Destructive interference in N2+ lasing.

We report an unexpected experimental observation in rotation-resolved N2+ lasing that the R-branch lasing intensity from a single rotational state in the vicinity of 391 nm can be greatly stronger than the P-branch lasing intensity summing over the total rotational states at suitable pressures. According to a combined measurement of the dependence of the rotation-resolved lasing intensity on the pump-probe delay and the rotation-resolved polarization, we speculate that the destructive interference can be induced for the spectrally-indistinguishable P-branch lasing due to the propagation effect while the R-branch lasing is little affected due to its discrete spectral property, after precluding the role of rotational coherence. These findings shed light on the air-lasing physics, and provide a feasible route to manipulate air lasing intensity.

Vertical and porous MoS2-CoS2heterojunction nanosheet arrays as highly efficient bifunctional electrocatalysts for oxygen and hydrogen evolutions.

Highly efficient water electrolytic agents are restricted by the lack of cheap and Earth-abundant catalysts that can manipulate at unharsh conditions and be prepared with a simple procedure. Here, hierarchically vertical and porous MoS2-CoS2heterojunction nanosheet arrays are designed and fabricated. The MoS2-CoS2nanosheets are composed of ultrasmall nanocrytallites with the dimension of ∼62 nm. This special and novel architecture presents synergistic properties to create excellent oxygen evolution reaction (OER) and hydrogen evolution reaction (HER), where high density active sites generated by ultrasmall nanocrytallites with heterostructures, and the vertical and porous structure accelerates electrolyte transport with luxuriant channels while this hierarchically collaborative framework guarantees completely exposed active sites to electrolytes. This electrode shows low overpotentials of 295 and 103 mV at 10 mA cm-2, small Tafel slopes of 70 and 78 mV dec-1, and long stability for OER and HER, respectively. This work indicates that vertical and porous heterojunction nanosheet arrays with hierarchically ultrasmall secondary nanostructures are a promising catalyst for widespread application.

An integrated strategy by absorbed component characterization, pharmacokinetics, and activity evaluation for identification of potential nephroprotective substances in Zhu-Ling decoction.

An efficient strategy for the identification of potential nephroprotective substances in Zhu-Ling decoction has been established with the integration of absorbed components characterization, pharmacokinetics, and activity evaluation. A qualitative method was developed to characterize the chemical constituents absorbed components in vivo of Zhu-Ling decoction by using ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry. A quantitative method was established and validated for the simultaneous determination of eight compounds in rat plasma by using ultra-performance liquid chromatography-triple quadruple tandem mass spectrometry. Finally, the nephroprotective activities of absorbed components with high exposure were assessed by cell survival rate, superoxide dismutase, and malondialdehyde activities in hydrogen peroxide-induced Vero cells. As a result, 111 compounds in Zhu-Ling decoction and 36 absorbed components were identified in rat plasma and urine, and poricoic acid A, poricoic acid B, alisol A, 16-oxo-alisol A, and dehydro-tumulosic acid had high exposure levels in rat plasma. Finally, poricoic acid B, poricoic acid A, 16-oxo-alisol A, and dehydro-tumulosic acid showed remarkable nephroprotective activity against Vero cells damage induced by hydrogen peroxide. Besides, superoxide dismutase and malondialdehyde activities were obviously regulated in hydrogen peroxide-induced Vero cells by treatment with the four compounds mentioned above. Therefore, these four compounds were considered to be effective substances of Zhu-Ling decoction due to their relatively high exposure in vivo and biological activity. This study provided a chemical basis for the action mechanism of Zhu-Ling decoction in the treatment of chronic kidney diseases.

Advanced data post-processing method for rapid identification and classification of the major triterpenoids of Alismatis rhizoma by ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry.

