Developments of pyridodipyrimidine heterocycles and their biological activities.

The entitled review aimed to assemble and highlight the synthetic approaches and biological aspects of heterocycles with pyridodipyrimidine motifs. The recent synthetic approaches were categorized according to the accomplishments of the approaches under catalyst or catalyst-free conditions. The topic involved the synthesis of substituted tricyclic systems and spirocyclic systems. The present study offered an overview of the recent literature in addition to a scope of the preceding literature. The proposed mechanisms of the varied target products were discussed. Pyridodipyrimidine displayed potential and privileged cytotoxic, antioxidant, and antimicrobial performances. The competitions, challenges, and prospects are also deliberated.

Innovative binary sorption of Cobalt(II) and methylene blue by Sargassum latifolium using Taguchi and hybrid artificial neural network paradigms.

The present investigation has been designed by Taguchi and hybrid artificial neural network (ANN) paradigms to improve and optimize the binary sorption of Cobalt(II) and methylene blue (MB) from an aqueous solution, depending on modifying physicochemical conditions to generate an appropriate constitution for a highly efficient biosorption by the alga; Sargassum latifolium. Concerning Taguchi's design, the predicted values of the two responses were comparable to actual ones. The biosorption of Cobalt(II) ions was more efficient than MB, the supreme biosorption of Cobalt(II) was verified in run L21 (93.28%), with the highest S/N ratio being 39.40. The highest biosorption of MB was reached in run L22 (74.04%), with a S/N ratio of 37.39. The R2 and adjusted R2 were in reasonable values, indicating the validity of the model. The hybrid ANN model has exclusively emerged herein to optimize the biosorption of both Cobalt(II) and MB simultaneously, therefore, the ANN model was better than the Taguchi design. The predicted values of Cobalt(II) and MB biosorption were more obedience to the ANN model. The SEM analysis of the surface of S. latifolium showed mosaic form with massive particles, as crosslinking of biomolecules of the algal surface in the presence of Cobalt(II) and MB. Viewing FTIR analysis showed active groups e.g., hydroxyl, α, ß-unsaturated ester, α, ß-unsaturated ketone, N-O, and aromatic amine. To the best of our knowledge, there are no reports deeming the binary sorption of Cobalt(II) and MB ions by S. latifolium during Taguchi orthogonal arrays and hybrid ANN.

Insights into the recent progress in the medicinal chemistry of pyranopyrimidine analogs.

Heterocycles containing the pyranopyrimidine motif have attracted the interest of researchers in recent decades due to their ability to synthesize and explore at a large scale to explore the biological diversity. Therefore, this review highlights the biological characteristics and synthetic approaches adopted to prepare pyranopyrimidine analogs in the last five years. Several novel preparation procedures have been summarized to synthesize these compounds using ionic, basic, or nanocatalysts or catalyst-free conditions to obtain these compounds in good yields. Pyranopyrimidines could also be used as ligands in the preparation of metal complexes with increased biological potency. The different sections include the antimicrobial, antitubercular, antimalarial, antiviral "SARS-CoV-2 inhibitors", antidiabetic, antitumor, cytotoxic, antiinflammatory, antioxidant, anticoagulant, urease inhibitory activities, and tyrosine inhibitors. The results are discussed based on the structure-activity relationships (SARs) and the mechanism of action.

Recent advancements in the multicomponent synthesis of heterocycles integrated with a pyrano[2,3-d]pyrimidine core.

Heterocyclic compounds incorporated with a pyranopyrimidine skeleton have received substantial consideration owing to their privileged, and intelligible biodiversity. Accordingly, this review highlights the multicomponent synthetic routes adopted to prepare heterocyclic compounds incorporated with the pyrano[2,3-d]pyrimidine skeleton in the preceding two years. The different sections comprise the synthesis of bicyclic, tricyclic, polycyclic, and spirocyclic systems along with the estimation of the probable mechanistic routes for the reaction pathways. Commonly, the pyran ring closure was the major idea of most studies, and the mechanistic pathways of these reactions involved Knoevenagel condensation, Michael addition, and intramolecular cyclocondensation. Besides, the significant biological potency of the compounds recently synthesized from multicomponent reactions is deliberated.

Involvement of INF-γ functional single nucleotide polymorphism +874 T/A (rs2430561) in breast cancer risk.

