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Abstract A new group of thiazolidine-2,4-dione derivatives of ciprofloxacin having butyryl linker 3a-l was synthesized via an alkylation of thiazolidine-2,4-diones with butyryl ciprofloxacin with yield range 48–77% andfully characterized by various spectroscopic and analytical tools. Anti-cancer screening outcomes indicated that 3a and 3i possess antiproliferative activities against human melanoma LOX IMVI cancer cell line with IC50 values of 26.7 ± 1.50 and 25.4 ± 1.43 µM, respectively, using doxorubicin and cisplatin as positive controls with an IC50 of 7.03 ± 0.40 and 5.07 ± 0.29 µM, respectively. Additionally, compound 3j showed promising anticancer activity against human renal cancer A498 cell line with IC50 value of 33.9 ± 1.91 µM while doxorubicin and cisplatin showed IC50 values of 3.59 ± 0.20 and 7.92 ± 0.45, respectively. On the other hand, compound 3i did not show considerable anti-bacterial activity against S. aureus, E. coli and P. aeruginosa, and only moderate activity against K. pneumoniae with only a tenth of the activity of ciprofloxacin, confirming the cytotoxicity observed. Mechanistically, compound 3i inhibited both topoisomerase I and II with IC50 of 4.77 ± 0.26 and 15 ± 0.81 µM. Furthermore, it induced cell cycle arrest at S phase in melanoma LOX IMVI cells. Moreover, 3i provoked substantial levels of early, late apoptosis and necrosis in melanoma LOX IMVI cell line comparable to that induced by doxorubicin. Furthermore, compound 3i increased the expression level of active caspase-3 by 49 folds higher in LOX IMVI cell, increased protein expression level of Bax more than the control by 3 folds and inhibited PARP-1by 33% in LOX IMVI. All results were supported by theoretical docking studies on both tested enzymes confirming potential cytotoxicity for the synthesized hybrids.

Abstract Background Lignocellulosic biomass provides a great starting point for the production of energy, chemicals, and fuels. The major component of lignocellulosic biomass is cellulose, the employment of highly effective enzymatic cocktails, which can be produced by a variety of microorganisms including species of the genus Aspergillus, is necessary for its utilization in a more productive manner. In this regard, molecular biology techniques should be utilized to promote the economics of enzyme production, whereas strategies like protoplast fusion could be employed to improve the efficacy of the hydrolytic process. Results The current study focuses on cellulase production in Aspergillus species using intrageneric protoplast fusion, statistical optimization of growth parameters, and determination of antioxidant activity of fermentation hydrolysate. Protoplast fusion was conducted between A. flavus X A. terreus (PFFT), A. nidulans X A. tamarii (PFNT) and A. oryzae X A. tubingensis (PFOT), and the resultant fusant PFNT revealed higher activity level compared with the other fusants. Thus, this study aimed to optimize lignocellulosic wastes-based medium for cellulase production by Aspergillus spp. fusant (PFNT) and studying the antioxidant effect of fermentation hydrolysate. The experimental strategy Plackett-Burman (PBD) was used to assess how culture conditions affected cellulase output, the best level of the three major variables namely, SCB, pH, and incubation temperature were then determined using Box-Behnken design (BBD). Consequently, by utilizing an optimized medium instead of a basal medium, cellulase activity increased from 3.11 U/ml to 7.689 U/ml CMCase. The following medium composition was thought to be ideal based on this optimization: sugarcane bagasse (SCB), 6.82 gm; wheat bran (WB), 4; Moisture, 80%; pH, 4; inoculum size, (3 × 106 spores/ml); and incubation Temp. 31.8 °C for 4 days and the fermentation hydrolysate has 28.13% scavenging activities. Conclusion The results obtained in this study demonstrated the significant activity of the selected fusant and the higher sugar yield from cellulose hydrolysis over its parental strains, suggesting the possibility of enhancing cellulase activity by protoplast fusion using an experimental strategy and the fermentation hydrolysate showed antioxidant activity.

