Dibenzocyclooctadiene Lignans from Schisandra chinensis with Anti-Inflammatory Effects.

Schisandra chinensis (Schisandraceae) is a medicinal plant widely used in traditional Chinese medicine. Under the name Wu Wei Zi, it is used to treat many diseases, especially as a stimulant, adaptogen, and hepatoprotective. Dibenzocyclooctadiene lignans are the main compounds responsible for the effect of S. chinensis. As a part of ongoing studies to identify and evaluate anti-inflammatory natural compounds, we isolated a series of dibenzocyclooctadiene lignans and evaluated their biological activity. Furthermore, we isolated new sesquiterpene 7,7-dimethyl-11-methylidenespiro[5.5]undec-2-ene-3-carboxylic acid. Selected dibenzocyclooctadiene lignans were tested to assess their anti-inflammatory potential in LPS-stimulated monocytes by monitoring their anti-NF-κB activity, antioxidant activity in CAA assay, and their effect on gap junction intercellular communication in WB-ras cells. Some S. chinensis lignans showed antioxidant activity in CAA mode and affected the gap junction intercellular communication. The anti-inflammatory activity was proven for (-)-gomisin N, (+)-γ-schisandrin, rubrisandrin A, and (-)-gomisin J.

Establishment of cluster of differentiation 20 immobilized cell membrane chromatography for the screening of active antitumor components in traditional Chinese medicine.

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of malignant tumors occurring in B or T lymphocytes, and no small molecule-positive drugs to treat NHL have been marketed. Cluster of differentiation 20 (CD20) is an important molecule regulating signaling for the life and differentiation of B lymphocytes and possesses the characteristics of a drug target for treating NHL. 2-Methoxyestradiol induces apoptosis in lymphoma Raji cells and CD20 protein is highly expressed by Raji lymphoma cells. Therefore, in this study, a CD20-SNAP-tag/CMC model was developed to validate the interaction of 2-methoxyestradiol with CD20. 2-Methoxyestradiol was used as a small molecule control compound, and the system was validated for good applicability. The cell membrane chromatography model was combined with high-performance liquid chromatography ion trap time-of-flight mass spectroscopy (HPLC-IT-TOF-MS) in a two-dimensional system to successfully identify, analyze, and characterize the potential active compounds of Schisandra chinensis (Turcz.) Baill. extract and Lysionotus pauciflorus Maxim. extract, including Schisandrin A, Schizandrol A, Schizandrol B, Schisantherin B, and Nevadensin, which can act on CD20 receptors. The five potential active compounds were analyzed by non-linear chromatography. The thermodynamic and kinetic parameters of their interaction with CD20 were also analyzed, and the mode of interaction was simulated by molecular docking. Their inhibitory effects on lymphoma cell growth were assessed using a Cell Counting Kit-8 (CCK-8). Nevadensin and Schizandrin A were able to induce apoptosis in Raji cells within a certain concentration range. In conclusion, the present experiments provide some bases for improving NHL treatment and developing small molecule lead compounds targeting CD20 with low toxicity and high specificity.

Lignan contents of Schisandra chinensis (Turcz.) Baill. from different origins-A new model for evaluating the content of prominent components of Chinese herbs.

