Self-Delivery Nanomedicines Reverse Thermal Resistance to Enhance Tumor Mild-Temperature Photothermal Therapy.

Tumoral thermal defense mechanisms considerably attenuate the therapeutic outcomes of mild-temperature photothermal therapy (PTT). Thus, developing a simple, efficient, and universal therapeutic strategy to sensitize mild-temperature PTT is desirable. Herein, we report self-delivery nanomedicines ACy NPs comprising a near-infrared (NIR) photothermal agent (Cypate), mitochondrial oxidative phosphorylation inhibitor (ATO), and distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000), which have a high drug-loading efficiency that can reverse tumoral thermal resistance, thereby increasing mild-temperature PTT efficacy. ACy NPs achieved targeted tumor accumulation and performed NIR fluorescence imaging capability in vivo to guide tumor PTT for optimized therapeutic outcomes. The released ATO reduced intracellular ATP levels to downregulate multiple heat shock proteins (including HSP70 and HSP90) before PTT, which reversed the thermal resistance of tumor cells, contributing to the excellent results of mild-temperature PTT in vitro and in vivo. Therefore, this study provides a simple, biosafe, advanced, and universal heat shock protein-blocking strategy for tumor PTT.

Houttuynia cordata thunb. alleviates inflammatory bowel disease by modulating intestinal microenvironment: a research review.

Inflammatory bowel disease (IBD) is a complex group of chronic intestinal diseases, the cause of which has not yet been clarified, but it is widely believed that the disorder of the intestinal microenvironment and its related functional changes are key factors in the development of the disease. Houttuynia cordata thunb. is a traditional plant with abundant resources and long history of utilization in China, which has attracted widespread attention in recent years due to its potential in the treatment of IBD. However, its development and utilization are limited owing to the aristolochic acid alkaloids contained in it. Therefore, based on the relationship between the intestinal microenvironment and IBD, this article summarizes the potential mechanisms by which the main active ingredients of Houttuynia cordata thunb., such as volatile oils, polysaccharides, and flavonoids, and related traditional Chinese medicine preparations, such as Xiezhuo Jiedu Formula, alleviate IBD by regulating the intestinal microenvironment. At the same time, combined with current reports, the medicinal and edible safety of Houttuynia cordata thunb. is explained for providing ideas for further research and development of Houttuynia chordate thunb. in IBD disease, more treatment options for IBD patients, and more insights into the therapeutic potential of plants with homology of medicine and food in intestinal diseases, and even more diseases.

Qi-Long-Tian capsule alleviates pulmonary fibrosis development by modulating inflammatory response and gut microbiota.

