Increased susceptibility of cystic fibrosis airway epithelial cells to ferroptosis.

BACKGROUND: Defective chloride transport in airway epithelial cells (AECs) and the associated lung disease are the main causes of morbidity and early mortality in cystic fibrosis (CF). Abnormal airway iron homeostasis and the presence of lipid peroxidation products, indicative of oxidative stress, are features of CF lung disease. RESULTS: Here, we report that CF AECs (IB3-1) are susceptible to ferroptosis, a type of cell death associated with iron accumulation and lipid peroxidation. Compared to isogenic CFTR corrected cells (C38), the IB3-1 cells showed increased susceptibility to cell death upon exposure to iron in the form of ferric ammonium citrate (FAC) and the ferroptosis inducer, erastin. This phenotype was accompanied by accumulation of intracellular ferrous iron and lipid peroxides and the extracellular release of malondialdehyde, all indicative of redox stress, and increased levels of lactate dehydrogenase in the culture supernatant, indicating enhanced cell injury. The ferric iron chelator deferoxamine (DFO) and the lipophilic antioxidant ferrostatin-1 inhibited FAC and erastin induced ferroptosis in IB3-1 cells. Glutathione peroxidase 4 (GPX4) expression was decreased in IB3-1 cells treated with FAC and erastin, but was unchanged in C38 AECs. Necroptosis appeared to be involved in the enhanced susceptibility of IB3-1 AECs to ferroptosis, as evidenced by partial cell death rescue with necroptosis inhibitors and enhanced mixed lineage kinase domain-like (MLKL) localisation to the plasma membrane. CONCLUSION: These studies suggest that the increased susceptibility of CF AECs to ferroptosis is linked to abnormal intracellular ferrous iron accumulation and reduced antioxidant defences. In addition, the process of ferroptotic cell death in CF AECs does not appear to be a single entity and for the first time we describe necroptosis as a potential contributory factor. Iron chelation and antioxidant treatments may be promising therapeutic interventions in cystic fibrosis.

Increased susceptibility of cystic fibrosis airway epithelial cells to ferroptosis

BACKGROUND: Defective chloride transport in airway epithelial cells (AECs) and the associated lung disease are the main causes of morbidity and early mortality in cystic fibrosis (CF). Abnormal airway iron homeostasis and the presence of lipid peroxidation products, indicative of oxidative stress, are features of CF lung disease. RESULTS: Here, we report that CF AECs (IB3-1) are susceptible to ferroptosis, a type of cell death associated with iron accumulation and lipid peroxidation. Compared to isogenic CFTR corrected cells (C38), the IB3-1 cells showed increased susceptibility to cell death upon exposure to iron in the form of ferric ammonium citrate (FAC) and the ferroptosis inducer, erastin. This phenotype was accompanied by accumulation of intracellular ferrous iron and lipid peroxides and the extracellular release of malondialdehyde, all indicative of redox stress, and increased levels of lactate dehydrogenase in the culture supernatant, indicating enhanced cell injury. The ferric iron chelator defer-oxamine (DFO) and the lipophilic antioxidant ferrostatin-1 inhibited FAC and erastin induced ferroptosis in IB3-1 cells. Glutathione peroxidase 4 (GPX4) expression was decreased in IB3-1 cells treated with FAC and erastin, but was unchanged in C38 AECs. Necroptosis appeared to be involved in the enhanced susceptibility of IB3-1 AECs to ferroptosis, as evidenced by partial cell death rescue with necroptosis inhibitors and enhanced mixed lineage kinase domain-like (MLKL) localisation to the plasma membrane. CONCLUSION: These studies suggest that the increased susceptibility of CF AECs to ferroptosis is linked to abnormal intracellular ferrous iron accumulation and reduced antioxidant defences. In addition, the process of ferroptotic cell death in CF AECs does not appear to be a single entity and for the first time we describe necroptosis as a potential contributory factor. Iron chelation and antioxidant treatments may be promising therapeutic interventions in cystic fibrosis.

Barriers and facilitators influencing facility-based childbirth in rural Haiti: a mixed method study with a convergent design.

