Evaluation of Immune Response against Leishmaniasis in BALB/c Mice Immunized with Cationic DOTAP/DOPE/CHOL Liposomes Containing Soluble Leishmania major Antigens

Background: Whole killed Leishmania vaccine reached phase III clinical trials but failed to display significant efficacy in human mainly due to limited Th1 inducer adjuvant. Liposomes consisting of 1, 2-dioleoyl-3trimethylammonium-propane (DOTAP) bearing an inherent adjuvanticity and 1, 2-dioleoyl-L-α-glycero-3-phosphatidylethanolamine (DOPE) is well known to intensify the efficacy of positively charged liposomes. Methods: Soluble Leishmania major antigens (SLA) encapsulated in cationic liposomes using lipid film method in 2016). BALB/c mice were immunized subcutaneously (SC), three times in a 2-wk interval, with Lip (DOTAP)-SLA+, Lip (DOTAP/DOPE)-SLA+, Lip (DOTAP/DOPE/CHO)-SLA+, Lip (DOTAP/DOPE/CHO), Lip (DOPE/CHO), SLA or HEPES buffer. At week 2 after the last booster injection, immunized mice have challenged SC in the footpad with L. major parasites. To investigate the rate of protection and the type of immune response generated in mice, lesions development was assessed, IL-4 and IFN-γ levels with the ratio of IgG2a/IgG1 isotype were studied to describe the type of generated immune response. Results: Mice immunized with all liposomal form of SLA showed smaller footpad swelling and lower parasite burden in the spleen and footpad compared to the group of mice received buffer. However, these formulations did not show protection against leishmaniosis because of a generated mixed Th1/Th2 response in mice characterized by high production of IFN-γ and IL4 and a high titer of IgG1 and IgG2a antibody. Conclusion: Immunization with Lip (DOTAP/DOPE/CHO)-SLA+ was not an appropriate strategy to protect mice against leishmaniosis

Nanolipoparticles-mediated MDR1 siRNA delivery reduces doxorubicin resistance in breast cancer cells and silences MDR1 expression in xenograft model of human breast cancer

Objective(s): P-glycoprotein (P-gp) is an efflux protein, the overexpression of which has been associated with multidrug resistance in various cancers. Although siRNA delivery to reverse P-gp expression may be promising for sensitizing of tumor cells to cytotoxic drugs, the therapeutic use of siRNA requires effective carriers that can deliver siRNA intracellularly with minimal toxicity on target cells. We investigated a special class of PEGylated lipid-based nanoparticles (NP), named nanolipoparticles (NLPs), for siRNA- mediated P-gp downregulation. Materials and Methods: NLPs were prepared based on low detergent dialysis method. After characterization, we evaluated the effect of NLPs on siRNA delivery, and P-gp downregulation compared to oligofectamineTM (OFA) in vitro and in vivo. Results: Our results showed a significant decrease in P-gp expression and subsequent enhancement of chemosensitivity to doxorubicin in vitro. Although the effectiveness of NLPs for in vitro siRNA delivery compared to OFA was limited, the results of in vivo studies showed noticeable effectiveness of NLPs for systemic siRNA delivery. siRNA delivery using NLPs could downregulate MDR1 in tumor cells more than 80%, while OFA had a reverse effect on MDR1 expression in vivo. Conclusion: The results indicated that the prepared NLPs could be suitable siRNA delivery systems for tumor therapy

Antifungal effect of sesame medicinal herb on Candida Species: original study and mini-review

The aim of this study was to evaluate the antifungal susceptibility patterns of three antifungals, methanolic extracts and N-hexane oil of sesame seeds on C. albicans and C. glabrata, isolated from oral cavity of liver transplant recipients. The results were compared with other reports to develop a mini review as well. Candida species were isolated from liver transplant recipients. To evaluate the antifungal activity of sesame seed oil and methanolic extract, fluconazole, caspofungin and nystatin, the corresponding minimum inhibitory concentrations were determined by CLSI M27-A3 standard method. Minimum fungicidal concentration was also evaluated. The most prevalent species was C. albicans, followed by C. glabrata. Findings indicated sensitivity to antifungal agents and resistance to methanolic extract and N-hexane oil for all C. albicans and C. glabrata isolates. The rate of Candida colonization in the oral cavity of liver transplant recipients was high. Our results revealed that the methanolic and N-hexan extracts of sesame seeds are not effective on C. albicans and C. glabrata species, isolated from the patients. The sesame seed oil pulling and mouthwash cannot effectively cleanse and remove the Candida species in the mouth. Investigation of other medicinal plants or other parts of sesame like leaves and roots are suggested

A Novel Model for the Analysis of Interactions Between Governments and Agricultures in a Study of Social Beneficial Externalities Based on the Stackelberg Game: A Case Study on Cotton Production

