Comparative Analysis of the Anti-Inflammatory Effects of Liraglutide and Dulaglutide.

Inflammation plays a pathophysiological role in atherosclerosis and its clinical consequences. In addition to glycemic control, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are of wide concern for cardioprotective effects. The structure, half-life, homology, and clinical efficacy of GLP-1RAs exhibit remarkable disparity. Several studies have compared the disparities in anti-inflammatory effects between daily and weekly GLP-1RAs. This study aimed to compare the similarities and differences between liraglutide and dulaglutide in terms of inhibiting atherosclerotic inflammation and improving co-cultured endothelial cell function. The expression of inflammation markers was examined by immunofluorescence, Western blotting, and real-time PCR. The tube-forming ability of endothelial cells was tested on Matrigel. The results verify that 10/50/100 nmol/L liraglutide and 100 nmol/L dulaglutide markedly suppressed the expression of inflammatory factors in LPS-induced atherosclerosis after 24 and 72 hours, respectively. Moreover, they promoted the polarization of M1 macrophages toward the M2 phenotype and improved the function of co-cultured endothelial cells. Both liraglutide and dulaglutide ameliorate atherosclerosis development. The difference between the two resided in the extended intervention duration required to observe the effect of dulaglutide, and liraglutide demonstrated a superior dose-dependent manner. We provide a potential strategy to understand the dynamics of drug action and possible timing administration.

Antimicrobial and Antioxidant Polyketides from a Deep-Sea-Derived Fungus Aspergillus versicolor SH0105.

Fifteen polyketides, including four new compounds, isoversiol F (1), decumbenone D (2), palitantin B (7), and 1,3-di-O-methyl-norsolorinic acid (8), along with 11 known compounds (3-6 and 9-15), were isolated from the deep-sea-derived fungus Aspergillus versicolor SH0105. Their structures and absolute configurations were determined by comprehensive spectroscopic data, including 1D and 2D NMR, HRESIMS, and ECD calculations, and it is the first time to determine the absolute configuration of known decumbenone A (6). All of these compounds were evaluated for their antimicrobial activities against four human pathogenic microbes and five fouling bacterial strains. The results indicated that 3,7-dihydroxy-1,9-dimethyldibenzofuran (14) displayed obvious inhibitory activity against Staphylococcus aureus (ATCC 27154) with the MIC value of 13.7 µM. In addition, the antioxidant assays of the isolated compounds revealed that aspermutarubrol/violaceol-I (15) exhibited significant 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity with the IC50 value of 34.1 µM, and displayed strong reduction of Fe3+ with the ferric reducing antioxidant power (FRAP) value of 9.0 mM under the concentration of 3.1 µg/mL, which were more potent than ascorbic acid.

Intermittent protein restriction before but not after the onset of diabetic kidney disease attenuates disease progression in mice.

Background: High dietary protein intake exacerbates proteinuria in individuals with diabetic kidney disease (DKD). However, studies on the impacts of low protein diet (LPD) on DKD have yielded conflicting results. Furthermore, patient compliance to continuous protein restriction is challenging. Objective: The current study aims to investigate the effects of intermittent protein restriction (IPR) on disease progression of DKD. Methods: Diabetic KK-Ay mice were used in this study. For the IPR treatment, three consecutive days of LPD were followed by four consecutive days of normal protein diet (NPD) within each week. For early intervention, mice received IPR before DKD onset. For late intervention, mice received IPR after DKD onset. In both experiments, age-matched mice fed continuous NPD served as the control group. Kidney morphology, structure and function of mice in different groups were examined. Results: Intermittent protein restriction before DKD onset ameliorated pathological changes in kidney, including nephromegaly, glomerular hyperfiltration, tubular injuries and proteinuria, without improving glycemic control. Meanwhile, IPR initiated after DKD onset showed no renoprotective effects despite improved glucose homeostasis. Conclusion: Intermittent protein restriction before rather than after DKD onset protects kidneys, and the impacts of IPR on the kidneys are independent of glycemic control. IPR shows promise as an effective strategy for managing DKD and improving patient compliance.

Serum branched chain amino acids: an effective indicator of diabetic kidney disease.

