PMID: 

Mol Cell Endocrinol. 2016 10 15 ;434:135-43. Epub 2016 Jun 27. PMID: 27364889

Abstract Title: 

Betulinic acid ameliorates experimental diabetic-induced renal inflammation and fibrosis via inhibiting the activation of NF-κB signaling pathway.

Abstract: 

Diabetic nephropathy (DN) is the leading cause of end-stage renal failure and is characterized by excessive deposition of extracellular matrix (ECM) proteins such as fibronectin (FN), in the glomerular mesangium and tubulointerstitium. Betulinic acid (BA), a pentacyclic triterpene derived from the bark of the white birch tree, has been demonstrated to have many pharmacological activities. However, the effect of BA on DN has not been fully elucidated. To explore the possible anti-inflammatory effects of BA and their underlying mechanisms, we used streptozotocin-induced diabetic rat kidneys and high glucose-treated glomerular mesangial cells. Our study showed BA could inhibit the degradation of IκBα and the activity of NF-κB in diabetic rat kidneys and high glucose-induced mesangial cells, resulting in reduction of FN expression. In addition, BA suppressed the DNA binding activity and transcriptional activity of NF-κB in high glucose-induced glomerular mesangial cells (GMCs). Furthermore, BA enhanced the interaction between IκBα and β-arrestin2 in mesangial cells. Taken together, our data suggest BA inhibits NF-κB activation through stabilizing NF-κB inhibitory protein IκBα, thereby preventing diabetic renal fibrosis.

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PMID: 

Eur J Pharmacol. 2017 Feb 5 ;796:224-232. Epub 2016 Nov 26. PMID: 27894808

Abstract Title: 

Protective effect of betulinic acid on early atherosclerosis in diabetic apolipoprotein-E gene knockout mice.

Abstract: 

Atherosclerosis, a chronic and progressive disease, is a leading cause of endothelial dysfunction, diabetes mellitus, hypertension, and hypercholesterolemia. Betulinic acid (BA), a pentacyclic triterpene, has been reported to have a variety of biological effects, including anti-inflammatory and immunomodulatory properties. This study was designed to determine whether BA could prevent atherosclerosis in diabetic apolipoprotein-E gene knockout (ApoE KO) mice. The mice were treated with BA for 12 weeks to examine its beneficial effects on atherosclerosis in ApoE KO mice. Male ApoE KO mice and age-matched control group mice (C57BL/6Jms) were used as experimental systems and their systolic blood pressure, insulin resistance, and vascular inflammation were measured. BA-treated ApoE KO mice showed lowered systolic blood pressure. The metabolic parameter showed that BA decreased blood urea nitrogen, triglyceride, and total cholesterol levels. Blood glucose, insulin, glucose tolerance results, and the homeostasis model assessment of insulin resistance (HOMA-IR) index were found to be better in BA-treated ApoE KO mice than untreated ApoE KO mice. Consistent with the change in lipid profiles, oil red O and H&E staining revealed that treatment with BA reduced atherosclerotic lesions such as roughened endothelial layers. BA ameliorated the reduction of endothelial nitric oxide synthase (eNOS) expression, leading to the inhibition of intracellular adhesion molecule 1 (ICAM-1) and endothelin 1 (ET-1) expression. These results suggest that BA may be useful in the treatment and prevention of early atherosclerosis via the attenuation of endothelial dysfunction in diabetic ApoE KO mice.

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PMID: 

Mol Med Rep. 2016 Nov ;14(5):4489-4495. Epub 2016 Oct 4. PMID: 27748864

Abstract Title: 

Betulinic acid and the pharmacological effects of tumor suppression (Review).

Abstract: 

Betulinic acid (BA), a lupane-type pentacyclic triterpenoid saponin from tree bark, has the potential to induce the apoptosis of cancer cells without toxicity towards normal cells in vitro and in vivo. The antitumor pharmacological effects of BA consist of triggering apoptosis via the mitochondrial pathway, regulating the cell cycle and the angiogenic pathway via factors, including specificity protein transcription factors, cyclin D1 and epidermal growth factor receptor, inhibiting the signal transducer and activator of transcription 3 and nuclear factor‑κB signaling pathways, preventing the invasion and metastasis of tumor cells, and affecting the expression of topoisomerase I, p53 and lamin B1. In previous years, several studies have shown its antitumor effect,initially applied to malignant melanoma, however, it also has broad efficacies against most solid types of tumor from different regions of the body. There have been few investigations in hematological malignancies, however, this direction may offer potential in such a novel field of research. In this review, the primary pharmacological effects of BA in tumors, particularly in hematological malignancies are discussed.

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PMID: 

Sci Rep. 2019 Dec 2 ;9(1):18029. Epub 2019 Dec 2. PMID: 31792261

Abstract Title: 

Genetic and epigenetic alterations induced by bisphenol A exposure during different periods of spermatogenesis: from spermatozoa to the progeny.

