Monocyte NLRP3 inflammasome and interleukin-1ß activation modulated by alpha-1 antitrypsin therapy in deficient individuals.

INTRODUCTION: Altered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this study was to investigate whether C3d, a cleavage-product of C3, triggers interleukin (IL)-1ß secretion via activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The objective was to explore the effect of AAT augmentation therapy in patients with AATD on the C3d/complement receptor 3 (CR3) signalling axis of monocytes and on circulating pro-inflammatory markers. METHODS: Inflammatory mediators were detected in blood from patients with AATD (n=28) and patients with AATD receiving augmentation therapy (n=19). Inflammasome activation and IL-1ß secretion were measured in monocytes of patients with AATD, and following C3d stimulation in the presence or absence of CR3 or NLRP3 inhibitors. RESULTS: C3d acting via CR3 induces NLRP3 and pro-IL-1ß production, and through induction of endoplasmic reticulum (ER) stress and calcium flux, triggers caspase-1 activation and IL-1ß secretion. Treatment of individuals with AATD with AAT therapy results in decreased plasma levels of C3d (3.0±1.2 µg/mL vs 1.3±0.5 µg/mL respectively, p<0.0001) and IL-1ß (115.4±30 pg/mL vs 73.3±20 pg/mL, respectively, p<0.0001), with a 2.0-fold decrease in monocyte NLRP3 protein expression (p=0.0303), despite continued ER stress activation. DISCUSSION: These results provide strong insight into the mechanism of complement-driven inflammation associated with AATD. Although the described variance in C3d and NLRP3 activation decreased post AAT augmentation therapy, results demonstrate persistent C3d and monocyte ER stress, with implications for new therapeutics and clinical practice.

Exposure to Cadmium Telluride Quantum Dots and Gene Expression Profile of Huh-7 Hepatocellular Carcinoma Cell Line.

Nanoparticles have shown promising potential for efficient drug delivery, circumventing biological interferences like immunological and renal clearance and mechanical and enzymatic destruction. However, a handful of research papers have questioned the biomedical use of metal-based nanoparticles like cadmium telluride quantum dots (CdTe-QDs) for their cytotoxic, genotoxic, and carcinogenic potential. Herein, we examined the effects of CdTe-QD NPs on gene expression profile of hepatocellular carcinoma (Huh-7) cell line. Huh-7 cells were treated with CdTe-QD NPs (10 µg/ml for 6, 12, and 24 hours, and 25 µg/ml for 6 and 12 hours), and transcriptomic analysis was performed using microarray to evaluate the global gene expression profile. Differential expressed genes (DEGs) were observed for both the doses (10 and 25 µg/ml) of CdTe-QD NPs at different time points. Gene ontology (GO) analysis revealed that genes involved in molecular function of cell cycle, organizational injury and abnormalities, cell death and survival, gene expression, cancer, organismal survival, and cellular development were differentially expressed. Overall, we have demonstrated differential expression of several genes, involved in maintaining cell survival, metabolism, and genome integrity. These findings were confirmed by RT-qPCR study for some canonical pathway genes signifying possible implication in NP toxicity-mediated cell survival and inhibition of cell death.

Nanoparticles as Drug Delivery Systems: A Review of the Implication of Nanoparticles' Physicochemical Properties on Responses in Biological Systems.

In the last four decades, nanotechnology has gained momentum with no sign of slowing down. The application of inventions or products from nanotechnology has revolutionised all aspects of everyday life ranging from medical applications to its impact on the food industry. Nanoparticles have made it possible to significantly extend the shelf lives of food product, improve intracellular delivery of hydrophobic drugs and improve the efficacy of specific therapeutics such as anticancer agents. As a consequence, nanotechnology has not only impacted the global standard of living but has also impacted the global economy. In this review, the characteristics of nanoparticles that confers them with suitable and potentially toxic biological effects, as well as their applications in different biological fields and nanoparticle-based drugs and delivery systems in biomedicine including nano-based drugs currently approved by the U.S. Food and Drug Administration (FDA) are discussed. The possible consequence of continuous exposure to nanoparticles due to the increased use of nanotechnology and possible solution is also highlighted.

Targeting of Glycosaminoglycans in Genetic and Inflammatory Airway Disease.

In the lung, glycosaminoglycans (GAGs) are dispersed in the extracellular matrix (ECM) occupying the interstitial space between the capillary endothelium and the alveolar epithelium, in the sub-epithelial tissue and in airway secretions. In addition to playing key structural roles, GAGs contribute to a number of physiologic processes ranging from cell differentiation, cell adhesion and wound healing. Cytokine and chemokine-GAG interactions are also involved in presentation of inflammatory molecules to respective receptors leading to immune cell migration and airway infiltration. More recently, pathophysiological roles of GAGs have been described. This review aims to discuss the biological roles and molecular interactions of GAGs, and their impact in the pathology of chronic airway diseases, such as cystic fibrosis and chronic obstructive pulmonary disease. Moreover, the role of GAGs in respiratory disease has been heightened by the current COVID-19 pandemic. This review underlines the essential need for continued research aimed at exploring the contribution of GAGs in the development of inflammation, to provide a better understanding of their biological impact, as well as leads in the development of new therapeutic agents.