Production is a key economic activity with potential long-term social benefits that can be thoroughly realised only if governments comply with their duties towards domestic production. Governments are responsible for the production of sustainable agricultural products via appropriate allocation of subsidies and regulation of price policies that would help take advantage of the potentials underlying agricultural production. In this paper, a model is developed to investigate the interaction between two decision makers in the stackelberg game, government as leader and agriculture as follower, with the ultimate aim of providing benefits to all sectors in the society in the sustainable agriculture paradigm. The proposed model is validated and its efficiency demonstrated via a case study of cotton production as a strategic agricultural production. The model is first solved using a combination of fuzzy mathematical and grey quadratic programming methods to account for the inherent uncertainty in a number of problem parameters. The model is then analyzed against various government-producer interaction scenarios and finally, the analysis results are compared

The COVID-19 pandemic and healthcare utilization in Iran: evidence from an interrupted time series analysis

Objectives This study aimed to examine the effect of the coronavirus disease 2019 (COVID-19) outbreak on the hospitalization rate, emergency department (ED) visits, and outpatient clinic visits in western Iran. Methods We collected data on the monthly hospitalization rate, rate of patients referred to the ED, and rate of patients referred to outpatient clinics for a period of 40 months (23 months before and 17 months after the COVID-19 outbreak in Iran) from all 7 public hospitals in the city of Kermanshah. An interrupted time series analysis was conducted to examine the impact of COVID-19 on the outcome variables in this study. Results A statistically significant decrease of 38.11 hospitalizations per 10,000 population (95% confidence interval [CI], 24.93–51.29) was observed in the first month of the COVID-19 outbreak. The corresponding reductions in ED visits and outpatient visits per 10,000 population were 191.65 (95% CI, 166.63–216.66) and 168.57 (95% CI, 126.41–210.73), respectively. After the initial reduction, significant monthly increases in the hospitalization rate (an increase of 1.81 per 10,000 population), ED visits (an increase of 2.16 per 10,000 population), and outpatient clinic visits (an increase of 5.77 per 10,000 population) were observed during the COVID-19 pandemic. Conclusion Our study showed that the utilization of outpatient and inpatient services in hospitals and clinics significantly declined after the COVID-19 outbreak, and use of these services did not return to pre-outbreak levels as of June 2021

The role of nanoliposome bilayer composition containing soluble leishmania antigen on maturation and activation of dendritic cells

Objective(s): Dendritic cells (DCs) play a critical role in activation of T cell responses. Induction of type1 T helper (Th1) immune response is essential to generate protective immunity against cutaneous leishmaniasis. The intrinsic tendency of liposomes to have interaction with antigen-presenting cells is the main rationale to utilize liposomes as antigen carriers. In the present study, the effect of lipid phase transition temperature on DCs maturation and liposome uptake by murine bone marrow derived dendritic cells and human monocyte derived dendritic cells was investigated.Materials and Methods: Two cationic liposomal formulations consisting of DOTAP and DSPC/DOTAP were prepared and contained soluble leishmania antigen. Liposomes were incubated with immature or mature DCs derived from bone marrow (BMDCs) of C57BL/6 (which are resistant to cutaneous leishmaniasis), BALB/c mice (susceptible to cutaneous leishmaniasis) or DCs derived from human monocytes (MoDCs). The expression of DCs co-stimulatory markers and liposomal uptake were evaluated by flow cytometry method. Results: DCs which were encountered to liposomes consisting of DSPC showed significantly more expression of co-stimulatory molecules in cells from both human and C57BL/6 mice but not in cells from BALB/c mice. Conclusion: It is concluded that cationic liposomes consisting of DSPC are an effective adjuvant for antigen delivery in case of MoDCs and BMDCs from C57BL/6 mice. Moreover, DCs from different origins act differently in uptake of liposomes

Nanocarriers call the last shot in the treatment of brain cancers

Our brain is protected by physio-biological barriers. The blood–brain barrier (BBB) main mechanism of protection relates to the abundance of tight junctions (TJs) and efflux pumps. Although BBB is crucial for healthy brain protection against toxins, it also leads to failure in a devastating disease like brain cancer. Recently, nanocarriers have been shown to pass through the BBB and improve patients’ survival rates, thus becoming promising treatment strategies. Among nanocarriers, inorganic nanocarriers, solid lipid nanoparticles, liposomes, polymers, micelles, and dendrimers have reached clinical trials after delivering promising results in preclinical investigations. The size of these nanocarriers is between 10 and 1000 nm and is modified by surface attachment of proteins, peptides, antibodies, or surfactants. Multiple research groups have reported transcellular entrance as the main mechanism allowing for these nanocarriers to cross BBB. Transport proteins and transcellular lipophilic pathways exist in BBB for small and lipophilic molecules. Nanocarriers cannot enter via the paracellular route, which is limited to water-soluble agents due to the TJs and their small pore size. There are currently several nanocarriers in clinical trials for the treatment of brain cancer. This article reviews challenges as well as fitting attributes of nanocarriers for brain tumor treatment in preclinical and clinical studies

