Synthesis and evaluation of antisense oligonucleotides prodrug with G-quadruplex assembly and lysosome escape capabilities for oncotherapy.

The applications of antisense oligonucleotides (ASOs) in rare or common diseases treatment have garnered great attention in recent years. Nevertheless, challenges associated with stability and bioavailability still persist, hampering the efficiency of ASOs. This work presents an ASO prodrug with parallel G-quadruplex assembly and lysosome escape capabilities for oncotherapy. Our findings revealed that the end-assembled quadruplex structure effectively shielded the ASO from enzymatic degradation. Meanwhile, the conjugation of maleimide within the quadruplex enhanced cellular uptake, potentially offering an alternative cell entry mechanism that circumvents lysosome involvement. Notably, an optimized molecule, Mal2-G4-ASO, exhibited remarkable therapeutic effects both in vitro and in vivo. This work presents a promising avenue for enhancing the activity of nucleic acid drugs in oncotherapy and potentially other disease contexts.

Study on the performance and mechanism of cobaltous ion removal from water by a high-efficiency strontium-doped hydroxyapatite adsorbent.

In this study, a high-efficiency strontium-doped hydroxyapatite (Sr-HAP) adsorbent was synthesized by a sol-gel method for removing cobaltous ions (Co(II)) from water. The effects of adsorbent dose, initial solution pH, initial Co(II) concentration and temperature on the removal performance of Co(II) were investigated. Experimental results indicated that the optimum Sr-HAP dose was 0.30 g/50 mL solution, the Sr-HAP adsorbent could effectively remove Co(II) in a wide pH range of 3-8. Increasing temperature was conducive to the adsorption, and the maximum Co(II) adsorption capacity by Sr-HAP reached 48.467 mg/g at 45 °C. The adsorption of Co(II) followed the pseudo-second-order kinetic model, indicating that the Co(II) adsorption by Sr-HAP was attributed mainly to chemisorption. The isothermal adsorption results showed that at lower Co(II) equilibrium concentration, the Langmuir model fitted the data better than the Freundlich model but opposite at higher Co(II) equilibrium concentration. Therefore, the adsorption of Co(II) was a process from monolayer adsorption to multilayer adsorption with the increase of the Co(II) equilibrium concentration. The diffusion analysis of Co(II) to Sr-HAP indicated that the internal diffusion and surface adsorption were the rate-controlled steps of Co(II) adsorption. Thermodynamic study demonstrated that the Co(II) adsorption process was spontaneous and endothermic. The mechanism study revealed that in addition to chemisorption, Sr-HAP also removed Co(II) ions from water via ion exchange and surface complexation.

Anisamide-conjugated hairpin antisense oligonucleotides prodrug co-delivering doxorubicin exhibited enhanced anticancer efficacy.

Antisense oligonucleotides (ASONs)-based therapeutics offers tremendous promise for the treatment of diverse diseases. However, there is still a need to develop ASONs with enhanced stability against enzymes, improved drug delivery, and enhanced biological potency. In this study, we propose a novel anisamide (AA)-conjugated hairpin oligonucleotide prodrug loading with chemotherapeutic agent (doxorubicin, DOX) (AA-loop-ASON/DOX) for oncotherapy. Results indicated that the introduction of a hairpin conformation and AA ligand in prodrug significantly improved the stability against enzymatic hydrolysis, as well as the cellar uptake of ASONs and DOX. The incorporation of disulfide bonds could trigger mechanical opening, resulting in the release of ASON and DOX in response to the intracellular glutathione (GSH) in tumors. Moreover, the composite of DOX-loading ASONs prodrug exhibited a robust and selective inhibition of tumor cell proliferation. This paper introduces a novel design concept for nucleic acid-based therapeutics, aiming to enhance the delivery of drug and improve biological effectiveness.

Physiological and transcriptomic analysis of the mangrove species Kandelia obovata in response to flooding stress.