BACKGROUND: As a traditional Chinese herbal medicine, Schisandra chinensis exhibits various effects such as liver protection, blood sugar regulation, blood lipid regulation, immune function regulation, antidepressant activity, etc. However, because of its intricate composition, diverse origins, and medicinal effects depending on complex compound groups, there are differences in the lignan composition of S. chinensis from different origins. Therefore, it is currently difficult to evaluate the quality of medicinal materials from plants of different origins using a single qualitative quality control index. PURPOSE: This paper aims to investigate the potential relationship between the lignan components of S. chinensis from different origins and to establish stable assessment indices for determining the lignan content of S. chinensis from multiple perspectives. METHODS: In this study, we collected S. chinensis samples of seven major origins in China, and randomly sampled 6-9 batches of each origin for a total of 60 batches. The lignan content was determined by HPLC, and its distribution law of the ratio of each lignan component of S. chinensis to Schisandrol A content was analyzed. Combining network pharmacology and differential analysis between samples, the stable and effective substances used as quality markers were determined. RESULTS: There were some correlations among the lignan contents of S. chinensis, some correlations between schisandrin A and other lignans of S. chinensis could be determined. The ratio of each component to the indicator component schisandrol A was evenly distributed and reflected the lignan content of S. chinensis to some extent. Four substances (schisandrol A, schisandrol B, schisantherin A, and schisandrin C) were determined by network pharmacology combined with the analysis results of HCA, PCA and PLS-DA to further optimize the model. They displayed a strong connection with the core target, a large contribution rate to the principal components, and a stable content in each batch of samples, suggesting that these components may be the main active substances of S. chinensis lignans. Therefore, they could be used as main indicators evaluating the advantages and disadvantages of S. chinensis by examining the consistency of component proportions. CONCLUSION: This method can intuitively evaluate the content of main lignans in S. chinensis. This quality assessment model is an exploration of the multi-component comprehensive evaluation system of S. chinensis, providing a new concept for the quality evaluation system of Chinese herbal medicines.

Schisandrin B from Schisandra chinensis alleviated pain via glycine receptors, Nav1.7 channels and Cav2.2 channels.

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis, the dried and ripe fruit of the magnolia family plant Schisandra chinensis (Turcz.) Baill, was commonly used in traditional analgesic prescription. Studies have shown that the extract of Schisandra chinensis (SC) displayed analgesic activity. However, the analgesic active component and the exact mechanisms have yet to be revealed. AIM OF THE STUDY: The present study was to investigate the anti-nociceptive constituent of Schisandra chinensis, assess its analgesic effect, and explore the potential molecular mechanisms. MATERIALS AND METHODS: The effects of a series of well-recognized compounds from SC on glycine receptors were investigated. The analgesic effect of the identified compound was evaluated in three pain models. Mechanistic studies were performed using patch clamp technique on various targets expressed in recombinant cells. These targets included glycine receptors, Nav1.7 sodium channels, Cav2.2 calcium channels et al. Meanwhile, primary cultured spinal dorsal horn (SDH) neurons and dorsal root ganglion (DRG) neurons were also utilized. RESULTS: Schisandrin B (SchB) was a positive allosteric modulator of glycine receptors in spinal dorsal horn neurons. The EC50 of SchB on glycine receptors in spinal dorsal horn neurons was 2.94 ± 0.28 µM. In three pain models, the analgesic effect of SchB was comparable to that of indomethacin at the same dose. Besides, SchB rescued PGE2-induced suppression of α3 GlyR activity and alleviated persistent pain. Notably, SchB could also potently decrease the frequency of action potentials and inhibit sodium and calcium channels in DRG neurons. Consistent with the data from DRG neurons, SchB was also found to significantly block Nav1.7 sodium channels and Cav2.2 channels in recombinant cells. CONCLUSION: Our results demonstrated that, Schisandrin B, the primary lignan component of Schisandra chinensis, may exert its analgesic effect by acting on multiple ion channels, including glycine receptors, Nav1.7 channels, and Cav2.2 channels.

Exposure to individual polycyclic aromatic compounds impairs the cardiac performance of American lobster (Homarus americanus) larvae.

The potential for oil spills poses a threat to marine organisms, the toxicity of which has been attributed primarily to polycyclic aromatic compounds (PACs). Predictive tools such as the target lipid model (TLM) have been developed to forecast and assess these risks. The aim of the present study was to characterize the cardiotoxicity of 10 structurally diverse PACs in American lobster (Homarus americanus) larvae by assessing heart rate following a 48 h exposure in a passive dosing system, and subsequently use the TLM framework to calculate a critical target lipid body burden (CTLBB) for bradycardia. Exposure to 8 of the 10 PACs resulted in concentration-dependent bradycardia, with phenanthrene causing the greatest effect. The TLM was able to effectively characterize bradycardia in American lobsters, and the cardiotoxic CTLBB value determined in this study is among the most sensitive endpoints included in the CTLBB database. This study is one of the first to apply the TLM to a cardiac endpoint and will improve predictive models for assessing sublethal impacts of oil spills on American lobster populations.

