Hypoxia Induces Alterations in the Circadian Rhythm in Patients with Chronic Respiratory Diseases.

The function of the circadian cycle is to determine the natural 24 h biological rhythm, which includes physiological, metabolic, and hormonal changes that occur daily in the body. This cycle is controlled by an internal biological clock that is present in the body's tissues and helps regulate various processes such as sleeping, eating, and others. Interestingly, animal models have provided enough evidence to assume that the alteration in the circadian system leads to the appearance of numerous diseases. Alterations in breathing patterns in lung diseases can modify oxygenation and the circadian cycles; however, the response mechanisms to hypoxia and their relationship with the clock genes are not fully understood. Hypoxia is a condition in which the lack of adequate oxygenation promotes adaptation mechanisms and is related to several genes that regulate the circadian cycles, the latter because hypoxia alters the production of melatonin and brain physiology. Additionally, the lack of oxygen alters the expression of clock genes, leading to an alteration in the regularity and precision of the circadian cycle. In this sense, hypoxia is a hallmark of a wide variety of lung diseases. In the present work, we intended to review the functional repercussions of hypoxia in the presence of asthma, chronic obstructive sleep apnea, lung cancer, idiopathic pulmonary fibrosis, obstructive sleep apnea, influenza, and COVID-19 and its repercussions on the circadian cycles.

Estrogenic Modulation of Ionic Channels, Pumps and Exchangers in Airway Smooth Muscle.

To preserve ionic homeostasis (primarily Ca2+, K+, Na+, and Cl-), in the airway smooth muscle (ASM) numerous transporters (channels, exchangers, and pumps) regulate the influx and efflux of these ions. Many of intracellular processes depend on continuous ionic permeation, including exocytosis, contraction, metabolism, transcription, fecundation, proliferation, and apoptosis. These mechanisms are precisely regulated, for instance, through hormonal activity. The lipophilic nature of steroidal hormones allows their free transit into the cell where, in most cases, they occupy their cognate receptor to generate genomic actions. In the sense, estrogens can stimulate development, proliferation, migration, and survival of target cells, including in lung physiology. Non-genomic actions on the other hand do not imply estrogen's intracellular receptor occupation, nor do they initiate transcription and are mostly immediate to the stimulus. Among estrogen's non genomic responses regulation of calcium homeostasis and contraction and relaxation processes play paramount roles in ASM. On the other hand, disruption of calcium homeostasis has been closely associated with some ASM pathological mechanism. Thus, this paper intends to summarize the effects of estrogen on ionic handling proteins in ASM. The considerable diversity, range and power of estrogens regulates ionic homeostasis through genomic and non-genomic mechanisms.

Early life exposure and its association with diseases in adulthood: review of longitudinal studies / Exposiciones tempranas en la vida y su asociación con enfermedades en la edad adulta: revisión de estudios longitudinales

Abstract Background: We describe the evidence of the effects of early life exposures on health and aging during adulthood. Methods: A narrative review of cohorts and systematic reviews of studies initiated early in life and followed up to adulthood was conducted. Results: Most studies were carried out in developed countries. The long-term effects of birth weight and, to a lesser extent, height at birth on chronic-degenerative diseases, functionality, bone, renal and respiratory pathology, and mortality have been consistent. Breastfeeding is associated with metabolic and cardiovascular diseases and functionality. Adiposity, bone pathophysiology, functionality in old age, and high blood pressure are associated with socioeconomic status at birth. Conclusions: Several exposures from intrauterine life to adolescence that exert discrete but significant effects on adult health have been consistently described. It is necessary to carry out these studies in developing countries.

Resumen Introducción: En este artículo se describe la evidencia acerca de los efectos de las exposiciones tempranas sobre la salud y el envejecimiento en la edad adulta. Métodos: Revisión narrativa de cohortes y revisiones sistemáticas de estudios iniciados en la vida temprana y seguidos hasta la edad adulta. Resultados: La mayoría de los estudios se realizaron en países desarrollados. Los efectos a largo plazo del peso al nacer, y en menor medida de la talla al nacer, en las enfermedades crónico-degenerativas, la funcionalidad, la fisiopatología ósea, renal y respiratoria, y la mortalidad, han sido consistentes. La lactancia materna se ha asociado con enfermedades metabólicas y cardiovasculares, y con la funcionalidad. La adiposidad, la fisiopatología ósea, la funcionalidad en la vejez y la hipertensión arterial están asociadas con el nivel socioeconómico al nacer. Conclusiones: Diferentes exposiciones desde la vida intrauterina hasta la adolescencia ejercen efectos discretos, pero significativos, sobre la salud de los adultos. Se requiere realizar estos estudios en las poblaciones que viven en países en desarrollo.

