Enhancing the bioavailability and activity of natural antioxidants with nanobubbles and nanoparticles.

KEY POLICY HIGHLIGHTSNanobubbles and nanoparticles may enhance the polyphenols' bioavailabilityNanobubbles may stimulate the activation of Nrf2 and detox enzymesArmoured oxygen nanobubbles may enhance radiotherapy or chemotherapy effects.

Nanoparticles in Medicine: Current Status in Cancer Treatment.

Cancer is still a leading cause of deaths worldwide, especially due to those cases diagnosed at late stages with metastases that are still considered untreatable and are managed in such a way that a lengthy chronic state is achieved. Nanotechnology has been acknowledged as one possible solution to improve existing cancer treatments, but also as an innovative approach to developing new therapeutic solutions that will lower systemic toxicity and increase targeted action on tumors and metastatic tumor cells. In particular, the nanoparticles studied in the context of cancer treatment include organic and inorganic particles whose role may often be expanded into diagnostic applications. Some of the best studied nanoparticles include metallic gold and silver nanoparticles, quantum dots, polymeric nanoparticles, carbon nanotubes and graphene, with diverse mechanisms of action such as, for example, the increased induction of reactive oxygen species, increased cellular uptake and functionalization properties for improved targeted delivery. Recently, novel nanoparticles for improved cancer cell targeting also include nanobubbles, which have already demonstrated increased localization of anticancer molecules in tumor tissues. In this review, we will accordingly present and discuss state-of-the-art nanoparticles and nano-formulations for cancer treatment and limitations for their application in a clinical setting.

Study of zeolite clinoptilolite d-glucose adsorption properties in vitro and in vivo.

Beneficial effects of a natural zeolite clinoptilolite in vivo on mammals, including humans, have been empirically observed and documented in literature. The positive biological activities have been associated to its detoxifying and antioxidative properties, and its immunostimulative and adsorption properties. Herein, we present the in vitro and in vivo study of clinoptilolite zeolite materials adsorption properties for d-glucose. In particular, we present data on the interaction of d-glucose on the tested zeolites' surface obtained by scanning electron microscope (SEM) and Energy-dispersive X-ray spectroscopy (EDS) and quantification by ultra high-performance liquid chromatography (UHPLC). We also present results on the reduction of blood glucose levels in mice pre-treated with clinoptilolite in vivo upon feeding with d-glucose. In vivo results were in line with the in vitro adsorption and/or interaction properties of tested zeolite materials for d-glucose and were quantified by UHPLC as well (11.34% for TMAZ; 10.82% for PMA and 8.76% for PMAO2). In vivo experiments in mice showed that PMA zeolite reduces blood glucose levels upon 15 min for 13% (at p < 0.05) up to 19.11% upon 120 min (without statistical significance) in clinoptilolite pre-treated mice fed by addition of d-glucose. Due to lack of explicit mechanistic knowledge on zeolite clinoptilolite interactions or adsorption with sugars in vitro and in vivo, presented study provides novel insights into these aspects for researchers in the field. The presented data merit further investigations as the material clearly shows a potential in management of hyperglycemia, such as for example in obese people, people with diabetes and people with metabolic syndrome where it could help regulate blood glucose levels.

The Interplay of Lung Cancer, COVID-19, and Vaccines.

Patients with cancer are more susceptible to a higher risk of coronavirus infection and its severe complications than the general population. In addition, these patients were not included in the pivotal clinical trials for COVID-19 vaccines. Therefore, considerable uncertainty remains regarding the management of cancer patients during the COVID-19 pandemic and the safety of COVID-19 vaccinations in cancer patients. In this review, we summarize the current knowledge generated from the beginning of the COVID-19 pandemic on the vulnerability of cancer patients to the coronavirus disease, as well as the effectiveness of COVID-19 vaccines in this population. We also discuss the available data on the effects of anticancer treatment with immune checkpoint inhibitors on the immune responses to SARS-CoV-2 in cancer patients. Special attention in this review will be given to patients with lung cancer, as such patients are at an increased risk for severe effects from COVID-19.

