Search Results (4,505)

Background/Objectives: Copper is an essential micronutrient required for physiological functions, but elevated serum levels impair vascular reactivity and blood pressure regulation. Given PVAT’s critical role in vascular function, this study aimed to investigate the effects of chronic copper overload on the secretory function of mesenteric PVAT, focusing on its vasoregulatory role. Methods: In the first phase, 8-week-old male Wistar rats were assigned to two groups, namely control (saline, i.p.) or copper (25.72 µg/kg/day Cu, i.p., for 30 days), corresponding to twice the recommended daily dose of copper. In the second phase, rats were divided into four groups: control (saline, i.p., water by gavage), copper (Cu, i.p., water by gavage), losartan (saline, i.p., 10 mg/kg/day losartan by gavage), or copper + losartan (Cu, i.p., 10 mg/kg/day losartan by gavage). After euthanasia, mesenteric PVAT was collected for morphometric analysis, gene and protein expression of adipokines, inflammatory molecules, and the renin–angiotensin system. Serum was used for hormone and biochemical measurements. Results: In mesenteric PVAT, chronic copper overload increased adipocyte diameter and reduced lipolysis. It also elevated the secretion of TNF-α and PAI-1 while decreasing IL-10 levels. Additionally, it upregulated the mRNA expression of MCP-1, F4/80, CD86, TLR4, arginase-1, iNOS, ACE1, and AT1R, alongside an increase in serum angiotensin II levels. When copper treatment was combined with losartan, an AT1R antagonist, adipocyte hypertrophy; TNF-α secretion; and the gene expression of TLR4, F4/80, and arginase-1 were attenuated. Conclusions: Chronic exposure to double the recommended dose of Cu disrupts the secretory function of mesenteric PVAT, promoting inflammation and altering the local RAS. These effects appear to occur, at least in part, alongside the activation of the AT1R–TLR4–angiotensin II signaling pathway, triggering the upregulation of vasoregulatory inflammatory markers. Full article

Neurosteroids pregnenolone, progesterone, allopregnanolone, and dehydroepiandrosterone have been actively studied in the last years as candidates for the treatment of neurodegenerative diseases and postinjury rehabilitation. The neuroprotective mechanisms of these neurosteroids have been shown in clinical studies of depression, epilepsy, status epilepticus, traumatic brain injury, fragile X syndrome, and chemical neurotoxicity. However, only the allopregnanolone analogs brexanolone and zuranolone have been recently approved by the FDA for the treatment of depression. The aim of this review was to evaluate whether the endogenous neurosteroids can be used in clinical practice as neuroprotectors. Neurosteroids are multitarget compounds with strong anti-inflammatory, immunomodulatory, and cytoprotective action; they stimulate the synthesis and release of BDNF and increase remyelination and regeneration. In addition to nuclear and membrane steroid hormone receptors, such as PR, mPR, PGRMC1,2, ER, AR, CAR, and PXR, they can bind to GABAA receptors, NMDA receptors, Sigma-1 and -2 receptors (σ1-R/σ2-R). Among these, mPRs, PGRMC1,2, sigma receptors, and mitochondrial proteins attract comprehensive attention because of strong binding with the P4 and DHEA, but subsequent signaling is poorly studied. Other plasma membrane and mitochondrial proteins are involved in the rapid nongenomic neuroprotective action of neurosteroids. P-glycoprotein, BCL-2 proteins, and the components of the mitochondrial permeability transition pore (mPTP) play a significant role in the defense against the injuries of the brain and the peripheral nervous system. The role of these proteins in the molecular mechanisms of action in neuroprotection and neuroinflammation has not yet been clearly established. The aspects of their participation in these pathological processes are discussed. New formulations, such as lipophilic emulsions, nanogels, and microneedle array patches, are attractive strategies to overcome the low bioavailability of these neurosteroids for the amelioration and treatment of various nervous disorders. Full article

Zinc finger-homeodomain (ZF-HD) transcription factors are a unique class that only exist in plants and are essential for plant growth and development, various stress responses, and quality formation and regulation. In recent years, an increasing number of reports regarding this class of transcription factors have been published, identifying their novel functions. In this paper, the evolution, structural characteristics, and subfamily classification of ZF-HD transcription factors are comprehensively introduced and the roles of the ZF-HD in abiotic and biotic stress responses, plant hormone signal transduction, and quality regulation are extensively investigated. In future studies, more efforts should be focused on the in-depth exploration of the mechanisms through which the ZF-HD could act at various stages of plant growth and development. We also determine the current research status and future directions related to the ZF-HD, with the aim of providing a comprehensive knowledge base and research insights for the further exploration of ZF-HD transcription factors in plant molecular biology. Full article