Flooding stress on mangroves is growing continually with rising sea level. In this study, the physiology and transcriptome of the mangrove species Kandelia obovata under flooding stress were analyzed. With increasing inundation time, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), soluble sugar (SS), soluble protein (SP), and proline (Pro) content declined, while peroxidase (POD) and ascorbate peroxidase (APX) activity rose significantly. According to the KEGG pathway enrichment analysis, upregulated differentially expressed genes (DEGs) were enriched in the plant hormone signaling pathway. Furthermore, MYB44 and MYB108 genes from the MYB transcription factor family and RAP2.12, DREB2B, and ERF4 genes from the AP2/ERF family were up-regulated under flooding conditions. A strong correlation was established between the expression levels of 12 DEGs under flooding stress and RNA sequencing data and was verified by qRT-PCR. These results provide new insights into the molecular mechanism of K. obovata in response to flooding stress.

NAD+ exhaustion by CD38 upregulation contributes to blood pressure elevation and vascular damage in hypertension.

Hypertension is characterized by endothelial dysfunction and arterial stiffness, which contribute to the pathogenesis of atherosclerotic cardiovascular diseases. Nicotinamide adenine dinucleotide (NAD+) is an indispensable cofactor in all living cells that is involved in fundamental biological processes. However, in hypertensive patients, alterations in NAD+ levels and their relation with blood pressure (BP) elevation and vascular damage have not yet been studied. Here we reported that hypertensive patients exhibited lower NAD+ levels, as detected by high-performance liquid chromatography-mass spectrometry (HPLC-MS), in both peripheral blood mononuclear cells (PBMCs) and aortas, which was parallel to vascular dysfunction. NAD+ boosting therapy with nicotinamide mononucleotide (NMN) supplement reduced BP and ameliorated vascular dysfunction in hypertensive patients (NCT04903210) and AngII-induced hypertensive mice. Upregulation of CD38 in endothelial cells led to endothelial NAD+ exhaustion by reducing NMN bioavailability. Pro-inflammatory macrophages infiltration and increase in IL-1ß generation derived from pro-inflammatory macrophages resulted in higher CD38 expression by activating JAK1-STAT1 signaling pathway. CD38 KO, CD38 inhibitors treatment, or adeno-associated virus (AAV)-mediated endothelial CD38 knockdown lowered BP and improved vascular dysfunction in AngII-induced hypertensive mice. The present study demonstrated for the first time that endothelial CD38 activation and subsequently accelerated NAD+ degradation due to enhanced macrophage-derived IL-1ß production was responsible for BP elevation and vascular damage in hypertension. NAD+ boosting therapy can be used as a novel therapeutic strategy for the management of hypertensive patients.

Vaginal Epithelial Cell Membrane-Based Phototherapeutic Decoy Confers a "Three-in-One" Strategy to Treat against Intravaginal Infection of Candida albicans.

Phototherapy is an effective strategy to control Candida albicans (C. albicans) infection without raising the concern of drug resistance. Despite its effectiveness, a higher dose of phototherapeutic power is required for C. albicans elimination compared to bacteria that have to be used, which is readily accompanied by off-target heat and toxic singlet oxygen to damage normal cells, thus limiting its usefulness for antifungal applications. Here to overcome this, we develop a "three-in-one" biomimetic nanoplatform consisting of an oxygen-dissolved perfluorocarbon camouflaged by a photosensitizer-loaded vaginal epithelial cell membrane. With a cell membrane coating, the nanoplatform is capable of specifically binding with C. albicans at the superficial or deep vaginal epithelium, thereby centering the phototherapeutic agents on C. albicans. Meanwhile, the cell membrane coating endows the nanoplatform to competitively protect healthy cells from candidalysin-medicated cytotoxicity. Upon candidalysin sequestration, pore-forming on the surface of the nanoplatform accelerates release of the preloaded photosensitizer and oxygen, resulting in enhanced phototherapeutic power for improved anti-C. albicans efficacy under near-infrared irradiation. In an intravaginal C. albicans-infected murine model, treatment with the nanoplatform leads to a significantly decreased C. albicans burden, particularly when leveraging candidalysin for further elevated phototherapy and C. albicans inhibition. Also, the same trends hold true when using the nanoplatform to treat the clinical C. albicans isolates. Overall, this biomimetic nanoplatform can target and bind with C. albicans and simultaneously neutralize the candidalysin and then transform such toxins that are always considered a positive part in driving C. albicans infection with the power of enhancing phototherapy for improved anti-C. albicans efficacy.

