A comprehensive clinical evaluation of HER2-TKIs in patients with previously treated HER2-positive metastatic breast cancer.

Human epidermal growth factor receptor 2-tyrosine kinase inhibitors (HER2-TKIs) have been extensively utilized for treating HER2-positive metastatic breast cancer (MBC), with numerous clinical trial reports available. We aim to systematically perform a comprehensive clinical evaluation on HER2-TKIs, provide a reference for the clinical rational use of drugs, and serve for the decision-making of the national drug policy. We performed comprehensive clinical evaluation in six dimensions including safety, effectiveness, economy, suitability, accessibility, and innovation through meta-analysis, literature review, drug administration websites, and other relevant medication data to analyze HER2-TKIs in treating HER2-positive MBC. For safety, the risk of ≥ grade 3 adverse events among pyrotinib, lapatinib, and neratinib is not significantly different. Furthermore, pyrotinib and neratinib were found to be higher in the risk of ≥ grade 3 diarrhea than lapatinib, however the risk could be reversed and prevented with loperamide. Regarding effectiveness and economy, pyrotinib was confirmed to have the best efficacy and cost-utility value, neratinib the second, and lapatinib the third. As regards innovation and suitability, pyrotinib showed better than other HER2-TKIs. In addition, pyrotinib received a higher recommendation than other HER2-TKIs in patients with HER2-positive MBC. The accessibility of pyrotinib was found to be the best with better urban, rural, and national affordability and lower annual treatment costs. Pyrotinib is more valuable in clinics with better safety, effectiveness, economy, suitability, accessibility, and innovation in HER2-positive MBC. This study could provide references for the clinical application of HER2-TKIs in treating HER2-positive MBC.

Construction of a Metal-Silica Interface for Semihydrogenation of Alkynes.

Fabricating optimum surface structures represents an attractive approach for synthesizing supported catalysts with high activity and specific selectivity. New active sites could be flexibly constructed via the strong metal-support interaction under the redox condition. Herein, we demonstrated the formation of a new Rh-Si surface on a silica-modified carbon nanotube supported Rh catalyst under the high-temperature reduction condition as well as a thin amorphous silica coating layer and weak chemisorption toward the CO molecule. The electronic interactions between Rh and Si, along with the particular structure, guarantee desirable catalytic performance for the semihydrogenation of phenylacetylene under mild conditions. This facile approach might be extensively used in constructing new active sites with robust activity and specific selectivity in diverse heterogeneous catalysis systems.

Comparative pharmacokinetics of 11 major bioactive components between two dosage forms of Qixue Shuangbu Prescription in rats by ultra-high-performance liquid chromatography-tandem mass spectrometry.

Although Qixue Shuangbu Prescription (QSP) is a classic Chinese medicine prescription for treating chronic heart failure. Low bioavailability due to the insolubility and poor biofilm permeability of the main bioactive ingredients of QSP is still a key factor limiting its efficacy. In this study, a novel self-microemulsifying drug delivery system was proposed to effectively improve the bioavailability of QSP. The qualified ultra-high-performance liquid chromatography-tandem mass spectrometry methodology was established to investigate the pharmacokinetics characteristics of the QSP self-microemulsifying drug delivery system. Our results showed that 11 components in the self-microemulsifying drug delivery system group had prolonged T1/2 and MRT0-t values compared with QSP extract. The Cmax of calycosin-7-glucoside (CG), vanillic acid and paeoniflorin increased 2.5 times, 2.4 times and 2.3 times, respectively. The relative bioavailability values of CG, paeoniflorin and ononin were most significantly affected, increasing by 383.2%, 336.5% and 307.1%, respectively. This study promoted the development of new dosage forms of QSP and provided a useful reference for improving dosage forms to solve the problem of low bioavailability of traditional Chinese medicine.

Comparative pharmacokinetics of four bioactive components in normal and chronic heart failure rats after oral administration of Qiangxin Lishui Prescription by microdialysis combined with ultra-high-performance liquid chromatography.

