Summary
High‐osmolarity glycerol (HOG) pathway required for yeast osmoregulation relies upon the mitogen‐activated protein kinase (MAPK) Hog1 cascade that comprise the MAPKKKs Ssk2/Ssk22 and Ste11 ...converging on the MAPKK Pbs2. Here we show a Hog1 cascade with the unique MAPKKK Ssk2 acting in Beauveria bassiana. Hypersensitivity to high osmolarity and high resistance to fludioxonil fungicide appeared in Δssk2, Δpbs2 and Δhog1 mutants whereas the two hallmark phenotypes were reversed in Δste11. Increased sensitivity to heat shock and decreased sensitivity to cell wall perturbation also occurred in the three mutants but not in Δste11 although antioxidant phenotypes were different in all deletion mutants. Intriguingly, signals of Hog1 phosphorylation induced by osmotic, oxidative and thermal cues were present in Δste11 but absent in Δssk2 and Δpbs2. Moreover, vegetative growth on minimal media with different carbon/nitrogen sources was much more suppressed in Δste11 and Δssk2 than in Δpbs2 and Δhog1 although all mutants suffered similar, but severe, conidiation defects on a standard medium. Normal host infection was abolished in Δste11 while virulence was differentially attenuated in other mutants. Our findings exclude Ste11 from the Hog1 cascade that regulates multiple stress responses and environmental adaptation of B. bassiana and perhaps other filamentous fungi.
CD44 is a marker of cancer stem cell (CSC) in many types of tumors. Alternative splicing of its 20 exons generates various CD44 isoforms that have different tissue specific expression and functions, ...including the CD44 standard isoform (CD44s) encoded by the constant exons and the CD44 variant isoforms (CD44v) with variant exon insertions. Switching between the CD44v and CD44s isoforms plays pivotal roles in tumor progression. Here we reported a novel mechanism of CD44 alternative splicing induced by TGF-β1 and its connection to enhanced epithelial-to-mesenchymal transition (EMT) and stemness in human prostate cancer cells. TGF-β1 treatment increased the expression of CD44s and N-cadherin while decreased the expression of CD44v and E-cadherin in DU-145 prostate cancer cells. Other EMT markers and cancer stem cell markers were also upregulated after TGF-β1 treatment. RNAi knockdown of CD44 reversed the phenotype, which could be rescued by overexpressing CD44s but not CD44v, indicating the alternatively spliced isoform CD44s mediated the activity of TGF-β1 treatment. Mechanistically, TGF-β1 treatment induced the phosphorylation, poly-ubiquitination, and degradation of PCBP1, a well-characterized RNA binding protein known to regulate CD44 splicing. RNAi knockdown of PCBP1 was able to mimic TGF-β1 treatment to increase the expression of CD44s, as well as the EMT and cancer stem cell markers. In vitro and in vivo experiments were performed to show that CD44s promoted prostate cancer cell migration, invasion, and tumor initiation. Taken together, we defined a mechanism by which TGF-β1 induces CD44 alternative splicing and promotes prostate cancer progression.
Osteoarthritis (OA) is the most common form of arthritis and joint disorder worldwide. Metabolic reprogramming of osteoarthritic chondrocytes from oxidative phosphorylation to glycolysis results in ...the accumulation of lactate from glycolytic metabolite pyruvate by lactate dehydrogenase A (LDHA), leading to cartilage degeneration. In the present study, we investigated the protective effects of the intra-articular administration of oxamate (LDHA inhibitor) against OA development and glycolysis-related protein expression in experimental OA rats. The animals were randomly allocated into four groups: Sham, anterior cruciate ligament transection (ACLT), ACLT + oxamate (0.25 and 2.5 mg/kg). Oxamate-treated groups received an intra-articular injection of oxamate once a week for 5 weeks. Intra-articular oxamate significantly reduced the weight-bearing defects and knee width in ACLT rats. Histopathological analyses showed that oxamate caused significantly less cartilage degeneration in the ACLT rats. Oxamate exerts hypertrophic effects in articular cartilage chondrocytes by inhibiting glucose transporter 1, glucose transporter 3, hexokinase II, pyruvate kinase M2, pyruvate dehydrogenase kinases 1 and 2, pyruvate dehydrogenase kinase 2, and LHDA. Further analysis revealed that oxamate significantly reduced chondrocyte apoptosis in articular cartilage. Oxamate attenuates nociception, inflammation, cartilage degradation, and chondrocyte apoptosis and possibly attenuates glycolysis-related protein expression in ACLT-induced OA rats. The present findings will facilitate future research on LDHA inhibitors in prevention strategies for OA progression.
