AimsThis study aimed to address the lack of comprehensive reviews on the comorbidity between depression and type 2 diabetes mellitus (T2DM) by investigating their complex connections and identifying emerging research trends.MethodsWe conducted an in-depth review combining macro bibliometric analysis and micro content interpretation of literature. Based on the bibliometric analysis of 3,986 papers in Web of Science Core Collection and 238 clinical trials in PubMed published between 2016 and 2025, the institutions, countries, authors and keywords were investigated, and the research maps were drawn by bibliometric software such as VOSviewer, Citespace and Bibliometrix. Meanwhile, micro interpretation entails in-depth content analysis of key articles to develop personal insights.ResultsThe analysis identified 3,986 relevant papers and 238 clinical trials, revealing a consistent overall growth in research volume. Key contributing entities and potential future research hotspots are mapped, such as the link between comorbidity and Parkinson’s disease and obesity. Also, our micro-interpretation identified the comorbidity mechanism through hypothalamic pituitary adrenal axis (HPA axis) and Brain derived neurotrophic factor (BDNF) and integrated treatment strategy of depression and T2DM.ConclusionThe results of the study outlined the evolving knowledge and research focus in this field. This study provides a comprehensive review of the comorbidity of depression and T2DM, emphasizing the mechanism and treatment of the comorbidity. The current research focus is on the HPA axis and BDNF, and the integrated treatment idea to solve depression and T2DM at the same time has the potential to change in chronic disease management and clinical practice.

Hengyu Chi,1,* Qunqi Hu,1,* Jingqi Liang,1,* Jingjing Zhang,1 Siying Qu,1 Hanzhi Wang,2 Yurong Kang,1 Zhouqi Liu,1 Yuran Chen,1 Yongliang Jiang,1 Xiaofen He,1 Jianqiao Fang,1 Yinhang Zhong31Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China; 2Department of Gynecology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, 310012, People’s Republic of China; 3Department of Traditional Chinese Pharmacy, Zhejiang Xiaoshan Hospital, Hangzhou, Zhejiang, 311200, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yinhang Zhong, Department of Traditional Chinese Pharmacy, Zhejiang Xiaoshan Hospital, Hangzhou, Zhejiang, 311200, People’s Republic of China, Email yinhzh@qq.com Jianqiao Fang, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China, Email fangjianqiao7532@163.comPurpose: Perimenopause represents a critical neuroendocrine transition stage in the lives of women, characterized by metabolic disorders and physiological vulnerability, which also commonly manifests as depression and cognitive impairment. This study explores associations between the triglyceride-glucose-frailty index (TyGFI) and depression/cognitive impairment in perimenopausal women.Methods: Data were obtained from the 2015 China Health and Retirement Longitudinal Study (CHARLS) and 2,596 perimenopausal women were included. Logistic regression models were used to evaluate the association between TyGFI and depression/cognitive impairment. Restricted cubic spline (RCS) curves were plotted to visualize the dose–response relationship. Subgroup analyses and receiver operating characteristic (ROC) curves were used to assess interaction effects and evaluate the discriminatory ability of TyGFI. The results were expressed as odds ratios (OR) with 95% confidence intervals (CI).Results: Perimenopausal women with higher TyGFI levels exhibited a greater tendency towards depression and cognitive impairment, older age, higher blood pressure, and poorer self-reported health. In the fully adjusted model, each one-point increase in TyGFI was associated with elevated risk of depression (OR = 3.70, 95% CI: 3.18– 4.32) and cognitive impairment (OR = 1.51, 95% CI: 1.34– 1.71). RCS curves confirmed non-linear, positive associations and clear dose–response trends. Subgroup analysis revealed that the associations remained largely robust across most subgroups. ROC analysis demonstrated moderate-to-good discriminatory ability, with area under the curve (AUC) of 0.786 for depression and 0.634 for cognitive impairment.Conclusion: The TyGFI was concurrently correlated with depression and cognitive impairment in Chinese perimenopausal women, which may serve as a potential indicator for clinical risk screening.Keywords: perimenopause, triglyceride-glucose index, frailty index, depression, cognitive impairment, CHARLS

