Caffeic acid phenethyl ester suppresses intestinal FXR signaling and ameliorates nonalcoholic fatty liver disease by inhibiting bacterial bile salt hydrolase activity.

Propolis is commonly used in traditional Chinese medicine. Studies have demonstrated the therapeutic effects of propolis extracts and its major bioactive compound caffeic acid phenethyl ester (CAPE) on obesity and diabetes. Herein, CAPE was found to have pharmacological activity against nonalcoholic fatty liver disease (NAFLD) in diet-induced obese mice. CAPE, previously reported as an inhibitor of bacterial bile salt hydrolase (BSH), inhibited BSH enzymatic activity in the gut microbiota when administered to mice. Upon BSH inhibition by CAPE, levels of tauro-ß-muricholic acid were increased in the intestine and selectively suppressed intestinal farnesoid X receptor (FXR) signaling. This resulted in lowering of the ceramides in the intestine that resulted from increased diet-induced obesity. Elevated intestinal ceramides are transported to the liver where they promoted fat production. Lowering FXR signaling was also accompanied by increased GLP-1 secretion. In support of this pathway, the therapeutic effects of CAPE on NAFLD were absent in intestinal FXR-deficient mice, and supplementation of mice with C16-ceramide significantly exacerbated hepatic steatosis. Treatment of mice with an antibiotic cocktail to deplete BSH-producing bacteria also abrogated the therapeutic activity of CAPE against NAFLD. These findings demonstrate that CAPE ameliorates obesity-related steatosis at least partly through the gut microbiota-bile acid-FXR pathway via inhibiting bacterial BSH activity and suggests that propolis enriched with CAPE might serve as a promising therapeutic agent for the treatment of NAFLD.

Fruit, vegetable, and fruit juice consumption and risk of gestational diabetes mellitus: a systematic review and meta-analysis : List of all authors.

BACKGROUND: Fruit, vegetable, and fruit juice intake is associated with the risk of gestational diabetes mellitus (GDM). However, the conclusion is limited and conflicted. The purpose of this systematic review and meta-analysis is to investigate the association between fruit, vegetable, and fruit juice consumption and the risk of GDM. METHODS: To find relevant studies, we searched PubMed, The Cochrane Library, Web of Science, Embase, ScienceDirect, PsycINFO, CINAHL, Ovid, EBSCO, CBM, CNKI, Wanfang Data, and VIP for the report on prospective cohort studies published from inception to April 8, 2022. Summary relative risks (RR) and 95% confidence intervals (Cis) were estimated using a random-effects model. RESULTS: A total of 12 studies with 32,794 participants were included in the meta-analysis. Total fruit consumption was associated with a lower risk of GDM (RR = 0.92, 95% CI = 0.86-0.99). Whereas an increasing the consumption of vegetable, including all vegetable (RR = 0.95, 95% CI = 0.87-1.03), starchy vegetable (RR = 1.01, 95% CI = 0.82-1.26), and fruit juice (RR = 0.97, 95% CI = 0.91-1.04) was not associated with a reduction in the risk of GDM. In a dose‒response analysis of eight studies, a 3% reduction in risk of GDM for a 100 g/d increase in fruit consumption (RR = 0.97, 95% CI = 0.96-0.99). CONCLUSIONS: The findings suggest that higher fruit consumption may reduce the risk of GDM, with a 3% reduction in the risk of GDM for every 100 g/d increase in fruit intake. Higher-quality prospective studies or randomized clinical trials are required to validate the effect of different variations of fruits, vegetables, and fruit juice consumption on the risk of GDM.

Ascomylactam C Induces an Immunogenic Cell Death Signature via Mitochondria-Associated ER Stress in Lung Cancer and Melanoma.

