Search Results (1,199)

Background/Objectives: The epithelial-to-mesenchymal transition (EMT) process provides cancer cells with morpho-functional characteristics for invasion and metastasis. A reduction in serum adiponectin (APN) has been detected in prostate cancer (PCa) patients. Since AdipoRon (AdR), an agonist of APN, has been demonstrated to exert potent antitumor effects on cancer cells, including PCa, we explored the effects of AdR on PCa cells with different EMT-related traits. Methods: DU145 and PC3 cells were grown in 3D spheroids and treated with AdR or left untreated (CT). The expression of APN receptors, EMT markers, and invasive potential were analyzed using an integrated molecular and morphological approach. Results: APN receptor mRNA levels were higher in DU145 than in PC3 cells and were markedly increased only in DU145 spheroids upon AdR administration, while remaining unchanged in PC3 spheroids. AdR treatment was associated with MAPK signaling activation and modulation by AdR only in DU145 spheroids. Molecular and morphological analysis confirmed the “more epithelial” phenotype of DU145, compared with the “more mesenchymal” PC3 cells with higher N-cadherin expression, and EMT markers were not broadly affected by AdR administration in either cell line. MMP-2 activity was similar across experimental conditions, whereas MMP-9 activity was higher in PC3 than in DU145 spheroids and was not directly modulated by AdR. Although TIMP-2 mRNA levels were similar in the different experimental conditions, TIMP-1 mRNA and protein levels were higher in PC3 than in DU145 spheroids, and AdR increased TIMP-1 protein expression in PC3 cells. However, the MMP-2/TIMP-2 ratio strongly decreased in both AdR-treated DU145 and PC3 spheroids, compared with the CT, and a similar modulation for MMP-9/TIMP-1 was limited to DU145 cells. Conclusions: Overall, our results suggest that AdR activity can be associated with the modulation of invasion-associated molecular features of PCa spheroids, depending on their EMT-related phenotype. Full article

T1 high-grade (T1HG) urothelial carcinoma of the bladder presents a persistent clinical challenge: despite uniform high-risk classification under EAU guidelines, BCG failure and disease progression rates range from 10% to 40% across published series. Standard clinicopathological variables do not adequately explain this heterogeneity. Three pathological parameters evaluable from routine TURBT specimens—T1 substaging by lamina propria invasion depth, tumour budding at the invasion front, and E-cadherin (CDH1) immunohistochemistry—share a common mechanistic basis in CDH1-driven partial epithelial-to-mesenchymal transition and may refine escalation-oriented risk stratification without requiring additional tissue or molecular testing. We conducted a narrative critical review of PubMed/MEDLINE (January 2000–February 2026; 28 included studies) to evaluate the quantitative evidence for each parameter, with emphasis on reproducibility and BCG-specific outcome data. T1 substaging carries the strongest evidence: pooled progression HR 3.29 (95% CI 2.39–4.51) across 36 studies (n = 6781), with BCG failure of 41% vs. 21% in a centralised BCG-treated registry cohort of 264 patients on multivariable analysis. Tumour budding shows consistent adverse associations in BCG-treated pT1 NMIBC; zero progression was observed in the low-budding subgroup in the only available BCG-specific full-text cohort. CDH1 IHC is directionally supportive but limited by scoring heterogeneity (I² = 63%). All three parameters are mechanistically coherent and assessable from routine TURBT slides. Prospective validation with pre-specified thresholds and standardised scoring protocols is required before clinical implementation can be recommended. Full article

