Biological Effects Research Articles

Uncovering the interleukin-12 pharmacokinetic desensitization mechanism and its consequences with mathematical modeling.

The cytokine interleukin-12 (IL-12) is a potential immunotherapy because of its ability to induce a Th1 immune response. However, success in the clinic has been limited due to a phenomenon called IL-12 desensitization - the trend where repeated exposure to IL-12 leads to reduced IL-12 concentrations (pharmacokinetics) and biological effects (pharmacodynamics). Here, we investigated IL-12 pharmacokinetic desensitization via a modeling approach to (i) validate proposed mechanisms in literature and (ii) develop a mathematical model capable of predicting IL-12 pharmacokinetic desensitization. Two potential causes of IL-12 pharmacokinetic desensitization were identified: increased clearance or reduced bioavailability of IL-12 following repeated doses. Increased IL-12 clearance was previously proposed to occur due to the upregulation of IL-12 receptor on T cells that causes increased receptor-mediated clearance in the serum. However, our model with this mechanism, the accelerated-clearance model, failed to capture trends in clinical trial data. Alternatively, our novel reduced-bioavailability model assumed that upregulation of IL-12 receptor on T cells in the lymphatic system leads to IL-12 sequestration, inhibiting the transport to the blood. This model accurately fits IL-12 pharmacokinetic data from three clinical trials, supporting its biological relevance. Using this model, we analyzed the model parameter space to illustrate that IL-12 desensitization occurs over a robust range of parameter values and to identify the conditions required for desensitization. We next simulated local, continuous IL-12 delivery and identified several methods to mitigate systemic IL-12 exposure. Ultimately, our results provide quantitative validation of our proposed mechanism and allow for accurate prediction of IL-12 pharmacokinetics over repeated doses.

Proton Therapy in Uveal Melanoma

Background/Objectives: Uveal melanoma is the most common primary intraocular malignancy in adults. Treatment options for localized, early-stage disease include enucleation, brachytherapy, and proton beam therapy. This review aims to evaluate the role of proton therapy in the definitive management of uveal melanoma, focusing on its physics, radiobiology, treatment techniques, and associated outcomes. Methods: This narrative review synthesizes current literature on proton therapy for uveal melanoma, emphasizing case selection, treatment efficacy, and side effects. Results: Proton therapy offers significant advantages for thicker uveal melanomas (over 8 mm) due to its unique physical properties, including a rapid dose fall-off that protects critical structures like the retina and optic nerve. Proton therapy may have benefits in tumor control for ocular melanomas given its increased relative biological effectiveness relative to photon therapy for these typically more radioresistant melanomas. Proton therapy may also hold special value for uveal melanomas in close proximity to the optic nerve, as patients are at high risk of visual toxicities with brachytherapy. The review discusses the efficacy of proton therapy across small, medium, and large tumors, along with strategies for improving patient survival through combined systemic therapy. Additionally, the potential of ocular reirradiation with proton therapy is addressed. Conclusions: Proton therapy is an effective treatment for uveal melanoma. It offers advantages over brachytherapy for large tumors, tumors that are close to the optic nerve or insertion of extra-ocular muscles.

The long non-coding RNA NEAT1 contributes to aberrant STAT3 signaling in pancreatic cancer and is regulated by a metalloprotease-disintegrin ADAM8/miR-181a-5p axis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and several studies demonstrate that STAT3 has critical roles throughout the course of PDAC pathogenesis. TCGA, microarray, and immunohistochemistry data from a PDAC cohort were used for clinical analyses. Panc89 cells with ADAM8 knockout, re-expression of ADAM8 mutants, and Panc1 cells overexpressing ADAM8 were generated. Gene expression analyses of ADAM8, STAT3, long non-coding (lnc) RNA NEAT1, miR-181a-5p and ICAM1 were performed by quantitative PCR. Subcellular fractionation quantified NEAT1 expression in cytoplasm and nucleus of PDAC cell lines. Cell proliferation, scratch, and invasion assays were performed to detect growth rate, migration and invasion capabilities of cells. Gain and loss of function experiments were carried out to investigate the biological effects of lncRNA NEAT1 and miR-181a-5p on PDAC cells and downstream genes. Dual-luciferase reporter gene assay determined interaction and binding sites of miR-181a-5p in lncRNA NEAT1. Pull down assays, RNA binding protein immunoprecipitation (RIP), and ubiquitination assays explored the molecular interaction between lncRNA NEAT1 and STAT3. High ADAM8 expression causes aberrant STAT3 signaling in PDAC cells and is positively correlated with NEAT1 expression. NEAT1 binding to STAT3 was confirmed and prevents STAT3 degradation in the proteasome as increased degradation of STAT3 was observed in ADAM8 knockout cells and cells treated with bortezomib. Furthermore, miRNA-181a-5p regulates NEAT1 expression by direct binding to the NEAT1 promoter. ADAM8 regulates intracellular STAT3 levels via miR-181a-5p and NEAT1 in pancreatic cancer.

