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5-Hydroxy-3′,4′,6,7-tetramethoxyflavone (TMF) is a plant-origin flavone known for its anti-cancer properties. In the present study, the cytotoxic effect of TMF was evaluated in the U87MG and T98G glioblastoma (GBM) cell lines. The effect of TMF on cell viability was assessed with trypan blue exclusion assay and crystal violet staining. In addition, flow cytometry was performed to examine its effect on the different phases of the cell cycle, and in vitro scratch wound assay assessed the migratory capacity of the treated cells. Furthermore, the effect of in vitro radiotherapy was also evaluated with a combination of TMF and radiation. In both cell lines, TMF treatment resulted in G0/G1 cell cycle arrest, reduced cell viability, and reduced cell migratory capacity. In contrast, there was an antagonistic property of TMF treatment with radiotherapy. These results demonstrated the antineoplastic effect of TMF in GBM cells in vitro, but the antagonistic effect with radiotherapy indicated that TMF should be further evaluated for its possible antitumor role post-radiotherapy.

Simple Summary: This review highlights the recent advances in the development and application of dual function kinase inhibitors that also bear fluorescent properties (fluorescent kinase inhibitors), thus can be used as theranostics in the field of cancer. This is a rapidly growing field with significant potential for cancer therapy and diagnosis. This work mainly focuses on the key design principles that guide the development of these multifunctional compounds, emphasizing the integration of essential components such as the kinase cytotoxic warhead, the fluorophore, the linkers, and additional modular elements to enhance the efficacy of the final assembled compound. We anticipate this review to propel the advancement of this field by improving the understanding of the design principles and ultimately leading to the development of more effective tools for the concurrent diagnosis and treatment of cancer. Kinase inhibitors are potent therapeutic agents in cancer treatment, but their effectiveness is frequently restricted by the inability to image the tumor microenvironment. To address this constraint, kinase inhibitor–fluorophore conjugates have emerged as promising theranostic agents, allowing for simultaneous cancer diagnosis and treatment. These conjugates are gaining attention for their ability to visualize malignant tissues and concurrently enhance therapeutic interventions. This review explores the design principles governing the development of multimodal inhibitors, highlighting their potential as platforms for kinase tracking and inhibition via bioimaging. The structural aspects of constructing such theranostic agents are critically analyzed. This work could shed light on this intriguing field and provide adequate impetus for developing novel theranostic compounds based on small molecule inhibitors and fluorophores. [ABSTRACT FROM AUTHOR]

The multiplexity of cancer has rendered it the second leading cause of mortality worldwide and theragnostic prodrugs have gained popularity in recent years as a means of treatment. Theragnostic prodrugs enable the simultaneous diagnosis and therapy of tumors via high‐precision real‐time drug release monitoring. Herein, we report the development of the small theragnostic prodrug GF, based on the nucleoside anticancer agent gemcitabine and the fluorescent dye 5(6)‐carboxyfluorescein. We have successfully demonstrated its efficient internalization in tumor cells, showing localization throughout both the early and late endocytic pathways. Its mechanism of cell internalization was evaluated, confirming its independence from nucleoside transporters. Its cellular localization via confocal microscopy revealed a clathrin‐mediated endocytosis mechanism, distinguishing it from analogous compounds studied previously. Furthermore, GF exhibited stability across various pH values and in human blood plasma. Subsequently, its in vitro cytotoxicity was assessed in three human cancer cell lines (A549, U87 and T98). Additionally, its pharmacokinetic profile in mice was investigated and the consequent drug release was monitored. Finally, its in vivo visualization was accomplished in zebrafish xenotransplantation models and its in vivo efficacy was evaluated in A549 xenografts. The results unveiled an intriguing efficacy profile, positioning GF as a compelling candidate warranting further investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer has a major impact on societies across the world. In an attempt to find new treatment options for cancer, attention has shifted to natural compounds. Curcumin is a polyphenol isolated from the roots of turmeric that possesses many biological properties. It acts on the regulation of different aspects of tumor development and interconnects with major signaling pathways that are dysregulated in cancer, such as the phosphatidylinositol-3-kinase/protein kinase B pathway. In this review, the diverse effects of curcumin on the regulation of this pathway in different malignancies will be discussed. Cancer is a life-threatening disease and one of the leading causes of death worldwide. Despite significant advancements in therapeutic options, most available anti-cancer agents have limited efficacy. In this context, natural compounds with diverse chemical structures have been investigated for their multimodal anti-cancer properties. Curcumin is a polyphenol isolated from the rhizomes of Curcuma longa and has been widely studied for its anti-inflammatory, anti-oxidant, and anti-cancer effects. Curcumin acts on the regulation of different aspects of cancer development, including initiation, metastasis, angiogenesis, and progression. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway is a key target in cancer therapy, since it is implicated in initiation, proliferation, and cancer cell survival. Curcumin has been found to inhibit the PI3K/Akt pathway in tumor cells, primarily via the regulation of different key mediators, including growth factors, protein kinases, and cytokines. This review presents the therapeutic potential of curcumin in different malignancies, such as glioblastoma, prostate and breast cancer, and head and neck cancers, through the targeting of the PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

