Lennart Mucke
Jun 1, 2000; 20:4050-4058
Cellular

Scientists discover neurotoxin-producing bacteria living on the skin of rough-skinned newts

Animal studies document dose-dependent and duration-of-therapy-dependent fluoroquinolone cartilage toxicity in weight-bearing joints. Preliminary pediatric data collected after fluoroquinolone treatment and up to 1 year posttreatment in blinded and unblinded studies suggest the possibility of cartilage toxicity in children.

These are the first prospectively collected data on fluoroquinolone musculoskeletal safety collected posttherapy from randomized, comparative studies of respiratory tract infections and analyzed at 5 years. Long-term musculoskeletal adverse events occurred with equal frequency in both levofloxacin and comparator groups. (Read the full article)

Tapentadol is used in the treatment of chronic pain, specifically diabetic neuropathy. It has known action on the μ-opioid receptor leading to drowsiness and apneas. There is no published information on the effects of tapentadol in small children.

After an accidental overdose in a child, tapentadol may be expected to cause μ-opioid clinical effects similar to other opioids. While the opioid effects predominate sympathomimetic effects are also seen. The risk of respiratory depression and dyspnea should be acknowledged. (Read the full article)

'New type of analysis' deployed to determine plastics' toxicity

Rapid innovation and decreasing production costs have dramatically increased our access to electronic products and digital technology and, together with humankind’s unquenchable demand for electronic devices, the unintended consequence of this...

The Environmental Audit Committee (“EAC”) has launched an inquiry to investigate the impact of toxic chemicals on everyday life (launched 12 February 2019). The inquiry will focus on the use of toxic chemicals in everyday products includ...

Indian officials evacuated more people on Friday from the area around a chemical plant in the south of the country that leaked toxic gas, killing at least 12 people and left about 1,000 struggling to breathe.There was confusion about whether the wider evacuation orders were sparked by a renewed leak at the LG Chem factory in Andhra Pradesh, or by the fear that rising temperatures at the plant could lead to another leak.“No, there was not another leakage,’’ National Disaster Response Force…

Villagers placed the bodies of three victims of a deadly gas leak from an LG Polymers plant in southern India at the gates of the site on Saturday, and demanded the factory be shut down immediately and its top management arrested.

Title: Lipsticks, Glosses Contain Toxic Metals: Report
Category: Health News
Created: 5/2/2013 10:35:00 AM
Last Editorial Review: 5/2/2013 12:00:00 AM

There is a need to develop novel approaches to improve the balance between efficacy and toxicity for transcription factor–targeted therapies. In this study, we exploit context-dependent differences in RNA polymerase II processivity as an approach to improve the activity and limit the toxicity of the EWS-FLI1–targeted small molecule, mithramycin, for Ewing sarcoma. The clinical activity of mithramycin for Ewing sarcoma is limited by off-target liver toxicity that restricts the serum concentration to levels insufficient to inhibit EWS-FLI1. In this study, we perform an siRNA screen of the druggable genome followed by a matrix drug screen to identify mithramycin potentiators and a synergistic "class" effect with cyclin-dependent kinase 9 (CDK9) inhibitors. These CDK9 inhibitors enhanced the mithramycin-mediated suppression of the EWS-FLI1 transcriptional program leading to a shift in the IC₅₀ and striking regressions of Ewing sarcoma xenografts. To determine whether these compounds may also be liver protective, we performed a qPCR screen of all known liver toxicity genes in HepG2 cells to identify mithramycin-driven transcriptional changes that contribute to the liver toxicity. Mithramycin induces expression of the BTG2 gene in HepG2 but not Ewing sarcoma cells, which leads to a liver-specific accumulation of reactive oxygen species (ROS). siRNA silencing of BTG2 rescues the induction of ROS and the cytotoxicity of mithramycin in these cells. Furthermore, CDK9 inhibition blocked the induction of BTG2 to limit cytotoxicity in HepG2, but not Ewing sarcoma cells. These studies provide the basis for a synergistic and less toxic EWS-FLI1–targeted combination therapy for Ewing sarcoma.

