BackgroundIdiopathic Pulmonary Fibrosis (IPF), an interstitial lung disease of unknown etiology, remains incurable with current therapies, which fail to halt disease progression or restore lung function. However, Feibi Recipe No. 2 (FBR2), a clinically validated traditional Chinese medicine formula, exhibits potential as an IPF treatment.ObjectiveThis study aimed to investigate the regulatory effect of FBR2 on ferroptosis through the SIRT3/p53 pathway and its therapeutic potential in improving IPF.MethodsPulmonary fibrosis was induced in C57BL/6J mice by intratracheal instillation of Bleomycin (BLM), followed by FBR2 treatment via gavage. Assessments encompassed histopathology, ELISA for cytokine detection, IHC and Western blot for protein expression analysis, and qRT-PCR for gene expression quantification. Transmission electron microscopy (TEM) was used to observe mitochondrial morphology. The roles of Erastin and the SIRT3 inhibitor 3-TYP were also explored to elucidate FBR2’s mechanisms of action.ResultsFBR2 treatment significantly mitigated BLM-induced lung injury in mice, as evidenced by improved body weight and survival rates, and reduced levels of inflammatory cytokines, including IL-6 and TNF-α. FBR2 decreased collagen deposition in lung tissue, as shown by Masson’s staining and IHC detection of Col-I and α-SMA, confirming its anti-fibrotic effects. It also reduced iron and MDA levels in lung tissue, increased GSH-Px activity, improved mitochondrial morphology, and enhanced the expression of GPX4 and SLC7A11, indicating its ferroptosis-inhibitory capacity. Furthermore, FBR2 increased SIRT3 levels and suppressed p53 and its acetylated forms, promoting the translocation of p53 from the nucleus to the cytoplasm where it co-localized with SIRT3. The protective effects of FBR2 were reversed by Erastin, confirming the central role of ferroptosis in pulmonary fibrosis treatment. The use of 3-TYP further confirmed FBR2’s intervention in ferroptosis and cellular senescence through the SIRT3/p53 pathway.ConclusionFBR2 shows therapeutic potential in a BLM-induced pulmonary fibrosis mouse model, with its effects mediated through modulation of the ferroptosis pathway via the SIRT3/p53 mechanism. This study provides novel evidence for the targeted treatment of IPF and offers further insights into its pathogenesis.

This study explored the therapeutic potential of Number 2 Feibi Recipe (FBR2), a traditional Chinese medicine prescription, in the treatment of idiopathic pulmonary fibrosis (IPF). Specifically, it investigated whether FBR2 mediated its effects by modulating miR-199a-5p expression, activating the SIRT1/AMPK/mTOR pathway and then promoting autophagy. Eighty-four mice were divided into seven groups: Control, bleomycin (BLM), FBR2, self-complementary adeno-associated virus expressing miR-199a-5p (scAAV-miR-199a-5p), scAAV-negative control (scAAV-NC), FBR2 + BLM + scAAV-miR-199a-5p, and FBR2 + BLM + scAAV-NC. Fluorescence staining, miR-199a-5p expression levels, histopathological changes, protein expression and autophagy activity were assessed using various techniques, including RT-qPCR, histopathological staining, Western blotting, Elisa and transmission electron microscopy (TEM). FBR2 treatment significantly reduced miR-199a-5p expression elevated by BLM and improved histopathology, reduced levels of α-smooth muscle actin (α-SMA) and collagen-III, and increased E-cadherin expression. FBR2 also enhanced autophagy, as evidenced by elevated LC3-II and Beclin-1 levels and reduced p62 expression. Additionally, it activated the SIRT1/AMPK/mTOR pathway. Finally, network pharmacology identified 227 compounds in FBR2, among which Kaempferol and Quercetin (two major shared constituents) showed strong binding to miR-199a-5p in molecular docking, suggesting their potential as key active components. This study showed FBR2 attenuated BLM-induced pulmonary fibrosis in mice by reducing miR-199a-5p expression and promoting autophagy which may be achieved by modulating the SIRT1/AMPK/mTOR pathway. These findings provide novel insights into the mechanism of FBR2 and its potential as a therapeutic approach for IPF.

Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease that seriously threatens human life and health. Our previous study demonstrated the unique superiority of traditional Chinese medicine cryptotanshinone (CTS) combined with sustained pulmonary drug delivery for treating PF. In this study, we aimed to enhance the selectivity, targeting efficiency and sustained-release capability based on this delivery system. To this end, we developed and evaluated CTS-loaded modified liposomes-chitosan (CS) microspheres SM(CT-lipo) and liposome-exosome hybrid bionic vesicles-CS microspheres SM(LE). The prepared nano-in-micro particles system integrates the advantages of the carriers and complements each other. SM(CT-lipo) and SM(LE) achieved lung myofibroblast-specific targeting through CREKA peptide binding specifically to fibronectin (FN) and the homing effect of exosomes on parent cells, respectively, facilitating efficient delivery of anti-fibrosis drugs to lung lesions. Furthermore, compared with daily administration of conventional microspheres SM(NC) and positive control drug pirfenidone (PFD), inhaled administration of SM(CT-lipo) and SM(LE) every two days still attained similar efficacy, exhibiting excellent sustained drug release ability. In summary, our findings suggest that the developed SM(CT-lipo) and SM(LE) delivery strategies could achieve more accurate, efficient and safe therapy, providing novel insights into the treatment of chronic PF.

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology characterized by a constant incidence rate. Unfortunately, effective pharmacological treatments for this condition are lacking and the identification of novel therapeutic approaches and underlying pathological mechanisms are required. This study investigated the potential of quercetin in alleviating pulmonary fibrosis by promoting autophagy and activation of the SIRT1/AMPK pathway. Mouse models of IPF were divided into four treatment groups: control, bleomycin (BLM), quercetin (Q), and quercetin + EX-527 (Q + E) treatment. Pulmonary fibrosis was induced in the mouse models through intratracheal instillation of BLM. Various indexes were identified through histological staining, Western blotting analysis, enzyme-linked immunosorbent assay, immunohistochemistry, and transmission electron microscopy. Quercetin treatment ameliorated the pathology of BLM-induced pulmonary fibrosis of mice by reducing α-smooth muscle actin (α-SMA), collagen I (Col I), and collagen III (Col III) levels, and also improved the level of E-cadherin in lung tissue. Furthermore, Quercetin significantly enhanced LC3II/LC3I levels, decreased P62 expression, and increased the number of autophagosomes in lung tissue. These effects were accompanied by the activation of the SIRT1/AMPK pathway. Treatment with EX-527, an inhibitor for SIRT1, reversed all effects induced by quercetin. This study showed that quercetin could alleviate pulmonary fibrosis and improve epithelial-mesenchymal transition by acting on the SIRT1/AMPK signaling pathway, which may be achieved by regulating the level of autophagy.

Multiple randomized controlled studies have shown that pirfenidone and nintedanib are effective and safe for treating idiopathic pulmonary fibrosis. This study aimed to evaluate their efficacy, safety, and tolerability in a real-world setting. We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases for real-world studies published up to March 3, 2023, on pirfenidone and nintedanib for idiopathic pulmonary fibrosis. A total of 74 studies with 23,119 participants were included. After 12 months of treatment, the change from baseline in percent predicted FVC (