The contamination of fish diets with aflatoxin B1 (AFB1) poses a significant hazard to the aquaculture sector. This study investigates the efficacy of supplementing Nile tilapia (Oreochromis niloticus) diets with garden cress (Lepidium sativum) seeds (GCS) to mitigate the adverse effects of AFB1. For this purpose, a factorial design was utilized, consisting of a 2×3 arrangement of treatments. This included two contamination levels of AFB1: (0 and 2 mg kg−1 diet). Within each contamination level, three dietary levels of GCS were used (0 %, 1 %, and 2 %). The study involved 270 healthy O. niloticus with an average weight of 25.14 ± 0.39 g (45 fish/group and 15 fish/replicate). The duration of the trial was 60 days. The study evaluated growth performance, hematological indices, hepatorenal function, immune and antioxidant indicators, histomorphology of organs, AFB1 residues in muscles, and fish resistance to Aeromonas hydrophila. The results indicated that GCS dietary supplementation significantly counteracted AFB1-induced growth retardation and reduced fish survival. Additionally, GCS effectively reversed the anemia, leukopenia, hypoproteinemia, hypoalbuminemia, and hypoglobulinemia that were produced by AFB1. Moreover, GCS dietary supplementation significantly suppressed the AFB1-induced increase in serum bilirubin, hepatic enzymes, kidney damage products, cortisol, and glucose. Additionally, the inclusion of GCS in the fish's diet effectively eliminated the accumulation of AFB1 in their muscles. Moreover, GCS supplementation demonstrated significant restoration of depleted antioxidant and innate immune components induced by AFB1. Furthermore, GCS significantly reduced the degenerative changes in renal, hepatic, splenic, and small intestine tissues caused by AFB1. Fish fed a GCS-fortified diet and exposed to AFB1 displayed restored disease resistance when challenged with A. hydrophila. In conclusion, supplementing Nile tilapia diets with GCS at 2 %, even in the presence the AFB1 contamination, significantly enhanced the fish growth, improved health, and increased disease resistance while reducing AFB1 residues, thereby benefiting consumer health.

Abstract Objectives the primary aim of this study was to examine the prevalence and risk factors of low bone mineral density in Bahrain. Methods this was a retrospective study, which targeted a cohort of 4822 Bahraini subjects (mean age 59.36 years: 93% females). Demographic data and results of lumbar and femur DEXA scan for the targeted sample, over the period 2016–2018, were retrieved from four hospitals. Results The prevalence of low BMD was 62.3% (46.4% had osteopenia and 15.9% had osteoporosis). The highest rate of osteopenia was detected at the age group younger than 44 years. However, with increasing age, the rate of osteopenia declined, whereas osteoporosis increased (P

المخلص: أهداف البحث: للتحقيق في تأثير التذبذبات داخل الصدر على وظائف الرئة لدى الأطفال المصابين بالشلل الدماغي الرباعي التشنجي. طرق البحث: شملت هذه الدراسة 24 طفلا من كلا الجنسين مصابين بالشلل الدماغي الرباعي التشنجي. تراوحت أعمار الأطفال بين 6 و 8 سنوات. وفقا لمقياس أشوورث المعدل، كانت درجة الشناج 2 إلى 2+. كان الأطفال قادرين على الجلوس بشكل مستقل واتباع التعليمات. تم تقسيم الأطفال بشكل عشوائي إلى مجموعتين (مجموعة الدراسة والمجموعة الضابطة). تم استخدام مقياس التنفس لفحص كل طفل قبل وبعد 6 أسابيع. تلقى الأطفال في المجموعة الضابطة العلاج الطبيعي التقليدي للصدر (التصريف الوضعي والقرع)، بينما خضع الأطفال في مجموعة الدراسة للتدريب على جهاز الزلزال. لمدة ستة أسابيع، تلقت المجموعتان أربع جلسات في الأسبوع. تم جمع نتائج العلاج بعد. تم تطبيق اختبار ت المقترن واختبار ت للعينات المستقلة لمقارنة متوسط نتائج المجموعة الواحدة ونتائج المجموعتين على التوالي. النتائج: أظهرت نتائج ما بعد العلاج لحجم الزفير القسري في ثانية واحدة، ذروة تدفق الزفير، السعة الحيوية القسرية، وحجم الزفير القسري في ثانية واحدة إلى نسبة السعة الحيوية القسرية أهمية كبيرة الفرق لصالح مجموعة الدراسة على مجموعة التحكم. الاستنتاجات: قد تؤدي التذبذبات داخل الصدر إلى تحسين وظائف الرئة لدى الأطفال المصابين بالشلل الدماغي الرباعي. Abstract: Objectives: This study was aimed at investigating the effects of intrathoracic oscillations on pulmonary function in children with spastic quadriplegic cerebral palsy. Methods: This study comprised 24 boys and girls 6–8 years of age with spastic quadriplegic cerebral palsy. According to the modified Ashworth scale, the degree of spasticity was 2 to 2+. The children were able to sit independently and follow instructions. The children were randomly divided into a study group and control group. A spirometer was used to examine each child before and after 6 weeks. Children in the control group received traditional chest physiotherapy (postural drainage and percussion), whereas children in the study group underwent quake device training. For 6 weeks, both groups received four sessions per week. After treatment, the results were collected. Paired t-test and independent-samples t-test were applied to compare the means for each group. p-values

