ObjectivesRitanine (HR20013) is a fixed-dose combination of fosrolapitant (218 mg, a rolapitant prodrug) and palonosetron (0.25 mg), designed to enhance rolapitant’s solubility and reduce allergic reactions associated with intravenous administration. Metabolized primarily by the liver, hepatic impairment may affect its pharmacokinetics (PK) and safety.MethodsThis nonrandomized, open-label, single-dose study evaluated the effect of moderate hepatic impairment on Ritanine’s PK and safety. Eight subjects with moderate hepatic impairment and eight healthy controls each received a single intravenous infusion.ResultsCompared with healthy controls, the geometric least-squares mean ratios for Cmax, AUC0-t, and AUC0−∞ in subjects with moderate hepatic impairment were 1.27, 1.51, and 1.51 for fosrolapitant; 0.61, 1.15, and 1.24 for rolapitant; 0.74, 0.85, and 1.13 for metabolite M19; and 0.90, 1.77, and 1.46 for palonosetron, respectively. Hepatic impairment did not significantly alter the Tmax or elimination half-life (t1/2) of the above components. Ritanine exhibited good safety and tolerability in this study.ConclusionModerate hepatic impairment has a minimal impact on the pharmacokinetics of Ritanine, suggesting that no dosage adjustment is necessary for patients with moderate hepatic impairment in clinical practice.Clinical Trail Registrationhttp://www.chinadrugtrials.org.cn, identifier CTR20233771.

Breast cancer is the most prevalent cancer and the second leading cause of cancer-related mortality among women globally, resulting in considerable psychological and physical distress for patients. Our previous study synthesized a novel derivative, 2-Deoxy-Rh2, which exhibited anticancer properties by influencing glycolysis and mitochondrial respiration. The objective of the current study was to investigate the anti-proliferative effects and underlying mechanisms of 2-Deoxy-Rh2 on human breast cancer cell lines MCF-7 and MDA-MB-231. In our experiments, we observed that 2-Deoxy-Rh2 reduced cell viability and induced cell cycle arrest, reactive oxygen species accumulation, and mitochondrial dysfunction. Furthermore, treatment with 2-Deoxy-Rh2 affected autophagic flux and induction, leading to increased expression of microtubule-associated protein light chain 3B (LC3B) and decreased expression of sequestosome 1 (P62) expression in both two breast cancer cell lines, which could be reversed by 3-Methyladenine (3-MA). Additionally, the AMPK signaling pathway plays a crucial role in 2-Deoxy-Rh2-induced autophagy. 2-Deoxy-Rh2 modulated the expression levels of mTOR and AMPK in MCF-7 and MDA-MB-231 cells, resulting in the cellular homeostasis disruption, autophagy and apoptosis, which was further corroborated by compound C (CC). Finally, the study validated the antitumor activity and mechanism of 2-Deoxy-Rh2 in vivo using Balb/c mice bearing 4T1 tumor cells. Overall, the results suggest that 2-Deoxy-Rh2 can induce apoptosis and autophagic cell death through the AMPK/mTOR signaling pathway, positioning it as a promising candidate for an antitumor agent against breast cancer.

The phenomena of intramolecular self-assembly of bidesmosidic kalopanaxsaponins was identified for the first time in this paper. NMR (1H-NMR, NOESY), transmission electron microscopy (TEM), and molecular dynamics (MD) simulation techniques were used to compare the spatial structures of bidesmosidic kalopanaxsaponins and monodesmosidic kalopanaxsaponins. The results showed that the bidesmosidic kalopanaxsaponins formed a clustered and twisted structure in space, whereas the monodesmosidic kalopanaxsaponins were in an extended state. This discovery confirmed the presence of intramolecular self-assembly in bidesmosidic kalopanaxsaponins.

Abstract Periodontitis is a chronic inflammatory disease characterized by periodontal tissue destruction and tooth loss. Clinically, the failure of periodontal therapy stems largely from an inability to control the inflammatory response. Resolution of inflammation is an active, energy-requiring repair process, not merely a passive termination of inflammation. AMP-activated protein kinase (AMPK), a key energy sensor, has been shown to negatively regulate inflammatory signaling pathways. ETC-1002 is an activator of AMPK. This study aimed to investigate the anti-inflammatory effects of ETC-1002 through modulating AMPK in periodontitis. Results suggested that ETC-1002 exerts anti-inflammatory effects in Pg-LPS-treated RAW264.7 cells via the AMPK/NF-κB pathway in vitro, and inhibits the progress of experimental periodontitis in mice in an AMPK signaling-dependent manner in vivo. These results provide evidence for the beneficial effects of ETC-1002 in the treatment of periodontitis.