Influence of Electrostatic Field on Optical Rotation of D-Glucose Solution: Experimental Research for Electric Field-Induced Biological Effect

At present, the effects of environmental electromagnetic irradiation on the metabolism of organisms have attracted extensive attention, but the mechanism is still not clear. D-glucose plays an important role in the metabolism of organisms. In this work, the change in the optical rotation of D-glucose solution under an electrostatic field is measured experimentally, so as to explain the mechanism of the electric field-induced biological effect. The experimental results show that the electrostatic field can alter the optical rotation of D-glucose solution at different temperatures. Under the different strengths of electrostatic field, the specific rotation of D-glucose solution increases at different temperatures; the maximum increase can reach 2.07%, but the effect of temperature and electric field strength on the rotation increment is nonlinear and very complex. Further, it turns out that the proportion of α-D-glucose in solution increases by up to 3.25% under the electrostatic field, while the proportion of β-D-glucose decreases by as much as 1.75%. The experimental study confirms that electrostatic field can change the proportion of two conformation molecules (α and β-D-glucose) in D-glucose solution, which can provide a novel explanation for the mechanism of the electric field-induced biological effect.

Alpha Hydroxyl Acids from Mume Fructus and Schisandrae Chinensis Fructus Prevent Obesity by Inhibiting Intestinal Lipase in Diet-Induced Obese Mice.

Restriction of lipid uptake and absorption from the diet is regarded as an efficient strategy for the management of obesity, while lipase inhibition could successfully block the digestion of dietary lipids. Mume Fructus (MF) and Schisandrae Chinensis Fructus (SCF) were used as fruits, the biological effect of which on obesity desired more attention. Herein, the extracts of MF and SCF displayed significant efficacy in managing obesity in mice fed with a high-fat diet, via the inhibition of hydrolase activity of lipase in the digestive tract. Using the bioactivity guidance strategy, citric acid and malic acid were identified as the major lipase inhibitors from MF and SCF, respectively, which could prevent body weight gain, along with adipose tissue formation, and alleviate hyperlipidemia and hepatic steatosis in obese mice. Above all, MF and SCF could be used for the management of obesity via the lipase inhibition by citric acid and malic acid, displaying potential applications in healthy foods, nutritional supplements, and pharmaceutical materials.

Influence of Mobile Phone Electromagnetic Radiation Exposure on Behavior of Protozoan Population

For the first time, the effect that mobile phone electromagnetic radiation had on water in the presence of protozoan population and induced a significant change in water properties has been experimentally studied. The results of our experiment demonstrate that changes that occur in the “water–protozoa population” system are the biological effects the cells have in response to the direct effect of radiation. This conclusion is supported by the fact that the calculated order of magnitude of a time interval during which information exchange takes place between some microorganisms of the protozoan population is the same as that over course of the experiment. The minimum concentration of protozoa (1000 pcs/liter) at which this effect was observed was determined. It is concluded that the proposed technique for alteration of physical properties of water in the presence of protozoan population after exposure to electromagnetic fields can be used to uncover the mechanisms of the interaction of biological systems with electromagnetic fields.

Histopathological changes in the human tissues in various types of poisoning: A cross-sectional autopsy study