In this study, the effects of melatonin treatment on growth, redox status and immunity in prenatally stressed newborn lambs were evaluated. Thirty-seven newborn lambs were allocated into two groups (melatonin-MEL and control-CON), based on whether their mothers were treated with melatonin implants or not, respectively. All pregnant ewes were exposed to heat stress. The body weight of lambs was recorded at birth (L0), and then on days 15 (L15) and 40 (L40). Redox biomarkers [total antioxidant capacity (TAC), glutathione (GSH), thiobarbituric acid reactive substances (TBARS)] were assayed in blood samples collected from lambs on days L0, L1, L2, L5, L10 and L40. Chemical analysis and antioxidant capacity were evaluated in colostrum and milk samples collected at the same time points with blood samples. Cytokines (IL-1β, IL-6, IL-10, IFN-γ) and immunoglobulin (IgG) were assayed in blood and colostrum samples collected from ewes on days L0 and L1, and in lambs’ blood on days L0, L1 and L2. The results revealed that body weight gain of newborn lambs did not differ between the two groups (p > 0.05). Better redox status was found in MEL lambs until L2, as well as higher antioxidant capacity in the colostrum of MEL ewes compared to CON ones on day L0 (p < 0.05). In MEL ewes’ colostrum, higher protein content was measured on day L0 and higher fat content on L1 compared to CON group (p < 0.05). The highest level of IL-6 was found in MEL ewes on L1, with a concomitant increase of IL-10 level in MEL lambs in comparison to CON lambs on L2. Moreover, CON colostrum resulted in a higher level of IL-10 within time, coupled with an increased level of IgG found in lambs’ plasma on L2 (p = 0.04). This study indicated that melatonin could be administered as antioxidant and immune-modulatory regime in prenatally stressed offspring in order to cope with the crucial first days of their life. This effect of melatonin was also amplified by crosstalk between IL-6, IL-10 and IgG production, resulting in an improved quality of produced milk.

To date, many potent compounds have been found which are derived from plants and herbs and possess anticancer properties due to their antioxidant effects. 9″-Lithospermic acid methyl ester is an effective natural compound derived from the Thymus thracicus Velen. It has been proven that this compound has substantial properties in different diseases, but its effects in cancer have not been thoroughly evaluated. The aim of this work was to study the effects of 9″-Lithospermic acid methyl ester (9″-methyl lithospermate) in U87 and T98 glioblastoma cell lines. Its effects on cellular viability were assessed via Trypan Blue and Crystal Violet stains, the cell cycle analysis through flow cytometry, and cell migration by employing the scratch wound healing assay. The results demonstrated that 9″-methyl lithospermate was able to inhibit cellular proliferation, induce cellular death, and inhibit cell migration. Furthermore, these results were intensified by the addition of temozolomide, the most prominent chemotherapeutic drug in glioblastoma tumors. Further studies are needed to reproduce these findings in animal models and investigate if 9″-lithospermic acid methyl ester represents a potential new therapeutic addition for gliomas. [ABSTRACT FROM AUTHOR]