Introduction: In recent years, there has been a growing association between elevated circulating levels of branched-chain amino acids (BCAA) and diabetes mellitus. However, the relationship between serum BCAA levels and diabetic kidney disease (DKD) remains ambiguous. This study aims to investigate serum BCAA levels in DKD patients at various stages and assess the correlation between BCAA and clinical characteristics. Materials and methods: We enrolled patients with type 2 diabetes mellitus (T2DM) who were admitted to our hospital and categorized them into three groups based on different DKD stages: normal proteinuria, microproteinuria, and macroalbuminuria groups. Forty healthy volunteers were included as the control group, and we measured serum BCAA concentrations using liquid chromatography-mass spectrometry (LC-MS). Subsequently, we conducted correlation and regression analyses to assess the associations between BCAA and clinical indicators. Results: Serum BCAA levels were significantly elevated in T2DM patients compared to healthy controls. However, these levels exhibited a gradual decline with the progression of DKD. Furthermore, after adjusting for age, gender, and disease duration, we observed an independent association between serum albumin, urinary transferrin, and urinary microalbumin with BCAA. Discussion: Our findings suggest a noteworthy decline in serum BCAA levels alongside the advancement of DKD. Additionally, serum BCAA exhibits an independent correlation with renal function indicators. These observations point to the possibility that serum BCAA concentrations in individuals with T2DM hold promise as a crucial predictor for both the initiation and progression of DKD.

Design and syntheses of a bimolecular STING agonist based on the covalent STING antagonist.

Cyclic GMP-AMP synthase and stimulator of interferon genes (cGAS-STING) signaling stimulators, an essential innate immunity component, monitor invading pathogen DNA and damaged self-DNA, making them an appealing target for drug development. The natural STING agonist, 2'3'-cGAMP, mounts and stabilizes the STING homodimer to trigger an antiviral or antitumor immune responses. However, cyclic-dinucleotide-based STING agonists show limited clinical effects owing to their short half-lives. To explore whether STING-dimer stabilizers could trigger STING signaling instead of cyclic dinucleotide-based molecules, we analyzed the structural characteristics of STING to design and synthesize a series of compounds based on the covalent STING inhibitor C-170, three of which were 23, 26, and 27, exhibited STING-dependent immune activation, both in vitro and in vivo. Compound 23 could act synergistically with cGAMP and other STING agonists as a promising moderate STING agonist. This indicates that promoting STING dimerization is a promising strategy for designing next-generation STING agonists.

Co-culture: stimulate the metabolic potential and explore the molecular diversity of natural products from microorganisms.

Microbial secondary metabolites have long been considered as potential sources of lead compounds for medicinal use due to their rich chemical diversity and extensive biological activities. However, many biosynthetic gene clusters remain silent under traditional laboratory culture conditions, resulting in repeated isolation of a large number of known compounds. The co-culture strategy simulates the complex ecological environment of microbial life by using an ecology-driven method to activate silent gene clusters of microorganisms and tap their metabolic potential to obtain novel bioactive secondary metabolites. In this review, representative studies from 2017 to 2020 on the discovery of novel bioactive natural products from co-cultured microorganisms are summarized. A series of natural products with diverse and novel structures have been discovered successfully by co-culture strategies, including fungus-fungus, fungus-bacterium, and bacterium-bacterium co-culture approaches. These novel compounds exhibited various bioactivities including extensive antimicrobial activities and potential cytotoxic activities, especially when it came to disparate marine-derived species and cross-species of marine strains and terrestrial strains. It could be concluded that co-culture can be an effective strategy to tap the metabolic potential of microorganisms, particularly for marine-derived species, thus providing diverse molecules for the discovery of lead compounds and drug candidates.

A new epimer of azaphilone derivative pinophilin B from the gorgonian-derived fungus Aspergillus fumigatus 14-27.

A new epimer of azaphilone derivative pinophilin B, epi-pinophilin B (1), and three known analogues (2-4) were obtained from the culture of the gorgonian-derived fungus Aspergillus fumigatus 14-27. The structures of 1-4, including their relative configurations were determined by extensive spectroscopic analysis and comparing with literature data. The absolute configuration of 1 was determined by electronic circular dichroism (ECD) and optical rotatory (OR) calculations methods. Compounds 1-4 were isolated from A. fumigatus for the first time. Their antibacterial and cytotoxic activities were also evaluated.