Solid lipid nanoparticles (SLNs), the potential novel vehicle for enhanced in vivo efficacy of hesperidin as an anti-inflammatory agent.

Hesperidin (C28H34O15), a flavanone glycoside abundantly present in citrus fruits, has proven therapeutic effects including anti-inflammatory activities. Herein, we report a novel formulation of HESP loaded solid lipid nanoparticles (SLNs) using hot homogenization and ultrasound to improve the poor solubility and bioavailability. In the present study, the formulation was developed and optimized by response surface method and then characterized by scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy (FT-IR), and dynamic light scattering (DLS). Encapsulation efficiency was determined and the anti-inflammatory effect was assessed through in vivo ear edema inflammation model. According to the electron microscopy results, the product has a spherical shape. The optimized parameters produced small size (179.8 ± 3.6 nm) HESP-SLNs with high encapsulation efficiency (93.0 ± 3.8 %). The outcomes exhibited that encapsulation in SLNs carriers improves the anti-inflammatory potential of HESP.

Assessment of Cytotoxicity and Odontogenic/Osteogenic Differentiation Potential of Nano-Dentine Cement Against Stem Cells from Apical Papilla.

OBJECTIVE: Assessment of the cytotoxicity of novel calcium silicate-based cement is imperative in endodontics. This experimental study aimed to assess the cytotoxicity and odontogenic/osteogenic differentiation potential of a new calcium silicate/pectin cement called Nano-dentine against stem cells from the apical papilla (SCAPs). MATERIALS AND METHODS: In this experimental study, the cement powder was synthesized by the sol-gel technique. Zirconium oxide was added as opacifier and Pectin, a plant-based polymer, and calcium chloride as the liquid to prepare the nano-based dental cement. Thirty-six root canal dentin blocks of human extracted single-canal premolars with 2 mm height, flared with #1, 2 and 3 Gates-Glidden drills were used to prepare the cement specimens. The cement, namely mineral trioxide aggregate (MTA), Biodentine, and the Nano-dentine were mixed according to the manufacturers' instructions and applied to the roots of canal dentin blocks. The cytotoxicity and odontogenic/osteogenic potential of the cement were evaluated by using SCAPs. RESULTS: SCAPs were characterized by the expression of routine mesenchymal cell markers and differentiation potential to adipocytes, osteoblasts, and chondrocytes. Cement displayed no significant differences in cytotoxicity or calcified nodules formation. Gene expression analysis showed that all three types of cement induced significant down- regulation of COLA1; however, the new cement induced significant up-regulation of RUNX2 and SPP1 compared to the control group and MTA. The new cement also induced significant up-regulation of TGFB1 and inducible nitric oxide synthase (iNOS) compared with Biodentine and MTA. CONCLUSION: The new Nano-dentin cement has higher odontogenic/osteogenic potential compared to Biodentine and MTA for differentiation of SCAPs to adipocytes, osteoblasts, and chondrocytes.

Short-term celecoxib (celebrex) adjuvant therapy: a clinical trial study on COVID-19 patients.

