Scorpion venom polypeptide governs alveolar macrophage M1/M2 polarization to alleviate pulmonary fibrosis.

The onset of connective tissue disease-related interstitial lung disease (CTD-ILD) is generally insidious and progressive, with pulmonary fibrosis in the middle stage, and eventually respiratory failure and death. This study aimed to explore the role of scorpion venom polypeptide (SVP), the primary active constituent of the entire scorpion, in alveolar macrophages and pulmonary fibrosis. Pulmonary fibrosis mouse models were established, and then SVP and JAK inhibitor (tofacitinib) was used to treat models. Alveolar macrophages were isolated and the impacts of SVP on M1/M2 polarization and the JAK/STAT6 pathway in vitro were assessed. H&E and Masson staining revealed that SVP and tofacitinib treatment alleviated lung damage and fibrosis. They also hindered the M2-polarization of macrophages in lung tissue and declined cytokine levels associated with M2 polarization (IL-4, IL-13) and fibrosis drivers (TGF-ß, VEGF) in mice. Consistent with the trend presented by tofacitinib treatment, SVP suppressed the phosphorylation of proteins in the JAK/STAT6 pathway. In addition, the in vitro treatment of SVP on the isolated macrophages represented consistent results with in vivo experiments. The findings of the present study indicated that SVP suppressed the JAK/STAT6 signaling pathway, hindered alveolar macrophage M2-type polarization, and possessed the potential to ameliorate pulmonary fibrosis.

ST36 Acupuncture Alleviates the Inflammation of Adjuvant-Induced Arthritic Rats by Targeting Monocyte/Macrophage Modulation.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic systemic chronic autoimmune disease characterized by the aggregation of immune cells and secretion of cytokines in the joint synovium, causing hyperblastosis and even bone destruction. Acupuncture has been proven effective in RA treatment. This study aimed to investigate the anti-inflammatory action of acupuncture, specifically, in relation to immune cell interactions and key mediators. METHODS: Rats with adjuvant-induced arthritics (AIA) were treated with manual acupuncture (MA) at Zusanli (ST36). Joint edema and paw withdrawal latency were monitored to observe the effects on inflammation. The levels of 24 cytokines, chemokines, and growth factors in ankle joints during the treatment (on days 1, 7, 15, and 21) were detected by multiplex immunoassay. A bioinformatics analysis based on a directed weighted mathematical model was used to construct cell communication network diagrams and identify the key cells through calculation. The monocyte/macrophage polarization in inflamed joints was investigated by detecting M1- and M2-phenotypic populations and their related cytokines. RESULTS: ST36 MA alleviated paw edema and upregulated the nociceptive threshold of AIA rats. Several innate and adaptive immune cytokines were dynamically regulated by MA, and MA-treated rats showed a significant improvement in symptoms compared with AIA rats by day 21. The immune cell-cell communication networks were intensified with the development of RA but were significantly reduced after treatment with MA. MA was found to specifically regulate monocytes/macrophages in inflamed ankle joints ST36 MA also inhibited M1-phenotype macrophages accompanied by decreased levels of IL-1ß. CONCLUSIONS: ST36 MA showed anti-inflammatory and analgesic effects as well as inhibition of immune cell communication networks in inflamed joints of AIA rats. Inhibiting the polarization of macrophages to the M1-phenotype in inflamed joints may be one of the key mechanisms of MA anti-inflammatory action. This research highlighted a systematic research paradigm for investigating mechanisms of acupuncture action.

Chemokine CXCL1 in serum mediates the antinociceptive effect of manual acupuncture at ST36.

