Involvement of spinal NADPH oxidase 4 and endoplasmic reticulum stress in morphine-tolerant rats.

Morphine tolerance (MT) is currently a challenging issue related to intractable pain treatment. Studies have shown that reactive oxygen species (ROSs) derived from NADPH oxidase (NOX) and produced in response to endoplasmic reticulum (ER) stress participate in MT development. However, which NOX subtype initiates ER stress during MT development is unclear. NOX4 is mainly expressed on intracellular membranes, such as the ER and mitochondrial membranes, and its sole function is to produce ROS. Whether NOX4 is activated during MT development and the mechanisms underlying the association between NOX4 and ER stress during this process still need to be confirmed. In our study, we used the classic morphine-tolerant rat model and evaluated the analgesic effect of intrathecally injected morphine through a hot water tail-flick assay. Our research demonstrated for the first time that chronic morphine administration upregulates NOX4 expression in the spinal cord by activating three ER stress sensors, protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6), subsequently leading to the activation of microtubule-associated protein 1 light chain 3 b (LC3B) and P62 (a well-known autophagy marker) in GABAergic neurons. Our results may suggest that regulating NOX4 and the key mechanism underlying ER stress or autophagy may be a promising strategy to treat and prevent MT development.

Construction of Enantioenriched Quaternary C-Cl Oxindoles through Palladium-Catalyzed Asymmetric Allylic Substitution with Chloroenolates.

A palladium-catalyzed asymmetric chloroenolate allylation with vinyl benzoxazinanones under mild reaction conditions has been developed, affording a series of optically active 3,3-disubstituted oxindoles exhibiting a chloro-group and a linear aryl amino side chain in good yields with up to 96% ee. Versatile functional group tolerance on the benzene ring has been demonstrated, and the utility of this method was probed by a scale-up synthesis and highlighted by product derivatizations.

Functionalization of Olefinic C-H Bonds by an Aryl-to-Vinyl 1,4-Nickel Migration/Reductive Coupling Sequence.

An attractive approach to selective functionalization of remote C-H bonds is a metal/hydride shift/cross-coupling reaction sequence. Complimentary to the heavily exploited 1,2-nickel/hydride shift along an sp3 chain, a chain-walking process, the 1,4-nickel/hydride shift along an sp2 chain is more complex. Here we report an unprecedented aryl-to-vinyl 1,4-nickel/hydride shift reaction, in which the migratory alkenylnickel species generated in situ is selectively trapped by one of various coupling partners, such as isocyanates, alkyl bromides, aryl chlorides or alkynyl bromides, allowing regio- and stereoselective access to trisubstituted alkenes. In contrast to the well-reported ipso-aryl coupling reactions, this strategy provides remote alkenyl C-H functionalized products with good yield and with excellent chemo-, regio- and E/Z-selectivity.

Stem cells from human exfoliated deciduous teeth affect mitochondria and reverse cognitive decline in a senescence-accelerated mouse prone 8 model.

BACKGROUND AIMS: Stem cell therapy is a novel therapy being explored for AD. The molecular mechanism of its effect is still unclear. The authors investigated the effects and mechanism by injection of SHEDs into an AD mouse model. METHODS: SHEDs were cultured in vitro and injected into AD SAMP8 mice by caudal vein, and SHEDs labeled via synthetic dye showed in vivo migration to the head. The cognitive ability of SAMP8 mice was evaluated via Barnes maze and new object recognition. The pathological indicators of AD, including Tau, amyloid plaques and inflammatory factors, were examined at the protein or RNA level. Next, macro-proteomics analysis and weighted gene co-expression network analysis (WGCNA) based on protein groups and behavioral data were applied to discover the important gene cluster involved in the improvement of AD by SHEDs, which was further confirmed in an AD model in both mouse and cell lines. RESULTS: SHED treatment improved the cognitive ability and pathological symptoms of SAMP8 mice. Proteomics analysis indicated that these improvements were tightly related to the mitochondria, which was proved through examination of the shape and function of mitochondria both in vivo (SAMP8 brain) and in vitro (SH-SY5Y cells). Finally, the core targets of SHEDs in the mitochondrial pathway, Hook3, Mic13 and MIF, were screened out and confirmed in vivo. CONCLUSIONS: SHED treatment significantly relieved AD symptoms, improved cognitive ability and reversed memory loss in an AD mouse model, possibly through the recovery of dysfunctional mitochondria. These results raise the possibility that SHED may ease the symptoms of AD by targeting the mitochondria.

