Mutation Analysis of PAH Gene in Phenylketonuria Patients from the North of Iran: Identification of Three Novel Pathogenic Variants.

Background: There are more than 1100 different pathogenic variants in the phenylalanine hydroxylase (PAH) gene that are responsible for phenylketonuria (PKU) diseases, and the spectrum of these mutations varies in different ethnic groups. The aim of the present study was to identify the frequency of pathogenic variants in all 13 exons of the PAH gene among patients with PKU in Mazandaran and Golestan provinces in the north of Iran. Methods: Forty unrelated PKU patients from Mazandaran and Golestan provinces were enrolled in the study. Genomic DNA was extracted from leukocytes using a Qiagen DNA extraction kit and polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP), and Sanger sequencing methods were applied to detect the variants. In the case of new variants, the InterVar online tool (PMID: 28132688) was used to classify the variants. Results: Twenty-one different pathogenic variants were observed among the 40 investigated patients. The c.106611G>A variant had the highest frequency (27.5%) in the region, and the c.168+5G>C, c.473G>A, and c.782 G>A variants were the other most frequent mutations with allelic frequencies of 7.5, 5, and 5%, respectively. Three novel pathogenic variants including c.773T>G, c.878 T>C, and c. 1245del variants were observed among the investigated patients. Conclusions: The introduction of pathogenic variants in the PAH gene in each ethnic group provides valuable data regarding the understanding of the pathogenesis of the disease and can be helpful for prenatal diagnosis programs.

Design of new α-glucosidase inhibitors based on the bis-4-hydroxycoumarin skeleton: Synthesis, evaluation, and in silico studies.

In this work, we have reported the design, synthesis, in vitro, and in silico enzymatic evaluation of new bis-4-hydroxycoumarin-based phenoxy-1,2,3-triazole-N-phenylacetamide derivatives 5a-m as potent α-glucosidase inhibitors. All the synthesized analogues showed high inhibition effects against α-glucosidase (IC50 values ranging between 6.0 ± 0.2 and 85.4 ± 2.3 µM) as compared to the positive control acarbose (IC50 = 750.0 ± 0.6 µM). Among the newly synthesized compounds 5a-m, 2,4-dichloro-N-phenylacetamide derivative 5i with inhibition effect around 125-folds more than the acarbose was identified as the most potent entry. A structure-activity relationship (SAR) study about the title compounds 5a-m demonstrated that the inhibition effects of these compounds depend on the pattern of substitution on the N-phenylacetamide ring. The interaction modes and binding energies in the active site of enzyme of the important analogues (in term of SAR study) were evaluated through molecular docking study. Molecular dynamics and prediction of pharmacokinetic properties and toxicity of the most potent compound 5i also evaluated and the obtained data was compared with the acarbose.

Transition metal-catalyzed transformations of 2-formylarylboronic acids.

2-Formylarylboronic acids are easily available precursors in organic chemistry. Different types of transition metal catalysts, such as Pd(0), Pd(II), Rh(I), Ir(I), Ni(II), Cu(I), Cu(II), and Co(II), can efficiently catalyze coupling reactions of 2-formylarylboronic acids with other organic reactants. In this review, we describe the synthesis of a diverse range of carbocyclic and heterocyclic compounds, as well as acyclic compounds, via transition metal-catalyzed reactions of 2-formylarylboronic acids over the past two decades.

Unveiling the synergy: Biocompatible alginate-cellulose hydrogel loaded with silk fibroin and zinc ferrite nanoparticles for enhanced cell adhesion, and anti-biofilm activity.

