Search Results (5,920)

Collagen peptides, as a natural source of peptides, possess multiple advantages such as anti-aging, anti-inflammatory properties, tissue repair, and the ability to inhibit melanin production. In this study, type I collagen extracted from pig skin was hydrolyzed with 1% and 3% hydrochloric acid, yielding collagen peptides CPH1 and CPH3. The melanin content and tyrosinase activity in B16F10 cells were compared via direct and paracrine action when CPH1 and CPH3 were used to interfere with melanogenesis. It was found that CPH3 significantly inhibited melanogenesis in B16F10 through the paracrine action involving HaCaT keratinocytes. The intracellular melanin content was measured at 65.23 ± 1.30%, and the mRNA levels of tyrosinase and microphthalmia transcription factor in cells were 55.77 ± 6.09% and 50.70 ± 8.18% of the negative control, respectively. Furthermore, pigment deposition assays in zebrafish showed that, at a concentration of 1.0 mg/mL, CPH3 significantly inhibited melanogenesis compared to the negative control. Finally, tyrosinase inhibitory peptides were identified from CPH3 through peptide segment sequence identification and molecular dynamics simulation. The peptides of Nona-AGPPGFPGA, Octa-APGPVGPA, and Octa-GLPGPPGP have a double effect on the inhibition of tyrosinase and melanin content in B16F10 cells. Full article

Nicotinamide (NAM), the amide form of vitamin B3, is a precursor to essential cofactors nicotinamide adenine dinucleotide (NAD⁺) and NADPH. NAD⁺ is integral to numerous cellular processes, including metabolism regulation, ATP production, mitochondrial respiration, reactive oxygen species (ROS) management, DNA repair, cellular senescence, and aging. NAM supplementation has demonstrated efficacy in restoring cellular energy, repairing DNA damage, and inhibiting inflammation by suppressing pro-inflammatory cytokines release. Due to its natural presence in a variety of foods and its excellent safety profile—even at high doses of up to 3 g/day—NAM is extensively used in the chemoprevention of non-melanoma skin cancers and the treatment of dermatological conditions such as blistering diseases, atopic dermatitis, rosacea, and acne vulgaris. Recently, its anti-aging properties have elevated NAM’s prominence in skincare formulations. Beyond DNA repair and energy replenishment, NAM significantly impacts oxidative stress reduction, cell cycle regulation, and apoptosis modulation. Despite these multifaceted benefits, the comprehensive molecular mechanisms underlying NAM’s actions remain not fully elucidated. This review consolidates recent research to shed light on these mechanisms, emphasizing the critical role of NAM in cellular health and its therapeutic potential. By enhancing our understanding, this work underscores the importance of continued exploration into NAM’s applications, aiming to inform future clinical practices and skincare innovations. Full article

Background: Cutaneous melanoma (CM) is a malignant tumor originating from melanocytes. Despite improvements in prevention, Central and Eastern European countries continue to report higher rates of advanced-stage melanoma and lower survival rates. This study aims to characterize CM and the associated risk factors in Northwestern Romania. Methods: This cross-sectional cohort study was conducted in Cluj and Bihor counties. Between January 2023 and May 2024, 172 patients with histopathologically confirmed melanoma completed a standardized questionnaire addressing demographics, sun exposure history, nevi count, and melanoma-specific characteristics. Results: The median age at diagnosis of participants was 44 years. The median Breslow index (BI) was 1.5 mm, and 39% of cases presented with a BI > 2 mm. Superficial spreading melanoma (SSM) was the most common subtype, predominantly affecting women, while nodular melanoma (NM) was more frequent in men. Higher BI was associated with NM and acral lentiginous melanoma (ALM). Limbs were women’s most frequent tumor site, whereas the trunk was predominant in men. Significant associations were observed between younger age at diagnosis and factors such as high nevus count, indoor activity, and smoking status. Rural residents reported a higher history of sunburns compared to urban residents. Conclusions: Our findings underscore the importance of targeted public health interventions to promote early detection and primary prevention of melanoma. Establishing a national melanoma registry is crucial to improving epidemiological surveillance and reducing the burden of melanoma in Romania. Full article

