Network pharmacology and experimental verification to decode the action of Qing Fei Hua Xian Decotion against pulmonary fibrosis.

BACKGROUND: Pulmonary fibrosis (PF) is a common interstitial pneumonia disease, also occurred in post-COVID-19 survivors. The mechanism underlying the anti-PF effect of Qing Fei Hua Xian Decotion (QFHXD), a traditional Chinese medicine formula applied for treating PF in COVID-19 survivors, is unclear. This study aimed to uncover the mechanisms related to the anti-PF effect of QFHXD through analysis of network pharmacology and experimental verification. METHODS: The candidate chemical compounds of QFHXD and its putative targets for treating PF were achieved from public databases, thereby we established the corresponding "herb-compound-target" network of QFHXD. The protein-protein interaction network of potential targets was also constructed to screen the core targets. Furthermore, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to predict targets, and pathways, then validated by in vivo experiments. RESULTS: A total of 188 active compounds in QFHXD and 50 target genes were identified from databases. The key therapeutic targets of QFHXD, such as PI3K/Akt, IL-6, TNF, IL-1ß, STAT3, MMP-9, and TGF-ß1 were identified by KEGG and GO analysis. Anti-PF effects of QFHXD (in a dose-dependent manner) and prednisone were confirmed by HE, Masson staining, and Sirius red staining as well as in vivo Micro-CT and immunohistochemical analysis in a rat model of bleomycin-induced PF. Besides, QFXHD remarkably inhibits the activity of PI3K/Akt/NF-κB and TGF-ß1/Smad2/3. CONCLUSIONS: QFXHD significantly attenuated bleomycin-induced PF via inhibiting inflammation and epithelial-mesenchymal transition. PI3K/Akt/NF-κB and TGF-ß1/Smad2/3 pathways might be the potential therapeutic effects of QFHXD for treating PF.

Phytosterols Alleviate Hyperlipidemia by Regulating Gut Microbiota and Cholesterol Metabolism in Mice.

Phytosterols (PS) have been shown to regulate cholesterol metabolism and alleviate hyperlipidemia (HLP), but the mechanism is still unclear. In this study, we investigated the mechanism by which PS regulates cholesterol metabolism in high-fat diet (HFD) mice. The results showed that PS treatment reduced the accumulation of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) in the serum of HFD mice, while increasing the serum levels of high-density lipoprotein cholesterol (HDL-C). Compared with HFD mice, PS not only increased the antioxidant activity of the liver but also regulated the mRNA expression levels of enzymes and receptors related to cholesterol metabolism. The hypolipidemic effect of PS was abolished by antibiotic (Abx) intervention and reproduced by fecal transplantation (FMT) intervention. The results of 16S rRNA sequencing analysis showed that PS modulated the gut microbiota of mice. PS reduced the relative abundance of Lactobacillus and other bile salt hydrolase- (BSH-) producing gut microbiota in HFD mice, which are potentially related to cholesterol metabolism. These findings partially explain the mechanisms by which PS regulates cholesterol metabolism. This implies that regulation of the gut microbiota would be a potential target for the treatment of HLP.

Qing Fei Hua Xian Decoction ameliorates bleomycin-induced pulmonary fibrosis by suppressing oxidative stress through balancing ACE-AngII-AT1R/ACE2-Ang-(1-7)-Mas axis.

