On the basis of the contribution of the gut microbiota to hypertension development, a novel strategy involving fecal microbiota transplantation (FMT) has been proposed to treat hypertension, but its efficacy has not been investigated in the clinic. In a randomized, blinded, placebo-controlled clinical trial (2021/03–2021/12, ClinicalTrials.gov, NCT04406129), hypertensive patients were recruited from seven centers in China, and received FMT or placebo capsules orally at three visits. The patients were randomized at a 1:1 ratio in blocks of four and stratified by center by an independent statistician. The intention-to-treat principle was implemented, as all randomized participants who received at least one intervention were included. The primary outcome was the decrease in office systolic blood pressure (SBP) from baseline to the day 30 visit. Adverse events (AEs) were recorded through the 3-month follow-up to assess safety measures. Alterations in BP, the fecal microbiome, and the plasma metabolome were assessed via exploratory analyses. This study included 124 patients (mean age 43 years, 73.4

The escalation of jellyfish stings has drawn attention to severe skin reactions, underscoring the necessity for novel treatments. This investigation assesses the potential of hydroxybenzoic acid derivatives, specifically protocatechuic acid (PCA) and gentisic acid (DHB), for alleviating Nemopilema nomurai Nematocyst Venom (NnNV)-induced injuries. By employing an in vivo mouse model, the study delves into the therapeutic efficacy of these compounds. Through a combination of ELISA and Western blot analyses, histological examinations, and molecular assays, the study scrutinizes the inflammatory response, assesses skin damage and repair mechanisms, and investigates the compounds’ ability to counteract venom effects. Our findings indicate that PCA and DHB significantly mitigate inflammation by modulating critical cytokines and pathways, altering collagen ratios through topical application, and enhancing VEGF and bFGF levels. Furthermore, both compounds demonstrate potential in neutralizing NnNV toxicity by inhibiting metalloproteinases and phospholipase-A2, showcasing the viability of small-molecule compounds in managing toxin-induced injuries.

Vascular smooth muscle cells (VSMCs) contribute to plaque stability. VSMCs are also a major source of CTH (cystathionine gamma-lyase)-hydrogen sulfide (H2S), a protective gasotransmitter in atherosclerosis. However, the role of VSMC endogenous CTH-H2S in pathogenesis of plaque stability and the mechanism are unknown. In human carotid plaques, CTH expression in ACTA2(+) cells was dramatically downregulated in lesion areas in comparison to non-lesion areas. Intraplaque CTH expression was positively correlated with collagen content, whereas there was a negative correlation with CD68(+) and necrotic core area, resulting in a rigorous correlation with vulnerability index (r = -0.9033). Deletion of Cth in VSMCs exacerbated plaque vulnerability, and were associated with VSMC autophagy decline, all of which were rescued by H2S donor. In ox-LDL treated VSMCs, cth deletion reduced collagen and heightened apoptosis association with autophagy reduction, and vice versa. For the mechanism, CTH-H2S mediated VSMC autophagosome formation, autolysosome formation and lysosome function, in part by activation of TFEB, a master regulator for autophagy. Interference with TFEB blocked CTH-H2S effects on VSMCs collagen and apoptosis. Next, we demonstrated that CTH-H2S sulfhydrated TFEB at Cys212 site, facilitating its nuclear translocation, and then promoting transcription of its target genes such as ATG9A, LAPTM5 or LDLRAP1. Conclusively, CTH-H2S increases VSMC autophagy by sulfhydration and activation of TFEB, promotes collagen secretion and inhibits apoptosis, thereby attenuating atherogenesis and plaque vulnerability. CTH-H2S may act as a warning biomarker for vulnerable plaque.

Metabolically heterogeneous tumors could rely on "metabolic symbiosis" to mutually regulate the access to extracellular nutrients between glycolytic and oxygenated tumor cells for impeding the development of therapies which aim at metabolic vulnerabilities. Herein, a yeast@MOF bioreactor has been designed as a tumor metabolic symbiosis disruptor to deprive the energy supply of both glycolytic and oxygenated tumor cells for the potent inhibition of metabolically heterogeneous tumors. The yeast@MOF bioreactor integrated the biocompatible probiotic yeast with functional enzyme-encapsulated metal-organic-framework. The bioreactors could competitively consume glucose to reduce their diffusion to glycolytic tumor cells and cut down the tumorous lactate pool. Meanwhile, they could decompose lactate to prevent their exploitation by oxygenated tumor cells. Moreover, the bioreactor could elevate oxidative stress for further amplifying the tumor inhibition effect. We anticipate that this study will not only promote the design of living bioma-terials-based therapy, but also facilitate the development of metabolic interventions-based cancer therapy. (c) 2021 Elsevier Ltd. All rights reserved.

