Insights into the antiosteoporotic mechanism of the soy‐derived isoflavone genistein: Modulation of the Wnt/beta‐catenin signaling

Insights into the antiosteoporotic mechanism of the soy-derived isoflavone genistein: Modulation of the Wnt/beta-catenin signaling

Glucocorticoid-induced osteoporosis (GIO) reduces bone formation, osteoblasts differentiation and function, and accelerates osteoblast and osteocyte apoptosis. Genistein induces bone remodeling through Wnt/β-catenin pathway activation in osteoblast and osteocytes. Genistein could represent an interesting new therapeutic approach for the management of GIO patients.


Abstract

Bone remodeling is a process that involves osteoblasts, osteoclasts, and osteocytes, and different intracellular signaling, such as the canonical Wnt/β-catenin pathway. Dysregulations of this pathway may also occur during secondary osteoporosis, as in the case of glucocorticoid-induced osteoporosis (GIO), which accelerates osteoblast and osteocyte apoptosis by reducing bone formation, osteoblast differentiation and function, accelerates in turn osteoblast, and osteocyte apoptosis. Genistein is a soy-derived nutrient belonging to the class of isoflavones that reduces bone loss in osteopenic menopausal women, inhibiting bone resorption; however, genistein may also favor bone formation. The aim of this study was to investigate whether estrogen receptor stimulation by genistein might promote osteoblast and osteocyte function during glucocorticoid challenge. Primary osteoblasts, collected from C57BL6/J mice, and MLO-A5 osteocyte cell line were used to reproduce an in vitro model of GIO by adding dexamethasone (1 μM) for 24 h. Cells were then treated with genistein for 24 h and quantitative Polymerase Chain Reaction (qPCR) and western blot were performed to study whether genistein activated the Wnt/β-catenin pathway. Dexamethasone challenge reduced bone formation in primary osteoblasts and bone mineralization in osteocytes; moreover, canonical Wnt/β-catenin pathway was reduced following incubation with dexamethasone in both osteoblasts and osteocytes. Genistein reverted these changes and this effect was mediated by both estrogen receptors α and β. These data suggest that genistein could induce bone remodeling through Wnt/β-catenin pathway activation.

Vegetation change over 140 years in a sagebrush landscape of the Rio Grande del Norte National Monument, New Mexico, USA

Vegetation change over 140 years in a sagebrush landscape of the Rio Grande del Norte National Monument, New Mexico, USA

We compared surveys from 1881 with modern vegetation to test for changes in a big sagebrush landscape in a National Monument in New Mexico, USA. We found an increase in sagebrush over 140 years, which contrasts with the sagebrush decline occurring in the Great Basin. These results provide insights into different trends and processes affecting similar vegetation in different regions.


Abstract

Questions

Big sagebrush (Artemisia tridentata) ecosystems across the western United States have experienced many changes in ecosystem dynamics and vegetation composition over the last century due to livestock grazing, non-native species, and changing climate and fire regimes. We conducted the first systematic investigation of historical vegetation composition and vegetation change in a sagebrush landscape in the southwestern United States, asking whether sagebrush or grass dominated the landscape historically?

Location

The Rio Grande del Norte National Monument (RGDN), northern New Mexico, USA.

Methods

We combined General Land Office (GLO) surveys from 1881 with modern vegetation maps, field vegetation surveys, and sagebrush ages from growth ring analysis to test for changes in vegetation in the RGDN over the last 140 years.

Results

We found that big sagebrush presence across the study area increased significantly, from being present on 16% of section lines in 1881 to 79% in 2019, and only three section lines lost sagebrush presence during that period. Concurrently, the number of section lines with low grass index more than doubled since 1881, while moderate and high grass index declined. Grass declined equally in areas where sagebrush increased and areas with no change in sagebrush, suggesting that changes in both vegetation types were catalyzed by external factors, likely including overgrazing. The growth ring analysis of 93 sagebrush revealed a maximum age of 87 years and establishment in every decade since the 1930s, consistent with the GLO results.

