Acupuncture alleviates inflammatory pain by activating CXCL1/CXCR2 signaling in the primary somatosensory cortex in adjuvant induced arthritis rats. / S1脑区CXCL1/CXCR2å‚ä¸Žé’ˆåˆºæ”¹å–„ä½å‰‚æ€§å ³èŠ‚ç‚Žå¤§é¼ ç‚Žæ€§ç—›çš„ä½œç”¨æœºåˆ¶.

OBJECTIVES: To observe whether acupuncture up-regulates chemokine CXC ligand 1 (CXCL1) in the brain to play an analgesic role through CXCL1/chemokine CXC receptor 2 (CXCR2) signaling in adjuvant induced arthritis (AIA) rats, so as to reveal its neuro-immunological mechanism underlying improvement of AIA. METHODS: BALB/c mice with relatively stable thermal pain reaction were subjected to planta injection of complete Freund adjuvant (CFA) for establishing AIA model, followed by dividing the AIA mice into simple AF750 (fluorochrome) and AF750+CXCL1 groups (n=2 in each group). AF750 labeled CXCL1 recombinant protein was then injected into the mouse's tail vein to induce elevation of CXCL1 level in blood for simulating the effect of acupuncture stimulation which has been demonstrated by our past study. In vivo small animal imaging technology was used to observe the AF750 and AF750+CXCL1-labelled target regions. After thermal pain screening, the Wistar rats with stable pain reaction were subjected to AIA modeling by injecting CFA into the rat's right planta, then were randomized into model and manual acupuncture groups (n=12 in each group). Other 12 rats that received planta injection of saline were used as the control group. Manual acupuncture (uniform reinforcing and reducing manipulations) was applied to bilateral "Zusanli" (ST36) for 4×2 min, with an interval of 5 min between every 2 min, once daily for 7 days. The thermal pain threshold was assessed by detecting the paw withdrawal latency (PWL) using a thermal pain detector. The contents of CXCL1 in the primary somatosensory cortex (S1), medial prefrontal cortex, nucleus accumbens, amygdala, periaqueductal gray and rostroventromedial medulla regions were assayed by using ELISA, and the expression levels of CXCL1, CXCR2 and mu-opioid receptor (MOR) mRNA in the S1 region were detected using real time-quantitative polymerase chain reaction. The immune-fluorescence positive cellular rate of CXCL1 and CXCR2 in S1 region was observed after immunofluorescence stain. The immunofluorescence double-stain of CXCR2 and astrocyte marker glial fibrillary acidic protein (GFAP) or neuron marker NeuN or MOR was used to determine whether there is a co-expression between them. RESULTS: In AIA mice, results of in vivo experiments showed no obvious enrichment signal of AF750 or AF750+CXCL1 in any organ of the body, while in vitro experiments showed that there was a stronger fluorescence signal of CXCL1 recombinant protein in the brain. In rats, compared with the control group, the PWL from day 0 to day 7 was significantly decreased (P<0.01) and the expression of CXCR2 mRNA in the S1 region significantly increased in the model group (P<0.05), while in comparison with the model group, the PWL from day 2 to day 7, CXCL1 content, CXCR2 mRNA expression and CXCR2 content, and MOR mRNA expression in the S1 region were significantly increased in the manual acupuncture group (P<0.05, P<0.01). Immunofluorescence stain showed that CXCR2 co-stained with NeuN and MOR in the S1 region, indicating that CXCR2 exists in neurons and MOR-positive neurons but not in GFAP positive astrocytes. CONCLUSIONS: Acupuncture can increase the content of CXCL1 in S1 region, up-regulate CXCR2 on neurons in the S1 region and improve MOR expression in S1 region of AIA rats, which may contribute to its effect in alleviating inflammatory pain.

Osteopathic manipulative treatment for chronic inflammatory diseases.

Chronic inflammatory diseases (CIDs) are debilitating and potentially lethal illnesses that affect a large proportion of the global population. Osteopathic manipulative treatment (OMT) is a manual therapy technique developed and performed by osteopathic physicians that facilitates the body's innate healing processes. Therefore, OMT may prove a beneficial anti-inflammatory modality useful in the management and treatment of CIDs. This work aims to objectively evaluate the therapeutic benefits of OMT in patients with various CIDs. In this review, a structured literature search was performed. The included studies involving asthma, chronic obstructive pulmonary disease, irritable bowel syndrome, ankylosing spondylitis, and peripheral arterial disease were selected for this work. Various OMT modalities, including lymphatic, still, counterstain, and muscle energy techniques, were utilized. Control treatments included sham techniques, routine care, or no treatment. OMT utilization led to variable patient outcomes in individuals with pathologies linked to CID.

