Antifungal activity of ruthenium (II) complex combined with fluconazole against drug-resistant Candida albicans in vitro and its anti-invasive infection in vivo.

With the abuse of antibiotics and azoles, drug-resistant Candida albicans infections have increased sharply and are spreading rapidly, thereby significantly reducing the antifungal efficacy of existing therapeutics. Several patients die of fungal infections every year. Therefore, there is an urgent requirement to develop new drugs. Accordingly, we synthesized a series of polypyridyl ruthenium (II) complexes having the formula [Ru (NN)2 (bpm)] (PF6)2 (N-N = 2,2'-bipyridine) (bpy, in Ru1), 1,10-phenanthroline (phen, in Ru2), 4,7-diphenyl-1,10-phenanthroline (DIP, in Ru3) (bpm = 2,2'-bipyrimidine) and studied their antifungal activities. Ru3 alone had no effect on the drug-resistant strains, but Ru3 combined with fluconazole (FLC) exhibited significant antifungal activity on drug-resistant strains. A high-dose combination of Ru3 and FLC exhibited direct fungicidal activity by promoting the accumulation of reactive oxygen species and damaging the cellular structure of C. albicans. Additionally, the combination of Ru3 and FLC demonstrated potent antifungal efficacy in vivo in a mouse model of invasive candidiasis. Moreover, the combination significantly improved the survival state of mice, restored their immune systems, and reduced renal injury. These findings could provide ideas for the development of ruthenium (II) complexes as novel antifungal agents for drug-resistant microbial stains.

Antipyretic effects of Xiangqin Jiere granules on febrile young rats revealed by combining pharmacodynamics, metabolomics, network pharmacology, molecular biology experiments and molecular docking strategies.

Xiangqin Jiere granules (XQJRG) is a proprietary Chinese medicine treating children's colds and fevers, but its mechanism of action is unclear. The aim of this study was to explore the antipyretic mechanisms of XQJRG based on pharmacodynamics, non-targeted metabolomics, network pharmacology, molecular biology experiments, molecular docking, and molecular dynamics (MD) simulation. Firstly, the yeast-induced fever model was constructed in young rats to study antipyretic effect of XQJRG. Metabolomics and network pharmacology studies were performed to identify the key compounds, targets and pathways involved in the antipyretic of XQJRG. Subsequently, MetScape was used to jointly analyze targets from network pharmacology and metabolites from metabolomics. Finally, the key targets were validated by enzyme-linked immunosorbent assay (ELISA), and the affinity and stability of key ingredient and targets were evaluated by molecular docking and MD simulation. The animal experimental results showed that after XQJRG treatment, body temperature of febrile rats was significantly reduced, 13 metabolites were significantly modulated, and pathways of differential metabolite enrichment were mainly related to amino acid and lipid metabolism. Network pharmacology results indicated that quercetin and kaempferol were the key active components of XQJRG, TNF, AKT1, IL6, IL1B and PTGS2 were core targets. ELISA confirmed that XQJRG significantly reduced the plasma concentrations of IL-1ß, IL-6, and TNF-α, and the hypothalamic concentrations of COX-2 and PGE2. Molecular docking demonstrated that the binding energies of kaempferol to the core targets were all below -5.0 kcal/mol. MD simulation results showed that the binding free energies of TNF-kaempferol, IL6-kaempferol, IL1B-kaempferol and PTGS2-kaempferol were -87.86 kcal/mol, -70.41 kcal/mol, -69.95 kcal/mol and -106.67 kcal/mol, respectively. In conclusion, XQJRG has antipyretic effects on yeast-induced fever in young rats, and its antipyretic mechanisms may be related to the inhibition of peripheral pyrogenic cytokines release by constituents such as kaempferol, the reduction of hypothalamic fever mediator production, and the amelioration of disturbances in amino acid and lipid metabolism.Communicated by Ramaswamy H. Sarma.

Three new diterpenoids isolated from Euphorbia nematocypha Hand.-Mazz and their anti-fungal activity.

Three new diterpenoids, named nematocynine A-C (1-3), together with twelve known compounds (4-15) were isolated from the aerial part of Euphorbia nematocypha Hand.-Mazz (Hereinafter referred to E. nematocypha). Their structures were elucidated by detailed spectroscopic analysis and comparison with literature data. In addition, all the compounds were tested for their anti-candida albicans activities used alone or in combination with fluconazole against sensitive strain and resistant strain in vitro. Wherein only compound 11 shows weak activity against candida albicans resistant strain (MIC50 = 128.15 µg/mL) when used alone. Compounds 1, 4, 7, 8, 9, 10, 12, 13 and 15 in combination with fluconazole showed potent anti-fungal activities (MIC50 = 15 ± 5 µg/mL, FICI = 0.05 ± 0.04) against the Candida albicans resistant strain SC5314-FR. The synergistic effects were weaker against the Candida albicans resistant strain SC5314-FR when the compounds 2, 3, 5 and 14 were combined with fluconazole (FICI = 0.16 ± 0.06).

