Current Pharmaceutical Design - Volume 25, Issue 10, 2019

The blood-brain barrier (BBB) is a barrier of the central nervous system (CNS), which can restrict the free exchange of substances, such as toxins and drugs, between cerebral interstitial fluid and blood, keeping the relative physiological stabilization. The brain capillary endothelial cells, one of the structures of the BBB, have a variety of ATP-binding cassette transporters (ABC transporters), among which the most widely investigated is Pglycoprotein (P-gp) that can efflux numerous substances out of the brain. The expression and activity of P-gp are regulated by various signal pathways, including tumor necrosis factor-α (TNF-α)/protein kinase C-β (PKC- β)/sphingosine-1-phosphate receptor 1 (S1P), vascular endothelial growth factor (VEGF)/Src kinase, etc. However, it remains unclear how hypoxic signaling pathways regulate the expression and activity of P-gp in brain microvascular endothelial cells. According to previous research, hypoxia affects the expression and activity of the transporter. If the transporter is up-regulated, some drugs enter the brain's endothelial cells and are pumped back into the blood by transporters such as P-gp before they enter the brain tissue, consequently influencing the drug delivery in CNS; if the transporter is down-regulated, the centrally toxic drug would enter the brain tissue and cause serious adverse reactions. Therefore, studying the mechanism of hypoxia-regulating P-gp can provide an important reference for the treatment of CNS diseases with a hypoxia/reoxygenation (H/R) component. This article summarized the mechanism of regulation of P-gp in BBB in normoxia and explored that of hypoxia.

Background: The purpose of this study was to evaluate the effect of types of surfactants and cosurfactants on physicochemical properties and permeability of sumatriptan-loaded microemulsions through rat skin. Methods: Different types of surfactants and cosurfactants were used to prepare drug-loaded microemulsions. The physicochemical characters and permeability parameters of these formulations were measured. Results: The experimental microemulsions with varying components had small droplet size ranging from 24.6 nm to 2568.8 nm, low viscosity ranging from 7.49 to 43.34 cps and significant permeation enhancement ratio ranging from 23.0 to 98.6 when compared to the control group. Conclusion: The composition and proportion of surfactants and cosurfactants were key factors for the physiochemical properties of drug-loaded microemulsions. The cumulative transdermal amount of the microemulsion containing mixture surfactant of Laureth-3/Laureth-23 was higher than that of the microemulsion with a mixture of Tween 80/Span 20. In the selected cosurfactant, diethylene glycol monoethyl ether (DEGMEE) showed highest permeation enhancement. Thermodynamic stability tests revealed that the experimental microemulsion was a stable enough formulation to be considered as a suitable carrier for sumatriptan.

Background: Although protein kinase D1 (PKD1) has been proved to be an efficient target for anticancer drug development, lack of structural details and substrate binding mechanisms are the main obstacles for the development of selective inhibitors with therapeutic benefits. Objective: The present study described the in silico dynamics behaviors of PKD1 in binding with selective and non-selective inhibitors and revealed the critical binding site residues for the selective kinase inhibition. Methods: Here, the three dimensional model of PKD1 was initially constructed by homology modeling along with binding site characterization to explore the non-conserved residues. Subsequently, two known inhibitors were docked to the catalytic site and the detailed ligand binding mechanisms and post binding dyanmics were investigated by molecular dynamics simulation and binding free energy calculations. Results: According to the binding site analysis, PKD1 serves several non-conserved residues in the G-loop, hinge and catalytic subunits. Among them, the residues including Leu662, His663, and Asp665 from hinge region made polar interactions with selective PKD1 inhibitor in docking simulation, which were further validated by the molecular dynamics simulation. Both inhibitors strongly influenced the structural dynamics of PKD1 and their computed binding free energies were in accordance with experimental bioactivity data. Conclusion: The identified non-conserved residues likely to play critical role on molecular reorganization and inhibitor selectivity. Taken together, this study explained the molecular basis of PKD1 specific inhibition, which may help to design new selective inhibitors for better therapies to overcome cancer and PKD1 dysregulated disorders.

