The Complexity of Neuropathic Pain and Central Sensitization: Exploring Mechanisms and Therapeutic Prospects.

Neuropathic pain is a common pain syndrome, which seriously affects the quality of life of patients. The mechanism of neuropathic pain is complex. Peripheral tissue injury can trigger peripheral sensitization; however, what really plays a key role is the sensitization of the central nervous system. Central sensitization is a key factor in the perception of chronic pain. Central sensitization refers to the increased sensitivity of the central nervous system to pain treatment, which is related to the change of the functional connection mode of the neural network. The current study aims to reveal the basic molecular mechanisms of central sensitization, including the involvement of P2 purine X4 receptor and brain-derived neurotrophic factor. In terms of treatment, although there are drugs and physical therapy, the accuracy of targeting is limited and the efficacy needs to be further improved. Future therapeutic strategies may involve the development of new drugs designed to specifically inhibit the central sensitization process. This article focuses on the effector molecules involved in central sensitization, aiming to elucidate the pathogenesis of neuropathic pain and provide a basis for the development of more effective treatment models.

Simultaneous enhancement of the bandwidth and responsivity in high-speed avalanche photodiodes with an optimized flip-chip bonding package.

The enhancement in responsivity of photodiodes (PDs) or avalanche photodiodes (APDs) with the traditional flip-chip bonding package usually comes at the expense of degradation in the optical-to-electrical (O-E) bandwidth due to the increase of parasitic capacitance. In this work, we demonstrate backside-illuminated In0.52Al0.48As based APDs with novel flip-chip bonding packaging designed to relax this fundamental trade-off. The inductance induced peak in the measured O-E frequency response of these well-designed and well-packaged APDs, which can be observed around its 3-dB bandwidth (∼30 GHz), effectively widens the bandwidth and becomes more pronounced when the active diameter of the APD is aggressively downscaled to as small as 3 µm. With a typical active window diameter of 14 µm, large enough for alignment tolerance and low optical coupling loss, the packaged APD exhibits a moderate damping O-E frequency response with a bandwidth (36 vs. 31 GHz) and responsivity (3.4 vs. 2.3 A/W) superior to those of top-illuminated reference sample under 0.9 Vbr operation, to attain a high millimeter wave output power (0 dBm at 40 GHz) and output current (12.5 mA at +8.8 dBm optical power). The excellent static and dynamic performance of this design open up new possibilities to further improve the sensitivity at the receiver-end of the next-generation of passive optical network (PON) and coherent communication systems.

Biocatalytic Synthesis of Metaxalone and Its Analogues.

A biocatalytic approach for the synthesis of metaxalone and its analogues was developed based on the reaction of epoxides and cyanate catalyzed by halohydrin dehalogenase. Gram-scale synthesis of chiral and racemic metaxalone was achieved with 44% (98% ee) and 81% yields, respectively, by protein engineering of the halohydrin dehalogenase HHDHamb from Acidimicrobiia bacterium. Additionally, various metaxalone analogues were synthesized at 28-40% yields (90-99% ee) for chiral forms and 77-92% yields for racemic forms.

Enantiocomplementary synthesis of ß-adrenergic blocker precursors via biocatalytic nitration of phenyl glycidyl ethers.

Enantiopure ß-nitroalcohols, as an important class of nitro-containing compounds, are essential building blocks in pharmaceutical and organic chemistry, particularly for the synthesis of ß-adrenergic blockers. In this study, we present the successful protein engineering of halohydrin dehalogenase HHDHamb for the enantioselective bio-nitration of various phenyl glycidyl ethers to the corresponding chiral ß-nitroalcohols, using the inexpensive, commercially available, and safer nitrite as a nitrating agent. The chiral (R)- and (S)-1-nitro-3-phenoxypropan-2-ols were synthesized by the several enantiocomplementary HHDHamb variants through the whole-cell biotransformation, which showed good catalytic efficiency (up to 43% isolated yields) and high optical purity (up to >99% ee). In addition, we also demonstrated that the bio-nitration method was able to tolerate the substrate at a high concentration of 1000 mM (150 g/L). Furthermore, representative synthesis of two optically active enantiomers of the ß-adrenergic blocker metoprolol was successfully achieved by utilizing the corresponding chiral ß-nitroalcohols as precursors.