Sociodemographic predictors of confirmed COVID-19 mortality and hospitalization among patients in Saudi Arabia: Analyzing a national COVID-19 database.

BACKGROUND: Even with the widespread availability of vaccines for the COVID-19 disease, there is no sign of decline in the rate of spread of the disease. Based on findings of different studies across the globe, the disease is characterized by poor outcomes in specific sociodemographic categories such as age, gender and presence of symptoms. METHODS: In this study, we carried out a multivariable logistic regression analysis on a national database (HESN+) of confirmed COVID-19 cases in Saudi Arabia to determine predictors of hospitalization and mortality for these patients. RESULTS: Data was extracted for 328,301 confirmed COVID- 19 patients (mean age (SD) = 37.79 (1.68)) with 34.92% females and 65.08% males. Of these, 59.87% were Saudi Arabian citizens and 40.13% were non-Saudi. 68.91% of cases were discovered in Riyadh (n = 67,384), Makkah (n = 72,590) and the Eastern Province (n = 79,666). 72.2% of all cases were diagnosed and treated by the Ministry of Health (MOH). Of all confirmed cases, 95.28% showed one or more symptoms associated with COVID-19. 5.48% of these were hospitalized and 1.11% died. Predictors of mortality and hospitalization, respectively, included age (OR; 1.088 and 1.03), being male (OR; 1.443 and 1.138), nationality (OR; 2.11 and 1.993), presence of symptoms (OR; 1.816 and 4.386), and the health care sector in which patients received treatment (MOH OR; 1.352 and 4.731). CONCLUSION: We found that COVID-19-related hospitalization or mortality was higher among males, older adults, and patients showing one or more symptoms, and mortality likelihood was more than fourfold for patients treated by the MOH. Immigrants were also more likely to be hospitalized or die from COVID-19 infection compared to Saudi nationals.

A Review of Alpha-1 Antitrypsin Binding Partners for Immune Regulation and Potential Therapeutic Application.

Alpha-1 antitrypsin (AAT) is the canonical serine protease inhibitor of neutrophil-derived proteases and can modulate innate immune mechanisms through its anti-inflammatory activities mediated by a broad spectrum of protein, cytokine, and cell surface interactions. AAT contains a reactive methionine residue that is critical for its protease-specific binding capacity, whereby AAT entraps the protease on cleavage of its reactive centre loop, neutralises its activity by key changes in its tertiary structure, and permits removal of the AAT-protease complex from the circulation. Recently, however, the immunomodulatory role of AAT has come increasingly to the fore with several prominent studies focused on lipid or protein-protein interactions that are predominantly mediated through electrostatic, glycan, or hydrophobic potential binding sites. The aim of this review was to investigate the spectrum of AAT molecular interactions, with newer studies supporting a potential therapeutic paradigm for AAT augmentation therapy in disorders in which a chronic immune response is strongly linked.

Physiological Response, Haematology and Stress Condition of Scavenging Chickens in Cement Production Areas.

This study investigated the physiological and stress indices of scavenging chickens in LAFARGE and Dangote cement factories located at Ewekoro and Ibese, respectively and respective adjourning communities of Ogun State, Nigeria. One hundred adult scavenging chickens comprising of 25 from each location were used. The birds were caught at night on their perch and kept in furnished cages till the next morning. Data were collected on their rectal temperature, pulse rate, and respiratory rate . Also 5 mL blood was collected through the wing vein of each chicken. Highest (p < 0.05) pulse rate (215.64 beat/minute) and respiratory rate (19.90 breath/minute) were recorded among the chickens at LAFARGE area. Highest (p < 0.05) packed cell volume (28.06%), hemoglobin (4.01 g/dL), monocyte (4.28%) and glucose (256.53 g/dL) were recorded among ones at Ibese (Dangote). White blood cell (6488.89 × 103µL) was highest (p < 0.05) in chickens at Ewekoro (LAFARGE). The study concluded that cement factories infringe on health status of scavenging chickens in the domains. Effective environmental mitigation programme should be put in place for enhanced welfare of the birds.

Growth, physiological performance, and pork quality of weaner large white piglets to different inclusion levels of nano zinc oxide.

