Metabolomics reveals that ferroptosis participates in bisphenol A-induced testicular injury.

Objective: Bisphenol A (BPA) is a common environmental endocrine disruptor that negatively impairs male reproductive ability. This study aimed to explore the alterations in serum metabolomics that occur following BPA exposure and the mechanism via which BPA induces the death of testicular cells in a male mouse model. Methods: The mice were classified into two groups: BPA-exposed and control groups, and samples were collected for metabolomic determination, semen quality analysis, electron microscopy, enzyme-linked immunosorbent assay, quantitative real-time PCR, pathological staining, and Western blot analysis. Results: BPA exposure caused testicular damage and significantly decreased sperm quality in mice. Combined with non-target metabolomic analysis, this was closely related to ferroptosis induced by abnormal metabolites of arachidonic acid and phosphatidylcholine, and the expression of its related genes, acyl CoA synthetase 4, glutathione peroxidase 4, lysophosphatidylcholine acyltransferase 3, and phosphatidylethanolamine-binding protein 1 were altered. Conclusion: BPA induced ferroptosis, caused testicular damage, and reduced fertility by affecting lipid metabolism in male mice. Inhibiting ferroptosis may potentially function as a therapeutic strategy to mitigate the male reproductive toxicity induced by BPA.

Sulfone-Decorated Conjugated Organic Polymers Activate Oxygen for Photocatalytic Methane Conversion.

Oxidizing CH4 into liquid products with O2 under mild conditions still mainly relies on metal catalysis. We prepared a series of sulfone-modified conjugated organic polymers and found that the catalyst with proper SVI content (0.10) could drive O2 →H2 O2 →⋅OH to oxidize CH4 into CH3 OH and HCOOH directly and efficiently at room temperature under light irradiation. Experimental results showed that after 4 h reaction, decomposition rate and residual amounts of H2 O2 were 81.21 % and 4.83 mmol gcat -1 respectively, and CH4 conversion rate was 22.81 %. Mechanism studies revealed that illumination could induce the homolytic dissociation of S=O bonds on catalyst to produce oxygen and sulfur radicals, where the ⋅O could adsorb and activate CH4 , and the ⋅S could supply electrons for 1 O2 to generate H2 O2 and then for decomposing the H2 O2 into ⋅OH timely to oxidize CH4 . This research provided a novel organic catalysis approach for oxygen activation and utilization.

Pharmacokinetics of cisplatin in the absence or presence of zengmian yiliu granules (a traditional Chinese medicine compound) in rats determined via ICP-MS: an investigation on drug-herb interactions.

CONTEXT: Cisplatin is a highly effective chemotherapeutic agent against many tumors; however, it has potent adverse effects. Zengmian Yiliu granule (ZMYL), a traditional Chinese medicine (TCM) compound, has been clinically used against platinum (Pt)-induced toxicity and to enhance the efficacy of cisplatin. OBJECTIVE: The study was conducted to investigate the likelihood of potential pharmacokinetics drug-herbs interaction (DHI) between cisplatin and ZMYL. MATERIALS AND METHODS: An improved ICP-MS method combined with ultrafiltration and microwave-assisted digestion was performed to determine the total and free Pt concentrations in rat plasma after intraperitoneal administration of cisplatin (9 mg/kg) or a combined administration with ZMYL (1 g/kg) by gavage. RESULTS: ZMYL produced a potential DHI on the pharmacokinetic parameters of cisplatin, calculated from the total Pt concentration. The clearance rate decreased from 110.52 to 66.12 mLh(-1 )kg(-1), the mean residence time extended from 63.1 to 164.54 h, the area under the plasma concentration-time curve increased from 86.58 to 152.93 µg h mL(-1), the elimination half-life extended from 48.38 to 126.4 h, and the elimination rate constant decreased from 0.017 to 0.006 h, in the ZMYL combination group (p < 0.05). In terms of free Pt concentration, the apparent volume of distribution and clearance rate was statistically different (p < 0.05). The Pt plasma protein binding ratios in the early dose stages were significantly boosted by the co-administration of ZMYL (p < 0.01). DISCUSSION AND CONCLUSION: ZMYL is a potential complementary and alternative medicine for cisplatin chemotherapy. The therapeutic benefits of ZMYL-cisplatin chemotherapy derived from pharmacokinetic interaction needs further investigation.

Clinical observations of sequential therapy with Chinese medicine and hysteroscopic mechanical stimulation of the endometrium in infertile patients with repeated implantation failure undergoing frozen-thawed embryo transfer.

