[Research progress on chemical constituents and pharmacological activities of halogenated sesquiterpenes from natural sources].

Halogenated sesquiterpenes are important derivatives of sesquiterpenes, referring to chemical components of sesquiterpenes that contain halogens such as chlorine, bromine, and iodine. Halogenated sesquiterpenes have attracted attention from researchers in China and abroad because of their diverse structures, unique halogen elements, and extensive pharmacological activities. Studies have shown that halogenated sesquiterpenes exhibit significant antimicrobial, anti-inflammatory, anticancer, insecticidal, hypoglycemic, and enzyme inhibitory activities. In order to better explore the potential pharmaceutical value of halogenated sesquiterpenes, this paper reviewed the structural characteristics and pharmacological activities of halogenated sesquiterpenes in the past two decades, aiming to provide references for further research and development of this class of compounds.

Design, synthesis and bioactivity evaluation of selenium-containing PI3Kδ inhibitors.

PI3Kδ inhibitors play an important role in the treatment of leukemia, lymphoma and autoimmune diseases. Herein, using our reported compounds as the lead compound, we designed and synthesized a series of selenium-containing PI3Kδ inhibitors based on quinazoline and pyrido[3,2-d]pyrimidine skeletons. Among them, compound Se15 showed sub-nanomolar inhibition against PI3Kδ and strong δ-selectivity. Moreover, Se15 showed potent anti-proliferative effect on SU-DHL-6 cells with an IC50 value of 0.16 µM. Molecular docking study showed that Se15 was able to form multiple hydrogen bonds with PI3Kδ and was close proximity and stacking with PI3Kδ selective region. In conclusion, the Se-containing compound Se15 bearing pyrido[3,2-d]pyrimidine scaffold is a novel potent and selective PI3Kδ inhibitor. The introduction of selenium can enrich the structure of PI3Kδ inhibitors and provide a new idea for design of novel PI3Kδ inhibitors.

A Yeast Cell Wall Derived Hybrid Hydrogel with Photothermal and Immune Combined Modality Therapy for Enhanced Anti-Melanoma Efficacy.

Introduction: The effect of traditional treatment for melanoma is quite limited, especially for its recurrence. As the major components of yeast cell wall, chitin and ß-glucan exhibit good immune activation effect and are promising candidates for adjuvant. Therefore, melanoma cell membrane (CM) and indocyanine green (ICG) was loaded in a chitin and ß-glucan hybrid hydrogel to achieve an enhanced anti-melanoma therapy. Methods: The novel hybrid hydrogel was prepared, and its physicochemical properties were examined. Its effect towards melanoma prevention and treatment was evaluated via a melanoma-bearing mice model. Results: The CM-ICG-hybrid hydrogel was successfully prepared with excellent injectability, self-healing, drug loading, rheological, in vitro and in vivo photothermal stability, and retention properties. It also exhibited good cellular and in vivo safety profiles. In the primary melanoma mice model, it quickly ablated the in-situ melanoma, effectively inhibited the tumor growth, increased the survival rate of melanoma-bearing mice, and increased the level of IFN-γ and TNF-α. In the distal secondary melanoma model, it efficiently prevented the reoccurrence of melanoma and activated the memory T cells. In both models, a synergistic effect of photothermal therapy and immune therapy was found. The hydrogel effectively recruited CD3+ CD4+ T cells and CD3+ CD8+ T cells, inhibited the proliferation of melanoma cells, and induced the apoptosis of melanoma cells. Conclusion: The hybrid hydrogel was successfully prepared, and it showed excellent efficacy towards melanoma prevention and treatment due to its efficient tumor ablation and immune activation capability.

Composite Hydrogel for Spatiotemporal Lipid Intervention of Tumor Milieu.

