Platycodin D facilitates antiviral immunity through inhibiting cytokine storm via targeting K63-linked TRAF6 ubiquitination.

Influenza virus infection is a worldwide challenge that causes heavy burdens on public health. The mortality rate of severe influenza patients is often associated with hyperactive immunological abnormalities characterized by hypercytokinemia. Due to the continuous mutations and the occurrence of drug-resistant influenza virus strains, the development of host-directed immunoregulatory drugs is urgently required. Platycodon grandiflorum is among the top 10 herbs of traditional Chinese medicine used to treat pulmonary diseases. As one of the major terpenoid saponins extracted from Platycodon grandiflorum, Platycodin D (PD) has been reported to play several roles, including anti-inflammation, analgesia, anti-cancer, hepatoprotection, and immunoregulation. However, the therapeutic roles of PD to treat influenza virus infection remains unknown. Here, we show that PD can protect the body weight loss in severely infected influenza mice, alleviate lung damage, and thus improve the survival rate. More specifically, PD protects flu mice via decreasing the immune cell infiltration into lungs and downregulating the overactivated inflammatory response. Western blot and immunofluorescence assays exhibited that PD could inhibit the activation of TAK1/IKK/NF-κB and MAPK pathways. Besides that, CETSA, SPR and immunoprecipitation assays indicated that PD binds with TRAF6 to decrease its K63 ubiquitination after R837 stimulation. Additionally, siRNA interference experiments exhibited that PD could inhibit the secretion of IL-1ß and TNF-α in TRAF6-dependent manner. Altogether, our results suggested that PD is a promising drug candidate for treating influenza. Our study also offered a scientific explanation for the commonly used Platycodon grandiflorum in many anti-epidemic classic formulas. Due to its host-directed regulatory role, PD may serve as an adjuvant therapeutic drug in conjunction with other antiviral drugs to treat the flu.

D-A Structured High-Performance Photothermal/Photodynamic Thionin-Synthetic Melanin Nanoparticles for Rapid Bactericidal and Wound Healing Effects.

Synthesized melanin nanoparticles (SMNPs) are used as advanced photothermal materials. However, their internal structures are complex and disordered, and tuning the photothermal performance of nanoparticles is still a hot spot of concern. This article presents thionin (Th)-doped SMNPs, namely Th-SMNPs, which are the first SMNPs formed using the one-pot polymerization of Th with Levodopa. Th can undergo Michael addition and Schiff base reaction between indole dihydroxy/indolequinone and their oligomers to form donor-acceptor pairs in the structure to modulate the photothermal performance of SMNPs. Structural and spectroscopic analyses and density functional theory simulations further confirm the existence of the donor-acceptor structure. Th-SMNPs exhibit excellent total photothermal efficiency (34.49%) in the near-infrared region (808 nm), which is a 60% improvement compared to SMNPs. This allows Th-SMNPs to exhibit excellent photothermal performance at low power 808 nm laser irradiation. Meanwhile, Th not only enhances the photothermal properties of SMNPs, but also imparts photodynamic effects to SMNPs. Th-SMNPs can produce 1 O2 under 660 nm laser irradiation. A dual-function photothermal and photodynamic textile named Th-SMNPs@cotton is constructed based on Th-SMNPs, which can act as a rapid photothermal/photodynamic sterilization and is promising for wound healing treatment of bacterial infections under low-power dual laser irradiation.

Processing Mechanism of Massa Medicata Fermentata Based on the Correlation Analysis of Strains, Chemical Compositions and Anti-Inflammatory Activity.

The traditional Chinese medicine of fermented medicine may be under the involvement of multiple strains and the interaction between these microorganisms. Liu Shenqu (Massa Medicata Fermentata, MMF) is one of the most widely used fermented medicines, whose potential processing mechanism is still unclear. In this work, UPLC/MS and GNPS methods were employed to rapidly predict chemical compositions in MMF. Moreover, the dynamic changes of strains, chemical compositions and anti-inflammatory activity of MMF during fermentation process were investigated, and subsequently strains-chemical compositions-efficacy interactions were revealed by Pearson correlation analysis and partial least squares regression (PLSR) analysis. As a result, 24 components were identified, and the potential strains including Bacillus, Burkholderia_Caballeronia_Paraburkholderia, Enterobacter, Aspergillus heterocaryoticus, Rhizopus arrhizus, Kazachstania bulderi, which related to the production of anti-inflammatory active ingredients were exposed. These results demonstrated chemical compositions-strains-efficacy interactions during fermentation of MMF, and provide reference for the exploration of the processing mechanism of MMF.