Pulmonary fibrosis (PF) is a chronic, progressive, and fibrotic interstitial lung disease with a high mortality rate. Qi-Long-Tian (QLT) capsule is an herbal formula with great potential for antifibrotic effects, consisting of San Qi (Notoginseng Radix et Rhizoma), Di Long [Pheretima aspergillum (E. Perrier)], and Hong Jingtian (Rhodiolae Crenulatae Radix et Rhizoma), and has been used in clinical practice for many years. To explore the relationship between the effects of Qi-Long-Tian capsule and gut microbiota of PF mice, pulmonary fibrosis model were established by tracheal drip injection of bleomycin. Thirty-six mice were randomly divided into 6 groups: control group (control), model group (model), QLT capsule low dose group (QL), QLT capsule medium dose group (QM), QLT capsule high dose group (QH), and pirfenidone group (PFD). After 21 days of treatment, after pulmonary function tests, the lung tissues, serums, and enterobacterial samples were collected for further analysis. HE staining and Masson's staining were used to detect changes as the main indicators of PF in each group, and the expression of hydroxyproline (HYP) related to collagen metabolism was detected by and alkaline hydrolysis method. qRT-PCR and ELISA were used to detect the mRNA and protein expressions of pro-inflammatory factors include interleukin 1ß (IL-1ß), interleukin 6 (IL-6), transforming growth factor ß1 (TGF-ß1), tumor necrosis factor α (TNF-α) in lung tissues and serums, and the inflammation-mediating factors include tight junction protein (ZO-1, Claudin, Occludin). ELISA was used to detect the protein expressions of secretory immunoglobulin A (sIgA), short-chain fatty acids (SCFAs), and lipopolysaccharide (LPS) in colonic tissues. 16sRNA gene sequencing was used to detect changes in the abundance and diversity of intestinal flora in the control, model, and QM groups, to search for differential genera, and analyze the correlation with inflammatory factors. QLT capsule effectively improved the status of pulmonary fibrosis and reduced HYP. In addition, QLT capsule significantly reduced the abnormal levels of pro-inflammatory factors, including IL-1ß, IL-6, TNF-α, and TGF-ß in lung tissue and serum, while improving the levels of pro-inflammatory related factors ZO-1, Claudin, Occludin, sIgA, SCFAs, and reducing LPS in the colon. The comparison between the alpha diversity and beta diversity in enterobacteria suggested that the composition of the gut flora in the control, model, and QLT capsule groups were different. QLT capsule significantly increased the relative abundance of Bacteroidia (which might limit the onset of inflammation) and decreased the relative abundance of Clostridia (which might promote inflammation). In addition, these two enterobacteria were closely associated with pro-inflammatory-related indicators and pro-inflammatory factors in PF. All these results suggest that QLT capsule intervenes in pulmonary fibrosis by regulating the differential genera of intestinal flora, increasing immunoglobulin secretion, repairing the intestinal mucosal barrier, reducing LPS entry into the blood, and decreasing inflammatory factor secretion in the serum, which in turn alleviates pulmonary inflammation. This study clarifies the therapeutic mechanism of QLT capsule in PF and provides a theoretical basis for it. It provides a theoretical basis for its further clinical application.

Integrated Network Pharmacology and Gut Microbiota Analysis to Explore the Mechanism of Sijunzi Decoction Involved in Alleviating Airway Inflammation in a Mouse Model of Asthma.

Background: Asthma is a chronic inflammatory disease of the airways with recurrent attacks, which seriously affects the patients' quality of life and even threatens their lives. The disease can even threaten the lives of patients. Sijunzi decoction (SJZD), a classical Chinese medicine formula with a long history of administration, is a basic formula used for the treatment of asthma and demonstrates remarkable efficacy. However, the underlying mechanism has not been elucidated. Materials and Methods: We aimed to integrate network pharmacology and intestinal flora sequencing analysis to study the mechanism of SJZD in the treatment of allergic asthmatic mice. The active compounds of SJZD and their asthma-related targets were predicted by various databases. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to identify potentially relevant pathways for target genes. Furthermore, the active compound-target and target-signaling pathway network maps were constructed by using Cytoscape 3.8.2. These results were combined with those of the intestinal flora sequencing analysis to study the influence of SJZD on airway inflammation in allergic asthmatic mice. Result: We obtained 137 active compounds from SJZD and associated them with 1445 asthma-related targets acquired from the databases. A total of 109 common targets were identified. We visualized active compound-target and target-signaling pathway network maps. The pathological analysis and inflammation score results suggested that SJZD could alleviate airway inflammation in asthmatic mice. Sequencing analysis of intestinal flora showed that SJZD could increase the relevant abundance of beneficial bacterial genus and maintain the balance of the intestinal flora. The core toll-like receptor (TLR) signaling pathway was identified based on network pharmacology analysis, and the important role TLRs play in intestinal flora and organismal immunity was also recognized. The analysis of the correlation between environmental factors and intestinal flora revealed that beneficial bacterial genera were negatively correlated with TLR2 and positively correlated with the TLR7 expression. Furthermore, they were positively correlated with IFN-γ and IL-10 levels and negatively correlated with IL-4 and IL-17 levels. Conclusion: SJZD alleviated the airway inflammation state in asthmatic mice. The findings suggest that increasing the relevant abundance of beneficial intestinal bacteria in mice with asthma, regulating intestinal flora, interfering with the level of TLR2 and TLR7 expression to adjust the secretion of inflammatory factors, and alleviating asthmatic airway inflammation may be the possible mechanism involved in the treatment of asthma by SJZD, providing a basis for further studies on SJZD.

