In vitro anti-HSV1 activity of aqueous extract of Areca catechu L.

Background and Objectives: HSV-1 is known as a very contagious virus and the main cause of cold sores or fever blisters. Herein, the aqueous extract of Areca catechu L. was evaluated for its anti-HSV-1 activity, compared to the standard control (acyclovir). Also, the effect of extract on the expression of UL46 and US6 genes that accumulate late in viral infection, was studied. Materials and Methods: The aqueous extract was obtained by the maceration of powdered plant in boiling water. Its antiviral activity was evaluated on Vero cells infected with HSV-1 at different times: 2 h pre-infection, simultaneous infection, and 4 h post-infection, using MTT assay. The effect of extract on the expression of genes was investigated with quantitative real-time PCR. Results: The aqueous extract of A. catechu induced the inhibition of infection with the IC50 value of 110.52 ± 1.36 µg/ml. Also, it reduced the expression of UL46 when it was added 2 h pre-infection at 100 µg/ml. Moreover, reduction of expression of US6 was observed at the same concentration when the extract was used simultaneously with the occurrence of infection and 4 h post-infection. Conclusion: A. catechu can be considered an essential element of natural-based anti-HSV-1 agents.

Synthesis of novel hybrids of 1,2,3-triazoles-hydrazone: targeting cholinesterases and Alzheimer's related genes.

Aim: A new series of 1,2,3-triazole-hydrazone derivatives were developed to evaluate their anti-Alzheimer's activity. Materials & methods: All compounds were screened toward cholinesterases via the modified Ellman's method. The toxicity assay on SH-SY5Y cells was performed using the MTT assay, and the expression levels of GSK-3α, GSK-3ß, DYRK1 and CDK5 were assessed in the presence of compounds 6m and 6p. Results: 6m and 6p; acting as mixed-type inhibitors, exhibited promising acetylcholinesterase and butyrylcholinesterase inhibitory activity, respectively. 6m demonstrated no toxicity under tested concentrations on the SH-SY5Y cells and positively impacted neurodegenerative pathways. Notably, 6m displayed a significant downregulation in mRNA levels of GSK-3α, GSK-3ß and CDK5. Conclusion: The target compounds could be considered in developing anti-Alzheimer's disease agents.

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"An unprecedented occurrence: a case report of pulmonary hypertension manifestation in Donohue syndrome".

INTRODUCTION: Donohue syndrome (DS), also referred to as leprechaunism, is a remarkably uncommon autosomal recessive disorder that primarily affects the endocrine system. Its incidence rate is exceedingly low, with only 1 case reported per 4 million live births. The syndrome is distinguished by a series of characteristic clinical features. CASE PRESENTATION: We present a case of a twenty-month-old male with DS who experienced a range of dysmorphic and clinical features with the involvement of multiple systems. These features include skin hyperpigmentation, hypertrichosis, distinct facial features, abdominal distension, and microcephaly, with the involvement of the endocrine, renal, respiratory, and cardiac systems. CONCLUSION: The primary features of DS involve severe insulin resistance and growth abnormalities, the association with pulmonary hypertension (PHTN) has not been reported before. This finding adds more complexity to the condition. To the best of the author's knowledge, this is the first report for a patient with DS who has PHTN. Further investigation is required since the mechanisms behind the development of PHTN in DS are not entirely understood. Shedding light on this association will contribute to better management strategies and outcomes for affected patients.

Assessing breast self-examination knowledge and practices among women in Iraq: A cross-sectional study.

