New pyranopyrazole based derivatives: Design, synthesis, and biological evaluation as potential topoisomerase II inhibitors, apoptotic inducers, and antiproliferative agents.

A new series of pyranopyrazole-based derivatives were designed and synthesized. The synthesized compounds were assessed for their cytotoxic efficacy against A549 human lung carcinoma and MCF-7 human breast carcinoma cell lines. Three compounds (1b, 4b, and 7b) exhibited 1.3- to 2.3-fold more antiproliferative activity than that of doxorubicin against the A549 cell line. In comparison to doxorubicin, compounds 1d and 3b were 4.1- and 1.04-fold, respectively more powerful against MCF-7 cancer cells. All the synthesized compounds were found to be more selective toward A549 cancer cells than the normal human fibroblast BJ cells. Of interest, compounds 1b and 7b exhibited promising cytotoxicity and SIs of 27.72 and 25.30, respectively, towards A549 cancer cells, higher than that of doxorubicin (SI 4.81). The most potent compounds 1b, 1d, 3b, 4b, and 7b were then subjected to in vitro Topo II inhibition assay. They showed IC50 values in the range of 2.07 to 8.86 µM. Of particular interest, compound 7b (IC50 = 2.07 µM), exhibited higher Topo II inhibitory activity than that of doxorubicin (IC50 = 2.56 µM). The significant Topo II inhibition of compound 7b was explained by molecular docking simulations into the Topo II active site. Compound 7b halted the cell cycle in the S phase in A549 cancer cells. It induced total apoptosis and necrosis of 20.73- and 4-fold, respectively, greater than the control. This evidence was supported by a 3.59-fold increase in the level of apoptotic caspase-9 and a remarkable elevation of the Bax/BCL-2 ratio. The physiochemical parameters of compound 7b were aligned with Lipinski's rule of five.

Synthesis, COX-2 inhibition, anti-inflammatory activity, molecular docking, and histopathological studies of new pyridazine derivatives.

Five new pyridazine scaffolds were synthesized and assessed for their inhibitory potential against both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) compared with indomethacin and celecoxib. The majority of the synthesized compounds demonstrated a definite preference for COX-2 over COX-1 inhibition. Compounds 4c and 6b exhibited enhanced potency towards COX-2 enzyme with IC50 values of 0.26 and 0.18 µM, respectively, compared to celecoxib with IC50 = 0.35 µM. The selectivity index (SI) of compound 6b was 6.33, more than that of indomethacin (SI = 0.50), indicating the most predominant COX-2 inhibitory activity. Consequently, the in vivo anti-inflammatory activity of compound 6b was comparable to that of indomethacin and celecoxib and no ulcerative effect was detected upon the oral administration of compound 6b, as indicated by the histopathological examination. Moreover, compound 6b decreased serum plasma PEG2 and IL-1ß. To rationalize the selectivity and potency of COX-2 inhibition, a molecular docking study of compound 6b into the COX-2 active site was carried out. The COX-2 inhibition and selectivity of compound 6b can be attributed to its ability to enter the side pocket of the COX-2 enzyme and interact with the essential amino acid His90. Together, these findings suggested that compound 6b is a promising lead for the possible design of COX-2 inhibitors that could be employed as safe and effective anti-inflammatory drugs.

Impact of sub chronic administration of deltamethrin on autoimmune activity in rat.

Deltamethrin (DLM) is a newer kind of insecticide that is used on pets, livestock, and crops, as well as to combat malaria vectors and household pests. It belongs to the synthetic pyrethroid group and is being promoted as an alternative to organophosphate chemicals due to its persistent and destructive effects. The current study aimed to evaluate the impact of sub-chronic oral exposure to DLM on autoimmune activity in rats. Three groups of male albino rats (15 rats/group) including the control group, the ethanol-treated group (1 ml/rat), and the DLM-treated group (5 mg/kg b.w). Samples of blood were taken from all groups at 4-, 8- and 12-week intervals for the determination of hematological, cytokines, and immunological parameters. T lymphocyte subsets and Treg lymphocytes were determined in serum using flow cytometric acquisition. The results revealed that DLM significantly increased TNF-α, IL-33, IL-6, IL-17, IgG, IgM, WBCs, differential count, and platelets while decreasing Hb concentration and RBCs. Additionally, DLM decreased the number of T-cell subsets (CD3, CD4, CD5, and CD8) and Treg lymphocytes. All of these impacts became more severe over time. It is possible to conclude that the sub-chronic oral exposure to DLM disturbed autoimmune activity through the disturbances in immunological indices, CDs subset Treg lymphocytes.

