PMID: 

Biomed Pharmacother. 2019 Nov 7 ;121:109602. Epub 2019 Nov 7. PMID: 31707349

Abstract Title: 

Chlorogenic acid inhibits esophageal squamous cell carcinoma growth in vitro and in vivo by downregulating the expression of BMI1 and SOX2.

Abstract: 

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in China, accompanied by an extremely high mortality rate. Chlorogenic acid (CGA) is a small-molecule compound, that has been shown to have a wide range of biological activities, including antitumor. However, the efficacy and molecular mechanism of CGA on ESCC remains unknown. In this study, we confirmed the inhibition of proliferation by CGA in ESCC cells, as well as the reduction of ESCC xenograft volume by CGA in vivo. In addition, CGA also suppressed both the migration and invasion of ESCC cells in vitro. In a carcinogen-induced murine model of ESCC, hyperplasia of the esophagus was slowed by CGA, while mice suffering from ESCC that were treated with CGA had longer survival times than mice in the control group. The measurement of pluripotency factors (BMI1, SOX2, OCT4 and Nanog) that are related to poor prognosis revealed reduced expression of both BMI1 and SOX2, but not of OCT4 or Nanog, in ESCC cells, in both a dose- and time-dependent manner. Together, our initial findings demonstrate that CGA suppresses ESCC progression, downregulates the expression of BMI1 and SOX2, and provide an anti-tumor candidate for ESCC therapy.

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PMID: 

Przegl Lek. 2000 ;57(11):665-8. PMID: 11293216

Abstract Title: 

[Aluminum–occurrence and toxicity for organisms].

Abstract: 

Aluminium (Al.) is an ubiquitous element found in every food product. The sources of Al. are especially corn, yellow cheese, salt, herbs, spices, tea and tap water. In household Al.-made ware is a major source of the element. Al. may cause diseases in humans, especially hampers many metabolic processes especially turnover of calcium, phosphorus and iron. Salts of Al. may bind to DNA, RNA, inhibit such enzymes as hexokinase, acid and alkaline phosphatases, phosphodiesterase and phosphooxydase. Al. salts are especially harmful to nervous, hematopoietic systems and to skeleton. Al. gets to organism with food, water, cosmetics, from aluminium ware and containers. Toxicity comes from substitution of Mg and Fe ions effecting in disturbances in intracellular signaling, excretory functions and cellular growth. Neurotoxic action of Al. probably comes from substitution of Mg ions in ATP, what finally influences function of every ATP using-enzymes. There are observations in experimental models proving Al. salts are responsible for Alzheimer disease development. Toxicity of Al. to skeletal system results in diminished resistance thus tendencies to breaking, and comes from lower collagen synthesis and slowing down of mineralisation. Low erythropoietin production, inhibition of hem-synthesing enzymes and binding of Al. to transferrin, effects in anaemia. Carcinogenic effects of Al. were nor proved nor denied, but high concentrations of Al. were found in many neoplastic cells. In conclusion, we should introduce prophylactic measures effecting in less Al. intake esp. avoiding use of Al.-made ware nad controlling food for Al. content.

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PMID: 

J Alzheimers Dis. 2014 ;40(4):765-838. PMID: 24577474

Abstract Title: 

Chronic aluminum intake causes Alzheimer's disease: applying Sir Austin Bradford Hill's causality criteria.

Abstract: 