Abstract There are many paper manuscripts at museums, stores, and libraries that have different stains. The dust stains and soil remains played an important role in the degradation of these manuscripts. Therefore, the cleaning process for these stains is important to process. Unfortunately, the removal of stains by some traditional techniques can be hazardous to the paper's fibers. Therefore, this study aims to evaluate innovative nanoparticle gels in the cleaning process of dust stains from paper manuscripts. The synthesized nanomaterials [Fe3O4, TiO2, and ZnO]/Carbopol hybrid nanogel were examined in order to investigate the surface morphology, determine the physio-chemical properties, for phase structure, using scanning electron microscope (SEM), transmission electron microscope (TEM), AFM, DLS, XRD, and Zeta potential. Some stained paper samples were prepared and exposed to accelerated thermal aging at 100 °C for 72 h. The evaluation of the cleaning by nanogel was performed by different analytical procedures containing investigation with a USB digital microscope, SEM, color change, mechanical properties, and ATR-FTIR analysis. The results of this study showed that ZnO/Carbopol hybrid nanogel at high viscosity gave the best results in the cleaning process of mud stains through the ability to dismantle mud particles and increase surface contact with the solvent. The aged treated sample with high viscosity form of ZnO NPs/carbopol hybrid nanogel gave the highest tensile strength value of (56.0 N). The treated samples with the high viscosity form of ZnO NPs/carbopol hybrid nanogel gave the highest value of elongation (1.398%) before aging. It also does not affect the chemical composition of the paper after cleaning it, but rather on the whole, it bites the hydration of the paper, which positively affects the properties of the treated paper.

With increasing longevity globally, the search for effective and patient-friendly anti-aging solutions has been growing. Retinoic acid (Ret) is an FDA-approved anti-aging and anti-wrinkling formula, however, its poor solubility and poor tolerability hamper its use in cosmetically accepted formulations. In this study, cyclodextrins and arginine were investigated for improving the solubility and tolerability of retinoic acid through the formation of inclusion complexes and salt formation, respectively. Two different methods were employed: physical mixing and kneading. The prepared dispersions were investigated for molecular docking (MD), solubility, thermal and spectral analyses, cytotoxicity, and scratch assays. The optimized disperse systems were formulated in a gel formulation and characterized for rheological, in vitro release, and kinetics. The MD, DSC, and FTIR results indicated that both β- and hydroxy propyl (HP) β-cyclodextrins could host RA in their cavities and form inclusion complexes. Ret can form a salt with the basic amino acid arginine. Solubility studies of RA significantly (p < 0.01) enhanced by 14- to 81-fold increases with the investigated cyclodextrins and arginine. The cell viability recorded for Ret:HP β-CD K and Ret:arginine K was significantly increased compared to that for Ret alone. The IC50% recorded for azelaic acid (mild to non-irritant control), Ret, Ret:HP β-CD K, and Ret:arginine K were 1000, 485, 1100, and 895 µg/mL, respectively. The two carriers (HP β-CD and the amino acid arginine) were able to significantly (p < 0.05) reduce the irritation potential of Ret. Furthermore, comparable gap closure rates were recorded for Ret alone, Ret:HP β-CD K, and Ret:arginine K, indicating that inclusion complexation and ion pair formation reduced the irritation potentials without undermining the efficacy.

Numerous intracellular bacterial pathogens interfere with macrophage function, including macrophage polarization, to establish a niche and persist. However, the spatiotemporal dynamics of macrophage polarization during infection within host remain to be investigated. Here, we implement a model of persistent Salmonella Typhimurium infection in zebrafish, which allows visualization of polarized macrophages and bacteria in real time at high resolution. While macrophages polarize toward M1-like phenotype to control early infection, during later stages, Salmonella persists inside non-inflammatory clustered macrophages. Transcriptomic profiling of macrophages showed a highly dynamic signature during infection characterized by a switch from pro-inflammatory to anti-inflammatory/pro-regenerative status and revealed a shift in adhesion program. In agreement with this specific adhesion signature, macrophage trajectory tracking identifies motionless macrophages as a permissive niche for persistent Salmonella. Our results demonstrate that zebrafish model provides a unique platform to explore, in a whole organism, the versatile nature of macrophage functional programs during bacterial acute and persistent infections.

