Synthesis and Molecular Dynamic Simulation of Novel Cationic and Non-cationic Pyrimidine Derivatives as Potential G-quadruplex-ligands.

BACKGROUND: Drug resistance has been a problem in cancer chemotherapy, which often causes shortterm effectiveness. Further, the literature indicates that telomere G-quadruplex could be a promising anti-cancer target. OBJECTIVE: We synthesized and characterized two new pyrimidine derivatives as ligands for G-quadruplex DNA. METHODS: The interaction of novel non-cationic and cationic pyrimidine derivatives (3a, b) with G-quadruplex DNA (1k8p and 3qsc) was explored by circular dichroism (CD) and ultraviolet-visible spectroscopy and polyacrylamide gel electrophoresis (PAGE) methods. The antiproliferative activity of desired compounds was evaluated by the MTT assay. Apoptosis induction was assessed by Propidium iodide (P.I.) staining and flow cytometry. Computational molecular modeling (CMM) and molecular dynamics simulation (MD) were studied on the complexes of 1k8p and 3qsc with the compounds. The van der Waals, electrostatic, polar solvation, solventaccessible surface area (SASA), and binding energies were calculated and analyzed. RESULTS: The experimental results confirmed that both compounds 3a and 3b interacted with 1k8p and 3qsc and exerted cytotoxic and proapoptotic effects on cancer cells. The number of hydrogen bonds and the RMSD values increased in the presence of the ligands, indicating stronger binding and suggesting increased structural dynamics. The electrostatic contribution to binding energy was higher for the cationic pyrimidine 3b, indicating more negative binding energies. CONCLUSION: Both experimental and MD results confirmed that 3b was more prone to form a complex with DNA G-quadruplex (1k8p and 3qsc), inhibit cell growth, and induce apoptosis, compared to the non-cationic pyrimidine 3a.

Targeted delivery of SN38 to breast cancer using amphiphilic diblock copolymers PHPMA-b-PBAEM as micellar carriers with AS1411 aptamer.

Breast cancer treatment can be challenging, but a targeted drug delivery system (DDS) has the potential to make it more effective and reduce side effects. This study presents a novel nanotherapeutic targeted DDS developed through the self-assembly of an amphiphilic di-block copolymer to deliver the chemotherapy drug SN38 specifically to breast cancer cells. The vehicle was constructed from the PHPMA-b-PEAMA diblock copolymer synthesized via RAFT polymerization. A single emulsion method was then used to encapsulate SN38 within nanoparticles (NPs) formed from the PHPMA-b-PEAMA copolymer. The AS1411 DNA aptamer was covalently bonded to the surface of the micellar NPs, producing a targeted DDS. Molecular dynamics (MD) simulation studies were also performed on the di block polymeric system, demonstrating that SN38 interacted well with the di block. The in vitro results demonstrated that AS1411- decorated SN38-loaded HPMA NPs were highly toxic to breast cancer cells while having a minimal effect on non-cancerous cells. Remarkably, in vivo studies elucidated the ability of the targeted DDS to enhance the antitumor effect of SN38, suppressing tumor growth and improving survival rates compared to free SN38.

Wortmannin Inhibits Cell Growth and Induces Apoptosis in Colorectal Cancer Cells by Suppressing the PI3K/AKT Pathway.

BACKGROUND: Colorectal cancer (CRC) remains a significant contributor to mortality, often exacerbated by metastasis and chemoresistance. Novel therapeutic strategies are imperative to enhance current treatments. The dysregulation of the PI3K/Akt signaling pathway is implicated in CRC progression. This study investigates the therapeutic potential of Wortmannin, combined with 5-fluorouracil (5-FU), to target the PI3K/Akt pathway in CRC. METHODS: Anti-migratory and antiproliferative effects were assessed through wound healing and MTT assays. Apoptosis and cell cycle alterations were evaluated using Annexin V/Propidium Iodide Apoptosis Assay. Wortmannin's impact on the oxidant/antioxidant equilibrium was examined via ROS, SOD, CAT, MDA, and T-SH levels. Downstream target genes of the PI3K/AKT pathway were analyzed at mRNA and protein levels using RTPCR and western blot, respectively. RESULTS: Wortmannin demonstrated a significant inhibitory effect on cell proliferation, modulating survivin, cyclinD1, PI3K, and p-Akt. The PI3K inhibitor attenuated migratory activity, inducing E-cadherin expression. Combined Wortmannin with 5-FU induced apoptosis, increasing cells in sub-G1 via elevated ROS levels. CONCLUSION: This study underscores Wortmannin's potential in inhibiting CRC cell growth and migration through PI3K/Akt pathway modulation. It also highlights its candidacy for further investigation as a promising therapeutic option in colorectal cancer treatment.