Objectives: We aimed to investigate the preventative effect of Qing Fei Hua Xian Decoction (QFHXD) against pulmonary fibrosis (PF) and its potential mechanisms. Materials and Methods: Bleomycin (BLM)-induced rats were respectively treated with 413.3, 826.6, and 1239.9 mg/kg of QFHXD and prednisone for 28 days. The lung tissues of rats were collected on day 28 for histological and western blotting analysis. Results: QFHXD significantly reduced alveolus inflammation, collagen accumulation, and fibrosis deposition in BLM-induced PF rats (P<0.05). Collagen I and III, vimentin, and α-smooth muscle actin(α-SMA) expression levels were likewise decreased in PF rats treated with QFHXD (P<0.05). Additionally, QFHXD increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) while decreasing NADPH oxidase 4 (NOX4) expression (P<0.05). Furthermore, QFHXD suppressed the PF progression by down-regulating Angiotensin-Converting Enzyme (ACE) -Angiotensin II (AngII) -Angiotensin II Type 1 Receptor (AT1R) axis (P<0.01) and up-regulating Angiotensin-Converting Enzyme 2 (ACE2) -Angiotensin-(1-7) (Ang-(1-7)) -Mas axis (P<0.05). Conclusion: QFHXD suppressed inflammatory infiltration and PF brought on by BLM in lung tissues through reducing oxidative stress by maintaining the equilibrium of ACE-AngII-AT1R and ACE2-Ang-(1-7) -Mas axes. This study may provide a novel clinical therapy option for PF.

Neuroprotective Mechanisms of Puerarin in Central Nervous System Diseases: Update.

Due to global population aging and modern lifestyle changes, the incidence of central nervous system (CNS) disorders, such as neurodegenerative diseases, neuropsychiatric disorders, and cerebrovascular diseases, is increasing and has become a major public health challenge. Current medications commonly used in the clinic are far from satisfactory and may cause serious side effects. Therefore, the identification of novel drugs for the effective management of CNS diseases is very urgent. Puerarin, a highly bioactive ingredient isolated from Pueraria lobata, is known to possess a broad spectrum of pharmacological properties including anti-diabetic, anti-inflammatory, anti-antioxidant, neuroprotective, and cardioprotective features. However, its clinical application is limited due to its poor water solubility. Since puerarin has demonstrated a wide range of neuroprotective functions in various CNS diseases, such as Alzheimer's disease, Parkinson's disease, cerebral ischemia, depression, and spinal cord injury, it has been attracting increasingly intense attention worldwide. In this review, we intend to extensively summarize the research progress on neuroprotective mechanisms of puerarin in recent years and discuss the future directions of its application in CNS disease treatment.

Active Components of Traditional Chinese Medicinal Material for Multiple Myeloma: Current Evidence and Future Directions.

Multiple myeloma (MM) is a hematological malignancy characterized by clonal expansion of plasma cells in bone marrow, leading to the overproduction of monoclonal immunoglobulins. The clinical manifestations resulting from monoclonal proteins and malignant cells include signs of end-organ damage, such as hypercalcemia, renal failure, anemia, and bone lesions. Despite improvement in the survival of MM patients with use of myeloma-targeted and immunomodulatory therapies, MM remains an incurable disease. Moreover, patients with relapsed or refractory MM show poor survival outcomes. In recent years, there has been a growing interest in the use of traditional Chinese medicinal materials (TCMMs) for management of a wide spectrum of diseases. The bioactive ingredients derived from TCMMs hold great potential for the development of anticancer drugs. Here we summarize the evidence of the pharmacological effects of the active components in TCMMs on MM, including curcumin, resveratrol, baicalein, berberine, bufalin, cinobufagin, gambogic acid, ginsenoside, icariin, daidzin, formononetin, polysaccharides extracts from Hedyotis difus, and scutellarein. Available evidence indicates that the anti-MM effects of these bioactive ingredients are mediated via regulation of proliferation, apoptosis, autophagy, cell cycle, osteogenic differentiation, and drug resistance. In the future, the underlying mechanisms of the anti-MM effects of these components should be further investigated. Large-scale and well-designed clinical trials are also required to validate the efficacy of these bioactive constituents for MM.

[Conception and framework of land ecological restoration for a new stage in China.] / 新时期我国国土空间生态修复理念与模式探讨.

