Sex-related differences in the structure and function of the adrenal cortex in mature rats are well recognized, largely driven by the action of sex hormones on the hypothalamic-pituitary-adrenal axis (HPA). By replacing testosterone or estradiol in gonadectomized rats, we aimed to elucidate the regulation of micro RNA (miRNA) profiles by sex hormones and their role in physiological adrenal function, providing new insights into gene expression modulation in the adrenal gland. This paper focuses on the description of miRNA profiles using the microarray technique. In our study, we observed significant sex differences in miRNA and mRNA expression levels. These differences are as follows: miRNA expression profiles Male C vs. Female C-0 down, 25 up-regulated, while mRNA profiles were 43 down and 27 up-regulated. Moreover, we observed the most significant differences in miRNA profiles between orchiectomized male rats supplemented with testosterone (ORX + T) and ovariectomized female rats treated with estradiol (OVX + E). Furthermore, we described changes in target gene expression and biological processes regulated by miRNAs. The processes most differentially expressed between the ORX + T and OVX + E groups are those related to the metabolism and synthesis of sterol compounds, the positive and negative regulation of metabolic processes in cells, e.g., cholesterol metabolism, response to various external factors, e.g., hormones, regulation of processes related to cell motility. We also identified several miRNAs, such as miR-370, miR-377, and miR-503, that exhibited interesting changes in their expression after testosterone or estradiol replacement. These results contribute to a deeper understanding of adrenal physiology.

Giardiasis is a common intestinal infection caused by Giardia lamblia. The standard treatment for this parasitic infection involves the administration of nitroimidazoles, albendazoles, and nitrothiazoles. However, in recent years, Giardia lamblia strains resistant to these treatments have been reported. Additionally, the current therapies exhibit considerable side effects, highlighting the need for new compounds that specifically target this parasite. The aim of this study was to evaluate nitrothiazole analogs and assess their impact on the metabolic, redox, and structural gene expression of this parasite. First, the compounds CNZ-7, CNZ-8, FLP-2, FLP-6, and FLP-8 were tested at concentrations ranging from 0 to 50 µM to determine their IC50 in G. lamblia cultures. Subsequently, gene expression changes and structural cell damage in trophozoites were analyzed following incubation with the IC50 of each compound. The giardicidal activity of the compounds was also evaluated in a nitazoxanide-resistant strain. The results showed that FLP-2, FLP-6, and FLP-8 exhibited a stronger effect on trophozoite viability compared to nitazoxanide (NTZ) and metronidazole (MTZ). Both compounds induced an increase in the expression of phosphofructokinase (PFK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase (PK), pyruvate phosphate dikinase (PPDK), and pyruvate:ferredoxin oxidoreductase (PFOR). Additionally, FLP-2 caused ultrastructural alterations in trophozoites. Furthermore, FLP-2, FLP-6, and FLP-8 demonstrated efficacy against drug-resistant strains. These findings suggest that FLP-2, FLP-6, and FLP-8 are promising candidates for the treatment of giardiasis, as they effectively reduce parasite viability, modify gene expression, and exhibit activity against drug-resistant G. lamblia strains.

This study aims to investigate the endogenous gibberellin levels and related genes analysis of noxious invasive weed Heracleum sosnowskyi. Genome-wide identification, phylogenetic analysis, conserved motif analysis, and gene structure characterization of GA-oxidases were performed. We analysed endogenous GAs levels and the expression of target HsGAoxs in response to GA3 within H. sosnowskyi developing ovaries. Twenty-seven HsGAoxs genes were identified, distributed across eleven chromosomes. Phylogenetic analysis classified proteins into the HsGA20ox, C19-HsGA2ox, and HsGA3ox subfamilies, facilitating functional predictions. Among the thirteen HsGA2ox protein members, there were no C20-GA2ox subfamily that distinguish H. sosnowskyi from other model plant species. The analysis of gene structure and conserved motifs confirmed the phylogenetic grouping and suggested that the evolutionary pattern was maintained within these subfamilies. The observed increase in precursor and bioactive GA levels provides evidence that they play a crucial role in promoting fruit growth. Ovary phenotypes reflected the timing of peak gibberellin levels, specifically during the cell expansion period. Exogenous GA3 treatment promoted HsGA3ox1 expression within both the central and lateral regions of the umbel ovaries. Overall, the results show that GA levels are precisely regulated by multiple HsGAox genes for stable early fruit development, and that disturbances in this stability affect fruit development. This opens up the possibility of investigating the role of GA in H. sosnowskyi fruit formation and developing measures for invasion control.

