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Traditionally, many coatings were merely concentrated on settling the inherent fire protection problem of steel structures, while surface contamination and corrosion susceptibility should also be considered. Concurrently addressing these problems in fireproof efficiency and surface multifunctionality has become an issue of great significance in further expanding the application value in industrial and daily scenarios. Based on this condition, ecofriendly, graphene-based, and superhydrophobic coatings with multifunctional integration were constructed on steel via a one-step spraying method. The as-prepared coatings mainly consist of epoxy resin (EP), silicone resin (SR), a cyclodextrin-based flame retardant (MCDPM), expandable graphite (EG), and multilayered graphene (MG). The results demonstrate that the water contact angle (WCA) and water sliding angle (WSA) of as-prepared coatings can reach 156.8 ± 1.6 and 5.8 ± 0.7°, respectively, revealing good water repellency and self-cleaning properties. The coatings can also exhibit adequate adaptability for various substrates including wood, polyurethane foam, and cotton fabrics. Besides, good durability and robustness of coatings have been also verified via acid/alkali immersion, outdoor exposure, O 2 /plasma etching, and linear abrasion tests. Simultaneously, the coatings can exhibit excellent anticorrosion capacity for steel materials via a double barrier effect. Most importantly, the coatings have exhibited the lowest backside temperature (234.5 °C) during fire impact tests, suggesting excellent fireproof and heat insulation performance. This fact can be ascribed to the conjunct action between the physical/chemical charring process of flame retardants and the remarkable thermal stability of graphene. Consequently, this article can be expected to further promote the development and application of multifunctional-integrated coatings for steel structures in more fields.

Fungal azaphilones have attracted widespread attention due to their significant potential as sources of food pigments and pharmaceuticals. Genome mining and gene cluster activation represent powerful tools and strategies for discovering novel natural products and bioactive molecules. Here, a putative azaphilone biosynthetic gene cluster lut from the endophytic fungus Talaromyces sp. was identified through genome mining. By overexpressing the pathway-specific transcription factor LutB, five new sclerotiorin-type azaphilones ( 1 , 6 , 8 , and 10 - 11 ) together with seven known analogues ( 2 - 5 , 7 , 9 , 12 ) were successfully produced. Compounds 8 and 9 exhibited antibacterial activity against Bacillus subtilis with MIC values of 64 and 16 μg/mL, respectively. Compound 11 showed cytotoxic activity against HCT116 and GES-1 with IC 50 values of 10.9 and 4.9 μM, respectively, while 1 , 4 , 5 , and 7 - 10 showed no obvious cytotoxic activity. Gene inactivation experiments confirmed the role of the lut cluster in the production of compounds 1 - 12 . Subsequent feeding experiments unveiled the novel functional diversity of the dual megasynthase system. Furthermore, a LutC-LutD binary oxidoreductase system was discovered, and in combination with DFT calculations, the basic biosynthetic pathway of the sclerotiorin-type azaphilones was characterized. This study provided a good example for the discovery of new azaphilones and further uncovered the biosynthesis of these compounds.

Background: Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease and is associated with high mortality rates. The influence of routine clinical parameters on DKD onset in patients with type 2 diabetes mellitus (T2DM) remains uncertain., Methods: In this systematic review and meta-analysis, we searched multiple databases, including PubMed, Embase, Scopus, Web of Science, and Cochrane Library, for studies published from each database inception until January 11, 2024. We included cohort studies examining the association between DKD onset and various clinical parameters, including body mass index (BMI), hemoglobin A1c (HbA1c), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and serum uric acid (UA). Random-effect dose-response meta-analyses utilizing one-stage and/or cubic spline models, were used to estimate correlation strength. This study is registered in PROSPERO (CRD42022326148)., Findings: This analysis of 46 studies involving 317,502 patients found that in patients with T2DM, the risk of DKD onset increased by 3% per 1 kg/m 2 increase in BMI (relative risk (RR) = 1.03, confidence interval (CI) [1.01-1.04], I 2  = 70.07%; GRADE, moderate); a 12% increased risk of DKD onset for every 1% increase in HbA1c (RR = 1.12, CI [1.07-1.17], I 2  = 94.94%; GRADE, moderate); a 6% increased risk of DKD onset for every 5 mmHg increase in SBP (RR = 1.06. CI [1.03-1.09], I 2  = 85.41%; GRADE, moderate); a 2% increased risk of DKD onset per 10 mg/dL increase in TG (RR = 1.02, CI [1.01-1.03], I 2  = 78.45%; GRADE, low); an 6% decreased risk of DKD onset per 10 mg/dL increase in HDL (RR = 0.94, CI [0.92-0.96], I 2  = 0.33%; GRADE, high), and a 11% increased risk for each 1 mg/dL increase in UA (RR = 1.11, CI [1.05-1.17], I 2  = 79.46%; GRADE, moderate). Subgroup analysis revealed a likely higher risk association of clinical parameters (BMI, HbA1c, LDL, and UA) in patients with T2DM for less than 10 years., Interpretation: BMI, HbA1c, SBP, TG, HDL and UA are potential predictors of DKD onset in patients with T2DM. Given high heterogeneity between included studies, our findings should be interpreted with caution, but they suggest monitoring of these clinical parameters to identify individuals who may be at risk of developing DKD., Funding: Shenzhen Science and Innovation Fund, the Hong Kong Research Grants Council, and the HKU Seed Funds, and Scientific and technological innovation project of China Academy of Chinese Medical Sciences., Competing Interests: All authors declare no competing interests., (© 2024 The Author(s).)