Ascomylactam C (AsC) is a new 13-membered-ring macrocyclic alkaloid, which was first isolated and identified in 2019 from the secondary metabolites of the mangrove endophytic fungus Didymella sp. CYSK-4 in the South China Sea. AsC has been found to have a broad-spectrum cytotoxic activity. However, the antitumor effects in vivo and mechanisms of AsC remain unclear. The aim of this study was to describe the effects of AsC on lung cancer and melanoma cells and to explore the antitumor molecular mechanism of AsC. In vitro, we used plate colony formation experiments and demonstrated the ability of AsC to inhibit low-density tumor growth. An Annexin V/PI cell apoptosis detection experiment revealed that AsC induced tumor cell apoptosis. In vivo, AsC suppressed the tumor growth of LLC and B16F10 allograft significantly in mice, and promoted the infiltration of CD4+ T and CD8+ T cells in tumor tissues. Mechanistically, by analyses of Western blotting, immunofluorescence and ELISA analysis, we found that AsC increased ROS formation, induced endoplasmic reticulum (ER) stress, activated the protein kinase RNA-like ER kinase (PERK)/eukaryotic translation initiation factor (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP) signaling pathway, and induced immunogenic cell death (ICD) of tumor cells. Our results suggest that AsC may be a potentially promising antitumor drug candidate.

Saikosaponins regulate bile acid excretion in mice liver and ileum by activating farnesoid X receptor and bile acid transporter.

Radix Bupleuri exerts effective hepatoprotective and cholagogic effects through its Saikosaponins (SSs) component. Therefore, we attempted to determine the mechanism of saikosaponins used to promote bile excretion by studying their effects on intrahepatic bile flow, focusing on the synthesis, transport, excretion, and metabolism of bile acids. C57BL/6N mice were continuously gavaged with saikosaponin a (SSa), saikosaponin b2 (SSb2 ), or saikosaponin D (SSd) (200 mg/kg) for 14 days. Liver and serum biochemical indices were determined using Enzyme-linked immunosorbent assay (ELISA) kits. In addition, an ultra-performance liquid chromatography-mass spectrometer (UPLC-MS) was used to measure the levels of the 16 bile acids in the liver, gallbladder, and cecal contents. Furthermore, SSs pharmacokinetics and docking between SSs and farnesoid X receptor (FXR)-related proteins were analyzed to investigate the underlying molecular mechanisms. Administration of SSs and Radix Bupleuri alcohol extract (ESS) did not cause significant changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) levels. Saikosaponin-regulated changes in bile acid (BA) levels in the liver, gallbladder, and cecum were closely related to genes involved in BA synthesis, transport, and excretion in the liver. Pharmacokinetic studies indicated that SSs were characterized by rapid elimination (t1/2 as 0.68-2.47 h), absorption (Tmax as 0.47-0.78 h), and double peaks in the drug-time curves of SSa and SSb2 . A molecular docking study revealed that SSa, SSb2 , and SSd docked well with the 16 protein FXR molecules and target genes (<-5.2 kcal/mol). Collectively, saikosaponins may maintain BA homeostasis in mice by regulating FXR-related genes and transporters in the liver and intestine.

Anti-Inflammatory Phomalones from the Deep-Sea-Derived Fungus Trichobotrys effuse FS522.

Four new phomalones A-D (1-4), together with five known analogues (5-9) were isolated from the deep-sea-derived fungus Trichobotrys effuse FS522. Their structures of the new compounds established by analysis of their NMR and HR-ESI-MS spectroscopic data, and the absolute configurations of 2 was determined by electronic circular dichroism (ECD) calculations. compounds 4, 6 and 8 substantially inhibited the production of nitric oxide (NO) with IC50 values of 4.64, 13.90, and 34.07 µM.

A Meroterpenoid from Tibetan Medicine Induces Lung Cancer Cells Apoptosis through ROS-Mediated Inactivation of the AKT Pathway.

