Advances in therapeutic applications of silver nanoparticles.

Nanotechnology is one of the most appealing area for developing new applications in biotechnology and medicine. For decades, nanoparticles have been extensively studied for a variety of biomedical applications. Silver has evolved into a potent antibacterial agent that can be used in a variety of nanostructured materials of various shapes and sizes. Silver nanoparticles (AgNP) based antimicrobial compounds are employed in a wide range of applications, including medicinal uses, surface treatment and coatings, the chemical and food industries, and agricultural productivity. When designing formulations for specific applications, the size, shape, and surface area of AgNPs are all crucial structural aspects to consider. Different methods for producing AgNPs with varying sizes and forms that are less harmful have been devised. The anticancer, anti-inflammatory, antibacterial, antiviral, and anti-angiogenic properties of AgNPs have been addressed in this review, as well as their generation and processes. Herein, we have reviewed the advances in therapeutic applications of AgNPs, as well as their limitations and barriers for future applications.

Efficacy of polyacrylate silver salt/polyvinylpyrrolidone-based liquid oral gel in management of concurrence chemoradiotherapy-induced oral mucositis.

BACKGROUND/PURPOSE: Acute oral mucositis (OM) is a painful complication of concurrent chemoradiotherapy (CCRT). This severe adverse symptom may impact on patient's quality of life, lead to malnutrition. Thus, finding more effective methods in OM management is very important. The purpose of this study is to evaluate the efficacy of polyacrylate silver salt/Polyvinylpyrrolidone-based liquid oral gel (named as polyacrylate silver salt oral gel) in improving the symptomatic relief of CCRT-induced oral mucositis and oral dysfunction in neck and head cancer patients. METHODS: In this study, 24 oral cancer patients underwent CCRT and having OM grade 2 or higher were randomly assigned into the test group and the control group. Both groups followed Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) clinical practice guidelines for the management of mucositis, but adding rinsing with 15 g oral gel right after oral hygiene treaded the test group. Clinical OM and oral function were assessed weekly for 4 consecutive weeks till 5-10 days after the completion of radiotherapy. For evaluation, Common Terminology Criteria for Adverse Events (CTCAE) v3.0 was used for collecting the data of OM grade. RESULTS: The results showed that polyacrylate silver salt oral gel had better effect for relieving the oral mucositis. There were statistically significant differences in OM grades (1.59 vs. 2.8, p < 0.0001) between the test group and the control group. CONCLUSION: Our clinical studies demonstrated that polyacrylate silver salt oral gel is an effective interventional option in terms of rapid mucositis healing.

Silver nanoparticles induced testicular damage targeting NQO1 and APE1 dysregulation, apoptosis via Bax/Bcl-2 pathway, fibrosis via TGF-ß/α-SMA upregulation in rats.

In medicine, silver nanoparticles (AgNPs) are employed often. They do, however, have negative impacts, particularly on the reproductive organs. This research aimed to assess AgNP impact on the testis and the possible intracellular mechanisms to induce testicular deteriorations in rats at various concentrations and different time intervals. Sprague Dawley rats (n = 40) were allocated into four equal groups: the control one, and three other groups injected intra-peritoneally with AgNP solution 0.25, 0.5, and 1 mg/kg b.w. respectively for 15 and 30 days. Our findings revealed that AgNPs reduced body and testicular weights, estradiol (E2) and testosterone (T) hormone levels, and sperm parameters while elevating the nitric oxide and malondialdehyde levels with inhibition of reduced glutathione contents in testicular tissue. Interestingly, AgNPs significantly upregulated the testicular inducible nitric oxide synthase, B cell lymphoma 2 (Bcl-2)-associated X, transforming growth factor, and alpha-smooth muscle actin (α-SMA) expression levels. However, apurinic/apyrimidinic endo deoxyribonuclease 1 (APE1), NAD (P) H quinone dehydrogenase 1 (NQO1), and Bcl-2 expression levels were all downregulated indicating exhaustion of body antioxidant and repairing defense mechanisms in testicles in comparison with the control rats. Various histological alterations were also detected which dramatically increased in rats sacrificed after 30 days such as loss of the lining cells of seminiferous tubules with no spermatozoa and tubular irregularities associated with thickening of their basement membranes. Immunolabeling implicated in the apoptotic pathway revealed a negative expression of Bcl-2 and marked immunoreactivity for caspase-3 after 30 days of AgNP treatment in comparison to the control rats. To our knowledge, there have been no previous publications on the role of the α-SMA, APE1, and NQO1 genes in the molecular pathogenesis of AgNP testicular cytotoxicity following AgNP acute and chronic exposure.

