Receptor Activity Research Articles

Multiancestry Genome-Wide Association Study of Early Childhood Caries.

Early childhood caries (ECC) is the most common noncommunicable childhood disease-an important health problem with known environmental and social/behavioral influences lacking consensus genetic risk loci. To address this knowledge gap, we conducted a genome-wide association study of ECC in a multiancestry population of U.S. preschool-age children (N = 6,103) ages 3 to 5 y participating in a community-based epidemiologic study of early childhood oral health. Calibrated examiners used International Caries Detection and Assessment System criteria to measure ECC; the primary trait was the number of primary tooth surfaces with caries experience (i.e., dmfs index). We estimated heritability and concordance rates and conducted genome-wide association analyses to estimate overall genetic effects as well as stratified by sex, household water fluoride, and dietary sugar and leveraged combined gene/gene-environment effects using 2-degree-of-freedom joint tests. Common genetic variants explained 24% of ECC phenotypic variance among unrelated individuals, while concordance rates were 0.64 (95% confidence interval [CI] = 0.42-0.79) among monozygotic twins and 0.44 (95% CI = 0.34-0.53) among first-degree relatives. Across all analyses, we identified 21 novel nonoverlapping genome-wide significant loci (P < 5 × 10-8) and 1 genome-wide significant gene (TAAR6) associated with ECC. The taste receptor activity gene set, with known roles in chemosensing, bacterial recognition, and innate immunity in the oral cavity, was strongly associated with ECC. While no locus remained significant after studywise multiple-testing correction, 3 loci were nominally significant (P < 0.05) and directionally consistent in external cohorts of 285,248 adults (rs1442369, DLGAP1 and rs74606067, RP11-856F16.2) and 18,994 children (rs71327750, SLC41A3). Meanwhile, the strongest marker known to be associated with adult caries (rs1122171, tagging the long noncoding RNA PITX1-AS1) was nominally significant (P = 0.01) and directionally consistent with ECC in our study. Taken together, the results of this study add to the genomics knowledge base for early childhood caries, offer several plausible candidates for future mechanistic studies, and underscore the importance of accounting for sex and pertinent environmental exposures in genetic investigations.

Epigenome-wide mediation analysis of the relationship between psychosocial stress and cardiometabolic risk factors in the Health and Retirement Study (HRS)

BackgroundExposure to psychosocial stress is linked to a variety of negative health outcomes, including cardiovascular disease and its cardiometabolic risk factors. DNA methylation has been associated with both psychosocial stress and cardiometabolic disease; however, little is known about the mediating role of DNA methylation on the association between stress and cardiometabolic risk. Thus, using the high-dimensional mediation testing method, we conducted an epigenome-wide mediation analysis of the relationship between psychosocial stress and ten cardiometabolic risk factors in a multi-racial/ethnic population of older adults (n = 2668) from the Health and Retirement Study (mean age = 70.4 years).ResultsA total of 50, 46, 7, and 12 CpG sites across the epigenome mediated the total effects of stress on body mass index, waist circumference, high-density lipoprotein cholesterol, and C-reactive protein, respectively. When reducing the dimensionality of the CpG mediators to their top 10 uncorrelated principal components (PC), the cumulative effect of the PCs explained between 35.8 and 46.3% of these associations.ConclusionsA subset of the mediating CpG sites were associated with the expression of genes enriched in pathways related to cytokine binding and receptor activity, as well as neuron development. Findings from this study help to elucidate the underlying mechanisms through which DNA methylation partially mediates the relationship between psychosocial stress and cardiometabolic risk factors.

Conformational dynamics of a nicotinic receptor neurotransmitter site

Agonists enhance receptor activity by providing net-favorable binding energy to active over resting conformations, with efficiency (η) linking binding energy to gating. Previously, we showed that in nicotinic receptors, η-values are grouped into five structural pairs, correlating efficacy and affinity within each class, uniting binding with allosteric activation (Indurthi and Auerbach, 2023). Here, we use molecular dynamics (MD) simulations to investigate the low-to-high affinity transition (L→H) at the Torpedo α−δ nicotinic acetylcholine receptor neurotransmitter site. Using four agonists spanning three η-classes, the simulations reveal the structural basis of the L→H transition where: the agonist pivots around its cationic center (‘flip’), loop C undergoes staged downward displacement (‘flop’), and a compact, stable high-affinity pocket forms (‘fix’). The η derived from binding energies calculated in silico matched exact values measured experimentally in vitro. Intermediate states of the orthosteric site during receptor activation are apparent only in simulations, but could potentially be observed experimentally via time-resolved structural studies.