Bibliometric and visual analysis of microglia-related neuropathic pain from 2000 to 2021.

Background: Microglia has gradually gained researchers' attention in the past few decades and has shown its promising prospect in treating neuropathic pain. Our study was performed to comprehensively evaluate microglia-related neuropathic pain via a bibliometric approach. Methods: We retrospectively reviewed publications focusing on microglia-related neuropathic pain from 2000 to 2021 in WoSCC. VOS viewer software and CiteSpace software were used for statistical analyses. Results: A total of 2,609 articles were finally included. A steady increase in the number of relevant publications was observed in the past two decades. China is the most productive country, while the United States shares the most-cited and highest H-index country. The University of London, Kyushu University, and the University of California are the top 3 institutions with the highest number of publications. Molecular pain and Pain are the most productive and co-cited journals, respectively. Inoue K (Kyushu University) is the most-contributed researcher and Ji RR (Duke University) ranks 1st in both average citations per article and H-index. Keywords analyses revealed that pro-inflammatory cytokines shared the highest burst strength. Sex differences, neuroinflammation, and oxidative stress are the emerging keywords in recent years. Conclusion: In the field of microglia-related neuropathic pain, China is the largest producer and the United States is the most influential country. The signaling communication between microglia and neurons has continued to be vital in this field. Sexual dimorphism, neuroinflammation, and stem-cell therapies might be emerging trends that should be closely monitored.

Intrathecal administration of botulinum toxin type a antagonizes neuropathic pain by countering increased vesicular nucleotide transporter expression in the spinal cord of chronic constriction injury of the sciatic nerve rats.

Botulinum toxin type A (BoNT/A) induces direct analgesic effects in neuropathic pain by inhibiting the release of substance P, calcitonin gene-related peptide (CGRP) and glutamate. Vesicular nucleotide transporter (VNUT) was responsible for the storage and release of ATP in vivo, and one of the mechanisms underlying neuropathic pain is VNUT-dependent release of extracellular ATP from dorsal horn neurons. However, the analgesic effect of BoNT/A by affecting the expression of VNUT remained largely unknown. Thus, in this study, we aimed to elucidate the antinociceptive potency and analgesic mechanism of BoNT/A in chronic constriction injury of the sciatic nerve (CCI) induced neuropathic pain. Our results showed that a single intrathecal injection of 0.1 U BoNT/A seven days after CCI surgery produced significant analgesic activity and decreased the expression of VNUT in the spinal cord of CCI rats. Similarly, BoNT/A inhibited the CCI-induced increase in ATP content in the rat spinal cord. Overexpression of VNUT in the spinal cord of CCI-induced rats markedly reversed the antinociceptive effect of BoNT/A. Furthermore, 33 U/mL BoNT/A dramatically reduced the expression of VNUT in pheochromocytoma (PC12) cells but overexpressing SNAP-25 increased VNUT expression in PC12 cells. Our current study is the first to demonstrate that BoNT/A is involved in neuropathic pain by regulating the expression of VNUT in the spinal cord in rats.

Identification of Scoparone from Chinese Olive Fruit as a Modulator of Macrophage Polarization.

Chinese olive (Canarium album L.) has been highlighted for its remarkable health benefits. We previously showed that the ethyl acetate fraction of Chinese olive (COE) is an effective anti-inflammatory agent. In this study, we used a luciferase-based RAW 264.7 cell platform to detect the transcriptional activity of NF-κB, a key mediator of inflammation, and the promoter activity of its downstream target, COX-2. Through functional-oriented screening using these platforms, we further divided COE into several subfractions. Subsequently, we used silica gel column chromatography for purification, and the active compounds were separated and isolated by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC). The structure of the resulting compound with high anti-inflammatory activity was then identified as scoparone. Our results showed that scoparone not only inhibited lipopolysaccharide (LPS)-induced secretion of nitric oxide and suppressed M1 macrophage markers (iNOS, Il-6, Ccl2, and Tnf-α) but also markedly decreased the production of pro-inflammatory cytokines (IL-6, CCL2, and TNF-α). Treatment with scoparone significantly reduced the protein level of TNF-α in LPS-treated bone-marrow-derived macrophages (BMDMs). In addition, scoparone promoted macrophages toward an M2 anti-inflammatory phenotype, as determined by the significantly increased gene expression of M2 macrophage markers (Arg1, Ym1, Mrc1, Il-10, and Cd206) and the protein level of Arg1. This study indicates that COE fruit has high therapeutic potential for various inflammatory diseases as a result of switching the macrophage phenotype from pro-inflammatory M1 to anti-inflammatory M2.