Clinical Parameters in Osteoporosis Patients Supplemented With PMA-Zeolite at the End of 5-Year Double-Blinded Clinical Trial.

Osteoporosis is among the most common pathologies. Associated complications in osteoporotic patients, in particular hip fractures and vertebral fractures, cause disabilities and significant quality of life deterioration. Standard treatment of osteoporosis, based on pharmacotherapy does still not yield adequate results, and the problem of osteoporosis remains incompletely solved. Additionally, adverse drug events and fractures after long-termed pharmacotherapy pose additional challenges within designing a proper therapy regimen. Improved clinical approach and new synergistic treatment modalities are consequently still needed. The rationale of the presented study was accordingly, to expand our preclinical animal study on human patients with osteoporosis, based on positive effects on bones observed in animals with osteopenia treated with PMA-zeolite. We specifically monitored effects of PMA-zeolite on the bone quality parameters, fracture risk and quality of life in a cohort of initially recruited 100 osteoporosis patients during a follow-up period of 5 years within a randomized, placebo-controlled and double blinded clinical study (TOP study). Obtained results provide evidence on the PMA-zeolite positive effects on the bone strength of osteoporotic patients as the risk of fractures was significantly decreased in PMA-zeolite-treated patients with respect to time before entering the study (p = 0.002). Statistical evidence point also to positive bone changes in the 5-years TOP study course as evidenced through osteocalcin and beta-cross laps values showing a prevalence of the bone-formation process (p < 0.05). BMD values were not significantly affected after the 5-years follow-up in PMA-zeolite-treated patients in comparison with the Placebo group. Results support the initial expectations based on our previously published preclinical studies on clinoptilolite product PMA-zeolite in animals that could be a new therapeutic option in osteoporosis patients.

Clinical Evaluation of a Defined Zeolite-Clinoptilolite Supplementation Effect on the Selected Blood Parameters of Patients.

The natural clinoptilolite material is an inorganic crystal mineral called zeolite. It has been extensively studied and used in industrial applications and veterinary and human medicine due to positive effects on health. Limited data is available in the scientific literature about its effects on the levels of physiologically relevant minerals in the human organism. Accordingly, we performed a comprehensive and controlled monitoring of the relevant mineral and contaminants levels in human subjects supplemented with a certified clinoptilolite material within three clinical trials with different supplementation regimens. Effects of a registered and certified clinoptilolite material PMA-zeolite on selected mineral and metal levels were determined by standard biochemical methods and inductively coupled plasma mass spectrometry (ICP-MS) in the blood of subjects enrolled in three clinical trials: short-term (28 days, Mineral Metabolism and selected Blood Parameters study MMBP), medium-term (12 weeks, Morbus Crohn study), and long-term (4 years, Osteoporosis TOP study) supplementation. Lower concentrations were observed for copper (Cu) in patients with osteoporosis, which normalized again in the long-term supplementation trial, whereas sodium (Na) and calcium (Ca) levels diminished below the reference values in patients with osteoporosis. In the short- and long-term supplementation trials, increased levels of lead (Pb) were observed in PMA-zeolite-supplemented subjects, which decreased in the continued long-term supplementation trial. Increased levels of aluminum (Al) or Pb attributable to eventual leakage from the material into the bloodstream were not detected 1 h after intake in the short-term supplementation trial. Nickel (Ni) and Al were statistically significantly decreased upon long-term 4-year supplementation within the long-term supplementation trial, and arsenic (As) was statistically significantly decreased upon 12-weeks supplementation in the medium-term trial. Alterations in the measured levels for Na and Ca, as well as for Pb, in the long-term trial are probably attributable to the bone remodeling process. Checking the balance of the minerals Cu, Ca, and Na after 1 year of supplementation might be prescribed for PMA-supplemented patients with osteoporosis. Clinical Trial Registration: [https://clinicaltrials.gov], identifiers [NCT03901989, NCT05178719, NCT04370535, NCT04607018].