Wine is an alcoholic beverage of complex composition obtained through the fermentation of grape must. The consumption of wine has already been associated with a multitude of beneficial effects due to its high polyphenolic content. In this study, four Greek emblematic wines from two red (i.e., Xinomavro and Agiorgitiko) and two white (i.e., Assyrtiko and Malagouzia) varieties were analyzed for the estimation of their antioxidant profiles. To address this question, we assessed their ability to scavenge both synthetic and endogenous free radicals, such as DPPH•, ABTS+•, OH•, O2−, their potential reducing power, and their antimutagenic and antigenotoxic properties. All varieties exhibited potent antioxidant activity, as indicated by the results of methods above, with the red wines appearing more effective than the white ones regarding antioxidant capacity. Our small-scale study is the first to reveal that these wine varieties may have the ability to scavenge the most reactive endogenous radicals. In the future, this finding must be accompanied by larger studies to fill a knowledge gap in the scientific literature concerning a holistic approach of the in vitro antioxidant action of plant polyphenolic compounds. Conclusively, we believe that wines possess high bioactivity that allow them to settle in the industry of food additives and medicinal products.

Cancer theragnostics is a novel approach that combines diagnostic imaging and radionuclide therapy. It is based on the use of a pair of radiopharmaceuticals, one optimized for positron emission tomography imaging through linkage to a proper radionuclide, and the other bearing an alpha- or beta-emitter isotope that can induce significant damage to cancer cells. In recent years, the use of theragnostics in nuclear medicine clinical practice has increased considerably, and thus investigation has focused on the identification of novel radionuclides that can bind to molecular targets that are typically dysregulated in different cancers. The major advantages of the theragnostic approach include the elimination of multi-step procedures, reduced adverse effects to normal tissues, early diagnosis, better predictive responses, and personalized patient care. This review aims to discuss emerging theragnostic molecules that have been investigated in a series of human malignancies, including gliomas, thyroid cancer, neuroendocrine tumors, cholangiocarcinoma, and prostate cancer, as well as potent and recently introduced molecular targets, like cell-surface receptors, kinases, and cell adhesion proteins. Furthermore, special reference has been made to copper radionuclides as theragnostic agents and their radiopharmaceutical applications since they present promising alternatives to the well-studied gallium-68 and lutetium-177. [ABSTRACT FROM AUTHOR]

Glioblastoma is one of the most malignant and lethal forms of primary brain tumors in adults. Linearol, a kaurane diterpene isolated from different medicinal plants, including those of the genus Sideritis, has been found to possess significant anti-oxidant, anti-inflammatory and anti-microbial properties. In this study, we aimed to determine whether linearol could exhibit anti-glioma effects when given alone or in combination with radiotherapy in two human glioma cell lines, U87 and T98. Cell viability was examined with the Trypan Blue Exclusion assay, cell cycle distribution was tested with flow cytometry, and the synergistic effects of the combination treatment were analyzed with CompuSyn software. Linearol significantly suppressed cell proliferation and blocked cell cycle at the S phase. Furthermore, pretreatment of T98 cells with increasing linearol concentrations before exposure to 2 Gy irradiation decreased cell viability to a higher extent than linearol or radiation treatment alone, whereas in the U87 cells, an antagonistic relationship was observed between radiation and linearol. Moreover, linearol inhibited cell migration in both tested cell lines. Our results demonstrate for the first time that linearol is a promising anti-glioma agent and further studies are needed to fully understand the underlying mechanism of this effect. [ABSTRACT FROM AUTHOR]

