Levistolide A ameliorates fibrosis in chronic kidney disease via modulating multitarget actions in vitro and in vivo.

AIMS: The increasing incidence of chronic kidney disease (CKD) urgently calls for effective nephroprotective agents. Traditional Chinese Medicine Angelica sinensis and its formula are well known for CKD therapy, but the underlying mechanisms and effective substances of reno-protective effects remain unclear. To this end, we isolated eleven ligustilide dimers (1-11) from A. sinensis and examined the molecular mechanism of their nephroprotective effects. MAIN METHODS: Because of internal RAS playing an important role in CKD, we used renin expression as a target and screened preliminarily for antifibrotic effects of ligustilide dimers (1-11) by constructing a dual luciferase reporter gene in vitro. Furthermore, the reno-protective effects of the ligustilides and their underlying mechanism were investigated in TGF-ß1-stimulated HK-2 cells and 5/6 nephrectomy (Nx) mice. KEY FINDINGS: The ligustilide dimers exhibited anti-fibrotic effects by inhibiting human renin (hREN) promoter activity to decrease renin expression and down-regulate the expression of fibrosis-related factors, including α-SMA, collagen I, and fibronectin in vitro. Levistolide A (LA) and angeolide keto ester (AK) were screened out to identify their ability and underlying mechanism for treating CKD. Experimental validation further indicated that LA or AK treatment inhibited the expression of key molecules in RAS, TGF-ß1/Smad, and MAPK pathways to downregulate ECM deposition. Furthermore, LA obviously meliorated renal injury in 5/6 Nx mice through ameliorating oxidant stress, inflammation, apoptosis and renal fibrosis. SIGNIFICANCE: The experimental results demonstrated that ligustilide dimers were potential nephroprotective agents. LA might be an attractive drug candidate for renin-targeted CKD therapy.

The Anti-inflammatory Effects of Isoflavonoids from Radix Astragali in Hepatoprotective Potential against LPS/D-gal-induced Acute Liver Injury.

Radix Astragali (RA) is an important Traditional Chinese Medicine widely used in the treatment of various diseases, such as pneumonia, atherosclerosis, diabetes, kidney and liver fibrosis. The role of isoflavonoids from RA in the treatment of liver injury remains unclear. The study aimed to explore hepatoprotective and anti-inflammatory effects of isoflavonoids from Astragalus mongholicus. Network pharmacological analysis showed that RA had a multi-target regulating effect on alleviating liver injury and inhibiting inflammation through its active ingredients, among which isoflavones were closely related to its key molecular targets. The anti-inflammatory and liver protection effects of isoflavonoids of RA were investigated using lipopolysaccharide (LPS)-induced RAW 264.7 cells in vitro and LPS/D-galactosamine (D-gal)-induced acute liver injury mice in vivo. The experimental results showed that methylnissolin (ML) and methylnissolin-3-O-ß-D-glucoside (MLG) presented more notable anti-inflammatory effects. Both of them suppressed the release of pro-inflammatory cytokines, such as iNOS, COX-2, IL-1ß, IL-6, and TNF-α in LPS-stimulated RAW 264.7 cells. In vivo investigation demonstrated that ML markedly meliorated liver injury in LPS/D-gal-induced mice. Western blot results revealed that ML and MLG down-regulated the expression of proinflammatory cytokines via NF-κB signaling pathway. The isoflavonoids, methylnissolin (ML), and methylnissolin-3-O-ß-D-glucoside (MLG), play a vital role in the hepatoprotective and anti-inflammatory effects of RA.

Riligustilide alleviates hepatic insulin resistance and gluconeogenesis in T2DM mice through multitarget actions.