The effect of hyperbaric oxygen therapy on hematological indices and biochemical parameters in patients with diabetic foot.

BACKGROUND: Diabetes Mellitus (DM) is a metabolic disease with a high morbidity and mortality and increasing in prevalence all over the world. Due to the hypoxic, ischemic, inflammatory, and infective environment in DM, diabetic foot ulcers have been treated with medico-surgical interventions and adjuvant hyperbaric oxygen Therapy (HBOT). The purpose of this study was to evaluate the effects of HBOT on hematological indices and biochemical parameters in patients with diabetic foot. METHODS: The study group was formed from the file records of 103 male patients who applied to Yunus Emre State Hospital HBOT Center between September 1, 2016 and December 31, 2020, and were treated HBOT with a multidisciplinary approach. RESULTS: There were negative low correlations between number of HBOT sessions and Mean Corpuscular Hemoglobin (MCH) (P = .037, r = -0.207) and Blood Urea Nitrogen (BUN) (P = .037, r = -0.222). White Blood Cell Count (WBC), Neutrophils (NEU), Monocytes (MON), Platelet Count (PLT), and Plateletcrit (PTC) parameters were found to be decreased, and an increase in lymphocytes (LYM), Eosinophils (EOS), Mean Corpuscular Hemoglobin Concentration (MCHC), and Red Cell Distribution Width (RDW) parameters were detected after the treatments (P < .05). Again, after the treatment, glucose (Glu), C-Reactive Protein (CRP), direct bilirubin, and total protein (TP) levels were decreased, and uric acid (UA) levels increased (P < .05). CONCLUSION: HBOT improved hematological indices in patients and had a beneficial effect on biochemical parameters, particularly Glu and CRP levels. Adjuvant HBOT alleviates diabetic inflammation and has a beneficial effect on diabetic patient treatment.

Moxibustion of Zusanli (ST36) and Shenshu (BL23) alleviates the inflammation of rheumatoid arthritis in rats through regulating macrophage migration inhibitory factor/glucocorticoids signaling.

OBJECTIVE: To test the hypothesis that moxibustion may inhibit rheumatoid arthritis (RA) synovial inflammation by regulating the expression of macrophage migration inhibitory factor (MIF)/glucocorticoids (GCs). METHODS: Fifty male Sprague-Dawley rats were randomly divided into five groups (n = 10 each): blank Control (CON) group, RA Model (RA) group, Moxibustion (MOX) group, MIF inhibitor (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) group, and Moxibustion + MIF inhibitor ISO-1 (MOX + ISO-1) group. Rats in the ISO-1 group and ISO-1 + MOX group were intraperitoneally injected with the inhibitor ISO-1. The rats in the RA group, ISO-1 group, MOX group, and ISO-1 + MOX group were injected with Freund's complete adjuvant (FCA) in the right hind footpad to establish an experimental RA rat model. In the MOX group and MOX + ISO-1 group, rats were treated with Moxa. The thickness of the footpads of the rats in each group was measured at three-time points before, after modeling and after moxibustion treatment. The contents of serum MIF, corticosterone (CORT), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were detected by enzyme-linked immunosorbent assay; and the contents of synovial MIF were detected by Western blot. Hematoxylin-eosin (HE) staining method was used to observe the pathological changes of synovial tissue under a section light microscope, and pathological scoring was performed according to the grading standard of the degree of synovial tissue disease. RESULTS: Moxibustion was found to reduce the level of MIF and alleviate inflammation in RA rats in this study. In addition, after inhibiting the expression of MIF, the level of CORT increased, and the level of TNF-α decreased. Treating RA rats with inhibited MIF by moxibustion, the level of CORT was almost unchanged, but the level of TNF-α further decreased. The correlation analysis data suggested that MIF was positively related to the expression of TNF-α and negatively correlated with the expression of CORT. CONCLUSION: Reducing MIF to increase CORT and decrease TNF-α by moxibustion treatment in RA. MIF may be a factor for moxibustion to regulate the expression of CORT, but the expression of TNF-α is due to the incomplete regulation of the MIF. This study added to the body of evidence pointing to moxibustion's anti-inflammatory mechanism in the treatment of RA.

Inhibitory effect of acupoint electrostimulation with different layers and intensities on muscular inflammatory pain and spinal WDR neuron activity. / ç©´ä½ä¸åŒå±‚æ¬¡å’Œå¼ºåº¦ç”µåˆºæ¿€ç¼“è§£è‚Œè‚‰ç‚Žæ€§ç—›åŠå¯¹è„Šé«“èƒŒè§’å¹¿åŠ¨åŠ›ç¥žç»å ƒçš„æŠ‘åˆ¶ä½œç”¨.

