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The present study investigates the chemotherapeutic potential of two platinum (IV) complexes, P-PENT and P-HEX, against skin cancer in vitro and in vivo . Both complexes exhibited potent cytotoxicity against HaCaT-II-4 cells with IC 50 values of 0.8 ± 0.08 μM and 1.3 ± 0.16 μM respectively, while demonstrating 8-10-fold selectivity compared to mesenchymal stem cells (MSCs). Western blot analysis revealed significant modulation of key apoptotic and survival pathways, including upregulation of Bax/Bcl2 ratio, cleaved caspase 3, and cytochrome c , suggesting induction of intrinsic apoptosis. The complexes also inhibited PI3K and MAPK pathways, as evidenced by decreased p-AKT/AKT and p-ERK/ERK ratios. Flow cytometry confirmed significant apoptotic cell death. Both complexes also increased reactive oxygen species production. In a DMBA/TPA-induced skin carcinogenesis mouse model, both complexes significantly suppressed tumor growth at doses considerably lower than the maximum tolerated dose, with no detectable toxicity. A dose escalation study in BALB/c mice showed that P-PENT and P-HEX were approximately 5-fold and 4-fold more tolerated than cisplatin, respectively. In conclusion, the present study provides evidence that P-PENT and P-HEX may have the characteristics of an effective and potentially safe anti-tumor drug that could be used in skin cancer treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Chlorambucil-platinum(IV) prodrugs exhibit multi-mechanistic chemotherapeutic activity with promising anticancer potential. The platinum(II) precursors of the prodrugs have been previously found to induce changes in the microtubule cytoskeleton, specifically actin and tubulin of HT29 colon cells, while chlorambucil alkylates the DNA. These prodrugs demonstrate significant anticancer activity in 2D cell and 3D spheroid viability assays. A notable production of reactive oxygen species has been observed in HT29 cells 72 h post treatment with prodrugs of this type, while the mitochondrial membrane potential was substantially reduced. The cellular uptake of the chlorambucil-platinum(IV) prodrugs, assessed by ICP-MS, confirmed that active transport was the primary uptake mechanism, with platinum localisation identified primarily in the cytoskeletal fraction. Apoptosis and necrosis were observed at 72 h of treatment as demonstrated by Annexin V-FITC/PI assay using flow cytometry. Immunofluorescence measured via confocal microscopy showed significant changes in actin and tubulin intensity and in architecture. Western blot analysis of intrinsic and extrinsic pathway apoptotic markers, microtubule cytoskeleton markers, cell proliferation markers, as well as autophagy markers were studied post 72 h of treatment. The proteomic profile was also studied with a total of 1859 HT29 proteins quantified by mass spectroscopy, with several dysregulated proteins. Network analysis revealed dysregulation in transcription, MAPK markers, microtubule-associated proteins and mitochondrial transport dysfunction. This study confirms that chlorambucil-platinum(IV) prodrugs are candidates with promising anticancer potential that act as multi-mechanistic chemotherapeutics.

Development of resistance to cisplatin, oxaliplatin and carboplatin remains a challenge for their use as chemotherapies, particularly in breast and colorectal cancer. Here, we compare the anticancer effect of novel complexes [Pt(1,10-phenanthroline)(1 S ,2 S -diaminocyclohexane)](NO 3 ) 2 ( Pt II PHEN SS ), [Pt(5-methyl-1,10-phenanthroline)(1 S ,2 S -diaminocyclohexane)](NO 3 ) 2 ( Pt II 5ME SS ) and [Pt(5,6-dimethyl-1,10-phenanthroline)(1 S ,2 S -diaminocyclohexane)](NO 3 ) 2 ( Pt II 56ME SS ) and their platinum(IV)-dihydroxy derivatives with cisplatin. Complexes are greater than 11-fold more potent than cisplatin in both 2D and 3D cell line cultures with increased selectivity for cancer cells over genetically stable cells. ICP-MS studies showed cellular uptake occurred through an active transport mechanism with considerably altered platinum concentrations found in the cytoskeleton across all complexes after 24 h. Significant reactive oxygen species generation was observed, with reduced mitochondrial membrane potential at 72 h of treatment. Late apoptosis/necrosis was shown by Annexin V-FITC/PI flow cytometry assay, accompanied by increased sub-G0/G1 cells compared with untreated cells. An increase in S and G2+M cells was seen with all complexes. Treatment resulted in significant changes in actin and tubulin staining. Intrinsic and extrinsic apoptosis markers, MAPK/ERK and PI3K/AKT activation markers, together with autophagy markers showed significant activation of these pathways by Western blot. The proteomic profile investigated post-72 h of treatment identified 1597 MDA-MB-231 and 1859 HT29 proteins quantified by mass spectroscopy, with several differentially expressed proteins relative to no treatment. GO enrichment analysis revealed a statistically significant enrichment of RNA/DNA-associated proteins in both the cell lines and specific additional processes for individual drugs. This study shows that these novel agents function as multi-mechanistic chemotherapeutics, offering promising anticancer potential, and thereby supporting further research into their application as cancer therapeutics.