Doxorubicin Detoxification in Healthy Organs Improves Tolerability to High Drug Doses for Enhanced Antitumor Therapy.

With its well-documented toxicity, the use of doxorubicin (Dox) for cancer treatment requires trade-offs between safety and effectiveness. This limited use of Dox also hinders its functionality as an immunogenic cell death inducer, thus impeding its usefulness for immunotherapeutic applications. Here, we develop a biomimetic pseudonucleus nanoparticle (BPN-KP) by enclosing GC-rich DNA within erythrocyte membrane modified with a peptide to selectively target healthy tissue. By localizing treatment to organs susceptible to Dox-mediated toxicity, BPN-KP acts as a decoy that prevents the drug from intercalating into the nuclei of healthy cells. This results in significantly increased tolerance to Dox, thereby enabling the delivery of high drug doses into tumor tissue without detectable toxicity. By lessening the leukodepletive effects normally associated with chemotherapy, dramatic immune activation within the tumor microenvironment was also observed after treatment. In three different murine tumor models, high-dose Dox with BPN-KP pretreatment resulted in significantly prolonged survival, particularly when combined with immune checkpoint blockade therapy. Overall, this study demonstrates how targeted detoxification using biomimetic nanotechnology can help to unlock the full potential of traditional chemotherapeutics.

(±)-Gentiovarisin A and gentiovarisin B, unusual secoiridoid dimer skeletons from gentiopicroside.

Gentiana scabra, a famous traditional Chinese medicine (TCM), has been documented in Chinese Pharmacopoeia for the treatment of hepatitis. Its index component gentiopicroside could not be detected in the decoction, which suggested that the quality control of the TCM with this ingredient needs attention. The transformed products were obtained from gentiopicroside, mimicking the traditional process of G. scabra. Further investigation of the heat-transformed products yielded two secoiridoid dimers, gentiovarisin A (1) and B (2), with an unprecedented 6/6/6/6/6-fused pentacyclic skeletons. Their structures were elucidated by extensive spectroscopic analyses and single-crystal X-ray diffraction analysis, and the absolute configurations of 1 were confirmed as (+)-1 and (-)-1 by ECD method. Plausible transformation pathways of the isolates were also proposed. Compounds 1 and 2 exhibited in vitro hepatoprotective activity similar to gentiopicroside, while (+)-1 displayed a more potent hepatoprotective activity than N-Acetyl-L-cysteine.

Single-cell RNA sequencing analysis reveals the relationship of bone marrow and osteopenia in STZ-induced type 1 diabetic mice.

