Secondary metabolites and their bioactivities from Paecilomyces gunnii YMF1.00003.

Four new polyketides (1-4) and seven known compounds (5-11) including three polyketides and four sterols were isolated from the fermented extracts of Paecilomyces gunnii YMF1.00003. The new chemical structures were determined through the analysis of the nuclear magnetic resonance and high-resolution electrospray ionization mass spectrometry, and their configurations were subsequently confirmed by nuclear overhauser effect spectroscopy, the calculated electronic circular dichroism (ECD) spectra, and quantum chemical calculations of the NMR data (qcc NMR). Based on the results of pre-activity screening and compound structure target prediction, certain metabolites were assayed to evaluate their cytotoxic and protein kinase Cα inhibitory activities. Results indicated that 3ß-hydroxy-7α-methoxy-5α,6α-epoxy-8(14),22E-dien-ergosta (8) exhibited potent cytotoxic activity, with half-maximal inhibitory concentration values of 3.00 ± 0.27 to 15.69 ± 0.61 µM against five tumor cells, respectively. The new compound gunniiol A (1) showed weak cytotoxic activity at a concentration of 40 µM. At a concentration of 20 µg/mL, compounds 1, 6, and 7 exhibited protein kinase Cα inhibition by 43.63, 40.93, and 57.66%, respectively. This study is the first to report steroids demonstrating good cytotoxicity and polyketides exhibiting inhibitory activity against protein kinase Cα from the extracts of P. gunnii.

Metabolites and Their Bioactivities from the Genus Cordyceps.

The Cordyceps genus is a group of ascomycete parasitic fungi, and all known species of this genus are endoparasites; they mainly feed on insects or arthropods and a few feed on other fungi. Fungi of this genus have evolved highly specific and complex mechanisms to escape their host's immune system and coordinate their life cycle coefficients with those of their hosts for survival and reproduction; this mechanism has led to the production of distinctive metabolites in response to the host's defenses. Herein, we review approximately 131 metabolites discovered in the genus Cordyceps (including mycelium, fruiting bodies and fungal complexes) in the past 15 years, which can be used as an important source for new drug research and development. We summarize chemical structures, bioactivity and the potential application of these natural metabolites. We have excluded some reports that originally belonged to Cordyceps, but whose taxonomic attribution is no longer the Cordyceps genus. This can and will serve as a resource for drug discovery.

Paeoniflorin-6'-o-benzene sulfonate ameliorates the progression of adjuvant-induced arthritis by inhibiting the interaction between Ahr and GRK2 of fibroblast-like synoviocytes.

Aryl hydrocarbon receptor (Ahr) is thought to be a crucial factor that regulates immune responses, which may be involved in the pathogenesis of autoimmune inflammation including rheumatoid arthritis (RA). The results of our group in recent years have shown that Paeoniflorin-6'-O-benzene sulfonate (code: CP-25), a novel ester derivative of paeoniflorin, has a good effect on improving RA animal models. However, whether the anti-arthritis effect of CP-25 is related to Ahr remains unclear. Here, we showed that CP-25 treatment ameliorated adjuvant-induced arthritis (AA), a rat model of RA, by inhibiting Ahr-related activities in fibroblasts like synoviocytes (FLS). AA rats were treated with CP-25 or paroxetine from days 17 to 33 after immunization. We showed that CP-25 alleviated arthritis symptoms and the pathological changes. Treatment with CP-25 decreased the expression of Ahr in the synovium of AA rats. CP-25 inhibited the expression of Ahr and the G protein-coupled receptor kinase 2 (GRK2) as well as the co-expression of GRK2 with Ahr in FLS of AA rats. Furthermore, CP-25 down-regulated the production of Kyn in FLS of AA rats. These results suggested that CP-25 may inhibit the expression and activation of Ahr. Besides, treatment with CP-25 reduced the proliferation and migration of MH7A caused by Ahr activation. In addition, we also demonstrated that CP-25 down-regulated the total and nuclear expression of Ahr and the expression of GRK2 in Kyn-treated MH7A. Moreover, the co-expression and co-localization of Ahr and GRK2in Kyn-treated MH7A were also repressed by CP-25. The data presented here demonstrated that CP-25 suppressed FLS dysfunction in rats with AA, which were associated with reduced Ahr activation and the interaction between Ahr and GRK2.

Stereumamides E-H, four new minor quaternary ammonium hybrids from Stereum hirsutum.

In our preview research, four novel quaternary ammonium hybrids were isolated from the Stereum hirsutum FP-91666. To further discover this type of compounds, S. hirsutum was fermented in 30 L YMG broth, and eight hybrid compounds including four new quaternary ammoniums were obtained, which are sesquiterpenes combined with α-amino acids. Their structures were elucidated by extensive spectroscopic analyses, including 1D- and 2D-NMR, and HR-MS experiments.

