Identification of the serum metabolites associated with cow milk consumption in Chinese Peri-/Postmenopausal women.

Cow milk consumption (CMC) and downstream alterations of serum metabolites are commonly considered important factors regulating human health status. Foods may lead to metabolic changes directly or indirectly through remodelling gut microbiota (GM). We sought to identify the metabolic alterations in Chinese Peri-/Postmenopausal women with habitual CMC and explore if the GM mediates the CMC-metabolite associations. 346 Chinese Peri-/Postmenopausal women participants were recruited in this study. Fixed effects regression and partial least squares discriminant analysis (PLS-DA) were applied to reveal alterations of serum metabolic features in different CMC groups. Spearman correlation coefficient was computed to detect metabolome-metagenome association. 36 CMC-associated metabolites including palmitic acid (FA(16:0)), 7alpha-hydroxy-4-cholesterin-3-one (7alphaC4), citrulline were identified by both fixed effects regression (FDR < 0.05) and PLS-DA (VIP score > 2). Some significant metabolite-GM associations were observed, including FA(16:0) with gut species Bacteroides ovatus, Bacteroides sp.D2. These findings would further prompt our understanding of the effect of cow milk on human health.

Unconventional hcp/fcc Nickel Heteronanocrystal with Asymmetric Convex Sites Boosts Hydrogen Oxidation.

Developing non-platinum group metal catalysts for the sluggish hydrogen oxidation reaction (HOR) is critical for alkaline fuel cells. To date, Ni-based materials are the most promising candidates but still suffer from insufficient performance. Herein, we report an unconventional hcp/fcc Ni (u-hcp/fcc Ni) heteronanocrystal with multiple epitaxial hcp/fcc heterointerfaces and coherent twin boundaries, generating rugged surfaces with plenty of asymmetric convex sites. Systematic analyses discover that such convex sites enable the adsorption of *H in unusual bridge positions with weakened binding energy, circumventing the over-strong *H adsorption on traditional hollow positions, and simultaneously stabilizing interfacial *H2O. It thus synergistically optimizes the HOR thermodynamic process as well as reduces the kinetic barrier of the rate-determining Volmer step. Consequently, the developed u-hcp/fcc Ni exhibits the top-rank alkaline HOR activity with a mass activity of 40.6 mA mgNi-1 (6.3 times higher than fcc Ni control) together with superior stability and high CO-tolerance. These results provide a paradigm for designing high-performance catalysts by shifting the adsorption state of intermediates through configuring surface sites.

A new glance at autophagolysosomal-dependent or -independent function of transcriptional factor EB in human cancer.

Autophagy-lysosome system plays a variety of roles in human cancers. In addition to being implicated in metabolism, it is also involved in tumor immunity, remodeling the tumor microenvironment, vascular proliferation, and promoting tumor progression and metastasis. Transcriptional factor EB (TFEB) is a major regulator of the autophagy-lysosomal system. With the in-depth studies on TFEB, researchers have found that it promotes various cancer phenotypes by regulating the autophagolysosomal system, and even in an autophagy-independent way. In this review, we summarize the recent findings about TFEB in various types of cancer (melanoma, pancreatic ductal adenocarcinoma, renal cell carcinoma, colorectal cancer, breast cancer, prostate cancer, ovarian cancer and lung cancer), and shed some light on the mechanisms by which it may serve as a potential target for cancer treatment.

Effects of Pretreated Phosphogypsum and Granulated Blast-Furnace Slag on the Rheological Properties of the Paste Excited by NaOH.

The main component of phosphogypsum (PG) is CaSO4·2H2O. PG contains a few impurities, heavy metals, and radioisotopes, which limit the use of PG and pose a danger to the environment. In this study, under the excitation of a sodium hydroxide solution, the rheological properties of a paste with granulated blast-furnace slag (GGBS) and PG treated with ultrasonic water washing were investigated. Experimental results showed that the ratio of GGBS to PG and the amount of sodium hydroxide solution significantly affect the density and viscosity of the paste, but the effect patterns of both are different. The maximum viscosity was 498 mPa·s when the ratio of GGBS to PG was 4:1. When the ratio changed from 3:2 to 1:4, the viscosity of the paste gradually decreased by 15.5%, 32.1%, 36.1%, and 46.8%, respectively. In contrast, the ratio of GGBS to PG had a greater effect on the viscosity than the amount of sodium hydroxide solution in terms of the standard consistency water consumption, viscosity, and water release ratio. The larger the PG ratio, the smaller the density, viscosity, and water release ratio of the paste. The variation in the ratio of GGBS to PG had a significant effect on the water film thickness of the paste, demonstrating that the larger the PG mixture, the larger the water film thickness of the paste, which reached 1.122 µm, 2.31 times the minimum water film thickness of the paste. At the same time, the water film thickness of the paste was negatively correlated with the water consumption of the standard consistency, viscosity, and water release ratio, and was positively correlated with the fluidity.