Kinetically inert platinum(IV) complexes are a chemical strategy to overcome the impediments of standard platinum(II) antineoplastic drugs like cisplatin, oxaliplatin and carboplatin. In this study, we reported the syntheses and structural characterisation of three platinum(IV) complexes that incorporate 5-benzyloxyindole-3-acetic acid, a bioactive ligand that integrates an indole pharmacophore. The purity and chemical structures of the resultant complexes, P-5B3A , 5-5B3A and 56-5B3A were confirmed via spectroscopic means. The complexes were evaluated for anticancer activity against multiple human cell lines. All complexes proved to be considerably more active than cisplatin, oxaliplatin and carboplatin in most cell lines tested. Remarkably, 56-5B3A demonstrated the greatest anticancer activity, displaying GI 50 values between 1.2 and 150 nM. Enhanced production of reactive oxygen species paired with the decline in mitochondrial activity as well as inhibition of histone deacetylase were also demonstrated by the complexes in HT29 colon cells.

The present study investigates the anti-neoplastic activity of a platinum (II) complex, Pt(II)5ClSS, and its platinum (IV) di-hydroxido analogue, Pt(IV)5ClSS, against mesenchymal cells (MCs), lung (A549), melanoma (A375) and breast (MDA-MB-231) cancer cells. Both complexes exhibited up to 14-fold improved cytotoxicity compared to cisplatin. NMR was used to determine that ∼25 % of Pt(IV)5ClSS was reduced to Pt(II)5ClSS in the presence of GSH (Glutathione) after 72 h. The complex 1 H NMR spectra acquired for Pt(II)5ClSS with GSH shows evidence of degradation and environmental effects (∼30 %). The prominence of the 195 Pt peak at ∼ -2800 ppm suggests that a significant amount of Pt(II)5ClSS remained in the mixture. Pt(II)5ClSS and Pt(IV)5ClSS have shown exceptional selectivity to cancer cells in comparison to MCs (IC 50  > 150 μM). Western blot analysis of Pt(II)5ClSS and Pt(IV)5ClSS on A549 cells revealed significant upregulation of cleaved PARP-1, BAX/Bcl 2 ratio, cleaved caspase 3 and cytochrome thus suggesting apoptosis was induced through the intrinsic pathway. Flow cytometry also revealed significant cell death by apoptosis. Treatment with Pt(II)5ClSS and Pt(IV)5ClSS also showed significant amounts of free radical production while the COMET assay showed that both complexes cause minimal DNA damage. Cellular uptake results via ICP-MS suggest a time-dependent active mode of transport for both complexes with Pt(II)5ClSS being transported at a higher rate compared to Pt(IV)5ClSS. A Dose Escalation Study carried out on BALB/c mice showed that Pt(II)5ClSS and Pt(IV)5ClSS were approximately 8- folds and 12.5-folds, respectively, more tolerated than cisplatin. The present study provides evidence that both complexes may have the characteristics of an efficient and potentially safe anti-tumor drug that could support NSCLC treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Developing new and versatile platinum(IV) complexes that incorporate bioactive moieties is a rapidly evolving research strategy for cancer drug discovery. In this study, six platinum(IV) complexes ( 1 - 6 ) that are mono-substituted in the axial position with a non-steroidal anti-inflammatory molecule, naproxen or acemetacin, were synthesised. A combination of spectroscopic and spectrometric techniques confirmed the composition and homogeneity of 1 - 6 . The antitumour potential of the resultant complexes was assessed on multiple cell lines and proved to be significantly improved compared with cisplatin, oxaliplatin and carboplatin. The platinum(IV) derivatives conjugated with acemetacin ( 5 and 6 ) were determined to be the most biologically potent, demonstrating GI 50 values ranging between 0.22 and 250 nM. Remarkably, in the Du145 prostate cell line, 6 elicited a GI 50 value of 0.22 nM, which is 5450-fold more potent than cisplatin. A progressive decrease in reactive oxygen species and mitochondrial activity was observed for 1 - 6 in the HT29 colon cell line, up to 72 h. The inhibition of the cyclooxygenase-2 enzyme was also demonstrated by the complexes, confirming that these platinum(IV) complexes may reduce COX-2-dependent inflammation and cancer cell resistance to chemotherapy.