Background:Pruritus is a common skin symptom, frequently associated with substantial psychological burden. Recent advances in neuroscience and clinical practice suggest a clinically significant reciprocal association between chronic pruritus and negative emotions (e.g., anxiety and depression), moving beyond simple models of causality. Despite increasing research interest, this interdisciplinary field still lacks a comprehensive bibliometric overview. Therefore, this study aims to systematically visualize the research landscape and identify emerging hotspots, underexplored areas, and translational priorities regarding the pruritus-emotion interplay. Methods:Literature data were retrieved from the Web of Science Core Collection (WoSCC) and supplemented with targeted PubMed clinical trials published from January 1, 1980, to May 31, 2026. WoSCC records served as the main bibliometric dataset, whereas PubMed clinical trials were screened according to predefined eligibility criteria and used as a supplementary clinical-trial dataset. The final included records and records excluded after full-text assessment were verified by a second reviewer. Advanced bibliometric tools, including VOSviewer, CiteSpace, Charticulator and Bibliometrix were used to evaluate collaboration networks, co-citation relationships, and keyword evolution. Results:A total of 2549 publications from WoSCC and 46 clinical trials from PubMed were included. The United States exhibited absolute advantages in publication volume, citation influence, and international cooperation. The leading institutions were mainly located in North America and Europe, including the University of Toronto, University of Miami, and Wroclaw Medical University. Szepietowski J.C., Yosipovitch G., and Ständer S. were the most productive authors, while Yosipovitch G. and Silverberg J.I. occupied central positions in the co-citation network. The supplementary PubMed clinical trial analysis indicated that targeted pharmacological therapies were more frequently represented than psychological, behavioral, or integrative interventions. The integrated findings identified five interrelated themes: anxiety and depression as the principal emotional constructs, the crucial implementation of multidimensional patient-reported outcome measures (PROMs), sleep and cognitive amplifiers, targeted and integrative care, and skin-brain axis mechanisms. Conclusion:This bibliometric analysis provides a structured overview of the research landscape on pruritus and negative emotions. By revealing emerging trends and future research priorities, this study serves as a valuable reference for scholars and clinicians exploring interdisciplinary interventions to break this vicious cycle.

BackgroundThe prevalence of adolescent major depressive disorder (MDD) is rising; however, diagnosis relies on subjective measures due to a lack of objective biomarkers. This study explored infrared thermography (IRT) as a non-invasive tool to quantify thermal radiation characteristics of acupoints in adolescents with MDD. The objective was to establish diagnostic models based on acupoint temperature-derived biomarkers.MethodsA prospective, multi-center observational study enrolled 108 participants (65 adolescents with MDD and 43 healthy controls [HCs]). We first examined correlations between acupoint temperatures and depression severity using Pearson analysis. Multiple linear and binary logistic regression models were developed to diagnose MDD and assess severity. The diagnostic model for MDD was visualized as a nomogram and validated using Receiver Operating Characteristic (ROC) curves, Hosmer-Lemeshow tests, calibration plots, and decision curve analysis (DCA). Internal validation was performed using the bootstrap method.ResultsAmong 27 acupoints analyzed, adolescents with MDD exhibited altered acupoint temperatures at Taiyang (EX-HN5), Quchi (LI11), Yanggu (SI5), and Waiqiu (GB36). Subsequent Pearson correlation analysis revealed negative correlations between the infrared relative temperatures of Taiyang (EX-HN5), Quchi (LI11), and Waiqiu (GB36) and depression severity (P = 0.001, r = -0.319; P = 0.022, r = -0.229; P = 0.001, r = -0.325) and a weak positive correlation between the infrared relative temperature of Yanggu (SI5) and depression severity (P = 0.043, r = 0.202). Building on these findings, two diagnostic models were developed: a linear regression model for depression severity of adolescents (Y = 52.25-9.52*TEX-HN5-13.07*TGB36) and a logistic regression model for adolescents with MDD diagnosis (P = ex/(1+ex), x = 0.22-1.14*TEX-HN5+0.45*TSI5-2.19*TGB36). The nomogram-based model demonstrated good calibration (Hosmer-Lemeshow P = 0.855), discrimination (AUC = 0.785, 95%CI: 0.693 - 0.876), and clinical utility. Internal validation using the bootstrap method produced a C-index of 0.752 (95% CI: 0.617 - 0.877), further confirming the model’s robustness.ConclusionsIn conclusion, acupoint temperature-based models show promising efficacy for the objective and non-invasive diagnosis and severity quantification of adolescents with MDD, offering valuable tools for early clinical intervention. Future studies should validate these findings across diverse populations and integrate multi-modal biomarkers to enhance diagnostic precision.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT06750640.

