Antifungal activity and potential mechanism of action of Huangqin decoction against Trichophyton rubrum.

Introduction. Trichophyton rubrum is a major causative agent of superficial dermatomycoses such as onychomycosis and tinea pedis. Huangqin decoction (HQD), as a classical traditional Chinese medicine formula, was found to inhibit the growth of common clinical dermatophytes such as T. rubrum in our previous drug susceptibility experiments.Hypothesis/Gap Statement. The antifungal activity and potential mechanism of HQD against T. rubrum have not yet been investigated.Aim. The aim of this study was to investigate the antifungal activity and explore the potential mechanism of action of HQD against T. rubrum.Methodology. The present study was performed to evaluate the antifungal activity of HQD against T. rubrum by determination of minimal inhibitory concentrations (MICs), minimal fungicidal concentrations (MFCs), mycelial growth, biomass, spore germination and structural damage, and explore its preliminary anti-dermatophyte mechanisms by sorbitol and ergosterol assay, HPLC-based ergosterol test, enzyme-linked immunosorbent assay and mitochondrial enzyme activity test.Results. HQD was able to inhibit the growth of T. rubrum significantly, with an MIC of 3.125 mg ml-1 and an MFC of 12.5 mg ml-1. It also significantly inhibited the hyphal growth, conidia germination and biomass growth of T. rubrum in a dose-dependent manner, and induced structural damage in different degrees for T. rubrum cells. HQD showed no effect on cell wall integrity, but was able to damage the cell membrane of T. rubrum by interfering with ergosterol biosynthesis, involving the reduction of squalene epoxidase (SE) and sterol 14α-demethylase P450 (CYP51) activities, and also affect the malate dehydrogenase (MDH), succinate dehydrogenase (SDH) and ATPase activities of mitochondria.Conclusion. These results revealed that HQD had significant anti-dermatophyte activity, which was associated with destroying the cell membrane and affecting the enzyme activities of mitochondria.

Dulaglutide Protects Mice against Diabetic Sarcopenia-Mediated Muscle Injury by Inhibiting Inflammation and Regulating the Differentiation of Myoblasts.

Background: Type 2 diabetes mellitus increases the risk of sarcopenia, which is characterized by decreased muscle mass, strength, and function. However, there are no effective drugs to treat diabetic sarcopenia, and its underlying mechanism remains unknown. Here, we aimed to determine whether the GLP-1 receptor agonist (GLP-1RA) dulaglutide (Dul) affects the progression of diabetic sarcopenia. Methods: db/db mice were injected intraperitoneally with 0.6 mg/kg dulaglutide for 10 weeks. Mouse muscle tissues were then pathologically evaluated and stained with F4/80 or MPO to detect macrophages and neutrophils, respectively. In addition, inflammatory factors and FNDC5 in the muscle tissues were detected using qRT-PCR. Moreover, C2C12 cells were induced to enable their differentiation into skeletal muscle cells, and muscle factor levels were then detected. Furthermore, changes in muscle factor levels were detected at various glucose concentrations (11 mM, 22 mM, and 44 mM). Results: In vivo, dulaglutide alleviated muscle tissue injury; reduced levels of the inflammatory factors, IL-1ß, IL-6, CCL2, and CXCL1; and reversed the level of FNDC5 in the muscle tissues of db/db mice. In vitro, a C2C12 cell differentiation model was established through the observation of cell morphology and determination of myokine levels. Upon stimulation with high glucose, the differentiation of C2C12 cells was inhibited. Dulaglutide improved this inhibitory state by upregulating the levels of both FNDC5 mRNA and protein. Conclusions: Treatment with the GLP-1RA dulaglutide protects db/db mice against skeletal muscle injury by inhibiting inflammation and regulating the differentiation of myoblasts. High glucose inhibited the differentiation of C2C12 cells and decreased the mRNA and protein levels of myokines. Dulaglutide could reverse the differentiation state induced in C2C12 cells by high glucose.

Dulaglutide provides protection against sepsis-induced lung injury in mice by inhibiting inflammation and apoptosis.