OBJECTIVES: To observe the analgesic effects of different levels and intensities of electrical stimulation on the local acupoints in the pain source area and their impact on wide dynamic range (WDR) neurons in the spinal dorsal horn, in order to provide a basis for selecting appropriate parameters for electroacupuncture (EA) stimulation. METHODS: Wistar rats were used in 3 parts of the experiment. Complete Freund's adjuvant was used to establish a model of inflammation-induced pain in the gastrocnemius muscle. After modeling, 6 rats were randomly selected for multi-channel extracellular electrophysiological recording of the electrical activity of WDR neurons, to determine the threshold for activating the A-component (Ta) and the C-component (Tc), which were used as the intervention intensities for skin transcutaneous electrical acupoint stimulation (TEAS) or EA. Thirty-six rats were randomly divided into normal , model , TEAS-Ta , TEAS-Tc, EA-Ta , and EA-Tc groups, with 6 rats in each group. In the pain source area , Ta or Tc intensity of TEAS or EA intervention at"Chengshan"(BL57) was performed for 30 min each time, once a day, for 3 consecutive days. A small animal pressure pain measurement instrument was used to measure the mechanical pressure pain threshold of the gastrocnemius muscle in rats, and the Von Frey filament was used to measure the mechanical pain threshold of the footpad. Thirteen rats were randomly selected to observe the immediate responsiveness of WDR neurons to Ta/Tc intensity of EA or TEAS in BL57. RESULTS: The thresholds of TEAS to activate WDR neuron A-component or C-component were (2.43±0.57) mA and (7.00±1.34) mA, respectively, while the thresholds for EA to activate muscle WDR neuron A-component or C-component were (0.72±0.34) mA and (1.58±0.35) mA, respectively. After injection of CFA into the gastrocnemius muscle, compared with the normal group both the mechanical pressure pain threshold of the gastrocnemius muscle and the mechanical pain threshold of the footpad of rats in the model group were significantly decreased (P<0.001). After TEAS-Ta, TEAS-Tc or EA-Ta intervention in the BL57, both the mechanical pressure pain threshold of the gastrocnemius muscle and the mechanical pain threshold of the footpad were significantly higher than those in the model group (P<0.05, P<0.001). Compared with the normal group, the electrical threshold for evoking WDR neuron C-component discharge was significantly decreased (P<0.001) in the model group, while increased after TEAS-Ta, TEAS-Tc, or EA-Ta intervention (P<0.01) compared with the model group. The evoked discharge frequency of muscle WDR neurons decreased significantly after immediate intervention with TEAS-Ta, TEAS-Tc, or EA-Ta (P<0.01, P<0.05). EA-Tc had no significant improvement on the evoked electrical activity of WDR neurons or pain behavior. CONCLUSIONS: TEAS-Ta, TEAS-Tc, or EA-Ta can all alleviate the local and footpad mechanical pain in rats with muscle inflammation and inhibit the responsiveness of WDR neurons, indicating that different intensities are required for analgesic effects at different levels of acupoints in the pain source area.

Warm Acupuncture Reduces Pain and Inflammation in Rats with Lumbar Disc Herniation Induced by Autologous Nucleus Pulposus Transplantation via Regulating p38MAPK/NF-κB Pathway.

Background: : Warm acupuncture (WA) has analgesic and anti-inflammatory effects. However, the underlying mechanism of these effects remain unclear. Objectives: : To explore the analgesic and anti-inflammatory effects of WA and the potential underlying mechanism in male Sprague-Dawley rats with non-compressive lumbar disk herniation (LDH) caused by autologous nucleus pulposus (NP) transplantation. Methods: : We used low-frequency (2 Hz) electrical stimulation and WA (40℃) to treat GB30 and BL54 acupoints in rats for 30 mins per day. We monitored the paw withdrawal threshold of rats during the experiment and measured serum cytokine levels using commercial kits. Dorsal root ganglion (DRG) tissue pathology was analyzed via H&E staining. We used qRT-PCR to measure the mRNA expression levels of IL-1ß, IL-6, and TNF-α genes in DRG. Western blot was used to analyze the expression levels of IL-1ß, IL-6, TNFα, P-p38MAPK, p38MAPK, P-IκBα, IκB α, and NF-κB p65 proteins. Results: : WA treatment significantly increased the pain threshold of rats, reduced serum IL-6, PEG2, NO, SP, NP-Y, and MMP-3 levels, and effected histopathological improvements in the DRG in rats. Moreover, WA treatment significantly downregulated the expression levels of inflammation-associated genes (Il-1ß, Il-6, and Tnf-α) and proteins (IL-1ß, IL-6, TNF-α, P-p38MAPK, P-IκBα, and NF-κB p65) in the DRG of non-compressive LDH rats. Conclusion: : WA can alleviate pain and inhibit inflammatory response in rats with non-compressive LDH caused by autologous NP transplantation, and these effects are likely associated with the inhibition of the p38MAPK/NF-κB pathway.

