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Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been the most commonly used class of medications worldwide for the last three decades. Objectives: This study aimed to design and synthesize a novel series of methoxyphenyl thiazole carboxamide derivatives and evaluate their cyclooxygenase (COX) suppressant and cytotoxic properties. Methods: The synthesized compounds were characterized using 1H, 13C-NMR, IR, and HRMS spectrum analysis and were evaluated for their selectivity towards COX-1 and COX-2 using an in vitro COX inhibition assay kit. Besides, their cytotoxicity was evaluated using the Sulforhodamine B (SRB) assay. Moreover, molecular docking studies were conducted to identify the possible binding patterns of these compounds within both COX-1 and COX-2 isozymes, utilizing human X-ray crystal structures. The density functional theory (DFT) analysis was used to evaluate compound chemical reactivity, which was determined by calculating the frontier orbital energy of both HOMO and LUMO orbitals, as well as the HOMO–LUMO energy gap. Finally, the QiKProp module was used for ADME-T analysis. Results: The results revealed that all synthesized molecules have potent inhibitory activities against COX enzymes. The percentage of inhibitory activities at 5 µM concentration against the COX2 enzyme was in the range of 53.9–81.5%, while the percentage against the COX-1 enzyme was 14.7–74.8%. That means almost all of our compounds have selective inhibition activities against the COX-2 enzyme, and the most selective compound was 2f, with selectivity ratio (SR) value of 3.67 at 5 µM concentration, which has a bulky group of trimethoxy on the phenyl ring that could not bind well with the COX-1 enzyme. Compound 2h was the most potent, with an inhibitory activity percentage at 5 µM concentration of 81.5 and 58.2% against COX-2 and COX-1, respectively. The cytotoxicity of these compounds was evaluated against three cancer cell lines: Huh7, MCF-7, and HCT116, and negligible or very weak activities were observed for all of these compounds except compound 2f, which showed moderate activities with IC50 values of 17.47 and 14.57 µM against Huh7 and HCT116 cancer cell lines, respectively. Analysis of the molecular docking suggests 2d, 2e, 2f, and 2i molecules were bound to COX-2 isozyme favorably over COX-1 enzyme, and their interaction behaviors within COX-1 and COX-2 isozymes were comparable to celecoxib, as an ideal selective COX-2 drug, which explained their high potency and COX-2 selectivity. The molecular docking scores and expected affinity using the MM-GBSA approach were consistent with the recorded biological activity. The calculated global reactivity descriptors, such as HOMO and LUMO energies and the HOMO–LUMO gaps, confirmed the key structural features required to achieve favorable binding interactions and thus improve affinity. The in silico ADME-T studies asserted the druggability of molecules and have the potential to become lead molecules in the drug discovery process. Conclusion: In general, the series of the synthesized compounds had a strong effect on both enzymes (COX-1 and COX-2) and the trimethoxy compound 2f was more selective than the other compounds. [ABSTRACT FROM AUTHOR]

Previously developed fluorophenyl-isoxazole-carboxamides derivatives were re-synthesized and their scavenging activity against DPPH free radical and inhibitory activity against lipase and α-amylase enzymes were evaluated. The inhibition of the tested enzymes was weak while the most potent activities were observed in the DPPH assay. In particular, compounds 2a and 2c demonstrated high antioxidant potency with IC50 values of 0.45 ± 0.21 and 0.47 ± 0.33 µg/ml, respectively, when compared to Trolox, the positive control compound, which has an IC50 value of 3.10 ± 0.92 µg/ml. Based on the in vitro results, the most potent compound 2a was chosen for in vivo evaluation of antioxidant properties using 20 male mice injected intra-peritoneally and divided into four groups. The in vivo results revealed that total antioxidant capacity (TAC) obtained for mice treated