Fabrication of a three-dimensional bone marrow niche-like acute myeloid Leukemia disease model by an automated and controlled process using a robotic multicellular bioprinting system.

BACKGROUND: Acute myeloid leukemia (AML) is a hematological malignancy that remains a therapeutic challenge due to the high incidence of disease relapse. To better understand resistance mechanisms and identify novel therapies, robust preclinical models mimicking the bone marrow (BM) microenvironment are needed. This study aimed to achieve an automated fabrication process of a three-dimensional (3D) AML disease model that recapitulates the 3D spatial structure of the BM microenvironment and applies to drug screening and investigational studies. METHODS: To build this model, we investigated a unique class of tetramer peptides with an innate ability to self-assemble into stable hydrogel. An automated robotic bioprinting process was established to fabricate a 3D BM (niche-like) multicellular AML disease model comprised of leukemia cells and the BM's stromal and endothelial cellular fractions. In addition, monoculture and dual-culture models were also fabricated. Leukemia cell compatibility, functionalities (in vitro and in vivo), and drug assessment studies using our model were performed. In addition, RNAseq and gene expression analysis using TaqMan arrays were also performed on 3D cultured stromal cells and primary leukemia cells. RESULTS: The selected peptide hydrogel formed a highly porous network of nanofibers with mechanical properties similar to the BM extracellular matrix. The robotic bioprinter and the novel quadruple coaxial nozzle enabled the automated fabrication of a 3D BM niche-like AML disease model with controlled deposition of multiple cell types into the model. This model supported the viability and growth of primary leukemic, endothelial, and stromal cells and recapitulated cell-cell and cell-ECM interactions. In addition, AML cells in our model possessed quiescent characteristics with improved chemoresistance attributes, resembling more the native conditions as indicated by our in vivo results. Moreover, the whole transcriptome data demonstrated the effect of 3D culture on enhancing BM niche cell characteristics. We identified molecular pathways upregulated in AML cells in our 3D model that might contribute to AML drug resistance and disease relapse. CONCLUSIONS: Our results demonstrate the importance of developing 3D biomimicry models that closely recapitulate the in vivo conditions to gain deeper insights into drug resistance mechanisms and novel therapy development. These models can also improve personalized medicine by testing patient-specific treatments.

The Quality of Blood Donation Services and Its Association with Blood Donors' Trust and Loyalty at Makkah Blood Donation Centers in Saudi Arabia: A Cross-Sectional Study.

The current cross-sectional study was conducted to determine the quality of blood donation services and its association with blood donors' trust and loyalty at Makkah blood donation centers in Saudi Arabia. A total of 373 healthy blood donors aged ≥18 years who visited blood donation centers in Makkah, Saudi Arabia, between 1st and 28th February 2023 were recruited using a census sampling method. A pre-tested and validated Arabic language questionnaire was employed. The study survey included a checklist of sociodemographic variables (seven items), as well as seven-point Likert-scale questions on the quality of blood donation services (21 items), questions to assess the participant's level of trust in blood donation centers (4 items), and questions to evaluate the level of loyalty to blood donations (4 items). SPSS (version 24) was used for data analysis. A total of 373 blood donors were included in this study. Of them, 240 (64.3%) were males and 133 (35.7%) were females. The vast majority of the study participants, 330 (88.5%), had a high educational level. The overall average agreement score for the quality of blood donation services was 71.7%. Furthermore, the overall average item agreement score for trust in blood donation centers and places was 83.0%, while the overall average item agreement score for loyalty to blood donation was 72.1%. Moreover, after adjustment for potential confounding factors, high levels of quality in blood donation services were associated with high levels of trust and loyalty among the blood donors (OR: 1.518, CI 95%: 0.321-0.864 and OR: 2.466, CI 95%: 0.285-0.763, respectively) (p-value < 0.05 for all). The overall quality of, trust in, and loyalty to blood donation services were 71.7%, 83.0%, and 72.1%, respectively. In addition, high levels of quality in blood donation services could improve blood donors' trust and loyalty levels at Makkah blood donation centers in Saudi Arabia.