Source attributions of Cadmium contamination in rice grains by Cadmium isotope composition analysis: A field study.

Cd contamination in rice grains has become a topic of great concern because of the high health risks associated with the long-term consumption of Cd-contaminated rice. Identification of Cd sources in rice grains by scientific methods is important for controlling heavy metal pollution and protecting human health. Here, the Cd concentrations and Cd isotopic compositions of rice plants (root, stem, leaf, and grain) and topsoil, and possible pollution sources (agricultural fertilizers, industrial dust, and automobile exhaust) were analyzed using an instrument of inductively coupled plasma mass spectrometry (ICP-MS) and multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS). The results showed variations in the Cd isotopes of different components of rice plants and the fractionation coefficient of rice grains relative to topsoil (Δ114/110Cdrice grains-topsoil = 0.25‰). The contributions of pollution sources to rice grains were realized by combining the Cd isotopic composition with an isotopic mixing model (Isosource). The analysis showed that all three possible pollution sources contributed to the Cd in the rice grains in the field, the average Cd contribution of industrial dust, agricultural fertilizers and automobile exhaust was 87%, 9%, and 4%, respectively. Our study provides a feasible method for the identification of pollution sources of Cd in rice grains at the field scale and demonstrates that Cd isotopic composition is one of the powerful tools to trace the pollution sources of Cd in crops.

Facile Synthesis of Chiral Arylamines, Alkylamines and Amides by Enantioselective NiH-Catalyzed Hydroamination.

Regio- and enantioselective hydroarylamination, hydroalkylamination and hydroamidation of styrenes have been developed by NiH catalysis with a simple bioxazoline ligand under mild conditions. A wide range of enantioenriched benzylic arylamines, alkylamines and amides can be easily accessed by nitroarenes, hydroxylamines and dioxazolones, respectively as amination reagents. The chiral induction in these reactions is proposed to proceed through an enantiodifferentiating syn-hydronickellation step.

Functional Characterization Reveals the Significance of Rare Coding Variations in Human Organic Anion Transporting Polypeptide 2B1 (SLCO2B1).

The organic anion transporting polypeptide 2B1 (OATP2B1), which is encoded by the SLCO2B1 gene, plays important roles in the absorption and disposition of its substrate drugs. Nonsynonymous variations of SLCO2B1 change its amino acid sequence and may alter its function. However, so far, very few genetic variants of SLCO2B1 have been functionally characterized. In the present study, first of all, 14 nonsynonymous single nucleotide variants (SNVs) of SLCO2B1 have been identified from the dbSNP database. Then, human embryonic kidney (HEK293) cells were employed as the expression system and functional studies were carried out for these 14 SNVs using substrates 4',5'-dibromofluorescein (DBF), estrone-3-sulfate (E3S), atorvastatin, and rosuvastatin. Our results showed that four nonsynonymous rare variants, namely, SLCO2B1 c.332G > A (p.R111Q), c.1184C > A (p.P395H), c.1624G > A (p.V542M), and c.1998C > A (p.F666L), have great effect on the function of OATP2B1. Surface biotinylation and immunoblot analysis indicated that the variant c.1184C > A (p.P395H) almost completely disrupted OATP2B1's expression on the plasma membrane. According to the three-dimensional structural model of OATP2B1 we developed, these four mutated residues are not located at the substrate binding region of OATP2B1. Their significant effect on the function of OATP2B1 could probably be attributed to jeopardizing OATP2B1's surface expression as exemplified by c.1184C > A (p.P395H), altering the transporter's overall structure and affecting its interactions with other proteins or the lipid bilayer. Taken together, our results demonstrated that rare coding variants could have a great impact on the function and expression of OATP2B1.

Genetic polymorphisms of human hepatic OATPs: functional consequences and effect on drug pharmacokinetics.