Background and Objectives: Eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) is characterized by type 2 inflammation, marked eosinophil infiltration, and enhanced epithelial–mesenchymal transition (EMT). Although interleukin-5 (IL-5) is central to eosinophil differentiation and activation, its role in EMT in human nasal epithelial cells (HNECs) remains unclear. This study aimed to elucidate the contribution of IL-5Rα/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signaling in eosinophils in EMT in ECRSwNP. Materials and Methods: Nasal mucosal tissues from control and ECRSwNP or non-ECRSwNP group patients (n = 12 each) were analyzed for type 2 cytokine, EMT marker, and IL-5Rα/JAK2/STAT5 axis component levels using Western blotting, immunohistochemistry, and quantitative real-time polymerase chain reaction. HL-60 cells were differentiated into eosinophil-like cells using butyric acid and stimulated with IL-5, and HNECs were co-cultured with undifferentiated, differentiated, or IL-5-activated differentiated HL-60 cells. EMT induction and migration were assessed using immunofluorescence, wound-healing assays, and Western blotting. IL-5RA, JAK2, or STAT5 was silenced using small interfering RNA to determine pathway dependency. Results: ECRSwNP tissues showed elevated type 2 cytokine and EMT marker expression and enhanced IL-5Rα/JAK2/STAT5 pathway activation. Co-culture with IL-5-activated differentiated HL-60 cells induced EMT in HNECs, evidenced by decreased E-cadherin and zonula occludens-1, increased N-cadherin and vimentin levels, and enhanced migration. Moreover, silencing IL-5RA, JAK2, or STAT5 significantly attenuated these effects. Conclusions: IL-5-activated IL-5Rα/JAK2/STAT5 signaling in eosinophils may contribute to EMT in HNECs. Thus, this pathway could be a potential therapeutic target for tissue remodeling and polyp formation in type 2 chronic rhinosinusitis. Full article

Endothelial dysfunction is a defining feature of diabetic vascular disease and is characterized by impaired nitric oxide signaling, inflammatory activation, altered mechanotransduction, and disturbed angiogenic responses. The present study investigated whether hyperglycemia modulates endothelial phenotype in a model-dependent manner under distinct structural and mechanical culture conditions. EA.hy926 endothelial cells were cultured for 7 days under normoglycemic (5.5 mM) or high-glucose (25 mM) conditions as static monolayers (G-force = 1 g), adherent clinorotated cells, multicellular spheroids (MCSs) generated during clinorotation, and Matrigel-derived endothelial structures. Gene expression was assessed by qPCR using marker panels related to nitric oxide signaling, PI3K CA-AKT-mTOR signaling, inflammatory adhesion, angiogenesis, and structural adhesion, whereas protein abundance and spatial distribution of eNOS, AKT1, VCAM1, vinculin, and VEGFA together with CDH5/VE-cadherin were analyzed by Western blotting and confocal microscopy. Clinorotation generated both adherent endothelial cells and MCSs. High glucose reduced eNOS-related expression in most models, with the strongest decreases in adherent clinorotated cells and MCSs, whereas Matrigel cultures showed a divergent transcriptional response. PI3K CA expression was markedly suppressed by high glucose in clinostat-derived populations, while mTOR was differentially regulated in spheroids and Matrigel cultures. VCAM1 expression was most prominent in MCSs, whereas ICAM1 was highest in Matrigel cultures. VEGF-related signaling differed substantially among models, and Matrigel cultures showed the strongest VEGFA-associated protein signal and the clearest angiogenic organization under normoglycemic conditions, which became less distinct under high glucose. Vinculin protein abundance was highest in MCSs and Matrigel cultures, reflecting pronounced differences in structural organization. Overall, these findings show that endothelial responses to hyperglycemia are strongly shaped by mechanical and structural context and support the use of complementary in vitro models for studying diabetic endothelial dysfunction. Full article

Hepatic fibrosis is characterized by excessive extracellular matrix deposition and progressive impairment of liver structure and function. Ellagic acid (EA) has been reported to have antioxidant and anti-inflammatory properties, but its role in hepatic fibrosis remains incompletely understood. A CCl₄-induced mouse model of hepatic fibrosis was established. EA was administered by oral gavage at 30, 60, or 120 mg/kg; colchicine was used as a positive control. Histopathological changes and collagen deposition were assessed using hematoxylin and eosin and Sirius Red staining, respectively. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), interleukin-6 (IL-6), and interleukin-10 (IL-10) concentrations, as well as hepatic malondialdehyde (MDA) and hydroxyproline (Hyp) contents and total superoxide dismutase (T-SOD) activity, were determined. Immunohistochemistry and Western blotting were used to assess fibrosis-associated, EMT-associated, and PI3K/AKT-related proteins. Network pharmacology analysis was performed to identify candidate targets and pathways. EA treatment ameliorated histopathological injury and collagen deposition in CCl₄-treated mice. EA, particularly at the high dose, reduced serum ALT and AST activities and hepatic MDA and Hyp contents while increasing hepatic T-SOD activity. EA treatment was also associated with lower serum IL-6 and higher IL-10 concentrations. In the EA-H group, α-SMA and collagen I (COL1A1) immunoreactivity were reduced; the abundance of N-cadherin, PI3K, and AKT was lower; and E-cadherin expression was higher. Network pharmacology identified PI3K/AKT-related signaling as a candidate pathway associated with the anti-fibrotic effects of EA. EA attenuated CCl₄-induced hepatic fibrosis and was associated with lower oxidative stress, inflammation, and HSC activation. Direct PI3K/AKT inhibition was not established. Full article