BackgroundPoisoning is a critical health issue caused by exposure to harmful substances, leading to a range of biological effects from mild irritation to severe organ damage and death. Acute poisoning is particularly prevalent in developing countries reliant on agriculture, where agricultural poisons such as organophosphates, carbamates, pyrethroids, and aluminum/zinc phosphide are common. This study aims to analyze the histopathological changes in various organs in autopsy of poisoning cases to understand the extent and nature of organ damage. MethodsAutopsies were performed on cases with an established or suspected history of poison ingestion. Tissue samples from the stomach, intestine, liver, spleen, kidneys, brain, and lungs were examined for histopathological changes. ResultsOut of 52 cases analyzed, aluminum phosphide was the predominant poison, accounting for 76.92 % of cases. Histopathological findings in poisoning cases included significant pulmonary edema (55.77 %), intra-alveolar hemorrhage (48.08 %), liver ballooning degeneration (48.08 %), acute tubular necrosis (51.92 %) in kidney, and universal brain and spleen congestion (100 %). Stomach findings showed partial loss of rugosity (80.77 %), congestion (51.92 %), necrosis of the mucosa (30.77 %), congestion (71.15 %), denudation of the epithelium (48.08 %), and mucosal inflammation (48.08 %) as predominant findings. Aluminum phosphide caused severe histopathological changes across all examined organs. ConclusionThe study highlights the critical role of histopathological examination in diagnosing and understanding organ damage in poisoning cases. Forensic pathologists can use these histopathological patterns as reference points to differentiate poisoning from other causes of death, aiding in accurate diagnosis and targeted treatment.

Cell Type-Specific Anti- and Pro-Oxidative Effects of Punica granatum L. Ellagitannins.

Pomegranate and its by-products contain a broad spectrum of phytochemicals, such as flavonoids, phenolic acids and tannins, having pleiotropic preventive and prophylactic properties in health disorders related to oxidative stress and microbial contamination. Here, we examined the biological effects of a pomegranate peel ellagitannins-enriched (>90%) extract, PETE. In vitro studies revealed that PETE has a strong antiradical action towards synthetic radicals and biologically relevant ROS surpassing or comparable to that of Trolox. In cellular models, it showed concentration-dependent (25-100 µg/mL) yet opposing effects depending on the cell membrane type and exposure conditions. In erythrocytes, PETE protected membrane integrity in the presence of the strong oxidant HClO and restored reduced glutathione levels to up to 85% of the control value while having much weaker acute and long-term intrinsic effects. Such protection persisted even after the removal of the extract from cells, indicating strong membrane interaction. In HeLa cancer cells, and at concentrations lower than those used for red blood cells, PETE induced robust potentiation of ROS production and mitochondrial potential dissipation, leading to autophagy-like membrane morphology changes and cell death. In S. aureus, the growth arrest and bacterial death in the presence of PETE (with MIC = 31.25 µg/mL and MBC = 125 µg/mL, respectively) can be linked to the tripled ROS induction by the extract in the same concentration range. This study indicates a specificity of ROS production by the pomegranate extract depending on the type of cell, the concentration of the extract and the time of incubation. This specificity witnesses a strong potential of the extract components as candidates in antioxidant and pro-oxidant therapy.

The Effect of Polyethylene Microplastics on Growth and Antioxydant Response of Oscillatoria Princeps and Chlorella Pyrenoidosa.

This study investigated the impacts of polyethylene microplastics (PE-MPs) with varying particle sizes (13μm and 6.5μm) on the growth and antioxidant responses of two freshwater algae species, Oscillatoria princeps (O. princeps) and Chlorella pyrenoidosa (C. pyrenoidosa). The results revealed a significant reduction in chlorophyll a content in both algal species upon exposure to PE-MPs, indicating a disruption of photosynthesis. Furthermore, Superoxide Dismutase (SOD) activity decreased in O. princeps, while Catalase (CAT) activity increased in both species, indicating complex physiological responses to microplastic stress. Notably, phycotoxin levels in O. princeps decreased with PE-MP exposure, while those in C. pyrenoidosa increased, particularly with 6.5μm PE-MPs. These findings underscore the potential toxic effects of PE-MPs on freshwater algal growth and metabolism, as well as their influence on toxin production. This study contributes valuable insights into the ecotoxicological impacts of microplastics in freshwater environments, highlighting the need for further research on their biological effects and environmental health implications.

Weathering of Buried Standard Pieces of Serpentine under Varied Soil Treatments and Relevant Analysis of Microbial Community Structure