Conformational dynamics of a nicotinic receptor neurotransmitter site.

Agonists enhance receptor activity by providing net-favorable binding energy to active over resting conformations, with efficiency (η) linking binding energy to gating. Previously, we showed that in nicotinic receptors, η-values are grouped into five structural pairs, correlating efficacy and affinity within each class, uniting binding with allosteric activation (Indurthi and Auerbach, 2023). Here, we use molecular dynamics (MD) simulations to investigate the low-to-high affinity transition (L→H) at the Torpedo α-δ nicotinic acetylcholine receptor neurotransmitter site. Using four agonists spanning three η-classes, the simulations reveal the structural basis of the L→H transition where: the agonist pivots around its cationic center ('flip'), loop C undergoes staged downward displacement ('flop'), and a compact, stable high-affinity pocket forms ('fix'). The η derived from binding energies calculated in silico matched exact values measured experimentally in vitro. Intermediate states of the orthosteric site during receptor activation are apparent only in simulations, but could potentially be observed experimentally via time-resolved structural studies.

Macrophages promote pre-metastatic niche formation of breast cancer through aryl hydrocarbon receptor activity

Macrophages that acquire an immunosuppressive phenotype play a crucial role in establishing the pre-metastatic niche (PMN), which is essential for facilitating breast cancer metastasis to distant organs. Our study showed that increased activity of the aryl hydrocarbon receptor (AHR) in lung macrophages plays a crucial role in establishing the immunosuppressive PMN in breast cancer. Specifically, AHR activation led to high expression of PD-L1 on macrophages by directly binding to the promoter of Pdl1. This upregulation of PD-L1 promoted the differentiation of regulatory T cells (Tregs) within the PMN, further enhancing immunosuppressive conditions. Mice with Ahr conditional deletion in macrophages had reduced lung metastasis of breast cancer. The elevated AHR levels in PMN macrophages were induced by GM-CSF, which was secreted by breast cancer cells. Mechanistically, the activated STAT5 signaling pathway induced by GM-CSF prevented AHR from being ubiquitinated, thereby sustaining its activity in macrophages. In breast cancer patients, the expression of AHR and PD-L1 was correlated with increased Treg cell infiltration, and higher levels of AHR were associated with a poor prognosis. These findings reveal that the crosstalk of breast cancer cells, lung macrophages, and Treg cells via the GM-CSF-STAT5-AHR-PD-L1 cascade modulates the lung pre-metastatic niche during breast cancer progression.

Receptor Activator of Nuclear Factor Kappa-B-Expressing Mesenchymal Stem Cells-Derived Extracellular Vesicles for Osteoporosis Therapy.

The dynamic balance between bone resorption and formation is critical for maintaining healthy bone homeostasis. However, the receptor activator of the nuclear factor B ligand (RANKL) primarily stimulates mature osteoclasts to resorb bone, and its upregulation leads to osteoporosis in patients. Here, we designed RANK-expressing extracellular vesicles (EVs) derived from mesenchymal stem cells to maintain bone homeostasis in mice. This engineered EV (EV@R) effectively neutralizes excess RANKL in bone tissue due to the RANK-RANKL interaction, thereby attenuating osteoclast differentiation. Additionally, we found that miRNA-21a-5p in EV@R contributes to restoring bone metabolic homeostasis. We demonstrate the protective and therapeutic efficacy of EV@R against osteoporosis in the ovariectomy-induced osteoporosis mouse model with a lasting effect and minimal side effects. Our study provides an alternative way to use engineered EVs for bone homeostasis treatment.