LC-HRMS Profiling and Cytotoxic Potential of Actinomycetes Associated with the Red Sea Soft Coral Sarcophyton glaucum: In vitro and In silico Studies.

In the current study, the actinomycetes associated with the red sea-derived soft coral Sarcophyton glaucum were investigated in terms of biological and chemical diversity. Four different media, M1, ISP2, Marine Agar (MA), and Actinomycete isolation agar (AIA) were used for the isolation of three strains of actinomycetes that were identified as Streptomyces sp. UR 25, Micromonospora sp. UR32 and Saccharomonospora sp. UR 19. LC-HRMS analysis was used to investigate the chemical diversity of the isolated actinobacteria. The LC-HRMS data were statistically processed using MetaboAnalyst 5.0 viz to differentiate the extract groups and determine the optimal growth culturing conditions. Multivariate data statistical analysis revealed that the Micromonospora sp. extract cultured on (MA) medium is the most distinctive extract in terms of chemical composition. While, the Streptomyces sp. UR 25 extracts are differ significantly from Micromonospora sp. UR32 and Saccharomonospora sp. UR 19. Biological investigation using in vitro cytotoxic assay for actinobacteria extracts revealed the prominent potentiality of the Streptomyces sp. UR 25 cultured on oligotrophic medium against human hepatoma (HepG2), human breast adenocarcinoma (MCF-7) and human colon adenocarcinoma (CACO2) cell lines (IC50 =3.3, 4.2 and 6.8 µg/mL, respectively). SwissTarget Prediction speculated that among the identified compounds, 16-deethyl, indanomycin (8) could have reasonable affinity on HDM2 active site. In this respect, molecular docking study was performed for compound (8) to reveal a substantial affinity on HDM2 active site. In addition, molecular dynamics simulations were carried out at 200 ns for the most active compound (8) compared to the co-crystallized inhibitor DIZ giving deeper information regarding their thermodynamic and dynamic properties as well.

Anti-persister efficacy of colistin and meropenem against uropathogenic Escherichia coli is dependent on environmental conditions.

Antibiotic persistence is a phenomenon observed when genetically susceptible cells survive long-term exposure to antibiotics. These 'persisters' are an intrinsic component of bacterial populations and stem from phenotypic heterogeneity. Persistence to antibiotics is a concern for public health globally, as it increases treatment duration and can contribute to treatment failure. Furthermore, there is a growing array of evidence that persistence is a 'stepping-stone' for the development of genetic antimicrobial resistance. Urinary tract infections (UTIs) are a major contributor to antibiotic consumption worldwide, and are known to be both persistent (i.e. affecting the host for a prolonged period) and recurring. Currently, in clinical settings, routine laboratory screening of pathogenic isolates does not determine the presence or the frequency of persister cells. Furthermore, the majority of research undertaken on antibiotic persistence has been done on lab-adapted bacterial strains. In the study presented here, we characterized antibiotic persisters in a panel of clinical uropathogenic Escherichia coli isolates collected from hospitals in the UK and Australia. We found that a urine-pH mimicking environment not only induces higher levels of antibiotic persistence to meropenem and colistin than standard laboratory growth conditions, but also results in rapid development of transient colistin resistance, regardless of the genetic resistance profile of the isolate. Furthermore, we provide evidence for the presence of multiple virulence factors involved in stress resistance and biofilm formation in the genomes of these isolates, whose activities have been previously shown to contribute to the formation of persister cells.