Carbon sink processes related to the weathering of silicate minerals are often accompanied by physical, chemical, and biological effects. In particular, plant-microbe synergistic effects are important for soil mineral weathering, but relevant correlation analyses and quantitative studies remain sparse. In this research, a standard serpentine test specimens (STSs) with specific specifications were used to study serpentine weathering under different environmental conditions (abiotic or biotic) and correlated it with the microbial community structure under the growth of Setaria viridis. The results showed that the environment with growing S. viridis had the strongest weathering capacity for STSs, which was 35 times higher than that of the abiotic environment group, and a significant increase in soil inorganic and organic carbon contents compared with the abiotic environment and the environment without plant growth. The bacteria with strong weathering ability were enriched in the soil of around STSs, such as Pseudomonas spp. and Sphingomonas spp. In addition, the fungal community of Ascomycetes is also heavily enriched, accelerating STSs weathering. The addition of bacterial agent (Bacillus subtilis) further promoted the STSs weathering under the growth conditions of S. viridis. The soil surrounding the buried STSs was also enriched with heavy metal tolerant Massilia spp. and disease suppressing Lysobacter spp., while the abundance of fungi functionally associated with pathotypes was reduced, thereby benefiting plant growth. This study provides basic information for the serpentine bio-weathering coupled with carbon sequestration by using plant-microbe synergistic effects.

Green synthesis of cerium oxide nanoparticles via Linum usitatissimum seeds extract and assessment of its biological effects

AbstractIn the current work, CeO2‐NPs were produced via a green chemistry process via Linum usitatissimum seeds extract as the stabilizing agent. The CeO2‐NPs were characterized by the results of analytical techniques such as TGA/DTA, FTIR, UV–vis, XPS, XRD, and FESEM/PSA/EDX. The outcomes of the XRD pattern affirmed the crystalline structure of this product with the suggested size of about 20 nm, while the FESEM/PSA pictures presented spherical morphology. Additionally, the XPS analysis of CeO2‐NPs affirmed the presence of a Ce+3 oxidation state in the sample, as well as Ce+4 as the major valence of cerium oxide. The results of the MTT test on Huh‐7 cancer cells and HFF normal cells displayed the lack of any significant cytotoxicity even at concentrations up to 1000 µg/mL. Therefore, the obtained synthesized CeO2‐NPs through this green method could be suggested as a prospective agent for medical applications due to its non‐toxic effects.

The Role of Mast Cells in the Remodeling Effects of Molecular Hydrogen on the Lung Local Tissue Microenvironment under Simulated Pulmonary Hypertension

Molecular hydrogen (H2) has antioxidant, anti-inflammatory, and anti-fibrotic effects. In a rat model simulating pulmonary fibrotic changes induced by monocrotaline-induced pulmonary hypertension (MPH), we had previously explored the impact of inhaled H2 on lung inflammation and blood pressure. In this study, we further focused the biological effects of H2 on mast cells (MCs) and the parameters of the fibrotic phenotype of the local tissue microenvironment. MPH resulted in a significantly increased number of MCs in both the pneumatic and respiratory parts of the lungs, an increased number of tryptase-positive MCs with increased expression of TGF-β, activated interaction with immunocompetent cells (macrophages and plasma cells) and fibroblasts, and increased MC colocalization with a fibrous component of the extracellular matrix of connective tissue. The alteration in the properties of the MC population occurred together with intensified collagen fibrillogenesis and an increase in the integral volume of collagen and elastic fibers of the extracellular matrix of the pulmonary connective tissue. The exposure of H2 together with monocrotaline (MCT), despite individual differences between animals, tended to decrease the intrapulmonary MC population and the severity of the fibrotic phenotype of the local tissue microenvironment compared to changes in animals exposed to the MCT effect alone. In addition, the activity of collagen fibrillogenesis associated with MCs and the expression of TGF-β and tryptase in MCs decreased, accompanied by a reduction in the absolute and relative content of reticular and elastic fibers in the lung stroma. Thus, with MCT exposure, inhaled H2 has antifibrotic effects involving MCs in the lungs of rats. This reveals the unknown development mechanisms of the biological effects of H2 on the remodeling features of the extracellular matrix under inflammatory background conditions of the tissue microenvironment.

Therapeutic effects of DOX-loaded hydrogel MOF nanocarriers on triple negative breast cancer and derivative design via reinforcement learning