RATIONALE:Panax ginseng (PG) and American ginseng (AMG) are both medicinal plants of the Panax genus in the Acanthopanax family. Although PG and AMG have similar components of ginsenosides, there are many differences of their bioactivities. In this study, the biochemical mechanisms of different bioactivities of PG and AMG were explored by researching the differential metabolites in plasma after administration of each of PG and AMG.METHODS:In order to explore the material basis of differential bioactivities, two groups of mice were administrated orally with PG and AMG, and the method of metabolomics was used to identify the differential metabolites in plasma. Then network pharmacology was used based on the differential metabolites. Afterward, the metabolite-target-pathway network of PG and AMG was constructed; thus the pathways related to different bioactivities were analyzed.RESULTS:Through principal component analysis and orthogonal projections to latent structures discriminant analysis, there were 10 differential metabolites identified in the PG group and 8 differential metabolites identified in the AMG group. Based on network pharmacology, the differential metabolites were classified and related to differential bioactivities of PG and AMG. In the PG group, there were 6 metabolites related to aphrodisiac effect and exciting the nervous system, and 5 metabolites associated with raised blood pressure. In the AMG group, 5 metabolites were classified as having the effect of inhibiting the nervous system, and 6 metabolites were related to antihypertensive effect.CONCLUSIONS:This study explored the material basis of the differential biological activities between PG and AMG, which is significant for the research of PG and AMG use and to promote human health.

Background. Clinically, the failure of periodontal therapy stems largely from an inability to control the inflammatory response. Resolution of inflammation is an active, energy-requiring repair process, not merely a passive termination of inflammation. AMP-activated protein kinase (AMPK), a key energy sensor, has been shown to negatively regulate inflammatory signaling pathways. Thus, there is a crucial need for new therapeutic strategies to modulate AMPK and to promote enhanced resolution of inflammation. This study is aimed at investigating the anti-inflammatory effects of ETC-1002 through modulating AMPK in periodontitis. Methods. RAW264.7 cells were infected with Pg-LPS in the presence or absence of ETC-1002, following which the expression levels of proinflammatory cytokines and inflammation signaling-related proteins were evaluated by real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. ETC-1002 was applied in a murine model of periodontitis to determine its anti-inflammatory effect in vivo. Histological changes were investigated by hematoxylin and eosin (H&E) staining, the levels of proinflammatory cytokines were detected using immunohistochemistry, and alveolar bone height was measured using micro-CT imaging. Results. ETC-1002 inhibited the production of proinflammatory cytokines, promoted AMPK phosphorylation, and decreased IκBα and NF-κB p65 phosphorylation levels in Pg-LPS-treated RAW264.7 macrophages. The inhibitory effects of ETC-1002 on the production of proinflammatory mediators were significantly abrogated by siRNA-mediated silencing of AMPKα in RAW264.7 cells. In vivo, ETC-1002 inhibited inflammatory cell infiltration, the expression of proinflammatory cytokines, and the inflammation-mediated destruction of alveolar bone in mice with experimental periodontitis. The anti-inflammatory effect of ETC-1002 in the periodontium could be reversed by the administration of Compound C, an AMPK inhibitor. Conclusions. ETC-1002 exerts anti-inflammatory effects in Pg-LPS-treated RAW264.7 cells via the AMPK/NF-κB pathway in vitro and inhibits the progress of experimental periodontitis in mice in an AMPK signaling-dependent manner in vivo. These results provide evidence for the beneficial effects of ETC-1002 in the treatment of periodontitis.

Monitoring the concentration of dopamine (DA) is vital for preventing and diagnosing DA related diseases. In contrast to the traditional sensing methods for DA, in which direct or indirect effects on the optical probes are often recorded, a novel sensing concept is disclosed based on as a result of the in situ formation of polydopamine (PDA) originating from the synergetic effect between boron nitride quantum dots (BNQDs) and Cu2+. In the co-presence of BNQDs and Cu2+, DA was catalytically oxidized to PDA, accompanied by an obvious color change from colorless to brown. In contrast to previous reports, in which BNQDs have been employed as an optical probe, herein, the BNQDs not only acted as the optical energy donor, but also as the catalysts for the formation of PDA. The quenching efficiency resulting from the inner filter effect and the electron transfer between the BNQDs and PDA was directly proportional to the concentration of DA, ranging linearly from 2 to 80 μM with a limit of detection of 0.49 μM. The present system exhibited an outstanding selectivity for DA among other interfering coexisting biomolecules. Furthermore, the practical application of the proposed platform was verified by assaying DA in human plasma samples, and satisfactory recoveries ranging from 101.24% to 111.98% were obtained. With the satisfactory reliability, repeatability and stability, the proposed simple sensor showed significant potential for use in DA detection in other biomedical applications.