Riligustilide (RG), one of the dimeric phthalides of Angelica sinensis and Ligusticum chuanxiong, was confirmed effective against many diseases. However, its effects on type 2 diabetes mellitus (T2DM) and the underlying molecular mechanisms have not been clearly elucidated yet. The current study was designed to investigate the hypoglycemic potential by which RG affects the pathogenesis of T2DM. Comprehensive insights into the effects and underlying molecular mechanisms of RG on attenuating aberrant metabolism of glucose were determined in high-fat diet-induced T2DM mice and insulin-resistant (IR) HepG2 cells. In high-fat diet-induced C57BL/6J mice, RG administration significantly reduced hyperglycemia, decreased hyperinsulinemia, and ameliorated glucose intolerance. Mechanistically, RG activated PPARγ and insulin signaling pathway to improve insulin sensitivity, and increase glucose uptake as well as glycogenesis. In addition, RG also upregulated AMPK-TORC2-FoxO1 axis to attenuate gluconeogenesis in vivo and in vitro. According to the findings, RG may be a promising candidate for the treatment of T2DM.

New phenolic glycosides from Anemone chinensis Bunge and their antioxidant activity.

ABATRACTNine compounds, five phenolic glycosides (1, 2, 4-6), three phenylpropanoids (7-9), and a furanone glycoside (3), were isolated from aqueous soluble extract of the dried roots of Anemone chinensis Bunge. The structures of new compounds (1-4) were elucidated by comprehensive spectroscopic data analysis as well as chemical evidence. Pulsatillanin A (1) demonstrated significant antioxidant effects through scavenging free radical in DPPH assay, and relieved the oxidative stress in LPS-induced RAW 264.7 cells by reducing ROS production, enhancing antioxidant enzyme SOD activity, replenishing depleted GSH in a dose-dependent manner. Western blot analysis revealed that 1 showed antioxidant activity via activating Nrf2 signaling pathway.[Formula: see text].

Discovery of Anti-TNBC Agents Targeting PTP1B: Total Synthesis, Structure-Activity Relationship, In Vitro and In Vivo Investigations of Jamunones.

Twenty-three natural jamunone analogues along with a series of jamunone-based derivatives were synthesized and evaluated for their inhibitory effects against breast cancer (BC) MDA-MB-231 and MCF-7 cells. The preliminary structure-activity relationship revealed that the length of aliphatic side chain and free phenolic hydroxyl group at the scaffold played a vital role in anti-BC activities and the methyl group on chromanone affected the selectivity of molecules against MDA-MB-231 and MCF-7 cells. Among them, jamunone M (JM) was screened as the most effective anti-triple-negative breast cancer (anti-TNBC) candidate with a high selectivity against BC cells over normal human cells. Mechanistic investigations indicated that JM could induce mitochondria-mediated apoptosis and cause G0/G1 phase arrest in BC cells. Furthermore, JM significantly restrained tumor growth in MDA-MB-231 xenograft mice without apparent toxicity. Interestingly, JM could downregulate phosphatidylinositide 3-kinase (PI3K)/Akt pathway by suppressing protein-tyrosine phosphatase 1B (PTP1B) expression. These findings revealed the potential of JM as an appealing therapeutic drug candidate for TNBC.

The anti-inflammatory effects of jiangrines from Jiangella alba through inhibition of p38 and NF-κB signaling pathways.

Three pyrrol-2-aldehyde derivatives, including one new compound, jiangrine G (JG), two known compounds, jiangrine A (JA), and pyrrolezanthine (PZ), were isolated from the fermentation broth of Jiangella alba associated with a traditional Chinese medicinal plant Maytenus austroyunnanensis. The structure of jiangrine G was elucidated by a detailed spectroscopic data analysis including data from CD spectra. The anti-inflammatory activities assay demonstrated that JG and JA suppressed the production of pro-inflammatory cytokines including NO, IL-1ß, and IL-6 as well as inhibited the expression of iNOS in LPS-induced RAW 264.7 cells in a dose-dependent manner. While high concentration of PZ dramatically suppressed the protein expression of TNF-α, but stimulated the release of IL-1ß and IL-6. Western blot results revealed that JG, JA, and PZ modulated the expression of pro-inflammatory cytokines via MAPK p38 and NF-κB signaling pathways. For the unique structure of PZ, difference from JG and JA, the signaling pathway involved in mediating its effects on regulating the synthesis of IL-1ß and IL-6 are probably more complicated than that of JG and JA.