INTRODUCTION: Alismatis rhizoma (AR), a distinguished diuretic traditional Chinese herbal medicine, is widely used for the treatment of diarrhea, edema, nephropathy, hyperlipidemia, and tumors in clinical settings. Most beneficial effects of AR are attributed to the major triterpenoids, whose contents are relatively high in AR. To date, only 25 triterpenoids in AR have been characterized by LC-MS because the low-mass diagnostic ions are hardly triggered in MS, impeding structural identification. Herein, we developed an advanced data post-processing method with abundant characteristic fragments (CFs) and neutral losses (NLs) for rapid identification and classification of the major triterpenoids in AR by UPLC-Q-TOF-MSE . OBJECTIVE: We aimed to establish a systematic method for rapid identification and classification of the major triterpenoids of AR. METHODS: UPLC-Q-TOF-MSE coupled with an advanced data post-processing method was established to characterize the major triterpenoids of AR. The abundant CFs and NLs of different types of triterpenoids were discovered and systematically summarized. The rapid identification and classification of the major triterpenoids of AR were realized by processing the data and comparing with information described in the literature. RESULTS: In this study, a total of 44 triterpenoids were identified from AR, including three potentially new compounds and 41 known ones, which were classified into six types. CONCLUSION: The newly established approach is suitable for the chemical profiling of the major triterpenoids in AR, which could provide useful information about chemical constituents and a basis for further exploration of its active ingredients in vivo.

Pharmacokinetics, hepatic disposition, and heart tissue distribution of 14 compounds in rat after oral administration of Qi-Li-Qiang-Xin capsule via ultra-high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry.

In the present study, a specific and sensitive approach using ultra-high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry was developed and validated for the quantitative analysis of 14 constituents in rat plasma, liver, and heart. The method was fully validated and successfully applied to pharmacokinetic, hepatic disposition, and heart tissue distribution studies of 14 compounds after the oral administration of Qi-Li-Qiang-Xin capsule. Ginsenoside Rb1, alisol A, astragaloside IV, and periplocymarin were found to be highly exposed in rat plasma, while toxic components such as hypaconitine, mesaconitine, and periplocin had low circulation levels in vivo. Moreover, sinapine thiocyanate, neoline, formononetin, calycosin, and alisol A exhibited significant liver first-pass effects. Notably, high levels of alisol A, periplocymarin, benzoylmesaconine, and benzoylhypaconine were observed in the heart. Based on high exposure and appropriate pharmacokinetic features in the systemic plasma and heart, astragaloside IV, ginsenoside Rb1, periplocymarin, benzoylmesaconine, benzoylhypaconine, and alisol A can be considered as the main potentially effective components. Ultimately, the results provide relevant information for discovery of effective substances, as well as further anti-heart failure action mechanism investigations of Qi-Li-Qiang-Xin capsule.

Reoperation with Total Hysterectomy after Incomplete Surgery Is Helpful in Patients with Incidentally Diagnosed Uterine Leiomyosarcoma.

OBJECTIVE: The aim of this study was to evaluate the impact of initial surgical treatments and surgical re-exploration on the oncological outcomes of patients with incidentally diagnosed uterine leiomyosarcoma (uLMS). DESIGN: A retrospective analysis of 87 patients who underwent re-exploration for incidentally diagnosed uLMS at the Fudan University Shanghai Cancer Center was performed. METHODS: Kaplan-Meier and Cox proportional hazards regression models were used for analyses. RESULTS: The median age (range) at diagnosis was 49 (23-76) years. The median disease-free survival (DFS) and overall survival (OS) were 15.1 and 56.7 months, respectively. The Kaplan-Meier curves and log-rank tests showed the median DFS was longer in patients with restaging operation (N = 30) than without (N = 55) (p = 0.017) but no significant difference in median OS (p = 0.142). In patients who underwent myomectomy/subtotal hysterectomy, 5 patients (28.5%) had remnant sarcoma during re-exploration with complete uterine removal, and re-exploration was associated with longer DFS (p = 0.038) and OS (p = 0.042). LIMITATIONS: The limitation of this study is its retrospective observational design with a limited number of patients. CONCLUSION: Reoperation with total hysterectomy after incomplete surgery may be helpful in patients with incidentally diagnosed uLMS at the first treatment.

An integrated strategy for profiling the chemical components of Scutellariae Radix and their exogenous substances in rats by ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry.