BACKGROUND: Inflammatory pain is the most common type of pain encountered clinically. The analgesic effect of acupuncture has been well-documented. OBJECTIVE: The aim of this study was to investigate the involvement of chemokine CXCL1 in the serum on manual acupuncture (MA)-induced antinociception. METHODS: Rats with inflammatory pain of the right hind paw were induced by intraplantar (i.pl.) administration of complete Freund's adjuvant (CFA). After wards, the CFA-injected rats were treated daily with MA at ST36 from Day 1 to Day 7, and thermal nociceptive thresholds (paw withdrawal latency; PWL) were analyzed. The concentration of CXCL1 in the serum of the rats was measured by enzyme-linked immunosorbent assay (ELISA) after the first and the last MA treatment. Subsequently, the rats were injected with two doses (5 or 10 µg) of recombinant CXCL1 through the tail vein daily from Day 1 to Day 7 or injected with two doses (6.4 or 16 µg) of anti-CXCL1 antibody using the same methods and course at 30 min before MA, and the PWLs were measured again. Finally, naloxone (500 µg, 0.1 mL) was administered by i.pl. injection into the inflamed paw 5 min before the last MA treatment or last injection of recombinant CXCL1. RESULTS: MA significantly increased the PWLs and upregulated the expression of serum CXCL1 in the CFA-injected rats. Without acupuncture, repeated tail vein injection of recombinant CXCL1 showed an analgesic effect on CFA-induced inflammatory pain. Conversely, the neutralization of serum CXCL1 by anti-CXCL1 antibody decreased MA-induced antinociception in a time-dependent manner. Anti-CXCL1 antibody injected just once before the first MA did not affect MA-induced antinociception. The analgesic effects of MA and recombinant CXCL1 were reversed by an i.pl. injection of naloxone. CONCLUSION: This study indicates MA at ST36 had an analgesic effect on inflammatory pain and found a novel function of CXCL1. Increased serum CXCL1 had an antinociceptive effect on inflammatory pain induced by CFA. CXCL1 in serum appeared to be a key molecule involved in the peripheral mechanism of MA-induced antinociception. The analgesic effect of MA or recombinant CXCL1 on inflammatory pain might be mediated through a peripheral opioid pathway, which needs further investigation.

Applying Complex Network and Cell-Cell Communication Network Diagram Methods to Explore the Key Cytokines and Immune Cells in Local Acupoint Involved in Acupuncture Treating Inflammatory Pain.

Manual acupuncture (MA) can effectively treat a variety of diseases, but its specific mechanism remains unclear. The "acupoint network" activated by MA participates in MA signal transduction, in which immune-related cells and cytokines play an important role. However, which cells and cytokines in the acupoint have changed after MA? What is the network relationship between them? Which cells and cytokines may play the most important role in MA effect? These problems are unclear. In this study, on the basis of affirming the analgesic, detumescence, and anti-inflammatory effect of MA, the concentration of 24 cytokines in ST36 acupoint in rats with inflammatory pain after MA treatment was detected by multiplex immunoassay technology. Then, using statistical and complex network and cell-cell communication (CCC) network diagram method to analyze the detected data depicts the network relationship between the cytokines and related cells objectively and establishes cytokine connection network and CCC network, respectively. The results showed that MA reinforced communication intensity between cells while reducing the overall correlation intensity. On this basis, the key cytokines and key cells at three MA time-points were screened out, cytokines IL-6, MCP-1, fibroblasts cell, and monocyte macrophage screened by the three methods at three MA time-points might be the key cytokines or key cells. After that, we detected the macrophages in ST36 acupoint by flow cytometry and immunofluorescence and found that the relative amount of macrophages increased significantly after MA, especially the macrophage of the dermis of skin. This study provided a basis for revealing the initiated mechanism of MA effect.

