Gallic acid ameliorates dextran sulfate sodium-induced ulcerative colitis in mice via inhibiting NLRP3 inflammasome.

Background: Ulcerative colitis (UC) is a chronic recurrent inflammatory bowel disease (IBD). The conventional drugs for UC may induce severe side effects. Herbal medicine is considered as a complementary and alternative choice for UC. Purpose: This study aims to estimate the effect of natural polyphenol gallic acid (GA) on the NLRP3 inflammasome with dextran sulfate sodium (DSS)-induced colitis in mice. Study design: The body weights and symptoms of BALB/c mice were recorded. Histological evaluation, ELISA, q-PCR, immunohistochemistry, and western blotting were carried out to observe the morphology, cytokine contents, mRNA expressions, and protein expressions, respectively. Lipopolysaccharide (LPS)-induced RAW264.7 macrophage was used to probe GA's effect on relative protein expression. Results: GA attenuated weight loss (p < 0.05), relieved symptoms, and ameliorated colonic morphological injury (p < 0.05) in mice with colitis induced by DSS. GA also lowered the contents of TNF-α, IL-1ß, IL-18, IL-33, and IFN-γ in the serum and colon of mice, which were elevated by DSS, downregulated protein, and mRNA expressions of the NLRP3 pathway in the colon tissue. Furthermore, GA downregulated the expressions of NLRP3 (p < 0.05), iNOS (p < 0.01), COX2 (p < 0.01), and P-p65 (p < 0.05), and suppressed NO release (p < 0.001) in LPS-induced RAW264.7 cells. Conclusion: GA ameliorated DSS-induced UC in mice via inhibiting the NLRP3 inflammasome. These findings furnish evidence for the anti-inflammatory effect of herbal medicines containing GA on UC.

[Vitamins and Immune System Health].

Keeping the immune system healthy forms an effective way to fight infections. Past experience has shown that, in addition to effective interventions including vaccination, drug therapy, and non-pharmaceutical intervention (NPI), dietary nutrition and mental health are also key factors in maintaining immune system health and combating emerging and sudden outbreaks of infections. As the main dietary nutrients, vitamins are active regulators of the immune response and exert a critical impact on the immunity of the human body. Vitamin deficiency causes increased levels of inflammation and decreased immunity, which usually starts in the oral tissues. Appropriate vitamin supplementation can help the body optimize immune function, enhance oral immunity, and reduce the negative impact of pathogen infection on the human body, which makes it a feasible, effective, and universally applicable anti-infection solution. This review focuses on the immunomodulatory effects of vitamin A, B, C, D, and E and proposes that an omics-based new systemic approach will lead to a breakthrough of the limitations in traditional single-factor single-pathway research and provide the direction for the basic and applied research of vitamin immune regulation and anti-infection in all aspects.

The Efficacy and Safety of Zaoren Anshen Capsule in Combination with Zolpidem for Insomnia: A Multicentre, Randomized, Double-Blinded, Placebo-Controlled Trial.