Synthesis of novel nicotinic acid derivatives of potential antioxidant and anticancer activity.

This study comprises the design and synthesis of novel nicotinic acid-based cytotoxic agents with selective inhibitory efficacy against the vascular endothelial growth factor receptor-2 (VEGFR-2). Screening of novel compounds for cytotoxicity was assessed against 60 human cancer cell lines. The two most active compounds, 5b and 5c, and the reference drugs sorafenib and doxorubicin were investigated against HCT-15, PC-3, and CF-295 cancer cell lines. Compound 5c exhibited the highest cytotoxic potential compared to doxorubicin against the HCT-15 and PC-3 tumor cell lines. Moreover, it exhibited higher cytotoxic potential and selectivity toward the HCT-15 cell panel compared with sorafenib. Compound 5c demonstrated promising VEGFR-2 inhibition (concentration needed to inhibit cell viability by 50%, IC50 = 0.068 µM) and superior VEGFR-2 selectivity over the epidermal growth factor receptor and platelet-derived growth factor receptor-ß enzymes. It also reduced the total and phosphorylated VEGFR-2 and induced apoptosis, as evidenced by a 4.3-fold rise in caspase-3 levels. The antioxidant potential of the new compounds was determined via measuring the superoxide dismutase (SOD) levels, among which compound 5c exhibited an SOD level almost comparable to ascorbic acid. These results suggested that compound 5c exhibited dual cytotoxic and antioxidant activities. Docking of 5c into the VEGFR-2 pocket showed a similar binding mode to sorafenib. Moreover, the ADME (absorption, distribution, metabolism, and excretion) profile of 5c outlined drug-likeness. Finally, The density functional theory calculations displayed an increased binding affinity of 5c to the target enzyme.

Design, synthesis, and evaluation of 4'-phosphonomethoxy pyrimidine ribonucleosides as potential anti-influenza agents.

Influenza viruses belong to the Orthomyxoviridae family and cause acute respiratory distress in humans. The developed drug resistance toward existing drugs and the emergence of viral mutants that can escape vaccines mandate the search for novel antiviral drugs. Herein, the synthesis of epimeric 4'-methyl-4'-phosphonomethoxy [4'-C-Me-4'-C-(O-CH2 P═O)] pyrimidine ribonucleosides, their phosphonothioate [4'-C-Me-4'-C-(O-CH2 P═S)] derivatives, and their evaluation against an RNA viral panel are described. Selective formation of the α- l-lyxo epimer, [4'-C-(α)-Me-4'-C-(ß)-(O-CH2 -P(═O)(OEt)2 )] over the ß- d-ribo epimer [4'-C-(ß)-Me-4'-C-(α)-(O-CH2 -P(═O)(OEt)2 )] was explained by DFT equilibrium geometry optimizations studies. Pyrimidine nucleosides having the [4'-C-(α)-Me-4'-C-(ß)-(O-CH2 -P(═O)(OEt)2 )] framework showed specific activity against influenza A virus. Significant anti-influenza virus A (H1N1 California/07/2009 isolate) was observed with the 4'-C-(α)-Me-4'-C-(ß)-O-CH2 -P(═O)(OEt)2 -uridine derivative 1 (EC50 = 4.56 mM, SI50 > 56), 4-ethoxy-2-oxo-1(2H)-pyrimidin-1-yl derivative 3 (EC50 = 5.44 mM, SI50 > 43) and the cytidine derivative 2 (EC50 = 0.81 mM, SI50 > 13), respectively. The corresponding thiophosphonates 4'-C-(α)-Me-4'-C-(ß)-(O-CH2 -P( S)(OEt)2 ) and thionopyrimidine nucleosides were devoid of any antiviral activity. This study shows that the 4'-C-(α)-Me-4'-(ß)-O-CH2 -P(═O)(OEt)2 ribonucleoside can be further optimized to provide potent antiviral agents.