气候变化及人类活动严重影响着湿地的生态系统健康和可持续发展,进而对区域生态安全产生威胁. 以京津冀坝上地区典型内陆湖泊安固里淖湿地为例,结合1985—2016年的Landsat TM/ETM+影像数据生成MVWR指数( modified vegetation water ratio,修正化植被水体指数),基于"杯球"模型量化分析安固里淖湿地稳态转变与生态弹性,并进一步探究湿地稳态转变与生态弹性对气候变化的响应. 结果表明: ①1985—2016年来安固里淖湿地于1995年、2004年发生了稳态转变,其RSI( regime shifts index,稳态转变指数)分别为0. 973、2. 108;1995年发生恢复性稳态转变,使得湿地水量增加、水域面积扩大,植被生长状态有所恢复;2004年发生退化性稳态转变,使得湿地进入严重受损状态,且2004年后湿地干涸的时期持续时间增加. ②就湿地稳态转变的空间分布而言,安固里淖湿地发生波动和剧烈波动的面积达9. 26 km2,占比为17. 81%,主要分布在湿地外围东部和南部,虽然湿地核心区域发生稳态转变的强度不及湿地外围东部和南部,但是在核心区小的转变仍能导致湿地生态系统的严重退化,使湿地整体发生稳态转变. ③1985—2016年安固里淖湿地生态系统弹性水平呈持续性下降,降幅达37. 5%,从干涸中的恢复难度增加. ④气候要素中气温与降水对安固里淖湿地稳态转变均有影响,其中降水的影响更加显著,尤其是受前期降水影响明显,湿地稳态转变与长期的水量变化有关. 研究对湿地较长时间内的稳态转变及弹性状态变化定量化分析,以揭示湿地的退化过程,将生态系统弹性的持续下降作为湿地退化预警的一个信号,可为湿地的管理及修复提供理论依据和方法借鉴.

The first description of the medical use of licorice appeared in “Shennong Bencao Jing”, one of the well-known Chinese herbal medicine classic books dated back to 220–280 AD. As one of the most commonly prescribed Chinese herbal medicine, licorice is known as “Guo Lao”, meaning “a national treasure” in China. Modern pharmacological investigations have confirmed that licorice possesses a number of biological activities, such as antioxidation, anti-inflammatory, antiviral, immune regulation, and liver protection. 18β-glycyrrhetinic acid is one of the most extensively studied active integrants of licorice. Here, we provide an overview of the protective effects of 18β-glycyrrhetinic acid against various acute and chronic liver diseases observed in experimental models, and summarize its pharmacological effects and potential toxic/side effects at higher doses. We also make additional comments on the important areas that may warrant further research to support appropriate clinical applications of 18β-glycyrrhetinic acid and avoid potential risks.

