PMID: 

Artif Cells Nanomed Biotechnol. 2018 ;46(sup3):S707-S716. Epub 2018 Oct 4. PMID: 30284484

Abstract Title: 

Nanoparticle-mediated delivery of Tanshinone IIA reduces adverse cardiac remodeling following myocardial infarctions in a mice model: role of NF-κB pathway.

Abstract: 

Our previous works have shown that tanshinone IIA inhibited maladaptive extracellular matrix remodeling in cardiac fibroblasts implicating its potential role in treating of pathologic cardiac remodeling. However, the intrinsically poor solubility and bioavailability of tanshinone IIA hindered its clinical application. Here we develop monomethoxy-poly (ethylene glycol)-poly (lactic acid)-D-α-Tocopheryl polyethylene glycol 1000 succinate (mPEG-PLA-TPGS) nanoparticle incorporating tanshinone IIA (tanshinone IIA-NPs) and study its efficacy in post-infarction left ventricular (LV) remodeling. Male C57BL/6 mice underwent left coronary artery ligation followed by subsequent intravenously injected tanshinone IIA-NPs therapy for 5 consecutive days. Treatment with tanshinone IIA-NP improved cardiac function, limited infarct expansion, and prevented left ventricle dilation at 4 weeks post-MI. Furthermore, cardiomyocytes inflammation, apoptosis and myocardial fibrosis were significantlyattenuated in tanshinone IIA-NP treated mice. These effects also correlated with inhibition of IκB protein phosphorylation and NF-κB activation, leading to suppression of proinflammatory cytokine expression. Together, these results demonstrate tanshinone IIA-NP attenuated adverse cardiac remodeling and dysfunction mediated through prevention of IκB phosphorylation and NF-κB activation. Tanshinone IIA-NP is a novel approach to treat myocardial IR injury in patients with MI.

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PMID: 

Am J Transl Res. 2019 ;11(5):2995-3006. Epub 2019 May 15. PMID: 31217869

Abstract Title: 

Tanshinone IIA induces apoptosis and autophagy in acute monocytic leukemia via downregulation of PI3K/Akt pathway.

Abstract: 

Acute myeloid leukemia (AML) is characterized by unrestrained proliferation of myeloid cells. In has been shown that tanshinone IIA (Tan IIA), exhibited anti-tumor activities on different types of cancers. However, the underlying mechanisms by which Tan IIA regulates apoptosis and autophagy in AML remain unclear. Thus, this study aimed to investigate the effects of Tan IIA on AMLand. CCK-8 assay, EdU staining, flow cytometry, MDC staining, immunofluorescence, transwell migration and invasion assay were used to detect cell proliferation, apoptosis, autophagy, migration and invasion, respectively. In addition, western blotting was used to examine the protein levels of Bax, Bcl-2, active caspase-3, Beclin-1, Atg-5, p-mTOR and p-Akt in cells. Moreover, animal studies were performed to evaluate anti-tumor effect of Tan IIA on AML. The results revealed that Tan IIA significantly suppressed the growth of U937 cellsand. Meanwhile, Tan IIA induced apoptosis in U937 cells via up-regulating the levels of active caspase-3 and Bax, and down-regulating Bcl-2and. In addition, Tan IIA inhibited the capacity of migration and invasion in U937 cells. Moreover, Tan IIA induced autophagy in U937 cells via upregulation of the expression of LC3 II, Atg5 and Beclin 1, which was further confirmed by MDC staining and immunofluorescence assays. For the first time, we have shown that autophagy inhibitor 3MA significantly enhanced Tan IIA-induced apoptosis in U937 cells. Furthermore, Tan IIA induced apoptosis and autophagy via downregulation of PI3K/Akt pathwayand. Therefore, the accumulating evidences suggested that Tan IIA could be a potential agent for improving the symptoms of AML in the future.

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PMID: 

Am J Transl Res. 2019 ;11(5):3140-3149. Epub 2019 May 15. PMID: 31217883

Abstract Title: 

Tanshinone IIA ameliorates oxaliplatin-induced neurotoxicity via mitochondrial protection and autophagy promotion.