Pyridazine derivatives as selective COX-2 inhibitors: A review on recent updates.

Selective cyclooxygenase (COX)-2 inhibitors have several advantages over nonselective COX inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs]), including the absence of adverse effects (renal and hepatic disorders) associated with the long-term use of standard NSAIDs, as well as an improved gastrointestinal profile. The pyridazine nucleus is regarded as a promising scaffold for the development of powerful COX-2 inhibitors, particularly when selectively functionalized. This article summarizes some methods for the synthesis of pyridazine derivatives. Furthermore, it covers all of the pyridazine derivatives that have appeared as selective COX-2 inhibitors, making it useful as a reference for the rational design of novel selective COX-2 inhibitors.

Ameliorative effect of selenium yeast supplementation on the physio-pathological impacts of chronic exposure to glyphosate and or malathion in Oreochromis niloticus.

BACKGROUND: Pesticide exposure is thought to be a major contributor to living organism health deterioration, as evidenced by its impact on both cultured fish species and human health. Commercial fish diets are typically deficient in selenium (Se); hence, supplementation may be necessary to meet requirements during stress. Therefore, this study was conducted to investigate the protective role of selenium yeast (SY) supplementation for 60 days against the deleterious effects of glyphosate and or malathion chronic toxicity at sublethal concentrations in Oreochromis niloticus . METHODS: Two hundred and ten fish were divided into seven groups (n = 30/group) as follows: G1 (negative control); G2 (2 mg L- 1 glyphosate); G3 (0.5 mg L- 1 malathion); G4 (glyphosate 1.6 mg L- 1 and malathion 0.3 mg L- 1); G5 (glyphosate 2 mg L- 1 and SY 3.3 mg kg- 1); G6 (malathion 0.5 mg L- 1 and SY 3.3 mg kg- 1); and G7 (glyphosate 1.6 mg L- 1; malathion 0.3 mg L- 1 and SY 3.3 mg kg- 1). RESULTS: Results revealed significant alteration in growth performance parameters including feed intake (FI), body weight (BW), body weight gain (BWG), specific growth rate (SGR), feed conversion ratio (FCR), and protein efficiency ratio (PER). G4 has the highest documented cumulative mortalities (40%), followed by G3 (30%). Additionally, the greatest impact was documented in G4, followed by G3 and then G2 as severe anemia with significant thrombocytopenia; leukocytosis; hypoproteinemia; increased Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST), urea, and creatinine, as well as malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Considering the previously mentioned parameters, selenium yeast (Saccharomyces cerevisiae) (3.3 mg kg- 1 available selenium) mitigated the negative impact of both the agrochemicals, whether exposed singly or in combination, in addition to their antioxidative action. CONCLUSIONS: In conclusion, our study found that organophosphorus agrochemicals, single or combined, had negative impacts on Oreochromis niloticus regarding growth performance, biochemical and hematological changes in the serum, as well as induced oxidative damage in liver and kidney tissues. Supplementation of SY at the rate of 3.3 mg kg- 1 diet (2.36 mg kg- 1 selenomethionine and 0.94 mg organic selenium) ameliorated the fish performance and health status adversely affected by organophosphorus agrochemical intoxication.

Immunostimulatory effects of Nannochloropsis oculata supplementation on Barki rams growth performance, antioxidant assay, and immunological status.