Combining a biocompatible hydrogel scaffold with the cell-supportive properties of silk fibroin (SF) and the unique functionalities of ZnFe2O4 nanoparticles creates a promising platform for advanced nanobiomaterials. The research is centered on synthesizing a natural hydrogel using cellulose (Cellul) and sodium alginate (SA) combined with SF and zinc ferrite nanoparticles. A range of analytical and biological assays were conducted to determine the biological and physicochemical properties of the nanobiocomposite. The hemolysis and 2,5-diphenyl-2H-tetrazolium bromide (MTT) assays indicated that the SA-Cellul hydrogel/SF/ZnFe2O4 nanobiocomposite was a biocompatible against human dermal fibroblasts (Hu02) and red blood cells (RBC). In addition, aside from demonstrating outstanding anti-biofilm activity, the nanobiocomposite also promotes the Hu02 cells adhesion, showcasing the synergistic effect of incorporating SF and ZnFe2O4 nanoparticle. These promising results show that this nanobiocomposite has potential applications in various biomedical fields.

Transition Metal-Catalyzed Dual C-H Activation/Annulation Reactions Involving Internal Alkynes.

Recently, transition metal-catalyzed ortho-C-H bond activation/annulations involving two internal alkyne molecules have been extensively used to synthesize highly substituted polycyclic aromatic scaffolds. Such reactions have emerged as a powerful atom and step-economical strategy for the assembly of multifunctional bioactive molecules. In this context, we focused on the recent achievements of dual C-H bond activation/annulations, as well as functionalization reactions involving diaryl/alkyl alkynes.

Phthalimides: developments in synthesis and functionalization.

Phthalimides, an important class of biologically active N-heterocycles, are not only found in pharmaceuticals, natural products, agrochemicals, polymers, and dyes, but also serve as building blocks in organic transformations. Many synthetic methods, including metal catalysis and metal-free systems, have been developed to prepare functionalized phthalimides. In this review, we describe the developments in the synthesis and functionalization of phthalimides over the past two decades.

α-Glucosidase inhibition assay of galbanic acid and it amide derivatives: New excellent semi-synthetic α-glucosidase inhibitors.

α-Glucosidase inhibitory activity of galbanic acid and its new amide derivatives 3a-n were investigated. Galbanic acid and compounds 3a-n showed excellent anti-α-glucosidase activity with IC50 values ranging from 0.3 ± 0.3 µM to 416.0 ± 0.2 µM in comparison to positive control acarbose with IC50 value of = 750.0 ± 5.6. In the kinetic study, the most potent compound 3h demonstrated a competitive mode of inhibition with Ki = 0.57 µM. The interaction of the most potent compound 3h with the α-glucosidase was further elaborated by in vitro Circular dichroism assessment and in silico molecular docking and Molecular dynamics studies. Compound 3h was also non-cytotoxic on human normal cells. In silico study on pharmacokinetics and toxicity profile of the most potent galbanic acid derivatives demonstrated that these compounds are valuable lead compounds for further study in order to achieve new anti-diabetic agents.

Patient-specific Effective Dose Estimation from Dose-Length Product in Lung Computed Tomography Using Monte Carlo Simulation.

Background: Computed tomography (CT) imaging has a large portion in the dose of patients from radiological procedures; therefore, accurate calculation of radiation risk estimation in this modality is inevitable. In this study, a method for determining the patient-specific effective dose using the dose-length product (DLP) index in lung CT scan using Monte Carlo (MC) simulation is introduced. Methods: EGSnrc/BEAMnrc MC code was used to simulate a CT scanner. The DOSxyznrc simulation code was used to simulate a specific voxelized phantom from the patient's lungs and irradiate it according to X-ray parameter of routing lung CT scan, and dose delivered to thorax organs was calculated. Three types of phantoms were simulated according to three different body habits (slim, standard, and fat patients) in two groups of men and women. A factor was used to convert the relative dose per particle in MC code to the absolute dose. The dose was calculated in all lung organs, and the effective dose was calculated for all three groups of patient body habits. DLP index and volume CT dose index (CTDIvol) were extracted from the patient's dose report in the CT scanner. The DLP to effective dose conversion factor (k-factor) for patients with different body habitus was calculated. Results: Lung radiation dose in slim, standard, and fat patients in men was 0.164, 0.103, and 0.078 mGy/mAs and in women was 0.164, 0.105, and 0.079 mGy/mAs, respectively. The k-factor in the group of slim patients, especially in women, was higher than in other groups. Conclusions: CT scan dose indexes for slim patients are reported to be underestimated in studies. The dose report in CT scan systems should be modified in proportion to the patient's body habitus, to accurately estimate the radiation risk.