Lung inflammation and fibrogenesis are the two main characteristics during the development of pulmonary fibrosis (PF), which are particularly associated with pulmonary macrophages. In this context, whether cryptotanshinone (CTS) could alleviate PF through regulating macrophage polarization were preliminarily demonstrated in vitro. Then the time course of PF and its relationship with macrophage polarization was determined in BLM-induced mice based on cytokine levels in bronchoalveolar lavage fluid (BALF), lung histopathology, flow cytometric analysis, mRNA and protein expression. CTS was loaded into macrophage-targeted and responsively released mannose-modified liposomes (Man-lipo), and the liposomes were then embedded into mannitol microparticles (M-MPs) using spray drying to achieve efficient pulmonary delivery. Afterwards, how CTS regulates macrophage polarization in vivo during different time courses of PF was probed. Furthermore, the molecular mechanisms of CTS against PF by regulating macrophage polarization were elucidated in vivo and in vitro. The full-course therapy group could achieve comparable therapeutic effects compared with the positive control drug PFD group. CTS can alleviate PF through regulating macrophage polarization, mainly by inhibiting NLRP3/TGF-β1 pathway during the inflammation course and modulating MMP-9/TIMP-1 balance during the fibrosis development course, providing new insights into chronic PF treatment.

基于朱震亨"六郁"理论,提出肺结节的形成与气郁、血郁、痰郁、火郁、湿郁、食郁六郁密切相关.认为六郁皆可导致肺结节,其中以气郁为主导,气郁久则化为火郁,导致脾失运化可成痰郁、湿郁、食郁,气不行血则成血郁,六郁相因为病且病机之间相互关联,共同促进肺结节的发生发展.治疗以畅通气机为主,以治疗六郁的经典名方越鞠丸为基本方,并根据六郁偏颇在越鞠丸基础上灵活配伍疏肝理气、清热散结、化痰散结、健脾化湿、消食化积、活血化瘀之品.

Number 2 Feibi Recipe (N2FBR) is a traditional Chinese medicine formula for treating idiopathic pulmonary fibrosis. N2FBR inhibits H2O2-mediated oxidative stress damage in alveolar epithelial cells by increasing autophagy, as we previously demonstrated. However, it is unknown if similar mechanisms occur in vivo. We established a pulmonary fibrosis model by instilling bleomycin (BLM) from the airway to examine the effects of N2FBR on pulmonary fibrosis and investigate its probable mechanism in this work. We discovered that N2FBR treatment effectively alleviated interstitial fibrosis as well as collagen deposition, primarily in upregulating SOD, GSH-Px, T-AOC and downregulating MDA content. N2FBR also increased the expression of LC3B, Beclin-1, LAMP1, TFEB and downregulated the expression of p62, legumain. N2FBR treatment boosted the production of autophagosomes, according to the results of the TEM observation. Furthermore, we explored that N2FBR exerted its anti-oxidative stress and pro-autophagy effects via GSK-3β/mTOR signalling pathway. Therefore, these results provide further evidence for the protective effect of N2FBR in pulmonary fibrosis. Our findings could have ramifications for the development of antifibrosis therapies.

Cryptotanshinone (CTS) is a promising therapeutic option for pulmonary fibrosis (PF). However, clinical applications of CTS are limited owing to high photosensitivity and poor oral bioavailability. Pulmonary drug delivery, especially sustained pulmonary drug delivery, is promising for local treatment of chronic lung diseases. In this study, CTS was encapsulated in an optimized chitosan/L-leucine-based swellable microparticles (SMs) system, which exhibited an appropriate aerosolization performance, sustained release and storage stability. SMs enhanced the in vitro anti-fibrosis efficacy of CTS as shown by the improved cellular uptake. The effect of PF status on in vivo fate of the pulmonary delivered drug was also assessed. Pharmacokinetics and tissue distribution of oral and pulmonary delivery CTS in bleomycin-induced PF rats were compared. Pulmonary delivery exhibited high drug concentrations in pulmonary lesion areas, with reduced exposure to blood and non-targeted tissues after administration at a significantly lower dose compared with oral delivery. Moreover, PF pathological status enhanced activity of SMs, implying that pulmonary delivery was highly effective for PF treatment. Compared to oral delivery, Inhaled SMs showed comparable or even better efficacies at approximately 60-fold low dose compared with oral delivery. A sustained efficacy was observed under a prolonged administration interval (corresponding to half the total dose). Inhalation safety of SMs was established, and important mechanism-related signaling pathways against PF were investigated in vitro and in vivo. In summary, the findings showed that the developed CTS-loaded sustained pulmonary delivery system is a safe and effective strategy for chronic PF treatment.

