This study describes the first and efficient syntheses of the naturally occurring ugonstilbenes A, B, and C. The stilbene skeleton was prepared using the Horner–Wadsworth–Emmons reaction. On the ...basis of their specific rotations, the absolute configurations of ugonstilbenes A and C were both determined to be R, while the absolute configuration of ugonstilbene B was determined as 4aS,9aR. The synthesized compounds showed cytotoxic activities against selected human cancer cell lines.
The cytosolic non-receptor protein kinase, spleen tyrosine kinase (SYK), is an attractive drug target in autoimmune, inflammatory disorder, and cancers indications. Here, we employed ...pharmacophore-based drug screening combined with biochemical assay and molecular dynamics (MD) simulations to identify and characterize inhibitors targeting SYK. The built pharmacophore model,
phar-TanI
, successfully identified tanshinone (
TanI
(IC
50
= 1.72 μM)) and its analogs (
TanIIA
(IC
50
= 3.2 μM), ST32da (IC
50
= 46 μM), and ST32db (IC
50
= 51 μM)) which apparently attenuated the activities of SYK
in vitro
. Additionally, the MD simulations followed by Ligplot analyses revealed that
TanI
and
TanIIA
interfered SYK activity through binding deeply into the active site. Besides,
TanI
and
TanIIA
mainly interact with residues L377, A400, V433, M448, M450, A451, E452, L453, G454, P455, and L501, which are functional hotspots for structure-based inhibitor optimization against SYK. The structure-activity relationships (SAR) study of the identified SYK inhibitors demonstrated that the pharmacophore model,
phar-TanI
is reliable and precise in screening inhibitors against SYK. This study disclosed the structure-function relationships of tanshinones from Traditional Chinese Medicine (Danshen), revealing their binding site and mode of action in inhibiting SYK and provides applicability in developing new therapeutic agents.
The cytosolic non-receptor protein kinase, spleen tyrosine kinase (SYK), is an attractive drug target in autoimmune, inflammatory disorder, and cancers indications.
Pharmacological studies indicate that
extract (SME) can improve cardiac and blood vessel function. However, there is limited knowledge regarding the effects (exerted through epigenetic regulation) of ...SME and newly derived single compounds, with the exception of tanshinone IIA and IB, on obesity-induced metabolic disorders. In this study, we administered SME or dimethyl sulfoxide (DMSO) as controls to male C57BL/J6 mice after they were fed a high-fat diet (HFD) for 4 weeks. SME treatment significantly reduced body weight, fasting plasma glucose, triglyceride levels, insulin resistance, and adipogenesis/lipogenesis gene expression in treated mice compared with controls. Transcriptome array analysis revealed that the expression of numerous transcriptional factors, including activating transcription factor 3 (ATF3) and C/EBPα homologous protein (CHOP), was significantly higher in the SME group. ST32db, a novel synthetic derivative similar in structure to compounds from
extract, ameliorates obesity and obesity-induced metabolic syndrome in HFD-fed wild-type mice but not ATF3
mice. ST32db treatment of 3T3-L1 adipocytes suppresses lipogenesis/adipogenesis through the ATF3 pathway to directly inhibit C/EBPα expression and indirectly inhibit the CHOP pathway. Overall, ST32db, a single compound modified from
extract, has anti-obesity effects through ATF3-mediated C/EBPα downregulation and the CHOP pathway. Thus, SME and ST32db may reduce obesity and diabetes in mice, indicating the potential of both SME and ST32db as therapeutic drugs for the treatment of obesity-induced metabolic syndrome.
Billions of people have obesity-related metabolic syndromes such as diabetes and hyperlipidemia. Promoting the browning of white adipose tissue has been suggested as a potential strategy, but a drug ...still needs to be identified. Here, genetic deletion of activating transcription factor 3 (
) in mice under a high-fat diet (HFD) resulted in obesity and insulin resistance, which was abrogated by virus-mediated ATF3 restoration. ST32da, a synthetic ATF3 inducer isolated from
, promoted ATF3 expression to downregulate adipokine genes and induce adipocyte browning by suppressing the carbohydrate-responsive element-binding protein-stearoyl-CoA desaturase-1 axis. Furthermore, ST32da increased white adipose tissue browning and reduced lipogenesis in HFD-induced obese mice. The anti-obesity efficacy of oral ST32da administration was similar to that of the clinical drug orlistat. Our study identified the ATF3 inducer ST32da as a promising therapeutic drug for treating diet-induced obesity and related metabolic disorders.