Neolignans and Diarylheptanoids with Anti-Inflammatory Activity from the Rhizomes of Alpinia zerumbet.

The dried leaves and rhizomes of Alpinia zerumbet have been traditionally used as food and medicine. Anti-inflammatory activity-guided phytochemical investigation into the rhizomes of A. zerumbet led to the isolation of 17 compounds including 10 neolignans (1-10, 1a, 1b, 2a, 2b, 3a, 3b, 4, and 5 are new compounds) and seven diarylheptanoids (11-17) in which 1-3 were three pairs of enantiomers. 4 was only one enantiomer and 5 was a racemic mixture. Compounds 1a, 1b, 2a, and 2b incorporated an 8',9'-dinorneolignan skeleton, which was rare in the lignan family. The planar structures of these compounds were elucidated by extensive analyses of spectroscopic data. The relative and absolute configurations were determined by the time-dependent density functional theory (TDDFT)-based electronic circular dichroism (ECD) calculation method. The 95% ethanol extract and ethyl acetate extract of A. zerumbet were found to show anti-inflammatory activity against croton oil-induced ear edema in mice with inhibition rates of 20.0 and 47.6% at a dose of 80 mg/kg, respectively. Bioassays showed that compounds 1a, 1b, 2a, 2b, and 12 moderately inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW264.7 cells with IC50 values of 3.62, 7.63, 6.51, 5.60, and 8.33 µM, respectively.

Emodin palliates high-fat diet-induced nonalcoholic fatty liver disease in mice via activating the farnesoid X receptor pathway.

BACKGROUND: Cassia mimosoides Linn (CMD) is a traditional Chinese herb that clears liver heat and dampness. It has been widely administered in clinical practice to treat jaundice associated with damp-heat pathogen and obesity. Emodin (EMO) is a major bioactive constituent of CMD that has apparent therapeutic efficacy against obesity and fatty liver. Here, we investigated the protective effects and underlying mechanisms of EMO against high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD). OBJECTIVE: We aimed to investigate whether EMO activates farnesoid X receptor (FXR) signaling to alleviate HFD-induced NAFLD. MATERIALS AND METHODS: In vivo assays included serum biochemical indices tests, histopathology, western blotting, and qRT-PCR to evaluate the effects of EMO on glucose and lipid metabolism disorders in wild type (WT) and FXR knockout mice maintained on an HFD. In vitro experiments included intracellular triglyceride (TG) level measurement and Oil Red O staining to assess the capacity of EMO to remove lipids induced by oleic acid and palmitic acid in WT and FXR knockout mouse primary hepatocytes (MPHs). We also detected mRNA expression of FXR signaling genes in MPHs. RESULTS: After HFD administration, body weight and serum lipid and inflammation levels were dramatically increased in the WT mice. The animals also presented with impaired glucose tolerance, insulin resistance, and antioxidant capacity, liver tissue attenuation, and pathological injury. EMO remarkably reversed the foregoing changes in HFD-induced mice. EMO improved HFD-induced lipid accumulation, insulin resistance, inflammation, and oxidative stress in a dose-dependent manner in WT mice by inhibiting FXR expression. EMO also significantly repressed TG hyperaccumulation by upregulating FXR expression in MPHs. However, it did not improve lipid accumulation, insulin sensitivity, or glucose tolerance in HFD-fed FXR knockout mice. CONCLUSIONS: The present study demonstrated that EMO alleviates HFD-induced NAFLD by activating FXR signaling which improves lipid accumulation, insulin resistance, inflammation, and oxidative stress.

