Cryptosporidium life cycle small molecule probing implicates translational repression and an Apetala 2 transcription factor in macrogamont differentiation.

The apicomplexan parasite Cryptosporidium is a leading cause of childhood diarrhea in developing countries. Current treatment options are inadequate and multiple preclinical compounds are being actively pursued as potential drugs for cryptosporidiosis. Unlike most apicomplexans, Cryptosporidium spp. sequentially replicate asexually and then sexually within a single host to complete their lifecycles. Anti-cryptosporidial compounds are generally identified or tested through in vitro phenotypic assays that only assess the asexual stages. Therefore, compounds that specifically target the sexual stages remain unexplored. In this study, we leveraged the ReFRAME drug repurposing library against a newly devised multi-readout imaging assay to identify small-molecule compounds that modulate macrogamont differentiation and maturation. RNA-seq studies confirmed selective modulation of macrogamont differentiation for 10 identified compounds (9 inhibitors and 1 accelerator). The collective transcriptomic profiles of these compounds indicates that translational repression accompanies Cryptosporidium sexual differentiation, which we validated experimentally. Additionally, cross comparison of the RNA-seq data with promoter sequence analysis for stage-specific genes converged on a key role for an Apetala 2 (AP2) transcription factor (cgd2_3490) in differentiation into macrogamonts. Finally, drug annotation for the ReFRAME hits indicates that an elevated supply of energy equivalence in the host cell is critical for macrogamont formation.

Loss of RAS Mutations in Liquid Biopsies of Patients With Multi-Treated Metastatic Colorectal Cancer.

BACKGROUND: Liquid biopsy (LB) is a non-invasive tool to evaluate the heterogeneity of tumors. Since RAS mutations (RAS-mut) play a major role in resistance to antiepidermal growth factor receptor inhibitors (EGFR) monoclonal antibodies (Mabs), serial monitoring of RAS-mut with LB may be useful to guide treatment. The main aim of this study was to evaluate the prognostic value of the loss of RAS-mut (NeoRAS-wt) in LB, during the treatment of metastatic colorectal cancer (mCRC). METHODS: A retrospective study was conducted on patients with mCRC between January 2018 and December 2021. RAS-mut were examined in tissue biopsy, at mCRC diagnosis, and with LB, during treatment. RESULTS: Thirty-nine patients with RAS-mut mCRC were studied. LB was performed after a median of 3 lines (0-7) of systemic treatment including anti-vascular endothelial growth factor (anti-VEGF) Mabs. NeoRAS-wt was detected in 13 patients (33.3%); 9 (69.2%) of them received further treatment with anti-EGFR Mabs with a disease control rate of 44.4%. Median overall survival (OS), from the date of LB testing, was 20 months in the NeoRAS-wt group and 9 months in the persistent RAS-mut group (log-rank 2.985; P = .08), with a 12-month OS of 84.6% and 57.7%, respectively. NeoRAS-wt was identified as a predictor of survival (HR = 0.29; P = .007), with an 11-month improvement in median OS and a 71% decrease in risk of death, in heavily pretreated patients. CONCLUSIONS: In conclusion, monitoring clonal evolution in mCRC by LB may provide an additional treatment line for patients with NeoRAS-wt in advanced disease.

RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease.

