Journal of Integrative Medicine-Jim最新文献

Objective: Enhancing innate immunity through interferons (IFNs) and IFN-stimulated genes (ISGs) offers a promising strategy for preventing herpes simplex virus type 1 (HSV-1) infection. Prunella vulgaris L., a medicinal herb, has demonstrated significant anti-HSV activity; in particular, its derived polysaccharide complex (PVE30) effectively inhibits viral replication. In this study, we investigate whether PVE30 exerts an anti-HSV-1 activity through activation of the innate immune response.

Methods: To determine the primary stage at which PVE30 exerts its effects during the HSV-1 life cycle, plaque reduction assays were conducted. Viral infection was further assessed by investigating the DNA copies, mRNA levels and protein expression of HSV-1 in infected cells using real-time polymerase chain reaction (RT-PCR) and Western blotting. The activation of the innate immune response was evaluated by detecting mRNA levels of ISGs, including MX dynamin-like GTPase 1 (Mx1), Mx2, 2'-5'-oligoadenylate synthetase 1 (OAS1), ISG15 and IFN regulatory factor 7 (IRF7) using RT-PCR, and levels of TANK-binding kinase 1 (TBK1) and IRF3 proteins using Western blotting. The translocation of phosphorylated IRF3 and stimulator of IFN genes (STING) was observed through fluorescence microscopy.

Results: PVE30 pre-treatment exerted protective effects against HSV-1 infection in human immortalized keratinocytes by enhancing the innate immune response. This was shown by increased transcriptional levels of IFN-β and antiviral ISGs, along with a significant reduction in HSV-1 DNA copies, mRNA expression and protein levels. Mechanistically, PVE30 promoted TBK1 phosphorylation, leading to nuclear translocation of IRF3 and subsequent IFN-β transcription; these effects were diminished by TBK1 inhibitor GSK8612. Additionally, STING was identified as a key mediator in PVE30-activated TBK1 signaling, as its inhibition induced by C-176 reduced PVE30's efficacy.

Conclusion: This study elucidated the molecular mechanisms underlying the protective effects of PVE30 against HSV-1 infection. PVE30 exerted its protective role by enhancing STING-TBK1-IRF3 pathway-mediated innate immune response. Please cite this article as: Zhang YB, Xu L, Yuan M, Liu MF, Li Y, Zhong XL, Lin ZX, Xian YF, Lu P, Xi ZC, Xu HX. Protective effects of Prunella vulgaris polysaccharides against herpes simplex virus type 1 infection through the STING-TBK1-IRF3 pathway. J Integr Med. 2025; Epub ahead of print.

Objective: This study investigated the effects of distinct electroacupuncture (EA) intensities in alleviating mechanical hypersensitivity by attenuating spinal dorsal horn (SDH) neuronal sensitization in inflammatory muscle pain.

Methods: Male Sprague-Dawley rats received an intra-muscular injection of complete Freund's adjuvant (CFA) in the left gastrocnemius muscle to induce inflammatory muscle pain. EA with distinct intensities activating Aβ-, Aδ- and C-fibers (EA_Aβ, EA_Aδ and EA_C) was applied after CFA injection. Pain behaviors were evaluated by weight-bearing asymmetry, the Randall-Selitto test, and the von Frey test. Spinal neuronal activities were observed by in vivo extracellular recordings with a microelectrode array. Neuronal sensitization was assessed through wind-up phenomenon of wide dynamic range (WDR) neurons and long-term potentiation (LTP) of spinal C-fiber-evoked field potential (CFEFP).

Results: Both EA_Aδ and EA_C significantly alleviated CFA-induced hyperalgesia. Moreover, EA_Aδ and EA_C interventions markedly reduced the activity of WDR neurons in response to stimulation. Importantly, the wind-up phenomenon of WDR neurons evoked by repetitive noxious stimuli was both immediately and sustainably reduced after EA intervention, with EA_C showing a more pronounced effect. Furthermore, EA_Aδ and EA_C increased the threshold of the spinal CFEFP, while EA_C intervention additionally significantly attenuated the occurrence of LTP.