1. Organic anion transporting polypeptides (OATPs) belong to the superfamily of solute carriers (SLC), which are important membrane transporters in animals and humans. Liver is an important organ for drug disposition. In human liver, three OATPs, namely OATP1B1, 1B3 and 2B1, are expressed on the basolateral membrane of hepatocytes.2. OATPs have multiple substrate specificity, mediating transport of a wide range of endo- and exogenous substances such as bile salts, bilirubin, hormones and their conjugates, toxins and various drugs. Therefore, they are important for drug disposition in human body. In this review, we compiled a complete list of the substrates for human hepatic OATPs.3. OATP genes have single-nucleotide polymorphisms (SNPs), which could lead to the alteration of their function, and thus might result in the change of pharmacokinetic properties for their substrate drugs. In this review, we summarized the genetic polymorphisms of the three hepatic OATPs and their effect on in vitro transport function and in vivo pharmacokinetics of substrate drugs.4. Finally, some concerns and perspectives on OATP polymorphism research are discussed.

gem-Difluoroalkylation of Cyclic Ethers Enabled by Cobalt-Catalyzed C(sp3)-H Oxidation under Mild Conditions.

Fluorinated rings have emerged as privileged structural modules in the fields of drug discovery and materials research. The incorporation of fluorine atoms into aromatic rings or heterocycles can lead to significant improvements in the physicochemical and biological properties of small molecules, making them valuable components in the design of new drugs and functional materials. Herein, we presented a cobalt-catalyzed C-H oxidation/gem-difluorination cascade reaction of readily available cyclic ethers with difluoroenoxysilanes, affording a series of gem-difluorinated analogues with moderate to high yields. The obtained products as versatile fluoroalkyl building blocks were showcased through divergent-oriented transformations.

MD-DFT Calculations on Dissociative Absorption Configurations of FOX-7 on (001)- and (101)-Oriented Crystalline Parylene Protective Membranes.

Crystalline poly-para-xylylene (parylene) has the potential for use as a protective membrane to delay the nucleation of explosives by separating the explosives and their decomposition products to decrease the explosive sensitivity. Here, molecular dynamics (MD) and density functional theory (DFT) techniques were used to calculate the dissociative adsorption configurations of 1,1-diamino-2,2-dinitroethylene (FOX-7) on (001)- and (101)-oriented crystalline parylene membranes. Based on the results of the calculations, this work demonstrates that the -NO2-π electrostatic interactions are the dominant passivation mechanism of FOX-7 on these oriented surfaces. FOX-7 can dissociatively adsorb on oriented parylene membranes due to the interactions between the LUMO of the toluene (or methyl) groups on parylene and the HOMO of the -NO2 (or -NH2) groups on FOX-7. The formation of a new intermolecular H-bond with the ONO group leads to FOX-7 decomposition via intramolecular C-NO2 bond fission and nitro-to-nitrite rearrangement. The most likely adsorption configurations are described in terms of the decomposition products, surface active groups of parylene, binding behaviors, and N charge transfer. Importantly, the (001)-oriented parylene AF8 membrane is promising for use as a protective membrane to passivate the high-energy -NO2 bonds during the dissociative adsorption of FOX-7. This study offers a new perspective on the development of protective membranes for explosives.

Impact of Noodle Formulation, Boiling Methodology and Their Interactions on Stable Hydrogen and Oxygen Isotope Ratios.

Stable isotopes are commonly utilized for the geographical origin verification of foods, including wheat. However, assessing processed products poses a greater challenge due to the alterations that take place during processing and which have not been fully elucidated yet. In the current study, the effects of the formulation (the mass ratios of gluten to starch), boiling process and their interaction on the stable hydrogen (δ2H) and oxygen (δ18O) isotopic ratios of wheat noodles were evaluated. The δ2H and δ18O of noodles with different formulations (the mass ratios of gluten to starch) as raw materials, in uncooked and cooked (boiled in water) noodles, were examined. The results indicated that the δ2H of the boiled noodles ranged from -80.1‱ to -46.8‱ and were significantly lower than those of the raw materials, which ranged from -73.0‱ to -39.2‱, and the uncooked noodles, which ranged from -73.3‱ to -39.6‱. Oppositely, 18O was enriched in the boiled noodles, ranging from 27.7‱ to 31.3‱, compared with the uncooked noodles, ranging from 28.4‱ to 29.6‱. In addition, a significant interaction effect between the formulation and the boiling process was recorded for δ18O. This study shows that the hydrogen and oxygen stable isotopic compositions of noodles were significantly changed during the boiling process, and the isotopic fractionation varies with the different formulations.

Clay minerals/sodium alginate/polyethylene hydrogel adsorbents control the selective adsorption and reduction of uranium: Experimental optimization and Monte Carlo simulation study.