BackgroundOlfactory dysfunction (OD) has gained prominence in neurodegenerative diseases and COVID-19 sequelae in recent years. Its mechanisms have also attracted increasing research interest. However, there is currently a scarcity of bibliometric analyses in this field.MethodsArticles related to OD mechanisms were searched in the Web of Science Core Collection (WoSCC) and Scopus. Data merging and bibliometric analysis were conducted using CiteSpace, VOSviewer, Excel, Scimago Graphica, and the bibliometrix in R package. Simultaneously, PubMed was used to search and summarize interventional clinical trials in this field, and their protocols were tracked through trial registration information and ethical approval records.ResultsA total of 7,915 articles met the inclusion criteria in WoSCC and Scopus. Overall, the number of articles published annually on the mechanisms of OD is on the rise. The USA (2635 publications), University of California System (143 publications), and Thomas Hummel (174 publications) are the most productive country, institution, and author, respectively. Keyword analysis shows that “COVID-19,” “Parkinson’s disease,” “inflammation,” “odorant receptor,” and other related topics are hot topics and trends in research. PubMed retrieved and included 14 interventional clinical trials. These trials mainly focus on pharmacological interventions, non-pharmacological interventions, surgical interventions, and mechanistic studies.ConclusionMechanistic research on OD is advancing from macroscopic observations to precise molecular mechanisms. This review synthesizes evidence on how distinct etiologies, ranging from post-viral and inflammatory damage to neurodegeneration and metabolic imbalances, contribute to OD. Notably, the dysregulation of the inflammatory NF-κB, signal-transducing cAMP, and neuroregenerative Wnt/β-catenin pathways may collectively contribute to the development of OD. By integrating bibliometric trends with clinical trial evaluations, this study delineates a clear translational pipeline from mechanism exploration to clinical interventions.

BackgroundSleep disorders not only impair nocturnal rest but also significantly compromise daytime functioning, emotional regulation, and overall mental well-being. Beyond conventional pharmacological treatments, manual therapy has emerged as a promising non-pharmacological intervention. Specifically, emerging evidence suggests its benefits may extend to alleviating psychological distress and enhancing mood. This study employs a bibliometric approach to systematically investigate the current status, research hotspots, and future trends of manual therapy for sleep disorders, with an emphasis on its psycho-physiological outcomes.MethodsPublications related to manual therapy for sleep disorders were retrieved from the Web of Science Core Collection (WoSCC). Bibliometric visualizations and analyses were conducted using VOSviewer and CiteSpace. Furthermore, clinical trial records from PubMed were extracted to assess the translational and clinical advancements in this field.ResultsThe analysis included 594 publications originating from 321 institutions across 63 countries. The overall trend demonstrates a consistent annual increase in both publication volume and citation impact, reflecting escalating academic interest. Keyword and literature co-occurrence analyses indicate that exploring neurobiological mechanisms and circadian rhythm regulation are the predominant research frontiers.ConclusionBibliometric evidence indicates that research on manual therapy for sleep disorders is evolving toward multidimensional and interdisciplinary integration. Manual therapy increasingly emerges as a key complementary treatment, exerting therapeutic effects via the regulation of 5-hydroxytryptamine (5-HT) and the Hypothalamic-Pituitary-Adrenal axis (HPA axis). Its safety and efficacy represent distinct advantages; however, future clinical translation necessitates multi-center validation and standardized sham-controlled protocols.