Induction of immunogenic cell death (ICD) plays crucial roles in cancer immunotherapy, whereas its efficacy is severely compromised by redundant antioxidant defenses in cancer cells and aberrant lipid metabolism in immunosuppressive cell populations. In this work, it is found that hollow mesoporous CuS nanoparticles (NPs) possess an intrinsic capacity of inhibiting glutathione peroxidase 4 (GPX4). When loaded with an inhibitor of the ferroptosis suppressor protein 1 (FSP1), these NPs block two parallel redox systems and cooperate with near-infrared irradiation to reinforce ICD. A hydrogel co-delivering cancer-cell-targeting CuS NPs and immunosuppressive-cell-targeting sulfo-N-succinimidyl oleate (SSO) for spatiotemporal lipid intervention i further fabricated. While the CuS NPs augment ICD via synergistic lipid peroxidation, SSO reinstates immune perception via lipid metabolic reprogramming, thereby coordinately triggering robust innate and adaptive immunity to restrain tumor growth, relapse, and metastasis. This study provides an immunometabolic therapy via orchestrated lipid modulation in the tumor milieu.

A Multigranularity Text Driven Named Entity Recognition CGAN Model for Traditional Chinese Medicine Literatures.

Recognition of Traditional Chinese Medicine (TCM) entities from different types of literature is challenging research, which is the foundation for extracting a large amount of TCM knowledge existing in unstructured texts into structured formats. The lack of large-scale annotated data makes unsatisfactory application of conventional deep learning models in TCM text knowledge extraction. Some other unsupervised methods rely on other auxiliary data, such as domain dictionaries. We propose a multigranularity text-driven NER model based on Conditional Generation Adversarial Network (MT-CGAN) to implement TCM NER with small-scale annotated corpus. In the model, a multigranularity text features encoder (MTFE) is designed to extract rich semantic and grammatical information from multiple dimensions of TCM texts. By differentiating the conditional constraints of the generator and discriminator of MT-CGAN, the synchronization between the generated tag labs and the named entities is guaranteed. Furthermore, seeds of different TCM text types are introduced into our model to improve the precision of NER. We compare our method with other baseline methods to illustrate the effectiveness of our method on 4 kinds of gold-standard datasets. The experiment results show that the standard precision, recall, and F1 score of our method are higher than the state-of-the-art methods by 0.24∼8.97%, 0.89∼12.74%, and 0.01∼10.84%. MT-CGAN is able to extract entities from different types of TCM literature effectively. Our experimental results indicate that the proposed approach has a clear advantage in processing TCM texts with more entity types, higher sparsity, less regular features, and a small-scale corpus.

Supplemental Blue Light Frequencies Improve Ripening and Nutritional Qualities of Tomato Fruits.

Tomatoes (Solanum lycopersicum L. Micro-Tom) were grown in a plastic greenhouse. When plants anthesis, the 100 µmol m-2 s-1 blue light-emitting diode (LED) light (430 ± 10 nm) was supplemented from 6:00 to 18:00. There were 5 treatments, which contained different blue light frequencies with the same intensity: S6 (30 min blue light and 30 min pause), S8 (30 min blue light and 15 min pause), S10 (30 min blue and 8 min pause), S12 (continuous blue light for 12 h), and control (CK) (natural light, without any supplemental light). Agronomic traits and nutritional qualities of tomato fruits were measured at 30, 34, 38, 42, and 46 days after anthesis (DAA), respectively. Different frequencies of supplemental blue light could accelerate flowering of tomato plants and promote fruit ripening about 3-4 days early via promoting ethylene evolution of fruits, which significantly facilitated the processes of color change and maturity in tomato fruits. The contents of lycopene, total phenolic compounds, total flavonoids, vitamin C, and soluble sugar, as well as the overall antioxidant activity of tomato fruits were significantly enhanced by all the supplemental blue light treatments. In all, different frequencies of supplemental blue light prominently reinforced the antioxidant levels and nutritional qualities of tomato fruits, especially lycopene content, and S10 was more optimal for tomato fruits production in a plastic greenhouse.

Diosgenin revealed potential effect against cerebral ischemia reperfusion through HIKESHI/HSP70/NF-κB anti-inflammatory axis.