Do interventions for mood improve inflammatory biomarkers in inflammatory bowel disease?: a systematic review and meta-analysis.

BACKGROUND: Psychoneuroimmunological mechanisms and the gut-brain axis appear relevant to disease activity and progression in Inflammatory Bowel Disease (IBD). A recent review showed no effect of psychological therapies on self-reported disease activity in IBD. This meta-analysis aims to establish whether interventions targeting mood outcomes (e.g., depression, anxiety and stress) impact inflammation levels in IBD and possible moderators of these effects. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. We searched five electronic databases and included randomised controlled trials where interventions targeted mood and assessed inflammatory outcomes pre- and post-intervention in adults with IBD. Independent reviewers screened studies, extracted data, and assessed methodological quality. Data were pooled to estimate standardised mean differences (SMDs) with 95% Confidence Intervals (CIs). A random-effects robust variance estimation accounted for studies measuring multiple biomarkers. Intervention type, mood as a primary or secondary outcome, effect on mood outcomes and IBD subtype were investigated as treatment effect moderators. Where there were sufficient biomarkers, individual meta-analyses were run (Pre-registration PROSPERO: CRD42023389401). FINDINGS: 28 RCTs involving 1789 participants met inclusion criteria. Interventions demonstrated small, statistically significant effects on biomarkers (-0.35, 95% CI: -0.48, -0.22, p < 0.001) and medium effects on mood outcomes (-0.50, 95% CI: -0.73, -0.27, p < 0.001), without evidence of substantive heterogeneity or publication bias. Individual analyses showed small effects for improved faecal calprotectin (-0.19, 95% CI: -0.34, -0.03, p = 0.018) and C-Reactive Protein (-0.29, 95% CI: -0.47, -0.10, p = 0.002). Effect sizes were larger for psychological therapy interventions (compared with exercise or antidepressants) and when there was an effect (SMD ≥0.2) on mood. INTERPRETATION: Treatments which address mood outcomes have beneficial effects on generic inflammation as well as disease-specific biomarkers (faecal calprotectin and C-Reactive Protein). Psychological interventions and interventions with larger treatment effects on mood accentuated the effect on biomarkers. More research is required to understand the biological or behavioural mechanisms underlying this effect. FUNDING: The Medical Research Council and the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre.

The Impact of Mindfulness Treatment on Maternal Inflammation and Fetal Neurodevelopment Among Participants with Histories of Hypertensive Disorders.

This was a secondary analysis of a prenatal mindfulness training (MT) RCT versus treatment as usual (TAU) on neutrophil-to-lymphocyte ratio (NLR), a measure of maternal inflammation, and fetal head circumference. Fifteen participants were randomized to MT and 14 to TAU. NLR in third trimester was significantly lower in the MT group (F = 7.11, p = 0.019) relative to those in TAU. Higher NLR values in second (r = -0.644, p = 0.013) and third trimesters (r = -0.601, p = 0.030) were associated with lower fetal HC%. There was no group difference in fetal HC%. A future, fully powered study is needed to replicate these findings. Clinical Trials Number: NCT03679117.

Transcutaneous electrical acupoint stimulation attenuated neuroinflammation and oxidative stress by activating SIRT1-induced signaling pathway in MCAO/R rat models.