Purpose: Insomnia is the most common sleep disorder with high rate of prevalence, persistence, and leads to negative consequences. The mainstays of insomnia treatment have limitations due to either the side effects of hypnotics or limited accessibility to cognitive behavioral therapy. This study aims to compare the efficacy and safety of the traditional Chinese medicine (TCM) Zaoren Anshen capsule alone or as an adjunct treatment with different doses of the nonbenzodiazepine medication zolpidem tartrate in treating insomnia. Method: This randomized, double-blind, multicentre placebo control trial was conducted in 131 patients with chronic insomnia. The patients were randomly assigned to one of the following four regimen groups: Group ZA + Z5 : Zaoren Anshen capsule and 5 mg zolpidem tartrate (n = 32); Group Z5: 5 mg zolpidem tartrate and placebo capsule (n = 35); Group Z10 : 10 mg zolpidem tartrate and placebo capsule (n = 32); Group ZA : Zaoren Anshen capsule and placebo pill (n = 32). The drugs were administered for 4 weeks. All patients were evaluated by the Insomnia Severity Index (ISI) at 0, 2, 4, 5, and 6 weeks, and adverse events were recorded. Result: There are significant differences in the comparison between the four groups at each treatment stage (P < 0.05). Repeated measurement analysis of variance (ANOVA) of ISI scores in each treatment stage of the four groups exhibits significant differences in time effect, intergroup effect, and interaction effect (P < 0.05). After four weeks of drug administration, the treatment efficacy is similar in Groups ZA + Z5 and Z10 (93%) and in Groups Z5 and ZA (62% and 65%, respectively). Groups ZA + Z5 and Z10 present significantly lower ISI scores compared with Groups Z5 and ZA (P < 0.05), which indicates better treatment response of Groups ZA + Z5 and Z10. No significant difference was observed in the incidence of adverse events between the groups. Conclusion: Zaoren Anshen capsule can effectively treat insomnia disorder either alone or in combination with zolpidem tartrate. A preferred combination of TCM Zaoren Anshen capsule with zolpidem can provide a magnified therapeutic efficacy with fewer side effects than zolpidem-only management, clinical trial registration number: Chinese Clinical Trial Registry ChiCTR-IPR-1600969.

Production of Soluble Murine TRAILs in Escherichia coli with Zn2+ Supplementation.

BACKGROUND: Accumulating evidence has demonstrated the immunomodulatory effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in rheumatoid arthritis and the tumor microenvironment, besides its known capacity of specifically inducing the apoptosis of cancer cells. Mice are common available animal models for studying the roles of TRAIL. However, mice express only a single TRAIL receptor (mTRAILR) with an intracellular death domain, in contrast to the two TRAIL receptors (TRAILR1 and TRAILR2) in humans. Moreover, human TRAIL binds weakly to mTRAILR, whereas mouse TRAIL has a high affinity for human TRAIL-Rs. Therefore, we considered that murine TRAIL would be more suitable than human TRAIL for exploring the immunoregulatory effect of TRAIL in immunocompetent mice or when using mouse cells as the target. To our knowledge, the detailed method for the production of recombinant murine TRAIL has not been reported. OBJECTIVE: In this study, we aimed to design and express two soluble forms of murine TRAIL and verify the properties of the protein. METHODS: Recombinant murine TRAILs were expressed in Escherichia coli BL21 (DE3, and Nichelating affinity chromatography was used for protein purification. SDS-PAGE, GDS-PAGE and HPLC were applied to analyze the protein structure. The cytotoxicity of our purified murine TRAILs was evaluated in the TRAIL-sensitive human breast cancer ZR-75-30 cells and murine breast cancer 4T1 cells. Finally, validation of the tumor-killing ability of the murine protein in vivo. RESULTS: Two soluble forms of murine TRAILs (mT_N99 and mT_N188) were purified and demonstrated with high purity and trimeric structure. In addition, Zn2+ supplement was essential to produce soluble murine TRAILs in E.coli BL21 (DE3). The two purified soluble mTRAILs showed similar cytotoxicity to cancer cells, moreover, mT_N99 also showed a good anti-tumor effect in vivo and is more suitable for the treatment of murine tumor models. CONCLUSION: A production approach for recombinant murine TRAIL was determined, which covered the design of shortened forms, expression, purification and characterization.

Physiological and Transcriptome Analyses Revealed the Mechanism by Which Deferoxamine Promotes Iron Absorption in Cinnamomum camphora.