The Influence of Prenatal Exposure to Methamphetamine on the Development of Dopaminergic Neurons in the Ventral Midbrain.

Methamphetamine, a highly addictive central nervous system (CNS) stimulant, is used worldwide as an anorexiant and attention enhancer. Methamphetamine use during pregnancy, even at therapeutic doses, may harm fetal development. Here, we examined whether exposure to methamphetamine affects the morphogenesis and diversity of ventral midbrain dopaminergic neurons (VMDNs). The effects of methamphetamine on morphogenesis, viability, the release of mediator chemicals (such as ATP), and the expression of genes involved in neurogenesis were evaluated using VMDNs isolated from the embryos of timed-mated mice on embryonic day 12.5. We demonstrated that methamphetamine (10 µM; equivalent to its therapeutic dose) did not affect the viability and morphogenesis of VMDNs, but it reduced the ATP release negligibly. It significantly downregulated Lmx1a, En1, Pitx3, Th, Chl1, Dat, and Drd1 but did not affect Nurr1 or Bdnf expression. Our results illustrate that methamphetamine could impair VMDN differentiation by altering the expression of important neurogenesis-related genes. Overall, this study suggests that methamphetamine use may impair VMDNs in the fetus if taken during pregnancy. Therefore, it is essential to exercise strict caution for its use in expectant mothers.

Bioactive hybrid membrane-based cellulose acetate/bioactive glass/hydroxyapatite/carbon nanotubes nanocomposite for dental applications.

The present work aimed to fabricate a set of hybrid bioactive membrane in the form of bio-nanocomposite films for dental applications using the casting dissolution procedures. The formulation of the targeted materials was consisting of cellulose acetate/bioactive glass/hydroxyapatite/carbon nanotubes with a general abbreviation CA-HAP-BG-SWCNTs. The nanocomposites were characterized using XRD, FTIR, SEM-EDX and Raman spectroscopy. XRD, FTIR and SEM characters confirm the nanocomposites formation with good compatibility. The fabricated materials had a semi crystalline structure. The mechanical and thermal properties, as well as contact angle and bioactivity of the fabricated nanocomposites were investigated. The SEM images for showed beehive-like architectures with a thicker frame for the second material. All fabricated materials showed good thermal behaviors. Furthermore, the agar diffusion antimicrobial study showed that the prepared nanocomposites do not exhibit an antibacterial activity against five pathogenic bacterial strains. Additionally, cytotoxicity of a dental nanocomposite filling agent was evaluated. Vero normal cells were incubated with test materials for 72h at 37 °C and 5% CO2. Cell viability was detected using a SRB assay. All nanocomposites were mildly to non-cytotoxic to Vero cells at high concentration in contrast to the inhibitory effect of doxorubicin which was added at 10-fold lower concertation than the nanocomposites. Hence, the proposed nanocomposite is promising candidates for dental applications.

Enhanced Solubility and Biological Activity of Dexibuprofen-Loaded Silica-Based Ternary Solid Dispersions.

The current study was designed to formulate ternary solid dispersions (TSDs) of dexibuprofen (Dex) by solvent evaporation to augment the solubility and dissolution profile, in turn providing gastric protection and effective anti-inflammatory activity. Initially, nine formulations (S1 to S9) of binary solid dispersions (BSDs) were developed. Formulation S1 comprising a 1:1 weight ratio of Dex and Syloid 244FP® was chosen as the optimum BSD formulation due to its better solubility profile. Afterward, 20 TSD formulations were developed using the optimum BSD. The formulation containing Syloid 244FP® with 40% Gelucire 48/16® (S18) and Poloxamer 188® (S23) successfully enhanced the solubility by 28.23 and 38.02 times, respectively, in pH 6.8, while dissolution was increased by 1.99- and 2.01-fold during the first 5 min as compared to pure drug. The in vivo gastroprotective study in rats suggested that the average gastric lesion index was in the order of pure Dex (8.33 ± 2.02) > S1 (7 ± 1.32) > S18 (2.17 ± 1.61) > S23 (1.83 ± 1.04) > control (0). The in vivo anti-inflammatory study in rats revealed that the percentage inhibition of swelling was in the order of S23 (71.47 ± 2.16) > S18 (64.8 ± 3.79) > S1 (54.14 ± 6.78) > pure drug (18.43 ± 2.21) > control (1.18 ± 0.64) after 6 h. ELISA results further confirmed the anti-inflammatory potential of the developed formulation, where low levels of IL-6 and TNF alpha were reported for animals treated with S23. Therefore, S23 could be considered an effective formulation that not only enhanced the solubility and bioavailability but also reduced the gastric irritation of Dex.

