Design and synthesis of chromene-1,2,3-triazole benzene sulfonamide hybrids as potent carbonic anhydrase-IX inhibitors against prostate cancer.

Considering the promising effects of molecular hybridization on drug discovery in recent years and the ongoing endeavors to develop bioactive scaffolds tethering the 1,2,3-triazole core, the present study sought to investigate whether the 1,2,3-triazole-linked chromene and benzene sulfonamide nucleus could exhibit activity against the human breast cancer cell line MCF-7 and prostate cancer cell line PC-3. To this end, three focused bioactive series of mono- and -bis-1,2,3-triazoles were effectively synthesized via copper-assisted cycloaddition of mono- and/or di-alkyne chromenone derivatives 2a and b and 9 with several sulfa drug azides 4a-d and 6. The resulting molecular derivatives were tested for cytotoxicity against prostate and breast cancer cells. Among the derivatives, 10a, 10c, and 10e exhibited potent cytotoxicity against PC-3 cells with IC50 values of 2.08, 7.57, and 5.52 µM compared to doxorubicin (IC50 = 2.31 µM) with potent inhibition of CA IX with IC50 values of 0.113, 0.134, and 0.214 µM. The most active compound, 10a, was tested for apoptosis-induction; it induced apoptosis by 31.9-fold cell cycle arrest at the G1-phase. Further, the molecular modeling approach highlighted the relevant binding affinity for the top-active compound 10a against CA IX as one of the most prominent PC-3 prostate cancer-associated biotargets.

A quinoxaline-based derivative exhibited potent and selective anticancer activity with apoptosis induction in PC-3 cells through Topo II inhibition.

Quinoxaline constitutes a variety of derivatives that exhibit a range of biological characteristics, including anti-inflammatory and antitumor effects, and their importance in therapeutic chemistry is rising. The cytotoxicity effects of four quinoxaline compounds (I, II, III, and IV) against liver cancer cells (HepG2), prostate cancer cells (PC-3), and normal cells (Vero) were evaluated using the MTT assay. Compounds III and IV had the most anti-proliferative effects and highly selective indices against PC-3 cells with IC50 values of 4.11 and 2.11 µM, respectively. The apoptotic cell death for compounds III and IV in PC-3 cells was investigated using cell cycle, Annexin V-FITC/PI double staining-based flow cytometry, and DNA fragmentation assay. Compounds III or IV arrested the cell cycle at the S phase and caused apoptosis in PC-3 cells. Compounds III and IV showed inhibitory effects against topoisomerase II enzyme with IC50 values 21.98 and 7.529 µM, respectively, when compared to doxorubicin as a reference drug. Western Blot analysis displayed that compound IV treatment has significantly upregulated the pro-apoptotic proteins (p53, caspase-3, caspase-8) and downregulated the anti-apoptotic protein Bcl-2 in PC-3 cells in a dose-dependent manner, leading to cell apoptosis. The molecular docking study exhibited that compound IV had a good binding affinity for inhibiting topoisomerase II, consistent with the apoptotic mechanism. In vivo study using Ehrlich solid tumor model demonstrated that compound IV significantly reduced tumor volume and weight in vivo with minimal toxicity. This study reveals significant evidence for the antitumor efficacy of compound IV against prostate cancer cells as a topoisomerase II inhibitor.Communicated by Ramaswamy H. Sarma.

Impact of micro/nano cadmium oxide on shielding properties of cement-ball clay matrix.

This study investigates the gamma radiation shielding properties of cement-ball clay matrix composites doped with micro- and nano-sized cadmium oxide (CdO) particles. The linear attenuation coefficient (LAC) was determined using a sodium iodide (NaI) detector and five radioactive point sources with energies ranging from 59.5 to 1408 keV. The LAC values obtained were compared to the XCOM database and found to be in good agreement. The composites' half-value layer (HVL), tenth value layer (TVL), mean free path (MFP), effective atomic number (Zeff), equivalent atomic number (Zeq), and absorption buildup factor (EABF) were determined. The results showed that the addition of CdO particles improved the radiation-shielding behavior of the composites and increasing the weight fraction of CdO particles increased the shielding effectiveness. The results also illustrated that when nano-sized CdO particles were compared to their micro-sized counterparts, there was a significant enhancement in radiation shielding effectiveness. For instance, a composite material composed of 50% cement, 41.7% ball clay, and 3.8% nano CdO at an energy level of 0.0595 MeV exhibited a remarkable 12.2% increase in attenuation, surpassing the performance of the micro-sized sample with an equivalent concentration. Similarly, another composite consisting of 50% cement, 33.3% ball clay, and 16.7% nano CdO demonstrated a significant 15.4% increase in attenuation at the same energy level, when compared to the micro-sized sample. The study demonstrates the potential of CdO-doped cement-ball clay matrix composites for gamma radiation shielding applications.