INTRODUCTION: Haiti has the highest maternal mortality rate in the Western Hemisphere. Facility-based childbirth is promoted as the standard of care for reducing maternal and neonatal mortality. We conducted a convergent, mixed methods study to assess barriers and facilitators to facility-based childbirth at Hôpital Universitaire de Mirebalais (HUM) in Mirebalais, Haiti. METHODS: We conducted secondary analyses of a prospective cohort of pregnant women seeking antenatal care at HUM and quantitatively assessed predictors of not having a facility-based childbirth at HUM. We prospectively enrolled 30 pregnant women and interviewed them about their experiences delivering at home or at HUM. RESULTS: Of 1105 pregnant women seeking antenatal care at the hospital between May and December 2017, 773 (70%) returned to the hospital for facility-based childbirth. In multivariable analyses, living farther from the hospital (adjusted OR (AOR)=0.73; 95% CI 0.56 to 0.96), poverty (AOR=0.93; 95% CI 0.88 to 0.99) and household hunger (AOR=0.45; 95% CI 0.26 to 0.79) were associated with not having a facility-based childbirth. Primigravid women were more likely to have a facility-based childbirth (AOR=1.34, 95% CI 1.02 to 1.76). Qualitative data provided insight into the value women place on traditional birth attendants ('matrons') during home-based childbirths. While women perceived facility-based childbirths as better equipped to handle birth complications, barriers such as distance, costs of transportation and supplies, discomfort of facility birthing practices and mistreatment by medical staff resulted in negative perceptions of facility-based childbirths. CONCLUSION: Pregnant women in rural Haiti must overcome substantial structural barriers and forfeit valued support from traditional birth attendants when they pursue facility-based childbirths. If traditional birth attendants could be involved in care alongside midwives at facilities, women may be more inclined to deliver there. While complex structural barriers remain, the inclusion of matrons at facilities may increase uptake of facility-based childbirths, and ultimately improve maternal and neonatal outcomes.

Cirrhosis in Hemochromatosis: Independent Risk Factors in 368 HFE p.C282Y Homozygotes.

INTRODUCTION AND AIM: We sought to identify independent risk factors for cirrhosis in HFE p.C282Y homozygotes in a cross-sectional study. MATERIAL AND METHODS: We evaluated 368 p.C282Y homozygotes who underwent liver biopsy and compared characteristics of those with and without cirrhosis. We performed multivariable logistic regression on cirrhosis with: age; sex; race/ethnicity; diabetes; blood pints/units donated voluntarily; erythrocyte pints/units received; iron supplement use; alcohol intake, g/d; body mass index, kg/m2; swollen/tender 2nd/3rd metacarpophalangeal joints; elevated alanine aminotransferase; elevated aspartate aminotransferase; steatosis/fatty liver; iron removed by phlebotomy, g; and GNPAT p.D519G positivity. RESULTS: Mean age of 368 participants (73.6% men) was 47 ± 13 (standard deviation) y. Cirrhosis was diagnosed in 86 participants (23.4%). Participants with cirrhosis had significantly greater mean age, proportion of men, diabetes prevalence, mean daily alcohol intake, prevalence of swollen/ tender 2nd/3rd metacarpophalangeal joints, mean serum ferritin, elevated alanine aminotransferase, elevated aspartate aminotransferase, and mean iron removed; and significantly fewer mean blood pints/units donated. GNPAT p.D519G positivity was detected in 82 of 188 participants (43.6%). In a multivariable model for cirrhosis, there were four significant positive associations: age (10-y intervals) (odds ratio 2.2 [95% confidence interval 1.5, 3.3]); diabetes (3.3; [1.1, 9.7]); alcohol intake (14 g alcohol drinks/d) (1.5 [1.2, 1.8]); and iron removed, g (1.3 [1.2, 1.4]). There was no statistical evidence of two-way interactions between these variables. CONCLUSION: In conclusion, cirrhosis in HFE p.C282Y homozygotes is significantly associated with age, diabetes, daily alcohol intake, and iron removed by phlebotomy, taking into account the effect of other variables.

The ecology, evolution, and biogeography of dioecy in the genus Solanum: with paradigms from the strong dioecy in Solanum polygamum, to the unsuspected and cryptic dioecy in Solanum conocarpum.

UNLABELLED: • PREMISE OF THE STUDY: Island plants are over-exploited and "under-explored." Understanding the reproductive biology of plants, especially rare species, is fundamental to clarifying their evolution, estimating potential for change, and for creating effective conservation plans. Clarification of sexual systems like dioecy, and unusual manifestations of it in specific studies within Solanum, helps elucidate evolutionary patterns and genetic and ecological control of sex expression.• METHODS: Studies of reproductive systems of two Caribbean endemics, S. polygamum and S. conocarpum, combined multifaceted analyses of field populations and of multiple generations of greenhouse plants.• KEY RESULTS: The dioecy in both species is, like that in other solanums, largely cryptic, although the gender of S. polygamum flowers is obvious. The rare S. conocarpum is recognized as dioecious; floral gender is not obvious. Variation in sex expression facilitated experiments and promoted hypotheses on control and significance of morphological features and sex expression.• CONCLUSIONS: Confirmed dioecy in at least 15 solanums is distributed across the genus, with perhaps 6 independent origins, and with crypticity in the form of morphologically hermaphroditic, but functionally unisexual, flowers characterizing all species. Dioecy is not more strongly associated with islands. Inaperturate pollen in pistillate flowers characterizes almost all, but not the two dioecious species studied herein. Dioecy in both species indicates leakiness (rare hermaphroditic flowers on male plants) that helps explain island colonization and radiation. Leakiness allowed confirmation-usually impossible for dioecious species-of self-compatibility for S. polygamum, and thus support for the hypothesis that dioecy evolved to promote outcrossing.

