Search Results (897)

Cutaneous malignant melanoma is an extraordinarily aggressive and heterogeneous cancer that contains a small subpopulation of tumor stem cells (CSCs) responsible for tumor initiation, metastasis, and recurrence. Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack of specific markers (CD271, ABCB5, ALDH, Nanog) and the ability of cells to dynamically change their phenotype. Phenotype-maintaining signaling pathways (Wnt/β-catenin, Notch, Hedgehog, HIF-1) promote self-renewal, treatment resistance, and epithelial–mesenchymal transitions. Tumor plasticity reflects the ability of differentiated cells to acquire stem-like traits and phenotypic flexibility under stress conditions. The interaction of CSCs with the tumor microenvironment accelerates disease progression: they induce the formation of cancer-associated fibroblasts (CAFs) and neo-angiogenesis, extracellular matrix remodeling, and recruitment of immunosuppressive cells, facilitating immune evasion. Emerging therapeutic strategies include immunotherapy (immune checkpoint inhibitors), epigenetic inhibitors, and nanotechnologies (targeted nanoparticles) for delivery of chemotherapeutic agents. Understanding the role of CSCs and tumor plasticity paves the way for more effective innovative therapies against melanoma. Full article

Among synanthropic species, European hedgehogs are widely distributed throughout Europe. In recent decades, these animals have increasingly adapted to anthropogenic environments, where they find abundant shelter and food resources, along with fewer natural predators. As with other wildlife, it is likely that their coexistence in cities is also affecting their microbiota, promoting the development of antimicrobial resistance (AMR). This study aimed to assess the occurrence and patterns of AMR in commensal enteric Escherichia coli isolated from hedgehogs (n = 53) living in anthropogenic environments upon admission to a wildlife rescue center in Turin (Italy). The effects of hospitalization on the prevalence and trends of AMR were also assessed. Our results confirm that hedgehogs can harbor resistant E. coli upon admission, in particular against cefazolin (41.5%), ampicillin (37.7%), and enrofloxacin (22.6%). In addition, hospitalization promoted an increase in minimum inhibitory concentration (MIC) values of all antibiotics except imipenem, which led to a significant increase in E. coli that was resistant towards doxycycline, enrofloxacin, and trimethoprim-sulfamethoxazole. Admitted hedgehogs were also carriers of extended-spectrum beta-lactamase-producing E. coli (5.7%), whose presence increased during hospitalization (to 20.8%). These results highlight the role of hospitalizations longer than five days in the acquisition of AMR and suggest that European hedgehogs can become potential carriers of resistant E. coli following hospitalization. Full article

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

Seed germination is recognized for enhancing the accumulation of bioactive compounds. Perilla frutescens (L.) Britt., commonly known as perilla seed, is rich in fatty acids that may be beneficial for anti-hair loss. This study investigated the hair regeneration potential of perilla seed extracts—non-germinated (NG-PS) and germinated in distilled water (0 ppm selenium; G0-PS), and germinated with 80 ppm selenium (G80-PS)—obtained from supercritical fluid extraction (SFE) and screw compression (SC). SFE extracts exhibited significantly higher levels of polyphenols, tocopherols, and fatty acids compared to SC extracts. Among the germinated groups, G0-PS showed the highest bioactive compound content and antioxidant capacity. Remarkably, treatment with SFE-G0-PS led to a significant increase in the proliferation and migration of hair follicle cells, reaching 147.21 ± 2.11% (p < 0.05), and resulted in complete wound closure. In addition, its antioxidant and anti-inflammatory properties were reflected by a marked scavenging effect on TBARS (59.62 ± 0.66% of control) and suppressed nitrite amounts (0.44 ± 0.01 µM). Moreover, SFE-G0-PS markedly suppressed SRD5A1-3 gene expression—key regulators in androgenetic alopecia—in both DU-145 and HFDPCs, with approximately 2-fold and 1.5-fold greater inhibition compared to finasteride and minoxidil, respectively. Simultaneously, it upregulated the expression of hair growth-related genes, including CTNNB1, SHH, SMO, GLI1, and VEGF, by approximately 1.5-fold, demonstrating stronger activation than minoxidil. These findings suggest the potential of SFE-G0-PS as a natural therapeutic agent for promoting hair growth and preventing hair loss. Full article