Conclusion: Suppressing the SDH neuronal sensitization by activating Aδ- and C-fiber inputs may be the potential mechanism by which EA alleviates hyperalgesia in inflammatory muscle pain. Please cite this article as: Yu QQ, Sun XY, Chen JK, Li M, Wang XY, Su YS, Zhang ZY, Jing XH. Distinct intensity of electroacupuncture ameliorates mechanical hypersensitivity by attenuating neuronal sensitization in spinal dorsal horn in a rat model of inflammatory muscle pain. J Integr Med. 2025; Epub ahead of print.

Background: Auriculotherapy is a simple, convenient, nonpharmacological option that has shown positive effects for insomnia patients, but its efficacy and safety remain unknown.

Objective: The aim of this study is to evaluate the efficacy and safety of auricular therapy for insomnia.

Design, setting, participants and intervention: An 18-week (2-week screening, 4-week treatment, and 12-week follow-up), recruiter- and assessor-blinded, randomized, sham-controlled trial was performed. Patients were recruited from outpatient settings at three clinical centers in China from 2 February 2023 to 26 January 2024. Participants had insomnia for more than 3 months and met the criteria classified in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). Patients were randomly assigned in a 1:1 ratio to receive auricular therapy (AT) or sham AT (SAT) for 4 consecutive weeks, twice a week, and once every 3 days.

Main outcome measures: Primary outcome was the response rate at week 4 after treatment, defined as the percentage of patients with at least a 50% reduction in Pittsburgh Sleep Quality Index (PSQI) from baseline. Secondary outcomes consisted of response rates at other time points, PSQI and 4 related scales, actigraphy-recorded sleep efficiency, sleep arousal frequency, and total sleep time.

Results: A total of 234 participants were screened, and 156 patients (122 female [78.2%]; mean [SD] age, 37.2 [13.5] years) were included in the intention-to-treat analysis, with 78 participants randomized to each group. A total of 117 participants (75%) were followed up for 3 months. The AT group had a higher response rate at week 4 than the SAT group (39.73% [29/73] vs 23.29% [17/73], P = 0.03), and the response rates for the AT and SAT groups at week 2 were 28.38% (21/74) and 13.33% (10/75), respectively (P = 0.02). The differences between the two groups in the PSQI at each time point (P < 0.05) and the Insomnia Severity Index at weeks 4 and 12 (both P = 0.03) were also statistically significant. The other partial outcomes also showed statistically significant differences. Adverse events occurred in 2 cases in the AT group (2.60%).

Conclusion: Four-week AT treatment was an effective and safe alternative therapy for insomnia, although the difference with the SAT treatment did not reach the minimal clinically important difference. Adverse events were mild or transient.

Trial registration: Chinese Clinical Trial Registry, identifier ChiCTR2200065187. Please cite this article as: Chen H, Zhang XF, Yuan ZC, Wang XS, Gao YB, Li XX, Zhang JC, da Silva Oliveira MD, de Barros Nunes CA, Liu J, She YF. Efficacy and safety of auriculotherapy for insomnia disorder: A randomized controlled trial. J Integr Med. 2025; Epub ahead of print.

Objective: Xinyang Tablet (XYAT) and Xinyin Tablet (XYIT) have been used to treat chronic heart failure (CHF) for 20 years. This study investigated their pharmacodynamic material basis and underlying mechanisms of action.

Methods: Ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS) was used to identify the components of XYAT and XYIT, and to profile their metabolites in plasma and urine samples from both rats and human volunteers. Furthermore, the prototype compounds and their pharmacokinetics were evaluated using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Network pharmacology predicted potential targets and pathways, which were subsequently validated through flow cytometry and Western blot. The efficacy of XYAT, XYIT and their active components was evaluated in oxidative stress and cardiotoxicity models.

