Search Results (216)

Sprouty-related proteins with enabled/vasodilator-stimulated phosphoprotein homology 1 (EVH1) domain (SPREDs) are negative regulators of the Ras/MAPK signaling pathway and are known to modulate developmental and endocrine processes. While the roles of SPRED1 and SPRED2 are increasingly understood, the physiological relevance of SPRED3 remains elusive. To elucidate its function, we generated SPRED3 knockout (KO) mice and performed phenotypic, molecular, and hormonal analyses. SPRED3-deficient mice exhibited growth retardation and a non-Mendelian genotype distribution. X-Gal staining revealed Spred3 promoter activity in the thyroid, adrenal gland, pituitary, cerebral cortex, and kidney. Hormonal profiling identified elevated thyroid-stimulating hormone (TSH) and reduced thyroxine (T₄) levels, indicating primary hypothyroidism. Thyroidal extracellular signal-regulated kinase (ERK) signaling was mildly reduced in SPRED3 KO mice, and immunoblotting revealed altered expression of autophagy regulators, including reduced sequestosome 1 (p62), increased autophagy-related gene 5 (ATG5), as well as an elevated microtubule-associated protein 1 light chain 3 (LC3) II/I ratio and a decreased pBeclin/Beclin ratio in SPRED3 KO mice. Our findings indicate that SPRED3 is involved in thyroidal homeostasis and plays a regulatory role in autophagy processes within the thyroid gland. Full article

Polyvinyl chloride (PVC) is commonly employed as mulch in agriculture to boost crop yields. However, its toxicity is often overlooked. Due to its chemical stability, resistance to degradation, and the inadequacy of the recycling system, PVC tends to persist in farm environments, where it can decompose into microplastics (MPs) or nanoplastics (NPs). The radish (Raphanus sativus L.) was chosen as the model plant for this study to evaluate the underlying toxic mechanisms of PVC NPs on seedling growth through the integration of multi-omics approaches with oxidative stress evaluations. The results indicated that, compared with the control group, the shoot lengths in the 5 mg/L and 150 mg/L treatment groups decreased by 33.7% and 18.0%, respectively, and the root lengths decreased by 28.3% and 11.3%, respectively. However, there was no observable effect on seed germination rates. Except for the peroxidase (POD) activity in the 150 mg/L group, all antioxidant enzyme activities and malondialdehyde (MDA) levels were higher in the treated root tips than in the control group. Both transcriptome and metabolomic analysis profiles showed 2075 and 4635 differentially expressed genes (DEGs) in the high- and low-concentration groups, respectively, and 1961 metabolites under each treatment. PVC NPs predominantly influenced seedling growth by interfering with plant hormone signaling pathways and phenylpropanoid production. Notably, the reported toxicity was more evident at lower concentrations. This can be accounted for by the plant’s “growth-defense trade-off” strategy and the manner in which nanoparticles aggregate. By clarifying how PVC NPs coordinately regulate plant stress responses via hormone signaling and phenylpropanoid biosynthesis pathways, this research offers a scientific basis for assessing environmental concerns related to nanoplastics in agricultural systems. Full article

Drought stress severely limits the productivity of sweet potato (Ipomoea batatas L.), yet the stage-specific molecular mechanisms of its adaptation remain poorly understood. Therefore, we integrated transcriptomics and extensive targeted metabolomics analysis to investigate the drought responses of the sweet potato cultivar ‘Luoyu 11’ during the branching and tuber formation stage (DS1) and the storage root expansion stage (DS2) under controlled drought conditions (45 ± 5% field capacity). Transcriptome analysis identified 8292 and 13,509 differentially expressed genes in DS1 and DS2, respectively, compared with the well-watered control (75 ± 5% field capacity). KEGG enrichment analysis revealed the activation of plant hormone signaling, carbon metabolism, and flavonoid biosynthesis pathways, and more pronounced transcriptional changes were observed during the DS2 stage. Metabolomic analysis identified 415 differentially accumulated metabolites across the two growth periods, with flavonoids being the most abundant (accounting for 30.3% in DS1 and 23.7% in DS2), followed by amino acids and organic acids, which highlighted their roles in osmotic regulation and oxidative stress alleviation. Integrated omics analysis revealed stage-specific regulation of flavonoid biosynthesis under drought stress. Genes such as CYP75B1 and IF7MAT were consistently downregulated, whereas flavonol synthase and glycosyltransferases exhibited differential expression patterns, which correlated with the selective accumulation of trifolin and luteoloside. Our findings provide novel insights into the molecular basis of drought tolerance in sweet potato and offer actionable targets for breeding and precision water management in drought-prone regions. Full article

