Association of mechanical power during one-lung ventilation and post-operative pulmonary complications among patients undergoing lobectomy: a protocol for a prospective cohort study.

The association of intra-operative mechanical power (MP) with post-operative pulmonary complications (PPCs) has been described before, but it is uncertain whether the potential inherent bias can limit the use of this parameter, particularly in the context of one-lung ventilation. This single-center study aims to investigate the effect of MP during one-lung ventilation (OLV), and the risks of PPCs in patients undergoing thoracoscopic lobectomy. This prospective observational study is being conducted in an academic tertiary hospital in mainland China. Participants diagnosed with lung cancer, and aged 50 to 80 years are eligible. Video-assisted thoracoscopic surgery (VATS) lobectomy is performed for all patients. The primary outcome is the occurrence of PPCs over 5 consecutive days after the surgery, or until discharge from the hospital. Secondary outcomes include the composite conditions of PPCs, in-hospital stay, systematic inflammation tested by blood samples, and changes in aeration compartments in the ventilated lung as assessed by CT scans. We aim to evaluate the association of mean MP and the temporal patterns in the trend of MP during OLV with the occurrence of PPCs. A total of 120 patients will be enrolled in this study. The study protocol has received approval from the Ethics Committee of the affiliated hospital of Southwest Medical University, China (Reference number: KY2022162). The findings will be made available to the funder and researchers via scientific conferences and peer-reviewed publications. This controlled trial was approved by the Ethics Committee of Southwest Medical University(ChiCTR2200062173), and registered in the Chinese Clinical Trial Register website ( http://www.chictr.org.cn/edit.aspx?pid=172533&htm=4 , ChiCTR2200062173). A written consent was obtained from each patient.

Discovery of tetrahydroisoquinolineindole derivatives as first dual PRMT5 inhibitors/hnRNP E1 upregulators: Design, synthesis and biological evaluation.

Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as an important therapeutic target for treating various types of cancer. Upregulation of tumor suppressor hnRNP E1 has also been considered as an effective antitumor therapy. In this study, a series of tetrahydroisoquinolineindole hybrids were designed and prepared, and compounds 3m and 3s4 were found to be selective inhibitors of PRMT5 and upregulators of hnRNP E1. Molecular docking studies indicated that compounds 3m occupied the substrate site of PRMT5 and formed essential interactions with amino acid residues. Furthermore, compounds 3m and 3s4 exerted antiproliferative effects against A549 cells by inducing apoptosis and inhibiting cell migration. Importantly, silencing of hnRNP E1 eliminated the antitumor effect of 3m and 3s4 on the apoptosis and migration in A549 cells, suggesting a regulatory relationship between PRMT5 and hnRNP E1. Additionally, compound 3m exhibited high metabolic stability on human liver microsomes (T1/2 = 132.4 min). In SD rats, the bioavailability of 3m was 31.4%, and its PK profiles showed satisfactory AUC and Cmax values compared to the positive control. These results suggest that compound 3m is the first class of dual PRMT5 inhibitor and hnRNP E1 upregulator that deserves further investigation as a potential anticancer agent.

Traditional uses, phytochemistry, pharmacology and clinical applications of Cortex Juglandis Mandshuricae: A comprehensive review.

ETHNOPHARMALOGICAL RELEVANCE: Cortex Juglandis Mandshuricae (CJM) is the dry branch or stem bark of the Juglans mandshurica Maxim. and is widely used as a traditional Chinese medicine in Asia and Africa. Its use was first recorded in Kaibao Bencao. AIM OF THE STUDY: The present review provides a deeper insight, better awareness and detailed knowledge of phytochemistry, pharmacology, quality control, along with clinical applications of Cortex Juglandis Mandshuricae. METHODS: The relevant information of Cortex Juglandis Mandshuricae was obtained from several databases including Web of Science, PubMed, and CNKI. The medical books, PhD and MSc dissertations in Chinese were also used to perform this work. RESULTS: CJM has been traditionally used against a wide range of diseases, including dysentery, acute conjunctivitis, bacterial infections, and cancer. A total of 249 compounds have been isolated from CJM; they mainly include quinones and their derivatives, flavonoids, tannins, diarylheptanoids, triterpenoids, coumarins, phenylpropanoids, and volatile oils. These compounds exert anti-tumor, anti-oxidant, anti-inflammatory, bacteriostatic, anti-complement, immunomodulatory, anti-parasitic activities. Specifically, the effects of juglone, alkaloids and unsaturated fatty acid CJM components against hepatic cancer occur through exertion of apoptosis through a mitochondria-dependent pathway. In addition, taxifolin and several tannins have been found to have anti-HIV activity, and (±)-juglanaloid A and (±)-juglanaloid B target Alzheimer disease. Quality control is monitored through identification of juglone, quercetin, and volatile oils. A clinical preparation of CJM, Compound Muji Granules, is used in the treatment of various liver diseases with good therapeutic effect. CONCLUSION: While CJM has been used extensively as a folk medicine, the relationships between structure and activity remain unclear. More in vivo models are needed to study the pharmacological mechanisms of action and to assess potential toxic components, in addition to which the evidence used to demonstrate the quality standards of medicinal materials is clearly inadequate. Therefore, more in-depth research is needed to provide a reasonable scientific basis improve its clinical utilization.