As a traditional Tibetan medicine in China, Meconopsis grandis Prain has been used to treat a variety of illnesses by local people for thousands of years. However, the active ingredients contained in Meconopsis grandis Prain and its pharmacodynamic mechanisms have scarcely been reported. We isolated a meroterpenoid named D1399 from Meconopsis grandis Prain endophytic fungi with strong antitumor activity. The structure analysis showed that D1399 is an alkaloid containing a 13-membered macrocyclic structure. The IC50 of D1399 for human lung cancer cells' viability ranged from 0.88 to 2.45 µM. Furthermore, we utilized TUNEL assay and western blotting to investigate the antitumor effectiveness of D1399. The results have shown that D1399 induced the apoptosis of lung cancer cells on the extrinsic and intrinsic pathways by boosting ROS generation and repressing AKT activity. In the mouse xenograft model, the average tumor weight with 30 mg·kg-1 D1399 treatment exhibited 73.19% inhibition compared with the untreated control, without affecting body weight loss. Above all, for the first time, our study provides a possible mechanism for the antitumor activity of D1399 in vitro and in vivo as a natural product from Tibetan medicine with Meconopsis grandis Prain, which may be a potentially promising antitumor drug candidate.

Correction: Gong et al. Neuroprotective and Cytotoxic Phthalides from Angelicae Sinensis Radix. Molecules 2016, 21, 549.

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Dapoxetine, a Selective Serotonin Reuptake Inhibitor, Suppresses Zika Virus Infection In Vitro.

Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family, and is a pathogen posing a significant threat to human health. Currently, there is a lack of internationally approved antiviral drugs for the treatment of ZIKV infection, and symptomatic management remains the primary clinical approach. Consequently, the exploration of safe and effective anti-ZIKV drugs has emerged as a paramount imperative in ZIKV control efforts. In this study, we performed a screening of a compound library consisting of 1789 FDA-approved drugs to identify potential agents with anti-ZIKV activity. We have identified dapoxetine, an orally administered selective serotonin reuptake inhibitor (SSRI) commonly employed for the clinical management of premature ejaculation (PE), as a potential inhibitor of ZIKV RNA-dependent RNA polymerase (RdRp). Consequently, we conducted surface plasmon resonance (SPR) analysis to validate the specific binding of dapoxetine to ZIKV RdRp, and further evaluated its inhibitory effect on ZIKV RdRp synthesis using the ZIKV Gluc reporter gene assay. Furthermore, we substantiated the efficacy of dapoxetine in suppressing intracellular replication of ZIKV, thereby demonstrating a concentration-dependent antiviral effect (EC50 values ranging from 4.20 µM to 12.6 µM) and negligible cytotoxicity (CC50 > 50 µM) across diverse cell lines. Moreover, cell fluorescence staining and Western blotting assays revealed that dapoxetine effectively reduced the expression of ZIKV proteins. Collectively, our findings suggest that dapoxetine exhibits anti-ZIKV effects by inhibiting ZIKV RdRp activity, positioning it as a potential candidate for clinical therapeutic intervention against ZIKV infection.

[Characterization and phylogenetic analysis of complete chloroplast genome of cultivated Qinan agarwood].

"Tangjie" leaves of cultivated Qinan agarwood were used to obtain the complete chloroplast genome using high-throughput sequencing technology. Combined with 12 chloroplast genomes of Aquilaria species downloaded from NCBI, bioinformatics method was employed to determine the chloroplast genome characteristics and phylogenetic relationships. The results showed that the chloroplast genome sequence length of cultivated Qinan agarwood "Tangjie" leaves was 174 909 bp with a GC content of 36.7%. A total of 136 genes were annotated, including 90 protein-coding genes, 38 tRNA genes, and 8 rRNA genes. Sequence repeat analysis detected 80 simple sequence repeats(SSRs) and 124 long sequence repeats, with most SSRs composed of A and T bases. Codon preference analysis revealed that AUU was the most frequently used codon, and codons with A and U endings were preferred. Comparative analysis of Aquilaria chloroplast genomes showed relative conservation of the IR region boundaries and identified five highly variable regions: trnD-trnY, trnT-trnL, trnF-ndhJ, petA-cemA, and rpl32, which could serve as potential DNA barcodes specific to the Aquilaria genus. Selection pressure analysis indicated positive selection in the rbcL, rps11, and rpl32 genes. Phylogenetic analysis revealed that cultivated Qinan agarwood "Tangjie" and Aquilaria agallocha clustered together(100% support), supporting the Chinese origin of Qinan agarwood from Aquilaria agallocha. The chloroplast genome data obtained in this study provide a foundation for studying the genetic diversity of cultivated Qinan agarwood and molecular identification of the Aquilaria genus.