Meningiomas are the most frequent central nervous system tumors in adults. The majority of these tumors are benign. Nevertheless, the intraoperative identification of meningioma grade is important for modifying surgical strategy in order to reduce postoperative complications. Here, we set out to investigate the role of intraoperative flow cytometry for the differentiation of low-grade (grade 1) from high-grade (grade 2–3) meningiomas. The study included 59 patients. Intraoperative flow cytometry analysis was performed using the 'Ioannina Protocol' which evaluates the G0/G1 phase, S-phase, mitosis and tumor index (S + mitosis phase fraction) of a tumor sample. The results are available within 5 min of sample receipt. There were 41 grade 1, 15 grade 2 and 3 grade 3 meningiomas. High-grade meningiomas had significantly higher S-phase fraction, mitosis fraction and tumor index compared to low-grade meningiomas. High-grade meningiomas had significantly lower G0/G1 phase fraction compared to low-grade meningiomas. Thirty-eight tumors were diploids and twenty-one were aneuploids. No significant difference was found between ploidy status and meningioma grade. ROC analysis indicated 11.4% of tumor index as the optimal cutoff value thresholding the discrimination between low- and high-grade meningiomas with 90.2% sensitivity and 72.2% specificity. In conclusion, intraoperative flow cytometry permits the detection of high-grade meningiomas within 5 min. Thus, surgeons may modify tumor removal strategy. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most aggressive primary central nervous system (CNS) tumor in adults with dismal prognosis. Currently, the therapeutic interventions include gross total resection, when possible, followed by radiotherapy and chemotherapy. However, despite treatment, tumor usually recurs within 7–9 months. The presence of glioma cells with stem-like properties and tumor's heterogeneity have been identified as the most important factors driving recurrence. Recently, research efforts have been focused on the use of natural substances as treatment for GBM. Siderol is an ent-kaurane diterpenoid, isolated from the genus Sideritis. Sideritis extracts have already been investigated for their anti-inflammatory, antioxidant, and anticancer effects. In this study, we investigated the antitumoral effects of siderol in GBM T98 and U87 cell lines, as well as the effects of combined treatment with temozolomide (TMZ). Cell viability was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue exclusion assay. Different concentrations of siderol were used in order to calculate the IC50 values at 72 h after treatment. Flow cytometry used for the DNA cell cycle analysis after treatment with siderol in concentrations of IC50 and twice the IC50 values for 72 h. Furthermore, the effect of siderol in cell's migratory ability was tested using wound healing assay. Cell viability and proliferation, after combined treatment with siderol and TMZ, also were evaluated with the trypan blue exclusion assay and the effects of the combination treatment were analyzed with CompuSyn software. Treatment with siderol significantly reduced cell viability in T98 and U87 cell lines in a dose-dependent manner and IC50 values were calculated, 18 μM and 13 μM, respectively. Moreover, siderol induced G0/G1 cell cycle arrest in a dose-dependent manner and inhibited the migration in both cell lines. In addition, siderol and TMZ seem to have synergistic action in the majority of tested concentrations in both T98 and U87 cells. In conclusion, siderol may represent an innovative strategy for the treatment of GBM, and further studies are needed on siderol's efficacy and mode of action. [ABSTRACT FROM AUTHOR]

Calciphylaxis is a rare yet potentially fatal condition, resulting from ectopic calcification of the small arterioles of the dermis with resulting necrotic lesions infection, sepsis, and death. In hemodialysis patients, its prevalence ranges between 1 and 4%, while mortality amounts to 30–80%. We present in here a 45-year-old female on chronic dialysis with morbid obesity, who was admitted for painful nodules in the lower abdomen and necrotic lesions at the lower extremities. Severe uremia and uncontrolled secondary hyperparathyroidism were the main characteristics in this patient, and thus, a clinical diagnosis of calciphylaxis was made. Treatment modalities included wound care plus antibiotics and analgesics, daily hemodialysis, and strategies targeting calcification with sodium thiosulfate, cinacalcet, and non-calcium-containing binders. A crucial factor for overcoming the infection-lesion vicious circle is thorough and daily care of the lesions. Nursing attention was focused on the motivation of her self-care, for the prevention of institutionalization and the psychological support of the patient and her family. The most intriguing feature was the fact that she experienced several exacerbations during the follow-up time. During the final relapse, she was prescribed hyperbaric oxygen sessions that actually put the disease under control thereafter. The good outcome for this patient was probably related to the combination of close follow-up along with a multidisciplinary approach. [ABSTRACT FROM AUTHOR]