BACKGROUND AND AIMS: Receptor-interacting protein kinase 3 (RIPK3) mediates NAFLD progression, but its metabolic function is unclear. Here, we aimed to investigate the role of RIPK3 in modulating mitochondria function, coupled with lipid droplet (LD) architecture in NAFLD. APPROACH AND RESULTS: Functional studies evaluating mitochondria and LD biology were performed in wild-type (WT) and Ripk3-/- mice fed a choline-deficient, amino acid-defined (CDAA) diet for 32 and 66 weeks and in CRISPR-Cas9 Ripk3 -null fat-loaded immortalized hepatocytes. The association between hepatic perilipin (PLIN) 1 and 5, RIPK3, and disease severity was also addressed in a cohort of patients with NAFLD and in PLIN1 -associated familial partial lipodystrophy. Ripk3 deficiency rescued impairment in mitochondrial biogenesis, bioenergetics, and function in CDAA diet-fed mice and fat-loaded hepatocytes. Ripk3 deficiency was accompanied by a strong upregulation of antioxidant systems, leading to diminished oxidative stress upon fat loading both in vivo and in vitro. Strikingly, Ripk3-/- hepatocytes displayed smaller size LD in higher numbers than WT cells after incubation with free fatty acids. Ripk3 deficiency upregulated adipocyte and hepatic levels of LD-associated proteins PLIN1 and PLIN5. PLIN1 upregulation controlled LD structure and diminished mitochondrial stress upon free fatty acid overload in Ripk3-/- hepatocytes and was associated with diminished human NAFLD severity. Conversely, a pathogenic PLIN1 frameshift variant was associated with NAFLD and fibrosis, as well as with increased hepatic RIPK3 levels in familial partial lipodystrophy. CONCLUSIONS: Ripk3 deficiency restores mitochondria bioenergetics and impacts LD dynamics. RIPK3 inhibition is promising in ameliorating NAFLD.

Polymyxin B-Enriched Exogenous Lung Surfactant: Thermodynamics and Structure.

The use of an exogenous pulmonary surfactant (EPS) to deliver other relevant drugs to the lungs is a promising strategy for combined therapy. We evaluated the interaction of polymyxin B (PxB) with a clinically used EPS, the poractant alfa Curosurf (PSUR). The effect of PxB on the protein-free model system (MS) composed of four phospholipids (diC16:0PC/16:0-18:1PC/16:0-18:2PC/16:0-18:1PG) was examined in parallel to distinguish the specificity of the composition of PSUR. We used several experimental techniques (differential scanning calorimetry, small- and wide-angle X-ray scattering, small-angle neutron scattering, fluorescence spectroscopy, and electrophoretic light scattering) to characterize the binding of PxB to both EPS. Electrostatic interactions PxB-EPS are dominant. The results obtained support the concept of cationic PxB molecules lying on the surface of the PSUR bilayer, strengthening the multilamellar structure of PSUR as derived from SAXS and SANS. A protein-free MS mimics a natural EPS well but was found to be less resistant to penetration of PxB into the lipid bilayer. PxB does not affect the gel-to-fluid phase transition temperature, Tm, of PSUR, while Tm increased by ∼+ 2 °C in MS. The decrease of the thickness of the lipid bilayer (dL) of PSUR upon PxB binding is negligible. The hydrophobic tail of the PxB molecule does not penetrate the bilayer as derived from SANS data analysis and changes in lateral pressure monitored by excimer fluorescence at two depths of the hydrophobic region of the bilayer. Changes in dL of protein-free MS show a biphasic dependence on the adsorbed amount of PxB with a minimum close to the point of electroneutrality of the mixture. Our results do not discourage the concept of a combined treatment with PxB-enriched Curosurf. However, the amount of PxB must be carefully assessed (less than 5 wt % relative to the mass of the surfactant) to avoid inversion of the surface charge of the membrane.

Thermodynamic and Structural Study of Budesonide-Exogenous Lung Surfactant System.

The clinical benefits of using exogenous pulmonary surfactant (EPS) as a carrier of budesonide (BUD), a non-halogenated corticosteroid with a broad anti-inflammatory effect, have been established. Using various experimental techniques (differential scanning calorimetry DSC, small- and wide- angle X-ray scattering SAXS/WAXS, small- angle neutron scattering SANS, fluorescence spectroscopy, dynamic light scattering DLS, and zeta potential), we investigated the effect of BUD on the thermodynamics and structure of the clinically used EPS, Curosurf®. We show that BUD facilitates the Curosurf® phase transition from the gel to the fluid state, resulting in a decrease in the temperature of the main phase transition (Tm) and enthalpy (ΔH). The morphology of the Curosurf® dispersion is maintained for BUD < 10 wt% of the Curosurf® mass; BUD slightly increases the repeat distance d of the fluid lamellar phase in multilamellar vesicles (MLVs) resulting from the thickening of the lipid bilayer. The bilayer thickening (~0.23 nm) was derived from SANS data. The presence of ~2 mmol/L of Ca2+ maintains the effect and structure of the MLVs. The changes in the lateral pressure of the Curosurf® bilayer revealed that the intercalated BUD between the acyl chains of the surfactant's lipid molecules resides deeper in the hydrophobic region when its content exceeds ~6 wt%. Our studies support the concept of a combined therapy utilising budesonide-enriched Curosurf®.

