PMID: 

ACS Med Chem Lett. 2019 Oct 10 ;10(10):1400-1406. Epub 2019 Sep 10. PMID: 31620225

Abstract Title: 

A Bioreductive Prodrug of Cucurbitacin B Significantly Inhibits Tumor Growth in the 4T1 Xenograft Mice Model.

Abstract: 

Cucurbitacin B (CuB), a highly cytotoxic constituent of the Cucurbitaceae plant, was identified to exhibit potent inhibitory activity against human cancer cells as well as normal cells. This disadvantage hampers the possibility of developing this compound into an anticancer drug candidate. In this work, several bioreductive prodrugs of CuB were designed to reduce toxicity to normal cells while maintaining the cytotoxic effect to cancer cells. Embedded with a bioreductive delivery and cleavable system in cancer tissues, cucurbitacin B-based prodrugs,, andwere synthesized and evaluated byandexperiments. Compared with the parent CuB, prodrugwas found to significantly reduce the toxicity down to 310-fold lower against noncancerous cells. LC-MS analyses show that prodrugefficiently releases the parent compound in the reductase-overexpressed MCF-7 cells. In addition, prodrugshows satisfactory and comparable effectiveness in controlling tumor growth as that by tamoxifen in the 4T1 xenograft mice model.

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PMID: 

ACG Case Rep J. 2019 Feb ;6(2):1-3. Epub 2019 Mar 7. PMID: 31157284

Abstract Title: 

Acute Pancreatitis Caused by Tamoxifen-Induced Severe Hypertriglyceridemia After 4 Years of Tamoxifen Use.

Abstract: 

We report a case of a 55-year-old woman with hypertension and diabetes mellitus, who took tamoxifen for the past 4 years. She presented with acute pancreatitis caused by markedly elevated serum triglycerides (3,883 mg/dL). Tamoxifen is known to cause a mild increase in serum triglycerides, but it rarely increases to such high levels to cause acute pancreatitis. The patient recovered well, and tamoxifen was switched to letrozole. It is crucial to monitor serum lipids up to 4 years and beyond for patients on tamoxifen, particularly in patients with known dyslipidemia or diabetes mellitus.

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PMID: 

Int J Surg Case Rep. 2019 ;60:186-190. Epub 2019 Feb 27. PMID: 31229774

Abstract Title: 

Tamoxifen-induced acute eosinophilic pneumonia in a breast cancer patient.

Abstract: 

INTRODUCTION: Tamoxifen is often used as antihormonal therapy in patients with breast cancer. However, it has various side effects, of which pneumonia is a rare occurrence.PRESENTATION OF CASE: A 46-year-old female patient with breast cancer underwent surgical treatment. Tamoxifen was administered as adjuvant therapy on post-operative day 14; 2 days after administration of tamoxifen, the patient developed high fever of more than 39 °C and cough with dyspnea. Based on chest computed tomography findings of ground glass opacity, interlobular septal thickening, and mild pleural effusion in both lungs, eosinophilic pneumonia was suspected. Tamoxifen was discontinued and methylprednisolone injection was administered; the patientshowed improvement of symptoms and radiographic findings.DISCUSSION: Tamoxifen was suspected as the cause of eosinophilic pneumonia since the patient developed high-grade fever at the time of tamoxifen administration, which subsided after discontinuation of the treatment. Other factors considered as the cause of pneumonia were examined, but all showed negative results. In order to confirm tamoxifen as the cause of pneumonia, tamoxifen treatment was restarted at follow-up (post-operative day 47); however, after 1 month, regular administration was not possible due to the development of itching symptom and difficulty in obtaining the patient's cooperation.CONCLUSION: The study highlights that if the patient on tamoxifen develops high fever and cough with dyspnea at 2-3days after the first administration, tamoxifen-induced pneumonia should be suspected.

