Chronic pain is a complex condition shaped by long-standing alterations in both physiological and psychological processes. Rather than representing a simple continuation of acute nociceptive signaling, chronic pain is increasingly understood as the outcome of progressive dysregulation within distributed neural systems that govern sensation, affect, motivation, and cognitive control. Neuroimaging and electrophysiological studies indicate that this state is accompanied by extensive plastic changes in deep brain structures and large-scale networks. Beyond well-described central sensitization processes, chronic pain is characterized by disrupted oscillatory rhythms and altered connectivity within large-scale brain networks, including thalamo-cortical circuits and prefrontal-limbic-reward networks. These findings support a conceptual shift from viewing chronic pain as a focal, lesion-driven phenomenon toward recognizing it as a disorder of distributed network pathology. Pharmacological treatments remain central to clinical practice, yet their long-term efficacy is often limited and frequently accompanied by substantial side effects. The ongoing concerns about opioid-related risks and the inadequate therapeutic response in a subset of patients highlight the need for safe, non-pharmacological approaches that can address not only pain but also comorbid disturbances in mood, sleep, and social functioning. Neuromodulation provides a promising path toward mechanism-based and non-pharmacological management of chronic pain by employing physical or chemical stimulation to alter the excitability and synchrony of specific neural populations within central, peripheral, and autonomic systems. While invasive deep brain stimulation demonstrates that targeting deep brain structures can be effective, its clinical application is restricted by surgical risks and cost, highlighting the importance of non-invasive techniques capable of reaching deep targets. Current non-invasive approaches, such as transcranial electric stimulation, are constrained by limited penetration depth and insufficient spatial precision. These limitations hinder reliable engagement of deep regions implicated in pain, including the thalamus and nucleus accumbens, and tend to produce broad, non-specific modulation of cross-network oscillatory activity. Temporal interference (TI) stimulation has emerged as a means of overcoming these obstacles. By delivering interacting high-frequency currents that generate a low-frequency envelope within the head, TI enables focal stimulation of deep targets while minimizing superficial current delivery. Recent multiscale modeling and animal studies indicate that TI exploits the nonlinear rectification properties of neuronal membranes in response to high-frequency carriers, as well as their phase-locked responses to low-frequency envelopes, to generate “peak-focused” electric fields in deep regions under relatively low superficial current loads. Moreover, TI appears to exhibit potential advantages in terms of cell-type selectivity and rhythm-specific engagement, including differential responses across neuronal subtypes and distinct coupling to θ-, β-, and γ-band oscillations. These features suggest a promising avenue for correcting abnormal rhythms and network dynamics that contribute to chronic pain. This review summarizes current knowledge of the neural mechanisms underlying chronic pain and recent advances in TI research. It examines functional disturbances across key pain-related regions and networks, outlines the principles and technical characteristics of TI, and discusses potential deep-brain targets and stimulation strategies relevant to chronic pain. Evidence to date indicates that TI, with its non-invasiveness, tolerability, and capacity for precise deep brain modulation, holds great promise for the management of treatment-resistant chronic pain and may evolve into a new generation of precise and efficient non-pharmacological analgesic strategies.

