PMID: 

Biomed Pharmacother. 2019 Jul 29 ;118:109263. Epub 2019 Jul 29. PMID: 31369988

Abstract Title: 

Roman chamomile inhalation combined with clomipramine treatment improves treatment-resistant depression-like behavior in mice.

Abstract: 

It is well known that chamomile is one of the oldest known medicinal herbs and has been used to treat various disorders, but it is mainly German chamomile. The effects of Roman chamomile on depression still unclear. In this study, we used chronically stressed mice to investigate whether inhalation of Roman chamomile essential oil affects depression-like behavior. We previously reported that restraint and water immersion stress produce depression-like behavior and a blunted response to the tricyclic antidepressant clomipramine. Each mouse was exposed to restraint and water immersion stress for 15 days, and resistance to the effect of clomipramine was induced in a behavioral despair paradigm. In the present study, we found that cotreatment with clomipramine and inhalation of Roman chamomile attenuated depression-like behavior in a forced swim test. Next, we examined the hippocampal mRNA levels of two cytokines, tumor necrosis factor (TNF) alpha and interleukin-6 (IL-6); a neurotrophic factor, brain derived-neurotrophic factor (BDNF); and nerve growth factor (NGF). TNF alpha, IL-6 and BDNF mRNA levels did not change in the hippocampus of stressed mice. However, the NGF mRNA level was significantly decreased, and this decrease was not attenuated by treatment with clomipramine or inhalation of Roman chamomile alone. We also examined whether Roman chamomile combined with clomipramine treatment affects hippocampal neurogenesis and serum corticosterone levels. Stressed mice had fewer doublecortin (DCX)-positive cells in the subgranular zone of the dentate gyrus, but this was significantly attenuated by Roman chamomile and clomipramine treatment. In addition, the serum corticosterone level was also significantly decreased by treatment with Roman chamomile and clomipramine. These results suggest that Roman chamomile inhalation may enhance the antidepressant effect of clomipramine by increasing hippocampal neurogenesis and modulating corticosterone levels in patients with treatment-resistant depression.

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PMID: 

Toxicol Sci. 2006 Jul ;92(1):246-53. Epub 2006 Apr 19. PMID: 16624850

Abstract Title: 

Thimerosal induces apoptosis in a neuroblastoma model via the cJun N-terminal kinase pathway.

Abstract: 

The cJun N-terminal kinase (JNK)-signaling pathway is activated in response to a variety of stimuli, including environmental insults, and has been implicated in neuronal apoptosis. In this study, we investigated the role that the JNK pathway plays in neurotoxicity caused by thimerosal, an ethylmercury-containing preservative. SK-N-SH cells treated with thimerosal (0-10 microM) showed an increase in the phosphorylated (active) form of JNK and cJun with 5 and 10 microM thimerosal treatment at 2 and 4 h. To examine activator protein-1 (AP-1) transcription, cells were transfected with a pGL2 vector containing four AP-1 consensus sequences and then treated with thimerosal (0-2.5 microM) for 24 h. Luciferase studies showed an increase in AP-1 transcriptional activity upon thimerosal administration. To determine the components of the AP-1 complex, cells were transfected with a dominant negative to either cFos (A-Fos) or cJun (TAM67). Reporter analysis showed that TAM67, but not A-Fos, decreased AP-1 transcriptional activity, indicating a role for cJun in this pathway. To assess which components are essential to apoptosis, cells were treated with a cell-permeable JNK inhibitor II (SP600125) or transfected with TAM67, and the downstream effectors of apoptosis were analyzed. Cells pretreated with SP600125 showed decreases in activation of caspases 9 and 3, decreases in degradation of poly(ADP-ribose) polymerase (PARP), and decreased levels of proapoptotic Bim, in comparison to cells treated with thimerosal alone. However, cells transfected with TAM67 showed no changes in those same components. Taken together, these results indicate that thimerosal-induced neurotoxicity occurs through the JNK-signaling pathway, independent of cJun activation, leading ultimately to apoptotic cell death.

