Anti-pulmonary fibrosis activity analysis of methyl rosmarinate obtained from Salvia castanea Diels f. tomentosa Stib. using a scalable process.

Pulmonary fibrosis is a progressive, irreversible, chronic interstitial lung disease associated with high morbidity and mortality rates. Current clinical drugs, while effective, do not reverse or cure pulmonary fibrosis and have major side effects, there are urgent needs to develop new anti-pulmonary fibrosis medicine, and corresponding industrially scalable process as well. Salvia castanea Diels f. tomentosa Stib., a unique herb in Nyingchi, Xizang, China, is a variant of S. castanea. and its main active ingredient is rosmarinic acid (RA), which can be used to prepare methyl rosmarinate (MR) with greater drug potential. This study presented an industrially scalable process for the preparation of MR, which includes steps such as polyamide resin chromatography, crystallization and esterification, using S. castanea Diels f. tomentosa Stib. as the starting material and the structure of the product was verified by NMR technology. The anti-pulmonary fibrosis effects of MR were further investigated in vivo and in vitro. Results showed that this process can easily obtain high-purity RA and MR, and MR attenuated bleomycin-induced pulmonary fibrosis in mice. In vitro, MR could effectively inhibit TGF-ß1-induced proliferation and migration of mouse fibroblasts L929 cells, promote cell apoptosis, and decrease extracellular matrix accumulation thereby suppressing progressive pulmonary fibrosis. The anti-fibrosis effect of MR was stronger than that of the prodrug RA. Further study confirmed that MR could retard pulmonary fibrosis by down-regulating the phosphorylation of the TGF-ß1/Smad and MAPK signaling pathways. These results suggest that MR has potential therapeutic implications for pulmonary fibrosis, and the establishment of this scalable preparation technology ensures the development of MR as a new anti-pulmonary fibrosis medicine.

A novel fluorescence platform for specific detection of tetracycline antibiotics based on [MQDA-Eu3+] system.

Tetracycline antibiotics (TCs) are extensively used in clinical medicine, animal husbandry, and aquaculture because of their cost-effectiveness and high antibacterial efficacy. However, the presence of TCs residues in the environment poses risks to humans. In this study, an inner filter effect (IFE) fluorescent probe, 2,2'-(ethane-1,2-diylbis((2-((2-methylquinolin-8-yl)amino)-2-oxoethyl)azanediyl))diacetic acid (MQDA), was developed for the rapid detection of Eu3+ within 30 s. And its complex [MQDA-Eu3+] was successfully used for the detection of TCs. Upon coordination of a carboxyl of MQDA with Eu3+ to form a [MQDA-Eu3+] complex, the carboxyl served as an antenna ligand for the effective detection of Eu3+ to intensify the emission intensity of MQDA via "antenna effect", the process was the energy absorbed by TCs via UV excitation was effectively transferred to Eu3+. Fluorescence quenching of the [MQDA-Eu3+] complex was caused by the IFE in multicolor fluorescence systems. The limits of detection of [MQDA-Eu3+] for oxytetracycline, chlorotetracycline hydrochloride, and tetracycline were 0.80, 0.93, and 1.7 µM in DMSO/HEPES (7:3, v/v, pH = 7.0), respectively. [MQDA-Eu3+] demonstrated sensitive detection of TCs in environmental and food samples with satisfactory recoveries and exhibited excellent imaging capabilities for TCs in living cells and zebrafish with low cytotoxicity. The proposed approach demonstrated considerable potential for the quantitative detection of TCs.

Research Progress on the Mechanism of the Antitumor Effects of Cannabidiol.

Cannabidiol (CBD), a non-psychoactive ingredient extracted from the hemp plant, has shown therapeutic effects in a variety of diseases, including anxiety, nervous system disorders, inflammation, and tumors. CBD can exert its antitumor effect by regulating the cell cycle, inducing tumor cell apoptosis and autophagy, and inhibiting tumor cell invasion, migration, and angiogenesis. This article reviews the proposed antitumor mechanisms of CBD, aiming to provide references for the clinical treatment of tumor diseases and the rational use of CBD.

A novel mechanism of 6-methoxydihydroavicine in suppressing ovarian carcinoma by disrupting mitochondrial homeostasis and triggering ROS/ MAPK mediated apoptosis.