BACKGROUND: It is known that severe acute respiratory coronavirus 2 (SARS-CoV-2) is the viral strain responsible for the recent coronavirus disease 2019 (COVID-19) pandemic. Current documents have demonstrated that the virus causes a PGE2 storm in a substantial proportion of patients via upregulating cyclooxygenase-2 (COX-2) and downregulating prostaglandin E2 (PGE2)-degrading enzymes within the host cell. AIM: Herein, we aimed to study how short-term treatment with celecoxib (Celebrex), a selective COX-2 inhibitor, affects demographic features, early symptoms, O2 saturation, and hematological indices of cases with COVID-19. METHODS: A total of 67 confirmed COVID-19 cases with a mild or moderate disease, who had been referred to an institutional hospital in south-eastern Iran from October 2020 to September 2021, were enrolled. Demographic characteristics, symptoms, and hematological indices of the patients were recorded within different time periods. One-way ANOVA or Kruskal-Wallis tests were used to determine differences between data sets based on normal data distribution. RESULTS: O2 saturation was statistically different between the control group and patients receiving celecoxib (p = 0.039). There was no marked difference between the groups in terms of the symptoms they experienced (p > 0.05). On the first days following Celebrex therapy, analysis of complete blood counts showed that white blood cell (WBC) counts were markedly lower in patients treated with a high dose of celecoxib (0.4 g/day) than in controls (p = 0.026). However, mean lymphocyte levels in patients receiving a high dose of celecoxib (0.4 g/day) were markedly higher than in patients receiving celecoxib with half of the dose (0.2 g/day) for one week or the untreated subjects (p = 0.004). Changes in platelet count also followed the WBC alteration pattern. CONCLUSION: Celecoxib is a relatively safe, inexpensive, and widely available drug with non-steroidal anti-inflammatory properties. The therapeutic efficacy of celecoxib depends on the administrated dose. Celecoxib might improve disease-free survival in patients with COVID-19.

Effects of folate-conjugated Fe2O3@Au core-shell nanoparticles on oxidative stress markers, DNA damage, and histopathological characteristics: evidence from in vitro and in vivo studies.

The aim of this work was to assess the cytotoxicity, genotoxicity, and histopathological effects of Fe2O3@Au-FA NPs using in vitro and in vivo models. Cytotoxicity and cellular uptake of nanoparticles (NPs) by HUVECs were examined via 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and inductively coupled plasma-mass-spectrometry (ICP-MS). This safe dose was then used for cytotoxicity assays, including total protein, total antioxidant capacity, lipid peroxidation, cell membrane integrity, reactive oxygen species, enzyme activity, and DNA damage. In the animal model, 32 Wistar rats were randomly categorized into 4 groups and received intraperitoneal injections of NPs. Blood samples for biochemical properties and histopathological changes were investigated. MTT results indicated 20 µg/ml as the safe dose for NPs. According to ICP-MS, treated cells showed significantly higher levels of the intracellular content of Fe (p < 0.001) and Au (p < 0.01) compared with the control group. In vitro tests did not show any significant cytotoxicity or genotoxicity at the safe dose of NPs. We found no significant elevation in intracellular γ-H2AX levels after treatment of HUVEC cells with Fe2O3@Au core-shell NPs (P > 0.05). As for the in vivo analysis, we observed no marked difference in serum biochemical parameters of rats treated with 50 mg/kg and 100 mg/kg doses of our NPs. Histopathological assessments indicated that liver, kidney, and testis tissues were not significantly affected at 50 mg/kg (liver), 50 mg/kg, and 100 mg/kg (kidney and testis) on NPs administration. These findings imply that the nanotoxicity of Fe2O3@Au-FA NPs in HUVECs and animals depends largely on the administrated dose. Our study suggests that Fe2O3@Au-FA NPs at a safe dose could be considered as new candidates in nanobiomedicine.

SARS-CoV-2 and influenza viruses: Strategies to cope with coinfection and bioinformatics perspective.

Almost a century after the devastating pandemic of the Spanish flu, humankind is facing the relatively comparable global outbreak of COVID-19. COVID-19 is an infectious disease caused by SARS-CoV-2 with an unprecedented transmission pattern. In the face of the recent repercussions of COVID-19, many have argued that the clinical experience with influenza through the last century may have tremendous implications in the containment of this newly emerged viral disease. During the last 2 years, from the emergence of COVID-19, tremendous advances have been made in diagnosing and treating coinfections. Several approved vaccines are available now for the primary prevention of COVID-19 and specific treatments exist to alleviate symptoms. The present review article aims to discuss the pathophysiology, diagnosis, and treatment of SARS-CoV-2 and influenza A virus coinfection while delivering a bioinformatics-based insight into this subject matter.

Convalescent Blood: Current Perspective on the Efficacy of a Legacy Approach in COVID-19 Treatment.