INTRODUCTION: Type 1 diabetes (T1D) is a multifactorial autoimmune disease. Broad knowledge about the genetics, epidemiology and clinical management of T1D has been achieved, but understandings about the cell varieties in the bone marrow during T1D remain limited. OBJECTIVES: We aimed to present a profile of the bone marrow cells and reveal the relationship of bone marrow and osteopenia in streptozotocin (STZ)-induced T1D mice. METHODS: The whole bone marrow cells from the femurs and tibias of healthy (group C) and STZ-induced T1D mice (group D) were collected for single-cell RNA sequencing analysis. Single-cell flow cytometry and immunohistochemistry were performed to confirm the proportional changes among bone marrow neutrophils (BM-neutrophils) (Cxcr2+, Ly6g+) and B lymphocytes (Cd19+). X-ray and micro-CT were performed to detect bone mineral density. The correlation between the ratio of BM-neutrophils/B lymphocytes and osteopenia in STZ-induced T1D mice was analyzed by nonparametric Spearman correlation analysis. RESULTS: The bone marrow cells in groups C and D were divided into 12 clusters, and 249 differentially expressed genes were found. The diversity of CD45+ immune cells between groups C and D were greatly affected: the proportion of BM-neutrophils showed a significant increase while the proportion of B lymphocytes in group D showed a significant decrease. X-ray and micro-CT analyses confirmed that osteopenia occurred in group D mice. In addition, the results of single-cell flow cytometry and correlation analysis showed that the ratio of BM-neutrophils/B lymphocytes negatively correlated with osteopenia in STZ-induced T1D mice. CONCLUSION: A single-cell RNA sequencing analysis revealed the profile and heterogeneity of bone marrow immune cells in STZ-induced T1D mice for the first time. The ratio of BM-neutrophils/B lymphocytes negatively correlated with osteopenia in STZ-induced T1D mice, which may enhance understanding for treating T1D and preventing T1D-induced osteopenia.

Effects of Compound Elicitors on the Biosynthesis of Triterpenoids and Activity of Defense Enzymes from Inonotus hispidus (Basidiomycetes).

Inonotus hispidus has various health-promoting activities, such as anticancer effects and immune-stimulating activity. The commercialization of valuable plant triterpenoids faces major challenges, including low abundance in natural hosts and costly downstream purification procedures. In this work, orthogonal design was used to compound methyl jasmonate (MeJA), salicylic acid (SA), oleic acid, and Cu2+, and the effects of combinations on the total triterpenes biosynthesized were studied. The optimal combination was screened out and its effect on the activity of PAL, CAT, and SOD was studied. The optimal concentration of oleic acid was 2% when MeJA was 100 mol/L, and the total triterpenoid content and mycelia production were 3.918 g and 85.17 mg/g, respectively. MeJA treatment induced oxidative stress, and at the same time increased the activity of related defense enzymes. Oleic acid is thought to regulate cell permeability by recombining cell membranes. It promotes the material exchange process between cells and the environment without affecting cell growth. When oleic acid was used in combination with MeJA, a synergistic effect on triterpene production was observed. In conclusion, our findings provide a strategy for triterpenoid enrichment of I. hispidus.

Dickkopf-1: A Promising Target for Cancer Immunotherapy.

Clinical studies in a range of cancers have detected elevated levels of the Wnt antagonist Dickkopf-1 (DKK1) in the serum or tumors of patients, and this was frequently associated with a poor prognosis. Our analysis of DKK1 gene profile using data from TCGA also proves the high expression of DKK1 in 14 types of cancers. Numerous preclinical studies have demonstrated the cancer-promoting effects of DKK1 in both in vitro cell models and in vivo animal models. Furthermore, DKK1 showed the ability to modulate immune cell activities as well as the immunosuppressive cancer microenvironment. Expression level of DKK1 is positively correlated with infiltrating levels of myeloid-derived suppressor cells (MDSCs) in 20 types of cancers, while negatively associated with CD8+ T cells in 4 of these 20 cancer types. Emerging experimental evidence indicates that DKK1 has been involved in T cell differentiation and induction of cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms of DKK1 affecting cancers and immune cells have received great attention. This review introduces the rapidly growing body of literature revealing the cancer-promoting and immune regulatory activities of DKK1. In addition, this review also predicts that by understanding the interaction between different domains of DKK1 through computational modeling and functional studies, the underlying functional mechanism of DKK1 could be further elucidated, thus facilitating the development of anti-DKK1 drugs with more promising efficacy in cancer immunotherapy.

Correction: The chemopreventive effects of Huangqin-tea against AOM-induced preneoplastic colonic aberrant crypt foci in rats and omics analysis.