Conclusions

The significant vegetation changes in the RGDN over the last century, including an increase of sagebrush, provide important context about the shifting mosaic of grasslands and shrublands relevant to current and future management and ecosystem dynamics.

From the severity patch to the landscape: Wildfire and spatial heterogeneity in northern Sierra Nevada conifer forests

From the severity patch to the landscape: Wildfire and spatial heterogeneity in northern Sierra Nevada conifer forests

Habitat mosaics due to shrub establishment in mixed conifer forest after fire creates high spatial heterogeneity at broader scales. However, reburned patches from high to high and low and moderate to low and moderate severities have less spatial heterogeneity. Under climate change-induced increase in wildfire within short return interval, conifer regeneration within large stand-replaced patches is uncertain.


Abstract

Aims

Prolonged fire suppression in conifer forests of the Sierra Nevada Mountain range, California, USA, has led to ingrowth of conifer seedlings, converting the open heterogeneous structure into uniformly dense and layered forest. The threat of a stand-replacing fire has increased because of fuel buildup in combination with rising drought and extreme heat frequency caused by climate change. With such high severity fire, there is also rising concern regarding conifer forest converting to shrublands as severe fire favors the establishment of large shrub patches altering landscape vegetation pattern and heterogeneity. However, a clear understanding of the effects of increased fire severity, size, and frequency on landscape-scale heterogeneity and postfire patch dynamics is lacking, which is critical in implementing restoration and forest management activities. Our aim was to understand multiscale dynamics and spatial heterogeneity patterns of conifer forests and chaparral shrublands due to repeated mixed-severity fire.

Location

A mosaic of burned and unburned patches spanning the boundary of Lassen and Plumas National Forests, CA, USA.

Methods

We used secondary geospatial landcover data classified by cover type before modern fires (1999) and after eight modern fires (2014). We calculated various landscape diversity and fragmentation metrics at patch and landscape scales using FRAGSTATS for comparison before and after fires.

Results

At the fire severity patch scale, high-severity fire reduced vegetation cover type heterogeneity by half, but reburning at low to moderate severity nearly doubled cover type heterogeneity. At the full landscape scale mixed-severity fire, including all burn severities, increased vegetation cover type heterogeneity. Fragmentation indexes confirmed that fire created larger patches of shrub and fragmented patches of conifer forest.

Conclusions

The effects of frequent large fire events on vegetation pattern and heterogeneity vary with the scale of analysis. Hence, heterogeneity and vegetation pattern change need to be evaluated at more than one scale to understand past and future ecological processes before prioritizing management actions for the conifer forests of the Sierra Nevada Mountain range.

Nifuroxazide repurposing for protection from diabetes‐induced retinal injury in rats: Implication of oxidative stress and JAK/STAT3 axis

Nifuroxazide repurposing for protection from diabetes-induced retinal injury in rats: Implication of oxidative stress and JAK/STAT3 axis

Nifuroxazide (Nifu), the potent STAT3 inhibitor successfully protected the diabetic rats against diabetic retinopathy as it ameliorated the retinal structure deterioration. This effect could be attributed to modulating JAK/STAT3 axis and oxidative stress.


Abstract

The prevalence of diabetes mellitus (DM) is alarmingly increasing worldwide. Diabetic retinopathy (DR) is a prevailing DM microvascular complication, representing the major cause of blindness in working-age population. Inflammation is a crucial player in DR pathogenesis. JAK/STAT3 axis is a pleotropic cascade that modulates diverse inflammatory events. Nifuroxazide (Nifu) is a commonly used oral antibiotic with reported JAK/STAT3 inhibition activity. The present study investigated the potential protective effect of Nifu against diabetes-induced retinal injury. Effect of Nifu on oxidative stress, JAK/STAT3 axis and downstream inflammatory mediators has been also studied. Diabetes was induced in Sprague Dawley rats by single intraperitoneal injection of streptozotocin (50 mg/kg). Animals were assigned into four groups: normal, Nifu control, DM, and DM + Nifu. Nifu was orally administrated at 25 mg/kg/day for 8 weeks. The effects of Nifu on oxidative stress, JAK/STAT3 axis proteins, inflammatory factors, tight junction proteins, histological, and ultrastructural alterations were evaluated using spectrophotometry, gene and protein analyses, and histological studies. Nifu administration to diabetic rats attenuated histopathological and signs of retinal injury. Additionally, Nifu attenuated retinal oxidative stress, inhibited JAK and STAT3 phosphorylation, augmented the expression of STAT3 signaling inhibitor SOCS3, dampened the expression of transcription factor of inflammation NF-κB, and inflammatory cytokine TNF-α. Collectively, the current study indicated that Nifu alleviated DR progression in diabetic rats, suggesting beneficial retino-protective effect. This can be attributed to blocking JAK/STAT3 axis in retinal tissues with subsequent amelioration of oxidative stress and inflammation.