Background: Hydrogen sulfide (H2S) has antihypertension and anti-inflammatory effects, and its endogenous-generation key enzyme cystathionine gamma lyase (CSE) is expressed in CD4(+) T cells. However, the role of CD4(+) T-cell endogenous CSE/H2S in the development of hypertension is unclear. Methods: Peripheral blood lymphocytes were isolated from hypertensive patients or spontaneously hypertensive rats, then H2S production and expression of its generation enzymes, cystathionine beta synthase and CSE, were measured to determine the major H2S generation system changes in hypertension. Mice with CSE-specific knockout in T cells (conditional knockout, by CD4(cre) mice hybridization) and CD4 null mice were generated for investigating the pathophysiological relevance of the CSE/H2S system. Results: In lymphocytes, H2S from CSE, but not cystathionine beta synthase, responded to blood pressure changes, supported by lymphocyte CSE protein changes and a negative correlation between H2S production with systolic blood pressure and diastolic blood pressure, but positive correlation with the serum level of interleukin 10 (an anti-inflammatory cytokine). Deletion of CSE in T cells elevated BP (5-8 mm Hg) under the physiological condition and exacerbated angiotensin II-induced hypertension. In keeping with hypertension, mesenteric artery dilation impaired association with arterial inflammation, an effect attributed to reduced immunoinhibitory T regulatory cell (Treg) numbers in the blood and kidney, thus causing excess CD4(+) and CD8(+) T cell infiltration in perivascular adipose tissues and kidney. CSE knockout CD4(+) T cell transfer into CD4 null mice, also showed the similar phenotypes' confirming the role of endogenous CSE/H2S action. Adoptive transfer of Tregs (to conditional knockout mice) reversed hypertension, vascular relaxation impairment, and immunocyte infiltration, which confirmed that conditional knockout-induced hypertension was attributable, in part, to the reduced Treg numbers. Mechanistically, endogenous CSE/H2S promoted Treg differentiation and proliferation by activating AMP-activated protein kinase. In part, it depended on activation of its upstream kinase, liver kinase B1, by sulfhydration to facilitate its substrate binding and phosphorylation. Conclusion: The constitutive sulfhydration of liver kinase B1 by CSE-derived H2S activates its target kinase, AMP-activated protein kinase, and promotes Treg differentiation and proliferation, which attenuates the vascular and renal immune-inflammation, thereby preventing hypertension.

Recent studies reported some long noncoding RNAs (lncRNAs)–mediated vascular smooth muscle cells (VSMCs) phenotypic switch, which was a common pathophysiological process of vascular diseases. However, whether human-specific expressed lncRNAs would modulate VSMCs phenotype and participate into the pathogenesis of essential hypertension remains unclear. By comparing the circulating lncRNAs expression profiles between hypertensive patients and healthy controls, we identified a lncRNA-AK098656, strongly upregulated in the plasma of hypertensive patients, and predominantly expressed in VSMCs. AK098656 promoted VSMCs synthetic phenotype evidenced by increasing VSMC proliferation and migration, elevating extracellular matrix proteins, whereas lowering contractile proteins. Furthermore, AK098656 was demonstrated to directly bind with the VSMCs-specific contractile protein, myosin heavy chain-11, and an essential component of extracellular matrix, fibronectin-1, and finally lowered these protein levels through protein degradation. AK098656 was also shown to bind with 26S proteasome non-ATPase regulatory subunit 11 and facilitated myosin heavy chain-11 to interact with this protein. In vivo, AK098656 transgenic rats showed spontaneous development of hypertension, with elevated VSMCs synthetic phenotype and narrowed resistant arteries. Transgenic rats also showed slight cardiac hypertrophy without other complications, which was similar with early pathophysiological changes of hypertension. All these data indicated AK098656 as a new human VSMC-dominant lncRNA, which could promote hypertension through accelerating contractile protein degradation, increasing VSMC synthetic phenotype, and finally narrowed resistance arteries.

Berberine, berberrubine, thalifendine, demethyleneberberine, jatrorrhizine, and columbamine are six natural protoberberine alkaloid (PA) compounds that display extensive pharmacological properties and share the same protoberberine molecular skeleton with only slight substitution differences. The oral delivery of most PAs is hindered by their poor bioavailability, which is largely caused by P-glycoprotein (P-gp)-mediated drug efflux. Meanwhile, P-gp undergoes large-scale conformational changes (from an inward-facing to an outward-facing state) when transporting substrates, and these changes might strongly affect the P-gp-binding specificity. To confirm whether these six compounds are substrates of P-gp, to investigate the differences in efflux capacity caused by their trivial structural differences and to reveal the key to increasing their binding affinity to P-gp, we conducted a series of in vivo, in vitro, and in silico assays. Here, we first confirmed that all six compounds were substrates of P-gp by comparing the drug concentrations in wild-type and P-gp-knockout mice in vivo. The efflux capacity (net efflux) ranked as berberrubine > berberine > columbamine ~ jatrorrhizine > thalifendine > demethyleneberberine based on in vitro transport studies in Caco-2 monolayers. Using molecular dynamics simulation and molecular docking techniques, we determined the transport pathways of the six compounds and their binding affinities to P-gp. The results suggested that at the early binding stage, different hydrophobic and electrostatic interactions collectively differentiate the binding affinities of the compounds to P-gp, whereas electrostatic interactions are the main determinant at the late release stage. In addition to hydrophobic interactions, hydrogen bonds play an important role in discriminating the binding affinities.