Epithelial–mesenchymal transition (EMT) emerged as a phenotypic change associated with the resistance to epidermal growth factor receptor tyrosine kinase inhibitors, both in vitro and in vivo. The mechanisms underlying this biological process have not yet been fully understood. E-cadherin loss, N-cadherin, and vimentin increase are the main markers characterizing EMT, together with the expression of some transcription factors, such as Snail, Slug, Zeb1, Zeb2, and Twist. In this study, we explore the expression of these markers in lung cancer cell lines bearing wild-type or mutated epidermal growth factor receptor (EGFR), A549 and PC9, respectively. We treated PC9 cells with Gefitinib or Osimetinib, alone or combined with the transforming growth factor beta (TGF-β). We evaluated the expression of E-cadherin, N-cadherin, vimentin, and the transcription factors at 24 and 96 h timepoints, to verify the role of EMT in the early phases of the treatment with tyrosine kinase inhibitors (TKIs). At the 96 h timepoint, we found that in PC9 cells, the treatment with gefitinib or osimertinib, regardless of TGF-β, induces E-cadherin reduction and N-cadherin increase, similar to the effects induced by TGF-β in A549 cells at 24 h. Among the transcription factors, at 96 h, Slug mainly increases when PC9 cells are treated with gefitinib or osimertinib. These results imply that changes in the expression of these epithelial–mesenchymal transition markers may have facilitated the development of drug resistance. Full article

Cancer remains one of the most frightening global health challenges, contributing substantially to morbidity and mortality across diverse populations. In recent years, naturally derived compounds have attracted considerable attention due to their potential therapeutic efficacy and fewer adverse effects. Among these, the flavokawain subclass of chalcones, comprising Flavokawains A, B, and C, obtained from various plant sources, has emerged as a promising group of bioactive phytochemicals exhibiting a broad spectrum of pharmacological activities, with notable anticancer potential. This review critically compiles and evaluates the existing preclinical evidence regarding the anticancer mechanisms of flavokawains across various cancer models. It was found that these compounds have significant potential to inhibit cancer cell proliferation, induce apoptosis, disrupt cell-cycle progression, and modulate multiple molecular pathways implicated in tumorigenesis, including phosphoinositide 3 kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), extracellular-signal regulated kinase/c-Jun N-terminal kinase/mitogen-activated protein kinase (ERK/JNK/MAPK) and so on. Importantly, flavokawains exert significant modulatory effects within the tumor microenvironment by suppressing angiogenesis through downregulation of vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1), attenuating epithelial-mesenchymal transition via restoration of E-cadherin and suppression of vimentin and Snail1, inhibiting matrix metalloproteinase (MMP)-mediated extracellular matrix remodeling, and disrupting cancer stem cell (CSC)-supportive niches. Preclinical toxicity profiles suggest a favorable safety margin, though further investigation is required to fully elucidate their therapeutic index. Due to their multifaceted mechanisms of action and selective cytotoxicity toward cancer cells, flavokawains are considered promising preclinical candidates for development as adjuncts or alternatives to conventional chemotherapeutic agents. Full article