Silvernanoparticle-induced hemolysis confounded with direct antiglobulin test-negative autoimmune hemolytic anemias diagnosis.

BACKGROUND: We describe here the first patient with recurrent hemolysis related to disinfectant containing silver nanoparticles (AgNps). METHODS: A 58-year-old chemist repeatedly experienced DAT-negative (Coombs-negative) hemolysis during the last 5 years. He was treated with a number of immunosuppressive drugs including 18 times rituximab. The attempt to treat him with cyclosporine A served only to increase the rate of hemolysis. Only by chance, we revealed that the patient regularly used a hand disinfectant containing AgNps. Serological testing was performed using standard techniques. Eryptosis was measured by binding annexin to exposed phosphatidylserine (PS) of the circulating red blood cells (RBCs). RESULTS: Antiglobulin tests remained negative, and PS exposing RBCs were detected two times during the last hemolytic episodes. Hemolysis completely disappeared following discontinuation of AgNp containing products. CONCLUSION: AgNps are increasingly being used in a large variety of products. Recently, it was reported that they induce in vitro prohemolytic and procoagulant effects via oxidative stress and eryptosis. The clinical findings imply the hemolysis was provoked by the patient's regular use of cleansing products containing AgNps. Our finding might help to explain the etiology of hemolytical disorders that may remain obscure in many cases.

Effects of biogenic silver and iron nanoparticles on soybean seedlings (Glycine max).

BACKGROUND: Biogenic metallic nanoparticles have been emerging as a promising alternative for the control of phytopathogens and as nanofertilizers. In this way, it is essential to investigate the possible impacts of these new nanomaterials on plants. In this study, the effects of soil contamination with biogenic silver (AgNPs) and iron (FeNPs) with known antifungal potential were investigated on morphological, physiological and biochemical parameters of soybean seedlings. RESULTS: The exposure of plants/seedlings to AgNPs induced the reduction of root dry weight followed by oxidative stress in this organ, however, adaptive responses such as a decrease in stomatal conductance without impacts on photosynthesis and an increase in intrinsic water use efficiency were also observed. The seedlings exposed to FeNPs had shown an increase in the levels of oxygen peroxide in the leaves not accompanied by lipid peroxidation, and an increase in the expression of POD2 and POD7 genes, indicating a defense mechanism by root lignification. CONCLUSION: Our results demonstrated that different metal biogenic nanoparticles cause different effects on soybean seedlings and these findings highlight the importance of investigating possible phytotoxic effects of these nanomaterials for the control of phytopathogens or as nanofertilizers.

Pro-inflammatory effects of silver nanoparticles in the intestine.

Nanotechnology is a promising technology of the twenty-first century, being a rapidly evolving field of research and industrial innovation widely applied in our everyday life. Silver nanoparticles (AgNP) are considered the most commercialized nanosystems worldwide, being applied in diverse sectors, from medicine to the food industry. Considering their unique physical, chemical and biological properties, AgNP have gained access into our daily life, with an exponential use in food industry, leading to an increased inevitable human oral exposure. With the growing use of AgNP, several concerns have been raised, in recent years, about their potential hazards to human health, more precisely their pro-inflammatory effects within the gastrointestinal system. Therefore a review of the literature has been undertaken to understand the pro-inflammatory potential of AgNP, after human oral exposure, in the intestine. Despite the paucity of information reported in the literature about this issue, existing studies indicate that AgNP exert a pro-inflammatory action, through generation of oxidative stress, accompanied by mitochondrial dysfunction, interference with transcription factors and production of cytokines. However, further studies are needed to elucidate the mechanistic pathways and molecular targets involved in the intestinal pro-inflammatory effects of AgNP.

