventing mast cell-immediate and delayed allergic diseases.

Quercetin inhibits Mrgprx2-induced pseudo-allergic reaction via PLCγ-IP3R related Ca2+ fluctuations.

An allergic reaction is a potentially fatal hypersensitivity response caused by mast cell activation, particularly histamine and lipid mediators. Histamine release caused by reaction to drugs is considered a pseudo-allergic reaction. Quercetin is known for its anti-allergic immune effect. However, at present, its anti-pseudo-allergic effect and its mechanism are less investigated. Therefore, the purpose of this study was to evaluate the anti-pseudo-allergic effect of Quercetin in vivo and to explore the mechanism in vitro. The anti-pseudo-allergic activity of Quercetin was evaluated in vivo using a mouse model, while Quercetin mechanism of action was examined in vitro using HEK293 cells expressing Mrgprx2, a mast cell specific receptor, and LAD2 mast cell line. Our in vivo results showed that Quercetin could attenuate Evans blue leakage in the paws and hind paw thickness in C57BL/6 mice in a dose-dependent manner, and could significantly inhibit serum histamine and chemokines release. In addition, it suppressed calcium mobilization and attenuated the release of histamine and MCP-1 in peritoneal mast cells in a dose-dependent manner. Furthermore, it inhibited the vasodilation due to histamine, the release of eosinophils, and the percentage of degranulated mast cells, indicating that Quercetin antagonized mast cell mediators in vivo, histamine-induced vasodilation and eosinophil release. In vitro results showed that Quercetin reduced pseudo-allergic induced calcium influx, suppressed degranulation and chemokines release in a similar way as dexamethasone (100 µM) (mast cell stabilizer) in LAD2 mast cell line. In addition, Quercetin inhibited Mrgprx2-induced both calcium influx and pseudo-allergic reaction in HEK293 cells expressing Mrgprx2. C48/80, a histamine promoter, and Substance P (a neuropeptide) EC50 was higher when combined with Quercetin compared to the EC50 of these compounds alone, suggesting that Quercetin could inhibit Mrgprx2-induced pseudo-allergic reaction. Furthermore, Quercetin decreased PLCγ-IP3R signaling pathway activation induced by C48/80 in LAD2 mast cell line. In Mrgprx2 knockdown LAD2 cells, the effect of Quercetin (200 µM) reduced C48/80 induced calcium flux and the release of ß­hexosaminidase, histamine, MCP-1 and IL-8 compared with non-atopic control (NC) transfected LAD2 human mast cells, suggesting that Quercetin anti-pseudo-allergic effect was related to Mrgprx2. The docking results showed that Quercetin had a good binding affinity with Mrgprx2 similar to the one of Substance P and C48/80. Therefore, Quercetin inhibited Mrgprx2-induced pseudo-allergic reaction via PLCγ-IP3R associated Ca2+ fluctuations. Our results validated Quercetin as an effective small molecule inhibiting Mrgprx2-induced pseudo-allergic reaction via PLCγ-IP3R associated Ca2+ fluctuations, thus highlighting a potential candidate to suppress Mrgprx2 induced pseudo-allergic related diseases.

Relationship between MRGPRX2 and pethidine hydrochloride- or fentanyl citrate-induced LAD2 cell degranulation.

OBJECTIVES: Pethidine hydrochloride (PH) and fentanyl citrate (FC) are opioid receptor agonists commonly used to treat pain clinically. PH and FC have been reported to have a high potential for pseudoallergic effects, but the underlying mechanism has not been well studied. MRGPRX2 is a novel atypical opioid receptor that is mainly expressed in human mast cells and considered to mediate drug-induced pseudoallergic reactions. This study aimed to investigate the allergy effect of these two opioid receptor agonists and the possible association of MRGPRX2 with this response. METHODS: HEK293-MRGPRX2/CMC assay, molecular docking assay, calcium mobilization assay, the test of ß-hexosaminidase, histamine and cytokine release assay were performed in this article. KEY FINDINGS: PH but not FC induced LAD2 cell activation and degranulation dose-dependently. Histamine, tumour necrosis factor (TNF)-α, interleukin (IL)-8, monocyte chemotactic protein 1 (MCP-1) and macrophage inflammatory protein (MIP-1ß) levels were upregulated by PH, but not FC. The PH-induced activation of mast cell was MRGPRX2-dependent. CONCLUSIONS: PH but not FC activated mast cells, leading to degranulation mediated via MRGPRX2 receptors, which could be greatly significant in future clinical applications of opioid receptor drugs.

