Search Results (31,504)

The retinoblastoma (RB) gene is an important tumor suppressor gene with a higher mutation frequency than other tumor suppressor genes. The mutation or inactivation of RB has been found in various cancers. The discovery of small molecules to promote RB expression is an effective anti-cancer strategy. Special DNA secondary structures with G-quadruplex and i-motif on the RB promoter could act as “molecular switches” for gene transcriptional regulation and are potentially important targets for the development of new anti-cancer drugs. After extensive screening, we found that the bisacridine derivative A06 had selective binding and destabilization for both the G-quadruplex and i-motif on the RB promoter, which significantly up-regulated RB gene transcription and translation, resulting in the inhibition of tumor cell proliferation and metastasis. A06 exhibited potent anti-tumor activity on Hela cells and strongly suppressed tumor growth on the Hela xenograft mice model without significant toxicity. In comparison, A02 exhibited strong binding and destabilization to the RB promoter G-quadruplex only, which showed a much weaker effect than A06 on regulating RB expression and producing anti-tumor activity. As we know, this is the first study for up-regulating a tumor suppressor gene through destabilization of both the G-quadruplex and i-motif on the gene promoter, which provides a new strategy for innovative anti-cancer drug discovery and development. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer. Late diagnosis and acquisition of chemoresistance contribute to its dismal prognosis. While surgical resection improved the clinical outcome of patients, only ~20% of them are eligible due to advanced disease at diagnosis. Thus, the development of new therapeutic approaches is a master priority for an improved management of this cancer. The helicase DDX21 was proposed as a prognostic marker in several tumors, including PDAC. Methods: DDX21 expression was evaluated in PDAC samples and cell lines; RNA sequencing and bioinformatics analyses of DDX21-depleted PANC-1 silenced cells; functional analyses of autophagy, cell cycle and proliferation. Results: DDX21 is expressed at higher levels in liver metastasis of PDAC patients. Transcriptomics analyses of DDX21-depleted cells revealed an enrichment in genes involved in autophagy and cell cycle progression. The inactivation of DDX21 by RNA interference enhanced the basal autophagic flux and altered the cell cycle by reducing the rate of G1-S transition. Coherently, PDAC cell proliferation and clonogenic activity was significantly reduced. Conclusions: Our results support the oncogenic role of DDX21 in PDAC and uncover a new role for this helicase in the regulation of basal autophagy. Full article

This study aimed to evaluate the effect of a newly formulated Commiphora molmol (CM) nano-irrigant on the morphology, viability, proliferation, migration, and wound healing of human bone marrow-derived mesenchymal stem cells (hBMMSCs). Different concentrations of CM nano-irrigant were prepared. The minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were determined to be 25 and 30 mg/mL, respectively. The solution was dispersed into liposomes, which were subsequently coated with chitosan-forming chitosomes. Three concentrations of CM chitosomes were evaluated (25, 30, and 35 mg/mL) along with positive (5.25% NaOCl) and negative (basal culture media) control groups. Cellular viability and proliferation were quantified using AlamarBlue, while wound-healing ability was determined using the scratch assay, and 3D cellular migration was evaluated using the transwell migration assay. All tested concentrations induced observable changes in cellular morphology without any detrimental effects. Viability was monitored at 1, 6, and 24 h, with only Group 1 (25 mg/mL) showing no significant effect on cellular viability. Cellular proliferation was observed over 14 days, with Group 3 (35 mg/mL) being the only group that showed a significantly slower proliferative rate. All tested concentrations resulted in significant differences in transwell migration compared to the negative control. Significant differences were observed within each group across different time points (24–48 h). The results confirm the biocompatibility of the newly formulated CM nano-irrigant in terms of hBMMSCs’ viability, proliferation, morphology, migration, and wound healing. Full article

