Design and synthesis of new spirooxindole candidates and their selenium nanoparticles as potential dual Topo I/II inhibitors, DNA intercalators, and apoptotic inducers.

A new wave of dual Topo I/II inhibitors was designed and synthesised via the hybridisation of spirooxindoles and pyrimidines. In situ selenium nanoparticles (SeNPs) for some derivatives were synthesised. The targets and the SeNP derivatives were examined for their cytotoxicity towards five cancer cell lines. The inhibitory potencies of the best members against Topo I and Topo II were also assayed besides their DNA intercalation abilities. Compound 7d NPs exhibited the best inhibition against Topo I and Topo II enzymes with IC50 of 0.042 and 1.172 µM, respectively. The ability of compound 7d NPs to arrest the cell cycle and induce apoptosis was investigated. It arrested the cell cycle in the A549 cell at the S phase and prompted apoptosis by 41.02% vs. 23.81% in the control. In silico studies were then performed to study the possible binding interactions between the designed members and the target proteins.

A new wave of dual Topo I/II inhibitors was designed and synthesised via the hybridisation of spirooxindoles and pyrimidines.In situ selenium nanoparticles (SeNPs) for some derivatives were synthesised.Cytotoxicity, Topo I and Topo II inhibitory assays, and DNA intercalation abilities were evaluated.Compound 7d NPs showed the best Topo I and Topo II inhibition.Cell cycle arrest, apoptosis induction, and molecular docking studies were performed.

Novel pyrimidine Schiff bases and their selenium-containing nanoparticles as dual inhibitors of CDK1 and tubulin polymerase: design, synthesis, anti-proliferative evaluation, and molecular modelling.

Nanotechnology-based strategies can overcome the limitations of conventional cancer therapies. Hence, novel series of pyrimidine Schiff bases (4-9) were employed in the synthesis of selenium nanoparticle forms (4NPs-9NPs). All selenium nano-sized forms exerted greater inhibitions than normal-sized compounds, far exceeding 5-fluorouracil activity. Compound 4 showed effective anti-proliferative activity against MCF-7(IC50 3.14 ± 0.04 µM), HepG-2(IC50 1.07 ± 0.03 µM), and A549(IC50 1.53 ± 0.01 µM) cell lines, while its selenium nanoform 4NPs showed excellent inhibitory effects, with efficacy increased by 96.52%, 96.45%, and 93.86%, respectively. Additionally, 4NPs outperformed 4 in selectivity against the Vero cell line by 4.5-fold. Furthermore, 4NPs exhibited strong inhibition of CDK1(IC50 0.47 ± 0.3 µM) and tubulin polymerase(IC50 0.61 ± 0.04 µM), outperforming 4 and being comparable to roscovitine (IC50 0.27 ± 0.03 µM) and combretastatin-A4(IC50 0.25 ± 0.01 µM), respectively. Moreover, both 4 and 4NPs arrested the cell cycle at G0/G1 phase and significantly forced the cells towards apoptosis. Molecular docking demonstrated that 4 and 4NPs were able to inhibit CDK1 and tubulin polymerase binding sites.

Synthesis and Molecular Docking Study of Novel Pyrimidine Derivatives against COVID-19.

A novel series of pyrido[2,3-d]pyrimidines; pyrido[3,2-e][1,3,4]triazolo; and tetrazolo[1,5-c]pyrimidines were synthesized via different chemical transformations starting from pyrazolo[3,4-b]pyridin-6-yl)-N,N-dimethylcarbamimidic chloride 3b (prepared from the reaction of o-aminonitrile 1b and phosogen iminiumchloride). The structures of the newly synthesized compounds were elucidated based on spectroscopic data and elemental analyses. Designated compounds are subjected for molecular docking by using Auto Dock Vina software in order to evaluate the antiviral potency for the synthesized compounds against SARS-CoV-2 (2019-nCoV) main protease M pro. The antiviral activity against SARS-CoV-2 showed that tested compounds 7c, 7d, and 7e had the most promising antiviral activity with lower IC50 values compared to Lopinavir, "the commonly used protease inhibitor". Both in silico and in vitro results are in agreement.

Aggresomes predict poor outcomes and implicate proteostasis in the pathogenesis of pediatric choroid plexus tumors.