Since early 2020, COVID-19 has wreaked havoc in many societies around the world. As of the present, the SARS-CoV-2-borne disease is propagating in almost all countries, affecting hundreds of thousands of people in an unprecedented way. As the name suggests, the novel coronavirus, widely known as SARS-CoV-2, is a new emerging human pathogen. A novel disease of relatively unknown origin, COVID-19 does not seem to be amenable to the currently available medicines since there is no specific cure for the disease. In the absence of any vaccine or effective antiviral medication, we have no tools at our disposal, but the method of quarantine, be it domestic or institutional, to hinder any further progression of this outbreak. However, there is a record of physicians in the past who practiced convalescent blood transfusion. To their awe, the method seemed to be useful. It is anticipated that these contemporary methods will outdo any other vaccination process in the time being, as blood transfusion is instead a cost-effective and time-friendly technique. Following a successful trial, this new approach of contemporary nature to a viral disease may serve as an emergency intervention to intercept infectious outbreaks and prevent an impending epidemic/pandemic. In this review, we document the most recent evidence regarding the efficiency of convalescent plasma and serum therapy on SARS, MERS, and particularly COVID-19, while discussing potential advantages and possible risks of such practice.

Chromium (III) Complexes of 4,5-diazafluoren-9-one Ligand as Potential Anti-proliferative Agents: Synthesis, Characterization, DNA Binding, Molecular Docking and In-vitro Cytotoxicity Evaluation.

Three novel Cr(III) complexes, [Cr(dafone)2(H2O)2](NO3)3 (1), [Cr(opd) (dafone)2](NO3)3 (2) and [Cr (phen-dione) (dafone) (H2O)2].(NO3)3 (3) were synthesized and characterized by different techniques. Fluorescence spectroscopy, gel electrophoresis, viscosity measurement, and circular dichroism (CD) were applied to explore the interaction of Cr complexes with FS-DNA. The binding constant (Kb) was obtained from UV-Vis measurements. The obtained results exhibited the effective binding of target complexes to DNA double-strand. The fluorescence data appraised both binding and thermodynamic constants of complexes-DNA interactions. The measured thermodynamic factors (∆S˚, ∆H˚, ∆G˚) revealed that hydrogen bonding and van der Waals forces for DNA- Cr(III) complexes bear the most important roles. As well, the Stern-Volmer quenching constants (Ksv) and the binding constants (Kb) of synthesized compounds and DNA were calculated. The results of thermodynamic parameters showed that the binding of synthesized Cr(III) compounds to DNA was driven mainly through hydrogen bonds and van der Waals interactions. Viscosity measurement results showed that increasing the concentration of synthesized compounds, did not make any major changes in specific viscosity of FS-DNA. The data of viscosity and circular dichroism (CD) support the groove binding mode.

An Updated Review on Implications of Autophagy and Apoptosis in Tumorigenesis: Possible Alterations in Autophagy through Engineered Nanomaterials and Their Importance in Cancer Therapy.

Most commonly recognized as a catabolic pathway, autophagy is a perplexing mechanism through which a living cell can free itself of excess cytoplasmic components, i.e., organelles, by means of certain membranous vesicles or lysosomes filled with degrading enzymes. Upon exposure to external insult or internal stimuli, the cell might opt to activate such a pathway, through which it can gain control over the maintenance of intracellular components and thus sustain homeostasis by intercepting the formation of unnecessary structures or eliminating the already present dysfunctional or inutile organelles. Despite such appropriateness, autophagy might also be considered a frailty for the cell, as it has been said to have a rather complicated role in tumorigenesis. A merit in the early stages of tumor formation, autophagy appears to be salutary because of its tumor-suppressing effects. In fact, several investigations on tumorigenesis have reported diminished levels of autophagic activity in tumor cells, which might result in transition to malignancy. On the contrary, autophagy has been suggested to be a seemingly favorable mechanism to progressed malignancies, as it contributes to survival of such cells. Based on the recent literature, this mechanism might also be activated upon the entry of engineered nanomaterials inside a cell, supposedly protecting the host from foreign materials. Accordingly, there is a good chance that therapeutic interventions for modulating autophagy in malignant cells using nanoparticles may sensitize cancerous cells to certain treatment modalities, e.g., radiotherapy. In this review, we will discuss the signaling pathways involved in autophagy and the significance of the mechanism itself in apoptosis and tumorigenesis while shedding light on possible alterations in autophagy through engineered nanomaterials and their potential therapeutic applications in cancer. SIGNIFICANCE STATEMENT: Autophagy has been said to have a complicated role in tumorigenesis. In the early stages of tumor formation, autophagy appears to be salutary because of its tumor-suppressing effects. On the contrary, autophagy has been suggested to be a favorable mechanism to progressed malignancies. This mechanism might be affected upon the entry of nanomaterials inside a cell. Accordingly, therapeutic interventions for modulating autophagy using nanoparticles may sensitize cancerous cells to certain therapies.