Neocucurbins A-G, novel macrocyclic diterpenes and their derivatives from Neocucurbitaria unguis-hominis FS685.

Three novel phomactin diterpenes neocucurbins A-C (1-3) and their derivatives, neocucurbins D-G (4-7), were isolated from the marine-derived fungus Neocucurbitaria unguis-hominis FS685. Among them, neocucurbins A-C represent the first examples of the phomactin family with an unprecedented skeleton sharing a novel polyoxygen-hetero 5/6/12 or 5/6/13 fused tricyclic ring system; whereas neocucurbins D-G feature a 5/6 fused bicyclic ring system with the opening of the macrocyclic ring, which was found in the phomactin family for the first time. Moreover, spectroscopic data analyses, single-crystal X-ray diffraction experiments, and ECD calculations were conducted to illustrate the absolute configurations of their structures. Furthermore, all seven compounds (1-7) were evaluated for their cytotoxic and antimicrobial activities.

Synergistic neuroprotective effect of saikosaponin A and albiflorin on corticosterone-induced apoptosis in PC12 cells via regulation of metabolic disorders and neuroinflammation.

BACKGROUND: Saikosaponin A (SSA) and albiflorin (AF) are major bioactive compounds of Radix Bupleuri and Radix Paeoniae alba respectively, which possess antidepressant effects in pharmacological experiments. However, whether SSA and AF have synergistic neuroprotective effects and the synergistic mechanisms are still unknown. METHODS AND RESULTS: The corticosterone-induced PC12 cells apoptosis model was employed to assess the neuroprotective effects of SSA and AF, and the synergistic effect was analyzed using three mathematical models. Meanwhile, cell metabolomics was used to detect the effects on metabolite regulation of SSA and AF. Furthermore, the key metabolites, metabolic enzymes, and cellular markers were verified by ELISA and Western blotting. The results showed that the combination of SSA and AF has a synergistic neuroprotective effect. Besides, the combination could regulate more metabolites than a single agent and possessed a stronger adjustment effect on metabolites. The TCA cycle was regulated by SSA and AF via improving mitochondrial function. The purine metabolism was regulated by SSA via inhibition xanthine oxidase activity and the glutamate metabolism was regulated by AF via inhibition glutaminase activity. Moreover, the oxidative stress induced by the purine metabolism was attenuated by SSA via a reduction in the ROS level. Additionally, the inflammation induced by the oxidative stress was attenuated by the SSA and AF via inhibition of the NLRP3 protein expression. CONCLUSIONS: This study for the first time demonstrated the synergistic neuroprotective effects of SSA and AF, and the synergistic mechanisms were involved in metabolic disorders regulation and neuroinflammation inhibition.

Neocucurbols A-H, Phomactin Diterpene Derivatives from the Marine-Derived Fungus Neocucurbitaria unguis-hominis FS685.

Neocucurbols A-D (1-4) are diterpene derivatives that possess a complex 6/6/5/5/6 polycyclic ring system with a characteristic tetrahedrofuran bridge ring skeleton. Neocucurbols E-H (5-8) are diterpenes that feature a 6/8/6 tricyclic ring system. Their structures were unambiguously determined by detailed spectroscopic analyses, X-ray diffractions studies, and ECD calculations. All compounds (1-8) were evaluated for in vitro antimicrobial and cytotoxic activities.

Research on Deep Learning Method and Optimization of Vibration Characteristics of Rotating Equipment.

CNN extracts the signal characteristics layer by layer through the local perception of convolution kernel, but the rotation speed and sampling frequency of the vibration signal of rotating equipment are not the same. Extracting different signal features with a fixed convolution kernel will affect the local feature perception and ultimately affect the learning effect and recognition accuracy. In order to solve this problem, the matching between the size of convolution kernel and the signal (rotation speed, sampling frequency) was optimized with the matching relation obtained. Through the study of this paper, the ability of extracting vibration features of CNN was improved, and the accuracy of vibration state recognition was finally improved to 98%.

