Involvement of Inflammation and Its Resolution in Disease and Therapeutics.

Inflammation plays a critical role in the response to and survival from injuries and/or infections. It occurs in two phases: initiation and resolution; however, when these events do not resolve and persist over time, the inflammatory response becomes chronic, prompting diseases that affect several systems and organs, such as the vasculature and the skin. Here, we reviewed inflammation that occurs in selected infectious and sterile pathologies. Thus, the immune processes induced by bacterial sepsis as well as T. cruzi and SARS-CoV-2 infections are shown. In addition, vaccine adjuvants as well as atherosclerosis are revised as examples of sterile-mediated inflammation. An example of the consequences of a lack of inflammation resolution is given through the revision of wound healing and chronic wounds. Then, we revised the resolution of the latter through advanced therapies represented by cell therapy and tissue engineering approaches, showing how they contribute to control chronic inflammation and therefore wound healing. Finally, new pharmacological insights into the management of chronic inflammation addressing the resolution of inflammation based on pro-resolving mediators, such as lipoxin, maresin, and resolvins, examining their biosynthesis, biological properties, and pharmacokinetic and pharmaceuticals limitations, are given. We conclude that resolution pharmacology and advanced therapies are promising tools to restore the inflammation homeostasis.

A Methodology for Data-Driven Decision-Making in the Monitoring of Particulate Matter Environmental Contamination in Santiago of Chile.

Atmospheric pollution derives mainly from anthropogenic activities that use combustion and may lead to adverse effects in exposed populations. It is generally accepted that air contamination causes cardiovascular and pulmonary morbidity in addition to increased mortality after exposure, but other epidemiological associations have also been described, including cancer as well as reproductive and immunological toxicity. Thus the concentration of chemicals in the air must be controlled. We propose that monitoring of air quality may be achieved by employing data analytics to generate information within the context of data-driven decision making to prevent and/or adequately alert the population about possible critical episodes of air contamination. In this paper, we propose a methodology for monitoring particulate matter pollution in Santiago of Chile which is based on bivariate control charts with heavy-tailed asymmetric distributions. This methodology is useful for monitoring environmental risk when the particulate matter concentrations follow bivariate Birnbaum-Saunders or Birnbaum-Saunders-t-Student distributions. A case study with real particulate matter pollution from Santiago is provided, which shows that the methodology is suitable to alert early episodes of extreme air pollution. The results are in agreement with the critical episodes reported with the current model used by the Chilean health authority.

A simple short term method to study thyroid disruption using a fetal rat thyroid culture.

INTRODUCTION: Thyroid modulation activity has not been investigated for many chemical substances. Due to ethical, practical and financial reasons, in vivo evaluation of a large number of compounds is not feasible. It has been proposed that an in vitro mechanism-based strategy could be more adequate for the identification of thyroid hormone disrupting chemicals. Here we describe a simple and mostly inexpensive, short term culture assay to study thyroid disruption. METHODS: Fetal thyroids collected from gestation day 20.5 were cultured up to 24h in Hank's saline solution, at 37°C with oxygenation at 0 and 12h. Viability of the cultured explants was evaluated by the MTT assay. Positive (thyroid stimulating hormone, TSH) and negative (6-propyl-2-thiouracil, PTU) modulation of cultured thyroids was assessed with morphometrical analysis of H & E stained gland sections. Thyroxine expression was evaluated by immunohistochemistry. RESULTS: Viability was shown to increase with time of culture with higher metabolic activity being achieved at 24h as compared to shorter periods of incubation. Follicular epithelial cells exhibited a statistically significant dependence on thyrotropin concentration, although more evident in the inner than in the outer portion of the glands. As expected, TSH induced expression of thyroxin while PTU inhibited it. DISCUSSION: GD20.5 fetal thyroids may be cultured up to 24h under relatively simple laboratory conditions during which viability and function of the gland are preserved showing that it is possible to reproduce in vivo response under in vitro conditions. This culture could be a suitable short term assay to study mechanism of thyroid disruption.

[Developmental toxicity of misoprostol: an update]. / Toxicidad del misoprostol sobre la gestación: Revisión de la literatura.

Misoprostol, a synthetic analog of prostaglandin E1, is currently used in Chile and other countries as an antiulcer medication, mainly for the prevention of non-steroidal anti-inflammatory-induced gastric ulcers. Due to its uterotonic properties, it is also indicated in obstetrics for induction of labor and termination of pregnancy. In this last case, misoprostol is either used alone or in combination with other oxytocic drugs such as methotrexate or mifepristone. The use of misoprostol as an abortifacient agent is considered to be safe since it rarely causes serious side effects. However up to 15 % of misoprostol-induced-abortions may not be successful, even under medical supervision, leading to in utero exposure to the drug and to the induction of a series of birth defects including limb and joints defects and Moebius syndrome. Reports from the nineties failed to show a strong epidemiological association between in utero drug exposure and induction of defects, a situation that has changed now that the number of cases reported has increased. Since the practice of abortion is illegal in Chile, many women turn to off-medical procedures to interrupt their pregnancy and use misoprostol as an easy and cheap alternative, readily available in the INTERNET. The lack of medical supervision in these cases may lead to situations that favor the induction of congenital defects. Here, we present an updated review of scientific data, to evaluate the risk of birth defects in babies exposed to the drug during pregnancy termination failed attempts.