Sepsis is a dangerous condition with a high mortality rate. In addition to promoting insulin secretion in a glucose-dependent manner, glucagon-like peptide-1 (GLP-1) also exhibits anti-inflammatory properties. Dulaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA). In this study, we investigated the effects and mechanism of action of dulaglutide (Dul) in lipopolysaccharide (LPS) induced lung injury in mice with sepsis. In mice with LPS (15 mg/kg, ip, qd)-induced acute lung injury, the administration of dulaglutide (0.6 mg/kg, ip, qd) improved weight loss, reduced lung injury, reversed the increase in IL-1ß, TNF-α, IL-6, CXCL1, CCL2 and CXCL2 expression in the lung, and reduced the infiltration of neutrophils and macrophages in the lung tissues. The decline in caspase-3, cleaved caspase-3, caspase-8, and Bcl-2/Bax expression and the increase in the number of TUNEL positive cells in the lung were reversed, suggesting that GLP-1RA could play a protective role in the lung by inhibiting inflammation and apoptosis. In addition, GLP-1RA could reduce the expression of P-STAT3 and NLRP3, suggesting that P-STAT3 and NLRP3 may be potential targets against lung injury in sepsis. Collectively, our data demonstrated that GLP-1RA exerts a protective effect against sepsis-induced lung injury through mechanisms related to the inhibition of inflammation, apoptosis, and STAT3 signaling.

High Prevalence of HIV-Related Cryptococcosis and Increased Resistance to Fluconazole of the Cryptococcus neoformans Complex in Jiangxi Province, South Central China.

Background: Cryptococcosis is caused by a fungi of the Cryptococcus neoformans/Cryptococcus gattii complex and is a severe concern for public health worldwide. C. neoformans species are globally distributed, and C. gattii species are mostly found in America, Australia, and Sub-Saharan Africa. Cryptococcus usually infects an immunocompromised population; however, the majority of cryptococcosis in China has been reported in patients without any recognizable immunosuppression, i.e., HIV infection. To date, very few studies investigated this disease in South Central China. Methods: The present study recruited 230 clinically suspected cryptococcosis cases in the last 5 years at two hospitals in Jiangxi Province, South Central China. All isolated strains were subjected to multilocus sequence typing (MLST) and phylogenetic analysis. Serotype and mating type were assessed by PCR, in vitro antifungal susceptibility was assessed by the CLSI-M27-A3 protocol. Results: A total of 230 patients were identified as infected by C. neoformans, including 12 cases with Talaromyces marneffei coinfection. All seven MLST markers were successfully amplified and used to identify the ST genotype in 199 strains. C. gattii strains were not detected. In contrast to previous studies, 59.3% of the patients had an immunocompromised status, and 61.9% of these patients were infected with HIV. All isolates manifested serotype A and mating type α. The ST5 genotype was common (89.5%) in the Jiangxi region, and three novel genotypes (ST656, ST657, and ST658 in six isolates) were detected in the present study. A total of 86 of the isolates (43.2%) were not sensitive to fluconazole at a MIC50 ≥ 8 µg/ml, most of the isolates were resistant to amphotericin B, and nearly all isolates were resistant to itraconazole and posaconazole. Resistances to 5-Flucytosine and voriconazole were very rare. Conclusions: The results of the present study indicated that C. neoformans is the predominant species for cryptococcosis in Jiangxi Province, and a large proportion of the strains were not sensitive to fluconazole, which may be related to treatment failure and relapse. A high percentage of HIV-related C. neoformans infections was reported in Jiangxi, supporting a previous hypothesis that cryptococcosis is more frequent among the HIV-infected population in China. Continuous monitoring of species distribution and antifungal sensitivity is important for the investigation of this severe disease in the Jiangxi region.

Density functional theory calculations for resveratrol.

The calculations based on the density functional theory (DFT) have been used to study the structure-activity of resveratrol in the chain reaction of autooxidation. According to the geometry obtained by using a B3LYP/6-31G**, the HOMO, LUMO of resveratrol and the spin density, the single electron distribution of the 4'- and 5-radical of resveratrol were calculated, it was found that resveratrol is a potential antioxidant. The 4'-hydroxyl group of resveratrol is more reactive than 3- and 5-positions because of the resonance effects. The dominant structure of the resveratrol radicals is a semiquinone structure which determines the stability of radicals, and the unpaired electron is mainly distributed to the O-atom and its ortho and para positions. The antioxidant activity of resveratrol is related to the spin density and the unpaired electron distribution of the O-atom.