OBJECTIVE: To investigate whether the presence or absence of improvement in chronic severe functional constipation (CSFC) at the early stage of treatment with electroacupuncture predicts subsequent response or non-response, and to determine the optimal treatment duration for assessing subsequent responses to electroacupuncture. METHODS: This is a post hoc analysis using data pooled from two large-scale randomized controlled trials. Patients with CSFC were recruited, and those in the electroacupuncture groups were included in the present study. Early improvement was defined as a weekly increase of ≥1 complete spontaneous bowel movement (CSBM) compared to baseline. Three treatment response criteria were evaluated: ≥ 3 CSBMs per week, overall CSBM response, and sustained CSBM response. Predictive statistics, including sensitivity, specificity, positive predictive value, and negative predictive value, were calculated at weeks 1-4. Receiver operating characteristic curves and accuracy rates were used to determine the optimal timepoint for differentiation between responders and non-responders. RESULTS: Cases from a total of 813 participants who received electroacupuncture were analyzed. The proportion of improvers was 40.34% by week 1, increasing to 52.52% by week 4. After 8 weeks of treatment, the response rates were 30.14%, 25.83% and 25.58% according to the three aforementioned criteria, respectively. Early improvement was a strong predictor of treatment response, with week 3 demonstrating the highest predictive accuracy. CONCLUSION Early improvement with electroacupuncture, especially at week 3, can predict subsequent outcomes. Our findings suggest that acupuncturists may identify non-responders who might require adjustments to therapeutic strategies early in treatment. Please cite this article as: Xiong ZY, Yan SY, Liu SX, Liu ZS. Early improvement to electroacupuncture at week 3 predicts ultimate response in patients with chronic severe functional constipation. J Integr Med. 2025; 23(3): 274-281.
Humans ; Constipation/physiopathology* ; Electroacupuncture ; Male ; Female ; Middle Aged ; Chronic Disease ; Adult ; Treatment Outcome ; Aged

Epigallocatechin-3-gallate (EGCG), a prominent plant-based catechin predominantly derived from Camellia sinensis and widely available on the market as a health supplement, has garnered significant attention for its potential therapeutic benefits, particularly in the context of type 2 diabetes mellitus (T2DM). This review explores the multifaceted role of EGCG in addressing the "ominous octet"-the 8 core pathophysiological defects associated with T2DM. The literature search was carried out using key terms "EGCG" OR "epigallocatechin-3-gallate" OR "epigallocatechin gallate" AND "diabetes" OR "insulin resistance" OR "hyperglycemia" in the PubMed and Scopus databases. The search was constrained to articles published between January 2018 and April 2024, focusing on the document type. Full-text articles published in English and relevant to EGCG that featured a single active ingredient, included clearly explained diabetes relief mechanism, and included ominous octet aspects were included in the final review. The outcomes of the included studies were reviewed and categorized based on 8 core pathophysiological defects, collectively referred to as the ominous octet in T2DM. This review concludes that EGCG is a potent hypoglycemic agent that has beneficial effects against the ominous octet in addition to its pharmacological activities in modulating gut microbiota dysbiosis, carbohydrate digestion and metabolism, glucose transporter-mediated intestinal glucose-uptake, endothelial dysfunction, and renal damage that are significantly associated with pathogenesis of T2DM. This extensive scientific evidence suggests that EGCG may offer a novel approach to traditional antidiabetic therapies, potentially improving glycemic control and mitigating complications associated with T2DM. The inhibitory effects of EGCG on sodium-glucose transport proteins and their role in reducing renal glucose reabsorption remain unexplored, highlighting a significant research gap. Future research should also aim to broaden the scope by investigating the "egregious eleven," which comprise a more comprehensive range of diabetic pathophysiological features. This review underscores the therapeutic promise of EGCG for managing T2DM and encourages ongoing research to fully elucidate its clinical applications. Please cite this article as: Wong CN, Lim YM, Liew KB, Chew YL, Chua AL, Lee SK. A review on mechanistic actions of epigallocatechin-3-gallate in targeting the ominous octet of type 2 diabetes mellitus. J Integr Med. 2025; 23(4): 344-356.
Diabetes Mellitus, Type 2/physiopathology* ; Humans ; Catechin/therapeutic use* ; Hypoglycemic Agents/therapeutic use* ; Animals ; Insulin Resistance

