Advances and limitations of drug delivery systems formulated as eye drops.

Topical instillation of eye drops remains the most common and easiest route of ocular drug administration, representing the treatment of choice for many ocular diseases. Nevertheless, low ocular bioavailability of topically applied drug molecules can considerably limit their efficacy. Over the last several decades, numerous drug delivery systems (DDS) have been developed in order to improve drug bioavailability on the ocular surfaces. This review systematically covers the most recent advances of DDS applicable by topical instillation, that have shown better performance in in vivo models compared to standard eye drop formulations. These delivery systems are based on in situ forming gels, nanoparticles and combinations of both. Most of the DDS have been developed using natural or synthetic polymers. Polymers offer many advantageous properties for designing advanced DDS including biocompatibility, gelation properties and/or mucoadhesiveness. However, despite the high number of studies published over the last decade, there are several limitations for clinical translation of DDS. This review article focuses on the recent advances for the development of ocular drug delivery systems. In addtion, the potential challenges for commercialization of new DDS are presented

Crosstalk between Peroxisome Proliferator-Activated Receptors andToll-Like Receptors: A Systematic Review

As one of the four major families of pattern recognition receptors (PRRs), toll like receptors (TLRs)are crucial and important components of the innate immune system. Peroxisome proliferatoractivatedreceptors (PPARs) with three isoforms are transcription factors classified as a subfamilyof nuclear receptor proteins, and are of significant regulatory activity in cellular differentiation,development, metabolism, and tumorigenesis. It is well established that PPARs agonists displayanti-inflammatory effects through inhibition of the nuclear factor-kappa B (NF-κB) pathway, akey regulator of immune and inflammatory responses, in a sense that TLRs signaling pathwaysare mainly toward activation of NF-κB. Through a systematic review of previous studies, weaimed to address and clarify the reciprocal interaction between TLRs and PPARs in hope to findalternative therapeutic approaches for inflammatory diseases. Among the available scientificdatabase, 31 articles were selected for this review. A comprehensive review of this databaseconfirms the presence of a cross-talk between PPARs and TLRs, indicating that not onlyPPARs stimulation may affect the expression level of TLRs via several mechanisms leading tomodulating TLRs activities, but also TLRs have the potential to moderate the expression of PPARs.We, therefore, conclude that, as a key regulator of the innate immune system, the interactionbetween PPARs and TLRs is a potential therapeutic target in disease treatment

A comprehensive review on novel targeted therapy methods and nanotechnology-based gene delivery systems in melanoma.

Melanoma, a malignant form of skin cancer, has been swiftly increasing in recent years. Although there have been significant advancements in clinical treatment underlying a well-understanding of melanoma-susceptible genes and the molecular basis of melanoma pathogenesis, the permanency of response to therapy is frequently constrained by the emergence of acquired resistance and systemic toxicity. Conventional therapies, including surgical resection, chemotherapy, radiotherapy, and immunotherapy, have already been used to treat melanoma and are dependent on the cancer stage. Nevertheless, ineffective side effects and the heterogeneity of tumors pose major obstacles to the therapeutic treatment of malignant melanoma through such strategies. In light of this, advanced therapies including nucleic acid therapies (ncRNA, aptamers), suicide gene therapies, and gene therapy using tumor suppressor genes, have lately gained immense attention in the field of cancer treatment. Furthermore, nanomedicine and targeted therapy based on gene editing tools have been applied to the treatment of melanoma as potential cancer treatment approaches nowadays. Indeed, nanovectors enable delivery of the therapeutic agents into the tumor sites by passive or active targeting, improving therapeutic efficiency and minimizing adverse effects. Accordingly, in this review, we summarized the recent findings related to novel targeted therapy methods as well as nanotechnology-based gene systems in melanoma. We also discussed current issues along with potential directions for future research, paving the way for the next-generation of melanoma treatments.Sección Deptal. de Bioquímica y Biología Molecular (Biológicas)Fac. de Ciencias BiológicasTRUEEuropean UnionNextGeneration (EU/PRTR)Ministerio de Ciencia e Innovación (MICINN)/Agencia Estatal de Investigación (AEI)Ministerio de UniversidadesUniversidad Complutense de Madrid (UCM)pu