Sclerostin and OPG/RANK-L system take part in bone remodeling in patients with acromegaly

IntroductionAcromegaly is a disease characterized by enhanced bone turnover with persistently high vertebral fracture risk. Sclerostin is a glycoprotein, which acts as an inhibitor of bone formation and activates osteoclast-mediated bone resorption. The osteoprotegerin (OPG)/receptor activator for the nuclear factor κ B ligand (RANK-L) system is crucial for controlling bone metabolism.ObjectiveThe study aimed primarily at evaluating sclerostin, OPG, and RANK-L concentrations in patients at different stages of acromegaly activity. The secondary aim was to identify an association of sclerostin with the OPG/RANK-L system and bone mineral density (BMD).Materials and methodsThe study enrolled 126 patients aged 40 to 80 years, including 72 patients with acromegaly and 54 controls (CG). The acromegaly patients were further classified into the following subgroups: active acromegaly (AA), controlled acromegaly (CTA), and cured acromegaly (CA). Blood samples were taken from the participants to measure sclerostin, OPG, RANK-L, growth hormone (GH), and insulin-like growth factor-1 (IGF-1). Dual-energy X-ray absorptiometry was performed at the lumbar spine and hip.ResultsSignificantly lower sclerostin concentrations were observed in acromegaly patients compared with CG (AA, CTA, CA, CTA+CA, AA+CTA+CA vs CG; p &amp;lt; 0.001). Significant differences in OPG concentrations were revealed between the following groups: CTA vs CA (p=0.002), CTA vs CG (p&amp;lt;0.001), CTA+CA vs. CG (p&amp;lt;0.001), and AA+CTA+CA vs. CG (p&amp;lt;0.001). There were no significant differences in RANK-L concentrations between studied groups, regardless of the adopted classification (p&amp;gt;0.05). There were no statistically significant correlations between sclerostin and GH/IGF-1 or BMD. In the AA+CTA+CA group, there was a statistically significant positive correlation between SCL and OPG concentrations (r=0.271; p=0.022). A significant negative correlation between SCL and RANK-L was found in the AA group (r=-0.738; p=0.046).ConclusionsPatients with acromegaly have lower sclerostin concentrations than healthy controls, which may be a result of a compensatory mechanism to increased bone loss. The influence of the GH/IGF-I axis on bone remodeling may be mediated in part by the OPG/RANK-L system. The interaction between SCL and OPG/RANK-L system in acromegaly should be further elucidated.

Progress in the treatment of giant cell tumors of extremities with pathological fracture

Giant cell tumor of bone (GCTB) is a common locally aggressive junctional primary bone tumor, whose clinical treatment becomes more difficult once combined with pathological fracture. Extended curettage and en-bloc resection are common surgical procedures for treating GCTB, and drugs such as receptor activator of nuclear factor-κB ligand(RANKL) inhibitors and bisphosphonates have been successfully used. Curettage is recommended for patients with Campanaccigrade Ⅱor Campanaccigrade Ⅲ with localized soft tissue invasion only and simple fractures with intact bone structure. Resection may be considered for Campanaccigrade Ⅲ with extensive soft tissue invasion or complex fractures with incomplete bone structure. RANKL inhibitors such as denosumab may be recommended if surgery is not possible or before performing resection. This article summarizes the common treatment modalities of pathological fractures combined with giant cell tumors of extremities, including the current status of surgical and pharmacological treatments, analyzing the choice of surgical modalities in different clinical situations, in order to provide clinical inspirations for diagnosis and treatment.

Elevated IL-6 Expression in Autologous Adipose-Derived Stem Cells Regulates RANKL Mediated Inflammation in Osteoarthritis