Anticancer Potential of a Synthetic Quinoline, 9IV-c, by Inducing Apoptosis in A549 Cell and In vivo BALB/c Mice Models.

BACKGROUND: In a previous work from the author of this study, the compound of 9IV-c, ((E)-2-(3,4- dimethoxystyryl)-6,7,8-trimethoxy-N-(3,4,5-trimethoxyphenyl)quinoline-4-amine) was synthesized, and the effects of potent activity on the multiple human tumor cell lines were evaluated considering the spindle formation together with the microtubule network. METHODS: Accordingly, cytotoxic activity, apoptotic effects, and the therapeutic efficiency of compound 9IV-c on A549 and C26 cell lines were investigated in this study. RESULTS: The compound 9IV-c demonstrated high cytotoxicity against A549 and C26 cell lines with IC50 = 1.66 and 1.21 µM, respectively. The flow cytometric analysis of the A549 cancer cell line treated with compound 9IVc showed that This compound induced cell cycle arrest at the G2/M phase and apoptosis. Western blotting analysis displayed that compound 9IV-c also elevated the Bax/Bcl-2 ratio and increased the activation of caspase-9 and -3 but not caspase-8. CONCLUSION: These data presented that the intrinsic pathway was responsible for 9IV-c -induced cell apoptosis. In vivo studies demonstrated that treatment with the compound of 9IV-c at 10 mg/kg dose led to a decrease in tumor growth compared to the control group. It was found that there was not any apparent body weight loss in the period of treatment. Also, in the vital organs of the BALB/c mice, observable pathologic changes were not detected.

In Silico Evaluation of NO-Sartans against SARS-CoV-2.

INTRODUCTION: Numerous clinical trials are currently investigating the potential of nitric oxide (NO) as an antiviral agent against coronaviruses, including SARS-CoV-2. Additionally, some researchers have reported positive effects of certain Sartans against SARS-CoV-2. METHOD: Considering the impact of NO-Sartans on the cardiovascular system, we have compiled information on the general structure, synthesis methods, and biological studies of synthesized NOSartans. In silico evaluation of all NO-Sartans and approved sartans against three key SARS-CoV- -2 targets, namely Mpro (PDB ID: 6LU7), NSP16 (PDB ID: 6WKQ), and ACE-2 (PDB ID: 1R4L), was performed using MOE. RESULTS: Almost all NO-Sartans and approved sartans demonstrated promising results in inhibiting these SARS-CoV-2 targets. Compound 36 (CLC-1280) showed the best docking scores against the three evaluated targets and was further evaluated using molecular dynamics (MD) simulations. CONCLUSION: Based on our in silico studies, CLC-1280 (a Valsartan dinitrate) has the potential to be considered as an inhibitor of the SARS-CoV-2 virus. However, further in vitro and in vivo evaluations are necessary for the drug development process.

Dual-targeting CD44 and mucin by hyaluronic acid and 5TR1 aptamer for epirubicin delivery into cancer cells: Synthesis, characterization, in vitro and in vivo evaluation.