Resilience was widely used in ecology,economics,sociology,psychology etc.There were two relatively clear definitions of resilience in describing ecosystems.The Holling resilience,indicated the ability of a system to absorb interference without system transitions or qualitative changes;while Pimm resilience was defined as the system recovery speed and as the time required to recover to the original state after interference.Ecosystem resilience could be applied to demonstrate the current state of ecological recovery and to predict the ecological evolution in the future.It played an important role in disaster prevention and reduction.Strengthening the ecosystem resilience can reduce the risk of disaster,and the evaluation of ecosystem resilience can make post-disaster reconstruction more scientific.Three aspects are the directions of ecosystem resilience in future research:the scientific definition of ecosystem resilience driven by disaster,the evaluation indicators of disaster ecosystem resilience and the method for "absolute value" assessment of ecosystem resilience.

湿地是水陆生态系统的转换区,是地球上生物多样性和生产力最高的生态系统之一。在快速城镇化和社会经济发展的推动下,京津冀地区湿地生态环境面临较大地威胁。利用1980年代末到2015年7期土地生态遥感解译数据,运用GIS空间分析和主成分分析方法,分析了京津冀地区湿地景观时空变化及其驱动力。研究结果表明:（1）1980s末—2015年期间,京津冀地区湿地面积的变化呈现从略微增长到快速减少趋势,近十年减少趋势略有减缓。湿地总面积减少了2695.05 km2,较1980s末年减少了20.08%;河北省湿地面积减少最多,且天然湿地减少占据主导地位,其次是天津市和北京市。（2）湿地面积损失较为严重的区域主要分布在环渤海区域、北京市和河北省张家口市和唐山市。湿地受损主要是水田和滩涂向非湿地转换引起的。（3）水田和水库坑塘构成的人工湿地是京津冀地区优势景观类型。湖泊、河渠、滩地破碎度增加,且空间分布离散,连通性差。（4）选取9个驱动因素指标进行主成分分析,人类活动是影响湿地景观格局变化的主要因素,城市扩张和农业发展是侵占湿地的主要表现形式,此外气候和政策等因素也对湿地变化存在一定影响。

Ulcerative colitis (UC) is a recurrent, chronic intestinal disease. Available treatments for UC are poor effective and/or cause severe adverse events. X-box binding protein 1 (XBP1) and nuclear factor-κB (NF-κB) have been reported to play important roles in UC. Specifically, deletion or downregulation of XBP1 leads to spontaneous enteritis and results in imbalanced secretion of NF-κB and other proinflammatory cytokines. (±)-8-acetonyl-dihydrocoptisine, i.e., (±)-8-ADC, is a monomer semi-synthesized from coptisine. In vitro, (±)-8-ADC activated the transcriptional activity of XBP1, inhibited expression of NF-κB, and reduced production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β), in lipopolysaccharide-stimulated IEC6 cells. Therefore, silencing XBP1 would reduce the inhibition effect of (±)-8-ADC on NF-κB expression and the cytokines secretion in vitro. In a dextran sulfate sodium-induced colitis mouse model, oral administration of (±)-8-ADC ameliorated weight loss and colon contracture, and decreased the average disease activity index score and pathological damage. Simultaneously, (±)-8-ADC also increased XBP1 expression, and decreased NF-κB expression and secretion of myeloperoxidase, TNF-α, IL-6 and IL-1β in the colon. Therefore, (±)-8-ADC may ameliorate UC via the XBP1-NF-κB pathway and should be considered as a therapeutic candidate for UC.