Trypanocidal and toxicological assessment in vitro and in silico of three sesquiterpene lactones from Asteraceae plant species.

We report the effect of the Sesquiterpene Lactones Ambrosin, Incomptine B and Glaucolide E against seven strains of Trypanosoma cruzi, the etiological agent of Chagas Disease. These compounds were isolated from Parthenium hysterophorus, Decachaeta incompta, and Vernonia liatroides, respectively. We evaluated by flow cytometry the viability of epimastigotes. Ambrosin was the most effective, then Incomptine B, and Glaucolide E (IC50 = 67.1, 123.7, and 215.1 µM, respectively). These compounds were more potent than the drugs Benznidazole (IC50 > 400 µM) and Nifurtimox (IC50 = 199.7 to >400 µM). Toxicity to mammalian Vero and Jurkat cells was also determined in vitro. All the compounds had a poor selective index (0.003-1.859). Toxicoinformatics is useful to forecast in silico toxicological and pharmacokinetic properties. Ambrosin and Incomptine B may not possess mutagenic, tumorigenic, or reproductive effects. Glaucolide E could possess a low mutagenic and high tumorigenic effects, and probably target the Amine Oxidase A, Prostaglandin and G/H Synthase I. Interestingly, Ambrosin, Incomptine B and Glaucolide E, comply with Lipinsky Rule of Five, indicating a suitable pharmacokinetic profile. Ambrosin and Incomptine B possess high trypanocidal activity, and pharmaceutical properties suitable for development; however, their safety profile should be optimized by structural modifications.

Macrophage Migration Inhibitory Factor -173 G/C Polymorphism: A Global Meta-Analysis across the Disease Spectrum.

Human macrophage migration inhibitory factor (MIF) is a cytokine that plays a role in several metabolic and inflammatory processes. Single nucleotide polymorphism (SNP) -173 G/C (rs755622) on MIF gene has been associated with numerous diseases, such as arthritis and cancer. However, most of the reports concerning the association of MIF with these and other pathologies are inconsistent and remain quite controversial. Therefore, we performed a meta-analysis from 96 case-control studies on -173 G/C MIF SNP and stratified the data according to the subjects geographic localization or the disease pathophysiology, in order to determine a more meaningful significance to this SNP. The polymorphism was strongly associated with an increased risk in autoimmune-inflammatory, infectious and age-related diseases on the dominant (OR: 0.74 [0.58-0.93], P < 0.01; OR: 0.81 [0.74-0.89], P < 0.0001; and OR: 0.81 [0.76-0.87], P < 0.0001, respectively) and the recessive models (OR: 0.74 [0.57-0.095], P < 0.01; OR: 0.66 [0.48-0.92], P < 0.0154; and OR: 0.70 [0.60-0.82], P < 0.0001, respectively). Also, significant association was found in the geographic localization setting for Asia, Europe and Latin America subdivisions in the dominant (OR: 0.76 [0.69-0.84], P < 0.0001; OR: 0.77 [0.72-0.83], P < 0.0001; OR: 0.61 [0.44-0.83], P-value: 0.0017, respectively) and overdominant models (OR: 0.85 [0.77-0.94], P < 0.0001; OR: 0.80 [0.75-0.86], P < 0.0001; OR: 0.73 [0.63-0.85], P-value: 0.0017, respectively). Afterwards, we implemented a network meta-analysis to compare the association of the polymorphism for two different subdivisions. We found a stronger association for autoimmune than for age-related or autoimmune-inflammatory diseases, and stronger association for infectious than for autoimmune-inflammatory diseases. We report for the first time a meta-analysis of rs755622 polymorphism with a variety of stratified diseases and populations. The study reveals a strong association of the polymorphism with autoimmune and infectious diseases. These results may help direct future research on MIF-173 G/C in diseases in which the relation is clearer and thus assist the search for more plausible applications.

Volatile organic compounds from pachyrhizus ferrugineus and pachyrhizus erosus (Fabaceae) leaves / Compuestos orgánicos volátiles de las hojas de pachyrhizus ferrugineus y pachyrhizus erosus (Fabaceae)