Depression is a common but serious mental health illness affected human’s physiology and psychology. In contemporary times, neurophysiological research on depression has emerged as a prominent area of investigation, yet there remains a paucity of review elucidating the central mechanisms of depression in the brain. Consequently, we undertook a bibliometric analysis and visualization assessment to underscore recent advancements in research pertaining to the neural underpinnings of depression. By employing these methods, we have collected articles spanning the period from 2013 to 2024, shedding light on the latest insights into the brain mechanisms associated with depression. Bibliometric analysis found 16327 research papers in the field of brain mechanism underlying depression, overall showing a sustained growth trend. Through meticulous analysis of collected data on institutions and countries, authors, co-cited literature, keywords, etc., this paper humbly aims to tentatively identify future research hotspots and frontiers, hoping to modestly contribute to and stimulate further scholarly progress in the field.

IntroductionPostherpetic Neuralgia (PHN) constitutes a severe sequelae following herpes zoster (HZ) Infection, and one of the most problematic issues is the treatment of cephalo-facial PHN in patients over 50 years of age, which severely affects the patient’s work mood, sleep and activities of daily living. The efficacy of conventional treatments for PHN remains unsatisfactory. Therefore, there is an urgent need for alternative approaches to explore simpler, more convenient, effective, and inexpensive treatment options in the clinical treatment of PHN. This trial aims to thoroughly evaluate the effectiveness and safety of EA as a therapeutic modality for individuals suffering from cephalo-facial PHN.Methods and analysisThe protocol outlines a double-center, randomized, and controlled trial design where both patients and assessors are blinded to the intervention being administered. The duration of the trial’s therapeutic intervention will span 4 weeks, followed by a 2-month observation period for monitoring any subsequent effects or outcomes. The 124 qualified individuals will be randomly allocated in a balanced 1:1 ratio to either the EA group or the drug group. All variables will undergo evaluation at the start of the study (week 0, baseline), during the treatment period at weeks 2 and 4, and during the follow-up period at weeks 8 and 12. The primary outcome is the Visual Analog Scale (VAS). Secondary outcomes include the Brief pain inventory-Facial scale (BPI-Facial), Pittsburgh Sleep Quality Index Scale (PSQI), Self-rating depression scale (SDS), Hamilton depression scale (HAMD), and Quality of Life Rating Scale (SF-36). The occurrence of any adverse reactions will be monitored and assessed throughout the duration of the trial.ConclusionThis study will preliminarily evaluate the efficacy and safety of electroacupuncture (EA) in the treatment of patients with postherpetic neuralgia (PHN).Ethics and disseminationEthical approval for this trial has been obtained from the Institutional Ethics Review Board of the Third Affiliated Hospital of Zhejiang Chinese Medical University (No. ZSLL-KY-2023-029-01) and Zhejiang Hospital (No. 2024-030-K). Before enrollment, participants will be required to sign a form of informed consent.Clinical trial registrationIdentifier NCT06420778, https://clinicaltrials.gov/study/NCT06420778.

BackgroundMajor depressive disorder (MDD) has emerged as the fifth leading cause of years lived with disability, with a high prevalent, affecting nearly 4% of the global population. While available evidence suggests that intradermal acupuncture may enhance the effectiveness of antidepressants, whether its efficacy is a specific therapeutic effect or a placebo effect has not been reported. Moreover, the cerebral mechanism of intradermal acupuncture as a superficial acupuncture (usually subcutaneous needling to a depth of 1–2 mm) for MDD remains unclear.MethodsA total of 120 participants with MDD will be enrolled and randomized to the waiting list group, sham intradermal acupuncture group and active intradermal acupuncture group. All 3 groups will receive a 6-week intervention and a 4-week follow-up. The primary outcome will be measured by the Hamilton Depression Rating Scale-17 and the secondary outcome measures will be the Self-Rating depression scale and Pittsburgh sleep quality index. Assessments will be conducted at baseline, 3 weeks, 6 weeks, and during the follow-up period. In addition, 20 eligible participants in each group will be randomly selected to undergo head magnetic resonance imaging before and after the intervention to explore the effects of intradermal acupuncture on brain activity in MDD patients.DiscussionIf the intradermal acupuncture is beneficial, it is promising to be included in the routine treatment of MDD.Clinical Trial RegistrationClinicaltrials.gov, NCT05720637.