Based on the theories of geography and landscape ecology, land ecological restoration is an important strategy to promote ecological civilization and build a beautiful China. Land ecological restoration in China has the characteristics of multi-disciplinary theoretical system, diverse work mode, integration of technology and methods, and diversified practice and exploration. The overall effectiveness of the work coexists with arduous tasks. Based on the new challenges in land ecological restoration, we summarized the overall framework and technical path of land ecological restoration, the working mechanism and mode of regional land ecological restoration, the content system and technical standards of land ecological restoration. In the new stage, the top-level design of land ecological restoration in China should focus on the work system, business boundary and institutional system, identify the responsibility boundary of different business processes, and realize the closed management of the whole work chain from the perspective of theory, system, engineering and technology. Rural settlement area, urban built-up area, industrial and mining gathering area, ecological function area and blue ocean area are the five major elements of regional scale land space, which correspond to five different ecological restoration modes, namely, comprehensive land improvement, urban renewal and double repair, mine geological environment restoration, mountain-river-forest-farmland-lake-grassland restoration, and blue bay restoration. It is necessary to comprehensively use the thinking of "Three Integrations" (information, technology, and process) to build a set of regional land ecological restoration work mode covering the integration of investigation, monitoring and evaluation, land space planning, project implementation, project acceptance and ecosystem monitoring and evaluation.

A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version).

In December 2019, a new type viral pneumonia cases occurred in Wuhan, Hubei Province; and then named "2019 novel coronavirus (2019-nCoV)" by the World Health Organization (WHO) on 12 January 2020. For it is a never been experienced respiratory disease before and with infection ability widely and quickly, it attracted the world's attention but without treatment and control manual. For the request from frontline clinicians and public health professionals of 2019-nCoV infected pneumonia management, an evidence-based guideline urgently needs to be developed. Therefore, we drafted this guideline according to the rapid advice guidelines methodology and general rules of WHO guideline development; we also added the first-hand management data of Zhongnan Hospital of Wuhan University. This guideline includes the guideline methodology, epidemiological characteristics, disease screening and population prevention, diagnosis, treatment and control (including traditional Chinese Medicine), nosocomial infection prevention and control, and disease nursing of the 2019-nCoV. Moreover, we also provide a whole process of a successful treatment case of the severe 2019-nCoV infected pneumonia and experience and lessons of hospital rescue for 2019-nCoV infections. This rapid advice guideline is suitable for the first frontline doctors and nurses, managers of hospitals and healthcare sections, community residents, public health persons, relevant researchers, and all person who are interested in the 2019-nCoV.

Saponin from Tupistra chinensis Bak Inhibits NF-κB Signaling in Sarcoma S-180 Cell Mouse Xenografts.

This study examined the effect of saponins from Tupistra chinensis Bak (STCB) on the growth of sarcoma S-180 cells in vitro and in mouse xenografts as well as the underlying mechanisms. Cell proliferation was assessed by MTT assay. Cell cycle distribution was determined by flow cytometry. Sarcoma S-180 tumor-bearing mice were treated with different doses of STCB with 10 µg/mL 5-fluorouracil (5-Fu) as a positive control. The activity of nuclear factor (NF)-κB was detected by gel mobility shift assay. The mRNA level of NF-κB was determined by real-time quantitative RT-PCR. The results showed that in vitro STCB inhibited the growth of S-180 cells in a concentration-dependent manner, which was accompanied by cell cycle arrest at S-phase. In vivo STCB significantly inhibited the growth of S-180 tumor mouse xenografts in a dose-dependent manner with apparent induction of cell apoptosis. Moreover, STCB inhibited the activity of NF-κB p65 and reduced the expression of NF-κB p65 mRNA in mouse xenografts. It was concluded that STCB inhibits the proliferation and cell cycle progression of S-180 cells by suppressing NF-κB signaling in mouse xenografts. Our findings suggest STCB is a promising agent for the treatment of sarcoma.

Involvement of glucose-regulated protein 78 and spliced X-box binding protein 1 in the protective effect of gliclazide in diabetic nephropathy.

