[Assessment and Source Analysis of Heavy Metal Pollution in Farmland Soil Around Tin Mine].

Studying the status and source analysis of heavy metal pollution in farmland in typical mining and processing areas is an important prerequisite for promoting farmland soil ecological restoration and farmland protection in concentrated mining areas. In this study, the heavy metal content of farmland soil around a mining area in southwest China was detected, and the pollution status, distribution law, health risks, and sources of heavy metals were studied by using the land accumulation index method, comprehensive pollution index method, kriging interpolation method, health risk assessment method, and PMF receptor model on the sampling data. The results showed that the mean values of eight heavy metals in farmland soil except Ni exceeded the local soil background values, and the results of the ground accumulation index evaluation showed that Cd and Hg were extremely polluted； Pb and As showed medium pollution-heavy pollution； and Cr, Zn, Ni, and Cu were lightly polluted. In the health risk assessment, oral ingestion was the main exposure route posing a health risk to the human body； the main element that constituted non-carcinogenic health risks was As, and the carcinogenic risks were from As and Cd. PMF model analysis showed that the contribution rate of weathering natural sources of iron-bearing ore was 28.02%, and the main factors were Ca and Fe. The contribution rate of agricultural sources was 3.02%, and the main factors were Pb and As. The contribution rate of industrial and atmospheric deposition composite sources was 33.09%, and the main factor was Hg. The contribution rate of the parent material source was 17.27%, and the main factor was Ca. The contribution rate of mining activities such as mining and smelting was 18.60%, and the main factors were Zn and Cd.

NSE5 subunit interacts with distant regions of the SMC arms in the Physcomitrium patens SMC5/6 complex.

Structural maintenance of chromosome (SMC) complexes play roles in cohesion, condensation, replication, transcription, and DNA repair. Their cores are composed of SMC proteins with a unique structure consisting of an ATPase head, long arm, and hinge. SMC complexes form long rod-like structures, which can change to ring-like and elbow-bent conformations upon binding ATP, DNA, and other regulatory factors. These SMC dynamic conformational changes are involved in their loading, translocation, and DNA loop extrusion. Here, we examined the binding and role of the PpNSE5 regulatory factor of Physcomitrium patens PpSMC5/6 complex. We found that the PpNSE5 C-terminal half (aa230-505) is required for binding to its PpNSE6 partner, while the N-terminal half (aa1-230) binds PpSMC subunits. Specifically, the first 71 amino acids of PpNSE5 were required for binding to PpSMC6. Interestingly, the PpNSE5 binding required the PpSMC6 head-proximal joint region and PpSMC5 hinge-proximal arm, suggesting a long distance between binding sites on PpSMC5 and PpSMC6 arms. Therefore, we hypothesize that PpNSE5 either links two antiparallel SMC5/6 complexes or binds one SMC5/6 in elbow-bent conformation, the later model being consistent with the role of NSE5/NSE6 dimer as SMC5/6 loading factor to DNA lesions. In addition, we generated the P. patens Ppnse5KO1 mutant line with an N-terminally truncated version of PpNSE5, which exhibited DNA repair defects while keeping a normal number of rDNA repeats. As the first 71 amino acids of PpNSE5 are required for PpSMC6 binding, our results suggest the role of PpNSE5-PpSMC6 interaction in SMC5/6 loading to DNA lesions.

Analgesic effect of a cholinergic agonist (carbachol) in a sural nerve ligation-induced hypersensitivity mouse model.

OBJECTIVES: Neuropathic pain is characterized by long-lasting, intractable pain. Sciatic nerve ligation is often used as an animal model of neuropathic pain, and the spared nerve injury (SNI) model, in which the common peroneal nerve (CPN) and tibial nerve (TN) are ligated, is widely used. In the present study, we evaluated the analgesic effect of a cholinergic agonist, carbachol, on a neuropathic pain model prepared by sural nerve (SN) ligation in mice. METHODS: The SN was tightly ligated as a branch of the sciatic nerve. Mechanical and thermal allodynia, and hyperalgesia were assessed using von Frey filaments and heat from a hot plate. The analgesic effects of intracerebroventricularly-administered morphine and carbachol were compared. RESULTS: SN ligation resulted in a significant decrease in pain threshold for mechanical stimulation 1 day after ligation. In response to thermal stimulation, allodynia was observed at 50°C and hyperalgesia at 53 and 56°C 3 days after ligation. Content of thiobarbituric acid reactive substances (TBARS) in the spinal cord increased significantly at 6 and 12 h after ligation. Acetylcholine content of the spinal cord also increased at 5 and 7 days after ligation. Intracerebroventricular administration of carbachol at 7 days after ligation produced a marked analgesic effect against mechanical and thermal stimuli, which was stronger and longer-lasting than morphine at all experimental time points. CONCLUSION: These findings suggest that cholinergic nerves are involved in allodynia and hyperalgesia of the SN ligation neuropathic pain model.