RATIONALE: Traditional Chinese medicines (TCMs) attract worldwide attention because of their effects in clinical application recorded in China historical ancient codes and in records, such as 'Treatise on Febrile Diseases'. With the developments of drug analysis and research, evaluating the in vivo substances in TCMs has become of great importance. Scutellariae Radix (SR, named as huang-qing in China), the root of Scutellaria baicalensis Georgi, has shown favorable clinical effects and safety in the treatment of infection diseases; however, its in vivo compounds are unclear and need detailed investigation. METHODS: An ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC/QTOF MS) method coupled to an integrated strategy involving diagnostic ions, neutral losses and a prediction platform was used to explore the constituents of SR, and their exogenous substances in rats. RESULTS: A total of 118 chemical constituents mainly featuring five chemical structure types (flavone C-glycosides, flavone O-glycosides, free flavones, flavanones and phenylethanoid glycosides) were identified or tentatively characterized in SR, and 175 xenobiotics (68 prototypes and 107 metabolites) were profiled in rat plasma, urine, bile and feces after ingestion of SR. The metabolites were classified into four related chemical groups: flavone C-glycosides, flavone O-glycosides, flavanones and phenylethanoid glycosides. Phase II metabolism reactions, such as glucuronidation and sulfation, were the major metabolic reactions in addition to phase I reactions of hydrolysis and hydrogenation. The corresponding main metabolic features of SR in rats were also elucidated. CONCLUSIONS: The metabolism of SR, as a whole, was systemically revealed for the first time, and our work also provided meaningful information for pharmacokinetics studies and pharmacological analysis of SR in future work.

Characterization of chemical components of Periplocae Cortex and their metabolites in rats using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.

Periplocae Cortex, named Xiang-Jia-Pi in China, has been widely used to treat autoimmune diseases, especially rheumatoid arthritis. However, the in vivo substances of Periplocae Cortex remain unknown yet. In this study, an ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used for profiling the chemical components and related metabolites of Periplocae Cortex. A total of 98 constituents were identified or tentatively characterized in Periplocae Cortex: 42 C21 steroidal glycosides, 10 cardiac glycosides, 23 organic acids, 4 aldehydes, 7 triterpenes, and 12 other types. Among them, 18 components were unambiguously identified by comparison with reference standards. In addition, 176 related xenobiotics (34 prototypes and 142 metabolites) were screened out and characterized in rats' biosamples (plasma, urine, bile, and feces) after the oral administration of Periplocae Cortex. Moreover, the metabolic fate of periplocoside S-4a, a C21 steroidal glycoside, was proposed for the first time. In summary, phase II reactions (methylation, glucuronidation, and sulfation), phase I reactions (hydrolysis reactions, oxygenation, and reduction), and their combinations were the predominant metabolic reactions of Periplocae Cortex in rat. It is the first report to reveal the in vivo substances and metabolism feature of Periplocae Cortex. This study also provided meaningful information for further pharmacodynamics study of Periplocae Cortex, as well as its quality control research.

Population Redistribution Among Multiple Electronic States of Molecular Nitrogen Ions in Strong Laser Fields.

We carry out a combined theoretical and experimental investigation on the population distributions in the ground and excited states of tunnel-ionized nitrogen molecules at various driver wavelengths in the near- and midinfrared range. Our results reveal that efficient couplings (i.e., population exchanges) between the ground N_{2}^{+}(X^{2}Σ_{g}^{+}) state and the excited N_{2}^{+}(A^{2}Π_{u}) and N_{2}^{+}(B^{2}Σ_{u}^{+}) states occur in strong laser fields. The couplings result in a population inversion between the N_{2}^{+}(X^{2}Σ_{g}^{+}) and N_{2}^{+}(B^{2}Σ_{u}^{+}) states at wavelengths near 800 nm, which is verified by our experimental observation of the amplification of a seed at ∼391 nm. The result provides insight into the mechanism of free-space nitrogen ion lasers generated in remote air with strong femtosecond laser pulses.

Hybridization of bimetallic cobalt-molybdenum oxide multihole nanosheets with selenium adulteration as advanced bifunctional electrocatalysts for boosting overall water splitting.

