Monochasma savatieri Franch. protects against acute lung injury via α7nAChR-TLR4/NF-κB p65 signaling pathway based on integrated pharmacology analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) is a life-threatening condition with high morbidity and mortality, underscoring the urgent need for novel treatments. Monochasma savatieri Franch. (LRC) is commonly used clinically to treat wind-heat cold, bronchitis, acute pneumonia and acute gastroenteritis. However, its role in the treatment of ALI and its mechanism of action are still unclear. AIM OF THE STUDY: This study aimed to demonstrate the pharmacological effects and underlying mechanisms of LRC extract, and provide important therapeutic strategies and theoretical basis for ALI. MATERIALS AND METHODS: In this study, a research paradigm of integrated pharmacology combining histopathological analysis, network pharmacology, metabolomics, and biochemical assays was used to elucidate the mechanisms underlaying the effects of LRC extract on LPS-induced ALI in BALB/c mice. RESULTS: The research findings demonstrated that LRC extract significantly alleviated pathological damage in lung tissues and inhibited apoptosis in alveolar epithelial cells, and the main active components were luteolin, isoacteoside, and aucubin. Lung tissue metabolomic and immunohistochemical methods confirmed that LRC extract could restore metabolic disorders in ALI mice by correcting energy metabolism imbalance, activating cholinergic anti-inflammatory pathway (CAP), and inhibiting TLR4/NF-κB signaling pathway. CONCLUSIONS: This study showed that LRC extract inhibited the occurrence and development of ALI inflammation by promoting the synthesis of antioxidant metabolites, balancing energy metabolism, activating CAP and suppressing the α7nAChR-TLR4/NF-κB p65 signaling pathway. In addition, our study provided an innovative research model for exploring the effective ingredients and mechanisms of traditional Chinese medicine. To the best of our knowledge, this is the first report describing the protective effects of LRC extract in LPS-induced ALI mice.

Inhibition of inflammasome activation via sphingolipid pathway in acute lung injury by Huanglian Jiedu decoction: An integrative pharmacology approach.

BACKGROUND: Acute lung injury (ALI) is a serious health issue which causes significant morbidity and mortality. Inflammation is an important factor in the pathogenesis of ALI. Even though ALI has been successfully managed using a traditiomal Chinese medicine (TCM), Huanglian Jiedu Decoction (HLD), its mechanism of action remains unknown. PURPOSE: This study explored the therapeutic potential of HLD in lipopolysaccharide (LPS)-induced ALI rats by utilizing integrative pharmacology. METHODS: Here, the therapeutic efficacy of HLD was evaluated using lung wet/dry weight ratio (W/D), myeloperoxide (MPO) activity, and levels of tumor necrosis factor (TNF-α), interleukin (IL)-1ß and IL-6. Network pharmacology predictd the active components of HLD in ALI. Lung tissues were subjected to perform Hematoxylin-eosin (H&E) staining, metabolomics, and transcriptomics. The acid ceramidase (ASAH1) inhibitor, carmofur, was employedto suppress the sphingolipid signaling pathway. RESULTS: HLD reduced pulmonary edema and vascular permeability, and suppressed the levels of TNF-α, IL-6, and IL-1ß in lung tissue, Bronchoalveolar lavage fluid (BALF), and serum. Network pharmacology combined with transcriptomics and metabolomics showed that sphingolipid signaling was the main regulatory pathway for HLD to ameliorate ALI, as confirmed by immunohistochemical analysis. Then, we reverse verified that the sphingolipid signaling pathway was the main pathway involed in ALI. Finally, berberine, baicalein, obacunone, and geniposide were docked with acid ceramidase to further explore the mechanisms of interaction between the compound and protein. CONCLUSION: HLD does have a better therapeutic effect on ALI, and its molecular mechanism is better elucidated from the whole, which is to balance lipid metabolism, energy metabolism and amino acid metabolism, and inhibit NLRP3 inflammasome activation by regulating the sphingolipid pathway. Therefore, HLD and its active components can be used to develop new therapies for ALI and provide a new model for exploring complex TCM systems for treating ALI.