The GLABROUS1 enhancer-binding protein (GeBP) gene family, a plant-specific class of transcriptional regulators, is involved in multiple biological processes, including the formation of trichomes, plant growth, and environmental adaptation. However, the functional characterization of SlGeBP genes in tomato remains poor, particularly regarding their roles in regulating developmental processes and stress response mechanisms. In this study, 11 SlGeBP family members were identified from the tomato genome and 97 GeBP proteins from six species were classified into three groups. A wide range of elements linked to phytohormone, stress, and plant development were presented on the promoter sequences. Gene expression profile analysis revealed a comprehensive expression during the vegetative and immature fruit development stages. Analysis of the expression level under nine hormones and seven stresses can help us to understand the responsiveness of SlGeBP genes associated with hormone induction and stress tolerance. Subcellular localization analysis exhibited that SlGeBP1 and SlGeBP5 were localized in the nucleus, and the yeast two-hybrid assay confirmed that SlGeBP1 could interact with SlGeBP5. This study will help us to understand the potential function of the SlGeBP family and may establish a basis for further research on phytohormone signaling and stress resistance. Full article

The parathyroid and thymus glands are key components of the endocrine and immune systems, respectively, with intriguing developmental, anatomical, and functional interrelationships. This study starts from the hypothesis that, given their shared embryological origin, it is plausible that the thymus and parathyroid glands interact functionally and may share pathological pathways. The present study explores the developmental pathways, spatial proximity, and potential cross-talk between these glands. Recent studies suggest that parathyroid hormone (PTH) may influence thymic function, including T-cell maturation and immune regulation, while thymic signaling molecules could impact calcium homeostasis and parathyroid activity. Understanding the functional and etiopathogenical relations between these endocrine glands offers new insights into endocrine–immunological crosstalk, and therapeutic approaches targeting disorders such as hypoparathyroidism, thymomas, myasthenia gravis and thymic hypoplasia. Perspectives and conclusion: Future research is essential to discover the molecular mechanisms underpinning this dynamic interrelation and its broader implications for health and disease. Because there is still very little data on this interaction, in-depth studies are necessary on large groups of patients. This research proposes a cross-study of the receptors for the main substances secreted by the two categories of endocrine glands. At the same time, it is essential to carry out an in-depth study on the cervico-pericardial ligaments through the lens of this glandular interaction. These ligaments could contain the main blood and nerve communication pathway between the parathyroids and the glands. Full article

Endometriosis is a chronic, hormone-dependent disease that affects women of reproductive age. It leads to numerous adverse clinical symptoms, which significantly impact women’s quality of life. The chronic nature of the disease and its recurrence are the main reasons for the search for new, non-hormonal drugs and drug candidates, either as adjunct treatment options or alternative therapies. The catechin found in green tea, epigallocatechin gallate (EGCG), has been shown to exhibit a wide array of biological activities, which may also contribute to its potential effectiveness in treating endometriosis. The poor physicochemical stability and relatively low bioavailability of EGCG have stimulated the development of a peracetylated prodrug (pro-EGCG) and other solutions, based on nanotechnology, that would eliminate the problems with EGCG. In this review article, we summarize the studies on the effects of EGCG, pro-EGCG, and EGCG-based nanoparticles on the course of endometriosis published in the GoogleScholar and PubMed databases. Of note is the fact that the results of in vitro and animal model studies have suggested that EGCG and pro-EGCG can reduce the number of endometriosis foci and their size and volume, and they can prevent fibrosis by affecting multiple molecular factors and signaling pathways. The promising results provide a basis for using green herbal extracts for endometriosis treatment in a clinical trial. Nevertheless, it should be emphasized that the number of studies on the topic is currently very limited; further expansion in the coming years is necessary. Broad, well-designed clinical trials are also essential to validate the true potential of EGCG and related compounds in the fight against endometriosis. Full article