[Comparative pharmacokinetics of syringin, eleutheroside E and isofraxidin in rat plasma after intravenous administration of each monomer and Ciwujia injection].

To compare the pharmacokinetics of syringin, eleutheroside E and isofraxidin after intravenous administration of each monomer and Ciwujia injection. Twenty-four Sprague-Dawley rats were randomly divided into four groups and intravenously administrated with syringin, eleutheroside E, isofraxidin, and Ciwujia injection, respectively. The concentrations of the three components in rat plasma were determined by LC-MS/MS. DAS 2.0 software was applied to calculate the pharmacokinetic parameters while the SPSS 17.0 software was used for statistical analysis. Significant difference (P < 0.05) was found between each monomer and the injection on the main pharmacokinetic parameters such as AUC, CL and t1,/2. Compared with the injection, the group treated with the syringin has obvious decrease in AUC, and increase in CL while the group treated with eleutheroside E has obvious increase in AUC, and decrease in CL The t1/2 of isofraxidin was prolonged in Ciwujia injection. Pharmacokinetic characters of the ingredients in the injection varied greatly from the monomer. Other constituents in the injection may have an impact on the pharmacokinetic profiles of these three components.

[Study on in vivo pharmacokinetics of cucurbitacin injection in rats].

To establish a method for the determination of cucurbitacin in plasma samples, in order to study the in vivo pharmacokinetic characteristics of cucurbitacin in rats. Rats were intravenously injected with cucurbitacin. With diphenhydramine as the internal standard (IS), the plasma concentrations of cucurbitacin in rat plasma at different time points were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS). With electrospray ionization source, the positive ion detection in the multiple reaction monitoring mode was conducted to determine the ion-pairs for target compound and IS were m/z 503.2/113.1 and m/z 256.0/167.2, respectively. Agilent ZOBAX SB-C18 column (2.1 mm x 50 mm, 1.8 microm) was adopted and eluted with methanol and 0.1% formic acid (55:45), and the flow rate was 0.2 mL x min(-1). DAS 2.0 software was applied to fit the blood concentration and calculate corresponding pharmacokinetic parameters. The rats were intravenously injected with cucurbitacin at the concentration of 3.0 mg x kg(-1). The target blood quality concentration show good linear relations within the range of 10.5-3 150 microg x L(-1) (R2 = 0.996), the lower limit of the standard curve was 10.5 microg x L(-1), and the signal to noise ratio S/N = 12. Intra- and inter-day precisions RSD was less than 6.9% and 14%, respectively; The accuracy RE ranged between 0.20% and 3.7%; The extraction recoveries ranged between 92.7% and 97.1%. Regarding the pharmacokinetic parameters of tail intravenous injection of cucurbitacin, AUC (0-t) was (811.615 +/- 111.578) microg x h x L(-1), (t1/2) was (1.285 +/- 1.390) h, CL was (3.627 +/- 0.487) L x h x kg(-1), and V(d) was (6.721 +/- 7.429) L x kg(-1). In this study, researchers established a simple, accurate, sensitive and highly specific method for determining the blood concentration of cucurbitacin, and reported the in vivo pharmacokinetic characteristics of cucurbitacin in rats for the first time.

Covalent protein binding and tissue distribution of houttuynin in rats after intravenous administration of sodium houttuyfonate.

AIM: To investigate the potential of houttuynin to covalently bind to proteins in vitro and in vivo and to identify the adduct structures. METHODS: Male Sprague-Dawley rats were intravenously injected with sodium houttuyfonate (10 mg/kg). The concentrations of houttuynin in blood, plasma and five tissues tested were determined using an LC/MS/MS method. The covalent binding values of houttuynin with hemoglobin, plasma and tissue proteins were measured in rats after intravenous injection of [1-(14)C]sodium houttuyfonate (10 mg/kg, 150 mCi/kg). Human serum albumin was used as model protein to identify the modification site(s) and structure(s) through enzymatic digestion and LC/MS(n) analysis. RESULTS: The drug was widely distributed 10 min after intravenous injection. The lungs were the preferred site for disposition, followed by the heart and kidneys with significantly higher concentrations than that in the plasma. The extent of covalent binding was correlated with the respective concentrations in the tissues, ranging from 1137 nmol/g protein in lung to 266 nmol/g protein in liver. Houttuynin reacted primarily with arginine residues in human serum albumin to form a pyrimidine adduct at 1:1 molar ratio. The same adduct was detected in rat lungs digested by pronase E. CONCLUSION: This study showed that the ß-keto aldehyde moiety in houttuynin is strongly electrophilic and readily confers covalent binding to tissue proteins, especially lung proteins, by a Schiff's base mechanism. The findings explain partially the idiosyncratic reactions of houttuyniae injection in clinical use.