Correction for 'The chemopreventive effects of Huangqin-tea against AOM-induced preneoplastic colonic aberrant crypt foci in rats and omics analysis' by Jie Shen et al., Food Funct., 2020, 11, 9634-9650, DOI: 10.1039/D0FO01731K.

Zearalenone and deoxynivalenol inhibited IL-4 receptor-mediated Th2 cell differentiation and aggravated bacterial infection in mice.

The immunotoxicity of zearalenone (ZEA) and deoxynivalenol (DON), two of the most common environmental mycotoxins, has been well investigated. However, due to the complexity of the immune system, especially during bacterial infection, many types of immune cells are involved in invasion resistance and bacterial clearance. Of these, T helper 2 (Th2) cells, which are members of the helper T cell family, assist B cells to activate and differentiate into antibody-secreting cells, participate in humoral immune response, and, ultimately, eliminate pathogens. Thus, it is important to identify the stage at which these toxins affect the immune function, and to clarity the underlying mechanisms. In this study, mice infected with Listeria monocytogenes (Listeria) were used to study the effects of ZEA, DON, and ZEA + DON on Th2 differentiation, Interleukin-4 Receptor (IL-4R) expression, costimulatory molecules expression and cytokine secretion after Listeria infection. Naive CD4+ T cells, isolated from mice, were used to verify the in vivo effects and the associated mechanisms. In vivo experiments showed that these toxins aggravated spleen damage after Listeria infection and reduced the differentiation of Th2 cells by affecting the synthesis of IL-4R of CD4+ T cells. In addition, the level of the costimulatory molecule CD154 decreased. Consistent with this, in vitro studies showed that these toxins inhibited the differentiation of mouse naive CD4+ T cell into Th2 subtype and decreased IL-4R levels. In addition, the levels of costimulatory molecules CD154, CD278 and the Th2 cells secrete cytokines IL-4, IL-6, and IL-10 decreased. Based on our in vivo and in vitro experiments, we suggest that ZEA, DON, and ZEA + DON inhibit the expression of costimulatory molecules on CD4+ T cell, and inhibit the IL-4R-mediated Th2 cell differentiation. This may indicate that the body cannot normally resist or clear the pathogen after mycotoxin poisoning.

A novel tricyclic BTK inhibitor suppresses B cell responses and osteoclastic bone erosion in rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by joint leukocyte infiltration, synovial inflammation and bone damage result from osteoclastogenesis. Bruton's tyrosine kinase (BTK) is a key regulator of B cell receptor (BCR) and Fc gamma receptor (FcγR) signaling involved in the pathobiology of RA and other autoimmune disorders. SOMCL-17-016 is a potent and selective tricyclic BTK inhibitor, structurally distinct from other known BTK inhibitors. In present study we investigated the therapeutic efficacy of SOMCL-17-016 in a mouse collagen-induced arthritis (CIA) model and underlying mechanisms. CIA mice were administered SOMCL-17-016 (6.25, 12.5, 25 mg·kg-1·d-1, ig), or ibrutinib (25 mg·kg-1·d-1, ig) or acalabrutinib (25 mg·kg-1·d-1, ig) for 15 days. We showed that oral administration of SOMCL-17-016 dose-dependently ameliorated arthritis severity and bone damage in CIA mice; it displayed a higher in vivo efficacy than ibrutinib and acalabrutinib at the corresponding dosage. We found that SOMCL-17-016 administration dose-dependently inhibited anti-IgM-induced proliferation and activation of B cells from CIA mice, and significantly decreased anti-IgM/anti-CD40-stimulated RANKL expression in memory B cells from RA patients. In RANKL/M-CSF-stimulated RAW264.7 cells, SOMCL-17-016 prevented osteoclast differentiation and abolished RANK-BTK-PLCγ2-NFATc1 signaling. In summary, this study demonstrates that SOMCL-17-016 presents distinguished therapeutic effects in the CIA model. SOMCL-17-016 exerts a dual inhibition of B cell function and osteoclastogenesis, suggesting that it to be a promising drug candidate for RA treatment.