Electrocatalytic water splitting produces green and pollution-free hydrogen as a clean energy carrier, which can effectively alleviate energy crisis. In this paper, bimetallic and selenium doped cobalt molybdate (Se-CoMoO4) nanosheets with rough surface are resoundingly prepared. The multihole Se-CoMoO4 nanosheets display ultrathin and rectangular architecture with the dimensions of âˆ¼ 3.5 µm and 700 nm for length and width, respectively. The Se-CoMoO4 electrocatalyst shows remarkable water electrolysis activity and stability. The overpotentials of oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) are 270 and 63.3 mV at 10 mA cm-2, along with low Tafel slopes of 51.6 and 62.0 mV dec-1. Furthermore, the Se-CoMoO4 couple electrolyzer merely requires a cell voltage of 1.48 V to achieve 10 mA cm-2 current density and presents no apparent attenuation for 30 h. This investigation declares that the hybridization of transition bimetallic oxide with nonmetallic adulteration can afford a tactic for the preparation of bifunctional non-precious metal-based electrocatalysts.

[Acupuncture of revised acupoint combination around the skull base for post-stroke mild cognitive impairment: a randomized controlled trial].

OBJECTIVE: To observe the clinical efficacy of acupuncture of revised acupoint combination around the skull base in treating post-stroke mild cognitive impairment (PSMCI), and preliminary explore its action mechanism. METHODS: A total of 76 PSMCI patients were randomly divided into an observation group (38 cases, 4 cases dropped off) and a control group (38 cases, 3 cases dropped off, 1 case was removed). In the observation group, acupuncture of revised acupoint combination around the skull base (bilateral Fengchi [GB 20], Wangu [GB 12], Tianzhu [BL 10] and Yamen [GV 15], Baihui [GV 20]) was used for treatment. In the control group, 8 non-meridian and non-acupoint points at the distal end were selected for shallow puncture treatment. Retaining the needles of 30 min, once every other day,3 times a week for 4 weeks in both groups. The scores of Montreal cognitive assessment (MoCA), mini-mental state examination (MMSE), Barthel index (BI) and serum levels of cystatin C (Cys-C) and homocysteine (Hcy) were compared in the two groups before and after treatment, and the clinical efficacy was evaluated. RESULTS: After treatment, the scores of MoCA were increased compared with those before treatment in the two groups (P<0.05), and the score in the observation group was higher than that in the control group (P<0.05). The scores of MMSE and BI were increased compared with those before treatment in the observation group (P<0.05), and the score of MMSE in the observation group was higher than that in the control group (P<0.05). After treatment, the serum levels of Cys-C and Hcy were decreased compared with those before treatment in the observation group (P<0.05), and lower than those in the control group (P<0.05). After treatment, the serum level of Cys-C was increased compared with that before treatment in the control group (P<0.05). The total effective rate of the observation group was 88.2% (30/34), which was higher than 32.4% (11/34) of the control group (P<0.05). CONCLUSION: Acupuncture of revised acupoint combination around the skull base can improve cognitive function and daily living ability of PSMCI patients, which may be related to the down regulation of serum levels of Cys-C and Hcy.

Simultaneous determination of multiple constituents of Qi-Lin pill by UPLC-MS/MS: Applications to pharmacokinetics and testicular tissue distribution in rats.

Qi-Lin pill (QLP) is an effective traditional Chinese medicine prescription (TCMP) that has been used for the treatment of the oligoasthenozoospermia in China. Recently, some articles described the pharmacological effects of QLP and multiple ingredients in QLP contribute to its effects. However, the pharmacokinetic and target tissue distribution data of QLP are still unknown. In the present study, according to the Bioanalytical Method Validation Guidance of FDA, a sensitive and selective UPLC-MS/MS method was developed and validated for simultaneous determination of multiple constituents in rat plasma and testicular tissue, including morusimic acid A, codonopyrridium B, magnoflorine, emodin, 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (THSG), ecliptasaponin A, paeoniflorin, albiflorin, gallic acid, danshensu, salvianolic acid A, catechin, isosinensetin, nobiletin, formononetin, calycosin, icariside II, icariin and epimedin C. For 19 analytes, the LLOQs reached 0.01-4 ng/mL. And all calibration curves showed favorable linearity (r ≥ 0.9903) in linear ranges. The intra-day and inter-day precision (relative standard deviation) for all analytes was less than 14.92 %, and the accuracies (as relative error) were in the range of - 6.44 % to 6.22 %. Extraction recoveries and matrix effects of analytes and IS were acceptable. All analytes were stable during the assay and storage in plasma samples. The method was successfully applied for the pharmacokinetics and testis distribution of multiple chemical constituents in QLP after a single oral dose. As a result, high exposure of danshensu, gallic acid, paeoniflorin and albiflorin were observed in rat plasma and testicular tissue. Among the flavonoids, isosinensetin and nobiletin had high exposure in testicular tissue. Moreover, alleviation of progesterone reduction was evaluated in H2O2-induced R2C leydig cells, and danshensu, gallic acid, paeoniflorin, albiflorin and nobiletin showed potent activity. Therefore, these five components were considered to be the effective components of QLP due to their relatively high exposure in vivo and biological activity. This finding also provided relevant information on action mechanism of QLP in the treatment of oligoasthenozoospermia.