Extraction, purification, structural characterization, and bioactivities of the genus Schisandra polysaccharides: A review.

The genus Schisandra, a member of the Magnoliaceae family, is a well-known tonic traditional Chinese medicine with a long history of traditional medicinal and functional food used in China. Polysaccharides are one of its main active constituents, which have a wide range of bioactivities, such as anti-inflammatory, anti-tumor, neuroprotection, anti-diabetes, hepatoprotection, immunomodulation, and anti-fatigue. In this paper, we review the extraction, isolation, purification, structural characterization, bioactivities, as well as structure-activity relationship of polysaccharides from the genus Schisandra. In conclusion, we hope that this review could provide reference for the subsequent research on structural, bioactivities, development and application of the genus Schisandra polysaccharides.

Schisandrin A alleviates renal fibrosis by inhibiting PKCß and oxidative stress.

BACKGROUND: Renal fibrosis is a common pathway that drives the advancement of numerous kidney maladies towards end-stage kidney disease (ESKD). Suppressing renal fibrosis holds paramount clinical importance in forestalling or retarding the transition of chronic kidney diseases (CKD) to renal failure. Schisandrin A (Sch A) possesses renoprotective effect in acute kidney injury (AKI), but its effects on renal fibrosis and underlying mechanism(s) have not been studied. STUDY DESIGN: Serum biochemical analysis, histological staining, and expression levels of related proteins were used to assess the effect of PKCß knockdown on renal fibrosis progression. Untargeted metabolomics was used to assess the effect of PKCß knockdown on serum metabolites. Unilateral Ureteral Obstruction (UUO) model and TGF-ß induced HK-2 cells and NIH-3T3 cells were used to evaluate the effect of Schisandrin A (Sch A) on renal fibrosis. PKCß overexpressed NIH-3T3 cells were used to verify the possible mechanism of Sch A. RESULTS: PKCß was upregulated in the UUO model. Knockdown of PKCß mitigated the progression of renal fibrosis by ameliorating perturbations in serum metabolites and curbing oxidative stress. Sch A alleviated renal fibrosis by downregulating the expression of PKCß in kidney. Treatment with Sch A significantly attenuated the upregulated proteins levels of FN, COL-I, PKCß, Vimentin and α-SMA in UUO mice. Moreover, Sch A exhibited a beneficial impact on markers associated with oxidative stress, including MDA, SOD, and GSH-Px. Overexpression of PKCß was found to counteract the renoprotective efficacy of Sch A in vitro. CONCLUSION: Sch A alleviates renal fibrosis by inhibiting PKCß and attenuating oxidative stress.

Pharmacokinetic interactions between tacrolimus and Wuzhi capsule in liver transplant recipients: Genetic polymorphisms affect the drug interaction.

Wuzhi capsule (WZC), a commonly used Chinese patent medicine to treat various types of liver dysfunction in China, increases the exposure of tacrolimus (TAC) in liver transplant recipients. However, this interaction has inter-individual variability, and the underlying mechanism remains unclear. Current research indicates that CYP3A4/5 and drug transporters influence the disposal of both drugs. This study aims to evaluate the association between TAC dose-adjusted trough concentration (C/D) and specific genetic polymorphisms of CYP3A4/5, drug transporters and pregnane x receptor (PXR), and plasma levels of major WZC components, deoxyschisandrin and γ-schisandrin, in liver transplant patients receiving both TAC and WZC. Liquid chromatography-tandem-mass spectrometry was used to detect the plasma levels of deoxyschisandrin and γ-schisandrin, and nine polymorphisms related to metabolic enzymes, transporters and PXR were genotyped by sequencing. A linear mixed model was utilized to assess the impact of the interaction between genetic variations and WZC components on TAC lnC/D. Our results indicate a significant association of TAC lnC/D with the plasma levels of deoxyschisandrin and γ-schisandrin. Univariate analysis demonstrated three polymorphisms in the genes ABCB1 (rs2032582), ABCC2 (rs2273697), ABCC2 (rs3740066), and PXR (rs3842689) interact with both deoxyschisandrin and γ-schisandrin, influencing the TAC lnC/D. In multiple regression model analysis, the interactions between deoxyschisandrin and both ABCB1 (rs2032582) and ABCC2 (rs3740066), post-operative day (ß < 0.001, p < 0.001), proton pump inhibitor use (ß = -0.152, p = 0.008), body mass index (ß = 0.057, p < 0.001), and ABCC2 (rs717620, ß = -0.563, p = 0.041), were identified as significant factors of TAC lnC/D, accounting for 47.89% of the inter-individual variation. In summary, this study elucidates the influence of the interaction between ABCB1 and ABCC2 polymorphisms with WZC on TAC lnC/D. These findings offer a scientific basis for their clinical interaction, potentially aiding in the individualized management of TAC therapy in liver transplant patients.