Aidi injection induces apoptosis of hepatocellular carcinoma cells through the mitochondrial pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The incidence and mortality rates of hepatocellular carcinoma are very high all over the world, which seriously threatens human life and health. Aidi injection as a Chinese medicine preparation has a positive curative effect on hepatocellular carcinoma, but its mechanism remains unclear. AIM OF THE STUDY: The purpose of this study is to evaluate the anti-hepatocellular carcinoma effects of Aidi injection and explore its mechanism of action vitro and vivo. MATERIALS AND METHODS: The main components of Aidi injection were determined by LC-MS/MS. The effects of Aidi injection on the viability of HepG2 and PLC/PRF/5 cells were detected via CCK-8 analysis and Calcein AM/PI staining. DAPI staining and flow cytometry were applied to analyze the apoptosis-induced effects of Aidi injection on hepatocellular carcinoma cells (HCCs). The growth inhibition of Aidi injection on hepatocellular carcinoma was observed in nude mice bearing PLC/PRF/5 cells. The related signal transduction and apoptosis pathways were investigated through assays for JC-1 mitochondrial membrane potential (MMP), RNA-seq, KEGG, PPI and WB. RESULTS: There were 12 main chemical components contained in Aidi injection, viz. cantharidin, syringin, calycosin-7-o-ß-Dglucoside, isozinpidine, ginsenosides Rd, Rc, Rb1, Re, and Rg1, astragalosides II and IV, and eleutheroside E. Aidi injection significantly inhibited the proliferation of HepG2 and PLC/PLF/5 cells with IC50 of 20.66 mg/ml and 27.5 mg/ml at 48h, respectively, increased the proportion of dead cells, induced cell apoptosis, suppressed the tumor growth of nude mice bearing PLC/PLF/5 cells, reduced MMP, activated PI3K/Akt and MAPK signal transduction pathways, down-regulated the expression of p-PI3K and Bcl-xL, and up-regulated the expression of p-JNK, p-p38 and Bim. CONCLUSION: Aidi injection inhibits the growth of liver cancer probably through regulating PI3K/Akt and MAPK signal transduction pathways, inducing MMP collapse to activate the mitochondrial apoptosis pathway, and then eliciting apoptosis of HCCs.

Exploring the mechanism of pullulan delay potato starch long-term retrogradation from the viewpoint of amylopectin chain motion.

Starch retrogradation is an inevitable process in the natural state caused by movement of starch chains. Therefore, the objective of this study was to explore the essence of starch long-term retrogradation from the viewpoint of amylopectin chain motion. The radius of gyration (Rg) and form factor (ρ) values of potato starch (PS) and PS with pullulan (PS-PUL) gradually increased during the retrogradation process. Furthermore, the conformation of molecular chains evolved from spherical to ellipsoidal to rod-like during starch retrogradation. Based on the analysis of condensed matter theory, these results illustrated that starch chains from gelatinization to retrogradation experienced shrinkage to extension. The values of Rg and ρ of PS-PUL were lower than PS, and the evolution of conformations showed that PUL delayed the long-term retrogradation of PS by decreasing the motion of amylopectin molecular chains to increase chain flexibility, and decrease the degree of entanglement and crosslinking. This study provides a novel method for characterizing starch retrogradation on the molecular level.

Sipi soup inhibits cancer­associated fibroblast activation and the inflammatory process by downregulating long non­coding RNA HIPK1­AS.

Sipi soup (SPS), the aqueous extract derived from the root bark of Sophora japonical L, Salix babylonica L., Morus alba L., as well as Amygdalus davidiana (Carr.) C. de Vos, is a traditional Chinese medicine frequently used to prevent and treat infection and inflammation. However, the role of SPS in cancer­associated fibroblasts (CAFs) require further investigation. In the present study, the effects of SPS on fibroblast inactivation and the underlying mechanism were investigated. Reverse transcription­quantitative polymerase chain reaction was used to analyze the mRNA expression levels of fibroblast activation protein (FAP), interleukin (IL)­6, α­smooth muscle actin (α­SMA) and programmed cell death 4 (PDCD4). Flow cytometry was used to evaluate cell apoptosis. Immunofluorescence was used to determine the number of activated fibroblasts. The present study reported that SPS treatment did not affect the proliferative apoptotic potential of fibroblasts. Treatment with HeLa cell culture medium (CM) induced a significant increase in the expression levels of FAP, IL­6 and α­SMA, but reduced the expression of PDCD4. SPS reversed the effects of HeLa CM on the expression of these genes. Analysis with a long non­coding (lnc)RNA array of numerous differentially expressed lncRNAs revealed that the expression levels of the lncRNA homeodomain­interacting protein kinase 1 antisense RNA (HIPK1­AS) were increased in cervicitis tissues and cervical squamous cell carcinoma tissues compared with in normal cervical tissues. HIPK1­AS expression levels were upregulated in response to HeLa CM, but were decreased under SPS treatment. The downregulation of HIPK1­AS expression via short hairpin RNA abolished the effects of HeLa CM on the expression of inflammation­associated genes. The findings of the present study suggested that SPS may prevent the progression of cervical cancer by inhibiting the activation of CAF and the inflammatory process by reducing HIPK1­AS expression.

Higher iron bioavailability of a human-like collagen iron complex.