Triple negative breast cancer (TNBC) is one of the most difficult of all types of breast cancer to treat. TNBC is characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The development of effective drugs can help to alleviate the suffering of patients. The novel nickel(II)-based coordination polymer (CP), [Ni2(HL)(O)(H2O)3·H2O] (1) (where H4L=[1,1’:2’,1’’-triphenyl]-3,3’’,4’,5’-tetracarboxylic acid), was synthesized via solvothermal reaction in this study. The overall structure of CP1 was fully identified by SXRD, Fourier transform infrared spectroscopy and elemental analysis. Using advanced chemical synthesis, we developed Hyaluronic Acid/Carboxymethyl Chitosan-CP1@Doxorubicin (HA/CMCS-CP1@DOX), a nanocarrier system encapsulating doxorubicin (DOX), which was thoroughly characterized using Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectroscopy (FTIR), and Thermogravimetric Analysis (TGA). These analyses confirmed the integration of doxorubicin and provided data on the nanocarriers’ stability and structure. In vitro experiments showed that this system significantly downregulated Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) in triple-negative breast cancer cells and inhibited their proliferation. Molecular docking simulations revealed the biological effects of CP1 are derived from its carboxyl groups. Using reinforcement learning, multiple new derivatives were generated from this compound, displaying excellent biological activities. These findings highlight the potential clinical applications and the innovative capacity of this nanocarrier system in drug development.

Metabolomic Profiling and Network Toxicology: Mechanistic Insights into Effect of Gossypol Acetate Isomers in Uterine Fibroids and Liver Injury

Objective: Gossypol is a natural polyphenolic dialdehyde product that is primarily isolated from cottonseed. It is a racemized mixture of (−)-gossypol and (+)-gossypol that has anti-infection, antimalarial, antiviral, antifertility, antitumor and antioxidant activities, among others. Gossypol optical isomers have been reported to differ in their biological activities and toxic effects. Method: In this study, we performed a metabolomics analysis of rat serum using 1H-NMR technology to investigate gossypol optical isomers’ mechanism of action on uterine fibroids. Network toxicology was used to explore the mechanism of the liver injury caused by gossypol optical isomers. SD rats were randomly divided into a normal control group; model control group; a drug-positive group (compound gossypol acetate tablets); high-, medium- and low-dose (−)-gossypol acetate groups; and high-, medium- and low-dose (+)-gossypol acetate groups. Result: Serum metabolomics showed that gossypol optical isomers’ pharmacodynamic effect on rats’ uterine fibroids affected their lactic acid, cholesterol, leucine, alanine, glutamate, glutamine, arginine, proline, glucose, etc. According to network toxicology, the targets of the liver injury caused by gossypol optical isomers included HSP90AA1, SRC, MAPK1, AKT1, EGFR, BCL2, CASP3, etc. KEGG enrichment showed that the toxicity mechanism may be related to pathways active in cancer, such as the PPAR signaling pathway, glycolysis/glycolysis gluconeogenesis, Th17 cell differentiation, and 91 other closely related signaling pathways. Conclusions: (−)-gossypol acetate and (+)-gossypol acetate play positive roles in the treatment and prevention of uterine fibroids. Gossypol optical isomers cause liver damage through multiple targets and pathways.

MODERN PARAMETERS OF LABORATORY EXPRESS DIAGNOSTICS IN INTENSIVE NEUROLOGY AND NEUROSURGICAL PRACTICE IN PATIENTS WITH CRANIOCEREBRAL INJURIES

The parameters listed in the article show the huge path that laboratory express diagnosis of emergency conditions in neurology has taken over the past 50 years. And this is not the limit - new unique technologies appear. The range of measured and calculated parameters continues to expand, which makes it possible to more fully and adequately assess the condition of a critically ill patient. Thus, a timely and qualitative study of the gaseous composition of blood is important for carrying out differential diagnosis, prescribing adequate treatment and monitoring the therapy effectiveness. The aim of the study was to highlight the current parameters of laboratory rapid diagnostics in intensive neurology and neurosurgical practice in patients with traumatic brain injury. There are two situations that necessitate the development of rapid methods for monitoring hemostasis in the neurological intensive care unit and neurosurgical operating room: the need to immediately determine the concentration or biological effect of anticoagulants. Some areas of surgical intervention are associated with increased blood loss due to coagulopathy, which requires timely replacement therapy. A long process of determining hemostatic parameters by routine methods in a general laboratory leads to a delay in diagnosis and, as a result, untimely treatment. Quite a few express methods designed to obtain specific information about the hemostasis process are currently available in the operating room. If these monitoring methods are used correctly, the research results are reliable, so some researchers use them to develop algorithms for determining the need for transfusion of blood components. However, the development of new monitoring methods requires close collaboration with scientists specialized in hemostasis, plus quality control must be established. It is necessary to prove the positive effect of rapid diagnostic methods on the result to ensure the possibility of their wide application in various operations.