Previous studies have demonstrated corilagin’s inhibitory effects on the growth of various cancer cells. Given the limited research on corilagin’s impact on ovarian cancer, a particularly deadly gynecological malignancy, this study aimed to investigate corilagin’s influence on A2780 ovarian cancer cell apoptosis and its underlying mechanisms. The goal was to evaluate corilagin’s potential as a therapeutic agent for ovarian cancer. The results of the CCK-8 assay showed that corilagin inhibited the proliferation of A2780 ovarian cancer cells while exhibiting lower toxicity to normal ovarian surface epithelial cells (IOSE-80). We found that corilagin significantly altered the A2780 cell cycle, decreasing the proportion of cells in the G₀/G₁ and G₂/M phases and inducing cell cycle arrest in the S phase. At low concentrations, corilagin induced apoptosis in A2780 cells, accompanied by a decline in mitochondrial membrane potential and calcium influx. Transcriptome sequencing analysis identified differentially expressed apoptosis-related genes in corilagin-treated A2780 cells, primarily within the PI3K-AKT pathway. Furthermore, qPCR and Western blot results confirmed the upregulation of p53 and Bax genes and the downregulation of BCL-2. Corilagin also increased the expression of apoptotic factors caspase-9, caspase-3, PUMA, and cytochrome C, indicating its ability to induce apoptosis. Overall, corilagin effectively inhibited A2780 cell proliferation, induced cell cycle arrest, and triggered apoptosis. Its anti-tumor effect in vitro suggests its potential as a therapeutic agent for ovarian cancer A2780, especially through the PI3K/p53 pathway. Full article

The study objectives were to investigate the heat resistance using peripheral blood mononuclear cells (PBMCs) and hair follicles in beef and dairy calves based on heat shock protein (HSP) 70 genetic polymorphisms. The hair follicle samples from sixty calves (6 months old; 30 Korean native beef calves and 30 Holstein dairy calves) were collected for DNA extraction. The HSP70 single nucleotide polymorphism (SNP) was genotyped using a 5′-exonuclease activity (TaqMan) assay. In Study 1, PBMCs were isolated from 20 calves categorized by their HSP70 genotypes during a thermoneutral period: 10 Korean native beef calves (B-CC and B-C/-type) and 10 Holstein dairy calves (D-CC, D-C/-type). The PBMCs were then exposed to heat stress at 37 °C (control, CON) and 42 °C (heat stress, HS) for 3 h. Following this, the cells were returned to the 37 °C incubator at 0, 1, 3, 6, and 12 h for further recovery analysis. In Study 2, hair follicles were collected from 20 calves (six times every 30 days; threshold, mild, and moderate stress levels) and HSP70 gene expression was measured. Data were analyzed via two-way analysis of variance (ANOVA) and Tukey’s honestly significant difference (HSD) test. The cell proliferation in the D-C/-group was significantly higher (p < 0.05) than in the D-CC and B-C/-groups at 0 and 1 h after HS for 3 h. The mRNA gene expression of HSP70 was greater (p < 0.01) in all HS groups compared to the CON groups after heat exposure. The expression of the HSP70 gene in the D-C/-group was significantly higher (p < 0.05) compared to the B-CC and B-C/-groups immediately (0 h) following 3 h of HS. The expression in the D-CC group also higher (p < 0.05) than in the B-C/-group. The gene expression of HSP70 in hair follicles increased more at the moderate HS level than that at the threshold level. In addition, overexpression of HSP70 was noted (p < 0.05) in the D-CC and D-C/-groups compared to the B-CC and B-C/-groups. In conclusion, our results indicate that breeds and HSP70 genetic polymorphisms exhibit a distinctive pattern of immune cell proliferation and HSP70 expression profiles. Additionally, the HSP70 gene expression in hair follicles may serve as an indicator of heat resistance across different breeds, making it a potential novel barometer for HS. Full article