The Prevalence of Transfusion-Transmitted Infection Markers among Blood Donors at Saudi Hospital, Makkah.

BACKGROUND: Testing of blood donors for markers of transfusion-transmitted infections (TTIs) such as HBV, HCV, HIV, HTLV, syphilis, and malaria is mandatory in Saudi Arabia. This study determined the prevalence of all tested TTIs among blood donors in the western region of Saudi Arabia. METHODS: This retrospective study included 5,473 blood donors who attended the blood donation center at the Security Force Hospital (SFH) located in the western region of Saudi Arabia from January 1, 2015 to December 31, 2018. The prevalence of TTIs was determined and classified as per year, gender, age, type of donors (first-time vs. returned donors), category of donation (replacement vs. volunteer), and blood group. RESULTS: All donors (100%) were screened for TTIs by serological assays and nucleic acid tests (NATs). "Reactive" samples to serological assays were as follow: 57 (1.07%) HBsAg, 292 (5.34%) HBsAb, 388 (7.1%) HBcAbs, 13 (0.24%) HCV, 5 (0.09%) HIV, 8 (0.15%) HTLV-I and -II, 21 (0.83%) syphilis, and 0 (0%) malaria. The NAT results for HBV, HCV, and HIV revealed 50 (0.91%), 1 (0.0002%), and 3 (0.05%) reactive samples, respectively. Reactive donations to screening serology tests of syphilis and HTLV-I/-II were neither confirmed nor declined by their corresponding confirmatory assays. Most "reactive" samples to TTI tests were associated with male gender, first-time donor, replacement donation, and O+ blood group. CONCLUSIONS: This study highlights the strong adherence to TTI testing policy and low prevalence of TTI markers among blood donors in the western region of Saudi Arabia.

Utilization of a nanostructured lipid carrier encapsulating pitavastatin-Pinus densiflora oil for enhancing cytotoxicity against the gingival carcinoma HGF-1 cell line.

Oral squamous cell carcinoma (OSCC) is the most common epithelial tumor of the oral cavity. Gingival tumors, a unique type of OSCC, account for 10% of these malignant tumors. The antineoplastic properties of statins, including pitavastatin (PV), and the essential oil of the Pinus densiflora leaf (Pd oil) have been adequately reported. The goal of this investigation was to develop nanostructured lipid carriers (NLCs) containing PV combined with Pd oil and to determine their cytotoxicity against the cell line of human gingival fibroblasts (HGF-1). A central composite quadratic design was adopted to optimize the nanocarriers. The particle size and stability index of the nano-formulations were measured to evaluate various characteristics. TEM analysis, the entrapment efficiency, dissolution efficiency, and the cytotoxic efficiency of the optimized PV-loaded nanostructured lipid carrier drug delivery system (PV-Pd-NLCs) were evaluated. Then, the optimal PV-Pd-NLCs was incorporated into a Carbopol 940® gel base and tested for its rheological features and its properties of release and cell viability. The optimized NLCs had a particle size of 98 nm and a stability index of 89%. The gel containing optimum PV-Pd-NLCs had reasonable dissolution efficiency and acceptable rheological behavior and acquired the best cytotoxic activity against HGF-1 cell line among all the formulations developed for the study. The in vitro cell viability studies revealed a synergistic effect between PV and Pd oil in the treatment of gingival cancer. These findings illustrated that the gel containing PV-Pd-NLCs could be beneficial in the local treatment of gingival cancer.

Development of nanoemulsions for the delivery of hydrophobic and hydrophilic compounds against carbapenem-resistant Klebsiella pneumoniae.

