[1H-NMR based metabonomic approach to evaluate detoxification effect of vinegar-processed Euphorbia kansui].

Euphorbia kansui (EK) is a toxic herbal drug, and often used after vinegar-processing to reduce its toxicity. In present study, a 1H-NMR based metabonomic approach was used to evaluate the detoxification effect of vinegar-processed EK. The water extracts of EK and VEK were administered orally to male SD rats at doses of 9 g x kg(-1) x d(-1) for 1 week, respectively, and one more week observation was further conducted. The control group was orally given with saline. Histopathological studies of liver samples on the 8th and 15th day were conducted, and the metabolites of rat urine and liver were analysed by 1H-NMR. Histopathological studies of liver samples from EK and VEK treated rats showed no negative impacts. In metabonomic analyses of urines, changes of metabolites indicated liver damages, kidney lesions and imbalance of gut microbes in the second week. VEK-treated rats showed a quite lower toxicity compared with EK-treated ones. The present study revealed that the metabonomic approach might be helpful for the evaluation of toxicity of EK and detoxic effect of VEK.

The efficacy of cetuximab plus PD-1 inhibitors as salvage therapy in PD-1 refractory patients with recurrent or metastatic head and neck squamous cell carcinoma.

Purpose: The prognosis of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) that are refractory to programmed cell death protein 1 (PD-1) immunotherapy is relatively poor. The salvage therapy was rarely investigated and urgently needed. Methods: We conducted a single center retrospective real-world study to explore the efficacy of cetuximab plus PD-1 inhibitors as salvage therapy in patients progressed from first-line immunotherapy. Results: In the present study, 28 eligible patients were included between October 2020 and May 2023. By the cut-off date (Sep 24th, 2023), the objective response rate (ORR) was 46.4% (95% CI, 29.5%-64.2%). Kaplan-Meier survival analysis revealed the median progression free survival (mPFS) in the study was 6.87 months (95% CI, 4.77-8.97 months), and median overall survival (mOS) was 9.67 months (95% CI, 4.79-14.55 months). Multivariate Cox regression analysis indicated that ECOG performance status and best response to salvage therapy was found to be the prognosis factor of salvage therapy. For the safety, the most common treatment related adverse events (TRAEs) were rash (72.1%), anemia (64.3%) and fatigue (46.5%) during the salvage therapy. The most common potential irAEs were hypothyroidism (25%), and pneumonitis (14.3%). Only 3 patients (10.7%) experienced grade 3 TRAEs, and no treatment-related deaths occurred. Conclusions: Our study showed the combination of cetuximab with PD-1 inhibitors might be a potential efficacy and safety choice in PD-1 refractory patients with R/M HNSCC which need further investigation.

The clinical outcome of pembrolizumab for patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a single center, real world study in China.

Background: The KEYNOTE-048 and KEYNOTE-040 study have demonstrated the efficacy of pembrolizumab in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC), we conducted this real-world study to investigate the efficacy of pembrolizumab in patients with R/M HNSCC. Methods: This is a single-center retrospective study conducted in the Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Shanghai, China). Between December 2020 and December 2022, a total of 77 patients with R/M HNSCC were included into analysis. The primary endpoint of the study was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), overall response rate (ORR)and toxicity.Efficacy was assessed according to RECIST version 1.1.SPSS 27.0 and GraphPad Prism 8.0 software were utilized to perform the statistical analysis. Results: By the cut-off date (February 28, 2023), the median OS,PFS and ORR were 15.97 months,8.53 months and 48.9% in patients treated with the pembrolizumab regimen in the first line therapy. Among these patients, 17 patients received pembrolizumab with cetuximab,and 18 received pembrolizumab with chemotherapy.We observed no significant differences between two groups neither in median OS (13.9 vs 19.4 months, P=0.3582) nor PFS (unreached vs 8.233 months, P= 0.2807). In the ≥2nd line therapy (n=30), the median OS, PFS and ORR were 5.7 months, 2.58 months and 20% respectively. Combined positive score (CPS) was eligible from 54 patients. For first line therapy, the median OS and PFS were 14.6 and 8.53 months in patients with CPS ≥1, and median OS and PFS were 14.6 and 12.33 months in patients with CPS ≥20. The immune-related adverse events (irAEs) were occurred in the 31 patients (31/77, 40.26%), and the most common potential irAEs were hypothyroidism (25.97%), and pneumonitis (7.79%). Conclusion: Our real-world results indicated that pembrolizumab regimen is a promising treatment in patients with R/M HNSCC.

A metabonomic approach to a unique detoxification effect of co-use of Euphorbia kansui and Zizyphus jujuba.

Euphorbia kansui (EK) has been widely used in traditional Chinese medicine (TCM); however, it possesses toxic effects. The fruits of Zizyphus jujuba (ZJ) are frequently co-used with EK to reduce EK's toxicity. The present study is to clarify the toxicity of water extract of EK and explore the detox effect of ZJ using (1) H NMR-based metabonomic approach. The water extracts of ZJ, EK and the co-use of EK and ZJ (CEZ) were orally administered to SD rats at designed doses for 1 week, respectively, and one more week observation was further conducted. Histopathological studies of liver samples from all groups showed no negative impacts. In metabonomic analyses of urines, ZJ showed no toxicity, while significant changes of metabolites indicating liver damages, kidney lesions and imbalance of gut microbes were clearly observed during the second week in EK-treated rats. Very meaningfully, CEZ clearly indicated that the toxicities appeared at the first week and became weaker, and furthermore, was recovered during the second week. These results clearly demonstrated the rationality of traditional co-use of EK together with ZJ, and the metabonomic approach should be a promising tool to research the toxicity of TCM.