This study aimed to evaluate the effect of general anesthesia (GA) on the 1-year outcome of Root Canal Treatment (RCT) performed in pediatric patients and to compare it to the outcome of RCT in pediatric patients without GA. Patients admitted for RCT in permanent dentition in a public hospital, dated 2015 to 2020, age 8-15 with a minimum of one year follow-up period, were included in the study. The sample consisted of 326 teeth from 269 patients treated by a single operator, with a recall rate of 81%. Overall, 124 teeth were treated under GA and 142 teeth were without GA. The mean follow-up time was 31.5 months. Data underwent statistical analysis and the significance threshold was set for p < 0.05. Of the total cases, 90% showed favorable outcomes. A significantly higher favorable outcome was seen in the GA group than in the non-GA group (98% and 85%, respectively, p < 0.001). The outcome was significantly affected by the type and quality of the coronal restoration, degree of root development, and lesion size ( p < 0.05). According to the current study, in uncooperative pediatric patients, a more favorable outcome of root canal treatment can be obtained under GA than LA if the procedure is carried out with immediate restoration.

A new series of cytotoxic platinum(IV) complexes ( 1 - 8 ) incorporating halogenated phenylacetic acid derivatives (4-chlorophenylacetic acid, 4-fluorophenylacetic acid, 4-bromophenylacetic acid and 4-iodophenylacetic acid) were synthesised and characterised using spectroscopic and spectrometric techniques. Complexes 1 - 8 were assessed on a panel of cell lines including HT29 colon, U87 glioblastoma, MCF-7 breast, A2780 ovarian, H460 lung, A431 skin, Du145 prostate, BE2-C neuroblastoma, SJ-G2 glioblastoma, MIA pancreas, the ADDP-resistant ovarian variant, and the non-tumour-derived MCF10A breast line. The in vitro cytotoxicity results confirmed the superior biological activity of the studied complexes, especially those containing 4-fluorophenylacetic acid and 4-bromophenylacetic acid ligands, namely 4 and 6 , eliciting an average GI 50 value of 20 nM over the range of cell lines tested. In the Du145 prostate cell line, 4 exhibited the highest degree of potency amongst the derivatives, displaying a GI 50 value of 0.7 nM, which makes it 1700-fold more potent than cisplatin (1200 nM) and nearly 7-fold more potent than our lead complex, 56ME SS (4.6 nM) in this cell line. Notably, in the ADDP-resistant ovarian variant cell line, 4 (6 nM) was found to be almost 4700-fold more potent than cisplatin. Reduction reaction experiments were also undertaken, along with studies aimed at determining the complexes' solubility, stability, lipophilicity, and reactive oxygen species production.

The DNA-alkylating derivative chlorambucil was coordinated in the axial position to atypical cytotoxic, heterocyclic, and non-DNA coordinating platinum(IV) complexes of type, [Pt IV (H L )(A L )(OH) 2 ](NO 3 ) 2 (where H L is 1,10-phenanthroline, 5-methyl-1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, A L is 1 S ,2 S -diaminocyclohexane). The resultant platinum(IV)-chlorambucil prodrugs, PCLB , 5CLB , and 56CLB , were characterized using high-performance liquid chromatography, nuclear magnetic resonance, ultraviolet-visible, circular dichroism spectroscopy, and electrospray ionization mass spectrometry. The prodrugs displayed remarkable antitumor potential across multiple human cancer cell lines compared to chlorambucil, cisplatin, oxaliplatin, and carboplatin, as well as their platinum(II) precursors, PHEN SS , 5ME SS , and 56ME SS . Notably, 56CLB was exceptionally potent in HT29 colon, Du145 prostate, MCF10A breast, MIA pancreas, H460 lung, A2780, and ADDP ovarian cell lines, with GI 50 values ranging between 2.7 and 21 nM. Moreover, significant production of reactive oxygen species was detected in HT29 cells after treatment with PCLB , 5CLB , and 56CLB up to 72 h compared to chlorambucil and the platinum(II) and (IV) precursors.