Throughout the evolutionary time, all organisms and species on Earth evolved with an adaptation to consistent oscillations of sunlight and darkness, now recognized as ‘circadian rhythm.’ Single-cellular to multisystem organisms use circadian biology to synchronize to the external environment and provide predictive adaptation to changes in cellular homeostasis. Dysregulation of circadian biology has been implicated in numerous prevalent human diseases, and subsequently targeting the circadian machinery may provide innovative preventative or treatment strategies. Discovery of ‘peripheral circadian clocks’ unleashed widespread investigations into the potential roles of clock biology in cellular, tissue, and organ function in healthy and diseased states. Particularly, oxygen-sensing pathways (e.g. hypoxia inducible factor, HIF1), are critical for adaptation to changes in oxygen availability in diseases such as myocardial ischemia. Recent investigations have identified a connection between the circadian rhythm protein Period 2 (PER2) and HIF1A that may elucidate an evolutionarily conserved cellular network that can be targeted to manipulate metabolic function in stressed conditions like hypoxia or ischemia. Understanding the link between circadian and hypoxia pathways may provide insights and subsequent innovative therapeutic strategies for patients with myocardial ischemia. This review addresses our current understanding of the connection between light-sensing pathways (PER2), and oxygen-sensing pathways (HIF1A), in the context of myocardial ischemia and lays the groundwork for future studies to take advantage of these two evolutionarily conserved pathways in the treatment of myocardial ischemia.

Background and Objectives: Insulin-like growth factor-1 (IGF-1) levels have been investigated in rheumatoid arthritis (RA), however, produced inconsistent results. The purpose of this meta-analysis was to derive a more precise conclusion about serum/plasma IGF-1 levels in RA patients. Methods: PubMed, Embase and the Cochrane Library databases were searched up to December 2018 in English, and the studies comparing serum/plasma IGF-1 levels between RA group and healthy control group were what we are interested in. The Newcastle-Ottawa Scale (NOS) was used to assess the methodological quality of the included studies. The heterogeneity test was performed by the Cochrane Q statistic and I2 –statistic. The publication bias was evaluated by the funnel plot and Egger’s test. The standard mean difference (SMD) with 95% confidence interval (CI) was calculated by the fixed-effects or random-effects model. Results: A total of eleven articles with 334 cases and 261 controls were finally included. Compared with the healthy group, the RA group had lower circulating IGF-1 levels (pooled SMD= -0.936, 95% CI= -1.382 to -0.489, p<0.001). The subgroup analysis showed that RA patients from Asia (SMD= -0.645, 95% CI= -1.063 to -0.228, p= 0.002) and Europe (SMD= -1.131, 95% CI= -1.767 to -0.495, p<0.001) had lower circulating IGF-1 levels, no significant difference in plasma/serum IGF-1 levels was observed in RA patients from America. Sensitivity analysis indicated the stability and credibility of the overall effect sizes. Conclusion: Patients with RA have lower circulating IGF-1 level than healthy controls, particularly for patients from Asia and Europe. Further studies are necessary to elucidate the role of IGF-1 in the pathological process of RA.

Osteonecrosis of the femoral head (ONFH) is a common disease that occurs frequently. Due to various etiologies, the blood supply directed to the femoral head is interrupted in patients with ONFH. This disease can result in degeneration and necrosis of the subchondral bone of the femoral head, which ultimately cause a collapse of the femoral head. Of note, ONFH can extremely affect the quality of living of patients with a high disability rate. Also, this disease often includes middle-aged and younger people. However, effective treatments of ONFH are still challenging in clinics. In recent years, stem cells have been profoundly studied and a relevant new technology has been developed rapidly and applied for regenerative medicine. A number of reports have demonstrated successful results of the treatment of ONFH by using stem cell transplantation. By the combination of minimally invasive hip decompression and injection of mesenchymal stem cells into the necrotic lesion, the retrospective analysis of patients treated revealed that significant pain relief was observed in 86% patients and they had no major complications after treatment. Thus, stem cell transplantation is anticipated to be applied as an innovative approach in the treatment of ONFH. This review will summarize results obtained from recent human and animal studies, which include the pathophysiological process of ONFH, current techniques and effects of using stem cells on the treatment of ONFH together with pharmacological aspects. Overall, the current evidence reveals the treatment of ONFH using stem cell technology as promising. Nonetheless, additional in-depth studies are necessary to better explore the application of this technology and seek more ideal approaches to minimize difficulties related to stem cells.

RAS (H-ras, K-ras, and N-ras), as the second largest mutated gene driver in various human cancers, has long been a vital research target for cancer. Its function is to transform the extracellular environment into a cascade of intracellular signal transduction. RAS mutant protein regulates tumor cell proliferation, apoptosis, metabolism and angiogenesis through downstream MAPK, PI3K and other signaling pathways. In KRAS or other RAS-driven cancers, current treatments include direct inhibitors and upstream/downstream signaling pathway inhibitors. However, the research on these inhibitors has been largely restricted due to their escape inhibition and off-target toxicity. In this paper, we started with the role of normal and mutant RAS genes in cancer, elucidated the relevant RAS regulating pathways, and highlighted the important research advancements in RAS inhibitor research. We concluded that for the crosstalk between RAS pathways, the effect of single regulation may be limited, and the multi-target drug combined compensation mechanism is becoming a research hotspot.