Breast cancer (BC) is the most common malignancy and the second-leading cause of cancer-related mortalities in women. Epidemiological studies suggested the reduced BC incidence in Mediterranean populations due to the daily consumption of diets rich in extra-virgin olive oil (EVOO). EVOO secoiridoid phenolics are widely known for their positive outcomes on multiple cancers, including BC. The current study investigates the suppressive effects of individual and combined EVOO phenolics for BC progression and motility. Screening of a small library of EVOO phenolics at a single dose of 10 µM against the viability of the BC cell lines ZR-75-1 (luminal A) and MDA-MB-231 (triple negative BC, TNBC) identified oleocanthal (OC) and ligstroside aglycone (LA) as the most active hits. Screening of EVOO phenolics for BC cells migration inhibition identified OC, LA, and the EVOO lignans acetoxypinoresinol and pinoresinol as the most active hits. Combination studies of different olive phenolics showed that OC combined with LA had the best synergistic inhibitory effects against the TNBC MDA-MB-231 cells migration. A combination of 5 µM of each of OC and LA potently suppressed the migration and invasion of the MDA-MB-231 cells versus LA and OC individual therapies and vehicle control (VC). Animal studies using the ZR-75-1 BC cells orthotopic xenografting model in female nude mice showed significant tumor progression suppression by the combined OC-LA, 5 mg/kg each, ip, 3X/week treatments compared to individual LA and OC treatments and VC. The BC suppressive effects of the OC-LA combination were associated with the modulation of SMYD2–EZH2–STAT3 signaling pathway. A metastasis–clonogenicity animal study model using female nude mice subjected to tail vein injection of MDA-MB-231-Luc TNBC cells also revealed the effective synergy of the combined OC-LA, 5 mg/kg each, compared to their individual therapies and VC. Thus, EVOO cultivars rich in OC with optimal LA content can be useful nutraceuticals for invasive hormone-dependent BC and TNBC progression and metastasis. Full article

Equine lutropin hormone/choriogonadotropin receptor (LH/CGR) is a G protein-coupled receptor that binds to both luteinizing hormone and choriogonadotropin, with multiple potential N-linked glycosylation sites in the long extracellular domain region. The roles of these glycosylation sites in hormone binding have been widely studied; however, their relationships with cyclic adenosine monophosphate (cAMP) activation, loss of cell surface receptors, and phosphorylated extracellular signal-regulated kinases1/2 (pERK1/2) expression are unknown. We used site-directed mutagenesis with the substitution of Asn for Gln to alter the consensus sequences for N-linked glycosylation, and cAMP signaling was analyzed in the mutants. Specifically, the N174Q and N195Q mutants exhibited markedly reduced expression levels, reaching approximately 15.3% and 2.5%, respectively, of that observed for wild-type equine LH/CGR. Correspondingly, the cAMP EC₅₀ values were decreased by 7.6-fold and 5.6-fold, respectively. Notably, the N195Q mutant displayed an almost complete loss of cAMP activity, even at high concentrations of recombinant eCG, suggesting a critical role for this glycosylation site in receptor function. Despite these alterations, Western blot analysis revealed that pERK1/2 phosphorylation peaked at 5 min following agonist stimulation across all mutants, indicating that the ERK1/2 signaling pathway remains functionally intact. This study demonstrates that the specific N-linked glycosylation site, N195, in equine LH/CGR is indispensable for cAMP activity but is normally processed in pERK1/2 signaling. Thus, we suggest that in equine LH/CGR, agonist treatment induces biased signaling, differentially activating cAMP signaling and the pERK1/2 pathway. Full article