Multifunctionally Reusing Waste Solder to Prepare Highly Efficient Sn-Pb Perovskite Solar Cells.

The preparation of perovskite components (PbI2 and SnI2) using waste materials is of great significance for the commercialization of perovskite solar cells (PSCs). However, this goal is difficult to achieve due to the purity of the recovered products and the easy oxidation of Sn2+. Here, a simple one-step synthetic process to convert waste Sn-Pb solder into SnI2/PbI2 and then applied as-prepared SnI2/PbI2 to PSCs for high additional value is adopted. During fabrication, Sn-Pb waste solder is also employed to serve as a reducing agent to reduce the Sn4+ in Sn-Pb mixed narrow perovskite precursor and hence remove the deep trap states in perovskite. The target PSCs achieved an efficiency of 21.04%, which is better than the efficiency of the device with commercial SnI2/PbI2 (20.10%). Meanwhile, the target PSC maintained an initial efficiency of 80% even after 800 h under continuous illumination, which is significantly better than commercial devices. In addition, the method achieved a recovery rate of 90.12% for Sn-Pb waste solder, with a lab-grade purity (over 99.8%) for SnI2/PbI2, and the cost of perovskite active layer reduced to 39.81% through this recycling strategy through calculation.

PolyphyllinVI alleviates the spared nerve injury-induced neuropathic pain based on P2X3 receptor-mediated the release of inflammatory mediators.

ETHNOPHARMACOLOGICAL RELEVANCE: PolyphyllinVI (PPⅥ) is the main bioactive component of Chonglou which is a traditional Chinese herbal with various effects, including antitumor, anti-inflammatory, and analgesia. AIM OF THE STUDY: This study aimed to investigate the properties and mechanisms of the analgesia of PPⅥ by using neuropathic pain (NPP) mice. MATERIALS AND METHODS: The potential targets and mechanisms of PPⅥ in alleviating NPP were excavated based on the network pharmacology. Subsequently, the construction of a spared nerve injury (SNI) mice model was used to evaluate the effect of PPⅥ on NPP and the expression of the P2X3 receptor. We identified the signaling pathways of PPⅥ analgesia by RNA sequencing. RESULTS: The results of network pharmacology showed that BCL2, CASP3, JUN, STAT3, and TNF were the key targets of the analgesic effect of PPⅥ. PPⅥ increased the MWT and TWL of SNI mice and decreased the level of P2X3 receptors in the dorsal root ganglion (DRG) and spinal cord (SC). Additionally, PPⅥ reduced the release of pro-inflammatory mediators (TNF-α, IL-1ß, and IL-6) in the DRG, SC, and serum. Based on the KEGG enrichment of differentially expressed genes (DEGs) identified by RNA-Seq, PPVI may relieve NPP by regulating the AMPK/NF-κB signaling pathway. Western blotting results showed that the AMPK signaling pathway was activated, followed by inhibition of the NF-κB signaling pathway. CONCLUSION: PPⅥ increased the MWT and TWL of SNI mice maybe by inhibiting the expression of the P2X3 receptor and the release of inflammatory mediators. The properties of the analgesia of PPⅥ may be based on the AMPK/NF-κB pathway.

2D Ruddlesden-Popper Sn-Based Perovskite Weak Light Detector for Image Transmission and Reflection Imaging.