According Global Cancer Statistics 2020 GLOBOCAN estimates female breast cancer was found as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), and the fourth leading cause (6.9%) of cancer death among women worldwide. Identification of new diagnostic marker sharply characterize the tumor feature is intensive need. The present work was performed to investigate the involvement of the INF-γ + 874 T/A gene polymorphism in different breast cancer prognostic factors. Polymorphism detection analysis was performed on 163 subjects from breast cancer patients, 79 with inflamed cells of breast patients and 144 controls. The gene polymorphism was detected using the amplification refractory mutation system- polymerase chain reaction method (ARMS-PCR). The distribution of INF-γ T + 874A gene polymorphism shows strong significant association between INF-γ + 874 T/A genotypes TT in BC patients (ORTT: 6.41 [95% CI = 2.72-15.1] P < 0.0001) as well as strong significant association regarding T allele (ORT: 1.99 [95% CI = 1.43-2.76] P < 0.0001) when compared to the healthy control. In ICB group the strong association was noted with INF-γ + 874 T/A genotypes AT genotype (ORAT: 2.28 [95% CI = 1.22-4.29] P = 0.007). From the different histological BC hormonal markers the human epidermal growth factor receptor 2 (HER2) was showing significant association in INF-γ + 874 T/A genotypes TT (P = 0.03) and recessive model (TT versus AA + AT P = 0.03). Concerning different BC prognostic models, the poor prognostic one of luminal B, (ER+ve PR+ve Her2+ve) show significant association in the host INF-γ + 874 T/A genotype (TT, P = 0.03) and recessive model (TT versus AA + AT P = 0.02) when compared to the good prognostic hormonal status luminal A model, (ER+ve PR+ve Her2-ve). It seems that this is the first study that interested in correlate the INF-γ + 874 T/A gene polymorphisms in Egyptian BC patients. T allele, TT genotype and recessive model of the INF-γ + 874 T/A gene variants were documented as risk factors for BC pathogenesis. It may be used as practical biomarker to guide the BC carcinogenesis and risk process.

Effects of ecofriendly synthesized calcium nanoparticles with biocompatible Sargassum latifolium algae extract supplementation on egg quality and scanning electron microscopy images of the eggshell of aged laying hens.

In the present study, 200 Brown commercial egg-type layers (60 wk old) were used to study the effects of different levels of ecofriendly synthesis of calcium (Ca) nanoparticles (0.0, 0.50, 1.0, and 1.5 g/kg diet) with biocompatible Sargassum latifolium algae extract (SL-CaNps) on exterior egg quality traits, electronic microscopic view of eggshells, Ca and phosphorus (P) retention, serum Ca and P concentrations, and the histology of the uterus. Hens fed with dietary SL-CaNps powder had higher egg weight and shell weight % values than those of the control group. All SL-CaNps treatment groups had the greatest values of shell weight per unit surface area and shell thickness. Dietary supplementation of SL-CaNps at graded levels up to 1.5 g/kg diet had higher serum Ca and inorganic P levels than that of the control. Laying hens fed with SL-CaNps-added diets had beneficial effects on shell ultrastructure in terms of well-developed palisade and mammillary layers. The numbers of apical cells along the branched tubular gland were greater in SL-CaNps-treated groups than those of control. Conclusively, supplementing SL-CaNps powder up to 1.5 g/kg to the diet of laying hens improved eggshell thickness, shell weight% and shell weight per unit surface and has no adverse effect on their eggshell quality or electronic microscopic view of their eggshell.

Potential Activity of Aqueous Fig Leaves Extract, Olive Leaves Extract and Their Mixture as Natural Preservatives to Extend the Shelf Life of Pasteurized Buffalo Milk.

The aim of this study was to evaluate fig (Ficus carica L.) leaves' extract (FLE), olive (Olea europaea L.) leaves' extract (OLE), and their mixture (MLE), to extend the shelf life of pasteurized milk. OLE, FLE, and their mixture MLE (1:1) were added to the pasteurized milk in different concentrations (0.2%, 0.4%, and 0.6%). Several tests were then conducted to determine the activity of these extracts. The antioxidant activity as IC50 was determined by using DPPH radical assay. FLE showed higher IC50 (30.21 µg/mL) compared to the IC50 of OLE (22.43 µg/mL). Phenolic compounds were identified by using high-performance liquid chromatography (HPLC). The highest antimicrobial activity was obtained with 0.6% concentration. Organoleptic properties indicated that the addition of these extracts did not affect the sensory properties of pasteurized milk. Pasteurized milk treated with 0.6% of FLE, OLE, and MLE has significantly decreased (p ≤ 0.05) lipase and protease activity during the storage period, at 5 °C. The results indicated that extending the shelf life of pasteurized milk from 5 to 16 days was successfully achieved through using 0.6% of FLE, OLE, and MLE. The combination of the two extracts (MLE) provides an efficient and safe method to prolong the shelf life of pasteurized milk, without altering the properties of pasteurized buffalo milk.