Immunogenicity and antitumor activity of the superlytic λF7 phage nanoparticles displaying a HER2/neu-derived peptide AE37 in a tumor model of BALB/c mice

The final publication is available at Elsevier via http://dx.doi.org/10.1016/j.canlet.2018.03.030 © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/Phage display technique has been increasingly researched for vaccine design and delivery strategies in recent years. In this study, the AE37 (Ii-Key/HER-2/neu 776–790) peptide derived from HER2 (human epidermal growth factor receptor protein) was used as a fused peptide to the lambda phage (λF7) coat protein gpD, and the phage nanoparticles were used to induce antitumor immunogenicity in a TUBO model of breast cancer in mice. Mice were immunized with the AE37 peptide displaying phage, λF7 (gpD::AE37) every 2-week intervals over 6-weeks, then the generated immune responses were evaluated. An induction of CTL immune response by the λF7 (gpD::AE37) construct compared to the control λF7 and buffer groups was observed in vitro. Moreover, in the in vivo studies, the vaccine candidate showed promising prophylactic and therapeutic effects against the HER2 overexpressing cancer in BALB/c mice.Mashhad University of Medical Sciences, Mashhad, Iran bach (MUMS GN: 922610)NSERC, Canada (NSERC GN: 214684

Preparation, characterization, and biodistribution of glutathione PEGylated nanoliposomal doxorubicin for brain drug delivery with a post-insertion approach

Objective(s): Brain cancer treatments have mainly failed due to their inability to cross the blood-brain barrier. Several studies have confirmed the presence of glutathione (GSH) receptors on BBB’s surface, as a result, products like 2B3-101, which contain over 5% pre-inserted GSH PEGylated liposomal Doxorubicin, are being tested in clinical trials. Here we conducted the PEGylated nanoliposomal Doxorubicin particles that are covalently attached to the glutathione using the post-insertion technique. Compared with the pre-insertion approach, the post-insertion method is notably simpler, faster, and more cost-effective, making it ideal for large-scale pharmaceutical manufacturing. Materials and Methods: The ligands of the DSPE PEG(2000) Maleimide-GSH were introduced in the amounts of 25, 50, 100, 200, and 400 on the available Caelyx. Following physicochemical evaluations, animal experiments such as biodistribution, fluorescence microscopy, and pharmacokinetics were done. Results: In comparison with Caelyx, the 200L and 400L treatment arms were the most promising formulations. We showed that nanocarriers containing 40 times fewer GSH micelles than 2B3-101 significantly increased blood-brain barrier penetrance. Due to the expressed GSH receptors on tissues as an endogenous antioxidant, Doxorubicin will likely concentrate in the liver, spleen, heart, and lung in comparison with Caelyx, according to other tissue analyses. Conclusion: The post-insertion technique was found a successful approach with more pharmaceutical aspects for large-scale production. Moreover, further investigations are highly recommended to determine the efficacy of 5% post-inserted GSH targeted nanoliposomes versus 2B3-101 as a similar formulation with a different preparation method

Compilation of the neonatal palliative care clinical guideline in neonatal intensive care unit

Background: Clinical guidelines are important instruments for increasing the quality of clinical practice in the treatment team. Compilation of clinical guidelines is important due to special condition of the neonates and the nurses facing critical conditions in the neonatal intensive care unit (NICU). With 98% of neonatal deaths occurring in NICUs in the hospitals, it is important to pay attention to this issue. This study aimed at compilation of the neonatal palliative care clinical guidelines in NICU. Materials and Methods: This study was conducted with multistage comparative strategies with localization in Isfahan in 2013. In the first step, the components of the neonatal palliative care clinical guidelines were determined by searching in different databases. In the second stage, the level of expert group′s consensus with each component of neonatal palliative care in the nominal group and focus group was investigated, and the clinical guideline was written based on that. In the third stage, the quality and applicability were determined with the positive viewpoints of medical experts, nurses, and members of the science board of five cities in Iran. Data were analyzed by descriptive statistics through SPSS. Results: In the first stage, the draft of neonatal palliative care was designed based on neonates′, their parents′, and the related staff′s requirements. In the second stage, its rank and applicability were determined and after analyzing the responses, with agreement of the focus group, the clinical guideline was written. In the third stage, the means of indication scores obtained were 75%, 69%, 72%, 72%, and 68% by Appraisal of Guidelines for Research and Evaluation (AGREE) instrument. Conclusions: The compilation of the guideline can play an effective role in provision of neonatal care in nursing