Basal cell carcinoma (BCC), the most common skin cancer, is primarily driven by Hedgehog (Hh) and TP53 pathway alterations. Although additional pathways were implicated, the mutational landscape in Asian populations, particularly Koreans, remains underexplored. We performed whole-exome sequencing of BCC tumor tissues from Korean patients and analyzed mutations in 11 established BCC driver genes (PTCH1, SMO, GLI1, TP53, CSMD1/2, NOTCH1/2, ITIH2, DPP10, and STEAP4). Mutational profiles were compared with Caucasian cohort profiles to identify ethnicity-specific variants. Ultraviolet (UV)-exposed and non-UV-exposed tumor sites were compared; genes unique to non-UV-exposed tumors were further analyzed with protein–protein interaction analysis. BCCs in Koreans exhibited distinct features, including fewer truncating and more intronic variants compared to Caucasians. Korean-specific mutations in SMO, PTCH1, TP53, and NOTCH2 overlapped with oncogenic gain-of-function/loss-of-function (GOF/LOF) variants annotated in OncoKB, with some occurring at hotspot sites. BCCs in non-exposed areas showed recurrent mutations in CSMD1, PTCH1, and NOTCH1, suggesting a UV-independent mechanism. Novel mutations in TAS1R2 and ADCY10 were exclusive to non-exposed BCCs, with protein–protein interaction analysis linking them to TP53 and NOTCH2. We found unique ethnic-specific and UV-independent mutational profiles of BCCs in Koreans. TAS1R2 and ADCY10 may contribute to tumorigenesis of BCC in non-exposed areas, supporting the need for population-specific precision oncology. Full article

Background/Objectives: European hedgehogs (Erinaceus europaeus) are present in areas where there is human activity; therefore, they can be a source of pathogens for other animals and humans. Methods: Eighteen hedgehog carcasses were collected and analyzed for Staphylococcus spp. Isolated strains were typed and analyzed for exfoliative toxins genes and the phenotypic and genotypic characteristics of antimicrobial resistance. Results: A total of 54 strains were isolated and typed as S. aureus, S. xylosus, S. sciuri, S. pseudintermedius, S. simulans, S. chromogenes, S. epidermidis, S. hyicus, and S. lentus. No strains had the eta and etb genes coding for exfoliative toxins. Overall, 39/54 (72.20%) isolates showed phenotypic resistance to at least one antimicrobial and 21/54 (38.80%) showed more than one resistance. The lowest efficacy was observed for erythromycin, with 40/54 (74.08%) strains classified as intermediate and 6/54 (11.11%) classified as resistant. Among the 29 isolates shown to be penicillin-resistant, 11 (37.93%) were oxacillin-resistant, with a minimum inhibitory concentration (MIC). Among the 54 staphylococcal strains, 2 (3.70%) were resistant to vancomycin, both with an MIC value equal to the maximum concentration of the antibiotic tested (256 μg/mL) and 2 (3.70%) had an intermediate resistance profile with an 8 μg/mL MIC value. No strains had the genes vanA and vanB. Two of the 29 (6.90%) penicillin-resistant strains had the blaZ gene; 8 (27.13%) strains had the mecA gene. Overall, 2/54 (3.70%) isolates were classified as extensively drug-resistant (XDR) and 9/54 (16.66%) were classified as multidrug-resistant (MDR). Conclusions: Hedgehogs can harbor antimicrobial-resistant staphylococci and can be sources of these bacteria for other animals and humans. They can also serve as bioindicators of the pathogens and antimicrobial-resistant bacteria circulating in a given habitat. Full article