Toxicidad del misoprostol sobre la gestación: Revisión de la literatura / Developmental toxicity of misoprostol: An update

Misoprostol, a synthetic analog of prostaglandin E1, is currently used in Chile and other countries as an antiulcer medication, mainly for the prevention of non-steroidal anti-infammatory-induced gastric ulcers. Due to its uterotonic properties, it is also indicated in obstetrics for induction of labor and termination of pregnancy. In this last case, misoprostol is either used alone or in combination with other oxytocic drugs such as methotrexate or mifepristone. The use of misoprostol as an abortifacient agent is considered to be safe since it rarely causes serious side effects. However up to 15 percent of misoprostol-induced-abortions may not be successful, even under medical supervision, leading to in utero exposure to the drug and to the induction of a series of birth defects including limb and joints defects and Moebius syndrome. Reports from the nineties failed to show a strong epidemiological association between in utero drug exposure and induction of defects, a situation that has changed now that the number of cases reported has increased. Since the practice of abortion is illegal in Chile, many women turn to off-medical procedures to interrupt their pregnancy and use misoprostol as an easy and cheap alternative, readily available in the INTERNET. The lack of medical supervision in these cases may lead to situations that favor the induction of congenital defects. Here, we present an updated review of scientifc data, to evaluate the risk of birth defects in babies exposed to the drug during pregnancy termination failed attempts.

Lack of effects of 2,4-dichlorophenoxyacetic acid administration on markers of oxidative stress during early pregnancy in mice.

Induction of oxidative stress by 2,4-dichlorophenoxyacetic acid (2,4-D) both as a pure compound and in commercial formulation was investigated during early pregnancy in mice. Pregnant animals were exposed to increasing doses of the herbicide (0.01, 0.1 and 100mg/kg/d) during gestation days 0-9, after which animals were euthanized and their blood analyzed for catalase activity, thiobarbituric acid reactive substances (TBARs) and total antioxidant capacity (TAC). Number of corpora lutea and uterine implantations and resorptions were also determined. Herbicide exposure did not cause any overt signs of maternal toxicity at any of the doses administered; neither did it cause an effect on developmental parameters. Catalase activity and TBARs were not modified by herbicide exposure although TAC was significantly decreased at 100mg/kg/d of both pure and formulated compound. Thus, 2,4-D does not seem to induce oxidative stress during early pregnancy in mice at the doses administered, indicating that this mechanism is probably not involved in mediating herbicide toxicity at these dose levels. Furthermore, since no manifestations of developmental toxicity were observed after administration of the herbicide, it is also possible that 2,4-D may not produce any early developmental toxicity at the low environmentally relevant doses tested in this animal model.

[Pesticide exposure and reproductive and birth defects. Critical analysis of epidemiological and experimental evidence]. / Exposición a pesticidas y toxicidad reproductiva y del desarrollo en humanos. Análisis de la evidencia epidemiológica y experimental.

Several epidemiological studies link pesticide exposure to reproductive and developmental toxicity. However, additional studies have shown little or no evidence to support such relationship. On the other hand, experimental data show that some pesticides may indeed alter the reproductive function or produce birth defects (as evidenced by intrauterine death, in utero growth retardation, visceral and skeletal malformations or functional deficits) in laboratory animals. This review is a critical analysis of the epidemiological and experimental evidence available to date, that links pesticide exposure with induction of reproductive or developmental defects. Factors that must be considered when establishing a cause-effect relationship are also discussed, including the shape of the dose-response curve, exposure to pesticides in chemical mixtures and the influence of genetic background.

Developmental toxicity of a commercial herbicide mixture in mice: I. Effects on embryo implantation and litter size.

We investigated the developmental toxicity in mice of a common commercial formulation of herbicide containing a mixture of 2,4-dichlorophenoxyacetic acid (2,4-D), mecoprop, dicamba, and inactive ingredients. Pregnant mice were exposed to one of four different doses of the herbicide mixture diluted in their drinking water, either during preimplantation and organogenesis or only during organogenesis. Litter size, birth weight, and crown-rump length were determined at birth, and pups were allowed to lactate and grow without additional herbicide exposure so that they could be subjected to additional immune, endocrine, and behavioral studies, the results of which will be reported in a separate article. At weaning, dams were sacrificed, and the number of implantation sites was determined. The data, although apparently influenced by season, showed an inverted or U-shaped dose-response pattern for reduced litter size, with the low end of the dose range producing the greatest decrease in the number of live pups born. The decrease in litter size was associated with a decrease in the number of implantation sites, but only at very low and low environmentally relevant doses. Fetotoxicity, as evidenced by a decrease in weight and crown-rump length of the newborn pups or embryo resorption, was not significantly different in the herbicide-treated litters.