BACKGROUND: It is a research hotspot to use natural compounds in treatment of cerebral ischemia reperfusion (I/R) for a refractory disease throughout the worldwide without available drugs or treatments at present. Our previous study has demonstrated that diosgenin (DIO), a starting material to synthesize various steroid anti-inflammatory drugs in medical industry, showed medicinal effect against I/R via inhibiting aberrant inflammatory reaction induced by I/R. However, the detailed anti-inflammatory network of DIO in treatment of I/R still remains to be further explored. PURPOSE: HIKESHI was firstly identified as a novel target of DIO used for I/R by rat brain proteomic analysis, and mechanistic efforts were focused based on this gene. Hopefully, extensive detailed molecular mechanisms of DIO against I/R was established and confirmed. METHODS: The effect of DIO against I/R was examined in vitro and in vivo, which cells (SH-SY5Y and PC12) and rats were experienced to ORD/RP and MCAO exposures, respectively, to establish I/R modes. Staining was used to evaluate the pathological procedure of DIO used for I/R. Protein changes including expression, interaction, and activity during DIO's anti-I/R effect were assessed with real time PCR, western blot, Co-IP, luciferase reporter assay. RESULTS: In the current study, HIKESHI and HSP70 were both upregulated, when I/R cells and rats were treated with DIO in vitro and in vivo. Mechanistically, DIO stimulated the binding of HIKESHI to HSP70 and facilitated the translocation of HSP70 into nucleus. Subsequently, HSP70 blunted the transcription activity of NF-κB after physical interaction with this transcription factor, and therefore led to the suppression of its downstream pro-inflammatory cytokine (TNF-α, IL-1ß, and IL-6) release into surrounding I/R lesion area. Conversely, HIKESHI or HSP70 knockdowns attenuated the nuclear translocation and restraint on NF-κB-mediated inflammation, finally resulting in the abolishment of DIO-induced anti-I/R effect. NF-κB activation also relieved the inhibitory inflammation and reversed DIO's effect against I/R, suggesting that NF-κB was the downstream target of HIKESHI and HSP70 in I/R treatment with DIO. CONCLUSIONS: These findings established a novel HIKESHI/HSP70/NF-κB signaling pathway associated with DIO-treated I/R, which might be as therapeutic targets or drugs with potential implications for the therapeutic use of I/R in clinic.

In vitro and in vivo effects of the combination of myricetin and miconazole nitrate incorporated to thermosensitive hydrogels, on C. albicans biofilms.

BACKGROUND: Candida albicans-related infections are common infections in clinic, among which biofilm-associated infections are most devastating and challenging to overcome. Myricetin (MY) is a plant-derived natural product with various pharmacological activities. Its anti-biofilm effect against C. albicans and its ability to increase the antifungal effect of miconazole nitrate (MN) were unclear and yet need to be explored. HYPOTHESIS/PURPOSE: In this study the anti-biofilm effect of MY and its ability to increase the antifungal effect of MN were investigated in vitro and in vivo. STUDY DESIGN AND METHODS: MY or/and MN were incorporated into a thermosensitive hydrogel (TSH) of poloxamer. The safety of MY or/and MN loaded TSHs towards human umbilical vein endothelial cells (HUVEC) was evaluated by a MTT assay and the in vivo safety towards mice knees was confirmed by histopathological examination. The anti-biofilm effect of MY and its ability to increase the antifungal effect of MN were investigated in vitro with C. albicans ATCC 10231 by broth microdilution method, crystal violet staining and scanning electron microscopy (SEM), as well as in vivo in an established mouse model of periprosthetic joint infection (PJI) by SEM, histological analysis, microorganism culture and detection of the serum levels of interleukin-6 (IL-6). The mechanism of action of MY was analyzed by qRT-PCR assay with C. albicans SC5314. RESULTS: Our results showed that MY and MN incorporated into TSHs exhibited good stability and safety, excellent temperature sensitivity and controlled drug release property. MY (5-640 µg/ml) exhibited no effect on C. albicans cell viability and MY (≥80 µg/ml) showed a significantly inhibitory effect on biofilm formation. MIC50 (the lowest concentrations of drugs resulting in 50% decrease of C. albicans growth) and MIC80 (the lowest concentrations of drugs resulting in 80% decrease of C. albicans growth) of MN were respectively decreased from 2 µg/ml to 0.5 µg/ml and from 4 µg/ml to 2 µg/ml when used in combination with MY (80 µg/ml). The mouse PJI was effectively prevented by MY and MN incorporated into TSH. CONCLUSIONS: Local application of MY and MN incorporated into TSH might be useful for clinical biofilm-associated infections.