Introduction: Alkaloids derived from M. cordata (Papaveraceae family), have been found to display antineoplastic activity in several types of cancer. However, the antitumor effects and mechanisms of a new alkaloid extracted from the fruits of M. cordata, named 6-Methoxydihydroavicine (6-ME), remains unclear in the case of ovarian cancer (OC). Methods: CCK-8 assay was employed to analyze the cell viabilities of OC cells. RTCA, and colony-formation assays were performed to measure OC cell growth. Alterations in apoptosis and ROS levels were detected by flow cytometry in accordance with the instructions of corresponding assay kits. A Seahorse XFe96 was executed conducted to confirm the effects of 6-ME on cellular bioenergetics. Western blot and q-RT-PCR were conducted to detect alterations in target proteins. The subcutaneous xenografted tumor model of OC was used to further validate the anti-tumor activity of 6-ME in vivo. Results: Here, we reported for the first time that 6-ME inhibits OC cells growth in vitro and in vivo. Meanwhile, we found that 6-ME showed great antineoplastic activities by disrupting mitochondria homeostasis and promoting apoptosis in OC cells. Further investigation of the upstream signaling of apoptosis revealed that 6-ME-triggered apoptosis was induced by reactive oxygen species (ROS)-mediated mitogen-activated protein kinase (MAPK) activation and mitochondria dysfunction in OC cells. Furthermore, we found oxaloacetic acid (OAA), a crucial metabolite has been proved to be related to NADPH production, can block the cytotoxicity and accumulation of ROS caused by 6-ME in OC cells. Discussion: In summary, our data show that 6-ME exhibits cytotoxicity to OC cells in a ROS-dependent manner by interrupting mitochondrial respiration homeostasis and inducing MAPK-mediated apoptosis. This evidence suggests that 6-ME is a promising remedy for OC intervention.

Effect of esketamine on postoperative depressive symptoms in patients undergoing thoracoscopic lung cancer surgery: A randomized controlled trial.

Background: Depressive symptoms are common among patients with lung cancer. We aimed to assess the effects of esketamine on postoperative depressive symptoms after thoracoscopic lung cancer surgery. Methods: In this randomized, double-blind, placebo-controlled trial, 156 patients undergoing thoracoscopic lung cancer surgery were randomly allocated in a 1:1 ratio to receive intravenous esketamine (intraoperatively and in patient-controlled analgesia until 48 h postoperatively) or normal saline placebo. The primary outcome was the proportion of patients with depressive symptoms at 1 month postoperatively, assessed using the Beck Depression Inventory-II (BDI-II). Secondary outcomes included depressive symptoms at 48 h postoperatively, hospital discharge and 3 months postoperatively, BDI-II scores, anxious symptoms, Beck Anxiety Inventory scores, Quality of Recovery-15 (QoR-15) scores, and 1- and 3-month mortality. Main results: A total of 151 patients (75 in the esketamine group and 76 in the normal saline group) completed the 1-month follow-up. The esketamine group had a significantly lower incidence of depressive symptoms at 1 month compared to the normal saline group (1.3% vs. 11.8%; risk difference = -10.5, 95%CI = -19.6% to -0.49%; p = 0.018). After excluding patients without lung cancer diagnosis, the incidence of depressive symptoms was also lower in the esketamine group (1.4% vs. 12.2%; risk difference = -10.8, 95%CI = -20.2% to -0.52%; p = 0.018). The secondary outcomes were similar between groups, except that the esketamine group had higher QoR-15 scores at 1 month postoperatively (median difference = 2; 95%CI = 0 to 5; p = 0.048). The independent risk factors for depressive symptoms were hypertension (odds ratio = 6.75, 95%CI = 1.13 to 40.31; p = 0.036) and preoperative anxious symptoms (odds ratio = 23.83, 95%CI = 3.41 to 166.33; p = 0.001). Conclusion: Perioperative administration of esketamine reduced the incidence of depressive symptoms at 1 month after thoracoscopic lung cancer surgery. History of hypertension and preoperative anxious symptoms were independent risk factors for depressive symptoms.Clinical trial registration: Chinese Clinical Trial Registry http://www.chictr.org.cn, Identifier (ChiCTR2100046194).

Sevoflurane-induced P300 promotes neuron apoptosis via Sp1/CDK9 pathway.