OBJECTIVES: To investigate the clinical effect of sequential therapeutic intervention Yupei Qisun [compensating for weakness by invigorating Kidney (Shen) and Spleen (Pi) in advance] in Chinese medicine (CM) and hysteroscopic endometrial mechanical stimulation on the treatment of infertile patients with repeated implantation failure (RIF); and to study the differences in patients' endometrial thickness and type on the day of embryo transfer, serum hormone levels on embryo transfer day and clinical pregnancy outcomes. METHODS: In the clinical study, 168 frozen-thawed embryo transfer (FET) cycles for couples with RIF conforming to the research protocol were randomly divided into three groups: a CM group with 56 cycles (CM combined with FET), a hysteroscopy group with 55 cycles (hysteroscopic endometrial mechanical stimulation), and a control group with 57 cycles (conventional FET). Differences in endometrial thickness on the embryo transfer day, levels of serum estradiol (E2) and progesterone (P) on the embryo transfer day, the E2/P ratio on the embryo transfer day, biochemical and clinical pregnancy rates, implantation rate, abnormal pregnancy rate and other indices were compared among the three groups. RESULTS: Endometrial thickness, E2 and P levels, and the E2/P ratio on embryo transfer day and other factors had no significant differences among groups. The biochemical pregnancy, clinical pregnancy, and implantation rates of the CM and hysteroscopy groups were significantly higher than the control group (P<0.05), and there were no significant differences between these two groups. The abnormal pregnancy rate had no significant difference among the three groups. CONCLUSIONS: Sequential therapy of Yupei Qisun could significantly improve the clinical outcomes of rif-fet cycles, being equivalent to hysteroscopic endometrial mechanical stimulation, and provided a reliable method to treat such infertile couples.

Protective effect of quercetin on the development of preimplantation mouse embryos against hydrogen peroxide-induced oxidative injury.

Quercetin, a plant-derived flavonoid in Chinese herbs, fruits and wine, displays antioxidant properties in many pathological processes associated with oxidative stress. However, the effect of quercetin on the development of preimplantation embryos under oxidative stress is unclear. The present study sought to determine the protective effect and underlying mechanism of action of quercetin against hydrogen peroxide (H2O2)-induced oxidative injury in mouse zygotes. H2O2 treatment impaired the development of mouse zygotes in vitro, decreasing the rates of blastocyst formation and hatched, and increasing the fragmentation, apoptosis and retardation in blastocysts. Quercetin strongly protected zygotes from H2O2-induced oxidative injury by decreasing the reactive oxygen species level, maintaining mitochondrial function and modulating total antioxidant capability, the activity of the enzymatic antioxidants, including glutathione peroxidase and catalase activity to keep the cellular redox environment. Additionally, quercetin had no effect on the level of glutathione, the main non-enzymatic antioxidant in embryos.

[Anti-angiogenic effects of zengmian YiIiu granule on ovarian carcinoma xenograft].

OBJECTIVE: To investigate the anti-angiogenic effects and mechanisms of Zengmian Yiliu Granule (ZMYLG) on ovarian carcinoma xenograft. METHODS: The SKOV3 ovarian carcinoma bearing mouse model was established. The tumor-bearing mice were randomly divided into the control group, the paclitaxel group, the high, medium, and low dose ZMYLG group, 8 in each group. The medication was lasted for ten days. The microvessel density (MVD) in the xenograft was calculated by the method of using cell membrane differentiation antigen 34 (CD34) antibody marking new vascular endothelial cells. The protein and mRNA expressions of vascular endothelial growth factor (VEGF) and its receptor fetal liver kinase-1 (FLK-1), hypoxia inducible factor-1alpha (HIF-1alpha) in the tumor were determined using immunohistochemical assay and RT-PCR. RESULTS: The MVD of ovarian carcinoma xenografts in the paclitaxel group, the high, medium, and low dose ZMYLG group obviously decreased, showing statistical difference when compared with the control group (P < 0.01, P < 0.05). Each ZMYLG dose group could down-regulate the protein and mRNA expressions of VEGF, FLK-1, and HIF-1alpha (P < 0.01, P < 0.05). CONCLUSIONS: ZMYLG could inhibit neogenesis of tumor vessels. Its mechanisms might be associated with down-regulating the expression of HIF-1alpha, modifying the hypoxic state, inhibiting the expressions of VEGF and FLK-1, and exerting its anti-angiogenic effects.

[Effects of Zengmian Yiliu Recipe combined cisplatin on the tumor inhibition rate in platinum-resistant ovarian cancer].

OBJECTIVE: To observe the effects of Zengmian Yiliu Recipe (ZYR) combined cisplatin on the growth of subcutaneous tumor in nude mice with platinum-resistant ovarian cancer, and to explore its possible mechanisms. METHODS: The model of ovarian cancer subcutaneous tumor was established in nude mice using platinum-resistant ovarian cancer line COC1/DDP. The mice were randomly divided into six groups, i. e., the high Chinese materia medica (CMM) group, the medium CMM group, the low CMM group, the cisplatin group (DDP), the combined treatment group (with DDP combined CMM), and the control group (with normal saline). The medication lasted for 3 successive weeks. The tumor weight and the tumor inhibition rate were calculated. The expressions of Bcl-associated x protein (Bax) and B-cell lymphoma/leukemia-2 (Bcl-2) were detected using quantitative RT-PCR and immunohistochemical assay. The ultra-structure of tumor cells was observed by electron microscopy. RESULTS: The tumor inhibition rate was the highest in the combined treatment group, being (59. 26 +/- 6.86) %, showing statistical difference when compared with the rest groups (P < 0.01). Results of RT-PCR showed the Bax mRNA expression was the highest in the combined treatment group and the lowest in the control group (P < 0.01). Anti-apoptotic gene Bcl-2 mRNA expression was the highest in the control group and the lowest in the high CMM group (P < 0.01). The Bcl-2 mRNA expression was lower in the combined treatment group than in the cisplatin group (P < 0.01). Immunohistochemical results showed the Bax protein expression was the highest and the expression of Bcl-2 was the lowest in the combined treatment group, showing statistical difference when compared with the rest groups (P < 0.01). The middle- and late-stage manifestations of apoptosis could be seen in each CMM group and the combined treatment group under electron microscope. CONCLUSIONS: ZYR combined with chemotherapy could reverse the cisplatin-resistance of resistant ovarian cancer nude mice, and enhance its tumor inhibitory effect. Its mechanisms were correlated with up-regulating the expression of Bax, down-regulating the expression of Bcl-2, and promoting cisplatin resistant ovarian cancer cell apoptosis.