Soil heavy metal pollution by chromium (Cr) and copper (Cu) is a global environmental concern.

Cardiovascular disorders (CVDs) are the leading cause of mortality worldwide, highlighting an urgent need for innovative therapeutic strategies. Recent advancements highlight the potential of naturally derived bioproducts with epigenetic properties to offer protection against CVDs. These compounds act on key epigenetic mechanisms, DNA methylation, histone modifications, and non-coding RNA regulation to modulate gene expression essential for cardiovascular health. This review explores the effects of various bioproducts, such as polyphenols, flavonoids, and other natural extracts, on these epigenetic modifications and their potential benefits in preventing and managing CVDs. We discuss recent discoveries and clinical applications, providing insights into the epigenetic regulatory mechanisms of these compounds as potential epidrugs, naturally derived agents with promising therapeutic prospects in epigenetic therapy for CVDs.

The increasing global incidence of breast cancer calls for the identification of new therapeutic targets and the assessment of possible neem-derived inhibitors by means of computational modeling and integrated genomic research.

Hatchery fumigation is recognized as a crucial step to control microbial bloom in the environment, and formaldehyde is one of the most widely used disinfectants to ensure successful hatchability and healthy production. While many of the benefits are thought to be derived from disinfectant properties, it is possible that additional host gene and genetic pathway modulation could contribute to these outcomes. The current study aimed to capture the in ovo transcriptional response of liver tissue to formaldehyde treatment.

PEIG-1/GPRC5A (phorbol ester induced gene-1/G-protein Coupled Receptor Class C Group 5 Member A) was the first identified member of the orphan G protein-coupled receptor family GPRC5. Deregulation of its expression is associated with the development and progression of various types of tumours, particularly colon carcinoma. In this work, we study the effects of vitamin D (VD, cholecalciferol) and retinoic acid (RA) on GPRC5A mRNA expression in the colorectal cancer cell lines Caco-2 and T84. Both VD (10 µM) and all-trans retinoic acid (ATRA, atRA, RA) (10 µM) increased GPRC5A mRNA levels. Protein kinase C (PKC) inhibition with Gö6983 (10 µM) completely abolished the effects of VD and RA on GPRC5A expression. In parallel, VD and RA increased cytosolic and mitochondrial ROS levels (cROS and mtROS). However, the antioxidants NAC (10 mM) and MitoTEMPO (10 µM) raised GPRC5A gene expression levels in the presence of VD or RA, suggesting that elevated ROS may inhibit GPRC5A expression. In conclusion, both VD and RA stimulate GPRC5A expression. The mechanisms involve a common and essential PKC signalling pathway, as Gö6983 inhibited both VD- and RA-induced signalling.

Multiple myeloma (MM) remains an incurable hematologic malignancy due to the inevitable development of drug resistance, particularly in relapsed or refractory cases. Post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation, and glycosylation, play pivotal roles in regulating protein function, stability, and interactions, thereby influencing MM pathogenesis and therapeutic resistance. This review comprehensively explores the mechanisms by which dysregulated PTMs contribute to drug resistance in MM, focusing on their impact on key signaling pathways, metabolic reprogramming, and the tumor microenvironment. We highlight how PTMs modulate drug uptake, alter drug targets, and regulate cell survival signals, ultimately promoting resistance to PIs, IMiDs, and other therapeutic agents. Furthermore, we discuss emerging therapeutic strategies targeting PTM-related pathways, which offer promising avenues for overcoming resistance to treatment. By integrating preclinical and clinical insights, this review underscores the potential of PTM-targeted therapies to enhance treatment efficacy and improve patient outcomes in MM.