Intraspecific Variability in Proteomic Profiles and Biological Activities of the Honey Bee Hemolymph.

Pollinator declines have raised major concerns for the maintenance of biodiversity and food security, calling for a better understanding of environmental factors that affect their health. Here we used hemolymph analysis to monitor the health status of Western honey bees Apis mellifera. We evaluated the intraspecific proteomic variations and key biological activities of the hemolymph of bees collected from four Egyptian localities characterized by different food diversities and abundances. Overall, the lowest protein concentrations and the weakest biological activities (cytotoxicity, antimicrobial and antioxidant properties) were recorded in the hemolymph of bees artificially fed sucrose solution and no pollen. By contrast, the highest protein concentrations and biological activities were recorded in bees that had the opportunity to feed on various natural resources. While future studies should expand comparisons to honey bee populations exposed to more different diets and localities, our results suggest hemolymph samples can be used as reliable indicators of bee nutrition.

Cytotoxic, apoptotic activities and chemical profiling of dimorphic forms of Egyptian halophyte Cakile maritima scop.

Cakile maritima ssp. aegyptiaca (Wild.) Nyman is growing with dimorphic leaf forms (entire or pinnatifid lamina) along the Mediterranean coast of Egypt. The cytotoxic activities of dried shoot systems of the two morphological forms were evaluated by testing and comparing the effects of ethanolic and aqueous extracts on the viability of five human cell lines. GC-MS analysis was performed to identify the bioactive and anticancer compounds present in the most active extracts. MTT assay indicated that both aqueous and ethanolic extracts have selective cytotoxic activities against cancer cell lines with no inhibitory activities against normal Wi38 or Vero cell lines. The underlying mechanism of cytotoxicity involved the induction of G2/M phase arrest in targeted cells MCF-7 and HCT-116 associated with inducing apoptosis in both cell lines, as indicated by Annexin-V assay. Apoptosis investigation in MCF-7 and HCT-116 cells treated with ethanolic extracts, was further investigated through RT-PCR, which exhibited elevation of proapoptotic genes of P53, BAX, Capase-3,6,7,8,9, and downregulation of antiapoptotic gene (BCL-2) upon treatment. The GC-MS analysis of ethanolic extracts of pinnatifid and entire forms revealed the existence of 18 and 13 compounds, respectively, with eleven compounds that were detected in pinnatifid form only and seven compounds were identified exclusively in the entire form. Molecular Docking study revealed that the identified compounds exhibited good binding affinity towards BCL-2 inhibition, and this agreed with the suggested apoptotic mechanism. To the best of authors' knowledge, this is the first scientific evidence underline the variability in the chemical composition associated with variable anticancer activities of dimorphic forms of C. maritima.Communicated by Ramaswamy H. Sarma.

Potential Apoptotic Activities of Hylocereus undatus Peel and Pulp Extracts in MCF-7 and Caco-2 Cancer Cell Lines.

There is a huge demand for novel anticancer agents with fewer side effects compared to current therapies. Pitaya, or dragon fruit, is a reservoir of potent anticancer compounds. This research aimed to analyze the phytochemical components of Hylocereus undatus pulp and peel extracts using LC-MS and GC-MS, and to investigate the in vitro effects of both extracts against cancer (breast, MCF-7, and colon, Caco-2) and normal (lung; WI-38 and breast; MCF-10A) cell proliferation using the MTT assay. The apoptosis potential of the anticancer effects was also evaluated using flow cytometry, RT-PCR, and Western blot. The total phenolic and flavonoid contents in the peel extract were significantly higher than those in the pulp extract. Compared to the flavonoid and phenolic acid standards, the LC-MS analysis revealed the presence of nine compounds, which were represented as 84.32 and 5.29 µg/g of the flavonoids and 686.11 and 148.72 µg/g of the phenolic acids in the peel and pulp extracts, respectively. Among the identified compounds, chlorogenic acid, caffeic acid, ferulic acid, and rutin were found at the highest concentration in both plant extracts. Both extracts displayed cytotoxic activity against MCF-7 and Caco-2 cancer cells after 48 h of treatment at IC50 values ranging from 14 to 53 µg/mL with high selective indices against normal WI-38 and MCF-10A cell lines. The increase in apoptosis was revealed by the overexpression of p53, BAX, and caspase-9 and the downregulation of antiapoptotic Bcl-2 mRNA and protein expressions. The results indicate that H. undatus extracts can be a plant source for cancer therapy.