Background and Aims: The present study aims to shed light on the knowledge, attitude, and practice of breast self-examination with breast cancer (BC) among female patients in the oncology department of Baghdad Medical City. Methods: This cross-sectional study involved 100 female participants at the Oncology Teaching Hospital in Baghdad Medical City between June 15 and October 15, 2022. Using convenient sampling, the study targeted females aged 30-75, recently or previously diagnosed with BC, admitted for treatment and follow-ups. Results: Regarding the assessment of knowledge, among the surveyed patients, 71 are aware of breast self-examination (BSE), primarily through social media (42 patients). The study also explores the link between BSE and education levels. While Pearson's chi-square shows no significance (0.107), the likelihood ratio suggests a significant association (0.041). Regarding the analysis of attitudes, the study assessment for the reasons for compliance showed that 19 patients cite medical reasons, and 48 patients attribute noncompliance to a lack of knowledge of how to perform BSE. Regarding the examination of practice, high statistical significance is evident in both Pearson's chi-square (0.000) and likelihood ratio (0.000) tests, emphasizing the substantial relationship between the post-diagnosis initiation timing of BSE and its correct execution. Additionally, a statistically significant association exists between performing BSE correctly and discovering BC (p = 0.000). Conclusion: Regarding the assessment of knowledge, our study found high awareness of BSE within the population, primarily through social media and health organizations. Regarding the analysis of attitudes, a notable proportion refrained from practicing BSE, primarily due to a perceived lack of knowledge about the methods. Regarding the examination of practice, the observed significant associations between performing BSE correctly, discovering BC, and the frequency of examinations underscore the pivotal role of consistent and accurate BSE in early detection.

A review: FDA-approved fluorine-containing small molecules from 2015 to 2022.

Fluorine-containing small molecules have occupied a special position in drug discovery research. The successful clinical use of fluorinated corticosteroids in the 1950s and fluoroquinolones in the 1980s led to an ever-increasing number of approved fluorinated compounds over the last 50 years. They have shown various biological properties such as antitumor, antimicrobial, and anti-inflammatory activities. Fluoro-pharmaceuticals have been considered a strong and practical tool in the rational drug design approach due to their benefits from potency and ADME (absorption, distribution, metabolism, and excretion) points of view. Herein, approved fluorinated drugs from 2015 to 2022 were reviewed.

Novel N'-substituted benzylidene benzohydrazides linked to 1,2,3-triazoles: potent α-glucosidase inhibitors.

Herein, various N'-substituted benzylidene benzohydrazide-1,2,3-triazoles were designed, synthesized, and screened for their inhibitory activity toward α-glucosidase. The structure of derivatives was confirmed using 1H- and 13C-NMR, FTIR, Mass spectrometry, and elemental analysis. All derivatives exhibited good inhibition with IC50 values in the range of 0.01 to 648.90 µM, compared with acarbose as the positive control (IC50 = 752.10 µM). Among them, compounds 7a and 7h showed significant potency with IC50 values of 0.02 and 0.01 µM, respectively. The kinetic study revealed that they are noncompetitive inhibitors toward α-glucosidase. Also, fluorescence quenching was used to investigate the interaction of three inhibitors 7a, 7d, and 7h, with α-glucosidase. Accordingly, the binding constants, the number of binding sites, and values of thermodynamic parameters were determined for the interaction of candidate compounds toward the enzyme. Finally, the in silico cavity detection plus molecular docking was performed to find the allosteric site and key interactions between synthesized compounds and the target enzyme.

Chemical composition, cholinesterase, and α-glucosidase inhibitory activity of the essential oils of some Iranian native Salvia species.