with 2a was two folds greater than that of mice treated with the positive control Quercetin. Although further biological and preclinical investigations need to be performed to assess the therapeutic potential of 2a, the results of this study show promising antioxidant activities both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Throughout history, therapeutically active plant products have received substantial attention due to their valuable role in the discoveries of specific medications. The aim of this study was to assess, for the first time, the antimicrobial, antioxidant, antilipase, anti-α-amylase and cytotoxic properties of four fractions derived from Anchusa ovata Lehm. (AO) leaves. Antioxidant, antilipase and anti-amylase potentials of (AO) were established using DPPH (1,1-diphenyl-2-picrylhydrazyl), p-nitrophenyl butyrate and dinitro-salicylic acid procedures, respectively, while antimicrobial activity was conducted using broth microdilution assay against eight Gram-positive, Gram-negative bacterial strains in addition to one fungal strain. Moreover, the MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] cytotoxic assay was utilized against cervical cancer cells (HeLa). The methanol fraction of AO showed potential antioxidant, antilipase, and α-amylase inhibitory activities with IC 50 values of 9.55 ± 0.13, 53.7 ± 0.41 and 16.55 ± 1.84 μg/ml, respectively compared with the positive controls Trolox, Orlistat and Acarbose that had IC 50 values of 3.23 ± 0.92, 12.3 ± 0.35 and 28.18 ± 1.22 μg/ml, respectively. Moreover, the hexane, acetone, and methanol fractions had wide ranges of antimicrobial potential. In addition, the cytotoxic activity outcomes which showed the best activity was for the aqueous followed by acetone, hexane and methanol fractions with IC 50 values of 1.04, 2.72, 3.96 and 17.67 mg/ml, respectively. Our data demonstrate a wide range of biological characteristics for each AO plant fraction. This profiling information about the methanol fraction provided important data for further research and pharmaceutical applications. [ABSTRACT FROM AUTHOR]

Plant products are a rich source of pharmacologically active molecules and are considered an important and attractive field of scientific investigation for the development of new drugs. The present study aimed to assess the α-amylase, α-glucosidase and lipase enzymes inhibitory activities and the cytotoxic effects of Carlina curetum four solvents fractions in order to better understand the anti-obesity, hypoglycemic and anticancer effects of this plant. Several qualitative and quantitative phytochemical tests were performed on Carlina curetum solvent fractions utilizing standard phytochemical procedures, followed by an investigation into their ability to inhibit the enzymes α-amylase, α-glucosidase, and lipase and an assessment of cytotoxic activity against HeLa and Colo-205 cells using standard biochemical and biotechnological methods. The results revealed that the aqueous and methanol fractions had the highest α-amylase enzyme inhibitory activity with IC 50 values of 21.37 ± 0.31 and 30.2 ± 0.42 μg/mL, respectively, in comparison with Acarbose, which had an IC 50 value of 28.18 ± 0.42 μg/mL. The methanol fraction showed potent α-glucosidase inhibitory activity with an IC 50 value of 27.54 ± 4.28 μg/mL; the α-glucosidase inhibitory activity Acarbose was 37.15 ± 0.33 μg/mL. The hexane fraction had greater anti-lipase activity than Orlistat. In addition, 0.5 mg/mL of the C. curetum acetone and hexane fractions had pronounced cytotoxic effects on the Colo-205 cancer cell line, and 0.625 mg/ml of the C. curetum hexane fraction had potential cytotoxic effects against the cervical epithelial carcinoma (HeLa) cell line. This study revealed that C. curetum has potential α-amylase, α-glucosidase, porcine pancreatic lipase enzyme inhibitory activity and cytotoxic activity against the HeLa and Colo-205 cancer cell lines, which indicates the presence of biologically active and cytotoxic compounds in this plant species. This may be considered a challenge for developing bioactive compounds in diabetes, obesity and cancer management. [ABSTRACT FROM AUTHOR]