20(S)-Rh2 is a ginsenoside isolated from Panax ginseng, which exhibits anti-cancer activities on various human cancer cells. A novel 20(S)-Rh2 derivative, 2-Deoxy-Rh2 was synthesized and hybridized with protopanaxadiol and 2-deoxy-glucose in an attempt to enhance the anticancer activity. Through screening the antitumor effect against various cell lines by MTT assay, 2-Deoxy-Rh2 especially resulted in a concentration-dependent and time-dependent inhibition of viability in MCF-7 human breast cancer cells. Multiple methods were used to explore the cellular and molecular mechanisms of 2-Deoxy-Rh2 as a potent anti-cancer agent. In MCF-7 cells, 2-Deoxy-Rh2 triggered apoptosis, stimulated ROS production and disrupted normal mitochondrial membrane potential. Meantime, 2-Deoxy-Rh2 eff ;ectively suppressed the glucose uptake capabilities and intracellular ATP production. The cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were significantly decreased in response to 2-Deoxy-Rh2, which were carried out to assess the overall glycolytic flux and mitochondrial respiration. Docking studies and molecular dynamics simulations were performed to verify the binding mode of 2-DG and 2-Deoxy-Rh2 with hexokinase II, with results showing that 2-Deoxy-Rh2 could easily fit into the similar active site of 2-DG, finally binding to hexokinase II to suppress glycolysis. Taken together, the results suggest that 2-Deoxy-Rh2 exhibited remarkable anticancer activity based on regulating mitochondrial apoptosis pathway, dampening glycolysis and inhibiting mitochondrial respiration, which support development of 2-Deoxy-Rh2 as a potential agent for cancer therapy.

A new facile method for determination of anesthetic drug propofol based on quenching of electrochemiluminescence (ECL) was presented. When propofol was introduced to tris(2,2’-bipyridyl)-ruthenium (II)/tripropylamine system, an obvious decrease of ECL signal was observed due to the energy transfer between the excited state of Ru(bpy)32+ * and the electro-oxidation products of propofol. Under optimum conditions, the inhibited ECL response was linearly with the propofol concentration in the range of 20–8000 ng/mL with a detection limit of 10 ng/mL (S/N = 3). Moreover, the proposed sensing platform showed good reproducibility with relative standard deviation of 5.6% for 5 µg/mL propofol (n = 5). Finally, the proposed method was applied for detection of propofol in human serum with satisfactory recoveries. As a sensitive, rapid, simple and cost-effective method, the sensing platform holds great potential in determination of propofol.

Rationale Panax ginsengC.A. Meyer (PG), which contains polysaccharides and ginsenosides as the major bioactive components, has been used to promote health and treat diseases for thousands of years in China. Total ginsenosides were extracted from a decoction ofPanax ginseng(GD), which included both ginsenosides and polysaccharides, and dissolved in water to obtain a total ginsenosides aqueous solution (TGAS). To study their absorption and metabolism, the pharmacokinetics (PK) and metabolites of ginsenosidesin vivowere investigated after the administration of GD and TGAS. Methods Rat and mice plasma samples were collected after the administration of GD and TGAS. Ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry was used with the UNIFI platform to identify metabolites in the plasma sample. The pharmacokinetic parameters were calculated using a noncompartmental method in the Drug and Statistics software package. Results Thirty ginsenoside metabolites were identified in mice plasma, of which only seven were found in the rat plasma after the administration of GD. The PK of ginsenosides Rb-1, Rc, and Rd were also determined after the oral administration of GD and TGAS and showed significant differences in the pharmacokinetic parameters. Conclusions There was no difference in the biotransformation pathways after the oral administration of GD and TGAS, indicating that there was no influence of polysaccharides on the biotransformation of ginsenosidesin vivo. However, the pharmacokinetic parameters were different after the administration of GD and TGAS, possibly because of the polysaccharides in GD. This study should be of significance in exploring the basis of PG bioactivities and lays the foundation for the further development of new drugs using PG.