Visible light has long been recognized as a treatment for many diseases and an essential component of photo-induced chemotherapy. While previous data proved its inherent cytotoxicity, this study is the first to explore the use of a commercially available, high-intensity white LED light (24.5 mW.cm -2 ) as a treatment for skin tumors. After a 9-h exposure in vitro, the viability of Human Malignant Melanoma cells (A375) decreased by around 70%. Western blot analysis suggested an apoptotic cell death confirmed by the upregulation of Bax, cleaved PARP/caspase-3/8, cytochrome c, and t-bid. Additionally, cellular ROS accumulation and DNA damage were induced upon irradiation with blue light. When tested on a DMBA/TPA skin carcinogenesis model, a 90-min exposure to white light thrice weekly resulted in a significant decrease in tumor volumes/incidence compared to control and cisplatin groups, and restored normal morphological features, as confirmed by histopathology. Toxicological evaluation of ight-treated animals indicated a 100% survival rate, no skin irritation, no signs of discomfort or changes in body weight/behavior, and no toxicities to vital organs. Although these results must be confirmed by further studies, this research showed that short-exposure by commercially available high-intensity white LED light irradiation may be a promising approach for the treatment of superficial malignancies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Photoactivated chemotherapy (PACT) is an emerging strategy for targeted cancer therapy. Strained Ru complexes with pseudo-octahedral geometry may undergo photo-induced ligand dissociation, forming aquated photoproducts that are significantly more cytotoxic compared to the precursor complex. The complexes investigated were the strained complex [Ru(bpy) 2 BC]Cl 2 (where bpy = 2,2'-bipyridine and BC = bathocuproine) and its unstrained control [Ru(bpy) 2 phen]Cl 2 (where phen = 1,10-phenanthroline). The uptake of [Ru(bpy) 2 BC]Cl 2 , assessed by ICP/MS, started immediately post-incubation and plateaued after 24 h. Active transport was found as the main mode of intracellular transport. Cell viability assays on A375 cells indicated a mean phototoxicity index of 340-fold, and the effect was shown to be primarily mediated by the aquated photoproducts rather than the dissociating ligands. A significant increase in ROS production and DNA damage was also observed. Flow cytometry confirmed the induction of early apoptosis at 48 h that proceeds to late apoptosis/necrosis by 72 h post-treatment. Western blot analysis of pro- and anti-apoptotic proteins revealed that apoptosis was mediated through an interplay between the intrinsic and extrinsic pathways, as well as autophagy and via inhibition of the MAPK and PI3K pathways. In conclusion, this study demonstrates that [Ru(bpy) 2 BC]Cl 2 is a multi-mechanistic PACT drug which exhibits promising anticancer potential., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Mast cells (MC) are important immune sentinels found in most tissue and widely recognized for their role as mediators of Type I hypersensitivity. However, they also secrete anti-cancer mediators such as tumor necrosis factor alpha (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The purpose of this study was to investigate adipose tissue as a new source of MC in quantities that could be used to study MC biology focusing on their ability to bind to and kill breast cancer cells. We tested several cell culture media previously demonstrated to induce MC differentiation. We report here the generation of functional human MC from adipose tissue. The adipose-derived mast cells (ADMC) are phenotypically and functionally similar to connective tissue expressing tryptase, chymase, c-kit, and FcεRI and capable of degranulating after cross-linking of FcεRI. The ADMC, sensitized with anti-HER2/ neu IgE antibodies with human constant regions (trastuzumab IgE and/or C6MH3-B1 IgE), bound to and released MC mediators when incubated with HER2/ neu -positive human breast cancer cells (SK-BR-3 and BT-474). Importantly, the HER2/ neu IgE-sensitized ADMC induced breast cancer cell (SK-BR-3) death through apoptosis. Breast cancer cell apoptosis was observed after the addition of cell-free supernatants containing mediators released from FcεRI-challenged ADMC. Apoptosis was significantly reduced when TNF-α blocking antibodies were added to the media. Adipose tissue represents a source MC that could be used for multiple research purposes and potentially as a cell-mediated cancer immunotherapy through the expansion of autologous (or allogeneic) MC that can be targeted to tumors through IgE antibodies recognizing tumor specific antigens.