Iron deficiency causes chlorosis and growth inhibition in Cinnamomum camphora, an important landscaping tree species. Siderophores produced by plant growth-promoting rhizobacteria have been widely reported to play an indispensable role in plant iron nutrition. However, little to date has been determined about how microbial siderophores promote plant iron absorption. In this study, multidisciplinary approaches, including physiological, biochemical and transcriptome methods, were used to investigate the role of deferoxamine (DFO) in regulating Fe availability in C. camphora seedlings. Our results showed that DFO supplementation significantly increased the Fe2+ content, SPAD value and ferric-chelate reductase (FCR) activity in plants, suggesting its beneficial effect under Fe deficiency. This DFO-driven amelioration of Fe deficiency was further supported by the improvement of photosynthesis. Intriguingly, DFO treatment activated the metabolic pathway of glutathione (GSH) synthesis, and exogenous spraying reduced glutathione and also alleviated chlorosis in C. camphora. In addition, the expression of some Fe acquisition and transport-related genes, including CcbHLH, CcFRO6, CcIRT2, CcNramp5, CcOPT3 and CcVIT4, was significantly upregulated by DFO treatment. Collectively, our data demonstrated an effective, economical and feasible organic iron-complexing agent for iron-deficient camphor trees and provided new insights into the mechanism by which siderophores promote iron absorption in plants.

Endogenous Hydrogen Sulfide Persulfidates Caspase-3 at Cysteine 163 to Inhibit Doxorubicin-Induced Cardiomyocyte Apoptosis.

Doxorubicin (DOX) is an efficient antitumor anthracycline drug, but its cardiotoxicity adversely affects the prognosis of the patients. In this study, we explored whether endogenous gasotransmitter hydrogen sulfide (H2S) could protect against DOX-induced cardiomyocyte apoptosis and its mechanisms. The results indicated that DOX significantly downregulated endogenous H2S production and endogenous synthetase cystathionine γ-lyase (CSE) expression and obviously stimulated the apoptosis in H9C2 cells. The supplement of H2S donor sodium hydrosulfide (NaHS) or overexpression of CSE inhibited DOX-induced H9C2 cell apoptosis. DOX enhanced the activities of caspase family members in cardiomyocytes, while NaHS attenuated DOX-enhanced caspase-3, caspase-2, and caspase-9 activities by 223.1%, 73.94%, and 52.29%, respectively. Therefore, taking caspase-3 as a main target, we demonstrated that NaHS or CSE overexpression alleviated the cleavage of caspase-3, suppressed caspase-3 activity, and inhibited the cleavage of poly ADP-ribose polymerase (PARP). Mechanistically, we found that H2S persulfidated caspase-3 in H9C2 cells and human recombinant caspase-3 protein, while the thiol-reducing agent dithiothreitol (DTT) abolished H2S-induced persulfidation of caspase-3 and thereby prevented the antiapoptotic effect of H2S on caspase-3 in H9C2 cells. The mutation of caspase-3 C148S and C170S failed to block caspase-3 persulfidation by H2S in H9C2 cells. However, caspase-3 C163S mutation successfully abolished the effect of H2S on caspase-3 persulfidation and the corresponding protection of H9C2 cells. Collectively, these findings indicate that endogenous H2S persulfidates caspase-3 at cysteine 163, inhibiting its activity and cardiomyocyte apoptosis. Sufficient endogenous H2S might be necessary for the protection against myocardial cell apoptosis induced by DOX. The results of the study might open new avenues with respect to the therapy of DOX-stimulated cardiomyopathy.

Beware of the Potential Risks for Polygoni Multiflori Caulis-Induced Liver Injury.

Background: Reynoutria multiflora (Thunb.) Moldenke (PM) is a widely-used medicinal plant in China, whose root and stem are included in the Chinese Pharmacopoeia as Polygoni Multiflori Radix (RPM), Polygoni Multiflori Radix Preparata (PMP), and Polygoni Multiflori Caulis (PMC). The hepatotoxicity of RPM and PMP is concerned by the public, while the risk of PMC is ignored. Purpose: Here, we investigate the potential risks for PMC-induced liver injury from clinical, chemical, and animal features. Study design: First, we analyzed the 12-month usage of RPM, PMP, and PMC in Longhua Hospital. Second, we determined the contents of gallic acid, cis-2,3,5,4'-tetrahydroxy-stilbene-2-O-ß-D-glucoside (cis-SG), trans-2,3,5,4'-tetrahydroxy-stilbene-2-O-ß-D-glucoside (trans-SG), emodin-8-O-ß-D-glucoside (EG), physcion-8-O-ß-D-glucoside (PG), emodin, and physcion in the water extracts from 15 batches of RPM, PMP, and PMC. Third, we probed the hepatotoxic effect of RPM, PMP, and PMC in mice and explored the mechanism of cis-SG and trans-SG causing the liver injury at the dosages based on our results from the first and second parts. Results: PMC had nearly five times the amount of usage in both outpatient prescriptions and inpatient orders than RPM and PMP. Overall, 68% dosage of PMC was 30 g. The contents of cis-SG, trans-SG, and emodin in PMC water extracts were significantly lower than those in RPM and PMP water extracts. PMC induced milder idiosyncratic liver injury for its lower content of cis-SG and trans-SG than its root counterparts. Conclusion: The potential risks for PMC-induced liver injury should be fully aware of.