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PMID: 

Lab Anim. 2019 Jun 27:23677219856918. Epub 2019 Jun 27. PMID: 31248325

Abstract Title: 

Tamoxifen administration in pregnant mice can be deleterious to both mother and embryo.

Abstract: 

Since it was introduced 20 years ago, tamoxifen-inducible genetic recombination in vivo has become a standard tool in many fields. This technique has great utility, allowing precise temporal and spatial gene recombination mediated by expression of a Cre recombinase-oestrogen receptor hormone binding domain fusion protein. It is frequently used in developmental biology, either for accurate spatio-temporal gene deletion or for lineage-labelling. Administration of high doses of tamoxifen can rapidly induce abortion in pregnant mice but this can be partially overcome by progesterone co-administration. However, administration of tamoxifen to pregnant mice early in pregnancy mayhave potentially lethal effects on the mother independently of abortion, and can also severely perturb embryonic development. Despite this, only a few published studies mention this fact in passing, and standard parameters for successful or unsuccessful use of tamoxifen in pregnant mice have not been reported. Therefore, in the interests of providing a framework for more humane animal research, we describe our experiences of tamoxifen administration during early gestation in mice. These observations should assist the design of future studies in accordance with the principles of the three Rs (Replacement, Reduction and Refinement of Animals in Research).

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PMID: 

Am J Physiol Gastrointest Liver Physiol. 2019 Oct 1 ;317(4):G518-G530. Epub 2019 Aug 1. PMID: 31369292

Abstract Title: 

Tamoxifen-induced, intestinal-specific deletion ofin adult mice leads to spontaneous inflammation: involvement of NF-κB, NLRP3, and gut microbiota.

Abstract: 

The sodium-dependent multivitamin transporter (SMVT;) is involved in intestinal absorption of vitamin B7 (biotin). We have previously shown that mice with an embryonic intestinal-specific SMVT knockout (KO) develop biotin deficiency and severe spontaneous intestinal inflammation in addition to growth retardation, developmental delays, and death within the first 6-7 wk of life. The profound morbidity and mortality associated with the SMVT-KO has limited our ability to further characterize the intestinal inflammation and other sequelae of this deletion in adult mice with a mature gut microbiota. To overcome this limitation, we generated an intestine-specific, tamoxifen-inducible, conditional SMVT-KO (SMVT-icKO). Our results showed that adult SMVT-icKO mice have reduced body weight, biotin deficiency, shorter colonic length, and bloody diarrhea compared with age- and sex-matched control littermates. All SMVT-icKO mice also developed spontaneous intestinal inflammation associated with induction of calprotectin (S100a8/S100a9), proinflammatory cytokines (IL-1β, TNF-α, IFN-γ, and IL-6), and an increase in intestinal permeability. Additionally, the intestines of SMVT-icKO showed activation of the NF-κB pathway and the nucleotide-binding domain and leucine-rich repeat pyrin 3 domain (NLRP3) inflammasome. Notably, administration of broad-spectrum antibiotics reduced lethality and led to normalization of intestinal inflammation, proinflammatory cytokines, altered mucosal integrity, and reduced expression of the NLRP3 inflammasome. Overall, these findings support our conclusion that the biotin transport pathway plays an important role in the maintenance of intestinal homeostasis, and that NF-κB and the NLRP3 inflammasome, as well as gut microbiota, drive the development of intestinal inflammation when SMVT is absent.This study demonstrates that deletion of the intestinal biotin uptake system in adult mice leads to the development of spontaneous gut inflammation and that luminal microbiota plays a role in its development.

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PMID: 

Medicine (Baltimore). 2018 Dec ;97(51):e12842. PMID: 30572423

Abstract Title: 

Correlation of the tamoxifen use with the increased risk of deep vein thrombosis and pulmonary embolism in elderly women with breast cancer: A case-control study.