Our previous studies have shown that miR-130b can significantly inhibit subcutaneous fat deposition in pigs. This study aims to further investigate its effect on lipid accumulation at early-stage (24 and 48 h) and late-stage (7 d) adipogenic differentiation and to clarify potential mechanisms using primary rat intramuscular preadipocytes (IMAs). Results showed that at 24 h and 48 h, miR-130b overexpression significantly reduced lipid deposition by inhibiting proliferation and inducing apoptosis. Furthermore, miR-130b overexpression significantly inhibited the expression of cell cycle and apoptosis marker genes. Specifically, the mRNA expression of Ccnd1 tended to decrease, while the BCL2 protein level was significantly decreased at 48 h. In contrast, miR-130b inhibition significantly increased the BCL2 protein level. At 7 d, the miR-130b mimic significantly decreased intracellular TG content and tended to decrease Hsd11b1 mRNA expression while significantly promoting Lpl mRNA expression. Additionally, the miR-130b mimic significantly increased the CASP3 protein level and tended to decrease the BCL2 protein level. In conclusion, our data indicated for the first time that miR-130b could reduce lipid deposition in rat IMAs through different mechanisms: at the early stage of differentiation by inhibiting proliferation and promoting apoptosis and at the late stage by inhibiting adipogenic differentiation, promoting lipid hydrolysis, and promoting apoptosis. Full article

Viruses can manipulate the host metabolism to achieve optimal replication conditions, and central carbon metabolism (CCM) pathways are often crucial in determining viral infections. Feline calicivirus (FCV), a diminutive RNA viral agent, induces upper respiratory tract infections in feline hosts, with highly pathogenic strains capable of precipitating systemic infections and subsequent host cell necrosis, thereby presenting a formidable challenge to feline survival and protection. However, the relationship between FCV and host cell central carbon metabolism (CCM) remains unclear, and the precise pathogenic mechanisms of FCV are yet to be elucidated. Upon FCV infection of Crandell-Rees Feline Kidney (CRFK) cells, an enhanced cellular uptake of glucose and glutamine was observed. Metabolomics analyses disclosed pronounced alterations in the central carbon metabolism of the infected cells. FCV infection was found to augment glycolytic activity while sustaining the tricarboxylic acid (TCA) cycle flux, with cellular ATP levels remaining invariant. Concurrently, both glutamine metabolism and the flux of the pentose phosphate pathway (PPP) were noted to be intensified. The application of various inhibitory agents targeting glycolysis, glutamine metabolism, and the PPP resulted in a significant suppression of FCV proliferation. Experiments involving glucose and glutamine deprivation demonstrated that the absence of either nutrient markedly curtailed FCV replication. Collectively, these findings suggest a critical interplay between central carbon metabolism and FCV proliferation. FCV infection stimulates CRFK cells to augment glucose and glutamine uptake, thereby supplying the necessary metabolic substrates and energy for viral replication. During the infection, glutamine emerges as the primary energy substrate, ensuring ATP production and energy homeostasis, while glucose is predominantly channeled into the pentose phosphate pathway to facilitate nucleotide synthesis. Full article

In recent years, the exploration of bioactive molecules derived from natural sources has gained interest in several application fields. Among these, macroalgae have garnered significant attention due to their functional properties, which make them interesting in therapeutic applications, including cancer treatment. Cancer constitutes a significant global health burden, and the side effects of existing treatment modalities underscore the necessity for the exploration of novel therapeutic models that, in line with the goal of reducing drug treatments, take advantage of natural compounds. This review explores the anticancer properties of macroalgae, focusing on their bioactive compounds and mechanisms of action. The key findings suggest that macroalgae possess a rich array of bioactive compounds, including polysaccharides (e.g., fucoidans and alginates), polyphenols (e.g., phlorotannins), and terpenoids, which exhibit diverse anticancer activities, such as the inhibition of cell proliferation, angiogenesis, induction of apoptosis, and modulation of the immune system. This review provides an overview of the current understanding of macroalgae’s anticancer potential, highlighting the most promising compounds and their mechanisms of action. While preclinical studies have shown promising results, further research is necessary to translate these findings into effective clinical applications. Full article