BACKGROUND: Silent information regulator 1 (SIRT1) plays a beneficial role in cerebral ischemic injury. Previous reports have demonstrated that transcutaneous electrical acupoint stimulation (TEAS) exerts a beneficial effect on ischemic stroke; however, whether SIRT1 participates in the underlying mechanism for the neuroprotective effects of TEAS against ischemic brain damage has not been confirmed. METHODS: The rat models of middle cerebral artery occlusion/reperfusion (MCAO/R) were utilized in the current experiment. After MCAO/R surgery, rats in TEAS, EC and EX group received TEAS intervention with or without the injection of EX527, the SIRT1 inhibitor. Neurological deficit scores, infarct volume, hematoxylin eosin (HE) staining and apoptotic cell number were measured. The results of RNA sequencing were analyzed to determine the differential expression changes of genes among sham, MCAO and TEAS groups, in order to investigate the possible pathological processes involved in cerebral ischemia and explore the protective mechanisms of TEAS. Moreover, oxidative stress markers including MDA, SOD, GSH and GSH-Px were measured with assay kits. The levels of the proinflammatory cytokines, such as IL-6, IL-1ß and TNF-α, were detected by ELISA assay, and Iba-1 (the microglia marker protein) positive cells was measured by immunofluorescence (IF). Western blot and IF were utilized to examine the levels of key molecules in SIRT1/FOXO3a and SIRT1/BRCC3/NLRP3 signaling pathways. RESULTS: TEAS significantly decreased brain infarcted size and apoptotic neuronal number, and alleviated neurological deficit scores and morphological injury by activating SIRT1. The results of RNA-seq and bioinformatic analysis revealed that oxidative stress and inflammation were the key pathological mechanisms, and TEAS alleviated oxidative injury and inflammatory reactions following ischemic stroke. Then, further investigation indicated that TEAS notably attenuated neuronal apoptosis, neuroinflammation and oxidative stress damage in the hippocampus of rats with MCAO/R surgery. Moreover, TEAS intervention in the MCAO/R model significantly elevated the expressions of SIRT1, FOXO3a, CAT, BRCC3, NLRP3 in the hippocampus. Furthermore, EX527, as the inhibitor of SIRT1, obviously abolished the anti-oxidative stress and anti-neuroinflammatory roles of TEAS, as well as reversed the TEAS-mediated elevation of SIRT1, FOXO3a, CAT and reduction of BRCC3 and NLRP3 mediated by following MCAO/R surgery. CONCLUSIONS: In summary, these findings clearly suggested that TEAS attenuated brain damage by suppressing apoptosis, oxidative stress and neuroinflammation through modulating SIRT1/FOXO3a and SIRT1/BRCC3/NLRP3 signaling pathways following ischemic stroke, which can be a promising treatment for stroke patients.

Electroacupuncture alleviates intrauterine adhesion through regulating autophagy in rats.

Autophagy is a well-conserved metabolic system that maintains homeostasis by relying on lysosomal breakdown. The endometrium of patients with intrauterine adhesion (IUA) and an animal model exhibits impaired autophagy. Autophagy is negatively correlated with inflammation. Activation of autophagy can inhibit the inflammatory response, while defects in autophagy will activate the inflammatory response. Here, we studied whether electroacupuncture (EA) inhibits inflammation and promotes endometrial injury repair by activating endometrial autophagy. The IUA animal model was established by mechanical injury plus lipopolysaccharide infection. EA stimulation was applied to the acupoints Guanyuan (CV4), bilateral Sanyinjiao (SP6), and Zusanli (ST36). The results indicated that EA could improve endometrial morphology, attenuate endometrial fibers, and enhance endometrial receptivity in the rat. EA could increase the autophagosomes of endometrial epithelial cells, increase the levels of LC3 and Beclin1, and decrease the level of p62. Additionally, EA may also suppress the nuclear factor kappa-B (NF-κB) signaling pathway and reduce the release of inflammatory factors. Additionally, the effect of EA was comparable to that of the autophagy agonist rapamycin, and the autophagy inhibitor 3-methyladenine reversed the therapeutic effect of EA. Therefore, we assume that EA may facilitate endometrial healing by activating autophagy and reducing NF-κB signal pathway-mediated inflammation.

Anti-inflammatory effects of acupuncture in the treatment of chronic obstructive pulmonary disease.

Numerous randomised controlled trials have suggested the positive effects of acupuncture on chronic obstructive pulmonary disease (COPD). However, the underlying therapeutic mechanisms of acupuncture for COPD have not been clearly summarized yet. Inflammation is central to the development of COPD. In this review, we elucidate the effects and underlying mechanisms of acupuncture from an anti-inflammatory perspective based on animal studies. Cigarette smoke combined with lipopolysaccharide is often used to establish animal models of COPD. Electroacupuncture can be an effective intervention to improve inflammation in COPD, and Feishu (BL13) and Zusanli (ST36) can be used as basic acupoints in COPD animal models. Different acupuncture types can regulate different types of inflammatory cytokines; meanwhile, different acupuncture types and acupoint options have similar effects on modulating the level of inflammatory cytokines. In particular, acupuncture exerts anti-inflammatory effects by inhibiting the release of inflammatory cells, inflammasomes and inflammatory cytokines. The main underlying mechanism through which acupuncture improves inflammation in COPD is the modulation of relevant signalling pathways: nuclear factor-κB (NF-κB) (e.g., myeloid differentiation primary response 88/NF-κB, toll-like receptor-4/NF-κB, silent information regulator transcript-1/NF-κB), mitogen-activated protein kinase signalling pathways (extracellular signal-regulated kinase 1/2, p38 and c-Jun NH2-terminal kinase), cholinergic anti-inflammatory pathway, and dopamine D2 receptor pathway. The current synthesis will be beneficial for further research on the effect of acupuncture on COPD inflammation. Please cite this article as: Jiang LH, Li PJ, Wang YQ, Jiang ML, Han XY, Bao YD, Deng XL, Wu WB, Liu XD. Anti-inflammatory effects of acupuncture in the treatment of chronic obstructive pulmonary disease. J Integr Med. 2023; 21(6): 518-527.