ABSTRACT

RepA is a bacterial protein that builds intracellular amyloid oligomers acting as inhibitory complexes of plasmid DNA replication. When carrying a mutation enhancing its amyloidogenesis (A31V), the N-terminal domain (WH1) generates cytosolic amyloid particles that are inheritable within a bacterial lineage. Such amyloids trigger in bacteria a lethal cascade reminiscent of mitochondrial impairment in human cells affected by neurodegeneration. To fulfill all the criteria to qualify as a prion-like protein, horizontal (intercellular) transmissibility remains to be demonstrated for RepA-WH1. Since this is experimentally intractable in bacteria, here we transiently expressed in a murine neuroblastoma cell line the soluble, barely cytotoxic RepA-WH1 wild type [RepA-WH1(WT)] and assayed its response to exposure to in vitro-assembled RepA-WH1(A31V) amyloid fibers. In parallel, murine cells releasing RepA-WH1(A31V) aggregates were cocultured with human neuroblastoma cells expressing RepA-WH1(WT). Both the assembled fibers and donor-derived RepA-WH1(A31V) aggregates induced, in the cytosol of recipient cells, the formation of cytotoxic amyloid particles. Mass spectrometry analyses of the proteomes of both types of injured cells pointed to alterations in mitochondria, protein quality triage, signaling, and intracellular traffic. Thus, a synthetic prion-like protein can be propagated to, and become cytotoxic to, cells of organisms placed at such distant branches of the tree of life as bacteria and mammalia, suggesting that mechanisms of protein aggregate spreading and toxicity follow default pathways.

IMPORTANCE Proteotoxic amyloid seeds can be transmitted between mammalian cells, arguing that the intercellular exchange of prion-like protein aggregates can be a common phenomenon. RepA-WH1 is derived from a bacterial intracellular functional amyloid protein, engineered to become cytotoxic in Escherichia coli. Here, we have studied if such bacterial aggregates can also be transmitted to, and become cytotoxic to, mammalian cells. We demonstrate that RepA-WH1 is capable of entering naive cells, thereby inducing the cytotoxic aggregation of a soluble RepA-WH1 variant expressed in the cytosol, following the same trend that had been described in bacteria. These findings highlight the universality of one of the central principles underlying prion biology: No matter the biological origin of a given prion-like protein, it can be transmitted to a phylogenetically unrelated recipient cell, provided that the latter expresses a soluble protein onto which the incoming protein can readily template its amyloid conformation.

Human adenoviruses have many attractive features for gene therapy applications. However, the high prevalence of preexisting immunity against these viruses in general populations worldwide has greatly limited their clinical utility. In addition, the most commonly used human adenovirus, human adenovirus subgroup C serotype 5 (HAd5), when systemically administered, triggers systemic inflammation and toxicity, with the liver being the most severely affected organ. Here, we evaluated the utility and safety of a new low-seroprevalence gorilla adenovirus (GAd; GC46) as a gene transfer vector in mice. Biodistribution studies revealed that systemically administered GAd had a selective and robust lung endothelial cell (EC) tropism with minimal vector expression throughout many other organs and tissues. Administration of a high dose of GAd accomplished extensive transgene expression in the lung yet elicited no detectable inflammatory histopathology in this organ. Furthermore, GAd, unlike HAd5, did not exhibit hepatotropism or induce liver inflammatory toxicity in mice, demonstrating the exceptional safety profile of the vector vis-à-vis systemic utility. We further demonstrated that the GAd capsid fiber shared the flexibility of the HAd5 equivalent for permitting genetic modification; GAd with the pan-EC-targeting ligand myeloid cell-binding peptide (MBP) incorporated in the capsid displayed a reduced lung tropism and efficiently retargeted gene expression to vascular beds in other organs.