Schisandrin B Alleviates LPS Induced Mitochondrial Damage in C28I2 Cells.

Osteoarthritis is a common joint disease characterized by damage to the joint cartilage that occurs throughout the entire joint tissue. This damage primarily manifests as pain in the affected area. In clinical practice, medication is commonly used to relieve pain, but the treatment's effectiveness is poor and recurrent attacks are likely. Schisandrin B is the most abundant biphenylcyclohexene lignan found in the traditional Chinese medicine Schisandra chinensis, and it possesses various pharmacological effects. This study aims to investigate the protective effect of Schisandrin B on mitochondrial damage in osteoarthritis (C28I2 cells) under an inflammatory environment induced by LPS. Cell proliferation and activity, scratch tests, and LDH release tests are utilized to assess cell growth and migration ability. The immunofluorescence assay was used to detect the expression levels of proliferation and apoptosis proteins. The Western Blot assay was used to detect the expression levels of mitochondrial fusion and division proteins. The JC-1 assay was used to detect changes in mitochondrial membrane potential. The mitochondrial fluorescence probe assay was used to detect mitochondrial activity. Through research, it was found that Schisandrin B promotes the proliferation, growth, and migration of C28I2 cells, reduces apoptosis of C28I2 cells, balances mitochondrial fusion and division, stabilizes mitochondrial membrane potential, and promotes mitochondrial activity in an LPS induced inflammatory environment.

Target attainment of intravenous lefamulin for treatment of acute bacterial skin and skin structure infections.

OBJECTIVES: Lefamulin is a pleuromutilin antibiotic approved for the treatment of community-acquired bacterial pneumonia (CABP). Its spectrum of activity, good penetration into soft tissues and low rates of cross-resistance also make lefamulin a potentially valuable option for treatment of acute bacterial skin and skin structure infections (ABSSSIs). A Phase 2 trial of lefamulin for ABSSSI indicated similar efficacy of 100 and 150 mg q12h IV dosing regimens. In the present study, the potential of lefamulin for this indication was further evaluated from a translational pharmacokinetic/pharmacodynamic perspective. METHODS: PTA was determined for various dosages using Monte Carlo simulations of a population pharmacokinetic model of lefamulin in ABSSSI patients and preclinical exposure targets associated with bacteriostasis and a 1-log reduction in bacterial count. Overall target attainment against MSSA and MRSA was calculated using lefamulin MIC distributions. RESULTS: Overall attainment of the bacteriostasis target was 94% against MSSA and 84% against MRSA for the IV dosage approved for CABP (150 mg q12h). Using the same target, for the 100 mg q12h regimen, overall target attainment dropped to 68% against MSSA and 50% against MRSA. Using the 1-log reduction target, overall target attainment for both regimens was <40%. CONCLUSIONS: Lefamulin at the currently approved IV dosage covers most Staphylococcus aureus isolates when targeting drug exposure associated with bacteriostasis, suggesting potential of lefamulin for the treatment of ABSSSIs. Lefamulin may not be appropriate in ABSSSI when rapid bactericidal activity is warranted.