Thirty intensively reared piglets averaged 7.6 ± 0.32 kg were used for the experiment. The piglets were randomly allotted to 5 different treatments: 200 mg/kg, 400 mg/kg, 600 mg/kg nano zinc oxide (nZnO; 50 nm), positive control (tylosin 10%), and the negative control (no additive) in a completely randomized design. Data were collected for weight changes, blood parameters, and carcass and meat quality characteristics. Piglets supplemented with 200 mg/kg had elevated (P < 0.05) weight gain, while those supplemented with 400 and 600 mg/kg nZnO had higher comparable weight gains, while the control groups had the least comparable weight gain values. Pigs fed 600 mg/kg of nano zinc had the highest albumin concentrations with the least values observed in 200 and 400 mg/kg groups. Pigs offered tylosin 10% and 600 mg/kg had higher comparable total protein, while those fed control diet had the lowest total protein concentration. Pigs supplemented with nZnO had highest comparable values for slaughter weights. The supplementation of 600 mg/kg had elevated values of villi height, while the groups supplemented with 200 and 400 mg/kg had a similar trend, and the control had the least comparable values of villi height. It could be concluded that the supplementation of nZnO at a dietary dose of 600 mg/kg gave the best performance in terms of intestinal morphology (villus height), growth performance, meat quality, and immune response.

Monitoring of emerging contaminants of concern in the aquatic environment: a review of studies showing the application of effect-based measures.

Water scarcity is increasingly a global cause of concern mainly due to widespread changes in climate conditions and increased consumptive water use driven by the exponential increase in population growth. In addition, increased pollution of fresh water sources due to rising production and consumption of pharmaceuticals and organic chemicals will further exacerbate this concern. Although surface water contamination by individual chemicals is often at very low concentration, pharmaceuticals for instance are designed to be efficacious at low concentrations, creating genuine concern for their presence in freshwater sources. Furthermore, the additive impact of multiple compounds may result in toxic or other biological effects that otherwise will not be induced by individual chemicals. Globally, different legislative frameworks have led to pre-emptive efforts which aim to ensure good water ecological status. Reports detailing the use and types of effect-based measures covering specific bioassay batteries that can identify specific mode of actions of chemical pollutants in the aquatic ecosystem to evaluate the real threat of pollutants to aquatic lives and ultimately human lives have recently emerged from monitoring networks such as the NORMAN network. In this review, we critically evaluate some studies within the last decade that have implemented effect-based monitoring of pharmaceuticals and organic chemicals in aquatic fauna, evaluating the occurrence of different chemical pollutants and the impact of these pollutants on aquatic fauna with special focus on pollutants that are contaminants of emerging concern (CEC) in urban wastewater. A critical discussion on studies that have used effect-based measures to assess biological impact of pharmaceutical/organic compound in the aquatic ecosystem and the endpoints measurements employed is presented. The application of effect-based monitoring of chemicals other than assessment of water quality status is also discussed.

A comprehensive study of the basic formulation of supersaturated self-nanoemulsifying drug delivery systems (SNEDDS) of albendazolum.

Albendazolum (ABZ) is a BCS class II drug. It has challenging biopharmaceutical properties, which include poor solubility and dissolution rate. These properties have laid the ground for developing a supersaturated self-nanoemulsifying drug delivery system (S-SNEDDS) to form oil-in-water nanoemulsion in situ to improve the oral bioavailability of ABZ. Based on the ABZ solubility, emulsifying ability, and stability after dispersion in an aqueous phase, an optimal self-nanoemulsifying drug delivery system (SNEDDS) consisting of oleic acid, Tween® 20, and PEG 600 (X:Y:Z, w/w) was identified, having 10% (w/w) hydroxypropyl methylcellulose (HPMC) E15 lv as its precipitation inhibitor. The optimized system possessed a small mean globule size value (89.2 nm), good dispersion properties (polydispersity index (PDI): 0.278), and preserved the supersaturated state of ABZ. S-SNEDDS was transformed into solid supersaturated self-nanoemulsifying drug delivery systems (SS-SNEDDS) using microcrystalline cellulose as a solid material. The developed S-SNEDDS were characterized for globule size, pH, turbidity, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and flow properties. The data obtained from the results suggest that this S-SNEDDS formulation can enhance the solubility and oral bioavailability of ABZ for appropriate clinical application.

A review of pharmaceutical occurrence and pathways in the aquatic environment in the context of a changing climate and the COVID-19 pandemic.