The safety of radium-223 combined with new-generation hormonal agents in bone metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis.

Patients with bone metastatic castration-resistant prostate cancer (mCRPC) might benefit from radium-223 (223Ra) combined with new-generation hormonal agents (NHAs) in terms of survival and quality of life (QoL). However, the safety of combination therapies remains unclear. Therefore, we aimed to perform a network meta-analysis by reviewing the literature about the combination of 223Ra with abiraterone acetate plus prednisone (AAP) or enzalutamide and to evaluate the safety of combination therapy in bone mCRPC patients. Ultimately, ten studies (2835 patients) were selected, including four randomized controlled trials (RCTs), five retrospective cohort studies, and one single-arm study. Overall, there was no difference in the incidence of fracture between the 223Ra+NHA combination group and the 223Ra monotherapy group (odds ratio [OR]: 1.46, 95% confidence interval [CI]: 0.91-2.34, P = 0.66), but the incidences in both the 223Ra+NHA combination group (OR: 3.22, 95% CI: 2.24-4.63, P < 0.01) and the 223Ra monotherapy group (OR: 2.24, 95% CI: 1.23-4.08, P < 0.01) were higher than that in the NHA monotherapy group. However, in the meta-analysis involving only RCTs, there was no difference between the 223Ra monotherapy group and the NHA monotherapy group (OR: 1.14, 95% CI: 0.22-5.95, P = 0.88), while the difference between the 223Ra+NHA combination group and the NHA monotherapy group remained significant (OR: 3.22, 95% CI: 2.24-4.63, P < 0.01). Symptomatic skeletal events (SSEs), SSE-free survival (SSE-FS), all grades of common adverse events (AEs), and ≥grade 3 AEs among all groups did not show any significant difference. Our results indicate that the combination of 223Ra with NHAs was well tolerated in bone mCRPC patients compared to 223Ra monotherapy, even though the incidence of fracture was higher in patients who received 223Ra than that among those who received NHA monotherapy. More evidence is needed to explore the safety and efficiency of 223Ra combination therapies.

Cooperative Tertiary Amine/Palladium-Catalyzed Sequential [4 + 3] Cyclization/[1,3]-Rearrangement for Stereoselective Synthesis of Spiro [Methylenecyclopentane-1,3'-oxindolines].

A cooperative tertiary amine/palladium-catalyzed sequential reaction process, proceeding via a [4 + 3] cyclization of isatin-derived Morita-Baylis-Hillman Expansion (MBH) carbonates and tert-butyl 2-(hydroxymethyl)allyl carbonates followed by a [1,3]-rearrangement, has been found and developed. A range of structurally diverse spiro[methylene cyclopentane-1,3'-oxindolines] bearing two adjacent ß,γ-acyl quaternary carbon stereocenters, which are difficult to obtain by conventional strategies, were obtained in good yields. Further synthetic utility of this protocol is highlighted by its excellent regio- and stereocontrol as well as the large-scale synthesis and diverse functional transformations of the synthetic compounds. Moreover, the control experiments probably established the plausible mechanism for this sequential [4 + 3] cyclization/[1,3]-rearrangement process.

Discovery of a novel phosphotransferase from Bacillus subtilis that phosphorylates a broad spectrum of flavonoids.