One of the revolutionized cancer treatment is active targeting nanomedicines. This study aims to create a dual-targeted drug delivery system for Epirubicin (EPI) to cancer cells. Hyaluronic acid (HA) is the first targeting ligand, and 5TR1 aptamer (5TR1) is the second targeting ligand to guide the dual-targeted drug delivery system to the cancer cells. HA is bound to highly expressed receptors like CD44 on cancer cells. 5TR1, DNA aptamer, is capable of recognizing MUC1 glycoprotein, which is overexpressed in cancer cells. The process involved binding EPI and 5TR1 to HA using adipic acid dihydrazide (AA) as a linker. The bond between the components was confirmed using 1H NMR. The binding of 5TR1 to HA-AA-EPI was confirmed using gel electrophoresis. The particle size (132.6 ± 9 nm) and Zeta Potential (-29 ± 4.4 mV) were measured for the final nanoformulation (HA-AA-EPI-5TR1). The release of EPI from the HA-AA-EPI-5TR1 nanoformulation was also studied at different pH levels. In the acidic pH (5.4 and 6.5) release pattern of EPI from the HA-AA-EPI-5TR1 nanoformulation was higher than physiological pH (7.4). The cytotoxicity and cellular uptake of the synthetic nanoformula were evaluated using MTT and flow cytometry analysis. Flow cytometry and cellular cytotoxicity studies were exhibited in a negative MUC1-cell line (CHO) and two positive MUC1+cell lines (MCF-7 and C26). Results confirmed that there is a notable contrast between the dual-targeted (HA-AA-EPI-5TR1) and single-targeted (HA-AA-EPI) nanoformulation in MCF-7 and C26 cell lines (MUC1+). In vivo studies showed that HA-AA-EPI-5TR1 nanoformulation has improved efficiency with limited side effect in C26 tumor-bearing mice. Also, Fluorescence imaging and pathological evaluation showed reduced side effects in the heart tissue of mice receiving HA-AA-EPI-5TR1 than free EPI. So, this targeted approach effectively delivers EPI to cancer cells with reduced side effects.

The Application of Kinesin Inhibitors in Medical Issues.

Kinesins are a group of motor proteins in charge of several crucial functions in the cell. These proteins often bind to microtubules and perform their functions using the energy produced by ATP hydrolysis. One function of mitotic kinesin, a subclass of kinesin that is expressed during cell division at the mitotic phase, is to create the mitotic spindle. Uncontrolled cell growth is one trait of cancerous cells. Traditional anticancer medications still used in clinics include taxanes (paclitaxel) and vinca alkaloids (vincristine, vinblastine), which interfere with microtubule dynamics. However, because non-dividing cells like post-mitotic neurons contain microtubules, unwanted side effects like peripheral neuropathy are frequently found in patients taking these medications. More than ten members of the mitotic kinesin family play distinct or complementary roles during mitosis. The mitotic kinesin family's KSP, or Eg5, is regarded as its most dramatic target protein. The current work systematically reviews the use of kinesin inhibitors in the medical field. The challenges of KSP and the practical solutions are also examined, and the outcomes of the previous works are reported. The significant gaps and shortcomings of the related works are also highlighted, which can be an onset topic for future works.

Discovery of non-peptide GLP-1r natural agonists for enhancing coronary safety in type 2 diabetes patients.

This study explores the computational discovery of non-peptide agonists targeting the Glucagon-Like Peptide-1 Receptor (GLP-1R) to enhance the safety of major coronary outcomes in individuals affected by Type 2 Diabetes. The objective is to identify novel compounds that can activate the GLP-1R pathway without the limitations associated with peptide agonists. Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD) and mortality, which is attributed to the accumulation of fat in organs, including the heart. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are frequently used to manage T2DM and could potentially offer cardiovascular benefits. Therefore, this study examines non-peptide agonists of GLP-1R to improve coronary safety in type 2 diabetes patients. After rigorous assessments, two standout candidates were identified, with natural compound 12 emerging as the most promising. This study represents a notable advancement in enhancing the management of coronary outcomes among individuals with type 2 diabetes. The computational methodology employed successfully pinpointed potential GLP-1R natural agonists, providing optimism for the development of safer and more effective therapeutic interventions. Although computational methodologies have provided crucial insights, realizing the full potential of these compounds requires extensive experimental investigations, crucial in advancing therapeutic strategies for this critical patient population.Communicated by Ramaswamy H. Sarma.