Traditional Chinese medicines as effective agents against influenza virus-induced pneumonia.

Influenza virus-induced pneumonia (IVP) is a high morbidity and contagiousness pulmonary infectious disease caused by invasion of the influenza virus into the lower respiratory tract. Currently, the treatment of IVP is mainly based on an anti-influenza virus infection strategy, which includes the use of anti-influenza vaccines and drugs. However, the clinical use of these treatment options is limited as the influenza virus has a high level of variability and drug resistance may occur. Traditional Chinese medicines (TCMs) for the treatment of IVP have unique advantages, a variety of precise curative effects and have been widely used in clinical practice in China both historically and in the present day. However, there are only few literature reviews on the prevention and treatment of IVP using TCMs. Therefore, we conducted a review of relevant literature from the past 10 years and a comprehensive analysis of various databases containing reports on TCMs used for IVP prevention and treatment to provide basic data for future research and development of drugs against IVP. Herein, we summarize research progress on the pathogenesis of IVP, the TCMs effective in prevention or treatment of IVP, their underlying molecular mechanisms and active components. Overall, we provide a theoretical basis for the clinical use of TCM in the prevention and treatment of IVP. Furthermore, we provide a reference for the development of new multi-component, multi-target, low-toxicity drugs, which is of great academic and clinical significance.

Physalis alkekengi L. var. franchetii (Mast.) Makino: A review of the pharmacognosy, chemical constituents, pharmacological effects, quality control, and applications.

BACKGROUND: Physalis alkekengi L. var. franchetii (Mast.) Makino (PAF) (Chinese name Jin-Deng-Long) from the Solanaceae family is a traditional Chinese medicine with various pharmacological effects, such as removing heat, detoxification, improving throat conditions, removing phlegm, and ameliorating diuresis. PURPOSE: This paper reviews the existing literature and patents and puts forward some suggestions for future PAF research. METHODS: Using the PubMed, Google Scholar, Web of Science, and China National Knowledge Infrastructure databases, we performed comprehensive search of literature and patents published before April 2022 on PAF and its active ingredients. RESULTS: We comprehensively reviewed the research progress of PAF from aspects of the traditional application, botany, chemical composition, pharmacological effects, and toxicology, and first discussed quality control and modern applications, which have not been explored in previous reviews. Thereafter, we reviewed the limitations of pharmacological mechanism and quality control studies and proposed appropriate solutions, which is of great practical significance to subsequent studies. CONCLUSION: In this review, we present a comprehensive overview on PAF, and put forward new insights on studies regarding quality control, material basis, and mechanisms in classical prescription, providing theoretical guidance for the clinical application and development of Chinese medicine.

Integrative pharmacology reveals the mechanisms of Erzhi Pill, a traditional Chinese formulation, against diabetic cardiomyopathy.