Sesquiterpenoids and their quaternary ammonium hybrids from the mycelium of mushroom Stereum hirsutum by medium optimization.

The fungal genus Stereum (Stereaceae) produces a broad variety of specialised metabolites, including a wide range of terpenes. This probably relates to the presence of an extensive biosynthetic machinery for this group of compounds: genomic analysis of Stereum hirsutum has identified 16 terpene synthase gene clusters, 6 polyketide synthase gene clusters, and 1 polyketide synthase non-ribosomal polypeptide heterodimer gene cluster in S. hirsutum FP-91666. In the present study, the One Strain Many Compounds (OSMAC) approach was employed to discover undescribed metabolites from this strain. Fermentation was carried out in five media and the products of the strain cultivated on different media were analyzed by LC-MS. From cultures grow in WGB medium (30.0 g wheat bran, 20.0 g glucose, 1.5 g KH2PO4, and 1.5 g MgSO4), four previously undescribed metabolites, a sesquiterpene sterostrein X and three mixed terpenes (stereumamides I-K) were isolated, together with seven known compounds (drimene-2,11-diol, stereumamide E, stereumamide D, stereumamide B, stereumamide A, stereumamide C, and sterostrein Q). The drimane-type sesquiterpene drimene-2,11-diol was found in S. hirsutum FP-91666 for the first time. All structures were elucidated by spectroscopic data analysis. The absolute configurations of stereumamides I, J and K were assigned by comparing their experimental and calculated electronic circular dichroism (ECD) spectra. An anti-Mycobacterium tuberculosis experiment showed that stereumamides I-K and sterostrein Q had weak antibacterial activity against this pathogen.

Hsp70 Gene Polymorphisms Are Associated With Disease Susceptibility and HRQOL Improvement in Chinese Han Population With Systemic Lupus Erythematosus.

OBJECTIVES: The aim of this study is to investigate whether heat shock protein 70 (Hsp70) gene polymorphisms are implicated in systemic lupus erythematous (SLE) susceptibility, the efficacy of glucocorticoids (GCs) treatment, and improvement of health-related quality of life. METHODS: A total of 499 SLE patients and 499 controls were included in a case-control study, and 468 SLE patients treated with GCs for 12 weeks were involved in a follow-up study. Patients who completed the 12-week follow-up were divided into GCs-sensitive and GCs-insensitive group by using the SLE disease activity index. The SF-36 was used to evaluate the health-related quality of life of SLE patients, and genotyping was performed by improved multiplex ligation detection reaction. RESULTS: rs2075800 was associated with SLE susceptibility (adjusted odds ratio [ORadj], 1.437; 95% confidence interval [CI], 1.113-1.855; Padj = 0.005; PBH = 0.020 by dominant model; ORadj, 1.602; 95% CI, 1.072-2.395; Padj = 0.022; PBH = 0.029 by TT vs CC model; ORadj = 1.396; 95% CI = 1.067-1.826; Padj = 0.015; PBH = 0.029 by TC vs CC model). In the follow-up study, rs2075799 was associated with the improvement in mental health (p = 0.004, PBH = 0.044), but we failed to find any association between the efficacy of GCs and Hsp70 gene polymorphisms. CONCLUSIONS: Hsp70 gene polymorphisms may be associated with susceptibility to SLE and improvement of mental health in Chinese Han population.

Association of oestrogen receptor alpha gene polymorphisms with systemic lupus erythematosus risk: An updated meta-analysis.

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex, chronic autoimmune disease, and oestrogen is considered to be a predisposing factor for SLE. Although some studies are conducted to explore the association between oestrogen receptor alpha (ERα) gene polymorphisms and SLE susceptibility, their results are inconsistent. METHODS: Meta-analysis was conducted to confirm whether ERα gene polymorphisms were associated with SLE susceptibility, and the strength of association was anticipated by pooled ORs with 95% CIs. Stata software package version 12.0 was used to calculate all the statistical analyses. RESULTS: Twelve studies included 2494 cases and 4176 controls were incorporated in our meta-analysis. A significant association was found for ERα PvuII polymorphism in the overall population (CC+CT vs TT: OR = 1.334, 95% CI = 1.195-1.490, P < 0.001; CC vs TT: OR = 1.401, 95% CI = 1.096-1.791, P = 0.007; CT vs TT: OR = 1.284, 95% CI = 1.141-1.444, P < 0.001; C vs T: OR = 1.221, 95% CI = 1.084-1.375, P = 0.001), while there was no significant association for ERα XbaI polymorphism. Besides, in stratification analyses by ethnicity, the PvuII polymorphism was associated with an increased risk of SLE in Asians (CC+CT vs TT: OR = 1.379, 95% CI = 1.203-1.581, P < 0.001; CT vs TT: OR = 1.308, 95% CI = 1.130-1.515, P < 0.001; C vs T: OR = 1.240, 95% CI = 1.052-1.462, P = 0.010), while for ESR1 XbaI polymorphism, a significantly increased risk of SLE susceptibility was found in Asians (GA vs AA: OR = 1.271, 95% CI = 1.101-1.467, P = 0.001). CONCLUSION: Our meta-analysis indicated that the ERα PvuII polymorphism was significantly associated with SLE susceptibility in the overall and Asian populations, while the ERα XbaI GA genotype only played a key role in SLE susceptibility in Asian populations.