PURPOSE: Protein misfolding and aggregation result in proteotoxic stress and underlie the pathogenesis of many diseases. To overcome proteotoxicity, cells compartmentalize misfolded and aggregated proteins in different inclusion bodies. The aggresome is a paranuclear inclusion body that functions as a storage compartment for misfolded proteins. Choroid plexus tumors (CPTs) are rare neoplasms comprised of three pathological subgroups. The underlying mechanisms of their pathogenesis remain unclear. This study aims to elucidate the prognostic role and the biological effects of aggresomes in pediatric CPTs. METHODS: We examined the presence of aggresomes in 42 patient-derived tumor tissues by immunohistochemistry and we identified their impact on patients' outcomes. We then investigated the proteogenomics signature associated with aggresomes using whole-genome DNA methylation and proteomic analysis to define their role in the pathogenesis of pediatric CPTs. RESULTS: Aggresomes were detected in 64.2% of samples and were distributed among different pathological and molecular subgroups. The presence of aggresomes with different percentages was correlated with patients' outcomes. The ≥ 25% cutoff had the most significant impact on overall and event-free survival (p-value < 0.001) compared to the pathological and the molecular stratifications. CONCLUSIONS: These results support the role of aggresome as a novel prognostic molecular marker for pediatric CPTs that was comparable to the molecular classification in segregating samples into two distinct subgroups, and to the pathological stratification in the prediction of patients' outcomes. Moreover, the proteogenomic signature of CPTs displayed altered protein homeostasis, manifested by enrichment in processes related to protein quality control.

Green synthesis of AgNP-ligand complexes and their toxicological effects on Nilaparvata lugens.

BACKGROUND: Despite developments in nanotechnology for use in the pharmaceutical field, there is still a need for implementation of this technology in agrochemistry. In this study, silver nanoparticles (AgNPs) were successfully prepared by a facile and an eco-friendly route using two different ligands, 2'-amino-1,1':4',1″-terphenyl-3,3″,5,5″-tetracarboxylic acid (H4L) and 1,3,6,8-tetrakis (p-benzoic acid)-pyrene (TBAPy), as reducing agents. The physiochemical properties of the as-obtained AgNPs were characterized by scanning electron microscopy (SEM), energy-dispersive X-ray (EDX), X-ray diffraction (XRD) and transmission electron microscopy (TEM). The toxicity of H4L-AgNP and TBAPy-AgNP against the brown planthopper (BPH, Nilaparvata lugens) was also measured. RESULTS: SEM and TEM analyses demonstrated the formation of quasi-spherical AgNP structures in the presence of H4L and TBAPy. Insecticidal assays showed that TBAPy is less effective against N. lugens, with a median lethal concentration (LC50) of 810 mg/L, while the toxicity of H4L increased and their LC50 reached 786 mg/L 168 h posttreatment at a high concentration of 2000 mg/L. H4L-AgNPs were also highly toxic at a low concentration of 20 mg/L, with LC50 = ~ 3.9 mg/L 168 h posttreatment, while TBAPy-AgNPs exhibited less toxicity at the same concentration, with LC50 = ~ 4.6 mg/L. CONCLUSIONS: These results suggest that the synthesized AgNPs using the two ligands may be a safe and cheaper method compared with chemical insecticides for protection of rice plants from pests and has potential as an effective insecticide in the N. lugens pest management program.

Protective prospects of eco-friendly synthesized selenium nanoparticles using Moringa oleifera or Moringa oleifera leaf extract against melamine induced nephrotoxicity in male rats.