ETHNOPHARMACOLOGICAL RELEVANCE: Erzhi Pill (EZP) is a traditional Chinese prescription that has marked effects in treating type 2 diabetes mellitus and diabetic nephropathy. However, its underlying pharmacological mechanisms in the treatment of diabetic cardiomyopathy (DCM), remain to be elucidated. AIM OF THE STUDY: This study aimed to apply an integrative pharmacological strategy to systematically evaluate the pharmacological effects and molecular mechanisms of EZP, and provide a solid theoretical basis for the clinical application of EZP in the treatment of DCM. MATERIALS AND METHODS: In this study, the potential targets and key pathways of EZP were predicted and validated using network pharmacology and molecular docking, respectively. Changes in cardiac metabolites and major metabolic pathways in rat heart samples were examined using 1H-nuclear magnetic resonance (NMR) metabolomics. Finally, biochemical analysis was conducted to detect the protein expression levels of key pathways. RESULTS: We found that EZP decreased fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), and low-density lipoprotein (LDL) levels, increased high-density lipoprotein (HDL) levels in the serum, and alleviated the morphological abnormalities of the heart tissue in diabetic rats. Furthermore, EZP effectively restored superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), caspase-3, caspase-8, and caspase-9 activity levels, as well as the levels of reactive oxygen species (ROS), malondialdehyde (MDA), B-cell lymphoma (Bcl)-2, and Bcl-2-associated X protein (Bax) in the heart tissue. Network pharmacology prediction results indicated that the mechanism of EZP in treating DCM was closely related to apoptosis, oxidative stress, and the HIF-1, PI3K-Akt, and FoxO signaling pathways. In addition, 1H-NMR metabolomics confirmed that EZP primarily regulated both energy metabolism and amino acid metabolism, including the tricarboxylic acid (TCA) cycle, ketone bodies metabolism, glutamine and glutamate metabolism, glycine metabolism, and purine metabolism. Finally, immunohistochemistry results indicated that EZP reduced the expression levels of p-AMPK, p-PI3K, p-Akt, and p-FoxO3a proteins, in the heart tissue of DCM rats. CONCLUSION: The results confirmed that the overall therapeutic effect of EZP in the DCM rat model is exerted via inhibition of oxidative stress and apoptosis, alongside the regulation of energy metabolism and amino acid metabolism, as well as the AMPK and PI3K/Akt/FoxO3a signaling pathways. This study provides an experimental basis for the use of EZP in DCM treatment.

Identification of active compounds and molecular mechanisms of Dalbergia tsoi Merr.et Chun to accelerate wound healing.

As a traditional Chinese medicine, Dalbergia tsoi Merr.et Chun (JZX) has been used for the treatment of wounds since ancient times. However, the active compounds and molecular mechanisms of JZX in the acceleration of wound healing are still unknown. Herein, we explored the main active compounds and key molecular mechanisms by which JZX accelerates wound healing. The ethanol extract of JZX was subjected to UPLC-Q-Orbitrap HRMS analysis to identify the main compounds. The pharmacological effect of JZX on wound healing was evaluated using a mouse excision wound model. Network pharmacology was utilized to predict the effective compounds and related signal transduction pathways of JZX that were involved in accelerating wound healing. The predicted key signaling pathways were then validated by immunohistochemical analysis. Interactions between the active compounds and therapeutic targets were confirmed by molecular docking analysis. JZX accelerated wound healing, improved tissue quality, and inhibited inflammation and oxidative stress. Moreover, our results suggested that the active components of JZX, such as butin, eriodyctiol, and formononetin, are the key compounds that facilitate wound treatment. Our studies also indicated that JZX accelerated wound healing by regulating the PI3K/Akt signaling pathway and inducing the expression of TGF-ß1, FGF2, VEGFA, ECM1, and α-SMA at different stages of skin wound healing. The JZX extract accelerates wound healing by reducing inflammation and inhibiting oxidative stress, regulating the PI3K/Akt signaling pathway, and promoting the expression of growth factors, suggesting that JZX has potential clinical applicability in wound treatment.