Comparative pharmacokinetics of verapamil and norverapamil in normal and ulcerative colitis rats after oral administration of low and high dose verapamil by UPLC-MS/MS.

In this study, UC rat model was established by administration of 5% (w/v) dextran sulfate sodium, and the pharmacokinetics of verapamil and norverapamil were evaluated in normal and UC rats using UPLC-MS/MS after oral administration of 5 mg/kg and 50 mg/kg verapamil.The peak concentration (Cmax) and the area under plasma concentration-time curves (AUC) of verapamil in UC rats after oral administration of 5 mg/kg were significantly greater (2.5 times and 2 times, respectively) than those in normal rats, but the clearance rate (Cl) was significantly lower (by 50%). For norverapamil, Cmax and AUC were significantly greater (2.8 times and 2.5 times, respectively), and Cl was significantly lower (by 45%). But, pharmacokinetic parameters of verapamil and norverapamil after oral administration of 50 mg/kg were no significant differences between UC and normal rats.The better absorption and poor excretion for low-dose verapamil may be attributed to down-regulation of P-gp expression in the intestine and kidney. No significant differences of pharmacokinetic parameters for high-dose verapamil may be explained as the saturation of an efflux mechanism.The findings of this study suggested that in UC patients, doses of verapamil should be decreased when low-dose verapamil was orally administrated.

Hydroxytyrosol NO regulates oxidative stress and NO production through SIRT1 in diabetic mice and vascular endothelial cells.

BACKGROUND: Vascular complications are major causes of disability and death in people with diabetes mellitus (DM). Nitric oxide (NO) supplement may help prevent vascular complications and is an attractive treatment option for DM. Hydroxytyrosol (HT) is a major polyphenol in olive oil. It is mainly used as a dietary supplement because of its antioxidant effect. PURPOSE: We aimed to determine the effects of hydroxytyrosol nitric oxide (HT-NO) on oxidative stress and NO level as well as related mechanisms. STUDY DESIGN/METHODS: The effects of HT-NO on oxidative stress and NO level were examined by using diabetic mouse model and HUVECs. RESULTS: Our results showed that HT-NO has antioxidant and NO-releasing activities in vitro and in DM mice. HT-NO not only decreased blood glucose and oxidative stress but also increased NO level and deacetylase Sirtuin 1 (SIRT1) expression in DM mice and high glucose (HG)-stimulated HUVECs. Further studies found that SIRT1 activation augmented the effect of HT-NO on eNOS phosphorylation in HG-stimulated HUVECs. However, the promotive effect of HT-NO on eNOS phosphorylation was abolished by SIRT1 knockdown. Most importantly, HT-NO inhibited reactive oxygen species (ROS) production through SIRT1 in HUVECs. The ROS scavenger enhanced the effect of HT-NO on eNOS phosphorylation. CONCLUSION: These results suggest that HT-NO regulates oxidative stress and NO production partly through SIRT1 in DM mice and HG-stimulated HUVECs.

Nicotinic acid inhibits vascular inflammation via the SIRT1-dependent signaling pathway.

Nicotinic acid (NA) has recently been shown to inhibit inflammatory response in cardiovascular disease. Sirtuin1 (SIRT1), a NAD(+)-dependent class III histone deacetylase, participates in the regulation of cellular inflammation. We hypothesized that dietary supplementation of NA could attenuate vascular inflammation via modulation of SIRT1 pathway. New Zealand White rabbits received chow or chow supplemented with 0.6% (wt/wt) NA for 2 weeks. Acute vascular inflammation was induced in the animals by placing a non-occlusive silastic collar around the left common carotid artery. At 24 h after collar implantation, the collar-induced production of C-reactive protein and monocyte chemotactic protein-1 was significantly suppressed in the NA-supplemented animals. Meanwhile, NA also decreased the expression of cluster of differentiation 40 (CD40) and CD40 ligand, but up-regulated SIRT1 expression, both in rabbits and in lipopolysaccharide-stimulated endothelial cells. Moreover, knockdown of SIRT1 reversed the inhibitory effect of NA on CD40 expression. Further study revealed that NA also decreased the expression of CD40 partly through mammalian target of rapamycin. These results indicate that NA protects against vascular inflammation via the SIRT1/CD40-dependent signaling pathway.