BACKGROUND: Natural feed supplements are gaining popularity in the animal production sector due to their safety and potential immunostimulatory properties, as well as the ban of some antibiotics and their negative residual effects. This study was carried out for 1 month to investigate the effect of Nannochloropsis oculata supplementation on growth performance and cell-mediated immunological status of rams assessed by leukogram assessment, lipid oxidation product malondialdehyde (MDA), total antioxidant capacity (TAC), interleukin assay after lymphocyte transformation test (LTT) including interleukin 6 (IL6), tumor necrosis factor-alpha (TNF-α), interleukin 12 (IL12), and gamma interferon (γ-IF), as well as Comet assay (% of DNA damage, tail length (px), % DNA in tail, tail moment and Olive tail moment). METHODS: Eighteen Barki rams (26.21 ± 0.64 kg) were divided into 3 equal treatment groups (6 sheep/each), G1: animals served as the control group that was fed the basal diet only, while the other treated groups (G2 and G3 (Nan 1.5% and Nan 3%) were fed the basal diet supplemented with 1.5% and 3% N. oculata (dry matter basis), respectively. RESULTS: The obtained results revealed that G3 showed a significant (P < 0.05) improvement in performance (body weight and body weight gain), the highest significant count (P < 0.05) in lymphocytes, and the lowest significant (P < 0.05) levels of neutrophils and neutrophils and lymphocytes ratio (N/L) ratio. Meanwhile, both levels of N. oculata significantly (P < 0.05) decreased MDA and increased TAC than control which seemed to be directly correlated with supplemented dose. There was a significant (P < 0.05) enhancement in the lymphocyte transformation assay produced significant (P < 0.05) high cytokines (IL6, γ-IF, IL12, and TNF-α) and the lowest significant (P <0.05) percent of DNA damage. The conducted principal component analysis estimated the inter-relationship between parameters and revealed that microalgae correlated strongly with cytokine assay and TAC, and negatively with Comet assay parameters; MDA, and neutrophils. CONCLUSIONS: It can be noted that dietary addition of N. oculata 3% increased sheep's performance while also producing significant-high cytokines. It also enhanced sheep immunology by considerably enhancing lymphocyte transformation ability. The antioxidant activity of Nannochloropsis appears to influence these findings. It was proposed that the Barki rams' basal diet be supplemented with 3% N. oculata.

Prognostic Significance of Platelet Activation Marker CD62P in Hospitalized Covid-19 Patients.

BACKGROUND: CD62P is a surface marker for platelet activation. Platelet dysfunction contributes to disproportionate intravascular microthrombosis in SARS-CoV-2. We aimed to assess the clinical significance of CD62P as a biomarker of platelet activation and its correlation to the clinical severity and outcome of COVID-19 infections. METHODS: The study included 80 COVID-19 patients and, in addition, there were 20 age and gender-matched healthy controls. Laboratory measurements included CBC, serum ferritin, LDH, CRP, D-dimer and flow cytometric assessments of the platelet markers CD42b and CD62P. The primary study outcome was patients' survival at the end of study. RESULTS: Among the studied patients, 24 patients (30.0%) died by the end of the study. Survivors had significantly lower CD62P values when compared with non-survivors [median (IQR): 75.5 (73.0 - 91.0) versus 96.0 (93.5 - 97.8), p < 0.001]. Patients with severe disease had significantly higher levels of CD62P levels [median (IQR): 95.5 (92.0 - 97.8) versus 75.0 (72.0 - 76.8), p < 0.001]. Logistic regression analysis identified D-dimer levels [OR (95% CI): 0.14 (0.03 - 0.74) and CD62P levels: OR (95% CI): 0.4 (0.17 - 0.94)] as significant predictors of mortality in multivariate analysis. CONCLUSIONS: CD62P expression on admission may be a useful prognostic maker in hospitalized Covid-19 patients. Its expression is related to other markers of inflammation and coagulopathy.

Anti-inflammatory activity of pyridazinones: A review.

The pyridazinone core has emerged as a leading structure for fighting inflammation, with low ulcerogenic effects. Moreover, easy functionalization of various ring positions of the pyridazinone core structure makes it an attractive synthetic and therapeutic target for the design and synthesis of anti-inflammatory agents. The present review surveys the recent advances of pyridazinone derivatives as potential anti-inflammatory agents to provide insights into the rational design of more effective anti-inflammatory pyridazinones.

New benzothienopyrimidine derivatives as dual EGFR/ARO inhibitors: Design, synthesis, and their cytotoxic effect on MCF-7 breast cancer cell line.