Fingerprinting and Determination of Hepatotoxic Constituents in Polygoni Multiflori Radix Praeparata of Different Producing Places by HPLC.

Polygoni Multiflori Radix Praeparata (PMRP) is used as Chinese herbal medicine with long history. However, reports about PMRP hepatotoxicity have increased recently, and producing area might be one reason. This article aims to figure out the relationship between producing area and hepatotoxic ingredients in PMRP. HPLC fingerprint for PMRP was established and the contents of gallic acid, trans-stilbene glycoside (TSG), emodin-8-O-ß-D-glucoside (EG), emodin and physcion were determined. Clustering heatmap was implemented by TCMNPAS software，and principal component analysis was implemented by SPSS and SIMCA-P software. Hepatotoxic constituents' contents of PMRP from separate producing area were different. PMRP from Guangxi had the highest content of gallic acid, TSG, EG, emodin and physcion, followed by Hubei, Guangdong, Guizhou, Yunnan. PMRP from Henan had the lowest contents of hepatotoxic components. Hepatotoxic components' contents of PMRP in southern were higher than central China. This study carried out a preliminary qualitative and quantitative investigation on the PMRP from different producing places, which provided a basis for safe medication of PMRP.

[Protective effects of Lonicerae Japonicae Flos against acute alcoholic liver injury in rats based on network pharmacology].

This study aims to explore underlying mechanism of Lonicerae Japonicae Flos(LJF) in protecting rats against acute alcoholic liver injury(ALI) based on mitogen-activated protein kinase(MAPK) pathway. First, the targets of LJF in preventing ALI were predicted by network pharmacology and the component-target-pathway network was constructed, so that the key targets of LJF components acting on MAPK pathway were screened. Second, male SD rats were randomized into the control(KB) group, model(MX) group, positive(YX) group, and LJF high-(GJ), medium-(ZJ), and low-(DJ) dose groups. Each administration group was given(ig) corresponding drugs for 7 days and KB group and MX group received(ig) equal volume of distilled water every day. Except for KB group, rats were given Chinese spirit(56%, 3 days) for ALI modeling. The levels of aspartate transaminase(AST), alanine transaminase(ALT), interleukin-6(IL6) and tumor necrosis factor-α(TNF-α) in serum and malondialdehyde(MDA), glutathione(GSH), superoxide dismutase(SOD) and glutathione peroxidase(GSH-Px) in liver tissue of rats in each group were detected. Furthermore, we employed quantitative real-time PCR(qRT-PCR) to probe the effects of LJF on the key targets of MAPK pathway in ALI rats. A total of 28 active components of LJF were screened from TCMSP database, and 317 intersected with ALI-related targets. According to Kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analysis, the 317 targets involved 226 pathways, which were mainly liver disease, inflammation, immunity, apoptosis and other related pathways. According to the MAPK pathway-target-active component network, the key active components of LJF, such as chlorogenic acid, hederagenol, and hyperoside, acted on 25 key targets of MAPK pathway. The results of in vivo experiments showed decreased levels of AST, ALT, and MDA in DJ, ZJ, and GJ groups(P<0.01 or P<0.05), reduced levels of IL6 in DJ and GJ groups(P<0.01 or P<0.05), and improved levels of SOD and GSH in ZJ and GJ groups(P<0.01 or P<0.05). The results of qRT-PCR demonstrated that the expression levels of mitogen-activated protein kinase kinase 4(MAPK2 K4) and mitogen-activated protein kinase 3(MAPK3) were decreased in DJ, ZJ, and GJ groups(P<0.01). The network pharmacology and experimental verification showed that the active components in LJF can reduce the inflammatory factor level and enhance the activities of SOD and GSH-Px by inhibiting the expression of key targets of MAPK pathway, thus alleviating and preventing liver damage caused by alcohol.

