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Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 μM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 μM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg -1 ·d -1 , i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE -/- mice (20, 60 mg·kg -1 ·d -1 , i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg -1 ·d -1 , i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Five isocoumarin derivatives including three new compounds, aspermarolides A-C ( 1-3 ), and two known analogues, 8-methoxyldiaporthin ( 4 ) and diaporthin ( 5 ) were obtained from the culture extract of Aspergillus flavus CPCC 400810. The structures of these compounds were elucidated by spectroscopic methods. The double bond geometry of 1 and 2 were assigned by the coupling constants. The absolute configuration of 3 was determined by electronic circular dichroism experiment. All compounds showed no cytotoxic activities against the two human cancer cells HepG2 and Hela.

In this paper, we present the discovery of a novel salicylic acid derivative, moldavica acid A ( 1 ), and a new natural dibenzo[b,f]oxepin, moldavica acid B ( 2 ), together with four known phenylpropionic acids ( 3 - 6 ) and protocatechuic acid ( 7 ) that were isolated from Dracocephalum moldavica L. Their structures were elucidated by comprehensive spectroscopic methods, including infrared and nuclear magnetic resonance. Compound 1 is the first example of salicylic acid linking a carboxylated α -pyrone via an ethyl bridge. Beyond expanding the knowledge of the chemical diversity of D. moldavica , both compounds 1 and 2 were shown to upregulate the expression of Kruppel-like factor 2, which could serve as a prospective therapeutic target for the treatment of atherosclerosis.

Background: Increasing evidence has suggested an association of adiponectin gene polymorphisms rs1501299, rs2241766, rs266729 and rs3774261 with risk of nonalcoholic fatty liver disease (NAFLD). This correlation has been extensively meta-analyzed for the first two polymorphisms, but not the second two., Methods: The PubMed, EMBASE, Google Scholar, and China National Knowledge Infrastructure databases were searched for relevant literature. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated., Results: A total of 10 case-control studies on rs266729 (2,619 cases and 1,962 controls) and 3 case-control studies on rs3774261 (562 cases and 793 controls) were included. Meta-analysis showed that rs266729 was associated with significantly higher NAFLD risk based on the following five models: allelic, OR 1.72, 95% CI 1.34-2.21, P < 0.001; recessive, OR 2.35, 95% CI 1.86-2.95, P < 0.001; dominant, OR 1.84, 95% CI 1.34-2.53, P < 0.001; homozygous, OR 2.69, 95% CI 1.84-3.92, P < 0.001; and heterozygous, OR 1.72, 95% CI 1.28-2.32, P < 0.001. This association between rs266729 and NAFLD risk remained significant for all five models among studies with Asian, Chinese and Caucasian samples. The rs2241766 polymorphism was associated with significantly higher NAFLD risk according to the recessive model (OR 1.87, 95% CI 1.15-3.04, P = 0.01)., Conclusion: Polymorphisms rs266729 and rs3774261 in the adiponectin gene may be risk factors for NAFLD. These findings may pave the way for novel therapeutic strategies, but they should be verified in large, well-designed studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zheng, Xiao, Wu, Cheng and Li.)

In this work, we isolated and characterized fusapyrone A ( 1 ), a new γ -pyrone derivative, along with six previously described compounds from the rice fermentation of Fusarium sp. CPCC 401218, a fungus collected from the desert. The structure of 1 was characterized using various spectroscopic analyses, such as MS, IR, 1D, and 2D NMR. The absolute configuration of 1 was determined through the use of 13 C NMR chemical shifts, electronic circular dichroism (ECD) and optical rotation (OR) calculations. Compound 1 was found to have weak antiproliferative activity for Hela cells, with an IC 50 of 50.6 μM.[Formula: see text].

Shirasu porous glass (SPG) membranes have been applied for microbubble aeration in aerobic wastewater treatment. In the present study, both hydrophilic and hydrophobic SPG membranes were used in a microbubble-aerated biofilm reactor with online chemical cleaning, and their membrane fouling and chemical durability were determined to be strongly dependent on the membrane wettability. The fouling layer formed on the surface of both membranes was confirmed to be mainly organic fouling, and the hydrophobic membrane showed a relatively stronger resistance to the organic fouling. The severe chemical corrosion of the hydrophilic membrane was observed due to exposure to the alkaline sodium hypochlorite solution used for chemical cleaning, which resulted in significant increases in the median pore diameter and the porosity. On the other hand, the pore structure of the hydrophobic membrane changed slightly when exposed to the alkaline sodium hypochlorite solution, suggesting its strong alkali-resistance due to the non-wetting surface. However, the surface hydrophobic groups of hydrophobic membrane could be oxidized by sodium hypochlorite solution, resulting in more wettable membrane surface. The hydrophobic membrane also showed better performance in the respects of oxygen transfer, contaminant removal and energy-saving. Therefore, the hydrophobic membrane seemed more appropriate to be applied for microbubble aeration in aerobic wastewater treatment process.

Membrane-aerated biofilm reactor (MABR) represent a novel membrane-biological wastewater treatment technology. In addition, bioaugmented treatment using genetically engineered microorganism (GEM) biofilm in MABR is proposed to improve refractory pollutant removal. In the present study, a SPG membrane aerated-biofilm reactor (SPG-MABR) with GEM biofilm formed on the SPG membrane surface was applied to treat atrazine wastewater. The influences of air pressure, biofilm biomass and liquid velocity on the performance of the SPG-MABR were investigated. The variation of GEM biofilm during the SPG-MABR operation was observed. The results indicated that the increased air pressure could promote atrazine and COD removal as well as re-oxygenation by increasing oxygen permeability coefficient. A higher biofilm biomass could also enhance atrazine and COD removal, but simultaneously reduce the re-oxygenation rate because biofilm thickness and oxygen transfer resistance increased. When liquid velocity in the SPG-MABR was decreased under laminar flow condition, atrazine and COD removal was improved due to the facilitated contaminant diffusion from wastewater to biofilm. The atrazine removal efficiency reached to 98.6% in the SPG-MABR after 5d treatment at air pressure of 300 kPa, biofilm biomass of 25 g x m(-2) and liquid velocity of 0.05 m x s(-1). The microbial polymorphism of GEM biofilm was observed during the SPG-MABR operation. The surface of GEM biofilm was gradually covered by other microbial cells and the distribution of GEM cells reduced, but inside the GEM biofilm, the GEM cells were still dominant.

Simultaneous nitrification and denitrification (SND) is a new wastewater treatment process for biological nitrogen removal, which shows some significant advantages compared with conventional biological nitrogen removal processes. The SND process in a fixed bed biofilm reactor with microbubble aeration was investigated in this study. The removal efficiencies of COD and nitrogen were determined under different operational conditions and the functional bacterial populations for nitrogen removal in the biofilm were detected. The results showed that efficient SND process could be achieved in the biofilm reactor with microbubble aeration. The SND could be improved at lower dissolved oxygen (DO) concentration and larger porosity of packing bed when the COD loading rate and C/N ratio were increased. The removal efficiencies of COD and total nitrogen (TN) were 97.6% and 70.2%, respectively, at a COD loading rate of 0.86 kg x (m3 x d)(-1), a TN loading rate of 0.10 kg x (m3 x d)(-1), and a packing bed porosity of 81%, indicating the simultaneous efficient removal of COD and TN. Under these conditions, the oxygen utilization efficiency reached as high as 91.8% due to the enhanced oxygen mass transfer by microbubble aeration. In addition, the biofilm activity and the abundance of nitrifiers and denitrifiers were consistent with the removal capacity of COD, ammonia and TN under different operational conditions.