Background: Major depressive disorder (MDD) exhibits a pronounced occurrence among adolescents, aligning closely with the lifetime prevalence rate of 16.6% observed in adults. It is difficult to treat and prone to recurrence. Acupuncture has shown potential in enhancing treatment effectiveness. Nonetheless, there is a lack of research on the use of intradermal acupuncture (IA) in treating adolescent MDD. Methods: This study is a double-blind, randomized controlled trial. A cohort of 120 participants will be assigned randomly to three distinct groups, namely a Selective Serotonin Reuptake Inhibitors (SSRIs)-only group, a sham intradermal acupuncture combined with SSRIs (SIA) group, and an active intradermal acupuncture combined with SSRIs (AIA) group. Hamilton Depression Rating Scale will serve as the primary outcome, while Patient Health Questionnaire-9, Self-Rating Depression Scale, Pittsburgh Sleep Quality Index, and Short Form 36 Questionnaire will serve as secondary outcomes in assessing the amelioration of depressive symptoms in patients. These data will be analyzed using SPSS26.0 software.Results: We will assess the efficacy and safety of IA for MDD using commonly employed clinical psychiatric scales.Conclusion: The efficacy of IA in treating adolescent MDD may be demonstrated in this study, suggesting its potential for optimizing MDD treatment schemes.Trial Registration: ClinicalTrials.gov Identifier: NCT 05832619 (April 27, 2023).

Diabetic neuropathic pain (DNP) is a common complication of diabetes. Streptozotocin (STZ)-induced changes of protein in dorsal root ganglion (DRG) and spinal cord dorsal horn (SCDH) are critical for DNP genesis. However, which proteins change remains elusive. Here, the DNP model was established by a single intraperitoneal injection of STZ, accompanied by increased fasting blood glucose (FBG), decreased body weight (BW), and decreased paw withdrawal latency (PWL). Proteins change in L4-L6 DRGs and SCDH of rats were detected. Western blot and immunofluorescence results showed that expression levels of phosphorylated protein kinase C (p-PKC), transient receptor potential vanilloid-1 (TRPV1), Substance P (SP) and calcitonin gene-related peptide (CGRP) in the DRG and the SCDH of rats were increased after STZ injection. A preliminary study from our previous study showed that 2 Hz electroacupuncture (EA) effectively alleviates DNP. However, the analgesic mechanism of EA needs further elucidation. Here, EA at the bilateral Zusanli (ST36) and KunLun (BL60) acupoints was applied for one week, and to investigate the effect on DNP. EA reversed thermal hyperalgesia in DNP rats and downregulated the expression of p-PKC, TRPV1, SP, and CGRP in DRG and SCDH.

Purpose: This bibliometric research aims to delineate global publication trends and emerging research interests in the use of acupuncture for breast cancer (BC)-related symptoms treatment over the past three decades. Furthermore, it identifies influential institutions, potential collaborative partners, and future research trends, thereby providing guidance for relevant, novel research directions. Methods: Scientific publications related to acupuncture for BC-related symptoms were gathered from the Web of Science Core Collection (WoSCC) from 1993 to 2023. Four software applications were principally used to analyze the resulting data: the "bibliometrix" package in the R environment (version 4.2.3), VOSviewer, CiteSpace6.1.R6, and the bibliometrics website. These applications were employed to evaluate different parameters. Results: A total of 621 papers on acupuncture in BC-related symptoms treatment were analyzed. The United States, China, and South Korea contributed the most, with Memorial Sloan Kettering Cancer Center, and Columbia University leading institutions. It is interesting to mention that Mao, Jun J. and Molassiotis, A. feature among the top 10 authors and co-cited authors. JAMA is the leading journal, with an ongoing focus on acupuncture's effectiveness. Keywords show that the initial research focus was mainly on "vasomotor symptoms", but in recent years there has been a gradual shift towards "pain", "chemotherapy-induced peripheral neuropathy (CIPN)", "electroacupuncture", and "non-specific effects". Conclusion: Acupuncture has demonstrated a unique value in the process of adjuvant treatment of BC-related symptoms, and has been shown to be effective in reducing pain, eliminating fatigue, and improving quality of life. The study of the mechanisms of acupuncture and the application of electroacupuncture are possible future research priorities in this field. This study offers a deep perspective on acupuncture for BC research, highlighting key points and future trends.