Acupuncture Alleviates Rheumatoid Arthritis by Immune-Network Modulation.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory and debilitating disease that involves the systemic imbalance of the immune network. Previous studies have shown that acupuncture can help treat RA. However, its specific mechanisms are not fully understood. Thus, the present study was designed to clarify the mechanisms of acupuncture acted on RA via immune network modulation using complete Freund's adjuvant (CFA)-induced arthritic rats. Results revealed that manual acupuncture (MA) could alleviate the inflammation and pain of infected joints. Moreover, MA could effectively stimulate the innate immune cytokines (IL-1[Formula: see text], IL-1[Formula: see text], IL-6, IL-7, IL-18, TNF-[Formula: see text]) and adaptive immunity cytokines (IL-2, IL-12, IFN-[Formula: see text], IL-4, IL-5, IL-10, IL-13, IL-17) as the main part of the immune response and repaired damage of RA. These complex immunomodulatory processes were analyzed quantitatively by cell-cell communication (CCC) networks. The CCC networks demonstrated that the immune networks were enhanced with the development of RA, while MA enhanced the immune networks in the early stage to act on RA and promoted the immune-network to a normal level at the late stage. Moreover, we found that monocyte/macrophage and endothelial cells were the key cells of innate immunity and body cells; TH1, TH2 and B cells were the key cells of adaptive immunity, which were also the main target cells for MA regulation.

A New Theory for Acupuncture: Promoting Robust Regulation.

Robustness, an ability of biological networks to uphold their functionalities in the face of perturbations, is a key characteristic of all living systems. Acupuncture is a procedure in which fine needles are inserted into an individual at discrete points and then manipulated, with the intent of preventing and curing diseases. Acupuncture does not directly eliminate pathogenic factors or pathological tissue; rather, acupuncture enhances the ability of the human body to self-medicate itself by activating complex regulatory systems and by maintaining physiological homeostasis to prevent or treat diseases. From this point of view, the effect of acupuncture on the human body is more likely a kind of regulation to promote robustness. That is to say, acupuncture has the ability to promote robustness. In this article, we review the properties and functions of acupuncture in preventing and treating diseases and in maintaining health by enhancing robustness.

[Literature study for acupoint selection rule of rheumatoid arthritis treated with acupuncture].

To explore the clinical acupoint selection rule of rheumatoid arthritis(RA) treated with acupuncture by literature analysis. The related articles were retrieved in 6 Chinese and English databases,including CNKI,VIP,WANFANG,PubMed,Medline and Cochrane. We established a holistic acupoint database and a disease location acupoint database. The results show that there are 120 acupuncture prescriptions and 143 acupoints,with the highest frequency of Zusanli(ST 36). Local acupoints are mainly used for disease locations. The highest acupoin-tcombination frequency of 32 for mandibular joint shows Kunlun(BL 60) and Jiexi(ST 41);22 for finger joint,Baxie(EX-UE 9) and Zusanli(ST 36);28 for wrist joint,Yangxi(LI 5) and Yangchi(TE 4);24 for elbow joint,Quchi(LI 11) and Zusanli(ST 36);21 for shoulder joint,Jianyu(LI 15) and Zusanli(ST 36);13 for spine joint,Yaoyangguan(GV 3) and Shenzhu(GV 12);18 for hip joint,Zhibian(BL 54) and Huantiao(GB 30);20 for knee joint,Shenshu(BL 23) and Yanglingquan(GB 34);32 for ankle joint,Kunlun(BL 60) and Jiexi(ST 41);22 for toe joint,Baxie(EX-UE 9) and Zusanli(ST 36);25 for whole body joints,Yanglingquan(GB 34) and Zusanli(ST 36). Thirty new acupoint prescriptions are found by entropy clustering analysis for different disease regions induced by RA. There exists the acupoint selection rule for acupuncture treating RA and the new prescriptions need to be clinical verification.

Efficacy and safety of manual acupuncture manipulations with different frequencies on epigastric pain syndrome (EPS) in functional dyspepsia (FD) patients: study protocol for a randomized controlled trial.