Nanotechnology is used in a wide range of applications, including medical therapies that precisely target disease prevention and treatment. The current study aimed firstly, to synthesize selenium nanoparticles (SeNPs) in an eco-friendly manner using Moringa oleifera leaf extract (MOLE). Secondly, to compare the protective effects of green-synthesized MOLE-SeNPs conjugate and MOLE ethanolic extract as remedies for melamine (MEL) induced nephrotoxicity in male rats. One hundred and five male Sprague Dawley rats were divided into seven groups (n = 15), including 1st control, 2nd MOLE (800 mg/kg BW), 3rd SeNPs (0.5 mg/kg BW), 4th MOLE-SeNPs (200 µg/kg BW), 5th MEL (700 mg/kg BW), 6th MEL+MOLE, and 7th MEL+MOLE SeNPs. All groups were orally gavaged day after day for 28 days. SeNPs and the colloidal SeNPs were characterized by TEM, SEM, and DLS particle size. SeNPs showed an absorption peak at a wavelength of 530 nm, spherical shape, and an average size between 3.2 and 20 nm. Colloidal SeNPs absorption spectra were recorded between 400 and 700 nm with an average size of 3.3-17 nm. MEL-induced nephropathic alterations represented by a significant increase in serum creatinine, urea, blood urea nitrogen (BUN), renal TNFα, oxidative stress-related indices, and altered the relative mRNA expression of apoptosis-related genes Bax, Caspase-3, Bcl2, Fas, and FasL. MEL-induced array of nephrotoxic morphological changes, and up-regulated immune-expression of proliferating cell nuclear antigen (PCNA) and proliferation-associated nuclear antigen Ki-67. Administration of MOLE or MOLE-SeNPs significantly reversed MEL-induced renal function impairments, oxidative stress, histological alterations, modulation in the relative mRNA expression of apoptosis-related genes, and the immune-expression of renal PCNA and Ki-67. Conclusively, the green-synthesized MOLE-SeNPs and MOLE display nephron-protective properties against MEL-induced murine nephropathy. This study is the first to report these effects which were more pronounced in the MOLE group than the green biosynthesized MOLE-SeNPs conjugate group.

A pain in the neck: Salmonella spp. as an unusual cause of a thyroid abscess. A case report and review of the literature.

BACKGROUND: Thyroid gland infections are rare. Their incidence is estimated to be less than 1% in immunocompromised hosts. Most common pathogens isolated are Gram positive aerobic cocci. Infections with Gram negative facultative aerobes such as Salmonella are rare. CASE PRESENTATION: A 55-year-old female with type II diabetes mellitus and a history of a colloid right thyroid lobe nodule presented with neck pain and fever. She was found to have a thyroid abscess 2 weeks following a non-specific diarrheal illness. A needle aspiration for symptomatic and diagnostic purposes was performed. Cultures grew Salmonella enterica serotype Heidelberg. She was treated with a 12-week course of oral antibiotics and serial aspiration. CONCLUSION: A thyroid abscess is a rare occurrence; however, a high index of suspicion is required to make the diagnosis. The management is directed at minimizing morbidity. The mainstay treatment is medical, but surgery is sometimes necessary to achieve adequate source control, particularly when complications arise.

Synthesis of Some New Pyridazine Derivatives for Anti-HAV Evaluation.

4-(2-(4-Halophenyl)hydrazinyl)-6-phenylpyridazin-3(2H)-ones 1a,b were prepared and treated with phosphorus oxychloride, phosphorus pentasulphide and ethyl chloroformate to give the corresponding chloropyridazine, pyridazinethione, oxazolopyridazine derivatives 2-4, respectively. Compound 2 reacted with hydrazine hydrate to afford hydrazinylpyridazine 7. The reaction of 4-(2-(4-chlorophenyl)hydrazinyl)-3-hydrazinyl-6-phenylpyridazine (7) with acetic anhydride, p-chlorobenzaldehyde and carbon disulphide gave the corresponding pyridazinotriazine derivatives 8-10. On the other hand, 5-(4-chlorophenylamino)-7-(3,5-dimethoxybenzylidene)-3-phenyl-5H-pyridazino[3,4-b][1,4]thiazin-6(7H)-one (11) was prepared directly from the reaction of compound 3 with chloroacetic acid in presence of p-chlorobenzaldehyde. Compound 11 reacted with nitrogen nucleophiles (hydroxylamine hydrochloride, hydrazine hydrate) and active methylene group-containing reagents (malononitrile, ethyl cyanoacetate) to afford the corresponding fused compounds 12-15, respectively. Pharmacological screening for antiviral activity against hepatitis A virus (HAV) was performed for the new compounds. 4-(4-Chlorophenylamino)-6-phenyl-1,2-dihydropyridazino[4,3-e][1,2,4]triazine-3(4H)-thione (10) showed the highest effect against HAV.

Synthesis and Characterization of New 1,2,4-Triazolo[1,5-a]pyridines That Extend the Life Span of Caenorhabiditis elegans via Their Anti-Inflammatory/Antioxidant Effects.

In the present study, we describe the synthesis of a new set of 1,2,4-triazolo[1,5-a]pyridines and their fused ring systems. The products were assayed for various types of biological activities like anti-inflammatory and antioxidative activity. Compounds 4c, 4f, 12a, 14, 16, and 19 were found to reduce carrageenan- and dextran-induced inflammation in rats. In addition, compounds 4f and 12a were found to have antioxidative radical scavenging activity. Furthermore, these compounds were tested in the model system Caenorhabiditis elegans and there increased heat stress resistance, reduced the formation of advanced glycation end products, and finally extended the life span.