Clay minerals formations are potential geological barrier (host rocks) for the long-rerm storage of uranium tailing in deep geological repositories. However, there are still obstacles to the efficient retardation of uranium because of the competition between negatively charged regions at the clay minerals end face, surface and between layers, as well as low mineralization capacity. Herein, employing a simple method, we used sodium alginate (SA), an inexpensive natural polymer material, polyethylene (PE), and the natural clay minerals montmorillonite (Mt), nontronite (Nt), and beidellite (Bd) to prepare three hydrogel adsorbents, (denoted as Mt/PE-@SA, Nt/PE-@SA, and Bd/PE-@SA), respectively. The application of obtained hydrogel adsorbents further extends to uranium(VI) removal from aqueous. Due to the synergistic action of SA group and PE group, hydrogel adsorbents showed select adsorption and mineralization effect on uranium(VI), among which the maximum uranium(VI) adsorption capacity of Nt/PE-@SA was 133.3 mg·g-1 and Mt/PE-@SA exhibited strong selectivity for uranium(VI) in the presence of coexisting metal ions. Cyclic voltammetry studies indicated the mitigation and immobilization of uranium species onto adsorbents by both reduction and mineralization. Besides, the synergistic adsorption of SA and PE on clay minerals was hypothesized, and the idea was supported by structure optimizations results from Monte Carlo dynamics simulation (MCD). Three obtained hydrogel adsorbents structural model was constructed based on its physicochemical characterization, the low energy adsorption sites and adsorption energies are investigated using MCD simulation. The simulation results show that obtained hydrogel adsorbents have a strong interaction with uranium(VI), which ensures the high adsorption capacity of those materials. Most importantly, this work demonstrates a new strategy for preparing mineral-based hydrogel adsorbents with enough stability and provides a new perspective for uranium(VI) removal in complex environment.

An Efficient Blue-Emission Crystalline Thin-Film OLED Sensitized by "Hot Exciton" Fluorescent Dopant.

Crystalline thin-film organic light-emitting diodes (C-OLEDs) can achieve a large light emission and a low Joule-heat loss under low driving voltage due to the high carrier mobility of the crystalline thin films. However, it is urgent for the C-OLEDs to improve their external quantum efficiency (EQE). Here, a novel strategy is proposed using a doped "hot exciton" material to sensitize a high PLQY blue emitter in C-OLEDs. Benefiting from the capability of the "hot exciton" material harnessing triplet/singlet excitons, the C-OLED exhibits an efficiency breakthrough with a maximum EQE of 6.2%, a much enhanced blue photon output with pure blue emission Commission International de L'Eclairage (CIE) (0.14, 0.15), a low turn-on/operation voltage of 2.6 V(@1 cd m-2 )/3.8 V (@1000 cd m-2 ), and a maximum power efficiency (PE) of 9.4 lm W-1 . This work unlocks the potential of C-OLEDs for achieving high photon output with high EQE.

Effects of Frozen Storage Time, Thawing Treatments, and Their Interaction on the Rheological Properties of Non-Fermented Wheat Dough.

In this study, the effects of frozen storage time, thawing treatments, and their interaction on the rheological properties of non-fermented dough were evaluated. Texture profile analysis (TPA), rheological measurements, including strain/frequency sweep, and creep-recovery measurement were applied to the dough. Compared with unfrozen fresh dough, the frozen storage time (S) and thawing treatment (T) influenced almost all indicators significantly, and their mutual effects (S × T) mainly affected the hardness and springiness. Frozen time was the main factor resulting in the destruction of non-fermented dough during the thawing treatments. Moreover, refrigerator thawing (4 °C) produced a dough with minimal changes in the rheological properties, regardless of the frozen storage time. Meanwhile, microwave thawing resulted in lower G' and lower zero shear viscosity (η0) values, as well as higher maximum creep compliance (Jmax) and hardness values. Moreover, the difference between the three thawing treatments was exacerbated after 30 days of frozen storage. SEM images also showed that long-term frozen storage combined with microwave thawing seriously destroyed the rheological properties, structural stability, and inner microstructure of the dough.

NR2F1-AS1: A Functional Long Noncoding RNA in Tumorigenesis.

