Pharmacokinetics, biodistribution, and biosafety of PEGylated gold nanoparticles in vivo

Despite the obvious advantages of gold nanoparticles for biomedical applications, controversial and incomplete toxicological data hamper their widespread use. Here, we present the results from an in vivo toxicity study using gold nanoparticles coated with polyethylene glycol (PEG-AuNPs). The pharmacokinetics and biodistribution of PEG-AuNPs were examined in the rat's liver, lung, spleen, and kidney after a single i.v. injection (0.7 mg/kg) at different time intervals. PEG-AuNPs had a relatively long blood circulation time and accumulated primarily in the liver and spleen, where they remained for up to 28 days after administration. Increased cytoplasmic vacuolation in hepatocytes 24 h and 7 days after PEG-AuNPs exposure and apoptotic-like cells in white splenic pulp 24 h after administration has been detected, however, 28 days post-exposure were no longer observed. In contrast, at this time point, we identified significant changes in lipid metabolism, altered levels of liver injury markers, and elevated monocyte count, but without marked biological relevance. In blood cells, no DNA damage was present in any of the studied time intervals, with the exception of DNA breakage transiently detected in primary kidney cells 4 h post-injection. Our results indicate that the tissue accumulation of PEG-AuNPs might result in late toxic effects

Dietary Phytochemicals Targeting Cancer Stem Cells

There is an increasing awareness of the importance of a diet rich in fruits and vegetables for human health. Cancer stem cells (CSCs) are characterized as a subpopulation of cancer cells with aberrant regulation of self-renewal, proliferation or apoptosis leading to cancer progression, invasiveness, metastasis formation, and therapy resistance. Anticancer effects of phytochemicals are also directed to target CSCs. Here we provide a comprehensive review of dietary phytochemicals targeting CSCs. Moreover, we evaluate and summarize studies dealing with effects of dietary phytochemicals on CSCs of various malignancies in preclinical and clinical research. Dietary phytochemicals have a significant impact on CSCs which may be applied in cancer prevention and treatment. However, anticancer effects of plant derived compounds have not yet been fully investigated in clinical research

Anticancer Activities of Thymus vulgaris L. in Experimental Breast Carcinoma In Vivo and In Vitro

Naturally-occurring mixtures of phytochemicals present in plant foods are proposed to possess tumor-suppressive activities. In this work, we aimed to evaluate the antitumor effects of Thymus vulgaris L. in in vivo and in vitro mammary carcinoma models. Dried T. vulgaris (as haulm) was continuously administered at two concentrations of 0.1% and 1% in the diet in a chemically-induced rat mammary carcinomas model and a syngeneic 4T1 mouse model. After autopsy, histopathological and molecular analyses of rodent mammary carcinomas were performed. In addition, in vitro evaluations using MCF-7 and MDA-MB-231 cells were carried out. In mice, T. vulgaris at both doses reduced the volume of 4T1 tumors by 85% (0.1%) and 84% (1%) compared to the control, respectively. Moreover, treated tumors showed a substantial decrease in necrosis/tumor area ratio and mitotic activity index. In the rat model, T. vulgaris (1%) decreased the tumor frequency by 53% compared to the control. Analysis of the mechanisms of anticancer action included well-described and validated diagnostic and prognostic markers that are used in both clinical approach and preclinical research. In this regard, the analyses of treated rat carcinoma cells showed a CD44 and ALDH1A1 expression decrease and Bax expression increase. Malondialdehyde (MDA) levels and VEGFR-2 expression were decreased in rat carcinomas in both the T. vulgaris treated groups. Regarding the evaluations of epigenetic changes in rat tumors, we found a decrease in the lysine methylation status of H3K4me3 in both treated groups (H3K9m3, H4K20m3, and H4K16ac were not changed); up-regulations of miR22, miR34a, and miR210 expressions (only at higher doses); and significant reductions in the methylation status of four gene promoters—ATM serin/threonine kinase, also known as the NPAT gene (ATM); Ras-association domain family 1, isoform A (RASSF1); phosphatase and tensin homolog (PTEN); and tissue inhibitor of metalloproteinase-3 (TIMP3) (the paired-like homeodomain transcription factor (PITX2) promoter was not changed). In vitro study revealed the antiproliferative and proapoptotic effects of essential oils of T. vulgaris in MCF-7 and MDA-MB-231 cells (analyses of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS); 5-bromo-20-deoxyuridine (BrdU); cell cycle; annexin V/PI; caspase-3/7; Bcl-2; PARP; and mitochondrial membrane potential). T. vulgaris L. demonstrated significant chemopreventive and therapeutic activities against experimental breast carcinoma

