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Male germ cell apoptosis and epigenetic histone modification induced by Tripterygium wilfordii Hook F.

ABSTRACT: Multiglycosides of Tripterygium wilfordii Hook f (GTW), a Chinese herb-derived medicine used as a remedy for rheumatoid arthritis, are considered to be a reversible anti-fertility drug affecting the mammalian spermatids. However, the mechanism behind this effect is still unknown. To study the possible mechanism behind the impact of GTW on spermatogenesis, we administered 4 groups of 4-week-old male mice with different doses of GTW. We found a dose-dependent decrease in the number of germ cells after 40 days of GTW treatment, and an increase in apoptotic cells from the low-dose to the high-dose group. During this same period the dimethylated level of histone H3 lysine 9 (H3K9me2) in GTW-treated testes germ cells declined. Additionally, spermatogonial stem cells (SSCs) from 6-day-old mice were isolated to evaluate the possible effect of GTW or triptolide on development of SSCs. We found a significantly higher incidence of apoptosis and lower dimethylation level of H3K9me2 in the SSCs of GTW or triptolide treatment than in controls. Thus, these data suggest that the GTW-induced apoptosis might be responsible for the fertility impairment in mice. This damage could be traced back to the early stages of spermatogenesis. GTW also affected the epigenetic modification of H3K9 in spermatogenesis. Molecular dynamics simulation suggested that triptolide and dimethylated or trimethylated H3K9 might have similar interaction mechanisms with EED (embryonic ectoderm development). These candidate activation mechanisms provide the first glimpse into the pathway of GTW-induced gonad toxicity, which is crucial for further research and clinical application.

SUBMITTER: Xiong J

PROVIDER: S-EPMC3115959 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Male germ cell apoptosis and epigenetic histone modification induced by Tripterygium wilfordii Hook F.

Xiong Ji J Wang Hu H Guo Guangming G Wang Shuzeng S He Liqun L Chen Haifeng H Wu Ji J

PloS one 20110615 6

Multiglycosides of Tripterygium wilfordii Hook f (GTW), a Chinese herb-derived medicine used as a remedy for rheumatoid arthritis, are considered to be a reversible anti-fertility drug affecting the mammalian spermatids. However, the mechanism behind this effect is still unknown. To study the possible mechanism behind the impact of GTW on spermatogenesis, we administered 4 groups of 4-week-old male mice with different doses of GTW. We found a dose-dependent decrease in the number of germ cells a ...[more]

PMID: 21698297

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Project description:ObjectivesTo summarize the quantity and quality of evidence for using Tripterygium wilfordii Hook. f. (TwHF) preparations in patients with rheumatoid arthritis (RA) and to find the reasons of the disparity by comprehensively appraising the related systematic reviews (SRs).MethodsWe performed an overview of evidence for the effectiveness and safety of TwHF preparations for patients with RA. We searched seven literature databases from inception to July 15, 2021. We included SRs of TwHF preparations in the treatment of RA. Four tools were used to evaluate the reporting quality, methodological quality, risk of bias, and the certainty of evidence for the included SRs, which are the PRISMA, the AMSTAR-2, the ROBIS, and the GRADE approach.ResultsWe included 27 SRs (with 385 studies and 33,888 participants) for this overview. The AMSTAR-2 showed that 19 SRs had critically low methodological quality and the remaining 8 had low methodological quality. The rate of overlaps was 68.31% (263/385), and the CCA (corrected covered area) was 0.53, which indicated the degree of overlap is slight. Based on the assessment of ROBIS, all 27 SRs were rated as low risk in phase 1; one SR was rated as low risk in domain 1, 9 SRs were in low risk in domain 2, 16 SRs were in low risk in domain 3, and 16 SRs were in low risk in domain 4 in phase 2; 7 SRs were rated as low risk in phase 3. Among 27 items of PRISMA, 15 items were reported over 70% of compliance, the reporting quality of 16 SRs was rated as "fair," and 11 were "good." Using GRADE assessment, moderate quality of evidence was found in 5 outcomes, and 5 outcomes were low quality.ConclusionThe use of TwHF preparations for the treatment of RA may be clinically effective according to the moderate-quality evidence. There are methodological issues, risk of bias, and reporting deficiencies still needed to be improved. SRs with good quality and further randomized clinical trials that focus on clinical important outcomes are needed.