Cancer represents a significant global health hazard marked by elevated morbidity and mortality rates. Furthermore, the majority of tumor therapies encounter challenges, including metastasis, recurrence, and drug resistance. Consequently, it is essential to identify a specific and efficient tumor treatment approach. In recent years, the ongoing investigation and comprehension of tumors have led to significant attention towards cancer stem cells (CSCs). CSCs can facilitate tumor progression via self-renewal, differentiation capabilities, and multidrug resistance. Their function as a fundamental contributor to tumor heterogeneity, drug resistance, recurrence, and metastasis has emerged as a significant focus in cancer therapy research. In recent years, microRNAs (miRNAs) have been identified as crucial post-transcriptional regulators in biological processes, including chemosensitivity, self-renewal, apoptosis, invasion, and metastasis of cancer stem cells (CSCs). This paper systematically reviews the molecular mechanisms through which miRNAs influence the characteristics of cancer stem cells by targeting essential genes (e.g., SOX2, EGFR, c-Met) and modulating signaling pathways, including Wnt/β-catenin, Notch, Hedgehog, and PI3K/Akt. Furthermore, we investigated the viability of miRNAs as non-invasive biomarkers for cancer diagnosis and prognosis evaluation, examined the similarities and attributes of pivotal miRNAs in modulating cancer stem cell functionality, and deliberated on therapeutic approaches stemming from miRNA regulation of cancer stem cell activity. We anticipate that this research will yield novel insights into targeted cancer therapy. Full article

Crowding stress is an inevitable stressor in intensive farming, yet its underlying mechanisms are still obscure, severely hindering the aquaculture industry’s healthy development. As the primary sensory and regulatory organ for stressors, the brain plays a crucial role in stress responses. In this study, the effect of crowding stress on the telencephalon (Tel) and hypothalamus (Hy) has been explored using RNA sequencing. After four weeks of crowding stress, neuroinflammation-related genes were significantly induced in both the Tel and Hy. Additionally, cell fate-related processes were markedly altered. Neurogenesis-related pathways, including the Wnt and Hedgehog signaling pathways, were significantly enriched in both regions. The apoptosis-related genes (caspase3, p53) were predominantly downregulated in the Tel (log₂Fold Change: −1.27 and −0.71, respectively), while ferroptosis-related genes (ho1, ncoa4) were specifically activated in the Hy (log₂Fold Change: 1.15 and 0.73, respectively). The synaptic plasticity-related genes (prkcg, cacna1d) were significantly downregulated in both the Tel (log₂Fold Change: −1.78 and −0.88) and Hy (log₂Fold Change: −1.99 and −1.52). Furthermore, neurotransmitter synthesis (γ-aminobutyric acid (GABA) and serotonin (5-HT)) was disrupted in the Tel, whereas growth-related hormone gene expression was markedly altered in the Hy. These findings provide novel insights into the neurobiological mechanisms of chronic crowding stress in fish, laying a foundation for developing brain-targeted strategies to enhance welfare and mitigate stress in intensive largemouth bass farming. Full article