Astragaloside trigger autophagy: Implication a potential therapeutic strategy for pulmonary fibrosis.

Pulmonary fibrosis is an abnormal wound-healing response to repeated alveolar injury, characterized by continuous inflammation and abnormal collagen deposition. Its treatment is problematic. Astragaloside (AST) is an active component of Astragalus membranaceus with anti-inflammatory and anti-tumor properties. Although the underlying mechanisms are unknown, AST is also used to treat fibrotic diseases. This study aimed to investigate the mechanisms of action of AST in pulmonary fibrosis treatment. We found that AST significantly improved restrictive ventilatory impairment, compliance, total lung capacity, and functional residual capacity. In mice with pulmonary fibrosis, extracellular matrix deposition in the pulmonary parenchyma and intemperate inflammation were reversed. This therapeutic effect can be attributed to autophagy, activating the genes for autophagy flux and autophagic vacuoles. Impaired autophagy increased susceptibility to pulmonary fibrosis by exacerbating collagen deposition in vitro and in vivo. Using a combination of molecular docking and network pharmacology, the Ras/Raf/MEK/ERK signaling pathway was identified as a possible candidate for the pharmacologic target of AST. Functional dephosphorylation of MEK and ERK inhibited the Ras/Raf/MEK/ERK signaling pathway, which converges at the rapamycin switch to initiate autophagy. Inhibitors of Ras and MEK regulated autophagy. These findings suggest that AST might treat pulmonary fibrosis by modulating the Ras/Raf/MEK/ERK signaling pathway mediated by depression.

Network Pharmacology-Based Analysis of Gegenqinlian Decoction Regulating Intestinal Microbial Activity for the Treatment of Diarrhea.

Gegenqinlian decoction (GD) has been extensively used for the treatment of diarrhea with intestinal dampness-heat syndrome (IDHS) with a satisfying therapeutic effect. The purpose of this study is to clarify the active ingredients and mechanism of GD in the treatment of diarrhea with IDHS. The TCMSP database was used to screen out the active ingredients of the four Chinese herbal medicines in GD, and the targets of the active ingredients were predicted. We selected the targets related to diarrhea through the DisGeNET database, then used the NCBI database to screen out related targets of lactase and sucrase, and constructed the visual network to search for the active ingredients of GD in the treatment of diarrhea and related mechanisms of the targets. Combined with network pharmacology, we screened out 146 active ingredients in GD corresponding to 252 ingredient targets, combined with 328 disease targets in diarrhea, and obtained 12 lactase targets and 11 sucrase targets. The key active ingredients involved quercetin, formononetin, ß-sitosterol kaempferol, and wogonin. Furthermore, molecular docking showed that these five potential active ingredients had good affinities with the core targets PTGS2. The active ingredients in GD (such as quercetin, formononetin, and ß-sitosterol) may increase the microbial activity of the intestinal mucosa of mice and reduce the microbial activity of the intestinal contents through multiple targets, thereby achieving the effect of treating diarrhea.

Gastrodia remodels intestinal microflora to suppress inflammation in mice with early atherosclerosis.

Atherosclsis is a critical actuator causing cardiac-cerebral vascular disease with a complicated pathogeneon, refered to the disorders of intestinal flora and persistent inflammation. Gastrodin (4-(hydroxymethyl) phenyl-ß-D- Glucopyranoside) is the most abundant glucoside extracted from the Gastrodiaelata, which is a traditional Chinese herbal medicine for cardiac-cerebral vascular disease, yet its mechanisms remain little known. In the present study, the gastrodia extract and gastrodin attenuate the lipid deposition and foam cells on the inner membrane of the inner membrane of the thoracic aorta in the early atherosclerosis mice. Blood lipid detection tips that TC and LDL-C were reduced in peripheral blood after treatment with the gastrodia extract and gastrodin. Furthermore, unordered gut microbes are remodeled in terms of bacterial diversity and abundance at family and genus level. Also, the intestinal mucosa damage and permeability were reversed, accompaniedwith the reducing of inflammatory cytokines. Our findings revealed that the functions of gastrodia extract and gastrodin in cardiac-cerebral vascular disease involved to rescued gut microbes and anti-inflammation may be the mechanismof remission lipid accumulation.