The role of fibrosis index FIB-4 in predicting liver fibrosis stage and clinical prognosis: A diagnostic or screening tool?

This review evaluates the ability of the fibrosis index based on four factors (FIB-4) identifying fibrosis stages, long-time prognosis in chronic liver disease, and short-time outcomes in acute liver injury. FIB-4 was accurate in predicting the absence or presence of advanced fibrosis with cut-offs of 1.0 and 2.65 for viral hepatitis B, 1.45 and 3.25 for viral hepatitis C, 1.30 (<65 years), 2.0 (≥65 years), and 2.67 for non-alcoholic fatty liver disease (NAFLD), respectively, but had a low-to-moderate accuracy in alcoholic liver disease (ALD) and autoimmune hepatitis. It performed better in excluding fibrosis, so we built an algorithm for identifying advanced fibrosis by combined methods and giving work-up and follow-up suggestions. High FIB-4 in viral hepatitis, NAFLD, and ALD was associated with significantly high hepatocellular carcinoma incidence and mortality. Additionally, FIB-4 showed the ability to predict high-risk varices with cut-offs of 2.87 and 3.91 in cirrhosis patients and predict long-term survival in hepatocellular carcinoma patients after hepatectomy. In acute liver injury caused by COVID-19, FIB-4 had a predictive value for mechanical ventilation and 30-day mortality. Finally, FIB-4 may act as a screening tool in the secondary prevention of NAFLD in the high-risk population.

The Efficacy and Safety of Disease-Modifying Osteoarthritis Drugs for Knee and Hip Osteoarthritis-a Systematic Review and Network Meta-Analysis.

BACKGROUND: Osteoarthritis (OA) is common and burdensome for patients and health care systems. Our study purpose was to evaluate the long-term efficacy and safety of DMOADs in adults with knee and hip osteoarthritis. METHODS: We searched Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Web of Knowledge without language, publication, or date restrictions from inception through November 2018 for randomized controlled trials assessing 12 classes of DMOADs with at least 12 months of follow-up. Therapeutic effects were evaluated with pairwise and network meta-analysis. Outcomes included pain, function, minimum joint space width or cartilage volume, radiographic progression, and total joint replacement. Analyses were also performed for drug safety. RESULTS: Twenty-eight randomized controlled trials with 11,890 patients were included. Glucosamine and chondroitin minimally improved both structure (minimum joint width or cartilage volume: network results: glucosamine: SMD 0.16; 95% CI [0.04, 0.28], chondroitin: SMD 0.21 [0.10, 0.32]) and symptoms (glucosamine: pain: - 0.15 [- 0.25, - 0.05]; function: - 0.17 [- 0.28, - 0.07], chondroitin: pain: - 0.06 [- 0.15, 0.03], and function: - 0.15 [- 0.26, - 0.03]). Strontium demonstrated improvement in structure (minimum joint width or cartilage volume: 0.20 [0.02, 0.38]), and vitamin D on symptoms (pain: - 0.15 [- 0.27, -0.03]; function: - 0.18 [- 0.31, - 0.06]). Although doxycycline also demonstrated a favorable efficacy ranking, its safety profile was poor (withdrawal: network relative risk 1.69 [1.03, 2.75]). The therapeutic effects of other medications were not ranked as highly. DISCUSSION: Glucosamine and chondroitin yielded statistically significant but clinically questionable long-term benefit on structure and symptoms, though both had favorable safety profiles. Strontium improved structure, and vitamin D improved symptoms. Although doxycycline had a favorable efficacy ranking, its safety profile was poor. None of the 12 classes of drugs appears to have long-term clinically significant benefit.