Accumulation, biochemical responses and changes in the redox proteome promoted by Ag and Cd in the burrowing bivalve Scrobicularia plana

Silver (Ag) and cadmium (Cd) are non-essential metals that, as a result of natural processes and human activities, reach the aquatic environment where they interact with biota inducing potential toxic effects. To determine the biological effects of these metals on the endobenthic bivalve Scrobicularia plana, specimens were exposed to Ag and Cd at two concentrations, 5 and 50 μg∙L-1, for 7 days in a controlled microcosm system. The levels of the metals were measured in the seawater, sediments and clam tissues. The possible toxic biological effects of Ag and Cd were studied using a battery of biochemical biomarkers that are responsive to oxidative stress: superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione-S-transferase (GST) activities, and metallothioneins (MTs) and lipid peroxidation (LPO) levels. Since both metals have been linked to oxidative stress, redox modifications to proteins were studied by differential isotopic labelling of the oxidised and reduced forms of cysteines (Cys). An accumulation of metals was observed in the digestive gland and gills following exposure, together with the activation of enzyme activities (SOD for the Cd exposure; SOD, CAT, GST, and GR for the Ag exposure). The MT and LPO levels (after individual exposure to Ag and Cd) increased, which suggests the existence of antioxidant and detoxification processes to mitigate the toxic oxidative effects of both metals. The redox proteomic analysis identified 771 Cys-containing peptides (out of 514 proteins), of which 195 and 226 changed after exposure to Ag and Cd, respectively. Bioinformatics analysis showed that exposure to metal affects relevant functional pathways and biological processes in S. plana, such as: “cellular respiration” (Ag), “metabolism of amino acids” and “synthesis and degradation of proteins” (Ag and Cd), “carbohydrate metabolism” and “oxidative stress” (Cd). The proteomic approach implemented here is a powerful complement to conventional biochemical biomarkers, since it evaluates changes at the protein level in a high-throughput unbiased manner, thus providing a general appraisal of the biological responses altered by exposure to the contaminants.

Enhanced Anti-Melanoma Activity of Nutlin-3a Delivered via Ethosomes: Targeting p53-Mediated Apoptosis in HT144 Cells.

This study evaluated ethosomes as a novel nanodelivery system for nutlin-3a, a known MDM2 inhibitor and activator of the p53 pathway, to improve nutlin-3a's poor solubility, limiting its bio-distribution and therapeutic efficacy. The potential of nutlin-3a-loaded ethosomes was investigated on two in vitro models of melanoma: the HT144 cell line p53wild-type and the SK-MEL-28 cell line p53mutated. Nutlin-3a-loaded ethosomes were characterized for their physicochemical properties and used to treat melanoma cells at different concentrations, considering nutlin-3a solution and empty ethosomes as controls. The biological effects on cells were evaluated 24 and 48 h after treatment by analyzing the cell morphology and viability, cell cycle, and apoptosis rate using flow cytometry and the p53 pathway's activation via Western blotting. The results indicate that ethosomes are delivery systems able to maintain nutlin-3a's functionality and specific biological action, as evidenced by the molecular activation of the p53 pathway and the biological events leading to cell cycle block and apoptosis in p53wild-type cells. Nutlin-3a-loaded ethosomes induced morphological changes in the HT144 cell line, with evident apoptotic cells and a reduction in the number of viable cells of over 80%. Furthermore, nutlin-3a-loaded ethosomes successfully modulated two p53-regulated proteins involved in survival/apoptosis, with up to a 2.5-fold increase in membrane TRAIL-R2 and up to an 8.2-fold decrease in Notch-1 (Notch intracellular domain, NICD) protein expression. The expression of these molecules is known to be altered or dysfunctional in a large percentage of melanoma tumors. Notably, ethosomes, regardless of their nutlin-3a loading, exhibited the ability to reduce HT144 melanoma cellular migration, as assessed in real time using xCELLigence, likely due to the modification of lipid rafts, suggesting their potential antimetastatic properties. Overall, nutlin-3a delivery using ethosomes appears to be a significantly effective means for upregulating the p53 pathway and downregulating active Notch-1, while also taking advantage of their unexpected ability to reduce cellular migration. The findings of this study could pave the way for the development of specific nutlin-3a-loaded ethosome-based medicinal products for cutaneous use.