The transformation of monocyte-derived macrophages into lipid-laden foam cells is one inflammatory process underlying atherosclerotic disease. Previous studies have demonstrated that fullerene derivatives (FDs) have inflammation-blunting properties. Thus, it was hypothesized that FD could inhibit the transformation process underlying foam cell formation. Fullerene derivatives inhibited the phorbol myristic acid/oxidized low-density lipoprotein-induced differentiation of macrophages into foam cells as determined by lipid staining and morphology.Lipoprotein-induced generation of TNF-α, C5a-induced MC activation, ICAM-1 driven adhesion, and CD36 expression were significantly inhibited in FD treated cells compared to non-treated cells. Inhibition appeared to be mediated through the NF-κB pathway as FD reduced expression of NF-κB and atherosclerosis-associated genes. Compared to controls, FD dramatically inhibited plaque formation in arteries of apolipoprotein E null mice. Thus, FD may be an unrecognized therapy to prevent atherosclerotic lesions via inhibition of foam cell formation and MC stabilization., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To identify characteristics related to smoking in hospitalized patients and to assess the knowledge that such patients have regarding the relationship between nicotine dependence and smoking-related diseases., Methods: The study included 186 patients (males, 59%; mean age, 51.3 +/- 16.8 years) who were evaluated regarding demographic characteristics, diagnosis at admission, smoking history and passive smoke exposure. All of the patients completed a questionnaire regarding their knowledge of the relationship between smoking and disease., Results: Of the 186 patients, 42 (22.6%) were smokers, 64 (34.4%) were former smokers and 80 (43%) stated they were never smokers; 136 (73%) reported passive smoke exposure. In the sample as a whole, 21.5% of the patients were diagnosed with a smoking-related disease at admission, compared with 39% of those who were smokers or former smokers. The proportion of individuals who were unaware of the relationship between smoking and the cause of hospitalization was similar among current smokers and former smokers (56% and 65%, respectively). Only 19% of the current smokers believed that smoking might have affected their health, compared with 32% of the former smokers (p = 0.22). The proportion of individuals who believed that quitting smoking depends on willpower was significantly higher among former smokers and never smokers than among current smokers (64% and 53%, respectively, vs. 24%; p < 0.001 and p = 0.008). Although 96% of the patients believed that smoking causes dependence, only 60% identified smoking as a disease., Conclusions: This study shows the disconnect between the recognition of smoking as a cause of dependence and the recognition of smoking as a disease, as well as the general lack of awareness that former and current smoking constitute a risk factor for the development and progression of disease.

Objective: In view of the controversies found in the literature, the present study was conducted to determine the effect of the use of exogenous human albumin on the nutritional status of newborn infants submitted to total parenteral nutrition., Methods: Thirty critically ill newborn infants weighing less than 2,500 g were divided into two groups: 15 infants receiving total parenteral nutrition without human albumin (C control group) and 15 with human albumin (group A). Total protein, albumin, prealbumin, and retinol-binding protein were determined at the beginning (3-4 days of postnatal age) and at the end of the study (10-11 days of postnatal age). On the seventh day of the study, nitrogen balance (retention) was measured. The following clinical parameters were evaluated: weight, age at the beginning of enteral nutrition, time to reach a full enteral volume, length of stay in the intensive care unit, total hospitalization time, and mortality., Results: The results showed a significant difference (p < 0.05) in serum albumin and total protein levels (p < 0.05) between groups at the end of the study. Median albumin levels were 2.95 g/dl in group C (2.71-3.16 g/dl), whereas group A showed median albumin levels of 4.10 g/dl, (3.76-4.66 g/dl). Total protein levels were 4.9 g/dl (4.4-5.2 g/dl) and 5.6 g/dl (5.5-6.3 g/dl), respectively, with no repercussions on any of the remaining parameters evaluated., Conclusions: On the basis of the results obtained in the present study, no benefits were derived from the use of human albumin in total parenteral nutrition in severely ill newborns; therefore its use cannot be recommended, unless the objective is exclusively to elevate albumin levels.