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PMID: 

Food Chem. 2020 Jan 30 ;304:125442. Epub 2019 Aug 28. PMID: 31491714

Abstract Title: 

Influence of moderate electric fields inβ-lactoglobulin thermal unfolding and interactions.

Abstract: 

In this study, the effects of moderate electric fields during thermal denaturation ofβ-lactoglobulin were examined through an in situ circular dichroism approach, complemented by intrinsic extrinsic fluorescence analysis. Results have shown that the effects of electric fields in protein unfolding were linearly dependent on the applied electric field intensity (V/cm) and increased by the use of low electric frequencies – i.e. 50 to 200 Hz. These electric effects caused significant changes on β-lactoglobulin melting temperature, unfolded conformation and subsequent intermolecular interactions, revealed by the increase of surface hydrophobicity (ANS affinity) and higher conservation of retinol binding. The obtained data provides a clear evidence that moderate electric fields contribute to distinct folding/unfolding of β-lactoglobulin, resulting in structural modifications. These findings are relevant for (bio)-technological applications involving electric fields processing, bringing new insights for the development of innovative strategies to control protein function and tune production of functional protein systems.

PMID: 

Cell Stress Chaperones. 2019 Sep ;24(5):991-1003. Epub 2019 Aug 6. PMID: 31388827

Abstract Title: 

Tanshinone IIA attenuates cardiac microvascular ischemia-reperfusion injury via regulating the SIRT1-PGC1α-mitochondrial apoptosis pathway.

Abstract: 

Cardiac microvascular ischemia-reperfusion (IR) injury has been a neglected topic in recent decades. In the current study, we investigated the mechanism underlying microvascular IR injury, with a focus on mitochondrial homeostasis. We also explored the protective role of tanshinone IIA (Tan IIA) in microvascular protection in the context of IR injury. Through animal studies and cell experiments, we demonstrated that IR injury mediated microvascular wall destruction, lumen stenosis, perfusion defects, and cardiac microvascular endothelial cell (CMEC) apoptosis via inducing mitochondrial damage. In contrast, Tan IIA administration had the ability to sustain CMEC viability and microvascular homeostasis, finally attenuating microvascular IR injury. Function studies have confirmed that the SIRT1/PGC1α pathway is responsible for the microvascular protection from the Tan IIA treatment. SIRT1 activation by Tan IIA sustained the mitochondrial potential, alleviated the mitochondrial pro-apoptotic factor leakage, reduced the mPTP opening, and blocked mitochondrial apoptosis, providing a survival advantage for CMECs and preserving microvascular structure and function. By comparison, inhibiting SIRT1 abrogated the beneficial effects of Tan IIA on mitochondrial function, CMEC survival, and microvascular homeostasis. Collectively, this study indicated that Tan IIA should be considered a microvascular-protective drug that alleviates acute cardiac microcirculation IR injury via activating the SIRT1/PGC1α pathway and thereby blocking mitochondrial damage.

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PMID: 

Front Pharmacol. 2019 ;10:850. Epub 2019 Jul 26. PMID: 31402870

Abstract Title: 

Tanshinone IIA Exerts Anti-Inflammatory and Immune-Regulating Effects on Vulnerable Atherosclerotic Plaque Partiallythe TLR4/MyD88/NF-κB Signal Pathway.

Abstract: 

Tanshinone IIA (Tan IIA), a lipophilic constituent fromBunge, has shown a promising cardioprotective effect including anti-atherosclerosis. This study aims at exploring Tan IIA's anti-inflammatory and immune-regulating roles in stabilizing vulnerable atherosclerotic plaque in ApoE-deficient (ApoE) mice.Male ApoEmice (6 weeks) were fed with a high-fat diet for 13 weeks and then randomized to the model group (MOD) or Tan IIA groups [high dose: 90 mg/kg/day (HT), moderate dose: 30 mg/kg/day (MT), low dose: 10 mg/kg/day (LT)] or the atorvastatin group (5 mg/kg/day, ATO) for 13 weeks. Male C57BL/6 mice (6 weeks) were fed with ordinary rodent chow as control. The plaque stability was evaluated according to the morphology and composition of aortic atherosclerotic (AS) plaque in H&E staining and Movat staining sections by calculating the area of extracellular lipid, collagenous fiber, and foam cells to the plaque. The expression of the Toll-like receptor 4 (TLR4)/myeloid differentiation factor88 (MyD88)/nuclear factor-kappa B (NF-κB) signal pathway in aorta fractions was determined by immunohistochemistry. Serum levels of blood lipid were measured by turbidimetric inhibition immunoassay. The concentrations of tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) were detected by cytometric bead array.Tan IIA stabilized aortic plaque with a striking reduction in the area of extracellular lipid (ATO: 13.15± 1.2%, HT: 12.2 ± 1.64%, MT: 13.93 ± 1.59%, MOD: 18.84 ± 1.46%,