The effect of zeolite incorporation on the physical properties of silver-reinforced glass ionomer cement.

Zeolite can impart antibacterial properties to dental materials in the long-term when incorporated with inorganic cations. However, due to its porosity, it may jeopardize the mechanical integrity of the dental material. The aim of this project was to determine the effect on physical properties when zeolite is added to commercially available Ag-reinforced Glass Ionomer Cement (GIC). Sample groups were prepared according to the percentage of zeolite-clinoptilolite (0% - control, 0.5%, 1%, 2%, and 4% wt) added to Ag-GIC. Water sorption, solubility, Vickers hardness, and flexural strength were determined. Specifically, 10 × 2 mm circular disks were fabricated for the Vickers hardness, water sorption, and water solubility tests and 25 × 5 × 2 mm bars were created for the flexural strength test. The results from the surface hardness, water sorption, and flexural strength tests suggested that adding 0.5-4% wt of zeolite to Ag-reinforced GIC did not diminish its physical properties. However, the water solubility results showed that higher concentrations (2-4% wt) of zeolite had a statistically significant increase in water solubility compared to the control. Up to 4% wt zeolite can be incorporated into Ag-reinforced GIC without compromising mechanical properties. Incorporation of 0.5-1% wt zeolite to Ag-reinforced GIC will maintain an adequate surface hardness, water sorption, and flexural strength without compromising water solubility. Further research is needed to determine the effects of higher water solubility on clinical efficacy of zeolite modified Ag-GIC. Graphical abstract.

Fighting Cancer with Bacteria and Their Toxins.

Cancer is one of the most important global health problems that continues to demand new treatment strategies. Many bacteria that cause persistent infections play a role in carcinogenesis. However, since bacteria are well studied in terms of molecular mechanisms, they have been proposed as an interesting solution to treat cancer. In this review, we present the use of bacteria, and particularly bacterial toxins, in cancer therapy, highlighting the advantages and limitations of bacterial toxins. Proteomics, as one of the omics disciplines, is essential for the study of bacterial toxins. Advances in proteomics have contributed to better characterization of bacterial toxins, but also to the development of anticancer drugs based on bacterial toxins. In addition, we highlight the current state of knowledge in the rapidly developing field of bacterial extracellular vesicles, with a focus on their recent application as immunotherapeutic agents.

Amidine- and Amidoxime-Substituted Heterocycles: Synthesis, Antiproliferative Evaluations and DNA Binding.

The novel 1,2,3-triazolyl-appended N- and O-heterocycles containing amidine 4-11 and amidoxime 12-22 moiety were prepared and evaluated for their antiproliferative activities in vitro. Among the series of amidine-substituted heterocycles, aromatic diamidine 5 and coumarine amidine 11 had the most potent growth-inhibitory effect on cervical carcinoma (HeLa), hepatocellular carcinoma (HepG2) and colorectal adenocarcinoma (SW620), with IC50 values in the nM range. Although compound 5 was toxic to non-tumor HFF cells, compound 11 showed certain selectivity. From the amidoxime series, quinoline amidoximes 18 and 20 showed antiproliferative effects on lung adenocarcinoma (A549), HeLa and SW620 cells emphasizing compound 20 that exhibited no cytostatic effect on normal HFF fibroblasts. Results of CD titrations and thermal melting experiments indicated that compounds 5 and 10 most likely bind inside the minor groove of AT-DNA and intercalate into AU-RNA. Compounds 6, 9 and 11 bind to AT-DNA with mixed binding mode, most probably minor groove binding accompanied with aggregate binding along the DNA backbone.

Effects of Zeolite as a Drug Delivery System on Cancer Therapy: A Systematic Review.