Background: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with a high mortality and poor prognosis. To elucidate the genetic underpinnings of ACCs, we have analyzed the transcriptome profiles of ACC tumor samples from patients enrolled in the TCGA and NCI cohorts. Methods: We developed a bimodal approach using Gaussian Mixture Models to identify genes with bimodal distribution in ACC samples. Among the 72 bimodally expressed genes that are used to stratify patients into prognostic groups, we focused on SEMA7A, as it encodes a glycosylphosphatidylinositol-anchored membrane glycoprotein (Semaphorin 7a) regulating integrin-mediated signaling, cell migration and immune responses. Results: Our findings reveal that high expression levels of SEMA7A gene are associated with poor prognosis (hazard ratio = 4.27; p-value < 0.001). In hormone-producing ACCs, SEMA7A expression is elevated and positively correlated with genes driving steroidogenesis, aldosterone and cortisol synthesis, including CYP17A1, CYP11A1, INHA, DLK1, NR5A1 and MC2R. Correlation analyses show that SEMA7A is co-expressed with the integrin-β1, FAK (focal adhesion kinase) and MAPK/ERK (mitogen-activated protein kinase/extracellular signal regulated kinases) signaling pathways. Immunohistochemistry (IHC) staining demonstrates the feasibility of evaluating SEMA7A in ACC tissues and shows a significant correlation between gene expression (RNA-Seq) and protein expression (IHC). Conclusions: These findings suggest SEMA7A as a candidate for further research in ACC biology and a candidate for cancer therapy, as well as a potential prognosis biomarker for ACC patients. Full article

It is well established that different fasting strategies offer a range of benefits and may even serve as potential therapeutic approaches for metabolic diseases. The biological effects of intermittent fasting (IF) are multidimensional, involving the induction of metabolic switching from glucose to fatty acid and ketone utilization, thereby enhancing fat metabolism and improving glucose tolerance and insulin sensitivity. In addition, IF modulates the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis by lowering IGF-1 levels, a change associated with enhanced cellular protection, reduced tumorigenesis, and delayed aging. Moreover, IF modulates key signaling pathways, including mitogen-activated protein kinases, Notch, and nuclear factor kappa B, which collectively contribute to reduced oxidative stress, attenuated inflammation, and hepatoprotection. Although fasting may present certain challenges, it is essential to be adequately informed about its potential benefits and appropriate preparatory strategies before undertaking various fasting protocols. This review summarizes the current knowledge on various IF protocols and periodic short-term fasting (PSTF) lasting more than 24 h and up to 72 h, highlighting the signaling pathways through which these interventions affect metabolic processes. Additionally, it aims to provide a practical guide for the safe preparation for PSTF lasting more than 24 h and up to 72 h. Full article

The potato is the fourth largest cultivated crop worldwide. Soil cadmium (Cd) pollution poses a significant threat to crop growth. Brassinosteroids (BRs) play a significant part in enhancing plant resistance against abiotic stresses. The DWF4 (dwarf4) gene is one of the rate-limiting enzyme genes involved in the synthesis of BRs. This study employed seedlings of transgenic potatoes overexpressing the StDWF4 gene (OE) and wild-type (WT) potatoes to clarify their alleviating effect on Cd stresses. The differences in phenotype, ultrastructure, physiological indicators, and plant hormone levels of Cd²⁺-treated potatoes were analyzed. The molecular mechanism of potatoes’ response to Cd²⁺ stress was revealed by transcriptomics. Results showed that the dry weight, fresh weight, plant height, root length, and stem diameter of OE potatoes under Cd stress were significantly higher than those of WT potatoes. Ultrastructural analysis revealed that the mitochondria, cell walls, and cell membranes of WT were more fragile than those of OE under Cd stress. The Cd²⁺ concentration in OE was always lower than that in WT, and both concentrations increased gradually as the duration of Cd²⁺ treatment was prolonged. The 24-epibrassionlide (EBL) content in OE was higher than that in WT. RNA-seq analysis manifested that the gene expression levels of OE and WT plants changed significantly under Cd²⁺ treatment. The differentially expressed genes (DEGs) were primarily connected to the moderation of the metabolic pathways, biosynthesis of secondary metabolites, phenylpropanoid biosynthesis, and plant hormone signal transduction. These findings indicated that overexpression of the StDWF4 gene in potatoes enhanced their alleviating effect on Cd stresses. Full article