IMPORTANCE In the aggregate, our mouse studies suggest that GAd is a promising gene therapy vector that utilizes lung ECs as a source of therapeutic payload production and a highly desirable toxicity profile. Further genetic engineering of the GAd capsid holds the promise of in vivo vector tropism modification and targeting.

Manganese (Mn) is an essential micronutrient required for the normal development of many organs, including the brain. Although its roles as a cofactor in several enzymes and in maintaining optimal physiology are well-known, the overall biological functions of Mn are rather poorly understood. Alterations in body Mn status are associated with altered neuronal physiology and cognition in humans, and either overexposure or (more rarely) insufficiency can cause neurological dysfunction. The resultant balancing act can be viewed as a hormetic U-shaped relationship for biological Mn status and optimal brain health, with changes in the brain leading to physiological effects throughout the body and vice versa. This review discusses Mn homeostasis, biomarkers, molecular mechanisms of cellular transport, and neuropathological changes associated with disruptions of Mn homeostasis, especially in its excess, and identifies gaps in our understanding of the molecular and biochemical mechanisms underlying Mn homeostasis and neurotoxicity.

Treatment of patients with triple-negative breast cancer (TNBC) is limited by a lack of effective molecular therapies targeting this disease. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care chemotherapy regimens. Using MDA-MB-468 and SUM-159PT TNBC cells, along with LC-MS/MS and HPLC metabolomics profiling, we found here that exposure of TNBC cells to the cytotoxic chemotherapy drugs cisplatin and doxorubicin alter arginine and polyamine metabolites. This alteration was because of a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). Using gene silencing and inhibitor treatments, we determined that the reduction in ODC was mediated by its negative regulator antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor difluoromethylornithine (DFMO) sensitized TNBC cells to chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines had greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. The alterations in polyamine metabolism in response to chemotherapy, as well as DFMO-induced preferential sensitization of TNBC cells to chemotherapy, reported here suggest that ODC may be a targetable metabolic vulnerability in TNBC.

Type 2 diabetes (T2D) is caused by loss of pancreatic β-cell mass and failure of the remaining β-cells to deliver sufficient insulin to meet demand. β-Cell glucolipotoxicity (GLT), which refers to combined, deleterious effects of elevated glucose and fatty acid levels on β-cell function and survival, contributes to T2D-associated β-cell failure. Drugs and mechanisms that protect β-cells from GLT stress could potentially improve metabolic control in patients with T2D. In a phenotypic screen seeking low-molecular-weight compounds that protected β-cells from GLT, we identified compound A that selectively blocked GLT-induced apoptosis in rat insulinoma cells. Compound A and its optimized analogs also improved viability and function in primary rat and human islets under GLT. We discovered that compound A analogs decreased GLT-induced cytosolic calcium influx in islet cells, and all measured β-cell–protective effects correlated with this activity. Further studies revealed that the active compound from this series largely reversed GLT-induced global transcriptional changes. Our results suggest that taming cytosolic calcium overload in pancreatic islets can improve β-cell survival and function under GLT stress and thus could be an effective strategy for T2D treatment.

Dramatically rising costs in drug development are in large part because of the high failure rates in clinical phase trials. The poor correlation of animal studies to human toxicity and efficacy have led many developers to question the value of requiring animal studies in determining which drugs should enter in-human trials. Part 1 of this 2-part series examined some of the data regarding the lack of concordance between animal toxicity studies and human trials, as well as some of the potential reasons behind it. This second part of the series focuses on some alternatives to animal trials (hereafter referred to as animal research) as well as current regulatory discussions and developments regarding such alternatives.

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.

Pollen has a natural tendency to adsorb mercury and forms the basis of a new class of tiny robots that speed through toxic water to purify it

Villagers placed the bodies of three victims of a deadly gas leak from an LG Polymers plant in southern India at the gates of the site on Saturday, and demanded the factory be shut down immediately and its top management arrested.

Moorabool Shire Mayor David Edwards says he fears his council is being shut out of any decisions around the dumping of contaminated soil from the West Gate Tunnel project.