[Impact of changing gross tumor volume delineation of intensity-modulated radiotherapy on the dose distribution and clinical treatment outcome after induction chemotherapy for the primary locoregionally advanced nasopharyngeal carcinoma].

BACKGROUND AND OBJECTIVE: The gross tumor volume (GTV) obviously reduces after induction chemotherapy (IC) for primary locoregionally advanced nasopharyngeal carcinoma (NPC). This study was to investigate the impact of changing gross tumor volume delineation on the dose distribution and clinical treatment outcome after IC. METHODS: From January 2008 to April 2009, 24 patients with Stage III-IVb primary locoregionally advanced NPC were treated with TPF regimen IC followed by intensity-modulated radiotherapy (IMRT) with concurrent chemotherapy . The primary GTVs were delineated into two parts: the post-IC primary GTV (GTVpost-IC-NP), and the region of pre-IC primary GTV minus GTVpost-IC-NP (GTVpre-post-IC-NP). The dose distributions of two plans with GTVpost-IC-NP or pre-IC primary GTV were assessed by analyzing ten cases. The clinical treatment outcome and toxicity of all patients were observed. RESULTS: The post-IC GTV was significantly smaller than the pre-IC GTV (primary GTV 25.5 cm3 vs. 51.1 cm(3),P=0.001; lymph nodes GTV 9.1 cm(3) vs. 31.4 cm(3), P=0.035; primary + lymph nodes GTV 33.2 cm(3) vs. 82.6 cm(3),P=0.004), the overall GTV with an average shrinkage of 61%. The high dose region was also smaller after IC (volumes covered by 64.4 Gy were 422.9 cm3 vs. 457.9 cm3, P=0.003; 274.2 cm(3) vs.334.5 cm(3) by 68 Gy, P=0.041). The complete response rate was 38% after IC, and 100% three month after radiotherapy. The toxicity of following IMRT with concurrent chemotherapy was similar to that of IMRT with concurrent chemotherapy alone. With median follow-up of 9 months, the locoregionally control rate was 100% and only one patient presented metastasis 15 months after treatment. CONCLUSIONS: TPF regimen IC could significantly reduce tumor volume. The following IMRT with GTVpost-IC-NP plan reduced the high dose region, which didn't add toxicity while had excellent short-term treatment outcome.

Influence of carrier proteins on the immunologic response to haptenic antitetrodotoxin vaccine.

Tetrodotoxin (TTX) is a haptenic, highly toxic neurotoxin with no specific antidote available yet. Anti-TTX vaccine is being studied for antitoxin development. The effectiveness of the carrier protein in eliciting TTX-specific antibody response was comparatively studied. TTX was conjugated to Tachypleus tridentatus hemocyanin (TTH), Limulus polyphemus hemocyanin (LPH), tetanus toxoid (TT), diphtheria toxoid (DT), and bovine serum albumin (BSA) chemically to form artificial antigens TTH-TTX, LPH-TTX, TT-TTX, DT-TTX, and BSA-TTX, respectively, with which BALB/c mice were immunized, and the antibody response and antitoxic efficacy were detected. The serum anti-TTX antibody response and antitoxic efficacy varied markedly with adopted carrier protein. TTH-TTX elicited the best and BSA-TTX the worst TTX-specific antibody response. The proportion of the immunized mice surviving a 3x lethal dose (LD) dose of TTX challenge was 92%, 75%, 42%, 8%, and 0% for TTH-, TT-, LPH-, DT-, and BSA-TTX conjugates, respectively. The rank order of total efficacy of carrier protein for both anti-TTX antibody response and antitoxic effect was TTH > TT > LPH > DT > BSA. As a result of formaldehyde treatment in coupling of TTX carriers, the relative immunogenicity of TTX vs carrier, that is, the ratio of TTX- to carrier-specific antibody response, evidently varied with respective carrier adopted, in a rank order of TT > BSA > TTH > DT > LPH. The results suggest that the carrier protein used in haptenic TTX vaccine is greatly important in eliciting potent anti-TTX antibody, and both TTH and TT are the preferred carriers for development of excellent experimental TTX vaccine.