The roles of buyang huanwu decoction in anti-inflammation, antioxidation and regulation of lipid metabolism in rats with myocardial ischemia.

Buyang Huanwu Decoction (BYHWD) is a well-known Chinese medicine formula. Recent studies have reported that BYHWD can be used to treat ischemic heart disease. This study investigated the potential mechanism underlying the roles of BYHWD in alleviating the myocardial ischemia induced by isoproterenol (ISO) in rats. Different doses of BYHWD (25.68, 12.84 and 6.42 g kg(-1)) were lavaged to rats, respectively. Then the expression of the cluster of differentiation 40 (CD40) in the mononuclear cells was measured using flow cytometry, and the expressions of CD40 and its ligand (CD40L) in myocardial tissues were determined by western blotting. The serum biochemical values of superoxide dismutase (SOD) activity, the malondialdehyde (MDA) level and the free fatty acid (FFA) content were measured. The results showed that the SOD activities of BYHWD groups were significantly higher than that of the ISO group, while the MDA levels and FFA contents of all BYHWD groups were lower than that of the ISO group. BYHWD could decrease the expression of CD40 in the mononuclear cells and the CD40 and CD40L expressions in myocardial tissues. Our data suggest that the roles of BYHWD are not only related to its antioxidative action and regulation of lipid metabolisms, but also to the inhibition of inflammatory pathway by the decreased CD40 and CD40L expressions in rats with myocardial ischemia.

Determination of paeoniflorin, calycosin-7-O-ß-D-glucoside, ononin, calycosin and formononetin in rat plasma after oral administration of Buyang Huanwu decoction for their pharmacokinetic study by liquid chromatography-mass spectrometry.

The purpose of this study was to simultaneously investigate the pharmacokinetics of five bioactive compounds in rat plasma after oral administration of Buyang Huanwu decoction (BYHWD) using high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS). The separations were performed on a Thermo Hypersil Gold C(18) analytical column (50 × 2.1 mm, 3 µm) with the column temperature kept at 30°C. The quantitative analysis was performed using a quadrupole mass spectrometer detector operated under selected ion monitoring mode. A linear gradient elution of A (0.1% formic acid solution) and B (100% acetonitrile) was used at a flow rate of 0.2 mL/min. The method was validated within the concentration ranges 1.8-450, 6.0-1500, 2.0-500, 1.2-300 and 1.2-150 ng/mL for paeoniflorin, calycosin-7-O-ß-d-glucoside, ononin, calycosin and formononetin, respectively. The calibration curves were linear with correlation coefficients > 0.99. The lower limits of quantitations were < 6.0 ng/mL. The method was further applied to assess the pharmacokinetics of the five bioactive constituents of BYHWD in rat plasma.