In vitro neutralization of HCV by goat antibodies against peptides encompassing regions downstream of HVR-1 of E2 glycoprotein.

This article aims at testing several in vitro systems with various viral sources and cell lines for propagation of HCV to evaluate goat antibodies raised against three E2 epitopes in viral neutralization experiments. Four human cell lines (Huh-7, Huh-7.5, HepG2, and CaCo2) were tested using two different HCV viral sources; Genotype 4 infected sera and J6/JFH HCV cc particles. Neutralization capacity of goat Abs against conserved E2 epitopes; p412 (a.a 412-419), p517 (a.a 517-531), and p430 (a.a 430-447) were examined in the above mentioned in vitro systems. Although infection with patients' sera seems to mimic the in vitro situation, it has limited replication rates as compared with HCV cc particularly in Huh7.5 cells. Non-HCV adapted Huh-7 cells were also found susceptible for transfection with J6/JFH virus but at much slower kinetics. The results of the neutralization assay showed that anti p412 and anti p517 were highly neutralizing to HCVcc. Our data demonstrate that antibodies directed against the viral surface glycoprotein E2 reduced the infectivity of the J6/JFH virus and are promising agents for immunotherapy and HCV vaccine development.

Hilfer-Katugampola fractional stochastic differential inclusions with Clarke sub-differential.

The objective of this paper is to investigate the existence of mild solutions and optimal controls for a class of stochastic Hilfer-Katugampola fractional differential inclusions (SHKFDIs) with non-instantaneous impulsive (NIIs) that is strengthened by Brownian motion (BM) and the Clarke sub-differential. First, we establish a new set of sufficient conditions for the existence of mild solutions of the aforementioned fractional systems by using stochastic analysis, the Clarke sub-differential's characteristics, and the multi-valued fixed point theorem. Subsequently, by employing Balder's theorem, the existence of optimal control pairs for the considered system is investigated. Eventually, an example is provided to validate the obtained results.

Plasma miRNA expression profile in pediatric pineal pure germinomas.

Background: Pure germinomas account for 40% of pineal tumors and are characterized by the lack of appreciable tumor markers, thus requiring a tumor biopsy for diagnosis. MicroRNAs (miRNA) have emerged as potential non-invasive biomarkers for germ cell tumors and may facilitate the non-invasive diagnosis of pure pineal germinomas. Material and methods: A retrospective chart review was performed on all patients treated at the Children's Cancer Hospital Egypt diagnosed with a pineal region tumor between June 2013 and March 2021 for whom a research blood sample was available. Plasma samples were profiled for miRNA expression, and DESeq2 was used to compare between pure germinoma and other tumor types. Differentially expressed miRNAs were identified. The area under the curve of the receive;r operating characteristic curve was constructed to evaluate diagnostic performance. Results: Samples from 39 pediatric patients were available consisting of 12 pure germinomas and 27 pineal region tumors of other pathologies, including pineal origin tumors [n = 17; pineoblastoma (n = 13) and pineal parenchymal tumors of intermediate differentiation (n = 4)] and others [n = 10; low-grade glioma (n = 6) and atypical teratoid rhabdoid tumor (n = 4)]. Using an adjusted p-value <0.05, three miRNAs showed differential expression (miR-143-3p, miR-320c, miR-320d; adjusted p = 0.0058, p = 0.0478, and p = 0.0366, respectively) and good discriminatory power between the two groups (AUC 90.7%, p < 0.001) with a sensitivity of 25% and a specificity of 100%. Conclusion: Our results suggest that a three-plasma miRNA signature has the potential to non-invasively identify pineal body pure germinomas which may allow selected patients to avoid the potential surgical complications.

Synthesis and larvicidal efficacy of pyrazolopyrimidine derivatives conjugated with selenium nanoparticles against Culex pipiens L. and Musca domestica L. larvae.