Ginsenoside Rh2 is a primary bioactive compound obtained from ginseng that indicated anticancer activities against several malignant tumors. However, previous studies have reported little about the inhibitory effect of Rh2 on osteosarcoma (OS). This study aims to explore whether Rh2 could exert anticancer effects in OS cells and further investigate the proliferation, migration, and apoptosis mechanisms induced by Rh2 in human OS U20S cell line. The viability of U20S cells was obtained by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay. Cell migration property was analyzed by wound-healing assay. Apoptosis was visualized using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), 4',6-diamidino-2-phenylindole (DAPI), and annexin V/propidium iodide (PI) staining. Relative protein expressed was confirmed through Western blot analysis. Mitochondrial membrane potential was evaluated by JC-1 staining. In this study, we used broad-spectrum anticancer drug cisplatin (CP) as a positive control. The results indicated that Rh2 remarkably inhibited cell viability of U20S cells in a dose- and time-dependent manner, and suppressed migration. TUNEL, DAPI, annexin V/PI, and JC-1 assay suggested that Rh2 could induce cellular apoptosis. Rh2 could reduce the levels of Bcl-2, caspase 3, and caspase 9, and promote the expression level of Bax in U20S cells. Moreover, Rh2 could induce apoptosis by promoting mitogen-activated protein kinase (MAPK) signaling pathway and inhibit PI3K/Akt/mTOR and nuclear factor-κB (NF-κB) signaling pathway in U20S cells. These findings indicated that Rh2 has an anticancer effect on U20S cells by regulating MAPK, PI3K/Akt/mTOR, and NF-κB signaling pathway.

Pharmacokinetic and metabolism studies were carried out on curculigoside C (CC), a natural product with good antioxidant and neuroprotective effects, with the purpose of investigating the effects of the hydroxyl group at C-3′ in curculigoside. A rapid and sensitive method with UPLC-MS was developed and fully validated for the first time in the pharmacokinetic analysis for quantification of CC in rat plasma. The assay was linear (R2 > 0.9984) over the concentration range of 1–2500 ng/mL, with the lower limit of quantification (LLOQ) being 1 ng/mL. The intra-day and inter-day precision (expressed as relative standard deviation, RSD) ranged from 4.10% to 5.51% and 5.24% to 6.81%, respectively. The accuracy (relative error, RE) ranged from −3.28% to 0.56% and −5.83% to −1.44%, respectively. The recoveries ranged from 92.14% to 95.22%. This method was then applied to a pharmacokinetic study of rats after intragastric administration of 15, 30 and 60 mg/kg CC. The results revealed that CC exhibited rapid oral absorption (Tmax = 0.106 h, 0.111 h, and 0.111 h, respectively), high elimination (t1/2 = 2.022 h, 2.061 h, and 2.048 h, respectively) and low absolute bioavailability (2.01, 2.13, and 2.39%, respectively). Furthermore, an investigation on the metabolism of CC was performed by UPLC-QTOF-MSE. Twelve metabolites of CC from plasma, bile, urine and faeces of rats were confirmed. The main metabolic pathways of CC, which involve dehydration, glucosylation, desaturation, formylation, cysteine conjugation, demethylation and sulfonation, were profiled. In conclusion, this research has developed a sensitive quantitative method and demonstrated the metabolism of CC in vivo.

The present study assessed the therapeutic potential of omeprazole (OME), the most commonly prescribed proton pump inhibitor (PPI) used to treat gastroesophageal hyperacidity, against cisplatin (CP)-induced toxicity in human renal tubular HK-2 cells and rat kidneys. Herein, we observed that exposure of HK-2 cells to OME reversed the injury caused by CP, including enhancing cell viability and alleviating intracellular reactive oxygen species (ROS) generation and membrane damage. Concomitantly, acute exposure of male SD rats to CP induced histopathological changes, which were prevented by co-administration with OME. Inflammation and oxidative stress were inhibited by OME during CP-induced renal injury by increasing the activity of superoxide dismutase, and reducing the levels of malondialdehyde, both in vivo and in vitro. The expression levels of major inflammatory response markers were significantly decreased in HK-2 cells and rat kidneys in response to OME. OME reduced CP cellular uptake through organic cation transporters 2 (OCT2) and the prompt efflux of CP by P-glycoprotein (P-gp), thereby reducing the accumulation of CP in kidney tissue and increasing its serum levels. These data demonstrate that CP-induced kidney damage is positively correlated with its cellular accumulation. Concurrently, OME showed renoprotective effect against CP-induced toxicity in HK-2 cells and rat kidneys, by suppressing oxidative stress and mediating NF-κB-dependent inflammation, apoptosis, and transporter function. As OME is commonly used in combination with CP during chemotherapy treatment, this study highlights the clinical significance of OME in alleviating CP-induced nephrotoxicity.