Urban development enhances soil organic carbon storage through increasing urban vegetation.

Anthropogenic activities can lead to the loss of soil organic carbon (SOC) or improve its storage, hence they have the potential to exacerbate or help mitigate climate change. Urban expansion results in an initial loss of soil carbon, but long-term SOC changes during urban development are poorly understood. Herein, we studied SOC changes in the suburban and urban areas of cities with high levels of urbanization based on a long-term resampling campaign in Beijing, and a compilation of SOC content data from 21 other cities with high levels of urbanization across China over the past three decades. Our results revealed that the SOC of topsoils decreased by 17.2% in the suburban areas and increased by 104.4% in the urban areas of cities with high levels of urbanization. The changes in SOC were positively correlated with the changes in vegetation coverage and productivity. Partial least square method structural equation model analyses showed that changes in vegetation could directly affect SOC changes, and the changes in vegetation coverage and productivity were induced by human activities and climate changes in Beijing. The topsoils in the urban areas of cities with high levels of urbanization can act as carbon sinks due to the increase in vegetation. This study can help improve our understanding of the role of the SOC content of cities within the global C cycle and provide suggestions for achieving the goal of carbon neutrality in China.

Metabolic map of the antiviral drug podophyllotoxin provides insights into hepatotoxicity.

Podophyllotoxin (POD) is a natural compound with antiviral and anticancer activities. The purpose of the present study was to determine the metabolic map of POD in vitro and in vivo.Mouse and human liver microsomes were employed to identify POD metabolites in vitro and recombinant drug-metabolizing enzymes were used to identify the mono-oxygenase enzymes involved in POD metabolism. All in vitro incubation mixtures and bile samples from mice treated with POD were analysed with ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry.A total of 38metabolites, including six phase-I metabolites and 32 phase-II metabolites, of POD were identified from bile and faeces samples after oral administration, and their structures were elucidated through interpreting MS/MS fragmentation patterns.Nine metabolites, including two phase-I metabolites, five glucuronide conjugates, and two GSH conjugates were detected in both human and mouse liver microsome incubation systems and the generation of all metabolites were NADPH-dependent. The main phase-I enzymes involved in metabolism of POD in vitro include CYP2C9, CYP2C19, CYP3A4, and CYP3A5.POD administration to mice caused hepatic and intestinal toxicity, and the cellular damage was exacerbated when 1-aminobenzotriazole, a broad-spectrum inhibitor of CYPs, was administered with POD, indicating that POD, but not its metabolites, induced hepatic and intestinal toxicities.This study elucidated the metabolic map and provides important reference basis for the safety evaluation and rational for the clinical application of POD.

Investigation on knowledge, attitudes and practices about food safety and nutrition in the China during the epidemic of corona virus disease 2019.

OBJECTIVE: To investigate the knowledge, attitudes and practices (K-A-P) about food safety and nutrition in Chinese adults who were recruited to the online survey during the epidemic of corona virus disease 2019 (COVID-19). DESIGN: Participants were recruited by an online snowball sampling method. An electronic questionnaire was sent to our colleagues, students, friends, other professionals and their referrals helped us recruit more participants. The questionnaire included socio-demographic information, the attention paid to COVID-19, K-A-P about food safety and nutrition. Multiple and logistic regression analyses were used to explore related factors of K-A-P. SUBJECTS: Totally, 2272 participants aged 24·09 ± 9·14 years, from twenty-seven provinces, autonomous districts or municipalities, with 18·3 % male and 83·4 % with a medical background. RESULTS: The total possible knowledge score was 8·0, the average score was 5·2 ± 1·6 and 4·2 % obtained 8·0. The total possible attitudes score was 8·0, the average score was 6·5 ± 1·4 and 36·1 % obtained 8·0. The total possible food safety practices score was 5·0, the average score was 3·7 ± 1·0 and 20·7 % obtained 5·0. During this public emergency, 79·4 % participants changed diet habits, including increasing vegetables, fruit and water intake and reducing sugary drinks and snacks. Gender, age, educational and professional background, disease history, the attention paid to COVID-19 and related knowledge were associated with K-A-P. CONCLUSION: There was room for the improvement of K-A-P in participants during this public health emergency and further strengthening education about food safety and nutrition is needed. Findings indicate that education should address biased or misleading information and promote nutritious food choices and safe food practices.