LncRNAs (long non-coding RNAs) are endogenous molecules lacking protein-encoding capacity, which have been identified as key regulators of ischemic stroke. Increasing evidence suggests that lncRNAs play critical roles in several aspects of ischemic stroke, including atherosclerosis, dyslipidemia, hypertension, and diabetes mellitus. Hence, lncRNAs may further broaden our understanding of stroke pathogenesis. Altered lncRNA expression has been found in rodent focal cerebral ischemia models and oxygen–glucose deprived mouse brain microvascular endothelial cells as well as stroke patients. LncRNAs are considered to be promising biomarkers for the diagnosis and prognosis of cerebral ischemia. Here, we have reviewed the latest advances in lncRNA-based therapeutic approaches for ischemic disease. Accordingly, we summarize the current understanding of lncRNAs and ischemic stroke, focusing on the regulatory role of lncRNAs in ischemic stroke, as well as their potential as biomarkers and therapeutic targets in cerebral ischemia.

Background: High global incidence of acute kidney injury (AKI) is an observable complication in critically ill patients. Long-term disease and medication complexity contribute to devastating chronic kidney disease (CKD), diminishing quality of life. Objectives: To establish new biomarkers to guide patient care and facilitate novel therapeutics development. Methods: Serum and urinary levels of creatinine, CysC, and NGAL were estimated in 86 renal patients and compared with healthy controls for AKI and CKD categorization. Creatinine and CysC measurements were used to estimate GFR. Kidney biopsies were prepared for light microscopy for further characterization. Patients’ demographic data were used in group association studies. Results: Thirty-six patients met the criteria for AKI and 50 for CKD. Both mean serum and urine creatinine levels were significantly elevated by 2.8 and 2.6, respectively, from baseline in 48 h in the AKI group but not CKD group. Mean serum Cystatin C (CysC) values were higher than controls but similar in both disease states, while urine levels were slightly higher in CKD patients, and remained steady by the end of the follow-up (EF-Up). Further, a significant 2.9-fold and 5.5-fold (p=0.001) increase in serum NGAL in AKI and CKD, respectively, and a dramatic 7.1-factor reduction in AKI group, but no appreciable change in the CKD group from admission to EF-Up were observed. Similarly, urine NGAL level for AKI and CKD increased 3.2-fold and 6-fold respectively, on admission, which decreased moderately with the AKI group (2.5-fold) but increased by a factor of 1-8 (10.7- fold; p=0.001) at EF-Up. ROC assessment curve revealed relatively higher NGAL performance at good predictive values than CysC (p < 0.009). Conclusion: Our data demonstrated creatinine elevation by a factor > 2 in 48 h in AKI group but not CKD group, which returned close to normal levels by the EF-Up, an indication of abrupt renal injury in AKI, compared with a persistent effect in the CKD group. Both serum and urine NGAL sensitivity and specificity provided powerful discriminative tool between AKI and CKD by reduction in the AKI group and an increase in the CKD group by the EF-UP, thus, contributing in establishing the basis for AKI and CKD classification. CysC, however, displayed less sensitivity than NGAL, indicating effects by enigmatic non-specific factors.

Background: Post-marketing pharmaceutical surveillance, a.k.a. pragmatic clinical trials (i.e., PCT), plays a vital role in preventing accidents in practical treatment. The most important and difficult task in PCT is to assess which drug causes adverse reactions (i.e., ADRs) from clinical texts. The confounding (i.e., factors cause confusions in causality assessment) is generated by the polypharmacy (i.e., multiple drugs use), which makes most of existing methods poor for detecting drugs that capably cause observed ADRs. Objective: We aim to improve the performance of detecting drug-ADR causal relations from clinical texts. To this end, a mechanism for reducing the impact of confounding on the detecting process is needful. Methods: We proposed a novel model which is called the analogy-based active voting (i.e., AAV) for improving the ability of detecting causal drug-ADR pairs, in case multiple drugs are prescribed for treating the comorbidity. This model is inspired by the analogy principle which was proposed by Bradford Hill. Results: The experimental results show the improvement of recognizing causal relations between drugs and ADRs that are confirmed by the SIDER. In addition, the proposed model is promising to detect infrequently observed causal drug-ADR pairs when the drug is not commonly used. Conclusion: The proposed model demonstrates its ability for controlling the polypharmacy-induced confounding, to improve the quality of causality assessment of ADRs. Additionally, this also shows that the analogy principle is applicable for the assessment.