8-Alkylmercaptocaffeine derivatives: antioxidant, molecular docking, and in-vitro cytotoxicity studies.

Due to their unique pharmacological characteristics, methylxanthines are known as therapeutic agents in a fascinating range of medicinal scopes. In this report, we aimed to examine some biological effects of previously synthesized 8-alkylmercaptocaffeine derivatives. Cytotoxic and antioxidative activity of 8-alkylmercaptocaffeine derivatives were measured in malignant A549, MCF7, and C152 cell lines. Assessment of cGMP levels and caspase-3 activity were carried out using a colorimetric competitive ELISA kit. Computational approaches were employed to discover the inhibitory mechanism of synthesized compounds. Among the twelve synthesized derivatives, three compounds (C1, C5, and C7) bearing propyl, heptyl, and 3-methyl-butyl moieties showed higher and more desirable cytotoxic activity against all the studied cell lines (IC50 < 100 µM). Furthermore, C5 synergistically enhanced cisplatin-induced cytotoxicity in MCF-7 cells (CI < 1). Both C5 and C7 significantly increased caspase-3 activity and intracellular cGMP levels at specific time intervals in all studied cell lines (P < 0.05). However, these derivatives did not elevate LDH leakage (P > 0.05) and exhibited no marked ameliorating effects on oxidative damage (P > 0.05). Computational studies showed that H-bond formation between the nitrogen atom in pyrazolo[4,3-D] pyrimidine moiety with Gln817 and creating a hydrophobic cavity result in the stability of the alkyl group in the PDE5A active site. We found that synthesized 8-alkylmercaptocaffeine derivatives induced cell death in different cancer cells through the cGMP pathway. These findings will help us to get a deeper insight into the role of methylxanthines as useful alternatives to conventional cancer therapeutics.

The role of autophagy in controlling SARS-CoV-2 infection: An overview on virophagy-mediated molecular drug targets.

Autophagy-dependent cell death is a prominent mechanism that majorly contributes to homeostasis by maintaining the turnover of organelles under stressful conditions. Several viruses, including coronaviruses (CoVs), take advantage of cellular autophagy to facilitate their own replication. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta-coronavirus (ß-CoVs) that mediates its replication through a dependent or independent ATG5 pathway using specific double-membrane vesicles that can be considered as similar to autophagosomes. With due attention to several mutations in NSP6, a nonstructural protein with a positive regulatory effect on autophagosome formation, a potential correlation between SARS-CoV-2 pathogenesis mechanisms and autophagy can be expected. Certain medications, albeit limited in number, have been indicated to negatively regulate autophagy flux, potentially in a way similar to the inhibitory effect of ß-CoVs on the process of autophagy. However, there is no conclusive evidence to support their direct antagonizing effect on CoVs. Off-target accumulation of a major fraction of FDA-approved autophagy modulating drugs may result in adverse effects. Therefore, medications that have modulatory effects on autophagy could be considered as potential lead compounds for the development of new treatments against this virus. This review discusses the role of autophagy/virophagy in controlling SARS-CoV-2, focusing on the potential therapeutic implications.