Electroacupuncture Stimulation Alleviates Inflammatory Pain in Male Rats by Suppressing Oxidative Stress.

In the present study, we focused on whether the analgesic effect of Electroacupuncture (EA) is related to the regulation of oxidative stress. We established a chronic inflammatory pain model in male rats by a single injection of complete Freund's adjuvant (CFA) and then treated the animals with daily EA stimulation at the site of "zusanli". The analgesic effect of EA was evaluated by measuring the paw withdrawal threshold (PWT) when rats received mechanical and thermal pain stimulation. The levels of inflammation-related molecules and oxidative stress-related markers in the spinal cord were measured by western blotting or ELISA kits. EA stimulation and antioxidants effectively increased the PWT in CFA rats. Co-treatment of CFA rats with the ROS donor t-butyl hydroperoxide (t-BOOH) further decreased the PWT and weakened the analgesic effect of EA. EA treatment inhibited inflammation and oxidative stress, as shown by decreased levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and MDA and increased activity of SOD and catalase. Moreover, EA reduced the expression of p-p38, p-ERK, and p-p65 and simultaneously downregulated the expression of TRPV1 and TRPV4 in CFA rats. In an in vitro study, direct stimulation with t-BOOH to the C6 cells increased the production of TNF-alpha, IL-1beta, IL-6, activated p38, ERK, and p65 and up-regulated the expression of TRPV1 and TRPV4, and these effects could be prevented by the ROS scavenger PBN. Taken together, our data indicate that the inhibition of oxidative stress and the generation of ROS contribute to the analgesic effect of EA in male CFA rats.

Electroacupuncture Relieves HuR/KLF9-Mediated Inflammation to Enhance Neurological Repair after Spinal Cord Injury.

Electroacupuncture (EA) is widely applied in clinical therapy for spinal cord injury (SCI). However, the associated molecular mechanism has yet to be elucidated. The current study aimed to investigate the underlying mechanism of EA in neurologic repair after SCI. First, we investigated the role of EA in the neurologic repair of the SCI rat model. The expression levels of human antigen R (HuR) and Krüppel-like factor 9 (KLF9) in spinal cord tissues were quantified after treatment. Second, we conducted bioinformatics analysis, RNA pull-down assays, RNA immunoprecipitation, and luciferase reporter gene assay to verify the binding of HuR and KLF9 mRNA for mRNA stability. Last, HuR inhibitor CMLD-2 was used to verify the enhanced effect of EA on neurologic repair after SCI via the HuR/KLF9 axis. Our data provided convincing evidence that EA facilitated the recovery of neuronal function in SCI rats by reducing apoptosis and inflammation of neurons. We found that EA significantly diminished the SCI-mediated upregulation of HuR, and HuR could bind to the 3' untranslated region of KLF9 mRNA to protect its decay. In addition, a series of in vivo experiments confirmed that CMLD-2 administration increased EA-mediated pain thresholds and motor function in SCI rats. Collectively, the present study showed that EA improved pain thresholds and motor function in SCI rats via impairment of HuR-mediated KLF9 mRNA stabilization, thus providing a better understanding of the regulatory mechanisms regarding EA-mediated neurologic repair after SCI.

An Immunomodulatory Hydrogel by Hyperthermia-Assisted Self-Cascade Glucose Depletion and ROS Scavenging for Diabetic Foot Ulcer Wound Therapeutics.

Current therapeutic protocols for diabetic foot ulcers (DFUs), a severe and rapidly growing chronic complication in diabetic patients, remain nonspecific. Hyperglycemia-caused inflammation and excessive reactive oxygen species (ROS) are common obstacles encountered in DFU wound healing, often leading to impaired recovery. These two effects reinforce each other, forming an endless loop. However, adequate and inclusive methods are still lacking to target these two aspects and break the vicious cycle. This study proposes a novel approach for treating DFU wounds, utilizing an immunomodulatory hydrogel to achieve self-cascade glucose depletion and ROS scavenging to regulate the diabetic microenvironment. Specifically, AuPt@melanin-incorporated (GHM3) hydrogel dressing is developed to facilitate efficient hyperthermia-enhanced local glucose depletion and ROS scavenging. Mechanistically, in vitro/vivo experiments and RNA sequencing analysis demonstrate that GHM3 disrupts the ROS-inflammation cascade cycle and downregulates the ratio of M1/M2 macrophages, consequently improving the therapeutic outcomes for dorsal skin and DFU wounds in diabetic rats. In conclusion, this proposed approach offers a facile, safe, and highly efficient treatment modality for DFUs.