Pulmonary Capillary Hemangiomatosis as a Rare Underlying Cause of Primary Pulmonary Hypertension: A Case Report in an Adolescent.

Despite its rarity, pulmonary capillary hemangiomatosis (PCH) presents a significant diagnostic challenge. Due to its similarity to other pulmonary vascular diseases, such as pulmonary veno-occlusive disease, it is characterized by abnormal pulmonary capillary proliferation, which is a rare cause of primary pulmonary hypertension. This case was the first reported instance of PCH in Shahid Rajaee Heart Hospital in Tehran, Iran, in 2023, which was confirmed by genetic testing. It highlighted the importance of considering PCH among the differential diagnoses for pulmonary hypertension, even in adolescent patients. The 13-year-old patient's main complaints were progressive exertional dyspnea and chest pain. He had no previous medical history and had not taken any pharmaceutical or herbal medications. Critical clinical findings included a heart murmur, an electrocardiogram revealing right ventricular hypertrophy, and echocardiogram evidence of pulmonary hypertension. The main diagnosis was PCH, as shown by CT findings of pulmonary artery dilatation and diffuse nodular ground glass opacities. Genetic tests indicated pathogenic EIF2AK4 mutations and suspicion of PCH. Therapeutic intervention included vasodilator therapy, which exacerbated the patient's condition. This case emphasized the importance of maintaining a high index of suspicion for rare causes of pulmonary hypertension, such as PCH. The outcome was to prepare the patient for lung transplantation. To differentiate PCH from other pulmonary vascular diseases, a combination of clinical presentation, radiologic studies, genetic analysis, and response to treatment is required to determine appropriate management, particularly lung transplantation.

Synthesis, α-glucosidase inhibitory activity, and molecular dynamic simulation of 6-chloro-2-methoxyacridine linked to triazole derivatives.

Α-glucosidase inhibition can be useful in the management of carbohydrate-related diseases, especially type 2 diabetes mellitus. Therefore, in this study, a new series of 6-chloro-2-methoxyacridine bearing different aryl triazole derivatives were designed, synthesized, and evaluated as potent α-glucosidase inhibitors. The most potent derivative in this group was 7h bearing para-fluorine with IC50 values of 98.0 ± 0.3 µM compared with standard drug acarbose (IC50 value = 750.0 ± 10.5 µM). A kinetic study of compound 7h revealed that it is a competitive inhibitor against α-glucosidase. Molecular dynamic simulations of the most potent derivative were also executed and indicated suitable interactions with residues of the enzyme which rationalized the in vitro results.

Design, synthesis, in vitro, and in silico anti-α-glucosidase assays of N-phenylacetamide-1,2,3-triazole-indole-2-carboxamide derivatives as new anti-diabetic agents.

In this work, a novel series of N-phenylacetamide-1,2,3-triazole-indole-2-carboxamide derivatives 5a-n were designed by consideration of the potent α-glucosidase inhibitors containing indole and carboxamide-1,2,3-triazole-N-phenylacetamide moieties. These compounds were synthesized by click reaction and evaluated against yeast α-glucosidase. All the newly title compounds demonstrated superior potency when compared with acarbose as a standard inhibitor. Particularly, compound 5k possessed the best inhibitory activity against α-glucosidase with around a 28-fold improvement in the inhibition effect in comparison standard inhibitor. This compound showed a competitive type of inhibition in the kinetics. The molecular docking and dynamics demonstrated that compound 5k with a favorable binding energy well occupied the active site of α-glucosidase.