Guideline development should be based on the quality of evidence, balance of benefits and harms, economic evaluation and patients' views and preferences. Therefore, these factors were considered in ...the development of a new guideline for therapeutic drug monitoring (TDM) of vancomycin.
To develop an evidence-based guideline for vancomycin TDM and to promote standardized vancomycin TDM in clinical practice in China.
We referred to the WHO Handbook for Guideline Development and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to rate the quality of evidence and grade the strength of recommendations, according to economic evaluation and patients' views and preferences. We used the GRADE Grid method to formulate the recommendations.
The guideline presents recommendations about who should receive vancomycin TDM, how to monitor vancomycin efficacy and renal safety, therapeutic trough concentrations, time to start initial vancomycin TDM, loading dose and how to administer and adjust the vancomycin dose.
We developed an evidence-based guideline for vancomycin TDM, which provides recommendations for clinicians and pharmacists to conduct vancomycin TDM in China.
Introduction
Agarwood, a fragrant resinous wood mainly formed by Aquilaria spp., is used worldwide as a natural fragrance and traditional medicine. A large amount of Aquilaria sinensis (Lour.) Gilg ...leaves are underutilised during the process of the agarwood industry, and the development of A. sinensis leaves as tea has recently attracted more and more attention. However, the small molecule profile of A. sinensis leaves and their bioactivities has been rarely reported.
Objective
To conduct a rapid untargeted liquid chromatography–mass spectrometry (LC–MS) analysis of A. sinensis leaves with a molecular networking (MN) strategy and evaluate its antioxidant and antidiabetic value.
Method
A MN‐assisted tandem mass spectrometry (MS/MS) analysis strategy was used to investigate the small molecule profile of A. sinensis leaves. Additionally, the integration of antioxidant and α‐glucosidase inhibitory assays with MN analysis was executed to expeditiously characterise the bioactive compounds for potential prospective application.
Results
Five main chemical groups including phenol C‐glycosides, organic acids, 2‐(2‐phenylethyl) chromones, benzophenone O‐glycosides and flavonoids were rapidly revealed from the A. sinensis leaves. Eighty‐one compounds were provisionally identified by comparing their MS/MS fragments with canonical pathways. The featured xanthone C‐glycosides and benzophenone C‐glycosides were recognised as the primary components of A. sinensis leaves. Several dimers and a trimer of mangiferin were reported firstly in A. sinensis leaves. Furthermore, 17 and 14 potential bioactive molecules were rapidly annotated from antioxidant and α‐glucosidase inhibitory fraction, respectively.
Conclusion
Our findings will help expand the utilisation of A. sinensis leaves and thus promote the high‐quality development of agarwood industry.
The current work clarifies the phytochemical makeup of A. sinensis leaves using the MN strategy. The phenol C‐glycosides including xanthone C‐glycosides and benzophenone C‐glycosides were characterized as the primary components in the methanolic extract of A. sinensis leaves. Several dimers and a trimer of mangiferin were reported firstly in A. sinensis leaves in our research. Moreover, 17 and 14 potential bioactive molecules were rapidly annotated from antioxidant and α‐glucosidase inhibitory fraction through the integration of MN.
The proposal of the aggregation-induced emission (AIE) effect shines a light on the practical application of luminescent materials. The AIE-active luminescence microgels (TPEC MGs) with photo-induced ...color-changing behavior were developed by integrating positively charged AIE luminogens (AIEgens) into the anionic network of microgels, where AIEgens of TPEC were obtained from the quaternization reaction between tetra-(4-pyridylphenyl)ethylene (TPE-4Py) and 7-(6-bromohexyloxy)-coumarin. The aqueous suspensions of TPEC MGs exhibit a significant AIE effect following the enhancement of quantum yield. In addition, further increase in fluorescence intensity and blueshift occur at elevated temperatures due to the collapse of microgels. The distinctive photochromic behavior of TPEC MGs was observed, which presents as the transition from orange-yellow to blue-green color under UV irradiation, which is different from TPEC in good organic solvents. The phenomenon of color changing can be ascribed to the competition between photodimerization of the coumarin part and photocyclization of TPE-4Py in TPEC. The photochromic TPEC MG aqueous suspensions can be conducted as aqueous microgel inks for information display, encryption, and dynamic anticounterfeiting.