2D Ruddlesden-Popper Sn-based perovskite has excellent optoelectronic properties and weak halide ion migration characteristics, making it an ideal candidate for weak light detection, which has great potential in light communication, and medical applications. Although Sn-based perovskite photodetectors are developed, weak light detection is not demonstrated yet. Herein, a high-performance self-powered photodetector with the capability to detect ultra-weak light signals is designed based on vertical PEA2 SnI4 /Si nanowires heterojunction. Due to the low dark current and high light absorption efficiency, the devices present a remarkable responsivity of 42.4 mA W-1 , a high detectivity of 8 × 1011 Jones, and an ultralow noise current of 2.47 × 10-13 A Hz-1/2 . Especially, the device exhibits a high on-off current ratio of 18.6 at light signals as low as 4.60 nW cm-2 , revealing the capacity to detect ultra-weak light. The device is applied as a signal receiver and realized image transmission in light communication system. Moreover, high-resolution reflection imaging and multispectral imaging are obtained using the device as the sensor in the imaging system. These results reveal that 2D PEA2 SnI4 -based self-powered photodetectors with low-noise current possess enormous potential in future weak light detection.

Catalytic Mechanism of Nonglycosidic C-N Bond Formation by the Pseudoglycosyltransferase Enzyme VldE.

The pseudoglycosyltransferase (PsGT) enzyme VldE is a homologue of the retaining glycosyltransferase (GT) trehalose 6-phosphate synthase (OtsA) that catalyzes a coupling reaction between two pseudo-sugar units, GDP-valienol and validamine 7-phosphate, to give a product with α,α-N-pseudo-glycosidic linkage. Despite its biological importance and unique catalytic function, the molecular bases for its substrate specificity and reaction mechanism are still obscure. Here, we report a comparative mechanistic study of VldE and OtsA using various engineered chimeric proteins and point mutants of the enzymes, X-ray crystallography, docking studies, and kinetic isotope effects. We found that the distinct substrate specificities between VldE and OtsA are most likely due to topological differences within the hot spot amino acid regions of their N-terminal domains. We also found that the Asp158 and His182 residues, which are in the active site, play a significant role in the PsGT function of VldE. They do not seem to be directly involved in the catalysis but may be important for substrate recognition or contribute to the overall architecture of the active site pocket. Moreover, results of the kinetic isotope effect experiments suggest that VldE catalyzes a C-N bond formation between GDP-valienol and validamine 7-phosphate via an SNi-like mechanism. The study provides new insights into the substrate specificity and catalytic mechanism of a member of the growing family of PsGT enzymes, which may be used as a basis for developing new PsGTs from GTs.

First-principles predictions of enhanced thermoelectric properties for Cs2SnI2Cl2and Cs2PbI2Cl2monolayers with spin-orbit coupling.

Inspired by the exceptional charge transport properties and ultra-low thermal conductivity of halide perovskite, we investigate the electronic nature, thermal transport, and thermoelectric properties for Ruddlesden-Popper all-inorganic perovskite, Cs2SnI2Cl2and Cs2PbI2Cl2monolayers, using first-principles calculations. During the calculations, spin-orbit coupling has been considered for electronic transport as well as thermoelectric properties. The results show that the Cs2SnI2Cl2and Cs2PbI2Cl2monolayers exhibit high carrier mobility and low thermal conductivity. Stronger phonon-phonon interaction is responsible for the fact that thermal conductivity of Cs2SnI2Cl2monolayer is much lower than that of Cs2PbI2Cl2monolayer. At 700 K, the values of the figure of merit (ZT) for the n-type doped Cs2SnI2Cl2and Cs2PbI2Cl2monolayers are about 1.05 and 0.32 at the optimized carrier concentrations 5.42 × 1012cm-2and 9.84 × 1012cm-2. Moreover, when spin-orbit coupling is considered, the correspondingZTvalues are enhanced to 2.73 and 1.98 at 5.27 × 1011cm-2and 6.16 × 1011cm-2. These results signify that Cs2SnI2Cl2and Cs2PbI2Cl2monolayers are promising thermoelectric candidates.

Simple Solution Preparation of Cs2SnI6 Films and Their Applications in Solid-State DSSCs.