Aim: There is sparse research on the effect of factors related to the dentist and patient in the caries management decision-making process. This in vitro study explored the influence of factors related to dentists and patients on the management decision of occlusal noncavitated caries lesions in children. Materials and methods: Five investigators in the specialties of dental public health (DPH), paediatric, prosthetic, and operative dentistry and a general dentist (GDP) participated in this study. Initially, the investigators were asked to independently assess the occlusal surfaces of 175 noncavitated permanent molars and choose a management recommendation using 2 caries risk patients’ scenarios. After 1 month, investigators were trained and calibrated to use the International Caries Detection and Assessment System (ICDAS) scoring system. Then, they examined the same teeth, recorded the highest/worst ICDAS score, and chose a management recommendation. Two weeks later, the investigators repeated the teeth examination using magnification loupes and again chose a management recommendation. The teeth were sectioned to study the relationship between the presence of caries and the management recommendations. Results: For the low– and the high–caries risk scenarios, ICDAS training increased the operative intervention by 20% to 27% and 14% to 22%, respectively, for both the GDP and the paediatric dentist (P < .0001). For the low–caries risk scenario, using the magnifying loupes increased the operative recommendations for the DPH, GDP, and the operative dentist by 5% to 23% (P < .05). Compared to the low–caries risk scenario, teeth for patients with high caries risk received more surgical interventions (9%-30%) at all examination conditions for the GDP and the paediatric and operative dentists (P < .0001). Conclusions: For occlusal noncavitated caries lesions, enhancing dentists’ caries detection skills had a significant impact on decisions of surgical intervention. This also influenced the appropriateness of the treatment recommended for the different caries risk groups.

Proteases and RNA-Dependent RNA polymerase, major enzymes which are essential targets involved in the life and replication of SARS-CoV-2. This study aims at in silico examination of the potential ability of coumarins and their derivatives to inhibit the replication of SARS-Cov-2 through multiple targets, including the main protease, papain-like protease and RNA-Dependent RNA polymerase. Several coumarins as biologically active compounds were studied, including coumarin antibiotics and some naturally reported antiviral coumarins. Aminocoumarin antibiotics, especially coumermycin, showed a high potential to bind to the enzymes’ active site, causing possible inhibition and termination of viral life. They demonstrate the ability to bind to residues essential for triggering the crucial cascades within the viral cell. Molecular dynamics simulations for 50 ns supported these data pointing out the formation of rigid, stable Coumermycin/enzyme complexes. These findings strongly suggest the possible use of Coumermycin, Clorobiocin or Novobiocin in the fight against COVID-19, but biological evidence is still required to support such suggestions.

Abstract Background The B30.2 variants lead to most relevant severity forms of familial Mediterranean fever (FMF) manifestations. The B30.2 domain plays a key role in protein-protein interaction (PPI) of pyrin with other apoptosis proteins and in regulation the cascade of inflammatory reactions. Pyrin-casp1 interaction is mainly responsible for the dysregulation of the inflammatory responses in FMF. Lower binding affinity was observed between the mutant B30.2 pyrin and casp1 without the release of the complete pathogenicity mechanism. The aim of this study was to identify the possible effects of the interface pocked residues in B30.2/SPRY-Casp1/p20 complex using molecular mechanics simulation and in silico analysis. Results It was found that Lys671Met, Ser703Ile, and Ala744Ser variants led mainly to shift of the binding affinity (∆G), dissociation constant (Kd), and root mean square deviation (RMSD) in B30.2/SPRY-Casp1/p20 complex leading to dynamic disequilibrium of the p20-B30.2/SPRY complex toward its complex form. The current pathogenicity model and its predicted implementation in the relevant colchicine dosage were delineated. Conclusion The molecular mechanics analysis of B30.2/SPRY-p20 complex harboring Lys671Met, Ser703Ile, and Ala744Ser variants showed dynamic disequilibrium of B30.2/SPRY-casp1/p20complex in context of the studied variants that could be a new computational model for FMF pathogenicity. This study also highlighted the specific biochemical markers that could be useful to adjust the colchicine dose in FMF patients.

Introduction Obstructive sleep apnea (OSA) can be presented by diverse phenotypes with or without excessive daytime sleepiness (EDS). The present study was conducted to detect the prevalence and the predictors of OSA in a sample of habitual snorers without EDS nor nocturnal observed apnea. Patients and methods A total of 61 adult participants complaining of habitual snoring were included in the study and subjected to OSA screening questionnaire, anthropometric measures, tonsil examination, modified Mallampati score, and full polysomnography. Univariate analysis and regression analysis were done to detect the association of OSA with participants’ characteristics and polysomnography data. The statistically significant variables were entered into the receiver operating characteristic curve to estimate the best cutoff values for predictors of OSA in habitual snorers. Results The studied patients were divided into two groups: 11.5% had no OSA [apnea–hypopnea index (AHI)43 years), obese (BMI >37 kg/m2), and male patients.