There is a severe lack of effective treatments for ulcerative colitis (UC), a recurrent and intractable inflammatory bowel disease. The identification of valid targets and new drugs is an urgent need. In this study, we identified the XBP-1 agonist HLJ2 as a promising treatment candidate. In an in vivo mouse model of DSS-induced colitis, HLJ2 decreased weight loss, colon contracture, disease activity index (DAI), colon mucosa damage index (CMDI) and histopathological index (HI). HLJ2 also decreased myeloperoxidase (MPO) activity and reduced production of the inflammatory cytokines TNF-α, IL-1β, and IL-6. HLJ2 improved intestinal mucosa damage induced by dextran sodium sulfate (DSS) and increased the expression of ZO-1 and claudin-1. Fecal 16s rRNA high-throughput sequencing demonstrated a significant improvement in UC intestinal dysbacteriosis in mice treated with HLJ2, including increased abundance of probiotics such as Lachnospiraceae, Prevotellaceae, and Lactobacillaceae. At the same time there was a reduction in the abundance of pathogenic or conditional pathogenic microorganisms such as Bacteroidaceae, Porphyromonadaceae, Deferribacteraceae, and Pseudomonadaceae in HLJ2-treated mice compared with untreated mice. Our results demonstrated that the XBP1 agonist HLJ2 inhibits inflammation, regulates the intestinal flora, and protects the intestinal mucosa. It is thus a potential therapeutic agent for ulcerative colitis.

Ecologically vulnerable regions in China are not only the most serious areas of environmental degradation, but also the most poverty-stricken regions. However, these regions are still undefined. Three typical factors including land desertification, soil erosion and rocky desertification were selected to establish an evaluation model of eco-environmental sensitivity by using Remote Sensing (RS) and Geographic Infor- mation System (GIS) technology. We conducted a comprehensive research on eco-environmental sensitivity to reveal its spatial features in a quantitative way in China, and redefine the location of ecologically vulner- able regions integrated with the existing relevant government documents and the previous research. Results are demonstrated as follows: the extremely sensitive areas are distributed in northwestern, southwestern, southeastern parts of China and loess hilly regions; the highly sensitive areas are located in the Altai Moun- tains, the Tianshan Mountains, the southern part of Yinshan Mountains, the Horqin Sandy Land, the Hulun Buir Sandy Land, the western part of Chang Tang Plateau, the Hengduan Mountains and the hilly mountains regions in Southeast China. A total of 18 ecological vulnerable regions in China were defined, comprising a total area of 2.4 million km 2 . The name, type, area, spatial distribution and the main ecological problems of each region were characterized. The spatial distribution map of ecologically vulnerable regions in China can be used as a base map for the redline delimitation of national ecological protection.

Three typical factors including land desertification, soil erosion and rocky desertification are selected to establish the evaluation model of eco- environmental sensitivity by integrating the technologies of RS and GIS in the present study. This paper conducts comprehensive research on eco- environmental sensitivity, reveals its spatial features in quantitative way and defines the redline of ecological sensitivity in China. The results are as follows: 1) the moderate sensitivity is the main type of land desertification. The surrounding areas of deserts in semiarid areas of northern China are the most sensitive areas. This is due to the strong wind in winter and spring in these areas, and the soil that mainly consists of sand and is seldom covered by vegetation is also the reason. 2) The slight sensitivity and insensitive areas take great proportion in soil erosion. The southwestern and southeastern parts of China and loess hilly regions are the most environmental sensitive areas, which is mainly the result of the abrupt slopes and spatial variation of precipitation. 3) The insensitive area is the main type of rocky desertification. The karst areas of southwest China are the most sensitive areas. 4) The main types of comprehensive eco- environment sensitivity in the study area are slight, insensitive and moderate.The comprehensive eco- environment sensitivity in northwestern, southwestern, southeastern parts of China and loess hilly region is higher than other areas in China. 5) Based on the evaluation results of comprehensive eco-environment sensitivity, taking the extreme sensitive areas as the ecological redline areas, this paper uses top-down method to define the redline of eco-fragile areas in China. Three types and 23 important ecological redline areas are delimited across the country, and the ecological redline areas make up about 12.86% of the study area.