Results: A total of 162 and 130 compounds were detected in XYAT and XYIT, respectively; among these, 148 from XYAT and 119 from XYIT were structurally identified. A validated HPLC-MS/MS method quantified 20 key exposure components, five of which showed high systemic exposure and underwent pharmacokinetic analysis. Pharmacokinetic results indicated that the systemic exposure of most compounds was higher for XYAT than for XYIT. Using network pharmacology, seven candidate active compounds were identified, along with their predicted therapeutic targets and associated signaling pathways. Flow cytometry and Western blot confirmed that XYAT, XYIT, and their bioactive components alleviate CHF by modulating calcium signaling and phosphoinositide 3-kinase/protein kinase B signaling. Pharmacodynamic assays demonstrated that XYAT provides protection against hydrogen peroxide-induced injury, while XYIT mitigates doxorubicin-induced cytotoxicity. Further validation confirmed that 20(S)-ginsenoside Rg2 and 20(R)-ginsenoside Rh1 effectively reduced the H₂O₂-induced oxidative stress, while 20(S)-ginsenoside Rg2 and calycosin-7-O-β-D-glucoside significantly protected against doxorubicin-induced cytotoxicity.

Conclusion: These findings provide mechanistic insights into the pharmacodynamic material basis and anti-CHF mechanisms of XYAT and XYIT. The integrated strategy established herein offers robust evidence that the superior systemic exposure of key components underpins the rationale for XYAT's formulation and warrants its continued development in modern cardiology. Please cite this article as: Lan YL, Chen SM, Dai BX, Wu CS, Wei Y, Yang L, Yan JL, Guo YQ, Wang DW, Li QG, Yang ZQ, Xian SX, Yuan TH. Bioactive components of Xinyang and Xinyin tablets for treating chronic heart failure: pharmacokinetics, network pharmacology and experimental validation. J Integr Med. 2025; Epub ahead of print.

Objective: Alzheimer's disease (AD) and Parkinson's disease (PD) are major age-related neurodegenerative disorders that currently lack effective disease-modifying therapies. This study investigated the neuroprotective potential and underlying mechanisms of natural products derived from medicine-food homology (MFH) plants, with a focus on autophagy modulation in AD and PD models.

Methods: Twenty MFH plant extracts were screened using the Caenorhabditis elegans amyloid-β peptide (Aβ) proteotoxicity model CL4176. Mung bean coat extract (MBCE) was identified as a promising candidate and subsequently evaluated in transgenic C. elegans models of AD and PD to assess its effects on pathological protein aggregation, oxidative stress, and behavioral impairments. Autophagy activation was assessed using fluorescence microscopy and lysosomal activity assays. MBCE's effects on protein aggregation and apoptosis were further validated in rat pheochromocytoma (PC-12) cells. Mechanistic insights were obtained through pharmacological inhibition of autophagy and AMP-activated protein kinase (AMPK) signaling, as well as AMPK knockdown. A bioactivity-guided analysis was performed to identify the major active constituents of MBCE.

Results: MBCE significantly alleviated Aβ- and microtubule-associated protein tau (Tau)-induced neurotoxicity in C. elegans by reducing protein aggregation, oxidative stress, and locomotor deficits. It also suppressed α-synuclein accumulation and preserved dopaminergic neuron integrity in PD models. MBCE enhanced stress resistance and activated autophagy, as evidenced by increased autophagosome formation, decreased sequestosome-1 (p62/SQSTM1) levels, and elevated lysosomal activity. RNA interference knockdown assays confirmed that MBCE's neuroprotective effects were dependent on autophagy activation. In PC-12 cells, MBCE similarly induced AMPK-mediated autophagy, reduced the accumulation of disease-related proteins, and mitigated cytotoxicity. Notably, genetic knockdown or pharmacological inhibition of AMPK or autophagy abolished these effects. Vitexin and isovitexin, the main constituents of MBCE, were identified as key contributors to its autophagy-inducing and neuroprotective activities.

Conclusion: MBCE mitigates neurodegenerative pathology in AD and PD models by promoting AMPK-dependent autophagy and reducing toxic protein aggregation. These findings support the potential of MBCE as a functional food-based therapeutic strategy for neurodegenerative diseases. Please cite this article as: Chen ZX, Wang FP, Li YP, Wu MT, Chen MY, Huang FH, Wen YP, Wang XH, Yu L, Wu JM, Wu AG, Zhou XG. Neuroprotective activity of mung bean (Vigna radiata) coat extract via AMPK-dependent autophagy in Alzheimer's and Parkinson's models. J Integr Med. 2025; Epub ahead of print.