Associations of HSP90AA2 gene polymorphisms with disease susceptibility, glucocorticoids efficacy and health-related quality of life in Chinese systemic lupus erythematosus patients.

Although the current glucocorticoids (GCs) treatment for systemic lupus erythematosus (SLE) is effective to a certain extent, the difference in therapeutic effect between patients is still a widespread problem. Some patients can have repeated attacks that greatly diminish their quality of life. This study was conducted to investigate the relationship between HSP90AA2 polymorphisms and disease susceptibility, GCs efficacy and health-related quality of life (HRQoL) in Chinese SLE patients. A case-control study was performed in 470 SLE patients and 470 normal controls. Then, 444 patients in the case group were followed up for 12 weeks to observe efficacy of GCs and improvement of HRQoL. Two single nucleotide polymorphisms (SNPs) of HSP90AA2 were selected for genotyping: rs1826330 and rs6484340. HRQoL was assessed using the SF-36 questionnaire. The minor T allele of rs1826330 and the TT haplotype formed by rs1826330 and rs6484340 showed associations with decreased SLE risk (T allele: PBH = 0.022; TT haplotype: PBH = 0.033). A significant association between rs6484340 and improvement of HRQoL was revealed in the follow-up study. Five subscales of SF-36 were appeared to be influenced by rs6484340: total score of SF-36 (additive model: PBH = 0.026), physical function (additive model: PBH = 0.026), role-physical (recessive model: PBH = 0.041), mental health (dominant model: PBH = 0.047), and physical component summary (additive model: PBH = 0.026). No statistical significance was found between HSP90AA2 gene polymorphisms and GCs efficacy. These results revealed a genetic association between HSP90AA2 and SLE. Remarkably, HSP90AA2 has an impact on the improvement of HRQoL in Chinese population with SLE.

Association of HSP90B1 genetic polymorphisms with efficacy of glucocorticoids and improvement of HRQoL in systemic lupus erythematosus patients from Anhui Province.

Objective: The aim of this study was to investigate the associations between HSP90B1 gene polymorphisms and the efficacy of glucocorticoids (GCs) and the improvement of health-related quality of life (HRQoL) in Anhui patients with systemic lupus erythematosus (SLE). Method: A total of 305 patients with SLE were recruited to the study. These patients were treated with GCs for 12 weeks and classified into two groups (sensitivity and insensitivity) according to the response to GCs measured by the scores on SLE disease activity index (SLEDAI). The HRQoL of SLE patients were evaluated by 36-item Short Form Health Survey (SF-36) at baseline and 12 weeks respectively. HapMap database and Haploview software were used to select HSP90B1 gene tag single nucleotide polymorphisms (SNPs). Benjamini & Hochberg (BH) method based on false discovery rate (FDR) was used for multiple testing correction. Results: A total of 291 patients were included in final data analysis with 14 patients excluded due to loss to follow-up. Among these patients, 160 patients were sensitive to GCs and 131 patients were insensitive to GCs. Twelve tag SNPs of HSP90B1 gene were selected. The rs12426382 polymorphism was associated with the efficacy of GCs (dominant model: crude OR=0.514, 95% CI=0.321-0.824, P=0.006; adjusted OR=0.513, 95% CI=0.317-0.831, P=0.007). After BH correction, there was no association between rs12426382 polymorphism and efficacy of GCs (PBH =0.084). In haplotype analysis, the haplotype CCCGAACATCCC (OR=2.273, 95% CI=1.248-4.139, P=0.006) and CTGGGACGTTC (OR=0.436, 95% CI=0.208-0.916, P=0.025) showed significant associations with the efficacy of GCs. After corrected by BH method, CCCGAACATCCC was still associated with the efficacy of GCs (PBH =0.048). The rs3794241, rs1165681, rs2722188, rs3794240 and rs10861147 polymorphisms were associated with the improvement of HRQoL among SLE patients (P < 0.05). But no association existed after the correction of BH method (P > 0.05). Conclusions: The results of this study demonstrated that HSP90B1 genetic polymorphisms might be associated with the efficacy of GCs, but not associated with the improvement of HRQoL in Anhui population with SLE.