A prospective randomized controlled study on multiple neoadjuvant treatments for patients with stage IB2 to IIA cervical cancer.

OBJECTIVE: Patients with stage IB2 to IIA cervical cancer have a poor survival regardless of what primary treatment is performed. We conducted a study to demonstrate whether neoadjuvant treatment could offer survival benefits to those patients. METHODS: Between January 2006 and December 2009, 123 patients with stage IB2 to IIA cervical cancer were enrolled and randomly assigned to receive 1 of the following 4 treatments: radical surgery alone (arm RS), brachytherapy with a total dose of 15Gy to point A followed by radical surgery (arm BT), intravenous chemotherapy with cisplatin 50 mg/m plus 5-fluorouracil 750 mg/m at a 2-week interval for 2 courses followed by radical surgery (arm IVCT), or intra-arterial chemotherapy with the same regimen as the IVCT arm followed by radical surgery (arm IACT). Two weeks after neoadjuvant treatment, all patients underwent evaluation for response and operability. Those who were not amenable to surgery received concurrent chemoradiotherapy. RESULTS: With a mean follow-up of 34.8 months, 120 patients were evaluable. Baseline characteristics were similarly distributed in the 4 arms. Clinical overall response rates were 61.3%, 42.9%, and 79.3% in the BT, IVCT, and IACT groups, respectively. Two patients achieved pathological complete response. Three-year progression-free survival rates were 70.7%, 66.3%, 81.5%, and 79.7% in the RS, BT, IVCT, and IACT arms, respectively (P = 0.354). Three-year overall survival was 73.3%, 68.3%, 82.9% and 80.4%, respectively (P = 0.431). Multivariate analysis showed that only lymph node status correlated with progression-free survival. CONCLUSIONS: Neoadjuvant treatment had no significant impact on the outcomes of patients with stage IB2 to IIA cervical cancer.

Radical abdominal trachelectomy for cervical malignancies: surgical, oncological and fertility outcomes in 62 patients.

OBJECTIVE: To report our experience of radical abdominal trachelectomy for patients with cervical malignancies. METHODS: We conducted a retrospective review of a prospectively maintained database of patients undergoing fertility-sparing radical abdominal trachelectomy for cervical malignancies at our institution from 04/2004 to 09/2010. RESULTS: Sixty-four patients with cervical malignancies underwent laparotomy for planned radical abdominal trachelectomy. Two patients needed immediate completion of radical hysterectomy due to unfavorable intraoperative findings. Median age was 29.5 years (range, 11-41). Histology included 8 (12.9%) with adenocarcinoma, 50 (80.65%) with squamous carcinoma, 1 (1.61%) with adenosquamous carcinoma and 3 (4.84%) with botryoid sarcoma. Median number of nodes evaluated was 25 (range, 12-53); Ten (16.13%) patients with pathologic risk factors received adjuvant therapy. Fourteen of 36 IB1 cases had tumor size >2cm. No recurrences were observed at a median follow-up of 22.8 months. Five (8.06%) patients developed postoperative cervical stenosis--all occurred before we started to routinely install T-IUDs during the procedure. Thirty-eight patients completed the survey which aimed to understand what factors influenced these patients' reproductive outcomes. For various reasons, only 10 patients attempted to conceive and 2 of them succeeded. One of them delivered by cesarean section after 39 weeks and the other is currently pregnant. CONCLUSIONS: Radical abdominal trachelectomy seems to be a reasonable option for selected patients whose tumors are no larger than 4cm when conducted by experienced gynecologic oncologists. The main perioperative complication is postoperative cervical stenosis, which could be effectively prevented by installation of a tailed T-IUD during the surgery. Social, familial and physical factors can largely influence the patients' reproductive outcomes. The issues of reproductive concerns and quality of life require further investigation.