OBJECTIVE: The occurrence and development of atrial fibrillation (AF) are influenced by the autonomic nervous system and inflammation. Acupuncture is an effective treatment for AF. This study explored the protective effects of acupuncture in a rat model of paroxysmal AF and investigated its mechanisms. METHODS: Male Sprague-Dawley rats (n = 130) were randomly divided into blank control (Con), sham operation (Sham), AF, and acupuncture treatment (Acu) groups. A paroxysmal AF model was established by rapid atrial pacing through the jugular vein. Rats in the Acu group were immobilized to receive acupuncture treatment at Neiguan acupoint (PC6) for 20 min daily for seven days. The other groups were immobilized for the same duration over the treatment period but did not receive acupuncture. The AF induction rate, AF duration, cardiac electrophysiological parameters, and heart rate variability were evaluated by monitoring surface electrocardiogram and vagus nerve discharge signals. After the intervention, the rats were euthanized, and atrial morphology was assessed using haematoxylin and eosin staining. The expression of macrophage F4/80 antigen (F4/80) and cluster of differentiation (CD) 86 in atrial myocardial tissue was detected using immunohistochemistry, immunofluorescence and flow cytometry. The expression levels or contents of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), α7 nicotinic acetylcholine receptor (α7nAChR), phosphorylated Janus kinase 2 (p-JAK2), and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in atrial myocardial tissue were detected using Western blotting, reverse transcription-quantitative polymerase chain reaction, or enzyme-linked immunosorbent assay. The role of α7nAChR in acupuncture treatment was verified by intraperitoneal injection of the α7nAChR antagonist methyllycaconitine (MLA). RESULTS: Compared with the AF group, acupuncture significantly reduced AF duration and induction rate, improved cardiac electrophysiology by enhancing vagus nerve activity and regulating autonomic balance. It also decreased the pro-inflammatory M1 macrophage proportion, alleviating myocardial injury and infiltration. MLA weakened acupuncture's electrophysiological improvement and anti-inflammatory effect. Results suggest that acupuncture triggers the α7nAChR-JAK2/STAT3 pathway and exerts cardioprotection via neuroimmune regulation. CONCLUSION Acupuncture significantly reduced the AF induction rate, shortened AF duration, improved cardiac electrophysiological parameters, enhanced vagus nerve activity, and decreased the expression of pro-inflammatory M1 macrophages and inflammatory factors in rats with paroxysmal AF. Its positive effects are related to the activation of the α7nAChR-mediated JAK2/STAT3 signalling pathway, indicating that the interaction between cardiac vagus nerve and macrophages may be a potential target for acupuncture in the prevention and treatment of AF. Please cite this article as: Li ZH, Yang WM, Huang Q, Shi GX, Liu CZ, Zhang YQ. Acupuncture activates vagus nerve-macrophage axis and improves cardiac electrophysiology and inflammatory response in rats with atrial fibrillation via α7nAChR-JAK2/STAT3 pathway. J Integr Med. 2025; 23(4): 398-414.
Animals ; Male ; Rats, Sprague-Dawley ; STAT3 Transcription Factor/metabolism* ; alpha7 Nicotinic Acetylcholine Receptor/metabolism* ; Janus Kinase 2/metabolism* ; Atrial Fibrillation/metabolism* ; Vagus Nerve/physiopathology* ; Rats ; Acupuncture Therapy ; Signal Transduction ; Macrophages/metabolism* ; Inflammation/therapy*

OBJECTIVE: To elucidate the specific mechanisms by which electroacupuncture (EA) alleviates anxiety and fear behaviors associated with posttraumatic stress disorder (PTSD), focusing on the role of lipocalin-2 (Lcn2). METHODS: The PTSD mouse model was subjected to single prolonged stress and shock (SPS&S), and the animals received 15 min sessions of EA at Shenmen acupoint (HT7). Behavioral tests were used to investigate the effects of EA at HT7 on anxiety and fear. Western blotting and enzyme-linked immunosorbent assay were used to quantify Lcn2 and inflammatory cytokine levels in the prefrontal cortex (PFC). Additionally, the activity of PFC neurons was evaluated by immunofluorescence and in vivo electrophysiology. RESULTS: Mice subjected to SPS&S presented increased anxiety- and fear-like behaviors. Lcn2 expression in the PFC was significantly upregulated following SPS&S, leading to increased expression of the proinflammatory cytokines tumor necrosis factor-α and interleukin-6 and suppression of PFC neuronal activity. However, EA at HT7 inhibited Lcn2 release, reducing neuroinflammation and hypoexcitability in the PFC. Lcn2 overexpression mitigated the effects of EA at HT7, resulting in anxiety- and fear-like behaviors. CONCLUSION EA at HT7 can ameliorate PTSD-associated anxiety and fear, and its mechanism of action appears to involve the inhibition of Lcn2-mediated neural activity and inflammation in the PFC. Please cite this article as: Yang YD, Zhong W, Chen M, Tang QC, Li Y, Yao LL, et al. Electroacupuncture alleviates behaviors associated with posttraumatic stress disorder by modulating lipocalin-2-mediated neuroinflammation and neuronal activity in the prefrontal cortex. J Integr Med. 2025; 23(5):537-547.
Electroacupuncture ; Stress Disorders, Post-Traumatic/metabolism* ; Animals ; Lipocalin-2/metabolism* ; Prefrontal Cortex/physiopathology* ; Male ; Mice ; Neurons/physiology* ; Disease Models, Animal ; Fear ; Behavior, Animal ; Mice, Inbred C57BL ; Neuroinflammatory Diseases/metabolism* ; Anxiety/therapy* ; Acupuncture Points