Exploring the neurogenic potential of extraneural stem cells under the actions of proneurogenic biomolecules may enhance the success of autologous cell therapy for neurodegenerative diseases such as Parkinson’s. Neural stem and progenitor cells (NSPCs) from extraneural tissues have emerged as potential sources of functional dopaminergic (DA) neurons. Background/Objectives: This study aimed to generate DA neurons from ovarian cortical cells (OCC)-derived NSPCs to elucidate whether follicle-stimulating hormone (FSH) can enhance this process and to evaluate the electrophysiological functionality of differentiated neural cells using the patch-clamp technique. Methods: OCC-NSPCs were differentiated towards the DA pathway during the neurosphere (NS) assay after two culture periods for cell expansion (CEP-1, CEP-2) with one of these media: M1 (positive control with epidermal growth factor, EGF, and fibroblast growth factor2, FGF2), M2 (control), and M3 (M2 with FSH, 50 ng/mL). Image analysis, morphometric evaluation, cell proliferation assays, and gene expression analysis of NSPC-specific transcripts were performed. After CEP-2, NS cells were cultured for 30 days in a serum-free medium containing Sonic-Hedgehog, FGF2, FGF8, and brain-derived neurotrophic factor (BDNF) for differentiation. At the end of culture, expression, and immunolocalization of GFAP, Olig2, NeuN, and tyrosine hydroxylase (TH) were analyzed in cells, along with patch-clamp recordings in differentiated neurons. Results: Cell proliferation and NS development were larger in OCC-NSPCs from groups M1 and M3 than in M2. Expression of NSPC-related transcripts was higher in M2; however, M1 and M3 cultures showed greater expression of differentiation markers NeuN, GFAP, Olig2, and TH. NeuN, GFAP, and TH were immunolocalized in differentiated cells and NS that were generated during differentiation. TH was localized in neural precursor cells, some neurons, core cells of small-, medium-, and large-sized NS, and in cells close to the outer cell layer of large NS, with greatest immunolocalization percentages in NS primed with FSH during CEP-1/2 (M3). Electrophysiological recordings revealed a major incidence of plateau potentials and a significant proportion of complete action potentials, reflecting successful functional neuronal differentiation. Conclusions: DA precursors and functional neurons can be successfully obtained after OCC-NSPCs-directed differentiation. FSH priming during the expansion period enhances the neurogenic potential of these cells towards the DA pathway. Future research will explore the eventual therapeutic use of these findings for neurodegenerative diseases. Full article

The hedgehog pathway is a major regulator of cell growth and differentiation during embryogenesis and early development. The literature suggests that variations in this pathway’s genes play a role in tumor progression and response to therapy. This study aimed to assess the correlation between the expression levels of selected genes of this pathway and the progression-free and overall survival of ovarian cancer patients. Using the database Kaplan–Meier plotter, which includes the gene expression and survival data of 1565 ovarian cancer patients, higher expression levels of the genes SHH, PTCH1, PTCH2, and GLI1 displayed better survival correlations, while GLI, GLI3, and SUFU correlated with adverse outcomes. Further dissection revealed a differential impact of the genes in specific clinical-histopathological categories. Notably, higher expression levels of SUFU were associated with a negative impact on ovarian cancer patients under many clinical–histopathological aspects. These results shed new light on the role of these genes in the chemoresponsiveness of ovarian cancer, especially SUFU, which could be considered a novel indicator for poor prognosis in epithelial ovarian cancer. Full article

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with a poor prognosis. Activating mutations in the FLT3 gene occur in approximately 30% of AML cases, with internal tandem duplications in the juxtamembrane domain (FLT3-ITD; 75%) and mutations in the tyrosine kinase domain (FLT3-TKD; 25%). FLT3-ITD mutations are linked to poor prognosis and offer significant clinical predictive value, whereas the implications of FLT3-TKD mutations are less understood. The Hedgehog–Gli pathway is an established therapeutic target in AML, and emerging evidence suggests crosstalk between FLT3-ITD signaling and Gli expression regulation via non-canonical mechanisms. Post-translational modifications involving myristic and palmitic acids regulate various cellular processes, but their role in AML remains poorly defined. In this study, we investigated the role of fatty acid synthase (FASN), which synthesizes myristic and palmitic acids and catalyzes palmitoyl-acyltransferation, in regulating FLT3-ITD-Gli signaling. FASN knockdown using shRNA and the FASN inhibitor TVB-3166 was performed in FLT3-ITD-mutated AML cell lines (MOLM13, MV411) and Baf3-FLT3-ITD cells. The impact of FASN inhibition was assessed through Western blot and kinome profiling, while biological implications were evaluated by measuring cell viability and proliferation. FASN inhibition resulted in reduced levels of phospho-Akt (pAkt) and phospho-S6 kinase (pS6) and decreased expression of Hedgehog–Gli1, confirming non-canonical regulation of Gli by FLT3-ITD signaling. Combining TVB-3166 with the Gli inhibitor GANT61 significantly reduced the survival of MOLM13 and MV411 cells. Full article