Bioinformatics analysis of endophytic bacteria related to berberine in the Chinese medicinal plant Coptis teeta Wall.

Endophytic microorganisms absorb nutrients and prevent pathogen damage, supporting healthy plant growth. However, the relationship between endophytic bacteria and berberine synthesis in the medicinal plant Coptis teeta Wall. remains unclear. Herein, we explored the community composition of endophytic bacteria related to berberine in roots, stems, and leaves of wild-type and cultivated C. teeta. Endophytic bacterial communities were analyzed by 16S rRNA sequencing, and berberine content in roots was analyzed by high-performance liquid chromatography. Proteobacteria, Actinobacteria, and Bacteroidetes were the major phyla, and Mycobacterium, Salmonella, Nocardioides, Burkholderia-Paraburkholderia, and Rhizobium were the dominant genera in root, stem, and leaf tissues. Root berberine content was positively correlated with total N, total P, total K, and available K in rhizosphere soil. In addition, root berberine content was positively correlated with Microbacterium and norank_f_7B-8, whereas soil total K was positively correlated with Microbacterium and Burkholderia-Paraburkholderia in roots. Our results demonstrated a clear correlation between dominant endophytic bacteria and berberine synthesis in C. teeta. The findings are useful for the promotion of berberine production in C. teeta via manipulation of endophytic bacteria.

Effects of Hetiao Jianpi Decoction on Intestinal Injury and Repair in Rats with Antibiotic-Associated Diarrhea.

BACKGROUND Through observing the changes of indexes of the intestinal mucosal barrier and intestinal flora in rats, we explored the mechanism by which Hetiao Jianpi Decoction (HTJPD) treats antibiotic-associated diarrhea (AAD) by repairing intestinal mucosal injury and regulating intestinal flora. MATERIAL AND METHODS Samples of colon tissues were collected for HE staining. Enzyme-linked immunosorbent assay (ELISA) was used to assess levels of diamine oxidase (DAO) and D-lactic acid in rat plasma and the expression of secretory immunoglobulin A (SIgA) in colon tissue. We assessed the abundance of intestinal contents by high-throughput sequencing of the 16S rRNA gene. RESULTS Compared with the Model group, the muscle layer and intestinal mucosal edema were improved, and the continuity was restored; the levels of DAO and D-lactic acid in plasma decreased, and the SIgA level were increased in the HTJPD group. The structure of the intestinal flora changed, as indicated by increased levels of certain beneficial bacteria (Verrucomicrobia, Actinobacteria, CF231, and Akkermansia), decreased levels of pathogenic bacteria (Spirochaetes and Treponema), and increased species diversity. CONCLUSIONS By improving the permeability and immune function of the intestinal mucosa, Hetiao Jianpi decoction prevented the occurrence of AAD by repairing the intestinal mucosal damage and regulating the structure and diversity of intestinal flora.

Antifibrotic action of Yifei Sanjie formula enhanced autophagy via PI3K-AKT-mTOR signaling pathway in mouse model of pulmonary fibrosis.

Pulmonary fibrosis (PF) is a crippling disease characterized by progressive dyspnea and associated with a high mortality rate, but its origin is unknown and there is no effective treatment. Yifei Sanjie formula (YFSJF) is a Chinese medicine that is widely used for treatment of respiratory systems disease. However, the molecular basis for the function of YFSJF has not been determined. Here we investigate the contribution of YFSJF in BLM-induced PF mice. Administration with YFSJF significantly alleviated the degree of BLM-induced collagen I and III deposition and the inflammatory injuring in the lungs and suppressed hydroxyproline release in PF animals. The active components of YFSJF are comprised with flavonoid, amino acids, saponins, oligosaccharide, organic acid, vitamin, esters, purine nucleosides. Additionally, there was a significant increase in autophagosomes, after treatment with YFSJF in PF animals. Interestingly, autophagy dysfunction by the blocker chloroquine (CQ) resulted in collagen deposition and inducing the expression of fibrosis-related genes. In addition, YFSJF-induced autophagy is mediated by the PI3K-AKT-mTOR pathway, and knockdown of PI3K by siRNA up-regulated the expression of autophagy-related genes and down-regulated the expression of collagen in human lung fibroblasts (HLF). Our findings provide a detailed understanding that YFSJF-antifibrotic effects are mainly mediated by triggering autophagy, and suppressing phosphorylation of the PI3K-AKT-mTOR pathway is required for YFSJF-curative effect.