Hypnosis is a promising tool in the management of various conditions, such as anxiety and chronic pain. Preliminary studies have shown that hypnosis can directly affect the cardiovascular system, as it increases parasympathetic activation and reduces sympathetic activity. However, the literature related to the effects of hypnosis on cardiovascular health is scarce, mainly due to misconceptions about hypnosis among researchers and medical professionals. This opinion paper examines the role that hypnosis may play in cardiovascular health, highlighting the physiological mechanisms behind it. The evidence suggests that hypnosis has both direct (e.g., changes in the activity of the autonomic nervous system) and indirect (e.g., changes in healthy behaviours) effects on the cardiovascular system; however, further studies are needed to properly define its mechanisms of action and its applicability in improving cardiovascular health. Thus, this opinion paper advocates the adoption of the term "hypno-cardiac physiology" to identify a new research area that gathers experts from neuroscience and cardiovascular science with the joint aim of seeking further understanding of the effects of hypnosis on the cardiovascular system. The adoption of a dedicated term to identify the study of the cardiovascular response to hypnosis will encourage its implementation in cardiovascular health interventions, promoting awareness of its effects among the public and the healthcare community, and promoting the formation of dedicated multidisciplinary research groups and dedicated educational training for healthcare professional interested in its applications. Please cite this article as: Leo DG, Keller SS, Proietti R. Hypno-cardiac physiology: Aiming for an organised study of the physiological effects of hypnosis on the cardiovascular system. J Integr Med. 2025; 23(5):457-461.
Humans ; Autonomic Nervous System/physiology* ; Cardiovascular Physiological Phenomena ; Cardiovascular System/physiopathology* ; Hypnosis

OBJECTIVE: Diabetes-induced gastrointestinal (GI) motility disorders are increasingly prevalent. Damage to the enteric nervous system (ENS), composed primarily of enteric neurons and glial cells, is an essential mechanism involved in these disorders. Although electroacupuncture (EA) has shown the potential to mitigate enteric neuronal loss, its mechanism is not fully understood. Additionally, the effects of EA on enteric glial cells have not been investigated. Enteric neural precursor cells (ENPCs) contribute to the structural and functional integrity of the ENS, yet whether EA enhances their differentiation into enteric neurons and glial cells remains unexplored. This study investigates whether EA promotes ENS repair through enhancing ENPC-derived neurogenesis and gliogenesis and elucidates the potential molecular mechanisms involved. METHODS: Transgenic mice were used to trace Nestin⁺/nerve growth factor receptor (Ngfr)⁺ ENPCs labeled with green fluorescent protein (GFP) in vivo. Mice were randomly divided into four groups: control, diabetes mellitus (DM), DM + sham EA, and DM + EA. The effects of EA on diabetic mice were evaluated by GI motility, ENS structure, and ENPC differentiation. Glial cell line-derived neurotrophic factor (GDNF)/Ret signaling was detected to clarify the underlying molecular mechanisms. RESULTS: EA alleviated diabetes-induced GI motility disorders, as indicated by reduced whole gut transit time, shortened colonic bead expulsion time, and enhanced smooth muscle contractility. Furthermore, EA attenuated diabetes-induced losses of enteric neurons and glial cells, thereby restoring ENS integrity. Notably, EA reversed the diabetes-induced decrease in ENPCs and significantly increased the absolute number and the proportion of ENPC-derived enteric neurons. However, immunofluorescence analyses revealed no colocalization between EA-induced glial fibrillary acidic protein⁺ glial cells and GFP-labeled ENPCs. Mechanistically, GDNF/Ret signaling was elevated in intestinal tissues and upregulated in ENPCs in EA-treated diabetic mice. CONCLUSION EA facilitates ENS repair by promoting Nestin⁺/Ngfr⁺ ENPC differentiation into enteric neurons via upregulation of GDNF/Ret signaling, and driving enteric gliogenesis from non-Nestin⁺/Ngfr⁺ ENPCs. These findings highlight EA's role in ameliorating diabetes-induced GI dysmotility through ENPC-derived ENS restoration. Please cite this article as: Guo JL, Liu S, Ding SJ, Yang X, Du F. Electroacupuncture at ST36 improves gastrointestinal motility disorders by promoting enteric nervous system regeneration through GDNF/Ret signaling in diabetic mice. J Integr Med. 2025; 23(5):548-559.
Animals ; Electroacupuncture ; Enteric Nervous System/physiology* ; Gastrointestinal Motility/physiology* ; Glial Cell Line-Derived Neurotrophic Factor/metabolism* ; Diabetes Mellitus, Experimental/therapy* ; Signal Transduction ; Mice ; Gastrointestinal Diseases/physiopathology* ; Proto-Oncogene Proteins c-ret/metabolism* ; Mice, Transgenic ; Male ; Nerve Regeneration ; Neural Stem Cells ; Mice, Inbred C57BL ; Acupuncture Points