In vivo and in silico evaluations of a synthetic pyrano[3,2-c]quinoline derivative as a potent anti-diabetic agent.

Background: The in vivo assessment of a novel compound is a pivotal step in the development of a new drug. In this study, we selected 1-(2-bromophenyl)-1,11-dihydro-3H-benzo[h]pyrano[3,2-c]quinoline-3,12(2H)-dione (2-BDBPQD), identified as an exemplary α-glucosidase inhibitor in preliminary in vitro assays, for further evaluation in an in vivo anti-diabetic context. Methods: The in vivo anti-diabetic effect of 2-BDBPQD was assessed using a streptozotocin (STZ)-induced diabetic Wistar rat model. Recognizing the relevance of lipid factors in diabetes, we also investigated the impact of this compound on the lipid profile of diabetic Wistar rats. In silico studies, encompassing docking studies and pharmacokinetic predictions of 2-BDBPQD, were conducted. Results: The results obtained indicated a significant reduction in blood glucose levels with 2-BDBPQD treatment compared to acarbose. However, no significant effects on the lipid profile were observed. In silico studies revealed that 2-BDBPQD interacted with key residues in the α-glucosidase active site and exhibited favorable pharmacokinetic properties. Conclusion: In summary, the study demonstrated the in vivo anti-hyperglycemic activity of 2-BDBPQD. Nevertheless, further in vivo evaluations are recommended to comprehensively assess its potential as a new drug for the treatment of diabetes.

A doxycycline-loaded microfiber of poly-metformin/PCL for eradicating melanoma stem cells.

Nowadays, electrospun fibrous mats are used as drug delivery systems for loading of potential drugs in order to kill cancer cells. In the study, a skin patch for treating melanoma cancer after surgery was made using polycaprolactone and polymetformin microfibers that were loaded with doxycycline (PolyMet/PCL@DOX), an anti-cancer stem cell agent. The morphology, structure, mechanical characteristics, swelling, and porosity of the electrospun microfibers were examined. Drug release andanticancereffectiveness of PolyMet/PCL@DOXwas evaluated against A375 melanoma cancer stem cells using the MTS, Flow cytometry, colony formation and CD44 expression assays. Scanning electron microscopy (SEM) verified the micro fibrous structure with a diameter of about 2.31 µm. The porosity and swelling percentages for microfibers was 73.5 % and 2.9 %, respectively. The tensile strength at the breaking point was equal to 3.84 MPa. The IC50 of PolyMet/PCL@DOX was 7.4 µg/mL. The survival rate of A375 cells after 72 h of PolyMet/PCL@DOX treatment was 43.9 %. The colony formation capacity of A375 cells decreased after PolyMet/PCL@DOX treatment. The level of CD44 expression in the PolyMet/PCL@DOX group decreased compared to the control group. Generally, PolyMet/PCL@DOX microfibers can be a promising candidate as a patch after surgery to eradicate cancer stem cells, effectively.

Medicinal chemistry perspective on the structure-activity relationship of stilbene derivatives.

Stilbenes are a small family of polyphenolic secondary metabolites produced in a variety of closely related plant species. These compounds function as phytoalexins, aiding plant defense against phytopathogens and plants' adaptation to abiotic environmental factors. Structurally, some important phenolic compounds have a 14-carbon skeleton and usually have two isomeric forms, Z and E. Stilbenes contain two benzene rings linked by a molecule of ethanol or ethylene. Some derivatives of natural (poly)phenolic stilbenes such as resveratrol, pterostilbene, and combretastatin A-4 have shown various biological activities, such as anti-microbial, anti-cancer, and anti-inflammatory properties as well as protection against heart disease, Alzheimer's disease, and diabetes. Among stilbenes, resveratrol is certainly the most popular and extensively studied for its health properties. In recent years, an increasing number of stilbene compounds have been investigated for their bioactivity. This review focuses on the assessment of synthetic stilbene derivatives in terms of their biological activities and structure-activity relationship. The goal of this study is to consider the structural changes and different substitutions on phenyl rings that can improve the desired medicinal effects of stilbene-based compounds beyond the usual standards and subsequently discover biological activities by identifying effective alternatives of the evaluated compounds.