In México, Pachyrhizus erosus (Fabaceae) commonly called "jícama", is widely known for its edible tubers. It is cultivated since the pre-Columbian period, and the powdered seeds have been used for the treatment of mange, lice, and fleas, due to their content of rotenone, a well-known insecticidal compound. On the other hand, P. ferrugineus, a wild species can only be found in the Tropical Forests, and has no commercial value. It is known that plants release volatile organic compounds (VOCs) showing qualitative and quantitative differences if are wild or cultivated. VOCs are also involved as repelling or attracting chemical signals to insect herbivores, and their natural enemies. Until now, the VOCs of the leaves of P. erosus and P. ferrugineus have not been investigated. In the present contribution the VOCs of both species were characterized by headspace solid-phase (HS-SPME) extraction and gas chromatography-mass spectrometry (GC-MS-TOF). In P. erosus 21 VOCs were found, being the most abundant: cyclohexanone (32.8 percent), 3-hexen-1-ol (Z) (32.7 percent), 3-hexenal (Z) (10.5 percent). The majoritarian compounds were C6 or C5 derivatives In P. ferrugineus, the most abundant VOCs were: 5-hexene-1-ol acetate (51.5 percent), undecanal (22.4 percent), 2-hepten-1-al (14.5 percent). The majoritarian compounds were C6, C7 or C11 derivatives.

En México, Pachyrhizus erosus (Fabaceae) es llamada comúnmente "jícama" y es conocida por sus tubérculos comestibles. Se ha cultivado desde el período pre-Colombino y las semillas se han utilizado para el tratamiento tópico de la sarna, piojos, pulgas; las semillas contienen rotenona, un compuesto insecticida. Por otra parte, P. ferrugineus solo está presente en estado silvestre en los bosques tropicales y carece de valor comercial. Se sabe que las plantas liberan compuestos orgánicos volátiles (COV) y muestran diferencias cualitativas y cuantitativas dependiendo, si son silvestres o cultivadas. Los COV también son señales químicas atrayentes o repelentes de los insectos herbívoros y a sus enemigos naturales. Hasta ahora, los COV en las hojas de P. erosus y P. ferrugineus no han sido investigados. En el presente trabajo, los COV se identificaron mediante la microextracción (HS-SPME) en fase sólida, e identificados por cromatografía de gases acoplada a espectrometría de masas (GC-MS-TOF). En P. erosus se encontraron 21 COV, siendo los más abundantes: ciclohexanona (32.8 por ciento), 3-hexen-1-ol (Z) (32.7 por ciento) y 3-hexenal (Z) (10.5 por ciento). Los compuestos mayoritarios son C6 y C5. En P. ferrugineus los más abundantes fueron: 5-hexen-1-ol acetato (51.5 por ciento), undecanal (22.4 por ciento) y 2-hepten-1-al (14.5 por ciento). Los compuestos mayoritarios son C6, C7 o C11.

Rotenone isolated from Pachyrhizus erosus displays cytotoxicity and genotoxicity in K562 cells.

Pachyrhizus erosus (Fabaceae) is a herb commonly known as 'yam bean', which has been cultivated in México since pre-Columbian times for its edible tubers. The seeds are also known for their acaricidal and insecticidal properties due to rotenone and other isoflavonoid contents. Rotenone has exhibited cytotoxic activity against several human tumour cell lines; however, its mechanism of action is still not fully understood. In this study, we determined the cytotoxicity of rotenone isolated from P. erosus seeds on K562 human leukaemia cells. Rotenone exhibited significant cytotoxic activity (IC50 = 13.05 µM), as determined by the MTT assay. Three other isolated isoflavonoids were not cytotoxic. Rotenone genotoxicity was detected using the comet assay. Rotenone induced cell death, and caspase-3 activation as indicated by TUNEL assay, and immunocytofluorescence. Plasmid nicking assay indicated that rotenone does not interact directly with DNA.

Molecular mechanisms involved in the cytotoxicity induced by coumarins from Calophyllum brasiliense in K562 leukaemia cells.

OBJECTIVES: The aim of this study was to determine the cellular and molecular mechanisms of cell death induced by mammea A/BA and A/BB (3 : 1) on K562 cells. METHODS: These compounds were isolated from Calophyllum brasiliense and its cytotoxicity was tested using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell death was evaluated by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and immunocytofluorescence of active caspase-3. Genotoxicity was tested using comet assay. Lastly, a chemoinformatic analysis was performed with Osiris-Molinspiration software. KEY FINDINGS: The mixture of mammea A/BA and A/BB (3 : 1) showed cytotoxic activity against K562 cells (IC50 = 43.5 µm). TUNEL positive cells and active caspase-3 were detected after treatment. Genotoxicity of mammea A/BA and A/BB on K562 was detected since first hour of treatment. Additionally, mammea A/BA and A/BB were found to be in compliance with Lipinski 'rule of 5' suggesting that they possess strong potential of druglikeness. CONCLUSIONS: The overall results confirm and extend the knowledge about coumarins as an important resource of antitumor drugs, and indicate that these compounds could be used in further preclinical studies against leukaemia.