Glucocorticoids Induce G1 as Well as S-Phase Lengthening in Normal Human Stimulated Lymphocytes: Differential Effects on Cell Cycle Regulatory Proteins

In order to analyze dexamethasone effects on peripheral blood lymphocyte proliferation, we defined various experimental conditions: dexamethasone introduced (i) at the time of phytohemagglutinin stimulation, (ii) 48 h after the beginning of phytohemagglutinin stimulation, and (iii) on unstimulated lymphocytes. In stimulated lymphocytes, we observed an early G1 accumulation (P< 0.005), a delayed increase in the duration of S-phase (P< 0.03), and a consequent increase in cell-cycle duration. The expression of several cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CKIs) was modified. Cyclin D3, CDK4, and CDK6 involved in G1-phase control were significantly decreased under dexamethasone treatment whatever the level of stimulation of lymphocytes (stimulated or unstimulated PBL). Cyclin E and CDK2, acting in G1/S-phase transition and S-phase regulation, decreased in stimulated lymphocytes before any modification of S-phase (P< 0.002). The expression of CKIs, mainly of p27^Kip1, appeared to vary with the degree of cell stimulation: a decrease was observed on treated unstimulated lymphocytes, while p27^Kip1increased in dexamethasone-treated cells during stimulation. Our results indicate sequential modifications of the cell-cycle regulation by dexamethasone starting with an action on G1 followed by S-phase control modifications. The protein analysis pinpoints the major complexes concerned: CDK4 and CDK6/cyclin D are mainly involved in G1-phase modifications, while CDK2 and its partner, cyclin E, might be specifically involved in the lengthening of S-phase. The variations observed for p27^Kip1might amplify the functional effects of dexamethasone on kinasic complexes.     

StructureActivity Relationships of Antimicrobial Gallic Acid Derivatives from Pomegranate and Acacia Fruit Extracts against Potato Bacterial Wilt Pathogen

Bacterial wilts of potato, tomato, pepper, and or eggplant caused by Ralstonia solanacearum are among the most serious plant diseases worldwide. In this study, the issue of developing bactericidal agents from natural sources against R. solanacearum derived from plant extracts was addressed. Extracts prepared from 25 plant species with antiseptic relevance in Egyptian folk medicine were screened for their antimicrobial properties against the potato pathogen R. solancearum by using the disc‐zone inhibition assay and microtitre plate dilution method. Plants exhibiting notable antimicrobial activities against the tested pathogen include extracts from Acacia arabica and Punica granatum. Bioactivity‐guided fractionation of A. arabica and P. granatum resulted in the isolation of bioactive compounds 3,5‐dihydroxy‐4‐methoxybenzoic acid and gallic acid, in addition to epicatechin. All isolates displayed significant antimicrobial activities against R. solanacearum (MIC values 0.5–9 mg/ml), with 3,5‐dihydroxy‐4‐methoxybenzoic acid being the most effective one with a MIC value of 0.47 mg/ml. We further performed a structure–activity relationship (SAR) study for the inhibition of R. solanacearum growth by ten natural, structurally related benzoic acids.     

Targeting NF-κB/COX-2 signaling by soyasaponin I alleviates diclofenac-induced gastric ulceration in male albino rats