Thioester-Containing Benzoate Derivatives with α-Glucosidase Inhibitory Activity from the Deep-Sea-Derived Fungus Talaromyces indigoticus FS688.

Eurothiocins C-H (1-6), six unusual thioester-containing benzoate derivatives, were isolated from the deep-sea-derived fungus Talaromyces indigoticus FS688 together with a known analogue eurothiocin A (7). Their structures were elucidated through spectroscopic analysis and the absolute configurations were determined by X-ray diffraction and ECD calculations. In addition, compound 1 exhibited significant inhibitory activity against α-glucosidase with an IC50 value of 5.4 µM, while compounds 4 and 5 showed moderate effects with IC50 values of 33.6 and 72.1 µM, respectively. A preliminary structure-activity relationship is discussed and a docking analysis was performed.

[Research progress of circadian rhythm].

Circadian rhythm disorder is a common society issue caused by jet lag,shift work,sleep disruption and changes in food consumption. Light is the major factor affecting the circadian rhythm system. Disruption of the circadian rhythm system can cause damage to the body,leading to some diseases. Maintaining a normal circadian system is of great importance for good health. Ideal therapeutic effect can not only alleviate symptoms of the diseases,but also recovery the disturbed circadian rhythm to normal. The paper summarizes the modeling methods of animal circadian rhythm disorder,diseases of circadian rhythm abnormality,regulation of circadian clock genes and medicine which are related to circadian rhythm to diseases of circadian rhythm disorder.

Metabolic profiling of RB-2 and RB-4, two analogs of polyacetylene from Bupleurum.

RB-2 and RB-4 are two structural analogs of polyacetylene from Radix Bupleuri that show antidepressant effects. However, no metabolic data are available to elucidate their systemic homeostasis. Mass spectrometry combined with liver microsomes and recombinant drug-metabolizing enzymes were performed to profile the biotransformations of RB-2/RB-4 in vitro and in vivo. Oxidation should be the major metabolic pathways for them in phase I, while CYP2C9 and CYP2E1 was the major contributor. In phase II, conjugational groups usually combined with the metabolites from phase I. This study provides an important reference basis for the safety evaluation and rational application of RB-2/RB-4.

[Advances in research of traditional Chinese medicine for promoting bile secretion and excretion].

Cholagogic traditional Chinese medicines refer to those that can promote bile secretion and excretion, strengthen gallbladder contraction and promote gallbladder emptying. They are mainly used to treat cholecystitis, gallstones, cholestasis, biliary tract infection, jaundice hepatitis and other diseases in clinical application. As a traditional medicine in our country, Chinese herbal medicines have many advantages, such as extensive resources, low cost, little or no toxic and side effects, and in addition, it is not easy for animals to produce drug resistance. With the progress of science and technology and the rapid development of traditional Chinese medicine, many achievements have been made in the research of cholagogic traditional Chinese medicines. Traditional Chinese medicine plays a cholagogic role mainly by promoting bile secretion, regulating SCP2 mRNA, FXR, BSEP and efflux transporter protein, dissolving cholesterol, promoting the relaxation of Oddi's sphincter and changing the composition of bile, etc. Traditional Chinese medicine decoction, traditional Chinese medicine preparation, Chinese medicine combined with acupuncture, ear acupoint pressing, soaking bath, western medicine and alike are often used to treat biliary system diseases in clinical practice. The effective rate of combination of traditional Chinese medicine and other methods was significantly higher than that of compound prescription, western medicine, acupuncture and soaking bath alone. General attack therapy and new therapies are also used in clinical treatment. The clinical effect of traditional Chinese medicine is remarkable. By means of literature review, the pharmacological effects, mechanism and clinical application of Chinese herbal medicines and compound prescriptions with gallbladder-promoting effect in the past 15 years were summarized in this paper. At the same time, some existing problems were found and prospects were expected.