The treatment of choice for prostate cancer is androgen deprivation (ADT) and novel hormonal agents such as Abiraterone, Enzalutamide, or Apalutamide. Initially, this therapy is highly effective, but a significant challenge arises as most patients eventually develop resistance, resulting in castration-resistant prostate cancer (CRPC). Furthermore, the sequential use of these drugs can lead to cross-resistance, diminishing their efficacy. Tumor heterogeneity plays a pivotal role in the development of resistance to different treatments. This study utilized cellular models of CRPC to assess the response to Apalutamide when it was administered as a second- or third-line treatment. Functional and genetic analyses were conducted in various CRPC cell models exposed to Apalutamide. These analyses included real-time cell monitoring assays, flow cytometry, clonogenicity assays, and RT-qPCR. CRPC cell models were capable of continued proliferation, maintained cell cycle profiles similar to those of untreated cells, and retained their clonogenic potential. Cross-resistance to Apalutamide in models of ADT, ADT plus Enzalutamide, or Abiraterone resistance did not correlate with the expression levels of AR-V7 and AR-V9 variants. Gene expression analysis of resistant prostate cancer cell lines revealed that treatment with Apalutamide induced the emergence of more aggressive phenotypes, including cancer stem cells or neuroendocrine differentiation profiles. Most CRPC cell models developed cross-resistance to Apalutamide and were able to proliferate and retain their clonogenic capability. Apalutamide resistance was not linked to the expression of AR-V7 or AR-V9 variants but was instead associated to bypass of AR signaling pathway and the emergence of more aggressive expression profiles. Full article

Thyroid hormones (THs) play a central role in cardiovascular and metabolic regulation, influencing lipid metabolism, insulin sensitivity and resting energy expenditure. Inherited disorders of impaired sensitivity to THs—including resistance to thyroid hormone alpha (RTHα) and beta (RTHβ), monocarboxylate transporter 8 (MCT8) deficiency and selenoprotein deficiency—lead to complex, multisystemic clinical features. Although these conditions are rare, with RTHβ being the most common and affecting about 1 in 20,000 newborns, they share clinical features with more prevalent thyroid disorders, such as hypothyroidism and hyperthyroidism, as well as neurological manifestations including muscle wasting and spasticity. These conditions present abnormal patterns of thyroid function and are associated with tissue-specific comorbidities such as arrhythmias, heart failure, dyslipidemia, hepatic steatosis, insulin resistance, and metabolic syndrome. To date, no targeted or controlled studies have evaluated the impact of lifestyle modifications in these patient populations. Therefore, this narrative review proposes plausible management strategies based on pathophysiological insights into the effects of thyroid hormones on target organs, combined with clinical reasoning and evidence extrapolated from related disorders. Physical exercise and diet may complement pharmacological treatments (e.g., levothyroxine or TRIAC) to improve cardiovascular and metabolic outcomes. In RTHβ, aerobic exercise enhances cardiovascular health, while a Mediterranean diet supports lipid control and glycemic parameters. In RTHα, physical exercise may aid neuromotor development, and a fluid-rich, fiber-moderated diet can alleviate constipation. In MCT8 deficiency, physiotherapy may improve mobility and relieve contractures, while nutritional support (e.g., feeding tube, gastrostomy) can be necessary to tackle feeding difficulties and reduce pulmonary complications. In selenoprotein deficiency, low-to-moderate physical exercise and an antioxidant-rich diet may protect against oxidative stress at several tissue levels. Although quantitative evidence is limited, this narrative review synthesizes current insights, providing a meaningful basis for future validation and research. Full article

Background: The increasing prevalence of processed foods has significantly elevated dietary phosphorus intake globally, posing a risk to skeletal health. Elevated serum phosphate promotes parathyroid hormone (PTH) release, leading to bone resorption and decreased bone formation. Objective: This study investigated the influence of chronically elevated phosphorus intake on bone structure in rats with normal renal function, focusing on the Receptor Activator of Nuclear factor Kappa-B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway and its related components, leucine rich repeat containing G protein-coupled receptor 4 (LGR4), and R-spondins (RSPOs). Methods: Rats were fed a high-phosphorus diet, followed by assessment of the bone microstructure and of the expression of key signalling molecules. Results: Elevated phosphorus intake induced significant bone deterioration, particularly in the trabecular bone compartment, associated with alterations in the RANK/RANKL/OPG pathway and in the LGR4 and RSPO1 and RSPO4 signalling components in bone. Moreover, we also observed changes in RANKL, RSPO1 and RSPO4 serum levels in the rats that had received a high-phosphorus diet. Conclusions: These findings highlight the detrimental impact of excessive dietary phosphorus on skeletal health, even without renal impairment, and suggest that components of this pathway, particularly RSPO1 and RSPO4, could serve as potential biomarkers of bone deterioration. The widespread consumption of phosphorus-rich processed foods underscores the importance of nutritional education to mitigate these skeletal risks in industrialized populations. Full article