Schisandrin A enhances pathogens resistance by targeting a conserved p38 MAPK pathway.

Schizandrin A (SA), also known as deoxyschizandrin, is one of the most biologically active lignans isolated from the traditional Chinese medicine Fructus schisandrae chinensis. Schisandrin A has proven benefits for anti-cancer, anti-inflammation, hepatoprotection, anti-oxidation, neuroprotection, anti-diabetes. But the influence of Schisandrin A to the innate immune response and its molecular mechanisms remain obscure. In this study, we found that Schisandrin A increased resistance to not only the Gram-negative pathogens Pseudomonas aeruginosa and Salmonella enterica but also the Gram-positive pathogen Listeria monocytogenes. Meanwhile, Schisandrin A protected the animals from the infection by enhancing the tolerance to the pathogens infection rather than by reducing the bacterial burden. Through the screening of the conserved immune pathways in Caenorhabditis elegans, we found that Schisandrin A enhanced innate immunity via p38 MAPK pathway. Furthermore, Schisandrin A increased the expression of antibacterial peptide genes, such as K08D8.5, lys-2, F35E12.5, T24B8.5, and C32H11.12 by activation PMK-1/p38 MAPK. Importantly, Schisandrin A-treated mice also enhanced resistance to P. aeruginosa PA14 infection and significantly increased the levels of active PMK-1. Thus, promoted PMK-1/p38 MAPK-mediated innate immunity by Schisandrin A is conserved from worms to mammals. Our work provides a conserved mechanism by which Schisandrin A enhances innate immune response and boosts its therapeutic application in the treatment of infectious diseases.

A comprehensive review on Schisandrin and its pharmacological features.

Schisandrin stands as one of the primary active compounds within the widely used traditional medicinal plant Schisandra chinensis (Turcz.) Baill. This compound exhibits sedative, hypnotic, anti-aging, antioxidant, and immunomodulatory properties, showcasing its effectiveness across various liver diseases while maintaining a favorable safety profile. However, the bioavailability of schisandrin is largely affected by hepatic and intestinal first-pass metabolism, which limits the clinical efficacy of schisandrin. In this paper, we review the various pharmacological effects and related mechanisms of schisandrin, in order to provide reference for subsequent drug research and promote its medicinal value.

Schisandrin B, a dual positive allosteric modulator of GABAA and glycine receptors, alleviates seizures in multiple mouse models.

Epilepsy is a prevalent and severe neurological disorder and approximately 30% of patients are resistant to existing medications. It is of utmost importance to develop alternative therapies to treat epilepsy. Schisandrin B (SchB) is a major bioactive constituent of Schisandra chinensis (Turcz.) Baill and has multiple neuroprotective effects, sedative and hypnotic activities. In this study, we investigated the antiseizure effect of SchB in various mouse models of seizure and explored the underlying mechanisms. Pentylenetetrazole (PTZ), strychnine (STR), and pilocarpine-induced mouse seizure models were established. We showed that injection of SchB (10, 30, 60 mg/kg, i.p.) dose-dependently delayed the onset of generalized tonic-clonic seizures (GTCS), reduced the incidence of GTCS and mortality in PTZ and STR models. Meanwhile, injection of SchB (30 mg/kg, i.p.) exhibited therapeutic potential in pilocarpine-induced status epilepticus model, which was considered as a drug-resistant model. In whole-cell recording from CHO/HEK-239 cells stably expressing recombinant human GABAA receptors (GABAARs) and glycine receptors (GlyRs) and cultured hippocampal neurons, co-application of SchB dose-dependently enhanced GABA or glycine-induced current with EC50 values at around 5 µM, and application of SchB (10 µM) alone did not activate the channels in the absence of GABA or glycine. Furthermore, SchB (10 µM) eliminated both PTZ-induced inhibition on GABA-induced current (IGABA) and strychnine (STR)-induced inhibition on glycine-induced current (Iglycine). Moreover, SchB (10 µM) efficiently rescued the impaired GABAARs associated with genetic epilepsies. In addition, the homologous mutants in both GlyRs-α1(S267Q) and GABAARs-α1(S297Q)ß2(N289S)γ2L receptors by site-directed mutagenesis tests abolished SchB-induced potentiation of IGABA and Iglycine. In conclusion, we have identified SchB as a natural positive allosteric modulator of GABAARs and GlyRs, supporting its potential as alternative therapies for epilepsy.