Folate-conjugated stearic acid-grafted Bletilla striata polysaccharides copolymers (FA-BSPs-SA) were prepared and characterized using H-1 nuclear magnetic resonance spectroscopy (H-1 NMR), ultraviolet visible spectrophotometry (UV) and infrared spectroscopy (IR). Docetaxel-loaded FA-BSPs-SA (DTX-loaded FA-BSPs-SA) micelles were prepared by an emulsion-solvent evaporation method and characterized. The cytotoxicity of copolymers and DTX-loaded micelles was evaluated by MTT assay. The results of H-1 NMR and IR demonstrated that stearic acid and folic acid have been grafted on Bletilla striata polysaccharide. Docetaxel could be entrapped into micelles of FA-BSPs-SA copolymer. DTX-loaded BSPs-SA copolymer micelles displayed pH-dependent properties in the respects of in vitro release behavior ranging from pH = 5. 0 to pH = 7. 4. The particle sizes of DTX-loaded micelles decreased whereas encapsulation efficiency and loading capacity increased with the substitution degree increase of folic acid. The cell survival rates subjected to FA-BSPs-SA and BSPs-SA were still above 80% at the concentration of 40 mu g/mL. The anti-tumor effect in vitro of DTX-loaded FA-BSPs-SA and DTX-loaded BSPs-SA micelles were superior to that of DTX solution at the same concentration. More-over, DTX-loaded FA-BSPs-SA micelles exhibited stronger inhibitory effects on tumor cells with foate receptor expression in comparison to DTX-loaded BSPs-SA micelles. FA-BSPs-SA polymers are expected to be nanoscale materials for hydrophobic antitumor drugs.

A method was established for determination Gibberellin in Massoniana Pollen by UPLC/Q-TOF/MS.Samples were extracted with 80％ ethanol,and were extracted by butyl alcohol.The target analytes were separated on a BEH-C18 column with gradient elution using a mobile phase made up of acetonitrile and water.The result showed that contents of Gibberellin in Pius Massoniana Pollen is 0.075mg/g,The linearities of Gibberellin were in the concentration range of50μg/mL-250μg/mL(r=0.9994,n=3),the average recovery was 92.2％(RSD％=1.5,n=3).Providing a new chromatographic technology for the content analysis of Gibberellin in the Massoniana Pollen,the method was proved to be simple,convenient,sensitive and good stability.

OBJECTIVE To develop an UPLC-MS/MS method for the determination of neopanaxadiol (NPD) in rat plasma sample,and to investigate plasma protein binding rate of NPD in rats.METHODS Under three different concentrations,equilibrium dialysis method was utilized to imitate the binding process between NPD and plasma protein.The concentration of NPD in and out of the dialysis membrane was determined by UPLC-MS/MS and the plasma protein binding rate of NPD were calculated.RESULTS Excellent linearity was found between 0.05-8 μg · mL-1.Intra-and inter-day precision values (RSD) of QC samples were both below 15％ and the extraction recoveries of NPD from biological matrices were better than 79.37％.The plasma protein binding rates of NPD were (86.55 ± 4.50) ％、(76.50 ± 2.61) ％ and (78.25 ± 1.32) ％ at low,middle and high concentrations,respectively.There was no significant difference among three concentrations.CONCLUSION These results indicate the high plasma protein binding rates of NPD in plasma in combination mode.

Fermentation technology optimization of ginsenoside Re biotransformed into ginsenoside Rg 2 by orthogonal test and calculate yield of ginsenoside Rg2 ;Useing fermation time ,fermation temperature ,added content of composite enzymatic as model by HPLC ,to optimization gin-senoside fermentation condition and correlation analysis ;Ginsen fermentation technology was fermation temperature 60℃ ,added content of com-posite enzymatic 10% ,fermation time 10 days;To apply the fermentation technology optimization of ginsenoside ,it is the new way available for the ginsenoside Rg2 industrialized production .

The objective of this study was to investigate the effects of velvet antler protein (VAP) on fracture healing in mice .Analyzing X-ray radiography ,tissue pathological slices ,serum IGF-1 and alkaline phosphatase(ALP) content to observe the effects of intramuscular injection VAP on fracture model mice .Compared with the control group and Jiegupian group ,intramuscular injection VAP can obviously accelerated frac-ture healing .Fracture line disappeared and marrow cavity unobstructed from the test of X ray so 58mg/kg VAP can significantly promote the ef-fect of fracture healing in mice ;The HE staining shows 58mg/kg VAP makes bone marrow cavity was saturated with large number of bone mar-row cells and more dense bony connection .Given 58mg/kg VAP results serum IGF-1 and ALP levels higher than the control group and Jiegu-pian group .The dose of 58mg/kg VAP had the effect on promoting bone formation and fracture healing with high level of ALP and IGF -1 in mice blood .