Genus Paeonia: A comprehensive review on traditional uses, phytochemistry, pharmacological activities, clinical application, and toxicology.

ETHNOPHARMACOLOGICAL RELEVANCE: Paeonia, which comprises approximately 52 shrubs or herbaceous perennials around the world, is the only genus of the Paeoniaceae and is pervasively distributed in Asia, southern Europe, and North America. Many species of the genus Paeonia have been used for centuries in ethnomedical medical systems. AIM OF THE REVIEW: The present study aims to summarize the traditional uses, clinical applications, and toxicology of the genus Paeonia, to critically evaluate the state-of-the-art phytochemical and pharmacological studies of this genus published between 2011 and 2020, and to suggest directions for further in-depth research on Paeonia medicinal resources. MATERIALS AND METHODS: Popular and widely used databases such as PubMed, Scopus, Science Direct, and Google Scholar were searched using the various search strings; from these searches, a number of citations related to the traditional uses, phytochemistry, biological activities, clinical application, and toxicology of the genus Paeonia were retrieved. RESULTS: The use of 21 species, 2 subspecies, and 7 varieties of the genus Paeonia as traditional herbal remedies has been reported, and many ethnomedicinal uses, such as the treatment of hematemesis, blood stasis, dysmenorrhea, amenorrhea, epilepsy, spasms, and gastritis, have been recorded. The roots and root bark are the most frequently reported parts of the plants used in medicinal applications. In phytochemical investigations, 451 compounds have been isolated from Paeonia plants to date, which contains monoterpenoid glucosides, flavonoids, tannins, stilbenes, triterpenoids and steroids, and phenols. Studies of their pharmacological activities have revealed the antioxidant, anti-inflammatory, antitumour, antibacterial, antiviral, cardiovascular protective, and neuroprotective properties of the genus Paeonia. In particular, some bioactive extracts and compounds (total glucosides of peony (TGP), paeonol, and paeoniflorin) have been used as therapeutic drugs or tested in clinical trials. In addition to the "incompatibility" of the combined use of "shaoyao" and Veratrum nigrum L. roots in traditional Chinese medicine theory, Paeonia was considered to have no obvious toxicity based on the available toxicological tests. CONCLUSION: A large number of phytochemical and pharmacological reports have indicated that Paeonia is an important medicinal herb resource, and some of its traditional uses including the treatment of inflammation and cardiovascular diseases and its use as a neuroprotective agent, have been partially confirmed through modern pharmacological studies. Monoterpenoid glucosides are the main active constituents. Although many compounds have been isolated from Paeonia plants, the biological activities of only a few of these compounds (paeoniflorin, paeonol, and TGP) have been extensively investigated. Some paeoniflorin structural analogues and resveratrol oligomers have been preliminarily studied. With the exception of several species (P. suffruticosa, P. ostii, P. lactiflora, and P. emodi) that are commonly used in folk medicine, many medicinal species within the genus do not receive adequate attention. Conducting phytochemical and pharmacological experiments on these species can provide new clues that may lead to the discovery of medicinal resources. It is necessary to identify the effective phytoconstituents of crude extracts of Paeonia that displayed pharmacological activities by bioactivity-guided isolation. In addition, comprehensive plant quality control, and toxicology and pharmacokinetic studies are needed in the future studies.