Ongoing study on the chemical constituents of the roots of Macleaya microcarpa led to the isolation of eight compounds of derivatives of triterpenes and organic acids in addition to some previously identified benzophenanthridines. The eight compounds were identified by spectroscopic methods as well as comparison with literature values as 1-oxo-2, 22 (30)-hopandien-29-oic acid (1), 3-oxo-12-oleanen-30-oic acid (2), 3α-hydroxy-12-oleanen-30-oic acid (3), 3β-hydroxy-12-oleanen-30-oic acid (4), ferulic acid (5), ferulic acid 4-O-β-D-glucoside (6), 3-O-feruloylquinic acid (7), and methyl 3-O-feruloylquinate (8). Of which, 1 is a new triterpenoid of hopanes and 2-8 are isolated from M microcarpa for the first time. In order to discover natural active compounds as potential agents of anti-ulcerative colitis (UC), an in vitro drug high-throughput screening model targeted x-box-binding protein 1 (xbp1) was employed to evaluate the activity of the major chemical constituents of M microcarpa. The result confirmed that two dihydrobenzophenanthridines, dihydrosanguinarine (9) and dihydrochelerythrine (10), showed a certain activity on activating the transcription of xbpl, a transcription factor (TF) associated with the occurrence, development, and potential treatment of UC, with their relative activating ratios being 1.76 and 1.77 times, respectively, as compared with control group.

SY0916 is a new platelet-activating factor receptor antagonist developed by our institute. In this study, the inhibitory effect of SY0916 on pulmonary fibrosis was investigated in epithelial-mesenchymal transition (EMT) induced by transforming growth factor beta 1 (TGF-β1) in vitro and a pulmonary fibrosis animal model induced by bleomycin (BLM). The results showed that SY0916 could inhibit the EMT of A549 cells induced with TGF-β1. In vivo, SY0916 administration significantly ameliorated the BLM-mediated histological changes, reduced main biochemical parameters related to pulmonary fibrosis such as hydroxyproline and glutathione, and also notably attenuated the expression of key pro-fibrotic mediator, TGF-β1. These findings demonstrated that SY0916 could possibly be developed as a promising candidate for the treatment of pulmonary fibrosis.

Twenty five 13-substituted quaternary coptisine derivatives were synthesized to test their cytotoxicities against several cancer cell-lines and on intestinal epithelial cell-6 (IEC-6) in vitro to evaluate structure-activity relationship (SAR). Introduction of the alkyl groups into the C-13 position of quaternary coptisine (1) led to significant increase of the cytotoxic activity, while the substitution of arylmethyl groups and others at the same position showed no effect on improving cytotoxicities against the same cancer cell-lines. The cytotoxicities of quaternary 13-alkylcoptisines was significantly reinforced as the length of the aliphatic chain increased, with quaternary 13-n-undecylcoptisine (4l) showing 7, 23, 12, and 9 times, respectively, more active than quaternary coptisine (1) against HCT, A549, Be17402, and C33A, and being 4, 11, 2, and 3 times, respectively, more active than the positive control, fluorouracil (5-FU), against the same cell-lines, by IC50 values. In comparison to quaternary 13-n-undecylcoptisine (4l) and the above references, quaternary 13-n-dodecylcoptisine (4m) almost showed the same cytotoxicities. In contrast with the n-alkyl chains, the arylmethyl substituents at C-13 displayed low cytotoxicity, except for naphthyl rings or phenyl rings with CF3 or methyl substituents. However, their low cytotoxicity could make them useful as drug candidates for other diseases (bowel, etc). (C) 2014 Elsevier Masson SAS. All rights reserved.

Coptisine hydrochloride, as a natural protoberberine alkaloid quaternary ammonium salt, can be found in many species of Ranunculaceae and Papaveraceae plants. Despite no in-depth studies on coptisine hydrochloride, some literatures have reported that coptisine hydrochloride has such pharmacological activities as inhibition of monoamine oxidase of type A, selective inhibition and double inhibition against vascular smooth muscle cell proliferation, inhibition of differentiation and function of osteoclasts, selective regulation of multidrug-resistant and drug-resistant proteins in vascular smooth muscle cells, anti-fungus, protection of gastric-mucous membrane, cytotoxicity, and myocardial protection. Given to the fact of the lack of systematic review and summary of studies on coptisine hydrochloride, we summarize and analyze the study literatures on the pharmacological activity of coptisine hydrochloride published in recent years, so as to provide information for studies on new drugs of coptisine hydrochloride on the basis of the pharmacological activity.