Rhamnolipids: A biosurfactant for the development of lipid-based nanosystems for food applications.

Biosurfactants (surfactants synthesized by microorganisms) are produced by microorganisms and are suitable for use in different areas. Among biosurfactants, rhamnolipids are the most studied and popular, attracting scientists, and industries' interest. Due to their unique characteristics, the rhamnolipids have been used as synthetic surfactants' alternatives and explored in food applications. Besides the production challenges that need to be tackled to guarantee efficient production and low cost, their properties need to be adjusted to the final application, where the pH instability needs to be considered. Moreover, regulatory approval is needed to start being used in commercial applications. One characteristic of interest is their capacity to form oil-in-water nanosystems. Some of the most explored have been nanoemulsions, solid-lipid nanoparticles and nanostructured lipid carriers. This review presents an overview of the main properties of rhamnolipids, asserts the potential and efficiency of rhamnolipids to replace the synthetic surfactants in the development of nanosystems, and describes the rhamnolipids-based nanosystems used in food applications. It also discusses the main characteristics and methodologies used for their characterization and in the end, some of the main challenges are highlighted.

Endometrial hyperplasia with loss of APC in a novel population of Lyz2-expressing mouse endometrial epithelial cells.

Loss of heterozygosity and promoter hypermethylation of APC is frequently observed in human endometrial cancer, which is the most common gynecological cancer in the USA, but its carcinogenic driver status in the endometrial epithelium has not been confirmed. We have identified a novel population of progenitor endometrial epithelial cells (EECs) in mice that express lysozyme M (LysM) and give rise to approximately 15% of all EECs in adult mice. LysM is a glycoside hydrolase that is encoded by Lyz2 and functions to protect cells from bacteria as part of the innate immune system. Its expression has been shown in a subset of hematopoietic stem cells and in specialized lung and small intestinal epithelial cells. Conditional deletion of Apc in LysM + EECs results in significantly more epithelial cells compared to wild-type mice. At 5 months of age, the ApccKO mice have enlarged uterine horns with pathology that is consistent with endometrial hyperplasia with cystic endometrial glands, non-villous luminal papillae and nuclear atypia. Nuclear accumulation of ß-catenin and ERα, both of which are known to induce endometrial hyperplasia, was observed in the EECs of the ApccKO mice. These results confirm that loss of APC in EECs can result in a phenotype similar to endometrial hyperplasia.

PIK3CA mutation in endometriotic epithelial cells promotes viperin-dependent inflammatory response to insulin.

Endometrial epithelia are known to harbor cancer driver mutations in the absence of any pathologies, including mutations in PIK3CA. Insulin plays an important role in regulating uterine metabolism during pregnancy, and hyperinsulinemia is associated with conditions impacting fertility. Hyperinsulinemia also promotes cancer, but the direct action of insulin on mutated endometrial epithelial cells is unknown. Here, we treated 12Z endometriotic epithelial cells carrying the PIK3CAH1047R oncogene with insulin and examined transcriptomes by RNA-seq. While cells naively responded to insulin, the magnitude of differential gene expression (DGE) was nine times greater in PIK3CAH1047R cells, representing a synergistic effect between insulin signaling and PIK3CAH1047R expression. Interferon signaling and the unfolded protein response (UPR) were enriched pathways among affected genes. Insulin treatment in wild-type cells activated normal endoplasmic reticulum stress (ERS) response programs, while PIK3CAH1047R cells activated programs necessary to avoid ERS-induced apoptosis. PIK3CAH1047R expression alone resulted in overexpression (OE) of Viperin (RSAD2), which is involved in viral response and upregulated in the endometrium during early pregnancy. The transcriptional changes induced by insulin in PIK3CAH1047R cells were rescued by knockdown of Viperin, while Viperin OE alone was insufficient to induce a DGE response to insulin, suggesting that Viperin is necessary but not sufficient for the synergistic effect of PIK3CAH1047R and insulin treatment. We identified interferon signaling, viral response, and protein targeting pathways that are induced by insulin but dependent on Viperin in PIK3CAH1047R mutant cells. These results suggest that response to insulin signaling is altered in mutated endometriotic epithelial cells.