Medulloblastoma (MB) is a malignant brain tumor that requires intense multimodal treatment. There is significant treatment-related morbidity associated with MB, and overall prognosis varies between the subgroups of the disease. These tumors were previously risk-stratified based solely on histopathological features. However, advancements in oncologic molecular research have led to novel changes to MB tumor classification, which also affects the prognosis and treatment strategies for individual patients. The WHO CNS5 now recognizes four main molecular subgroups of MB. Each subgroup contains its own genomic heterogeneity that correlates with a unique way to risk stratify patients, determine overall prognosis, and inform treatment. These discoveries have already impacted the implications and outcomes of current treatments based on the subgroup of patients. Ongoing research to better understand this classification system has paved the way for the development of molecular targeted therapy. Full article

Breast cancer is one of the most common and difficult-to-treat cancers affecting women globally. Long-term treatment success is still limited by problems like drug resistance, toxicity, and recurrence, even with advancements in conventional therapies. The application of substances derived from plants for medical purposes, or phytotherapy, has become a viable adjunctive approach to the treatment of breast cancer. An integrative approach to phytotherapy is examined in this review, focusing on how it can alter important molecular pathways implicated in the development, progression, and metastasis of breast cancer. By focusing on important signaling cascades like TGF-β, Wnt, Hedgehog, Notch, IL-6, Integrins, VEGF, HER2, EGFR, PI3K/Akt, and MAPK, and estrogen receptor pathways, a variety of phytochemicals, such as flavonoids, alkaloids, terpenoids, and polyphenols, demonstrate strong anticancer effects. This review also discusses how they affect immune modulation, angiogenesis, cell cycle regulation, and apoptosis. Moreover, it also emphasizes the challenges with these natural compounds’ bioavailability, standardization, and clinical translation while highlighting preclinical and clinical research that supports their therapeutic potential. This review attempts to give a thorough grasp of how plant-based compounds can support efficient and focused breast cancer treatments by fusing molecular insights with phytotherapeutic approaches. Full article

Hedgehog (HH) signaling plays important roles in the development of the nervous system (Sonic hedgehog), bone, cartilage (Indian Hedgehog) and testis (Desert Hedgehog). Research on HH and testes has mostly been conducted in HH-knockout mice and rats, etc. The relationship between HH and cellular junctions has mostly been found in the nervous system and intestine. However, few research studies concerning the link between HH signaling and cell junctions in testis function have been reported. We identified the members of HH signaling that are involved in Eriocheir sinensis testes: HH, Smoothen, Patched, Kif27 and Ci. HH has only one homolog in E. sinensis and is expressed in several types of germ cells in the testes. We found that Kif27 colocalized with Ci in the testes. The knockdown of HH induced enlarged interstitial spaces of the seminiferous tubules. A biotin–streptavidin immunofluorescence experiment indicated that the hemolymph–testis barrier (HTB) was disrupted. Western blot results showed that pinin, HH signaling and cell proliferation- and apoptosis-related protein levels were downregulated. Further immunofluorescent results showed the dislocation of several junction proteins, the abnormality of F-actin and the slowdown of germ cell proliferation and apoptosis. While β-catenin entered the spermatocyte nucleus, it did not activate Wnt-β-catenin signaling, which indicated that the disturbance of the cell cycle in germ cells was not caused by Wnt-β-catenin signaling. In summary, HH signaling plays some roles beyond our understanding in the regulation of the HTB and the germ cell cycle in E. sinensis testes. Full article