Roles of Chinese Medicine and Gut Microbiota in Chronic Constipation.

Chronic constipation is a common gastrointestinal dysfunction, but its aetiology and pathogenesis are still unclear. Interestingly, the compositions of the gut microbiota in constipation patients and healthy controls are different. Various studies reported the different gut microbiota alterations in constipation patients, but most studies indicated that constipation patients showed the decreased beneficial bacteria and the reduced species richness of gut bacteria. Besides, the alterations in the gut microbiota may lead to constipation and constipation-related symptoms and the regulation of gut microbiota has a positive effect on gut functional diseases such as constipation. Microbial treatment methods, such as probiotics, prebiotics, synbiotics, and fecal microbiota transplantation, can be used to regulate gut microbiota. Increasing evidences have suggested that Chinese medicine (CM) has a good therapeutic effect on chronic constipation. Chinese medicine is well known for its multitarget and multimode effects on diseases as well as less side effects. In previous studies, after the treatment of constipation with CM, the gut microbiota was restored, indicating that the gut microbiota might be the target or important way for CM to exert its efficacy. In this review, we summarized the effects of microbial treatment and CM on the gut microbiota of constipation patients and discussed the relationship between CM and gut microbiota.

Curcumin and Curcumol Inhibit NF-κB and TGF-ß 1/Smads Signaling Pathways in CSE-Treated RAW246.7 Cells.

E-Zhu (Curcuma zedoaria) is known as a classical traditional Chinese medicine and widely used in the treatment of cancers, cardiovascular disease, inflammation, and other diseases. Its main components include curcumol and curcumin, which have anti-inflammatory and antifibrosis effects. Here we established an in vitro inflammatory injury model by stimulating RAW246.7 cells with cigarette smoke extract (CSE) and detected the intervention effects of curcumin and curcumol on CSE-treated Raw246.7 macrophage cells to explore whether the two compounds inhibited the expression of inflammatory cytokines by inhibiting the NF-κB signaling pathway. We detected the antifibrosis effects of curcumin and curcumol via TGF-ß 1/Smads signaling pathways. The model of macrophage damage group was established by CSE stimulation. Curcumol and curcumin were administered to Raw246.7 macrophage cells. The efficacy of curcumol and curcumin was evaluated by comparing the activation of proinflammatory factors, profibrotic factors, and NF-κB and TGF-ß 1/Smads signaling pathway. In addition, CSE-treated group was employed to detect whether the efficacy of curcumol and curcumin was dependent on the NF-κB signaling via the pretreatment with the inhibitor of NF-κB. Our findings demonstrated that curcumol and curcumin could reduce the release of intracellular ROS from macrophages, inhibit the NF-κB signaling pathway, and downregulate the release of proinflammatory factor. Curcumol and curcumin inhibited the TGF-ß 1/Smads signaling pathway and downregulated the release of fibrotic factors. Curcumin showed no anti-inflammatory effect in CSE-treated cells after the inhibition of NF-κB. Curcumol and curcumin showed an anti-inflammatory effect by inhibiting the NF-κB signaling pathway.

Regulation Effect of a Chinese Herbal Formula on Flora and Mucosal Immune Secretory Immunoglobulin A in Rats.