Interleukin-6 (IL-6) expression in mesenchymal stem cells (MSCs) has been shown to play a pivotal role in modulating cartilage regeneration and immune responses, particularly in the context of diseases that involve both degenerative processes and inflammation, such as osteoarthritis (OA). However, the precise mechanism through which IL-6 and other immune-regulatory factors influence the therapeutic efficacy of autologous adipose-derived stem cells (ASCs) transplantation in OA treatment remains to be fully elucidated. This study aims to investigate the relationship between IL-6 expression in autologous ASCs isolated from OA patients and their impact on immune modulation, particularly focusing on the regulation of Receptor Activator of Nuclear factor Kappa-Β Ligand (RANKL), a key mediator of immune-driven cartilage degradation in OA. Autologous ASCs were isolated from the stromal vascular fraction (SVF) of adipose tissue obtained from 22 OA patients. The isolated ASCs were cultured and characterized using reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and flow cytometry to the phenotype and immune regulatory factors of MSCs. Based on IL-6 expression levels, ASCs were divided into high and low IL-6 expression groups. These groups were then co-cultured with activated peripheral blood mononuclear cells (PBMCs) to evaluate their immune-modulatory capacity, including the induction of regulatory T cells, inhibition of immune cell proliferation, and regulation of key cytokines, such as interferon-gamma (IFN-γ). Additionally, RANKL expression, a critical factor in osteoclastogenesis and cartilage degradation, was assessed in both ASC groups. High IL-6-expressing ASCs demonstrated a significantly greater capacity to inhibit immune cell proliferation and IFN-γ production compared to their low IL-6-expressing counterparts under co-culture conditions. Moreover, the group of ASCs with high IL-6 expression showed a marked reduction in RANKL expression, suggesting enhanced potential to control osteoclast activity and subsequent cartilage defect in OA. Conclusion: Autologous ASCs with elevated IL-6 expression exhibit enhanced immunomodulatory properties, particularly in regulating over-activated immune response and reducing osteoclastogenesis through RANKL suppression. These findings indicate that selecting ASCs based on IL-6 expression could enhance the therapeutic efficacy of ASC-based treatments for OA by mitigating immune-driven joint inflammation and cartilage degradation, potentially slowing disease progression.

Plasma cell-free DNA chromatin immunoprecipitation profiling depicts phenotypic and clinical heterogeneity in advanced prostate cancer.

Cell phenotype underlies prostate cancer presentation and treatment resistance and can be regulated by epigenomic features. However, the osteotropic tendency of prostate cancer limits access to metastatic tissue, meaning most prior insights into prostate cancer chromatin biology are from preclinical models that do not fully represent disease complexity. Noninvasive chromatin immunoprecipitation of histones in plasma cell-free in humans may enable capture of disparate prostate cancer phenotypes. Here, we analyzed activating promoter- and enhancer-associated H3K4me2 from cfDNA in metastatic prostate cancer enriched for divergent patterns of metastasis and diverse clinical presentation. H3K4me2 density across prostate cancer genes, accessible chromatin, and lineage-defining transcription factor binding sites correlated strongly with circulating tumor DNA (ctDNA) fraction-demonstrating capture of prostate cancer-specific biology and informing the development of a statistical framework to adjust for ctDNA fraction. Chromatin hallmarks mirrored synchronously measured clinico-genomic features: bone versus liver-predominant disease, serum PSA, biopsy-confirmed histopathological subtype, and RB1 deletions convergently indicated phenotype segregation along an axis of differential androgen receptor activity and neuroendocrine identity. Detection of lineage switching after sequential progression on systemic therapy in select patients indicates potential utility for individualized resistance monitoring. Epigenomic footprints of metastasis-induced normal tissue destruction were evident in bulk cfDNA from two patients. Finally, a public epigenomic resource was generated using a distinct chromatin marker that has not been widely investigated in prostate cancer. These results provide insight into the adaptive molecular landscape of aggressive prostate cancer and endorse plasma cfDNA chromatin profiling as a biomarker source and biological discovery tool.

The role of osteoprotegerin (OPG) in exercise-induced skeletal muscle adaptation

Abstract Objectives The purpose of this narrative review is to offer an updated perspective on the current research on the glycoprotein Osteoprotegerin (OPG), including its potential therapeutic impact and mechanisms of action, and interaction with bone and muscle tissues. Content As health and social care advances people are living longer, with projections suggesting that in 2050 there will be 2 billion people who are aged over 60 years. Yet musculoskeletal health still declines into older age and as a result there is an increase in the proportion of older populations that spend more time with persistent disabilities. Although physical exercise is repeatedly demonstrated to minimise detrimental effects of ageing, it is not always a feasible intervention, and other directions must be considered. Summary and outlook OPG, a glycoprotein decoy receptor for the receptor activator of nuclear factor kappa-β ligand (RANKL) is a key regulator of bone formation yet emerging evidence has presented its potential to offer positive outcomes in regard to the preservation of skeletal muscle mass and function. Animal models have shown that OPG levels increase during exercise, and independently acts to restore losses of muscle strength and reduce bone resorption. Interventions to increase circulating OPG alongside exercise may act as a therapeutic target to combat the decline in quality of life in older age in humans. Further research is needed on the mechanisms of its action and interaction in humans in combination with exercise.

