Mechanisms of cuproptosis and its relevance to distinct diseases.

Copper is a trace element required by the organism, but once the level of copper exceeds the threshold, it becomes toxic and even causes death. The underlying mechanisms of copper-induced death are inconclusive, with different studies showing different opinions on the mechanism of copper-induced death. Multiple investigations have shown that copper induces oxidative stress, endoplasmic reticulum stress, nucleolar stress, and proteasome inhibition, all of which can result in cell death. The latest research elucidates a copper-dependent death and denominates it as cuproptosis. Cuproptosis takes place through the combination of copper and lipoylated proteins of the tricarboxylic acid cycle, triggering agglomeration of lipoylated proteins and loss of iron-sulfur cluster proteins, leading to proteotoxic stress and ultimately death. Given the toxicity and necessity of copper, abnormal levels of copper lead to diseases such as neurological diseases and cancer. The development of cancer has a high demand for copper, neurological diseases involve the change of copper contents and the binding of copper to proteins. There is a close relationship between these two kinds of diseases and copper. Here, we summarize the mechanisms of copper-related death, and the association between copper and diseases, to better figure out the influence of copper in cell death and diseases, thus advancing the clinical remedy of these diseases.

Insights into the metabolite profiles of Rubus chingii Hu at different developmental stages of fruit.

The fruits of Rubus chingii Hu have high medicinal and nutritional values. However, the metabolite profiles of R. chingii, especially the alterations during different development stages of fruit, have not been comprehensively analyzed, hindering the effective utilization of the unique species. In this study, we comprehensively analyzed the metabolites of R. chingii fruit at four developmental stages using systematic untargeted and targeted liquid chromatography-mass spectrometry metabolomics analysis and identified 682 metabolites. Significant changes were observed in metabolite accumulation and composition in fruits during the different developmental stages. The contents of the index components, kaempferol-3-O-rutinoside and ellagic acid, were the highest in immature fruit. The analysis identified 64 differentially expressed flavonoids and 39 differentially expressed phenolic acids; the accumulation of most of these differentially expressed metabolites decreased with the developmental stages of fruit from immaturity to maturity. These results confirmed that the developmental stages of fruit are a critical factor in determining its secondary metabolite compositions. This study elucidated the metabolic profile of R. chingii fruit at different stages of development to understand the dynamic changes in metabolites.

Molecular Mechanisms of Parthanatos and Its Role in Diverse Diseases.

Differential evolution of apoptosis, programmed necrosis, and autophagy, parthanatos is a form of cell death mediated by poly(ADP-ribose) polymerase 1 (PARP1), which is caused by DNA damage. PARP1 hyper-activation stimulates apoptosis-inducing factor (AIF) nucleus translocation, and accelerates nicotinamide adenine dinucleotide (NAD+) and adenosine triphosphate (ATP) depletion, leading to DNA fragmentation. The mechanisms of parthanatos mainly include DNA damage, PARP1 hyper-activation, PAR accumulation, NAD+ and ATP depletion, and AIF nucleus translocation. Now, it is reported that parthanatos widely exists in different diseases (tumors, retinal diseases, neurological diseases, diabetes, renal diseases, cardiovascular diseases, ischemia-reperfusion injury...). Excessive or defective parthanatos contributes to pathological cell damage; therefore, parthanatos is critical in the therapy and prevention of many diseases. In this work, the hallmarks and molecular mechanisms of parthanatos and its related disorders are summarized. The questions raised by the recent findings are also presented. Further understanding of parthanatos will provide a new treatment option for associated conditions.

Effect of piperine on the bioavailability and pharmacokinetics of rosmarinic acid in rat plasma using UPLC-MS/MS.

1. The purpose of the present study was to investigate the effect of piperine (PP) on the pharmacokinetics of rosmarinic acid (RA) in rat plasma and to determine whether PP could enhance the oral bioavailability of RA via inhibition of its glucuronidation. 2. The pharmacokinetic profiles of RA between oral administration of RA (50 mg/kg) alone and in combination with different oral dose PP (20, 40, 60, and 80 mg/kg) to rats were investigated via a validated UPLC/MS/MS method. 3. The AUC and Cmax of RA were significantly increased in combination with different dose PP dose dependently, especially in the presence of 60 and 80 mg/kg PP (p < 0.01). The relative bioavailability of RA in the presence of 20, 40, 60, and 80 mg/kg PP was 1.24-, 1.32-, 2.02-, and 2.26-folds higher, respectively, compared with the control group given RA alone. Compared with RA, the pharmacokinetic modulations of RA glucuronide were even more apparent, and the glucuronidation of RA was remarkedly inhibited. 4. This study demonstrated that PP significantly improved the in vivo bioavailability of RA partly attributing to the inhibition of gut and hepatic metabolism enzymes of RA.

Xanthone-rich dichloromethane fraction of Securidaca inappendiculata, the possible antirheumatic material base with anti-inflammatory, analgesic, and immunodepressive effects.