This study investigates the role of melatonin in alleviating the oxidative stress and apoptosis of TM3 Leydig cells induced by 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), the primary active metabolite of Bisphenol A, and clarifies its potential mechanisms involving the SIRT1/PGC-1α pathway. We found that melatonin effectively mitigated MBP-induced cytotoxicity in TM3 cells (p < 0.05). The testosterone levels and steroid hormone synthesis proteins were significantly restored by melatonin. Furthermore, there was a significant reduction in apoptosis after melatonin treatment both in MBP-treated TM3 cells and Bisphenol A-treated testicular interstitial tissues (p < 0.05), along with a significant decrease in the pro-apoptotic markers Bax and cleaved caspase 3, and a significant increase in the anti-apoptotic Bcl-2 level and the Bcl-2/Bax ratio in TM3 cells (p < 0.05). Additionally, the mitochondrial membrane potential improved significantly, ROS and MDA levels were down-regulated, and ATP production was elevated following melatonin treatment in TM3 cells. Mechanistically, melatonin promoted PGC-1α expression and activated the SIRT1 signaling pathway in MBP-treated TM3 cells and Bisphenol A-treated testicular interstitial tissues. This leads to increased expression of NRF2 and its downstream antioxidant genes, mitochondrial respiratory chain complex-related genes, mitochondrial biogenesis genes, and mitochondrial fusion genes while significantly reducing mitochondrial fission genes (p < 0.05). The PGC-1α inhibitor SR-18292 reversed these protective effects, confirming the critical role of this pathway. Conclusively, melatonin exerts a protective effect against MBP-induced oxidative stress and apoptosis in TM3 cells through the SIRT1/PGC-1α pathway, indicating its potential as a therapeutic agent for improving male reproductive health compromised by environmental toxins. Full article

L-type lectin receptor-like kinases (L-LecRLKs) play key roles in plant responses to environmental stresses and the regulation of growth and development. However, comprehensive studies of the L-LecRLK gene family in wheat (Triticum aestivum L.) are still limited. In this study, 248 L-LecRLK candidate genes were identified in wheat, which is the largest number reported in any species to date. Phylogenetic analysis grouped these genes into four clades (I–IV), with Group IV exhibiting significant monocot-specific expansion. Gene duplication analysis revealed that both whole-genome/segmental and tandem duplications contributed to family expansion, while Ka/Ks ratio analysis suggested that the genes have undergone strong purifying selection. The TaL-LecRLK genes displayed diverse exon-intron structures and conserved motif compositions. Promoter analysis revealed a cis-element associated with hormone signaling and abiotic stress responses. Transcriptome profiling showed that TaL-LecRLKs exhibit tissue- and stage-specific expression patterns. RNA-Seq data revealed that, under drought and heat stress conditions, TaL-LecRLK35-3D and TaL-LecRLK67-6B exhibited synergistic expression patterns, whereas TaL-LecRLK67-6A demonstrated antagonistic expression. A qRT-PCR further demonstrated that six TaL-LecRLKs may function through ABA-independent regulatory mechanisms. These findings provide valuable gene candidates for stress-resistant wheat breeding and shed light on the evolution and functional diversity of L-LecRLKs in plants. Full article

Insulin, a key hormone primarily involved in glucose metabolism, has emerged as a crucial modulator of bone metabolism. Increasing evidence suggests that insulin influences bone health, but its precise mechanism of action remains unestablished. This review explores the intricate relationship between insulin and bone health, as well as elucidating the mechanism of action involved. Animal models of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) demonstrated distinct skeletal alterations, largely attributed to differences in insulin availability and associated metabolic dysfunction. Insulin deficiency in T1DM was associated with the deterioration of trabecular and cortical bone, whereas insulin resistance in T2DM primarily compromised trabecular bone quality. The route, frequency, and duration of insulin administration have been shown to influence bone-related outcomes. Studies involving insulin receptor silencing have suggested that insulin signalling is essential for normal bone development and maintenance. In humans, inconsistent findings on the effects of circulating insulin levels and insulin resistance on bone health were mainly attributed to heterogeneity in age, gender, metabolic status, study designs, population characteristics, and assessment methods. This review also highlights current knowledge gaps and underscores the need for longitudinal studies and mechanistic research. A clearer understanding of the insulin–bone axis may guide the development of targeted strategies to mitigate skeletal complications in individuals with diabetes mellitus. Full article