Background: Tumour mutational burden (TMB) is an emerging biomarker for predicting the efficacy of immune checkpoint inhibitors (ICIs) in cancer therapy. While its role is well established in lung cancer and melanoma, its predictive value for breast and prostate cancers remains unclear. Objective: This systematic review aimed to assess the predictive value of TMB for ICI therapy across four major cancer types—lung, melanoma, breast, and prostate—and to explore factors contributing to the variability in its effectiveness as a biomarker. Methods: A systematic search and a review of the literature were conducted in accordance with PRISMA guidelines. Studies examining the relationship between TMB levels and clinical outcomes following ICI therapy in the specified cancers were analyzed. The data were synthesized to evaluate TMB’s predictive value and identify gaps in the current research. Results: High TMB consistently correlated with improved outcomes in lung cancer and melanoma, confirming its predictive utility in these cancers. Conversely, the findings for breast and prostate cancers were inconclusive. The variability in TMB’s predictive value for these cancers suggests the need for complementary biomarkers or refined criteria to enhance its reliability. Methodological inconsistencies in TMB evaluation were also noted as a significant limitation. Conclusions: TMB serves as a robust biomarker for predicting ICI response in lung cancer and melanoma, but demonstrates limited predictive utility in breast and prostate cancers. Future research should prioritize standardizing TMB assessment protocols and investigating additional biomarkers to improve treatment personalization for these cancer types. Full article

Background/Objectives: Interferon gamma (IFN-γ) in the melanoma tumor microenvironment plays opposing roles, orchestrating both pro-tumorigenic activity and anticancer immune responses. Our previous studies demonstrated the role of neuronal nitric oxide synthase (nNOS) in IFN-γ-stimulated melanoma progression. However, the underlying mechanism has not been well defined. This study determined whether the nNOS/NO and COX-2/PGE₂ signaling pathways crosstalk and augment the pro-tumorigenic effects of IFN-γ in melanoma. Methods: Bioinformatic analysis of patient and cellular proteomic data was conducted to identify proteins of interest associated with IFN-γ treatment in melanoma. Changes in protein expression were determined using various analytical techniques including western blot, flow cytometry, and confocal microscopy. The levels of PGE₂ and nitric oxide (NO) were analyzed by HPLC chromatography and flow cytometry. In vivo antitumor efficacy was determined utilizing a human melanoma xenograft mouse model. Results: Our omics analyses revealed that the induction of COX-2 was significantly predictive of IFN-γ treatment in melanoma cells. In the presence of IFN-γ, PGE₂ further enhanced PD-L1 expression and amplified the induction of nNOS, which increased intracellular NO levels. Cotreatment with celecoxib effectively diminished these changes induced by PGE₂. In addition, nNOS blockade using a selective small molecule inhibitor (HH044), efficiently inhibited IFN-γ-induced PGE₂ and COX-2 expression levels in melanoma cells. STAT3 inhibitor napabucasin also inhibited COX-2 expression both in the presence and absence of IFN-γ. Furthermore, celecoxib was shown to enhance HH044 cytotoxicity in vitro and effectively inhibit human melanoma tumor growth in vivo. HH044 treatment also significantly reduced tumor PGE₂ levels in vivo. Conclusions: Our study demonstrates the positive feedback loop linking nNOS-mediated NO signaling to the COX-2/PGE₂ signaling axis in melanoma, which further potentiates the pro-tumorigenic activity of IFN-γ. Full article