Novel hits for autosomal dominated polycystic kidney disease (ADPKD) targeting derived by in silico screening on ZINC-15 natural product database.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder that leads to growth cysts in the kidney, ultimately resulting in loss of function. Currently, no effective drug therapy can be safely used in the clinic. So, looking for effective therapeutic drugs is urgent for treating ADPKD. Our natural product library was prepared based on the ZINC-15 database. Lipinski's rule of five, drug-likeness, and toxicity screening of the designed library were evaluated. Swiss model online server was used for modeling of GANAB target. Finally, docking-based screening against ADPKD targets was done by MOE 2019 software. The top 14 favorable druglike and non-toxic hits were selected for docking studies. Our results showed that compound-10 (ZINC 6073947) as a sesquiterpene coumarin had more negative binding interaction into the active site of PPARG, OXSR1, GANAB, AVPR2, and PC2 with docking scores of -8.22, -7.52, -6.98, -6.61 and -6.05 kcal/mol, respectively, in comparison to Curcumin, as a natural product that is now in phase 4 clinical trial in ADPKD disease, with an affinity of -8.03, -6.42, -6.82, -5.84 and -5.10 kcal/mol, respectively. Furthermore, seven sesquiterpene coumarins similar to compound 10 were generated and docked. Farnesiferol B (16), compared to compound-10, showed binding affinity of -8.16, -6.4, -7.46, -6.92, and -6.11 kcal/mol against the above targets, respectively. Molecular dynamics, which was done on the compound-10 and 16 (Farnesiferol B) in complex with PPARG, GANAB, and AVPR2, showed more negative binding free-energy than Pioglitazone, Miglitol, and Tolvaptan as FDA-approved drugs for each target, respectively.Communicated by Ramaswamy H. Sarma.

Development of Sustained Release Formulations Based on Lipid-Liquid Crystal to Control the Release of Deoxycholate: In Vitro and In Vivo Assessment.

Subcutaneous injections of phosphatidylcholine (PC), sodium deoxycholate (NADC), and a mixture of them were found to be an effective option for treating cellulite. However, it is noteworthy that the injection of NADC may result in inflammation as well as necrosis in the injection area. The preparation of a sustained release formulation based on lipid-liquid crystal that controls the release of NADC could be a potential solution to address the issue of inflammation and necrosis at the site of injection. To present a practical and validated approach for accurately determining the concentration of NADC in LLC formulations, spectrofluorimetry was used based on the International Council for Harmonization (ICH) Q2 guidelines. Based on the validation results, the fluorometric technique has been confirmed as a reliable, efficient, and economical analytical method for quantifying NADC concentrations. The method demonstrated favorable attributes of linearity, precision, and accuracy, with an r2 value of 0.999. Furthermore, it exhibited excellent interday and intraday repeatability, with RSD values below 4%. The recovery percentages ranged from 97 to 100%, indicating the method's ability to accurately measure NADC concentrations. The subcutaneous injection of the LLC-NADC demonstrated a reduction in inflammation and tissue necrosis in skin tissue, along with an increase in fat lysis within 30 days, when compared to the administration of only NADC solution. Moreover, the histopathological assessment confirmed that the use of the LLC formulation did not result in any detrimental side effects for kidney or heart tissue.

Preparation, Characterization, and Molecular Dynamic Simulation of Novel Coenzyme Q10 Loaded Nanostructured Lipid Carriers.

BACKGROUND: Research proved that coenzyme Q10-loaded NLC effectively removes skin wrinkles, therefore, such a formulation with good characteristics is still the research goal. OBJECTIVE: This study investigated the effect of solid lipids and surfactant type on the physical characteristics of Q10-NLC. We aimed to achieve the optimum formulation for producing NLC with long-term stability and high Entrapment efficiency (E.E.) %. We compared the experimental results with the output of the Molecular dynamic (M.D.) simulations. METHODS: To develop Q10-NLC, various solid lipids, MCT oil, and surfactants were employed. The formulations were prepared by high-shear homogenization and ultrasound methods. Stability studies were carried out 1,3, and 6 months at 4, 25, and 40°C. The optimized NLC formulations were characterized by photon correlation spectroscopy (PCS), Transmission electron microscopy (TEM), Differential scanning calorimetry (DSC), and Fourier transform infrared (FT-IR). E.E. % was determined by HPLC analysis. Atomistic M.D. simulations of two model systems were performed to gain insights into the self-assembled process of co-Q10 with other formulation components. RESULTS: Statistical analysis (Two-way ANOVA) revealed that solid lipid and surfactant factors had a significant influence on particle size, PDI, and zeta potential (***p < 0.0001). According to the results, F1 and F6 formulations had desirable surface characterizations, physicochemical stability, and high E.E. %. The atomistic M.D. simulations confirmed that the F1 system (best) was more stable than the F31 system (worst). CONCLUSION: The solid lipids: tripalmitin and compritol, stabilized with 4% tween 80 and 1% span 80, have produced stable NLC with the best surface characteristics that could be a promising formulation for the delivery of Q10. Atomistic M.D. simulation has confirmed the stability of F1 in comparison to F31.