Is Curcumin the Answer to Future Chemotherapy Cocktail?

The rise in cancer cases in recent years is an alarming situation worldwide. Despite the tremendous research and invention of new cancer therapies, the clinical outcomes are not always reassuring. Cancer cells could develop several evasive mechanisms for their survivability and render therapeutic failure. The continuous use of conventional cancer therapies leads to chemoresistance, and a higher dose of treatment results in even greater toxicities among cancer patients. Therefore, the search for an alternative treatment modality is crucial to break this viscous cycle. This paper explores the suitability of curcumin combination treatment with other cancer therapies to curb cancer growth. We provide a critical insight to the mechanisms of action of curcumin, its role in combination therapy in various cancers, along with the molecular targets involved. Curcumin combination treatments were found to enhance anticancer effects, mediated by the multitargeting of several signalling pathways by curcumin and the co-administered cancer therapies. The preclinical and clinical evidence in curcumin combination therapy is critically analysed, and the future research direction of curcumin combination therapy is discussed.

Effects of Qing Chang Suppository Powder and its Ingredients on IL-17 Signal Pathway in HT-29 Cells and DSS-induced Mice.

BACKGROUND: Qingchang Suppository, a formula used for more than 30 years in Longhua Hospital, has shown satisfactory clinical effects on Ulcerative Colitis (UC). However, its therapeutic mechanism has not been fully elucidated. PURPOSE: The study aims to investigate the effects of Qingchang Suppository powder (QCSP) and its ingredients by regulating the IL-17A signaling pathway which plays an important role in the development of UC. METHODS: HPLC was used to analyze the main ingredients (Gallic acid, Indigo, Indirubin) in QCSP. HT-29 cells were induced by rhIL-17A and TNF-α, and IL-17A related protein expressions were determined by western blot. BALB/C mice were induced by 4% Dextran Sodium sulfate (DSS). The effects of QCSP and its ingredients were evaluated by measuring weight loss, disease activity index (DAI), colon length, histological analysis. Western blot was used for analysis of IL-17A and MAPK related proteins p-ERK, p-JNK, p-P38. Quantitative reverse transcription polymerase chain reaction (q-PCR) was used to detect the expression of IL-17A, HSP90 and ACT1 in colon tissue. Cytokines such as IL-17A, IL-1ß, IFN-γ and TNF-α were determinated by enzyme-linked immunosorbent assay (ELISA). RESULTS: QCSP had good therapeutic effect on DSS-induced colitis in mice. QCSP significantly relieved weight loss, restored colon length, repaired colon lesions, reduced histological scores and DAI, decreased TNF-α, IL-1ß, IL-17 and IFN-γ contents, significantly suppressed the gene expressions of IL-17A, ACT1 and HSP90, and up-regulated the expressions of tight junction proteins like ZO-1 and Occludin. IL-17A pathway related proteins such as IL-17A, IL-17RA, HSP90, MAPKs, P-iκbα and iNOS were significantly increased in vitro and in vivo. CONCLUSIONS: This paper reveals that QCSP inhibited the IL-17A signaling pathway in HT-29 cells and DSS induced mice, presenting a new mechanism of QCS on treating UC.

Bufothionine induces autophagy in H22 hepatoma-bearing mice by inhibiting JAK2/STAT3 pathway, a possible anti-cancer mechanism of cinobufacini.