JMJD3: a critical epigenetic regulator in stem cell fate.

The Jumonji domain-containing protein-3 (JMJD3) is a histone demethylase that regulates the trimethylation of histone H3 on lysine 27 (H3K27me3). H3K27me3 is an important epigenetic event associated with transcriptional silencing. JMJD3 has been studied extensively in immune diseases, cancer, and tumor development. There is a comprehensive epigenetic transformation during the transition of embryonic stem cells (ESCs) into specialized cells or the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs). Recent studies have illustrated that JMJD3 plays a major role in cell fate determination of pluripotent and multipotent stem cells (MSCs). JMJD3 has been found to enhance self-renewal ability and reduce the differentiation capacity of ESCs and MSCs. In this review, we will focus on the recent advances of JMJD3 function in stem cell fate. Video Abstract.

Mutations in key driver genes of pancreatic cancer: molecularly targeted therapies and other clinical implications.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a minimal difference between its incidence rate and mortality rate. Advances in oncology over the past several decades have dramatically improved the overall survival of patients with multiple cancers due to the implementation of new techniques in early diagnosis, therapeutic drugs, and personalized therapy. However, pancreatic cancers remain recalcitrant, with a 5-year relative survival rate of <9%. The lack of measures for early diagnosis, strong resistance to chemotherapy, ineffective adjuvant chemotherapy and the unavailability of molecularly targeted therapy are responsible for the high mortality rate of this notorious disease. Genetically, PDAC progresses as a complex result of the activation of oncogenes and inactivation of tumor suppressors. Although next-generation sequencing has identified numerous new genetic alterations, their clinical implications remain unknown. Classically, oncogenic mutations in genes such as KRAS and loss-of-function mutations in tumor suppressors, such as TP53, CDNK2A, DPC4/SMAD4, and BRCA2, are frequently observed in PDAC. Currently, research on these key driver genes is still the main focus. Therefore, studies assessing the functions of these genes and their potential clinical implications are of paramount importance. In this review, we summarize the biological function of key driver genes and pharmaceutical targets in PDAC. In addition, we conclude the results of molecularly targeted therapies in clinical trials and discuss how to utilize these genetic alterations in further clinical practice.

Synthesis of Novel 2-(Pyridin-2-yl) Pyrimidine Derivatives and Study of Their Anti-Fibrosis Activity.

A pyrimidine moiety exhibiting a wide range of pharmacological activities has been employed in the design of privileged structures in medicinal chemistry. To prepare libraries of novel heterocyclic compounds with potential biological activities, a series of novel 2-(pyridin-2-yl) pyrimidine derivatives were designed, synthesized and their biological activities were evaluated against immortalized rat hepatic stellate cells (HSC-T6). Fourteen compounds were found to present better anti-fibrotic activities than Pirfenidone and Bipy55'DC. Among them, compounds ethyl 6-(5-(p-tolylcarbamoyl)pyrimidin-2-yl)nicotinate (12m) and ethyl 6-(5-((3,4-difluorophenyl)carbamoyl)pyrimidin-2-yl)nicotinate (12q) show the best activities with IC50 values of 45.69 µM and 45.81 µM, respectively. Furthermore, the study of anti-fibrosis activity was evaluated by Picro-Sirius red staining, hydroxyproline assay and ELISA detection of Collagen type I alpha 1 (COL1A1) protein expression. Our study showed that compounds 12m and 12q effectively inhibited the expression of collagen, and the content of hydroxyproline in cell culture medium in vitro, indicating that compounds 12m and 12q might be developed the novel anti-fibrotic drugs.

[Study on safflower yellow for injection based on cell degranulation and acute anaphylactoid model].