Revealing the biological mechanism of acupuncture in alleviating excessive inflammatory responses and organ damage in sepsis: a systematic review.

Sepsis is a systemic inflammation caused by a maladjusted host response to infection. In severe cases, it can cause multiple organ dysfunction syndrome (MODS) and even endanger life. Acupuncture is widely accepted and applied in the treatment of sepsis, and breakthroughs have been made regarding its mechanism of action in recent years. In this review, we systematically discuss the current clinical applications of acupuncture in the treatment of sepsis and focus on the mechanisms of acupuncture in animal models of systemic inflammation. In clinical research, acupuncture can not only effectively inhibit excessive inflammatory reactions but also improve the immunosuppressive state of patients with sepsis, thus maintaining immune homeostasis. Mechanistically, a change in the acupoint microenvironment is the initial response link for acupuncture to take effect, whereas PROKR2 neurons, high-threshold thin nerve fibres, cannabinoid CB2 receptor (CB2R) activation, and Ca2+ influx are the key material bases. The cholinergic anti-inflammatory pathway of the vagus nervous system, the adrenal dopamine anti-inflammatory pathway, and the sympathetic nervous system are key to the transmission of acupuncture information and the inhibition of systemic inflammation. In MODS, acupuncture protects against septic organ damage by inhibiting excessive inflammatory reactions, resisting oxidative stress, protecting mitochondrial function, and reducing apoptosis and tissue or organ damage.

Effects of Dopamine on stem cells and its potential roles in the treatment of inflammatory disorders: a narrative review.

Inflammation is the host's protective response against harmful external stimulation that helps tissue repair and remodeling. However, excessive inflammation seriously threatens the patient's life. Due to anti-inflammatory effects, corticosteroids, immunosuppressants, and monoclonal antibodies are used to treat various inflammatory diseases, but drug resistance, non-responsiveness, and severe side effect limit their development and application. Therefore, developing other alternative therapies has become essential in anti-inflammatory therapy. In recent years, the in-depth study of stem cells has made them a promising alternative drug for the treatment of inflammatory diseases, and the function of stem cells is regulated by a variety of signals, of which dopamine signaling is one of the main influencing factors. In this review, we review the effects of dopamine on various adult stem cells (neural stem cells, mesenchymal stromal cells, hematopoietic stem cells, and cancer stem cells) and their signaling pathways, as well as the application of some critical dopamine receptor agonists/antagonists. Besides, we also review the role of various adult stem cells in inflammatory diseases and discuss the potential anti-inflammation function of dopamine receptors, which provides a new therapeutic target for regenerative medicine in inflammatory diseases.

Peripheral Activation of Formyl Peptide Receptor 2/ALX by Electroacupuncture Alleviates Inflammatory Pain by Increasing Interleukin-10 Levels and Catalase Activity in Mice.

In the context of the electroacupuncture (EA) neurobiological mechanisms, we have previously demonstrated the involvement of formyl peptide receptor 2 (FPR2/ALX) in the antihyperalgesic effect of EA. The present study investigated the involvement of peripheral FPR2/ALX in the antihyperalgesic effect of EA on inflammatory cytokines levels, oxidative stress markers and antioxidant enzymes in an animal model of persistent inflammatory pain. Male Swiss mice underwent intraplantar (i.pl.) injection with complete Freund's adjuvant (CFA). Mechanical hyperalgesia was assessed with von Frey monofilaments. Animals were treated with EA (2/10 Hz, ST36-SP6, 20 minutes) for 4 consecutive days. From the first to the fourth day after CFA injection, animals received i.pl. WRW4 (FPR2/ALX antagonist) or saline before EA. Levels of inflammatory cytokines (TNF, IL-6, IL-4 and IL-10), antioxidant enzymes (catalase and superoxide dismutase), oxidative stress markers (TBARS, protein carbonyl, nitrite/nitrate ratio), and myeloperoxidase activity were measured in paw tissue samples. As previously demonstrated, i.pl. injection of the FPR2/ALX antagonist prevented the antihyperalgesic effect induced by EA. Furthermore, animals treated with EA showed higher levels of IL-10 and catalase activity in the inflamed paw, and these effects were prevented by the antagonist WRW4. EA did not change levels of TNF and IL-6, SOD and MPO activity, and oxidative stress markers. Our work demonstrates that the antihyperalgesic effect of EA on CFA-induced inflammatory pain could be partially associated with higher IL-10 levels and catalase activity, and that these effects may be dependent, at least in part, on the activation of peripheral FPR2/ALX.

Effect of 10.6 µm laser moxibustion on inflammation in diabetic peripheral neuropathy rats.