This external scientific report summarises the results from thearticle 36 grant GA/EFSA/SCER/2015/01″Modelling human variability in toxicokinetic and toxicodynamic processes using Bayesian meta‐analysis, physiologically‐based (PB) modelling and in vitro systems". Extensive literature searches, data collection and modelling of human variability in toxicokinetics (TK) (phase I, Phase II enzymes and transporters) and toxicodynamics (TD) are summarised and further elaborated in supplementary material and EFSA knowledge junction, open source databases(MS Excel) and peer reviewed publications (objective 1 and 2). In addition,in vitro TK and TD information from laboratory studies and literature searches are summarised for a range of case studies relevant to EFSA including pesticides (i.e. triflumuron, chlorpyrifos, phosmet), natural toxins (e.g. microcystin variants, mycotoxins), food additives and polyphenols (i.e. resveratrol, tyrosol), food additives as well as drugs (i.e.amiodarone). These include isoform‐specific metabolism and kinetic parameters for single chemicals and inhibition constants for multiple chemicals (TK) and identification of molecular targets (TD). Finally, generic quantitative in vitro in vivo extrapolation (QIVIVE) models, PB‐kinetic (PBK) and PBK‐dynamic (PBKD) models were developed in the R freeware, calibrated and validated usingcase studies for single and multiple chemicals. Supplementary material and model codes are available on EFSA knowledge junction. The results are in line with EFSA priorities for the implementation of the use of new approach methodologies (NAMs) for human risk assessment (RA) of chemicals and the need to develop open source TK TD databases data and PB‐K and PB‐KD models have been identified as key steps of this process. Future perspectives are discussedincluding the integration of pathway‐related variability and generic human QIVIVE and PB‐K models and PB‐K‐D models into TKplate, a Toxicokinetic Modelling Platform under development in EFSA. [ABSTRACT FROM AUTHOR]

Radiation therapy plays an important role in almost every cancer treatment. However, radiation toxicity to normal tissues, mainly due to the generation of reactive free radicals, has limited the efficacy of radiotherapy in clinical practice. Curcumin has been reported to possess significant antitumor properties. Although curcumin can sensitize cancer cells to irradiation, healthy cells are much less sensitive to this effect, and thus, curcumin is thought to be a potent, yet safe anti-cancer agent. In this review, a summary of the role of curcumin as both a radiosensitizer and radioprotector has been presented, based on the most recent data from the experimental and clinical evaluation of curcumin in different cancer cell lines, animal models, and human patients. [ABSTRACT FROM AUTHOR]

Curcumin, a bioactive polyphenol, is known to have anticancer properties. In this study, the effectiveness of curcumin pretreatment as a strategy for radio-sensitizing glioblastoma cell lines was explored. For this, U87 and T98 cells were treated with curcumin, exposed to 2 Gy or 4 Gy of irradiation, and the combined effect was compared to the antiproliferative effect of each agent when given individually. Cell viability and proliferation were evaluated with the trypan blue exclusion assay and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The synergistic effects of the combination treatment were analyzed with CompuSyn software. To examine how the co-treatment affected different phases of cell-cycle progression, a cell-cycle analysis via flow cytometry was performed. Treatment with curcumin and radiation significantly reduced cell viability in both U87 and T98 cell lines. The combination treatment arrested both cell lines at the G2/M phase to a higher extent than radiation or curcumin treatment alone. The synergistic effect of curcumin when combined with temozolomide resulted in increased tumor cell death. Our results demonstrate for the first time that low doses of curcumin and irradiation exhibit a strong synergistic anti-proliferative effect on glioblastoma cells in vitro. Therefore, this combination may represent an innovative and promising strategy for the treatment of glioblastoma, and further studies are needed to fully understand the molecular mechanism underlying this effect. [ABSTRACT FROM AUTHOR]