Prophylaxis against renal ischemia-reperfusion injury in canine model: Stem cell approach.

INTRODUCTION: Stem cell therapy at the time of ischemia/reperfusion (I/R) injury has been hypothesized to attenuate the severity of acute kidney injury and to accelerate the regeneration process in lower animal models. Data in higher animal models is limited and discordant. We aimed to explore the reno-protective effects of stem cells on I/R related renal injury in a canine model. MATERIALS AND METHODS: Twenty-seven dogs that were treated with bone marrow-derived mesenchymal stem cells (BM-MSCs) were compared with another 27 dogs treated with adipose tissue-derived MSCs (AT-MSCs) following 90 min of warm ischemia to assess IR injury. Each group was divided into three subgroups (nine dogs each), according to the stem cell dose (5, 10, 15 × 106 in 500 µl volume) injected directly into the renal cortex after reperfusion. All dogs were re-evaluated by renogram, histopathology, and pro-inflammatory markers at 2 weeks, 2, and 3 months. RESULTS: In Group I, there was a mean reduction of creatinine clearance by 78%, 64%, and 74% at the three used doses, respectively, at 2 weeks. At 3 months, these kidneys regained a mean of 84%, 92%, and 72%, respectively, of its basal function. In Group II, the reduction of clearance was much more modest with mean of 14%, 6%, and 24% respectively at 2 weeks with more intense recovery of renal function by mean of 90%, 100%, and 76%, respectively, at 3 months. Group I had significantly more tubular necrosis and delayed regeneration compared with the Group II. Expressions of pro-inflammatory markers were upregulated in both the groups with a higher and more sustained expression in Group I. CONCLUSION: Stem cells protected against ischemic reperfusion injury in a canine model. AT-MSCs provided better protection than BM-MSCs.

Hidden Y Chromosome Mosaicism in 48 Egyptian Patients with Turner's Syndrome.

Background. The presence of Y chromosome material in Turner's syndrome (TS) patients is a risk factor for the development of gonadoblastoma. Although conventional cytogenetic analysis is the definitive diagnosis of TS, low level Y chromosome mosaicism may be missed. Molecular analysis has demonstrated a higher proportion of mosaicism, but there is controversy regarding the prevalence of Y chromosome-derived material in those patients. Aim and Methods. This study was conducted to investigate the prevalence of hidden Y chromosome mosaicism in 48 TS Egyptian patients using polymerase chain reaction (PCR) for molecular DNA analysis of SRY gene and compare our results with those in the literature. Results. None of TS patients had a cytogenetically obvious Y chromosome; Y chromosome material was detected only at molecular analysis. SRY gene was found in 9 TS patients (18.75%) with the classical 45,X karyotype, whereas all other patients were SRY negative. Conclusion. Cytogenetically undetected Y chromosome mosaicism is common in TS patients; these data reinforce the need for adequate diagnosis of Y chromosome material in those patients. Molecular screening for Y chromosome-derived DNA should be routinely carried out in all TS patients.

Is solitary kidney really more resistant to ischemia? An experimental canine study.

PURPOSE: To our knowledge there are no evidence-based medicine data to date to critically judge the vulnerability of a solitary kidney to warm ischemia compared to paired kidneys. MATERIALS AND METHODS: Ten dogs were exposed to open right nephrectomy to create a solitary kidney model (group 1). Ten dogs with both kidneys were considered group 2. All dogs underwent warm ischemia by open occlusion of the left renal artery for 90 minutes. Dogs were sacrificed at different intervals (3 days to 4 weeks). All dogs were reevaluated by renogram before sacrifice and histopathology of the investigated kidney. The proinflammatory markers CD95 and tumor necrosis factor-α were assessed using real-time polymerase chain reaction. RESULTS: In group 1 clearance decreased by 20% at 1 week but basal function was regained starting at week 2. In group 2 clearance decreased more than 90% up to week 2. Recovery started at week 3 and by 4 weeks there was a 23% clearance reduction. Histopathological examination in group 1 revealed significant tubular necrosis (60%) at 3 days with regeneration starting at 1 week. In group 2 there was more pronounced tubular necrosis (90%) with regeneration starting at 2 weeks. The expression of proinflammatory markers was up-regulated in each group with higher, more sustained expression in group 2. CONCLUSIONS: Solitary kidney in a canine model is more resistant to ischemia than paired kidneys based on radiological, pathological and genetic evidence.