Key plants preserve elements of culture: a study over distance and time of fresh crops in Puerto Rican markets in Hartford, Connecticut, "A moveable feast".

PREMISE OF THE STUDY: People retain culinary customs when they migrate. We tested this commitment via the study of Puerto Rican fresh produce markets in the continental United States over time, 18 yr, and space, by comparisons with source markets in Puerto Rico (PR). METHODS: A survey of Puerto Rican markets in Hartford (HT), Connecticut in 1993-1994 was repeated in 2009-2010. A comparative study was made at open-air markets in PR in 2009. Surveys recorded fresh crops, and interviews with vendors and Hartford Puerto Rican residents provided context. KEY RESULTS: We recorded 84 plant crops (64 species; 32 families) for seven categories. The largest category was viandas (fresh, starchy "root" crops and immature fruits), followed by saborizantes (flavorings). In the second HT survey, 80% of the crops were still present. And ∼90% of the HT 1993-1994 crops and ∼75% of the HT 2009-2010 crops were shared with markets in PR. CONCLUSIONS: On the basis of our results, we suggest two new concepts. The persistence of these largely tropical foods in a temperate market far removed from tropical PR shows the importance of basic foods as an element of cultural identification. We recognize this stability as an example of "culinary cultural conservation". Second, analysis of these fresh produce markets leads to the conclusion that viandas are the most prominent in diversity, persistence over time and distance, volume, and in terms of consumers' "willingness to pay". Accordingly, we consider the viandas a good example of a "cultural keystone food group", a food group that is emblematic of a community's culinary conservation.

The good and the bad: alkaloid screening and brineshrimp bioassays of aqueous extracts of 31 medicinal plants of eastern Nicaragua.

CONTEXT: Presence/absence tests for alkaloids of 31 medicinal vascular plant species from 31 genera and 26 families of eastern Nicaragua provided a baseline for bioactivity tests. OBJECTIVE: To determine the bioactivity and cytoxicity of aqueous extracts of widely used medicinal species in eastern Nicaragua. MATERIALS AND METHODS: Ethnomedicinal applications were obtained from interviews of traditional healers. We used Dragendorff's reagent to test alkaloids and brine shrimp for cytotoxicity of aqueous extracts. RESULTS: Twenty-nine of the 31 species tested positive for alkaloids. The median lethal concentration that kills 50% of the larvae within 24 h of contact with the extract (LC(50) was less than 1000 µg/mL for 4 (13%) species (the usual cytotoxic category), 1001-5000 µg/mL for 23 (74%) species, and between 5001-7500 µg/mL for the remaining 4 (13%) species. DISCUSSION AND CONCLUSION: Twenty-five of the ethnomedicines contain alkaloids but are not cytotoxic. In contrast to first suppositions, we suggest that this is a good and desirable, and perhaps expected, outcome. Medicinal plants that are cytotoxic may obviously control or kill bacteria or other pathogens, but may also negatively affect the patient; some high alkaloid levels have been associated with carcinogens. Thus, perhaps the majority of effective medicinals should be expected to be noncytotoxic. We suggest that this is a new paradigm for consideration of the overall value and effectiveness of medicinals. Of course, medicinals also can be effective in numerous ways (e.g., organ stimulation or other physiological functions) other than simply as antimicrobials or antipathogens.

Snakebite ethnopharmacopoeia of eastern Nicaragua.

Results of an ethnopharmacognostic study of snakebite treatments in eastern Nicaragua are presented. Data and specimens were collected during several years of field studies. Field work consisted of plant collecting trips and interviews of snakedoctors. The annual mortality from snakebites in eastern Nicaragua is about 25% and most bites are caused by the fer-de-lance (Bothrops asper). The vascular flora of the region is estimated at 2500 species of which 435 have medicinal application including 81 that are used in snakebite treatment. The majority of species used in snakebite cures are flowering plants, 76% dicots and 20% monocots, and 80% are obtained from the second-growth forest. About half the species are herbs. Leaves are the most frequently utilized plant part. Most herbal remedies are prepared as decoctions and are administered orally. Remedies are mostly prepared with native wild species, but some are introduced domesticates, derived from either the American or Old World Tropics. All the species used contain at least one bioactive compound, and most of these bioactives have been shown in other studies to have pharmacological effects. The use of species in snakebite treatments does not necessarily imply efficacy, but it does give a limited list of species that can be studied pharmacologically for possible bioactive effects. Studies like this one are also important because they document traditional practices and species utilized for the people of the region studied as well.