Stroke is the second leading cause of disability and mortality worldwide, imposing a substantial socioeconomic burden on individuals and healthcare systems. Annually, approximately 14 million people experience stroke, with ischemic stroke comprising nearly 85% of cases, of which 10% to 20% involve large vessel occlusions. Currently, recombinant tissue plasminogen activator (tPA) remains the only approved pharmacological intervention. However, its utility is limited due to a narrow therapeutic window and low recanalization rates, making it applicable to only a minority of patients. Therefore, there is an urgent need for novel therapeutic strategies, including pharmacological advancements and combinatory treatments. Small-molecule natural medicines, particularly those derived from traditional Chinese herbs, have demonstrated significant therapeutic potential in ischemic stroke management. These compounds exert multiple neuroprotective effects, such as antioxidation, anti-inflammatory action, and inhibition of apoptosis, all of which are critical in mitigating stroke-induced cerebral damage. This review comprehensively examines the pathophysiology of acute ischemic stroke (AIS) and highlights the recent progress in the development of small-molecule natural medicines as promising therapeutic agents for cerebral ischemic stroke.
Humans ; Ischemic Stroke/physiopathology* ; Animals ; Neuroprotective Agents/therapeutic use* ; Drugs, Chinese Herbal/chemistry* ; Biological Products/therapeutic use* ; Stroke/drug therapy*

Xiaoaiping (XAP) Injection demonstrates the anti-prostate cancer (PCa) effects, yet the underlying mechanism remains unclear. This study aims to investigate the impact of XAP on PCa and elucidate its mechanism of action. PCa cell proliferation was evaluated using a cell counting kit-8 (CCK-8) assay. Cell apoptosis was assessed through Hoechst staining and Western blotting assays. Proteomics technology was employed to identify key molecules and significant signaling pathways modulated by XAP in PCa cells. To further validate potential key genes and important pathways, a series of assays were conducted, including acridine orange (AO) staining, transmission electron microscopy, and immunofluorescence assays. The molecular mechanism of XAP against PCa in vivo was examined using a PC3 xenograft mouse model. Results demonstrated that XAP significantly inhibited cell proliferation in multiple PCa cell lines. In C4-2 and prostate cancer cell line-3 (PC3) cells, XAP induced cellular apoptosis, evidenced by reduced B-cell lymphoma 2 (Bcl-2) levels and elevated Bcl-2-associated X (Bax) levels. Proteomic, immunofluorescence, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) investigations revealed a strong correlation between forkhead box O3a (FoxO3a) autophagic degradation and the anti-PCa action of XAP. XAP hindered autophagy by reducing the expression levels of autophagy-related protein 5 (Atg5)/autophagy-related protein 12 (Atg12) and enhancing FoxO3a expression and nuclear translocation. Furthermore, XAP exhibited potent anti-PCa action in PC3 xenograft mice and triggered FoxO3a nuclear translocation in tumor tissue. These findings suggest that XAP induces PCa apoptosis via inhibition of FoxO3a autophagic degradation, potentially offering a novel perspective on XAP injection as an effective anticancer therapy for PCa.
Male ; Humans ; Prostatic Neoplasms/physiopathology* ; Autophagy/drug effects* ; Animals ; Drugs, Chinese Herbal/pharmacology* ; Proteomics ; Mice ; Apoptosis/drug effects* ; Cell Line, Tumor ; Cell Proliferation/drug effects* ; Forkhead Box Protein O3/genetics* ; Xenograft Model Antitumor Assays ; Mice, Nude ; Mice, Inbred BALB C