Antimicrobial resistance (AR), particularly the limited antimicrobial activities of antibiotics and natural compounds, has prompted research into new antimicrobials. Nanoemulsions (NEs) have been found to improve the activity of antimicrobial compounds. This study developed clove essential oil-in-water NEs (CEO-NEs) and water-in-oil-in-water NEs co-encapsulating CEO and meropenem (CEO-MEM-NEs) to investigate the antibacterial activity of these loaded NEs against carbapenem-resistant Klebsiella pneumoniae. Ultrasonication was used to prepare CEO-NEs and CEO-MEM-NEs. Tween 80 and Imwitor 375 surfactants were used to produce CEO-NEs while Tween 80, Imwitor 375, and PGPR were used to produce CEO-MEM-NEs. Droplets' sizes were 138 ± 1.769 and 183.600 ± 0.889 for CEO-NEs and CEO-MEM-NEs, respectively. The resultant NEs were monodispersed, negatively charged, and physically stable. The antibacterial activities of NEs were investigated using broth microdilution, checkerboard, and time-kill assays to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). CEO-NEs (0.16% CEO MIC) and CEO-MEM-NEs (0.08% CEO and 1 µg mL-1 MEM MICs) completely inactivated K. pneumoniae, and showed functional stability after two weeks of storage at 4 °C. In conclusion, the formulated NEs significantly enhanced the antibacterial activity of CEO and MEM and have great potential as delivery systems of antimicrobial compounds.

The Influence of Prenatal Exposure to Quetiapine Fumarate on the Development of Dopaminergic Neurons in the Ventral Midbrain of Mouse Embryos.

The effects of second-generation antipsychotics on prenatal neurodevelopment, apoptotic neurodegeneration, and postnatal developmental delays have been poorly investigated. Even at standard doses, the use of quetiapine fumarate (QEPF) in pregnant women might be detrimental to fetal development. We used primary mouse embryonic neurons to evaluate the disruption of morphogenesis and differentiation of ventral midbrain (VM) neurons after exposure to QEPF. The dopaminergic VM neurons were deliberately targeted due to their roles in cognition, motor activity, and behavior. The results revealed that exposure to QEPF during early brain development decreased the effects of the dopaminergic lineage-related genes Tyrosine hydroxylase(Th), Dopamine receptor D1 (Drd1), Dopamine transporter (Dat), LIM homeobox transcription factor 1 alfa (Lmx1a), and Cell adhesion molecule L1 (Chl1), and the senescent dopaminergic gene Pituitary homeobox 3 (Pitx3). In contrast, Brain derived neurotrophic factor (Bdnf) and Nuclear receptor-related 1 (Nurr1) expressions were significantly upregulated. Interestingly, QEPF had variable effects on the development of non-dopaminergic neurons in VM. An optimal dose of QEPF (10 µM) was found to insignificantly affect the viability of neurons isolated from the VM. It also instigated a non-significant reduction in adenosine triphosphate formation in these neuronal populations. Exposure to QEPF during the early stages of brain development could also hinder the formation of VM and their structural phenotypes. These findings could aid therapeutic decision-making when prescribing 2nd generation antipsychotics in pregnant populations.

Attempting to Increase the Effectiveness of the Antidepressant Trazodone Hydrochloride Drug Using π-Acceptors.

Major depressive disorder is a prevalent mood illness that is mildly heritable. Cases with the highest familial risk had recurrence and onset at a young age. Trazodone hydrochloride is an antidepressant medicine that affects the chemical messengers in the brain known as neurotransmitters, which include acetylcholine, norepinephrine, dopamine, and serotonin. In the present research, in solid and liquid phases, the 1:1 charge-transfer complexes between trazodone hydrochloride (TZD) and six different π-acceptors were synthesized and investigated using different microscopic techniques. The relation of dative ion pairs [TZD+, A-], where A is the acceptor, was inferred via intermolecular charge-transfer complexes. Additionally, a molecular docking examination was utilized to compare the interactions of protein receptors (serotonin-6BQH) with the TZD alone or in combination with the six distinct acceptor charge-transfer complexes. To refine the docking results acquired from AutoDock Vina and to better examine the molecular mechanisms of receptor-ligand interactions, a 100 ns run of molecular dynamics simulation was used. All the results obtained in this study prove that the 2,6-dichloroquinone-4-chloroimide (DCQ)/TZD complex interacts with serotonin receptors more efficiently than reactant donor TZD only and that [(TZD)(DCQ)]-serotonin has the highest binding energy value of all π-acceptor complexes.