The Effect of Water-Soluble Alpinia Galanga Extract on Sleep and the Activation of the GABAAergic/Serotonergic Pathway in Mice

Background/Objectives: With increasing interest in plant-based compounds that can enhance sleep quality without the side effects of caffeine, Alpinia galanga (AG) has emerged as a promising herbal supplement for improving mental alertness. This study assessed the impact of water-soluble AG extract on sleep quality; the activity of GABAergic, glutamatergic, and serotonergic receptors; and concentrations of dopamine and serotonin in the brains of mice. Methods: The study employed two experimental models using BALB/c mice to examine the impact of pentobarbital-induced sleep and caffeine-induced insomnia. In the first model, a set of 20 mice was assigned to four groups to assess the effects of pentobarbital (42 mg/kg) or pentobarbital with AG extract on sleep induction, with observations made 45 min post-administration. In the second model, 20 mice were divided into four groups to evaluate the impact of caffeine (25 mg/kg) alone or caffeine with varying doses of AG extract (61.25 or 205.50 mg/kg administered orally) on brain activity along with additional analyses on receptor proteins and neurotransmitters. Results: A higher dose of AG extract (205.50 mg/kg) significantly increased total deep sleep duration compared to the caffeine group (p &lt; 0.0001). Furthermore, this dose extended sleep latency and suppressed GABAergic and glutamatergic receptor activity compared to the lower AG dose (p &lt; 0.05). Additionally, the 205.50 mg/kg dose elevated serotonin and dopamine levels compared to caffeine (p &lt; 0.0001), suggesting improved sleep quality alongside enhanced wakefulness. Conclusions: Our data indicate that a higher dose of AG extract improved sleep latency and duration by regulating GABAergic and glutamatergic receptors through the GABAergic/serotonergic pathway in mice.

Discovery of a Novel Non-invasive AR PROTAC Degrader for the Topical Treatment of Androgenetic Alopecia.

Elevated expression levels and enhanced activity of androgen receptor (AR) proteins are key factors in the development of androgenetic alopecia (AGA). AR proteolysis-targeting chimera (PROTAC) degraders have shown therapeutic potential, but their poor skin permeability requires invasive delivery methods. In this study, we conducted a structure feature analysis to investigate the effects of different linkers and E3 ligands of AR PROTACs on skin retention properties and degradation potency. Among these, compound C6 was discovered with excellent skin retention properties and nanomolar level AR degradation. By degrading AR, C6 regulated the expression levels of downstream paracrine factors associated with AGA. Additionally, after non-invasive topical application, C6 demonstrated excellent skin accumulation and achieved hair regeneration in an AGA mouse model. Overall, the development of non-invasive C6 offers a promising new strategy for AGA treatment and highlights the potential for using PROTACs in treating other skin diseases.

The role of FOXM1 in acetylcysteine improving diabetic periodontitis.