ETHNOPHARMACOLOGICAL RELEVANCE: Cinobufacini is extracted from the skins and parotid venom glands of the toad for treating symptoms like swelling and pain in ancient times. Nowadays, cinobifucini injection has also achieved satisfactory therapeutic effects on hepatocellular carcinoma (HCC) in China. AIM OF THE STUDY: Our previous work found that bufothionine, an alkaloid abundant in cinobufacini injection, induced mitochondria-mediated apoptosis. In this work, the underlying effects of bufothionine on autophagy in HCC and its possible dependent pathway were investigated. METHODS: CCK-8 and Hoechst staining assays were performed to verify effects of drugs on proliferation and apoptosis of SMMC7721 cell. H22-tumor-bearing mice model was established by inoculating ascites fluid. HE staining was used to observe pathological changes in liver and tumor tissues. ELISA and Western blot experiments were conducted to investigate IL-6/JAK2/STAT3 signaling pathway. The effects of drugs on expressions of autophagic relative proteins were investigated by Western blot in vitro and in vivo. RESULTS: In vitro, CCK-8 and Hoechst staining assays showed that bufothionine inhibited SMMC7721 cell proliferation and promoted apoptosis at 100 µM. In vivo, bufothionine relieved symptoms of H22-tumor-bearing mice and exerted anti-inflammation activity. ELISA and Western blot demonstrated that bufothionine significantly reduced serum IL-6 concentration, suppressed p-Stat3tyr705, p-Stat3ser727 and Jak2 expressions in tumor tissues and upregulated Atg5, Atg7 and LC3Ⅱ expressions in SMMC7721 cell and H22 tumor. CONCLUSION: This is the first report showing that bufothionine might induce autophagy in HCC by inhibiting JAK2/STAT3 pathway, presenting a possible anti-cancer mechanism of bufothionine in cinobufacini injection.

Gender Modifies the Association of Cognition With Age-Related Hearing Impairment in the Health and Retirement Study.

Introduction: Despite growing recognition of hearing loss as a risk factor for late life cognitive disorders, sex and gender analysis of this association has been limited. Elucidating this is one means to advocate for holistic medicine by considering the psychosocial attributes of people. With a composite Gender Score (GS), we aimed to assess this among aging participants (50+) from the 2016 Health and Retirement Study (HRS) cohort. Methods: The GS was derived from gender-related variables in HRS by factor analyses and logistic regression, ranging from 0 (toward masculinity) to 100 (toward femininity). GS tertiles were also used to indicate three gender types (GS tertile 1: lower GS indicates masculinity; GS tertile 2: middle GS indicates androgyny; GS tertile 3: higher GS indicates femininity). Univariate followed by multiple logistic regressions were used to estimate the Odds Ratio (OR) and 95% confidence intervals (CI) of cognitive impairment (assessed by adapted Telephone Interview for Cognitive Status) from hearing acuity, as well as to explore the interactions of sex and gender with hearing acuity. The risk of cognitive impairment among hearing-impaired participants was assessed using multivariable models including sex and gender as exposure variables. Results: Five variables (taking risks, loneliness, housework, drinking, and depression) were retained to compute the GS for each participant. The distribution of GS between sexes partly overlapped. After adjusting for confounding factors, the OR for cognitive impairment associated with hearing impairment was significantly higher (OR = 1.65, 95% CI: 1.26, 2.15), and this association was not modified by female sex (OR = 0.77, 95% CI: 0.46, 1.27), but by androgynous gender (OR = 0.44, 95% CI: 0.24, 0.81). In the multivariable models for participants with hearing impairment, androgynous and feminine gender, as opposed to female sex, was associated with lower odds of cognitive impairment (OR of GS tertile 2 = 0.59, 95% CI: 0.41, 0.84; OR of GS tertile 3 = 0.60, 95% CI: 0.41, 0.87; OR of female sex = 0.78, 95% CI: 0.57, 1.08). Conclusions: Hearing impairment was associated with cognitive impairment among older people, and this association may be attenuated by a more feminine GS.