AIMS: To testing whether endoplasmic reticulum (ER) stress contributes to the development of diabetic nephropathy. Investigated the effect of gliclazide, an oral antihyperglycemic agent, in a rat model of diabetic nephropathy and the underlying mechanism related to the ER stress response. METHODS: Sixty SD rats were divided into six groups. Diabetic nephropathy was induced in 30 rats with a streptozotocin (STZ) injection and high fat diet, which were then treated with saline, gliclazide or 4-PBA. 20 rats were treated with Tunicamycin (TM) one-time intraperitoneal injection, following treated with saline or gliclazide. Blood glucose, kidney index and function were evaluated. Light and transmission electron microscopy (TEM) were used to observe kidney histological changes. Quantitative real-time PCR and western blot were performed to access the mRNA and protein levels of glucose-regulated protein 78 (GRP78) and spliced X-box binding protein 1 (sXBP1) in glomeruli. RESULT: STZ-induced diabetic rats evidenced nephropathy by higher serum creatinine (sCr), blood urea nitrogen (BUN), microalbuminuria (MAU), and kidney index. Histological examination and TEM assay showed abnormal renal structures including thick glomerular basement membrane and mesangial cell expansion. The same changes were found in TM-treated rats. Gliclazide-treated had similar kidney index, but lower glucose levels, sCr, BUN, and MAU, compared with both saline and 4-PBA-treated diabetic rats or saline-treated TM rats. Synchronize with significantly lower Grp78 and sXbp1 mRNA and protein levels. CONCLUSION: Diabetes-induced nephropathy is associated with ER stress. Gliclazide treatment lessens diabetic nephropathy, probably partially by suppressing the GRP78- and sXBP1-mediated ER response.

Anticancer activity of Astragalus polysaccharide in human non-small cell lung cancer cells.

BACKGROUND: We have reported that Chinese herbs Astragalus polysaccharide (APS) can inhibit nuclear factor kappaB (NF-κB) activity during the development of diabetic nephropathy in mice. NF-κB plays important roles in genesis, growth, development and metastasis of cancer. NF-κB is also involved in the development of treatment resistance in tumors. Here we investigated the antitumor activity of APS in human non-small cell lung cells (A549 and NCI-H358) and the related mechanisms of action. METHODS: The dose-effect and time-effect of antitumor of APS were determined in human lung cancer cell line A549 and NCI-H358. The inhibition effect of APS on the P65 mRNA and protein was detected by reverse transcriptase-PCR (RT-PCR) and Western blot in A549 cells respectively. The inhibition effect of APS on the p50, CyclinD1 and Bcl-xL protein was detected by Western blot in A549 cells respectively. The effect of APS on NF-κB transcription activity was measured with NF-κB luciferase detection. Finally, the nude mice A549 xenograft was introduced to confirm the antitumor activity of APS in vivo. RESULTS: Cell viability detection results indicated that APS can inhibit the proliferation of human lung cancer cell line A549 and NCI-H358 in the concentration of 20 and 40 mg/mL. NF-κB activator Phorbol 12-myristate13-acetate (PMA) can attenuate the antitumor activity of APS in both cell lines, but NF-κB inhibitor BAY 11-7082 (Bay) can enhance the effect of APS in both cell lines. In vivo APS can delay the growth of A549 xenograft in BALB/C nude mice. APS can down-regulate the expression of P65 mRNA and protein of A549 cells and decrease the expression of p50, CyclinD1 and Bcl-xL protein. The luciferase detection showed that the APS could reduce the P65 transcription activity in A549 cells. PMA can partially alleviate the inhibition activity of P65 transcription activity of APS in A549 cells, and Bay can enhance the down-regulation of the P65 transcription activity induced by APS in A549 cells. CONCLUSION: APS has a significant antitumor activity in human lung cancer cells A549 and NCI-H358. NF-κB inhibition may mediate the antitumor effect.

Effects of Dangguibuxue decoction on rat glomerular mesangial cells cultured under high glucose conditions.