Traditional uses, ten-years research progress on phytochemistry and pharmacology, and clinical studies of the genus Scutellaria.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria (Lamiaceae), which includes approximately 360-469 accepted species, is widespread in Europe, North America, East Asia, and South America. Several species have a long history being used as traditional medicines to treat respiratory, peptic, neurological, and hepatic and gall diseases. The phytochemistry and pharmacology of the genus Scutellaria have been developed dramatically in the past ten years, and the traditional uses and clinical studies of the genus have not been systematically summarized. Therefore, it is especially valuable to review the current state of knowledge to provide a basis for further exploration of its medicinal potential. AIM OF THE REVIEW: The review aims to provide updated information on the ethnopharmacology, the ten-year research progress of phytochemistry and pharmacology, and clinical studies of Scutellaria and to explore the potential medicinal values and further studies of Scutellaria. MATERIALS AND METHODS: This review is based on published studies and books from the library and electronic sources, including SciFinder, Scopus, PubMed, Web of Science, Baidu Scholar, CNKI, the online ethnobotanical database, and ethnobotanical monographs. This literature is related to ethnopharmacology, the ten-year research progress on the phytochemistry and pharmacology, and clinical studies of Scutellaria. RESULTS: A total of 50 species, 5 subspecies and 17 varieties of the genus Scutellaria are used as traditional medicine with various biological activities. In the past ten years, 208 chemical constituents have been identified from 16 species and 1 variety of the genus Scutellaria, such as neo-clerodane diterpenoids, sesterterpenoids, terpenoids, flavonoids. Pharmacological research has demonstrated that the extracts and compounds identified from this genus exhibit extensive biological activities, including anticancer, antioxidant, anti-inflammatory, antiviral and antibacterial activities, effects on cardiovascular, cerebrovascular diseases as well as hepatoprotective and neuroprotective effects. The species S. baicalensis, S. barbata, and S. lateriflora and the main compounds baicalein, baicalin and wogonin are involved in clinical trials, which point the way for us to conduct further studies, such as study on the anticancer, antihypertensive, anti-infective, anti-inflammatory, neuroprotective and other effects of Scutellaria. CONCLUSIONS: The species included in the genus Scutellaria can be used to treat cancer, infection, hepatic disorders, cardiovascular and cerebrovascular diseases, neurodegenerative diseases, and other diseases. Some indications in traditional medicines have been confirmed by modern pharmacological studies, such as anticancer, anti-inflammatory, anti-infective activity, and hepatoprotective and neuroprotective effects. The available literature indicated that most of the bioactivities could be attributed to flavonoids and neo-clerodane diterpenoids. Although there are some uses of Scutellaria in clinical practice, the existing research on this genus is still limited. In order to expand the development of medicinal resources of Scutellaria, the already studied species in this genus are recommended for more comprehensive investigation on their active substances, pharmacological mechanisms, quality control, clinical use and new drug research. Additionally, it is necessary to study species that their chemical composition or pharmacological activity have not yet been investigated, especially those used in folk medicine.

The chemopreventive effects of Huangqin-tea against AOM-induced preneoplastic colonic aberrant crypt foci in rats and omics analysis.

Despite that colorectal cancer (CRC) is a severe global health problem, effective chemopreventive strategies against CRC are still lacking. Huang-qin tea (HQT), a healthy herbal tea, is prepared from the aerial parts of Scutellaria baicalensis Georgi and has been consumed in China for thousands of years. HQT contains abundant flavonoids, which display potent anticancer effects, but no research studies have investigated the cancer-preventive effects of HQT on CRC in vivo. Here, we found that HQT inhibits azoxymethane-induced aberrant crypt foci (ACF) formation in a preneoplastic colonic ACF rat model. The essential role of the gut microbiota in the chemopreventive effect of HQT on CRC in a pseudo-germ-free rat model was confirmed. Besides, HQT modulates inflammatory cytokine expression by significantly decreasing IL-1ß, IL-6, IL-10, and TNF-α expression, and elevating IFN-γ production. 16S rDNA sequencing analysis indicated that HQT regulated the gut microbiota by increasing the abundance of beneficial bacteria (Lachnoclostridium, Alistipes, Roseburia, and Lactococcus) and reducing the levels of Bacteroides, Parasutterella, and unidentified_Clostridiales. Fecal metabolomics showed that HQT modulated the AOM-induced metabolomic disorder, and these altered metabolites were almost involved in the lipid metabolic pathways. The Spearman correlation analysis revealed a correlation between the gut microbiota and fecal metabolites. Collectively, these results suggested that HQT exerted beneficial effects on host health by inhibiting inflammation, and by regulating the gut microbiota profile and certain metabolic pathways. In conclusion, HQT inhibits AOM-induced ACF formation by modulating the gut microbiota composition and improving metabolomic disorders, indicating the potential of HQT as a functional beverage candidate for the prevention and treatment of CRC.