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PMID: 

Mol Med Rep. 2019 Aug ;20(2):1621-1628. Epub 2019 Jun 20. PMID: 31257487

Abstract Title: 

Tanshinone IIA attenuates cerebral aneurysm formation by inhibiting the NF‑κB‑mediated inflammatory response.

Abstract: 

The inflammatory response plays a vital role in cerebral aneurysm (CA) formation and progression. Tanshinone IIA (Tan IIA) is one of the major active components of Chinese medicine Danshen (Salvia miltiorrhiza Bunge) and is widely used for the treatment of cardiovascular diseases, due to its anti‑inflammatory effects. The aim of the present study was to investigate whether Tan IIA can attenuate CA formation in rat models, and determine its underlying mechanisms. CAs were induced in rats surgically and through high‑salt diet treatments. The Tan IIA‑treated group displayed relatively mild symptoms, as compared with the control group. Tan IIA treatment reduced macrophage infiltration and nuclearfactor (NF)‑κB activation in aneurysmal walls. Next, lipopolysaccharide (LPS)‑stimulated RAW 264.7 murine macrophage cells were used to examine the anti‑inflammatory effects of Tan IIA on macrophages. It was found that Tan IIA reversed LPS‑induced differentiation of RAW 264.7 cells and suppressed NF‑κB pathway activation. In conclusion, these findings demonstrated that Tan IIA can suppress CA formation by inhibiting inflammatory responses in macrophages.

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PMID: 

J Cell Biochem. 2019 Sep 12. Epub 2019 Sep 12. PMID: 31512787

Abstract Title: 

Tanshinone IIA inhibits the adipogenesis and inflammatory response in ox-LDL-challenged human monocyte-derived macrophages via regulating miR-130b/WNT5A.

Abstract: 

Atherosclerosis is a kind of chronic cardiovascular disease, characterized by oxidized low-density lipoprotein (ox-LDL) accumulation in macrophage. Tanshinone IIA (Tan), a lipophilic pharmacologically activate compound from Salvia miltiorrhiza Bunge, has been indicated to exert cardioprotective roles. Nevertheless, the biological role of Tan and regulatory mechanism in atherosclerosis are not fully established. In present study, atherosclerosis model was established in THP-1-derived macrophages by treatment of ox-LDL. The adipogenesis was measured by Nile red staining. The expressions of inflammatory factors, microRNA-130b (miR-130b) and WNT5A were measured by quantitative real-time polymerase chain reaction or Western blot. The target association between miR-130b and WNT5A was explored via luciferase activity and RNA immunoprecipitation assay. The results showed that exposure of Tan inhibited ox-LDL-induced adipogenesis and expressions of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-alpha in THP-1-derived macrophages. miR-130b expression was decreased in THP-1-derived macrophages treated by ox-LDL and its overexpression attenuated adipogenesis as well as inflammatory response. miR-130b knockdown reversed the regulatory effect of Tanon adipogenesis and inflammatory response in THP-1-derived macrophages stimulated by ox-LDL. In addition, WNT5A acted as a functional target of miR-130b and inhibited by Tan and miR-130b. As a conclusion, Tan decreased the adipogenesis and inflammatory response by mediating miR-130b and WNT5A, providing a novel theoretical foundation for treatment of atherosclerosis.

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PMID: 

Phytother Res. 2019 Sep ;33(9):2298-2309. Epub 2019 Jul 3. PMID: 31268205

Abstract Title: 

Tanshinone IIA combined with cisplatin synergistically inhibits non-small-cell lung cancer in vitro and in vivo via down-regulating the phosphatidylinositol 3-kinase/Akt signalling pathway.