Multispectral and Molecular Docking Studies Reveal Potential Effectiveness of Antidepressant Fluoxetine by Forming π-Acceptor Complexes.

Poor mood, lack of pleasure, reduced focus, remorse, unpleasant thoughts, and sleep difficulties are all symptoms of depression. The only approved treatment for children and adolescents with major depressive disorder (MDD) is fluoxetine hydrochloride (FXN), a serotonin selective reuptake inhibitor antidepressant. MDD is the most common cause of disability worldwide. In the present research, picric acid (PA); dinitrobenzene; p-nitro benzoic acid; 2,6-dichloroquinone-4-chloroimide; 2,6-dibromoquinone-4-chloroimide; and 7,7',8,8'-tetracyanoquinodimethane were used to make 1:1 FXN charge-transfer compounds in solid and liquid forms. The isolated complexes were then characterized by elemental analysis, conductivity, infrared, Raman, and 1H-NMR spectra, thermogravimetric analysis, scanning electron microscopy, and X-ray powder diffraction. Additionally, a molecular docking investigation was conducted on the donor moiety using FXN alone and the resulting charge transfer complex [(FXN)(PA)] as an acceptor to examine the interactions against two protein receptors (serotonin or dopamine). Interestingly, the [(FXN)(PA)] complex binds to both serotonin and dopamine more effectively than the FXN drug alone. Furthermore, [(FXN)(PA)]-serotonin had a greater binding energy than [FXN]-serotonin. Theoretical data were also generated by density functional theory simulations, which aided the molecular geometry investigation and could be beneficial to researchers in the future.

Prenatal Exposure to Gabapentin Alters the Development of Ventral Midbrain Dopaminergic Neurons.

Background: Gabapentin is widely prescribed as an off-label drug for the treatment of various diseases, including drug and alcohol addiction. Approximately 83-95% of the usage of gabapentin is off-label, accounting for more than 90% of its sales in the market, which indicates an alarming situation of drug abuse. Such misuse of gabapentin has serious negative consequences. The safety of the use of gabapentin in pregnant women has always been a serious issue, as gabapentin can cross placental barriers. The impact of gabapentin on brain development in the fetus is not sufficiently investigated, which poses difficulties in clinical decisions regarding prescriptions. Methods: The consequences effect of prenatal gabapentin exposure on the development of ventral midbrain dopaminergic neurons were investigated using three-dimensional neuronal cell cultures. Time-mated Swiss mice were used to isolate embryos. The ventral third of the midbrain was removed and used to enrich the dopaminergic population in 3D cell cultures that were subsequently exposed to gabapentin. The effects of gabapentin on the viability, ATP release, morphogenesis and genes expression of ventral midbrain dopaminergic neurons were investigated. Results: Gabapentin treatment at the therapeutic level interfered with the neurogenesis and morphogenesis of vmDA neurons in the fetal brain by causing changes in morphology and alterations in the expression of key developmental genes, such as Nurr1, Chl1, En1, Bdnf, Drd2, and Pitx3. The TH + total neurite length and dominant neurite length were significantly altered. We also found that gabapentin could halt the metabolic state of these neuronal cells by blocking the generation of ATP. Conclusion: Our findings clearly indicate that gabapentin hampers the morphogenesis and development of dopaminergic neurons. This implies that the use of gabapentin could lead to serious complications in child-bearing women. Therefore, caution must be exercised in clinical decisions regarding the prescription of gabapentin in pregnant women.

A Parkinson's disease model composed of 3D bioprinted dopaminergic neurons within a biomimetic peptide scaffold.