The difference in chicken egg production is closely related to the efficiency of follicle selection, which is marked by granulosa cell differentiation and progesterone production with cholesterol as the substrate. The conversion of 7-dehydrocholesterol to cholesterol catalyzed by 7-Dehydrocholesterol reductase (DHCR7) is the rate-limiting step in cholesterol synthesis. Our previous study revealed that estrogen enhanced the mRNA expression of three DHCR7 transcript variants (T1, T3, and T4) in a dose-dependent manner in the granulosa cells of chicken pre-hierarchical follicles (Pre-GCs). This study investigates the molecular mechanisms through which estrogen regulates DHCR7 in chicken Pre-GCs. At the transcriptional level, through CUT&RUN-qPCR, we found that under basal conditions, sterol-regulatory element binding protein 2 (SREBP2) bound to the promoters of three DHCR7 transcript variants to promote cholesterol synthesis in Pre-GCs to maintain low cholesterol levels; meanwhile upon estrogen treatment, estrogen receptors α and β bound to the regulatory regions of three chicken DHCR7 transcript variants, leading to a reduction in the interaction between SREBP2 and DHCR7. At the translational level, the upstream open reading frames (uORFs) and N6-methyladenosine (m6A) modification in the 5'UTR of different DHCR7 transcripts differentially regulate the expression of T3 and T4, as detected by dual-luciferase reporter assays, but this regulation is not affected by estrogen. This study systematically explores the molecular mechanisms through which estrogen upregulates DHCR7 expression in chicken Pre-GCs and provides a clue for understanding the molecular mechanisms underlying cholesterol synthesis in chicken ovarian follicles.

Inhibitors of cytosolic phospholipase A2 (GIVA cPLA2) have received great attention, since this enzyme is involved in a number of inflammatory diseases, including cancer and auto-immune and neurodegenerative diseases. Traditionally, the effects of GIVA cPLA2 inhibitors in cells have been studied by determining the inhibition of arachidonic acid release. However, although to a lesser extent, GIVA cPLA2 may also hydrolyze glycerophospholipids, releasing other free fatty acids (FFAs), such as linoleic acid or oleic acid. In the present work, we applied a liquid chromatography-high-resolution mass spectrometry method to study the levels of intracellular FFAs, after treating cells with selected GIVA cPLA2 inhibitors. Six inhibitors belonging to different chemical classes were studied, using SH-SY5Y neuroblastoma cells as a model. This lipidomic approach revealed that treatment with each inhibitor created a distinct intracellular FFA profile, suggesting not only inhibitory potency against GIVA cPLA2, but also other parameters affecting the outcome. Potent inhibitors were found to reduce not only arachidonic acid, but also other long-chain FAs, such as adrenic or linoleic acid, even medium-chain FAs, such as caproic or caprylic acid, suggesting that GIVA cPLA2 inhibitors may affect FA metabolic pathways in general. The downregulation of intracellular FFAs may have implications in reprogramming FA metabolism in neurodegenerative diseases and cancer.

FAM46C is a tumor suppressor initially identified in multiple myeloma (MM) but increasingly recognized for its role also in other cancers. Despite its significance, studies exploring the therapeutic potential of FAM46C in combination with targeted treatments remain limited. Sphingosine kinases (SphK1 and SphK2) are key regulators of sphingolipid signaling, a pathway essential for maintaining cell structure and function but frequently deregulated in tumors, making them promising targets for cancer therapy. Preliminary work from our laboratory showed that FAM46C expression synergizes with administration of SKI-I, a pan-inhibitor of sphingosine kinases. In this study, we focused specifically on SphK1, the sphingosine kinase predominantly implicated in cancer and investigated the combinatorial effect of forced FAM46C expression and treatment with PF-543, a selective SphK1 inhibitor. We found that FAM46C overexpression enhances, whereas its downregulation reduces, the cytotoxic efficacy of PF-543 in MM cell lines. Using an in vivo xenograft model, we further validated these findings, showing that FAM46C-expressing MM tumors are indeed sensitive to PF-543 while tumors harboring the D90G loss-of-function variant of FAM46C are not. Overall, our results uncover a novel synergistic interaction between FAM46C expression and SphK1 inhibition, highlighting a promising therapeutic strategy for MM treatment.