Silk yield enhancement in sericulture has plateaued. Sodium butyrate (NaB) is known to improve production performance in livestock and poultry, yet its effects on silkworm silk yield remain uncharacterized. Here, we evaluated the impact of dietary NaB supplementation on silkworm growth, silk gland development, and cocoon output. Mulberry leaves were immersed in NaB solutions at concentrations of 0, 2.5, 5, 10, 20, 40, or 80 mM, and subsequently provided as feed to third- to fifth-instar larvae. Among these, 10 mM NaB treatment most effectively promoted larval and pupal weight gain and increased food intake. Phenotypic and economic trait analyses revealed that 10 mM NaB treatment significantly enlarged the silk gland and boosted overall silk yield. Mechanistically, NaB enhanced body growth by increasing feeding intake and influencing the juvenile hormone and ecdysteroid signaling pathways; moreover, it promoted DNA replication in silk gland cells, thereby influencing silk gland development. Taken together, our findings demonstrate that dietary supplementation with an appropriate concentration of NaB concurrently enhances body growth and silk gland development, leading to higher silk production, and underscore the potential of short-chain fatty acid salts in advancing sericulture. Full article

(1) Background: As society progresses, increasing numbers of individuals are experiencing hair loss, which can be attributed to factors such as unhealthy diets, insufficient sleep, stress, and hormonal imbalances. Currently available pharmacological treatments for hair loss often cause undesirable side effects, highlighting the urgent need to explore safer and more effective agents to promote hair restoration. This study investigated the role of recombinant human type XVII collagen derived from the α1 chain (rhCOL17A1) in facilitating hair growth and restoration. (2) Methods: We analyzed the impact of rhCOL17A1 on the mRNA expression of several growth factors, as well as Bcl-2 and Bax, at the cellular level. Moreover, the effects of rhCOL17A1 on the expression of key proteins in the Wnt/β-catenin and Sonic Hedgehog (SHH)/GLI signaling pathways were examined by Western blotting (WB). At the organismal level, we established a model in C57BL/6 mice through chronic subcutaneous administration of 5% testosterone propionate. We subsequently assessed the effect of rhCOL17A1 on hair regrowth via histological analysis using hematoxylin and eosin (H&E) staining and immunofluorescence staining. (3) Results: rhCOL17A1 contributes to the resistance of hair follicle dermal papilla cells (HFDPCs) to apoptosis. rhCOL17A1 activates the Wnt/β-catenin and SHH/GLI signaling pathways, and increases the expression of type XVII collagen (COLXVII), thereby creating a favorable environment for hair growth. Furthermore, rhCOL17A1 exerts a significant growth-promoting effect at the animal level. (4) Conclusions: rhCOL17 promotes hair growth by activating the Wnt/β-catenin and SHH/GLI signaling pathways and upregulating COLXVII expression. Full article