Diabetic periodontitis (DP) stems from hyperglycemia-driven oxidative stress amplification and chronic inflammation, leading to periodontal tissue breakdown. Misregulated forkhead box protein M1 (FOXM1) play key roles in this process, exacerbating both inflammation and oxidative stress. In light of N-Acetylcysteine (NAC)'s potent anti-oxidative capacity and anti-inflammatory potential, understanding how it modulates these central pathways to alleviate DP holds high scientific and clinical importance. An animal model of diabetic mice periodontitis was established, and the model mice were injected with FOXM 1 adenovirus to enrich FOXM 1, and the periodontal pathological histology of each group was evaluated by HE staining. Western blotting and RT-PCR evaluated the expression levels of factors involved in bone destruction. ELISA evaluated the amount of inflammatory factors in mice serum. FOXM 1 over-expression and NAC were treated in murine macrophages, and the intracellular reactive oxygen species(ROS) levels in macrophages were measured using a DCFH-DA probe. Receptor activator of NF-κB ligand (RANKL) and lipopolysaccharide (LPS) were used to establish the macrophage osteoclast differentiation model and test the expression level of osteoclast differentiation factors after giving NAC. Hydrogen peroxide was used to establish a peroxidation environment, the plasmid silenced C-JUN, and the DNA binding activity of activating protein-1(AP1) was detected by EMSA. The effect of peroxidation on the osteoclast differentiation level was determined by WB. Mice with DP model had epithelial damage and inflammatory infiltration in periodontal tissues, and in the FOXM1 enriched group, the periodontal epithelial damage was repaired and inflammation was alleviated. FOXM1 enrichment resulted in DP model lower expression of RANKL (P < 0.01), macrophage colony-stimulating factor (M-CSF) (P < 0.01) and elevated expression of osteoprotegerin (OPG) (P < 0.001). Serum levels of pro-inflammatory factors interleukin (IL)-1β, tumor necrosis factor (TNF-α), and inducible nitric oxide synthase (iNOS) were elevated in DP mice (P < 0.001), and anti-inflammatory factor IL-10 was reduced(P < 0.001),, and FOXM1 enrichment significantly reversed inflammatory factor levels (P < 0.01). Overexpression of FOXM1 reduced ROS content in macrophages (P < 0.001), and NAC was performed to further reduce ROS content (P < 0.01). Silencing of FOXM1 elevated the expression of osteoclast-specific genes NFATc1, TRAP and OSCAR (P < 0.01), and the addition of NAC on top of silencing of FOXM1 markedly suppressed the expression level of osteoclast-specific genes (P < 0.01). ROS increased the transcriptional activity of AP1 (P < 0.001), which promoted osteoclast-specific gene expression (P < 0.001), and osteoclast-specific gene expression was decreased after silencing C-JUN (P < 0.01). FOXM1 relieve diabetic periodontitis inflammation and promote bone formation, regulates ROS production and ROS increases the transcriptional activity of AP1 and affects the osteoclastic differentiation of macrophages, which plays a positive role in bone protection in diabetic periodontitis.

The pivotal role of the Hes1/Piezo1 pathway in the pathophysiology of glucocorticoid-induced osteoporosis.

Glucocorticoid-induced osteoporosis (GIOP) lacks fully effective treatments. This study investigated the role of Piezo1, a mechanosensitive ion channel component 1, in GIOP. We found reduced Piezo1 expression in cortical bone osteocytes from patients with GIOP and a GIOP mouse model. Yoda1, a Piezo1 agonist, enhanced the mechanical stress response and bone mass and strength, which were diminished by dexamethasone (DEX) administration in GIOP mice. RNA-seq revealed that Yoda1 elevated Piezo1 expression by activating the key transcription factor Hes1, followed by enhanced CaM kinase II and Akt phosphorylation in osteocytes. This improved the lacuno-canalicular network and reduced sclerostin production and the receptor activator of NF-κB/osteoprotegerin ratio, which were mitigated by DEX. Comparative analysis of mouse models and human GIOP cortical bone revealed downregulation of mechanostimulated osteogenic factors, such as osteocrin, and cartilage differentiation markers in osteoprogenitor cells. In human periosteum-derived cells, DEX suppressed differentiation into osteoblasts, but Yoda1 rescued this effect. Our findings suggest that reduced Piezo1 expression and activity in osteocytes and periosteal cells contribute to GIOP, and Yoda1 may offer a novel therapeutic approach by restoring mechanosensitivity.

RANKL treatment restores thymic function and improves T cell-mediated immune responses in aged mice.