Application of Nanobiotechnology for Early Diagnosis of SARS-CoV-2 Infection in the COVID-19 Pandemic.

A most discussed topic of the new decade, COVID-19 is an infectious disease caused by the recently discovered SARS-CoV-2. With an exceedingly high transmission rate, COVID-19 has affected almost all the countries in the world. Absent any vaccine or specific treatment, the humanity is left with nothing but the legacy method of quarantine. However, quarantine can only be effective when combined with early diagnosis of suspected cases. With their high sensitivity and unmatched specificity, biosensors have become an area of interest for development of novel diagnostic methods. Compared to the more traditional diagnostics, nanobiotechnology introduces biosensors as different diagnostics with greater versatility in application. Today, a growing number of analytes are being accurately identified by these nanoscopic sensing machines. Several reports of validated application with real samples further strengthen this idea. As of recent, there has been a rise in the number of studies on portable biosensors. Despite the slow progression, certain devices with embedded biosensors have managed to be of diagnostic value in several countries. The perceptible increase in development of mobile platforms has revolutionized the healthcare delivery system in the new millennium. The present article reviews the most recent advancements in development of diagnostic nanobiosensors and their application in the clinical fields. KEY POINTS: • There is no specific treatment for highly transmissible SARS-CoV-2. • Early diagnosis is critical for control of pandemic. • Highly sensitive/specific nanobiosensors are emerging assets against COVID-19.

Two novel bipyridine-based cobalt (II) complexes: synthesis, characterization, molecular docking, DNA-binding and biological evaluation.

Bipyridine derivatives have shown different applications in chemistry such as electron transfer, catalysis, biological systems and artificial photosynthesis. Two cobalt(II) complexes with formula [Co(5,5'-dmbipy)2(NCS)2]1 and [Co(5,5'-dmbipy)3] [Co(NCS)4]2 were prepared. The metal complexes 1 and 2 were characterized through FT-IR, electronic absorption, elemental analysis and 1H-NMR. The interaction of complexes 1 and 2 with FS-DNA was investigated by fluorescence, UV-Vis and gel electrophoresis. The antibacterial properties have been studied in vitro against two gram-negative and two gram-positive standard bacterial strains. The synthesized complexes were further investigated against MCF-7 cells at 25, 50, 100 and 200 µM. The results revealed that the metal complexes can bind effectively to FS-DNA. The measured thermodynamic factors (ΔH°, ΔS° and ΔG°) displayed that hydrogen bonding, van der Waals forces (for DNA-compound 1) and electrostatic binding (for DNA-compound 2) are the most important interactions. The binding forces in metal complexes 1 and 2 are spontaneous as suggested by the negative ΔG°. Specific viscosity of FS-DNA remained without significant changes while the concentration of complexes 1 and 2 increased. The results of molecular docking with FS-DNA illustrate the binding sites and binding modes that are in acceptable agreement with experimental results. The biological results determined that complexes 1 and 2 exhibit antibacterial activities that are better than those shown for their corresponding metal salt and free ligand. The target compounds showed low-to-moderate cytotoxicity activities. The obtained results revealed that the synthesized complexes are stronger antibacterial agents against the gram-positive than gram-negative bacteria. In the present study, for the first time we reported two Co(II) complexes bearing 5,5'-dimethyl-2,2'-bipyridine ligands.Communicated by Ramaswamy H. Sarma.

A binuclear iron(III) complex of 5,5'-dimethyl-2,2'-bipyridine as cytotoxic agent.