Iron deficiency remains a public health problem around the world due to low iron intake and/or bioavailability. FeSO4, ferrous succinate, and ferrous glycinate chelate are rich in iron but have poor bioavailability. To solve the problem of iron deficiency, following previous research studies, a thiolated human-like collagen-ironcomplex supplement with a high iron content was prepared in an anaerobic workstation. In addition, cell viability tests were evaluated after conducting an MTT assay, and a quantitative analysis of the thiolated human-like collagen-iron digesta samples was performed using the SDS-PAGE method coupled with gel filtration chromatography. The iron bioavailability was assessed using Caco-2 cell monolayers and iron-deficiency anemia mice models. The results showed that (1) one mole of thiolated human-like collagen-iron possessed approximately 35.34 moles of iron; (2) thiolated human-like collagen-iron did not exhibit cytotoxity and (3) thiolated human-like collagen- iron digesta samples had higher bioavailability than other iron supplements, including FeSO4, ferrous succinate, ferrous glycine chelate and thiolated human-like collagen-Fe iron. Finally, the iron bioavailability was significantly enhanced by vitamin C. These results indicated that thiolated human-like collagen-iron is a promising iron supplement for use in the future.

Protective effect of Periplaneta americana extract in ulcerative colitis rats induced by dinitrochlorobenzene and acetic acid.

CONTEXT: Periplaneta americana L. (Dictyoptera; Blattaria) has been traditional used to treat ulcers, burns and heart disease in southwestern China. Recent reports indicate that P. americana can be used as an alternative medicine in therapy of ulcerative colitis, but the mechanism involved remains obscure. OBJECTIVE: This study investigated the therapeutic effect of P. americana extract (PAE) in rat colitis and elucidated its potential mechanism. MATERIALS AND METHODS: Dinitrochlorobenzene and acetic acid-induced colitis rat model was applied. Colitis rats were treated with PAE for 10 d and estimated disease activity index daily. Rectal inflammation was assessed by myeloperoxidase activity and histological changes. Another colitis rats were treated with PAE for 4 d, meanwhile gavage with Escherichia coli labelled with green fluorescent protein. Mesenteric lymph nodes, colon, liver, spleen and kidney were harvested for bacteria culture. PAE was suspended in distilled water then partitioned with ethyl acetate and n-butanol to obtain ethyl acetate fraction, n-butanol fraction and water fraction, respectively. Fibroblasts proliferation and collagen accumulation of each fraction was determined. RESULTS: PAE treatment reduced the severity of colitis and tissue myeloperoxidase accumulation (p < 0.001). Also, PAE at 80 mg/kg significantly inhibited labelled E. coli from translocating to distant organs, especially to MLN and liver. Additionally, PAE significantly stimulated fibroblasts proliferation (126.9%) and collagen accumulation (130.8%) for 48 h incubation. Among the partitions, ethyl acetate fraction generally had higher fibroblast viability enhanced-activity. CONCLUSIONS: PAE can protect against ulcerative colitis and this protection is attributed to anti-inflammation and fibroblasts viability.

Molecular Selection, Modification and Development of Therapeutic Oligonucleotide Aptamers.

Monoclonal antibodies are the dominant agents used in inhibition of biological target molecules for disease therapeutics, but there are concerns of immunogenicity, production, cost and stability. Oligonucleotide aptamers have comparable affinity and specificity to targets with monoclonal antibodies whilst they have minimal immunogenicity, high production, low cost and high stability, thus are promising inhibitors to rival antibodies for disease therapy. In this review, we will compare the detailed advantages and disadvantages of antibodies and aptamers in therapeutic applications and summarize recent progress in aptamer selection and modification approaches. We will present therapeutic oligonucleotide aptamers in preclinical studies for skeletal diseases and further discuss oligonucleotide aptamers in different stages of clinical evaluation for various disease therapies including macular degeneration, cancer, inflammation and coagulation to highlight the bright commercial future and potential challenges of therapeutic oligonucleotide aptamers.

Saponins of Panax notoginseng: chemistry, cellular targets and therapeutic opportunities in cardiovascular diseases.

INTRODUCTION: Among the notable breakthroughs in the past two decades of research in natural drug discovery is the identification of saponins (saponins in Panax notoginseng, PNS) as the primary ingredient of Panax notoginseng, an iconic herbal medicine in East Asia. Increasing evidences suggest that PNS have versatile effects against a variety of cardiovascular diseases (CVDs), leading to four clinical trials completed and/or underway. There is a timely need to summarize our current understanding of these natural compounds. AREAS COVERED: In this review, the authors summarize and critically appraise the latest literature (mainly since 2008), which study PNS as potential therapeutic agents against CVDs. Furthermore, they introduce the structures of major PNS types, analyze their cellular targets and associated signaling pathways and discuss the emerging opportunities for their clinical applications. A major focus here is on how these compounds affect the cardiovascular system via diverse mechanisms of action. EXPERT OPINION: The authors believe that future research should head in two directions. The first direction taken should involve establishing a PNS compounds library to correlate their functions with structures; the second direction should be by integrating network pharmacology and pharmaceutical techniques in the future development of these natural compounds as new vascular medicine.