Zeolites and zeolitic imidazolate frameworks (ZIFs) are widely studied as drug carrying nanoplatforms to enhance the specificity and efficacy of traditional anticancer drugs. At present, there is no other systematic review that assesses the potency of zeolites/ZIFs as anticancer drug carriers. Due to the porous nature and inherent pH-sensitive properties of zeolites/ZIFs, the compounds can entrap and selectively release anticancer drugs into the acidic tumor microenvironment. Therefore, it is valuable to provide a comprehensive overview of available evidence on the topic to identify the benefits of the compound as well as potential gaps in knowledge. The purpose of this study was to evaluate the potential therapeutic applications of zeolites/ZIFs as drug delivery systems delivering doxorubicin (DOX), 5-fluorouracil (5-FU), curcumin, cisplatin, and miR-34a. Following PRISMA guidelines, an exhaustive search of PubMed, Scopus, Embase, and Web of Science was conducted. No language or time limitations were used up to 25th August 2021. Only full text articles were selected that pertained to the usage of zeolites/ZIFs in delivering anticancer drugs. Initially, 1279 studies were identified, of which 572 duplicate records were excluded. After screening for the title, abstract, and full texts, 53 articles remained and were included in the qualitative synthesis. An Inter-Rater Reliability (IRR) test, which included a percent user agreement and reliability percent, was conducted for the 53 articles. The included studies suggest that anticancer drug-incorporated zeolites/ZIFs can be used as alternative treatment options to enhance the efficacy of cancer treatment by mitigating the drawbacks of drugs under conventional treatment.

Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation.

Novel symmetrical bis-pyrrolo[2,3-d]pyrimidines and bis-purines and their monomers were synthesized and evaluated for their antiproliferative activity in human lung adenocarcinoma (A549), cervical carcinoma (HeLa), ductal pancreatic adenocarcinoma (CFPAC-1) and metastatic colorectal adenocarcinoma (SW620) cells. The use of ultrasound irradiation as alternative energy input in Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) shortened the reaction time, increased the reaction efficiency and led to the formation of exclusively symmetric bis-heterocycles. DFT calculations showed that triazole formation is exceedingly exergonic and confirmed that the presence of Cu(I) ions is required to overcome high kinetic requirements and allow the reaction to proceed. The influence of various linkers and 6-substituted purine and regioisomeric 7-deazapurine on their cytostatic activity was revealed. Among all the evaluated compounds, the 4-chloropyrrolo[2,3-d]pyrimidine monomer 5f with 4,4'-bis(oxymethylene)biphenyl had the most pronounced, although not selective, growth-inhibitory effect on pancreatic adenocarcinoma (CFPAC-1) cells (IC50 = 0.79 µM). Annexin V assay results revealed that its strong growth inhibitory activity against CFPAC-1 cells could be associated with induction of apoptosis and primary necrosis. Further structural optimization of bis-chloropyrrolo[2,3-d]pyrimidine with aromatic linker is required to develop novel efficient and non-toxic agent against pancreatic cancer.

PERSONALIZED NEOANTIGEN VACCINE AGAINST CANCER.

No significant therapeutic solutions for advanced cancer are available to date. However, an old idea based on usage of tumor-specific antibodies as the basis for a new vaccination form in patients with advanced tumors, has attracted recent research and is possible due to development of personalized neoantigenic vaccines. Each tumour has indeed, its own mutation content, only a small percentage are shared between patients. Technological advances and the established genome databases, allowed for a rapid mapping of mutations in the genome. The latter allows for a rational selection of targets for personalized vaccines and on-demand production of customized therapy according to the patient's individual tumour properties. This article accordingly, summarizes basic principles of vaccines for personalized neoantigens, translational research and clinical studies related to these vaccines. Finally, the future of such therapy with personalized vaccines is discussed.

Antimicrobial and Mechanical Effects of Zeolite Use in Dental Materials: A Systematic Review.