The synthesized pyrazolopyrimidine derivatives conjugated with selenium nanoparticles were prepared via a reaction of pyrazolone 1 with aryl-aldehyde and malononitrile or 3-oxo-3-phenylpropanenitrile in the presence ammonium acetate or pipridine using an ultrasonic bath as a modified method in the organic synthesis for such materials. The structure of the synthesized compounds was elucidated through various techniques. All the synthesized pyrazolopyrimidines were used in the synthesis of selenium nanoparticles (SeNPs). These nanoparticles were confirmed using UV-spectra, Dynamic Light scattering and (TEM) techniques. The larvicidal efficiency;of the synthesized;compounds; was investigated against some strains such as Culex pipiens;and Musca domestica larvae. Bioassay test showed pyrazolopyrimide derivatives to exhibit an acceptable larvicidal;bio-efficacy. The derivative (3) exhibited;the highest;efficiency for more than; lab strains of both species. Moreover, C. pipiens larvae were more sensitive towards the examined compounds than M. domestica. The field;strain displayed lower affinity for the 2 folds compounds. Some biochemical changes were tracked through analysis of insect main metabolites (protein, lipid and carbohydrate), in addition to measuring the changes in seven enzymes after treatment. Generally, there was a reduction in the protein, lipids and carbohydrates after treatment with all tested compounds. Moreover, a decrement was noticed for acetylcholine esterase and glutathione;S-transferase; enzymes. There was an increment in the acid;phosphatase; and alkaline phosphatase. In addition, there was elevation in Phenoloxidase level but it noticed the declination in both Cytochrome P450 and Ascorbate peroxidase activity after treatment both flies with derivatives of selenium-nanoparticles in both lab and field strain. Generally, the experiments carried out indicate that antioxidant and detoxification enzymes may play a significant role in mechanism of action of our novel nanocompounds. The cytotoxicity of the synthesized compounds and conjugated with SeNPs showed enhanced compatibility with human normal fibroblast cell line (BJ1) with no toxic effect.

New Medical Device and Therapeutic Approvals in Otolaryngology: State of the Art Review of 2022.

Objective: To review new drugs and devices relevant to otolaryngology approved by the Food and Drug Administration (FDA) in 2022. Data Sources: Publicly available FDA data on drugs and devices approved in 2022. Review Methods: A preliminary screen was conducted to identify drugs and devices relevant to otolaryngology. A secondary screen by members of the American Academy of Otolaryngology-Head and Neck Surgery's (AAO-HNS) Medical Devices and Drugs Committee differentiated between minor updates and new approvals. The final list of drugs and devices was sent to members of each subspecialty for review and analysis. Conclusion: A total of 1251 devices and 37 drugs were identified on preliminary screening. Of these, 329 devices and 5 drugs were sent to subspecialists for further review, from which 37 devices and 2 novel drugs were selected for further analysis. The newly approved devices spanned all subspecialties within otolaryngology. Many of the newly approved devices aimed to enhance patient experience, including over-the-counter hearing aids, sleep monitoring devices, and refined CPAP devices. Other advances aimed to improve surgical access, convenience, or comfort in the operating room and clinic. Implications for Practice: Many new devices and drugs are approved each year to improve patient care and care delivery. By staying up to date with these advances, otolaryngologists can leverage new innovations to improve the safety and quality of care. Given the recent approval of these devices, further studies are needed to assess long-term impact within the field of otolaryngology.

Ferulsinaic acid attenuation of diabetic nephropathy.

BACKGROUND: Different factors are involved in the development of diabetic nephropathy (DN). Oxidative stress and inflammation play an important role in the pathogenesis of DN. Ferulsinaic Acid (FA) was isolated in 2007. In 2011, we found that FA prolonged the lifespan of C. elegans due to its antioxidative effect, and we hypothesized that FA restores the kidney function of diabetic rats via its antioxidant activity. METHODS: Male Wistar rats were injected with STZ and divided into 5 groups of 10 each: control, diabetic untreated, diabetic treated with 500, 750 and 1000 ng/kg FA. FA treatment was continued for 21 weeks after induction of diabetes. RESULTS: In the diabetic rats treated with FA, fasting blood sugar, HbA1C kidney/body weight ratio, creatinine, BUN, sodium and albuminurea were significantly decreased compared with untreated diabetic rats. Diabetic rats showed decreased activities of superoxide dismutase, glutathione peroxidase and catalase, increased concentrations of malondialdehyde and IL-6 in the kidney homogenate. In addition levels of 8-hydroxy-2'-deoxyguanosine in the urine and in the renal cortex DNA were increased. Moreover, severe destruction in glomerular and tubulointerstitial lesions such as glomerular sclerosis, atrophy, interstitial expansion and interstitial cellular infiltration was seen in the kidney of the diabetic untreated rats. Furthermore, the diabetic kidney was found to be positive for NF-κB p65 antigen in the immunohistochemistry examinations. Treatment with FA restored all the altered parameters in a dose-dependent manner. Furthermore, all the ultra-morphologic abnormalities and NF-κB activation in the kidney of diabetic rats were markedly ameliorated by FA treatment. CONCLUSION: FA confers a considerable protection against kidney injuries of the diabetic rats by increasing activities of antioxidant enzymes, attenuating the formation of AGEs, attenuating the NF-κB activation, ameliorating the inflammatory markers and inhibiting the accumulation of oxidized DNA in the kidney, suggesting a potential drug for the prevention and therapy of DN.

