Hexachlorobenzene induces TGF-β1 expression,which is a regulator of p27 and cyclin D1 modifications

Hexachlorobenzene (HCB) is an organochlorine pesticide widely distributed in the environment. In this study we have demonstrated that HCB induced loss of cell viability and alterations in cell cycle regulation in FRTL-5 rat thyroid cells. Analysis of cell cycle distribution by flow cytometric analysis demonstrated that HCB induced cell cycle arrest at G2/M and at G0/G1 phase, inhibiting cell cycle progression at the G1/S phase, after 24 h and 72 h of treatment.     

Reframing the Question: Does Mitochondrial Damage Set the Stage for Future Inflammation?

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In the 1970s, evidence emerged that environmental exposures could damage mitochondria, the primary regulators of cellular energetics.1^,2 More recently, researchers are studying how stressed mitochondria may initiate a signaling cascade that culminates in inflammation. At the center of this increased investigation is a multiprotein complex called the NLRP3 inflammasome.3^,4 The elusive link between environmentally induced mitotoxicity and inflammasome activation is the subject of a new study published in Environmental Health Perspectives.5Inflammation is a vital physiological response to invading agents or stressors, and inflammasomes are major players in this response. These multiprotein complexes sense pathogen- or damage-associated molecular patterns and trigger the release of proinflammatory cytokines that enhance and sustain inflammation.3 Most inflammasomes contain proteins in the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family; among these, the NLRP3 inflammasome is sensitive to the broadest variety of stimuli and has therefore sparked the most research interest.6 Abnormal activation of NLRP3 has been implicated in disorders such as Alzheimer’s and Parkinson’s diseases, diabetes, and atherosclerosis,4 raising huge clinical interest as a drug development target.7Open in a separate windowAn inflammasome is a complex molecule made up of different proteins. Inflammasomes are activated by sensing the presence of viruses, bacteria, particulate matter, and molecules produced by tissue stress. On activation, they mediate the release of proinflammatory cytokines, which help the body clear foreign substances and repair tissue. Abnormal activation of inflammasomes is implicated in a variety of human diseases. Image: © RAMON ANDRADE 3DCIENCIA/Science Source.“This study may lay the foundation for new directions in research examining agents that contribute to disease via mitochondrial function and inflammasome modulation,” says EHP deputy editor B. Paige Lawrence, a professor at the University of Rochester Medical Center. “Being able to connect exposures with specific, measurable molecular pathways helps to inform our understanding of pathways that lead from exposure to disease.”Previous research has linked inflammasome activation to by-products of mitochondrial damage, such as production of reactive oxygen species (ROS) and loss of membrane potential.8^,9^,10 However, it remains unclear whether pollutant exposures directly alter mitochondria or indirectly affect them by other injury to the cell.11National Institute of Environmental Health Sciences (NIEHS) neurotoxicologist Jean Harry, senior author of the present report, says her team set out to clarify this link. “We wanted to separate biological responses from toxicological ones by looking at a specific shift in the ability of the cell to respond to a secondary hit,” she says. To do this, the investigators exposed specialized immune cells called macrophages to tri-organotins, which are prevalent environmental contaminants that have been shown to alter mitochondrial function.12^,13^,14^,15^,16^,17One group of macrophages was activated, or primed, by exposure to bacterial lipopolysaccharide (LPS), and then both primed and unprimed groups were treated with tri-organotin compounds. Two known neurotoxicants, triethyltin bromide (TETBr) and trimethyltin hydroxide (TMTOH), enhanced formation of inflammasome aggregates and release of proinflammatory cytokines in LPS-primed macrophages. These compounds suppressed mitochondrial bioenergetics but did not alter ROS production, demonstrating that inflammasome activation can occur independently of ROS release. In the reverse scenario, however, pre-exposure to TETBr and TMTOH blunted the appropriate macrophage response to proinflammatory LPS.“Overall, I think the study demonstrates that, rather than looking at apical end points, we should reframe the environmental and public health question: How does an exposure modify the system such that we may change a relative risk to something else coming down the pike later?” says Harry. The environmental toxicants were tested at sublethal levels—not high enough to elicit cell death, but sufficient to change the cells’ responses to a secondary insult. Harry says such changes could manifest as an earlier onset of disease, progression of a disease process, or—of particular interest in the context of the current global pandemic—reduced vaccine response. These effects may be seen as two sides of the same coin.“On the one hand, having an underlying chronic inflammatory condition might change my susceptibility to [any] environmental exposures that might act upon the immune system,” Harry says. “On the other hand, a low-level environmental exposure could change how I respond to an immune challenge later.”Matthew Havrda, an assistant professor at the Geisel School of Medicine at Dartmouth, cautions that the generalized suppression of metabolism observed in exposed macrophages may suggest general distress due to lack of adenosine triphosphate (ATP; the energy currency of the cell) and that inflammasome activation could therefore be part of a bigger stress response. Havrda, who was not involved in the current study, suggests that to find the direct link—the molecular smoking gun—scientists should look at whether the response elicited by tri-organotin exposure is specific to NLRP3. “[NLRP3] drugs and biomarker assays are out there, so if [NLRP3 activation is] specific for this type of toxic exposure, you could potentially screen and treat people to circumvent the deleterious effects,” he says.Harry agrees, noting that inflammasome-blocking drugs currently in development may simply be blocking ATP release and that the specificity of the inflammasome response calls for further studies. She adds that the role of inflammasome aggregate formation should also be clarified. “These aggregates are very sticky and hard to break up, and they have a major stimulatory effect on [surrounding] macrophages, so the acute inflammatory response elicited by environmental exposures may have long-term consequences through the release of those aggregates,” she says. Recent studies18 have proposed these aggregates may act as scaffolds in the formation of plaques in Alzheimer’s disease, supporting the need for further investigation.     