The Justice Department, along with federal and state partners, today announced a $13 billion settlement with JPMorgan - the largest settlement with a single entity in American history - to resolve federal and state civil claims arising out of the packaging, marketing, sale and issuance of residential mortgage-backed securities (RMBS) by JPMorgan, Bear Stearns and Washington Mutual prior to Jan. 1, 2009. As part of the settlement, JPMorgan acknowledged it made serious misrepresentations to the public - including the investing public - about numerous RMBS transactions. The resolution also requires JPMorgan to provide much needed relief to underwater homeowners and potential homebuyers, including those in distressed areas of the country. The settlement does not absolve JPMorgan or its employees from facing any possible criminal charges.

The Justice Department, along with federal and state partners, today announced a $7 billion settlement with Citigroup Inc. to resolve federal and state civil claims related to Citigroup’s conduct in the packaging, securitization, marketing, sale and issuance of residential mortgage-backed securities (RMBS) prior to Jan. 1, 2009

“If an institution is unwilling to admit its wrongful conduct in a statement of facts; or balks at paying a substantial penalty that reflects that conduct; or refuses to do right by those affected, then we will not shrink from litigating as long as we must to fulfill our law enforcement mandate.”

There's no doubt that geoengineering brings out passionate emotions both pro and con, as recent debate on TreeHugger about the sort of-moratorium on some research coming out of the Convention on Biological Diversity

Be sure to dispose of these toys if they are in the attic, and know how to stay on top of product recalls

If the harmful chemicals weren't bad enough, new research finds that many e-cigarettes also include unhealthy biological contaminants.

It clogs our oceans and tampers with our bodies, yet without it, all modern life would skid to a stop. Susan Freinkel's new book, Plastic: A Toxic Love Story, explores the rise of plastic into ubiquity, hails it for its life-saving wonders, and explores

It sounds like a plot-line from a bad 1950's sci-fi movie, but unfortunately there's nothing fiction about it. Several towns in western Hungary were flooded today with a toxic red sludge after the waste product from

Wastewater or sludge storage lagoons are designed, in part, based on statistical probability of annual precipitation and evaporation amounts. The data behind these estimates generally don't take into account contemporary

A state of emergency has been declared in Hungary where four people are dead, 120 injured and six missing as torrents of red toxic sludge, the byproduct of bauxite refining for aluminum, burst from a containment pond and poured through six villages in

And the company that makes the chemical, Bayer CropScience, refuses to agree.

Chevron Toxico: Chevron Produces Phony Online News Coverage to Spread Misinformation about Ecuador Disaster "To promote a misinformation campaign about its role in the oil contamination of a pristine area of the rainforest in Ecuador, Chevron recently

The breakthrough also scored 18-year-old Hayley Todesco a Google Science Fair Award.

A mixture of leftover citrus rinds and vinegar is an easy, food-safe way to cut ants off at the pass.

Jason Aramburu is trying to revolutionize how we garden by expanding the production of "Black Revolution" biochar, a soil-less growing medium made from farm waste.

Join the DETOX campaign to pressure the fashion industry to stop exposing our kids to hazardous chemicals and contaminating waterways.

Greenpeace has taken some of the most popular outdoor gear to a lab in order to measure concentration of PFCs. What it found is disturbing.

Blooming Lake Erie. Photo Credit: NASA EO Pure Michigan is a slogan used in the Great Lakes State, to bring in tourists and celebrate the beauty of nature. You probably won't be seeing these images in any Pure Michigan ad campaign. They're of algae,

Studies of humans, mice, monkeys, and sheep all point to the same scary conclusion -- that BPA wreaks havoc on the female reproductive system.

Many in-home drinking water filters may not remove the most concerning contaminants.

Researchers find that the neurotoxin is carried in by coastal fog, deposited on the land, and then makes its way up the food chain where it is approaching toxic thresholds in pumas.

Four people are dead, 120 injured and six missing in Hungary as torrents of red toxic sludge, the byproduct of bauxite refining for aluminum, burst from a containment pond and poured through six villages in three counties. A