Berberine in the treatment of metabolism-related chronic diseases: A drug cloud (dCloud) effect to target multifactorial disorders.

Berberine (BBR) is a multi-target drug (MTD) that has proven effective in the treatment of metabolism-related chronic diseases (CDs). However, the mode of action (MOA) of BBR remains to be clarified. At a cellular level, the inhibitory effect of BBR on mitochondrial enzymes is probably responsible for many of its biological activities, including the activation of low-density lipoprotein receptor (LDLR), AMP-activated protein kinase (AMPK) and insulin receptor (InsR); these biological activities contribute to ameliorate peripheral blood metabolic profiles, e.g. by reducing plasma lipids and glucose levels, thus improving signs and symptoms of metabolic disorders. In this perspective, BBR acts as a targeted therapy. However, it also exerts pleiotropic systemic activities on some root causes of CDs that include antioxidant / anti-inflammatory effects and modifications of gut microbiota composition and metabolism, which may also contribute to its disease-modifying effects. After reviewing the different MOA of BBR, here we propose that BBR acts through a drug-cloud (dCloud) mechanism, as different to a drug-target effect. The dCloud here is defined as a group of terminal molecular events induced by the drug (or/and related metabolites), as well as the network connections among them. In this scenario, the therapeutic efficacy of BBR is the result of its dCloud effect acting on symptoms/signs as well as on root causes of the diseases. The dCloud concept is applicable to other established MTDs, such as aspirin, metformin, statins as well as to nutrient starvation, thus providing a novel instrument for the design of effective therapies against multifactorial metabolism-related CDs.

Using near-infrared enhanced thermozyme and scFv dual-conjugated Au nanorods for detection and targeted photothermal treatment of Alzheimer's disease.

Investigation of targeting inhibitors of Aß aggregation, heme-Aß peroxidase-like activity and efficient detectors of Aß aggregation, are of therapeutic value and diagnostics significance for the treatment of Alzheimer's disease (AD). Due to the complex pathogenesis of AD, theranostics treatment with multiple functions are necessary. Herein we constructed the NIR absorption property of gold nanorods (GNRs) loaded with single chain variable fragment (scFv) 12B4 and thermophilic acylpeptide hydrolase (APH) ST0779 as a smart theranostic complex (GNRs-APH-scFv, GAS), which possesses both rapid detection of Aß aggregates and NIR photothermal treatment that effectively disassembles Aß aggregates and inhibits Aß-mediated toxicity. Methods: We screened targeting anti-Aß scFv 12B4 and thermophilic acylpeptide hydrolase as amyloid-degrading enzyme, synthesized GAS gold nanorods complex. The GAS was evalued by Aß inhibition and disaggregation assays, Aß detection assays, Aß mediated toxicity assays in vitro. In vivo, delaying Aß-induced paralysis in AD model of Caenorhabditis elegans was also tested by GAS. Results: In vitro, GAS has a synergistic effect to inhibit and disassociate Aß aggregates, in addition to decrease heme-Aß peroxidase-like activity. In cultured cells, treatment with GAS reduces Aß-induced cytotoxicity, while also delaying Aß-mediated paralysis in CL4176 C.elegans model of AD. Furthermore, the photothermal effect of the GAS upon NIR laser irradiation not only helps disassociate the Aß aggregates but also boosts APH activity to clear Aß. The GAS, as a targeting detector and inhibitor, allows real-time detection of Aß aggregates. Conclusion: These results firstly highlight the combination of scFv, APH and nanoparticles to be theranostic AD drugs. Taken together, our strategy provides a new thought into the design of smart compounds for use as efficiently therapeutic and preventive agents against AD. Moreover, our design provides broad prospects of biomedical strategy for further theranostics application in those diseases caused by abnormal protein.

[Research progress of pretreatment technology for mycotoxin detection in Chinese materia medica and complex matrices].