This paper was aimed to establish screening methods of anaphylactoid reaction caused by safflower yellow for injection based on RBL-2 H3 cell degranulation model and mice model for acute anaphylactoid reaction,and evaluate the hypersensitivity caused by safflower yellow for injection from different batches. An in vitro cell model was used to keep the cells stimulated for an hour with different batches of safflower yellow for injection as the drug group,serum-free MEM medium as negative control group and 30 mg·L-1 C48/80 as positive control group respectively. The supernatant was then absorbed,and neutral red staining technique was used to detect the effect of safflower yellow injection on the degranulation of RBL-2 H3 cells with the positive cell rate of degranulation as the indicator.An in vivo model was established to validate the experimental results,and mice model for acute anaphylactoid reaction and ELISA method were adopted to detect the plasma histamine content,and screen the hypersensitivity caused by safflower yellow for injection at the animal level by using plasma histamine content as a test index. The results of the neutral red staining experiments showed that the positive control C48/80 could cause cell degranulation,and most of the cells were deeply stained. There was significant difference in positive cell rate between different batches of safflower yellow and positive control group. In the mice model for acute anaphylactoid reaction,it was found that the positive control C48/80 significantly increased the histamine content in the plasma of mice,while the safflower yellow in each batch did not cause a significant increase in plasma histamine( P<0. 000 1). The mechanism of anaphylactoid reaction is relatively complicated. This study was mainly based on the release of histamine and other active substances by degranulation of mast cells. No significant degranulation reaction of RBL-2 H3 cells induced by safflower yellow for injection was detected,nor was the plasma histamine level significantly increased in mice from the in vitro and in vivo aspects.

A near ambient pressure XPS study of subnanometer silver clusters on Al2O3 and TiO2 ultrathin film supports.

We have investigated model systems of silver clusters with different sizes (3 and 15 atoms) deposited on alumina and titania supports using ambient pressure X-ray photoelectron spectroscopy. The electronic structures of silver clusters and support materials are studied upon exposure to various atmospheres (ultrahigh vacuum, O2 and CO) at different temperatures. Compared to bulk silver, the binding energies of silver clusters are about 0.55 eV higher on TiO2 and 0.95 eV higher on Al2O3 due to the final state effect and the interaction with supports. No clear size effect of the silver XPS peak is observed on different silver clusters among these samples. Silver clusters on titania show better stability against sintering. Al 2p and Ti 2p core level peak positions of the alumina and titania support surfaces change upon exposure to oxygen while the Ag 3d core level position remains unchanged. We discuss the origin of these core level shifts and their implications for catalytic properties of Ag clusters.

Ecotoxicity of hexavalent chromium [Cr (VI)] in soil presents predominate threats to agricultural production with the increase of soil Cr contamination.

The relative severity between chromium (Cr)-mediated ecotoxicity and its bioaccumulation has rarely been compared and evaluated. This study employed pot incubation experiments to simulate the soil environment with increased Cr pollution and study their effects on the growth of crops, including pepper, lettuce, wheat, and rice. Results showed that increasing total Cr presented ascendant ecotoxicity in upland soils when pH > 7.5, and significantly reduced the yield of pepper, lettuce and wheat grain by 0.3-100 %, whereas, this effect was weakened even reversed as the pH decreased. Surprisingly, a series of soils with Cr concentration of 22.7-623.5 mg kg-1 did not cause Cr accumulation in four crops over the Chinese permissible limit. The toxicity of Cr was highly associated with extractable Cr, where Cr (VI) made the greater contributions than Cr (III). Conclusively, the ecotoxicity of Cr poses a greater environmental issue as compared to the bioaccumulation of Cr in crops in upland soils, while extractable Cr (VI) makes the predominant contributions to the ecotoxicity of Cr as the total Cr increased. Our study proposes a synchronous consideration involving total Cr and Cr (VI) as the theoretical basis to establish a more reliable soil quality standard for safe production in China.