Qiangxin Lishui Prescription (QLP) has been clinically applied for treating heart failure with remarkable curative effects. A multi-component pharmacokinetic research is very necessary for determining active substances in it. This study aims to profile the traits and differences in the pharmacokinetics of salvianolic acid B, astragaloside IV, calycosin-7-O-ß-D-glucoside and kaempferol in QLP between normal and chronic heart failure (CHF) rats by microdialysis combined with ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Sensitive, selective, and online microdialysis combined with the UHPLC-MS/MS method was successfully established and applied to study the pharmacokinetics of QLP. The pathological condition of CHF could lead to the enhancement of systematic exposure and reduction of the metabolic rate of four bioactive components for better bioavailability and therapeutic efficacy. The pharmacokinetic results will provide data support for the clinical application of QLP.

Synergistic mechanism of processing method for Qixue Shuangbu prescription in the treatment of chronic heart failure based on plasma metabolomics-Systematic bioinformatics.

Previous clinical studies have found that the efficacy of processed Qixue Shuangbu Prescription has been significantly improved in the treatment of chronic heart failure. However, the absorbed constituents and synergistic mechanisms of processed Qixue Shuangbu Prescription to enhance the therapeutic effect of chronic heart failure remain unclear. In this study, we propose an integrated strategy combining plasma metabolomics, network pharmacology, and molecular docking to study the absorbed constituents and synergistic mechanisms of processed Qixue Shuangbu Prescription. A total of 34 prototype constituents and 24 metabolites were identified in rat plasma after administration of crude and processed Qixue Shuangbu Prescription. As a result, six potential absorbed constituents and six potential targets for the treatment of chronic heart failure were identified. In addition, the result of molecular docking indicated that the key constituents exhibited good affinity to hub targets. This study showed that the multiomics approach could effectively clarify absorbed constituents and synergistic mechanisms of traditional Chinese medicine processing from a new perspective.

Identification and quality evaluation of different processed products of Aconitum carmichaelii by ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry and ultra-high-performance liquid chromatography-tandem mass spectrometry.

Aconitum carmichaelii is widely used to treat chronic and intractable diseases due to its remarkable curative effect, but it is also a highly toxic herb with severe cardiac and neurotoxicity. It has been combined with honey for thousands of years to reduce toxicity and enhance efficacy, but there has been no study on the chemical constituent changes in the honey-processing so far. In this study, the chemical constituents of A. carmichaelii before and after honey-processing were characterized by ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry. The results showed that a total of 118 compounds were identified, of which six compounds disappeared and five compounds were newly produced after honey-processing, and the cleavage pathway of main components was elucidated. At the same time, 25 compounds were found to have significant effects on different products, among which four compounds with the biggest difference were selected for quantitative analysis by ultra-high-performance liquid chromatography-tandem mass spectrometry. This study not only explained the chemical differences between the different products, but also helped to control the quality of the honey-processed products more effectively, and laid a foundation for further elucidating the mechanism of chemical constituent change during the honey-processing of A. carmichaelii.

[Pharmacokinetic study of Polydopamine Guttate Pills loaded with active components of Sarcandrae Herba in rats].

An ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS) method was established for the determination of active components of Sarcandrae Herba, and applied to the pharmacokinetics study of multiple dosage forms. After SD rats were administered by gavage with three dosage forms [Sarcandrae Herba extract, commercial Sarcandrae Herba Guttate Pills, and polydopamine guttate pills loaded with active components of Sarcandrae Herba(PDA-Sg Guttate Pills)], blood samples were collected from the inner canthus at different time points. After protein precipitation, plasma samples were separated on ACQUITY UPLC C_(18) column(2.1 mm×100 mm, 1.7 µm). The mobile phase consisted of water containing 0.2% formic acid and acetonitrile in gradient elution. The negative ions were measured simultaneously in the multi-reaction monitoring(MRM) mode. The pharmacokinetic parameters were calculated and fitted by DAS 2.0. All four components could be detected in the plasma of rats in each group at each time point except the neochlorogenic acid and cryptochlorogenic acid in the Sarcandrae Herba extract group. The guttate pills group showed a significant increase in drug content at each time point. The exposure of the main components of Sarcandrae Herba in blood was effectively increased by PDA-drug loading effect in PDA-Sg Guttate Pills(The AUC_(0-24 h) of neochlorogenic acid, cryptochlorogenic acid, isaziridin and rosmarinic acid reached 2.45, 32.90, 1.54, 4.81 times that of the commercial guttate pills). This study proves the measurability of the above-mentioned multi-component in vitro-in vivo delivery process. The pharmacokinetic study has shown that PDA-Sg Guttate Pills can effectively delay the elimination time and improve the bioavailability of the four components, which can provide theoretical data for the production of the drug.