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PMID: 

Toxicol Appl Pharmacol. 2006 Jul 1 ;214(1):43-54. Epub 2006 Jan 27. PMID: 16443248

Abstract Title: 

Alteration of the spontaneous systemic autoimmune disease in (NZB x NZW)F1 mice by treatment with thimerosal (ethyl mercury).

Abstract: 

Inorganic mercury may aggravate murine systemic autoimmune diseases which are either spontaneous (genetically determined) or induced by non-genetic mechanisms. Organic mercury species, the dominating form of mercury exposure in the human population, have not been examined in this respect. Therefore, ethyl mercury in the form of thimerosal, a preservative recently debated as a possible health hazard when present in vaccines, was administered in a dose of 0.156-5 mg/L drinking water to female (NZB x NZW)F1 (ZBWF1) mice. These mice develop an age-dependent spontaneous systemic autoimmune disease with high mortality primarily due to immune-complex (IC) glomerulonephritis. Five mg thimerosal/L drinking water (295 microg Hg/kg body weight (bw)/day) for 7 weeks induced glomerular, mesangial and systemic vessel wall IC deposits and antinuclear antibodies (ANA) which were not present in the untreated controls. After 22-25 weeks, the higher doses of thimerosal had shifted the localization of the spontaneously developing renal glomerular IC deposits from the capillary wall position seen in controls to the mesangium. The altered localization was associated with less severe histological kidney damage, less proteinuria, and reduced mortality. The effect was dose-dependent, lower doses having no effect compared with the untreated controls. A different effect of thimerosal treatment was induction of renal and splenic vessel walls IC deposits. Renal vessel wall deposits occurred at a dose of 0.313-5 mg thimerosal/L (18-295 microg Hg/kg bw/day), while splenic vessel wall deposits developed also in mice given the lowest dose of thimerosal, 0.156 mg/L (9 microg Hg/kg bw/day). The latter dose is 3- and 15-fold lower than the dose of Hg required to induce vessel wall IC deposits in genetically susceptible H-2s mice by HgCl2 and thimerosal, respectively. Further studies on the exact conditions needed for induction of systemic IC deposits by low-dose organic mercurials in autoimmune-prone individuals, as well as the potential effect of these deposits on the vessel walls, are warranted.

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PMID: 

Drug Chem Toxicol. 2018 Jul ;41(3):294-301. Epub 2018 Mar 26. PMID: 29578368

Abstract Title: 

Protective effects of banana pectin against aluminum-induced cognitive impairment and aluminum accumulation in mice.

Abstract: 

To investigate the effect of pectin on absorption and bio-toxicity of aluminum, pectin extract (100 mg kg d) from banana pulp was orally administrated to aluminum exposed mice (35 mg kg d) for 6 weeks. Our result showed that body weight gain of the mice treated with aluminum plus banana pectin was 32.5% higher than that of mice exposed to aluminum alone after 6 weeks of the administration. In both the step-down inhibitory avoidance task and Morris water maze test, memory retention of aluminum-exposed mice was significantly improved by the pectin administration. Treatment with banana pectin effectively prevented absorption of aluminum from the gastrointestinal tract, total aluminum excretion of mice treated with banana pectin plus aluminum was 9.3% higher than that of mice exposedto aluminum alone on the 12th day. Aluminum level in serum, cerebrum, or cerebellum of mice treated with aluminum plus banana pectin was 30.8%, 17.5%, or 17.9% lower than that of mice exposed to aluminum alone on the 42nd day, respectively. In conclusion, banana pectin extract can effectively reduce aluminum toxicity in mice.

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PMID: 

In Vivo. 2018 Nov-Dec;32(6):1373-1379. PMID: 30348691

Abstract Title: 

Banana Flower Extract Suppresses Benign Prostatic Hyperplasia by Regulating the Inflammatory Response and Inducing GCell-cycle Arrest.