Background and Aims: The common characteristics of alcohol-associated liver injury (ALI) include abnormal liver function, infiltration of inflammatory cells, and generation of oxidative stress. The gastrin-releasing peptide receptor (GRPR) is activated by its neuropeptide ligand, gastrin-releasing peptide (GRP). GRP/GRPR appears to induce the production of cytokines in immune cells and promotes neutrophil migration. However, the effects of GRP/GRPR in ALI are unknown., Approach and Results: We found high GRPR expression in the liver of patients with alcohol-associated steatohepatitis and increased pro-GRP levels in peripheral blood mononuclear cells of these patients compared with that of the control. Increased expression of GRP may be associated with histone H3 lysine 27 acetylation induced by alcohol, which promotes the expression of GRP and then GRPR binding. Grpr-/- and Grprflox/floxLysMCre mice alleviated ethanol-induced liver injury with relieved steatosis, lower serum alanine aminotransferase, aspartate aminotransferase, triglycerides, malondialdehyde, and superoxide dismutase levels, reduced neutrophil influx, and decreased expression and release of inflammatory cytokines and chemokines. Conversely, the overexpression of GRPR showed opposite effects. The pro-inflammatory and oxidative stress roles of GRPR might be dependent on IRF1-mediated Caspase-1 inflammasome and NOX2-dependent reactive oxygen species pathway, respectively. In addition, we verified the therapeutic and preventive effects of RH-1402, a novel GRPR antagonist, for ALI., Conclusions: A knockout or antagonist of GRPR during excess alcohol intake could have anti-inflammatory and antioxidative roles, as well as provide a platform for histone modification-based therapy for ALI., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Tylosin is a 16-membered macrolide antibiotic widely used in veterinary medicine to control infections caused by Gram-positive pathogens and mycoplasmas. To improve the fermentation titer of tylosin in the hyperproducing Streptomyces xinghaiensis strain TL01, we sequenced its whole genome and identified the biosynthetic gene cluster therein. Overexpression of the tylosin efflux gene tlrC , the c luster- s ituated S -adenosyl methionine (SAM) synthetase gene metK cs , the SAM biosynthetic genes adoK cs - metF cs , or the pathway-specific activator gene tylR enhanced tylosin production by 18%, 12%, 11%, and 11% in the respective engineered strains TLPH08-2, TLPH09, TLPH10, and TLPH12. Co-overexpression of metK cs and adoK cs - metF cs as two transcripts increased tylosin production by 22% in the resultant strain TLPH11 compared to that in TL01. Furthermore, combinational overexpression of tlrC , metK cs , adoK cs - metF cs , and tylR as four transcripts increased tylosin production by 23% (10.93g/L) in the resultant strain TLPH17 compared to that in TL01. However, a negligible additive effect was displayed upon combinational overexpression in TLPH17 as suggested by the limited increment of fermentation titer compared to that in TLPH08-2. Transcription analyses indicated that the expression of tlrC and three SAM biosynthetic genes in TLPH17 was considerably lower than that of TLPH08-2 and TLPH11. Based on this observation, the five genes were rearranged into one or two operons to coordinate their overexpression, yielding two engineered strains TLPH23 and TLPH24, and leading to further enhancement of tylosin production over TLPH17. In particular, the production of TLPH23 reached 11.35 g/L. These findings indicated that the combinatorial strategy is a promising approach for enhancing tylosin production in high-yielding industrial strains., Competing Interests: The authors indicate that they have no conflict of interest., (© 2023 The Authors.)