Comparative pharmacokinetics study of six effective components between two dosage forms of Qixue-Shuangbu Prescription in rats by UPLC-MS/MS.

Qixue-Shuangbu Prescription (QSP) is an efficacious prescription for treating heart failure, myocardial ischemia and other diseases. It is composed of nine Chinese herbs. This study investigated and compared the pharmacokinetics of QSP in rats by UPLC-MS/MS between two dosage forms of traditional decoction (TD) and compound tincture (CT). Owing to the complexity of the chemicals in QSP, ginsenoside Rg1, ginsenoside Re, ferulic acid, astragaloside IV, rhein and calycosin were chosen for the pharmacokinetics study. The method established for detecting serum specimens was shown to have acceptable selectivity, linearity, lower limit of quantitation, precision, accuracy, recovery, matrix effect and stability. The peak concentration, AUC0-t and AUC0-∞ of ginsenoside Re, ginsenoside Rg1, ferulic acid and rhein were significantly increased after oral administration of CT (P < 0.05), the half-life of ferulic acid in the CT group was lower than that in the TD group (P < 0.05) and the half-life and AUC0-∞ of astragaloside IV in the CT group were significantly increased (P < 0.05), which revealed that wine-processing could influence the bioavailability and the elimination of these compounds. For better clinical efficacy, we suggest that the CT dosage form of QSP should be selected.

Optimizing the Void Size of Yolk-Shell Bi@Void@C Nanospheres for High-Power-Density Sodium-Ion Batteries.

Bismuth (Bi) has been demonstrated as a promising anode for Na-ion batteries (NIBs) because it has high gravimetry (386 mA h g-1) and volumetric capacity (3800 mA h cm-3). However, Bi suffers from large volume expansion during sodiation, leading to poor electrochemical performance. The construction of a nanostructure with sufficient void space to accommodate the volume change has been proven effective for achieving prolonged cycling stability. However the excessive void space will definitely decrease the volumetric energy density of the battery. Herein, we design optimized Bi@Void@C nanospheres (Bi@Void@C-2) with yolk-shell structure that exhibit the best cycling performance and enhanced volumetric energy density. The optimized void space not only could buffer the volume change of the Bi nanosphere but also could keep the high volumetric energy density of the battery. The Bi@Void@C-2 shows an excellent rate capacity of 173 mA h g-1 at ultrahigh current density of 100 A g-1 and long-cycle life (198 mA h g-1 at 20 A g-1 over 10 000 cycles). The origin of the superior performance is achieved through in-depth fundamental studies during battery operation using in situ X-ray diffraction (XRD) and in situ transmission electron microscope (TEM), complemented by theoretical calculations and ex situ TEM observation. Our rational design provides insights for anode materials with large volume variation, especially for conversion type and alloying type mechanism materials for batteries (i.e., Li-ion batteries, Na-ion batteries).

Design, Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents.

Phenanthroindolizidines, such as antofine and tylophorine, are a family of natural alkaloids isolated from different species of Asclepiadaceas. They are characterized by interesting biological activities, such as pronounced cytotoxicity against different human cancerous cell lines, including multidrug-resistant examples. Nonetheless, these derivatives are associated with severe neurotoxicity and loss of in vivo activity due to the highly lipophilic nature of the alkaloids. Here, we describe the development of highly polar prodrugs of antofine and tylophorine as hypoxia-targeted prodrugs. The developed quaternary ammonium salts of phenanthroindolizidines showed high chemical and metabolic stability and are predicted to have no penetration through the blood-brain barrier. The designed prodrugs displayed decreased cytotoxicity when tested under normoxic conditions. However, their cytotoxic activity considerably increased when tested under hypoxic conditions.

Radiographic and clinical outcome of lateral lumbar interbody fusion for extreme lumbar spinal stenosis of Schizas grade D: a retrospective study.