In vitro models as a tool to study the role of gut microbiota in obesity.

Obesity, a highly prevalent condition worldwide that leads to the development of multiple metabolic diseases, has been related to gut microbial dysbiosis. To understand this correlation, in vivo models have been extremely useful. However, its use is limited by associated ethical concerns, high costs, low representativeness, and low reproducibility. Therefore, new and improved in vitro models have been developed in recent years, representing a promising tool in the study of the role of gut microbiota modulation in weight management and metabolic health. This review aims to provide an update on the main findings obtained in vitro regarding gut microbiota modulation with probiotics, and food compounds, and its interaction with the host metabolism, associated with obesity. Available in vitro colon models currently used to study obesity are discussed, including batch and dynamic fermentation systems, and models that allow the study of microbiota-host interactions using cell cultures. In vitro models have demonstrated that homeostatic microbiota may help overcome obesity by producing satiety-related neurotransmitters and metabolites that protect the gut barrier and improve the metabolic activity of adipose tissue. In vitro models may be the key to finding new treatments for obesity-related disorders.

Structure-Activity relationships of replacements for the triazolopyridazine of Anti-Cryptosporidium lead SLU-2633.

Cryptosporidiosis is a diarrheal disease particularly harmful to children and immunocompromised people. Infection is caused by the parasite Cryptosporidium and leads to dehydration, malnutrition, and death in severe cases. Nitazoxanide is the only FDA approved drug but is only modestly effective in children and ineffective in immunocompromised patients. To address this unmet medical need, we previously identified triazolopyridazine SLU-2633 as potent against Cryptosporidium parvum, with an EC50 of 0.17 µM. In the present study, we develop structure-activity relationships (SAR) for the replacement of the triazolopyridazine head group by exploring different heteroaryl groups with the aim of maintaining potency while reducing affinity for the hERG channel. 64 new analogs of SLU-2633 were synthesized and assayed for potency versus C. parvum. The most potent compound, 7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine 17a, was found to have a Cp EC50 of 1.2 µM, 7-fold less potent than SLU-2633 but has an improved lipophilic efficiency (LipE) score. 17a was found to decrease inhibition in an hERG patch-clamp assay by about two-fold relative to SLU-2633 at 10 µM despite having similar inhibition in a [3H]-dofetilide competitive binding assay. While most other heterocycles were significantly less potent than the lead, some analogs such as azabenzothiazole 31b, have promising potency in the low micromolar range, similar to the drug nitazoxanide, and represent potential new leads for optimization. Overall, this work highlights the important role of the terminal heterocyclic head group and represents a significant extension of the understanding of the SAR for this class of anti-Cryptosporidium compounds.

Application of enterocin-whey films to reduce Listeria monocytogenes contamination on ripened cheese.

An enterocin whey solution, obtained by growing Enterococcus faecalis L2B21K3 and L3A21K6 in sweet whey - enterocin whey solution (EWS), was incorporated into gelatin/glycerol films that were tested for the control of Listeria monocytogenes. The films containing enterocins produced by either strain (EWS L2 and EWS K6 films) were shown to serve as a suitable matrix for bacteriocin release, preserve the anti-listerial activity for up to 90 days. When applied in cheese, EWS L2 and EWS K6 films were able to reduce L. monocytogenes contamination to undetected levels after 20 or 30 days, respectively, and prevented the migration of this pathogen from the films to cheese. The incorporation of EWS into films did not affect (p < 0.05) moisture content, solubility, permeability (water vapor and limonene), and elongation at break compared to control films (without EWS). However, thickness, swelling index and tensile strength were higher (p < 0.05) in EWS films. These results suggest that active EWS gelatin/glycerol films could be an effective, and safe application to control L. monocytogenes in cheese. In addition, the use of cheese whey as a culture medium for the production of the bacteriocins complemented with the incorporation in films formulation as a packaging material represents an alternative approach to reuse this by-product of cheese production.

