Gram-Scale Total Synthesis of TAB with Cardioprotective Activity and the Structure-Activity Relationship of Its Analogs.

Traditional Chinese medicine has been proven to be of great significance in cardioprotective effects. Clinopodium chinense (Lamiaceae) has unique advantages in the treatment and prevention of cardiovascular diseases. Tournefolic acid B (TAB) was proven to be a potent component against myocardial ischemia reperfusion injury (MIRI) from Clinopodium chinense (Lamiaceae). This article will attempt to establish a gram-scale synthesis method of TAB and discuss the structure-activity relationship of its analogs. The total synthesis of TAB was completed in 10 steps with an overall yield of 13%. In addition, analogs were synthesized, and their cardioprotective activity was evaluated on the hypoxia/reoxygenation of H9c2 cells. Amidation of the acid position is helpful to the activity, while methylation of phenolic hydroxyl groups greatly decreased the cardioprotective activity. The easily prepared azxepin analogs also showed cardioprotective activity. Most of the clogP values calculated by Molinspiration ranged from 2.5 to 5, which is in accordance with Lipinski's rule of 5. These findings represent a novel kind of cardioprotective agent that is worthy of further study.

Expeditious assembly of biuret-guanidine derivatives via the catalyst-free transformation.

We disclose a mild and practical catalyst-free transformation for the expeditious construction of biuret-guanidine derivatives using aromatic isocyanates. This synthetic transformation is featured with mild reaction conditions and high efficiency.

Ganoderma lucidum polysaccharides ameliorate lipopolysaccharide-induced acute pneumonia via inhibiting NRP1-mediated inflammation.

CONTEXT: Ganoderma lucidum polysaccharides (GLP), from Ganoderma lucidum (Leyss. ex Fr.) Karst. (Ganodermataceae), are reported to have anti-inflammatory effects, including anti-neuroinflammation and anti-colitis. Nevertheless, the role of GLP in acute pneumonia is unknown. OBJECTIVE: To explore the protective role of GLP against LPS-induced acute pneumonia and investigate possible mechanisms. MATERIALS AND METHODS: GLP were extracted and used for high-performance liquid chromatography (HPLC) analysis after acid hydrolysis and PMP derivatization. Sixty C57BL/6N male mice were randomly divided into six groups: Sham, Model, LPS + GLP (25, 50 and 100 mg/kg/d administered intragastrically for two weeks) and LPS + dexamethasone (6 mg/kg/d injected intraperitoneally for one week). Acute pneumonia mouse models were established by intratracheal injection of LPS. Haematoxylin and eosin (H&E) staining was examined to evaluate lung lesions. ELISA and quantitative real-time PCR were employed to assess inflammatory factors expression. Western blots were carried out to measure Neuropilin-1 expression and proteins related to apoptosis and autophagy. RESULTS: GLP suppressed inflammatory cell infiltration. In BALF, cell counts were 1.1 × 106 (model) and 7.1 × 105 (100 mg/kg). Release of GM-CSF and IL-6 was reduced with GLP (25, 50 and 100 mg/kg) treatment. The expression of genes IL-1ß, IL-6, TNF-α and Saa3 was reduced. GLP treatment also suppressed the activation of Neuropilin-1 (NRP1), upregulated the levels of Bcl2/Bax and LC3 and led to downregulation of the ratio C-Caspase 3/Caspase 3 and P62 expression. DISCUSSION AND CONCLUSIONS: GLP could protect against LPS-induced acute pneumonia through multiple mechanisms: blocking the infiltration of inflammatory cells, inhibiting cytokine secretion, suppressing NRP1 activation and regulating pneumonocyte apoptosis and autophagy.

Gastroprotective effects of Kangfuxin against water-immersion and restraint stress-induced gastric ulcer in rats: roles of antioxidation, anti-inflammation, and pro-survival.

Context: Kangfuxin (KFX) is widely used for the treatment of gastric and duodenal ulcer; however, more research is needed to determine the protective mechanisms of KFX in ameliorating gastric ulcer.Objective: To investigate the efficacy and potential mechanism of Kangfuxin liquid (KFX) in water-immersion and restraint stress (WIRS)-induced gastric ulcer.Materials and methods: Seventy rats were randomly divided into seven groups (n = 10) as follows: the control group (normal saline, i.g.), the model group (normal saline, i.g.), the KFX groups (2.5, 5 and 10 mL/kg, i.g.), the omeprazole group (20 mg/kg, i.p.) and Sanjiuweitai Granules group (1850 mg/kg, i.g.). The WIRS model was applied to induce stress ulcers after 7 days of drug administration. Afterwards, rats were sacrificed at 10 h induced by WIRS.Results: Pre-treatment with KFX (5,10 mL/kg) could effectively reduce the area of gastric ulcers and improve the pathological changes of ulcerated tissue. Moreover, KFX (5,10 mL/kg) increased the prostaglandin E2 (52%) and cyclooxygenase-1 (30%) levels, and improved malondialdehyde (54%), superoxide dismutase (58%), catalase (39%), and nitric oxide (11%) and TNF-α (9%), IL-6 (11%), MMP-9 (54%) and MMP-2 (53%) of ulcer tissue. Furthermore, pre-treatment with KFX dramatically increased IGF-1, PTEN, and Akt protein expression.Conclusions: Our results suggest that KFX has protective effects on WIRS-induced gastric ulcer via inflammatory reactions, oxidative stress inhibition, and pro-survival action, which were the results of activating the IGF-1/PTEN/Akt signalling pathway. Our results provide evidence of KFX for treating gastric ulcer.