Introduction: The need for patching of the penile tunica albuginea (TA) might arise during surgery for Peyronie's disease with or without a penile prosthesis. Clinically, TachoSil has evolved as an off-the-shelf hemostatic graft that does not need suturing. Results in patients are encouraging. However, its histopathological fate and its impact on the hemodynamics of erection are not known. Objective: We evaluate the long-term histopathology and pharmacologically induced erection after Tachosil patching of the TA in dogs. Methods: Under general anesthesia, the penis of two adult male beagle dogs was dissected through a midline incision, and TA was exposed. The femoral artery was cannulated and connected to an invasive pressure monitor to record BP. Intracavernous pressure (ICP) was measured on each cavernous side separately, as a complete septum isolates the two compartments of the penis. A 21-gauge butterfly needle was placed on either side proximally. Five minutes were allowed before taking baseline ICP. Ten mg of papaverine hydrochloride was injected intracavernosal. ICP was measured at 2 to10-min time points. On the left side, 2 cm proximal to the glans of the penis, a full-thickness defect was created in TA 1 cm long and 0.5 cm wide (Fig. 1. A, B &C). Four transverse incisions 1 cm long were made on the right side and placed 0.5 cm apart, exposing the corpus cavernosum (Fig. 1. D). A Tachosil patch (Takeda, Japan) was fashioned and applied to cover the defects. Proline 5/0 sutures were placed, marking the proximal and distal ends of the graft areas. The fascia, subcutaneous tissue, and skin were closed with absorbable sutures. Six months later, each dog was anesthetized, and the penis was dissected free from the covering fascia. Invasive BP and ICP measurements were repeated at baseline and after 10 mg papaverine injection. Silk and proline sutures were placed to identify the distal end and the left side of the penis. The penis was excised from the base of the glans penis distally to its root, at least 6 cm proximally and fixed in 10% formaldehyde solution. Transverse blocks of the penis were cut at 3 mm intervals and fixed in paraffin. Sections from each block were stained with H&E and trichrome and examined by a urology pathologist. Descriptive statistics are provided. Results: Gross appearance showed a well-healed scar, and the subcutaneous tissue did not show significant adhesions. The graft site was impossible to distinguish, and the sutures were not visible. ICP measurement did not show a drop in pressure pre- and post-surgery (Fig. 2). Histologically, minimal foreign body reaction was seen, and the tunica albuginea was completely regenerated (Fig. 3). The underlying cavernous tissue did not show inflammation or necrosis. Conclusions: Long-term histological results of Tachosil patching in the dog show complete tunica albuginea regeneration with minimal tissue reaction and no underlying cavernous tissue pathology. Hemodynamically the intracavernous pressure response to papaverine is maintained. Although only two animals are presented here, the results are striking. Further experimentation with more animals is warranted to support these findings. Disclosure: No. [ABSTRACT FROM AUTHOR]

In this study, we synthesized benzodioxol carboxamide derivatives and investigated their antidiabetic potential. The synthesized compounds (Ia-Ic and IIa-IId) underwent characterization via HRMS, 1H-, 13CAPT-NMR, and MicroED. Their efficacy against α-amylase was assessed in vitro, while MTS assays were employed to gauge cytotoxicity across cancer and normal cell lines. Additionally, the antidiabetic impact of compound IIc was evaluated in vivo using a streptozotocin-induced diabetic mice model. Notably, IIa and IIc displayed potent α-amylase inhibition (IC50 values of 0.85 and 0.68 µM, respectively) while exhibiting a negligible effect on the Hek293t normal cell line (IC50 > 150 µM), suggesting their safety. Compound IId demonstrated significant activity against four cancer cell lines (26–65 µM). In vivo experiments revealed that five doses of IIc