Chronic pain is a complex condition shaped by long-standing alterations in both physiological and psychological processes. Rather than representing a simple continuation of acute nociceptive signaling, chronic pain is increasingly understood as the outcome of progressive dysregulation within distributed neural systems that govern sensation, affect, motivation, and cognitive control. Neuroimaging and electrophysiological studies indicate that this state is accompanied by extensive plastic changes in deep brain structures and large-scale networks. Beyond well-described central sensitization processes, chronic pain is characterized by disrupted oscillatory rhythms and altered connectivity within large-scale brain networks, including thalamo-cortical circuits and prefrontal-limbic-reward networks. These findings support a conceptual shift from viewing chronic pain as a focal, lesion-driven phenomenon toward recognizing it as a disorder of distributed network pathology. Pharmacological treatments remain central to clinical practice, yet their long-term efficacy is often limited and frequently accompanied by substantial side effects. The ongoing concerns about opioid-related risks and the inadequate therapeutic response in a subset of patients highlight the need for safe, non-pharmacological approaches that can address not only pain but also comorbid disturbances in mood, sleep, and social functioning. Neuromodulation provides a promising path toward mechanism-based and non-pharmacological management of chronic pain by employing physical or chemical stimulation to alter the excitability and synchrony of specific neural populations within central, peripheral, and autonomic systems. While invasive deep brain stimulation demonstrates that targeting deep brain structures can be effective, its clinical application is restricted by surgical risks and cost, highlighting the importance of non-invasive techniques capable of reaching deep targets. Current non-invasive approaches, such as transcranial electric stimulation, are constrained by limited penetration depth and insufficient spatial precision. These limitations hinder reliable engagement of deep regions implicated in pain, including the thalamus and nucleus accumbens, and tend to produce broad, non-specific modulation of cross-network oscillatory activity. Temporal interference (TI) stimulation has emerged as a means of overcoming these obstacles. By delivering interacting high-frequency currents that generate a low-frequency envelope within the head, TI enables focal stimulation of deep targets while minimizing superficial current delivery. Recent multiscale modeling and animal studies indicate that TI exploits the nonlinear rectification properties of neuronal membranes in response to high-frequency carriers, as well as their phase-locked responses to low-frequency envelopes, to generate “peak-focused” electric fields in deep regions under relatively low superficial current loads. Moreover, TI appears to exhibit potential advantages in terms of cell-type selectivity and rhythm-specific engagement, including differential responses across neuronal subtypes and distinct coupling to θ-, β-, and γ-band oscillations. These features suggest a promising avenue for correcting abnormal rhythms and network dynamics that contribute to chronic pain. This review summarizes current knowledge of the neural mechanisms underlying chronic pain and recent advances in TI research. It examines functional disturbances across key pain-related regions and networks, outlines the principles and technical characteristics of TI, and discusses potential deep-brain targets and stimulation strategies relevant to chronic pain. Evidence to date indicates that TI, with its non-invasiveness, tolerability, and capacity for precise deep brain modulation, holds great promise for the management of treatment-resistant chronic pain and may evolve into a new generation of precise and efficient non-pharmacological analgesic strategies.

Objective To systematically reconstruct the evolution of schistosomiasis prevalence in China from 1950 to 2024, so as to fill the gap of national data on schistosomiasis prevalence in China before 1986. Methods Schistosomiasis control data were collected from schistosomiasis-endemic areas of China before 1986, which mainly included statistical data on schistosomiasis, compilations of control records, annual work reports, and academic papers. Data pertaining to the prevalence of schistosomiasis from each province (autonomous region, municipality) were collected and summarized annually, and integrated into national annual work reports for schistosomiasis control in China from 1986 to 2024 to build a national schistosomiasis epidemic database covering schistosomiasis patients, cattle with schistosomiasis, and Oncomelania hupensis snails. The provincial-level epidemic data of schistosomiasis were summarized annually from 1986 to 2024 with pivot tables, and then the national epidemic data of schis tosomiasis were summarized. The temporal trends in key epidemic indicators of schistosomiasis were analyzed in China from 1950 to 2024. Results A complete time-series dataset of schistosomiasis was established in China from 1950 to 2024 through systematic reconstruction of multi-source historical documents and materials. A total of 1.97 million newly detected schistosomiasis cases were recorded in China from 1950 to 2024, and the actual number of schistosomiasis patients was all more than 1 million each year from 1955 to 1978. There were only more than 20 000 advanced schistosomiasis patients in China by the end of 2024, and the prevalence of Schistosoma japonicum human infections reduced from 34.6% in 1950 to below 1.0% after 1996. A total of 2.47 million cattle were tested positive for schistosomiasis, and the prevalence of S. japonicum infections reduced from 21.4% in bovines since 1950. The area of emerging O. hupensis snail habitats was concentrated during the period between 1956 and 1958, accounting for 49.8% of total areas, while the area of emerging O. hupensis snail habitats significantly decreased since 1992, indicating a stable distribution pattern of O. hupensis snails. Data validation results showed that the cumulative variation in areas of O. hupensis snail habitats was 1.6%, and the cumulative variation in the number of schistosomiasis cases was 1.4%. Join-point regression analysis revealed four turning points in the prevalence of S. japonicum infections in humans and seven turning points in the prevalence of S. japonicum infections in livestock across China from 1955 to 2024. Conclusions Through the joint efforts of the Communist Party of China and government leadership, interdepartmental collaboration, professional teams, scientific and technological innovation, and public participation, the schistosomiasis epidemic has been effectively controlled in China following active control for more than 70 years. This study builds, for the first time, a complete time-series dataset on schistosomiasis in China, which provides insights into assessment of the effectiveness of schistosomiasis control programmes and refinement of the experience from schistosomiasis control programmes in China.