Genetic variants of neurotransmitter-related genes and miRNAs in Egyptian autistic patients.

Autism is a neurodevelopmental disorder with indisputable evidence for a genetic component. This work studied the association of autism with genetic variations in neurotransmitter-related genes, including MAOA uVNTR, MAOB rs1799836, and DRD2 TaqI A in 53 autistic patients and 30 healthy individuals. The study also analyzed sequence variations of miR-431 and miR-21. MAOA uVNTR was genotyped by PCR, MAOB and DRD2 polymorphisms were analyzed by PCR-based RFLP, and miR-431 and miR-21 were sequenced. Low expressing allele of MAOA uVNTR was frequently higher in female patients compared to that in controls (OR = 2.25). MAOB G allele frequency was more significantly increased in autistic patients than in controls (P < 0.001 for both males and females). DRD2 A1+ genotype increased autism risk (OR = 5.1). Severity of autism tends to be slightly affected by MAOA/B genotype. Plasma MAOB activity was significantly reduced in G than in A allele carrying males. There was no significant difference in patients and maternal plasma MAOA/B activity compared to controls. Neither mutations nor SNPs in miR-431 and miR-21 were found among studied patients. This study threw light on some neurotransmitter-related genes suggesting their potential role in Autism pathogenesis that warrants further studies and much consideration.

Autophagic reprogramming of bone marrow-derived macrophages.

Macro-autophagy is a highly conserved catabolic process among eukaryotes affecting macrophages. This work studies the genetic regulatory network involving the interplay between autophagy and macrophage polarization (activation). Autophagy-related genes (Atgs) and differentially expressed genes (DEGs) of macrophage polarization (M1-M2) were predicted, and their regulatory networks constructed. Naïve (M0) mouse bone marrow-derived monocytes were differentiated into M1 and M2a. Validation of the targets of Smad1, LC3A and LC3B, Atg16L1, Atg7, IL-6, CD68, Arg-1, and Vamp7 was performed in vitro. Immunophenotyping by flow cytometry revealed three macrophage phenotypes: M0 (IL-6 + /CD68 +), M1 (IL-6 + /CD68 + /Arg-1 +), and M2a (CD68 + /Arg-1). Confocal microscopy revealed increased autophagy in both M1 and M2a and a significant increase in the pre-autophagosomes size and number. Bafilomycin A increased the expression of CD68 and Arg-1 in all cell lineages. In conclusion, our approach predicted the protein targets mediating the interplay between autophagy and macrophage polarization. We suggest that autophagy reprograms macrophage polarization via CD68, arginase 1, Atg16L1-1, and Atg16L1-3. The current findings provide a foundation for the future use of macrophages in immunotherapy of different autoimmune disorders.

miRNome of Child A hepatocellular carcinoma in Egyptian patients.

Introduction: Hepatocellular carcinoma (HCC) has different etiologies that contribute to its heterogeneity. In regards to the number of HCC patients, Egypt ranks third in Africa and fifteenth worldwide. Despite significant advancements in HCC diagnosis and treatment, the precise biology of the tumor is still not fully understood, which has a negative impact on patient outcomes. Methods: Advances in next-generation sequencing (NGS) have increased our knowledge of the molecular complexity of HCC. Results & discussion: In this research, 16 HCC and 6 tumor adjacent tissues (control) of Child A Egyptian patients were successfully profiled for the expression profile of miRNAs by NGS. Forty-one differentially expressed miRNAs (DEMs) were found by differential expression analysis, with 31 being upregulated and 10 being downregulated. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was then conducted on these differentially expressed miRNAs revealing that Sensitivity and specificity analysis showed that hsa-miR-4488, hsa-miR-3178, and hsa-miR-3182 were unique miRNAs as they are expressed in HCC tissues only. These miRNAs were all highly involved in AMPK signaling pathways. However, hsa-miR-214-3p was expressed in control tissues about eight times higher than in cancer tissues and was most abundant in "pathways in cancer and PI3K-Akt signaling pathway" KEGG terms. As promising HCC diagnostic markers, we here suggest hsa-miR-4488, hsa-miR-3178, hsa-miR-3182, and hsa-miR-214-3p. We further urge future research to confirm these markers' diagnostic and prognostic potential as well as their roles in the pathophysiology of HCC.

