PMID: 

Oxid Med Cell Longev. 2019 ;2019:5083158. Epub 2019 Jun 9. PMID: 31281581

Abstract Title: 

Betulinic Acid Induces ROS-Dependent Apoptosis and S-Phase Arrest by Inhibiting the NF-B Pathway in Human Multiple Myeloma.

Abstract: 

Betulinic acid (BA), as a prospective natural compound, shows outstanding antitumor bioactivities against many solid malignancies. However, its mechanism against multiple myeloma (MM) remains elusive. Herein, for the first time, we studied the antitumor activity of BA against MM bothand. We showed that BA mediated cytotoxicity in MM cells through apoptosis, S-phase arrest, mitochondrial membrane potential (MMP) collapse, and overwhelming reactive oxygen species (ROS) accumulation. Moreover, when the ROS scavenger N-acetyl cysteine (NAC) effectively abated elevated ROS, the BA-induced apoptosis was partially reversed. Our results revealed that BA-mediated ROS overproduction played a pivotal role in anticancer activity. Molecularly, we found that BA resulted in marked inhibition of the aberrantly activated NF-B pathway in MM. As demonstrated by using the NF-B pathway-specific activator TNF-and the inhibitor BAY 11-7082, BA-mediated inhibition of the NF-B pathway directly promoted the overproduction of ROS and, ultimately, cell death. Furthermore, BA also exerted enormous tumor-inhibitory effects via repressing proliferation and inhibiting the NF-B pathway in our xenograft model. Overall, by blocking the NF-B pathway that breaks redox homeostasis, BA, as a potent NF-B inhibitor, is a promising therapeutic alternative for MM.

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PMID: 

Exp Biol Med (Maywood). 2015 Sep ;240(9):1123-35. Epub 2015 Feb 2. PMID: 25649190

Abstract Title: 

Exposure to non-ionizing radiation provokes changes in rat thyroid morphology and expression of HSP-90.

Abstract: 

Non-ionizing radiation at 2.45 GHz may modify the morphology and expression of genes that codify heat shock proteins (HSP) in the thyroid gland. Diathermy is the therapeutic application of non-ionizing radiation to humans for its beneficial effects in rheumatological and musculo-skeletal pain processes. We used a diathermy model on laboratory rats subjected to maximum exposure in the left front leg, in order to study the effects of radiation on the nearby thyroid tissue. Fifty-six rats were individually exposed once or repeatedly (10 times in two weeks) for 30 min to 2.45 GHz radiation in a commercial chamber at different non-thermal specific absorption rates (SARs), which were calculated using the finite difference time domain technique. We used immunohistochemistry methods to study the expression of HSP-90 and morphological changes in thyroid gland tissues. Ninety minutes after radiation with the highest SAR,the central and peripheral follicles presented increased size and the thickness of the peripheral septa had decreased. Twenty-four hours after radiation, only peripheral follicles radiated at 12 W were found to be smaller. Peripheral follicles increased in size with repeated exposure at 3 W power. Morphological changes in the thyroid tissue may indicate a glandular response to acute or repeated stress from radiation in the hypothalamic-pituitary-thyroid axis. Further research is needed to determine if the effect of this physical agent over time may cause disease in the human thyroid gland.

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PMID: 

Exp Cell Res. 2019 Jul 22:111509. Epub 2019 Jul 22. PMID: 31344390

Abstract Title: 

Betulinic acid derivatives can protect human Müller cells from glutamate-induced oxidative stress.

Abstract: 

Müller cells are the predominant retinal glial cells. One of the key roles of Müller cells is in the uptake of the neurotransmitter glutamate and in its conversion to glutamine. Müller cell dysfunction due to oxidative stress elicited by high glutamate concentrations can lead to toxicity, which promote the pathogenesis of retinal diseases like diabetic retinopathy and glaucoma. This study investigated the anti-oxidant activity and mechanisms of betulinic acid (BA) and its derivatives in human Müller cells. Human MIO-M1 Müller cells were pre-treated in the presence or absence of BA, BE as well as their derivatives (named H3-H20) followed by incubation with glutamate. Cell viability was evaluated with the MTT and calcein-AM assays. Reactive oxygen species (ROS) production in MIO-M1 cells was measured using CM-H2DCFDA and flow cytometry. The activation of cellular apoptosis and necrosiswas analyzed with annexin V/PI staining and flow cytometry. The modulation of signaling pathways involved in glutamate-mediated cytotoxicity and ROS production was evaluated by immunoblotting. The BA derivatives H3, H5 and H7 exhibited minimal cytotoxicity and significant anti-oxidant activity. These compounds significantly suppressed ROS production and attenuated cellular necrosis elicited by glutamate-induced oxidative stress. The protective effects of H3, H5 and H7 in MIO-M1 cells were associated with the attenuation of Akt, Erk, and JNK signaling. The BA analogues H3, H5 and H7 are protective against glutamate-induced oxidative stress in human Müller cells, and elicit their actions by modulation of the Erk, Akt and JNK signaling pathways. These agents are potential candidate molecules for the prevention or treatment of human retinal diseases.