Abstract: 

Peripheral neurotoxicity is a common adverse reaction in cancer patients undergoing chemotherapy. The neuropathologic changes were partly associated with mitochondrial dysfunction and autophagy. Tanshinone IIA, a compound extracted from the medicinal herb, has been shown to exhibit neuroprotective effects. The present study investigated the effects of tanshinone IIA on chemotherapy-induced neurotoxicity and to study the underlying mechanism. Neuroma cell line N2a and rats were treated with oxaliplatin and/or tanshinone IIA. The effects on neurotoxicity were evaluated using cell viability assay, flow cytometry detection of apoptosis, measurement of intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (Ψm), autophagy detection, nerve function assessment, and behavior assessment. The results showed that tanshinone IIA prevented oxaliplatin-induced inhibition of cell viability and reduced apoptosis. Tanshinone IIA also prevented excessive oxidative stress, as demonstrated by decreased ROS levels and reduced Ψm loss. Lastly, treatment with tanshinone IIA promoted autophagy through the PI3K/Akt/mTOR signaling pathway. Theexperiment showed that tanshinone IIA ameliorated oxaliplatin-induced allodynia and sciatic nerve dysfunction. An increase in serum nerve growth factor level was observed. In conclusion, the results of the study suggested a protective role of tanshinone IIA in neurotoxicity induced by oxaliplatin via mitochondrial protection and autophagy promotion.

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PMID: 

Med Sci Monit. 2019 Jun 28 ;25:4793-4800. Epub 2019 Jun 28. PMID: 31250836

Abstract Title: 

Effects and Mechanism of Tanshinone II A in Proliferation, Apoptosis, and Migration of Human Colon Cancer Cells.

Abstract: 

BACKGROUND The aim of this study was to explore the effect and mechanism of tanshinone II A on proliferation, apoptosis, and migration of human colon cancer cells. MATERIAL AND METHODS CCK-8 approach was carried out to evaluate proliferation after applying various levels of tanshinone II A to SW620 colon carcinoma cells. Flow cytometry (FC) was used to assess apoptosis. Transwell assay was performed to assess invasion in vitro, and the wound-healing assay was applied to assess migration. Western blot analysis was performed to evaluate translation of mTOR, while RT-PCR was carried out to assess transcription of VEGF. RESULTS CCK-8 assay showed that tanshinone II A inhibited SW620 proliferation in comparison to the control group subsequent to 24 h, 48 h, and 72 h (P

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PMID: 

Exp Ther Med. 2019 Jul ;18(1):729-734. Epub 2019 May 15. PMID: 31258708

Abstract Title: 

Tanshinone IIA ameliorates diabetic cardiomyopathy by inhibiting Grp78 and CHOP expression in STZ-induced diabetes rats.

Abstract: 

Diabetic cardiomyopathy (DCM), one of the common diabetic complications, causes a high rate of mortality in patients with diabetes. Tanshinone IIA (TSIIA), one of the components of(Danshen), has anti-oxidative stress activity and is widely used to treat diabetes-associated diseases. However, its efficacy on DCM remains unclear. The present study aimed to investigate the potential therapeutic function of TSIIA on DCM in an experimental diabetic rat model. Streptozotocin (STZ)-induced diabetic rats were intraperitoneally injected with TSIIA for 6 weeks. The present results indicated that blood glucose concentration was slightly reduced in the low-dose TSIIA treatment group. TSIIA injection was also noted to improve cardiac function, and restore loss of mitochondrial cristae, swollen mitochondrial matrix and disorganized myofibrils in myocardial cells, which are thought to be characteristics of apoptosis. Furthermore, TSIIA injection could increase the activity of superoxide dismutase in STZ-induced diabetic rats, and suppress the endoplasmic reticulum (ER) stress signaling pathway via reducing the expression of glucose-regulated protein 78 and C/EBP homologous protein. These results provide evidence that TSIIA may ameliorate DCM in diabetic rats, possibly via suppressing oxidative stress and ER stress activation.

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PMID: 

Cancers (Basel). 2019 Jun 28 ;11(7). Epub 2019 Jun 28. PMID: 31261758

Abstract Title: 

Tanshinone IIA Restores Dynamic Balance of Autophagosome/Autolysosome in Doxorubicin-Induced Cardiotoxicity via Targeting Beclin1/LAMP1.