Searching for bacteria able to metabolize polycyclic aromatic sulfur compounds in 12-years periodically fed bioreactor.

Biodesulfurization is a promising alternative for removing sulfur molecules from the polycyclic aromatic sulfur compounds (PASC) found in petroleum. PASC consists of recalcitrant molecules that can degrade fuel quality and cause a range of health and environmental problems. Therefore, identifying bacteria capable of degrading PASC is essential for handling these recalcitrant molecules. Microorganisms in environments exposed to petroleum derivatives have evolved specific enzymatic machinery, such as the 4S pathway associated with the dszABC genes, which are directly linked to sulfur removal and utilization as nutrient sources in the biodesulfurization process. In this study, bacteria were isolated from a bioreactor containing landfarm soil that had been periodically fed with petroleum for 12 years, using a medium containing dibenzothiophene (DBT), 4.6-dimethylbenzothiophene, 4-methylbenzothiophene, or benzothiophene. This study aimed to identify microorganisms capable of degrading PASC in such environments. Among the 20 colonies isolated from an inoculum containing DBT as the sole sulfur source, only four isolates exhibited amplification of the dszA gene in the dszABC operon. The production of 2-hydroxybiphenyl (HPB) and a decrease in DBT were detected during the growth curve and resting cell assays. The isolates were identified using 16S rRNA sequencing belonging to the genera Stutzerimonas and Pseudomonas. These isolates demonstrated significant potential for biodesulfurization and/or degradation of PASC. All isolates possessed the potential to be utilized in the biotechnological processes of biodesulfurization and degradation of recalcitrant PASC molecules.

Changes in Temperature Alter the Toxicity of Polycyclic Aromatic Compounds to American Lobster (Homarus americanus) Larvae.

Polycyclic aromatic compounds (PACs) present in the water column are considered to be one of the primary contaminant groups contributing to the toxicity of a crude oil spill. Because crude oil is a complex mixture composed of thousands of different compounds, oil spill models rely on quantitative structure-activity relationships like the target lipid model to predict the effects of crude oil exposure on aquatic life. These models rely on input provided by single species toxicity studies, which remain insufficient. Although the toxicity of select PACs has been well studied, there is little data available for many, including transformation products such as oxidized hydrocarbons. In addition, the effect of environmental influencing factors such as temperature on PAC toxicity is a wide data gap. In response to these needs, in the present study, Stage I lobster larvae were exposed to six different understudied PACs (naphthalene, fluorenone, methylnaphthalene, phenanthrene, dibenzothiophene, and fluoranthene) at three different relevant temperatures (10, 15, and 20 °C) all within the biological norms for the species during summer when larval releases occur. Lobster larvae were assessed for immobilization as a sublethal effect and mortality following 3, 6, 12, 24, and 48 h of exposure. Higher temperatures increased the rate at which immobilization and mortality were observed for each of the compounds tested and also altered the predicted critical target lipid body burden, incipient median lethal concentration, and elimination rate. Our results demonstrate that temperature has an important influence on PAC toxicity for this species and provides critical data for oil spill modeling. More studies are needed so oil spill models can be appropriately calibrated and to improve their predictive ability. Environ Toxicol Chem 2023;42:2389-2399. © 2023 SETAC.

Recommendations for advancing test protocols examining the photo-induced toxicity of petroleum and polycyclic aromatic compounds.