Background: Alternative NTRK1/TrkA splicing resulting in TrkAIII expression, originally discovered in advanced-stage metastatic neuroblastomas, is also pronounced in prostate, medullary thyroid, glioblastoma multiforme, MCPyV-positive Merkel cell, cutaneous malignant melanoma, and pituitary neuroendocrine tumor subsets. In tumor models, TrkAIII exhibits actionable oncogenic activity equivalent to the TrkT3-fused oncogene, and in tumor cell lines, alternative TrkAIII splicing is promoted by hypoxia, nutrient deprivation, endoplasmic reticulum stress, and SV40 large T antigen, implicating tumor microenvironmental conditions and oncogenic polyoma viruses in tumor-associated TrkAIII expression. Collectively, these observations characterize TrkAIII as a potentially frequent, actionable oncogenic alternative to TrkA gene fusion in different tumor types. Currently, therapeutic approval for efficacious Trk inhibitors is restricted to Trk-fused gene positive tumors and not for tumors potentially driven by TrkAIII. Methods: With the therapeutically relevant aim of improving the identification of tumors potentially driven by TrkAIII, we have developed a TaqMan-based qRT-PCR assay for evaluating TrkAIII expression in tumor cDNAs. Results: This assay, validated using gel-purified fs-TrkA and TrkAIII cDNAs alone and in complex cDNA mixtures, employs primers and probes designed from fs-TrkA and TrkAIII sequences, with specificity provided by a TaqMan probe spanning the TrkAIII exon 5–8 splice junction. It is highly efficient, reproducible, and specific and can detect as few as 10 TrkAIII copies in complex RNAs extracted from either fresh or FFPE tumor tissues. Conclusions: Inclusion of this assay into precision oncology algorithms, when paired with fs-TrkA qRT-PCR and TrkA immune histochemistry, will make it easier to identify patients with therapy-resistant, advanced-stage metastatic Trk-fused gene-negative tumors potentially driven by TrkAIII, for whom approval of third-line effective Trk inhibitors could be extended. Full article

Biologically active compounds of natural origin, such as betulin, are a source of obtaining new medicinal substances. The presence of chemically active hydroxyl groups in the betulin structure at C-3 and C-28 positions enables esterification with dicarboxylic acid anhydrides or carboxylic acids. As a result of a four-step synthesis, difunctional betulin derivatives were obtained, which were evaluated for their antiproliferative activity against the following human cell lines: leukemia (MV4-11), (A549), breast cancer (MCF-7), prostate adenocarcinoma (PC-3), colon cancer (HCT116), pancreatic cancer (MiaPaca-2), and melanoma (Hs294T). The target 3-carboxyacyl-28-alkynyloyl betulin derivatives showed significant antiproliferative activity against MV4-11 cells. For 3-carboxyacylbetulins and their selected alkynyl derivatives, studies to investigate the effect on the cell cycle and apoptosis process, as well as drug similarity analysis, were performed. Full article

Melanoma, a lethal type of cancer originating from melanocytes, is the leading cause of death among skin cancers. While surgical excision of the lesions is the primary treatment for melanoma, not all cases are candidates for surgical procedures. New treatments and complementary options are necessary, given the increasing diagnosis rate. In the present study, a norcantharidin-containing nanoemulsion was developed and evaluated in vivo using a syngeneic graft murine model. Norcantharidin is the demethylated analog of cantharidin, known for its anticancer properties. Our model contemplates surgical excision surgery simulating the standard treatment and the role of the nanoemulsion as a potential adjuvant therapy. We observed a significant decrease in the growth rate of the melanoma lesion in the treated groups compared to the control group, both at the 20th and 30th days of treatment. Moreover, we evaluated the drug bioavailability in serum samples, and the results showed that norcantharidin was detectable in a range of 0.1 to 0.18 mg/mL in the treated groups. Furthermore, histopathological analysis was performed on the amputated tumors, where significant differences were found regarding size, mitosis rate, lymphocytic infiltration, and multispectral quantitative image analysis compared to the control group. If more clinical studies are conducted, the norcantharidin-containing nanoemulsion could be a potential alternative or adjuvant therapy. Topical nanosystems can become or complement standard therapies, which is needed as melanoma affects not only in terms of mortality but also the patient’s morbidity and life quality. Full article