Cadmium exposure has been linked to elevated cystatin C levels, disruptions in epigenetic patterns, and increased mortality risk. However, the role of epigenetic modifications in the relationship between cadmium and cystatin C remains poorly understood. Furthermore, it is unclear how cystatin C and epigenetic changes influence the connection between cadmium exposure and mortality outcomes. The study explored the associations among blood cadmium levels, serum cystatin C, an epigenetic biomarker (DNA methylation-predicted cystatin C, DNAmCystatinC), and mortality outcomes.

Scutellarin, a natural compound extracted from Scutellaria barbata, has demonstrated antitumor activity in various cancers. However, its role in ovarian cancer has not been fully explored. This study aims to evaluate the therapeutic potential and underlying mechanisms of Scutellarin in ovarian cancer. The effects of Scutellarin on cell proliferation and migration were assessed in ovarian cancer cell lines including SKOV3, A2780, OVCAR3, and OVCAR8. Patient-derived ovarian cancer organoids were used to further validate the in vitro findings. Calcein-AM and PI staining were used to analyze cell viability, and ATP assays were performed to assess organoid activity. Western blot was used to evaluate the regulation of METTL5 protein by Scutellarin. The gene and protein expression levels of METTL5 and their association with ovarian cancer prognosis were assessed using the databases The Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis 2 (GEPIA2), TNMplot, KM-plotter and The Cancer Genome Atlas (TCGA). The functional role of METTL5 was assessed by transwell migration and colony formation assays, and its involvement in Scutellarin's mechanism of action was confirmed by rescue experiments using wound healing and transwell assays. Scutellarin significantly inhibited the proliferation and migration of ovarian cancer cells. In organoid models, Scutellarin markedly reduced organoid growth, induced cell damage, and decreased ATP levels. Compared to normal ovarian tissue, ovarian cancer tissue exhibited elevated RNA and protein expression levels of METTL5. High METTL5 expression was associated with poorer prognosis in ovarian cancer patients and promoted the migration and clonogenicity of ovarian cancer cells. Scutellarin downregulated METTL5 expression, and rescue experiments demonstrated that Scutellarin inhibited ovarian cancer migration by targeting METTL5. Scutellarin demonstrates potent, broad-spectrum anti-tumor activity in ovarian cancer cell lines, potentially mediated through targeting METTL5. These findings suggest a novel and promising therapeutic strategy for ovarian cancer treatment.

This study aims to evaluate the efficacy of chemotherapy and optimize treatment strategies for patients with advanced ovarian cancer.

Cardiovascular disease remains a leading cause of morbidity and mortality worldwide, frequently arising from platelet hyperactivation and subsequent thrombus formation. Although conventional antiplatelet therapies are available, challenges, such as drug resistance and bleeding complications, require the development of novel agents. In this study, dihydrogeodin (DHG) was isolated from Fennellia flavipes and evaluated using platelets derived from Sprague-Dawley rats. Platelet aggregation induced by collagen, adenosine diphosphate, or thrombin was assessed by light transmission aggregometry; DHG significantly reduced aggregation in a dose-dependent manner. Further assays demonstrated that DHG suppressed intracellular calcium mobilization, adenosine triphosphate release, and integrin αIIbβ3-dependent fibrinogen binding, thereby impairing clot retraction. Western blot analysis revealed that DHG reduced the phosphorylation of mitogen-activated protein kinases (ERK, JNK, p38) and PI3K/Akt, indicating inhibition across multiple platelet-signaling pathways. Additionally, SwissADME-assisted pharmacokinetics predicted favorable properties without violations of the Lipinski (Pfizer) filter, Muegge (Bayer) filter, Ghose filter, Veber filter, and Egan filter, and network pharmacology revealed inhibition of calcium and MAPK pathways. These results highlight the potential of DHG as a novel antiplatelet agent with broad-spectrum activity and promising drug-like characteristics. Further studies are warranted to assess its therapeutic window, safety profile, and potential for synergistic use with existing antiplatelet drugs.