Copper supported modified magnetic carrageenan as a bio-based catalyst for the synthesis of novel scaffolds bearing the 1,2,3-triazole unit through the click reaction.

The ongoing work delineates the design of a novel library of 1,2,3-triazole-attached phenylacetamides through molecular hybridization of propargyl and phenylacetamide derivatives. Copper-supported modified magnetic carrageenan serves as a green heterogeneous catalyst, ensuring high yield, efficient reaction times, high atom economy, utilization of an environmentally friendly catalyst from a natural source, and a straightforward workup procedure. The successful synthesis of the catalyst is confirmed and evaluated using various analytical techniques, while the synthetic compounds are characterized through 1H NMR and 13C NMR.

Developments and applications of α-bromonitrostyrenes in organic syntheses.

The presence of the bromo and nitro groups in the structure of α-bromonitrostyrene makes them highly reactive and versatile reagents in organic syntheses. α-Bromonitrostyrenes act as an effective dielectrophile in the reaction with various nucleophiles. In these reactions, the bromo and nitro groups behave as good leaving groups for the assembly of a diverse range of heterocyclic compounds, such as dihydrofurans, dihydropyranes, furans, pyrroles, pyrazoles, isooxazolines, spiropyrrolidines, etc. In the current review, we have focused on the transformations of α-bromonitrostyrenes under organocatalysis, metal catalysis, and base-catalysis systems as well as catalyst-free conditions, since 2010.

Agar-tragacanth/silk fibroin hydrogel containing Zn-based MOF as a novel nanobiocomposite with biological activity.

In this study, a novel nanobiocomposite consisting of agar (Ag), tragacanth gum (TG), silk fibroin (SF), and MOF-5 was synthesized and extensively investigated by various analytical techniques and basic biological assays for potential biomedical applications. The performed Trypan blue dye exclusion assay indicated that the proliferation percentage of HEK293T cells was 71.19%, while the proliferation of cancer cells (K-562 and MCF-7) was significantly lower, at 10.74% and 3.33%. Furthermore, the Ag-TG hydrogel/SF/MOF-5 nanobiocomposite exhibited significant antimicrobial activity against both E. coli and S. aureus strains, with growth inhibition rates of 76.08% and 69.19% respectively. Additionally, the hemolytic index of fabricated nanobiocomposite was found approximately 19%. These findings suggest that the nanobiocomposite exhibits significant potential for application in cancer therapy and wound healing.

Prussian Blue Analogues-Derived Molecularly Imprinted Nanozyme Array for Septicemia Detection.

Septicemia, a severe bacterial infection, poses significant risks to human health. Early detection of septicemia by tracking specific biomarkers is crucial for a timely intervention. Herein, we developed a molecularly imprinted (MI) TiO2-Fe-CeO2 nanozyme array derived from Ce[Fe(CN)6] Prussian blue analogues (PBA), specifically targeting valine, leucine, and isoleucine, as potential indicators of septicemia. The synthesized nanozyme arrays were thoroughly characterized using various analytical techniques, including Fourier transform infrared spectroscopy, X-ray diffraction, field-emission scanning electron microscope, and energy-dispersive X-ray. The results confirmed their desirable physical and chemical properties, indicating their suitability for the oxidation of 3,3',5,5'-tetramethylbenzidine serving as a colorimetric probe in the presence of a persulfate oxidizing agent, further highlighting the potential of these arrays for sensitive and accurate detection applications. The MITiO2 shell selectively captures valine, leucine, and isoleucine, partially blocking the cavities for substrate access and thereby hindering the catalyzed TMB chromogenic reaction. The nanozyme array demonstrated excellent performance with linear detection ranges of 5 µM to 1 mM, 10-450 µM, and 10-450 µM for valine, leucine, and isoleucine, respectively. Notably, the corresponding limit of detection values were 0.69, 1.46, and 2.76 µM, respectively. The colorimetric assay exhibited outstanding selectivity, reproducibility, and performance in the detection of analytes in blood samples, including C-reactive protein at a concentration of 61 mg/L, procalcitonin at 870 ng/dL, and the presence of Pseudomonas aeruginosa bacteria. The utilization of Ce[Fe(CN)6]-derived MITiO2-Fe-CeO2 nanozyme arrays holds considerable potential in the field of septicemia detection. This approach offers a sensitive and specific method for early diagnosis and intervention, thereby contributing to improved patient outcomes.