OBJECTIVE: Ion-incorporated zeolite is a widely used antimicrobial material studied for various dental applications. At present, there is no other systematic review that evaluates the effectiveness of zeolite in all dental materials. The purpose of this study was to review all available literature that analyzed the antimicrobial effects and/or mechanical properties of zeolite as a restorative material in dentistry. MATERIAL AND METHODS: Following PRISMA guidelines, an exhaustive search of PubMed, Ovid Medline, Scopus, Embase, and the Dentistry & Oral Sciences Source was conducted. No language or time restrictions were used and the study was conducted from June 1, 2020 to August 17, 2020. Only full text articles were selected that pertained to the usage of zeolite in dental materials including composite resin, bonding agents, cements, restorative root material, cavity base material, prosthesis, implants, and endodontics. RESULTS: At the beginning of the study, 1534 studies were identified, of which 687 duplicate records were excluded. After screening for the title, abstract, and full texts, 35 articles remained and were included in the qualitative synthesis. An Inter-Rater Reliability (IRR) test, which included a percent user agreement and reliability percent, was conducted for each of the 35 articles chosen. CONCLUSION: Although ion-incorporated zeolite may enhance the antimicrobial properties of dental materials, the mechanical properties of some materials, such as MTA and acrylic resin, may be compromised. Therefore, since the decrease in mechanical properties depends on zeolite concentration in the restorative material, it is generally recommended to add 0.2-2% zeolite by weight.

A Perspective on COVID-19 Management.

A novel coronavirus-Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2)-outbreak correlated with the global coronavirus disease 2019 (COVID-19) pandemic was declared by the WHO in March 2020, resulting in numerous counted cases attributed to SARS-CoV-2 worldwide. Herein, we discuss current knowledge on the available therapy options for patients diagnosed with COVID-19. Based on available scientific data, we present an overview of solutions in COVID-19 management by use of drugs, vaccines and antibodies. Many questions with non-conclusive answers on the measures for the management of the COVID-19 pandemic and its impact on health still exist-i.e., the actual infection percentage of the population, updated precise mortality data, variability in response to infection by the population, the nature of immunity and its duration, vaccine development issues, a fear that science might end up with excessive promises in response to COVID-19-and were raised among scientists. Indeed, science may or may not deliver results in real time. In the presented paper we discuss some consequences of disease, its detection and serological tests, some solutions to disease prevention and management, pitfalls and obstacles, including vaccination. The presented ideas and data herein are meant to contribute to the ongoing debate on COVID-19 without pre-selection of available information.

Treatment of osteoporosis with a modified zeolite shows beneficial effects in an osteoporotic rat model and a human clinical trial.

The severity of osteoporosis in humans manifests in its high incidence and by its complications that diminish quality of life. A societal consequence of osteoporosis is the substantial burden that it inflicts upon patients and their families. Several bone-modifying drugs have been prescribed to patients with osteoporosis. However, evidence for their anti-fracture efficacy remains inconclusive. To the contrary, long-term use of anti-osteoporotic drugs such as bisphosphonates and Denosumab, an RANKL inhibitor, have resulted in adverse events. We now present an alternative and adjuvant approach for treatment of osteoporosis. The data derive from in vivo studies in an ovariectomized rat model and from a randomized double blind, placebo-controlled human clinical study. Both studies involved treatment with Panaceo Micro Activation (PMA)-zeolite-clinoptilolite, a defined cation exchange clinoptilolite, which clearly improved all bone histomorphometric parameters examined from ovariectomized animals, indicative for increased bone formation. Moreover, intervention with PMA-zeolite-clinoptilolite for one year proved safe in humans. Furthermore, patients treated with PMA-zeolite-clinoptilolite showed an increase in bone mineral density, an elevated level of markers indicative of bone formation, a significant reduction in pain, and significantly improved quality of life compared with patients in the control (placebo) group. These encouraging positive effects of PMA-zeolite-clinoptilolite on bone integrity and on osteoporosis warrant further evaluation of treatment with PMA-zeolite-clinoptilolite as a new alternative adjuvant therapy for osteoporosis.

Nutraceuticals and Metastasis Development.