Flavonoids as an efective sensitizer for anti‑cancer therapy: insights into multi‑faceted mechanisms and applicability towards individualized patient profles

Cost-efficacy of currently applied treatments is an issue in overall cancer management challenging healthcare and causing tremendous economic burden to societies around the world. Consequently, complex treatment models presenting concepts of predictive diagnostics followed by targeted prevention and treatments tailored to the personal patient profiles earn global appreciation as benefiting the patient, healthcare economy, and the society at large. In this context, application of flavonoids as a spectrum of compounds and their nano-technologically created derivatives is extensively under consideration, due to their multi-faceted anti-cancer effects applicable to the overall cost-effective cancer management, primary, secondary, and even tertiary prevention. This article analyzes most recently updated data focused on the potent capacity of flavonoids to promote anti-cancer therapeutic effects and interprets all the collected research achievements in the frame-work of predictive, preventive, and personalized (3P) medicine. Main pillars considered are: - Predictable anti-neoplastic, immune-modulating, drug-sensitizing effects; - Targeted molecular pathways to improve therapeutic outcomes by increasing sensitivity of cancer cells and reversing their resistance towards currently applied therapeutic modalities

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Therapeutic Potential of Plant Phenolic Acids in the Treatment of Cancer

Globally, cancer is the second leading cause of death. Different conventional approaches to treat cancer include chemotherapy or radiotherapy. However, these are usually associated with various deleterious effects and numerous disadvantages in clinical practice. In addition, there are increasing concerns about drug resistance. In the continuous search for safer and more effective treatments, plant-derived natural compounds are of major interest. Plant phenolics are secondary metabolites that have gained importance as potential anti-cancer compounds. Phenolics display a great prospective as cytotoxic anti-cancer agents promoting apoptosis, reducing proliferation, and targeting various aspects of cancer (angiogenesis, growth and differentiation, and metastasis). Phenolic acids are a subclass of plant phenolics, furtherly divided into benzoic and cinnamic acids, that are associated with potent anticancer abilities in various in vitro and in vivo studies. Moreover, the therapeutic activities of phenolic acids are reinforced by their role as epigenetic regulators as well as supporters of adverse events or resistance associated with conventional anticancer therapy. Encapsulation of phyto-substances into nanocarrier systems is a challenging aspect concerning the efficiency of natural substances used in cancer treatment. A summary of phenolic acids and their effectiveness as well as phenolic-associated advances in cancer treatment will be discussed in this review

Anti-Angiogenic Effects of Phytochemicals on miRNA Regulating Breast Cancer Progression

Several phytochemicals have been identified for their role in modifying miRNA regulating tumor progression. miRNAs modulate the expression of several oncogenes and tumor suppressor genes including the genes that regulate tumor angiogenesis. Hypoxia inducible factor-1 alpha (HIF-1α) signaling is a central axis that activates oncogenic signaling and acts as a metabolic switch in endothelial cell (EC) driven tumor angiogenesis. Tumor angiogenesis driven by metabolic reprogramming of EC is crucial for tumor progression and metastasis in many different cancers, including breast cancers, and has been linked to aberrant miRNA expression profiles. In the current article, we identify different miRNAs that regulate tumor angiogenesis in the context of oncogenic signaling and metabolic reprogramming in ECs and review how selected phytochemicals could modulate miRNA levels to induce an anti-angiogenic action in breast cancer. Studies involving genistein, epigallocatechin gallate (EGCG) and resveratrol demonstrate the regulation of miRNA-21, miRNA-221/222 and miRNA-27, which are prognostic markers in triple negative breast cancers (TNBCs). Modulating the metabolic pathway is a novel strategy for controlling tumor angiogenesis and tumor growth. Cardamonin, curcumin and resveratrol exhibit their anti-angiogenic property by targeting the miRNAs that regulate EC metabolism. Here we suggest that using phytochemicals to target miRNAs, which in turn suppresses tumor angiogenesis, should have the potential to inhibit tumor growth, progression, invasion and metastasis and may be developed into an effective therapeutic strategy for the treatment of many different cancers where tumor angiogenesis plays a significant role in tumor growth and progression