Parkinson's disease (PD) is a progressive neurological disorder that affects movement. It is associated with lost dopaminergic (DA) neurons in thesubstantia nigra, a process that is not yet fully understood. To understand this deleterious disorder, there is an immense need to develop efficientin vitrothree-dimensional (3D) models that can recapitulate complex organs such as the brain. However, due to the complexity of neurons, selecting suitable biomaterials to accommodate them is challenging. Here, we report on the fabrication of functional DA neuronal 3D models using ultrashort self-assembling tetrapeptide scaffolds. Our peptide-based models demonstrate biocompatibility both for primary mouse embryonic DA neurons and for human DA neurons derived from human embryonic stem cells. DA neurons encapsulated in these scaffolds responded to 6-hydroxydopamine, a neurotoxin that selectively induces loss of DA neurons. Using multi-electrode arrays, we recorded spontaneous activity in DA neurons encapsulated within these 3D peptide scaffolds for more than 1 month without decrease of signal intensity. Additionally, vascularization of our 3D models in a co-culture with endothelial cells greatly promoted neurite outgrowth, leading to denser network formation. This increase of neuronal networks through vascularization was observed for both primary mouse DA and cortical neurons. Furthermore, we present a 3D bioprinted model of DA neurons inspired by the mouse brain and created with an extrusion-based 3D robotic bioprinting system that was developed during previous studies and is optimized with time-dependent pulsing by microfluidic pumps. We employed a hybrid fabrication strategy that relies on an external mold of the mouse brain construct that complements the shape and size of the desired bioprinted model to offer better support during printing. We hope that our 3D model provides a platform for studies of the pathogenesis of PD and other neurodegenerative disorders that may lead to better understanding and more efficient treatment strategies.

Zein-Stabilized Nanospheres as Nanocarriers for Boosting the Aphrodisiac Activity of Icariin: Response Surface Optimization and In Vivo Assessment.

Icariin (ICA), a main active compound of the Epimedium genus, is used as an aphrodisiac in traditional Chinese herbal medicine. Despite its therapeutic efficacy, ICA displays reduced oral absorption, and therefore, low bioavailability hindered its clinical application. Implementing nanotechnology in the field of formulation has been a focus to improve the efficacy of ICA. In this regard, polymeric nanoparticles find a potential application as drug delivery systems. A nanosphere formula was designed, aiming to improve the drug's efficacy. The proposed ICA nanosphere formula (tocozeinolate) was optimized using D-optimal response surface design. The concentrations of ICA (X1), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS, X2), zein (X3), and sodium deoxycholate (SDC, X4) expressed as percentages were investigated as quantitative independent variables. As per the experimental design, 23 formulations were developed, which were investigated for particle size (PS, nm), zeta potential (ZP, mV), and entrapment efficiency (EE, %) as response parameters. Numerical optimization and desirability approach were employed to predict the optimized variable levels that, upon combination, could result in minimized size and maximized zeta potential and ICA entrapment. The optimized ICA-tocozeinolate nanospheres showed a particle size of 224.45 nm, zeta potential of 0.961 mV, and drug entrapment of 65.29% that coincide well with the predicted values. The optimized ICA-tocozeinolate nanospheres were evaluated for sexual behavior in Wistar male rats compared to raw ICA at equivalent doses (20 mg/kg). In vivo assessment results showed significant sexual behavior enhancement by the optimized formulation, as evidenced by decreased average time of both mount latency (ML) and ejaculation latency (EL) to almost half those of raw ICA. Additionally, intromission latency (IL) time was reduced by 41% compared to the raw ICA. These results highlighted the potential of the proposed ICA-tocozeinolate nanospheres as a promising platform for improving the delivery and efficacy of therapeutic agents.

Increasing the Efficacy of Seproxetine as an Antidepressant Using Charge-Transfer Complexes.