Physalin B ameliorates inflammatory responses in lipopolysaccharide-induced acute lung injury mice by inhibiting NF-κB and NLRP3 via the activation of the PI3K/Akt pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Physalin B (PB) is an active constituent of Physalis alkekengi L. var. Franchetii, which is a traditional medicine for clearing heat and detoxification, resolving phlegm, and diuresis. It has been commonly applied to treat sore throat, phlegm-heat, cough, dysuria, pemphigus, and eczema. AIM OF STUDY: Physalin B has shown efficacy as an anti-acute lung injury (ALI) agent previously; however, its mechanisms of action remain unclear. In the present study, we established a lipopolysaccharide-induced septic ALI model using BALB/c mice to further confirm the therapeutic potential of PB and to assess the underlying molecular mechanisms. MATERIALS AND METHODS: We used 75% ethanol and macroporous resin for extraction, separation, and enrichment of PB. The LPS-induced ALI mouse model was used to determine anti-inflammatory effects of PB. The severity of acute lung injury was evaluated by hematoxylin and eosin staining, wet/dry lung ratio, and myeloperoxidase (MPO) activity in lung tissue. An automatic analyzer was used to measure the arterial blood gas index. Protein levels of pro-inflammatory cytokines in serum, bronchoalveolar lavage fluid (BALF), and lung tissue was measured using an ELISA. Quantitative RT-PCR was used to measure changes in RNA levels of pro-inflammatory cytokines in the lungs. A fluorometric assay kit was used for determination of apoptosis-related factors to assess anti-apoptotic effects of PB. Western blotting was used to assess levels of key pathway proteins and apoptosis-related proteins. Connections between the pathways were tested through inhibitor experiments. RESULTS: Pretreatment with PB (15 mg kg-1 d-1, i.g.) significantly reduced lung wet/dry weight ratios and MPO activity in blood and BALF of ALI mice, and it alleviated LPS-induced inflammatory cell infiltration in lung tissue. The levels of pro-inflammatory factors TNF-α, IL-6, and IL-1ß and their mRNA levels in blood, BALF, and lung tissue were reduced following PB pretreatment. PB pretreatment also downregulated the apoptotic factors caspase-3, caspase-9, and apoptotic protein Bax, and it upregulated apoptotic protein Bcl-2. The NF-κB and NLRP3 pathways were inhibited through activation of the PI3K/Akt pathway due to PB pretreatment, whereas administration of PI3K inhibitors increased activation of these pathways. CONCLUSIONS: Taken together, our results suggest that the anti-ALI properties of PB are closely associated with the inactivation of NF-κB and NLRP3 by altering the PI3K/Akt pathway. Furthermore, our findings provide a novel strategy for application of PB as a potential agent for treating patients with ALI. To the best of our knowledge, this is the first study to elucidate the underlying mechanism of action of PB against ALI.

Two new 3-hexenol glycosides from the calyces of Physalis alkekengi var. franchetii.

Two new hexenol glycosides, (Z)-hex-3-en-1-ol O-ß-d-xylcopyranosyl-(1-6)-ß -d-glucopyranosyl-(1-2)-ß-d-glucopyranoside (1) and (E)-hex-3-en-1-ol O-ß-d-xylcopyranosyl-(1-6)-ß-d-glucopyranosyl-(1-2)-ß-d-glucopyranoside (2), were isolated from the 50% ethanol elution of macroporous resin of Physalis alkekengi var. franchetii. Their structures were established by detailed spectroscopic analysis, including extensive 2D-NMR data. This is the first time to report the (Z) and (E) 3-hexenol glycosides from Physalis alkekengi var. franchetii.

Cardioprotective effect exerted by Timosaponin Bâ ¡ through the regulation of endoplasmic stress-induced apoptosis.

BACKGROUND: Timosaponin BⅡ (TBⅡ), one of the primary bioactive compounds from Anemarrhena asphodeloides Bunge, possesses potential cardioprotective effects. However, the mechanism underlying TBⅡ-mediated cardioprotection, especially the involvement of endoplasmic reticulum stress, remains largely unknown. PURPOSE: This study was designed to evaluate the role of TBⅡ in myocardial injury protection and explore its possible mechanisms. METHODS: In vivo models of isoproterenol-induced myocardial injury and H2O2-induced cytotoxicty were established to investigate the effect of anti-myocardial injury of TBⅡ. The potential mechanisms were investigated in vitro and in vivo using multiple detection methods like electrocardiography, histo-pathological examination, JC-1 staining, TUNEL staining, ELISA technology, and western blot analysis. RESULTS: In vivo study revealed that TBⅡ improved electrocardiography and heart vacuolation, reduced myocyte apoptosis, and improved the antioxidant potential. In vitro investigation demonstrated that TBⅡ pretreatment inhibited ER stress-mediated apoptosis pathways. Further investigation of the underlying mechanisms revealed that TBⅡ prevented H2O2-induced H9c2 cardiomyocytes injury by the PI3K/Akt pathways, whereas the addition of LY294002, the pharmacologic antagonist of PI3K, attenuated TBⅡ-induced expression of apoptotic protein and cytoprotective effects. CONCLUSION: These results suggested that TBⅡ protects against myocardial injury in vitro and enhances cellular defense capacity by inhibiting ER stress-mediated apoptosis pathways in vivo by activating the PI3K/Akt pathways.