Genome-wide effect of non-optimal temperatures under anaerobic conditions on gene expression in Saccharomyces cerevisiae.

Understanding of thermal adaptation mechanisms in yeast is crucial to develop better-adapted strains to industrial processes, providing more economical and sustainable products. We have analyzed the transcriptomic responses of three Saccharomyces cerevisiae strains, a commercial wine strain, ADY5, a laboratory strain, CEN.PK113-7D and a commercial bioethanol strain, Ethanol Red, grown at non-optimal temperatures under anaerobic chemostat conditions. Transcriptomic analysis of the three strains revealed a huge complexity of cellular mechanisms and responses. Overall, cold exerted a stronger transcriptional response in the three strains comparing with heat conditions, with a higher number of down-regulating genes than of up-regulating genes regardless the strain analyzed. The comparison of the transcriptome at both sub- and supra-optimal temperatures showed the presence of common genes up- or down-regulated in both conditions, but also the presence of common genes up- or down-regulated in the three studied strains. More specifically, we have identified and validated three up-regulated genes at sub-optimal temperature in the three strains, OPI3, EFM6 and YOL014W. Finally, the comparison of the transcriptomic data with a previous proteomic study with the same strains revealed a good correlation between gene activity and protein abundance, mainly at low temperature. Our work provides a global insight into the specific mechanisms involved in temperature adaptation regarding both transcriptome and proteome, which can be a step forward in the comprehension and improvement of yeast thermotolerance.

Revealing the Beauty Potential of Grape Stems: Harnessing Phenolic Compounds for Cosmetics.

Grape stems have emerged as a promising natural ingredient in the cosmetics industry due to their abundance of phenolic compounds, known for their antioxidant and anti-inflammatory properties. These compounds have shown great potential in promoting skin health, fighting signs of aging, and shielding against environmental stressors. With high concentrations of resveratrol, flavonoids, and tannins, grape stems have garnered attention from cosmetic scientists. Research has indicated that phenolic compounds extracted from grape stems possess potent antioxidant abilities, effectively combating free radicals that accelerate aging. Moreover, these compounds have demonstrated the capacity to shield the skin from UV damage, boost collagen production, and enhance skin elasticity. Cosmetic formulations incorporating grape stem extracts have displayed promising results in addressing various skin concerns, including reducing wrinkles, fine lines, and age spots, leading to a more youthful appearance. Additionally, grape stem extracts have exhibited anti-inflammatory properties, soothing irritated skin and diminishing redness. Exploring the potential of grape stem phenolic compounds for cosmetics paves the way for sustainable and natural beauty products. By harnessing the beauty benefits of grape stems, the cosmetics industry can provide effective and eco-friendly solutions for consumers seeking natural alternatives. Ongoing research holds the promise of innovative grape stem-based formulations that could revolutionize the cosmetics market, fully unlocking the potential of these extraordinary botanical treasures.

Challenges in Using Ionic Liquids for Cellulosic Ethanol Production.

The growing need to expand the use of renewable energy sources in a sustainable manner, providing greater energy supply security and reducing the environmental impacts associated with fossil fuels, finds in the agricultural by-product bioethanol an economically viable alternative with significant expansion potential. In this regard, a dramatic boost in the efficiency of processes already in place is required, reducing costs, industrial waste, and our carbon footprint. Biofuels are one of the most promising alternatives to massively produce energy sustainably in a short-term period. Lignocellulosic biomass (LCB) is highly recalcitrant, and an effective pretreatment strategy should also minimize carbohydrate degradation by diminishing enzyme inhibitors and other products that are toxic to fermenting microorganisms. Ionic liquids (ILs) have been playing an important role in achieving cleaner processes as a result of their excellent physicochemical properties and outstanding performance in the dissolution and fractionation of lignocellulose. This review provides an analysis of recent advances in the production process of biofuels from LCB using ILs as pretreatment and highlighting techniques for optimizing and reducing process costs that should help to develop robust LCB conversion processes.