A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome.

Mandibuloacral dysplasia (MAD) is a rare disease resulting from a mutation of LMNA gene encoding lamins A and C. The most common mutation associated with this disease is a homozygous arginine 527 replacement by histidine. Three female patients originating from two unrelated families from Northeast Egypt were examined. Their growth was retarded; they had microcephaly, widened cranial sutures, prominent eyes and cheeks, micrognathia, dental crowding, hypoplastic mandible, acro-osteolysis of distal phalanges, and joint contractures. In addition, they presented some progeroid features, such as pinched nose, premature loss of teeth, loss of hair, scleroderma-like skin atrophy, spine rigidity, and waddling gait. The clinical presentation of the disease varied between the patient originating from Family 1 and patients from Family 2, suggesting that unknown, possibly epigenetic factors, modify the course of the disease. The first symptoms of the disease appeared at the age of 2.5 (a girl from Family 1), 5, and 3 years (girls from Family 2). All patients had the same, novel homozygous c.1580G>T LMNA mutation, resulting in the replacement of arginine 527 by leucine. Computational predictions of such substitution effects suggested that it might alter protein stability and increase the tendency for protein aggregation, and as a result, might influence its interaction with other proteins. In addition, restriction fragment-length polymorphism analysis performed in 178 unrelated individuals showed that up to 1.12% of inhabitants of Northeast Egypt might be heterozygous carriers of this mutation, suggesting the presence of a founder effect in this area.

Schistosoma-induced amyloidosis in hamsters is gender-dependent.

BACKGROUND: A high serum level of female protein (FP), found to be a constituent of Syrian hamster amyloid was associated with enhanced amyloidosis. In this work, we studied the sex-limited factors in the induction of amyloidosis in Syrian hamsters infected with either Schistosoma mansoni or S. hematobium cercariae. METHODS: Hamsters were infected with different species of schistosome cercariae and sacrificed after different time periods of infection. Kidney and liver specimens were processed in paraffin, stained with Congo-red and examined by ordinary light and polarized light microscopy. RESULTS: Statistical analysis showed a significant difference in intensity of kidney and liver amyloid deposits (P<0.002 & <0.007 respectively) between females and male hamsters with extensive deposits in the former. Amyloid deposits were correlated significantly to the duration of infection (P<0.001) than the load of worm recovered. CONCLUSION: From this study, we conclude that, in hamster model, Schistosoma-induced amyloidosis is enhanced in females than male hamsters. This may be due to the high serum level of FP that is normally detected in females. As an experimental model for schistosomal nephropathy, we recommend to use male hamsters instead of females to minimize the effect of amyloid deposits, which may mask other pathological changes associated with schistosomal infection.

Accelerated induction of bladder cancer in patched heterozygous mutant mice.

The PATCHED (PTC) gene is recognized as a tumor suppressor in basal cell carcinoma. Mapping of a minimal region of deletion at 9q22.3 and observation of a decreased PTC expression in superficial papillary bladder tumors led us to hypothesize that it could also be involved in this cancer. To further investigate this hypothesis, we submitted Ptc(+/-) heterozygous mutant mice and their wild-type littermates to chemical carcinogenesis by adding N-butyl-N-(4-hydroxybutyl) nitrosamine to their drinking water. Preneoplastic and neoplastic changes were observed significantly earlier in the Ptc(+/-) than in the wild-type mice. Our data support the hypothesis of Ptc acting as a tumor suppressor gene in bladder cancer.

[The PATCHED/Sonic Hedgehog signalling pathway in superficial bladder cancer]. / La voie de signalisation PATCHED/Sonic Hedgehog dans le cancer superficiel de la vessie.

Superficial bladder cancer shows a high frequency of total or partial chromosome 9 losses. Loss of heterozygosity at position 9q22.3 is one of the most frequent and is associated with highly recurrent tumours. The PATCHED gene, ortholog of a gene first described in the drosophila as a segment polarity gene, is located at 9q22.3. It is a member of a signal transduction pathway and a tumour suppressor gene (TSG), involved in basal cell carcinoma. We propose PATCHED as a TSG candidate in superficial bladder cancer.