Background: Buyang Huanwu Decoction (BHD) is a classical Chinese Medicine formula empirically used for diabetic nephropathy (DN). However, its therapeutic efficacies and the underlying mechanisms remain obscure. In our study, we aim to evaluate the renoprotective effect of BHD on a streptozotocin (STZ)-induced diabetic nephropathy mouse model and explore the potential underlying mechanism in mouse mesangial cells (MCs) treated with high glucose in vitro, followed by screening the active compounds in BHD., Methods: Mice were received 50 mg/kg streptozotocin (STZ) or citrate buffer intraperitoneally for 5 consecutive days. BHD was intragastrically administrated for 12 weeks starting from week 4 after the diabetes induction. The quality control and quantitative analysis of BHD were studied by high-performance liquid chromatography (HPLC). Renal function was evaluated by urinary albumin excretion (UAE) using ELISA. The mesangial matrix expansion and renal fibrosis were measured using periodic acid-schiff (PAS) staining and Masson Trichrome staining. Mouse mesangial cells (MCs) were employed to study molecular mechanisms., Results: We found that the impaired renal function in diabetic nephropathy was significantly restored by BHD, as indicated by the decreased UAE without affecting the blood glucose level. Consistently, BHD markedly alleviated STZ-induced diabetic glomerulosclerosis and tubulointerstitial injury as shown by PAS staining, accompanied by a reduction of renal inflammation and fibrosis. Mechanistically, BHD inhibited the activation of TGF-β1/Smad3 and NF-κB signaling in diabetic nephropathy while suppressing Arkadia expression and restoring renal Smad7. We further found that calycosin-7-glucoside (CG) was one of the active compounds from BHD, which significantly suppressed high glucose-induced inflammation and fibrosis by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways in mesangial cells., Conclusion: BHD could attenuate renal fibrosis and inflammation in STZ-induced diabetic kidneys via inhibiting TGF-β1/Smad3 and NF-κB signaling while suppressing the Arkadia and restoring renal Smad7. CG could be one of the active compounds in BHD to suppress renal inflammation and fibrosis in diabetic nephropathy., (© 2021. The Author(s).)

We designed and fabricated a novel high throughput brain-on-chip with three dimensional structure with the aim to simulate the in vivo three-dimensional growth environment for brain tissues. The chip consists of a porous filter and 3D brain cell particles, and is loaded into a conventional 96-well plate for use. The filter and the particle molds were fabricated by using computer modeling, 3D printing of positive mold and agarose-PDMS double reversal mold. The 3D cell particles were made by pouring and solidifying a suspension of mouse embryonic brain cells with sodium alginate into a cell particle mold, and then cutting the resulting hydrogel into pieces. The loaded brain-on-chip was used to determine the neurotoxicity of pesticides. The cell particles were exposed to 0, 10, 30, 50, 100 and 200 µmol/L of chlorpyrifos or imidacloprid, separated conveniently from the medium by removing the porous filter after cultivation. Subsequently, cell proliferation, acetylcholinesterase activity and lactate dehydrogenase release were determined for toxicity evaluation. The embryonic brain cells were able to grow and proliferate normally in the hydrogel particles loaded into the filter in a 96-well plate. Pesticide neurotoxicity test showed that both chlorpyrifos and imidacloprid presented dose-dependent inhibition on cell growth and proliferation. Moreover, the pesticides showed inhibition on acetylcholinesterase activity and increase release of lactate dehydrogenase. However, the effect of imidacloprid was significantly weaker than that of chlorpyrifos. In conclusion, a novel brain-on-chip was developed in this study, which can be used to efficiently assess the drug neurotoxicity, pharmacodynamics, and disease mechanism by combining with a microtiterplate reader.

Photo-sensitive probes based on coumarin deserve extensive attention because of their high biocompatibility, quantum yield, and stability. The synthesis of coumarin and its derivatives is mainly based on four classical methods: Perkin synthesis, Knoevenagel synthesis, Wittig synthesis, and Pechmann synthesis. As everyone knows, fluorescent probes consist of a recognition group, a bridging group, and a luminescent group. Mechanism of fluorescent probes can be roughly summarized into four models: Chelation-induced enhanced fluorescence (CHEF), intramolecular charge transfer (ICT), photoinduced electron transfer (PET), and aggregation-induced luminescence (AIE), which can instruct the design of coumarin-based photo-sensitive probes. Since the fluorescence-based probe was first reported, probes based on coumarin have found widespread application in analytical chemistry, proving to be a selective, efficient, and convenient tool in ion monitoring, molecular monitoring, cell imaging, drug delivery, and many other fields. In this critical review, the synthetic routes of these compounds and the design for fluorescent probes were reported. Furthermore, the recent researches on the employment of coumarin in analytical chemistry were also introduced. Finally, the future research trends and application foreground of coumarin derivatives were forecasted herein.

A high-efficiency strategy for resin-free and large scale liquid phase synthesis of the anti-SARS octapeptide AVLQSGFR is described. Herein, tri(4'-diphenylphosphonyloxylbenzoyl phenyl)phosphate (TDPBP) derivatives were designed as C-terminal supports to aid octapeptide intermediate purification without the need for chromatographic separation. Furthermore, the ACE inhibitory structure-activity relationship (SAR) of the anti-SARS octapeptide and its alanine-scanning analogues was systematically studied by in vitro assay and 3D-QSAR via molecular docking. This paper provides a new strategy for the development of peptide-based drugs. Simultaneously, a study on the ACE inhibition and structure-activity relationship of the anti-SARS octapeptide also lays a foundation for further understanding how the anti-SARS octapeptide acts as an ACE inhibitor.