Abstract: 

Cisplatin represents one of the first-line drugs used for non-small-cell lung cancer treatment. However, considerable side effects and the emergence of drug resistance are becoming critical limitations to its application. Combinatorial strategies may be able to extend the use of cisplatin. Both Tanshinone IIA and cisplatin inhibit non-small-cell lung cancer cell growth in a time- and dose-dependent manner. When Tanshinone IIA was combined with cisplatin at a ratio of 20:1, they were observed to exert a synergistic inhibitory effect on non-small-cell lung cancer cells. The combination treatment was shown to impair cell migration and invasion, arrest the cell cycle in the S phases, and induce apoptosis in A549 and PC9 cells in a synergistic manner. KEGG pathway analysis and molecular docking indicated that Tanshinone IIA might mainly influence the phosphatidylinositol 3-kinase-Akt signalling pathway. In all treated groups, the expression levels of Bax and cleaved Caspase-3 were up-regulated, whereas the expression levels of Bcl-2, Caspase-3, p-Akt, and p-PI3K proteins were down-regulated. Among these, the combination of Tan IIA and cisplatin exhibited the most significant difference. Tanshinone IIA may function as a novel option for combination therapy for non-small-cell lung cancer treatment.

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PMID: 

Chem Biol Interact. 2019 Sep 1 ;310:108748. Epub 2019 Jul 12. PMID: 31306638

Abstract Title: 

Tanshinone IIA exerts beneficial effects on fracture healing in vitro and in vivo.

Abstract: 

BACKGROUND: Fracture healing is a very important process after fracture. Tanshinone IIA (Tan IIA) has been reported to possess beneficial impact on osteoblasts growth. Our study investigated the effects of Tan IIA on fracture healing.METHODS: In vitro, mouse pre-osteoblast MC3T3-E1 cells were treated with Tan IIA. Then, the protein levels of Runx2, Osx, Collagen I, JNK and c-Jun, alkaline phosphatase (ALP) activity and calcium deposition were detected, respectively. Furthermore, the roles of microRNA-424 (miR-424) and Bone morphogenetic protein 2 (BMP-2) in Tan IIA-caused MC3T3-E1 cell differentiation were probed. In vivo, mice open osteotomy at femur diaphysis model was established. The callus area, callus intensity, low-density bone volume/callus total volume (BV1/TV), tissue mineral density (TMD) and bone mineral density (BMD) were tested.RESULTS: In vitro, Tan IIA promoted MC3T3-E1 cell differentiation via increasing the Runx2, Osx and collagen I expression, along with enhancing ALP activity and calcium deposition. In addition, Tan IIA activated JNK pathway in MC3T3-E1 cells, while inhibition of JNK pathway mitigated the Tan IIA-caused MC3T3-E1 cell differentiation. Moreover, Tan IIA declined the miR-424 expression in MC3T3-E1 cells. Overexpression of miR-424 also weakened the Tan IIA-caused MC3T3-E1 cell differentiation. BMP-2 was a target gene of miR-424. BMP-2 silence reversed the Tan IIA-caused activation of JNK pathway. In vivo, Tan IIA increased the callus area, callus intensity, BV1/TV, TMD and BMD.CONCLUSION: Tan IIA could promote fracture healing. In vitro, Tan IIA promoted MC3T3-E1 cell differentiation might be via down-regulating miR-424, up-regulating BMP-2 and then activating JNK pathway.

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PMID: 

Exp Clin Endocrinol Diabetes. 2019 Jul 11. Epub 2019 Jul 11. PMID: 31295750

Abstract Title: 

Tanshinone II A Affects Diabetic Peripheral Neuropathic Pain via Spinal Dorsal Horn Neuronal Circuitry by Modulating Endoplasmic Reticulum Stress Pathways.

Abstract: 

Diabetic peripheral neuropathic pain (DPNP) is a common manifestation of diabetic peripheral neuropathy (DPN). Although the pathogenesis of DPNP remains unclear, the disinhibition of spinal dorsal horn neuronal circuitry mediated by endoplasmic reticulum stress (ERS) is an important mechanism underlying neuropathic pain (NP). Tanshinone II A is mainly used to treat cardiovascular diseases but has also been shown to relieve various types of neuralgia, including DPNP. This study investigated the effects of tanshinone IIA in DPNP model rats. We divided animals into two groups: 1) the model (diabetic) group and 2) the tanshinone II A-treatment group. Our results demonstrated that diabetic rats exhibited a decrease in the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL), and that NMT is increased and TWL is prolonged in rats treated with tanshinone II A. Additionally, the levels of ERS-signaling pathway factors in the spinal dorsal horns of rats were lower in the tanshinone IIA-treated group than in the diabetic group. Overall, our study demonstrated that the disinhibition of spinal dorsal horn neuronal circuitry mediated by endoplasmic reticulum stress underlies DPNP and is modulated by tanshinone IIA treatment.

