The enhanced hepatotoxicity of isobavachalcone in depigmented zebrafish due to calcium signaling dysregulation and lipid metabolism disorder.

Isobavachalcone (IBC) is a flavonoid component derived from Psoraleae Fructus that can increase skin pigmentation and treat vitiligo. However, IBC has been reported to be hepatotoxic. Current studies on IBC hepatotoxicity are mostly on normal organisms but lack studies on hepatotoxicity in patients. This study established the depigmented zebrafish model by using phenylthiourea (PTU) and investigated the difference in hepatotoxicity between normal and depigmented zebrafish caused by IBC and the underlying mechanism. Morphological, histological, and ultrastructural examination and RT-qPCR verification were used to evaluate the effects of IBC on the livers of zebrafish larvae. IBC significantly decreased liver volume, altered lipid metabolism, and induced pathological and ultrastructural changes in the livers of zebrafish with depigmentation compared with normal zebrafish. The RNA-sequencing and RT-qPCR results showed that the difference in hepatotoxicity between normal and depigmented zebrafish caused by IBC was closely related to the calcium signaling pathway, lipid decomposition and metabolism, and oxidative stress. This work delved into the mechanism of the enhanced IBC-induced hepatotoxicity in depigmented zebrafish and provided a new insight into the hepatotoxicity of IBC.

Moldavica acid A, a new salicylic acid derivative from Dracocephalum moldavica.

In this paper, we present the discovery of a novel salicylic acid derivative, moldavica acid A (1), and a new natural dibenzo[b,f]oxepin, moldavica acid B (2), together with four known phenylpropionic acids (3-6) and protocatechuic acid (7) that were isolated from Dracocephalum moldavica L. Their structures were elucidated by comprehensive spectroscopic methods, including infrared and nuclear magnetic resonance. Compound 1 is the first example of salicylic acid linking a carboxylated α-pyrone via an ethyl bridge. Beyond expanding the knowledge of the chemical diversity of D. moldavica, both compounds 1 and 2 were shown to upregulate the expression of Kruppel-like factor 2, which could serve as a prospective therapeutic target for the treatment of atherosclerosis.

Systems Pharmacology-Based Strategy to Investigate Pharmacological Mechanisms of Total Flavonoids in Dracocephalum moldavica on Chronic Heart Failure.

Heart failure (HF) is a clinical syndrome of cardiac insufficiency caused by abnormalities in cardiac structure and function that arise for various reasons, and it is the final stage of most cardiovascular diseases' progression. Total flavonoid extract from Dracocephalum moldavica L. (TFDM) has many pharmacological and biological roles, such as cardioprotective, neuroprotective, anti-atherogenic, antihypertensive, anti-diabetic, anti-inflammatory, antioxidant, etc. However, its effect on HF and its molecular mechanism are still unclear. In this study, we used systems pharmacology and an animal model of HF to investigate the cardioprotective effect of TFDM and its molecular mechanism. Eleven compounds in TFDM were obtained from the literature, and 114 overlapping genes related to TFDM and HF were collected from several databases. A PPI network and C-T network were established, and GO enrichment analysis and KEGG pathway analysis were performed. The top targets from the PPI network and C-T network were validated using molecular docking. The pharmacological activity was investigated in an HFpEF (heart failure with preserved ejection fraction) mouse model. This study shows that TFDM has a protective effect on HFpEF, and its protective mechanism may be related to the regulation of proinflammatory cytokines, apoptosis-related genes, fibrosis-related genes, etc. Collectively, this study offers new insights for researchers to understand the protective effect and mechanism of TFDM against HFpEF using a network pharmacology method and a murine model of HFpEF, which suggest that TFDM is a promising therapy for HFpEF in the clinic.

Phytochemical composition profile and space-time accumulation of secondary metabolites for Dracocephalum moldavica Linn. via UPLC-Q/TOF-MS and HPLC-DAD method.

The aerial parts of Dracocephalum moldavica L. are extensively used in traditional ethnic medicines in China as a remedy for cardiovascular and cerebrovascular damage. However, the chemical composition and the accumulation of main secondary metabolites of D. moldavica in different natural environments remain unclear. This study aimed to conduct a qualitative and quantitative analysis of the main secondary metabolites to explore the quality variation of D. moldavica in markets. The evaluation of space-time accumulation of main secondary metabolites in D. moldavica was carried out during different growth periods and in different geographical locations. A total of 35 ingredients were detected and 24 identified, including 21 flavonoids, two phenolic acids and one coumarin by UPLC-QTOF-MS method. Furthermore, a simple and convenient HPLC method was successfully developed for the simultaneous determination of lutelin-7-O-glucuronide and tilianin and rosmarinic acid in D. moldavica. The results of space-time accumulation analysis showed the distinct variation of secondary metabolites of D. moldavica with the growth period and geographical location. Finally, the current study provided a meaningful and useful approach for comprehensively evaluating the quality of D. moldavica.