In this study, we constructed a GLP-2R-HEK293 cell line and established a method for the determination of the in vitro biological activity of teduglutide based on HTRF, after optimizing experimental conditions and methodological verification. We also carried out relative potency detection of teduglutide pharmaceutical products using this method. The result showed that there was a quantitative-efficient relationship between the teduglutide activity and cAMP contents in GLP-2R-HEK293 cells, which conformed to four-parameter model. Method verification results of five concentrations of teduglutide (64%, 80%, 100%, 125% and 156%) met the requirements of the General Rules of Chinese Pharmacopoeia, 2020 edition, Volume IV (9401). We then analyzed the relative potency of three batches of teduglutide drug substances and three batches of drug products. The linearity, regression and parallelism of the obtained curves all fit the system suitability requirements. The relative potency of six batches of teduglutide was from 83% to 105%. In summary, the biological activity detection method established in this study was accurate, precise, simple and time-saving, which can be used for quality control of teduglutide pharmaceutical products.

Objective To analyze the structural and phylogenetic characteristics of the mitochondrial genome from Bulinus globosus, so as to provide a theoretical basis for classification and identification of species within the Bulinus genus, and to provide insights into understanding of Bulinus-schistosomes interactions and the mechanisms of parasite transmission. Methods B. globosus samples were collected from the Ruya River basin in Zimbabwe. Mitochondrial DNA was extracted from B. globosus samples and the corresponding libraries were constructed for high-throughput sequencing on the Illumina NovaSeq 6000 platform. After raw sequencing data were subjected to quality control using the fastp software, genome assembly was performed using the A5-miseq and SPAdes tools, and genome annotation was conducted using the MITOS online server. Circular maps and sequence plots of the mitochondrial genome were generated using the CGView and OGDRAW software, and the protein conservation motifs and structures were analyzed using the TBtools software. Base composition and codon usage bias were analyzed and visualized using the software MEGA X and the ggplot2 package in the R software. In addition, a phylogenetic tree was created in the software MEGA X after sequence alignment with the software MAFFT 7, and visualized using the software iTOL. Results The mitochondrial genome of B. globosus was a 13 730 bp double-stranded circular molecule, containing 2 ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and 13 protein-coding genes, with a marked AT preference. The mitochondrial genome composition of B. globosus was similar to that of other species within the Bulinus genus. Phylogenetic analysis revealed that the complete mitochondrial genome sequence of B. globosus was clustered with B. truncatus, B. nasutus, and B. ugandae into the same evolutionary clade, and gene superfamily analysis showed that the metabolism-related proteins of B. globosus were highly conserved, notably the cytochrome c oxidase family, which showed a significant consistency. Conclusions This is the first whole mitochondrial genome sequencing to decode the compositional features of the mitochondrial genome of B. globosus from Zimbabwe and its evolutionary relationship within the Bulinus genus, which provides important insights for further understanding of the phylogeny and mitochondrial genome characteristics of the Bulinus genus.

Objective To explore the role of the protein kinase R-like endoplasmic reticulum kinase(PERK)-mediated endoplasmic reticulum stress pathway in a model of lipopolysaccharide(LPS)-induced microglia inflammation.Methods To investigate its effects on endoplasmic reticulum(ER)stress,an inflammation model of microglia was established by stimulating with LPS at gradient concentrations for 24 hours and with 1 mg/L LPS for different durations.Cell viability was assessed by the CCK-8 assay;The mRNA and protein expression levels of related inflammatory factors were measured by Real-time PCR and ELISA kits.Cellular oxidative stress was evaluated by detecting reactive oxygen species(ROS),and Real-time PCR and Western blotting were used to examine the mRNA and protein expression levels of ER stress pathway markers associated with inflammation.Results 1.The effects of different concentrations of LPS on cell viability and morphology were not statistically significant after acting on BV-2 cells for 24 hours(P＞0.05);2.1 mg/L LPS incubated with BV-2 cells for different times and the cell viability decreased with the increase of time;3.Compared with the 0 hour group,the levels of pro-inflammatory cytokine interleukin(IL)-1β,tumor necrosis factor-α(TNF-α)mRNA and protein expression increased significantly(P＜0.05)in the LPS-stimulated 9 hours,12 hours,and 24 hours groups,and the inflammation model was successfully established;4.Compared with the 0 hour group,the protein and mRNA expression levels of the endoplasmic reticulum stress pathway-related indexes in the LPS-stimulated 9 hours,12 hours,and 24 hours groups increased significantly(P＜0.01),which showed the time-dependence;5.After adding the PERK inhibitor GSK2606414,the mRNA and protein expression levels of endoplasmic reticulum stress-related indicators in the PERK inhibitor group were significantly reduced compared with those in the LPS group(P＜0.05);6.The mRNA and protein expression levels of pro-inflammatory cytokines and the fluorescence intensity of ROS in the PERK inhibitor group were significantly reduced compared with those in the LPS group(P＜0.01).Conclusion Targeting PERK-mediated endoplasmic reticulum stress inhibits LPS-induced inflammatory responses in microglia.