NMR-based metabonomic approach on the toxicological effects of a Cimicifuga triterpenoid.

Cimicifugae Rhizoma, a well-known botanical dietary supplement, has been the subject of intense interest due to its potential application for alleviating menopausal symptom. Although there are clinic data that the Cimicifuga extract should have hepatotoxicity, no evidence on the main chemical components has been reported. Cimicidol-3-O-ß -d-xyloside (CX) is one of the main triterpenoids of the rhizome. This work studies the toxicological effects of CX after oral administration (50 mg kg(-1) per day) over a 7-day period in female SD rats using metabonomic analyses of (1) H NMR spectra of urine, serum and liver tissue extracts. Histopathological studies of liver and analyses of blood biochemical parameter, such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea nitrogen and creatinine revealed that CX had no negative impacts on liver and kidney. However, the metabolic signature of (1) H NMR-based urinalysis of daily samples displayed an increment in the levels of taurine, trimethylamine-N-oxide (TMAO), betaine and acetate. Elevated serum levels of creatinine, glucose, alanine, TMAO and betaine and lower levels of lactate were observed. Metabolic profiling on aqueous soluble extracts of liver showed simultaneously increases in succinate, glycogen, choline, glycerophosphorylcholine, TMAO and betaine levels and reduction in valine, glucose and lactate levels. Nevertheless, no changes in any metabonomic level were found in lipid-soluble extracts of liver. These findings indicate that CX has a slight toxicity in liver and kidney via disturbance of the metabolisms of energy and amino acids. The present study provides a reasonable explanation for the clinical hepatotoxicity of Cimicifuga extract.

Synthesis of a novel series of diphenolic chromone derivatives as inhibitors of NO production in LPS-activated RAW264.7 macrophages.

A novel series of diphenolic chromone derivatives were synthesized and their inhibitory activity on nitric oxide (NO) production and cytotoxicity were evaluated using LPS-activated murine macrophages RAW264.7 assay and MTT method, respectively. Among these compounds, (5,7-dihydroxy-4-oxo-4H-chromen-3-yl) methyl esters (6b, 6c, 6f, 6g, and 6h) showed quite potent inhibitory activities with IC(50) values of 2.20, 3.48, 0.35, 0.80, and 0.61microM, respectively. The MTT results showed that all of the active compounds exhibited no cytotoxicity at the effective concentrations. The preliminary mechanism of the most potent compounds (6b, 6c, 6f, 6g, and 6h) was further examined based on the RT-PCR results and the compounds 6f, 6g, and 6h inhibited NO production by suppressing the expression of iNOS mRNA in a dose dependent manner. Furthermore, a computational analysis of physicochemical parameters revealed that the most of the compounds possessed drug-like properties.

Ruthenium-catalyzed cyclization of ketoxime acetates with DMF for synthesis of symmetrical pyridines.

A novel ruthenium-catalyzed cyclization of ketoxime carboxylates with N,N-dimethylformamide (DMF) for the synthesis of tetrasubstituted symmetrical pyridines has been developed. A methyl carbon on DMF performed as a source of a one carbon synthon. And NaHSO3 plays a role in the reaction.

Osteoprotective effect of extract from Achyranthes bidentata in ovariectomized rats.

AIM OF THE STUDY: A Chinese herbal drug, root of Achyranthes bidentata showed a potent inhibitory activity on bone resorption induced by parathyroid hormone (PTH) in a bone organ culture using neonatal mouse parietal bones. The present study is to clarify the fractions responsible for the activity and further explore the osteoprotective effect of the fraction in vivo. MATERIALS AND METHODS: The hexane, ethyl acetate (EtOAc), n-butanol (n-BuOH) and water soluble fractions of methanol extract of the root of Achyranthes bidentata were prepared and screened for their anti-bone resorption activity using the bone organ culture system. The n-BuOH soluble fraction was further administered orally at doses of 25, 50 and 100mg/(kgday) to ovariectomized (OVX) rats. The analyses of the rat body weight, serum estradiol (E2), total cholesterol and triglyceride levels, uteri weight and measurement of bone mineral density (BMD) were conducted. RESULTS: The EtOAc and n-BuOH fractions showed the most potent inhibitory activity on PTH-induced bone resorption. Further research using OVX rat model revealed that the n-BuOH fraction significantly prevented BMD loss due to OVX operation. While, the uteri weight and serum estradiol (E2), total cholesterol and triglyceride levels displayed no differences compared with those of control group (OVX rats), suggesting the n-BuOH fraction should have no estrogen-like side effects. CONCLUSIONS: The results reveal that the n-BuOH soluble fraction of the root of Achyranthes bidentata is effective at preventing bone loss in OVX rats and has a great potential as an alternative tool for the treatment of osteoporosis.