Development of Meat Substitutes from Filamentous Fungi Cultivated on Residual Water of Tempeh Factories.

In recent years, there has been an increased motivation to reduce meat consumption globally due to environmental and health concerns, which has driven the development of meat substitutes. Filamentous fungal biomass, commonly known as mycoprotein, is a potential meat substitute since it is nutritious and has filaments to mimic meat fibrils. The current study aimed to investigate the potential use of a cheap substrate derived from the food industry, i.e., residual water in a tempeh factory, for mycoprotein production. The type of residual water, nutrient supplementation, optimum conditions for biomass production, and characteristics of the mycoprotein were determined. The results showed that the residual water from the first boiling with yeast extract addition gave the highest mycoprotein content. The optimum growth condition was a pH of 4.5 and agitation of 125 rpm, and it resulted in 7.76 g/L biomass. The mycoprotein contains 19.44% (w/w) protein with a high crude fiber content of 8.51% (w/w) and a low fat content of 1.56% (w/w). In addition, the amino acid and fatty acid contents are dominated by glutamic acid and polyunsaturated fatty acids, which are associated with an umami taste and are considered healthier foods. The current work reveals that the residual boiling water from the tempeh factory can be used to produce high-quality mycoprotein.

Microbial Hyaluronic Acid Production: A Review.

Microbial production of hyaluronic acid (HA) is an area of research that has been gaining attention in recent years due to the increasing demand for this biopolymer for several industrial applications. Hyaluronic acid is a linear, non-sulfated glycosaminoglycan that is widely distributed in nature and is mainly composed of repeating units of N-acetylglucosamine and glucuronic acid. It has a wide and unique range of properties such as viscoelasticity, lubrication, and hydration, which makes it an attractive material for several industrial applications such as cosmetics, pharmaceuticals, and medical devices. This review presents and discusses the available fermentation strategies to produce hyaluronic acid.

Structural and Physicochemical Properties of Starch from Rejected Chestnut: Hydrothermal and High-Pressure Processing Dependence.

The quality standards for the export of chestnuts generate large quantities of rejected fruits, which require novel processing technologies for their safe industrial utilization. This study aimed to investigate the impact of high-pressure processing (HPP) and hydrothermal treatments (HT) on the physicochemical properties of rejected chestnut starch. Chestnuts were treated by HPP at 400, 500, and 600 MPa for 5 min and HT at 50 °C for 45 min. In general, all HPP treatments did not induce starch gelatinization, and their granules preserved the integrity and Maltese-cross. Moreover, starch granules' size and resistant starch content increased with the intensity of pressure. Native and HT chestnut starches were the most susceptible to digestion. HPP treatments did not affect the C-type crystalline pattern of native starch, but the crystalline region was gradually modified to become amorphous. HPP-600 MPa treated starch showed modified pasting properties and exhibited the highest values of peak viscosity. This study demonstrates for the first time that after HPP-600 MPa treatment, a novel chestnut starch gel structure is obtained. Moreover, HPP treatments could increase the slow-digesting starch, which benefits the development of healthier products. HPP can be considered an interesting technology to obtain added-value starch from rejected chestnut fruits.

Quantification of training load across two competitive seasons in elite senior and youth male soccer players from an English Premiership club.