Background/Objectives: Facial lesions, including lentigo maligna and lentigo maligna melanoma (LM/LMM), both malignant, present significant diagnostic challenges due to their clinical similarity to benign conditions. Although standard dermoscopy is a well-established tool for diagnosis, its inability to reveal cellular-level details highlights the necessity of new magnified techniques. This study aimed to assess the role of standard dermoscopy, high-magnification dermoscopy, and fluorescence-advanced videodermatoscopy (FAV) in diagnosing LM/LMM and differentiating them from benign facial lesions. Methods: This retrospective, observational, multicenter study evaluated 85 patients with facial skin lesions (including LM, LMM, basal-cell carcinoma, solar lentigo, seborrheic keratosis, actinic keratosis, and nevi) who underwent dermatological examination for skin tumor screening. Standard dermoscopy at 30× magnification (D30), high-magnification dermoscopy at 150× magnification (D150), and FAV examination were performed. Dermoscopic images were retrospectively evaluated for the presence of fifteen 30× and twenty-one 150× dermoscopic features, and their frequency was calculated. To compare D30 with D150 and D150 with FAV, the Gwet AC1 concordance index and the correct classification rate (CCR) were estimated. Results: Among 85 facial lesions analyzed, LM/LMM exhibited distinctive dermoscopic features at D30, including a blue–white veil (38.9% vs. 1.7%, p < 0.001), regression structures (55.6% vs. 21.7%, p = 0.013), irregular dots or globules (50.0% vs. 10%, p = 0.001), angulated lines (72.2% vs. 6.7%, p < 0.001), an annular granular pattern (61.1% vs. 20%, p = 0.002), asymmetrical pigmented follicular openings (100.0% vs. 21.7%; p < 0.001), and follicular obliteration (27.8% vs. 3.3%). At D150, roundish melanocytes (87.5% vs. 18.2%, p < 0.001) and melanophages (43.8% vs. 14.5%, p = 0.019) were predominant. FAV examination identified large dendritic cells, isolated melanocytes, and free melanin in LM/LMM (all p < 0.001) with high concordance to D150. Conclusions: Integrating D30, D150, and FAV into clinical practice may enhance diagnostic precision for facial lesions by combining macroscopic and cellular insights, thereby reducing unnecessary biopsies. However, future studies are essential to confirm these results. Full article

(1) Background/Objectives: Primary and secondary brain tumours often hold devastating prognoses and low survival rates despite the application of maximal neurosurgical resection, and state-of-the-art radiotherapy and chemotherapy. One limiting factor in their management is that several antineoplastic agents are unable to cross the blood–brain barrier (BBB) to reach the tumour microenvironment. Nanomedicine could hold the potential to become an effective means of drug delivery to overcome previous hurdles towards effective neuro-oncological treatments. (2) Methods: A scoping review following the PRISMA-ScR guidelines and checklist was conducted using key terms input into PubMed to find articles that reflect emerging trends in the utilisation of nanomedicine in drug delivery for primary and secondary brain tumours. (3) Results: The review highlights various strategies by which different nanoparticles can be exploited to bypass the BBB; we provide a synthesis of the literature on the ongoing contributions to therapeutic protocols based on chemotherapy, immunotherapy, focused ultrasound, radiotherapy/radiosurgery, and radio-immunotherapy. (4) Conclusions: The emerging trends summarised in this scoping review indicate encouraging advantageous properties of nanoparticles as potential effective drug delivery mechanisms; however, there are still nanotoxicity issues that largely remain to be addressed before the translation of these innovations from laboratory to clinical practice. Full article

A comprehensive review of studies describing the role of G-protein coupled receptor (GPCR) behaviour contributing to metastasis in cancer, and the developments of biotherapeutic drugs towards targeting them, provides a valuable resource toward improving our understanding of the opportunities to effectively target this malignant tumour cell adaptation. Focusing on the five most common metastatic cancers of lung, breast, colorectal, melanoma, and prostate cancer, we highlight well-studied and characterised GPCRs and some less studied receptors that are also implicated in the development of metastatic cancers. Of the approximately 390 GPCRs relevant to therapeutic targeting, as many as 125 of these have been identified to play a role in promoting metastatic disease in these cancer types. GPCR signalling through the well-characterised pathways of chemokine receptors, to emerging data on signalling by orphan receptors, is integral to many aspects of the metastatic phenotype. Despite having detailed information on many receptors and their ligands, there are only thirteen approved therapeutics specifically for metastatic cancer, of which three are small molecules with the remainder including synthetic and non-synthetic peptides or monoclonal antibodies. This review will cover the existing and potential use of monoclonal antibodies, proteins and peptides, and nanobodies in targeting GPCRs for metastatic cancer therapy. Full article