To seek the novel application of organophosphorus compounds, the designed tri(4-formylphenyl) phosphonate (TFP) derivatives were successfully synthesized herein, which were used as C-terminal protecting groups of amino acid or greener triple-equivalent supports in liquid-phase peptide synthesis (LPPS). Through the support-aided precipitation effect of TFP derivatives, the peptide intermediates during peptide synthesis were separated and collected via rapid precipitation and facile filtration without chromatographic purification. Furthermore, the TFP derivative support can be directly recycled for reuse without further regeneration after being sheared from the target peptide.

Plecanatide is an oral guanylate cyclase-C agonist for the treatment of gastrointestinal disorders. The large-scale supply of plecanatide is restrained primarily by its industrial manufacture. Herein we developed diphenylphosphinyloxyl diphenyl ketone (DDK) derivatives as greener supports with unique precipitation-inducing properties to aid the liquid-phase total synthesis of plecanatide without the use of chromatography. Plecanatide could be obtained in high yield, and the ultimately sheared DDK derivative residue could be directly recycled or regenerated for reuse.

Acute liver injury (ALI) is characteristic of abrupt hepatic dysfunction and inflammatory response. Activaion of Kupffer cells (KCs) plays a central role in the pathogenesis of ALI. Since the High Mobility Group A protein2 (HMGA2) occurs as a driver at critical stage of hepatocellular carcinoma, herein, we investigated the role of HMGA2 in macrophage activation during ALI. Our study found that the expression of HMGA2 decreased dramatically both in KCs isolated from the liver in mice with ALI and in LPS-induced RAW264.7 cell lines. Moreover, loss- and gain-of-function studies suggested that HMGA2 could enhance the expression of pro-inflammatory cytokines including TNF-α, IL-6 and IL-1β. These results indicated that HMGA2 may play an essential role in macrophage activation during ALI. Additionally, our results showed the expression of HMGA2 was up-regulated when LPS-induced RAW264.7 cells were treated with 5-aza-2-deoxycytidine. Furthermore, silencing of DNMT1, DNMT3a, DNMT3b could respectively prevent the down-expression of HMGA2 in LPS-induced RAW264.7 cells. In conclusion, HMGA2 promotes the release of pro-inflammatory cytokines through NF-κB pathway, and the dysregulation of HMGA2 may involve with hypermethylation., (Copyright © 2017. Published by Elsevier Inc.)

Three new compounds were isolated from the adult insect of Allomyrina dichotoma L. for the first time. A new skeleton compound is named as Allomyrinanoid A (1) originated from the familiar norbornane derivatives and two new compounds of purine alkaloid are named as adenine-9-methylaldehyde oxime B (2) and 6-N-methyleneimine-adenine-9-methylaldehyde oxime B (3). The compounds (2) and (3) are the tautomers of imine-enamine and creatively separated form the solvent using column chromatography method. The structures of all isolated compounds were established by spectroscopic methods including analyses of their 1D, 2D NMR and HRESI-MS data, and confirmed by comparison of the literature data. These new components displayed antibacterial activities against both Gram-positive and Gram-negative strain., (Copyright © 2015. Published by Elsevier Ltd.)

Objective: To observe the change of the gene expression of N-methyl-D-aspartate receptors (NMDAR) subunits in rat hippocampus after scalding., Methods: The backs of the rats were shaved and immersed in warm water for 10 sec. to make control group (C), and the backs shaved and immersed in hot water (90 degrees C) for 10 sec to make 30% full skin scalding model as the scalding group (S). The mRNA expression of the subunits of rat hippocampus NMDAR-NMDAR1, NMDAR2A, NMDAR2B, NMDAR2D was determined with RT-PCR technique in C group and at 0.5, 1, 2 and 4 postburn hours (PBHs) in S group., Results: (1) There exhibited no obvious change of the mRNA expression of all the subunits of NMDAR at 0.5 and 1 PBH in S group when compared with that in C group. But the mRNA expression of NMDAR1 increased for 24.3% and 20.9% and that of NMDAR2A increased for 27.8% and 27.6% at 2 and 4 PBHs respectively when compared with that in C group (P < 0.05). In addition, the mRNA expression of NMDAR2B and NMDAR2D revealed no change after scalding., Conclusion: The receptor channel constructed by NMDAR1/NMDAR2A demonstrated increased mRNA expression at 2 PBH, which might lead to the further opening of NMDAR after scalding which might participate in the maladjustment of HPA axis during scalding stress and the following pathophysiological changes.