Liver injury protection of Artemisia stechmanniana besser through PI3K/AKT pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia stechmanniana Besser, one of the most prevalent botanical medicines in Chinese, has been traditionally used for hepatitis treatment. However, the bioactive components and pharmacological mechanism on alcohol-induced liver injury remains unclear. AIM OF THE STUDY: To investigate the effect of A. stechmanniana on alcohol-induced liver damage, and further explore its mechanism. MATERIALS AND METHODS: Phytochemical isolation and structural identification were used to determine the chemical constituents of A. stechmanniana. Then, the alcohol-induced liver damage animal and cell model were established to evaluate its hepato-protective potential. Network pharmacology, molecular docking and bioinformatics were integrated to explore the mechanism and then the prediction was further supported by experiments. Moreover, both compounds were subjected to ADMET prediction through relevant databases. RESULTS: 28 compounds were isolated from the most bioactive fraction, ethyl acetate extract A. stechmanniana, in which five compounds (abietic acid, oplopanone, oplodiol, hydroxydavanone, linoleic acid) could attenuate mice livers damage caused by alcohol intragastration, reduce the degree of oxidative stress, and serum AST and ALT, respectively. Furthermore, abietic acid and hydroxydavanone exhibited best protective effect against alcohol-stimulated L-O2 cells injury among five bioactive compounds. Network pharmacology and bioinformatics analysis suggested that abietic acid and hydroxydavanone exhibiting drug likeliness characteristics, were the principal active compounds acting on liver injury treatment, primarily impacting to cell proliferation, oxidative stress and inflammation-related PI3K-AKT signaling pathways. Both of them displayed strong binding energies with five target proteins (HRAS, HSP90AA1, AKT1, CDK2, NF-κB p65) via molecular docking. Western blotting results further supported the predication with up-regulation of protein expressions of CDK2, and down-regulation of HRAS, HSP90AA1, AKT1, NF-κB p65 by abietic acid and hydroxydavanone. CONCLUSION: Alcohol-induced liver injury protection by A. stechmanniana was verified in vivo and in vitro expanded its traditional use, and its two major bioactive compounds, abietic acid and hydroxydavanone exerted hepatoprotective effect through the regulation of PI3K-AKT signaling pathway.

Surgical interventions for treating distal humeral fractures in adults.

BACKGROUND: Distal humeral fractures in adults are relatively uncommon injuries that require surgical intervention in most cases. There is a lack of consensus regarding the best management of distal humeral fractures in adults, including the role of conservative treatment, appropriate surgical approach, fixation strategies, the role of total elbow arthroplasty and handling of nerves such as the ulnar nerve. OBJECTIVES: To assess the effects (benefits and harms) of surgical interventions for distal humeral fractures in adults. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (May 2012), the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2012 Issue 4), MEDLINE (1946 to April Week 4 2012), EMBASE (1980 to 2012 Week 17), Current Controlled Trials (1st May 2012), the WHO International Clinical Trials Registry Platform (1st May 2012) and the bibliographies of trial reports and relevant articles. SELECTION CRITERIA: All randomised and quasi-randomised controlled trials pertinent to the management of distal humeral fractures in adults were included. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, assessed of risk of bias and extracted data. Pooling of data was impossible due to study heterogeneity. MAIN RESULTS: Three small randomised controlled trials, with a total of 109 participants with Orthopaedic Trauma Association/Arbeitsgemeinschaft für Osteosynthesefragen (OTA/AO) type C distal humeral fractures, were included. Overall, the quality of the available evidence is limited. As well as the small sample sizes and detection bias from the lack of blinding of subjective outcomes, the methods and results of all three trials were incompletely reported.One trial, involving 42 participants, compared open reduction-internal fixation (ORIF) with total elbow arthroplasty (TEA) in patients aged over 65 years. Of the 40 participants followed up for two years, five allocated ORIF underwent intraoperative conversion to TEA. These participants were crossed-over to the TEA group in the analyses. The reported Mayo Elbow Performance Score (MEPS) results were consistently better in the TEA group at follow-up after 6, 12, and 24 months, whereas the Disability of the Arm, Shoulder, Hand (DASH) scores showed short term (after 6 months), but not longer term (after 12 and 24 months), superiority in the TEA group. The reoperation rate, complication rate and elbow range of motion results showed no statistically significant differences between the two groups. While an intention-to-treat analysis of treatment failure, where the five cross-over participants are placed in their original allocated group, is in favour of TEA, the result did not reach statistical significance (9/21 versus 3/21; RR 3.00, 95% CI 0.94 to 9.55).The second trial, involving 38 patients but reporting results for 35, compared perpendicular versus parallel double plate fixation strategies. There was a consistent finding of a lack of significant differences between the two treatment groups in terms of MEPS, re-operation for complications (3/17 versus 3/18; RR 1.06, 95% CI 0.25 to 4.54), complications and elbow joint range of motion.The third trial, which included 29 patients with preoperative ulnar nerve compression symptoms, compared anterior subfascial transposition with in situ decompression of the ulnar nerve. Although results for complete recovery of ulnar nerve function (12/15 versus 8/14; RR 1.4, 95% CI 0.83 to 2.35) and grades based on the Bishop rating system tended to favour the transposition group, none of the differences were statistically significant. AUTHORS' CONCLUSIONS: Overall, this review found there is either no or insufficient evidence from randomised or quasi-randomised controlled trials to determine whether surgery is, and which surgical interventions are, the most appropriate for the management of different types of distal humerus fractures. Well designed and reported large and multi-centre randomised controlled trials testing current interventions, such as pre-contoured and locking plating systems, are needed.