BACKGROUND: Dysfunction of glomerular mesangial cells (GMCs) plays an important role in pathogenesis of diabetic nephropathy. Here, we investigated the effects of Dangguibuxue decoction (DBD), an herbal traditional Chinese medicinal (TCM) formula composed of Astragali Radix and Angelicae Sinensis Radix, on GMC proliferation and fibrogenesis under high-glucose (HG) conditions. METHODS: Sixty male Sprague Dawley rats were divided into 5 groups and administered intragastric 0.9% saline, low concentration DBD (DBD-L, 1.75 g/kg/d), middle concentration DBD (DBD-M, 3.5 g/kg/d), high concentration DBD (DBD-H, 7.0 g/kg/d) and gliclazide (GL, 2 mg/kg/d), respectively, for 1 week, and then their sera were obtained. Rat mesangial cells (HBZY-1 cells) were treated with these sera under HG condition (30 mmol/L). RESULTS: The proliferation of GMCs under HG conditions was significantly greater than that under normal glucose condition. Low concentration DBD (DBD-L) inhibited proliferation of GMCs after 72-h incubation (P < 0.01), while high concentration DBD (DBD-H) inhibited GMCs proliferation at 24, 48 and 72 time points (P < 0.01). There was no significant difference between the inhibitory effect of DBD-H and GL sera on GMC proliferation (P > 0.05). Furthermore, all concentrations of DBD (DBD-L, DBD-M and DBD-H) significantly decreased the protein expression of α-SMA(α-smooth muscle actin) (P < 0.01), an indicator of interstitial fibrosis of GMCs. Finally, DBD-L, DBD-M, DBD-H sera obviously inhibited the increase of HYP (hydroxyproline)secretion under HG condition (P < 0.01). CONCLUSION: Our results demonstrate an inhibitory effect of DBD extract on proliferation and fibrogenesis of GMCs under HG conditions. The potential role of DBD in the treatment of diabetic neuropathy merits further investigation.

Protective effects of Danggui Buxue Tang on renal function, renal glomerular mesangium and heparanase expression in rats with streptozotocin-induced diabetes mellitus.

Danggui Buxue Tang (DBT) is a simple combination of Radix Astragali and Radix Angelica sinensis (5:1), with a variety pharmacological activities. In the present study, a single intravenous injection of 30 mg/kg streptozotocin and subsequent six weeks of high glucose diet in Sprague Dawley rats were used to induce diabetic nephropathy. Rats with diabetes mellitus showed increased levels of fasting blood glucose (FBG), blood urea nitrogen (BUN), serum creatinine (Scr), serum and urine ß2-microglobulins (ß2-MG), and type IV collagen (all P<0.05). DBT treatment significantly decreased the levels of FBG, BUN, Scr, serum and urine ß2-MG, and type IV collagen. Furthermore, DBT treatment significantly and dose-dependently restored the ultrastructural injury, and reduced the expression of heparanase, compared with the vehicle (P<0.05). Therefore, DBT may be a novel therapeutic approach for the prevention and treatment of diabetic nephrology.

Effects of Danggui Buxue Tang, a traditional Chinese herbal decoction, on high glucose-induced proliferation and expression of extracellular matrix proteins in glomerular mesangial cells.

Diabetic nephropathy (DN) is the leading cause of end-stage failure of the kidney, but the efficacy of currently available strategies for the prevention of DN remains unsatisfactory. In this study, we investigated the effects of Danggui Buxue Tang (DBT), a Chinese herbal decoction prepared from Radix Astragali (RA) and Radix Angelicae sinensis (RAS), on high glucose-induced proliferation and expression of laminin, type IV collagen (collagen IV) and fibronectin in glomerular mesangial cells (GMCs). The cell proliferation was determined by MTT assay, and the expression of collagen IV, laminin and fibronectin in GMCs was detected by ELISA assay. It was shown that high glucose clearly induced the proliferation of GMCs and increased the release of collagen IV, laminin and fibronectin. Treatment with RA, RAS and DBT inhibited cell proliferation and the expression of collagen IV, laminin and fibronectin induced by high glucose, with DBT, especially at the highest concentration (DBT20), exhibiting a stronger effect than RA and RAS alone. Thus, it is concluded that DBT inhibits increased cell proliferation and the expression of major extracellular matrix proteins that are induced by high glucose, indicating its value for prophylaxis and therapy of DN at the early stages.

