The emergence of natural products as potential therapeutics for male infertility.

Infertility is a major reproductive health problem. Approximately 50% of all documented cases of infertility are attributable to male factors, such as poor testicular function and semen quality. The recent significant global decline in sperm counts has serious implications for male fertility, but the armamentarium for improving testicular function and semen quality is limited. Natural products have a wide range of activities and are a major source of drugs for disease prevention and treatment. To provide ideas and a theoretical basis for the research and development of therapeutic drugs for male infertility, this review summarizes natural products (mostly monomers) that have been shown to improve testicular function and semen quality and their possible mechanisms of action. These natural products primarily improve testicular function and semen quality via antioxidant, antiapoptotic, and anti-inflammatory effects, in addition to increasing serum testosterone and reducing DNA damage in spermatozoa and testicular cells. Prospects for the application of natural products in the treatment of male infertility are discussed.

Biosynthetic pathways and related genes regulation of bioactive ingredients in mulberry leaves.

Mulberry leaves are served not only as fodder for silkworms but also as potential functional food, exhibiting nutritional and medical benefits due to the complex and diverse constituents, including alkaloids, flavonoids, phenolic acids, and benzofurans, which possess a wide range of biological activities, such as anti-diabete, anti-oxidant, anti-inflammatory, and so on. Nevertheless, compared with the well-studied phytochemistry and pharmacology of mulberry leaves, the current understanding of the biosynthesis mechanisms and regulatory mechanisms of active ingredients in mulberry leaves remain unclear. Natural resources of these active ingredients are limited owing to their low contents in mulberry leaves tissues and the long growth cycle of mulberry. Biosynthesis is emerging as an alternative means for accumulation of the desired high-value compounds, which can broaden channels for their large-scale green productions. Therefore, this review summarizes the recent research advance on the correlative key genes, enzyme biocatalytic reactions and biosynthetic pathways of valuable natural ingredients (i.e. alkaloids, flavonoids, phenolic acids, and benzofurans) in mulberry leaves, thereby offering important insights for their further biomanufacturing.

Synergistic effect of eravacycline combined with fluconazole against resistant Candida albicans in vitro and in vivo.

BACKGROUND: The limited availability of antifungal drugs for candidiasis and the persistent problem of drug resistance, necessitates the urgent development of new antifungal drugs and alternative treatment options. RESEARCH DESIGN AND METHODS: This study examined the synergistic antifungal activity of the combination of eravacycline (ERV) and fluconazole (FLC) both in vitro by microdilution checkerboard assay and in vivo by Galleria mellonella model. The underlying synergistic mechanisms of this drug combination was investigated using RNA-sequencing and qPCR. RESULTS: ERV (2 µg/mL) + FLC (0.25-0.5 µg/mL) had strong synergistic antifungal activity against resistant Candida albicans (C. albicans) in vitro, as evidenced by a fractional inhibitory concentration index of 0.0044-0.0088. In vivo experiments in Galleria mellonella larvae infected with resistant C. albicans revealed that ERV (2 µg/larva) + FLC (1 µg/larva) improved survival rates and reduced fungal burden. The results of RNA-sequencing and qPCR showed that the mechanism of synergistic inhibition on resistant C. albicans was related to the inhibition of DNA replication and cell meiosis. CONCLUSIONS: These results indicate that the combination of ERV and FLC effectively inhibits resistant C. albicans both in vitro and in vivo and lay the foundation for a potential novel treatment option for candidiasis.

Synergy and Mechanism of Leflunomide Plus Fluconazole Against Resistant Candida albicans: An in vitro Study.

Objective: The global rise in the resistance of Candida albicans to conventional antifungals makes Candida albicans infections harder to treat. The main objective of this study was to investigate the antifungal effects and underlying mechanisms of leflunomide in combination with triazoles against resistant Candida albicans. Methods: In this study, the microdilution method was used to determine the antifungal effects of leflunomide in combination with three triazoles on planktonic cells in vitro. The morphological transition from yeast to hyphae was observed under a microscope. The effects on ROS, metacaspase, efflux pumps, and intracellular calcium concentration were investigated, respectively. Results: Our findings suggested that leflunomide + triazoles showed a synergistic effect against resistant Candida albicans in vitro. Further study concluded that the synergistic mechanisms were resulted from multiple factors, including the inhibited efflux of triazoles, the inhibition of yeast-to-hyphae transition, ROS increasing, metacaspase activation, and [Ca2+]i disturbance. Discussion: Leflunomide appears to be a potential enhancer of current antifungal agents for treating candidiasis caused by resistant Candida albicans. This study can also serve as an example to inspire the exploration of new approaches to treating resistant Candida albicans.