Dissection of the potential anti-influenza materials and mechanism of Lonicerae japonicae flos based on in vivo substances profiling and network pharmacology.

Lonicerae japonicae flos.(LJF) was widely used as a drug to treat upper respiratory tract infection or a tea to clear heat in Asian countries for thousands of years. Despite of its curative effects confirmed by modern pharmacological methods, its functional materials and mechanism against influenza were still unclear and needed further investigation. In this study, an integrated strategy based on in vivo substances profiling and network pharmacology was proposed and applied to screen out the potential anti-influenza substances and mechanism of LJF. An UHPLC/Q-TOF MS method was utilized to profile the chemical components in LJF and their metabolites in rats. The targets of absorbed prototypes were predicted by Swiss Target Prediction, and they were further analyzed by String and Kyoto Encyclopedia of Genes and Genomes (KEGG). As a result, a total of 126 chemical components mainly featuring three chemical structure types were characterized, including 70 iridoid glycosides, 17 caffeoylquinic acids, 24 flavonoids, and 15 other types compounds. Among them, ten N-contained iridoid glycosides were characterized as potential novel compounds. Moreover, 141 xenobiotics (74 prototypes and 67 metabolites) were clearly screened out in rat plasma and urine after ingestion of LJF. Phase II reactions (sulfation, glucuronidation, methylation) and phase I reactions (dehydroxylation, hydrogenation, hydrolysis, N-heterocyclization) were the main metabolic reactions of LJF in rats. Further, a total of 338 targets were predicted and TNF, PTGS2 and EGFR were the three main targets involved in the pathology of influenza. In addition to normal NF-κB pathway, T cell signal pathway and mTOR signal pathway were the other patterns for LJF to achieve its anti-flu effects. Our work provided the meaningful data for further pharmacological validation of LJF against influenza, and a new strategy was also proposed for minimizing the process to reveal the mechanism and functional basis of TCMs.

Systematically characterization of in vivo substances of Ziziphi Spinosae Semen in rats by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry analysis.

Ziziphi Spinosae Semen (ZSS), the seeds of Ziziphus jujuba var. spinosa, is widely used in China or other Asian countries for the treatment of insomnia and palpitation. In our previous work, chemical constituents in ZSS were profiled by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UHPLC/Q-TOF MS). Notably, characterization of substances in vivo was of great importance to reveal the therapy basis or mechanism in further work. Till now, there were few reports about in vivo substances' investigation of ZSS. In the present study, an integrated strategy contained represented compounds and diagnostic ions extraction was applied to characterize metabolism feature of ZSS in rats based on UHPLC/Q-TOF MS method. First, the metabolic information of four compounds (spinosin, isovitexin, jujuboside B, betulinic acid) featuring three representative chemical structures (flavonoids, saponins, terpenes) in ZSS was conducted, and their metabolism features were summarized, especially for flavonoid C-glycosides. Second, the absorbed compounds and representative compounds-related metabolites were quickly screened out; during this time, the diagnostic ions were sorted out. Last, with the help of diagnostic ions and summarized metabolic reactions, other metabolites were characterized. As a result, a total of 151 xenobiotics (58 prototypes and 93 metabolites) were identified or tentatively characterized in rats after ingestion of ZSS. Among them, 16 substances were presented in plasma, 114 in urine, 51 in bile, and 120 in feces, respectively. Hydrogenation, hydrolysis, and glucuronidation were the major metabolic reactions of ZSS in rats. The present study provided meaningful data for further pharmacological mechanism research or pharmacokinetics evaluation of ZSS.

Discovery of potential Q-marker of traditional Chinese medicine based on plant metabolomics and network pharmacology: Periplocae Cortex as an example.