《金匮要略》载:"经为血,血不利则为水,名曰血分."张仲景认为,"血分""水分"关系密切,基于此创立了多首"血水同治"代表方,如温经利水的桂枝茯苓丸、活血利水的当归芍药散等.赵师探究血水同治法之精髓,运用此法治疗妇科杂病两则,效如桴鼓,现载之以飨同道.

Objective To explore the potential biological mechanisms of Houbao tang in the treatment of intrauterine adhesions(IUA)through network pharmacology and molecular docking.Methods The compounds of all herbal medicines in Houbao tang were screened and the related targets were predicted by Batman-TCM database.The targets of IUA were obtained from GeneCards,NCBIand DisGeNET databases.PPI network analysis,topology analysis and functional enrichment analysis were executed to obtain the common genes of Houbao tang and IUA by Venny software,and to construct the component-disease-pathway-target network.Finally,molecular docking prediction of compounds and targets was performed by AutoDock.Results A total of 1,868 drug targets of Houbao tang were screened and intersected with 1,842 targets related to IUA.Eventually,409 intersection targets were obtained.Further topological analysis yielded 106 key targets with high correlation coefficients of CREBBP,AKT1,TP53,SRC,etc.The shared targets of drug diseases were enriched to 3,785 biological processes including regulation of epithelial cell proliferation,128 molecular functions related to receptor ligand activity,signaling receptor activation,and 241 cell composition related to vesicle lumen and membrane area.KEGG pathway enrichment screening 184 signaling pathways.Molecular docking results showed that Melanin-JUN binding energy was minimal.Conclusion The anti-adhesive properties of Houbaotang through multiple target actions are analyzed using network pharmacology,and CREBBP,AKT1 and SMAD3 are screened as possible key targets of Houbao tang in the treatment of IUA,and fibrosis is regulated through several major signaling pathways such as PI3K-Akt,AGE-RAGE and TNF,which offer fresh concepts and techniques for in-depth research on the mechanism of action of Houbao tang in the treatment of IUA.

Background:Major depressive disorder (MDD) is highly prevalent, affecting more than 300 million individuals worldwide, and its occurrence may be related to the abnormality of the prefrontal cortex and bilateral temporal cortex. Acupuncture, rooted in the theories of acupoints and meridians, has demonstrated its efficacy in regulating cortical blood flow (CBF) in the brains of MDD patients. As one form of acupuncture, intradermal acupuncture (IA) can alleviate clinical symptoms such as depressive mood and insomnia in MDD patients. However, it remains unknown whether IA will have a specific effect on the prefrontal cortex and bilateral temporal cortex in MDD patients.Methods:In total, 60 participants will be recruited: 20 healthy control participants and 40 MDD patients. All healthy control participants will be allocated to the control group, whereas the 40 MDD patients will be randomly divided into two groups: the gallbladder meridian acupoint (GBA) group and the non-acupoint (NA) group, at a 1:1 allocation ratio. All groups will undergo a one-time IA intervention while their cortical activity is monitored using functional near-infrared spectroscopy (fNIRS). Total hemoglobin, oxygenated hemoglobin, and deoxygenated hemoglobin of the prefrontal and bilateral temporal cortices will be measured by fNIRS during the test procedure.Discussion:This trial aims to use fNIRS to compare real-time hemodynamic changes in the prefrontal and bilateral temporal cortices of healthy individuals and MDD patients during IA. The primary objective is to investigate whether MDD patients exhibit specific real-time responses to IA stimulation in these brain regions. The findings from this study will provide clinical data and a possible theoretical basis for the assumption that stimulation of IA may treat MDD by modulating the relevant brain regions.Trial Registration:The study protocol has been registered in the clinicaltrials.gov with the code NCT05707299.