Industrialized societies produce many convenience foods with aluminum additives that enhance various food properties and use alum (aluminum sulfate or aluminum potassium sulfate) in water treatment to enable delivery of large volumes of drinking water to millions of urban consumers. The present causality analysis evaluates the extent to which the routine, life-long intake, and metabolism of aluminum compounds can account for Alzheimer's disease (AD), using Austin Bradford Hill's nine epidemiological and experimental causality criteria, including strength of the relationship, consistency, specificity, temporality, dose-dependent response, biological rationale, coherence with existing knowledge, experimental evidence, and analogy. Mechanisms that underlie the risk of low concentrations of aluminum relate to (1) aluminum's absorption rates, allowing the impression that aluminum is safe to ingest and as an additive in food and drinking water treatment, (2) aluminum's slow progressive uptake into the brain over a long prodromal phase, and (3) aluminum's similarity to iron, in terms of ionic size, allows aluminum to use iron-evolved mechanisms to enter the highly-active, iron-dependent cells responsible for memory processing. Aluminum particularly accumulates in these iron-dependent cells to toxic levels, dysregulating iron homeostasis and causing microtubule depletion, eventually producing changes that result in disconnection of neuronal afferents and efferents, loss of function and regional atrophy consistent with MRI findings in AD brains. AD is a human form of chronic aluminum neurotoxicity. The causality analysis demonstrates that chronic aluminum intake causes AD.

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PMID: 

Neurosci Lett. 2016 Jan 1 ;610:200-6. Epub 2015 Nov 27. PMID: 26592479

Abstract Title: 

Chronic exposure to aluminum and risk of Alzheimer's disease: A meta-analysis.

Abstract: 

A meta-analysis was performed to investigate whether chronic exposure to aluminum (Al) is associated with increased risk of Alzheimer's disease (AD). Eight cohort and case-control studies (with a total of 10567 individuals) that met inclusion criteria for the meta-analysis were selected after a thorough literature review of PubMed, Web of Knowledge, Elsevier ScienceDirect and Springer databases up to June, 2015. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of included studies. Q test and I(2) statistic were used to examine heterogeneity between selected studies. The overall odds ratio (OR) was calculated using a fixed-effect model because no significant heterogeneity between studies was found. No publication bias was observed based on a funnel plot and Egger's test. Results showed that individuals chronically exposed to Al were 71% more likely to develop AD (OR: 1.71, 95% confidence interval (CI), 1.35-2.18). The finding suggests that chronic Al exposure is associated with increased risk of AD.

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PMID: 

Environ Health Perspect. 1986 Mar ;65:363-441. PMID: 2940082

Abstract Title: 

Metabolism and possible health effects of aluminum.

Abstract: 

Literature regarding the biochemistry of aluminum and eight similar ions is reviewed. Close and hitherto unknown similarities were found. A hypothetical model is presented for the metabolism, based on documented direct observations of Al3+ and analogies from other ions. Main characteristics are low intestinal absorption, rapid urinary excretion, and slow tissue uptake, mostly in skeleton and reticuloendothelial cells. Intracellular Al3+ is probably first confined in the lysosomes but then slowly accumulates in the cell nucleus and chromatin. Large, long-lived cells, e.g., neurons, may be the most liable to this accumulation. In heterochromatin, Al3+ levels can be found comparable to those used in leather tannage. It is proposed that an accumulation may take place at a subcellular level without any significant increase in the corresponding tissue concentration. The possible effects of this accumulation are discussed. As Al3+ is neurotoxic, the brain metabolism is most interesting. The normal and the lethally toxic brain levels of Al3+ are well documented and differ only by a factor of 3-10. The normal brain uptake of Al3+ is estimated from data on intestinal uptake of Al3+ and brain uptake of radionuclides of similar ions administered intravenously. The uptake is very slow, 1 mg in 36 years, and is consistent with an assumption that Al3+ taken up by the brain cannot be eliminated and is therefore accumulated. The possibility that Al3+ may cause or contribute to some specific diseases, most of them related to aging, is discussed with the proposed metabolic picture in mind.

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PMID: 

Insects. 2019 Apr 20 ;10(4). Epub 2019 Apr 20. PMID: 31010046

Abstract Title: 

Sensory Quality of Essential Oils and Their Synergistic Effect with Diatomaceous Earth, for the Control of Stored Grain Insects.