Project description:Background:Tripterygium wilfordii Hook. f. (T. wilfordii) is an important medicinal plant with anti-inflammatory, immunosuppressive and anti-tumor activities. The main bioactive ingredients are diterpenoids and triterpenoids, such as triptolide, triptophenolide and celastrol. However, the production of terpenoids from original plants, hairy roots and dedifferentiated cells (DDCs) are not satisfactory for clinical applications. To find a new way to further improve the production of terpenoids, we established a new culture system of cambial meristematic cells (CMCs) with stem cell-like properties, which had strong vigor and high efficiency to produce large amounts of terpenoids of T. wilfordii. Results:CMCs of T. wilfordii were isolated and cultured for the first time. CMCs were characterized consistent with stem cell identities based on their physiological and molecular analysis, including morphology of CMCs, hypersensitivity to zeocin, thin cell wall and orthogonal partial least square-discriminant analysis, combination of transcriptional data analysis. After induction with methyl jasmonate (MJ), the maximal production of triptolide, celastrol and triptophenolide in CMCs was 312%, 400% and 327% higher than that of control group, respectively. As for medium, MJ-induced CMCs secreted 231% triptolide and 130% triptophenolide at the maximum level into medium higher than that of control group. Maximal celastrol production of induced CMCs medium was 48% lower than that of control group. Long-term induction significantly enhanced the production of terpenoids both in cells and medium. The reason for increasing the yield of terpenoids was that expression levels of 1-deoxy-d-xylulose-5-phosphate synthase (DXS), 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) and hydroxymethylglutaryl-CoA synthase (HMGS) were upregulated in CMCs after induction. Conclusions:For the first time, CMCs of T. wilfordii were isolated, cultured, characterized and applied. Considering the significant enrichment of terpenoids in CMCs of T. wilfordii, CMCs could provide an efficient and controllable platform for sustainable production of terpenoids, which can be a better choice than DDCs.

Project description:BackgroundDiabetic nephropathy (DN) is the most common cause of end-stage renal failure. Although angiotensin II receptor blockers (ARBs) can be used to attenuate proteinuria in DN patients, their efficacy remains limited. This clinical trial aimed to evaluate the efficacy of Tripterygium wilfordii Hook F (TwHF) extract in the treatment of type 2 diabetes mellitus (DM)-induced nephropathy.MethodsA total of 65 DN patients with proteinuria levels ≥ 2.5 g/24 h and serum creatinine levels<3 mg/dl were enrolled in this six-month, prospective, randomized, controlled study. The patients were randomized into treatment groups that received either 120 mg of TwHF extract per day for three months, followed by 60 mg per day for three more months, or 160 mg of valsartan daily for six months. The urinary protein and estimated glomerular filtration (eGFR) level were measured at one, three, and six months after the commencement of treatment. The primary measure of treatment efficacy was a reduction in the 24-h urine protein level between baseline and the end of the study, and the secondary measure of treatment efficacy was a reduction in the eGFR value.ResultsAt the end of the treatment period, the mean urine protein level in the TwHF group was dramatically decreased (4.99 ± 2.25 g/24 h vs 2.99 ± 1.81 g/24 h, p< 0.01), with decreases at one, three, and six months of 32.9%, 38.8%, and 34.3%, respectively. In contrast, the proteinuria in the valsartan group was not significantly attenuated, and the decreases in urine protein levels at treatment months one, three, and six were 1.05%, 10.1%, and -11.7%, respectively. The mean decrease in eGFR in the valsartan group was greater than that in the TwHF group (26.4% vs. 13.7%, respectively; p =0.067).ConclusionsTwHF extract can reduce the urine protein level of DN patients and represents a novel, potentially effective, and safe drug for the treatment of DN patients with proteinuria.Trial registrationClinicalTrials.gov: NCT00518362.

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Male germ cell apoptosis and epigenetic histone modification induced by Tripterygium wilfordii Hook F.

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Male germ cell apoptosis and epigenetic histone modification induced by Tripterygium wilfordii Hook F.

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