Prognostic Factors in Metformin Intoxication; A Case Control Study

Background: Metformin is one of the most orally used antidiabetic agents. Intentional and unintentional overdose of metformin can be associated with life threatening condition. In this study we evaluate prognostic factors for metformin intoxication. Methods: This case-control study was performed on patients referred to Loghman Hakim toxicology emergency department due to metformin intoxication. The patient’s information and lab data were subsequently extracted from their medical file and data processing and analysis performed. Results: There was a significant difference between two groups in multiple items, patients in died group had higher age, blood sugar, BUN, Cr, PT, INR, WBC, on the other hand this group had lower blood pressure, O2 saturation, pH, HCO3 and PTT. Receiver operating characteristic curve showed that five items including: Bp, O2sat, pH, HCO3 and Cr had ability to predict the risk of mortality in patients with metformin poisoning. Univariate as well as multivariate analysis showed, factors including: BP<95 (P=0.0184), O2sat<93 (P=0.0094), pH<6.94 (P0.0032), HCO3<17.25 (P=0.0302), and Cr>1.15 (P=0.0216) were related to patient’s mortality. Discussion and conclusion: Our study showed that mentioned clinical and laboratory findings may have an important role in determining the prognosis of patients with metformin poisoning. Extracorporeal treatments may be considered sooner in those who have poorer prognostic factors since admission

Higher Disease and Pain Severity and Fatigue and Lower Balance Skills Are Associated with Higher Prevalence of Falling among Individuals with the Inflammatory Disease of Neuromyelitis Optica Spectrum Disorder (NMOSD)

Neuromyelitis optica spectrum disorder (NMOSD) is a chronic inflammatory and autoimmune disorder that is associated with impaired vision, sensory loss, pain, fatigue, and spasms in the upper and lower limbs. Typically, persons with this disorder are also at higher risks of falls. Given this, the aims of the study were to compare the prevalence rates of falling for NMOSD cases and healthy controls (HCs), and to predict falling in the former group based on sociodemographic, psychological, and illness-related factors.; A total of 95 adults with NMOSD (Mean age = 34.89 years; 70.5% females) and 100 matched HCs took part in the study. All participants completed a series of questionnaires covering sociodemographic information and falling rates. The NMOSD individuals also reported on disease duration, pain, fatigue, and fear of falling, while their balance performance was objectively assessed.; Compared to healthy controls, the NMOSD cases had a 2.5-fold higher risk of falling. In this latter group, higher scores for pain, fatigue, fear of falling, and higher EDSS scores were distinguished between fallers and non-fallers, and objective balance skills had no predictive value.; Compared to healthy controls, NMOSD sufferers had a 2.5-fold higher risk of experiencing falls. In this group, disease impairments (EDSS, fatigue, pain) predicted falling. Specific interventions such as regular resistance training might reduce the risk of falling

The effect of interferon γ on endothelial cell nitric oxide production and apoptosis

Background: Nitric oxide (NO) is an important molecule in maintaining endothelial survival and normal function. It is a unique mediator, which may promote or suppress both inflammation and apoptosis. Endothelial cell (EC) injury, dysfunction, and death in response to cytokines, especially interferon gamma (IFN-γ), represent the critical event for the initiation of several inflammatory diseases. Objective(s): EC injury or death result in endothelial dysfunction that precedes the development of atherosclerosis and its subsequent vascular events. We examine the effect of different concentrations of IFN-γ on human umbilical vein ECs (HUVECs) NO production and apoptosis. Materials and Methods: HUVECs were cultured at 37°C for 24 h in the absence (control) or presence of 10, 100, and 1000 μg IFN-γ, respectively. The apoptotic cells were determined as annexin V-positive propidium iodide (PI)-negative cells by flow cytometry. Total nitrite concentration was measured in cell cultures supernatant by Griess method. Results: A comparison of the effect of IFN-γ on EC NO production with untreated cells showed that pretreatment of HUVEC with IFN-γ failed to have a significant effect on NO production by these cells at 10 and 100 U/mL, whereas it led to a significant decreased NO production at 1000 U/mL ( P < 0.05). The cells stimulated with IFN-γ showed significantly higher apoptotic cells (PI negative and annexin V-positive cells) after 24 h, compared with cells with no stimulations ( P < 0.05). Conclusion: IFN-γ has detrimental effects on ECs in high doses. This might be due to inducible NO synthase activation

Role of peroxisome proliferator-activated receptor alpha and gamma in antiangiogenic effect of pomegranate peel extract