Improved oral delivery of tilianin through lipid-polymer hybrid nanoparticles to enhance bioavailability.

Tilianin (TIL) may prevent and treat myocardial ischemia reperfusion injuries. However, its oral administration is hampered by its low bioavailability. The present study aimed to formulate lipid-polymer hybrid nanoparticles (LPHNs) as carriers for the sustained release and oral bioavailability enhancement of TIL in vitro and in vivo. A nanodrug delivery system of TIL-loaded LPHNs (TIL-LPHNs) was constructed. TIL-LPHNs were prepared via a self-assembly method, and their particle size, polymer dispersity index (PDI), zeta potential, encapsulation efficiency (EE) and morphology were investigated. In addition, pharmacokinetic studies were performed in vivo. The TIL-LPHN formulation produced a spherical, homogeneous, smooth surface and multi-lamellar structured nanoparticles. The particle size and distribution profile of TIL-LPHNs had a mean particle diameter of 54.6 ±â€¯5.3 nm and PDI of 0.112 ±â€¯0.017. The zeta potential was -33.4 ±â€¯4.7 mV. The EE of TIL-LPHNs was 86.6 ±â€¯3.6%, which was determined with the dialysis method. The TIL-LPHNs significantly enhanced the oral bioavailability of TIL with a 3.7-fold increase in the area under the concentration-time curve in comparison with the TIL solution. These findings support the potential use of LPHNs in improving the stability and bioavailability of TIL via oral administration.

Pretreatment with Tilianin improves mitochondrial energy metabolism and oxidative stress in rats with myocardial ischemia/reperfusion injury via AMPK/SIRT1/PGC-1 alpha signaling pathway.

Mitochondrial energy metabolism and oxidative stress play a crucial role in ameliorating myocardial ischemia/reperfusion injury (MIRI). Tilianin has been reported to have a significant protection for mitochondrion in MIRI. However, the underlying mechanisms remain unknown. This study investigated whether Tilianin regulates mitochondrial energy metabolism and oxidative stress in MIRI via AMPK/SIRT1/PGC-1 alpha signaling pathway. The MIRI model was established by 30 min of coronary occlusion followed by 2 h of reperfusion in rats. The results revealed that Tilianin significantly reduced myocardial infarction, improved the pathological morphology of myocardium, markedly increased the contents of ATP and NAD+, decreased ADP and AMP contents and the ratio of AMP/ATP, reduced the level of ROS and MDA, enhanced SOD activity, evidently increased the levels of AMPK, SIRT1 and PGC-1 alpha mRNA, up-regulated the expressions of AMPK, pAMPK, SIRT1, PGC-1alpha, NRF1, TFAM and FOXO1 proteins. However, these effects were respectively abolished by Compound C (a specific AMPK inhibitor) and EX-527 (a specific SIRT1 inhibitor). Taken together, this study found that Tilianin could attenuate MIRI by improving mitochondrial energy metabolism and reducing oxidative stress via AMPK/SIRT1/PGC-1 alpha signaling pathway.

Construction and synthesis of tricyclic matrinic derivatives against influenza A virus by privileged structure strategy.

A series of new matrinic derivatives with an 11-adamantyl group were designed, synthesized and evaluated for their anti-influenza A H3N2 activities, based on the privileged structure strategy.SAR analysis indicated that introduction of an 11-adamantyl by ester linker might be helpful for the activity. Among them, compound 7b exhibited promising anti-H3N2 activities with IC50 value of 5.14 µM, slightly better than that of amantadine. Its activity was further confirmed at the protein level. In primary mechanism, compound 7b could inhibit virus replication cycle at early stage by targeting M2 protein, consistent with that of amantadine. This study represents a successful application of combined strategy of privileged amantadine segment for further structural optimization and development of a new class of anti-influenza agents.

Chitosan coated chlorogenic acid and rutincomposite phospholipid liposomes: Preparation, characterizations, permeability and pharmacokinetic.