Background: This study aimed to evaluate students’ perceptions of their educational experience of online learning in a blended learning dental education. It was also to investigate the online platform in a blended learning setting as an educational mode for future dental education. Methods: A qualitative phenomenological approach was used to gain insight into the students’ experiences. Fifteen students agreed to participate in three synchronous online focus groups held via WebEx; each group consisted of five students. Results: Thematic analysis was carried out iteratively and inductively, and three themes emerged that interrelated with each other and the research question. Students appreciated the blended learning educational experience, particularly the reduced time and cost of travelling to and from the school and the prospect of combining education with home comforts and commitments. Some students still preferred the face-to-face learning mode, as they believed they could concentrate more than on the online platform. The teachers’ communication skills on the online platform impacted on the students’ views on its suitability and its continuum in future education. Conclusions: Within the limitations of this study, students perceived online and blended learning as more convenient, particularly in a busy and expanding dental curriculum.

Objectives. Temporomandibular disorders (TMD) are a constellation of painful conditions that affect the craniofacial complex. The etiology and risk factors of these conditions have been extensively studied; however, the data available describing the epidemiology of TMD in the Middle East are scarce. We aimed to estimate the prevalence and risk factors of TMD-related pain in a sample population of dental school clinic patients. Methods. This observational cross-sectional study used a translated and culturally adapted temporomandibular disorders pain screener, a part of the Diagnostic Criteria/Temporomandibular Disorders (DC/TMD) criteria instrument, and questions related to demographic characteristics and risk factors for TMD. Data were analyzed through chi-square and Mann–Whitney U tests using SPSS. Results. The sample population included 199 participants (66% female and 34% male). The prevalence of TMD-related pain was 26.8% (n = 42); men and women did not differ statistically in their TMD-related pain. TMD-related pain cases differed significantly on the Center for Epidemiologic Studies Depression Scale (CES-D) and body pain scores compared with noncases. Conclusion. The prevalence of TMD-related pain in the clinical sample population was high. Hence, the onus is on dental health services to screen and educate patients on TMD conditions regularly.

Blending face-to-face and online learning should create a focused environment that supports deep and meaningful teaching and learning that engages learners in a more active and collaborative educational experience. The present study aimed to evaluate students’ online and blended learning educational environment self-perception at the Faculty of Dentistry, Kuwait University, during the COVID-19 pandemic. Methods: Undergraduate dental students who participated in blended learning with online lectures were invited to participate. The sample was a non-probability convenient sample, which included all clinical dental students invited to participate, who were enrolled in the fifth, sixth, and seventh (clinical year) years. All 69 students in these three clinical years were invited to participate. Electronic consent to participate and a self-administered questionnaire of two parts were completed. Part one of the questionnaire utilized the five subscales of the Dundee Ready Educational Environment Measure (DREEM) questionnaire; part two was developed in addition to evaluate the online teaching and learning subscales. Results: Descriptive statistics and analyses of variance were performed; Pearson correlations were made between the additional supplemental online teaching subscale and the original DREEM subscales. The mean students’ perception of the teacher was high, followed by the academic self-perception and then the learning perception. Students’ social self-perceptions had the lowest reported scores. Students’ perceptions varied by year of education in all subscales except for the online domain. In comparing all domains (DREEM and the online component), graduating students (final year) had a more favorable perception than other students. Conclusions: Within the limitations of the present study, online and blended learning were positively perceived, excluding the social self-perception and the perception that the online teaching time was not well used.

Since its introduction to the market in the 1970s, ketoprofen has been widely used due to its high efficacy in moderate pain management. However, its poor solubility and ulcer side effects have diminished its popularity. This study prepared forms of ketoprofen modified with three basic excipients: tris, L-lysine, and L-arginine, and investigated their ability to improve water solubility and reduce ulcerogenic potential. The complexation/salt formation of ketoprofen and the basic excipients was prepared using physical mixing and coprecipitation methods. The prepared mixtures were studied for solubility, docking, dissolution, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), in vivo evaluation for efficacy (the writhing test), and safety (ulcerogenic liability). Phase solubility diagrams were constructed, and a linear solubility (AL type) curve was obtained with tris. Docking studies suggested a possible salt formation with L-arginine using Hirshfeld surface analysis. The order of enhancement of solubility and dissolution rates was as follows: L-arginine > L-lysine > tris. In vivo analgesic evaluation indicated a significant enhancement of the onset of action of analgesic activities for the three basic excipients. However, safety and gastric protection indicated that both ketoprofen arginine and ketoprofen lysine salts were more favorable than ketoprofen tris.