Buyang Huanwu decoction ameliorates coronary heart disease with Qi deficiency and blood stasis syndrome by reducing CRP and CD40 in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Qi deficiency and blood stasis is traditional Chinese medicine (TCM) syndrome. It leads to many diseases including coronary heart diseases (CHD) and cerebrovascular diseases (CVD). Inflammatory biomarkers and many endothelium-derived vasoactive factors are considered to play pivotal roles in CHD. Buyang Huanwu decoction (BYHWD), a TCM formula, has been recognized as a treatment for CHD with Qi deficiency and blood stasis syndrome and CVD in clinic. The mechanisms of BYHWD effect on CHD with Qi deficiency and blood stasis syndrome are unclear. AIM OF THE STUDY: The aim is to investigate whether the effects of BYHWD on CHD with Qi deficiency and blood stasis syndrome in rats are associated with the inhibition of CRP, CD40 and vascular endothelial regulators. MATERIALS AND METHODS: The treated groups were lavaged with 25.68, 12.84 and 6.42 g/kg BYHWD respectively once a day for 21 days. The level of C-reactive protein (CRP) in serum and the expression of cluster of differentiation 40 (CD40) in the heart and aorta of rats were detected. Moreover, the levels of thromboxaneA(2) (TXA(2)) and prostacyclin (PGI(2)) in plasma were measured and the levels of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in serum were detected. RESULTS: BYHWD (25.68 g/kg) significantly decreased the level of CRP in serum and BYHWD (25.68 and 12.84 g/kg) decreased the expression of CD40 in the heart and aorta (P<0.01). The results also revealed that BYHWD (25.68 g/kg) inhibited the levels of iNOS in serum and TXA(2) in plasma and increased the levels of eNOS in serum and PGI(2) in plasma (P<0.01). CONCLUSION: The study shows that the ameliorative effects of BYHWD on CHD with Qi deficiency and blood stasis syndrome in rats are associated with the inhibition of CRP and CD40 and the regulation of endothelium-derived vasoactive factors.

[Protective effect of Buyanghuanwu Decoction on myocardial ischemia induced by isoproterenol in rats].

OBJECTIVE: To study the protective effect of Buyanghuanwu Decoction on myocardial ischemia induced by isoproterenol in rats. METHODS: Buyanghuanwu Decoction was given in different dose and the rat model of myocardial ischemia was established by peritoneal injection of isoproterenol. The expression of CD40 in whole blood was detected by flow cytometry,and the expression of CD40L in myocardial tissues was detected by immunohistochemistry. The activities of lactate dehydrogenase (LDH), creatine kinase (CK) and aspartate aminotransferase (AST) in blood serum were detected by biochemistry detector. RESULTS: Compared with the model group, Buyanghuanwu Decoction in high and middle dose significantly inhibited the expression of CD40 in blood serum and CD40L in myocardial tissues (P < 0.01), and obviously decreased the activities of LDH, CK and AST in blood serum (P < 0.01). CONCLUSION: Buyanghuanwu Decoction has a protective effect on myocardial ischemia induced by isoproterenol in rats, and it may be relevant to the decrease of the expression of CD40-CD40L and the activities of myocardial enzymes.

Simultaneous analysis of eight bioactive compounds in Danning tablet by HPLC-ESI-MS and HPLC-UV.

A high performance liquid chromatography (HPLC) coupled with electrospray tandem mass spectrometry (ESI-MS) and ultraviolet detector (UV) has been developed for the simultaneous analysis of eight bioactive compounds in Danning tablet (including hyperin, hesperidin, resveratrol, nobiletin, curcumine, emodin, chrysophanol, and physcion), a widely used prescription of traditional Chinese medicine (TCM). The chromatographic separation was performed on a ZORBAX Extend C(18) analytical column by gradient elution with acetonitrile and formate buffer (containing 0.05% formic acid, adjusted with triethylamine to pH 5.0) at a flow rate of 0.8 ml/min. The eight compounds in Danning tablet were identified and their MS(n) fractions were elucidated by using HPLC-ESI-MS, and the contents of these compounds were determined by using HPLC-UV method. The standard calibration curves were linear between 5.0 and 100 microg/ml for hyperin, 10-200 microg/ml for hesperidin, 1.0-150 microg/ml for resveratrol, 2.0-120 microg/ml for nobiletin, 2.0-225 microg/ml for curcumine, 20-300 microg/ml for emodin, 2.0-200 microg/ml for chrysophanol, and 20-250 microg/ml for physcion with regression coefficient r(2)>0.9995. The intra-day and inter-day precisions of this method were evaluated with the R.S.D. values less than 0.7% and 1.3%, respectively. The recoveries of the eight investigated compounds were ranged from 99.3% to 100.2% with R.S.D. values less than 1.5%. This method was successfully used to determine the 8 target compounds in 10 batches of Danning tablet.