BACKGROUND: Extreme lumbar spinal stenosis was thought to be a relative contraindication for lateral lumbar interbody fusion (LLIF) and was excluded in most studies. This is a retrospective study to analyze the radiographic and clinical outcome of LLIF for extreme lumbar spinal stenosis of Schizas grade D. METHODS: For radiographic analysis, we included 181 segments from 110 patients who underwent LLIF between June 2017 and December 2018. Lumbar spinal stenosis was graded according to Schizas' classification. Anterior and posterior disc heights, disc angle, foramen height, spinal canal diameter and central canal area were measured on CT and MRI. For clinical analysis, 18 patients with at least one segment of grade D were included. Visual analogue scale (VAS) and Oswestry disability index (ODI) scores were used to evaluate clinical outcome. Continuous variables were compared using Student's t-test, with P-values < 0.05 considered to indicate statistically significant differences. RESULTS: Among the 181 segments included for radiological evaluation, there were 23 grade A segments, 37 grade B segments, 103 grade C segments and 18 grade D segments. Postoperatively, the average change of midsagittal canal diameter of grade D was significantly greater than that of grade A, and not significantly different compared to grades B and C. As to the average change of disc height, bilateral foraminal height, disc angle and central canal area (CCA), grade D was not significantly different from the others. The average postoperative CCA of grade D was significantly smaller than the average preoperative CCA of grade C. Eighteen patients with grade D stenosis were followed up for an average of 19.61 ± 6.32 months. Clinical evaluation revealed an average improvement in the ODI and VAS scores for back and leg pain by 20.77%, 3.67 and 4.15 points, respectively. Sixteen of 18 segments with grade D underwent posterior decompression. CONCLUSION: The radiographic decompression effect of LLIF for Schizas grade D segments was comparable with that of other grades. Posterior decompression was necessary for LLIF to achieve a satisfactory clinical outcome for extreme lumbar spinal stenosis of Schizas grade D.

Design, Synthesis, and in Vitro Biological Evaluation of 14-Hydroxytylophorine-dichloroacetate Co-drugs as Antiproliferative Agents.

Co-drug, or mutual-prodrug, is a drug design approach consisting of covalently linking two active drugs so as to improve the pharmacokinetics and/or pharmacodynamics properties of one or both drugs. Co-drug strategy has proven good success in overcoming undesirable properties such as absorption, poor bioavailability, nonspecificity, and gastrointestine tract (GIT) side effects. In this work, we successfully developed a co-drug of 14-hydroxytylophorine, a phenanthroindolizidine derivative with remarkable antiproliferative activity, and dichloroacetate, a known inhibitor of pyruvate dehydrogenase kinase. Dichloroacetate steers tumour cell metabolism from glycolysis back to glucose oxidation, which in turn reverses the Warburg effect and renders tumour cells with a proliferative disadvantage. The obtained co-drugs retained the cytotoxicity of 14-hydroxytylophorine. However, they showed similar unselectivity towards normal cells.

Boronic Analogues of (R)-6-O-Desmethylantofine as Anticancer Agents.

Phenanthroindolizidines are naturally occurring alkaloids mainly isolated from different species of Asclepiadaceae. These alkaloids are characterized by an excellent anticancer activity against a very wide range of cancerous cell lines including those who are multi drug resistant. Nevertheless, phenanthroindolizidines are associated with sever neurotoxicity that prevented any candidate from this family to pass the clinical trials. A number of boron-based analogues of (R)-6-O-desmethylantofine have been synthesised. Their physochemical properties were evaluated, same as their in-vitro antiproliferative activity. The pinacol boronate ester derivative (3) showed interesting cytotoxicity against a panel of cancerous cell lines attested by a cancer cell growth-inhibitory potency (GI50) as low as 30 nM.

Expanding indole diversity: direct 1-step synthesis of 1,2-fused indoles and spiroindolines from 2-halo anilines for fast SAR antiviral elucidation against tobacco mosaic virus (TMV).