Cisplatin (CDDP) is a first-line chemotherapeutic drug for treating various cancers. However, CDDP also damages normal cells and causes many side effects. Recently, CDDP has been demonstrated to kill ...cancer cells by targeting mitochondria. Protecting mitochondria might be a potential therapeutic strategy for CDDP-induced side effects. β-Lapachone (β-lap), a recognized NAD+ booster, has been reported to regulate mitochondrial activity. However, it remains unclear whether maintaining mitochondrial activity is the key factor in the protective effects of β-lap in CDDP-treated normal cells.
In this study, the protective effects of β-lap on mitochondria against CDDP cytotoxicity in normal cells were evaluated.
In vitro cell models were used in this study, including 3T3 fibroblasts, human dermal fibroblasts, MCF-7 breast cancer cells, and MDA-MB-231 breast cancer cells.
Cells were treated with CDDP and β-lap, and cell survival, NAD+, mitochondrial activity, autophagy, and ATP production were measured. Various inhibitors and siRNAs were used to confirm the key signal underlying the protective effects of β-lap.
The results demonstrated that β-lap significantly decreased CDDP cytotoxicity in normal fibroblasts. With various inhibitors and siRNAs, β-lap reduced CDDP-induced damage to normal fibroblasts by maintaining mitochondrial activity and increasing autophagy through the NQO1/NAD+/SIRT1 axis. Most importantly, the protective effects of β-lap in fibroblasts did not affect the therapeutic effects of CDDP in cancer cells. This study indicated that mitochondrial activity, energy production, and NQO1 levels might be crucial responses separating normal cells from cancer cells under exposure to CDDP and β-lap.
β-lap could be a good synergistic drug for reducing the side effects of CDDP without affecting the anticancer drug effect.
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•Finding new therapeutic drugs for diabetic cardiomyopathy (DC), the major mortality of diabetes mellitus (DM), is urgent and necessary. Oxidative stress, the increasing of ROS, is the leading cause ...of DC.•Lap, a plant-extracted compound, can maintain heart functions and protect cardiomyocytes from DM-induced damages through reducing oxidative stress, increasing the antioxidant regulator and enzymes, decreasing inflammation, maintaining mitochondrial activity and biogenesis, decreasing heart size, and maintaining heart function.•With the detailed investigations in vitro, the protective effects of Lap are through the interaction of NQO1, Sirt 1, and mitochondrial activity.•To the best of our knowledge, the regulation of Lap on increasing mitochondria activity and biogenesis is a novel discovery in cardiomyocytes.•With the protection effects on cardiomyocytes, Lap has a great potential serving as a therapeutic agency for DC.
Diabetic cardiomyopathy (DC) is one of the major lethal complications in patients with diabetes mellitus (DM); however, no specific strategy for preventing or treating DC has been identified.
This study aimed to investigate the effects of β-lapachone (Lap), a natural compound that increases antioxidant activity in various tissues, on DC and explore the underlying mechanisms.
As an in vivo model, C57BL/6 mice were fed with the high-fat diet (HF) for 10 weeks to induce type 2 DM. Mice were fed Lap with the HF or after 5 weeks of HF treatment to investigate the protective effects of Lap against DC.
In the two in vivo models, Lap decreased heart weight, increased heart function, reduced oxidative stress, and elevated mitochondrial content under the HF. In the in vitro model, palmitic acid (PA) was used to mimic the effects of an HF on the differentiated-cardiomyoblast cell line H9c2. The results demonstrated that Lap reduced PA-induced ROS production by increasing the expression of antioxidant regulators and enzymes, inhibiting inflammation, increasing mitochondrial activity, and thus reducing cell damage. Via the use of specific inhibitors and siRNA, the protective effects of Lap were determined to be mediated mainly by NQO1, Sirt1 and mitochondrial activity.