Dietary lithium stimulates female fecundity in Drosophila melanogaster

Dietary lithium stimulates female fecundity in Drosophila melanogaster

Dietary lithium (0.1–5 mM LiCl) improved the lithium status of the female fruit fly Drosophila melanogaster and substantially increased egg production. These findings were accompanied by alterations in mRNA levels of genes encoding proteins involved with chorion formation and yolk protein biosynthesis, which are essential steps in Drosophila oogenesis. (Image created with BioRender.com).


Abstract

The trace element lithium exerts a versatile bioactivity in humans, to some extend overlapping with in vivo findings in the model organism Drosophila melanogaster. A potentially essential function of lithium in reproduction has been suggested since the 1980s and multiple studies have since been published postulating a regulatory role of lithium in female gametogenesis. However, the impact of lithium on fruit fly egg production has not been at the center of attention to date. In the present study, we report that dietary lithium (0.1–5.0 mM LiCl) substantially improved life time egg production in D. melanogaster w 1118 females, with a maximum increase of plus 45% when supplementing 1.0 mM LiCl. This phenomenon was not observed in the insulin receptor mutant InR E19 , indicating a potential involvement of insulin-like signaling in the lithium-mediated fecundity boost. Analysis of the whole-body and ovarian transcriptome revealed that dietary lithium affects the mRNA levels of genes encoding proteins related to processes of follicular maturation. To the best of our knowledge, this is the first report on dietary lithium acting as an in vivo fecundity stimulant in D. melanogaster, further supporting the suggested benefit of the trace element in female reproduction.

Greater variation in boreal plant community composition and community‐level traits at local‐ than regional‐scale

Greater variation in boreal plant community composition and community-level traits at local- than regional-scale

We explored variation in plant community processes in sites spanning the latitudinal extent of the boreal biome of western North America. We found that the majority of variation in plant community composition and functional traits occurred within sites, suggesting that local-scale environmental gradients were more strongly driving plant community dynamics than the regional-scale climatic gradient across our sites.


Abstract

Questions

Rapid climate change in northern latitudes is expected to influence plant functional traits of the whole community (community-level traits) through species compositional changes and/or trait plasticity, limiting our ability to anticipate climate warming impacts on northern plant communities. We explored differences in plant community composition and community-level traits within and among four boreal peatland sites and determined whether intra- or interspecific variation drives community-level traits.

Location

Boreal biome of western North America.

Methods

We collected plant community composition and functional trait data along dominant topoedaphic and/or hydrologic gradients at four peatland sites spanning the latitudinal extent of the boreal biome of western North America. We characterized variability in community composition and community-level traits of understorey vascular and moss species both within (local-scale) and among sites (regional-scale).

Results

Against expectations, community-level traits of vascular plant and moss species were generally consistent among sites. Furthermore, interspecific variation was more important in explaining community-level trait variation than intraspecific variation. Within-site variation in both community-level traits and community composition was greater than among-site variation, suggesting that local environmental gradients (canopy density, organic layer thickness, etc.) may be more influential in determining plant community processes than regional-scale gradients.

Conclusions

Given the importance of interspecific variation to within-site shifts in community-level traits and greater variation of community composition within than among sites, we conclude that climate-induced shifts in understorey community composition may not have a strong influence on community-level traits in boreal peatlands unless local-scale environmental gradients are substantially altered.