Objective: Gastric ulcers are a global health issue, often occurring in the stomach or duodenum and causing tissue necrosis. Talinum paniculatum (Jacq.) Gaertn (Erva-gorda) is used in traditional medicine for treating gastric ulcers. This study aimed to assess the gastroprotective effects of the ethanol-soluble fraction from T. paniculatum leaves (ESTP) in rodents.

Methods: The gastroprotective potential of ESTP was evaluated at 30, 100, and 300 mg/kg taken orally, or 30 mg/kg intraperitoneally against gastric lesions induced by a 60% ethanol solution containing 0.3 mol/L hydrochloric acid, in mice. Histological sections were examined after hematoxylin-eosin staining and their mucin content was determined using the periodic acid-Schiff method. Oxidative stress markers, including levels of reduced glutathione and lipid hydroperoxide, as well as inflammatory parameters such as myeloperoxidase activity and nitrite levels, were analyzed. Mechanistic studies involved pretreating the mice with N-ethylmaleimide (NEM), N-nitro-l-arginine methyl ester (L-NAME), and indomethacin.

Results: ESTP at 300 mg/kg orally and 30 mg/kg intraperitoneally significantly reduced ethanol/HCl-induced gastric injury. It decreased lipid hydroperoxide levels but did not increase levels of reduced glutathione. Myeloperoxidase activity and nitrite levels were reduced. However, ESTP did not restore mucin levels. Pretreatment with indomethacin nullified the protective effects of ESTP while NEM and L-NAME did not.

Conclusion: ESTP demonstrated a remarkable gastroprotective effect, as indicated by reductions in inflammatory and oxidative mediators. The observed decline in mucin activity, coupled with the absence of an effect following indomethacin pretreatment, implies a potential inhibition of the cyclooxygenase activity by the extract. These findings collectively support the traditional use of the species for gastrointestinal protection and highlight its potential as a therapeutic agent for managing gastric ulcers. Please cite this article as: Pegoraro Correa KG, do Carmo Barroso de Siqueira M, Zanovello M, Martins Belmudes M, de Souza P, Gasparotto Junior A, Boeing T. Gastroprotective activity of Talinum paniculatum (Jacq.) Gaertn. in mice: An ethnopharmacological validation. J Integr Med. 2025; Epub ahead of print.

Objective: Cerebral ischemic stroke (CIS) induces neuronal damage and activates neuronal autophagy through diverse mechanisms. Autophagy exerts adverse effects in acute neurological disorders, leading to neuronal apoptosis and death. The dried tuberous root of Aconitum coreanum (H.Lév l.) Rapaics is a traditional herbal medicine that has been used to treat stroke. This study explores the neuroprotective effects of A. coreanum through its role in autophagy and the mechanisms that underly this activity.

Methods: The middle cerebral artery occlusion/reperfusion technique was used to establish a CIS rat model. The neuroprotective effects of A. coreanum were explored using a suite of techniques: behavioral injury was assessed with the Longa method; infarct size was measured using 2,3,5-triphenyltetrazolium chloride; neuronal morphology was observed using hematoxylin-eosin and Nissl staining; neuronal apoptosis was observed with terminal-deoxynucleotidyl transferase dUTP nick-end labeling staining. Then, the mechanisms behind the neuroprotective effects were explored: the oxidative stress index was detected using enzyme-linked immunosorbent assay; the ultrastructure of rat neurons was observed using transmission electron microscopy; the protein expression was detected with Western blotting and immunofluorescence analyses; the mRNA expression was measured by quantitative reverse transcription-polymerase chain reaction analysis.

Results: A. coreanum significantly reduced the behavioral score and infarct size of CIS rats, increased the number of neurons in the cerebral cortex and hippocampus, improved the morphology and structure of neurons, and suppressed neuronal apoptosis. In addition, A. coreanum downregulated levels of malondialdehyde and myeloperoxidase and upregulated those of superoxide dismutase and glutathione. It inhibited the generation of autophagosomes and modulated the indicators of autophagy, including decreasing the ratio of microtubule-associated protein 1 light chain 3-II (LC3-II)/LC3-I, and increasing the expression of sequestosome 1. A. coreanum also upregulated the expression of phosphorylated mammalian target of rapamycin (mTOR) and phosphorylated unc-51-like kinase 1 (ULK1) and downregulated that of phosphorylated adenosine monophosphate-activated protein kinase (AMPK).