The binuclear iron(III) complex (1), namely, {[Fe(5,5'-dmbpy)2(OH2)]2(µ-O)}(NO3)4 with a distorted octahedral coordination, formed by four nitrogen and two oxygen atoms, was previously reported by our team. In this study the DNA-binding and cytotoxicity evaluation for target complex were studied. The results indicated strong cytotoxicity activity against A549 cells comparable to cisplatin values. The binding interaction between complex 1 and FS-DNA was investigated by UV-Vis, fluorescence spectroscopy, and gel electrophoresis at physiological pH (7.2). The DNA binding investigation has shown groove binding interactions with complex 1, therefore the hydrogen binding plays an important role in the interaction of DNA with complex 1. The calculated thermodynamic parameters (ΔH°, ΔS° and ΔG°) show that hydrogen bonding and Vander-Waals forces have an important function in Fe(III) complex-DNA interaction. Moreover, DNA cleavage was studied using agarose gel electrophoresis. Viscosity measurements illustrated that relative viscosity of DNA was unchanged with the adding concentrations of Fe(III) complex. Molecular docking simulation results confirmed the spectroscopic and viscosity titration outcomes.

COVID-19 under spotlight: A close look at the origin, transmission, diagnosis, and treatment of the 2019-nCoV disease.

Months after the outbreak of a new flu-like disease in China, the entire world is now in a state of caution. The subsequent less-anticipated propagation of the novel coronavirus disease, formally known as COVID-19, not only made it to headlines by an overwhelmingly high transmission rate and fatality reports, but also raised an alarm for the medical community all around the globe. Since the causative agent, SARS-CoV-2, is a recently discovered species, there is no specific medicine for downright treatment of the infection. This has led to an unprecedented societal fear of the newly born disease, adding a psychological aspect to the physical manifestation of the virus. Herein, the COVID-19 structure, epidemiology, pathogenesis, etiology, diagnosis, and therapy have been reviewed.

5-Oxo-hexahydroquinoline Derivatives and Their Tetrahydroquinoline Counterparts as Multidrug Resistance Reversal Agents.

Cancer is a leading cause of death worldwide. Multidrug resistance (MDR) is a main reason of chemotherapy failure in many patients and is often related to overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp/ABCB1). Agents that are capable of modulation of the activity of these transporters might be effective in overcoming MDR. In this study, a new set of 1,4,5,6,7,8-hexahydro 5-oxo quinoline-3-carboxamide derivatives bearing 4-methylthiazole moiety and their tetrahydroquinoline counterparts were synthesized. MDR reversal activity of these 16 newly synthesized derivatives was tested in P-gp overexpressing MES-SA-DX5 human uterine sarcoma cells by flow cytometric determination of Rhodamine123 efflux. The effect of the most potent compounds in induction of apoptosis and alterations of cell cycle was examined in these cells by a flow cytometric method. Inherent cytotoxicity of the synthesized compounds was evaluated against MCF-7, A-549 and K562 cancer cell lines, as well as MES-SA-DX5 and their parental non-resistant MES-SA and also HEK-293 non-cancerous cells by MTT assay. Compounds A1 and A2 with 5-oxo-hexahydroquinoline structure bearing 2,4-dichlorophenyl and 4-bromophenyl moieties, respectively, and their tetrahydroquinoline counterparts B1 and B2 significantly blocked P-gp efflux, induced apoptosis and showed the highest cytotoxicities against MES-SA-DX5 cells. However, only A2 and B2 compounds were relatively selective against cancer and MDR cells as compared to non-resistant and non-cancerous cells. These findings demonstrate that 5-oxo-hexahydroquinoline and 5-oxo-tetrahydroquinoline derivatives represent promising agents with therapeutic potential in drug resistant cancers.

Electrochemical Nano-biosensors as Novel Approach for the Detection of Lung Cancer-related MicroRNAs.

In both men and women around the world, lung cancer accounts as the principal cause of cancer-related death after breast cancer. Therefore, early detection of the disease is a cardinal step in improving prognosis and survival of patients. Today, the newly-defined microRNAs regulate about 30 to 60 percent of the gene expression. Changes in microRNA Profiles are linked to numerous health conditions, making them sophisticated biomarkers for timely, if not early, detection of cancer. Though evaluation of microRNAs in real samples has proved to be rather challenging, which is largely attributable to the unique characteristics of these molecules. Short length, sequence similarity, and low concentration stand among the factors that define microRNAs. Recently, diagnostic technologies with a focus on wide-scale point of care have recently garnered attention as great candidates for early diagnosis of cancer. Electrochemical nano-biosensors have recently garnered much attention as a molecular method, showing great potential in terms of sensitivity, specificity and reproducibility, and last but not least, adaptability to point-of-care testing. Application of nanoscale materials in electrochemical devices as promising as it is, brings multiplexing potential for conducting simultaneous evaluations on multiple cancer biomarkers. Thanks to their enthralling properties, these materials can be used to improve the efficiency of cancer diagnostics, offer more accurate predictions of prognosis, and monitor response to therapy in a more efficacious way. This article presents a concise overview of recent advances in the expeditiously evolving area of electrochemical biosensors for microRNA detection in lung cancer.