New cytotoxic agents based on benzothienopyrimidine scaffold were designed, synthesized, and evaluated against the MCF-7 breast cancer line in comparison to erlotinib and letrozole as reference drugs. Eight compounds demonstrated up to 20-fold higher anticancer activity than erlotinib, and five of these compounds were up to 11-fold more potent than letrozole in MTT assay. The most promising compounds were evaluated for their inhibitory activity against EGFR and ARO enzymes. Compound 12, which demonstrated potent dual EGFR and ARO inhibitory activity with IC50 of 0.045 and 0.146 µM, respectively, was further evaluated for caspase-9 activation, cell cycle analysis, and apoptosis. The results revealed that the tested compound 12 remarkably induced caspase-9 activation (IC50 = 16.29 ng/ml) caused cell cycle arrest at the pre-G1 /G1 phase and significantly increased the concentration of cells at both early and late stage of apoptosis. In addition, it showed a higher safety profile on normal MCF-10A cells, and higher antiproliferative activity on cancer cells (IC50 = 8.15 µM) in comparison to normal cells (IC50 = 41.20 µM). It also revealed a fivefold higher selectivity index than erlotinib towards MCF-7 cancer cells. Docking studies were performed to rationalize the dual inhibitory activity of compound 12.

The Glycemic Control Potential of Some Amaranthaceae Plants, with Particular Reference to In Vivo Antidiabetic Potential of Agathophora alopecuroides.

Natural products continue to provide inspiring moieties for the treatment of various diseases. In this regard, investigation of wild plants, which have not been previously explored, is a promising strategy for reaching medicinally useful drugs. The present study aims to investigate the antidiabetic potential of nine Amaranthaceae plants: Agathophora alopecuroides, Anabasis lachnantha, Atriplex leucoclada, Cornulaca aucheri, Halothamnus bottae, Halothamnus iraqensis, Salicornia persia, Salsola arabica, and Salsola villosa, growing in the Qassim area, the Kingdom of Saudi Arabia. The antidiabetic activity of the hydroalcoholic extracts was assessed using in vitro testing of α-glucosidase and α-amylase inhibitory effects. Among the nine tested extracts, A. alopecuroides extract (AAE) displayed potent inhibitory activity against α-glucosidase enzyme with IC50 117.9 µg/mL noting better activity than Acarbose (IC50 191.4 µg/mL). Furthermore, AAE displayed the highest α- amylase inhibitory activity among the nine tested extracts, with IC50 90.9 µg/mL. Based upon in vitro testing results, the antidiabetic activity of the two doses (100 and 200 mg/kg) of AAE was studied in normoglycemic and streptozotocin (STZ)-induced diabetic mice. The effects of the extract on body weight, food and water intakes, random blood glucose level (RBGL), fasting blood glucose level (FBGL), insulin, total cholesterol, and triglycerides levels were investigated. Results indicated that oral administration of the two doses of AAE showed a significant dose-dependent increase (p < 0.05) in the body weight and serum insulin level, as well as a significant decrease in food and water intake, RBGL, FBGL, total cholesterol, and triglyceride levels, in STZ-induced diabetic mice, compared with the diabetic control group. Meanwhile, no significant differences of both extract doses were observed in normoglycemic mice when compared with normal control animals. This study revealed a promising antidiabetic activity of the wild plant A. alopecuroides.

Impact of the COVID-19 pandemic on endoscopic retrograde cholangiopancreatography: a single center experience.