Chalcones are recognized for their diverse pharmacological properties, including anti-inflammatory and anti-melanogenic effects. However, studies on 2′-hydroxy-2-methoxychalcone derivatives remain limited. This study investigated the anti-inflammatory and melanin synthesis-inhibitory effects of three derivatives: 2′-hydroxy-2,4-dimethoxychalcone (2,4-DMC), 2′-hydroxy-2,5′-dimethoxychalcone (2,5′-DMC), and 2′-hydroxy-2,6′-dimethoxychalcone (2,6′-DMC). In lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, 2,6′-DMC demonstrated a superior inhibition of nitric oxide (NO) production, pro-inflammatory cytokines, and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) compared to the other derivatives. A mechanistic analysis revealed that 2,6′-DMC modulates the NF-κB and MAPK signaling pathways to attenuate inflammation. Additionally, 2,6′-DMC exhibited a significant inhibition of α-melanocyte-stimulating hormone (α-MSH)-induced melanin synthesis in B16F10 melanoma cells by downregulating tyrosinase, TRP-1, TRP-2, and MITF expression. This regulation was achieved through the suppression of the Wnt/β-catenin, PI3K/AKT, MAPK, and PKA/CREB pathways. Compared to 2,4-DMC and 2,5′-DMC, 2,6′-DMC’s structural configuration, characterized by methoxy groups at the 2- and 6′-positions, contributed to its enhanced molecular stability and binding affinity, amplifying its inhibitory effects. A primary skin irritation test confirmed that 2,6′-DMC exhibited minimal irritation, demonstrating its safety for dermal applications. These findings suggest that 2,6′-DMC holds promise as a dual-function agent for managing inflammatory conditions and hyperpigmentation-related disorders. Full article

Introduction: Metastatic uveal melanoma (mUM) is a rare and aggressive malignancy characterised by poor responsiveness to conventional chemotherapies, posing significant treatment challenges. Immune checkpoint inhibitor (ICI) therapies, including monotherapies with Ipilimumab, pembrolizumab, and nivolumab, as well as dual ICI therapy, have emerged as potential treatments. Whilst current research favours dual therapy over single therapy, comprehensive individualised comparisons of the efficacy and safety profiles of these therapies remain limited. This meta-analysis aims to evaluate the clinical outcomes of single ICI therapies individually and compare against combination therapy to guide optimal treatment strategies for mUM. Methods: A systematic literature review was conducted to identify studies reporting objective response rates (ORR), disease control rates (DCR), median progression-free survival (MPFS), and adverse event rates (AER) for Ipilimumab, pembrolizumab, nivolumab, and dual ICI therapy. Data were aggregated using forest plots and analysed to compare the efficacy and safety of each regimen. Results: Dual ICI therapy demonstrated the highest ORR and DCR but showed no statistically significant advantage over monotherapies. Dual therapy also had a lower MPFS than both pembrolizumab and nivolumab monotherapies. Furthermore, dual therapy was associated with a much greater AER compared to any single therapy, including pembrolizumab and nivolumab. Conclusions: While dual ICI therapy offers improved ORR and DCR on aggregate analyses, monotherapies like pembrolizumab provide comparable outcomes in specific metrics, particularly MPFS, with significantly reduced toxicity. These findings underscore the need for personalised ICI regimens tailored to individual patient profiles rather than defaulting to dual therapy. Further research is essential to refine treatment guidelines and optimise outcomes for mUM patients. Full article

Background/Objectives: Natural cytokinins are a promising group of anti-tumor agents. In this work, we hypothesized that modification of the ethylenediurea moiety with alkyl and oxygen-containing groups could be a way to enhance the anti-proliferative properties of the molecule. Methods: Ten new analogs of ethylenediurea with these substitutions were tested for anti-proliferative activity in the human cancer cell lines MDA-MB-231 (breast cancer), A-375 (melanoma), and U-87 MG (glioblastoma) during 72 h of incubation using resazurin test and evaluated the substances receptor using molecular docking. Results: The compound with the carbamate link and ethylene substituent on the phenyl ring inhibited proliferation in these models by 70–90% without cytotoxic effects. The compound did not affect the viability of the immortalized fibroblast cell line Bj-5ta. The compound was also able to enhance the action of doxorubicin and temozolomide by about 20%. According to the molecular modeling data, the probable receptor target for the synthesized compound was the A2AR adenosine receptor. Conclusions: The results obtained on the ethylenediurea analogs with ethyl substituent in the aromatic ring are promising for the development of novel anticancer therapeutics. Full article