To systematically investigate the influence of the variation of the original skeletons and spatial configuration of 2,3-fused indole natural products on antiviral activities, two types of structurally novel and potent pseudo-indole natural product derivatives, 1,2-fused indole and spiroindoline, with different substituents were direct synthesized from 2-halo anilines, and their antiviral activities against tobacco mosaic virus (TMV) were evaluated. The results showed that these compounds exhibited good anti-TMV activity, especially 3f, 3g, 3i, 5e, 5h, and 5l, which were more potent than the commercial anti-virus agent ribavirin. An SAR investigation demonstrates that the original ring size, arrangement, and planarity are not optimal; their anti-TMV activities can be improved by skeleton modification and spatial configuration variation. Both of the structurally novel skeletons provide a new template for antiviral studies, which may also provide some useful information for antiviral mechanism elucidation.

Elemental Analysis of Nine Herbal Drugs for Nourishing Blood by Inductively Coupled Plasma Atomic Emission Spectroscopy with Microwave Digestion.

An analytical method has been developed for the determination of traces of Zn, Mn, Na, K, Ca, Mg, Ni, Pb, Se, Fe, Cu, Al, B, Ti, Sn, Hg, and Li in nine herbal drugs for nourishing blood by ICP-AES. The data showed that nine herbal drugs for nourishing blood were abundant in the contents of major and trace elements which are healthy for human body, including the trace elements with higher contents, such as Fe, Se, Ni, Mn, and Zn, which are well known for nourishing blood. Elements (macro-elements, essential elements, non-essential elements, and toxic elements) classified in nine herbal drugs for nourishing blood were illustrated in cylindrical histograms. Principal component analysis and hierarchical cluster analysis were applied to the data matrix to evaluate analytical results. The results of hierarchical cluster analysis showed that dendrogram obtained by Ward's method of hierarchical cluster analysis for seventeen variables and nine samples mainly displayed three clusters. After optimizing the microwave digestion technology, the recoveries of seventeen elements were in the ranges from 97.89% to 103.25% and the RSDs were all lower than 3.0%. ICP-AES combined with microwave digestion is accurate and precise in determining major and trace elements in nine herbal drugs for nourishing blood.

[Research status and prospect of primary processing of traditional Chinese medicinal materials].

The primary processing is important links and closely related to the quality of traditional Chinese medicinal materials, and is not only cleaning of remove the non-officinal parts, drying for termination the physiological status of organisms, but also retaining the most active substances, decreasing the toxic components, and promoting the transformation among chemical ingredients through primary processing. So the traditional primary processing endows with characters, quality, specifications and properties of traditional Chinese medicine, and embodies some important science truth. The traditional primary processing method and technology systems are derived from the long-term practices and experiences, which are distinctive, colorful, diverse, and scientific, which are helpful to development and utilization of traditional Chinese medicine resources. This paper systemically expounds the research status of the Chinese medicine processing method, summarizes the problems in the primary processing of traditional Chinese medicinal materials research, and prospects its bright future.

Stromal cell-derived factor-1 and its receptor CXCR4 are upregulated expression in degenerated intervertebral discs.

BACKGROUND: Although chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 induce degradation of articular cartilage in rheumatoid arthritis (RA) and osteoarthritis (OA), the association between the SDF-1/CXCR4 pathway and degradation of the cartilaginous endplate and nucleus pulposus has not been thoroughly clarified. We investigated the expression of SDF-1 and CXCR4 in intervertebral discs (IVDs). METHODS: SDF-1 and CXCR4 levels in human IVDs and the rat L5/6 motion segment were quantified by enzyme-linked immunosorbent assay. SDF-1 staining was quantified using a microscope and Image-Pro Plus software. Integrated optical density (IOD) served as the measurement parameter. The number of CXCR4 immunoreactive cells was expressed as a percentage of the total number of cells. RESULTS: SDF-1 and CXCR4 were both expressed in IVDs, and the levels of SDF-1 and CXCR4 were both significantly higher in the degeneration group than in the normal group of human (or rat) discs. Both nucleus pulposus cells and cartilaginous endplate cells expressed the CXCR4 protein. Furthermore, a positive correlation was observed between the SDF-1 IOD value and the percentage of CXCR4-positive disc cells in the nucleus pulposus and cartilaginous endplate. The SDF-1 IOD values were significantly higher in the outer annular fibrosus and bone/endplate junction region than in the nucleus pulposus and cartilaginous endplate in the rat specimens. CONCLUSIONS: Our findings suggest upregulated expression of SDF-1 and its receptor CXCR4 in degenerated IVD.