Seasonal reproduction in sheep reduces reproductive efficiency. Melatonin (MT) plays a crucial role in reproductive processes. The purpose of this study was to assess the effects of a 5-day MT implant pretreatment on estrus synchronization and reproductive performance in sheep during seasonal anestrus. A total of 40 multiparous Mongolian sheep were selected and randomly divided into two groups. In the MT group (n = 20), the ewes received an MT implant for 5 days, and then, they were given a progesterone (P4)-containing vaginal sponge for 14 days with equine chorionic gonadotropin (eCG) administered (330 I.U. per ewe; I.M.) at sponge removal. Control (CON) ewes (n = 20) were similarly treated but did not receive MT implants. The results demonstrated that MT implantation significantly improved serum levels of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GSH-Px), increased post-ovulatory luteal diameter and serum P4 levels, and reduced ovarian apoptosis. Compared with the CON group, the MT group showed significantly higher pregnancy (68.23% vs. 50.59%) and lambing rates (63.53% vs. 47.06%; number of lambed ewes/number of total ewes) following cervical-timed artificial insemination. Ovarian transcriptome analysis revealed 522 differentially expressed genes (DEGs) in the MT group compared with the CON group, including 355 upregulated and 167 downregulated DEGs. In addition, MT significantly enhanced proliferation and inhibited apoptosis in cultured granulosa cells (GCs) and luteal cells (LCs) in vitro. Moreover, it enhanced the antioxidant capacity of GCs and LCs probably by activating the NRF2 signaling pathway as well as stimulating steroid hormone synthesis. In conclusion, MT implantation 5 days before applying the conventional P4-eCG protocol enhances ovine reproductive outcomes during seasonal anestrus. MT implantation has a beneficial role on the growth and function of ovarian cells. These findings offer novel evidence supporting the functional role of MT in mammalian reproduction, and would be informative for optimizing estrus synchronization in sheep. Full article

The discovery of bioactive natural compounds from microbes holds promise for regenerative medicine. In this study, we identified and characterized a steroid-like compound, 3,12-dioxochola-4,6-dien-24-oic acid (DOCDA), from a crude extract of Rhodococcus sp. DOCDA significantly promoted wound healing by enhancing HaCaT cell invasion and migration. It upregulated key growth factors (EGF, VEGF-A, IGF, TGF-β, and HGF), indicating the activation of regenerative signaling. Additionally, DOCDA increased the expression of genes related to focal adhesion and cytoskeletal regulation (ITGB1, ITGA4, FAK, SRC, RHOA, CDC42, RAC1, and paxillin), supporting enhanced cellular motility and remodeling. Notably, DOCDA promoted stem-like properties in HaCaT cells, as shown by increased spheroid formation and elevated levels of the stemness markers ALDH1 and CD44. Target prediction and molecular docking identified the glucocorticoid receptor (GR) as the primary target of DOCDA, with a docking score of −7.7 kcal/mol. Network and pathway enrichment analysis revealed that GR-linked pathways were significantly associated with wound healing, including steroid hormone signaling, inflammation, immune responses, and cell migration. In vivo, the topical application of DOCDA led to over 70% wound closure in mice by day 5. These findings suggest that DOCDA is a steroid-like compound that accelerates wound healing and may serve as a potential agent in regenerative therapy. Full article

Background/Objectives: Urolithin A (UA), a gut-derived metabolite of ellagitannins or ellagic acid, has recently gained attention for its potential benefits to brain health. The present research aimed to assess the antidepressant-like properties of UA in both in vitro and in vivo models and explored the molecular mechanisms underlying these effects. Methods: We investigated the antidepressant effects and mechanisms of UA in a model of corticosterone-induced damage to PC12 cells and in a model of chronic socially frustrating stress. Results: Our results demonstrate that UA treatment (5 and 10 μM) significantly alleviated cellular damage and inflammation in corticosterone (CORT)-treated PC12 cells. Furthermore, UA administration (50 and 100 mg/kg) significantly reduced immobility time in the mouse tail suspension test (TST) and forced swim test (FST), indicating its antidepressant-like activity. Additionally, treatment with UA led to the activation of the cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling cascade and triggered the activation of adenosine monophosphate-activated protein kinase (AMPK) during these processes. Importantly, pretreatment with AMPK-specific inhibitor Compound C abolished UA’s cytoprotective effects in PC12 cells, as well as its behavioral efficacy in the FST and TST, and its neurotrophic effects, highlighting the critical role of AMPK activation in mediating these effects. Furthermore, in the chronic social defeat stress (CSDS) mouse model, UA treatment (50 and 100 mg/kg) significantly alleviated depression-like behaviors, including reduced sucrose preference in the sucrose preference test, increased social avoidance behavior in the social interaction test, and anxiety-like behaviors, including diminished exploration, in the elevated plus maze test, suggesting the antidepressant-like and anxiolytic-like activities of UA. Moreover, UA treatment reversed elevated serum stress hormone levels, hippocampal inflammation, and the decreased AMPK/CREB/BDNF signaling pathway in the hippocampus of CSDS mice. Conclusions: Together, these results provide compelling evidence for UA as a viable dietary supplement or therapeutic option for managing depression. Full article