AIM To study the chemical constituents from the sticks and leaves of Croton cascarilloides Raeusch.and their biological activities.METHODS The 95％ethanol extract from the sticks and leaves of C.cascarilloides was isolated and purified by MCI,silica gel,Sephadex LH-20 and semi-preparative HPLC,then the structures of obtained compounds were identified by physicochemical properties and spectral data.LPS-induced NO RAW264.7 cell model induced by LPS was used to evaluate its anti-inflammatory activity in vitro.GES-1 injury model induced by taurocholic acid was used to screen the gastric mucosal protection activity.RESULTS Fourteen compounds were isolated and identified as bullatantriol(1),(-)-boscialin(2),(+)-dehydrovomifoliol(3),3-(hydroxylacetyl)-indole(4),pinoresinol(5),3,7-dimethyl-octa-1,7-diene-3,6-ol(6),(+)-syringaresinol(7),curcasinlignan B(8),cleomiscosin C(9),cleomiscosinD(10),2,6-dimethyl-octa-1,7-dien-3,6-diol(11),vanillin(12),vanillic acid(13),methyl vanillate(14).Compound 4 had certain anti-inflammatory activity,with IC50 values of 73.62 μmol/L.The protective rates of 25 μmol/L compounds 1-4,6,9-12 and 14 on gastric mucosal epithelial cells were 30.07％,34.18％,23.91％,30.92％,17.51％,19.69％,31.76％,22.46％,30.56％and 14.49％,respectively.CONCLUSION Compounds 1-14 are isolated from this plant for the first time.Compound 4 shows anti-inflammatory activity,1-4,6,9-12 and 14 show different degrees of gastric mucosal epithelial cell protective activity.

Objective To establish a chromatography-tandem mass spectrometry method for detecting chlorfenapyr and its metabolite tralopyril in blood,and to investigate the toxicokinetics in rats.Methods Chlorfenapyr(8 mg/kg)was administered orally to rats,and blood samples were collected from rats'canthus vein at 5 min,15 min,30 min,1 h,3 h,6 h,12 h,24 h and 48 h after administration.The blood samples were extracted using 100 μL of 5%formic acid solution and 400 μL of acetonitrile.Chlorfena-pyr was qualitatively and quantitatively detected by triple quadrupole gas chromatography-tandem mass spectrometry(GC-MS/MS)and tralopyril was detected by triple quadrupole liquid chromatography-tandem mass spectrometry(LC-MS/MS).The DAS 3.0 software was used to fit the toxicokinetic equa-tions and calculate the toxicokinetic parameters.Results Chlorfenapyr was detectable from 5 min to 24 h with a peak time of 1 h.Tralopyril was detectable from 15 min to 48 h with a peak time of 3 h.The toxicokinetic process of chlorfenapyr in rat blood conformed to a first-order absorption one-compartment open model,with the toxicokinetic equation described as C=e-0.265t-e-0.175t.Tralopyril con-formed to the first-order absorption three-compartment model,and the toxicokinetic equation was C=47 361.069e-2.209t-35 404.962e-1.486t+11 956.363e-0.512t.In the equations,C stands for the concentration of the target substance in the blood,e is the natural constant(≈2.718 28),and t stands for time.Conclu-sion This study optimized the detection method for chlorfenapyr and its metabolite tralopyril in blood.The toxicokinetic equations and parameters of chlorfenapyr and tralopyril can provide a reference for the estimation of oral intake time of chlorfenapyr.