The anti-anaphylactoid effects of hydroxysafflor yellow A on the suppression of mast cell Ca2+ influx and degranulation.

BACKGROUND: Anaphylaxis is a type of potentially fatal hypersensitivity reaction resulting from the activation of mast cell mediators, especially histamine and lipid mediators. Non-IgE-mediated anaphylaxis can occur because of the direct activation of mast cells. Hydroxysafflor yellow A (HSYA) is the main chemical component of safflower (Carthamus tinctorius) and has been reported to have pharmacological activities. However, the anti-anaphylactoid effect of HSYA has not yet been investigated. PURPOSE: The aims of this study were to evaluate the anti-anaphylactoid activity of HSYA in vivo and to investigate the underlying mechanism in vitro. METHODS: The anti-anaphylactoid activity of HSYA was evaluated in a mouse model of hindpaw extravasation. Calcium imaging was used to assess intracellular Ca2+ mobilization. The levels of cytokines and chemokines released by stimulated mast cells were measured using enzyme immunoassay kits. Western blotting was used to explore the related molecular signaling pathways. RESULTS: HSYA markedly inhibited mast cell degranulation by suppressing the activation of intracellular Ca2+ mobilization and preventing the release of cytokines and chemokines from mast cells in a dose-dependent manner via the PKC-PLCγ-IP3R signaling pathway. CONCLUSION: In summary, HSYA has anti-anaphylactoid pharmacological activity, which makes it a potential candidate for the development of a novel agent to suppress drug-induced anaphylactoid reactions.

Cisatracurium induces mast cell activation and pseudo-allergic reactions via MRGPRX2.

BACKGROUND: Pseudo-allergic reactions occur when patients receive muscle relaxants during perioperative anesthesia. These reactions may result in a serious threat to the patient's life, particularly to a child's life. Cisatracurium, a relatively new NMBA, has resulted in bronchospasms and cardiovascular collapse. However, the mechanisms underlying the anaphylactoid reactions caused by cisatracurium have not been fully elucidated. METHODS: In the present study, the MRGPRX2-related pseudo-allergic reactions induced by cisatracurium were investigated using hindpaw swelling and extravasation assays in vivo and mast cell degranulation assays. RESULTS: Cisatracurium caused anaphylactoid reactions in wild-type mice. However, cisatracurium did not induce a similar phenomenon in KitW-sh/W-sh mice. Furthermore, mast cell-related G protein-coupled receptor B2-knockout mice did not display an inflammatory response upon treatment with cisatracurium. Cisatracurium induced LAD2 cell degranulation, leading to the dose-dependent release of ß-hexosaminidase, histamine and TNF-α. However, cisatracurium only induced the release of low levels of these mediator LAD2 cells transfected with MRGPRX2 siRNA. Cisatracurium also stimulated intracellular Ca2+ influx in MRGPRX2-HEK293 cells compared with that in NC-HKE293 cells. Interestingly, cytokine release was not observed in LAD2 cells even with high dose of cisatracurium. CONCLUSIONS: Cisatracurium activated MRGPRX2 and triggered mast cell degranulation, leading to anaphylactoid reactions. Therefore, strategies targeting MRGPRX2 might potentially block cisatracurium-induced pseudo-allergic reactions.

Anti-pseudo-allergy effect of isoliquiritigenin is MRGPRX2-dependent.