Case study: risk associated to wearing silver or graphene nanoparticle-coated facemasks for protection against COVID-19.

The world is living a pandemic situation derived from the worldwide spreading of SARS-CoV-2 virus causing COVID-19. Facemasks have proven to be one of the most effective prophylactic measures to avoid the infection that has made that wearing of facemasks has become mandatory in most of the developed countries. Silver and graphene nanoparticles have proven to have antimicrobial properties and are used as coating of these facemasks to increase the effectivity of the textile fibres. In the case of silver nanoparticles, we have estimated that in a real scenario the systemic (internal) exposure derived from wearing these silver nanoparticle facemasks would be between 7.0 × 10-5 and 2.8 × 10-4 mg/kg bw/day. In addition, we estimated conservative systemic no effect levels between 0.075 and 0.01 mg/kg bw/day. Therefore, we estimate that the chronic exposure to silver nanoparticles derived form facemasks wearing is safe. In the case of graphene, we detected important gaps in the database, especially regarding toxicokinetics, which prevents the derivation of a systemic no effect level. Nevertheless, the qualitative approach suggests that the risk of dermal repeated exposure to graphene is very low, or even negligible. We estimated that for both nanomaterials, the risk of skin sensitisation and genotoxicity is also negligible.

Silver nanoparticles induce oxidative stress, apoptosis and impaired steroidogenesis in ovarian granulosa cells of cattle.

There have been increased effects of silver nanoparticle (Ag-NPs) on livestock during the past decade, but data related to adverse effects of Ag-NPs on reproductive tissues are limited. In the present study, the possible cytotoxic effects of Ag-NPs on oxidant/antioxidant balance, apoptosis and steroid hormone production in ovarian granulosa cells of cattle were studied.Cultured granulosa cells were treated with 10 nm Ag-NPs at various concentrations (1-100 µg/ml) for 24 h, and cell toxicity, oxidant/antioxidant markers, reactive oxygen species (ROS) production, abundances of apoptotic/antiapoptotic and steroidogenesis related mRNA transcripts were determined. The amount of DNA fragmentation was also determined using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Results indicated treatment of granulosa cells with Ag-NPs induced an increase of reactive oxygen species production concomitant with increased malondialdehyde concentrations and decreased antioxidant enzyme activities. There was a maximal percentage of TUNEL+ cells (46.6%) after treatment with 50 and 100 µg/ml of Ag-NPs. The Ag-NPs could induce apoptosis in granulosa cells as indicated by the increase in caspase-3 activity, and larger abundance of BCL2 associated X (BAX) and lesser abundance of B-cell lymphoma 2 (BCL2) mRNA transcripts. The abundance of steroidogenic enzyme mRNA transcripts decreased concomitant with suppression of steroid hormone synthesis from Ag-NP-treated cells. Findings indicate silver nanoparticles (SNP) induce apoptosis and oxidative stress and change the pattern of steroid hormone synthesis in granulosa cells of cattle. The results indicate Ag-NPs may inhibit the function and viability of ovarian cells.