Molecular dynamics simulation and molecular docking studies of 1,4-Dihydropyridines as P-glycoprotein's allosteric inhibitors.

P-glycoprotein (P-gp) is a main factor contributing to multidrug resistance. The effect of this transporter protein on limiting the effectiveness of chemotherapy has been shown by various studies. In a previous report, we synthesized some 14-dihydropyridine (DHP) derivatives as inhibitors of human P-gp. In the present study, a computational approach has been exploited to reveal the main interactions between DHPs and P-gp. In order to do this, homology modeling was performed to obtain a model of the protein. Then, molecular dynamics simulation was used to refine the constructed model of P-gp in the presence of the lipids bilayer. Model validation was performed with several tools. Finally, molecular docking followed by MD simulation of ligand-protein complex was employed to elucidate the binding mode and the dynamical changes of protein with/without DHPs bound. The results emphasized that interaction of the residues Gln912, Ser909, Arg905, Ser474, Val472 with DHPs play a crucial role in the inhibitory of these ligands and this was in a relatively good accordance with the results reported in the experimental studies.

Flavonoids as potent allosteric inhibitors of protein tyrosine phosphatase 1B: molecular dynamics simulation and free energy calculation.

Protein tyrosine phosphatase 1B (PTP1B) is a member of the PTP superfamily which is considered to be a negative regulator of insulin receptor (IR) signaling pathway. PTP1B is a promising drug target for the treatment of type 2 diabetes, obesity, and cancer. The existence of allosteric site in PTP1B has turned the researcher's attention to an alternate strategy for inhibition of this enzyme. Herein, the molecular interactions between the allosteric site of PTP1B with three non-competitive flavonoids, (MOR), (MOK), and (DPO) have been investigated. Three ligands were docked into allosteric site of the enzyme. The resulting protein-ligand complexes were used for molecular dynamics studies. Principal component and free-energy landscape (FEL) as well as cluster analyses were used to investigate the conformational and dynamical properties of the protein and identify representative enzyme substrates bounded to the inhibitors. Per residue energy decomposition analysis attributed dissimilar affinities of three inhibitors to the several hydrogen bonds and non-bonded interactions. In conclusion, our results exhibited an inhibitory pattern of the ligands against PTP1B.

Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study.

Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C4 and various carboxamide substituents at C3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells' sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C4 position and compounds with 4-chlorophenyl carboxamide at C3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100 µM, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25 µM, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal.

Structure-based design, synthesis, molecular docking study and biological evaluation of 1,2,4-triazine derivatives acting as COX/15-LOX inhibitors with anti-oxidant activities.

A set of 1,2,4-triazine derivatives were designed as cyclooxygenase-2 (COX-2) inhibitors. These compounds were synthesized and screened for inhibition of cyclooxygenases (COX-1 and COX-2) based on a cellular assay using human whole blood (HWB) and lipoxygenase (LOX-15) that are key enzymes in inflammation. The results showed that 3-(2-(benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine (G11) was identified as the most potent COX-2 inhibitor (78%) relative to COX-1 (50%). Ferric reducing anti-oxidant power (FRAP) assay revealed that compound G10 possesses the highest anti-oxidant activity. The compound G3 with IC50 value of 124 µM was the most potent compound in LOX inhibitory assay. Molecular docking was performed and a good agreement was observed between computational and experimental results.