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PMID: 

J Toxicol Environ Health A. 2015 ;78(6):353-6. PMID: 25734762

Abstract Title: 

Structural and ultrastructural study of rat liver influenced by electromagnetic radiation.

Abstract: 

Mobile communication systems are undoubtedly an environmental source of electromagnetic radiation (EMR). There is an increasing concern regarding the interactions of EMR with the humans. The aim of this study was to examine the effects of EMR on Wistar rat liver. Mature rats were exposed to electromagnetic field of frequency 2.45 GHz and mean power density of 2.8 mW/cm2 for 3 h/d for 3 wk. Samples of the liver were obtained 3 h after the last irradiation and processed histologically for light and transmission electron microscopy. Data demonstrated the presence of moderate hyperemia, dilatation of liver sinusoids, and small inflammatory foci in the center of liver lobules. Structure of hepatocytes was not altered and all described changes were classified as moderate. Electron microscopy of hepatocytes revealed vesicles of different sizes and shapes, lipid droplets, and proliferation of smooth endoplasmic reticulum. Occasionally necrotizing hepatocytes were observed. Our observations demonstrate that EMR exposure produced adverse effects on rat liver.

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PMID: 

Inflammopharmacology. 2019 Jul 27. Epub 2019 Jul 27. PMID: 31352642

Abstract Title: 

Betulinic acid attenuates lipopolysaccharide-induced vascular hyporeactivity in the rat aorta by modulating Nrf2 antioxidative function.

Abstract: 

Betulinic acid (BA), a pentacyclic triterpenoid, has been reported to inhibit cardiovascular dysfunction under sepsis-induced oxidative stress. Nuclear factor erythroid-2 related factor-2 (Nrf2) is regarded as a key transcription factor regulating expression of endogenous antioxidative genes. To explore the preventive effects of BA against vascular hyporeactivity and the related antioxidative mechanism in sepsis, contraction and relaxation in aortas isolated from lipopolysaccharide (LPS)-challenged rats were performed. Male Sprague-Dawley rats were pretreated with brusatol (Bru, 0.4 mg/kg/2 days, i.p.), an inhibitor of Nrf2, and BA (10, 25, 50 mg/kg/day, i.g.) for 3 days and injected with LPS (10 mg/kg, i.p.) at the 4th day. Rats were anesthetized and killed by cervical dislocation after they were treated with LPS for 4 h. Thoracic aortas were immediately dissected out to determine contraction and relaxation using the organ bath system. Pro-inflammatory factors interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) and oxidative stress were measured in aortic tissues and plasma. mRNA expression of Nrf2-regulated antioxidative enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GPx), and heme oxygenase-1 (HO-1), in rat aortas was determined. Increases of IL-1β, TNF-α, nitric oxide, and malondialdehyde and the decrease of glutathione induced by LPS were significantly attenuated by pretreatment with different doses of BA in plasma and aortas (p 

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PMID: 

Life Sci. 2015 Apr 15 ;127:1-11. Epub 2015 Feb 28. PMID: 25731700

Abstract Title: 

EMF radiation at 2450 MHz triggers changes in the morphology and expression of heat shock proteins and glucocorticoid receptors in rat thymus.

Abstract: 

AIMS: Electromagnetic fields (EMFs) can act as inducers or mediators of stress response through the production of heat shock proteins (HSPs) that modulate immune response and thymus functions. In this study, we analyzed cellular stress levels in rat thymus after exposure of the rats to a 2.45 GHz radio frequency (RF) using an experimental diathermic model in a Gigahertz Transverse Electromagnetic (GTEM) chamber.MAIN METHODS: In this experiment, we used H&E staining, the ELISA test and immunohistochemistry to examine Hsp70 and Hsp90 expression in the thymus and glucocorticoid receptors (GR) of 64 female Sprague–Dawley rats exposed individually to 2.45 GHz (at 0, 1.5, 3.0 or 12.0 W power). The 1 g averaged peak and mean SAR values in the thymus and whole body of each rat to ensure that sub-thermal levels of radiation were being reached.KEY FINDINGS: The thymus tissue presented several morphological changes, including increased distribution of blood vessels along with the appearance of red blood cells and hemorrhagic reticuloepithelial cells. Levels of Hsp90 decreased in the thymus when animals were exposed to the highest power level (12 W), but only one group did not show recovery after 24 h. Hsp70 presented no significant modifications in any of the groups. The glucocorticoid receptors presented greater immunomarking on the thymic cortex in exposed animals.SIGNIFICANCE: Our results indicate that non-ionizing sub-thermal radiation causes changes in the endothelial permeability and vascularization of the thymus, and is a tissue-modulating agent for Hsp90 and GR.

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PMID: 

Environ Res. 2010 Oct ;110(7):658-63. PMID: 20638656

Abstract Title: 

Comparison of personal radio frequency electromagnetic field exposure in different urban areas across Europe.