substantially reduced mice blood glucose levels from 252.2 mg/dL to 173.8 mg/dL in contrast to the control group. The compelling in vitro anticancer efficacy of IIc and its safety for normal cells underscores the need for further in vivo assessment of this promising compound. This research highlights the potential of benzodioxol derivatives as candidates for the future development of synthetic antidiabetic drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] This study focuses on the design and investigation a transethosomal formulation for enhanced topical delivery and improved analgesic activity of caryophyllene oxide. In addition, this work explores new potential mechanisms of analgesic activity of the active compound including alpha-amino-3-hydroxy-5-methyl-4-isooxazole-propionic acid (AMPA) and Cyclooxygenase 2 (COX-2). The transethosomal system containing various caryophyllene concentrations was prepared. The optimum formulation was characterized for the presence of nanovesicles by atomic force microscopy (AFM) and dynamic light scattering (DLS). FTIR was conducted to examine the interaction between the nanovesicle components. The ability of the representative system to enhance the delivery of caryophyllene oxide into and through the skin compared with a coarse emulsion, was examined using porcine ear skin, Franz diffusion cells, and HPLC analysis. The in vivo analgesic efficacy of caryophyllene oxide administrated from the nanovesicular carrier was assessed using the acetic acid-induced pain mouse model compared to a conventional topical formulation. In the second part of the study, the mechanism of analgesic activity of caryophyllene oxide was investigated using AMPA and COX-2 receptors activity in vitro assays. Characterization studies revealed the presence of spherical nanovesicles with an average size of 450.7 ± 55.03 nm. The transethosomal system demonstrated superior skin penetration compared to a conventional emulsion, as demonstrated by the in vitro skin penetration study, with a caryophyllene oxide permeated amount of 40.3 ± 0.881 µg/cm2 via the transethosomal system compared to the emulsion which delivered only 29.5 ± 10.5 µg/cm2. Moreover, a significantly greater amount of caryophyllene oxide was extracted from the skin following the application of the transethosomal formulation (251.8 ± 76.03 µg/cm2) compared to that extracted from the skin following the ointment application (13.5 ± 0.6 µg/cm2). The in vivo experiment demonstrated that the transethosomal formulation significantly reduced writhing episodes, achieving an 80.5 % Maximum Possible Effect (%MPE) compared to 24.7 % for the conventional topical formulation. In vitro mechanistic studies indicated that caryophyllene oxide exhibited a potent COX-2 selectivity and significantly modulated AMPA receptor subunit activity, highlighting a potential mechanism for pain therapy via the two investigated mechanisms. These findings underscore the effectiveness of the caryophyllene oxide transethosomal system in enhancing topical drug delivery and achieving adequate therapeutic efficacy, making it a promising candidate for further clinical development. The study's outcomes shed light on the possible mechanism of analgesia of caryophyllene oxide via COX and AMPAR modulation. [ABSTRACT FROM AUTHOR]

Pelargonium graveolens leaves are widely used in traditional medicine for relieving some cardiovascular, dental, gastrointestinal, and respiratory disorders. They are also used as food and tea additives in Palestine and many other countries. Consequently, this investigation aimed to describe the chemical markers, cytotoxic, antioxidant, antimicrobial, metabolic, and cyclooxygenase (COX) enzymes inhibitory characteristics of P. graveolens essential oil (PGEO) from Palestine utilizing reference methods. There were 70 chemicals found in the GCMS analysis, and oxygenated terpenoids were the most abundant group of the total PGEO. Citronellol (24.44%), citronellyl formate (15.63%), γ-eudesmol (7.60%), and iso-menthone (7.66%) were the dominant chemical markers. The EO displayed strong antioxidant activity (IC50 = 3.88 ± 0.45 µg/mL) and