Curcumin is a natural polyphenolic compound with well-known anticancer properties. Poor solubility and permeability hamper its use as an anticancer pharmaceutical product. In this study, L-arginine, a basic amino acid and a small hydrophilic molecule, was utilized to form a salt with the weak acid curcumin to enhance its solubility and potentiate the anticancer activities of curcumin. Two methods were adopted for the preparation of curcumin: L-arginine salt, namely, physical mixing and coprecipitation. The ion pair or salt was characterized for docking, solubility, DSC, FTIR, XRD, in vitro dissolution, and anticancer activities using MCF7 cell lines. The molecular docking suggested a salt/ion-pair complex between curcumin and L-arginine. Curcumin solubility was increased 335- and 440-fold by curcumin in L-arginine, physical, and co-precipitated mixtures, respectively. Thermal and spectral analyses supported the molecular docking and formation of a salt/ion pair between curcumin and L-arginine. The cytotoxicity of curcumin L-arginine salt significantly improved (p < 0.05) by 1.4-fold, as evidenced by the calculated IC50%, which was comparable to Taxol (the standard anticancer drug but with common side effects).

Alzheimer’s disease remains a global health challenge and an unmet need requiring innovative approaches to discover new drugs. The current study aimed to investigate the inhibitory activity of Albizia lucidior and Albizia procera leaves against acetylcholinesterase enzyme in vitro and explore their chemical compositions. Metabolic profiling of the bioactive plant, A. lucidior, via UHPLC/MS/MS-based Molecular Networking highlighted the richness of its ethanolic extract with budmunchiamine alkaloids, fourteen budmunchiamine alkaloids as well as four new putative ones were tentatively identified for the first time in A. lucidior. Pursuing these alkaloids in the fractions of A. lucidior extract via molecular networking revealed that alkaloids were mainly concentrated in the ethyl acetate fraction. In agreement, the alkaloid-rich fraction showed the most promising anticholinesterase activity (IC50 5.26 µg/mL) versus the ethanolic extract and ethyl acetate fraction of A. lucidior (IC50 24.89 and 6.90 µg/mL, respectively), compared to donepezil (IC50 3.90 µg/mL). Furthermore, deep in silico studies of tentatively identified alkaloids of A. lucidior were performed. Notably, normethyl budmunchiamine K revealed superior stability and receptor binding affinity compared to the two used references: donepezil and the co-crystallized inhibitor (MF2 700). This was concluded based on molecular docking, molecular dynamics simulations and molecular mechanics generalized born/solvent accessibility (MM–GBSA) calculations.

Curcumin is one of the most researched phytochemicals by pharmacologists and formulation scientists to unleash its potential therapeutic benefits and tackle inherent biopharmaceutic problems. In this study, the native β-cyclodextrin (CD) and three derivatives, namely, Captisol (sulfobutyl ether β-CD), hydroxypropyl β-cyclodextrin, and hydroxyethyl β-cyclodextrin were investigated for inclusion complexes with curcumin using two preparation methods (physical mixing and solvent evaporation). The prepared complexes were studied for docking, solubility, FTIR, DSC, XRD, and dissolution rates. The best-fitting curcumin: cyclodextrins (the latter of the two CDs) were evaluated for cytotoxicity using human breast cell lines (MCF-7). Dose-dependent cytotoxicity was recorded as IC50% for curcumin, curcumin: hydroxyethyl β-cyclodextrin, and curcumin: hydroxypropyl β-cyclodextrin were 7.33, 7.28, and 19.05 µg/mL, respectively. These research findings indicate a protective role for the curcumin: hydroxypropyl β-cyclodextrin complex on the direct cell lines of MCF-7.

A tightly regulated innate immune response to trypanosome infections is critical to strike a balance between parasite control and inflammation-associated pathology. In this study, we make use of the recently established Trypanosoma carassii infection model in larval zebrafish to study the early response of macrophages and neutrophils to trypanosome infections in vivo. We consistently identified high- and low-infected individuals and were able to simultaneously characterise their differential innate response. Not only did macrophage and neutrophil number and distribution differ between the two groups, but also macrophage morphology and activation state. Exclusive to high-infected zebrafish, was the occurrence of foamy macrophages characterised by a strong pro-inflammatory profile and potentially associated with an exacerbated immune response as well as susceptibility to the infection. To our knowledge, this is the first report of the occurrence of foamy macrophages during an extracellular trypanosome infection.