Electromagnetic fields for treating osteoarthritis.

BACKGROUND: This is an update of a Cochrane review first published in 2002. Osteoarthritis is a disease that affects the synovial joints, causing degeneration and destruction of hyaline cartilage and subchondral bone. Electromagnetic field therapy is currently used by physiotherapists and may promote growth and repair of bone and cartilage. It is based on principles of physics which include Wolff's law, the piezoelectric effect and the concept of streaming potentials. OBJECTIVES: To assess the benefits and harms of electromagnetic fields for the treatment of osteoarthritis as compared to placebo or sham. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 9), PreMEDLINE for trials published before 1966, MEDLINE from 1966 to October 2013, CINAHL and PEDro up to and including October 2013. Electronic searches were complemented by handsearches. SELECTION CRITERIA: Randomised controlled trials of electromagnetic fields in osteoarthritis, with four or more weeks treatment duration. We included papers in any language. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion in the review and resolved differences by consensus with a third review author. We extracted data using pre-developed data extraction forms. The same review authors assessed the risk of bias of the trials independently using the Cochrane 'Risk of bias' tool. We extracted outcomes for osteoarthritis from the publications according to Outcome Measures in Rheumatology Clinical Trials (OMERACT) guidelines. We expressed results for continuous outcome measures as mean difference (MD) or standardised mean difference (SMD) with 95% confidence interval (CI). We pooled dichotomous outcome measures using risk ratio (RR) and calculated the number needed to treat (NNT). MAIN RESULTS: Nine studies with a total of 636 participants with osteoarthritis were included, six of which were added in this update of the review. Selective outcome reporting was unclear in all nine included studies due to inadequate reporting of study design and conduct, and there was high risk of bias for incomplete outcome data in three studies. The overall risk of bias across the nine studies was low for the other domains.Participants who were randomised to electromagnetic field treatment rated their pain relief 15.10 points more on a scale of 0 to 100 (MD 15.10, 95% CI 9.08 to 21.13; absolute improvement 15%) after 4 to 26 weeks' treatment compared with placebo. Electromagnetic field treatment had no statistically significant effect on physical function (MD 4.55, 95% CI -2.23 to 11.32; absolute improvement 4.55%) based on the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) scale from 0 to 100 after 12 to 26 weeks' treatment. We also found no statistically significant difference in quality of life on a scale from 0 to 100 (SMD 0.09, 95% CI -0.36 to 0.54; absolute improvement 0.09%) after four to six weeks' treatment, based on the SF-36. No data were available for analysis of radiographic changes. Safety was evaluated in four trials including up to 288 participants: there was no difference in the experience of any adverse event after 4 to 12 weeks of treatment compared with placebo (RR 1.17, 95% CI 0.72 to 1.92). There was no difference in participants who withdrew because of adverse events (measured in one trial) after four weeks of treatment (RR 0.90, 95% CI 0.06 to 13.92). No participants experienced any serious adverse events. AUTHORS' CONCLUSIONS: Current evidence suggests that electromagnetic field treatment may provide moderate benefit for osteoarthritis sufferers in terms of pain relief. Further studies are required to confirm whether this treatment confers clinically important benefits in terms of physical function and quality of life. Our conclusions are unchanged from the previous review conducted in 2002.

Toxic effects of three strobilurins (trifloxystrobin, azoxystrobin and kresoxim-methyl) on mRNA expression and antioxidant enzymes in grass carp (Ctenopharyngodon idella) juveniles.