Role of Bone Morphogenetic Proteins-7 (BMP-7) in the Renal Improvement Effect of DangGui (Angelica sinensis) in Type-1 Diabetic Rats.

Hyperglycemia induced reactive oxygen species (ROS) generation is believed as major factors leading to diabetic nephropathy (DN). DangGui (Angelica sinensis) is mentioned to show renal protective effect in combination with other herbs. Bone morphogenetic proteins-7 (BMP-7) is produced merit in protection of DN. The role of BMP-7 in DangGui-induced renal improvement is not clear. The present study investigated the effects of DangGui on renal functions, BMP-7 expression and the levels of ROS in streptozotocin (STZ)-induced diabetic rats and high glucose-exposed rat mesangial cells (RMCs). After 1- or 4-week treatment, DangGui improved renal functions and increased renal BMP-7 expression in diabetic rats. The BMP-7 expression in RMCs was reduced by high glucose treatment and this could be reversed by DangGui. Moreover, RMCs exposed to high glucose were expired by BMP-7 RNAi transfection but those cells remained alive by scramble transfection. Thus, we employed regular RMCs to knock down BMP-7 with RNAi and we found that DangGui increased BMP-7 expression in these RMCs. Direct activation of BMP-7 expression by DangGui could be considered. The results of DPPH assay, DHE stain and lucigenin assay indicated that DangGui could inhibit high glucose-induced ROS in RMCs. These results suggest that DangGui has an ability to improve renal functions in STZ-diabetic rats through increasing endogenous BMP-7 expression and decreasing oxidative stress in kidney. The present study suggest that DangGui could be applied to improve renal functions in diabetic disorders.

Merit of Astragalus polysaccharide in the improvement of early diabetic nephropathy with an effect on mRNA expressions of NF-kappaB and IkappaB in renal cortex of streptozotoxin-induced diabetic rats.

AIM OF STUDY: Diabetic nephropathy (DN) is the leading cause of the end-stage failure of kidney, but the efficacy of currently available strategies for the prevention of DN remains poor. An activation of the transcription factor, nuclear factor-kappaB (NF-kappaB), has been suggested to be a key step in the pathogenesis of DN. In the present study, we investigated the effect of Astragalus polysaccharide (APS), an aqueous extract from the Astragalus membranaceus roots, on gene expressions of NF-kappaB and an inhibitory protein of nuclear factor-kappaB (IkappaB) in experimental DN induced by streptozotocin in male Sprague-Dawley rats. MATERIALS AND METHOD: Rats with DN were treated with APS (1g/kg p.o.) or benazepril (1.5mg/kg p.o.), an angiotensin-converting enzyme inhibitor, using as positive control. The biochemical parameters such as blood glucose, plasma lipid and microalbuminuria were measured. Also, the mRNA level of NF-kappaB or IkappaB in renal cortex was determined using reverse transcription-polymerase chain reaction. RESULTS: Eight weeks after the treatment, symptoms including shineless, bristly hair, polyuria, polydipsia, lethargy, physical inactivity, loss of body weight, kyphosis and decubitus position were ameliorated by APS. The levels of blood glucose, plasma lipid and microalbuminuria were lowered in APS-treated rats compared with control rats. The ratio of kidney weight over body weight was reduced and the renal function was improved after APS treatment. The mRNA level of NF-kappaB in renal cortex was decreased and IkappaB mRNA expression was raised by APS. These results suggest that APS has prophylactic and therapeutic effects on the progress of DN; CONCLUSIONS: therefore, APS is helpful for the prevention and/or treatment of DN at early stage.