BACKGROUND: The plants from Salvia genus contain widely distributed species which have been used in folk medicine as well as pharmaceutical and food industries. METHODS: The chemical composition of 12 native Iranian Salvia species (14 plants) was identified using gas chromatography-mass spectrometry (GC-MS). Also, the inhibitory activity of all essential oils (EOs) was evaluated toward α-glucosidase and two types of cholinesterase (ChE) using spectrophotometric methods. The in vitro α-glucosidase inhibition assay was performed by the determination of p-nitrophenol (pNP) obtained from the enzymatic dissociation of p-nitrophenol-α-D-glucopyranoside (pNPG) as the substrate. In vitro ChE inhibitory assay was conducted based on the modified Ellman's procedure using the measurement of 5-thio-2-nitrobenzoic acid produced from the hydrolysis of thiocholine derivatives as the substrate, in the presence of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). RESULTS: Totally, 139 compounds were detected and caryophyllene oxide and trans-ß-caryophyllene were the most abundant compounds in all EOs. The yield of EOs extracted from the plants were also calculated in the range of 0.06 to 0.96% w/w. Herein, α-glucosidase inhibitory activity of 8 EOs was reported for the first time and among all, S. spinosa L. was found to be the most potent inhibitor (90.5 inhibition at 500 µg/mL). Also, the ChE inhibitory activity of 8 species was reported for the first time and our results showed that the BChE inhibitory effect of all EOs was more potent than that of AChE. The ChE inhibition assay indicated that S. mirzayanii Rech.f. & Esfand. collected from Shiraz was the most potent inhibitor (72.68% and 40.6% at the concentration of 500 µg/mL, toward AChE and BChE, respectively). CONCLUSIONS: It seems that native Salvia species of Iran could be considered in the development of anti-diabetic and anti-Alzheimer's disease supplements.

Cedrus deodara: In Vivo Investigation of Burn Wound Healing Properties.

Objective: Cedrus deodara (Roxb. Ex Lamb.) G. Don possesses various biological activities, which have been documented in modern and traditional medicine. In this study, burn wound healing activity of the methanol extract of C. deodara wood was evaluated via a burn wound model in Wistar rats. Methods: The methanol extract of C. deodara was evaluated for the contents of phenolic compounds, flavonoids, and tannins. Also, its antioxidant activity was determined using the DPPH assay. Then, a topical ointment containing the methanol extract of C. deodara (10%) was used to evaluate the healing effects on a model of second-degree thermal burn in 4 groups of 7 rats within 21 days. In this respect, average wound surface area, wound closure, and various histological features were examined. Results: Our findings revealed that the wounds treated with the methanol extract of C. deodara showed higher wound contraction (33.6, 87.1, and 93.4% on days 7, 14, and 21, respectively) compared with the positive control (27.6, 80.7, and 88.3% on days 7, 14, and 21, respectively) and the negative control (20.1, 77.9, and 80.2% on days 7, 14, and 21, respectively). According to the results from epitheliogenesis score, the number of inflammatory cells, neovascularization, and collagen density, good burn wound healing activity of the methanol extract of C. deodarawas demonstrated. Conclusion: Using the methanol extract of C. deodara in an ointment formulation can be developed to prevent or reduce burn injury progression.

Evaluation of Renal Fibrosis Using Magnetization Transfer Imaging at 1.5T and 3T in a Porcine Model of Renal Artery Stenosis.

Renal fibrosis is an important marker in the progression of chronic kidney disease, and renal biopsy is the current reference standard for detecting its presence. Currently, non-invasive methods have only been partially successful in detecting renal fibrosis. Magnetization transfer imaging (MTI) allows estimates of renal fibrosis but may vary with scanning conditions. We hypothesized that MTI-derived renal fibrosis would be reproducible at 1.5T and 3T MRI and over time in fibrotic kidneys. Fifteen pigs with unilateral renal artery stenosis (RAS, n = 9) or age-matched sham controls (n = 6) underwent MTI-MRI at both 1.5T and 3T 6 weeks post-surgery and again 4 weeks later. Magnetization transfer ratio (MTR) measurements of fibrosis in both kidneys were compared between 1.5T and 3T, and the reproducibility of MTI at the two timepoints was evaluated at 1.5T and 3T. MTR at 3T with 600 Hz offset frequency successfully distinguished between normal, stenotic, and contralateral kidneys. There was excellent reproducibility of MTI at 1.5T and 3T over the two timepoints and no significant differences between MTR measurements at 1.5T and 3T. Therefore, MTI is a highly reproducible technique which is sensitive to detect changes in fibrotic compared to normal kidneys in the RAS porcine model at 3T.

Quinazolinone-1,2,3-triazole-acetamide conjugates as potent α-glucosidase inhibitors: synthesis, enzyme inhibition, kinetic analysis, and molecular docking study.