Simple Summary: Melatonin is a known antioxidant and anti-inflammatory regime, while in sheep it is broadly used to accelerate the onset of the breeding season. Our recent study showed that melatonin administration during pregnancy in heat-stressed ewes improved fertility rate and number of lambs born per ewe, the redox status of the maternal organism and the produced milk quantity until weaning. In this study, we present the impact of melatonin administration in stressed ewes during pregnancy considering: (a) humoral response of both maternal organism and offspring during the first two days after parturition, (b) chemical composition and antioxidant parameters of colostrum and milk until weaning and (c) redox status of the offspring until weaning. The results indicated that melatonin improved the redox status of the offspring and the quality of colostrum. Moreover, melatonin could be administered as immune-modulatory regime, apart from antioxidant, in prenatally stressed offspring in order to cope with the crucial first days of their life, as the humoral response results suggested. In this study, the effects of melatonin treatment on growth, redox status and immunity in prenatally stressed newborn lambs were evaluated. Thirty-seven newborn lambs were allocated into two groups (melatonin-MEL and control-CON), based on whether their mothers were treated with melatonin implants or not, respectively. All pregnant ewes were exposed to heat stress. The body weight of lambs was recorded at birth (L0), and then on days 15 (L15) and 40 (L40). Redox biomarkers [total antioxidant capacity (TAC), glutathione (GSH), thiobarbituric acid reactive substances (TBARS)] were assayed in blood samples collected from lambs on days L0, L1, L2, L5, L10 and L40. Chemical analysis and antioxidant capacity were evaluated in colostrum and milk samples collected at the same time points with blood samples. Cytokines (IL-1β, IL-6, IL-10, IFN-γ) and immunoglobulin (IgG) were assayed in blood and colostrum samples collected from ewes on days L0 and L1, and in lambs' blood on days L0, L1 and L2. The results revealed that body weight gain of newborn lambs did not differ between the two groups (p > 0.05). Better redox status was found in MEL lambs until L2, as well as higher antioxidant capacity in the colostrum of MEL ewes compared to CON ones on day L0 (p < 0.05). In MEL ewes' colostrum, higher protein content was measured on day L0 and higher fat content on L1 compared to CON group (p < 0.05). The highest level of IL-6 was found in MEL ewes on L1, with a concomitant increase of IL-10 level in MEL lambs in comparison to CON lambs on L2. Moreover, CON colostrum resulted in a higher level of IL-10 within time, coupled with an increased level of IgG found in lambs' plasma on L2 (p = 0.04). This study indicated that melatonin could be administered as antioxidant and immune-modulatory regime in prenatally stressed offspring in order to cope with the crucial first days of their life. This effect of melatonin was also amplified by crosstalk between IL-6, IL-10 and IgG production, resulting in an improved quality of produced milk. [ABSTRACT FROM AUTHOR]

Curcumin is a polyphenol extracted from the rhizomes of the turmeric plant, Curcuma longa which has anti-inflammatory, and anticancer properties. Chronic inflammation is associated with the development of cancer. Curcumin acts on the regulation of various immune modulators, including cytokines, cyclooxygenase-2 (COX-2), and reactive oxygen species (ROS), which partly explains its anticancer effects. It also takes part in the downregulation of growth factors, protein kinases, oncogenic molecules and various signaling pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), c-Jun N-terminal kinase (JNK) and signal transducer and activator of transcription 3 (STAT3) signaling. Clinical trials of curcumin have been completed or are ongoing for various types of cancer. This review presents the molecular mechanisms of curcumin in different types of cancer and the evidence from the most recent clinical trials. [ABSTRACT FROM AUTHOR]

Wine is an alcoholic beverage of complex composition obtained through the fermentation of grape must. The consumption of wine has already been associated with a multitude of beneficial effects due to its high polyphenolic content. In this study, four Greek emblematic wines from two red (i.e., Xinomavro and Agiorgitiko) and two white (i.e., Assyrtiko and Malagouzia) varieties were analyzed for the estimation of their antioxidant profiles. To address this question, we assessed their ability to scavenge both synthetic and endogenous free radicals, such as DPPH•, ABTS+•, OH•, O2−, their potential reducing power, and their antimutagenic and antigenotoxic properties. All varieties exhibited potent antioxidant activity, as indicated by the results of methods above, with the red wines appearing more effective than the white ones regarding antioxidant capacity. Our small-scale study is the first to reveal that these wine varieties may have the ability to scavenge the most reactive endogenous radicals. In the future, this finding must be accompanied by larger studies to fill a knowledge gap in the scientific literature concerning a holistic approach of the in vitro antioxidant action of plant polyphenolic compounds. Conclusively, we believe that wines possess high bioactivity that allow them to settle in the industry of food additives and medicinal products. [ABSTRACT FROM AUTHOR]