Injectable In-Situ Forming Depot Based on PLGA and PLGA-PEG-PLGA for Sustained-Release of Risperidone: In Vitro Evaluation and Pharmacokinetics in Rabbits.

In the current research, novel drug delivery systems based on in situ forming gel (ISFG) (PLGA-PEG-PLGA) and in situ forming implant (ISFI) (PLGA) were developed for one-month risperidone delivery. In vitro release evaluation, pharmacokinetics, and histopathology studies of ISFI, ISFG, and Risperdal CONSTA® were compared in rabbits. Formulation containing 50% (w/w %) of PLGA-PEG-PLGA triblock revealed sustained release for about one month. Scanning electron microscopy (SEM) showed a porous structure for ISFI, while a structure with fewer pores was observed in the triblock. Cell viability in ISFG formulation in the first days was more than ISFI due to the gradual release of NMP to the release medium. Pharmacokinetic data displayed that optimal PLGA-PEG-PLGA creates a consistent serum level in vitro and in vivo through 30 days, and histopathology results revealed nearly slight to moderate pathological signs in the rabbit's organs. The shelf life of the accelerated stability test didn't affect the results of the release rate test and demonstrated stability in 24 months. This research confirms the better potential of the ISFG system compared with ISFI and Risperdal CONSTA®, which would increase patients' compliance and avoid problems of further oral therapy.

Signal amplification strategies in biosensing of extracellular vesicles (EVs).

Extracellular vesicles (EVs) are membrane-enclosed vesicles secreted from mammalian cells. EVs act as multicomponent delivery vehicles to carry a wide variety of biological molecular information and participate in intercellular communications. Since elevated levels of EVs are associated with some pathological states such as inflammatory diseases and cancers, probing circulating EVs holds a great potential for early diagnostics. To this end, several detection methods have been developed in which biosensors have attracted great attentions in identification of EVs due to their simple instrumentation, versatile design and portability for point-of-care applications. The concentrations of EVs in bodily fluids are extremely low (i.e. 1-100 per µl) at early stages of a disease, which necessitates the use of signal amplification strategies for EVs detection. In this way, this review presents and discusses various amplification strategies for EVs biosensors based on detection modalities including surface plasmon resonance (SPR), calorimetry, fluorescence, electrochemical and electrochemiluminescence (ECL). In addition, microfluidic systems employed for signal amplification are reviewed and discussed in terms of their design and integration with the detection methods.

Simultaneous determination of mometasone furoate and calcipotriol in a binary mixture by validated HPLC and chemometric-assisted UV spectrophotometric methods and identification of degradation products by LC-MS.

Objectives: A new binary mixture containing mometasone furoate (MF) and calcipotriol (CP) is suggested to manage psoriasis; since the combined stability profile of these drugs is poorly understood. Materials and Methods: Herein MF, CP, and their mixtures were subjected to various stress conditions. Also, stability-indicating HPLC was developed and validated according to ICH guidelines with Box-Behnken design. The degradation products (DPs) were predicted in silico and identified using LC-MS. The bioactivity and toxicity of DPs were studied using molecular docking and alamarBlue assay, respectively. Spectroscopic techniques of the first derivative, first-derivative ratio, and the mean-centering of ratio spectra were also used to determine MF and CP in the mixture because of spectra overlapping. Results: The major degradants for MF in alkaline conditions were DP1, DP2, and DP3, while in thermal and UV conditions, only DP1 was generated. CP gave one degradant in all conditions. No new impurity was observed in the MF and CP mixtures. The results of spectrophotometry showed good linearity in the range of 4-50 and 2-20 µg/ml, while linearity for HPLC was in the range of 4-50 and 0.5-2.5 µg/ml for MF and CP, respectively. Recovery was 99.61-100.38% for UV and 100.4% for HPLC methods of MF and 100.6-101.4% for UV and 99.5% for HPLC methods of CP. Conclusion: The developed methods can be used as simple, accurate, precise, and rapid techniques for routine quality control of MF and CP mixtures.