Active pharmaceutical ingredients (APIs) are increasingly being identified as contaminants of emerging concern (CECs). They have potentially detrimental ecological and human health impacts but most are not currently subject to environmental regulation. Addressing the life cycle of these pharmaceuticals plays a significant role in identifying the potential sources and understanding the environmental impact that pharmaceuticals may have in surface waters. The stability and biological activity of these "micro-pollutants" can lead to a pseudo persistence, with ensuing unknown chronic behavioural and health-related effects. Research that investigates pharmaceuticals predominantly focuses on their occurrence and effect within surface water environments. However, this review will help to collate this information with factors that affect their environmental concentration. This review focuses on six pharmaceuticals (clarithromycin, ciprofloxacin, sulfamethoxazole, venlafaxine, gemfibrozil and diclofenac), chosen because they are heavily consumed globally, have poor removal rates in conventional activated sludge wastewater treatment plants (CAS WWTPs), and are persistent in the aquatic environment. Furthermore, these pharmaceuticals are included in numerous published prioritisation studies and/or are on the Water Framework Directive (WFD) "Watch List" or are candidates for the updated Watch List (WL). This review investigates the concentrations seen in European Union (EU) surface waters and examines factors that influence final concentrations prior to release, thus giving a holistic overview on the source of pharmaceutical surface water pollution. A period of 10 years is covered by this review, which includes research from 2009-2020 examining over 100 published studies, and highlighting that pharmaceuticals can pose a severe risk to surface water environments, with each stage of the lifecycle of the pharmaceutical determining its concentration. This review additionally highlights the necessity to improve education surrounding appropriate use, disposal and waste management of pharmaceuticals, while implementing a source directed and end of pipe approach to reduce pharmaceutical occurrence in surface waters.

Liposomal encapsulation of silver nanoparticles (AgNP) improved nanoparticle uptake and induced redox imbalance to activate caspase-dependent apoptosis.

Macrophages play a crucial role in several diseases' development and progression, such as in cancer and arthritis through ROS generation and inflammation. This makes macrophages a therapeutic target in these diseases. While silver nanoparticles (AgNP) have been widely used as an antibacterial and investigated as anticancer, its potential against macrophages may be limited due to its inherent oxidative mechanism. Here we encapsulated AgNP in a dipalmitoyl-phosphatidyl choline (DPPC) liposome (forming Lipo-AgNP) to suppress AgNP-induced ROS and enhance its cytotoxicity against THP1-differentiated macrophages (TDM). Our findings showed that while Lipo-AgNP had significantly more of a cytotoxic effect on TDMs (p < 0.01), it also significantly suppressed AgNP induced ROS generation and unexpectedly suppressed reduced glutathione (GSH) levels (p < 0.05) resulting in a redox imbalance in comparison to the unexposed control TDMs. Lipo-AgNP was also found to cause an increase DNA damage through H2AX histone phosphorylation and inhibition of Bcl-2 protein expression. This increased the Bax/Bcl2 ratio causing possible release of cytochrome C and subsequent caspase 3/7-dependent apoptosis. It was found that the difference between the mechanism of AgNP and Lipo-AgNP cytotoxicity may have been through the significantly increased Lipo-AgNP uptake by the TDMs as early as 30 min post-exposure (p < 0.05), changing the nanoparticle pharmacokinetic. In conclusion, the improved uptake of AgNP within the liposome caused ROS-independent caspase activation induced by Lipo-AgNP and this was facilitated by increased DNA damage, the induced redox imbalance and an increased Bax/Bcl-2 ratio.

Surface modification of silver nanoparticle (AgNP) by liposomal encapsulation mitigates AgNP-induced inflammation.

Silver nanoparticles (AgNP) are widely used in a variety of consumable products as antibacterial to prevent or treat infection. Unfortunately, evidence exits that AgNP induces inflammation which can worsen with repeated human exposure. However, there is little or no research on how to mitigate these adverse effects due to AgNP induced-toxicity. Here, we investigated if surface modification of AgNP by liposomal encapsulation suppresses AgNP-mediated inflammatory responses in THP1 monocytes and THP1 differentiated macrophages (TDM). AgNP was encapsulated in a dipalmitoyl phosphatidyl choline- (DPPC)/cholesterol-based liposome by extrusion through a 100-nm polycarbonate membrane to form Lipo-AgNP. It was found as expected that AgNP induced significant release of IL-1ß, IL-6, IL-8 and TNF-α in THP1 monocytes more than the basal level. Interestingly, release of these cytokines was suppressed by Lipo-AgNP. In TDMs, AgNP and Lipo-AgNP induced IL-8 release (p < .0001), but Lipo-AgNP maintained IL-8 release at levels significantly lower than that of AgNP (p < .01). However, both AgNP and Lipo-AgNP suppressed IL-1ß and TNF-α release in LPS-stimulated THP1 monocytes and LPS-stimulated or unstimulated TDM respectively. We finally showed that Lipo-AgNP inhibits STAT-3 and this may be responsible for regulating the uncontrolled inflammation induced by AgNP likely mediated STAT-3 protein expression in LPS stimulated THP1 monocytes and TDMs, both LPS-stimulated and unstimulated. This data showed that Lipo-AgNP suppressed AgNP induced inflammation, making Lipo-AgNP particularly useful in treatment of bacteria induced inflammatory diseases and inflammatory cancers.