In this study, new hybrids of quinazolinone-1,2,3-triazole-acetamide were designed, synthesized, and screened for their α-glucosidase inhibitory activity. The results obtained from the in vitro screening indicated that all analogs exhibited significant inhibitory activity against α-glucosidase (IC50 values ranging from 4.8-140.2 µM) in comparison to acarbose (IC50 = 750.0 µM). The limited structure-activity relationships suggested the variation in the inhibitory activities of the compounds affected by different substitutions on the aryl moiety. The enzyme kinetic studies of the most potent compound 9c, revealed that it inhibited α-glucosidase in a competitive mode with a K i value of 4.8 µM. In addition, molecular docking studies investigated the structural perturbation and behavior of all derivatives inside the α-glucosidase active site. Next, molecular dynamic simulations of the most potent compound 9c, were performed to study the behavior of the 9c-complex during the time. The results showed that these compounds can be considered as potential antidiabetic agents.

Investigation of biological activities of two cultivars of Cicer arietinum proteins mass associated with Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, with some known classical factors. Cicer arietinum (Leguminosae) is a source of protein for humans and contains albumin, globulin, glutelin, and prolamin. The protein content of two cultivars of C. arietinum, Hashem and Mansour, was isolated to evaluate their inhibition activity against acetylcholinesterase (AChE), butyrylcholine esterase (BChE), and ß-amyloid peptide (ßA) aggregation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and molecular docking were also applied to evaluate the content and determine the potential of each chickpea protein to interact with AChE, respectively. Obtained data showed that proteins from both cultivars could inhibit AChE with IC50 of 17.73 (0.03) and 22.20 (0.06) µg/mL, respectively, with no activity on BChE. The 50 µg/mL protein concentration of each cultivar suppressed ßA accumulation (Mansour: 25.66% and Hashem: 21.69%) and showed biometal chelating activity. SDS-PAGE analysis revealed relatively different protein patterns, though the Mansour cultivar contained some protein bands with molecular weights of 18, 24, and 70 kDa were estimated to belong to vicilin and legumin, which were absent in the Hashem protein mass. Molecular docking showed that legumin and especially vicilin have good potential to interact with AChE. The chickpea proteins showed inhibitory activity against AChE, which might be due to the vicilin and legumin fractions. The characterization of the inhibitory effect of each protein band could be promising in finding new therapeutic peptide candidates to treat Alzheimer's in the future, although more experimental work is needed in this issue.

Phytochemical investigation and biological activity of Doronicum pardalianches L. roots against Alzheimer's disease.

The methanol extract of Doronicum pardalianches L. was fractionated using n-hexane, chloroform, and ethyl acetate to evaluate their cholinesterase (ChE) inhibitory activity via modified Ellman's method. It was perceived that only the ethyl acetate fraction was active toward acetylcholinesterase (AChE) with IC50 value of 172.21 µg/mL. Also, all fractions showed no butyrylcholinesterase (BChE) inhibitory activity. The ethyl acetate fraction was also investigated for its neuroprotectivity and metal chelating ability (Zn2+, Fe2+, and Cu2+) which demonstrated desired activity. Phytochemical analysis of the ethyl acetate fraction led to isolation and identification of formononetin 7-O-ß-D-glucopyranoside which has not been previously reported for this plant.

Cinnamomum verum J. Presl. Bark essential oil: in vitro investigation of anti-cholinesterase, anti-BACE1, and neuroprotective activity.