Heart damage in DM is usually caused by excessive oxidative stress. This study showed that Lap can protect the heart from DC by upregulating antioxidant ability and mitochondrial activity in cardiomyocytes. Lap has the potential to serve as a novel therapeutic agent for both the prevention and treatment of DC.
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Neo-tanshinlactone (1) was isolated and synthesized for the first time and evaluated in vitro against several human cancer cell lines. Compound 1 showed significant inhibition against two ER+ human ...breast cancer cell lines and was 10-fold more potent and 20-fold more selective as compared to tamoxifen citrate. Compound 1 also potently inhibited an ER-, HER-2 overexpressing breast cancer cell line. Therefore, this novel compound merits further development as an anti-breast cancer drug candidate.
Chemical investigation of the dichloromethane extracts of the flowers of Dendranthema grandiflora cv. Yoko Ono afforded a new sesquiterpene lactone, grandiflorolide (
1
), ...1,2-dilinoleoyl-3-linolenoylglycerol (
2
), a mixture of pseudotaraxasterol (
3a
), taraxasterol (
3b
), β-amyrin (
3c
), α-amyrin (
3d
), and lupeol (
3e
) in about 2:1:1:0.5:0.5 ratio, and another mixture of β-sitosterol (
4a
) and stigmasterol (
4b
) in about 2:1 ratio. The structure of
1
was elucidated by extensive 1D and 2D NMR spectroscopy, while those of
2–4b
were identified by comparison of their NMR data with literature data.
Neobavaisoflavone (NBIF) is an isoflavone isolated from Psoralea corylifolia L, a plant claimed to have osteogenic activity and used to treat bone fractures, osteomalacia and osteoporosis. The ...present results showed that NBIF concentration-dependently promoted osteogenesis in MC3T3-E1cells, demonstrated by notable enhancement of alkaline phosphatase (ALP) activity, increase of bone-specific matrix proteins expression including type I collagen (Col-I), osteocalcin (OCN) and bone sialoprotein (BSP), and formation of bone nodules. However, cell proliferation in the presence of NBIF was not affected. Results also demonstrated that NBIF up-regulated the expression of runt-related transcription factor 2 (Runx2) and Osterix (Osx), the bone-specific transcription factors participating in regulation of bone marker genes expression. Application of p38 inhibitor SB203580 repressed not only NBIF-induced activation of ALP, the expression of Col-I, OCN and BSP, but also the matrix proteins mineralization. Western blot analysis further revealed that NBIF increased the phosphorylated level of p38 concentration-dependently. Additionally, inhibition of p38 abolished the stimulatory effect of NBIF on the expression of Runx2 and Osx. Taken together, the osteogenic activity of NBIF might probably act through activation of p38-dependent signaling pathway to up-regulate the mRNA levels of Runx2 and Osx then stimulate bone matrix proteins expression. The beneficial effect of NBIF on mineralization demonstrated that NBIF represented as an active component existed in P. corylifolia and might be a potential anabolic agent to treat bone loss-associated diseases.
Plants provide a rich source of lead compounds for a variety of diseases. A novel approach combining phytochemistry and chemotaxis assays was developed and used to identify and study the mechanisms ...of action of the active compounds in F. japonica, a medicinal herb traditionally used to treat inflammation. Based on a bioactivity-guided purification strategy, two anthranoids, emodin and physcion, were identified from F. japonica. Spectroscopic techniques were used to characterize its crude extract, fractions and phytochemicals. The crude extract, chloroform fraction, and anthranoids of F. japonica significantly inhibited CXCR4-mediated chemotaxis. Mechanistic studies showed that emodin and physcion inhibited chemotaxis via inactivating the MEK/ERK pathway. Moreover, the crude extract and emodin could prevent or treat type 1 diabetes in non-obese diabetic (NOD) mice. This study illustrates the applicability of a combinational approach for the study of anti-inflammatory medicine and shows the potential of F. japonica and its anthranoids for anti-inflammatory therapy.
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