Bisphenol A (BPA) is a widely used chemical to produce raw materials in plastic production, which has led to its ubiquity in the natural environment and toxicity to both plants and humans. In this study, we evaluated the phytotoxic effects of BPA on the growth and physiology of pepper (Capsicum annuum L.), a globally cultivated horticultural plant. Our high-performance liquid chromatography (HPLC) result revealed that 0.5 mg/kg of BPA treatment did not lead to the accumulation of BPA in the leaves and fruits of pepper plants. The exogenous application of 5 mg/kg of BPA prominently inhibited pepper growth, while 0.5 mg/kg of BPA had no obvious effects on pepper growth. Additionally, our transcriptomic assay revealed that BPA-regulated gene expression is associated with photosynthesis and reactive oxygen species (ROS) signaling. Physiological and qRT-PCR assays further demonstrated that BPA reduced chlorophyll content and increased ROS levels by regulating the expression of genes related to chlorophyll synthesis and ROS production. Our transcriptomic data also elucidated the potential role of plant hormones, including brassinolides (BR), salicylic acid (SA), jasmonic acid (JA), and strigolactone (SL) in mediating BPA-induced phytotoxicity. Furthermore, BPA activated the N⁶-methyladenosine (m⁶A) modification to exert its toxicity. Collectively, our findings offer additional insights into the mechanisms through which BPA attenuates pepper plant growth, which might contribute new knowledge toward a better scientific assessment of BPA exposure risks in horticultural species. Full article

Background: The management of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with the integration of androgen receptor signaling inhibitors (ARSIs) and metastasis-directed therapies (MDTs). Stereotactic body radiotherapy (SBRT) offers precise local control, yet real-world data on its combination with apalutamide remain limited. Methods: We conducted a multicenter retrospective cohort study including 134 patients with mHSPC treated with apalutamide and SBRT between February 2021 and December 2024. The primary endpoints were progression-free survival (PFS), local control (LC), and treatment safety. PSA kinetics and radiologic response were evaluated, and outcomes were analyzed according to PSA thresholds and treatment timing. Results: Most patients (93.3%) had low-volume disease; 97.1% presented with ≤5 metastases. At a median follow-up of 28 months, LC was 99.3% and 95.5% of patients were progression-free. Complete radiological response was achieved in 87.5% of patients, and 68.4% attained ultralow PSA levels (≤0.02 ng/mL). Undetectable PSA and radiologic complete response were independently associated with improved PFS (p = 0.010 and p = 0.011, respectively). Treatment was well tolerated, with grade ≥3 toxicity occurring in only 2.2% of patients. Conclusions: The combination of apalutamide and SBRT in mHSPC is associated with high local and systemic disease control and minimal toxicity in a real-world setting. This approach may delay systemic treatment intensification and the onset of castration resistance. Prospective studies are warranted to confirm these findings. Full article

