An Innovative Formulation Based on Nanostructured Lipid Carriers for Imatinib Delivery: Pre-Formulation, Cellular Uptake and Cytotoxicity Studies

Imatinib (IMT) is a tyrosine kinase enzyme inhibitor and extensively used for the treatment of gastrointestinal stromal tumors (GISTs). A nanostructured lipid carrier system (NLCS) containing IMT was developed by using emulsification–sonication methods. The characterization of the developed formulation was performed in terms of its particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, loading capacity, sterility, syringeability, stability, in vitro release kinetics with mathematical models, cellular uptake studies with flow cytometry, fluorescence microscopy and cytotoxicity for CRL-1739 cells. The particle size, PDI, loading capacity and zeta potential of selected NLCS (F16-IMT) were found to be 96.63 ± 1.87 nm, 0.27 ± 0.15, 96.49 ± 1.46% and −32.7 ± 2.48 mV, respectively. F16-IMT was found to be stable, thermodynamic, sterile and syringeable through an 18 gauze needle. The formulation revealed a Korsmeyer–Peppas drug release model of 53% at 8 h, above 90% of cell viability, 23.61 µM of IC50 and induction of apoptosis in CRL-1739 cell lines. In the future, F16-IMT can be employed to treat GISTs. A small amount of IMT loaded into the NLCSs will be better than IMT alone for therapy for GISTs. Consequently, F16-IMT could prove to be useful for effective GIST treatment.

Antimicrobial Usage and Resistance in Makkah Region Hospitals: A Regional Point Prevalence Survey of Public Hospitals

(1) Background: Inappropriate use of antimicrobials and subsequently rise of antimicrobial resistance (AMR) remains a major public health priority. Over-prescribing of broad-spectrum antibiotics is one of the main contributing factors for the emergence of AMR. We sought to describe antimicrobial prescribing trends among patients in public hospitals in Makkah hospitals. (2) Method: We undertook a point prevalence survey (PPS) in six hospitals in Makkah, Saudi Arabia, from January 2019 to July 2019. The survey included all the inpatients receiving antimicrobials on the day of PPS. Data was collected using the Global point prevalence survey (PPS) tool developed by the University of Antwerp, Belgium. (3) Results: Of 710 hospitalized patients, 447 patients (61.9%) were treated with one or more antimicrobials during the study period. The average bed occupancy among six hospitals was 74.4%. The majority of patients received antimicrobials parenterally (90.3%). Of the total prescribed antimicrobials, 415 (53.7%) antimicrobials were used in medical departments, 183 (23.7%) in surgical departments, and 175 (22.6%) in ICUs. Pneumonia (17.3%), skin and soft tissue infections (10.9%), and sepsis (6.6.%) were three common clinical indications. Ceftriaxones were the most commonly used antibiotics that were prescribed in 116 (15%) of patients, followed by piperacillin, with an enzyme inhibitor in 84 (10.9%). (4) Conclusion: There was a high prevalence of antibiotic use in the hospitals of Makkah, which could be a potential risk factor for the incidence of resistant strains, particularly MRSA infection. Public health decision-makers should take these findings into consideration to update national policies for antibiotic use in order to reduce the risks of further increases of AMR.

Dynamical Aspects of Corona Virus Infection

In this paper, we consider five mathematical models of corona virus infection. The first model is a mathematical model of corona virus entry. The second model is a mathematical model for interactions of virus N-protein and viral RNA. Here, we prove that phosphorylated N protein increases the affinity of viral RNA. The third model is a mathematical model of virion assembly. It is a six-dimensional model. But there is an invariant three-dimensional submodel, which we can prove has a positive stable equilibrium. The fourth model is a model of an enzyme inhibitor that blocks viral replication. The fifth model is a model of a virus and a vaccine.