BACKGROUND: Quality control exerted great importance on the clinical application of drugs for ensuring effectiveness and safety. Due to chemical complexity, diversity among different producing areas and harvest seasons, as well as unintentionally mixed with non-medicinal parts, the current quality standards of traditional Chinese medicine (TCM) still faced challenges in evaluating the overall chemical consistency. PURPOSE: We aimed to develop a new strategy to discover potential quality marker (Q-marker) of TCM by integrating plant metabolomics and network pharmacology, using Periplocae Cortex (GP, the dried root bark of Periploca sepium Bge.) as an example. METHODS: First, plant metabolomics analysis was performed by UPLC/Q-TOF MS in 89 batches of samples to discover chemical markers to distinguish medicinal parts (GP) and non-medicinal parts (the dried stem bark of Periploca sepium Bge. (JP)), harvest seasons and producing region of Periplocae Cortex. Second, network pharmacology was applied to explore the initial linkages among chemical constituents, targets and diseases. Last, potential Q-marker were selected by integrating analysis of plant metabolomics and network pharmacology, and the quantification method of Q-marker was developed by using UPLC-TQ-MS. RESULTS: The chemical profiling of GP and JP was investigated. Fifteen distinguishing features were designated as core chemical markers to distinguish GP and JP. Besides, the content of 4-methoxybenzaldehyde-2-O-ß-d-xylopyranosyl-(1→6)-ß-d-glucopyranoside could be used to identify Periplocae Cortex harvested in spring-autumn or summer. Meanwhile, a total of 15 components targeted rheumatoid arthritis were screened out based on network pharmacology. Taking absorbed constituents into consideration, 23 constituents were selected as potential Q-marker. A simultaneous quantification method (together with 11 semi-quantitative analysis) was developed and applied to the analysis of 20 batches of commercial Periplocae Cortex on the market. The PLS-DA model was successfully developed to distinguish GP and JP samples. In addition, the artificially mixed GP sample, which contained no less than 10% of the adulterant (JP), could also be correctly identified. CONCLUSION: Our results indicated that 9 ingredients could be considered as Q-marker of Periplocae Cortex. This study has also demonstrated that the plant metabolomics and network pharmacology could be used as an effective approach for discovering Q-marker of TCM to fulfill the evaluation of overall chemical consistency among samples from different producing areas, harvest seasons, and even those commercial crude drugs, which might be mixed with a small amount of non-medicinal parts.

Discovery of anti-flu substances and mechanism of Shuang-Huang-Lian water extract based on serum pharmaco-chemistry and network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Shuang-Huang-Lian preparation has captured wide attention since its clinical applications for the successful treatment of upper respiratory tract infection. However, its functional basis under actual therapeutic dose in vivo was still unrevealed. AIM OF THE STUDY: This study aimed to reveal the anti-flu substances and mechanism of Shuang-Huang-Lian water extract (SHL) on H1N1 infected mouse model by a strategy based on serum pharmaco-chemistry under actual therapeutic dose and network pharmacology. MATERIALS AND METHODS: H1N1 infected mouse model was employed for evaluation of the anti-flu effects of SHL. A simultaneous quantification method was developed by UPLC-TQ-XS MS coupled switch-ions mode and applied to characterize the pharmacokinetics of the multiple components of SHL under actual therapeutic dose. The potential active ingredients were screened out based on their pharmacokinetic parameters. And then, a compound mixture of these active candidates was re-evaluated for the anti-flu activity on H1N1 infected mouse model. Furthermore, the anti-flu mechanism of SHL was also predicted by network pharmacology coupled with the experimental result. RESULTS: SHL significantly increased the survival rate and prolonged survival days on H1N1 infected mice at a dosage of 20 g crude drug/kg/day by reversing the increased lung index, down-regulating the inflammatory cytokines (TNF-α, IL-1ß, IL-6) and inhibiting the release of IFN-ß in bronchoalveolar lavage fluids (BALF). Concomitantly, the pharmacokinetic parameters of fourteen quantified and twenty-one semi-quantified constituents of SHL were characterized. And then, five compounds (baicalin, sweroside, chlorogenic acid, forsythoside A and phillyrin), which displayed satisfactory pharmacokinetic features, were considered as potential active ingredients. Thus, a mixture of these five ingredients was administered to H1N1-infected mice at a dose of 4.24 mg/kg/day. As a result, the therapeutical effects of the mixture were similar to SHL in terms of survival rate, lung index and the release of cytokines (TNF-α, IL-1ß and IL-6) in BALF. Moreover, network pharmacology analysis indicated that the TNF-signal pathways might play a role in the anti-flu mechanism of SHL. CONCLUSIONS: A mixture of five compounds (baicalin, sweroside, chlorogenic acid, forsythoside A and phillyrin) were the anti-flu substances of SHL. The strategy based on serum pharmaco-chemistry under actual therapeutic dose provided a new sight on exploring in vivo effective substances of TCM.