Diabetic neuropathic pain (DNP) is a common and destructive complication of diabetes mellitus. The discovery of effective therapeutic methods for DNP is vitally imperative because of the lack of effective treatments. Although 2 Hz electroacupuncture (EA) was a successful approach for relieving DNP, the mechanism underlying the effect of EA on DNP is still poorly understood. Here, we established a rat model of DNP that was induced by streptozotocin (STZ) injection. P2X4R was upregulated in the spinal cord after STZ-injection. The upregulation of P2X4R was mainly expressed on activated microglia. Intrathecal injection of a P2X4R antagonist or microglia inhibitor attenuated STZ-induced nociceptive thermal hyperalgesia and reduced the overexpression of brain-derived neurotrophic factor (BDNF), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the spinal cord. We also assessed the effects of EA treatment on the pain hypersensitivities of DNP rats, and further investigated the possible mechanism underlying the analgesic effect of EA. EA relieved the hyperalgesia of DNP. In terms of mechanism, EA reduced the upregulation of P2X4R on activated microglia and decreased BDNF, IL-1β and TNF-α in the spinal cord. Mechanistic research of EA's analgesic impact would be beneficial in ensuring its prospective therapeutic effect on DNP as well as in extending EA's applicability.

Background Antidepressants still have some side effects in treating major depressive disorder (MDD), and acupuncture therapy is a complementary therapy of research interest for MDD. Acupoints are sensitive sites for disease response and stimulation points for acupuncture treatment. Prior studies suggest that the biological specificity of acupoints is altered in physiological and pathological situations. Therefore, we hypothesize that the biological specificity of acupoints is associated with the diagnosis of MDD and that stimulating acupoints with significant biological specificity can achieve a better therapeutic effect than clinical common acupoints. This study aims to investigate the efficacy and safety of intradermal acupuncture (IA) treatment for MDD based on changes in the biological specificity of acupoints. Methods The first part of the study will enroll 30 MDD patients and 30 healthy control (HC) participants to assess pain sensitivity and thermal specificity of MDD-related acupoints using a pressure pain threshold gauge (PTG) and infrared thermography (IRT). The potentially superior acupoints for treating MDD will be selected based on the results of PTG and IRT tests and referred to as pressure pain threshold strong response acupoints (PSA) and temperature strong response acupoints (TSA). The second part of the study will enroll 120 eligible MDD patients randomly assigned to waiting list (WL) group, clinical common acupoint (CCA) group, TSA group, and PSA group in a 1:1:1:1 ratio. The change in the Patient Health Questionnaire-9 Items (PHQ-9), the MOS item short-form health survey (SF-36), pressure pain threshold, temperature of acupoints, and adverse effects will be observed. The outcomes of PHQ-9 and SF-36 measures will be assessed before intervention, at 3 and 6 weeks after intervention, and at a 4-week follow-up. The biological specificity of acupoint measures will be assessed before intervention and at 6 weeks after intervention. All adverse effects will be assessed. Discussion This study will evaluate the therapeutic effect and safety of IA for MDD based on changes in the biological specificity of acupoints. It will investigate whether there is a correlation between the biological specificity of MDD-related acupoints and the diagnosis of MDD and whether stimulating strong response acupoints is superior to clinical common acupoints in the treatment of MDD. The study’s results may provide insights into the biological mechanisms of acupuncture and its potential as a complementary therapy for MDD. Clinical Trial Registration ClinicalTrials.gov , identifier: NCT05524519.