Cs2SnI6 powder is, for the first time, solution-prepared via the formula CsI + SnI2 + I2 → Cs2SnI6. The product is highly pure and air/thermal stable. It is found that N,N-dimethylformamide (DMF) and methanol induce severe Cs2SnI6 deterioration with the appearance of a CsI phase in film preparation from Cs2SnI6 powder, while solvents of γ-butyrolactone (GBL) and ethylene glycol methyl ether (EGME) (Film-EGME) give better results. Then, by introducing EGME solvent, in situ preparation of Cs2SnI6 films (Film-1 to Film-4) is realized under solution reaction, which is found to be dominated by thermal dynamic process, i.e., highly pure/oriented Film-4 is obtained under the maximum reagent-concentration. Besides, for good reaction, the solubility of solvent should be balanced among all the reagents and products. Solid-state dye sensitized solar cells (ss-DSSCs) comprising a Cs2SnI6 electrolyte are investigated. The power conversion efficiencies (PCEs) of the ss-DSSCs based on solution-casted Film-EGME and the in situ-prepared Film-4 are 1.81% and 3.30%, respectively. Particularly, with the in situ prepared Cs2SnI6 films, it is found that the open circuit voltages of the ss-DSSCs are closely related to their gap states. When additive is added in Cs2SnI6 electrolyte, a PCE of 6.14% is obtained in an ss-DSSC. Our work highlights the importance of solvent in film preparation and the role of Cs2SnI6 gap states in device performance.

Nerve Injury-Induced γH2AX Reduction in Primary Sensory Neurons Is Involved in Neuropathic Pain Processing.

Phosphorylation of the serine 139 of the histone variant H2AX (γH2AX) is a DNA damage marker that regulates DNA damage response and various diseases. However, whether γH2AX is involved in neuropathic pain is still unclear. We found the expression of γH2AX and H2AX decreased in mice dorsal root ganglion (DRG) after spared nerve injury (SNI). Ataxia telangiectasia mutated (ATM), which promotes γH2AX, was also down-regulated in DRG after peripheral nerve injury. ATM inhibitor KU55933 decreased the level of γH2AX in ND7/23 cells. The intrathecal injection of KU55933 down-regulated DRG γH2AX expression and significantly induced mechanical allodynia and thermal hyperalgesia in a dose-dependent manner. The inhibition of ATM by siRNA could also decrease the pain threshold. The inhibition of dephosphorylation of γH2AX by protein phosphatase 2A (PP2A) siRNA partially suppressed the down-regulation of γH2AX after SNI and relieved pain behavior. Further exploration of the mechanism revealed that inhibiting ATM by KU55933 up-regulated extracellular-signal regulated kinase (ERK) phosphorylation and down-regulated potassium ion channel genes, such as potassium voltage-gated channel subfamily Q member 2 (Kcnq2) and potassium voltage-gated channel subfamily D member 2 (Kcnd2) in vivo, and KU559333 enhanced sensory neuron excitability in vitro. These preliminary findings imply that the down-regulation of γH2AX may contribute to neuropathic pain.

Lead-Free FACsSnI3 Based Perovskite Solar Cell: Designing Hole and Electron Transport Layer.

In recent years, lead-based perovskites solar cells have demonstrated excellent power-conversion efficiency. Despite their remarkable progress, the commercialization of lead-based perovskites is hampered by lead toxicity concerns. The recently discovered non-toxic FACsSnI3 perovskite has the potential to replace lead-based perovskites in solar cell applications. Since the perovskite material FACsSnI3 (FA0.85Cs0.15SnI3) is relatively new, there is a lack of information, particularly regarding the design features required for electron and hole-transport layers for efficient photovoltaic responses. The important variables, such as electron affinity, energy band gap, film thickness, and doping density of both electron and hole-transport layers, were simulated and modeled separately and iteratively in this study to achieve the most efficient photovoltaic response. Finally, the absorber layer thickness of FACsSnI3 perovskite is tuned to achieve a maximum power-conversion efficiency of slightly more than 24%. We hope that the findings of this study will serve as a strong guideline for future research and the design of lead-free perovskite solar cells for efficient photovoltaic responses.

Characterization of the conserved features of the NSE6 subunit of the Physcomitrium patens SMC5/6 complex.