Glioblastoma (GBM) remains almost uniformly fatal, owing in part to therapy-resistant cancer stem-like cells (CSCs) and to temozolomide (TMZ) resistance driven by O6-methylguanine-DNA methyltransferase (MGMT). Differentiation therapy with all-trans retinoic acid (ATRA) has the potential to attenuate stemness and sensitize GBM to TMZ. We therefore asked whether ATRA reduces expression of key CSC markers and MGMT in established GBM lines.

We previously reported that the level of EGFR expression is directly associated with the survival rate of estrogen receptor-positive (ER+) breast cancer patients. Here, we investigated how ER activation by 17β-estradiol (E2), the most potent form of estrogen, affects the expression or activity of EGFR or EGFR-related genes in ER+ breast cancer cells. As expected, E2 enhanced cell proliferation, the induction of S phase, and tumor growth in ER+ breast cancer models. E2 also increased the expression of secretory proteins, including amphiregulin (AREG), angiogenin, artemin, and CXCL16. We focused on AREG, which is a ligand of the epidermal growth factor receptor (EGFR). The levels of AREG expression were positively correlated with ESR1 expression. Our results also showed higher AREG mRNA expression levels in ER+ breast cancer cells than in ER- breast cancer cells. We treated ER+ breast cancer cells with lapatinib to inhibit the AREG/EGFR signaling pathway and then completely inhibited E2-induced cell proliferation and S-phase induction. Similar to the lapatinib treatment, cell proliferation, S-phase induction, cell migration, and tumor growth were suppressed by AREG knockdown. Taken together, we demonstrated that the induction of AREG by E2 contributes to EGFR activation, which then affects cell proliferation and tumor growth. Therefore, we suggest that AREG acts as an intermediary between EGFR and ER and targeting both ERs and EGFRs through combination therapy could prevent tumor progression in EGFR+ ER+ breast cancer patients.

Age-related degenerative changes in intervertebral discs (IVDs) can lead to lower back pain, and even paralysis. This topic is therefore garnering growing attention in an increasingly ageing society. The oxidative stress-induced degenerative process is a major contributor to apoptosis in nucleus pulposus cells. However, the regulatory mechanism of NAD-dependent protein deacetylase Sirtuin-1 (SIRT1) on apoptosis in oxidative stress-induced rat nucleus pulposus cells remains unclear.

Nonsense mutations in gene coding regions introduce an in-frame premature termination codon (PTC) in the mRNA transcript, resulting in the early termination of translation and the production of a truncated, nonfunctional protein. The absence of protein expression and the consequent loss of essential cellular functions are responsible for the severe phenotypes in the so-called genetic nonsense-related diseases (NRDs), such as cystic fibrosis, hemophilia, Duchenne muscular dystrophy, Fabry disease, Choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and even certain types of cancer. Nonsense mutations pose a significant challenge in the treatment of NRDs, as a specific approach directly addressing this genetic defect is currently unavailable. Developing new therapeutic strategies for nonsense suppression is a crucial goal of precision medicine. This review describes some of the most promising therapeutic approaches and emerging strategies for treating NRDs. It considered both the use of small molecules to interfere with molecular mechanisms related to nonsense mutations, such as translational readthrough-inducing drugs (TRIDs) or inhibitors of the nonsense-mediated decay (NMD) pathway, and also innovative approaches involving nucleic acids, such as gene editing, anticodon engineered-tRNA (ACE-tRNA), or mRNA-based therapy. Future research should focus on refining these approaches and exploring integrated and personalized treatments to enhance therapeutic outcomes and ensure continuous improvement in the quality of care.