The charge transfer interactions between the seproxetine (SRX) donor and π-electron acceptors [picric acid (PA), dinitrobenzene (DNB), p-nitrobenzoic acid (p-NBA), 2,6-dichloroquinone-4-chloroimide (DCQ), 2,6-dibromoquinone-4-chloroimide (DBQ), and 7,7',8,8'-tetracyanoquinodi methane (TCNQ)] were studied in a liquid medium, and the solid form was isolated and characterized. The spectrophotometric analysis confirmed that the charge-transfer interactions between the electrons of the donor and acceptors were 1:1 (SRX: π-acceptor). To study the comparative interactions between SRX and the other π-electron acceptors, molecular docking calculations were performed between SRX and the charge transfer (CT) complexes against three receptors (serotonin, dopamine, and TrkB kinase receptor). According to molecular docking, the CT complex [(SRX)(TCNQ)] binds with all three receptors more efficiently than SRX alone, and [(SRX)(TCNQ)]-dopamine (CTcD) has the highest binding energy value. The results of AutoDock Vina revealed that the molecular dynamics simulation of the 100 ns run revealed that both the SRX-dopamine and CTcD complexes had a stable conformation; however, the CTcD complex was more stable. The optimized structure of the CT complexes was obtained using density functional theory (B-3LYP/6-311G++) and was compared.

Enhancement of Haloperidol Binding Affinity to Dopamine Receptor via Forming a Charge-Transfer Complex with Picric Acid and 7,7,8,8-Tetracyanoquinodimethane for Improvement of the Antipsychotic Efficacy.

Haloperidol (HPL) is a typical antipsychotic drug used to treat acute psychotic conditions, delirium, and schizophrenia. Solid charge transfer (CT) products of HPL with 7,7,8,8-tetracyanoquinodimethane (TCNQ) and picric acid (PA) have not been reported till date. Therefore, we conducted this study to investigate the donor-acceptor CT interactions between HPL (donor) and TCNQ and PA (π-acceptors) in liquid and solid states. The complete spectroscopic and analytical analyses deduced that the stoichiometry of these synthesized complexes was 1:1 molar ratio. Molecular docking calculations were performed for HPL as a donor and the resulting CT complexes with TCNQ and PA as acceptors with two protein receptors, serotonin and dopamine, to study the comparative interactions among them, as they are important neurotransmitters that play a large role in mental health. A molecular dynamics simulation was ran for 100 ns with the output from AutoDock Vina to refine docking results and better examine the molecular processes of receptor-ligand interactions. When compared to the reactant donor, the CT complex [(HPL)(TCNQ)] interacted with serotonin and dopamine more efficiently than HPL only. CT complex [(HPL)(TCNQ)] with dopamine (CTtD) showed the greatest binding energy value among all. Additionally, CTtD complex established more a stable interaction with dopamine than HPL-dopamine.

Pairing 3D-Printing with Nanotechnology to Manage Metabolic Syndrome.

Introduction: This work was aimed to develop a Curcuma oil-based self-nanoemulsifying drug delivery system (SNEDDS) 3D-printed polypills containing glimepiride (GMD) and rosuvastatin (RSV) for treatment of dyslipidemia in patients with diabetes as a model for metabolic syndrome (MS). Methods: Compartmentalized 3D printed polypills were prepared and studied in streptozotocin/poloxamer induced diabetic/dyslipidemic rats. The pharmacokinetic parameters of GMD and RSV in the prepared polypills were evaluated. Blood glucose level, lipid profile, antioxidant, and biochemical markers activities were investigated. Also, histopathological examination of the liver and pancreas was carried out. The atherosclerotic index, the area of islets of Langerhans, and liver steatosis lesion scores were calculated. Results: The developed SNEDDS-loaded GMD/RSV polypills showed acceptable quality control characteristics with a high relative bioavailability of 217.16% and 224.28% for GMD and RSV, respectively, when compared with the corresponding non-SNEDDS pills. The prepared polypills showed dramatic lowering in blood glucose levels and substantial improvement in lipid profile and hepatic serum biomarkers as well as remarkable decrease in serum antioxidants in response to Poloxamer 407 intoxication. The prepared polypills decreased the risk of atherosclerosis and coronary disease by boosting the level of high-density lipoprotein and lowering both triglyceride and low-density lipoprotein. Microscopic examination showed normal hepatic sinusoids and high protection level with less detectable steatosis in the examined hepatocytes. Normal size pancreatic islets with apparently normal exocrine acini and pancreatic duct were also noticed. Conclusion: This formulation strategy clearly shows the potential of the developed polypills in personalized medicine for treatment of patients with MS.