Exposure to sevoflurane leads to serious neurological side effects, including neuronal apoptosis and cognitive impairment. In the mouse model, cyclin dependent kinase 9 (CDK9) was significantly downregulated after exposure to sevoflurane, but the effect of CDK9 on neuronal apoptosis and cognitive impairment after sevoflurane exposure has not been elucidated. Here, we found that the upregulation of P300 by sevoflurane in vitro and in vivo inhibited the expression of CDK9 and induced neuron apoptosis. The effect of sevoflurane on CDK9 expression is based on inhibition of its transcription process. P300 inhibited the binding of Sp1 to DNA by affecting the level of Sp1 acetylation, thereby inhibiting the expression of CDK9, cell-cycle arrest and increasing neuron apoptosis. After the use of P300 inhibitor, the acetylation level of Sp1 decreased, thereby increasing binding in the CDK9 promoter region and exerting anti-apoptosis effects. Mice exposed to sevoflurane using P300 inhibitor also showed decreased levels of apoptosis of cortical cells and a decrease in recent cognitive impairment. In summary, sevoflurane-induced P300 inhibited activity of Sp1 by increasing Sp1 acetylation modification, down-modulates CDK9 expression and promotes the occurrence of neuronal apoptosis.

A novel mechanism of cannabidiol in suppressing ovarian cancer through LAIR-1 mediated mitochondrial dysfunction and apoptosis.

Cannabidiol (CBD) is a nonpsychoactive cannabinoid compound. It has been shown that CBD can inhibit the proliferation of ovarian cancer cells, but the underlying specific mechanism is unclear. We previously presented the first evidence for the expression of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), a member of the immunosuppressive receptor family, in ovarian cancer cells. In the present study, we investigated the mechanism by which CBD inhibits the growth of SKOV3 and CAOV3 ovarian cancer cells, and we sought to understand the concurrent role of LAIR-1. In addition to inducing ovarian cancer cell cycle arrest and promoting cell apoptosis, CBD treatment significantly affected the expression of LAIR-1 and inhibited the PI3K/AKT/mTOR signaling axis and mitochondrial respiration in ovarian cancer cells. These changes were accompanied by an increase in ROS, loss of mitochondrial membrane potential, and suppression of mitochondrial respiration and aerobic glycolysis, thereby inducing abnormal or disturbed metabolism and reducing ATP production. A combined treatment with N-acetyl-l-cysteine and CBD indicated that a reduction in ROS production would restore PI3K/AKT/mTOR pathway signaling and ovarian cancer cell proliferation. We subsequently confirmed that the inhibitory effect of CBD on the PI3K/AKT/mTOR signal axis and mitochondrial bioenergy metabolism was attenuated by knockdown of LAIR-1. Our animal studies further support the in vivo anti-tumor activity of CBD and suggest its mechanism of action. In summary, the present findings confirm that CBD inhibits ovarian cancer cell growth by disrupting the LAIR-1-mediated interference with mitochondrial bioenergy metabolism and the PI3K/AKT/mTOR pathway. These results provide a new experimental basis for research into ovarian cancer treatment based on targeting LAIR-1 with CBD.

The Use of Deep Learning Model for Effect Analysis of Conventional Friction Power Confinement.

Nonlinear friction could affect the high-precision motion system, resulting in poor tracking accuracy in the end. This is due to the fact that the Lugre friction model's parameter identification process comprises both static and dynamic parameter identification. The convolutional neural network (CNN) model is used in this study to create the friction identification system. We suggest a hybrid methodology that combines the CNN method and the classic least-squares technique. The convolutional layer (CONV), which is defined by a convolutional kernel, analyzes and extracts features from an input image. In terms of accuracy and convergence, the results reveal that the upgraded CNN friction model outperforms the original CNN friction model. You may successfully reduce the influence of friction on your system while improving its performance by applying the feedforward correction.

Case Report: Hemodynamic Instability Caused by Splenic Rupture During Video-Assisted Thoracoscopic Lobectomy.

Background: Video-assisted thoracoscopic surgery (VATS) has been widely performed for patients with lung cancer. Splenic rupture after VATS lung procedures is a very rare and serious event. Case Presentation: We reported a case with hemodynamic instability after left lower VATS lobectomy. There was no evidence of diaphragmatic injury during the surgery. Computed tomography (CT) showed spleen injury and large amount of fluid in the abdominal cavity. Emergent laparotomy was performed, and splenic rupture was diagnosed. The patient underwent splenectomy, with two lacerations at the diaphragmatic surface of the spleen. The patient did well postoperatively and was discharged from the hospital on postoperative day 5. Conclusion: There are few similar cases reported in the literature. Persistent hemodynamic instability due to the rupture of spleen is life-threatening. In the situation of unexplained hypotension during VATS procedures (especially left-sided approaches), the possibility of splenic injury and rupture should be considered. Abdominal ultrasonography and/or CT examinations should be carried out for prompt diagnosis and treatment of such rare complication.