BACKGROUND: Manual acupuncture (MA) manipulations are one of the key factors influencing acupuncture effects in traditional Chinese medicine theory. Different MA manipulations contain different stimulating parameters, thus generating different acupuncture responses or effects. Evidence has demonstrated that acupuncture is effective for functional dyspepsia (FD). However, the effects of different stimulating parameters of MA manipulations on FD remain unclear. METHODS/DESIGN: This study is a randomized controlled trial with a four-arm, parallel-group structure. Patients with FD with epigastric pain syndrome (EPS) will be included and randomly allocated into four groups: three MA manipulation groups (separately treated with a frequency of 1 Hz, 2 Hz, or 3 Hz) and a control group. All groups will receive omeprazole as a basic treatment and acupuncture: in the MA manipulation groups, the needles will be manipulated manually with three different frequencies on the basis when de qi is reached, while in the control group, the needles will be inserted without any manipulation. All patients will receive acupuncture treatment of five consecutive sessions per week for 2 weeks and be followed up at 4, 8, and 12 weeks. The primary outcomes of the study include patients' response to the treatment. The secondary outcomes include dyspeptic symptoms, quality of life, mental status, fasting serum gastrin, motilin, and ghrelin concentrations, and adverse events. The protocol was approved by the Ethics committee of the First Affiliated Hospital of Zhejiang Chinese Medical University (2016-K-057-01). DISCUSSION: The aim of this study is to evaluate the efficacy and safety of MA manipulations with different stimulating parameters (different frequencies) on EPS in patients with FD. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IOR-16008189 . Registered on 30 March 2016.

Differential effects of variable frequencies of manual acupuncture at ST36 in rats with atropine-induced inhibition of gastric motility.

OBJECTIVE: The 'intensity-response' relationship between acupuncture stimulation and therapeutic effect is currently the focus of much research interest. The same needling manipulation with different frequencies can generate differential levels of stimulus. This study aimed to examine the effects on gastric motility induced by four twirling frequencies based on relatively standardised manual acupuncture (MA) manipulations. METHODS: Twirling manipulations at 1, 2, 3, and 4 Hz were practised before the experiments by a single operator using an MA parameter measurement device and stability was evaluated through time-frequency analysis. Forty-eight Sprague-Dawley rats were randomly divided into six groups (n=8 each): Control, Model, Model+MA (1, 2, 3, and 4 Hz). Rats in the five Model groups received injections of atropine into the tail vein to inhibit gastric motility, which was continuously recorded by a balloon in the gastric antrum. Rats in the four Model+MA groups received MA at 1, 2, 3 and 4 Hz, respectively, for 70 s and needles were retained for a further 5 min. RESULTS: The amplitude of waveforms produced by the four twirling frequencies was relatively consistent and reproducible. The gastric motility amplitude in all groups decreased after modelling (injections of atropine) (p<0.01). Twirling manipulation at 1, 2, and 3 Hz (but not 4 Hz) increased gastric motility amplitude (p<0.05). The increase in gastric motility amplitude induced by MA at 2 Hz was greater than for all other frequencies (p<0.05). CONCLUSIONS: Acupuncture at ST36 helped recover gastric motility amplitude in rats with atropine-induced gastric inhibition and the effects induced by 1-3 Hz frequency were greater than those induced by 4 Hz.

[Development of Researches on Cytokine Mechanisms in Analgesia and Anti-inflammation in Acupuncture Therapy for Rheumatoid Arthritis].

Cytokines are closely related to the occurrence and development of rheumatoid arthritis(RA). Acupuncture exerts anti-inflammatory and analgesic effects via elevating anti-inflammatory cytokine level and reducing pro-inflammatory cytokine level and regulating Th 1/Th 2 balance, which reflects the dual directional regulatory effect of acupuncture. However, problems exist in the current researches, such as inadequate depth, limited breadth and not so up-to-date research focus. The mediocre research level and the phenomena of some contradictory results among studies also need being concerned. Therefore, progress may be attained if a holistic, dynamic and networked study is conducted on the influence of acupuncture on cytokines by combining the latest progress in the mechanisms of network of cytokines and neuroendocrine immune network, and high throughput cytokine capture assay. In this way, the mechanism of cytokines in multi-targets (such as local joints, peripheral blood circulation, central nervous system) involving the effects of acupuncture in improving RA will be known more.

Strong Manual Acupuncture Manipulation Could Better Inhibit Spike Frequency of the Dorsal Horn Neurons in Rats with Acute Visceral Nociception.