Structural maintenance of chromosomes (SMC) complexes are molecular machines ensuring chromatin organization at higher levels. They play direct roles in cohesion, condensation, replication, transcription, and DNA repair. Their cores are composed of long-armed SMC, kleisin, and kleisin-associated subunits. Additional factors, like NSE6 within SMC5/6, bind to SMC core complexes and regulate their activities. In the human HsNSE6/SLF2, we recently identified a new CANIN domain. Here we tracked down its sequence homology to lower plants, selected the bryophyte Physcomitrium patens, and analyzed PpNSE6 protein-protein interactions to explore its conservation in detail. We identified a previously unrecognized core sequence motif conserved from yeasts to humans within the NSE6 CANIN domain. This motif mediates the interaction between NSE6 and its NSE5 partner in yeasts and plants. In addition, the CANIN domain and its preceding PpNSE6 sequences bind both PpSMC5 and PpSMC6 arms. Interestingly, we mapped the PpNSE6-binding site at the PpSMC5 arm right next to the PpNSE2-binding surface. The position of NSE6 at SMC arms suggests its role in the regulation of SMC5/6 dynamics. Consistent with the regulatory role of NSE6 subunits, Ppnse6 mutant lines were viable and sensitive to the DNA-damaging drug bleomycin and lost a large portion of rDNA copies. These moss mutants also exhibited reduced growth and developmental aberrations. Altogether, our data showed the conserved function of the NSE6 subunit and architecture of the SMC5/6 complex across species.

Adaptive Content Tuning of Social Network Digital Health Interventions Using Control Systems Engineering for Precision Public Health: Cluster Randomized Controlled Trial.

BACKGROUND: Social media has emerged as an effective tool to mitigate preventable and costly health issues with social network interventions (SNIs), but a precision public health approach is still lacking to improve health equity and account for population disparities. OBJECTIVE: This study aimed to (1) develop an SNI framework for precision public health using control systems engineering to improve the delivery of digital educational interventions for health behavior change and (2) validate the SNI framework to increase organ donation awareness in California, taking into account underlying population disparities. METHODS: This study developed and tested an SNI framework that uses publicly available data at the ZIP Code Tabulation Area (ZCTA) level to uncover demographic environments using clustering analysis, which is then used to guide digital health interventions using the Meta business platform. The SNI delivered 5 tailored organ donation-related educational contents through Facebook to 4 distinct demographic environments uncovered in California with and without an Adaptive Content Tuning (ACT) mechanism, a novel application of the Proportional Integral Derivative (PID) method, in a cluster randomized trial (CRT) over a 3-month period. The daily number of impressions (ie, exposure to educational content) and clicks (ie, engagement) were measured as a surrogate marker of awareness. A stratified analysis per demographic environment was conducted. RESULTS: Four main clusters with distinctive sociodemographic characteristics were identified for the state of California. The ACT mechanism significantly increased the overall click rate per 1000 impressions (ß=.2187; P<.001), with the highest effect on cluster 1 (ß=.3683; P<.001) and the lowest effect on cluster 4 (ß=.0936; P=.053). Cluster 1 is mainly composed of a population that is more likely to be rural, White, and have a higher rate of Medicare beneficiaries, while cluster 4 is more likely to be urban, Hispanic, and African American, with a high employment rate without high income and a higher proportion of Medicaid beneficiaries. CONCLUSIONS: The proposed SNI framework, with its ACT mechanism, learns and delivers, in real time, for each distinct subpopulation, the most tailored educational content and establishes a new standard for precision public health to design novel health interventions with the use of social media, automation, and machine learning in a form that is efficient and equitable. TRIAL REGISTRATION: ClinicalTrials.gov NTC04850287; https://clinicaltrials.gov/ct2/show/NCT04850287.

Rapid injection of lumbar dorsal root ganglia under direct vision: Relevant anatomy, protocol, and behaviors.

Introduction: Dorsal root ganglia (DRG) are anatomically well-defined structures that contain all primary sensory neurons and are distension nodules of the dorsal root in the spinal cord near the medial surface of each foramen. Therefore, DRG is considered to be a desirable target for injection to manage chronic pain. But it presents a limitation in probing deep into it without in vivo injection technology. Methods: Here, we described a technique for administering intraganglionic injections of lumbar DRG under direct vision. We use partial osteotomy rather than laminectomy, which removes more bone, to preserve spinal structures while gaining adequate DRG access. To monitor the intraoperative progress of the DRG injection, a non-toxic dye was utilized. The effectiveness of the injection on the diffusion of AAV (adeno-associated virus) within the ganglion was assessed by histopathology at postoperative day 21. Results: Behavioral tests showed that neither motor nor sensory abilities were affected by saline or AAV injections. Meanwhile, the decreased pain threshold of SNI (spared nerve injury) was considerably restored by pharmacological inhibition of DRG neurons. Discussion: Our research achieved a new minimally invasive and intuitive intra-ganglionic injection in mice. In addition, the present protocol may serve as a valuable resource for planning preclinical studies of DRG injection.