Drought stress is one of the primary environmental factors affecting plant survival rates and productivity, and it is a key bottleneck restricting the development of the world kiwifruit industry. Therefore, studying the drought resistance-related genes and drought resistance mechanisms of kiwifruit is essential. The bHLH (basic helix-loop-helix) TF family plays a crucial role in the resistance of kiwifruit to abiotic stresses such as drought stress. In this study, we analyzed the response of the AcbHLH gene in kiwifruit under drought stress based on the kiwifruit genome database, transcriptome data, and metabolome data. One hundred eighty-seven AcbHLH genes were identified via bioinformatics and divided into eighteen subfamilies via phylogenetic analysis. The cis-acting elements of the AcbHLH gene are mainly hormone-related cis-acting elements. Under drought stress, 64 AcbHLH genes were significantly different, 5 AcbHLH genes whose expression significantly differed were randomly selected for qRT-PCR verification, and the correlation between the qRT-PCR results and the transcriptome data was high. The determination of plant hormone contents revealed that the contents of plant hormones, such as JA, changed markedly before and after drought stress. Through the combined analysis of transcriptome and metabolome data, it was speculated that AcbHLH84 and AcbHLH97 have functions similar to those of the MYC2 transcription factor and are the main downstream effectors in the JA signaling pathway; these functions could be activated and participate in the JA signaling pathway and that the activation of the JA signaling pathway would inhibit the production of reactive oxygen species. In turn, the drought resistance of kiwifruit is improved. The AcbHLH84 and AcbHLH97 genes could be candidate genes for breeding new transgenic drought-resistant kiwifruit varieties. Full article

Global climate change has led to an increased frequency of extreme weather events, with flooding caused by heavy rainfall posing a significant threat to plant growth and survival. Styrax japonicus, a species of ecological and economic importance, exhibits stronger flooding tolerance compared to its congener Styrax tonkinensis. Endogenous hormonal systems in plants are indispensable for integrating growth dynamics, developmental transitions, and ecological stress perception-transduction pathways. To investigate the response of S. japonicus to flooding stress at both hormonal and molecular levels, this study utilized annual seedlings of S. japonicus as experimental material. Two levels of flooding stress, waterlogging and submergence, were applied to examine the variations in endogenous hormone levels in S. japonicus roots under different stress conditions and durations. Combined with transcriptome sequencing, critical genes associated with hormone-mediated signaling and biosynthetic processes were identified. The results showed that the content of the ethylene precursor ACC exhibited a trend of “increase–decrease–increase”, with an earlier decline under submergence compared to waterlogging stress by approximately 10 days. Abscisic acid content sharply decreased at 5 d, followed by an initial increase and subsequent decrease, with higher ABA levels observed under waterlogging stress than under submergence. GA content significantly decreased after 10 d in both stress conditions. KEGG enrichment analysis revealed that the most prominently enriched pathway for DEGs was plant hormone signal transduction under both waterlogging and submergence stress, with 314 and 370 DEGs identified, respectively. Analysis of common genes indicated their association with ethylene, ABA, auxin, and BRs. After further investigation of DEGs in the ethylene and ABA biosynthesis process, we identified key enzyme genes encoding ACS, ACO, and NCED, which are critical for their biosynthesis. Full article

Hydrocortisone is a typical glucocorticoid commonly used in livestock production; however, its overuse can result in hormone residues in milk. Long-term consumption of such milk may lead to a series of health issues. Therefore, the timely and rapid detection of hydrocortisone in milk is crucial for protecting human health. In this study, a magnetic particle-based direct chemiluminescence immunoassay (MP-DCLIA) incorporating a streptavidin–biotin signal amplification system was developed for the rapid and high-throughput detection of hydrocortisone in milk. Automated operations reduce human error and enhance the accuracy and repeatability of tests. The assay can be completed in 12 min with a linear detection range of 13.09–261.71 μg/L, a limit of detection (LOD) of 4.94 μg/L, a limit of quantification (LOQ) of 14.84 μg/L, and intra- and inter-batch variations of less than 5%. The method demonstrated stability and exhibited no cross-reactivity with structural analogues. Spiked recoveries of milk samples ranged from 85.85% to 100.30%, with results strongly correlating with those obtained from LC-MS/MS. The MP-DCLIA offers rapidity, high efficiency, stability, and precision, making it a promising tool for practical testing applications. Full article