Age-related thymic involution, leading to reduced T cell production, is one of the major causes of immunosenescence. This results in an increased susceptibility to cancers, infections, and autoimmunity and in reduced vaccine efficacy. Here, we identified that the receptor activator of nuclear factor κB (RANK)-RANK ligand (RANKL) axis in the thymus is altered during aging. Using a conditional transgenic mouse model, we demonstrated that endothelial cells depend on RANK signaling for their cellularity and functional maturation. Decreased RANKL availability during aging resulted in a decline in cellularity and function of both endothelial cells and thymic epithelial cells, contributing to thymic involution. We then found that, whereas RANKL neutralization in young mice mimicked thymic involution, exogenous RANKL treatment in aged mice restored thymic architecture as well as endothelial cell and epithelial cell abundance and functional properties. Consequently, RANKL improved T cell progenitor homing to the thymus and boosted T cell production. This cascade of events resulted in peripheral T cell renewal and effective antitumor and vaccine responses in aged mice. Furthermore, we conducted a proof-of-concept study that showed that RANKL stimulates endothelial cells and epithelial cells in human thymic organocultures. Overall, our findings suggest that targeting the RANK-RANKL axis through exogenous RANKL administration could represent a therapeutic strategy to rejuvenate thymic function and improve T cell immunity during aging.

RANK drives structured intestinal epithelial expansion during pregnancy.

During reproduction, multiple species such as insects and all mammals undergo extensive physiological and morphological adaptions to ensure health and survival of the mother and optimal development of the offspring. Here we report that the intestinal epithelium undergoes expansion during pregnancy and lactation in mammals. This enlargement of the intestinal surface area results in a novel geometry of expanded villi. Receptor activator of nuclear factor-κΒ (RANK, encoded by TNFRSF11A) and its ligand RANKL were identified as a molecular pathway involved in this villous expansion of the small intestine in vivo in mice and in intestinal mouse and human organoids. Mechanistically, RANK-RANKL protects gut epithelial cells from cell death and controls the intestinal stem cell niche through BMP receptor signalling, resulting in the elongation of villi and a prominent increase in the intestinal surface. As a transgenerational consequence, babies born to female mice that lack Rank in the intestinal epithelium show reduced weight and develop glucose intolerance after metabolic stress. Whereas gut epithelial remodelling in pregnancy/lactation is reversible, constitutive expression of an active form of RANK is sufficient to drive intestinal expansion followed by loss of villi and stem cells, and prevents the formation of Apcmin-driven small intestinal stem cell tumours. These data identify RANK-RANKL as a pathway that drives intestinal epithelial expansion in pregnancy/lactation, one of the most elusive and fundamental tissue remodelling events in mammalian life history and evolution.

Breast cancer cells promote osteoclast differentiation in an MRTF-dependent paracrine manner.

Bone is a frequent site for breast cancer metastasis. The vast majority of breast cancer-associated metastasis is osteolytic in nature, and RANKL (receptor activator for nuclear factor κB)-induced differentiation of bone marrow-derived macrophages (BMDMs) to osteoclasts (OCLs) is a key requirement for osteolytic metastatic growth of cancer cells. In this study, we demonstrate that Myocardin-related transcription factor (MRTF) in breast cancer cells plays an important role in paracrine modulation of RANKL-induced osteoclast differentiation. This is partly attributed to MRTF's critical role in maintaining the basal cellular expression of connective tissue growth factor (CTGF), findings that align with a strong positive correlation between CTGF expression and MRTF-A gene signature in the human disease context. Luminex analyses reveal that MRTF depletion in breast cancer cells has a broad impact on OCL-regulatory cell-secreted factors that extend beyond CTGF. Experimental metastasis studies demonstrate that MRTF depletion diminishes OCL abundance and bone colonization breast cancer cells in vivo, suggesting that MRTF inhibition could be an effective strategy to diminish OCL formation and skeletal involvement in breast cancer. In summary, this study highlights a novel tumor-extrinsic function of MRTF relevant to breast cancer metastasis.

Clinical Outcomes and Cytokine Profile of Standard and Short Implant-supported Prostheses in Diabetics Treated for Periodontal Disease: A 5-year Study.