Abstract: 

Clinical use of the anti-cancer drug doxorubicin (DOX) is largely limited due to its severe cardiotoxicity. Dysregulation of autophagy is implicated in DOX-induced cardiotoxicity (DIC). Prior studies have indicated that Beclin1 and lysosomal-associated membrane proteins-1 (LAMP1) are critical mediators of autophagy. In this work, by assessing autophagic flux in a DOX-stimulated H9C2 model, we observed autolysosome accumulation caused by interruption of autolysosome degradation. Tanshinone IIA (TSA) is a well-known small molecule that exerts impressive cardioprotective effects on heart failure. Here, we investigated the regulation of TSA in DOX-treated zebrafish, mice, and H9C2 models. Results demonstrated that TSA remarkably improved heart function and reversed pathological changes in vivo, while TSA restored autophagic flux by promoting autolysosome degradation and autophagosome formation. Further experiments demonstrated that these effects were mediated through upregulation of Beclin1 and LAMP1. The mTOR agonist MHY1485 was shown to abrogate the effect of TSA via the UNC-51-like kinase 1 (ULK1)-Beclin1/TFEB-LAMP1 signaling pathway in vitro, demonstrating that TSA protects against DIC by promoting autophagy via the Beclin1/LAMP1 signaling pathway. We further employed a U87 model to assess whether TSA would compromise the antitumor activity of DOX. Intriguingly, the co-treatment of TSA was able to synergistically inhibit proliferative activity. Collectively, in this study we uncover the novel insight that TSA is able to reduce the cardiotoxicity of DOX without compromising antitumor activity.

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PMID: 

J Recept Signal Transduct Res. 2019 Apr ;39(2):134-145. Epub 2019 Jul 29. PMID: 31354004

Abstract Title: 

Inhibitory effect of Tanshinone IIA on inverted formin-2 protects HaCaT cells against oxidative injury via regulating mitochondrial stress.

Abstract: 

Epidermal cells play an important role in regulating the regeneration of skin after burns and wounds.The aim of our study is to explore the role of Tanshinone IIA (Tan IIA) in the apoptosis of epidermal HaCaT cells induced by HO, with a focus on mitochondrial homeostasis and inverted formin-2 (INF2).Cellular viability was determined using the MTT assay, TUNEL staining, western blot analysis and LDH release assay. Adenovirus-loaded INF2 was transfected into HaCaT cells to overexpress INF2 in the presence of Tan IIA treatment. Mitochondrial function was determined using JC-1 staining, mitochondrial ROS staining, immunofluorescence and western blotting.Oxidative stress promoted the death of HaCaT cells and this effect could be reversed by Tan IIA. At the molecular levels, Tan IIA treatment sustained mitochondrial energy metabolism, repressed mitochondrial ROS generation, stabilized mitochondrial potential, and blocked the mitochondrial apoptotic pathway. Furthermore, we demonstrated that Tan IIA modulated mitochondrial homeostasis via affecting INF2-related mitochondrial stress. Overexpression of INF2 could abolish the protective effects of Tan IIA on HaCaT cells viability and mitochondrial function. Besides, we also reported that Tan IIA regulated INF2 expression via the ERK pathway; inhibition of this pathway abrogated the beneficial effects of Tan IIA on HaCaT cells survival and mitochondrial homeostasis.Overall, our results indicated that oxidative stress-mediated HaCaT cells apoptosis could be reversed by Tan IIA treatment via reducing INF2-related mitochondrial stress in a manner dependent on the ERK signaling pathway.

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PMID: 

Electromagn Biol Med. 2019 Aug 26:1-18. Epub 2019 Aug 26. PMID: 31450976

Abstract Title: 

Exposure to Static and Extremely-Low Frequency Electromagnetic Fields and Cellular Free Radicals.

Abstract: 

This paper summarizes studies on changes in cellular free radical activities from exposure to static and extremely-low frequency (ELF) electromagnetic fields (EMF), particularly magnetic fields. Changes in free radical activities, including levels of cellular reactive oxygen (ROS)/nitrogen (RNS) species and endogenous antioxidant enzymes and compounds that maintain physiological free radical concentrations in cells, is one of the most consistent effects of EMF exposure. These changes have been reported to affect many physiological functions such as DNA damage; immune response; inflammatory response; cell proliferation and differentiation; wound healing; neural electrical activities; and behavior. An important consideration is the effects of EMF-induced changes in free radicals on cell proliferation and differentiation. These cellular processes could affect cancer development and proper growth and development in organisms. On the other hand, they could cause selective killing of cancer cells, for instance, via the generation of the highly cytotoxic hydroxyl free radical by the Fenton Reaction. This provides a possibility of using these electromagnetic fields as a non-invasive and low side-effect cancer therapy. Static- and ELF-EMF probably play important roles in the evolution of living organisms. They are cues used in many critical survival functions, such as foraging, migration, and reproduction. Living organisms can detect and respond immediately to low environmental levels of these fields. Free radical processes are involved in some of these mechanisms. At this time, there is no credible hypothesis or mechanism that can adequately explain all the observed effects of static- and ELF-EMF on free radical processes. We are actually at the impasse that there are more questions than answers.