Regulation of Expression of Extracellular Matrix Proteins by Differential Target Multiplexed Spinal Cord Stimulation (SCS) and Traditional Low-Rate SCS in a Rat Nerve Injury Model.

There is limited research on the association between the extracellular matrix (ECM) and chronic neuropathic pain. The objective of this study was twofold. Firstly, we aimed to assess changes in expression levels and the phosphorylation of ECM-related proteins due to the spared nerve injury (SNI) model of neuropathic pain. Secondly, two modalities of spinal cord stimulation (SCS) were compared for their ability to reverse the changes induced by the pain model back toward normal, non-injury levels. We identified 186 proteins as ECM-related and as having significant changes in protein expression among at least one of the four experimental groups. Of the two SCS treatments, the differential target multiplexed programming (DTMP) approach reversed expression levels of 83% of proteins affected by the pain model back to levels seen in uninjured animals, whereas a low-rate (LR-SCS) approach reversed 67%. There were 93 ECM-related proteins identified in the phosphoproteomic dataset, having a combined 883 phosphorylated isoforms. DTMP back-regulated 76% of phosphoproteins affected by the pain model back toward levels found in uninjured animals, whereas LR-SCS back-regulated 58%. This study expands our knowledge of ECM-related proteins responding to a neuropathic pain model as well as providing a better perspective on the mechanism of action of SCS therapy.

Altered Brain Expression of DNA Methylation and Hydroxymethylation Epigenetic Enzymes in a Rat Model of Neuropathic Pain.

The role of epigenetics in chronic pain at the supraspinal level is yet to be fully characterized. DNA histone methylation is crucially regulated by de novo methyltransferases (DNMT1-3) and ten-eleven translocation dioxygenases (TET1-3). Evidence has shown that methylation markers are altered in different CNS regions related to nociception, namely the dorsal root ganglia, the spinal cord, and different brain areas. Decreased global methylation was found in the DRG, the prefrontal cortex, and the amygdala, which was associated with decreased DNMT1/3a expression. In contrast, increased methylation levels and mRNA levels of TET1 and TET3 were linked to augmented pain hypersensitivity and allodynia in inflammatory and neuropathic pain models. Since epigenetic mechanisms may be responsible for the regulation and coordination of various transcriptional modifications described in chronic pain states, with this study, we aimed to evaluate the functional role of TET1-3 and DNMT1/3a genes in neuropathic pain in several brain areas. In a spared nerve injury rat model of neuropathic pain, 21 days after surgery, we found increased TET1 expression in the medial prefrontal cortex and decreased expression in the caudate-putamen and the amygdala; TET2 was upregulated in the medial thalamus; TET3 mRNA levels were reduced in the medial prefrontal cortex and the caudate-putamen; and DNMT1 was downregulated in the caudate-putamen and the medial thalamus. No statistically significant changes in expression were observed with DNMT3a. Our results suggest a complex functional role for these genes in different brain areas in the context of neuropathic pain. The notion of DNA methylation and hydroxymethylation being cell-type specific and not tissue specific, as well as the possibility of chronologically differential gene expression after the establishment of neuropathic or inflammatory pain models, ought to be addressed in future studies.

Impaired muscarinic modulation of the rat prelimbic cortex in neuropathic pain is sexually dimorphic and associated with cold allodynia.

Cholinergic modulation of the brain cortex is critical for cognitive processes, and altered cholinergic modulation of the prefrontal cortex is emerging as an important mechanism of neuropathic pain. Sex differences in pain prevalence and perception are well known, yet the precise nature of the mechanisms responsible for sexual dimorphism in chronic neuropathic pain are poorly understood. Here we investigated potential sex differences in cholinergic modulation of layer five commissural pyramidal neurons of the rat prelimbic cortex in control conditions and in the SNI model of neuropathic pain. We discovered that cholinergic modulation is stronger in cells from male compared with female rats, and that in neuropathic pain rats, cholinergic excitation of pyramidal neurons was more severely impaired in males than in females. Finally, we found that selective pharmacological blockade of the muscarinic M1 subunit in the prefrontal cortex induces cold sensitivity (but not mechanical allodynia) in naïve animals of both sexes.