Metformin alleviates the dysregulated testicular steroidogenesis and spermatogenesis induced by carbimazole in levothyroxine-primed rats.

Most of the published experiments about carbimazole (CMZ)-induced testicular injury are constructed in normal healthy animals, which lakes the translational identification. Despite metformin (MET) having advantageous effects on injured testicles, its impact on thyroid function is arguable. In the current levothyroxine (LT4)/CMZ model, Wistar rats were primed by LT4 for sixty days. CMZ was then given individually or simultaneously with different doses of MET, 100, 200, and 400 mg, daily for thirty days. Serum was assessed for thyroid profile panel, sex hormones, and gonadotropin levels. Testicular tissues were examined for steroidogenesis, spermatogenesis, inflammation, and apoptosis. Histopathology of thyroid and testes were examined, besides thyroidal nuclear factor (NF)-kB expression. MET in a dose-response manner improved the LT4/CMZ-induced testicular toxicity by increasing the steroidogenic acute regulatory protein (StAR), and 17-ß-hydroxysteroid dehydrogenase (17ßHSD) activities, the proliferating cell nuclear antigen (PCNA), sperm count and motility, sex hormones, and gonadotropin levels. MET-400 mg markedly decreased the elevated NF-kB expressions, tumour necrosis factor (TNF)-α, caspase-3, and BAX, and increased BCL-2. LT4/CMZ could be used as translational animal modelling. MET displayed a dose-dependent ameliorative effect on the LT4/CMZ model without significant harmful effects on thyroid functions. MET-testicular protective roles in diabetics with thyroidal diseases should be explored.

Nomad Jellyfish Rhopilema nomadica Venom Induces Apoptotic Cell Death and Cell Cycle Arrest in Human Hepatocellular Carcinoma HepG2 Cells.

Jellyfish venom is a rich source of bioactive proteins and peptides with various biological activities including antioxidant, antimicrobial and antitumor effects. However, the anti-proliferative activity of the crude extract of Rhopilema nomadica jellyfish venom has not been examined yet. The present study aimed at the investigation of the in vitro effect of R. nomadica venom on liver cancer cells (HepG2), breast cancer cells (MDA-MB231), human normal fibroblast (HFB4), and human normal lung cells (WI-38) proliferation by using MTT assay. The apoptotic cell death in HepG2 cells was investigated using Annexin V-FITC/PI double staining-based flow cytometry analysis, western blot analysis, and DNA fragmentation assays. R. nomadica venom displayed significant dose-dependent cytotoxicity on HepG2 cells after 48 h of treatment with IC50 value of 50 µg/mL and higher toxicity (3:5-fold change) against MDA-MB231, HFB4, and WI-38 cells. R. nomadica venom showed a prominent increase of apoptosis as revealed by cell cycle arrest at G2/M phase, upregulation of p53, BAX, and caspase-3 proteins, and the down-regulation of anti-apoptotic Bcl-2 protein and DNA fragmentation. These findings suggest that R. nomadica venom induces apoptosis in hepatocellular carcinoma cells. To the best of the authors' knowledge, this is the first scientific evidence demonstrating the induction of apoptosis and cell cycle arrest of R. nomadica jellyfish venom.

Scorpion Venom Antimicrobial Peptides Induce Siderophore Biosynthesis and Oxidative Stress Responses in Escherichia coli.