Construction of N-CDs and Calcein-Based Ratiometric Fluorescent Sensor for Rapid Detection of Arginine and Acetaminophen.

In our study, a unique ratiometric fluorescent sensor for the rapid detection of arginine (Arg) and acetaminophen (AP) was constructed by the integration of blue fluorescent N-CDs and yellowish-green fluorescent calcein. The N-CD/calcein ratiometric fluorescent sensor exhibited dual emission at 435 and 519 nm under the same excitation wavelength of 370 nm, and caused potential Förster resonance energy transfer (FRET) from N-CDs to calcein. When detecting Arg, the blue fluorescence from the N-CDs of the N-CD/calcein sensor was quenched by the interaction of N-CDs and Arg. Then, the fluorescence of our sensor was recovered with the addition of AP, possibly due to the stronger association between AP and Arg, leading to the dissociation of Arg from N-CDs. Meanwhile, we observed an obvious fluorescence change from blue to green, then back to blue, when Arg and AP were added, exhibiting the "on-off-on" pattern. Next, we determined the detection limits of the N-CD/calcein sensor to Arg and AP, which were as low as 0.08 µM and 0.02 µM, respectively. Furthermore, we discovered that the fluorescence changes of the N-CD/calcein sensor were only responsible for Arg and AP. These results suggested its high sensitivity and specificity for Arg and AP detection. In addition, we have successfully achieved its application in bovine serum samples, indicating its practicality. Lastly, the logic gate was generated by the N-CD/calcein sensor and presented its good reversibility. Overall, we have demonstrated that our N-CD/calcein sensor is a powerful sensor to detect Arg and AP and that it has potential applications in biological analysis and imaging.

Protective effects of dioscin against isoproterenol-induced cardiac hypertrophy via adjusting PKCε/ERK-mediated oxidative stress.

Cardiac hypertrophy (CH) plays a central role in cardiac remodeling and is an independent risk factor for cardiac events. It is imperative to find drugs with protective effect on CH. Dioscin, one natural product, shows various pharmacological activities, and PKCepsilon (PKCε) plays an important role in the physiological hypertrophic responses. Thus, we aimed to investigate the possible protective effect of dioscin on CH through PKCε. In the present study, the isoproterenol (ISO)-induced H9C2 cells and primary cardiomyocytes models, and the ISO-induced rat model were established, and the pharmacodynamics and mechanism of dioscin were investigated. In vitro results prompted that, dioscin significantly improved ISO-induced cardiomyocyte hypertrophy, decreased the levels of cell size, protein content of single cell, reactive oxygen species, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), beta-myosin heavy chain (ß-MHC). Moreover, in vivo, changes in histopathological of the animals caused by ISO are improved by dioscin. And dioscin decreased the index of CH and the levels of CK, MDA, LDH, and increased the levels of GSH, SOD and GSH-Px. Mechanism research showed that dioscin inhibited the expression levels of PKCε, and affected the expression levels of p-MEK, p-ERK, Nrf2, Keap1 and HO-1 to inhibit oxidative stress. In addition, the results of ISO-induced CH in PKCε siRNA transfected H9C2 cells and C57BL/6 mice further showed that the protective effect of dioscin on CH, which was mediated by inhibition of PKCε/ERK signal pathway. In summary, dioscin can effectively inhibit CH by regulating PKCε-mediated oxidative stress, which should be considered as one potent candidate for new drug research and development to treat CH in the future.

Inhibition of the INa/K and the activation of peak INa contribute to the arrhythmogenic effects of aconitine and mesaconitine in guinea pigs.