Objective(s): Herbal medicines are promising cancer preventive candidates. It has been shown that Punica granatum L. could inhibit angiogenesis and tumor invasion. In this study, we investigated whether the anti-angiogenic effect of pomegranate peel extract (PPE) is partly attributable to Peroxisome proliferator-activated receptors (PPARs) activation in the Human Umbilical Vein Endothelial Cells (HUVECs). Materials and Methods: Ethanol extract from PPE was prepared. HUVECs were treated in four groups (with PPE (10 μg/ml) alone, PPE with or without PPARγ (T0070907) and α (GW6471) antagonists, and control group). The possible effect of PPARs on angiogenic regulation was checked by Matrigel assay. The mRNA expression levels of vascular endothelial growth factor (VEGF) was detected by Quantitative reverse transcription-polymerase chain reaction (QRT-PCR).  Results: PPE significantly inhibited both tube formation (size, length, and junction of tubes) and VEGF mRNA expression (

Advances and limitations of drug delivery systems formulated as eye drops.

Topical instillation of eye drops remains the most common and easiest route of ocular drug administration, representing the treatment of choice for many ocular diseases. Nevertheless, low ocular bioavailability of topically applied drug molecules can considerably limit their efficacy. Over the last several decades, numerous drug delivery systems (DDS) have been developed in order to improve drug bioavailability on the ocular surfaces. This review systematically covers the most recent advances of DDS applicable by topical instillation, that have shown better performance in in vivo models compared to standard eye drop formulations. These delivery systems are based on in situ forming gels, nanoparticles and combinations of both. Most of the DDS have been developed using natural or synthetic polymers. Polymers offer many advantageous properties for designing advanced DDS including biocompatibility, gelation properties and/or mucoadhesiveness. However, despite the high number of studies published over the last decade, there are several limitations for clinical translation of DDS. This review article focuses on the recent advances for the development of ocular drug delivery systems. In addtion, the potential challenges for commercialization of new DDS are presented

Hyperinsulinemia may have a protective role in the early stages of atherosclerosis in rabbit model of hypercholesterolemia

BACKGROUND: Hypercholesterolemia causes inflammation and insulin resistance in the vasculature. Previous data suggest that vascular endothelium is a physiological target of insulin. Dyslipidemia and atherosclerosis are disorders with endothelial dysfunction that are associated with an increased production of superoxide anion, and early deficit of nitric oxide (NO) production. We examined alteration of plasma levels of insulin, C-reactive protein (CRP) and total NO metabolites (NOx), as well as fatty streak formation in the rabbit model of hypercholesterolemia. METHODS: White male rabbits were fed either a high-cholesterol diet (HC; 1% cholesterol, n = 6) or control diet (c, n = 6) for one month. The serum levels of Cholesterol, LDL, HDL, NOx, insulin and CRP were measured before and after study. By the end of study, rabbits' aorta was explored for fatty streak formation. RESULTS: The cholesterol-rich diet induced a significant increase in total cholesterol, LDL, and HDL as well as fatty streak lesions in HC group while there were no significant changes of these parameters in control group (p <0.05). There was significant difference in plasma levels of CRP, insulin and total NO metabolite between two groups of experiment. Negative significant correlation of CRP and insulin also was observed in HC rabbits (r = −0.99, p <0.05). CONCLUSION: Parallel NOx and insulin increment and negative correlation of CRP and insulin in HC rabbits may be suggestive a protective role of hyperinsulinemia in early atherosclerosis

Evaluation of the Anti-tuberculosis and Cytotoxic Potential of the Seaweed Padina australis: Antituberculosis and cytotoxic potential of the seaweed Padina australis

Marine seaweeds synthesize different types of compounds with various biological activities, including antituberculosis and anticancer effects. The aim of this study was to evaluate anti tuberculosis of Padina australis and cytotoxicity of different fractions of this seaweed. Padinaaustralis was collected from Persian Gulf, identified and extracted by maceration with methanol-ethyl acetate. The extract was evaporated and partitioned by Kupchan method to yield Hexane, dichloromethane, Butanol and water partitions. The anti-tuberculosis activity of the crude extract and cytotoxicity of fractions were investigated using GFPMA and MTT methods. The cell survivals of HeLa cell were decreased by increasing the concentration of extracts. The IC50 value of hexane, dichloromethane, butanol and water partitions were 2.0, 20, 19.7, and 182.7μg/ml, respectively. The crude extract was not active against tuberculosis. This study reveals that different partitions of Padina australis have cytotoxic activity against cancer cell lines