Photo-induced toxicity of petroleum products and polycyclic aromatic compounds (PACs) is the enhanced toxicity caused by their interaction with ultraviolet radiation and occurs by two distinct mechanisms: photosensitization and photomodification. Laboratory approaches for designing, conducting, and reporting of photo-induced toxicity studies are reviewed and recommended to enhance the original Chemical Response to Oil Spills: Ecological Research Forum (CROSERF) protocols which did not address photo-induced toxicity. Guidance is provided on conducting photo-induced toxicity tests, including test species, endpoints, experimental design and dosing, light sources, irradiance measurement, chemical characterization, and data reporting. Because of distinct mechanisms, aspects of photosensitization (change in compound energy state) and photomodification (change in compound structure) are addressed separately, and practical applications in laboratory and field studies and advances in predictive modeling are discussed. One goal for developing standardized testing protocols is to support lab-to-field extrapolations, which in the case of petroleum substances often requires a modeling framework to account for differential physicochemical properties of the constituents. Recommendations are provided to promote greater standardization of laboratory studies on photo-induced toxicity, thus facilitating comparisons across studies and generating data needed to improve models used in oil spill science.

Combustion of crude oil during in-situ burning can introduce polycyclic aromatic compounds (PACs) into small-scale freshwater systems.

In-situ burning (ISB) is the controlled combustion of an oil slick to remove large quantities of spilled oil from the aquatic environment. Prior to employing ISB as a remediation technique, an oil slick must often be corralled by physical or chemical means to achieve a sufficient thickness (typically >1 mm) for ignition. While ISB is an effective means to remove oil mass, less is known about the potential for ISB to mobilize polycyclic aromatic compounds (PACs) into the aquatic environment. The PACs are primary contaminants of concern in crude oil due to their environmental persistence and toxicity. We examined the potential for ISB to mobilize PACs into underlying waters in a series of small-scale burns conducted across a gradient of oil slick thicknesses (0-7 mm). Concentrations of PACs in underlying waters were evaluated and compared to reference conditions using an equivalent gradient of oil slick thicknesses that were not ignited. At thinner slick thicknesses (i.e. 0 - 4 mm) ISB enhanced the mobilization of total PACs, likely a result of heat transfer to underlying waters; this effect increased as slick thickness increased. Among thicker slicks (i.e. 4 - 7 mm), pyrogenic PACs became more prevalent and greater concentrations of 4-ring PACs were detected in underlying waters. The potential for PAC mobilization needs to be considered in scenarios where ISB may be the only viable oil spill remediation option (e.g. wetlands, marshes, or where oil is entrained) and in shallow systems susceptible to temperature changes.

A multidimensional strategy for uncovering comprehensive quality markers of Schisandra chinensis (Turcz.) Baill based on pharmacodynamics and chemical properties.

BACKGROUND: Quality control of Traditional Chinese Medicines (TCMs) has improved greatly, but there is still a lack of a convincing quality evaluation system for TCMs. Developing quality control markers of TCMs based on pharmacodynamics instead of content has been an attractive approach. However, on account of neglecting phytochemistry attributes of TCMs, part of effective markers might be short of specificity and inconvenient for detecting in production manufacture, which is adverse to control the quality of TCMs systematically. PURPOSE: To build a novel and multidimensional quality assessment approach for TCMs based on pharmacodynamics and chemical properties. METHODS: Schisandra chinensis (Turcz.) Baill (S. chinensis) was used as an example and a rat depression model was built by using a chronic unpredictable mild stress procedure. For identifying the antidepressive components of S. chinensis, we elucidated its antidepressant mechanism in first-step by using quantitative RT-PCR and immunoblotting techniques. And accordingly, correlation analysis between ingredients in vivo with target proteins and anti-inflammation experiments in vitro were carried out. On the other hand, HPLC fingerprint combinations with diverse chemometrics methods were applied to analyze 14 preparations of S. chinensis to obtain its characteristic chemical information. Finally, we ascertained the quality control markers of S. chinensis by integrating the efficacious and characteristic constituents. RESULTS: Our research indicated that S. chinensis treated depression by relieving disordered monoaminergic system and ameliorating neuroinflammation. Five effective substances (schisandrol A, schisandrin A, gomisin N, schisandrin B, and schisandrin C) were screened out according to their potential anti-depression efficacy. Besides, 21 common ingredients and 4 representative constituents of S. chinensis were identified by chemical analysis, whereas only 2 characteristic quantitative markers (schisandrol A, schisandrol B) were ultimately ascertained based on previous studies. CONCLUSION: 6 components, schisandrol A, schisandrin A, gomisin N, schisandrin B, schisandrin C, and schisandrol B, possessed efficacy, measurability, and specificity, were selected as the comprehensive markers for quality control of S. chinensis. We proposed a multidimensional strategy for identifying comprehensive quality markers for TCMs in this study.