Synergistic potential of teriflunomide with fluconazole against resistant Candida albicans in vitro and in vivo.

Introduction: Candida albicans is the primary cause of systemic candidiasis, which is involved in high morbidity and mortality. Drug resistance exacerbates these problems. In addition, there are limited antifungal drugs available. In order to solve these problems, combination therapy has aroused great interest. Teriflunomide is an immunosuppressant. In the present work, we aimed to identify whether teriflunomide can reverse the resistance of Candida albicans in the presence of sub-inhibitory concentrations of fluconazole in vitro and in vivo. Methods: Seven Candida albicans isolates were used in this study. Susceptibility of Candida albicans in vitro to the drugs was determined using a checkerboard microdilution assay in accordance with the recommendations of the Clinical and Laboratory Standards Institute. The effects of drugs on biofilm biomass of Candida albicans were determined by crystal violet staining. The development ability of Candida albicans hyphae was performed using a modified broth microdilution method. Galleria mellonella was used for testing the in vivo efficacy of the combination therapies. Results: We found that the combination of teriflunomide (64 µg/mL) and fluconazole (0.5-1 µg/mL) has a significant synergistic effect in all resistant Candida albicans isolates (n=4). Also, this drug combination could inhibit the immature biofilm biomass and hyphae formation of resistant Candida albicans. Galleria mellonella was used for testing the in vivo efficacy of this combination therapies. As for the Galleria mellonella larvae infected by resistant Candida albicans, teriflunomide (1.6 µg/larvae) combined with fluconazole (1.6 µg/larvae) significantly increased their survival rates, and reduced the fungal burden, as well as damage of tissue in comparison to that in the control group or drug monotherapy group. Conclusion: These results expand our knowledge about the antifungal potential of teriflunomide as an adjuvant of existing antifungal drugs, and also open new perspectives in the treatment of resistant Candida albicans based on repurposing clinically available nonantifungal drugs.

Associations between various possible promoter polymorphisms of MMPs genes and endometriosis risk: a meta-analysis.

BACKGROUND: Endometriosis is a common, benign gynecological disorder affecting life quality of reproductive-aged women. Several polymorphisms in the promoter regions of the MMPs genes have been reported that were related to endometriosis risk. However, there are many contradictory conclusions, and no meta-analysis focused on this association systematically. OBJECTIVES: To evaluate the associations between various possible polymorphisms of MMPs genes and endometriosis risk, and confirm which kinds of MMPs genetic polymorphisms are associated with endometriosis risk, in order to identify the etiology and pathogenesis of endometriosis and the potential effective markers for predicting the predisposition to endometriosis. SEARCH STRATEGY: An exhaustive electronic literature search was conducted, using keywords MMP, endometriosis and SNP, in English and Chinese. SELECTION CRITERIA: All eligible case-control studies by written in English or Chinese of the associations of MMPs polymorphisms with endometriosis risk, which had sufficient data for examining an odds ratio (OR) with 95% confidence interval (CI), were identified up to March 1, 2015. DATA COLLECTION AND ANALYSIS: A total of 1833 patients and 2190 controls from 12 studies were included. Allele frequency differences between cases and controls were performed with the use of odds ratios (ORs) and their respective 95% confidence intervals (CIs) for five genetic models. MAIN RESULTS: For MMP-1 -1607 1G>2G (rs1799750) polymorphism, significant associations were observed both in overall comparison and subgroup analyses based on the stage of endometriosis, ethnicity of each study population and method of genotyping under four genetic models. In contrast, for MMP-2 15918 T>C (rs243847), MMP-2 -753 C>T (rs2285053), MMP-7 -181 A>G (rs11568818), MMP-9 -1562 C>T (rs3918242) and MMP-9 R279Q (rs17576) polymorphisms, no association was found in overall comparison, but in subgroup analyses based on source of control, stage of endometriosis, or ethnicity. CONCLUSIONS: MMP-1 -1607 1G>2G polymorphism might modulate risk of endometriosis, so does the MMP-2 15918 T>C, MMP-2 -753 C>T, MMP-7 -181 A>G, MMP-9 -1562 C>T and MMP-9 R279Q polymorphisms in some subgroups.