Nutrigenomics is a discipline that studies the effects of various dietary components on gene expression and molecular mechanisms via "omics" technologies. Many studies are focused on revealing the pathways of the anticancer properties of various nutraceuticals. However, it has been shown that metastasis, a multifactorial disease that develops from primary tumors in cascades, is responsible for almost 90% of cancer deaths. Regrettably, the effects of consumption of different nutraceuticals on metastasis development have not yet been sufficiently explored. A few studies on the subject have revealed the promotional effects of some nutraceuticals on metastasis development. Additionally, it has been shown that certain compounds can have beneficial effects on reduction of the primary tumor, but afterwards promote the spread of metastases. Therefore, in this review we discuss results published in the past five years focused on the effects of different nutraceuticals on metastasis development.

Purine and Purine Isostere Derivatives of Ferrocene: An Evaluation of ADME, Antitumor and Electrochemical Properties.

Novel purine and purine isosteres containing a ferrocene motif and 4,1-disubstituted (11a-11c, 12a-12c, 13a-13c, 14a-14c, 15a-15c, 16a, 23a-23c, 24a-24c, 25a-25c) and 1,4-disubstituted (34a-34c and 35a-35c) 1,2,3-triazole rings were synthesized. The most potent cytotoxic effect on colorectal adenocarcinoma (SW620) was exerted by the 6-chloro-7-deazapurine 11c (IC50 = 9.07 µM), 6-chloropurine 13a (IC50 = 14.38 µM) and 15b (IC50 = 15.50 µM) ferrocenylalkyl derivatives. The N-9 isomer of 6-chloropurine 13a containing ferrocenylmethylene unit showed a favourable in vitro physicochemical and ADME properties including high solubility, moderate permeability and good metabolic stability in human liver microsomes.

Targeting Tumour Metastasis: The Emerging Role of Nanotechnology.

The metastatic process has still not been completely elucidated, probably due to insufficient knowledge of the underlying mechanisms. Here, we provide an overview of the current findings that shed light on specific molecular alterations associated with metastasis and present novel concepts in the treatment of the metastatic process. In particular, we discuss novel pharmacological approaches in the clinical setting that target metastatic progression. New insights into the process of metastasis allow optimisation and design of new treatment strategies, especially in view of the fact that metastatic cells share common features with stem cells. Nano- and micro-technologies are herein elaborated in details as a promising therapeutic concept in targeted drug delivery for metastatic cancer. Progression in the field could provide a more efficient way to tackle metastasis and thus bring about advancements in the treatment and management of patients with advanced cancer.

Antitumor and antiviral activities of 4-substituted 1,2,3-triazolyl-2,3-dibenzyl-L-ascorbic acid derivatives.

Two series of 6-(1,2,3-triazolyl)-2,3-dibenzyl-l-ascorbic acid derivatives with the hydroxyethylene (8a-8u) and ethylidene linkers (10c-10p) were synthesized and evaluated for their antiproliferative activity against seven malignant tumor cell lines and antiviral activity against a broad range of viruses. Conformationally unrestricted spacer between the lactone and 1,2,3-triazole units in 8a-8u series had a profound effect on antitumor activity. Besides, the introduction of a long side chain at C-4 of 1,2,3-triazole that led to the synthesis of decyl-substituted 2,3-dibenzyl-l-ascorbic acid 8m accounted for a selective and potent antiproliferative activity on breast cancer MCF-7 cells cells in the nM range. Further analysis showed that compound 8m strongly enhanced expression of hypoxia inducible transcription factor 1 α (HIF-1α) and to some extent decreased expression of nitric oxide synthase 2 (NOS2) suggesting its role in regulating HIF-1α signalling pathway. The p-methoxyphenyl-substituted derivative 10g displayed specific anti-cytomegalovirus (CMV) potential, whereas aliphatic-substituted derivatives 8l and 8m had the most potent, yet relatively non-specific, anti-varicella-zoster (VZV) activity.