Flora and mucosal immunity are considered to be the barrier, which is associated with multiple respiratory diseases, including recurrent respiratory tract infection (RRTI). Fei-Xi-Tiao-Zhi-Fang (FTF) is a traditional Chinese herbal formula used in the treatment of RRTI. However, the mechanism is little known. This study aims to identify the function of FTF in flora and mucosal immune secretory immunoglobulin A (sIgA) in the model of RRTI rats. The samples of intestine and lung were collected to detect sIgA, short chain fatty acids (SCFAS), and flora with enzyme-linked immunosorbent assay (ELISA), gas chromatography, and 16S rDNA sequencing. The body weight and viscera index were increased dynamically in RRTI rats after the administration of FTF. Furthermore, the types and proportions of aboriginal flora were significantly changed in the model group, whereas the altered flora was rescued in the FTF administration group. Desulfovibrio increased in the intestinal microflora and Ralstonia and Blautia decreased in the pulmonary microflora at the genus level, similar to that in the normal group. In addition, the expressions of sIgA in pulmonary and intestinal tissues were significantly upregulated and the level of SCFAS was increased in FTF group compared to the RRTI model group. Our study suggests that FTF can alleviate the symptoms of RRTI by increasing sIgA and SCFAS, recovering flora, and improving the immunity.

Anti-inflammatory effect of Yu-Ping-Feng-San via TGF-ß1 signaling suppression in rat model of COPD.

OBJECTIVES: Yu-Ping-Feng-San (YPFS) is a classical traditional Chinese medicine that is widely used for treatment of the diseases in respiratory systems, including chronic obstructive pulmonary disease (COPD) recognized as chronic inflammatory disease. However, the molecular mechanism remains unclear. Here we detected the factors involved in transforming growth factor beta 1 (TGF-ß1)/Smad2 signaling pathway and inflammatory cytokines, to clarify whether YPFS could attenuate inflammatory response dependent on TGF-ß1/Smad2 signaling in COPD rats or cigarette smoke extract (CSE)-treated human bronchial epithelial (Beas-2B) cells. MATERIALS AND METHODS: The COPD rat model was established by exposure to cigarette smoke and intratracheal instillation of lipopolysaccharide, YPFS was administered to the animals. The efficacy of YPFS was evaluated by comparing the severity of pulmonary pathological damage, pro-inflammation cytokines, collagen related genes and the activation of TGF-ß1/Smad2 signaling pathway. Furthermore, CSE-treated cells were employed to confirm whether the effect of YPFS was dependent on the TGF-ß1/Smad2 signaling via knockdown Smad2 (Si-RNA), or pretreatment with the inhibitor of TGF-ß1. RESULTS: Administration of YPFS effectively alleviated injury of lung, suppressed releasing of pro-inflammatory cytokines and collagen deposition in COPD animals (P<0.05), whereas exogenous TGF-ß1 promoted releasing of IL-1ß, IL-6, TNFα (P<0.05). Administration YPFS reduced inflammatory response significantly, also down-regulated TGF-ß1/Smad2 signaling in vivo and in vitro. Unexpectedly, knockdown Smad2 or inhibition of TGF-ß1 abolished anti-inflammatory effect of YPFS in CSE-treated cells. CONCLUSION: YPFS accomplished anti-inflammatory effects mainly by suppressing phosphorylation of Smad2, TGF-ß1/Smad2 signaling pathway was required for YPFS-mediated anti-inflammation in COPD rats or CSE-treated Beas-2B cells.

Earthworm extract attenuates silica-induced pulmonary fibrosis through Nrf2-dependent mechanisms.

Silicosis is an occupational pulmonary fibrosis caused by inhalation of silica (SiO2) and there are no ideal drugs to treat this disease. Earthworm extract (EE), a natural nutrient, has been reported to have anti-inflammatory, antioxidant, and anti-apoptosis effects. The purpose of the current study was to test the protective effects of EE against SiO2-induced pulmonary fibrosis and to explore the underlying mechanisms using both in vivo and in vitro models. We found that treatment with EE significantly reduced lung inflammation and fibrosis and improved lung structure and function in SiO2-instilled mice. Further mechanistic investigations revealed that EE administration markedly inhibited SiO2-induced oxidative stress, mitochondrial apoptotic pathway, and epithelial-mesenchymal transition in HBE and A549 cells. Furthermore, we demonstrate that Nrf2 activation partly mediates the interventional effects of EE against SiO2-induced pulmonary fibrosis. Our study has identified EE to be a potential anti-oxidative, anti-inflammatory, and anti-fibrotic drug for silicosis.