Efficacy and safety of low-dose apatinib in ovarian cancer patients with platinum-resistance or platinum-refractoriness: A single-center retrospective study.

BACKGROUND: This study aimed to evaluate the efficacy and safety of apatinib with a low dose of 250 mg/d in the treatment of platinum-resistant or platinum-refractory ovarian cancer patients. METHODS: Patients with platinum-resistant or platinum-refractory ovarian carcinoma treated with 250 mg/d apatinib in our institution from November 2016 to December 2017 were retrospectively reviewed. The tumor response and progression were evaluated according to the standard by incorporating the levels of CA125 and Response Evaluation Criteria in Solid Tumors 1.1. CTCAE 4.03 was used to evaluate adverse events (AEs). RESULTS: Fifty-two eligible patients were enrolled in per-protocol (PP) analysis and 65 patients (including 13 lost to follow-up) were included in the intention-to-treat (ITT) analysis. In PP analysis, 18 patients (34.6%) had partial response (PR), 22 patients (42.3%) had stable disease (SD), and the disease control rate (DCR) was 61.5%. Median progression-free survival (PFS) was 4.0 months (95% CI, 2.83-5.17 m), and median overall survival (OS) was 25.33 months (95% CI, 17.74-32.92 m). The objective response rate and DCR for patients in ITT analysis were 27.7% and 49.2%, respectively. The top three treatment-related AEs were hypertension, hand-foot syndrome, and leukopenia. Eight patients (15.4%) in PP population had grade 3 treatment-related AEs. Previous chemotherapy lines, number of recurrences, and AEs did not affect the efficacy of apatinib. Age older than 60 was associated with higher rates of disease control and prolonged PFS (P < .05). CONCLUSION: Apatinib 250 mg/d is a feasible treatment in platinum-resistant or platinum-refractory epithelial ovarian cancer (EOC) patients.

A combination of metabolite profiling and network pharmacology to explore the potential pharmacological changes of secoisolariciresinol-diglycoside.

The prototypes and metabolites formed from the use of traditional Chinese medicines (TCM) are typically the cause of both side side-effects and therapeutic results. Therefore, the characterization of in vivo substances and the determination of functional changes are of great importance for clinical applications. Secoisolariciresinol-diglycoside (SDG), one major compound in flaxseeds, was used as a potential drug to treat tumors in the clinic; however, the metabolism information and functional changes of SDG in vivo were limited, which limited its application. In this study, an integrated strategy based on metabolite profiling and network pharmacology was applied to explore the metabolism feature and functional changes of SDG. As a result, a total of 28 metabolites were found in rats, including 14 in plasma, 22 in urine, 20 in feces, 7 in the heart, 14 in the liver, 8 in the spleen, 10 in the lungs, 14 in the kidneys, and 4 in the brain. Among them, M8, M13 and M26 were the main metabolites of SDG in rats and 24 were characterized for the first time. The metabolic reactions contained phase I reactions of demethylation, dehydroxylation, deglycosylation, arabinosylation and glycosylation, and phase II reactions of glucuronidation and sulfation were also observed. Notably, the arabinosylation and glycosylation were found in SDG for the first time. Meanwhile, 121 targets of SDG and its metabolites were found, PRKCB was the main target of SDG, and the metabolites of SDG mainly targeted HSP90A1, IL6, AKT1, MAPK3, MTOR, PIK3CA, SRC, ESR1, AR, PIK3CB, and PIK3CB. The difference of targets between SDG and its metabolites could result in its additional functional pathways of neurotrophin signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway or indications of anti-prostate cancer. This work provided a new insight for exploring the mechanism and therapy indications of drugs.