Digital supply chains (DSCs) are value-driven and collaborative digital systems designed to generate business value for firms through various innovative technologies. Today, we are witnessing companies transitioning from traditional supply chain models to DSCs through digital technologies. The effective selection of digital suppliers during these digital transformation processes is a strategic research topic. Additionally, factors such as the proliferation of information and communication technologies, globalization, and the pandemic have contributed to the expansion of e-commerce platforms. In this rapid growth phase, identifying the right supplier is crucial for the success of e-commerce sites. This study aims to develop an innovative, integrated, and comprehensive decision-making methodology to assist e-commerce platforms in selecting appropriate suppliers for their DSCs. To achieve this, an extended fuzzy VlseKriterijuska Optimizacija I Komoromisno Resenje (VIKOR) method is tested, where criteria and alternative evaluations made by decision-makers (DMs) are characterized by interval-valued intuitionistic fuzzy numbers (IVIFNs). The proposed decision mechanism is tested on the DSS problem of an e-commerce platform specializing in household products. Findings of the application, which uses three experts’ opinion to evaluate four digital suppliers based on the seven criteria, are discussed to help e-commerce sites conduct the DSS process more effectively. Full article

Heart disease, including myocardial infarction, heart failure, cardiac hypertrophy, and cardiomyopathy, remains a leading cause of mortality worldwide. The mammalian target of rapamycin (mTOR) is a centrally regulated kinase that governs key cellular processes, including growth, proliferation, metabolism, and survival. Notably, mTOR plays a pivotal role in cardiovascular health and disease, particularly in the onset and progression of cardiac conditions. In this review, we discuss mTOR’s structure and function as well as the regulatory mechanisms of its associated signaling pathways. We focus on the molecular mechanisms by which mTOR signaling regulates cardiac diseases and the potential of mTOR inhibitors and related regulatory drugs in preventing these conditions. We conclude that the mTOR signaling pathway is a promising therapeutic target for heart disease. Full article

Background/Objectives: Cleft palate is a birth defect associated with environmental and genetic factors. Disturbance of microRNAs (miRNAs) and exposure to medicinal agents during pregnancy can cause cleft palate. Although an association between medicine-induced cleft palate and miRNAs has been suggested, it remains to be fully elucidated. This study aimed to clarify the molecular mechanism underlying mycophenolate mofetil (MPM)-induced inhibition of cell proliferation and miRNA expression in human embryonic palatal mesenchymal (HEPM) cells. Methods: Cell viability, apoptosis, and cell cycle-related markers were evaluated 48 h after MPM treatment. In addition, miRNA levels and expression of their downstream genes were measured, and a rescue experiment was performed using miR-4680-3p and/or let-7c-5p inhibitors. Results: MPM dose-dependently reduced HEPM cell viability. Additionally, MPM treatment suppressed cyclin-D1, cyclin E1, cyclin-dependent kinase (CDK)-2, and CDK6 expression in HEPM cells. Furthermore, MPM upregulated miR-4680-3p and let-7c-5p expression and downregulated the downstream genes of each miRNA. Moreover, miR-4680-3p and/or let-7c-5p inhibitors alleviated MPM-induced inhibition of cell proliferation. Conclusions: These results suggest that MPM-induced cleft palate is associated with miR-4680-3p and let-7c-5p expression in HEPM cells. Full article

Phosphodegrons are critical motifs that play a pivotal role in the regulation of protein stability and function via phosphorylation-dependent signaling pathways. These motifs serve as recognition elements for ubiquitin ligases, facilitating the targeted degradation of proteins. By modulating key cellular processes such as cell cycle progression, DNA repair, and apoptosis, phosphodegrons are essential for maintaining cellular homeostasis. Dysregulation of phosphodegrons has been implicated in a wide range of diseases, including cancer and neurodegenerative disorders, highlighting their potential as therapeutic targets. This review provides an overview of phosphodegron functions along with their biological significance in health and disease. Additionally, we discuss current methodologies for studying phosphodegrons and explore emerging trends in their identification and therapeutic targeting. By synthesizing recent advances in the field, this article aims to offer insights into the future directions and challenges in phosphodegron research, ultimately underscoring their importance in cellular regulation and disease pathology. Full article