Hepatocellular carcinoma is one of the most aggressive malignancies worldwide, with limited therapeutic options. Boswellia serrata Roxb., an Indian medicinal tree, produces a resin rich in essential oil and boswellic acids, particularly acetyl-11-keto-β-boswellic acid (AKBA), with demonstrated antiproliferative and pro-apoptotic activities. This study investigated the cytotoxic effects of B. serrata essential oil and AKBA on hepatocarcinoma Huh-7 cells in both monolayer and three-dimensional spheroid cultures and characterized the underlying molecular targets. Essential oil was extracted and analyzed by gas chromatography-mass spectrometry (GC-MS). Cytotoxicity was assessed using the cell counting kit-8 (CCK-8). Three-dimensional spheroid cultures were also established to evaluate anti-tumoral potential. Expression of cyclin D1, cyclin-dependent of kinase 4 (CDK4) (cyclin-dependent kinase inhibitor 1A (p21), E-cadherin, (alpha fetoprotein) AFP, epithelial cell adhesion molecule (EpCAM), Myeloid cell leukemia-1 (Mcl-1), and caspase-3 was analyzed by western blot. In addition, an in silico analysis was performed on the main constituents of B. serrata essential oil targeting 5-lipoxygenase (5LO). The results showed cytotoxic effects, with AKBA exhibiting greater potency than the essential oil. Cytotoxicity was associated with caspase-3-mediated apoptosis, with minimal effects on cell cycle and epithelial–mesenchymal transition markers. The in silico analysis predicted that some compounds may act as competitive inhibitors of the 5LO at the catalytic site and partially activate pro-apoptotic pathways. These data support the potential of B. serrata-derived compounds as novel anti-hepatocarcinoma agents, with AKBA and longifolene as leads for further preclinical and clinical research. Full article

Periodontitis is a chronic inflammatory disease initiated by dysbiotic biofilms and sustained by an altered host response, resulting in progressive destruction of the tooth-supporting tissues. Alongside immune-mediated damage, epithelial–mesenchymal transition has been proposed as a contributing mechanism in gingival barrier disruption and periodontal tissue remodeling. This narrative review examines the roles of the EMT-related transcription factors Snail1 and Twist1 in periodontitis, with particular focus on their involvement in epithelial junction loss, mesenchymal activation, and disease-associated tissue change. Relevant literature was identified through targeted searches of PubMed/MEDLINE and Google Scholar using terms related to periodontitis, gingival epithelium, EMT, Snail, and Twist, while selected non-periodontal studies were used only for mechanistic context where direct evidence was limited. Current findings suggest that periodontal disease is commonly associated with reduced epithelial adhesion markers and increased mesenchymal-associated markers, with Snail1 appearing more closely linked to epithelial repression and Twist1 to motility and matrix remodeling. However, the evidence remains largely preclinical or associative. Overall, Snail1 and Twist1 may participate in EMT-like remodeling in periodontitis, but periodontal-specific mechanistic and functional studies are still needed to clarify causality and clinical relevance. Full article

Background: Invasive lobular carcinoma (ILC) of the breast has a unique metastatic pattern due to E-cadherin deficiency, with a predilection for peritoneal, gastrointestinal, and pelvic organ involvement. Ovarian metastasis from ILC is rare but can mimic primary ovarian cancer clinically and radiologically, leading to misdiagnosis and unnecessary radical surgery. This study aimed to summarize the imaging features of ovarian metastasis from ILC and analyze the causes of misdiagnosis, while highlighting the value of preoperative biopsy. Methods: Clinical and imaging data of six patients with pathologically confirmed ovarian metastasis from ILC were retrospectively analyzed. All six patients were female (age range 33–65 years), had a history of breast cancer (ILC subtype), and were found to have ovarian masses either during follow-up or at initial diagnosis. Imaging findings of the ovaries, peritoneum, and ascites were analyzed and compared with initial clinical diagnoses and pathological results. Results: Among the six patients, five were initially clinically misdiagnosed as having primary ovarian cancer and underwent unnecessary total hysterectomy with bilateral salpingo-oophorectomy. One patient (case 6) was correctly diagnosed via percutaneous biopsy of the omentum and skin nodules, which confirmed metastatic ILC, thereby avoiding unnecessary gynecological surgery. Imaging findings: All six patients had bilateral ovarian masses, appearing as solid or cystic-solid lesions. Peritoneal changes were observed in four cases. Ascites was present in five cases. Laboratory findings showed marked variability in CA125 levels (normal in three cases, elevated in three cases). Immunohistochemistry confirmed breast origin in all cases (GATA3+, PAX8−, E-cadherin−). In case 6, after four cycles of chemotherapy (albumin-bound paclitaxel + carboplatin + bevacizumab), follow-up CT demonstrated significant reduction in ovarian masses and regression of peritoneal and omental lesions. Conclusions: Ovarian metastasis from ILC is easily misdiagnosed as primary ovarian cancer without histologic confirmation, leading to unnecessary radical surgery. However, as demonstrated in case 6, percutaneous biopsy of accessible metastatic sites (omentum, peritoneum, or skin nodules) can establish the correct diagnosis and guide systemic therapy, thereby avoiding unnecessary surgery. In case 6, the ILC ovarian metastasis showed a favorable response to chemotherapy, but this single-case finding requires cautious interpretation as ILC is generally considered less chemosensitive than invasive ductal carcinoma. In patients with a history of breast cancer or with suspected metastatic disease, ILC metastasis should be included in the differential diagnosis of ovarian masses. Full article