BACKGROUND: the COVID-19 pandemic has impacted on several aspects of health care services worldwide. The aim of the study was to determine its influence on the case volume, success rate and complication rate of endoscopic retrograde cholangiopancreatography (ERCP). METHOD: all patients who underwent ERCP one-year before and after applying COVID-19 safety measures at the Qena University Hospital were included. Data were collected from the patients' records, analyzed and compared. RESULTS: a total of 250 patients underwent ERCP between April 1st, 2019 and March 31st, 2021, and the mean age of participants was 52 ± 18 years. There was a 5 % increase in case volume after applying COVID-19 safety measures (128 vs 122) and the total procedure time was significantly shorter (42 vs 46 minutes, p = 0.04). There was no significant difference in the overall success rate and complication rate. Procedure success significantly correlated with cannulation attempts and total procedure time in both groups, and serum bilirubin and cannulation time in the pre-COVID-19 patients and alkaline phosphatase (ALP) in post-COVID patients. ERCP-related complications significantly correlated with cannulation attempts in both groups, and ALP, international normalized ratio (INR), cannulation time and total procedure time in pre-COVID-19 patients, and platelet count and amylase in post-COVID patients. Two patients were confirmed COVID-19 cases at the time of ERCP; therapeutic targets were achieved in both with a smooth post-ERCP recovery. Three out of nine ERCP team members caught a mild to moderate COVID-19 infection and recovered after receiving proper management. CONCLUSION: our result show that there was no negative impact of using COVID-19 safety measures and precautions on the case-volume, indications, overall outcome or complication rate of ERCP.

An ex vivo cystic fibrosis model recapitulates key clinical aspects of chronic Staphylococcus aureus infection.

Staphylococcus aureus is the most prevalent organism isolated from the airways of people with cystic fibrosis (CF), predominantly early in life. Yet its role in the pathology of lung disease is poorly understood. In mice, and many experiments using cell lines, the bacterium invades cells or interstitium, and forms abscesses. This is at odds with the limited available clinical data: interstitial bacteria are rare in CF biopsies and abscesses are highly unusual. Bacteria instead appear to localize in mucus plugs in the lumens of bronchioles. We show that, in an established ex vivo model of CF infection comprising porcine bronchiolar tissue and synthetic mucus, S. aureus demonstrates clinically significant characteristics including colonization of the airway lumen, with preferential localization as multicellular aggregates in mucus, initiation of a small colony variant phenotype and increased antibiotic tolerance of tissue-associated aggregates. Tissue invasion and abscesses were not observed. Our results may inform ongoing debates relating to clinical responses to S. aureus in people with CF.

Synthesis and biological evaluation of new nicotinate derivatives as potential anti-inflammatory agents targeting COX-2 enzyme.

Two novel series derived from nicotinic acid were synthesized and evaluated for their inhibitory activity against cyclooxygenases COX-1 and COX-2, and their selectivity indices were determined. Celecoxib, diclofenac and indomethacin were used as reference drugs. All compounds showed highly potent COX-2 inhibitory activity and higher selectivity towards COX-2 inhibition compared to indomethacin. In addition, these compounds except 3a showed clear preferential COX-2 over COX-1 inhibition compared to diclofenac. Compounds 3b, 3e, 4c and 4f showed COX-2 inhibitory activity equipotent to celecoxib. Compounds 4c and 4f demonstrated selectivity indices 1.8-1.9 fold higher than celecoxib. These two most potent and COX-2 selective compounds were further tested in vivo for anti-inflammatory activity by means of carrageenan induced rat paw edema method. Ulcerogenic activity with histopathological studies were performed. The results showed no ulceration, which implies their safe gastric profile. Compound 4f exhibited the most potent in vivo anti-inflammatory activity comparable to all reference drugs. Further, compounds 4c and 4f were investigated for their influence on certain inflammatory cytokines TNF-α and IL-1ß in addition to PEG2. The findings revealed that these candidates could be identified as promising potent anti-inflammatory agents. Molecular docking of 4c and 4f in the COX-2 active site was performed to rationalize their COX-2 inhibitory potency. The results were found to be in line with the biological findings as they exerted more favorable interactions compared to that of celecoxib, explaining their remarkable COX-2 inhibitory activity.

Bio-Guided Isolation of Antimalarial Metabolites from the Coculture of Two Red Sea Sponge-Derived Actinokineospora and Rhodococcus spp.