The effectiveness of antibacterial therapeutic clothing based on silver or chitosan as compared with non-antibacterial therapeutic clothing in patients with moderate to severe atopic dermatitis (ABC trial): study protocol for a pragmatic randomized controlled trial.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects 10 to 20% of children and between 2 and 15% of the adults in Western Europe. Since 2000, therapeutic clothing or functional textiles based on silver or chitosan as antibacterial agents were introduced for AD. These agents aim to reduce skin colonization with Staphylococcus (S.) aureus. Increased colonization with S. aureus is correlated with increased AD severity. The antimicrobial effects of silver and chitosan have been demonstrated before. At this point, there is insufficient evidence for the effectiveness of antibacterial therapeutic clothing in patients with AD. METHODS: This is a pragmatic randomized controlled double-blind multi-center trial comparing the effectiveness of antibacterial therapeutic clothing based on silver or chitosan as compared with non-antibacterial therapeutic clothing in patients with moderate to severe AD. A total of 165 participants, aged 0 to 80, diagnosed with moderate to severe AD are included. The study is performed in the Erasmus MC University Medical Center, University Medical Center Groningen, University Medical Center Utrecht, Amsterdam University Medical Centers, and St. Antonius Hospital Nieuwegein. Patients will be randomized 1:1:1 into one of the three intervention groups: group A will receive therapeutic clothing without antimicrobial agents, group B will receive microbial growth reducing therapeutic clothing based on chitosan, and group C will receive antimicrobial clothing based on silver. All therapeutic clothing is to be worn at night during the 12-month intervention period. Usual care is continued. The primary objective is to assess the effectiveness of antibacterial clothing (silver and chitosan group) as compared to non-antibacterial clothing assessed with the Eczema Area and Severity Index at 12 months compared to baseline. Secondary outcomes include between-group differences in physician- and patient-reported outcome measures, topical therapy use, S. aureus skin colonization, and safety. Data will be collected at baseline and after 1 month, 3 months, 6 months, and 12 months. A cost-effectiveness analysis will be performed. DISCUSSION: This trial will provide data on the effectiveness, cost-effectiveness, and safety of antibacterial therapeutic clothing for patients with AD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04297215. Registered on 5 March 2020.

Potential therapeutic effects of avenanthramide-C against lung toxicity caused by silver nanoparticles injection in rats.

Most clinical investigations about the impact of nanoparticles on cells and tissues show that nanoparticles may enter the human body by means of respiratory tracts. Humans, animals, plants and environments are continually presented to a wide scope of business items containing silver nanoparticles (Ag NPs) in their piece. Ag NPs, utilized in various consumer products as room showers, surface cleaners, wound dressings, food storage containers and many textiles. The current examination planned to explore the defensive role of Avenanthramide-C (Avns) contrary to the lung toxicity initiated by Ag NPs injection in rats. 40 male Wistar rats were separated into 4 groups (Gp1, control; Gp2, Avns; Gp3, Ag NPs; Gp4, Ag NPs+Avns). Current results revealed that; Ag NPs induced a significant depletion in RBCs count, hemoglobin, platelets counts and a significant increase in total WBCs, lung injury, cyclooxygenase-2 (COX2) and TNFα expressions as compared to control. Treatments of Ag NPs with Avenanthramide-C extract (Ag NPs+Avns) improved the lung structure and blood complete pictures as compared to Ag NPs group.

Role of bacterial motility in differential resistance mechanisms of silver nanoparticles and silver ions.

Unlike conventional antimicrobials, the study of bacterial resistance to silver nanoparticles (AgNPs) remains in its infancy and the mechanism(s) through which it evolves are limited and inconclusive. The central question remains whether bacterial resistance is driven by the AgNPs, released Ag(I) ions or a combination of these and other factors. Here, we show a specific resistance in an Escherichia coli K-12 MG1655 strain to subinhibitory concentrations of AgNPs, and not Ag(I) ions, as indicated by a statistically significant greater-than-twofold increase in the minimum inhibitory concentration occurring after eight repeated passages that was maintained after the AgNPs were removed and reintroduced. Whole-population genome sequencing identified a cusS mutation associated with the heritable resistance that possibly increased silver ion efflux. Finally, we rule out the effect of particle aggregation on resistance and suggest that the mechanism of resistance may be enhanced or mediated by flagellum-based motility.

Exposure Media and Nanoparticle Size Influence on the Fate, Bioaccumulation, and Toxicity of Silver Nanoparticles to Higher Plant Salvinia minima.