Abstract: 

The association between tamoxifen use and risk of deep vein thrombosis or pulmonary embolism in women with breast cancer has been reported in the Western population. The study aimed to evaluate the association between tamoxifen use and deep vein thrombosis or pulmonary embolism in older women with breast cancer in Taiwan.We conducted a retrospective case-control study using the database of the Taiwan National Health Insurance Program. A total of 281 women subjects with breast cancer aged≥65 years with newly diagnosed deep vein thrombosis/or pulmonary embolism from 2000 to 2011 were identified as the cases. Additionally, 907 women subjects with breast cancer aged ≥65 years without deep vein thrombosis or pulmonary embolism were randomly selected as the controls. The cases and the controls were matched with age and comorbidities. Ever use of tamoxifen was defined as subjects who had at least a prescription for tamoxifen before index date. Never use of tamoxifen was defined as subjects who never had a prescription for tamoxifen before index date. We used the multivariable logistic regression model to calculate the odds ratio (OR) and the 95% confidence interval (CI) of deep vein thrombosis or pulmonary embolism associated with tamoxifen use.After adjustment for confounding variables, the adjusted OR of deep vein thrombosis or pulmonary embolism was 1.95 for subjects with ever use of tamoxifen (95% CI 1.45, 2.62), as compared with never use of tamoxifen. In addition, atrial fibrillation (adjusted OR 3.73, 95% CI 1.89, 7.35) and chronic kidney disease (adjusted OR 1.72, 95% CI 1.06, 2.80) were also associated with deep vein thrombosis or pulmonary embolism.Tamoxifen use is associated with 1.95-fold increased odds of deep vein thrombosis or pulmonary embolism among older women with breast cancer in Taiwan.

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PMID: 

Sheng Li Xue Bao. 2019 Jun 25 ;71(3):424-430. PMID: 31218333

Abstract Title: 

[Astragaloside IV attenuates cerebral ischemia and reperfusion injury and reduces activation of NLRP3 inflammasome and NF-κB phosphorylation in rats following a transient middle cerebral artery occlusion].

Abstract: 

The present study was aimed to investigate the protective effect and anti-inflammation mechanism of astragaloside IV (AST-IV) on cerebral ischemia and reperfusion injury. Following the establishment of cerebral ischemia and reperfusion model in rats by modified suture method, neurological deficit scores and cerebral infarct volume were used to evaluate the pharmacological effect of AST-IV against cerebral ischemia-reperfusion injury. Western blot was used to detect the expression levels of NLRP3, pro-Caspase-1, Caspase-1, pro-IL-1β, IL-1β, pro-IL-18, IL-18, phosphorylated and total nuclear factor kappa B (NF-κB)/p65 protein in the brain tissue. The results showed that compared with model group, the intervention of AST-IV decreased the neurological deficit scores, reduced the cerebral infarct volume, decreased the levels of NLRP3, Caspase-1, pro-IL-1β, IL-1β, pro-IL-18 and IL-18, and inhibited the expression of phosphorylated NF-κB in brain tissue. The results suggest that AST-IV has a protective effect against cerebral ischemia and reperfusion injury, and its mechanism is related to inhibiting the phosphorylationof NF-κB and NLRP3 inflammasome activation.

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PMID: 

Int J Occup Med Environ Health. 2010 ;23(4):377-84. PMID: 21306983##

Abstract Title: 

Static magnetic field affects oxidative stress in mouse cochlea.