The Mevalonate Pathway Is Important for Growth, Spore Production, and the Virulence of Phytophthora sojae

The mevalonate (MVA) pathway in eukaryotic organisms produces isoprenoids, sterols, ubiquinone, and dolichols. These molecules are vital for diverse cellular functions, ranging from signaling to membrane integrity, and from post-translational modification to energy homeostasis. However, information on the MVA pathway in Phytophthora species is limited. In this study, we identified the MVA pathway genes and reconstructed the complete pathway in Phytophthora sojae in silico. We characterized the function of the MVA pathway of P. sojae by treatment with enzyme inhibitor lovastatin, deletion of the geranylgeranyl diphosphate synthase gene (PsBTS1), and transcriptome profiling analysis. The MVA pathway is ubiquitously conserved in Phytophthora species. Under lovastatin treatment, mycelial growth, spore production, and virulence of P. sojae were inhibited but the zoospore encystment rate increased. Heterozygous mutants of PsBTS1 showed slow growth, abnormal colony characteristics, and mycelial morphology. Mutants showed decreased numbers of sporangia and oospores as well as reduced virulence. RNA sequencing analysis identified the essential genes in sporangia formation were influenced by the enzyme inhibitor lovastatin. Our findings elucidate the role of the MVA pathway in P. sojae and provide new insights into the molecular mechanisms underlying the development, reproduction, and virulence of P. sojae and possibly other oomycetes. Our results also provide potential chemical targets for management of plant Phytophthora diseases.

Inhibition of Brain GTP Cyclohydrolase I Attenuates 3-Nitropropionic Acid-Induced Striatal Toxicity: Involvement of Mas Receptor/PI3k/Akt/CREB/ BDNF Axis

GTP cyclohydrolase I (GTPCH I) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis; the latter is an essential factor for iNOS activation that contributes neuronal loss in Huntington’s disease (HD). The aim of the study was to investigate the neuroprotective effect of 2,4-diamino-6-hydroxypyrimidine (DAHP), GTPCH I enzyme inhibitor, against neuronal loss in 3-nitropropinic acid (3-NP)-induced HD in rats and to reveal the possible involved mechanisms mediated through PI3K/Akt axis and its correlation to Mas receptor (MasR). Rats received 3-NP (10 mg/kg/day; i.p.) with or without administration of DAHP (0.5 g/kg/day; i.p.) or wortmannin (WM), a PI3K inhibitor, (15 μg/kg/day; i.v.) for 14 days. DAHP improved cognitive, memory, and motor abnormalities induced by 3-NP, as confirmed by striatal histopathological specimens and immunohistochemical examination of GFAP. Moreover, DAHP treatment inhibited GTPCH I activity, resulting in decreased BH4 levels and iNOS activation. Also, DAHP upregulated the protein expression of survival protein; p85/p55 (pY458/199)-PI3K and pS473-Akt that, in turn, boosted the activation of striatal neurotrophic factors and receptor, pS133-CREB, BDNF and pY515-TrKB, which positively affect MasR protein expression and improve mitochondrial dysfunction, as indicated by enhancing both SDH and PGC-1α levels. Indeed, DAHP attenuates oxidative stress by increasing SOD activity and Nrf2 expression in addition to reducing neuro-inflammatory status by inhibiting NF-κB p65 and TNF-α expression. Interestingly, all the previous effects were blocked by co-administration of WM with DAHP. In conclusion, DAHP exerts neuroprotective effect against neuronal loss induced by 3-NP administration via inhibition of GTPCH I and iNOS activity and activation of MasR/PI3K/Akt/CREB/BDNF/TrKB axis besides its antioxidant and anti-inflammatory effect.

Determining Risk Factors for Triple Whammy Acute Kidney Injury

Concurrent use of a diuretic, a renin-angiotensin system (RAS) inhibitor, and a non-steroidal anti-inflammatory drug (NSAID) significantly increases the risk of acute kidney injury (AKI). This phenomenon is known as "triple whammy". Diuretics and RAS inhibitors, such as an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, are often prescribed in tandem for the treatment of hypertension, whereas some NSAIDs, such as ibuprofen, are available over the counter. As such, concurrent treatment with all three drugs is common. The goals of this study are to better understand the mechanisms underlying the development of triple whammy AKI and to identify physiological factors that may increase an individual's susceptibility. To accomplish these goals, we utilize computational models of long-term blood pressure regulation. These models include variables describing the heart and circulation, kidney function, sodium and water reabsorption in the nephron and the RAS and are parameterized separately for men and women. Hypertension is modeled as overactive renal sympathetic nervous activity. Model simulations suggest that individual variations in water intake, the myogenic response, and drug sensitivity may predispose patients with hypertension to develop triple whammy-induced AKI.