Abstract: 

BACKGROUND: Only limited data are available on personal radio frequency electromagnetic field (RF-EMF) exposure in everyday life. Several European countries performed measurement studies in this area of research. However, a comparison between countries regarding typical exposure levels is lacking.OBJECTIVES: To compare for the first time mean exposure levels and contributions of different sources in specific environments between different European countries.METHODS: In five countries (Belgium, Switzerland, Slovenia, Hungary, and the Netherlands), measurement studies were performed using the same personal exposure meters. The pooled data were analyzed using the robust regression on order statistics (ROS) method in order to allow for data below the detection limit. Mean exposure levels were compared between different microenvironments such as homes, public transports, or outdoor.RESULTS: Exposure levels were of the same order of magnitude in all countries and well below the international exposure limits. In all countries except for the Netherlands, the highest total exposure was measured in transport vehicles (trains, car, and busses), mainly due to radiation from mobile phone handsets (up to 97%). Exposure levels were in general lower in private houses or flats than in offices and outdoors. At home, contributions from various sources were quite different between countries.CONCLUSIONS: Highest total personal RF-EMF exposure was measured inside transport vehicles and was well below international exposure limits. This is mainly due to mobile phone handsets. Mobile telecommunication can be considered to be the main contribution to total RF-EMF exposure in all microenvironments.

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PMID: 

J Biochem Mol Toxicol. 2019 Jul 31:e22373. Epub 2019 Jul 31. PMID: 31364231

Abstract Title: 

Protective effect of betulinic acid on Freund's complete adjuvant-induced arthritis in rats.

Abstract: 

The purpose of the experiment was to study the effects of betulinic acid (BA) on adjuvant-induced arthritis in rats. The rat model of rheumatoid arthritis (AA) was established by Freund's complete adjuvant. Arthritis index, joint pathology, toe swelling, hemorheology, related cytokines and ROCK/NF-κB signaling pathway were measured in rats. BA can significantly inhibit the arthritis index, improve joint pathology, reduce toe swelling, improve blood rheology, improve synovial cell apoptosis, and restore related cytokine negative regulation of ROCK/NF-κB signaling pathways. BA has an obvious therapeutic effect on joint inflammation of toes in AA model rats, which may be due to the regulation of ROCK/NF-κB signaling pathway.

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PMID: 

J Adv Res. 2013 Mar ;4(2):181-7. Epub 2012 Jun 25. PMID: 25685416

Abstract Title: 

Non-thermal continuous and modulated electromagnetic radiation fields effects on sleep EEG of rats.

Abstract: 

In the present study, the alteration in the sleep EEG in rats due to chronic exposure to low-level non-thermal electromagnetic radiation was investigated. Two types of radiation fields were used; 900 MHz unmodulated wave and 900 MHz modulated at 8 and 16 Hz waves. Animals has exposed to radiation fields for 1 month (1 h/day). EEG power spectral analyses of exposed and control animals during slow wave sleep (SWS) and rapid eye movement sleep (REM sleep) revealed that the REM sleep is more susceptible to modulated radiofrequency radiation fields (RFR) than the SWS. The latency of REM sleep increased due to radiation exposure indicating a change in the ultradian rhythm of normal sleep cycles. The cumulative and irreversible effect of radiation exposure was proposed and the interaction of the extremely low frequency radiation with the similar EEG frequencies was suggested.

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PMID: 

Sci Rep. 2014 May 29 ;4:5103. Epub 2014 May 29. PMID: 24869783

Abstract Title: 

Exposure to 1800 MHz radiofrequency radiation impairs neurite outgrowth of embryonic neural stem cells.

Abstract: 

A radiofrequency electromagnetic field (RF-EMF) of 1800 MHz is widely used in mobile communications. However, the effects of RF-EMFs on cell biology are unclear. Embryonic neural stem cells (eNSCs) play a critical role in brain development. Thus, detecting the effects of RF-EMF on eNSCs is important for exploring the effects of RF-EMF on brain development. Here, we exposed eNSCs to 1800 MHz RF-EMF at specific absorption rate (SAR) values of 1, 2, and 4 W/kg for 1, 2, and 3 days. We found that 1800 MHz RF-EMF exposure did not influence eNSC apoptosis, proliferation, cell cycle or the mRNA expressions of related genes. RF-EMF exposure also did not alter the ratio of eNSC differentiated neurons and astrocytes. However, neurite outgrowth of eNSC differentiated neurons was inhibited after 4 W/kg RF-EMF exposure for 3 days. Additionally, the mRNA and protein expression of the proneural genes Ngn1 and NeuroD, which are crucial for neuriteoutgrowth, were decreased after RF-EMF exposure. The expression of their inhibitor Hes1 was upregulated by RF-EMF exposure. These results together suggested that 1800 MHz RF-EMF exposure impairs neurite outgrowth of eNSCs. More attention should be given to the potential adverse effects of RF-EMFexposure on brain development.

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