The strobilurins are used widely in the world as effective fungicidal agents to control Asian soybean rust. In this study, the early life stage of grass carp (Ctenopharyngodon idella), which is one of the most important aquaculture species in China, was chosen to measure the acute toxicity of three common strobilurin-derived fungicides (trifloxystrobin (TFS), azoxystrobin (AZ) and kresoxim-methyl (KM)). As endpoints, normal developmental parameters (lethal concentration (LC50) and average heart rate), expression of relative genes, and three antioxidant enzyme activities in the developing juveniles were recorded during a 48 h exposure. The results revealed that values of LC50 were TFS 0.051 (0.046-0.058) mg L⁻¹, AZ 0.549 (0.419-0.771) mg L⁻¹ and KM 0.338 (0.284-0.407) mg L⁻¹ for juveniles. For the potential toxicity mechanisms, these three fungicides increased catalase (CAT) and peroxidase (POD) activity and decreased superoxide dismutase (SOD) activity, significantly inhibited expressions of three growth-related genes (IGF-1, IGF-2 and GHR) and two energy-related-genes (CCK and PYY), and caused pronounced up-regulation a stress-gene (HSP70). The present study demonstrated potential toxic effects of TFS, AZ and KM on the early development of C. idella. Overall, three strobilurins (TFS, AZ and KM) might cause serious damages to the aquatic species; therefore, their pollution supervision in water ecological environment should be strengthened.

Lactate-induced protein lactylation: A bridge between epigenetics and metabolic reprogramming in cancer.

Lactate is not only an endpoint of glycolysis but is gradually being discovered to play the role of a universal metabolic fuel for energy via the 'lactate shuttle' moving between cells and transmitting signals. The glycolytic-dependent metabolism found in tumours and fast-growing cells has made lactate a pivotal player in energy metabolism reprogramming, which enables cells to obtain abundant energy in a short time. Moreover, lactate can provide favourable conditions for tumorigenesis by shaping the acidic tumour microenvironment, recruiting immune cells, etc. and the recently discovered lactate-induced lactylation moves even further on pro-tumorigenesis mechanisms of lactate production, circulation and utilization. As with other epigenetic modifications, lactylation can modify histone proteins to alter the spatial configuration of chromatin, affect DNA accessibility and regulate the expression of corresponding genes. What's more, the degree of lactylation is inseparable from the spatialized lactate concentration, which builds a bridge between epigenetics and metabolic reprogramming. Here, we review the important role of lactate in energy reprogramming, summarize the latest finding of lactylation in tumorigenesis and try to explore therapeutic strategies in oncotherapy that can kill two birds with one stone.

Virtual Screening of Nrf2 Dietary-Derived Agonists and Safety by a New Deep-Learning Model and Verified In Vitro and In Vivo.

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an essential regulatory target of antioxidants, but the lack of Nrf2 active site information has hindered discovery of new Nrf2 agonists from food-derived compounds by large-scale virtual screening. Two deep-learning models were separately trained to screen for Nrf2-agonists and safety. The trained models screened potentially active chemicals from approximately 70,000 dietary compounds within 5 min. Of the 169 potential Nrf2 agonists identified via deep-learning screening, 137 had not been reported before. Six compounds selected from the new Nrf2 agonists significantly increased (p < 0.05) the activity of Nrf2 on carbon tetrachloride (CCl4)-intoxicated HepG2 cells (nicotiflorin (99.44 ± 18.5%), artemetin (97.91 ± 8.22%), daidzin (87.73 ± 3.77%), linonin (74.27 ± 5.73%), sinensetin (72.74 ± 10.41%), and tectoridin (77.78 ± 4.80%)), and their safety were demonstrated by an MTT assay. The safety and Nrf2 agonistic activity of nicotiflorin, artemetin, and daidzin were also reconfirm by a single-dose acute oral toxicity study and CCl4-intoxicated rat assay.

Inhibitory effect of p53 upregulated modulator of apoptosis targeting siRNA on hypoxia/reoxygenation-induced cardiomyocyte apoptosis in rats.