Silver nanoparticles (AgNPs) are favoured antibacterial agents in nano-enabled products and can be released into water resources where they potentially elicit adverse effects. Herein, interactions of 10 and 40 nm AgNPs (10-AgNPs and 40-AgNPs) with aquatic higher plant Salvinia minima at 600 µg/L in moderately hard water (MHW), MHW of raised calcium (Ca2+), and MHW containing natural organic matter (NOM) were examined. The exposure media variants altered the AgNPs' surface properties, causing size-dependent agglomeration. The bio-accessibility in the ascending order was: NOM < MHW < Ca2+, was higher in plants exposed to 10-AgNPs, and across all exposures, accumulation was higher in roots compared to fronds. The AgNPs reduced plant growth and the production of chlorophyll pigments a and b; the toxic effects were influenced by exposure media chemistry, and the smaller 10-AgNPs were commonly the most toxic relative to 40-AgNPs. The toxicity pattern was linked to the averagely higher dissolution of 10-AgNPs compared to the larger counterparts. The scanning electron microscopy and X-ray fluorescence analytical techniques were found limited in examining the interaction of the plants with AgNPs at the low exposure concentration used in this study, thus challenging their applicability considering the even lower predicted environmental concentrations AgNPs.

Developmental exposure to silver nanoparticles leads to long term gut dysbiosis and neurobehavioral alterations.

Due to their antimicrobial properties, silver nanoparticles (AgNPs) are used in a wide range of consumer products that includes topical wound dressings, coatings for biomedical devices, and food-packaging to extend the shelf-life. Despite their beneficial antimicrobial effects, developmental exposure to such AgNPs may lead to gut dysbiosis and long-term health consequences in exposed offspring. AgNPs can cross the placenta and blood-brain-barrier to translocate in the brain of offspring. The underlying hypothesis tested in the current study was that developmental exposure of male and female mice to AgNPs disrupts the microbiome-gut-brain axis. To examine for such effects, C57BL6 female mice were exposed orally to AgNPs at a dose of 3 mg/kg BW or vehicle control 2 weeks prior to breeding and throughout gestation. Male and female offspring were tested in various mazes that measure different behavioral domains, and the gut microbial profiles were surveyed from 30 through 120 days of age. Our study results suggest that developmental exposure results in increased likelihood of engaging in repetitive behaviors and reductions in resident microglial cells. Echo-MRI results indicate increased body fat in offspring exposed to AgNPs exhibit. Coprobacillus spp., Mucispirillum spp., and Bifidobacterium spp. were reduced, while Prevotella spp., Bacillus spp., Planococcaceae, Staphylococcus spp., Enterococcus spp., and Ruminococcus spp. were increased in those developmentally exposed to NPs. These bacterial changes were linked to behavioral and metabolic alterations. In conclusion, developmental exposure of AgNPs results in long term gut dysbiosis, body fat increase and neurobehavioral alterations in offspring.

Nanoparticles in the Food Industry and Their Impact on Human Gut Microbiome and Diseases.

The use of inorganic nanoparticles (NPs) has expanded into various industries including food manufacturing, agriculture, cosmetics, and construction. This has allowed NPs access to the human gastrointestinal tract, yet little is known about how they may impact human health. As the gut microbiome continues to be increasingly implicated in various diseases of unknown etiology, researchers have begun studying the potentially toxic effects of these NPs on the gut microbiome. Unfortunately, conflicting results have limited researcher's ability to evaluate the true impact of NPs on the gut microbiome in relation to health. This review focuses on the impact of five inorganic NPs (silver, iron oxide, zinc oxide, titanium dioxide, and silicon dioxide) on the gut microbiome and gastrointestinal tract with consideration for various methodological differences within the literature. This is important as NP-induced changes to the gut could lead to various gut-related diseases. These include irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), celiac disease, and colorectal cancer. Research in this area is necessary as the use of NPs in various industries continues to grow along with the number of people suffering from chronic gastrointestinal diseases.

Silver nanoparticles: Correlating particle size and ionic Ag release with cytotoxicity, genotoxicity, and inflammatory responses in human cell lines.