Biosynthetic gene cluster signature profiles of pathogenic Gram-negative bacteria isolated from Egyptian clinical settings.

Biosynthetic gene clusters (BGCs) are a subset of consecutive genes present within a variety of organisms to produce specialized metabolites (SMs). These SMs are becoming a cornerstone to produce multiple medications including antibacterial and anticancer agents. Natural products (NPs) also play a pivotal role in enhancing the virulence of ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), which represent a global health threat. We aimed to sequence and computationally analyze the BGCs present in 66 strains pertaining to three different ESKAPE pathogenic species: 21 A. baumannii, 28 K. pneumoniae, and 17 P. aeruginosa strains recovered from clinical settings in Egypt. DNA was extracted using QIAamp DNA Mini kit and Illumina NextSeq 550 was used for whole-genome sequencing. The sequences were quality-filtered by fastp and assembled by Unicycler. BGCs were detected by antiSMASH, BAGEL, GECCO, and PRISM, and aligned using Clinker. The highest abundance of BGCs was detected in P. aeruginosa (590), then K. pneumoniae (146) and the least in A. baumannii strains (133). P. aeruginosa isolates shared mostly the non-ribosomal peptide synthase (NRPS) type, K. pneumoniae isolates shared the ribosomally synthesized and post-translationally modified peptide-like (RiPP-like) type, while A. baumannii isolates shared the siderophore type. Most of the isolates harbored non-ribosomal peptide (NRP) BGCs with few K. pneumoniae isolates encoding polyketide BGCs. Sactipeptides and bottromycin BGCs were the most frequently detected RiPP clusters. We hypothesize that each species' BGC signature confers its virulence. Future experiments will link the detected clusters with their species and determine whether the encoded SMs are produced and cause their virulence. IMPORTANCE Our study analyzes the biosynthetic gene clusters (BGCs) present in 66 assemblies from clinical ESKAPE pathogen isolates pertaining to Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa strains. We report their sequencing and assembly followed by the analysis of their BGCs using several bioinformatics tools. We then focused on the most abundant BGC type in each species and we discussed their potential roles in the virulence of each species. This study is pivotal to further build on its experimental work that deciphers the role in virulence, possible antibacterial effects, and characterization of the encoded specialized metabolites (SMs). The study highlights the importance of studying the "harmful" BGCs and understanding the pathogenicity and virulence of those species, as well as possible benefits if the SMs were used as antibacterial agents. This could be the first study of its kind from Egypt and would shed light on BGCs from ESKAPE pathogens from Egypt.

Encapsulated polycaprolactone with triazole derivatives and selenium nanoparticles as promising antiproliferative and anticancer agents.

Background and purpose: Polycaprolactone nanocapsules incorporated with triazole derivatives in the presence and absence of selenium nanoparticles were prepared and evaluated as antiproliferative and anticancer agents. Polycaprolactone nanoparticles were prepared using the emulsion technique. Experimental approach: The prepared capsules were characterized using FT-IR, TEM and DLS measurements. The synthesized triazolopyrimidine derivative in the presence and absence of selenium nanoparticles encapsulated in polycaprolactone was tested for its in vitro antiproliferative efficiency towards human breast cancer cell line (MCF7) and murine fibroblast normal cell line (BALB/3T3) in comparison to doxorubicin as a standard anticancer drug. Key results: The results indicated that encapsulated polycaprolactone with selenium nanoparticles (SeNPs) and triazole-SeNPs were the most potent samples against the tested breast cancer cell line (MCF7). On the other hand, all compounds showed weak or moderate activities towards the tested murine fibroblast normal cell line (BALB/3T3). Conclusion: As the safety index (SI) was higher than 1.0, it expanded the way for newly synthesized compounds to express antiproliferative efficacy against tumour cells. Hence, these compounds may be considered promising ones. However, they should be examined through further in-vivo and pharmacokinetic studies.