Abstract: 

OBJECTIVE: It has been shown that oxidative stress plays an important role in development of noise induced hearing loss. Since static magnetic fields (SMF) exposure may alter dynamics of oxidative processes in the tissue, the aim of the study was to assess the influence of SMF on noise-induced alteration in the cochlear level of reactive oxygen species (ROS) and hearing thresholds.MATERIALS AND METHODS: Auditory brainstem response (ABR), lipid peroxidation (LPO) levels, super-oxide dismutase (SOD) activity and catalase activity were assessed in the cochlea prior to, and at five time-points over two weeks following exposure of C57BL/6 mice to 8h, 119 dB SPL, 4 kHz octave band noise.RESULTS: The ABR indicated no permanent functional damage due to noise exposure either for the 4 kHz and 8 kHz SMF-exposed group or for animals not exposed to SMF. However, significant differences in LPO level, catalase and SOD activity between animals exposed to noise and SMF and those exposed to noise only were observed.CONCLUSIONS: The results suggest that SMF causes an increase in ROS level in the cochlea after noise exposure and, at the same time, it speeds up activation of antioxidative enzymes.

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PMID: 

Neurochem Int. 2013 Mar ;62(4):418-24. Epub 2013 Feb 11. PMID: 23411410

Abstract Title: 

Electromagnetic fields induce neural differentiation of human bone marrow derived mesenchymal stem cells via ROS mediated EGFR activation.

Abstract: 

Even though the inducing effect of electromagnetic fields (EMF) on the neural differentiation of human bone marrow mesenchymal stem cells (hBM-MSCs) is a distinctive, the underlying mechanism of differentiation remains unclear. To find out the signaling pathways involved in the neural differentiation of BM-MSCs by EMF, we examined the CREB phosphorylation and Akt or ERK activation as an upstream of CREB. In hBM-MSCs treated with ELF-EMF (50 Hz, 1 mT), the expression of neural markers such as NF-L, MAP2, and NeuroD1 increased at 6 days and phosphorylation of Akt and CREB but not ERK increased at 90 min in BM-MSCs. Moreover, EMF increased phosphorylation of epidermal growth factor receptor (EGFR) as an upstream receptor tyrosine kinase of PI3K/Akt at 90 min. It has been well documented that ELF-MF exposure may alter cellular processes by increasing intracellular reactive oxygen species (ROS) concentrations. Thus, we examined EMF-induced ROS production in BM-MSCs. Moreover, pretreatment with a ROS scavenger, N-acetylcystein, and an EGFR inhibitor, AG-1478, prevented the phosphorylation of EGFR and downstream molecules. These results suggest that EMF induce neural differentiation through activation of EGFR signaling and mild generation of ROS.

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PMID: 

Arch Biochem Biophys. 2012 Nov 1 ;527(1):55-64. Epub 2012 Aug 15. PMID: 22910297

Abstract Title: 

Oxidative effects of nanosecond pulsed electric field exposure in cells and cell-free media.

Abstract: 

Nanosecond pulsed electric field (nsPEF) is a novel modality for permeabilization of membranous structures and intracellular delivery of xenobiotics. We hypothesized that oxidative effects of nsPEF could be a separate primary mechanism responsible for bioeffects. ROS production in cultured cells and media exposed to 300-ns PEF (1-13 kV/cm) was assessed by oxidation of 2',7'-dichlorodihydrofluoresein (H(2)DCF), dihidroethidium (DHE), or Amplex Red. When a suspension of H(2)DCF-loaded cells was subjected to nsPEF, the yield of fluorescent 2',7'-dichlorofluorescein (DCF) increased proportionally to the pulse number and cell density. DCF emission increased with time after exposure in nsPEF-sensitive Jurkat cells, but remained stable in nsPEF-resistant U937 cells. In cell-free media, nsPEF facilitated the conversion of H(2)DCF into DCF. This effect was not related to heating and was reduced by catalase, but not by mannitol or superoxide dismutase. Formation of H(2)O(2) in nsPEF-treated media was confirmed by increased oxidation of Amplex Red. ROS increase within individual cells exposed to nsPEF was visualized by oxidation of DHE. We conclude that nsPEF can generate both extracellular (electrochemical) and intracellular ROS, including H(2)O(2) and possibly other species. Therefore, bioeffects of nsPEF are not limited to electropermeabilization; concurrent ROS formation may lead to cell stimulation and/or oxidative cell damage.

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