Nicotinamide (NAM), a precursor of nicotinamide adenine dinucleotide (NAD⁺), and NAD⁺ are integral to a variety of cellular processes. NAM supplementation has been shown to have benefits for cellular senescence. However, the mechanism by which NAM improves skin photoaging remains unclear. In this study, the multi-omics analysis revealed that insufficient nicotinamide metabolism may be associated with a decrease in NAD⁺ synthesis during skin aging. Importantly, we found that NAM has an ameliorating effect on the skin photoaging in mice. Supplementation with NAM restored the expression of the salvage-pathway enzymes and NAD⁺ consumers. In addition, the supplementation with NAM was shown to restore the expression of skin barrier-related proteins (ZO1 and E-cadherin) and collagen I, while reducing the expression of senescence markers (γ-H2AX, p53, and p21). Furthermore, we found that NAM effectively suppresses the senescence-associated secretory phenotype (SASP) factors’ expression in skin photoaging. Our research reveals the dual role of NAM in attenuating skin photoaging, acting not only to delay cellular senescence but also to suppress the SASP. Full article

Colon cancer remains a leading cause of cancer-related deaths, and drug repurposing offers a promising strategy to identify new therapies. Hydroquinidine (HQ), a class I antiarrhythmic agent, has recently been suggested to possess anticancer properties; however, its preclinical safety and efficacy in colorectal cancer are not well defined. The safety of HQ was evaluated in Wistar rats following OECD guidelines. Rats received daily intraperitoneal doses (2.5–25 mg/kg) for 90 days, with hematological, biochemical, and histopathological assessments performed. HQ was well tolerated up to 12.5 mg/kg, whereas 25 mg/kg caused signs of hepatotoxicity without lethality. A 1,2-dimethylhydrazine-induced colorectal cancer model was then used to assess HQ at safe doses (6.25 and 12.5 mg/kg) compared with cisplatin. Tissue histopathology and selected molecular markers associated with inflammation, apoptosis, epithelial–mesenchymal transition, and PI3K/AKT/mTOR pathway activity were analyzed. In the DMH-induced colon cancer model, HQ improved colonic tissue architecture and was associated with lower histopathological scores compared with untreated tumor controls. HQ also modulated tumor-associated markers by reducing IL-6 immunoreactivity, increasing caspase-3 expression, enhancing E-cadherin immunoreactivity, and decreasing vimentin expression. Moreover, HQ was associated with reduced immunoreactivity of mTOR pathway-related markers, suggesting attenuation of pathway activation in this experimental context. Overall, HQ showed an acceptable safety profile at the selected doses and exerted favorable histopathological and molecular modulatory effects, supporting further investigation as a potential repurposing candidate. Full article