Curcumin ameliorates hippocampal neuron damage induced by human immunodeficiency virus-1.

Our previous studies have shown that infection with the gp120 V3 loop can cause human immunodeficiency virus-1 associated neurocognitive disorders. Curcumin has been shown to improve these effects to some degree, but the precise mechanisms remain unknown. The present study analyzed the neuroprotective effect and mechanism of curcumin in relation to hippocampal neurons. Results showed that 1 nmol/L gp120 V3 loop suppressed the growth of synapses. After administration of 1 µmol/L curcumin, synaptic growth improved. Curcumin is neuroprotective against gp120 V3 loop-induced neuronal damage by inhibiting the activation of L-type calcium currents, relieving intracellular Ca(2+) overload, promoting Bcl-2 expression, and inhibiting Bax activation. The effect of curcumin was identical to nimodipine, suggesting that curcumin has the same neuroprotective effects against gp120 V3 loop-induced neuronal damage.

Evaluation of the add-on effect of chinese patent medicine for patients with stable or unstable angina: a systematic review and meta-analysis.

Chinese herbal medicine (CHM) has been widely used as an adjunct to western medicine in treating angina in China. We carried out this systematic review to evaluate the effectiveness of CHM on top of western medicine for angina. This meta-analysis included 46 randomized control trials with 4212 patients. For trials that included stable angina patients, the CHM group had significant lower incidence of total heart events (relative risk (RR) = 0.50, 95% confidence interval (CI) 0.33-0.78), myocardial infarction (RR = 0.32, 95% CI 0.14-0.72), heart failure (RR = 0.37, 95% CI 0.15-0.91), and angina (RR = 0.46, 95% CI 0.30-0.71) than that of control group. For trials that included unstable angina patients, CHM led to significantly lower occurrence of total heart events (RR = 0.46, 95% CI 0.32-0.66), myocardial infarction (RR = 0.37, 95% CI 0.26-0.54), and angina (RR = 0.36, 95%CI 0.26-0.51). Likewise, for trials that included stable or unstable angina patients, the rates of myocardial infarction (RR = 0.34, 95% CI 0.17-0.68) and angina (RR = 0.46, 95% CI 0.30-0.70) in CHM group were significantly lower than that in control group. In conclusion, CHM is very likely to be able to improve the survival of angina patients who are already receiving western medicine.

[Analysis on layout of traditional Chinese medicine industry based on location quotient].

To observe the layout and evolution of the traditional Chinese medicine (TCM) medical industry, classify the industry by region and conduct a preliminary study on its professional advantages, competitiveness and possible cause by using the theory of location quotient in regional economics, in order to provide suggestions for the layout of the TCM medical industry.

Arabidopsis glabra2 mutant seeds deficient in mucilage biosynthesis produce more oil.

Seed oil, one of the major seed storage compounds in plants, is of great economic importance for human consumption, as an industrial raw material and as a source of biofuels. Thus, improving the seed oil yield in crops is an important objective. The GLABRA2 (GL2) gene in Arabidopsis thaliana encodes a transcription factor that is required for the proper differentiation of several epidermal cell types. GL2 has also been shown to regulate seed oil levels, as a loss-of-function mutation in the GL2 gene results in plants with a higher seed oil content than wild-type. We have extended this observation by showing that loss-of-function mutations in several positive regulators of GL2 also result in a high seed oil phenotype. The GL2 gene is expressed in both the seed coat and embryo, but the embryo is the main site of seed oil accumulation. Surprisingly, our results indicate that it is loss of GL2 activity in the seed coat, not the embryo, that contributes to the high seed oil phenotype. One target of GL2 in the seed coat is the gene MUCILAGE MODIFIED 4 (MUM4), which encodes a rhamnose synthase that is required for seed mucilage biosynthesis. We found that mum4 mutant seeds, like those of gl2 mutants, have an increased seed oil content in comparison with wild-type. Therefore, GL2 regulates seed oil production at least partly through its influence on MUM4 expression in the seed coat. We propose that gl2 mutant seeds produce more oil due to increased carbon allocation to the embryo in the absence of seed coat mucilage biosynthesis.