BACKGROUND: NR2F1-AS1 is a long non-coding RNA (lnc RNA) that is involved in different biological processes. It plays an integral role in the pathophysiology of human diseases, especially tumorigenesis and progression. Therefore, it may be a promising target for numerous tumor biotherapeutics. The current review study aimed to show the pathophysiological activities and processes of RNA NR2F1-AS1 in cancer cells. METHODS: The contents of the present review were based on information obtained from PubMed. In the data search, "NR2F1-AS1" was chosen as the first keyword, whereas "cancer" was chosen as the second keyword. This review selected and summarized studies published between 2019-2021, concerning the biological functions and mechanisms of NR2F1-AS1 in the development of tumorigenesis. RESULTS: It was found that NR2F1-AS1 regulates a variety of biological activities such as proliferation, invasion, migration, and apoptosis. It acts as an oncogene because it is abnormally expressed and promotes the progression of cancer in a variety of malignancies, including esophageal squamous cell carcinoma, non-small cell lung cancer, breast cancer, neuroblastoma, endometrial cancer, thyroid cancer, and gastric cancer. However, it was evident that NR2F1-AS1 inhibits the progression of cancer in cervical squamous cell carcinoma. CONCLUSION: NR2F1-AS1 is a potential new biomarker and therapeutic target for the treatment of different cancers.

Spinal cannabinoid receptor 2 activation alleviates neuropathic pain by regulating microglia and suppressing P2X7 receptor.

Neuropathic pain (NP) is the chronic pain in patients resulting from injuries or diseases in the somatosensory nervous system. However, effective treatment remains limited to opioids. Currently, there is an urgent need to develop new specific pharmaceuticals with low abuse potentiality. Cannabinoid receptor 2 (CB2R) is one of the significant receptors in the endocannabinoid system. It is widely expressed in the central nervous system, especially enriched in glial cells, and plays an important role in the occurrence and development of inflammation in the nervous system. CB2R activation has a neuroprotective effect on nerve injury. In this study, we report increased and more reactive microglia (with larger cell body, shorter processes, and fewer endpoints) observed in the spinal dorsal horn of spared nerve injury (SNI) rats. Continuous intrathecal administration of CB2R agonist PM226 attenuated mechanical and cold hyperalgesia in rats and prevented the transition of microglia to the proinflammatory stage. Thus, microglia transitioned into the neuroprotective stage. Meanwhile, the proinflammatory factors TNF-α and iNOS decreased, and the levels of anti-inflammatory factors Arg-1 and IL-10 increased. The content of P2X7 receptors in the spinal dorsal horn of rats increases with time after SNI. After continuous intrathecal administration of PM226, the content of P2X7 protein decreases significantly. The administration of P2X7 inhibitor A-438079 alleviated the mechanical hyperalgesia of rats, reduced the number of microglia, and decreased the content of P2X7. These results indicate that P2X7 is involved in the neuroprotective effect caused by CB2R activation. In conclusion, this study provides new insights into the neuroprotective mechanism of CB2R activation.

Prokineticin-2 Participates in Chronic Constriction Injury-Triggered Neuropathic Pain and Anxiety via Regulated by NF-κB in Nucleus Accumbens Shell in Rats.

Neuropathic pain (NP) is an intractable pain that results from primary nervous system injury and dysfunction. Herein, we demonstrated in animal models that peripheral nerve injury induced enhanced pain perception and anxiety-like behaviors. According to previous reports, nucleus accumbens (NAc) shell is required for complete expression of neuropathic pain behaviors and mood alternations, we found the elevated mRNA and protein level of Prokineticin-2 (Prok2) in the NAc shell after Chronic Constriction Injury (CCI). Prok2 knockdown in the NAc shell reversed NP and anxiety-like behaviors in rats, indicating that Prok2 might play a fundamental role in NP and anxiety co-morbidity. CCI significantly enhanced Prok2 co-expression with NF-κB P-p65 in comparison with control animals. In addition to reversing the established nociceptive hypersensitivities and anxiety simultaneously, NAc microinjection of NF-κB siRNA or specific inhibitor PDTC reversed Prok2 upregulation. Besides, Prok2 was significantly decreased in vitro when co-transfected with si-NF-κB. Dual-Luciferase assay showed NF-κB directly activated Prok2 gene transcriptional activity. Overall, these findings provide new insights into the neurobiological mechanisms behind NP and comorbid anxiety. The NF-κB/Prok2 pathway could be a potential therapeutic target for NP and anxiety disorders.