In the processes of planting, harvest, transport and storage, improper treatment of Chinese materia medica (CMM) and foodstuffs and agricultural products will result in fungal growth and mycotoxins contamination, which will not only directly affect the quality, safety and efficacy of these complex matrices, but also seriously threaten the consumers' health and lives. Therefore, the establishment of high-throughout analytical methods with high sensitivity for the determination of mycotoxins in CMM and foodstuffs and agricultural products at trace levels will provide reliable references for reducing the risk of mycotoxin exposure in humans. Due to the matrix complexity of CMM and foodstuffs and agricultural products, highly-effective pretreatment technologies are necessary for the establishment of such analytical techniques. In this review, the current extraction and purification methods commonly used for the detection of mycotoxins were summarized, the importance of pretreatment techniques for the precise quantification of mycotoxins in complex matrices such as Chinese herbal medicines was highlighted, as well as the development tendency about the pretreatment techniques for mycotoxins in complex matrices in the future was proposed.

[A new isoflavone derivative from Rosa Damascena and its antibacterial activity].

A new isoflavone derivative was isolated from Rosa damascena by using various chromatographic techniques including silica gel, Sephadex LH-20, and preparative RP-HPLC separation. Its structure was identified as 4'-hydroxy-7-(3-hydroxypropanoyl)-6-methoxy-isoflavone using combined examinations of their UV, IR, MS, and NMR spectroscopic data. Biological activity test showed that this compound showed prominent antibacterial activity with MIC90 value of (46±4) mg·L⁻¹ for methicillin resistant Staphylococcus aureus(MRSA) strain. This value is close to that of levofloxacin [with MIC90 value (53±5) mg·L⁻¹].

[Contamination distribution and control measures of aflatoxins in Chinese herbal pieces].

As an important part of traditional medicine in China, traditional Chinese medicine(TCM) plays a significant role because of its unique medical efficiency, less adverse reactions and extensive resources. However, in recent years, the aflatoxins in medicinal herbs have been detected excessive both at home and abroad, seriously affecting the reputation and credibility of traditional Chinese medicine. In this paper, the current status of aflatoxins contamination in medicinal herbs was analyzed, and the internal and external factors of aflatoxins contamination in traditional Chinese medicine were also summarized. In view of the high toxicity of aflatoxins, it is proposed to strengthen the mildew prevention and control from the early planting to storage stage, and the reasonable detoxification mode should also be considered. This review aims to provide a reference in guaranteeing the clinical safe administration of medicinal herbs and reducing the risk of being poisoned by aflatoxins.

Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents.

Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited. We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9-guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth) mouse model, even though the mutant Tmc1Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1Bth allele into the cochlea of neonatal Tmc1Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1Bth/+ mice. These findings suggest that protein-RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets.

Homocysteine is a sulphur-containing non-proteinogenic amino acid. Hyperhomocysteinaemia (HHcy), the pathogenic elevation of plasma homocysteine as a result of an imbalance of its metabolism, is an independent risk factor for various vascular diseases, such as atherosclerosis, hypertension, vascular calcification and aneurysm. Treatments aimed at lowering plasma homocysteine via dietary supplementation with folic acids and vitamin B are more effective in preventing vascular disease where the population has a normally low folate consumption than in areas with higher dietary folate. To date, the mechanisms of HHcy-induced vascular injury are not fully understood. HHcy increases oxidative stress and its downstream signalling pathways, resulting in vascular inflammation. HHcy also causes vascular injury via endoplasmic reticulum stress. Moreover, HHcy up-regulates pathogenic genes and down-regulates protective genes via DNA demethylation and methylation respectively. Homocysteinylation of proteins induced by homocysteine also contributes to vascular injury by modulating intracellular redox state and altering protein function. Furthermore, HHcy-induced vascular injury leads to neuronal damage and disease. Also, an HHcy-activated sympathetic system and HHcy-injured adipose tissue also cause vascular injury, thus demonstrating the interactions between the organs injured by HHcy. Here, we have summarized the recent developments in the mechanisms of HHcy-induced vascular injury, which are further considered as potential therapeutic targets in this condition. LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.