The widespread use of silver nanoparticles (AgNPs), their many sources for human exposure, and the ability of AgNPs to enter organisms and induce general toxicological responses have raised concerns regarding their public health and environmental safety. To elucidate the differential toxic effects of polyvinylpyrrolidone-capped AgNPs with different primary particle sizes (i.e. 5, 50, and 75 nm), we performed a battery of cytotoxicity and genotoxicity assays and examined the inflammatory responses in two human cell lines (i.e. HepG2 and A549). Concentration-dependent decreases in cell proliferation and mitochondrial membrane potential and increases in cytokine (i.e. interleukin-6 and interleukin-8) excretion indicated disruption of mitochondrial function and inflammation as the main mediating factors of AgNPs-induced cytotoxicity. An incremental increase in genotoxicity with decreasing AgNPs diameter was noted in HepG2 cells, which was associated with S and G2/M accumulation and transcriptional activation of the GADD45α promoter as reflected by luciferase activity. Dose-related genetic damage, as indicated by Olive tail moment and micronucleus formation, was also observed in A549 cells, but these effects as well as the AgNPs-induced cytotoxicity were more associated with ionic Ag release from nanoparticles (NPs). In summary, the present study addressed different toxicity mechanisms of AgNPs, depending on the cell model, toxicological endpoint, particle size, and degree of Ag+ release from NPs. The results suggest that the GADD45α promoter-driven luciferase reporter cell system provided a rapid screening tool for the identification of genotoxic properties of NPs across a range of different sizes and concentrations.

Silver in biology and medicine: opportunities for metallomics researchers.

The antibacterial properties of silver have been known for centuries and the threat of antibiotic-resistant bacteria has led to renewed focus on the noble metal. Silver is now commonly included in a range of household and medical items to imbue them with bactericidal properties. Despite this, the chemical fate of the metal in biological systems is poorly understood. Silver(I) is a soft metal with high affinity for soft donor atoms and displays much similarity to the chemistry of Cu(I). In bacteria, interaction of silver with the cell wall/membrane, DNA, and proteins and enzymes can lead to cell death. Additionally, the intracellular generation of reactive oxygen species by silver is posited to be a significant antimicrobial action. While the antibacterial action of silver is well known, bacteria found in silver mines display resistance against it through use of a protein ensemble thought to have been specifically developed for the metal, highlighting the need for judicious use. In mammals, ∼10-20% of ingested silver is retained by the body and thought to predominantly localize in the liver or kidneys. Chronic exposure can result in argyria, a condition characterized by blue staining of the skin, resulting from subdermal deposition of silver [as Ag(0)/sulfides], but more insidious side effects, such as inclusions in the brain, seizures, liver/kidney damage, and immunosuppression, have also been reported. Here, we hope to highlight the current understanding of the biological chemistry of silver and the necessity for continued study of these systems to fill existing gaps in knowledge.

A preliminary clinical trial comparing wet silver dressings versus wet-to-dry povidone-iodine dressings for wound healing in pemphigus vulgaris patients.

There is insufficient evidence concerning the efficacy of wet silver-containing dressings for wound healing in pemphigus vulgaris (PV). In this randomized, controlled clinical trial, 58 patients with PV skin erosions (10%-70% body surface area) were assigned to receive either wet silver-containing dressings (n = 28) or wet to dry povidone-iodine dressings as a control (n = 30). The patients in the treatment group demonstrated a significant improvement in the number of dressing changes, wound healing time, and duration of hospital stay compared with the control group. Patients treated with wet silver dressings had significantly lower NRS pain scores and reported better subjective satisfaction compared with the control group. The only adverse reactions were an occasional abnormal discharge or infection, but there was no difference between the two groups. In our study the wet silver-containing dressings were safe and effective for the treatment of wound healing in PV patients.

Radiation Dose Reduction for Computed Tomography Localizer Radiography Using an Ag Additional Filter.

OBJECTIVE: This study aimed to assess the potential of an Ag additional filter attached to the bow tie filter of a computed tomography (CT) scanner to reduce the radiation dose in CT localizer radiography. METHODS: Radiation doses in CT localizer radiography with Cu and Ag additional filters were evaluated based on dose measurements and Monte Carlo simulations. Image quality evaluations of an adult torso phantom were performed, and the automatic exposure control performance was evaluated in terms of the water-equivalent thickness estimated from CT localizer radiographs. RESULTS: With the Ag additional filter, effective doses were approximately 72% to 75% lower than those with the Cu additional filter. The image quality and water-equivalent thickness with the Ag additional filter were similar to those with the Cu additional filter. CONCLUSIONS: The Ag additional filter helped significantly reduce radiation doses in CT localizer radiography while maintaining image quality and performance.