Systems pharmacology reveals the mechanism of activity of Physalis alkekengi L. var. franchetii against lipopolysaccharide-induced acute lung injury.

Acute lung injury (ALI) is an important cause of mortality of patients with sepsis, shock, trauma, pneumonia, multiple transfusions and pancreatitis. Physalis alkekengi L. var. franchetii (Mast.) Makino (PAF) has been extensively used in Chinese folk medicine because of a good therapeutic effect in respiratory diseases. Here, an integrated approach combining network pharmacology, proton nuclear magnetic resonance-based metabolomics, histopathological analysis and biochemical assays was used to elucidate the mechanism of PAF against ALI induced by lipopolysaccharide (LPS) in a mouse model. We found that the compounds present in PAF interact with 32 targets to effectively improve the damage in the lung undergoing ALI. We predicted the putative signalling pathway involved by using the network pharmacology and then used the orthogonal signal correction partial least-squares discriminant analysis to analyse the disturbances in the serum metabolome in mouse. We also used ELISA, RT-qPCR, Western blotting, immunohistochemistry and TUNEL assay to confirm the potential signalling pathways involved. We found that PAF reduced the release of cytokines, such as TNF-α, and the accumulation of oxidation products; decreased the levels of NF-κB, p-p38, ERK, JNK, p53, caspase-3 and COX-2; and enhanced the translocation of Nrf2 from the cytoplasm to the nucleus. Collectively, PAF significantly reduced oxidative stress injury and inflammation, at the same time correcting the energy metabolism imbalance caused by ALI, increasing the amount of antioxidant-related metabolites and reducing the apoptosis of lung cells. These observations suggest that PAF may be an effective candidate preparation alleviating ALI.

Systems pharmacology reveals the mechanism of activity of Ge-Gen-Qin-Lian decoction against LPS-induced acute lung injury: A novel strategy for exploring active components and effective mechanism of TCM formulae.

Acute lung injury (ALI), a severe and life-threatening inflammation of the lung, with high morbidity and mortality, underscoring the urgent need for novel treatments. Ge-Gen-Qin-Lian decoction (GQD), a classic Chinese herbal formula, has been widely used to treat intestine-related diseases in the clinic for centuries. In recent years, a growing number of studies have found that GQD has a favorable anti-inflammatory effect. With the further study on the viscera microbiota, the link between the lungs and the gut-the gut-lung axis has been established. Based on the theory of the gut-lung axis, we used systems pharmacology to explore the effects and mechanisms of GQD treatment in ALI. Hypothesizing that GQD inhibits ALI progression, we used the experimental model of lipopolysaccharide (LPS)-induced ALI in Balb/c mice to evaluate the therapeutic potential of GQD. Our results showed that GQD exerted protective effects against LPS-induced ALI by reducing pulmonary edema and microvascular permeability. Meanwhile, GQD can downregulate the expression of LPS-induced TNF-α, IL-1ß, and IL-6 in lung tissue, bronchoalveolar lavage fluid (BLAF), and serum. To further understand the molecular mechanism of GQD in the treatment of ALI, we used the network pharmacology to predict the disease targets of the active components of GQD. Lung tissue and serum samples of the mice were separately analyzed by transcriptomics and metabolomics. KEGG pathway analysis of network pharmacology and transcriptomics indicated that PI3K/Akt signaling pathway was significantly enriched, suggesting that it may be the main regulatory pathway for GQD treatment of ALI. By immunohistochemical analysis and apoptosis detection, it was verified that GQD can inhibit ALI apoptosis through PI3K/Akt signaling pathway. Then, we used the PI3K inhibitor LY294002 to block the PI3K/Akt signaling pathway, and reversely verified that the PI3K/Akt signaling pathway is the main pathway of GQD anti-ALI. In addition, differential metabolites in mice serum samples indicate that GQD can inhibit the inflammatory process of ALI by reversing the imbalance of energy metabolism. Our study showed that, GQD did have a better therapeutic effect on ALI, and initially elucidated its molecular mechanism. Thus, GQD could be exploited to develop novel therapeutics for ALI. Moreover, our study also provides a novel strategy to explore active components and effective mechanism of TCM formula combined with TCM theory to treat ALI.