Stereocontrol of C-N Axial and Spiro-Central Chirality via Rh(II)-Catalyzed Enantioselective N-H Bond Insertion of Indolinone-Spiroacetal.

A rhodium-catalyzed carbene N-H insertion protocol for simultaneously controlling the C-N axial and spiro-central chiralities is disclosed, resulting in the rapid assembly of enantiopure N-arylindolinone-spiroacetal derivatives in high yields with excellent enantioselectivities. This promising strategy features the chiral C-N axis, spiro-central chirality, functional group tolerance, and late-stage diversification. DFT calculations indicate that the N-H insertion is the axial-chirality-determining step and that the 1,5-H shift step is regiospecifically caused by the spirocycle.

Saponins in Chinese Herbal Medicine Exerts Protection in Myocardial Ischemia-Reperfusion Injury: Possible Mechanism and Target Analysis.

Myocardial ischemia is a high-risk disease among middle-aged and senior individuals. After thrombolytic therapy, heart tissue can potentially suffer further damage, which is called myocardial ischemia-reperfusion injury (MIRI). At present, the treatment methods and drugs for MIRI are scarce and cannot meet the current clinical needs. The mechanism of MIRI involves the interaction of multiple factors, and the current research hotspots mainly include oxidative stress, inflammation, calcium overload, energy metabolism disorders, pyroptosis, and ferroptosis. Traditional Chinese medicine (TCM) has multiple targets and few toxic side effects; clinical preparations containing Panax ginseng C. A. Mey., Panax notoginseng (Burk.) F. H. Chen, Aralia chinensis L., cardioprotection, and other Chinese herbal medicines have been used to treat patients with coronary heart disease, angina pectoris, and other cardiovascular diseases. Studies have shown that saponins are the main active substances in TCMs containing Panax ginseng C. A. Mey., Panax notoginseng (Burk.) F. H. Chen, Aralia chinensis L., and Radix astragali. In the present review, we sorted the saponin components with anti-MIRI effects and their regulatory mechanisms. Each saponin can play a cardioprotective role via multiple mechanisms, and the signaling pathways involved in different saponins are not the same. We found that more active saponins in Panax ginseng C. A. Mey. are mainly dammar-type structures and have a strong regulatory effect on energy metabolism. The highly active saponin components of Aralia chinensis L. are oleanolic acid structures, which have significant regulatory effects on calcium homeostasis. Therefore, saponins in Chinese herbal medicine provide a broad application prospect for the development of highly effective and low-toxicity anti-MIRI drugs.

Araloside C attenuates atherosclerosis by modulating macrophage polarization via Sirt1-mediated autophagy.

Atherosclerosis-related cardiovascular disease is still the predominant cause of death worldwide. Araloside C (AsC), a natural saponin, exerts extensive anti-inflammatory properties. In this study, we explored the protective effects and mechanism of AsC on macrophage polarization in atherosclerosis in vivo and in vitro. Using a high-fat diet (HFD)-fed ApoE-/- mouse model and RAW264.7 macrophages exposed to ox-LDL, AsC was evaluated for its effects on polarization and autophagy. AsC significantly reduced the plaque area in atherosclerotic mice and lipid accumulation in ox-LDL-treated macrophages, promoted M2 phenotype macrophage polarization, increased the number of autophagosomes and modulated the expression of autophagy-related proteins. Moreover, the autophagy inhibitor 3-methyladenine and BECN1 siRNA obviously abolished the antiatherosclerotic and M2 macrophage polarization effects of AsC. Mechanistically, AsC targeted Sirt1and increased its expression, and this increase in expression was associated with increased autophagy and M2 phenotype polarization. In contrast, the effects of AsC were markedly blocked by EX527 and Sirt1 siRNA. Altogether, AsC attenuates foam cell formation and lessens atherosclerosis by modulating macrophage polarization via Sirt1-mediated autophagy.