Abstract: 

Exposure to bisphenol A (BPA) has been related to male reproductive disorders. Since this endocrine disruptor also displays genotoxic and epigenotoxic effects, it likely alters the spermatogenesis, a process in which both hormones and chromatin remodeling play crucial roles. The hypothesis of this work is that BPA impairs early embryo development by modifying the spermatic genetic and epigenetic information. Zebrafish males were exposed to 100 and 2000μg/L BPA during early spermatogenesis and during the whole process. Genotoxic and epigenotoxic effects on spermatozoa (comet assay and immunocytochemistry) as well as progeny development (mortality, DNA repairing activity, apoptosis and epigenetic profile) were evaluated. Exposure to 100 µg/L BPA during mitosis slightly increased sperm chromatin fragmentation, enhancing DNA repairing activity in embryos. The rest of treatments promoted high levels of sperm DNA damage, triggering apoptosis in early embryo and severely impairing survival. Regarding epigenetics, histone acetylation (H3K9Ac and H3K27Ac) was similarly enhanced in spermatozoa and embryos from males exposed to all the treatments. Therefore, BPA male exposure jeopardizes embryonic survival and development due to the transmission of a paternal damaged genome and of a hyper-acetylated histone profile, both alterations depending on the dose of the toxicant and the temporal window of exposure.

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PMID: 

Toxicol Rep. 2019 ;6:1253-1262. Epub 2019 Nov 17. PMID: 31788436

Abstract Title: 

Oral exposure to low dose bisphenol A aggravates allergic airway inflammation in mice.

Abstract: 

Bisphenol A (BPA) is widely used in many consumer products and has adverse effects on human health including allergic diseases. We investigated the effects of low dose BPA, comparable to actual human oral exposure, on allergic asthma in mice. C3H/HeJ male mice were fed a chow diet containing BPA (equivalent to 0.09, 0.90, or 9.01 μg/kg/day) and were intratracheally administered ovalbumin (OVA, 1 μg/animal) every two weeks from 5-11 weeks of age. All doses of BPA plus OVA enhanced pulmonary inflammation and airway hyperresponsiveness, and increased lung mRNA levels of Th2 cytokine/chemokine, and serum OVA-specific IgEand IgGcompared to OVA alone, with greater effects observed in the middle- and high-dose BPA plus OVA groups. Furthermore, high-dose BPA with OVA decreased lung mRNA levels of ERβ and AR compared with OVA. Furthermore, BPA enhanced OVA-restimulated cell proliferation and protein levels of IL-4 and IL-5 in mediastinal lymph node (MLN) cells in OVA-sensitized mice. In bone marrow (BM) cells, middle-dose BPA with OVA increased Gr-1 expression. In conclusion, oral exposure tolow-dose BPA at levels equivalent to human exposure can aggravate allergic asthmatic responses through enhancement of Th2-skewed responses, lung hormone receptor downregulation, and MLN and BM microenvironment change.

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PMID: 

Andrologia. 2019 Dec 3:e13492. Epub 2019 Dec 3. PMID: 31793690

Abstract Title: 

Studies on the phytomodulatory potential of fenugreek (Trigonella foenum-graecum) on bisphenol-A induced testicular damage in mice.

Abstract: 

Bisphenol A (BPA), an organic synthetic compound and endocrine disruptor, which majorly cause deleterious effects on male reproductory system. Fenugreek (Trigonella foenum-graecum), associated with Leguminosae family is used as a herbal medicine with potent antioxidant properties. The present study was aimed to scrutinise the preventative role of fenugreek seeds aqueous extract (FSEt) on BPA-induced testicular damage in mice. Study included four different groups of male Balb/c mice: contol (C), fenugreek (FSEt), bisphenol A (BPA) and fenugreek + bisphenol A (FSEt + BPA). After two months of treatment, assessment of sperm parameters, antioxidant defence system, histopathological studies, germ cell count and gene expression of intrinsic apoptotic pathway were carried out. Administration of FSEt improved the damage caused by BPA as indicated by improved sperm parameters. FSEt-administered mice showed improvement in the histoarchitecture compared with BPA-administered animals. In addition, fenugreek treatment showed reduced levels of malondialdehyde and elevated levels of antioxidant enzymes. Expression studies of apoptotic markersrevealed a significant decrease in the expression of Bcl-2 and significant increase in caspase-9 and caspase-3. However, FSEt restored the deleterious effects caused by BPA. The current findings plausibly might have promising protective role against BPA-induced testicular damage.

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PMID: 

Avicenna J Phytomed. 2019 Nov-Dec;9(6):574-586. PMID: 31763216

Abstract Title: 

Cytotoxic activity of caffeic acid and gallic acid against MCF-7 human breast cancer cells: Anandstudy.