BACKGROUND: Cinnamomum verum J. Presl. (Lauraceae), Myrtus communis L. (Myrtaceae), Ruta graveolens L. (Rutaaceae), Anethum graveolens L. (Apiaceae), Myristica fragrans Houtt. (Myristicaceae), and Crocus sativus L. (Iridaceae) have been recommended for improvement of memory via inhalation, in Iranian Traditional Medicine (ITM). In this respect, the essential oils (EOs) from those plants were obtained and evaluated for cholinesterase (ChE) inhibitory activity as ChE inhibitors are the available drugs in the treatment of Alzheimer's disease (AD). METHODS: EOs obtained from the plants under investigation, were evaluated for their potential to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro based on the modified Ellman's method. The most potent EO was candidate for the investigation of its beta-secretase 1 (BACE1) inhibitory activity and neuroprotectivity. RESULTS: Among all EOs, C. verum demonstrated the most potent activity toward AChE and BChE with IC50 values of 453.7 and 184.7 µg/mL, respectively. It also showed 62.64% and 41.79% inhibition against BACE1 at the concentration of 500 and 100 mg/mL, respectively. However, it depicted no neuroprotective potential against ß-amyloid (Aß)-induced neurotoxicity in PC12 cells. Also, identification of chemical composition of C. verum EO was achieved via gas chromatography-mass spectrometry (GC-MS) analysis and the major constituent; (E)-cinnamaldehyde, was detected as 68.23%. CONCLUSION: Potent BChE inhibitory activity of C. verum EO can be considered in the development of cinnamon based dietary supplements for the management of patients with advanced AD.

Phytochemical analysis and anticholinesterase activity of aril of Myristica fragrans Houtt.

In this study, the ethyl acetate fraction of Myristica fragrans Houtt. was investigated for its in vitro anticholinesterase activity as well as neuroprotectivity against H2O2-induced cell death in PC12 neuronal cells and the ability to chelate bio-metals (Zn2+, Fe2+, and Cu2+). The fraction was inactive toward acetylcholinesterase (AChE); however, it inhibited the butyrylcholinesterase (BChE) with IC50 value of 68.16 µg/mL, compared with donepezil as the reference drug (IC50 = 1.97 µg/mL) via Ellman's method. It also showed good percentage of neuroprotection (86.28% at 100 µg/mL) against H2O2-induced neurotoxicity and moderate metal chelating ability toward Zn2+, Fe2+, and Cu2+. The phytochemical study led to isolation and identification of malabaricone A (1), malabaricone C (2), 4-(4-(3,4-dimethoxyphenyl)-2,3-dimethylbutyl)benzene-1,2-diol (3), nectandrin B (4), macelignan (5), and 4-(4-(benzo[d][1,3]dioxol-5-yl)-1-methoxy-2,3-dimethylbutyl)-2-methoxyphenol (6) which were assayed for their cholinesterase (ChE) inhibitory activity. Compounds 1 and 3 were not previously reported for M. fragrans. Among isolated compounds, compound 2 showed the best activity toward both AChE and BChE with IC50 values of 25.02 and 22.36 µM, respectively, compared with donepezil (0.07 and 4.73 µM, respectively).

Recent developments in the design and synthesis of benzylpyridinium salts: Mimicking donepezil hydrochloride in the treatment of Alzheimer's disease.

Background: Alzheimer's disease (AD) is an advanced and irreversible degenerative disease of the brain, recognized as the key reason for dementia among elderly people. The disease is related to the reduced level of acetylcholine (ACh) in the brain that interferes with memory, learning, emotional, and behavior responses. Deficits in cholinergic neurotransmission are responsible for the creation and progression of numerous neurochemical and neurological illnesses such as AD. Aim: Herein, focusing on the fact that benzylpyridinium salts mimic the structure of donepezil hydrochlorideas a FDA-approved drug in the treatment of AD, their synthetic approaches and inhibitory activity against cholinesterases (ChEs) were discussed. Also, molecular docking results and structure-activity relationship (SAR) as the most significant concept in drug design and development were considered to introduce potential lead compounds. Key scientific concepts: AChE plays a chief role in the end of nerve impulse transmission at the cholinergic synapses. In this respect, the inhibition of AChE has been recognized as a key factor in the treatment of AD, Parkinson's disease, senile dementia, myasthenia gravis, and ataxia. A few drugs such as donepezil hydrochloride are prescribed for the improvement of cognitive dysfunction and memory loss caused by AD. Donepezil hydrochloride is a piperidine-containing compound, identified as a well-known member of the second generation of AChE inhibitors. It was established to treat AD when it was assumed that the disease is associated with a central cholinergic loss in the early 1980s. In this review, synthesis and anti-ChE activity of a library of benzylpyridinium salts were reported and discussed based on SAR studies looking for the most potent substituents and moieties, which are responsible for inducing the desired activity even more potent than donepezil. It was found that linking heterocyclic moieties to the benzylpyridinium salts leads to the potent ChE inhibitors. In this respect, this review focused on the recent reports on benzylpyridinium salts and addressed the structural features and SARs to get an in-depth understanding of the potential of this biologically improved scaffold in the drug discovery of AD.