Anticholinesterase activities of novel isoindolin-1,3-dione-based acetohydrazide derivatives: design, synthesis, biological evaluation, molecular dynamic study.

In pursuit of developing novel cholinesterase (ChE) inhibitors through molecular hybridization theory, a novel series of isoindolin-1,3-dione-based acetohydrazides (compounds 8a-h) was designed, synthesized, and evaluated as possible acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. In vitro results revealed IC50 values ranging from 0.11 ± 0.05 to 0.86 ± 0.02 µM against AChE and 5.7 ± 0.2 to 30.2 ± 2.8 µM against BChE. A kinetic study was conducted on the most potent compound, 8a, to ascertain its mode of inhibition, revealing its competitive mode against AChE. Furthermore, the binding interaction modes of the most active compound within the AChE active site was elucidated. Molecular dynamics simulations of compound 8a were performed to assess the stability of the 8a-AChE complex. In silico pharmacokinetic predictions for the most potent compounds indicated their potential as promising lead structure for the development of new anti-Alzheimer's disease (anti-AD) agents.

Fabrication and characterization of a novel magnetic nanostructure based on pectin-cellulose hydrogel for in vitro hyperthermia during cancer therapy.

Herein, a new magnetic nanobiocomposite based on a synthesized cross-linked pectin-cellulose hydrogel (cross-linked Pec-Cel hydrogel) substrate was designed and synthesized. The formation of the cross-linked Pec-Cel hydrogel with a calcium chloride agent and its magnetization process caused a new and efficient magnetic nanobiocomposite. Several spectral and analytical techniques, including FTIR, SEM, VSM, TGA, XRD, and EDX analyses, were performed to confirm and characterize the structural features of the magnetic cross-linked pectin-cellulose hydrogel nanobiocomposite (magnetic cross-linked Pec-Cel hydrogel nanobiocomposite). Based on SEM images, prepared Fe3O4 magnetic nanoparticles (MNPs) were uniformly dispersed in the Pec-Cel hydrogel context, representing an average particle size between 50.0 and 60.0 nm. The XRD pattern also confirms the crystallinity of the magnetic nanobiocomposite. All constituent elements and their distribution have been depicted in the EDX analysis of the magnetic nanobiocomposite. VSM curves confirmed the superparamagnetic behavior of Fe3O4 MNPs and the magnetic nanobiocomposite with a saturation magnetization of 77.31 emu g-1 and 48.80 emu g-1, respectively. The thermal stability of the nanobiocomposite was authenticated to ca. 800 °C based on the TGA thermogram. Apart from analyzing the structural properties of the magnetic cross-linked Pec-Cel hydrogel nanobiocomposite, different concentrations (0.5 mg mL-1, 1.0 mg mL-1, 2.0 mg mL-1, 5.0 mg mL-1, and 10.0 mg mL-1) of this new magnetic nanostructure were exposed to an alternating magnetic field (AMF) at different frequencies (100.0 MHz, 200.0 MHz, 300.0 MHz, and 400.0 MHz) to evaluate its capacity for an in vitro hyperthermia process; in addition, the highest specific absorption rate (126.0 W g-1) was obtained by the least magnetic nanobiocomposite concentration (0.5 mg mL-1).