Betulinic acid analogs inhibit N- and T-type voltage-gated calcium channels to attenuate nerve-injury associated neuropathic and formalin models of pain.

Over the past three decades, there has been a significant growth in the use of natural products, with approximately 80% of individuals using them for some aspect of primary healthcare. Our laboratories have identified and studied natural compounds with analgesic effects from dry land plants or their associated fungus during the past ten years. Here, we isolated and characterized thirteen betulin analogs and fifteen betulinic acid analogs for their capacity to prevent calcium influx brought on by depolarization in sensory neurons. The in vitro inhibition of voltage-gated calcium channels by the top drugs was then assessed using whole cell patch clamp electrophysiology. In vivo experiments, conducted at two sites, evaluated the best compound in acute and tonic, neuropathic, inflammatory, post-operative and visceral models of pain. We found that the betulinic acid analog 8 inhibited calcium influx in rat dorsal root ganglion neurons by inhibiting N- (CaV2.2) and T- (CaV3) type voltage-gated calcium channels. Moreover, intrathecal delivery of analog 8 had analgesic activity in both spared nerve injury model of neuropathic pain and acute and tonic pain induced by formalin. The results presented herein highlight the potential antinociceptive properties of betulinic acid analog 8 and set the stage for the development of novel non-opioid pain therapeutics based on the triterpenoid scaffold of betulinic acid.

Linalyl Acetate Ameliorates Mechanical Hyperalgesia Through Suppressing Inflammation by TSLP/IL-33 Signaling.

Neuropathic pain is a debilitating chronic disorder, significantly causing personal and social burdens, in which activated neuroinflammation is one major contributor. Thymic stromal lymphopoietin (TSLP) and interleukin (IL)-33 is important for chronic inflammation. Linalyl acetate (LA) is main component of lavender oil with an anti-inflammatory property through TSLP signaling. The aim of the study is to investigate how LA regulates mechanical hyperalgesia after sciatic nerve injury (SNI). Adult Sprague-Dawley male rats were separated into 3 groups: control group, SNI group and SNI with LA group. LA was administrated intraperitoneally one day before SNI. Pain behavior test was evaluated through calibration forceps testing. Ipsilateral sciatic nerves (SNs), dorsal root ganglions (DRGs) and spinal cord were collected for immunofluorescence staining and Western blotting analyses. SNI rats were more sensitive to hyperalgesia response to mechanical stimulus since operation, which was accompanied by spinal cord glial cells reactions and DRG neuro-glial interaction. LA could relieve the pain sensation, proinflammatory cytokines and decrease the expression of TSLP/TSLPR complex. Also, LA could reduce inflammation through reducing IL-33 signaling. This study is the first to indicate that LA can modulate pain through TSLP/TSLPR and IL-33 signaling after nerve injury.

Targeting 5-HT2A receptors and Kv7 channels in PFC to attenuate chronic neuropathic pain in rats using a spared nerve injury model.

Chronic pain remains a disabling disease with limited therapeutic options. Pyramidal neurons in the prefrontal cortex (PFC) express excitatory Gq-coupled 5-HT2A receptors (5-HT2AR) and their effector system, the inhibitory Kv7 ion channel. While recent publications show these cells innervate brainstem regions important for regulating pain, the cellular mechanisms underlying the transition to chronic pain are not well understood. The present study examined whether local blockade of 5-HT2AR or enhanced Kv7 ion channel activity in the PFC would attenuate mechanical allodynia associated with spared nerve injury (SNI) in rats. Following SNI, we show that inhibition of PFC 5-HT2ARs with M100907 or opening of PFC Kv7 channels with retigabine reduced mechanical allodynia. Parallel proteomic and RNAScope experiments evaluated 5-HT2AR/Kv7 channel protein and mRNA. Our results support the role of 5-HT2ARs and Kv7 channels in the PFC in the maintenance of chronic pain.