Gastric ulceration is a prevalent worldwide clinical presentation due to altered gastric defense mechanisms. Nonsteroidal anti-inflammatory drugs are one of the common causes of gastric ulcers mediated by the release of inflammatory mediators. The study aimed to investigate the potential protective effect of soyasaponin I (soya) against diclofenac (DIC)-induced gastric ulcer in rats and to highlight the underlying mechanisms. The experiment was conducted on 40 male Wistar albino rats, equally distributed into five groups: control, DIC-induced ulcer (9 mg/kg/d, orally, twice daily for 3 days), ulcer/soya-, ulcer/ranitidine-, and ulcer/soya/selective nuclear factor kappa B inhibitor (JSH-23)-treated groups. The doses of soya, ranitidine, and JSH were 20, 25, and 5 mg/kg/d, respectively, given orally. Gastric specimens were prepared for gene and histological study and for biochemical analysis of gastric prostaglandin E2 (PGE2), oxidative markers, and inflammatory cytokines. The gastric samples were formalin-fixed, paraffin-embedded, and subjected to hematoxylin and eosin (H&E), PAS staining, and immunohistochemical assay for identification of nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2), and proliferation marker (Ki67) expressions. The findings revealed decreased gastric PGE2 and altered inflammatory and oxidative markers in the ulcer model group. The H&E staining showed mucosal injury characterized by mucosal surface defects and inflammatory cell infiltrations. The polymerase chain reaction (PCR) and immunohistochemistry demonstrated an upregulation of NF-κB and COX-2 expression at gene/protein levels; meanwhile, Ki67 downregulation. The soya-treated group showed maintained biochemical, histological, and PCR findings comparable to the ranitidine-treated group. The JSH-23-treated group still showed partial gastric protection with biochemical and immunohistochemical changes. Soyasaponin I ameliorated DIC-induced gastric ulcers by targeting the COX-2 activity through modulation of NF-κB signaling.     

Preparation of photoluminescent nano-biocomposite nacre from graphene oxide and polylactic acid

Nano-biocomposites of inorganic and organic components wereprepared to produce long-persistent phosphorescent artificial nacre-like materials. Biodegradable polylactic acid (PLA), graphene oxide (GO), and nanoparticles (13–20 nm) of lanthanide-doped aluminate pigment (NLAP) were used in a simple production procedure of an organic/inorganic hybrid nano-biocomposite. Both polylactic acid and GO nanosheets were chemically modified to form covalent and hydrogen bonding. The high toughness, good tensile strength, and great endurance of those bonds were achieved by their interactions at the interfaces. Long-persistent and reversible photoluminescence was shown by the prepared nacre substrates. Upon excitation at 365 nm, the nacre substrates generated an emission peak at 517 nm. When ultraviolet light was shone on luminescent nacres, they displayed a bright green colour. The high superhydrophobicity of the generated nacres was obtained without altering their mechanical characteristics.     

Design and synthesis of thiazolidine-2,4-diones hybrids with 1,2-dihydroquinolones and 2-oxindoles as potential VEGFR-2 inhibitors: in-vitro anticancer evaluation and in-silico studies

A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids with potential activity against VEGFR-2. The cytotoxic effects of the synthesised derivatives against Caco-2, HepG-2, and MDA-MB-231 cell lines were investigated. Compound 12a was found to be the most potent candidate against the investigated cell lines with IC₅₀ values of 2, 10, and 40 µM, respectively. Furthermore, the synthesised derivatives were tested in vitro for their VEGFR-2 inhibitory activity showing strong inhibition. Moreover, an in vitro viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. Compound 12a was further investigated for its apoptotic behaviour by assessing the gene expression of four genes (Bcl2, Bcl-xl, TGF, and Survivin). Molecular dynamic simulations authenticated the high affinity, accurate binding, and perfect dynamics of compound 12a against VEGFR-2.     

Ellagic acid regulates hyperglycemic state through modulation of pancreatic IL-6 and TNF- α immunoexpression

BackgroundType 2 diabetes (T2DM) is a chronic metabolic disorder. Although therapeutic pharmaceutical agents continue to advance, herbal medicines are potential complementary treatments for the promotion of glucose homeostasis, with minimal adverse effects. Conventionally, ellagic acid (EA) has been utilized for the therapy of a range of pathologies owing to its anti-inflammatory and anti-diabetic actions.ObjectiveThe aim of this study is to determine the activity of EA on serum α-amylase and lipase titers, and on pancreatic tumor necrosis factor-α (TNF-α), proliferating cell nuclear antigen (PCNA) and interleukin-6 (IL-6) concentrations using the streptozocin-induced T2DM rodent model.MethodsEA extract synthesized from fresh strawberry fruit was employed for therapy. 50 adults male Wistar rats were randomized into either control, EA, diabetic, co-treated or post- treated cohorts.ResultsEA diminished fasting blood glucose levels, altered lipase, amylase, IL-6, PCNA and TNF- α expression and enhanced islet cell renewal, insulin, and immunoreactivities.ConclusionInflammatory indicators are elevated in the presence of T2DM. Extract of EA has overall tissue reparative and safeguarding properties, as indicated by the augmented β- cell population and enhanced glucose homeostasis. Thus, EA may be an innovative treatment approach for the maintenance of normoglycemia in individuals with T2DM.     