Abstract: 

BACKGROUND/AIM: The banana flower is used for ameliorating urinary disturbance. However, there is limited evidence to support the efficacy or mechanism of action of banana flower against benign prostatic hyperplasia (BPH). In the present study, the anti-BPH activity and mechanisms of banana flower extracts were investigated in vitro and in vivo.MATERIALS AND METHODS: The banana flower extract is a water-soluble extract obtained by sonication. MTT assay was used to examine whether banana flower extract exhibited cytotoxic effects on BPH-1 cells. The effect of banana flower extract on cell-cycle distribution was examined by flow cytometry. The expression of cell-cycle-regulatory molecules was determined by western blot analysis. Testosterone propionate (TP)-induced rat model of BPH was used to evaluate the anti-BPH activity of banana flower extract in vivo.RESULTS: Banana flower extract reduced epithelial cell line BPH-1 cell viability through cell-cycle arrest at Gphase. Moreover, banana flower extract reduced the expression of cyclin D1 and cyclin-dependent kinase 6, while it increased the expression of p53 and p27. Interestingly, banana flower extract suppressed BPH-related inflammatory responses through suppressing cyclo-oxygenase-2 expression and prostaglandin E2 production. Finally, banana flower extract administered orally to male rats reduced prostatic weight and serum dihydrotestosterone level, and improved prostate gland morphology. High-performance liquid chromatography revealed that banana flower extract contains citric acid, taurine, pantothenic acid and nicotinic acid components. In summary, banana flower extract may be used as a therapeutic agent for BPH via anti-proliferative and anti-inflammatory activities.

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The present-day definitions of Osteopenia and Osteoporosis were arbitrarily conceived by the World Health Organization (WHO) in the early 90’s and then projected upon millions of women’s bodies seemingly in order to convince them they had a drug-treatable, though symptomless, disease.

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PMID: 

Mutat Res. 2019 Jul – Sep;781:186-206. Epub 2019 Feb 10. PMID: 31342895

Abstract Title: 

Exposure to glyphosate-based herbicides and risk for non-Hodgkin lymphoma: A meta-analysis and supporting evidence.

Abstract: 

Glyphosate is the most widely used broad-spectrum systemic herbicide in the world. Recent evaluations of the carcinogenic potential of glyphosate-based herbicides (GBHs) by various regional, national, and international agencies have engendered controversy. We investigated whether there was an association between high cumulative exposures to GBHs and increased risk of non-Hodgkin lymphoma (NHL) in humans. We conducted a new meta-analysis that includes the most recent update of the Agricultural Health Study (AHS) cohort published in 2018 along with five case-control studies. Using the highest exposure groups when available in each study, we report the overall meta-relative risk (meta-RR) of NHL in GBH-exposed individuals was increased by 41% (meta-RR = 1.41, 95% confidence interval, CI: 1.13-1.75). For comparison, we also performed a secondary meta-analysis using high-exposure groups with the earlier AHS (2005), and we calculated a meta-RR for NHL of 1.45 (95% CI: 1.11-1.91), which was higher than the meta-RRs reported previously. Multiplesensitivity tests conducted to assess the validity of our findings did not reveal meaningful differences from our primary estimated meta-RR. To contextualize our findings of an increased NHL risk in individuals with high GBH exposure, we reviewed publicly available animal and mechanistic studies related to lymphoma. We documented further support from studies of malignant lymphoma incidence in mice treated with pure glyphosate, as well as potential links between glyphosate / GBH exposure and immunosuppression, endocrine disruption, and genetic alterations that are commonly associated with NHL or lymphomagenesis. Overall, in accordance with findings from experimental animal and mechanistic studies, our current meta-analysis of human epidemiological studies suggests a compelling link between exposures to GBHs and increased risk for NHL.

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PMID: 

Environ Pollut. 2019 Jul 20 ;254(Pt A):112906. Epub 2019 Jul 20. PMID: 31374489

Abstract Title: 

Effects of chronic glyphosate exposure to pregnant mice on hepatic lipid metabolism in offspring.