SAR study culminates in a series of HDAC6 selective inhibitors featuring Schisandrin C-analogous Cap as potential immunomodulatory agents for cancer therapy.

HDAC6 inhibitors (HDAC6is) represent an emerging therapeutic option for triggering anti-cancer immune response. In this work, a novel series of HDAC6is, derived from an in-house analog of the traditional Chinese medicine monomer Schisandrin C, were designed and synthesized for SAR study. Throughout the 29 target compounds, 24a, 24b and 24h exerted single-digit nanomolar enzymatic activity and remarkably elevated subtype selectivity compared to the clinically investigated HDAC6i Ricolinostat (Selectivity index = 3.3). In A549 tumor cells, 24h, as the representative in this series (IC50 = 7.7 nM; selectivity index = 31.4), was capable of reversing IL-6-mediated PD-L1 upregulation, highlighting its immunomodulatory capability. Importantly, unlike numerous other hydroxamate-based HDACis, 24h displayed an acceptable oral bioavailability in Sprague-Dawley rats, along with high plasma exposure, long elimination half-life and slow clearance. With the aforementioned attractive performance, 24h deserves further in vivo investigation as an immunomodulatory therapeutic agent for batting human malignance.

Schisandrin C improves leaky gut conditions in intestinal cell monolayer, organoid, and nematode models by increasing tight junction protein expression.

BACKGROUND: Leaky gut symptoms and inflammatory bowel disease (IBD) are associated with damaged intestinal mucosa, intestinal permeability dysfunction by epithelial cell cytoskeleton contraction, disrupted intercellular tight junction (TJ) protein expression, and abnormal immune responses and are intractable diseases. PURPOSE: We evaluated the effects of schisandrin C, a dibenzocyclooctadiene lignan from Schisandra chinensis, on intestinal inflammation and permeability dysfunction in gut mimetic systems: cultured intestinal cells, intestinal organoids, and a Caenorhabditis elegans model. METHODS: Schisandrin C was selected from 9 lignan compounds from S. chinensis based on its anti-inflammatory effects in HT-29 human intestinal cells. IL-1ß and Pseudomonas aeruginosa supernatants were used to disrupt intestinal barrier formation in vitro and in C. elegans, respectively. The effects of schisandrin C on transepithelial electrical resistance (TEER) and intestinal permeability were evaluated in intestinal cell monolayers, and its effect on intestinal permeability dysfunction was tested in mouse intestinal organoids and C. elegans by measuring fluorescein isothiocyanate (FITC)-dextran efflux. The effect of schisandrin C on TJ protein expression was investigated by western blotting and fluorescence microscopy. The signaling pathway underlying these effects was also elucidated. RESULTS: Schisandrin C ameliorated intestinal permeability dysfunction in three IBD model systems and enhanced epithelial barrier formation via upregulation of ZO-1 and occludin in intestinal cell monolayers and intestinal organoids. In Caco-2 cells, schisandrin C restored IL-1ß-mediated increases in MLCK and p-MLC expression, in turn blocking cytoskeletal contraction and subsequent intestinal permeabilization. Schisandrin C inhibited NF-ĸB and p38 MAPK signaling, which regulates MLCK expression and structural reorganization of the TJ complex in Caco-2 cells. Schisandrin C significantly improved abnormal FITC-dextran permeabilization in both intestinal organoids and C. elegans. CONCLUSION: Schisandrin C significantly improves abnormal intestinal permeability and regulates the expression of TJ proteins, long MLCK, p-MLC, and inflammation-related proteins, which are closely related to leaky gut symptoms and IBD development. Therefore, schisandrin C is a candidate to treat leaky gut symptoms and IBDs.