Afferent impulses from visceral nociception can be regulated by acupuncture at spinal cord level; however, the effects of different manual acupuncture (MA) manipulations on the afferent impulses are still unknown. Here, we analyzed the spike frequency of excitatory gastric-related wide dynamic range (WDR) neurons in spinal dorsal horn (SDH) following acute gastric distension (GD) in rats and compared their responses to MA manipulations with four different frequencies (0.5, 1, 2, and 3 Hz) at Zusanli (ST36). Results indicated that the spike frequency was increased by acute GD stimulation. Under acute GD circumstances, the spike frequency was further activated by weak MA stimulation (0.5 and 1 Hz), while being significantly inhibited by strong MA stimulation (2 and 3 Hz). After 10 minutes of the strong MA stimulation, same intensity of acute GD caused less spike frequency. Our previous researches had demonstrated that different MA manipulations could increase spike frequency in an intensity-dependent manner in normal rats; these findings suggest that acupuncture may have different modulatory effects depending on the state of the stomach. Since neuronal spike frequency was related to the level of nociception, the results suggest that strong MA manipulation may have better effect on acute visceral nociception.

[Analysis on literature regarding acupuncture-moxibustion with high impact factor journal of SCI during the recent 5 years].

The status of acupuncture-moxibustion is more and more recognized by mainstream medicine in the world in recent years, and literature regarding acupuncture-moxibustion with high impact factor (IF) published in the worldwide mainstream medicine journals is also gradually growing by years. To understand the situation of related literature, literature regarding acupuncture-moxibustion with IF of more than 10 in Science Citation Index (SCI) during the recent 5 years was retrieved. The number, the types, the diseases involved, the publishing states of the acquired articles and the source, the citation, the IF of the publishing journals were analyzed and summarized. Additionally, some of the research foci, the new research tendencies and the deficiencies of research were discussed. The thoughts and suggestions are expected to be provided for further research of acupuncture.

Acupuncture Therapy for the Treatment of Myelosuppression after Chemotherapy: A Literature Review over the Past 10 Years.

The aim of this study is to review current studies on the effect of acupuncture therapy on bone marrow suppression after chemotherapy. The authors of the present paper have searched related literature over the past 10 years at home and abroad, analyzing the features and the effects of acupuncture therapy (including acupuncture, moxibustion, point injection, point application, etc.) for treating myelosuppression after tumor chemotherapy. We also discuss the year of publication, document type, acupuncture therapy, acupoint selection, and adverse effects with figures. We analyzed 159 articles related to acupuncture therapy from 2004 to 2013, and the analysis revealed that point injection was the most frequently used therapy for clinical applications, and that Zusanli (ST36) was the most frequently used acupoint. The results showed that some problems regarding the design method, acupoint selection, and acupuncture intervention measure existed in those research studies. We hope to provide readers with an overall and objective understanding of acupuncture and moxibustion therapy for treating myelosuppression after tumor chemotherapy.

[Acupoint: the sensor of the information in the organic body].

Based on the structure and function of acupoint and in association of the definition and principle of sensor, the acupoint is the sensitive element, being sensitive to the physical stimulation with acupuncture and moxibustion and sensitively responded to the disorders; the acupoint is the sensing element, transforming the changes of the acupoint information via the complicated internet conduction, integration and regulation, so as to generate the effects on organic body; the acupoint is the conversion element, transforming every irritation into the bioelectric signal or optical signal so that the organic body could recognize it. Therefore, the acupoint is regarded as the sensor of information in the organic body.

[Study on the mechanisms of cupping therapy].

Computerized literature searches are performed for articles of the mechanism of cupping therapy in the past 10 years. The mechanism of action of local negative pressure applied to human body is studied in terms of specific changes in local tissue structure, stretch to the nerve and muscle, increasing blood circulation and causing autohemolysis. This paper aims to explain the mechanism of cupping therapy according to modern science.