This study aimed to compare the daily training load (TL) in first-team and U-18 soccer players from an English Premiership club. 36 first-team (age 23.2 ± 5.9 years, weight 75.2 ± 8.1 kg, height 1.83 ± 0.06 m), and 22 U-18 players (age 17.5 ± 1.1 years, weight 71.1 ± 8.2 kg, height 1.78 ± 0.08 m) participated. GPS metrics were measured during all pitch training sessions throughout the 2020-21 and 2021-22 seasons. Linear mixed-effect model analyses revealed that, irrespective of training day, U-18 players covered greater total and explosive distance than first-team players, and performed a higher number of accelerations and decelerations, whereas first-team players covered greater sprint distance. Irrespective of the team, all examined variables were greater at match-day (MD)-3, while the number of accelerations and decelerations were higher at MD-4. Significant team-by-training day interactions revealed that U-18 players covered greater total and high-intensity distances than first-team players at MD-4, MD-2, and MD-1, whereas first-team players covered greater total and high-intensity distances at MD-3. Sprint distance was greater for first-team players at MD-3 and MD-4, while explosive distance was greater for U-18 players at MD-2. Also, U-18 players performed a higher number of accelerations than first-team players at MD-3 and MD-2, and a higher number of decelerations at MD-4. The present results provide novel information on TL patterns in English Premiership soccer and contribute to understanding how training methods to physically develop players are implemented in different countries and leagues.

Modulation of cellular redox environment as a novel therapeutic strategy for Parkinson's disease.

Parkinson's disease (PD) is an incurable neurodegenerative movement disorder. PD affects 2% of the population above 65 years old; however, with the growing number of senior citizens, PD prevalence is predicted to increase in the following years. Pathologically, PD is characterized by dopaminergic cell neurodegeneration in the substantia nigra, resulting in decreased dopamine levels in the nigrostriatal pathway, triggering motor symptoms. Although the pathological mechanisms leading to PD are still unclear, large evidence indicates that oxidative stress plays an important role, not only because it increases with age which is the most significant risk factor for PD development, but also as a result of alterations in several processes, particularly mitochondria dysfunction. The modulation of oxidative stress, especially using dietary mitochondriotropic antioxidants, represents a promising approach to prevent or treat PD. Although most mitochondria-targeted antioxidants with beneficial effects in PD-associated models have failed to show any therapeutic benefit in clinical trials, several questions remain to be clarified. Hereby, we review the role played by oxidative stress in PD pathogenesis, emphasizing mitochondria as reactive oxygen species (ROS) producers and as targets for oxidative stress-related dysfunctional mechanisms. In addition, we also describe the importance of using dietary-based mitochondria-targeted antioxidants as a valuable strategy to counteract the deleterious effects of ROS in pre-clinical and/or clinical trials of PD, pointing out their significance to slow, and possibly halt, the progression of PD.

Obesity alters the mouse endometrial transcriptome in a cell context-dependent manner.

Obesity impacts fertility and is positively correlated with endometrial hyperplasia and endometrial cancer occurrence. Endometrial epithelia often harbor disease driver-mutations, while endometrial stroma are highly regulative of neighboring epithelia. Here, we sought to determine distinct transcriptome changes occurring in individual cell types in the obese mouse uterus. Outbred CD-1 mice were fed high-fat or control diets for 18 weeks, estrous cycle staged, and endometrial epithelia, macrophages, and stroma isolated for transcriptomic analysis. High-fat diet mice displayed increased body mass and developed glucose intolerance, hyperinsulinemia, and fatty liver. Obese mouse epithelia displayed differential gene expression for genes related to innate immunity and leukocyte chemotaxis. The obese mouse stroma differentially expressed factors related to circadian rhythm, and expression of these genes correlated with glucose tolerance or body mass. We observed correlations between F4/80 + macrophage numbers, Cleaved Caspase 3 (CC3) apoptosis marker staining and glucose intolerance among obese mice, including a subgroup of obese mice with high CC3 + luminal epithelia. This subgroup displayed differential gene expression among all cell types, with pathways related to immune escape in epithelia and macrophages, while the stroma dysregulated pathways related to regulation of epithelia. These results suggest an important role for differential response of both the epithelia and stroma in their response to obesity, while macrophages are dysregulated in the context of apoptotic epithelia. The obesity-related gene expression programs in cells within the uterine microenvironment may influence the ability of the endometrium to function during pregnancy and influence disease pathogenesis.