Abstract: 

Essential oils (EOs) have gained increasing interest as a low-toxic, eco-friendly alternative to synthetic repellents and insecticides against insect pests. However, they have scarce practical application in the protection of stored grain because of their limited efficacy and their interference with the organoleptic properties of the grain. In this study, we evaluated the olfactory profile of the EOs of,, andand their toxicity against the main stored grain pest. Trained assessors identifiedand, as more suitable than theEO for the wheat treatment. In laboratory tests, the most toxic EO was the(LC= 36.36μL∙kg) while, the least toxic, was theone (LC= 77.59μL∙kg). The EOs were also tested combined with diatomaceous earths (DEs) showing synergistic effects (co-toxicity coefficient values ranging from 1.36 to 3.35 forandEOs, respectively). Overall,resulted as the best EO for the wheat treatment, considering its insect toxicity and olfactory profile. In real storage conditions, the wheat co-treated withEO and DEs showed a significantly lower mean infestation (1.5 insect kg) than the non-treated wheat (7.0 insect kg).

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PMID: 

J Med Chem. 2018 12 27 ;61(24):11144-11157. Epub 2018 Dec 7. PMID: 30525586

Abstract Title: 

Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus.

Abstract: 

Celastrol is a natural pentacyclic triterpene used in traditional Chinese medicine with significant weight-lowering effects. Celastrol-administered mice at 100μg/kg decrease food consumption and body weight via a leptin-dependent mechanism, yet its molecular targets in this pathway remain elusive. Here, we demonstrate in vivo that celastrol-induced weight loss is largely mediated by the inhibition of leptin negative regulators protein tyrosine phosphatase (PTP) 1B (PTP1B) and T-cell PTP (TCPTP) in the arcuate nucleus (ARC) of the hypothalamus. We show in vitro that celastrol binds reversibly and inhibits noncompetitively PTP1B and TCPTP. NMR data map the binding site to an allosteric site in the catalytic domain that is in proximity of the active site. By using a panel of PTPs implicated in hypothalamic leptin signaling, we show that celastrol additionally inhibited PTEN and SHP2 but had no activity toward other phosphatases of the PTP family. These results suggest that PTP1B and TCPTP in the ARC are essential for celastrol's weight loweringeffects in adult obese mice.

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PMID: 

Int Immunopharmacol. 2019 Jan ;66:215-223. Epub 2018 Nov 22. PMID: 30472522

Abstract Title: 

Celastrol inhibits microglial pyroptosis and attenuates inflammatory reaction in acute spinal cord injury rats.

Abstract: 

Pyroptosis pathway is closely related to inflammation. However, Celastrol effect on pyroptosis pathway after spinal cord injury (SCI) are poorly understood. We studied the anti-inflammatory and neuroprotective effects of Celastrol on acute spinal cord injury in rats, and its anti-inflammatory effects on lipopolysaccharide (LPS)/ATP-induced microgliosis. Our results show that Celastrol can improve the recovery of hindlimb motor function after SCI in Sprague-Dawley (SD) rats, and reduce the cavity area of spinal cord injury along with the neuronal loss. Celastrol simultaneously reduced the activation of microglia (especially M1 microglia) in the spinal cord, inhibited the pyroptosis-related proteins (NLRP3 ASC Caspase-1 GSDMD), reduced the release of TNF-α IL-1β and IL-18 inflammatory factors, and increased the release of IL10 cytokines. In vitro studies showed that Celastrol reduced the toxicity resulting from the administration of LPS with ATP to BV-2 cells, inhibited the pyroptosis-related proteins (NLRP3 Caspase-1 GSDMD), and inhibited the release of corresponding inflammatory factors. Finally, Celastrol can inhibit the expression of NFκB/p-p65 in vitro and in vivo. Our results show that Celastrol can attenuate the inflammatory response of the spinal cord after SCI, which is associated with inhibition of microglial activation and pyroptosis pathway. Further study to explore the use of Celastrol to treat SCI is warranted.

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PMID: 

Front Pharmacol. 2018 ;9:1276. Epub 2018 Nov 15. PMID: 30498444

Abstract Title: 

Celastrol Alleviates Chronic Obstructive Pulmonary Disease by Inhibiting Cellular Inflammation Induced by Cigarette Smoke via the Ednrb/Kng1 Signaling Pathway.