[Perspective and application of metabonomics in modern study of traditional Chinese medicine].

Metabonomics is a new method to study on the metabolic network and the relationship between body and environment, which conforms to the way of traditional Chinese medicine (TCM) research. In the study process of modernization of traditional Chinese medicine, effectively conjunction with metabonomics method will facilitate the integration of TCM with modern biological science and technology, and promote the modernization of TCM. This paper introduce the application of metabonomics in the research of toxicity mechanism of TCM, compatibility mechanism of TCM formula, pharmacology effect of TCM and processing mechanism of TCM. This paper summarize the problems in the TCM metabonomics research and prospect its bright future.

Unveiling changes in the complexation of dissolved organic matter with Pb(II) by photochemical and microbial degradation using fluorescence EEMs-PARAFAC.

Dissolved organic matter (DOM) is very important in determining the speciation, behaviors, and risk of metal pollutants in aquatic ecosystems. Photochemical and microbial degradation are key processes in the cycling of DOM, yet their effects on the DOM-Pb(II) interaction remain largely unknown. This was studied by examining the complexation of river DOM with Pb(II) after degradation, using fluorescence quenching titration and excitation-emission matrices-parallel factor analysis (EEMs-PARAFAC). Three humic-like and two protein-like components were identified, with strong removals of humic-like components and decreasing average molecular weight and humification degree of DOM by photo- and photo-microbial degradation. The changes in humic-like abundance and structure resulted in notable weakening of their interaction with Pb(II). The tryptophan-like C2 was also mainly removed by photo-degradation, while the tyrosine-like C3 could be either removed or accumulated. The Pb(II)-binding of protein-like components was generally weaker but was enhanced in some degradation groups, which might be related to the lowering competition from humic-like components. The binding parameters correlated significantly with the DOM indices, which were dominated by photo-degradation for humic-like components but by seasonal variations for the tyrosine-like component. These results have implications for understanding the key mechanisms underlying the variability of the DOM-metal interaction in aquatic environments.

Exploring the Efficacy Enhancement Mechanism of Qixue Shuangbu prescription after TCM processing for treating chronic heart failure by regulating ERK/Bcl-2/Bax/Caspases-3 signaling pathway.

Qixue Shuangbu prescription (QSP) has been used for the treatment of chronic heart failure (CHF) with remarkable curative effect. Processed QSP (PQSP) could significantly improve the treatment of CHF after traditional Chinese medicine (TCM) processing. This study elucidated the underlying efficacy enhancement mechanism of QSP after TCM processing for treating CHF in vitro and in vivo. The injury of rat cardiomyoblast H9c2 cells was induced by anoxia/reoxygenation to mimic CHF state in vitro. Sixty Sprague-Dawley rats were used to established CHF model by intraperitoneally injecting doxorubicin (the accumulative dose 15 mg/kg). Biochemical examinations were performed in serum and cellular supernatant, respectively. Cardiac functions and histopathological changes were evaluated in CHF model rats. The protein and mRNA levels of ERK1/2, Bcl-2, Bax and Caspase-3 were evaluated by Western blot and RT-PCR, respectively. All above results of low dose crude QSP-treated group (L-CQSP), high dose CQSP-treated group (H-CQSP), low dose PQSP-treated group (L-PQSP), high dose PQSP-treated group (H-PQSP) were compared to systematically explore correlations between TCM processing and the efficacy enhancement for treating CHF of PQSP. Compared with the model group, the L-CQSP group showed significant improvement in cardiac function at 8th weeks, while no significant improvement in cardiomyocyte apoptosis and fibrosis. Both H-CQSP, L-PQSP and H-PQSP exerted beneficial therapeutic effects in injured H9c2 cardiomyocytes and CHF model rats. L-PQSP and H-PQSP significantly increased cell viability and the activity of SOD, decreased the activities of LDH, MDA and NO, up-regulated the expression of ERK1/2 and Bcl-2, down-regulated the expression of Bax and Caspase-3 compared to the same dosage of CQSP. The efficacy enhancement mechanism of PQSP after TCM processing for treating CHF was directly related to the regulation of ERK/Bcl-2/Bax/Caspases-3 signaling pathway.