Flavonoids are associated with health benefits, but most of them have poor oral bioavailability due to their extremely low aqueous solubility. Flavonoid O-phosphorylation suggests a potent modification to solve the problems. Here, we isolated, identified and characterized an unprecedented phosphotransferase, flavonoid phosphate synthetase (BsFPS), from B. subtilis. The enzyme catalyzes the ATP-dependent phosphorylation of flavonoid to generate flavonoid monophosphates, AMP and orthophosphate. BsFPS is a promiscuous phosphotransferase that efficiently catalyzes structurally-diverse flavonoids, including isoflavones, flavones, flavonols, flavanones and flavonolignans. Based on MS and NMR analysis, the phosphorylation mainly occurs on the hydroxyl group at C-7 of A-ring or C-4' of B-ring in flavonoid skeleton. Notably, BsFPS is regioselective for the ortho-3',4'-dihydroxy moiety of catechol-containing structures, such as luteolin and quercetin, to produce phosphate conjugates at C-4' or C-3' of B-ring. Our findings highlight the potential for developing biosynthetic platform to obtain new phosphorylated flavonoids for pharmaceutical and nutraceutical applications.

The measurement of critical quality attributes of Tongren niuhuang qingxin pills based on MIF-HEMT biosensor technology / 药学学报

There is still a serious challenge of the measurement of critical quality attributes (CQAs) related to clinical efficacy for Chinese materia medica manufacturing. To overcome this challenge, an integrated strategy of biosensor and ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was proposed using Tongren niuhuang qingxin pills as a trial. Firstly, an original biosensor was created using a semiconductor chip material high electron mobility transistor (HEMT) as the transducer and the macrophage migration inhibitory factor (MIF) as the identification element. By this MIF-HEMT biosensor, the efficacy on stoke of different components from Tongren niuhuang qingxin pills was measured. It was clear that all three components of Tongren niuhuang qingxin pills had strong therapeutic effects on stroke, especially the section A, the KD of which reached to 8.722×10-10 g·mL-1. Furthermore, MIF-HEMT biosensor integrated UPLC-MS/MS was introduced to identify the efficacy CQAs of different components of Tongren niuhuang qingxin pills. As a result, 19 potential CQAs, such as albiforin, paeoniflorin, and prim-O-glucosylcimifugin, were measured as the efficacy CQAs of Tongren niuhuang qingxin pills on stroke treatment by MIF. These results provided vital measurement techniques and methodological guidance for the CQAs study of Tongren niuhuang qingxin pills intervention in MIF-induced stroke treatment. This also provided an essential guideline for the efficient utilization and quality control measurement of high-quality classical recipes.

Identification of taste critical quality attribute and formulation optimization of Xiaoer Qingrening Granules based on electronic tongue and human senses / 药学学报

This study primarily concentrated on scientific problems of poor taste caused by unclear critical quality attributes of oral preparations manufactured by Chinese materia medica, successfully established an identification method for taste critical quality attribute and a taste improvement method combining electronic tongue with human senses, and determined the optimal taste formula, to improve patients' oral medication compliance. The study received ethical approval from the Review Committee of the Beijing University of Chinese Medicine. The results showed that the proportion of bitterness of Xiaoer Qingrening Granule was 61.8%, and its bitterness grade was 3.70, it was determined that bitterness is the critical quality attribute that caused the poor taste of Xiaoer Qingrening Granule. Additionally, the optimal taste formula per milliliter of Xiaoer Qingrening sugar-free intermediate was determined with allowable daily intake, solubility, and sweetness as the limiting conditions, which was 40 mg hydroxypropyl β-cyclodextrin, 180 mg trehalose, and 1.5 mg acesulfame potassium. Compared with the Xiaoer Qingrening Granule, the sensory evaluation score of the optimal taste formula was increased by 37.5 points. In conclusion, this study achieved the taste improvement of Xiaoer Qingrening Granule and formed a set of taste improvement strategies including the identification of taste critical quality attribute, the selection of the type and dosage of corrigent, and the optimization of taste formula, which provided a thought reference for the taste improvement of other oral preparations and a new perspective for quality control of intelligent manufacturing of traditional Chinese medicines.