Protease activated receptor 2 as a novel druggable target for the treatment of metabolic dysfunction-associated fatty liver disease and cancer.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is spreading worldwide, largely due to unhealthy lifestyles that contribute to the rise in diabetes, metabolic syndrome, and obesity. In this situation, the progression of injury to metabolic steatohepatitis can evolve to cirrhosis and, eventually, to hepatocellular carcinoma (HCC). It is well known that serine protease enzymes with different functions in cellular homeostasis act as signaling molecules that regulate liver inflammation by activating the protease-activated receptors (PARs) family members, expressed on the cellular plasma membrane. Among them, PAR2 plays a central role in the activation of signaling pathways in response to changes in the extracellular microenvironment. Experimental data have provided evidence that PAR2 is involved not only in inflammatory response but also in insulin resistance, lipid metabolism, and cancer. The major aims of this narrative review are addressed to assess PAR2 involvement in inflammation, metabolism, and liver disease progression and to explore possible therapeutic strategies, based on PAR2 inhibition, in order to prevent its biological effects in the context of MAFLD and cancer.

Synergistic combination of perphenazine and temozolomide suppresses patient-derived glioblastoma tumorspheres.

Glioblastoma (GBM), a primary malignant brain tumor, has a poor prognosis, even with standard treatments such as radiotherapy and chemotherapy. In this study, we explored the anticancer effects of the synergistic combination of perphenazine (PER), a dopamine receptor D2/3 (DRD2/3) antagonist, and temozolomide (TMZ), a standard treatment for GBM, in patient-derived human GBM tumorspheres (TSs). The biological effects of the combination of PER and TMZ in GBM TSs were assessed by measuring cell viability, ATP, stemness, invasiveness, and apoptosis. Changes in protein and mRNA expression were analyzed using western blotting and RNA sequencing. Co-administration of PER and TMZ was evaluated in vivo using a mouse orthotopic xenograft model. The Severance dataset showed that DRD2 and DRD3 expression was higher in tumor tissues than in the tumor-free cortex of patients with GBM. DRD2/3 knockout by CRISPR/Cas9 in patient-derived human GBM TSs inhibited cell growth and ATP production. The combined treatment with PER and TMZ resulted in superior effects on cell viability and ATP assays compared to those in single treatment groups. Flow cytometry, western blotting, and RNA sequencing confirmed elevated apoptosis in GBM TSs following combination treatment. Additionally, the combination of PER and TMZ downregulated the expression of protein and mRNA associated with stemness and invasiveness. In vivo evaluation showed that combining PER and TMZ extended the survival period of the mouse orthotopic xenograft model. The synergistic combination of PER and TMZ has potential as a novel combination treatment strategy for GBM.

Radioprotective potential of pomegranate peel extract against gamma irradiation-induced hazards

BackgroundWhile gamma irradiation’s damaging biological effects are well-established, the natural radioprotective agents from agricultural waste remain an underexplored area of significant potential.Aim of studyThis study was to investigate the novel use of pomegranate peel ethanol extract (PE) as a radioprotective agent against gamma radiation damage.MethodsWe pretreated Wistar rats with PE (100 mg/kg) for 14 days prior to 6 Gy gamma irradiation. We analyzed blood biochemicals, oxidative stress, and inflammatory markers. These included tests of red cell membrane integrity, lipid and protein oxidation, antioxidant enzyme levels, and cytokine profiles.ResultsThe study showed that PE demonstrated remarkable radioprotective effects across multiple parameters. Antioxidants were significantly enhanced, as evidenced by increased glutathione peroxidase activity (87.00 ± 6.11 mg/ml in PE-treated irradiated rats compared to 26.40 ± 1.21 mg/ml in irradiated controls). Oxidative damage was markedly reduced, with MDA levels dropping from 9.59 ± 0.24 nmol/ml in irradiated controls to near-control levels in PE-treated rats. Notably, PE treatment resulted in unprecedented maintenance of red blood cell membrane integrity post-irradiation. Furthermore, PE exhibited novel modulation of inflammatory cytokines, effectively reducing pro-inflammatory markers IL-6 and TNF-α while simultaneously boosting anti-inflammatory IL-4 and IL-10 levels. These multifaceted protective effects highlight PE’s potential as a comprehensive radioprotective agent.ConclusionThis study presents PE as an effective new natural radioprotective agent. Its protective effect is due to its high polyphenol content, which enhances antioxidant defenses, reduces oxidative damage, and prevents inflammation. The findings open new avenues for sustainable, cost-effective radioprotection strategies and demonstrate the potential for repurposing agricultural byproducts for critical health applications.