Coculture is a productive technique to trigger microbes' biosynthetic capacity by mimicking the natural habitats' features principally by competition for food and space and interspecies cross-talks. Mixed cultivation of two Red Sea-derived actinobacteria, Actinokineospora spheciospongiae strain EG49 and Rhodococcus sp. UR59, resulted in the induction of several non-traced metabolites in their axenic cultures, which were detected using LC-HRMS metabolomics analysis. Antimalarial guided isolation of the cocultured fermentation led to the isolation of the angucyclines actinosporins E (1), H (2), G (3), tetragulol (5) and the anthraquinone capillasterquinone B (6), which were not reported under axenic conditions. Interestingly, actinosporins were previously induced when the axenic culture of the Actinokineospora spheciospongiae strain EG49 was treated with signalling molecule N-acetyl-d-glucosamine (GluNAc); this finding confirmed the effectiveness of coculture in the discovery of microbial metabolites yet to be discovered in the axenic fermentation with the potential that could be comparable to adding chemical signalling molecules in the fermentation flask. The isolated angucycline and anthraquinone compounds exhibited in vitro antimalarial activity and good biding affinity against lysyl-tRNA synthetase (PfKRS1), highlighting their potential developability as new antimalarial structural motif.

Cloning of human cord blood-mesenchymal stem cells for isolation of enriched cell population of higher proliferation and differentiation potential.

Heterogeneity of Mesenchymal stem cells (MSCs) imposes limitations for their in vitro expansion and accounts for the lack of reproducibility in some clinical studies. So, this study was designed to isolate and enrich clones of multipotent and self-renewing MSCs from cord blood (CB). Enriched clones with higher proliferation and differentiation potential provide regenerative cells suitable for various clinical demands. MSCA and MSCB original (progenitor) cells were isolated from CB samples, and single cells were cloned by limiting dilution method, in mouse embryonic fibroblast conditioned media. Original MSCs and their single-cell derived clones were characterized by identifying their proliferation rate, immunophenotyping of surface antigens, expression of pluripotency and proliferation genes (Oct4, Sox2, Nanog, KLF4, c-Myc, and PDGFRA), and differentiation potential into multiple lineages (osteogenic, adipogenic, and chondrogenic). Some single-cell clones of MSCA showed a higher proliferation rate and greater differentiation potential than their original cells. However, original MSCB cells were of greater proliferation and differentiation potential than their derived single-cell clones, except for one clone which had comparable results. Cloning of MSCs was attainable when cultured in mouse embryonic fibroblast conditioned media. Single clones with higher proliferation and differentiation potential than their original progenitor cells were obtained by cloning of poorly functioning MSCs progenitor cells, enabling the selection of more therapeutically efficacious MSCs with better performance in clinical applications. Moreover, this study draws attention to the importance of CD105 as a possible MSCs biomarker associated with the multilineage commitment of MSCs.

New pyrazolopyrimidine derivatives with anticancer activity: Design, synthesis, PIM-1 inhibition, molecular docking study and molecular dynamics.

In this study, new pyrazolopyrimidine derivatives were designed and evaluated for anticancer activity. PIM-1 inhibitiory activity were measured for the most potent compounds. Molecular docking study and molecular dynamics were also done. Thus, the novel derivatives of pyrazolo[1,5-a]pyrimidine have been synthesized and characterized using different spectroscopic techniques. HMBC and NOESY experiments were used to confirm regiospecific structure of pyrimidine ring. The newly synthesized derivatives were evaluated for their antitumor activities against HCT-116 and MCF-7 cell lines. These derivatives showed clear in vitro antitumor activities. Compound 5h showed the highest bioactivity (IC50 = 1.51 µM) against HCT-116 cell line. While, compound 6c was the most potent derivative, its IC50 was 7.68 µM against MCF-7 cell line. Compounds 5c, 5g, 5h, 6a and 6c showed PIM-1 inhibitory activity with IC50 of 1.26, 0.95, 0.60, 1.82, 0.67, respectively µM that could be correlated with their cytotoxic effect. Molecular docking study was done to predict the mode of binding of the target compounds inside PIM-1 active site. The molecular dynamic simulation was conducted in order to evaluate stability of binding of the tested compounds.