Small-leaf Kuding Extract Decreases Hyperglycemia in Mice by Upregulating Nrf2 / INS Expression at the Protein Level / 中国生物化学与分子生物学报

In recent years, the prevalence of hyperglycemia has been increasing, and patients’ bodies have been seriously damaged. Compared with conventional Western drugs, natural products have fewer adverse reactions and delay the complications of hyperglycemia. As a valuable natural product resource, Small-leaf Kuding (SLK) contains various beneficial components for the human body. The aim of this study was to study the regulation effect of SLK extract at different doses on blood glucose metabolism in hyperglycemic mice. Lipopolysaccharide and streptozotocin were used to induce hyperglycemia in mice. Extract of SLK were administered intragastrically at low, medium, and high doses (5 g·kg

Recent research on chimeric antigen receptor T cells in children with refractory/relapsed acute lymphoblastic leukemia / 中国当代儿科杂志

At present, the treatment of refractory/relapsed acute lymphoblastic leukemia is still in a difficult situation, and even if the intensity of chemotherapy is increased or it is combined with hematopoietic stem cell transplantation, some children may have a poor prognosis and a short survival time. Chimeric antigen receptor T-cell (CAR-T) immunotherapy uses genetically engineered T cells and does not rely on the human leukocyte antigen pathway to recognize tumor-specific antigens, and then CAR-T cells bind to target antigen cells to trigger immune response, thereby exerting a sustained anti-leukemia effect. As the most rapidly developed tumor immunotherapy, major breakthroughs have been made for CAR-T cells in the treatment of various hematological tumors, but there still lacks a comprehensive system for the research, development, and production of CAR-T cells and standardized diagnosis and treatment protocols in China. This article reviews the recent research on CAR-T cells in children with refractory/relapsed acute lymphoblastic leukemia.

Risk Factors of Clopidogrel Resistance in the Elderly Patients with Atherosclerotic Cardiovascular Disease / 中国医学科学院学报

Objective To explore the risk factors of clopidogrel resistance (CR) in the elderly patients with atherosclerotic cardiovascular disease and to provide evidence for the antiplatelet therapy. Methods A total of 223 elderly patients (≥80 years old) with atherosclerotic cardiovascular disease treated in the Department of Geriatrics in the Peking University People's Hospital from January 18,2013 to November 30,2019 and meeting the inclusion criteria were enrolled in this study.The clinical data and laboratory test results were collected,including clinical disease,drug use,physical examination,complete blood cell analysis,biochemical indicators,and thromboelastogram (TEG).The rate of platelet inhibition induced by adenosine diphosphate was calculated according to the TEG.We assigned the patients into a CR group (n=84) and a control group (n=139) to analyze the incidence and influence factors of CR in the elderly patients with atherosclerotic cardiovascular disease. Results The incidence of CR was 37.7% in the elderly patients with atherosclerotic cardiovascular disease.The CR group had lower hemoglobin (t=3.533,P=0.001) and higher hypertension prevalence rate (χ2=6.581,P=0.006),proportion of multiple drugs (χ2=3.332,P=0.048),body mass index (BMI) (t=-2.181,P=0.030),total cholesterol (t=-2.264,P=0.025),triglycerides (Z=-2.937,P=0.003),low-density lipoprotein cholesterol (LDL-C) (t=-2.347,P=0.020),and proportion of women (χ2=5.562,P=0.014) than the control group.The results of multivariate Logistic regression showed that hemoglobin (OR=0.962,P<0.001),BMI (OR=1.154,P=0.003),and LDL-C (OR=1.688,P=0.018) were the factors influencing CR in the elderly patients with atherosclerotic cardiovascular disease. Conclusion Hemoglobin,BMI,and LDL-C may be independent factors associated with the occurrence of CR in the elderly patients with atherosclerotic cardiovascular disease.

Palladium-Catalyzed Domino Reaction for the Assembly of Norbornane-Containing Chromones with Dimethyl Squarate as the Solid C1 Source.

Reported herein is a novel palladium-catalyzed [2 + 2 + 1] domino annulation of 3-iodochromones, bridged olefins, and dimethyl squarate allowing the construction of chromone-containing polycyclic compounds in good to high yields. Importantly, dimethyl squarate is first employed as the solid C1 source in organic synthesis. Gram-scale experiments, late-stage modification of natural products, as well as transformations of products show potential for further synthetic elaborations.