Breast cancer diagnosis and management guided by data augmentation, utilizing an integrated framework of SHAP and random augmentation

Breast cancer diagnosis and management guided by data augmentation, utilizing an integrated framework of SHAP and random augmentation

The use of SHAP for feature engineering alongside random augmentation for data balancing for the diagnosis of breast cancer (BC) proposed some management strategies for BC before and after diagnosis Developed models that could help in the diagnosis of BC by prediction using various machine learning algorithms.


Abstract

Recent research indicates that early detection of breast cancer (BC) is critical in achieving favorable treatment outcomes and reducing the mortality rate associated with it. With the difficulty in obtaining a balanced dataset that is primarily sourced for the diagnosis of the disease, many researchers have relied on data augmentation techniques, thereby having varying datasets with varying quality and results. The dataset we focused on in this study is crafted from SHapley Additive exPlanations (SHAP)-augmentation and random augmentation (RA) approaches to dealing with imbalanced data. This was carried out on the Wisconsin BC dataset and the effectiveness of this approach to the diagnosis of BC was checked using six machine-learning algorithms. RA synthetically generated some parts of the dataset while SHAP helped in assessing the quality of the attributes, which were selected and used for the training of the models. The result from our analysis shows that the performance of the models used generally increased to more than 3% for most of the models using the dataset obtained by the integration of SHAP and RA. Additionally, after diagnosis, it is important to focus on providing quality care to ensure the best possible outcomes for patients. The need for proper management of the disease state is crucial so as to reduce the recurrence of the disease and other associated complications. Thus the interpretability provided by SHAP enlightens the management strategies in this study focusing on the quality of care given to the patient and how timely the care is.

Pioneers of post‐agricultural forest successions are adapted for herbivory avoidance but not biotic seed dispersal

Pioneers of post-agricultural forest successions are adapted for herbivory avoidance but not biotic seed dispersal

Natural reforestation through secondary succession in marginal agricultural land is an important component of climate mitigation and adaptation, but the fundamental ecological processes promoting or constraining it are poorly understood. This study provides national-scale evidence that species accumulation in post-agricultural forest successions may be slowed by intense mammalian herbivory and low rates of biotic seed dispersal. Naturally reforesting post-agricultural land, South Island, New Zealand.


Abstract

Question

Natural reforestation is an important component of climate mitigation and adaptation, but the ecological processes promoting or constraining it are poorly understood. In this study we employ a stand reconstruction approach (which uses ages of extant trees to estimate year of establishment for each individual tree) to test for general trait-based effects on tree species arrival order in post-agricultural forest successions.

Location

Naturally reforesting post-agricultural landscapes throughout New Zealand.

Methods

Ages were obtained for 2434 individuals spanning 30 tree species across a nationwide network of 128 plots in 14 naturally reforesting post-agricultural sites. These ages were used to calculate individual-level arrival times (relative to the oldest individual in each plot). We estimated species-level arrival times by fitting linear mixed-effects (LME) regressions (with species identity as the fixed effect, and plots nested within sites as the random effects) to individual arrival time data. We used back-casting (where arrival time data are used to document individual-level presence in plots through time) to track annual changes in species abundance and community-weighted mean (CWM) trait values.

We used standardised major axis (SMA) regressions to examine the effect of traits related to resource use strategy, herbivory avoidance, seed dispersal and disturbance response on species-level arrival times. We used LME regressions to test for changes in CWM trait values with stand age.

Results

The earliest-arriving species had traits associated with herbivory avoidance, were abiotically dispersed and had short predicted dispersal distances. There was no evidence that traits linked to resource use strategy or disturbance response affected species arrival times. Every significant species-level relationship was recovered in community-level LME analyses.

Conclusions

Our findings suggest that mammalian herbivore control and enhancement of biotic (bird) seed dispersal may be key management interventions in realising the full climate mitigation and adaptation potential of natural reforestation in post-agricultural landscapes.