Cyanoacetohydrazide linked to 1,2,3-triazole derivatives: a new class of α-glucosidase inhibitors.

In this work, a novel series of cyanoacetohydrazide linked to 1,2,3-triazoles (9a-n) were designed and synthesized to be evaluated for their anti-α-glucosidase activity, focusing on the fact that α-glucosidase inhibitors have played a significant role in the management of type 2 diabetes mellitus. All synthesized compounds except 9a exhibited excellent inhibitory potential, with IC50 values ranging from 1.00 ± 0.01 to 271.17 ± 0.30 µM when compared to the standard drug acarbose (IC50 = 754.1 ± 0.5 µM). The kinetic binding study indicated that the most active derivatives 9b (IC50 = 1.50 ± 0.01 µM) and 9e (IC50 = 1.00 ± 0.01 µM) behaved as the uncompetitive inhibitors of α-glucosidase with Ki = 0.43 and 0.24 µM, respectively. Moreover, fluorescence measurements were conducted to show conformational changes of the enzyme after binding of the most potent inhibitor (9e). Calculation of standard enthalpy (ΔHm°) and entropy (ΔSm°) values confirmed the construction of hydrophobic interactions between 9e and the enzyme. Also, docking studies indicated desired interactions with important residues of the enzyme which rationalized the in vitro results.

A review on α-glucosidase inhibitory activity of first row transition metal complexes: a futuristic strategy for treatment of type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is characterized by high blood glucose levels and has emerged as a controversial public health issue worldwide. The increasing number of patients with T2DM on one hand, and serious long-term complications of the disease such as obesity, neuropathy, and vascular disorders on the other hand, have induced a huge economic impact on society globally. In this regard, inhibition of α-glucosidase, the enzyme responsible for the hydrolysis of carbohydrates in the body has been the main therapeutic approach to the treatment of T2DM. As α-glucosidase inhibitors (α-GIs) have occupied a special position in the current research and prescription drugs are generally α-GIs, researchers have been encouraged to design and synthesize novel and efficient inhibitors. Previously, the presence of a sugar moiety seemed to be crucial for designing α-GIs since they can attach to the carbohydrate binding site of the enzyme mimicking the structure of disaccharides or oligosaccharides. However, inhibitors lacking glycosyl structures have also shown potent inhibitory activity and development of non-sugar based inhibitors is accelerating. In this respect, in vitro anti-α-glucosidase activity of metal complexes has attracted lots of attention and this paper has reviewed the inhibitory activity of first-row transition metal complexes toward α-glucosidase and discussed their probable mechanisms of action.

Phytochemical investigation and anticholinesterase activity of ethyl acetate fraction of Myristica fragrans Houtt. seeds.

In this work, n-hexane, chloroform, and ethyl acetate fractions of the methanol extract of Myristica fragrans Houtt. seeds were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) via Ellman's method. It was found that all fractions depicted no anti-AChE activity, however, they were active toward BChE with IC50 values of 361.8, 215.0, and 145.8 µg/mL, respectively comparing with donepezil as the reference drug (IC50 = 1.97 µg/mL). The ethyl acetate fraction which also showed high neuroprotectivity and metal chelating ability was selected for the phytochemical analysis. Our results confirmed the presence of trimyristin and 5,7-diacetyl chrysin (reported for the first time in M. fragrans) in the corresponding fraction.