Abstract: 

Glyphosate is the active ingredient in Roundup, one of the most popular herbicides in the world, and its toxicity has caused increasing concerns. The present study aims to investigate the toxic effects of prenatal exposure to pure glyphosate or Roundup on lipid metabolism in offspring. During gestational days (GDs), ICR mice (from Institute of Cancer Research) were given distilled water, 0.5% glyphosate solution (w/v, 0.5 g/100 ml) or 0.5%-glyphosate Roundup solution orally. The livers and serum samples of the offspring were collected on gestational day 19 (GD19), postnatal day 7 (PND7) and PND21. The results showed a significant decrease in the body weight and obvious hepatic steatosis with excessive lipid droplet formation in offspring. Moreover, the concentrations of lipids such as triglycerides (TGs), total cholesterol (T-CHO), and low-density lipoprotein cholesterols (LDL-C) increased to a significant extent in both the serum and livers. Furthermore, there were significant differences in the expression levels of the genes SREBP1C, SREBP2, Fasn, Hmgcr, Hmgcs and PPARα, which are related to lipid biosynthesis or catabolism in the liver. These results demonstrate that chronic prenatal exposure to glyphosate can result in lipid metabolism disruption in the offspring of mice, as glyphosate exerts anegative influence on the expression of lipogenesis genes.

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PMID: 

Dose Response. 2019 Apr-Jun;17(2):1559325819843380. Epub 2019 May 23. PMID: 31205454

Abstract Title: 

Inflammatory Effects of Subacute Exposure of Roundup in Rat Liver and Adipose Tissue.

Abstract: 

Roundup is a popular herbicide containing glyphosate as an active ingredient. The formulation of Roundup is speculated to have critical toxic effects, one among which is chronic inflammation. The present study analyzed adverse inflammatory effects in the liver and adipose tissue of rats after a subacute exposure of Roundup. Adult male rats were exposed to various doses of Roundup (0, 5, 10, 25, 50, 100 and 250 mg/kg bodyweight [bw] glyphosate) orally, everyday for 14 days. On day 15, liver and adipose tissues from dosed rats were analyzed for inflammation markers. C-reactive protein in liver, cytokines IL-1β, TNF-α, IL-6, and inflammatory response marker, and prostaglandin-endoperoxide synthase were upregulated in liver and adipose of rats exposed to higher (100 and 250 mg/kg bw/d) doses of Roundup. Cumulatively, our data suggest development of inflammation in lipid and hepatic organs upon exposureto Roundup. Furthermore, liver histological studies showed formation of vacuoles, fibroid tissue, and glycogen depletion in the groups treated with doses of higher Roundup. These observations suggest progression of fatty liver disease in Roundup-treated adult rats. In summary, our data suggest progression of multiorgan inflammation, liver scarring, and dysfunction post short-term exposure of Roundup in adult male rats.

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PMID: 

J Hematol Oncol. 2019 Jul 5 ;12(1):70. Epub 2019 Jul 5. PMID: 31277689

Abstract Title: 

Glyphosate induces benign monoclonal gammopathy and promotes multiple myeloma progression in mice.

Abstract: 

BACKGROUND: Glyphosate is the most widely used herbicide in the USA and worldwide. There has been considerable debate about its carcinogenicity. Epidemiological studies suggest that multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) have a positive and statistically significant association with glyphosate exposure. As a B cell genome mutator, activation-induced cytidine deaminase (AID) is a key pathogenic player in both MM and B cell NHL.METHODS: Vk*MYC is a mouse line with sporadic MYC activation in germinal center B cells and considered as the best available MM animal model. We treated Vk*MYC mice and wild-type mice with drinking water containing 1000 mg/L of glyphosate and examined animals after 72 weeks.RESULTS: Vk*MYC mice under glyphosate exposure developed progressive hematological abnormalities and plasma cell neoplasms such as splenomegaly, anemia, and high serum IgG. Moreover, glyphosate caused multiple organ dysfunction, including lytic bone lesions and renal damage in Vk*MYC mice. Glyphosate-treated wild-type mice developed benign monoclonal gammopathy with increased serum IgG, anemia, and plasma cell presence in the spleen and bone marrow. Finally, glyphosate upregulated AID in the spleen and bone marrow of both wild-type and Vk*MYC mice.CONCLUSIONS: These data support glyphosate as an environmental risk factor for MM and potentially NHL and implicate a mechanism underlying the B cell-specificity of glyphosate-induced carcinogenesis observed epidemiologically.

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