Mast cell (MC) is the key mediate during allergy accours. The classical MC degranulation pathway is mediated by FcεRI aggregation and varies in strength among subjects, whereas a non-classical but analogous pseudo-allergic way was recently reported to occur via MRGPRX2. However, few therapies can directly target pseudo-allergies and related Mrgprs. Isoliquiritigenin (ISL) exerts anti-inflammatory effect in many diseases. In this study, we investigated the anti-pseudo-allergy effects of ISL and its underlying mechanism. We first examined the effect of ISL on the IgE-independent response using a PCA model,and in vitro cultured MCs. Further, we evaluated whether the anti-pseudo-allergic effect was related to Mrgprs using in vitro MRGPRX2-expressing HEK293 cells. ISL dose-dependently suppressed compound 48/80 (C48/80)-induced PCA and MC degranulation in mice. Our in vitro studies revealed that ISL reduced C48/80-induced calcium flux and suppressed degranulation in LAD2 cells. ISL dose dependently inhibited C48/80-induced MRGPRX2-expressing HEK293 cell activation. Our finding that ISL could inhibit IgE-independent allergy, via the Mrgprx2 pathway provides a new insight into pseudo-allergy and its therapy.

Administrations of thalidomide into the rostral ventromedial medulla produce antinociceptive effects in a rat model of postoperative pain.

The rostral ventromedial medulla (RVM) is highly involved in pain signal transmissions. Previous studies have shown that thalidomide is anti-nociceptive. Thus, we evaluated the neurobiological mechanisms of thalidomide in the RVM in the regulation of postoperative pain. We used a rat model of postoperative pain to investigate the effects of intra-RVM thalidomide treatments on postoperative pain, and evaluate the role of cannabinoid receptors in the effects of intra-RVM thalidomide treatments on GABAergic neurotransmission in the RVM neurons. We found intra-RVM thalidomide treatments reduced incisional surgery induced mechanical allodynia. This phenomenon was associated with attenuation of the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) and spontaneous IPSCs (sIPSCs) in RVM neurons. Furthermore, applications of WIN 55,212-3 mesylate, a non-selective cannabinoid receptor antagonist reversed the effects of repeated thalidomide treatment on the frequency but not the amplitude of mIPSCs and sIPSCs. Finally, we found that repeated thalidomide treatment robustly enhanced CB2 receptor expression, but slightly reduced CB1 receptor expression, in the RVM. These results suggested that the antinociceptive effects of thalidomide in the RVM likely involve the attenuation of GABA release, which are critically regulated by cannabinoid receptors.

Saikosaponin A inhibits compound 48/80-induced pseudo-allergy via the Mrgprx2 pathway in vitro and in vivo.

Pseudo-allergic reactions-adverse, non-immunologic, anaphylaxis-like sudden onset reactions mediated through an IgE-independent pathway-are activated by various basic compounds and occur at least as frequently as IgE-mediated reactions to drugs. A large family of G protein coupled receptors (Mas-related genes; Mrgprs) is closely related to pseudo-allergies. However, few therapies can directly target pseudo-allergies and related Mrgprs. Saikosaponin A (SSA) is effective in the treatment of passive cutaneous anaphylaxis (PCA), adjuvant arthritis, and delayed hypersensitiveness. In this study, we investigated the anti-pseudo-allergy effect of SSA and its underlying mechanism. We examined the effect of SSA on both IgE-independent and IgE-dependent responses using PCA and active systemic anaphylaxis models, as well as in vitro-cultured mast cells. We also evaluated whether the anti-allergy effect is related to Mrgprs by using in vitro Mrgprx2-expressing HEK293 cells. SSA dose dependently suppressed compound 48/80 (C48/80)-induced PCA and mast cell degranulation in mice. When SSA and C48/80 were administered together through the vein, C48/80-induced systemic anaphylaxis did not occur, and C48/80-induced shock ratio decreased dose-dependently upon SSA treatment. However, SSA did not affect IgE-dependent allergy. When administered topically 24 h before antigen challenge, Evans blue leakage and paw swelling were induced in the SSA-treated group and the vehicle group. Our in vitro studies revealed that SSA reduced C48/80-induced calcium flux and suppressed degranulation in LAD2 cells. SSA could also dose-dependently inhibit C48/80-induced Mrgprx2-expressing HEK293 cell activation. As a conclusion, SSA could inhibits IgE-independent allergy, but not IgE-dependent allergy, and this effect involves the Mrgprx2 pathway. This study provided a new sight on pseudo-allergy and its therapy.