Anti-Inflammatory Effects, SAR, and Action Mechanism of Monoterpenoids from Radix Paeoniae Alba on LPS-Stimulated RAW 264.7 Cells.

Nine monoterpenoids from Radix Paeoniae Alba, including paeoniflorin derivatives, paeoniflorin (PF), 4-O-methylpaeoniflorin (MPF), 4-O-methylbenzoylpaeoniflorin (MBPF); paeonidanin derivatives, paeonidanin (PD), paeonidanin A (PDA), albiflorin derivatives, albiflorin (AF), benzoylalbiflorin (BAF), galloylalbiflorin (GAF), and debenzoylalbiflorin (DAF), were obtained in our previous phytochemistry investigations. Their anti-inflammatory effects were determined in the present study. The expression and production of pro-inflammatory cytokines in lipopolysaccharides (LPS)-stimulated RAW 264.7 cells were measured using an Elisa assay and nitric oxide (NO) release was determined using the Griess method. The results demonstrated that the most of the monoterpenoids suppressed the LPS-induced production of NO, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). The anti-inflammatory activities of these monoterpenoids were closely related to their structural characteristics. Paeoniflorins and paeonidanins presented stronger anti-inflammatory activities than those of albiflorin derivatives. Furthermore, the action mechanisms of MBPF, having a strong anti-inflammatory effect, were investigated using quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot methods. The results indicated that MBPF could down-regulate the mRNA and protein expression level of inducible nitric oxide synthase (iNOS) in LPS-stimulated RAW 264.7 cells. The mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/AKT and nuclear factor κB (NF-κB) signaling pathways are involved in mediating the role of MBPF in suppressing the expression and production of pro-inflammatory cytokines in RAW 264.7 cells.

Structures and biological activities of the triterpenoids and sesquiterpenoids from Alisma orientale.

Sixteen triterpenoids and nine sesquiterpenoids were isolated from the rhizome of Alisma orientale. Structures of 16-oxo-11-anhydroalisol A 24-acetate, 13ß,17ß-epoxy-24,25,26,27-tetranor-alisol A 23-oic acid, 1αH,5αH-guaia-6-ene-4ß,10ß-diol, and alisguaiaone were elucidated by comprehensive spectroscopic data analysis. The cytotoxic, antibacterial, antifungal, anti-inflammatory, and α-glucosidase inhibitory activities of isolated terpenoids were evaluated. Triterpenoids alisol A, alisol A 24-acetate, 25-O-ethylalisol A, 11-deoxyalisol A, alisol E 24-acetate, alisol G, alisol B 23-acetate and sesquiterpenoids 1αH,5αH-guaia-6-ene-4ß,10ß-diol, 10-hydroxy-7,10-epoxysalvialane exhibited cytotoxicities against the three tested human cancer cell lines with IC50 values ranging from 11.5 ± 1.7 µM to 76.7 ± 1.4 µM. Triterpenoids alisol A, 25-O-ethylalisol A, 11-deoxyalisol A, alisol E 24-acetate, alisol G, and 25-anhydroalisol F showed antibacterial activities against the Gram-positive strains Bacillus subtilis and Staphylococcus aureus with MIC values of 12.5-100 µg/mL. Sesquiterpenoid 4ß,10ß-dihydroxy-1αH,5ßH-guaia-6-ene exhibited antibacterial activity against B. subtilis with an MIC value of 50 µg/mL, and 10-hydroxy-7,10-epoxysalvialane exhibited activity against S. aureus with an MIC value of 100 µg/mL. Compounds 16-oxo-11-anhydroalisol A 24-acetate, alisol F, 25-anhydroalisol F, and alisguaiaone exhibited inhibitory effects on lipopolysaccharide-induced NO production in RAW 264.7 macrophage cells. None of the compounds showed obvious inhibitory activity against α-glucosidase.