First result from the Jinping Underground Nuclear Astrophysics experiment JUNA: precise measurement of the 92 keV 25Mg(p, γ)26Al resonance.

The 25Mg(p, γ)26Al reaction plays an important role in the study of cosmic 1.809 MeV γ-ray as a signature of ongoing nucleosynthesis in the Galaxy. At astrophysical temperature around 0.1 GK, the 25Mg(p, γ)26Al reaction rates are dominated by the 92 keV resonance capture process. We report a precise measurement of the 92 keV 25Mg(p, γ)26Al resonance in the day-one experiment at Jinping Underground Nuclear Astrophysics experiment (JUNA) facility in the China Jinping Underground Laboratory (CJPL). The resonance strength and ground state feeding factor are determined to be 3.8±0.3 ×10-10 eV and 0.66±0.04, respectively. The results are in agreement with those reported in the previous direct underground measurement within uncertainty, but with significantly reduced uncertainties. Consequently, we recommend new 25Mg(p, γ)26Al reaction rates which are by a factor of 2.4 larger than those adopted in REACLIB database at the temperature around 0.1 GK. The new results indicate higher production rates of 26gAl and the cosmic 1.809 MeV γ-ray. The implication of the new rates for the understanding of other astrophysical situations is also discussed.

Biocatalytic Thionation of Epoxides for Enantioselective Synthesis of Thiiranes.

Expanding the enzymatic toolbox for the green synthesis of valuable molecules is still of high interest in synthetic chemistry and the pharmaceutical industry. Chiral thiiranes are valuable sulfur-containing heterocyclic compounds, but relevant methods for their enantioselective synthesis are limited. Herein, we report a biocatalytic thionation strategy for the enantioselective synthesis of thiiranes, which was developed based on the halohydrin dehalogenase (HHDH)-catalyzed enantioselective ring-opening reaction of epoxides with thiocyanate and a subsequent nonenzymatic rearrangement process. A novel HHDH was identified and engineered for enantioselective biocatalytic thionation of various aryl- and alkyl-substituted epoxides on a preparative scale, affording the corresponding thiiranes in up to 43 % isolated yield and 98 % ee. Large-scale synthesis and useful transformations of chiral thiiranes were also performed to demonstrate the utility and scalability of the biocatalytic thionation strategy.

Neuropeptide apelin presented in the dopaminergic neurons modulates the neuronal excitability in the substantia nigra pars compacta.

The dopaminergic neurons in the substantia nigra pars compacta are characterized by autonomous pacemaking activity. The spontaneous firing activity of nigral dopaminergic neurons plays an important role in physiological function and is essential for their survival. Importantly, the spontaneous firing activity may also be involved in the preferential vulnerability of the nigral dopaminergic neurons in Parkinson's disease (PD). The neuropeptide apelin was reported to exert neuroprotective effects in neurodegenerative diseases, including PD. And it was noticed that apelin modulates neuronal activity in some brain regions. The present study investigated the electrophysiological and behavioral effects of apelin in the substantia nigra. Double-labeling immunofluorescence showed that apelin was present in nigral dopaminergic neurons and that these neurons expressed apelin receptor APJ. Further single unit in vivo electrophysiological recordings revealed that endogenous apelin tonically increased the firing rate of nigral dopaminergic neurons in both normal and parkinsonian animals. Exogenous apelin-13 exerted excitatory effects on the majority of nigral dopaminergic neurons, yet reduced excitability in a subset of neurons. In addition, nigral application of apelin-13 increased motor activity in normal rats and blocking endogenous apelin reduced motor activity. Considering the involvement of the spontaneous firing activity of nigral dopaminergic neurons in the development of PD and the possibility that apelin acts in an autocrine manner on apelin receptors expressed by nigral dopaminergic neurons, the modulation of the spontaneous firing activity of nigral dopaminergic neurons by apelin may serve as a neuroprotective factor in PD.