Mitochondriopathies as a Clue to Systemic Disorders—Analytical Tools and Mitigating Measures in Context of Predictive, Preventive, and Personalized (3P) Medicine

The mitochondrial respiratory chain is the main site of reactive oxygen species (ROS) production in the cell. Although mitochondria possess a powerful antioxidant system, an excess of ROS cannot be completely neutralized and cumulative oxidative damage may lead to decreasing mitochondrial efficiency in energy production, as well as an increasing ROS excess, which is known to cause a critical imbalance in antioxidant/oxidant mechanisms and a “vicious circle” in mitochondrial injury. Due to insufficient energy production, chronic exposure to ROS overproduction consequently leads to the oxidative damage of life-important biomolecules, including nucleic acids, proteins, lipids, and amino acids, among others. Different forms of mitochondrial dysfunction (mitochondriopathies) may affect the brain, heart, peripheral nervous and endocrine systems, eyes, ears, gut, and kidney, among other organs. Consequently, mitochondriopathies have been proposed as an attractive diagnostic target to be investigated in any patient with unexplained progressive multisystem disorder. This review article highlights the pathomechanisms of mitochondriopathies, details advanced analytical tools, and suggests predictive approaches, targeted prevention and personalization of medical services as instrumental for the overall management of mitochondriopathy-related cascading pathologies

Natural Compounds in Glioblastoma Therapy: Preclinical Insights, Mechanistic Pathways, and Outlook

Glioblastoma (GBM) is an aggressive, often fatal astrocyte-derived tumor of the central nervous system. Conventional medical and surgical interventions have greatly improved survival rates; however, tumor heterogeneity, invasiveness, and chemotherapeutic resistance continue to pose clinical challenges. As such, dietary natural substances—an integral component of the lifestyle medicine approach to chronic diseases—are examined as potential chemotherapeutic agents. These heterogenous substances exert anti-GBM effects by upregulating apoptosis and autophagy, inducing cell cycle arrest, interfering with tumor metabolism, and inhibiting proliferation, neuroinflammation, chemoresistance, angiogenesis, and metastasis. Although these beneficial effects are promising, natural substances’ efficacy in GBM is constrained by their bioavailability and blood–brain barrier permeability; various chemical formulations are proposed to improve their pharmacological properties. Many of the reviewed substances are available as over-the-counter dietary supplements, underscoring their viability as lifestyle interventions. However, clinical trials remain necessary to substantiate the in vitro and in vivo properties of natural substances

Berberine in Human Oncogenic Herpesvirus Infections and Their Linked Cancers

Human herpesviruses are known to induce a broad spectrum of diseases, ranging from common cold sores to cancer, and infections with some types of these viruses, known as human oncogenic herpesviruses (HOHVs), can cause cancer. Challenges with viral latency, recurrent infections, and drug resistance have generated the need for finding new drugs with the ability to overcome these barriers. Berberine (BBR), a naturally occurring alkaloid, is known for its multiple biological activities, including antiviral and anticancer effects. This paper comprehensively compiles all studies that have featured anti-HOHV properties of BBR along with promising preventive effects against the associated cancers. The mechanisms and pathways induced by BBR via targeting the herpesvirus life cycle and the pathogenesis of the linked malignancies are reviewed. Approaches to enhance the therapeutic efficacy of BBR and its use in clinical practice as an anti-herpesvirus drug are also discussed