Objective:To initially explore traditional Chinese medicine patterns in a bleomycin-induced pulmonary fibrosis mouse model.Methods:Thirty-six C57 BL/6 mice were divided by the random number table method（with 12 rats per group） into three groups:a blank group,a model group,and a number 2 Feibi recipe（FBR-2） group.The pulmonary fibrosis mouse model was established by intratracheal instillation of bleomycin.The FBR-2 group was treated with FBR-2 for 4 weeks.Symptoms in the mice such as mental behavior,food/water intake,body weight,body temperature,respiratory rate,and tongue image were observed.The samples were collected on the 14 th day and 28 th day after modeling,and lung tissues were visually assessed and microscopically evaluated by staining with hematoxylin-eosin and Masson.The expression levels of hydroxyproline,interleukin（IL）-33,IL-37,tissue plasminogen activator,and plasminogen activator inhibitor-1 were determined by enzyme-linked immunosorbent assay.Results:Mice in the model group were poor in spirit,less active,slow in response,showed reduced food/water intake,body temperature,and body weight,increased respiratory rate,and their tongue color had changed from light red to dark red.However,treatment with FBR-2 significantly improved these symptoms.Extensive inflammatory cell infiltration and collagen fiber deposition were observed in the lung tissues of the model group.Compared with the blank group,the levels of hydroxyproline,IL-33,and plasminogen activator inhibitor-1 in the model group significantly increased（all P ＜.05）,whereas that of tissue plasminogen activator significantly decreased on the 14 th day and 28 th day（P=.036 and P=.005,respectively）.Moreover,FBR-2 improved lung inflammation and fibrinolysis imbalance and reduced collagen fiber deposition.Conclusion:To some extent,our bleomycin-induced pulmonary fibrosis mouse model exhibited traditional Chinese medicine patterns of qi deficiency,blood stasis,and heat retention.

作为《金匮要略》五种水气病之一,黄汗病症状表现复杂多样,病机虚实兼见,并涉及多个脏腑.种种原因,导致其理论内涵尚未得到充分的阐发.系统性红斑狼疮是现代医学累及多系统的难治性疾病.其临床表现,发展转归与黄汗病具有极高的契合度,将系统性红斑狼疮归入黄汗病范畴具有合理性.素有肝肾亏虚、阳明热盛,又因调摄不慎,外感寒湿之邪,是系统性红斑狼疮的关键病机.基于《伤寒杂病论》黄汗病以及其余相关理论,针对系统性红斑狼疮肾脏、皮肤黏膜、骨骼肌肉、消化、呼吸、心脏、神经等系统受累所表现出的各种临床表现,以补益肝肾、清解阳明、散寒除湿为原则,分别提出了相应的经方治疗,为系统性红斑狼疮的现代中医诊治提供了思路.

Background Chinese herbs for supplementing qi and activating blood circulation (CH) combined with N-acetylcysteine (NAC) is widely used for idiopathic pulmonary fibrosis (IPF) in China, but there is a lack of literature to evaluate its efficacy and clinical value. Purpose This study compared CH + NAC with other treatments by network meta-analysis to clarify its clinical value. Methods Cochrane Library, PubMed, Embase, Web of Science, China National Knowledge Infrastructure, WanFang Data, VIP Database, and China Biology Medicine were searched. Outcomes included lung function (DLCO (%), VC (%), FVC (%), FVC (L)), 6-min walking distance (6MWD), score of St George’s respiratory questionnaire (SGRQ), blood gas analysis (PaO2, PaCO2). The data were analyzed by Review Manager 5.4, Stata 12.0 and ADDIS 1.16.5. Results 23 studies including 1390 patients (702 in intervention group and 688 in control group) were collected to compare 8 outcome indicators among different treatments involving CH, CH+NAC, CH+PFD, NAC, PFD and PFD+NAC on IPF. Network meta-analysis showed that CH was better than NAC in terms of DLCO (%) (MD = 5.14, 95%CI: 1.01 to 8.68) and 6MWD (MD = 49.17, 95%CI: 25.97 to 71.36) as well as PFD + NAC was better than NAC in terms of FVC (L) (MD = -0.56, 95%CI: -0.83 to -0.31). In rankings results, CH + NAC is the best in terms of FVC (%), SGRQ, PaO2 and PaCO2; CH is the best in terms of DLCO (%), VC (%) and 6MWD; CH + PFD is the best in terms of FVC (L). Conclusion CH related treatments may have advantages in the treatment of IPF and CH + NAC may have clinical application value. However, limited by the quality and quantity of researches included, more rational and scientific randomized controlled trials containing large sample sizes need to be conducted to further verify our conclusions.