Recent Progresses in Analytical Perspectives of Degradation Studies and Impurity Profiling in Pharmaceutical Developments: An Updated Review.

Forced degradation studies have been used to simplify analytical methodology development and achieve a deeper knowledge about the inherent stability of active pharmaceutical ingredients (API) and drug products. This provides insight into degradation species and pathways. Identification of impurities in pharmaceutical products is closely related to the selection of the most appropriate analytical methods like HPLC-UV, LC-MS/MS, LC-NMR, GC-MS, and capillary electrophoresis. Herein, recent trends in analytical perspectives during 2018-April 14, 2021, are discussed based on forced and impurity degradation profiling of pharmaceuticals. Literature review showed that several methods have been used for experimental design and analysis conditions such as matrix type, column type, mobile phase, elution modes, detection wavelengths, and therapeutic category. Thus, since these factors influence the separation and identification of the impurities and degradation products, we attempted to perform a statistical analysis for the developed methods according to the abovementioned factors.

Evaluation of apigenin-based biflavonoid derivatives as potential therapeutic agents against viral protease (3CLpro) of SARS-CoV-2 via molecular docking, molecular dynamics and quantum mechanics studies.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic COVID-19 disease that affects human respiratory function. Despite the scientific progression made in the development of the vaccine, there is an urgent need for the discovery of antiviral drugs for better performance at different stages of SARS-CoV-2 reproduction. The main protease (Mpro or 3CLpro) plays a pivotal role in the life cycle of the virus, making it an attractive target for the development of antiviral agents effective against the new strains of coronaviruses (CoVs). In this study, a series of apigenin-based natural biflavonoid derivatives as potential inhibitors of coronaviruses 3CLpro was investigated by in silico approaches. For this purpose, the molecular docking was performed to analyze the interaction of the natural biflavonoids with SARS-Cov-2 main protease and for further investigation, docking to the 3CLpro of SARS-CoV and MERS-CoV. Based on docking scores and comparison with the reference inhibitors (ritonavir and lopinavir), more than half of the biflavonoids had strong interactions with the residues of the binding pocket of the coronaviruses 3CLpro and exhibited better binding affinities toward the main protease than ritonavir and lopinavir. The top biflavonoids were further explored through molecular dynamics simulation, binding free energy calculation and residual energy contributions estimated by the MM-PBSA. Also, drug likeness property investigation by Swiss ADME tools and density functional theory (DFT) calculations were performed. The results confirmed that the 3CLpro-amentoflavone, 3CLpro-bilobetin, 3CLpro-ginkgetin, and 3CLpro-sotetsuflavone complexes possess a large amount of dynamic properties such as high stability, significant binding energy and fewer conformation fluctuations. Also, the pharmacokinetics and drug-likeness studies and HOMO-LUMO and DFT descriptor values indicated a promising result of the selected natural biflavonoids. Overall findings indicate that the apigenin-based biflavonoids may inhibit COVID-19 by significant interactions in the binding pocket and those results can pave the way in drug discovery although the effectiveness of these bioactive compounds should be further validated by in-vitro and in-vivo investigations.Communicated by Ramaswamy H. Sarma.

Preparation of porous PCL-PEG-PCL scaffolds using supercritical carbon dioxide.