[Simultaneous rapid detection of ten stilbenes in serum of mice by UPLC-MS/MS].

Stilbenes is a class of natural polyphenols with 1,2-diphenylethylene as the skeleton structure which have structural and active diversity. However, there are fewer studies on their metabolic process, which limits the in-depth research and development of such components. An UPLC-MS/MS method simultaneously determining contents of ten stilbenes was firstly established in this study and applied to study the ten stilbenes of peony seed coats in the serum of C57 mice.Piceatannol was the internal standard, and methanol was used for protein precipitation, UPLC-MS/MS with negative ion mode was used for analysis, and the method was validated.The serum samples were collected and detected after mice being oral administered with 800 mg·kg~(-1) peony seed coat extracts for 8 weeks. The results showed that suffruticosol A, suffruticosol B, suffruticosol C, trans-ε-viniferin, cis-gnetin H, trans-suffruticosol D and trans-gnetin H were detected in serum samples, and the highest is suffruticosol A. The method is simple and quick with high specificity and sensitivity, and it is suitable for quantitative determination of ten stilbenes in the serum of mice.

Resveratrol oligomers from Paeonia suffruticosa protect mice against cognitive dysfunction by regulating cholinergic, antioxidant and anti-inflammatory pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Paeonia suffruticosa Andr. has been widely used in traditional Chinese medicine as an anti-tumour, anti-oxidant, anti-inflammatory and neuroprotective agent. Resveratrol oligomers are the main components of the seed coat extracts of Paeonia suffruticosa (PSCE) and have DPPH free radical scavenging and ß-secretase inhibitory activity. However, studies of its effect on ameliorating cognitive deficits are limited, and analyses of the underlying mechanisms are insufficient. AIM OF STUDY: This study aimed to investigate the cholinesterase inhibitory activities of resveratrol oligomers from P. suffruticosa in vitro and their effects on diminishing the oxygen-glucose deprivation/reoxygenation (OGD/R) -induced cytotoxicity in PC12 cells and scopolamine-induced cognitive deficits in mice. Moreover, the underlying mechanisms were further explored. MATERIALS AND METHODS: In vitro, the inhibitory effects of PSCE and its 10 stilbenes on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated using the Ellman's assay, and its protective effects on normal and OGD/R-injured PC12 cells were evaluated using the MTT assay. For the in vivo assay, C57BL/6 mice were orally administered with PSCE at doses of 150 and 600 mg/kg for 28 days, and injected with scopolamine (1.5 mg/kg) to induce cognitive deficits. The memory behaviours were evaluated using the novel object recognition, Morris water maze and inhibitory avoidance test. Levels of various biochemical markers were also examined, including AChE, choline acetyltransferase (ChAT), acetylcholine (ACh), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) in the mouse brain and interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), interleukin-4 (IL-4) in serum. RESULTS: PSCE and its 10 stilbenes display good inhibition of AChE and BuChE activities and significantly increase the viability of normal and OGD/R-injured PC12 cells. PSCE improves the cognitive performance of scopolamine-treated mice in behavioural tests. Meanwhile, PSCE increases AChE, ChAT, SOD, and CAT activities and ACh, GSH, IL-4 levels, and decreases IL-1ß, IL-6, TNF-α levels in the model animals. CONCLUSIONS: Resveratrol oligomers from P. suffruticosa show neuroprotective effect in vitro and in vivo by regulating cholinergic, antioxidant and anti-inflammatory pathways, may have promising application in the treatment of Alzheimer's disease.