The multiplexity of cancer has rendered it the second leading cause of mortality worldwide and theragnostic prodrugs have gained popularity in recent years as a means of treatment. Theragnostic prodrugs enable the simultaneous diagnosis and therapy of tumors via high-precision real-time drug release monitoring. Herein, we report the development of the small theragnostic prodrug GF, based on the nucleoside anticancer agent gemcitabine and the fluorescent dye 5(6)-carboxyfluorescein. We have successfully demonstrated its efficient internalization in tumor cells, showing localization throughout both the early and late endocytic pathways. Its mechanism of cell internalization was evaluated, confirming its independence from nucleoside transporters. Its cellular localization via confocal microscopy revealed a clathrin-mediated endocytosis mechanism, distinguishing it from analogous compounds studied previously. Furthermore, GF exhibited stability across various pH values and in human blood plasma. Subsequently, its in vitro cytotoxicity was assessed in three human cancer cell lines (A549, U87 and T98). Additionally, its pharmacokinetic profile in mice was investigated and the consequent drug release was monitored. Finally, its in vivo visualization was accomplished in zebrafish xenotransplantation models and its in vivo efficacy was evaluated in A549 xenografts. The results unveiled an intriguing efficacy profile, positioning GF as a compelling candidate warranting further investigation., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Background: Coronavirus disease 2019 (COVID-19) is still a menacing pandemic, especially in vulnerable patients. Morbidity and mortality from COVID-19 in maintenance hemodialysis (MHD) patients are considered worse than those in the general population, but vary across continents and countries in Europe., Aim: To describe the clinical course and outcomes of hospitalized MHD patients with COVID-19 in a retrospective observational single center study in Greece., Methods: We correlated clinical, laboratory, and radiological data with the clinical outcomes of MHD patients hospitalized with COVID-19 during the pandemic. The diagnosis was confirmed by real-time polymerase chain reaction. Outcome was determined as survivors vs non-survivors and "progressors" (those requiring oxygen supplementation because of COVID-19 pneumonia worsening) vs "non-progressors"., Results: We studied 32 patients (17 males), with a median age of 75.5 (IQR: 58.5-82) years old. Of those, 12 were diagnosed upon screening and 20 with related symptoms. According to the World Health Organization (WHO) score, the severity on admission was mild disease in 16, moderate in 13, and severe in 3 cases. Chest computed tomography (CT) showed 1-10% infiltrates in 24 patients. Thirteen "progressors" were recorded among included patients. The case fatality rate was 5/32 (15.6%). Three deaths occurred among "progressors" and two in "non-progressors", irrespective of co-morbidities and gender. Predictors of mortality on admission included frailty index, chest CT findings, WHO severity score, and thereafter the increasing values of serum LDH and D-dimers and decreasing serum albumin. Predictors of becoming a "progressor" included increasing number of neutrophils and neutrophils/lymphocytes ratio., Conclusion: Patients on MHD seem to be at higher risk of COVID-19 mortality, distinct from the general population. Certain laboratory parameters on admission and during follow-up may be helpful in risk stratification and management of patients., Competing Interests: Conflict-of-interest statement: There is no conflict of interest to disclose., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

In this study, the effects of melatonin treatment on growth, redox status and immunity in prenatally stressed newborn lambs were evaluated. Thirty-seven newborn lambs were allocated into two groups (melatonin-MEL and control-CON), based on whether their mothers were treated with melatonin implants or not, respectively. All pregnant ewes were exposed to heat stress. The body weight of lambs was recorded at birth (L0), and then on days 15 (L15) and 40 (L40). Redox biomarkers [total antioxidant capacity (TAC), glutathione (GSH), thiobarbituric acid reactive substances (TBARS)] were assayed in blood samples collected from lambs on days L0, L1, L2, L5, L10 and L40. Chemical analysis and antioxidant capacity were evaluated in colostrum and milk samples collected at the same time points with blood samples. Cytokines (IL-1β, IL-6, IL-10, IFN-γ) and immunoglobulin (IgG) were assayed in blood and colostrum samples collected from ewes on days L0 and L1, and in lambs' blood on days L0, L1 and L2. The results revealed that body weight gain of newborn lambs did not differ between the two groups ( p > 0.05). Better redox status was found in MEL lambs until L2, as well as higher antioxidant capacity in the colostrum of MEL ewes compared to CON ones on day L0 ( p < 0.05). In MEL ewes' colostrum, higher protein content was measured on day L0 and higher fat content on L1 compared to CON group ( p < 0.05). The highest level of IL-6 was found in MEL ewes on L1, with a concomitant increase of IL-10 level in MEL lambs in comparison to CON lambs on L2. Moreover, CON colostrum resulted in a higher level of IL-10 within time, coupled with an increased level of IgG found in lambs' plasma on L2 ( p = 0.04). This study indicated that melatonin could be administered as antioxidant and immune-modulatory regime in prenatally stressed offspring in order to cope with the crucial first days of their life. This effect of melatonin was also amplified by crosstalk between IL-6, IL-10 and IgG production, resulting in an improved quality of produced milk.