Mild Hydrothermal Synthesis of 11Å-TA from Alumina Extracted Coal Fly Ash and Its Application in Water Adsorption of Heavy Metal Ions (Cu(II) and Pb(II)).

Non-biodegradable copper (Cu) and lead (Pb) contaminants in water are highly toxic and have series adverse effects. Therefore, it is very important to extract heavy metals from wastewater before it is discharged into the environment. Adsorption is a cost-effective alternative method for wastewater treatment. Choosing a low-cost adsorbent can help reduce the cost of adsorption. In this study, conversion of reside after extracting aluminum (REA) produced by sub-molten salt method transform high-alumina coal fly ash (CFA) into 11Å-tobermorite to adsorb Cu(II) and Pb(II) from aqueous solutions at room temperature. The synthesis of the adsorbent was confirmed using scanning electron microscope (SEM), X-ray diffractometer (XRD) and Brunauer-Emmett-Teller (BET) method surface analysis. To study the adsorption characteristics, factors such as initial Cu(II) and Pb(II) concentration, pH, contact time, adsorption characteristics and temperature were investigated in batch mode. The maximum adsorption capacity of Cu(II) and Pb(II) was 177.1 mg·g-1 and 176.2 mg·g-1, respectively. The Langmuir adsorption model was employed to better describe the isothermal adsorption behavior and confirm the monolayer adsorption phenomenon. The pseudo-second-order kinetic model was used to highlight Cu(II) and Pb(II) adsorption kinetics. Thermodynamic analysis indicated the removal Cu(II) and Pb(II) by TA-adsorbent was a nonspontaneous and exothermic reaction. The obtained results are of great significance to the conversion of industrial waste to low-cost adsorbent for Cu(II) and Pb(II) removal from water.

High-efficiency blue-emission crystalline organic light-emitting diodes sensitized by "hot exciton" fluorescent nanoaggregates.

Sensitizing fluorescent materials is an effective way to maximally use excitons and obtain high-efficiency blue organic light-emitting diodes (OLEDs). However, it is a persistent challenge for present amorphous thin-film OLEDs to improve photon emission under low driving voltage, severely impeding the development of OLED technology. Here, we propose a novel OLED architecture consisting of a crystalline host matrix (CHM) and embedded "hot exciton" nanoaggregates (HENAs), which effectively sensitize blue dopant (D) emission. Owing to the advantages of the crystalline thin-film route, the device exhibits largely enhanced blue photon output [Commission International de L'Eclairage coordinates of (0.15, 0.17)], with a low turn-on/operation voltage of 2.5 V (at 1 cd/m2)/3.3 V (at 1000 cd/m2), an extremely low Joule heat loss ratio (7.8% at 1000 cd/m2), and a maximum external quantum efficiency (EQE) up to 9.14%. These areal photon output features have outperformed the present amorphous thin-film blue OLEDs with high EQE, demonstrating that the CHM-HENA-D OLED is promising for future OLEDs.

The cAMP Response Element- Binding Protein/Brain-Derived Neurotrophic Factor Pathway in Anterior Cingulate Cortex Regulates Neuropathic Pain and Anxiodepression Like Behaviors in Rats.

Neuropathic pain is often accompanied by anxiety and depression-like manifestations. Many studies have shown that alterations in synaptic plasticity in the anterior cingulate cortex (ACC) play a critical role, but the specific underlying mechanisms remain unclear. Previously, we showed that cAMP response element-binding protein (CREB) in the dorsal root ganglion (DRG) acts as a transcription factor contributing to neuropathic pain development. At the same time, brain-derived neurotrophic factor (BDNF), as important targets of CREB, is intricate in neuronal growth, differentiation, as well as the establishment of synaptic plasticity. Here, we found that peripheral nerve injury activated the spinal cord and ACC, and silencing the ACC resulted in significant relief of pain sensitivity, anxiety, and depression in SNI rats. In parallel, the CREB/BDNF pathway was activated in the spinal cord and ACC. Central specific knockdown and peripheral non-specific inhibition of CREB reversed pain sensitivity and anxiodepression induced by peripheral nerve injury. Consequently, we identified cingulate CREB/BDNF as an assuring therapeutic method for treating neuropathic pain as well as related anxiodepression.