Abstract: 

Chronic obstructive pulmonary disease (COPD) is a debilitating disease caused by chronic exposure to cigarette smoke (CS). Celastrol is a pentacyclic triterpenoid compound exhibits potent antioxidant and anti-inflammatory activities. Also it is presently known to protect against liver damage induced by type II diabetes. However, its role in COPD is unclear. In this study, we investigated the effects of Celastrol on cellular inflammation in mice exposed to CS and Beas-2B cells treated with CS extract (CSE). C57BL/6 mice and Beas-2B cells were randomly divided into three groups: control group, COPD or CSE group, and Celastrol treatment group. The COPD mice models were subjected to smoke exposure and cell models were treated with CSE. Bioinformatics analysis was performed to identify differentially expressed genes following treatment with Celastrol in COPD, the molecular networks was mapped by Cytoscape. The levels of inflammatory cytokinesinterleukin-8, tumor necrosis factorα, monocyte chemoattractant protein-1, and oxidative stress factors superoxide dismutase and catalase were measured by enzyme-linked immunosorbent assay. Hematoxylin and eosin staining to detect the injury of mouse lung tissue. mRNA and protein levels of Ednrb and Kng1 in the tissues and cells weremeasured by quantitative polymerase chain reaction (PCR) and western blotting, respectively. Apoptosis was measured by flow cytometry and TUNEL staining. Compared to mice in the COPD group, mice treated with Celastrol had significantly reduced levels of inflammatory cytokines interleukin-8, tumor necrosis factor α and monocyte chemoattractant protein-1 in the serum and bronchoalveolar lavage fluid, and significantly increased levels of oxidative stress factors superoxide dismutase and catalase. The same results were obtained at the cellular level using Beas-2B cells. Compared to the model groups, Celastrol reduced lung injury in mice and significantly reduced cellular apoptosis. Bioinformatics analysis showed that Ednrb is a target gene of Celastrol and differentially expressed in COPD. Quantitative PCR analysis showed that Ednrb expression in patients with COPD was significantly increased compared to that in healthy controls. Additionally, Celastrol effectively reduced Ednrb/Kng1 expression in both cell and animal models. Celastrol has a therapeutic effect on COPD and may alleviate COPD by inhibiting inflammation development by suppressing the Ednrb/Kng1 signaling pathway.

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PMID: 

Onco Targets Ther. 2018 ;11:8977-8985. Epub 2018 Dec 11. PMID: 30588010

Abstract Title: 

Celastrol induces ubiquitin-dependent degradation of mTOR in breast cancer cells.

Abstract: 

Background: Celastrol is a major active component of the thunder god vine () used in traditional Chinese medicine to treat chronic inflammatory and autoimmune diseases. Celastrol inhibits PI3K-Akt-mTOR signaling, which is frequently dysregulated in tumors and critical for tumor-cell proliferation and survival, but the underlying mechanisms are still not fully understood. In the present study, we investigated detailed mechanisms of celastrol inhibition of mTOR signaling in breast cancer cells.Methods: First, we evaluated the effect of celastrol on breast cancer-cell growth using MTT assays. Second, we examined the effects of celastrol on mTOR phosphorylation and expression using Western blot. Furthermore, we investigated the cause of mTOR downregulation by celastrol using immunoprecipitation assays. In addition, we evaluated the effect of celastrol on an MDA-MB231 cell-derived xenograft model.Results: Celastrol suppressed breast cancer cell growth in vitro and in vivo. Celastrol inhibited mTOR phosphorylation and induced mTOR ubiquitination, resulting in its proteasomal degradation. Mechanistically, we found that mTOR is a client of Hsp90-Cdc37 chaperone complex, and celastrol disrupts mTOR interaction with chaperone Hsp90 while promoting mTOR association with cochaperone Cdc37.Conclusion: Our study reveals that celastrol suppresses mTOR signaling, at least in part through regulating its association with chaperones and inducing its ubiquitination.

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