Abstract: 

Objective: Phenolic compounds have been considered inhibitors of various cancers.Material and Methods: In this study, caffeic acid and gallic acid were appraised for their possible effects on apoptotic genes expression in a breast cancer cell line. We also evaluated ligand interaction and ligand binding with estrogen receptor alpha by molecular docking. To determine half maximal inhibitory concentration, MCF-7 cells were treated with different concentrations of caffeic acid and gallic acid by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. Furthermore, morphological changes in cells and alterations in,andgene expression were studied by real-time RT-PCR. Also, protein network and different interactions between the desired genes were analyzed using GeneMANIA database.Results: Evaluation of cell survival by MTT assay revealed that the half-maximal inhibitory concentration values for caffeic acid and gallic acid against MCF-7 cells, were 159 and 18µg/ml, respectively. These compounds were found to affect,andgene expression; this alteration in gene expression probably occurred along with the activation of intrinsic apoptotic signaling pathway.Conclusion: Via apoptosis induction, caffeic acid and gallic acid have induce toxic effects and morphological changes in breast cancer cells, suggesting their possible future application as antitumor agents.

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PMID: 

Sports Med. 2019 Oct 23. Epub 2019 Oct 23. PMID: 31643020

Abstract Title: 

Acute Effects of Caffeine Supplementation on Movement Velocity in Resistance Exercise: A Systematic Review and Meta-analysis.

Abstract: 

BACKGROUND: Several studies investigated the effects of caffeine supplementation on movement velocity in resistance exercise. However, these studies presented inconsistent findings.OBJECTIVE: This paper aimed to: (a) review the studies that explored the effects of caffeine supplementation on movement velocity in resistance exercise; and (b) pool their results using a meta-analysis.METHODS: A search for studies was performed through seven databases. Random-effects meta-analyses of standardized mean differences (SMD) were performed to analyze the data. Sub-group meta-analyses explored the effects of caffeine on different velocity variables (i.e., mean and peak velocity), different loads (i.e., low, moderate, and high loads), and upper- and lower-body exercises.RESULTS: Twelve studies met the inclusion criteria. In the main meta-analysis, in which we pooled all available studies, the SMD favored the caffeine condition (SMD = 0.62; 95% confidence interval [CI]: 0.39-0.84; p 

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PMID: 

Med Oncol. 2019 Oct 29 ;36(12):97. Epub 2019 Oct 29. PMID: 31664534

Abstract Title: 

Caffeine enhances the anti-tumor effect of 5-fluorouracil via increasing the production of reactive oxygen species in hepatocellular carcinoma.

Abstract: 

The development of drug resistance affecting the prognosis of patients with hepatocellular carcinoma (HCC) leads to low survival rate of HCC patients. Caffeine is reported to have a function of protecting the liver and anti-tumor activity. Therefore, caffeine may be an ideal enhancer for HCC chemotherapy regimens. Our study showed that the combination of caffeine and 5-FU significantly inhibited the proliferation of HCC cells in vivo and in vitro comparing with caffeine or 5-FU monotherapy. The CI values of caffeine (0.5 mM) combined with 5-FU (25, 50 μM) were all less than 1, confirming that the utilization of drug combination has a synergistic inhibitory effect on the proliferation of HCC cells. Meanwhile, results of Western blot and TUNEL assays demonstrated that the apoptotic level of HCC cells in the combined group was significantly increased. The protein expression level of cleaved PARP was up-regulated, while the protein level of Bcl-2 and Bcl-xL was down-regulated. In addition, we found that ROS levels were increased in the 1 mM caffeine and 25 μM 5-FU combination group comparing with the control or single drug group. Taken together, this is the first study to demonstrate that the combination of caffeine and 5-FU inhibits HCC cells proliferation and promotes cellular apoptosis by regulating intracellular ROS production. The present data provides a basis for the application of caffeine combined with 5-FU as a novel chemotherapy regimen for HCC.

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PMID: 

Eur J Dermatol. 2004 Mar-Apr;14(2):86-90. PMID: 15196997

Abstract Title: 

Autoimmune diseases and vaccinations.

Abstract: 

The potential association between vaccination and autoimmune diseases has been largely questioned in the past few years, but this assumption has mostly been based on case reports. The available evidence derived from several negative epidemiological studies is reassuring and at least indicates that vaccines are not a major cause of autoimmune diseases. However, there are still uncertainties as to whether a susceptible subpopulation may be at a higher risk of developing an autoimmune disease without causing an overall increase in the disease incidence. Based on selected examples, this review highlights the difficulties in assessing this issue. We suggest that a potential link between vaccines and autoimmune diseases cannot be definitely ruled out and should be carefully explored during the development of new candidate vaccines.

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