Secoisolariciresinol (SECO) is one of the major lignans occurring in various grains, seeds, fruits, and vegetables. The gut microbiota plays an important role in the biotransformation of dietary ...lignans into enterolignans, which might exhibit more potent bioactivities than the precursor lignans. This study aimed to identify, synthesize, and evaluate the microbial metabolites of SECO and to develop efficient lead compounds from the metabolites for the treatment of osteoporosis. SECO was fermented with human gut microbiota in anaerobic or micro-aerobic environments at different time points. Samples derived from microbial transformation were analyzed using an untargeted metabolomics approach for metabolite identification. Nine metabolites were identified and synthesized. Their effects on cell viability, osteoblastic differentiation, and gene expression were examined. The results showed that five of the microbial metabolites exerted potential osteogenic effects similar to those of SECO or better. The results suggested that the enterolignans might account for the osteoporotic effects of SECO in vivo. Thus, the presence of the gut microbiota could offer a good way to form diverse enterolignans with bone-protective effects. The current study improves our understanding of the microbial transformation products of SECO and provides new approaches for new candidate identification in the treatment of osteoporosis.
A ternary-salt solid polymer electrolyte (TS-SPE) consisting of LiPF
6
-LiTFSI-LiFSI salts and poly(1,3-dioxolane) is created by
in situ
polymerization. The TS-SPE possesses high ionic conductivity, ...high Li
+
ion transference number, and stable SEI with low interfacial impedance, thereby realizing excellent rate performance and long-life stability in Li metal batteries.
A ternary-salt solid polymer electrolyte consisting of LiPF
6
-LiTFSI-LiFSI salts and poly(1,3-dioxolane) was developed through an
in situ
polymerization for a stable Li metal anode.
•PGESs, especially mPGES-1 and mPGES-2, play important roles in the pathogenesis of liver diseases.•mPGES-1, an inflammation-inducible PGES, is involved in different liver diseases.•mPGES-2 has ...opposite effects on the liver disease models induced by STZ and APAP.•mPGES-1 may serve as a promising target for treating liver diseases because of less side effects.
Prostaglandin E synthases (PGESs) convert cyclooxygenase (COX)-derived prostaglandin H2 (PGH2) into prostaglandin E2 (PGE2) and comprise at least three types of structurally and biologically distinct enzymes. Two of these, namely microsomal prostaglandin E synthase-1 (mPGES-1) and mPGES-2, are membrane-bound enzymes. mPGES-1 is an inflammation-inducible enzyme that converts PGH2 into PGE2. mPGES-2 is a bifunctional enzyme that generally forms a complex with haem in the presence of glutathione. This enzyme can metabolise PGH2 into malondialdehyde and can produce PGE2 after its separation from haem. In this review, we discuss the role of PGESs, particularly mPGES-1 and mPGES-2, in the pathogenesis of liver diseases. A better understanding of the roles of PGESs in liver disease may aid in the development of treatments for patients with liver diseases.
The climatic characteristics of aneurysmal subarachnoid hemorrhage (aSAH) have been reported, but consensus has not yet been reached. It is of great significance to elucidate the relationships ...between meteorological variation and aSAH in regions with specific climate patterns. We analyzed the occurrence of aSAH in the capital city of Fujian Province, China, through a multicenter, 5-year study, and aimed to reveal the meteorological influences on aSAH in the coastal city of eastern Fujian under the subtropical marine monsoon condition.
A total of 2555 consecutive patients with aSAH in Fuzhou were collected using specialized stroke admission database from January 2013 to December 2017. Meteorological parameters including temperature, atmospheric pressure, and humidity were obtained from China Surface Meteorological Station during the same period. Poisson regression was used to explore the association between meteorological parameters and aSAH to calculate the incidence rate ratios (IRRs) with corresponding 95% confidence intervals (CIs). Generalized additive model analysis further revealed the nonlinear relationships between weather and aSAH.
Daily minimum temperature (IRR 0.976, 95% CI 0.958–0.996) and maximum pressure (IRR 1.022, 95% CI 1.001–1.042) were independently correlated with the onset of aSAH. Low temperature (below 16°C) and excessive atmospheric pressure (above 1008 hPa) increased the risk of aSAH. In addition, March in spring and December in winter were the 2 ictus peaks in Fuzhou throughout the year.
Cold and excessive atmospheric pressure are triggers for the occurrence of aSAH; March in spring and December in winter are the predominant onset periods in Fuzhou.
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