Conclusion: A. coreanum exerts neuroprotective effects in CIS by inhibiting autophagy through regulating the AMPK/mTOR/ULK1 signaling pathway. This finding provides a novel perspective on the treatment of CIS with A. coreanum. Please cite this article as: Yue L, Yang Q, Qian C. Aconitum coreanum (H.Lév l.) Rapaics exerts neuroprotective effects on cerebral ischemic stroke by inhibiting autophagy through the AMPK/mTOR/ULK1 pathway. J Integr Med. 2025; Epub ahead of print.

Objective: Laboratory tests are commonly used in Korean medicine (KM) clinics to monitor the safety of herbal medicine (HM). Although the incidence of herb-induced liver injury (HILI) in Republic of Korea has been reported, there is a lack of data from KM clinics, which account for over 90% of KM institutions. This absence is due to the lack of a systematic pharmacovigilance system for HMs. To partially understand this issue, this study investigated changes in liver function test (LFT) and renal function test (RFT) after HM prescriptions in primary settings.

Methods: This retrospective analysis utilized laboratory test results, including complete blood count, LFT and RFT, collected from 238 KM clinics across the Republic of Korea. The study population comprised patients who underwent laboratory testing before and after HM treatment between March 2020 and November 2021. We compared laboratory test results using paired t-tests or Wilcoxon signed-rank tests. Subgroup analyses were conducted by sex and elapsed time between tests. The McNemar test was used to compare the proportions of cases with abnormal LFT and RFT levels according to lifestyle habits and comorbidities. Additionally, the incidence of liver injury was estimated by identifying cases with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels exceeding five times the upper limit of normal after HM prescription.

Results: A total of 2791 cases were included in the analysis. The levels of AST and ALT decreased significantly after HM prescription (P < 0.0001). This result was consistent in subgroups stratified by sex and for test intervals of within 30 and 60 days (P < 0.05). The proportion of cases with abnormal AST and ALT levels significantly decreased after HM prescription (P < 0.001). Out of 2791 cases, only 2 (0.07%) were identified as having liver injury after HM prescription, but causality was not confirmed.

Conclusion: The findings suggest that the use of HM in KM clinics in Republic of Korea is generally safe. While a small number of HMs may be associated with liver injury, causality remains uncertain. Establishing a national pharmacovigilance system is crucial for accurately monitoring the incidence and risk factors of HILI. Please cite this article as: Cho E, Ko MM, Yang C, Kim S. Safety of herbal medicines in Korean medicine clinics in Republic of Korea: A nationwide retrospective longitudinal cohort study. J Integr Med. 2025; Epub ahead of print.

Over the past three decades, a growing body of research has been dedicated to the integration of traditional Chinese medicine (TCM) and modern medicine, highlighting the complementary benefits of both disciplines. However, in the context of skin wound treatment, such integration remains limited and warrants further exploration. During the wound healing process, the inflammatory response is a critical physiological event. A harmonious balance between pro-inflammatory and anti-inflammatory events is essential for the progression of inflammation and the overall wound healing process. This equilibrium reflects the dynamic and reciprocal interaction embodied in the TCM concept of yin and yang. This study analyzes the dynamic changes in wound inflammation from the perspective of TCM's yin-yang theory and pinpoints the key cellular and molecular factors that influence the yin-yang balance in wound inflammation. The findings offer significant theoretical and practical value for future clinical and translational research. These insights will inform more effective strategies for the treatment of skin wounds and to facilitate the development of novel therapeutics. Please cite this article as: Geng YF, Ma XY, Ge Y, Liu B, Deng JG, Liu S, Wu TQ, Jiang SR, Geng FN. Yin-yang dynamics in wound inflammation: yin and yang manifestations of inflammatory substances. J Integr Med. 2025; Epub ahead of print.