Developmental exposure to endocrine disruptor chemicals alters follicular dynamics and steroid levels in Caiman latirostris

Human and wildlife are exposed at critical periods of development to endocrine disruptor chemicals (EDC) that may be responsible for reproductive disorders. To test the hypothesis that in ovum exposure to EDC at a critical period for gonadal organogenesis alters post-hatching folliculogenesis and steroidogenesis in Caiman latirostris, we studied the impact of in ovum exposure to 17 beta-estradiol (E2), bisphenol A (BPA), endosulfan (END) and atrazine (ATZ) on gonadal differentiation, follicular dynamics and circulating levels of steroid hormones in neonatal and juvenile caiman. Since C. latirostris is a species with temperature dependent sex determination, eggs were incubated at male (33 degrees C) or female (30 degrees C) producing temperatures and the effect of EDC was evaluated. Neonatal ovaries exhibited germ cells mainly located in clusters evidencing proliferative activity and type I to III follicles. Juvenile ovaries exhibited germ cells and advanced stages of pre-vitellogenic follicles. Prenatal exposure to the highest doses of E2 (1.4 ppm) or BPA (140 ppm) overrode male temperature effect on sex determination. Neonatal females produced by sex reversion lacked type III follicles, while females prenatally exposed to the lowest doses of E2 (0.014 ppm) and BPA (1.4 ppm) or ATZ (0.2 ppm) showed an increase in type III follicles. Juvenile caiman prenatally exposed to E2 or BPA showed an augmented incidence of multioocyte follicles. Neonatal female caiman exposed in ovum to E2 or BPA had higher estrogen serum levels whereas exposure to E2, BPA, ATZ and END decreased T levels. Present data demonstrates that exposure to EDC during gonadal organogenesis alters follicular dynamics and steroid levels later in life. These effects might have an impact on caiman fertility.     

Elimination of hepatitis C virus infection from a hemodialysis unit and impact of treatment on the control of anemia

Introduction

In the interferon era, the treatment of hepatitis C virus (HCV) infection in patients on haemodialysis (HD) was limited due to the significant number of treatment-related adverse events (AEs). Direct-acting antivirals (DAAs) have demonstrated their efficacy and safety in the treatment of HCV in patients with advanced chronic kidney disease on haemodialysis. The objective of the study was to evaluate the success in eliminating HCV infection from our dialysis unit using DAAs, and to assess the impact of HCV elimination on clinical and analytical outcomes.

Fatigue assessment and its impact in the quality of life of patients with ankylosing spondylitis

Clinical Rheumatology - The most frequently reported symptoms by patients with ankylosing spondylitis (AS) are pain, stiffness, and fatigue. Previous studies have estimated a 63 %...     