In this study, the Supercritical Carbon Dioxide (scCO2) gas foaming procedure was used in the preparation of scaffolds containing the model drug dexamethasone (DXMT). The method used did not include an organic solvent thus making it a safe method. The ring-opening polymerization of PCL-PEG-PCL (PCEC) triblock was conducted using an organocatalyst [1,8 diazabicyclo [5.4.0] undec-7-ene (DBU)]. After mixing 5.0 g of DXMT with 50.0 g of PCEC, hydraulic pressure was applied to compress the mixed powder into disc-like tablets. The tablet-like scaffold of the triblock containing DXMT was inserted into a scCO2 gas-foaming device. The peak porosity percentage of the synthesized triblock was found to be 55.58 %. Pressure, temperature, soaking time and the time required to depressurize were recorded as 198 bar, 50 °C, 2.0 h, and 28 min respectively. After treatment with scCO2, the scaffolds experienced an almost full release of DXMT in vitro after 30 days (83.74 ± 1.54 % vs 52.24 ± 2.03 % before scCO2 treatment). In conclusion, the results proved that the scCO2 gas foaming procedure could be employed for constructing modifiable PCEC scaffolds with plausible porosity and structural and morphological features which can manipulate drug release.

In-vitro and in-vivo evaluation of sustained-release buprenorphine using in-situ forming lipid-liquid crystal gels.

AIMS: Sustained-release systems reduce the incidence of drug side effects and the need for frequent drug consumption, thus increasing patient compliance with treatment. In this study, we aimed to produce sustained-release buprenorphine (BP) using lipid-liquid crystal gels. MAIN METHODS: The three experimental groups in this study included: group I: lipid-liquid crystal formulation 5 (F5) containing BP, group II: BP-free F5, group III: BP solution in NMP, and group IV: control (no treatment). The formulations were injected subcutaneously into the rabbits' back neck. KEY FINDINGS: The results showed that the time required to reach the drug's maximum concentration (Tmax) was longer in group I than in group III. The maximum BP concentration (Cmax) and the constants of the drug removal rate and drug absorption rate (Ka) were significantly higher in group III compared to group I. The half-life (t1/2) of the drug in blood circulation was significantly longer in group I than in group III. Histopathological analysis revealed no histological abnormalities in the skin and heart in group I (BP-containing F5); however, mild hyperemia was observed in interstitial vessels in group III (BP-containing NMP). The kidney and liver tissues showed normal structure in the control group, as well as groups I and II. However, in the group receiving BP-containing NMP, significant congestion, tissue damage, necrosis, and fibrosis were observed in the kidney and liver. SIGNIFICANCE: The results showed that the lipid-liquid crystal system can be used to design slow-release platforms for BP, minimizing the side effects associated with the use of its conventional forms.

The Effects of Lycopene on Modulating Oxidative Stress and Liver Enzymes Levels in Metabolic Syndrome Patients: A Randomised Clinical Trial.

OBJECTIVE: The pathogenesis of metabolic syndrome (MetS) complications involves the excessive production of
reactive oxygen species, inflammation, and endothelial dysfunction. Due to Lycopene, a highly unstable structure and
its significant effects on modulating the metabolic system, there is a strong need for a formula that can increase its
stability. The aim of this study was to develop an approach for encapsulating Lycopene and investigate its effects on
inflammatory markers, oxidative stress, and liver enzymes in patients with MetS.
Materials and Methods: This study is a simple randomized, double-blind, objective-based clinical trial that involved
eighty subjects with MetS, who were equally and randomly assigned to two groups: one group received 20 mg of
Lycopene per day for 8 weeks, and the Placebo group followed the same protocol as the Lycopene group but received
a placebo instead of Lycopene. They were called Lycopene and placebo, respectively. During follow-up visits after 4
and 8 weeks, 20 ml of blood was collected for evaluation of liver enzymes and some inflammatory related markers.
Results: Prior to the assignment of volunteers to their respective groups, there were no notable differences in C-reactive
protein (CRP), serum liver enzymes, systolic and diastolic blood pressure, or pro-oxidant-antioxidant balance (PAB)
between the Lycopene and placebo groups. However, our subsequent analysis revealed a significant reduction in the
serum levels of CRP (P=0.001) and PAB (P=0.004) in the group that received Lycopene. Our encapsulated Lycopene
treatment was not associated with a significant difference in serum levels of alanine aminotransferase (ALT), aspartate
transferase (AST), or alkaline phosphatase (ALP) between our two groups.
Conclusion: This study investigated the impact of Lycopene on individuals with MetS, revealing a noteworthy
modulation effect on PAB and inflammation linked to MetS. However, no significant differences was demonstrated in
serum levels of ALT, AST and ALP between the studied group (registration number: IRCT20130507013263N3).