The rapid spread of bacterial infection caused by Staphylococcus aureus has become a problem to public health despite the presence of past trials devoted to controlling the infection. Thus, the current study aimed to explore the chemical composition of the extract of endophytic fungus Aspergillus fumigatus, isolated from Albizia lucidior leaves, and investigate the antimicrobial activity of isolated metabolites and their probable mode of actions. The chemical investigation of the fungal extract via UPLC/MS/MS led to the identification of at least forty-two metabolites, as well as the isolation and complete characterization of eight reported metabolites. The antibacterial activities of isolated metabolites were assessed against S. aureus using agar disc diffusion and microplate dilution methods. Compounds ergosterol, helvolic acid and monomethyl sulochrin-4-sulphate showed minimal inhibitory concentration (MIC) values of 15.63, 1.95 and 3.90 µg/mL, respectively, compared to ciprofloxacin. We also report the inhibitory activity of the fungal extract on DNA gyrase and topoisomerase IV, which led us to perform molecular docking using the three most active compounds isolated from the extract against both enzymes. These active compounds had the required structural features for S. aureus DNA gyrase and topoisomerase IV inhibition, evidenced via molecular docking.

A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound IC261, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The new molecular entities provoked significant growth inhibition against PC-3, MCF-7 and COLO-205 at a 10 μM dose. Compounds 6-chloro-3-(2,4,6-trimethoxybenzylidene) indolin-2-one, 4b, and 5-methoxy-3-(2,4,6-trimethoxybenzylidene)indolin-2-one, 4e, showed potent activity against the colon cancer COLO-205 cell line with an IC50 value of 0.2 and 0.3 μM. A mechanistic study demonstrated 4b’s efficacy in inhibiting microtubule assembly (IC50 = 1.66 ± 0.08 μM) with potential binding to the colchicine binding site (docking study). With an IC50 of 1.92 ± 0.09 μg/mL, 4b inhibited CK1 almost as well as IC261. Additionally, 4b and 4e were effective inhibitors of EGFR-TK with IC50s of 0.19 μg/mL and 0.40 μg/mL compared to Gifitinib (IC50 = 0.05 μg/mL). Apoptosis was induced in COLO-205 cells treated with 4b, with apoptotic markers dysregulated. Caspase 3 levels were elevated to more than three-fold, while Cytochrome C levels were doubled. The cell cycle was arrested in the pre-G1 phase with extensive cellular accumulation in the pre-G1 phase, confirming apoptosis induction. Levels of cell cycle regulating proteins BAX and Bcl-2 were also defective. The binding interaction patterns of these compounds at the colchicine binding site of tubulin and the Gifitinib binding site of EGFR were verified by molecular docking, which adequately matched the reported experimental result. Hence, 4b and 4e are considered promising potent multitarget agents against colon cancer that require optimization.

Recycling endosomes are generally thought to play a central role in endocytic recycling, but recent evidence has indicated that they also participate in other cellular events, including cytokinesis, autophagy, and neurite outgrowth. Rab small GTPases are key regulators in membrane trafficking, and although several Rab isoforms, e.g., Rab11, have been shown to regulate recycling endosomal trafficking, the precise mechanism by which these Rabs regulate recycling endosomes is not fully understood. In this study, we focused on a Rab-GTPase-activating protein (Rab-GAP), one of the key regulators of Rabs, and comprehensively screened 43 mammalian Tre-2/Bub2/Cdc16 (TBC)/Rab-GAP-domain-containing proteins (TBC proteins) for proteins that specifically localize on recycling endosomes in mouse embryonic fibroblasts (MEFs). Four of the 43 mammalian TBC proteins screened, i.e., TBC1D11, TBC1D12, TBC1D14, and EVI5, were found to colocalize well with transferrin receptor, a well-known recycling endosome marker. We further investigated the biochemical properties of TBC1D12, a previously uncharacterized TBC protein. The results showed that TBC1D12 interacted with active Rab11 through its middle region and that it did not display Rab11-GAP activity in vitro. The recycling endosomal localization of TBC1D12 was found to depend on the expression of Rab11. We also found that TBC1D12 expression had no effect on common Rab11-dependent cellular events, e.g., transferrin recycling, in MEFs and that it promoted neurite outgrowth, a specialized Rab11-dependent cellular event, of PC12 cells independently of its GAP activity. These findings indicated that TBC1D12 is a novel Rab11-binding protein that modulates neurite outgrowth of PC12 cells.