Diabetic peripheral neuropathy (DPN) is the main cause of disability in diabetes patients but the efficacy of available drugs is poor. Moxibustion is an adjunctive treatment for DPN that can reduce symptoms. The peak value of the far infrared wavelength of 10.6 µm laser moxibustion is close to the infrared radiation spectrum of traditional moxibustion. Its effect is similar to that of moxibustion and does not cause pain, infection or produce irritating smoke. Twenty-four male SD rats were divided into control (Con), DPN, laser moxibustion (LM), and pyrrolidine dithiocarbamate (PDTC) groups (n=6/group). The DPN, LM and PDTC group rats were intraperitoneally injected with 1% streptozotocin (STZ) to induce a model of DPN. LM group rats were irradiated with a laser at bilateral ST36 acupoints for 15 min, once every other day, for 14 days. PDTC group rats were intraperitoneally injected with PDTC once a day. Body weight, blood glucose, and paw withdrawal mechanical threshold (PWMT) were measured and laser speckle imaging (LSI) performed before and after modeling and at 1 and 2 weeks after intervention. Two weeks after intervention, changes in serum interleukin 1ß (IL1ß), interleukin 6 (IL6), tumor necrosis factor α (TNFα) and nerve growth factor (NGF) were analyzed, and the abundance of NF-κB and IκB-α proteins and levels of NF-κB and IκB-α mRNAs in the sciatic nerve were observed. The results showed that 10.6 µm laser moxibustion can relieve pain, improve microcirculation, and alleviate inflammation in DPN rats, possibly via the NF-κB inflammatory pathway.

[Research progress of acupuncture-moxibustion in treatment of spinal cord injury through mediating inflammatory reaction].

Inflammatory reaction after spinal cord injury (SCI) is the main obstacle to the recovery of neural function. In the occurrence and development of SCI, the complex regulatory mechanisms are involved in inflammatory reaction, including the activation of inflammatory cells (e.g.macrophages and microglia), and the release of cytokines (e.g. tumor necrosis factor, interleukin and chemokines). Acupuncture-moxibustion is significantly effective in clinical treatment of SCI, and its mechanism is related to adjusting the function of inflammatory cells after SCI, modulating the expression of cytokines and the activation of NLRP3 inflammatory bodies, as well as the expression of high mobility group protein B1 and calcitonin gene related peptide. This article summarizes the research progress of mechanism of inflammatory reaction after SCI and the effects of acupuncture-moxibustion intervention in recent years so that the new ideas can be provided to clarify the pathogenesis of SCI and the effect of acupuncture-moxibustion intervention.

Anti-inflammatory mechanism of electroacupuncture involves the modulation of multiple systems, levels and targets and is not limited to "driving the vagus-adrenal axis".

In October 2021, an international collaborative study on the use of electroacupuncture (EA) to treat inflammation was published in the journal Nature by Dr. Qiufu Ma's team. Based on the results of EA on inflammation in the mouse model of lipopolysaccharide inflammatory storm, the study showed that the distal effect of acupuncture can be achieved by "driving the vagus-adrenal axis (through the adrenal medulla, by releasing catecholamines)." PROKR2Cre-marked sensory neurons, which innervate the deep hindlimb fascia but not the abdominal fascia, are crucial for driving this axis. The study suggests the existence of specificity distribution of acupoints, that different EA stimulation intensities or different needle penetration depths have different therapeutic effects, that photosensitive stimulation may be a substitute for needle acupuncture, and that massage, stretching and body movements may also activate PROKR2Cre-markable dorsal root ganglion sensory neurons and elicit anti-inflammatory effects. However, results of some other studies are contrary to the conclusions of Ma's team. For examples: low-intensity EA at GB30 point significantly reduced the inflammation in the rat model of persistent inflammation, which is more relevant to the real daily acupuncture practice, and this effect was partly related to the adrenal cortex and associated with the stimulation of corticosterone and adrenocorticotropic hormone; manual acupuncture (similar to the low-intensity EA) at KI3, Zhichuan point (an extra point), etc. was effective in a severe COVID-19 patient with sepsis; stimulating ST25 with low-intensity EA or manual acupuncture was effective against gastrointestinal inflammations; the above mentioned points are not in an area enriched with PROKR2Cre-marked sensory nerve endings. Evidence shows that the mechanism of EA against inflammation includes modulating multi-systems, multi-levels and multi-targets, which does not limit to "driving the vagus-adrenal axis." Please cite this article as: Fan AY. Anti-inflammatory mechanism of electroacupuncture involves the modulation of multiple systems, levels and targets and is not limited to "driving the vagus-adrenal axis." J Integr Med. 2023; 21(4):320-323.