Background and Objectives: Uterine metastasis from breast carcinoma is rare but poses substantial diagnostic and therapeutic challenges. Invasive lobular carcinoma (ILC) demonstrates a documented predilection for unusual metastatic patterns including the female genital tract, while tamoxifen-associated endometrial pathology may complicate diagnosis in breast cancer survivors. Materials and Methods: We performed a structured PubMed/MEDLINE and Google Scholar search (1980–2025) for cases with histologically confirmed breast primary and uterine involvement; a pooled analysis of demographic, histological, molecular, and clinical variables was performed. Results: 105 individual cases were identified. ILC accounted for 58.0% of histologically classified cases despite representing only 10–15% of breast cancers. Endometrial involvement was present in 68.6%, myometrial in 25.7%, and cervical in 26.7%. Tamoxifen exposure was strongly associated with polyp-substrate metastasis (29.3% vs. 4.7%; Fisher’s exact p = 0.0009; OR 8.41, 95% CI 2.20–32.14). Abnormal uterine bleeding was the dominant presentation (68.1%); 19.8% were asymptomatic. Median latency was 36 months (range from 24 months before to 360 months after the breast cancer diagnosis). Conclusions: Uterine metastasis from breast carcinoma is dominated by invasive lobular histology and frequently involves tamoxifen-associated polyps. A combined immunohistochemical panel (GATA3, TRPS1, E-cadherin, hormone receptors, PAX8) is essential for distinguishing metastatic disease from primary uterine pathology. Endometrial sampling should be considered with a low threshold in breast cancer survivors with abnormal uterine bleeding, and breast imaging is warranted when discohesive cells are encountered without a known breast primary. These proportions describe the published case literature rather than population-based prevalence; because the evidence is limited to case reports and small series, they should not be read as the true frequency of uterine involvement among women with breast cancer. Full article

Background: Metastases to the uterine cervix from extragenital malignancies represent uncommon clinical events, with breast invasive lobular carcinoma (ILC) documented as the predominant primary source in reported literature. Objectives/Aim: To characterize the clinicopathologic features of ILCs metastatic to the uterine cervix. Methods: We performed a PubMed search using several keywords. Results: A total of 29 studies were included in the final analysis. The mean age at presentation of cervical metastasis was 56.8 ± 2.0 years. The mean interval between the initial diagnosis of ILC and the detection of cervical metastasis was 55.6 ± 8.2 months. Clinical presentations included vaginal bleeding, pelvic pain, and unhealthy enlarged, indurated uterine cervix on local examination. The diagnosis was established via tissue biopsy and immunohistochemical stains (positive reactivity for CK7, ER, PR, E-Cadherin, GATA3, GCDP-15 and mammaglobin). There are no consensus treatment protocols, and therapy should be tailored individually based on the extent of disease. Combined surgical and systemic therapy was the most commonly used modality. Conclusions: Metastasis of breast ILCs to the uterine cervix poses a significant diagnostic challenge. A high index of clinical suspicion and detailed clinical history are essential for accurate diagnosis. Full article

Protein arginine methyltransferase 5 (PRMT5) mediates arginine methylation of a wide range of proteins and plays context-dependent oncogenic or tumor-suppressive roles. In cancer, PRMT5 represses several tumor suppressor genes, including E-cadherin, TP53BP1, ST7, PTEN, and RB (retinoblastoma). Elevated PRMT5 expression has been reported across multiple cancer types, notably triple-negative breast cancer (TNBC). In TNBC, high PRMT5 levels are associated with enhanced cancer stem cell self-renewal, increased tumor growth and metastasis, and reduced patient survival. Mechanistically, PRMT5 promotes breast cancer stem cell maintenance and proliferation through stabilization of the transcription factors KLF4 and KLF5. Disruption of the PRMT5–KLF4 axis results in significant tumor reduction in TNBC models. Moreover, increased PRMT5 expression has been linked to resistance to chemotherapy and immunotherapy in TNBC. Notably, PRMT5 inhibitors demonstrate synergistic anticancer activity when combined with inhibitors of key oncogenic signaling pathways, including EGFR, PARP, and AKT. While several PRMT5 inhibitors are currently being evaluated in clinical trials for other malignancies, no clinical trials have yet been initiated specifically for TNBC. Full article