One of the central questions of developmental biology is how cells of equivalent potential-an equivalence group-come to adopt specific cellular fates. In this study we have used a combination of live imaging, single cell lineage analyses, and perturbation of specific signaling pathways to dissect the specification of the adaxial cells of the zebrafish embryo. We show that the adaxial cells are myogenic precursors that form a cell fate equivalence group of approximately 20 cells that consequently give rise to two distinct sub-types of muscle fibers: the superficial slow muscle fibers (SSFs) and muscle pioneer cells (MPs), distinguished by specific gene expression and cell behaviors. Using a combination of live imaging, retrospective and indicative fate mapping, and genetic studies, we show that MP and SSF precursors segregate at the beginning of segmentation and that they arise from distinct regions along the anterior-posterior (AP) and dorsal-ventral (DV) axes of the adaxial cell compartment. FGF signaling restricts MP cell fate in the anterior-most adaxial cells in each somite, while BMP signaling restricts this fate to the middle of the DV axis. Thus our results reveal that the synergistic actions of HH, FGF, and BMP signaling independently create a three-dimensional (3D) signaling milieu that coordinates cell fate within the adaxial cell equivalence group.

Abstract

A new group of thiazolidine-2,4-dione derivatives of ciprofloxacin having butyryl linker 3a-l was synthesized via an alkylation of thiazolidine-2,4-diones with butyryl ciprofloxacin with yield range 48–77% andfully characterized by various spectroscopic and analytical tools. Anti-cancer screening outcomes indicated that 3a and 3i possess antiproliferative activities against human melanoma LOX IMVI cancer cell line with IC50 values of 26.7 ± 1.50 and 25.4 ± 1.43 µM, respectively, using doxorubicin and cisplatin as positive controls with an IC50 of 7.03 ± 0.40 and 5.07 ± 0.29 µM, respectively. Additionally, compound 3j showed promising anticancer activity against human renal cancer A498 cell line with IC50 value of 33.9 ± 1.91 µM while doxorubicin and cisplatin showed IC50 values of 3.59 ± 0.20 and 7.92 ± 0.45, respectively. On the other hand, compound 3i did not show considerable anti-bacterial activity against S. aureus, E. coli and P. aeruginosa, and only moderate activity against K. pneumoniae with only a tenth of the activity of ciprofloxacin, confirming the cytotoxicity observed. Mechanistically, compound 3i inhibited both topoisomerase I and II with IC50 of 4.77 ± 0.26 and 15 ± 0.81 µM. Furthermore, it induced cell cycle arrest at S phase in melanoma LOX IMVI cells. Moreover, 3i provoked substantial levels of early, late apoptosis and necrosis in melanoma LOX IMVI cell line comparable to that induced by doxorubicin. Furthermore, compound 3i increased the expression level of active caspase-3 by 49 folds higher in LOX IMVI cell, increased protein expression level of Bax more than the control by 3 folds and inhibited PARP-1by 33% in LOX IMVI. All results were supported by theoretical docking studies on both tested enzymes confirming potential cytotoxicity for the synthesized hybrids. [ABSTRACT FROM AUTHOR]

With increasing longevity globally, the search for effective and patient-friendly anti-aging solutions has been growing. Retinoic acid (Ret) is an FDA-approved anti-aging and anti-wrinkling formula, however, its poor solubility and poor tolerability hamper its use in cosmetically accepted formulations. In this study, cyclodextrins and arginine were investigated for improving the solubility and tolerability of retinoic acid through the formation of inclusion complexes and salt formation, respectively. Two different methods were employed: physical mixing and kneading. The prepared dispersions were investigated for molecular docking (MD), solubility, thermal and spectral analyses, cytotoxicity, and scratch assays. The optimized disperse systems were formulated in a gel formulation and characterized for rheological, in vitro release, and kinetics. The MD, DSC, and FTIR results indicated that both β- and hydroxy propyl (HP) β-cyclodextrins could host RA in their cavities and form inclusion complexes. Ret can form a salt with the basic amino acid arginine. Solubility studies of RA significantly (p < 0.01) enhanced by 14- to 81-fold increases with the investigated cyclodextrins and arginine. The cell viability recorded for Ret:HP β-CD K and Ret:arginine K was significantly increased compared to that for Ret alone. The IC50% recorded for azelaic acid (mild to non-irritant control), Ret, Ret:HP β-CD K, and Ret:arginine K were 1000, 485, 1100, and 895 µg/mL, respectively. The two carriers (HP β-CD and the amino acid arginine) were able to significantly (p < 0.05) reduce the irritation potential of Ret. Furthermore, comparable gap closure rates were recorded for Ret alone, Ret:HP β-CD K, and Ret:arginine K, indicating that inclusion complexation and ion pair formation reduced the irritation potentials without undermining the efficacy. [ABSTRACT FROM AUTHOR]