In order to research and enhance bioavailability of chlorogenic acid and rutin(CA-R) via the oral route, chitosan coated composite phospholipid liposomes (C-CPLs) were applied to study on preparation, permeability and pharmacokinetic of C-CA-R-CPLs. TheC-CA-R-CPLs were prepared by the method of ethanol injection. The entrapment efficiency (EE), average particle sizes, polymer disperse index (PDI), zeta potential, shape and in vitro drug release were investigated to characterize physicochemical parameters of C-CA-R-CPLs. The penetration properties from C-CA-R-CPLs were studied through Caco-2 cells model and the pharmacokinetics in Sprague-Dawley (SD) rats were evaluated by rat jugular vein intubation tube. The EE of C-CA-R-CPLs of CA and R was 91.3±2.13% and 92.6±2.44%, particle size of C-CA-R-CPLs was 176.7±2.3 nm, PDI was 0.207±0.014 and zeta potential of 12.61±1.33 mV. CA-R-CPLs and C-CA-R-CPLs were spherical or elliptical sphere and the bilayer of the CPL was observed obviously under transmission electron. The Cmax, t1/2 and AUC0-12 h values of CA and R for groups of C-CA-R-CPLs were significantly increased.In conclusion, TheC-CA-R-CPLs as a novel nano-formulation have potential to be used to enhance the oral bioavailability of poorlywater-soluble drugs after oral administration.

Selectivity Enhancement in Electronic Nose Based on an Optimized DQN.

In order to enhance the selectivity of metal oxide gas sensors, we use a flow modulation method to exploit transient sensor information. The method is based on modulating the flow of the carrier gas that brings the species to be measured into the sensor chamber. We present an active perception strategy by using a DQN which can optimize the flow modulation online. The advantage of DQN is not only that the classification accuracy is higher than traditional methods such as PCA, but also that it has a good adaptability under small samples and labeled data. From observed values of the sensors array and its past experiences, the DQN learns an action policy to change the flow speed dynamically that maximizes the total rewards (or minimizes the classification error). Meanwhile, a CNN is trained to predict sample class and reward according to current actions and observation of sensors. We demonstrate our proposed methods on a gases classification problem in a real time environment. The results show that the DQN learns to modulate flow to classify different gas and the correct rates of gases are: sesame oil 100%, lactic acid 80%, acetaldehyde 80%, acetic acid 80%, and ethyl acetate 100%, the average correct rate is 88%. Compared with the traditional method, the results of PCA are: sesame oil 100%, acetic acid 24%, acetaldehyde 100%, lactic acid 56%, ethyl acetate 68%, the average accuracy rate is 69.6%. DQN uses fewer steps to achieve higher recognition accuracy and improve the recognition speed, and to reduce the training and testing costs.

Luteolin Inhibits Fibrillary ß-Amyloid1-40-Induced Inflammation in a Human Blood-Brain Barrier Model by Suppressing the p38 MAPK-Mediated NF-κB Signaling Pathways.

Amyloid-ß peptides (Aß) exist in several forms and are known as key modulators of Alzheimer's disease (AD). Fibrillary Aß (fAß) has been found to disrupt the blood-brain barrier (BBB) by triggering and promoting inflammation. In this study, luteolin, a naturally occurring flavonoid that has shown beneficial properties in the central nervous system, was evaluated as a potential agent to preserve barrier function and inhibit inflammatory responses at the BBB that was injured by fAß1-40. We established an in vitro BBB model by co-culturing human brain microvascular endothelial cells (hBMECs) and human astrocytes (hAs) under fAß1-40-damaged conditions and investigated the effect of luteolin by analyzing cellular toxicity, barrier function, cytokine production and inflammation-related intracellular signaling pathways. Our results demonstrated that, in cells injured by fAß1-40, luteolin increased cell viability of hBMECs and hAs. The cytoprotection of the co-culture against the damage induced by fAß1-40 was also increased at both the apical and basolateral sides. Luteolin protected the barrier function by preserving transendothelial electrical resistance and relieving aggravated permeability in the human BBB model after being exposed to fAß1-40. Moreover, in both the apical and basolateral sides of the co-culture, luteolin reduced fAß1-40-induced inflammatory mediator and cytokine production, including cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), interleukin 1 ß (IL-1ß), interleukin 6 (IL-6), and interleukin 8 (IL-8), however it did not show sufficient effects on scavenging intracellular reactive oxygen species (ROS) in hBMECs and hAs. The mechanism of BBB protection against fAß1-40-induced injury may be related to the regulation of inflammatory signal transduction, which involves inhibition of p38 mitogen-activated protein kinase (MAPK) activation, downregulation of phosphorylated inhibitory κB kinase (phosphor-IKK) levels, relief of inhibitory κB α (IκBα) degradation, blockage of nuclear factor κB (NF-κB) p65 nuclear translocation, and reduction of the release of inflammatory cytokines. Moreover, the employment of p38 MAPK and NF-κB inhibitors reversed luteolin-mediated barrier function and cytokine release. Taken together, luteolin may serve as a potential therapeutic agent for BBB protection by inhibiting inflammation following fAß1-40-induced injury.