MRGPRX2 is essential for sinomenine hydrochloride induced anaphylactoid reactions.

Mast cells are unique immunocytes that function as sentinel cells in host defense reactions such as immediate hypersensitivity responses and anaphylactic responses. The mast cell specific receptor MRGPRX2 (Mas-related G protein-coupled receptor X2) triggers mast cell degranulation-a key process in anaphylactic reactions. We sought to better understand anaphylactic reaction induced by sinomenine hydrochloride (SH). MRGPRX2-related pseudo-allergic reactions induced by SH were investigated using the hindpaw swelling and extravasation assay in vivo and mast cell degranulation assays in vitro. MrgprB2 knockout mice exhibit a reduced SH-induced inflammation effect. Furthermore, MRGPRX2 (the orthologous gene of MrgprB2) related human mast cells are activated by SH in a dose-dependent manner; however, MRGPRX2 knockdown mast cells showed reduced degranulation. The results showed a kind of mechanism that SH-induced anaphylactoid reactions were mediated by MRGPRX2 via activating PLC molecular signaling pathways to provoke mast cells Ca2+ mobilization and degranulation.

Tunable high-channel-count bandstop graphene plasmonic filters based on plasmon induced transparency.

A high-channel-count bandstop graphene plasmonic filter based on ultracompact plasmonic structure is proposed in this paper. It consists of graphene waveguide side-coupled with a series of graphene filtering units. The study shows that the waveguide-resonator system performs a multiple plasmon induced transparency (PIT) phenomenon. By carefully adjusting the Fermi level of the filtering units, any two adjacent transmitted dips which belong to different PIT units can produce coherent coupling superposition enhancement. This property prevents the attenuation of the high-frequency transmission dips of multiple PIT and leads to an excellent bandstop filter with multiple channels. Specifically, the bandwidth and modulation depth of the filters can be flexibly adjusted by tuning the Fermi energy of the graphene waveguide. This ultracompact plasmonic structure contributes to the achievement of frequency division multiplexing systems for optical computing and communications in highly integrated optical circuits.

Thalidomide Promotes Morphine Efficacy and Prevents Morphine-Induced Tolerance in Rats with Diabetic Neuropathy.

Opioid analgesics have less efficacy in diabetic neuropathy treatment, and tolerance often occurs after chronic usage. Given that thalidomide can potentiate the morphine efficacy in diabetic neuropathy treatment, we investigated the effects of intrathecal administrations of thalidomide on morphine tolerance during the treatment of diabetic neuropathy. We found that intrathecal administrations of thalidomide (25 mg/kg/ml) potentiated the analgesic effects of morphine on mechanical hyperalgesia and prevented the development of morphine tolerance. While this treatment regimen did not alter the protein levels of µ-opioid receptor (MOR) in the spinal cord of diabetic rats, chronic morphine treatment robustly increased MOR binding density in the synaptic plasma membranes fraction, but decreased it in the microsomal fraction. Furthermore, thalidomide was able to reverse the distribution of MOR altered by chronic morphine treatment. Finally, STZ-induced diabetes promoted PKC activation and enhanced TNFα level in the spinal cord, which were attenuated by intrathecal administrations of thalidomide. Taken together, these results suggested that thalidomide may potentiate morphine efficacy on diabetic neuropathy and prevent the development of morphine tolerance by suppressing PKC activation and TNFα level in the spinal cord.