A convenient total synthesis of the imidazo[1,2-f]phenanthridine-type Amaryllidaceae alkaloid zephycandidine A (3) was developed, which further allowed us to perform modifications of substituents on benzenoid ring A and imidazole ring D. The biological activities of all synthesized compounds were evaluated, and it was reported that activities against cancer cells of the parent alkaloid were poorly reproducible, while the closely related analogue THK-121 (11) showed a strong inhibitory effect on proliferation. Additionally, our novel analogue significantly induced cell death via the intrinsic apoptosis pathway, evident by the loss of mitochondrial membrane potential, increased mitochondrial oxidative stress, and disrupted mitochondrial structure in the same cells. At the same time, healthy cells were less affected by the treatment with THK-121 (11), indicating a potential therapeutic margin. Full article

Palatogenesis is a complex developmental process requiring temporospatially coordinated cellular and molecular events. The following review focuses on genetic, epigenetic, and environmental aspects directing palatal formation and their implication in orofacial clefting genesis. Essential for palatal shelf development and elevation (TGF-β, BMP, FGF, and WNT), the subsequent processes of fusion (SHH) and proliferation, migration, differentiation, and apoptosis of neural crest-derived cells are controlled through signaling pathways. Interruptions to these processes may result in the birth defect cleft lip and/or palate (CL/P), which happens in approximately 1 in every 700 live births worldwide. Recent progress has emphasized epigenetic regulations via the class of non-coding RNAs with microRNAs based on critically important biological processes, such as proliferation, apoptosis, and epithelial–mesenchymal transition. These environmental risks (maternal smoking, alcohol, retinoic acid, and folate deficiency) interact with genetic and epigenetic factors during palatogenesis, while teratogens like dexamethasone and TCDD inhibit palatal fusion. In orofacial cleft, genetic, epigenetic, and environmental impact on the complex epidemiology. This is an extensive review, offering current perspectives on gene-environment interactions, as well as non-coding RNAs, in palatogenesis and emphasizing open questions regarding these interactions in palatal development. Full article

Introduction: Equine chorionic girdle cells can give rise to the endometrial cup, a structure that secretes equine chorionic gonadotropin (eCG). To date, the mechanisms underlying the proliferation, differentiation, invasion, and hormone secretion of equine chorionic girdle cells are not fully understood. During human pregnancy, interleukin-6 (IL-6) is maternally expressed to stimulate the invasion and migration of human syncytiotrophoblast cells and influence the synthesis of human chorionic gonadotropin. Although many previous studies reported the same upregulation of IL-6 during equine placentation, its effects on equine chorionic girdle cells have never been tested. Methods: In this study, we tested the effects of different concentrations of IL-6 on the morphology, differentiation, proliferation, hormone production, invasion, migration, and gene expression profiles of equine chorionic girdle cells. Results: We found that, with respect to morphology and proliferation, IL-6 had no significant effect; with respect to eCG production, 30 ng/mL IL-6 significantly increased the expression of genes related to eCG production, whereas treatment with 70 ng/mL IL-6 downregulated these genes. However, no significant increase in intracellular protein levels or eCG secretion was observed following treatment with any concentration of IL-6. Regarding cell migration and invasion, we found that IL-6 treatment had no significant effect on the migration capability of equine chorionic girdle cells but did enhance the invasion capability of equine chorionic girdle cells and upregulated the expression of the invasion-related genes, Mmp2 and Mmp9. Finally, our transcriptomic study revealed that in equine chorionic girdle cells, IL-6 treatment mainly affected the expression of genes related to the NOD-like receptor signaling pathway and the JAK–STAT signaling pathways, which are involved in immune and inflammatory responses. Conclusions: In summary, this study demonstrates the positive effects of IL-6 on the cytokine secretion and invasive ability of equine chorionic girdle cells. Full article