Osteosarcoma (OS) is the most prevalent primary malignant bone tumor affecting children and adolescents. Despite ongoing research efforts, the 5-year survival rate has remained stagnant for many years, highlighting the critical need for novel drug development to enhance current treatment protocols. Ziyuglycoside II (ZYG II), a triterpenoid saponin extracted from S. officinalis, has recently demonstrated antitumor properties. This study evaluates the antitumor effect of ZYG II on osteosarcoma and elucidates its mechanism of action through the co-regulation of p53 and estrogen-related receptor gamma (ESRRG), which inhibits disease progression. The research employs in vitro experiments using multiple established osteosarcoma cell lines, as well as in vivo studies utilizing a nude mouse model of orthotopic xenograft osteosarcoma. Additionally, ESRRG shRNA was used to construct stable ESRRG-reducing OS cell lines to investigate the molecular mechanism by which ZYG II exerts its anti-osteosarcoma effects through the co-regulation of ESRRG and p53. Results indicate that ZYG II administration led to decreased OS cell viability and reduced tumor volumes. Furthermore, cell cycles were arrested at the G₀/G₁ phase, while the proportion of apoptotic cells increased. Expression of p53, ESRRG, p21, Bax, Cleaved Caspase-9, and Cleaved Caspase-3 proteins increased, while expression of CDK4, Cyclin D1, and Bcl-2 proteins decreased. Multiple ZYG II and ESRRG docking patterns were simulated through molecular docking. Comparing the pharmacodynamic response of ZYG II to OS cell lines with reduced ESRRG and normal expression demonstrated that ZYG II inhibits osteosarcoma progression, induces cell cycle arrest, and promotes cell apoptosis through the coordination of p53 and ESRRG. In conclusion, ZYG II inhibits osteosarcoma progression, leads to cell cycle arrest, and promotes cell apoptosis through synergistic regulation of p53 and ESRRG.
Osteosarcoma/physiopathology* ; Tumor Suppressor Protein p53/genetics* ; Humans ; Animals ; Saponins/chemistry* ; Bone Neoplasms/physiopathology* ; Signal Transduction/drug effects* ; Cell Line, Tumor ; Mice, Nude ; Mice ; Apoptosis/drug effects* ; Receptors, Estrogen/genetics* ; Mice, Inbred BALB C ; Female ; Male ; Xenograft Model Antitumor Assays

Ovarian cancer poses a significant threat to women's health, necessitating effective therapeutic strategies. Emd-D, an emodin derivative, demonstrates enhanced pharmaceutical properties and bioavailability. In this study, Cell Counting Kit 8 (CCK8) assays and Ki-67 staining revealed dose-dependent inhibition of cell proliferation by Emd-D. Migration and invasion experiments confirmed its inhibitory effects on OVHM cells, while flow cytometry analysis demonstrated Emd-D-induced apoptosis. Mechanistic investigations elucidated that Emd-D functions as an inhibitor by directly binding to the glycolysis-related enzyme PFKFB4. This was corroborated by alterations in intracellular lactate and pyruvate levels, as well as glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) expression. PFKFB4 overexpression experiments further supported the dependence of Emd-D on PFKFB4-mediated glycolysis and SRC3/mTORC1 pathway-associated apoptosis. In vivo experiments exhibited reduced xenograft tumor sizes upon Emd-D treatment, accompanied by suppressed glycolysis and increased expression of Bax/Bcl-2 apoptotic proteins within the tumors. In conclusion, our findings demonstrate Emd-D's potential as an anti-ovarian cancer agent through inhibition of the PFKFB4-dependent glycolysis pathway and induction of apoptosis. These results provide a foundation for further exploration of Emd-D as a promising drug candidate for ovarian cancer treatment.
Female ; Humans ; Ovarian Neoplasms/physiopathology* ; Phosphofructokinase-2/genetics* ; Apoptosis/drug effects* ; Glycolysis/drug effects* ; Animals ; Cell Line, Tumor ; Mice ; Cell Proliferation/drug effects* ; Emodin/administration & dosage* ; Mice, Nude ; Mice, Inbred BALB C ; Hexokinase/metabolism* ; Xenograft Model Antitumor Assays