Reactive oxygen species (ROS)-mediated alveolar epithelial cell (AEC) injury and apoptosis are considered to be the initiating link of idiopathic pulmonary fibrosis (IPF), and protecting AECs can alleviate IPF. This study aimed to explore the protective effect of number 2 Feibi recipe (FBR-2) medicated serum on H2O2-mediated oxidative stress injury in AECs and further explore its mechanism. We found that FBR-2 can regulate downstream antioxidant enzymes expression by activating nuclear factor erythroid 2-related factor 2 (Nrf2), reducing the level of intracellular ROS, protecting mitochondrial function and improving cell survival. FBR-2 can also activate mitophagy through the PINK1/Parkin pathway. Moreover, FBR-2 can inhibit apoptosis by blocking the mitochondrial apoptosis mechanism. In summary, these data indicate that FBR-2 medicated serum can inhibit H2O2-mediated oxidative stress damage in AECs by regulating the balance of mitophagy/apoptosis. This study provides new evidence for the antifibrotic effect of FBR-2 and provides new drug candidates for the clinical treatment of IPF.

周平安教授治疗慢性咳嗽时,讲究中西医医理汇通,辨病与辨证相结合,对于咳嗽变异性哮喘、嗜酸粒细胞性支气管炎及变应性咳嗽,抓住其过敏本质,缓解气道挛急及敏感状态;对于上气道咳嗽综合征及胃食管反流性咳嗽,详查其病位本源,消除刺激因素;同时,治咳时注重咽喉局部症状的辨证及整体气机的调理;治痰时,重视痰的真假及性质的辨证以及痰瘀同治理论的运用;参照患者宿疾、体质特点,详参药性,明辨药用,是中西医结合运用的典范,在临床中获效颇丰,其治疗思路和方法值得临床借鉴和学习.

Exposure to aerosolized citric acid (CA, 150 mM) and prostaglandin E-2 (PGE(2), 0.43 mM) for 10 min in guinea pigs reportedly produces the distinct cough patterns (Type I vs. II) and ventilatory responses (long-lasting hy-perventilation vs. brief tachypnea) even though triggering the same cough numbers. Type I and II coughs are primarily mediated by activation of TRPV1 and EP3 receptors (a PGE(2) receptor) of vagal C-fibers respectively. Substance P (SP) and neurokinin A (NKA) released by vagal pulmonary sensory fibers peripherally are capable of affecting CA-induced cough and ventilation via preferentially activating neurokinin 1 and 2 receptors (NK1R and NK2R) respectively. This study aimed to define the impacts of CA-and PGE2-exposure on pulmonary SP and NKA levels and the roles of NK1R and NK2R in modulating CA-and PGE2-evoked cough and ventilatory responses. In unanesthetized guinea pigs, we determined: (1) pulmonary SP and NKA contents induced by the CA-or PGE2- exposure; (2) effects of CP-99994 and SR-48968 (a NK1R and a NK2R antagonist respectively) given by intra-peritoneal injection (IP) or aerosol inhalation (IH) on the CA-and PGE2-evoked cough and ventilatory responses; and (3) immunocytochemical expressions of NK1R/NK2R in vagal C-neurons labeled by TRPV1 or EP3 receptors. We found that CA-and PGE2-exposure evoked Type I and II cough respectively associated with different degrees of increases in pulmonary SP and NKA. Applications of CP-99994 and SR-48968 via IP and IH efficiently sup-pressed the cough responses to CA with less impact on the cough response to PGE2. These antagonists inhibited or blocked the ventilatory response to CA and caused hypoventilation in response to PGE2. Moreover, NK1R and NK2R were always co-expressed in vagal C-neurons labeled by TRPV1 or EP3 receptors. These results suggest that SP and NKA endogenously released by CA-and PGE2-exposure play important roles in generating the cough and ventilatory responses to CA and PGE2, at least in part, via activation of NK1R and NK2R expressed in vagal C -neurons (pulmonary C-neurons).