weak lipase and α-amylase suppressant effects. Notably, the PGEO displayed high α-glucosidase inhibitory efficacy compared with Acarbose, with IC50 doses of 52.44 ± 0.29 and 37.15 ± 0.33 µg/mL, respectively. PGEO remarkably repressed the growth of methicillin-resistant Staphylococcus aureus (MRSA), even more than Ampicillin and Ciprofloxacin, and strongly inhibited Candida albicans compared with Fluconazole. The highest cytotoxic effect of the PGEO was noticed against MCF-7, followed by Hep3B and HeLa cancer cells, with IC50 doses of 32.71 ± 1.25, 40.71 ± 1.89, and 315.19 ± 20.5 µg/mL, respectively, compared with doxorubicin. Moreover, the screened EO demonstrated selective inhibitory activity against COX-1 (IC50 = 14.03 µg/mL). Additionally, PGEO showed a weak suppressant effect on COX-2 (IC50 = 275.97 µg/mL). The current research can be considered the most comprehensive investigation of the chemical and pharmacological characterization of the PGEO. The results obtained in this study demonstrate, without doubt, that this plant represents a rich source of bioactive substances that can be further investigated and authenticated for their medicinal potential. [ABSTRACT FROM AUTHOR]

The current study aimed to extract and identify the chemical compounds of Pistacia lentiscus essential oil (PLEO) from Palestine and to assess its antimicrobial, cytotoxic, and cyclooxygenase (COX) inhibitory activities. The hydro-distilled PLEO was analyzed utilizing the gas chromatography-mass spectroscopy (GC–MS) apparatus. Pistacia lentiscus essential oil (PLEO) was tested for its antimicrobial properties utilizing a broth microdilution method. In addition, an MTS assay was employed to test the cytotoxic activity on a cervical cancer cell line (HeLa). An in-vitro COX inhibition test kit was used to measure the COX inhibitory activity. Twenty-nine molecules were characterized, representing 100% of the total PLEO. Limonene (43.78%), α-pinene (29.45%), and β-pinene (7.54%) were characterized as the major PLEO components. The results revealed that PLEO has broad-spectrum antimicrobial activity against the tested microbial strains and has cytotoxic activity against HeLa cancer cells with an IC50 value of 169.68 ± 2.56 μg/ml. Promising COX-1 and COX-2 inhibitory activities were also demonstrated. The chemical components of PLEO from Palestine were identified here for the first time and showed biological effects against the screened microbes, HeLa cells, and COX enzyme. Further in-vivo investigations are required to assess these activities and other pharmacological effects. [ABSTRACT FROM AUTHOR]

In this study, a new series of Isoxazole-carboxamide derivatives were synthesized and characterized via HRMS, 1H-, 13C APT -NMR, and MicroED. The findings revealed that nearly all of the synthesized derivatives exhibited potent inhibitory activities against both COX enzymes, with IC 50 values ranging from 4.1 nM to 3.87 μM. Specifically, MYM1 demonstrated the highest efficacy among the compounds tested against the COX-1, displaying an IC 50 value of 4.1 nM. The results showed that 5 compounds possess high COX-2 isozyme inhibitory effects with IC 50 value in range 0.24–1.30 μM with COX-2 selectivity indexes (2.51–6.13), among these compounds MYM4 has the lowest IC 50 value against COX-2, with selectivity index around 4. Intriguingly, this compound displayed significant antiproliferative effects against CaCo-2, Hep3B, and HeLa cancer cell lines, with IC 50 values of 10.22, 4.84, and 1.57 μM, respectively, which was nearly comparable to that of doxorubicin. Compound MYM4 showed low cytotoxic activities on normal cell lines LX-2 and Hek293t with IC 50 values 20.01 and 216.97 μM respectively, with safer values than doxorubicin. Furthermore, compound MYM4 was able to induce the apoptosis, suppress the colonization of both HeLa and HepG2 cells. Additionally, the induction of Reactive oxygen species (ROS) production could be the mechanism underlying the apoptotic effect and the cytotoxic activity of the compound. In the 3D multicellular tumor spheroid model, results revealed that MYM4 compound hampered the spheroid