The present cross-sectional study aimed to assess the clinico-radiographic parameters as well as salivary levels of receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin (OPG), interleukin (IL)-6, and tumor necrosis factor-alpha (TNF-α) around standard and short dental implants (SDIs)-supported fixed partial denture in partially dentate type-II diabetes mellitus (T2DM) patients treated for periodontitis. The study comprised 4 groups: group 1 included T2DM patients with standard implants (n = 20); group II included non-T2DM patients with standard implants (n = 20); group III included T2DM patients with SDIs (n = 20); and group IV included non-T2DM patients with SDIs (n = 20). Participants eligible for the study included medically diagnosed T2DM patients with glycated hemoglobin (HbA1c) levels ≥ 6.5%, and non-T2DM participants with HbA1c levels between 4.0% and 5.0%. All had undergone previous periodontal therapy and had at least one standard implant and one SDI in the posterior maxillary or mandibular region. Exclusions were subjects with systemic conditions other than T2DM, recent use of steroids or antimicrobials, pregnancy or lactation, edentulism, misaligned dentition, or alcohol/tobacco use. Treatment involved non-surgical periodontal therapy, implant placement, and prosthetic procedures, with assessments including clinical (plaque index [PI], bleeding on probing [BOP], probing depth [PD]), radiographic (crestal bone loss [CBL]) parameters, and salivary cytokine levels including RANKL, OPG, IL-6, and TNF-α. The study groups, each comprising 20 participants, showed no significant differences in demographics, restoration type, T2DM duration, family history, body mass index, or brushing routine (p>0.05). At baseline and 5-year follow-up, T2DM participants exhibited poorer periodontal parameters compared to non-T2DM, with higher PI (baseline: 62.2 ± 5.8% vs 29.6 ± 3.7%; 5-year follow-up: 69.2 ± 6.1% vs 32.8 ± 3.8%), BOP (baseline: 30.5 ± 3.2% vs 18.2 ± 2.6%; 5-year follow-up: 35.5 ± 3.9% vs 20.5 ± 2.5%), PD (baseline: 5.5 ± 1.1 mm vs 3.1 ± 0.9 mm; 5-year follow-up: 4.2 ± 0.8 mm vs 2.4 ± 0.7 mm), and CBL (baseline: 4.4 ± 0.4 mm vs 2.0 ± 0.2 mm; 5-yearfollow-up: 4.9 ± 0.5 mm vs 2.3 ± 0.3 mm), regardless of implant type. Salivary cytokine levels (RANKL, OPG, IL-6, TNF-α) were consistently higher in T2DM groups than non-T2DM across both implant types. Participants with SDIs showed comparable clinico-radiographic outcomes and salivary levels of cytokines to standard implants. The application of SDI-supported rehabilitation in T2DM and non-diabetics showed comparable clinico-radiographic outcomes and salivary levels of cytokines to standard dental implants. Furthermore, T2DM patients exhibit poorer periodontal health and elevated inflammatory markers in patients with standard implants and SDIs.

The Docking and Dynamics Simulation of Natural Compounds from Abrus precatorius L. for Investigating the Possibility of GluR3 Inhibition to Treat Depression

Background The rising incidence of Major Depressive Disorder (MDD), in conjunction with the inadequate effectiveness and resistance observed in existing therapeutic approaches, emphasizes the urgent need to investigate novel therapeutics that provide enhanced efficacy with reduced adverse effects. Abrus precatorius L., an herb that is readily available and frequently utilized in traditional medicine, is frequently prescribed to patients suffering from neurological disorders. Purpose The goal of this study is to discover novel active compounds from the A. precatorius plant that can specifically target the GluR3 receptor using in silico techniques, to develop a safe and efficient treatment for MDD. Methods Homology modeling, molecular docking, molecular dynamics simulation, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis were employed in this investigation to screen compounds derived from A. precatorius. Their potential to inhibit α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activity, specifically glutamate receptor 3 (GluR3), which is associated with MDD, was the objective of this study. Results Among 31 compounds derived from A. precatorius, 15 successfully cleared the ADMET filter criteria. Subsequently, the best homology model of GluR3 was constructed using Phyre2. This facilitated an investigation into the intramolecular interactions exhibited by the filtered compounds. Notably, the four compounds with the most pronounced binding affinities are identified by their PubChem compound IDs (CIDs): 160511, 44257585, 1983, and 145857. The binding affinity and internal molecular interactions of the top-ranking compound, PubChem CID 160511, were subjected to further validation through MD simulations, affirming its sustained stability in binding. Conclusion CIDs: The compound 160511 cleared ADMET analysis with no notable side effects and high binding affinity and stability, making it a potential drug candidate for MDD. To ascertain the precise efficacy of medications, additional in vitro, in vivo, and clinical studies are required.