OBJECTIVES: The effect of p53 upregulated modulator of apoptosis (PUMA) in hypoxia/reoxygenation-induced cardiomyocyte injuries in rats was investigated. METHODS: PUMA-targeting (si-PUMA) and scramble siRNAs were designed and transfected into primarily rat cardiomyocytes in vitro. RESULTS: RT-PCR and Western blot analysis showed that 50 nmol/l of si-PUMA can specifically inhibit PUMA expression. MTT assay and lactate dehydrogenase activity detection showed that the cell survival rate in the si-PUMA group was enhanced and that the lactate dehydrogenase enzymatic activity dramatically decreased compared with the control group (p < 0.01). Spectrophotometry, as well as annexin V and propidium iodide staining, combined with flow cytometry, revealed that caspase-3 activity in the si-PUMA group was downregulated and the apoptotic rate was decreased (p < 0.01). RT-PCR also showed that Bax expression was downregulated and Bcl-2 expression was upregulated in the si-PUMA group, compared with the control group (p < 0.05). si-PUMA protects cardiomyocytes from apoptosis. CONCLUSION: PUMA mediates hypoxia/reoxygenation-induced cardiomyocyte apoptosis, which can be a potential target of gene therapy for ischemia/reperfusion cardiomyocyte injuries.

[Role of caspase-8 in stem cell transplantation alleviates rat cerebral cortex apoptosis after cardiopulmonary resuscitation].

OBJECTIVE: To explore the effects and the possible mechanism of bone marrow mesenchymal stem cell (BMMSC) transplantation on apoptosis in rats cerebral cortex after cardiac arrest/cardiopulmonary resuscitation (CA/CPR). METHODS: The BMMSC of 2 Sprague-Dawley (SD) rats aged 4-5weeks was extracted, and the 3rd passage was used in experimental study. Eighteen Sprague-Dawley (SD) rats were divided into sham group, model group (CA/CPR group) and intervention group (BMMSC group) according to random number table method, with 6 rats in each group. CPR was performed 6 minutes after asphyxia induced CA. In sham group, CA was not induced except performing general surgical procedure. At 1 hour after return of spontaneous circulation (ROSC), 0.5 mL phosphate buffered saline (PBS) was injected through tail vein in CA/CPR group. 2×109/L green fluorescence protein (GFP)-labeled BMMSC was injected through tail vein 1 hour after ROSC in BMMSC group. Neurological deficit score (NDS) were assessed in every group at 72 hours after CPR. Serum S100 calcium binding protein B (S100B) levels were assayed by enzyme linked immunosorbent assay (ELISA). Distribution of BMMSC in brain was observed under a fluorescent microscope. Apoptosis rate in cerebral cortex was assayed by TdT-mediated dUTP nick-end labeling (TUNEL). Western blotting was performed to measure the expression levels of active aspartic acid specific cysteine proteinase (caspase-8 and caspase-9) in cerebral cortex. RESULTS: At 3 days after CPR, compared with sham group, the apoptosis of cerebral cortex cells was increased and brain damage was obvious, NDS score was decreased significantly (56.6±5.5 vs. 80.0±0.0, P < 0.05), and serum S100B was increased markedly (ng/L: 45.1±4.7 vs. 19.1±1.4, P < 0.05), apoptosis rate of cerebral cortex cells increased significantly [(52.9±11.8)% vs. (10.1±1.5)%, P < 0.05], the level of active caspase-8 expression in cerebral cortex was significantly higher (caspase-8/GAPDH: 0.689±0.047 vs. 0.330±0.108, P < 0.05), and there was no significant difference in active caspase-9 protein expression (caspase-9/GAPDH: 0.428±0.014 vs. 0.426±0.021, P > 0.05) in CA/CPR group. After BMMSC transplantation, GFP-labeled BMMSC were primarily detected in cerebral cortex, compared with CA/CPR group, the apoptosis of cerebral cortex cells and brain injury were significantly improved in BMMSC group, NDS score increased significantly (70.6±2.1 vs. 56.6±5.5, P < 0.05), serum S100B levels in BMMSC group were lower (ng/L: 32.0±3.2 vs. 45.1±4.7, P < 0.05), apoptosis rate of cerebral cortex cells decreased significantly [(31.1±3.4)% vs. (52.9±11.8)%, P < 0.05], and the active caspase-8 expression in cerebral cortex in BMMSC group was significantly decreased (caspase-8/GAPDH: 0.427±0.067 vs. 0.689±0.047, P < 0.05). The active caspase-9 expression in cerebral cortex in BMMSC group and CA/CPR group were not significantly different (caspase-9/GAPDH: 0.431±0.022 vs. 0.428±0.014, P > 0.05). CONCLUSIONS: BMMSC transplantation can alleviate rat brain damage after CA/CPR possibly by inhibiting the death receptor mediated apoptotic pathway to inhibit the apoptosis of brain cells.