Synthesis and Antifungal Evaluation of New Azole Derivatives against Candida albicans.

In this study, we designed and prepared a series of new azole derivatives by recombination of fluconazole (FLC) and ketoconazole units, and in vitro antifungal activities against Candida albicans were evaluated. The results indicated that most azoles showed good antifungal activity against the drug-sensitive C. albicans strain, especially compounds 6a, 6e, 6n, 6p, 6r, 6s, 6t, and 6v, which displayed better antifungal activity (MIC50 < 1.0 µg/mL) than FLC against SC5314. The further mechanism study showed that compound 6r could significantly inhibit the formation of C. albicans biofilm, increase the permeability of the cell membrane, reduce the ergosterol level of the cell membrane, damage the membrane structure, and destroy the integrity of the cell structure to exert excellent antifungal activity. Subsequently, a molecular docking study indicated that azole compounds could inhibit cytochrome P450 14α-demethylase (CYP51). Therefore, these azole derivatives can be considered as potent antifungal drugs to treat fungal infections.

Cyclometalated iridium(III) complexes combined with fluconazole: antifungal activity against resistant C. albicans.

Candida albicans (C. albicans) is a ubiquitous clinical fungal pathogen. In recent years, combination therapy, a potential treatment method to overcome C. albicans resistance, has gained traction. In this study, we synthesized a series of cyclometalated iridium(III) complexes with the formula [Ir(C-N)2(tpphz)](PF6) (C-N = 2-phenylpyridine (ppy, in Ir1), 2-(2-thienyl)pyridine (thpy, in Ir2), 2-(2,4-difluorophenyl) pyridine (dfppy, in Ir3), tpphz = tetrapyrido[3,2-a:2',3'-c:3'',2''-h:2''',3'''-j]phenazine) and polypyridyl ruthenium(II) complexes with the formula [Ru(N-N)2(tpphz)](PF6)2 (N-N = 2,2'-bipyridine (bpy, in Ru1), 1,10-phenanthroline (phen, in Ru2), 4,7-diphenyl-1,10-phenanthroline (DIP, in Ru3)), and investigated their antifungal activities against drug-resistant C. albicans and their combination with fluconazole (FLC). Of which, the combination of the lead iridium(III) complex Ir2 and FLC showed strong antifungal activity against drug-resistant C. albicans. Mechanism studies have shown that they can inhibit the formation of hyphae and biofilm, damage mitochondrial function and accumulate intracellular ROS. Therefore, iridium(III) complexes combined with FLC can be used as a promising treatment to exert anti-drug-resistant C. albicans activity, in order to improve the treatment efficiency of fungal infection.

Lactobacillus murinus: A key factor in suppression of enterogenous Candida albicans infections in Compound Agrimony enteritis capsules-treated mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Agrimony (FuFangXianHeCao, FFXHC) Enteritis Capsules is an ethnomedicine that is derived from Yi Nationality Herbal Medicine for enteritis treatment. We found that FFXHC reduced the mortality outcomes in enterogenic Candida albicans infected mice models and increased the abundance of Lactobacillus murinus in the intestines. Lactobacillus murinus exhibited comparable therapeutic effects to those of FFXHC in enterogenic Candida albicans infected mice. This study provides novel perspectives into the pharmacological mechanisms of FFXHC. AIM OF THE STUDY: We investigated the mechanisms via which FFXHC inhibits C. albicans infections and its effects on L. murinus. MATERIALS AND METHODS: Enterogenous C. albicans infection mice models were established and various parameters, including survival rate, weight change, number of colonies, treatment effects on intestinal mucosa, microecology, and immune cytokines evaluated. Susceptibility of C. albicans to L. murinus was evaluated in vitro. RESULTS: Treatment with FFXHC reduced the number of colonies, improved the health status, enhanced the survival rates, increased the abundance of L. murinus, reduced damage to the intestinal mucosa, and elevated occludin as well as claudin-1 levels. Interestingly, TNF-α, IFN-γ, IL-10, IL-22, and IL-17A levels were increased while IL-1ß levels were suppressed in the intestinal mucosa without any change in peripheral blood cytokine levels. Moreover, FFXHC promoted L. murinus proliferation. This study also confirmed the incubation-dependent anti-C. albicans effects exerted by the metabolic supernatants of L. murinus. CONCLUSIONS: FFXHC effectively alleviated intestinal infections of C. albicans in mice and increased the abundance of L. murinus. Supplementation of L. murinus in food can achieve the effects that are comparable to those of FFXHC. Thus, L. murinus maybe essential in FFXHC-based treatment of intestinal C. albicans infections.