formation capacity of Hep3B and HeLa cancer cells. Moreover, the molecular docking of MYM4 compound revealed a high affinity for the COX2 enzyme, with energy scores (S) −7.45 kcal/mol, which were comparable to celecoxib (S) −8.40 kcal/mol. Collectively, these findings position MYM4 as a promising pharmacological candidate as COX inhibitor and anticancer agent. [Display omitted] • A new series of Isoxazole-carboxamide derivatives was synthesized and characterized using advanced techniques such as HRMS, 1H-, 13CAPT-NMR, and MicroED. • Specifically, MYM1 demonstrated remarkable efficacy with an IC50 value of 4.1 nM against COX-1. • MYM4 was the most potent compound against COX-2, with selectivity index around 4. • MYM4 displaying significant antiproliferative effects against CaCo-2, Hep3B, and HeLa cancer cell lines, with low cytotoxicity on normal cell lines, making it a safer option. • Compound MYM4 not only induced apoptosis but also suppressed the colonization of HeLa and HepG2 cells. • MYM4 hindered the spheroid formation capacity of Hep3B and HeLa cancer cells, indicating its potential as an effective anti-cancer agent. • MYM4 multifaceted pharmacological potential, demonstrating efficacy as a COX inhibitor and exhibiting significant promise as an anticancer agent. [ABSTRACT FROM AUTHOR]

Aim of the Work: To report a newborn infant with multiple congenital anomalies and apparent complete trisomy 9 in the blood. Review will be included. Methods: Clinical examination, TORCH screening, echocardiography, skeletal survey, ultrasound head and abdomen were done. In addition chromosomal analysis of a peripheral blood sample using GTG, CBG banding and FISH techniques were employed. Results: Multiple congenital anomalies including craniofacial features, central nervous, cardiovascular, skeletal, gastric and urogenital systems because of chromosomal abnormality which indicated: 47, XY, inv (9) (p12;q13) + inv (9) (p12;q13) mat. Conclusion: Our case could be a new case of apparently complete trisomy 9 syndrome with unusual findings. [ABSTRACT FROM AUTHOR]

Artemisia arborescens essential oil (EO), collected from two Palestinian regions, Bethlehem and Jenin, were extracted by hydro-distillation and examined for their chemical compositions, cytotoxic, antimicrobial, cyclooxygenase (COX) enzyme inhibitory effects, and their influence on neuronal (AMPA) receptors. The EO sample from Bethlehem A. arborescens had just 13 molecules, which accounted 100% of the total EO. Meanwhile, 18 molecules that accounted for 100% of the total EO were determined in the Jenin A. arborescens sample. β-thujone (89.64%), camphor (5.34%), and β-pinene (2.01%) were the major molecules in the Bethlehem EO sample, while β-thujone (79.16%), camphor (6.58%), and sabinene (3.44%) were the dominating components in the Jenin EO sample. Moreover, both EOs have antimicrobial effects against all of the examined microorganisms. The EO from Jenin has slightly higher cytotoxic potential against cervical adenocarcinoma (HeLa) cancer cells than the EO from Bethlehem, which has IC 50 of 0.326 and 0.467 mg/mL, respectively. The COX inhibitory IC 50 calculations showed that A. arborescens EO from Jenin has high potency against COX-1 (1.8 µg/mL). At the same time, the EO from Bethlehem was slightly more potent against COX-2 (IC 50 =81.7 µg/mL). Both EOs show significant impacts on the different AMPAR types, yet Jenin EO shows more significant inhibition on amplitude, desensitization, and deactivation mechanisms generated by the receptors. Both EOs may be effective in reducing overexcitation of AMPARs and reducing the effects of ischemia. These results support the possible therapeutic application of A. arborescens EO from both regions to prevent and treat certain pathogenic infections, cancers, inflammations, and neurodegenerative diseases. • Compositions of Artemisia arborescens from two Palestinian locations. • Both oils exhibited antimicrobial effects. • HeLa cells were shown to be cytotoxic by tested oils. • Essential oils have potent COX inhibitory effects. • AMPA neuronal receptors were affected by both of oils. [ABSTRACT FROM AUTHOR]