Objective:To observe any effect of electroacupuncture (EA) on the expression of phosphorylated extracellular signal-regulated protein kinase (p-ERK1/2) and phosphorylated cyclic adenosine monophosphate response element binding protein (p-CREB) in the spinal dorsal horns of diabetics experiencing neuropathic pain.Methods:Eight rats were randomly selected from 30 healthy male Sprague-Dawley rats as the normal group (N), and the remaining twenty-two rats were treated with a single high-dose intraperitoneal injection of streptozotocin (STZ) to establish a neuropathic pain model. The rats modeled successfully were randomly divided into a model group (M, n=8) and an EA group ( n=8). In the EA group, electroacupuncture was applied at the bilateral Hou san li and Kunlun acupoints starting on the 15th day after the STZ injection. The daily sessions lasted 30 minutes for 1 week. Body weight (BW), fasting blood glucose (FBG) and paw withdrawal latency (PWL) were observed before the STZ injection and on the 7th, 14th, and 21st days afterward. The expression of p-ERK1/2 and p-CREB in the dorsal horns of the rats′ spinal cords was detected using western blotting. The count of p-CREB-positive cells in the dorsal horns and their co-localization with neurons was detected using immunofluorescence. Results:In comparison with the N group, the average BW of the M group on the 7th, 14th and 21st days after the STZ injection was significantly lower, while the average FBG was significantly higher. There was no significant difference between the M and N groups in the average PWL on the 7th day after the STZ injection, but it had decreased significantly in the M group on the 14th and 21st days. Compared with the M group, the average PWL of the EA group was significantly longer on the 21st day after the injection. The expression of p-ERK1/2 and p-CREB protein in the spines of the M group was significantly higher than in the N group. p-CREB positive cells were more numerous in the M group compared with the N group, while in the EA group they were fewer. P-CREB was co-located with neurons in the spinal dorsal horn.Conclusion:EA can alleviate neuropathic pain effectively, perhaps by inhibiting the expression of p-ERK1/2 and p-CREB in the dorsal horns of the spinal cord.

Diabetic neuropathic pain (DNP) is highly common in diabetes patients. P2X receptors play critical roles in pain sensitization. We previously showed that elevated P2X3 expression in dorsal root ganglion (DRG) contributes to DNP. However, the role of other P2X receptors in DNP is unclear. Here, we established the DNP model using a single high-dose streptozotocin (STZ) injection and investigated the expression of P2X genes in the DRG. Our data revealed elevated P2X2, P2X4, and P2X7 mRNA levels in DRG of DNP rats. The protein levels of P2X4 and P2X7 in DNP rats increased, but the P2X2 did not change significantly. To study the role of P2X4 and P2X7 in diabetes-induced hyperalgesia, we treated the DNP rats with TNP-ATP (2',3'-O-(2,4,6-trinitrophenyl)-adenosine 5'-triphosphate), a nonspecific P2X1-7 antagonist, and found that TNP-ATP alleviated thermal hyperalgesia in DNP rats. 2 Hz electroacupuncture is analgesic against DNP and could downregulate P2X4 and P2X7 expression in DRG. Our findings indicate that P2X4 and P2X7 in L4-L6 DRGs contribute to diabetes-induced hyperalgesia, and that EA reduces thermal hyperalgesia and the expression of P2X4 and P2X7.

Abstract Management of diabetic neuropathic pain (DNP), a prevalent, refractory diabetic complication, remains a challenge. Previous research evidences have implicated microglia P2X4 receptor (P2X4R) in occurrence and development of DNP. To date, however, the specific mechanism of microglia P2X4R action in DNP needs to be further explored. We elucidated the role and underlying mechanism of microglia P2X4R in DNP. The DNP rat model was established by injection of streptozotocin (STZ). DNP rats developed thermal hyperalgesia from day 14. Western blot and immunofluorescence analyse revealed that microglia, P2X4R, p-p38 mitogen-activated protein kinase (p-p38 MAPK), and downstream targets brain-derived neurotrophic factor (BDNF), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were upregulated in the spinal cord. In addition, a P2X4R antagonist 5-BDBD and a microglia inhibitor minocycline (mino) not only alleviated DNP, but also suppressed P2X4R, microglia, p-p38 MAPK, BDNF, TNF-α and IL-1β levels in the spinal cord. Based on these findings, it was evident that central pain sensitization in DNP occurs via the microglia P2X4R/p38 signaling pathway, while p-p38 MAPK activates microglia to release BDNF, TNF-α and IL-1β in spinal cords. These results demonstrate that P2X4R/p38 signaling pathway in microglia residing in the spinal cord contribute to the establishment and long term maintenance of DNP and that these represent potential targets for pain therapy.