Gut microbiota contribution to selenium deficiency‐induced gut–liver inflammation

Gut microbiota contribution to selenium deficiency-induced gut–liver inflammation

Se deficient imbalance the intestinal microbiota. Se deficient effects gut–liver axis via lipopolysaccharide. Lactobacillus reuteri could alleviate selenium deficiency-induced gut–liver axis injury.


Abstract

There is limited knowledge about the factors that drive gut–liver axis changes after selenium (Se) deficiency-induced gut or liver injuries. Thus, we tested Se deficiency in mice to determine its effects on intestinal bacterial balance and whether it induced liver injury. Serum Se concentration, lipopolysaccharide (LPS) level, and liver injury biomarkers were tested using a biochemical method, while pathological changes in the liver and jejunum were observed via hematoxylin and eosin stain, and a fluorescence spectrophotometer was used to evaluate intestinal permeability. Tight junction (TJ)-related and toll-like receptor (TLR) signaling-related pathway genes and proteins were tested using quantitative polymerase chain reaction, western blotting, immunohistochemistry, and 16S ribosomal ribonucleic acid gene-targeted sequencing of jejunum microorganisms. Se deficiency significantly decreased glutathione peroxidase activity and disrupted the intestinal flora, with the most significant effect being a decrease in Lactobacillus reuteri. The expression of TJ-related genes and proteins decreased significantly with increased treatment time, whereas supplementation with Se, fecal microbiota transplantation, or L. reuteri reversed these decreases. Signs of liver injury and LPS content were significantly increased after intestinal flora imbalance or jejunum injury, and the levels of TLR signaling-related genes were significantly increased. The results indicated that Se deficiency disrupted the microbiota balance, decreased the expression of intestinal TJ factors, and increased intestinal permeability. By contrast, LPS increased due to a bacterial imbalance, which may induce inflammatory liver injury via the TLR4 signaling pathway.

Modulatory effects of point‐mutated IL‐32θ (A94V) on tumor progression in triple‐negative breast cancer cells

Modulatory effects of point-mutated IL-32θ (A94V) on tumor progression in triple-negative breast cancer cells

IL-32θ (A94V) inhibits phosphorylation of FAK and IκBα. IL-32θ (A94V) inhibits the expression and translocation of β-catenin by inhibiting phosphorylated FAK. Additionally, NF-κB is inhibited by IL-32θ (A94V) via the suppression of phosphorylated IκBα. Thus, IL-32θ (A94V) reduces migration, proliferation, and inflammation in breast cancer via the FAK-PI3K-GSK3 and NF-κB pathways.


Abstract

Breast cancer is a frequently diagnosed cancer and the leading cause of death among women worldwide. Tumor-associated macrophages stimulate cytokines and chemokines, which induce angiogenesis, metastasis, proliferation, and tumor-infiltrating immune cells. Although interleukin-32 (IL-32) has been implicated in the development and modulation of several cancers, its function in breast cancer remains elusive. Mutation of interleukin-32θ (IL-32θ) in the tissues of patients with breast cancer was detected by Sanger sequencing. RT-qPCR was used to detect the mRNA levels of inflammatory cytokines, chemokines, and mediators. The secreted proteins were detected using respective enzyme-linked immunosorbent assays. Evaluation of the inhibitory effect of mutant IL-32θ on proliferation, migration, epithelial–mesenchymal transition (EMT), and cell cycle arrest in breast cancer cells was conducted using MTS assays, migration assays, and Western blotting. A point mutation (281C>T, Ala94Val) was detected in IL-32θ in both breast tumors and adjacent normal tissues, which suppressed the expression of pro-inflammatory factors, EMT factors, and cell cycle related factors. Mutated IL-32θ inhibited the expression of inflammatory factors by regulating the NF-κB pathway. Furthermore, mutated IL-32θ suppressed EMT markers and cell cycle related factors through the FAK/PI3K/AKT pathway. It was inferred that mutated IL-32θ modulates breast cancer progression. Mutated IL-32θ (A94V) inhibited inflammation, EMT, and proliferation in breast cancer by regulating the NF-κB (p65/p50) and FAK-PI3K-GSK3 pathways.