Calycosin (CA) is a flavonoid extracted from the root of Astragalus membranaceus and has antioxidant, anti-inflammation, and antiapoptosis properties. The objective of this study was to investigate the efficacy of CA in protecting against pulmonary fibrosis. CA (14 mg/kg) and SB216763 (20 mg/kg) were administrated to bleomycin-induced pulmonary fibrosis mice for 3 weeks. The results concluded that CA alleviated the inflammation and collagen deposition in pulmonary fibrosis. In addition, CA reduced MDA level, enhanced SOD and TAC activities, and increased the activity of the Nrf2/HO-1 pathway. CA also regulated the expressions of apoptosis-related proteins. Moreover, CA enhanced autophagy via upregulating LC3, beclin1, PINK1, and reducing p62. CA also increased expression of LAMP1 and TFEB, and inhibited the release of lysosome enzymes from ruptured lysosomes. These results provide new evidence that CA protects against pulmonary fibrosis through inhibiting oxidative stress and apoptosis. In addition, autophagy abnormality and lysosome dysfunction are restored by CA.

Background: Chronic pain is the most common disease in the world, which lead the patients to suffer the disability both physically and psychologically. The chronic pain can affects the patients to work, socialize, sleep and can lead to depressive illness, decreased motivation, and a reduction in physical activity. Acupuncture is a promising treatment for the chronic pain which has a long history of use in China. This protocol aims to assess the effectiveness and safety of touching periosteum acupuncture therapy on patients with chronic pain. Methods: Randomized controlled trial literatures which include touching periosteum acupuncture therapy for treating chronic pain will be searched from 8 electronic databases including China Biology Medicine disc, VIP database, WanFang database, China National Knowledge Infrastructure, PubMed, Cochrane Library, Excerpt Medical Database, and Web of Science. The language will be restricted to Chinese and English. The primary outcome is to measure the relief of the pain by Visual Analogue Scale. Two or 3 reviewers will conduct the study selection, data extraction and the evaluation of the risk of bias. RevMan software (V.5.3) will be used to perform the assessment of the risk of bias and data synthesis. Results: From this study, we will confirm the effectiveness of safety of in the treatment of chronic pain. Conclusions: We will ascertain the effectiveness of safety of touching periosteum acupuncture therapy in the treatment of chronic pain, to provide evidence to guide touching periosteum acupuncture therapy for patients with chronic pain in the future. Ethics and dissemination: Ethics approval will not be necessary, because the included publications in our study are all from published articles. This systematic review will be published in a peer-reviewed journal or conference report to provide a reference in this field.

Abstract Background: Chronic pain is the most common disease in the world, which lead the patients to suffer the disability both physically and psychologically. The chronic pain can affects the patients to work, socialize, sleep and can lead to depressive illness, decreased motivation, and a reduction in physical activity. Acupuncture is a promising treatment for the chronic pain which has a long history of use in China. This protocol aims to assess the effectiveness and safety of touching periosteum acupuncture therapy on patients with chronic pain. Methods: Randomized controlled trial literatures which include touching periosteum acupuncture therapy for treating chronic pain will be searched from 8 electronic databases including China Biology Medicine disc, VIP database, WanFang database, China National Knowledge Infrastructure, PubMed, Cochrane Library, Excerpt Medical Database, and Web of Science. The language will be restricted to Chinese and English. The primary outcome is to measure the relief of the pain by Visual Analogue Scale. Two or 3 reviewers will conduct the study selection, data extraction and the evaluation of the risk of bias. RevMan software (V.5.3) will be used to perform the assessment of the risk of bias and data synthesis. Results: From this study, we will confirm the effectiveness of safety of in the treatment of chronic pain. Conclusions: We will ascertain the effectiveness of safety of touching periosteum acupuncture therapy in the treatment of chronic pain, to provide evidence to guide touching periosteum acupuncture therapy for patients with chronic pain in the future. Ethics and dissemination: Ethics approval will not be necessary, because the included publications in our study are all from published articles. This systematic review will be published in a peer-reviewed journal or conference report to provide a reference in this field. Trial registration: CRD42021243387.