Aconitine (ACO), a main active ingredient of Aconitum, is well-known for its cardiotoxicity. However, the mechanisms of toxic action of ACO remain unclear. In the current study, we investigated the cardiac effects of ACO and mesaconitine (MACO), a structurally related analog of ACO identified in Aconitum with undocumented cardiotoxicity in guinea pigs. We showed that intravenous administration of ACO or MACO (25 µg/kg) to guinea pigs caused various types of arrhythmias in electrocardiogram (ECG) recording, including ventricular premature beats (VPB), atrioventricular blockade (AVB), ventricular tachycardia (VT), and ventricular fibrillation (VF). MACO displayed more potent arrhythmogenic effect than ACO. We conducted whole-cell patch-clamp recording in isolated guinea pig ventricular myocytes, and observed that treatment with ACO (0.3, 3 µM) or MACO (0.1, 0.3 µM) depolarized the resting membrane potential (RMP) and reduced the action potential amplitude (APA) and durations (APDs) in a concentration-dependent manner. The ACO- and MACO-induced AP remodeling was largely abolished by an INa blocker tetrodotoxin (2 µM) and partly abolished by a specific Na+/K+ pump (NKP) blocker ouabain (0.1 µM). Furthermore, we observed that treatment with ACO or MACO attenuated NKP current (INa/K) and increased peak INa by accelerating the sodium channel activation with the EC50 of 8.36 ± 1.89 and 1.33 ± 0.16 µM, respectively. Incubation of ventricular myocytes with ACO or MACO concentration-dependently increased intracellular Na+ and Ca2+ concentrations. In conclusion, the current study demonstrates strong arrhythmogenic effects of ACO and MACO resulted from increasing the peak INa via accelerating sodium channel activation and inhibiting the INa/K. These results may help to improve our understanding of cardiotoxic mechanisms of ACO and MACO, and identify potential novel therapeutic targets for Aconitum poisoning.

Accumulation of vanadium and arsenic by cast iron pipe scales under drinking water conditions: A batch study.

Metal pollutants accumulation in the scales of drinking water distribution systems presents a potential threat to water quality. Therefore, a study was carried out on the accumulation of V(V) and As(V) by cast iron pipe scales. The accumulation of V(V) and As(V) by scales and the effects of scale dosage, pH, temperature, and anion content on the accumulation process were assessed. Results showed that scales could rapidly accumulate V(V) and As(V), with maximum accumulation amounts of 3.94 mg/g and 3.90 mg/g, respectively. An increase in pH (from 3.0 to 9.0) and sulfate concentration (from 0 to 250 mg/L) decreased V(V) and As(V) accumulation by scales. Increased chloride ion concentrations (from 0 to 250 mg/L) reduced the amount of As(V) accumulated, while increasing the amount of V(V) accumulated. The V(V) and As(V) accumulation kinetics were well described by the Elovich model, with thermodynamic and accumulation isotherms showing that the accumulation process occurred via an entropic endothermic reaction. The mechanisms of accumulation of V(V) and As(V) by the scales include surface complexation, ligand exchange, electrostatic attraction and repulsion, and competitive adsorption.

Efficacy and safety of bevacizumab-based combination therapy for treatment of patients with metastatic colorectal cancer.

AIM: The use of bevacizumab in combination therapy is an emerging trend in metastatic colorectal cancer treatment. However, the clinical value of different combination types remains under debate. Thus, a meta-analysis of randomized controlled trials (RCTs) comparing bevacizumab-based combination therapy with monotherapy (therapy that uses one type of treatment, such as chemotherapy or surgery alone, to treat metastatic colorectal cancer) was performed, aiming to evaluate the safety and efficacy of bevacizumab-based combination therapy and to find a more beneficial combination. METHODS: We searched for clinical studies that evaluated bevacizumab-based combination therapy in metastatic colorectal cancer. We extracted data from these studies to evaluate the relative risk (RR) of overall response rate (ORR) and grade 3/4 treatment-related adverse events (AEs), HRs of overall survival (OS), and progression-free survival (PFS). RESULTS: Eight RCTs were identified (n=3,424). Treatments included combinations of bevacizumab and oxaliplatin, fluorouracil, and leucovorin (FOLFOX4), combinations of bevacizumab and capecitabine and oxaliplatin, combinations of bevacizumab and fluorouracil/leucovorin, combinations of bevacizumab and irinotecan, fluorouracil, and leucovorin (IFL), and combinations of bevacizumab and capecitabine. Bevacizumab-based combination therapy showed higher ORR (RR: 1.40; 95% CI: 1.10-1.78; P=0.005), PFS (HR: 0.64; 95% CI: 0.55-0.73; P=0.000), and OS (HR: 0.82; 95% CI: 0.73-0.92; P=0.001) values than monotherapy. However, higher grade 3/4 treatment-related AEs (RR: 1.27; 95% CI: 1.15-1.41; P=0.000) were observed in combination therapy than in monotherapy. CONCLUSION: This meta-analysis showed that the addition of IFL to bevacizumab better benefits PFS and safety. Adding FOLFOX4 was associated with better ORR and OS. The efficacy and safety of an IFL-bevacizumab-FOLFOX4 combination should be given greater weight in future clinical trials, guidelines, and clinical practice.