OBJECTIVES: To investigate the effect of monotropein on motor function recovery of mice with spinal cord injury (SCI) and explore the underlying mechanism. METHODS: Forty-five adult female C57BL/6 mice were randomized equally into sham operation group, SCI group, and SCI group with daily intraperitoneal monotropein injection. The mice in the former two groups received daily saline injections. Motor function of the mice was evaluated using BMS scores, slant plate test, and footprint analyses. Pathological changes and neuronal counts in the spinal cord were observed using HE, LFB, and Nissl staining. The biological functions of monotropein were explored using GO and KEGG enrichment analyses. NeuN/cleaved caspase-3 immunofluorescence assay and Western blotting were used to detect neuronal apoptosis in the spinal cord of the mice. In cultured HT22 cells, the effect of monotropein on TNF-α-induced cell apoptosis was evaluated using TUNEL staining and Western blotting. In monotropein-treated HT22 cells and SCI mice, the changes in the PI3K/AKT pathway were examined, and the effect of a PI3K/AKT pathway activator (IGF-1) on HT22 cell apoptosis and motor function recovery of SCI mice were observed. RESULTS: SCI mice with monotropein treatment showed significantly improved motor functions with reduced SCI areas and increased myelin retention and neuron counts in the spinal cord. Bioinformatics analysis suggested a role of PI3K/AKT signaling pathway in mediating the anti-apoptotic effects of monotropein. In SCI mice, monotropein obviously reduced apoptotic neurons, decreased expressions of cleaved caspase-3 and Bax and increased Bcl-2 expression in the spinal cord. In HT22 cells, monotropein significantly inhibited TNF-α-induced apoptosis and PI3K/AKT pathway activation. Treatment with IGF-1 obviously increased apoptosis of HT22 cells and exacerbated locomotor dysfunction in SCI mice. CONCLUSIONS Monotropein promotes motor function recovery in SCI mice by reducing neuronal apoptosis possibly by inhibiting the PI3K/AKT signaling pathway.
Animals ; Spinal Cord Injuries/metabolism* ; Apoptosis/drug effects* ; Signal Transduction/drug effects* ; Mice, Inbred C57BL ; Mice ; Proto-Oncogene Proteins c-akt/metabolism* ; Female ; Phosphatidylinositol 3-Kinases/metabolism* ; Neurons/pathology* ; Recovery of Function

Objective To investigate the effects of organophosphate flame retardant tri(2-chloroethyl)phosphate(TCPP)on reproductive function in male mice by the approach of non-targeted metabolomics.Methods A total of twelve 6-week-old SPF male CD-1 mice were randomly divided into control group and TCPP group,with 6 mice in each group.TCPP group was given TCPP(at the dose of 100 mg/kg/d)intragastrically,and control group was intragastrically adminis-trated with the same amount of corn oil(solvent control).After 6 weeks,the mice were killed,and the sperm were isolated from the epididymis.The sperm concentration and viability were analyzed.Testicular tissue sections were stained with he-matoxylin,and ki67 expression was detected by immunohistochemistry.Non-targeted metabolomics was used to detect the difference of metabolites in testicular tissue between the two groups,and to analyze the difference of metabolites and related pathway changes between the two groups.Results Compared with control group,the total sperm motility of mice in TCPP treatment group was significantly decreased(P＜0.05).HE staining showed irregular arrangement of spermatogenic tubule supporting cell layer in TCPP treatment group.The expression level of ki67 in testicular tissue of mice treated with TCPP was significantly decreased(P＜0.05).Non-targeted metabolomics detected 266 up-regulated metabolites with statistical difference.And 554 down-regulated metabolites with statistical difference,among which the largest difference multiples were organic acids and amino acid metabolites.The pathways with the highest concentration of differential metabolites in-cluded purine metabolism,nucleotide metabolism,amino acid metabolism,cofactor synthesis,etc.,which were mainly re-lated to basic cell life activities,pathophysiology and chemical carcinogenesis.Conclusion TCPP can significantly re-duce sperm motility and ki67 expression in mice at the dosage of 100 mg/kg/d,which might be related to its influence on key metabolic pathways such as purine,amino acid and pyruvate.