PMID: 

Zhonghua Xin Xue Guan Bing Za Zhi. 2019 Aug 24 ;47(8):634-639. PMID: 31434435

Abstract Title: 

[TanshinoneⅡA attenuates carotid artery atherosclerosis by deactivating mast cells in adventitia].

Abstract: 

To investigate the effects of tanshinoneⅡA on atherosclerosis plaque formation and adventitial mast cells activation in high-fat-diet induced Apo E(-/-) mice model.Sixteen 8-week-old Apo E(-/-)male mice and eight 8-week-old C57BL/6 male mice were randomly allocated into following group: the control group (C57BL/6 + carboxymethyl cellulose per gavage), the atherogenic group (Apo E(-/-)+carboxymethyl cellulose per gavage) and the tanshinoneⅡA intervention group (Apo E(-/-)+30 mg/kg tanshinone ⅡA per gavage). All three groups were fed with high-fat-diet for 26 weeks. Tanshinone ⅡA/carboxymethyl cellulose was applied by the method of gavage administration 6 weeks before execution. After 26 weeks, tumor necrosis factor-α (TNF-α)andinterleukin (IL)-6 levels in serum were assessed by ELISA. Carotid artery was removed, fixed with paraformaldehyde, embedded with paraffin and sectioned. Percentage of stenosis was evaluated on HE stained sections. Plaque progression was assessed by Movat staining. Toluidine blue staining was used to evaluate mast cells infiltration and activation. Immunochemistry staining was used to assess 5-HT, TNF-α and IL-6 expression. mRNA expression of mast cell marker Fcer1a in adventitial tissue was detected by real time-PCR.After high-fat-diet for 26 weeks, the mice in the atherogenic group showed advanced atherosclerosis, tanshinoneⅡA intervention reduced the percentage of carotid artery stenosis caused by atherosclerotic plaque formation ((58.48±8.07)% vs. (80.31±4.08)%,0.05). Compared with the atherogenic group, tanshinoneⅡA intervention group had lower level of TNF-α ((12.39±1.62)pg/ml vs. (17.44±1.42)pg/ml) and IL-6 ((116.24±12.16)pg/ml vs. (166.05±19.09)pg/ml) in serum, lower TNF-α ((20 145±1 556) vs. (25 288±1 671)) and IL-6 ((25 688±1 604) vs. (35 286±4 198)) expression in adventitia (all0.05). TanshinoneⅡA intervention also decreased the number of mast cells infiltration and activation, reduced 5-HT expression and mast cell marker Fcer1a mRNA relative expression in adventitia (all0.05).TanshinoneⅡA could attenuate induced by high-fat-diet carotid artery atherosclerosis in Apo E(-/-) mice. The protective effect of tanshinoneⅡA is probably mediated through reducing the number and activation percentage of mast cells, decreasing the release of inflammatory cytokines and inflammation of carotid artery in adventitia.

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PMID: 

Oncol Lett. 2019 Sep ;18(3):3317-3322. Epub 2019 Jul 24. PMID: 31452810

Abstract Title: 

Tanshinone IIA inhibits proliferation and induces apoptosis of human nasopharyngeal carcinoma cells via p53-cyclin B1/CDC2.

Abstract: 

Tanshinone IIA exhibits natural antioxidative and antineoplastic activity. However, to the best of our knowledge, the effects of tanshinone IIA on human nasopharyngeal carcinoma cells remains unknown. The present study aimed to investigate whether tanshinone IIA inhibits proliferation and induces apoptosis of human nasopharyngeal carcinoma cells via p53-cyclin B1/cell division cycle gene 2 (CDC2). Cell proliferation, cytotoxicity and apoptosis of 13-9B cells were evaluated by an MTT assay, lactate dehydrogenase assay and flow cytometry, respectively. ELISA and western blot analysis were used to analyze caspase-3 activity and poly (ADP-ribose) polymerase (PARP), p53, cyclin B1 and CDC2 protein expression in 13-9B cells. Treatment of 13-9B cells with tanshinone IIA significantly suppressed cell proliferation and significantly induced cytotoxicity and apoptosis of 13-9B cells. Furthermore, tanshinone IIA significantly increased caspase-3 activity, and significantly increased the protein expression levels of PARP, p53, cyclin B1 and CDC2 in 13-9B cells. In summary, the current results indicate that tanshinone IIA inhibits proliferation and induces apoptosis of human nasopharyngeal carcinoma cells via PARP, p53, cyclin B1/CDC2 and caspase-3-mediated signaling.

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