Quinic acid and hypervalent chromium: a spectroscopic and kinetic study

The redox reaction between an excess of quinic acid (QA) and Cr^VI involves the formation of intermediates, namely, Cr^IV and Cr^V species, which in turn react with the organic substrates. As observed with other substrates that have already been studied, Cr^IV does not accumulate during this reaction because of the rate of the reaction. Its rate of disappearance is several times higher than that of the reaction of Cr^VI or Cr^V with QA. Kinetic studies indicate that the redox reaction proceeds via a combined mechanism that involves the pathways Cr^VI → Cr^IV → Cr^II and Cr^VI → Cr^IV → Cr^III, which is supported by the observation of superoxo-Cr^III (CrO₂²⁺) ions, free radicals, and oxo-Cr^V species as intermediates and the detection of Cr^VI ester species. The present study reports the complete rate laws for the QA/chromium redox reaction.

The redox reaction between an excess of quinic acid (QA) and Cr^VI involves the formation of intermediates, namely, Cr^IV and Cr^V species, which in turn react with the organic substrates.     

Current evidence linking diet to gut microbiota and brain development and function

The gut:brain axis is emerging as an important information highway linking the foods we eat with neurophysiological development and functions. Some gut microorganisms have shown to alleviate anxiety and depression, improve cognitive performance and play a role in brain development in early life. However, most studies were conducted in laboratory animals and these findings await confirmation in carefully designed human interventions. Similarly, little attention has been given to how diet:microbe interactions within the gut can impact on neurotransmitter production or their subsequent biological effects within the nervous system. In this review, we discuss the possible influence of carbohydrates, polyphenols, lipids and proteins colonic fermentation on production, bioavailability and biological activity of metabolites linked to the gut-microbiota-brain axis. An increased understanding of how nervous system may be regulated by diet will greatly enhance our ability to design dietary strategies to improve healthy brain development and functions.     

Inhibition of the PI3K/Akt pathway by Ly294002 does not prevent establishment of persistent Junín virus infection in Vero cells

In previous work, we demonstrated that the arenavirus Junín virus (JUNV) is able to activate Akt by means of the phosphatidylinositol-3-kinase (PI3K) survival pathway during virus entry. This work extends our study, emphasizing the relevance of this pathway in the establishment and maintenance of persistent infection in vitro. During the course of infection, JUNV-infected Vero cells showed a typical cytopathic effect that may be ascribed to apoptotic cell death. Treatment of infected cultures with Ly294002, an inhibitor of the PI3K/Akt pathway, produced an apoptotic response similar to that observed for uninfected cells treated with the drug. This result suggests that virus-induced activation of the PI3K/Akt pathway does not deliver a strong enough anti-apoptotic signal to explain the low proportion of apoptotic cells observed during infection. Also, inhibition of the PI3K/Akt pathway during the acute stage of infection did not prevent the establishment of persistence. Furthermore, treatment of persistently JUNV-infected cells with Ly294002 did not alter viral protein expression. These findings indicate that despite the positive modulation of the PI3/Akt pathway during Junín virus entry, this would not play a critical role in the establishment and maintenance of JUNV persistence in Vero cells.     

Pilot Study Assessing HIV Vaccine Trial Readiness Among Female Sex Workers, Injection and Non-injection Drug Users, and Men Who Have Sex with Men in Spain

The purpose of this study was to assess HIV risk and willingness to participate in HIV vaccine trials in three high risk populations in Spain. Eight hundred and forty-four participants, comprising female sex workers, injection and non-injection drug users (IDUs and NIDUs, respectively), and men who have sex with men were tested for HIV and surveyed for risk and willingness to participate in future preventive HIV vaccine trials. HIV seroprevalence was 3.8% (95% CI: 2–11). HIV infection was associated with transgender identification, IDU in the past year, and sex with an IDU or other drug-using partner. The majority (82%) expressed their willingness to participate in HIV vaccine trials. Substantial sexual and parenteral risk in all groups and concomitant willingness to participate in vaccine trials was found, particularly among women and IDUs. Additional longitudinal cohort studies in Spain are needed to plan future vaccine efficacy trials.