Advances in research into the mechanisms of Chinese Materia Medica against acute lung injury.

Acute lung injury (ALI) is a common and serious disease. Numerous treatment options are available but they do not improve quality of life or reduce mortality for ALI patients. Here, we review the treatments for ALI to provide basic data for ALI drug therapy research and development. Chinese Materia Medica (CMM) has long been the traditional clinical approach in China for the treatment of ALI and it has proven efficacy. The continued study of CMM has disclosed new potential therapeutic ingredients for ALI. However, few reviews summarize the currently available CMM-based anti-ALI drugs. Therefore, the systematic analysis of research progress in anti-ALI CMM is of great academic and clinical value. The aim of the present review is to describe CMM-based research progress in ALI treatment. Data were compiled by electronic retrieval (CNKI, SciFinder, PubMeds, Google Scholar, Web of Science) and from articles, patents and ethnopharmacological literature in university libraries were systematically studied. This review introduces progress in research on the etiology and mechanisms of ALI, the anti-ALI theory and modes of action in traditional Chinese medicine (TCM), anti-ALI active constituents of CMM, research progress in experimental methods of CMM anti-ALI, the anti-ALI molecular mechanisms of CMM, the anti-ALI efficacy of CMM formulae, and the potential toxicity of CMM and the antidotes for it. Scholars have investigated the anti-ALI molecular mechanism of CMM from various direction and have made substantial progress. This research explored the above aspects, enriched the anti-ALI theory of CMM and established the clinical significance and developmental prospects of ALI treatment by CMM. Because of the high frequency of drugs such as glucocorticoids or antibiotics, Western medicine lacks the advantages of CMM in terms of overall anti-ALI efficacy. In the future, the development of CMM-based anti-ALI therapies will become a major trend in the field of ALI drug development. Successful clinical safety and efficacy validations will promote and encourage the use of CMM. It provides fundamental theoretical support for the discovery and use of CMM resources through the comprehensive analysis of various anti-ALI CMM report databases.

Cardioprotective effects of a Fructus Aurantii polysaccharide in isoproterenol-induced myocardial ischemic rats.

CALB-3, a purified acidic hetero-polysaccharide isolated from Fructus aurantii, has been shown to exert cardioprotective effects in vitro. Recently, we investigated the protective effects of CALB-3 on myocardial injury and its possible mechanisms of action using a rat model of myocardial ischemia. In this study, a myocardial ischemia model was established via intragastric administration of 2 mg/kg isoproterenol (ISO) to male Sprague-Dawley rats (200-220 g) daily for 3 days. We found that pretreatment with CALB-3 (50, 100, and 200 mg/kg, i.g.) daily for 21 days prevented ISO-induced myocardial damage, including improvement in electrocardiographic parameters, and decrease in serum cardiac enzymes, heart vacuolation, and TUNEL-positive cells. We used western blotting to identify the underlying mechanisms and determine the possible signal pathways involved. We found that CALB-3 pretreatment prevented apoptosis, increased the expression of antioxidant enzymes, and enhanced the binding of Nrf2 to the antioxidant response element. In addition, CALB-3 activated the phosphorylation of PI3K/Akt and ERK to increase the cytoprotective effect. Overall, our results show that CALB-3 is a promising polysaccharide for protecting against myocardial injury induced by ISO.