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PMID: 

J Chem Neuroanat. 2019 Aug 26 ;101:101681. Epub 2019 Aug 26. PMID: 31465830

Abstract Title: 

Changes in pyramidal and granular neuron numbers in the rat hippocampus 7 days after exposure to a continuous 900-MHz electromagnetic field during early and mid-adolescence.

Abstract: 

The aim of this study was to investigate qualitative and quantitative changes in pyramidal and granule neurons in the male rat hippocampus after exposure to a continuous 900-megahertz (MHz) electromagnetic field (EMF) for 25 days during early and mid-adolescence. Three-week-old (21 day) healthy Sprague Dawley male rats were divided equally into control (CON), pseudo-exposed (PEX) and EMF groups. EMF rats were exposed to a 900-MHz EMF in an EMF-application cage, while the PEX rats were placed in the same cage without being exposed to EMF. No procedure was performed in CON. EMF was applied for 1 h/day, every day for 25 days. Following the 900-MHz EMF and pseudo-exposed applications, behavioral tests were performed for seven days. Then, all animals were euthanized and their brains were removed. Following histological tissue procedures, sections were taken from tissues and stained with toluidine blue. The optical fractionation technique was performed to estimate the pyramidal neuron numbers in the CA1, CA2-3 and hilus regions of the hippocampus and granule neuron numbers in the dentate gyrus region. Our findings indicated that the number of pyramidal and granule neurons in the hippocampus of the EMF group was statistically higher than PEX. Furthermore, the histopathological results showed that the cytoplasm of pyramidal (in the hilus, CA1, CA2 and CA3 region) and granular (in the dentate gyrus region) cells at the hippocampus were disrupted, as evident by intensive staining around cytoplasm and some artifacts were detected in the EMF group. In addition, statistical comparisons of the mean body weights and brain weights of the study groups revealed no significant differences. There was no statistically significant difference between the PEX and EMF groups in terms of temperature (p > 0.05) or humidity (p > 0.05) in the cages. In conclusion, higher numbers of both pyramidal and granule neurons were found in the male rat hippocampus after continuous 900-MHz EMF treatment.

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PMID: 

Environ Res. 2019 Nov ;178:108688. Epub 2019 Aug 24. PMID: 31476684

Abstract Title: 

Extremely low frequency electromagnetic fields and cancer: How source of funding affects results.

Abstract: 

While there has been evidence indicating that excessive exposure to magnetic fields from 50 to 60 Hz electricity increases risk of cancer, many argue that the evidence is inconsistent and inconclusive. This is particularly the case regarding magnetic field exposure and childhood leukemia. A major goal of this study is to examine how source of funding influences the reported results and conclusions. Several meta-analyses dating from about 2000 all report significant associations between exposure and risk of leukemia. By examining subsequent reports on childhood leukemia it is clear that almost all government or independent studies find either a statistically significant association between magnetic field exposure and childhood leukemia, or an elevated risk of at least OR = 1.5, while almost all industry supported studies fail to find any significant or even suggestive association. A secondary goal of this report is to examine the level of evidence for exposure and elevated riskof various adult cancers. Based on pooled or meta-analyses as well as subsequent peer-reviewed studies there is strong evidence that excessive exposure to magnetic fields increases risk of adult leukemia, male and female breast cancer and brain cancer. There is less convincing but suggestive evidence for elevations in several other cancer types. There is less clear evidence for bias based on source of funding in the adult cancer studies. There is also some evidence that both paternal and maternal prenatal exposure to magnetic fields results in an increased risk of leukemia and brain cancer inoffspring. When one allows for bias reflected in source of funding, the evidence that magnetic fields increase risk of cancer is neither inconsistent nor inconclusive. Furthermore adults are also at risk, not just children, and there is strong evidence for cancers in addition to leukemia, particularly brain and breast cancer.