Enhancement of Bioavailability and Pharmacodynamic Effects of Thymoquinone Via Nanostructured Lipid Carrier (NLC) Formulation

Thymoquinone (TQ), obtained from black cumin (Nigella sativa), is a natural product with anti-oxidant, anti-inflammatory, and hepatoprotective effects but unfortunately with poor bioavailability. Aiming to improve its poor oral bioavailability, TQ-loaded nanostructured lipid carriers (NLCs) were prepared by high-speed homogenization followed by ultrasonication and evaluated in vitro. Bioavailability and pharmacodynamic studies were also performed. The resultant NLCs showed poor physical homogeneity in Compritol 888 ATO Pluronic F127 system which consequently produced larger particle size and polydispersity index, smaller zeta potential values, and lower short-term (30 days) physical stability than other systems. Encapsulation efficiency percentage (EE%) lied between 84.6?±?5% and 96.2?±?1.6%. TQ AUC_0–t values were higher in animals treated with NLCs, with a relative bioavailability of 2.03- and 3.97-fold (for F9 and F12, respectively) higher than TQ suspension, indicating bioavailability enhancement by NLC formulation. Hepatoprotective effects of F12 showed significant (P?<?0.05) decrease in both serum alanine amino transferase and aspartate amino transferase to reach 305.0?±?24.88 and 304.7?±?23.55 U/ml, respectively, when compared with untreated toxic group. Anti-oxidant efficacy of F12 showed significant (P?<?0.05) decline of malondialdehyde and elevation of reduced glutatione. This improvement was also confirmed histopathologically.     

Novel chalcone/aryl carboximidamide hybrids as potent anti-inflammatory via inhibition of prostaglandin E2 and inducible NO synthase activities: design,synthesis, molecular docking studies and ADMET prediction

Two series of chalcone/aryl carboximidamide hybrids 4a–f and 6a–f were synthesised and evaluated for their inhibitory activity against iNOS and PGE2. The most potent derivatives were further checked for their in vivo anti-inflammatory activity utilising carrageenan-induced rat paw oedema model. Compounds 4c, 4d, 6c and 6d were proved to be the most effective inhibitors of PGE2, LPS-induced NO production, iNOS activity. Moreover, 4c, 4d, 6c and 6d showed significant oedema inhibition ranging from 62.21% to 78.51%, compared to indomethacin (56.27 ± 2.14%) and celecoxib (12.32%). Additionally, 4c, 6a and 6e displayed good COX2 inhibitory activity while 4c, 6a and 6c exhibited the highest 5LOX inhibitory activity. Compounds 4c, 4d, 6c and 6d fit nicely into the pocket of iNOS protein (PDB ID: 1r35) via the important amino acid residues. Prediction of physicochemical parameters exhibited that 4c, 4d, 6c and 6d had acceptable physicochemical parameters and drug-likeness. The results indicated that chalcone/aryl carboximidamides 4c, 4d, 6c and 6d, in particular 4d and 6d, could be used as promising lead candidates as potent anti-inflammatory agents.     

Isolation and characterization of acetonitrile utilizing bacteria

Summary Bacteria utilizing high concentrations of acetonitrile as the sole carbon source were isolated and identified asChromobacterium sp. andPseudomonas aeruginosa. Maximum growth was attained after 96 h of incubation andP. aeruginosa grew slightly faster thanChromobacterium sp. The strains were able to grow and oxidize acetonitrile at concentrations as high as 600 mM. However, higher concentrations inhibited growth and oxygen uptake. Degradation studies with (¹⁴C)acetonitrile indicated 57% of acetonitrile was degraded byPseudomonas aeruginosa as compared to 43% byChromobacterium. The isolates utilized different nitrile compounds as carbon substrates.