Enhancing the Antipsychotic Effect of Risperidone by Increasing Its Binding Affinity to Serotonin Receptor via Picric Acid: A Molecular Dynamics Simulation.

The aim of this study was to assess the utility of inexpensive techniques in evaluating the interactions of risperidone (Ris) with different traditional π-acceptors, with subsequent application of the findings into a Ris pharmaceutical formulation with improved therapeutic properties. Molecular docking calculations were performed using Ris and its different charge-transfer complexes (CT) with picric acid (PA), 2,3-dichloro-5,6-dicyanop-benzoquinon (DDQ), tetracyanoquinodimethane (TCNQ), tetracyano ethylene (TCNE), tetrabromo-pquinon (BL), and tetrachloro-p-quinon (CL), as donors, and three receptors (serotonin, dopamine, and adrenergic) as acceptors to study the comparative interactions among them. To refine the docking results and further investigate the molecular processes of receptor-ligand interactions, a molecular dynamics simulation was run with output obtained from AutoDock Vina. Among all investigated complexes, the [(Ris) (PA)]-serotonin (CTcS) complex showed the highest binding energy. Molecular dynamics simulation of the 100 ns run revealed that both the Ris-serotonin (RisS) and CTcS complexes had a stable conformation; however, the CTcS complex was more stable.

The Effects of Prenatal Exposure to Pregabalin on the Development of Ventral Midbrain Dopaminergic Neurons.

Pregabalin is widely used as a treatment for multiple neurological disorders; however, it has been reported to have the potential for misuse. Due to a lack of safety studies in pregnancy, pregabalin is considered the last treatment option for various neurological diseases, such as neuropathic pain. Therefore, pregabalin abuse in pregnant women, even at therapeutic doses, may impair fetal development. We used primary mouse embryonic neurons to investigate whether exposure to pregabalin can impair the morphogenesis and differentiation of ventral midbrain neurons. This study focused on ventral midbrain dopaminergic neurons, as they are responsible for cognition, movement, and behavior. The results showed that pregabalin exposure during early brain development induced upregulation of the dopaminergic progenitor genes Lmx1a and Nurr1 and the mature dopaminergic gene Pitx3. Interestingly, pregabalin had different effects on the morphogenesis of non-dopaminergic ventral midbrain neurons. Importantly, our findings illustrated that a therapeutic dose of pregabalin (10 µM) did not affect the viability of neurons. However, it caused a decrease in ATP release in ventral midbrain neurons. We demonstrated that exposure to pregabalin during early brain development could interfere with the neurogenesis and morphogenesis of ventral midbrain dopaminergic neurons. These findings are crucial for clinical consideration of the use of pregabalin during pregnancy.

Preparation and optimization of aloe ferox gel loaded with Finasteride-Oregano oil nanocubosomes for treatment of alopecia.

Alopecia areata is a skin disorder characterized by scarless, localized hair loss that is usually managed by topical treatments that might further worsen the condition. Therefore, the current study aimed to develop nano-cubosomes loaded with finasteride (FI) and oregano oil (Or) to improve drug solubility and permeation through skin and then incorporate it into an aloe ferox gel base. An l-optimal coordinate exchange design was adopted to optimize nano-cubosomes. Phytantriol and Alkyl Acrylate were employed as the lipid material, and surfactant respectively for cubosomes manufacture. The produced formulations were assessed for their particle size, entrapment efficiency (EE%), FI steady-state flux (Jss) and minimum inhibitory concentration (MIC) against Pro-pionibacterium acnes. Optimal FI-Or-NCu had a particle size of 135 nm, EE% equals 70%, Jss of 1.85 µg/cm2.h, and MIC of 0.44 µg/ml. The optimum formulation loaded gel gained the highest drug release percent and ex vivo skin permeation compared to FI aqueous suspension, and pure FI loaded gel. Aloe ferox and oregano oil in the optimized gel formulation had a synergistic activity on the FI permeation across the skin and against the growth of p. acne bacteria which could favor their use in treating alopecia. Thus, this investigation affirms the ability of FI-Or-NCu loaded aloe ferox gel could be an effective strategy that would enhance FI release and permeation through skin and maximize its favorable effects in treating alopecia.