CONTEXT: Securidaca inappendiculata Hassk. is an traditional Chinese medicine curing rheumatoid arthritis, but there is a lack of reports on material base research. OBJECTIVE: To find the active fraction of S. inappendiculata contributing the most to antirheumatic activity. MATERIALS AND METHODS: Prior to assays in vivo, mice were treated with different fractions from S. inappendiculata for 5 d at doses relative to 10, 5, and 2.5 g/kg of crude drug. Hot plate test and carrageenan-induced paw edema test were used to investigate analgesic and anti-inflammatory activities. PGE2 levels in inflammatory paws were determined by a colorimetric method. Carbon clearance test in vivo and lymphocyte transformation test in vitro were employed to assess the immune regulation activity. HPLC was used to explore the main compounds in the active fraction. RESULTS: All the fractions, especially the dichloromethane fraction (SID), alleviated inflammation. High dose of SID (112 mg/kg) inhibited paw swelling by 63.1%, and decreased PGE2 level to 38 ng/mL. The ethyl acetate fraction (SIE) and SID suppressed the carbon clearance rate (K = 0.044, 0.038 for high dose) efficiently. All fractions hindered the transformation and proliferation of lymphocyte, and prolonged the reaction time of rats in the hot plate test. The concentrations of two typical xanthones: 2-hydroxyl-1,7-dimethoxyl-xanthone and 1,7-dihydroxyl-xanthone in SID were 0.93% and 1.19%, respectively, by HPLC analysis. CONCLUSION: SID exhibited significant anti-inflammatory, analgesic, and immunodepressive effects in vivo and vitro, and deemed as the main material base for the antirheumatic activity.

Optimization of smashing tissue and ultrasonic extraction of tanshinones and their neuroprotective effect on cerebral ischemia/reperfusion injury by inhibiting parthanatos.

A green smashing tissue and ultrasonic (STU) extraction method, which combines smashing tissue and ultrasonic-assisted extraction, was developed for the first time. The extraction of tanshinones from Salvia miltiorrhiza Bunge (SM) was taken as an example to discuss the practicability of this method. Taking the total yield of eight tanshinones as an evaluation index, response surface methodology (RSM) and artificial neural network (ANN) models were used to optimize the extraction parameters, and these two models were also compared by investigating the extract yield of tanshinones and the antioxidant activity of the obtained SM extract. The optimal STU conditions by ANN were as follows: an ethanol concentration of 73%, a liquid/solid ratio of 30 mL g-1, a smashing tissue time of 97 s and an ultrasonic time of 40 min. Under these optimal conditions, the yield of the eight components was 0.30% ± 0.12, which was greater than 0.28% ± 0.03 optimized by RSM. The IC50 values of 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) of the obtained extract were 55.25 ± 3.72 µg mL-1 and 67.33 ± 2.62 µg mL-1, respectively, which were better than those of 75.49 ± 4.33 µg mL-1 and 112.10 ± 5.98 µg mL-1, respectively, optimized by RSM. Furthermore, the SM extract was found to exert neuroprotective effects by inhibiting parthanatos in middle cerebral artery occlusion/reperfusion (MCAO/R)-induced rats. The results supported the use of the SM extract, which was obtained by STU, as a potential product in the cosmetics, medicine, and food industries.

Optimisation of extraction conditions for total saponins from Cynanchum wallichii using response surface methodology and its anti-tumour effects.

Cynanchum wallichii Wight, is a traditional Chinese medicine herb, which is rich in saponins and has varieties of pharmacological activities. In this study, a standardized C. wallichii extract was established and the anti-tumor activity of the total saponins was evaluated by MTT assay. The extraction conditions of the standardized extract was optimized using response surface methodology. The experimental value was in good agreement (the yield 4.28%) with predicted values. The total saponins of the extract showed significant anti-tumor activity against three human tumor cell lines (A549, HepG2 and MCF-7), especially for MCF-7 (IC50. 67.63 µg/mL) cells in vitro.

Simultaneous Determination of 10 Active Components in Hulisan Tablets by a High-Performance Liquid Chromatographic-Diode Array Detector.

Hulisan tablets (HLST), a famous classic traditional Chinese prescriptions consisting of four medicinal herbs, have been applied for treating fractures, rheumatoid arthritis, mechanical phlebitis and traumatic bleeding extensively. In this study, a simple and reliable method using high-performance liquid chromatography with diode array detector (HPLC-DAD) was established for the simultaneous determination of 10 active compounds in HLST. The chromatographic analysis was performed on a Symmetry(®)-C18 column (4.6 × 250 mm, i.d., 5 µm; Waters, Wexford, Leinster, Ireland) at 30°C with a gradient elution of 0.1 mol/L ammonium acetate (containing 0.5 mL glacial acetic acid per 1,000 mL) and acetonitrile at a flow rate of 1.0 mL/min. The detection UV wavelengths were set at 232, 254 and 280 nm. The method was validated by linearity, precision, stability and recovery. Calibration curves for the 10 compounds showed good linear regressions (R(2) > 0.9992). The limits of detection and quantification fell in the ranges of 0.03-0.36 and 0.11-1.01 µg/mL, respectively. The results of the recovery test were 97.19-102.04% with a RSD value of 0.65-2.47%. The developed method was subsequently applied to evaluate five batches of HLST and testified to be suitable for the quality control.

Lipophilic constituents from two processed products and three different parts of Changium smyrnioides Wolff.

This article reports the lipophilic chemical composition of different processed products (Changii Radix, Changii Radix Alba) and parts (root bark, leaf and fruit) of Changium smyrnioides Wolff.. The lipophilic constituents were extracted with petroleum ether in Soxhlet apparatus, subsequently identified and determined by gas chromatography-mass spectroscopy (GC-MS). Yield of lipophilic constituents from Changii Radix (3.65%) was about three times more than Changii Radix Alba's (1.07%), which indicated processing by boiling in water had an impact on the content of lipophilic constituents. Moreover, the major compounds in different processed products and parts were found to be fatty acids and sesquiterpenes. The results are a contribution for the lipophilic chemical composition and can serve as a reference for product development of Changium smyrnioides Wolff..