Background:Chronic pain is the most common disease in the world, which lead the patients to suffer the disability both physically and psychologically. The chronic pain can affects the patients to work, socialize, sleep and can lead to depressive illness, decreased motivation, and a reduction in physical activity. Acupuncture is a promising treatment for the chronic pain which has a long history of use in China. This protocol aims to assess the effectiveness and safety of touching periosteum acupuncture therapy on patients with chronic pain. Methods:Randomized controlled trial literatures which include touching periosteum acupuncture therapy for treating chronic pain will be searched from 8 electronic databases including China Biology Medicine disc, VIP database, WanFang database, China National Knowledge Infrastructure, PubMed, Cochrane Library, Excerpt Medical Database, and Web of Science. The language will be restricted to Chinese and English. The primary outcome is to measure the relief of the pain by Visual Analogue Scale. Two or 3 reviewers will conduct the study selection, data extraction and the evaluation of the risk of bias. RevMan software (V.5.3) will be used to perform the assessment of the risk of bias and data synthesis. Results: From this study, we will confirm the effectiveness of safety of in the treatment of chronic pain. Conclusions:Wewill ascertain the effectiveness of safety of touching periosteum acupuncture therapy in the treatment of chronic pain, to provide evidence to guide touching periosteum acupuncture therapy for patients with chronic pain in the future. Ethics and dissemination: Ethics approval will not be necessary, because the included publications in our study are all from published articles. This systematic review will be published in a peer-reviewed journal or conference report to provide a reference in this field. Trial registration: CRD42021243387. Abbreviation: RCT = randomized controlled trial.

Swellable microparticles (SMs) provide a potential strategy for achieving sustained inhalation therapy. However, spray dried SMs are highly hygroscopic, exhibiting poor flowability and dispersibility properties. This study aimed at determining whether L-leucine (LL) can improve aerosolization performance of SMs with wrinkled surface and its potential mechanisms. Cryptotanshinone was co-spray dried with chitosan and LL (0-40%, mass fraction in carrier materials), after which the production yield, particle size, density, encapsulation efficiency, morphology, cohesion, crystallinity, surface LL distribution, hygroscopicity, water content and in vitro aerosolization performance of the developed formulations were characterized. In addition, we determined whether LL, as a hydrophobic amino acid, would impair swellability and macrophage phagocytosis of SMs. The possible impact of LL on in vitro drug release, cytotoxicity and anti-fibrosis effects on MRC-5 cells was also investigated. As the LL content increased, LL began to crystallize. At 7.5% LL, water content and hygroscopicity of the SMs were at their lowest. Moreover, at 7.5% LL, surface enrichment increased rapidly after which it achieved a comparatively complete coverage at 20-40% LL. However, LL >= 20% caused the formation of over-wrinkled, even dimpled or hollow particles, which significantly deteriorated powder properties. Optimum aerosolization performance was obtained at 10% LL, irrespective of its crystallization behavior, accompanied by the lowest cohesion, optimal flowability and production yield, and without impaired swellability, macrophage uptake and anti-fibrosis efficacy. The optimal formulation did not exhibit optimum surface LL coverage, implying that improvement of aerosolization performance of wrinkled SMs by LL not simply depended on its surface enrichment, but its significant influence on morphology and on related powder properties as well.