The increasing development of microbial resistance to classical antimicrobial agents has led to the search for novel antimicrobials. Antimicrobial peptides (AMPs) derived from scorpion and snake venoms offer an attractive source for the development of novel therapeutics. Smp24 (24 amino acids [aa]) and Smp43 (43 aa) are broad-spectrum AMPs that have been identified from the venom gland of the Egyptian scorpion Scorpio mauruspalmatus and subsequently characterized. Using a DNA microarray approach, we examined the transcriptomic responses of Escherichia coli to subinhibitory concentrations of Smp24 and Smp43 peptides following 5 h of incubation. Seventy-two genes were downregulated by Smp24, and 79 genes were downregulated by Smp43. Of these genes, 14 genes were downregulated in common and were associated with bacterial respiration. Fifty-two genes were specifically upregulated by Smp24. These genes were predominantly related to cation transport, particularly iron transport. Three diverse genes were independently upregulated by Smp43. Strains with knockouts of differentially regulated genes were screened to assess the effect on susceptibility to Smp peptides. Ten mutants in the knockout library had increased levels of resistance to Smp24. These genes were predominantly associated with cation transport and binding. Two mutants increased resistance to Smp43. There was no cross-resistance in mutants resistant to Smp24 or Smp43. Five mutants showed increased susceptibility to Smp24, and seven mutants showed increased susceptibility to Smp43. Of these mutants, formate dehydrogenase knockout (fdnG) resulted in increased susceptibility to both peptides. While the electrostatic association between pore-forming AMPs and bacterial membranes followed by integration of the peptide into the membrane is the initial starting point, it is clear that there are numerous subsequent additional intracellular mechanisms that contribute to their overall antimicrobial effect.IMPORTANCE The development of life-threatening resistance of pathogenic bacteria to the antibiotics typically in use in hospitals and the community today has led to an urgent need to discover novel antimicrobial agents with different mechanisms of action. As an ancient host defense mechanism of the innate immune system, antimicrobial peptides (AMPs) are attractive candidates to fill that role. Scorpion venoms have proven to be a rich source of AMPs. Smp24 and Smp43 are new AMPs that have been identified from the venom gland of the Egyptian scorpion Scorpio maurus palmatus, and these peptides can kill a wide range of bacterial pathogens. By better understanding how these AMPs affect bacterial cells, we can modify their structure to make better drugs in the future.

Cytotoxicity of Nubein6.8 peptide isolated from the snake venom of Naja nubiae on melanoma and ovarian carcinoma cell lines.

This study was conducted to examine the cytotoxic effects of Nubein6.8 isolated from the venom of the Egyptian Spitting Cobra Naja nubiae on melanoma (A375) and ovarian carcinoma cell lines and to reveal its mode of action. The size of Nubein6.8 (6801.8 Da) and its N-terminal sequence are similar to cytotoxins purified from the venom of other spitting cobras. Nubein6.8 showed a high significant cytotoxic effect on A375 cell line and moderate effect on A2780. A clonogenic assay showed that Nubein6.8 has a significant long-term potency on A375 cell survival when compared to A2780. The molecular intracellular signaling pathways of Nubein6.8 have been investigated using Western blotting analysis, flow cytometry, and microscale protein labeling. This data revealed that Nubein6.8 has DNA damaging effects and the ability to activate apoptosis in both tumor cell lines. Cellular uptake recordings revealed that the labeled-Nubein6.8 was intracellularly present in A375 cells while A2780 displayed resistance against it. SEM examination showed that Nubein6.8 was found to have high accessibility to malignant melanoma cells. The apoptotic effect of Nubein6.8 was confirmed by TEM examination that revealed many evident characteristics for Nubein6.8 apoptotic efficacy on A375 cell sections. Also, TEM reflected many resistant characteristics that faced Nubein6.8 acquisition through ovarian carcinoma cell sections. Accordingly, the snake venom peptide of Nubein6.8 is a promising template for developing potential cytotoxic agents targeting human melanoma and ovarian carcinoma.

Prospective, randomized study of long-term hemodialysis catheter removal versus guidewire exchange to treat catheter-related bloodstream infection.

BACKGROUND: Long-term (tunneled cuffed) hemodialysis catheters are frequently used vascular access in renal failure patients. Catheter-related bloodstream infection (CRBSI) is a common complication of long-term hemodialysis catheters, with severe morbidities and high risk of mortality. Management of CRBSI by systemic antibiotics while keeping the catheter in place is not effective. Among the different modalities of CRBSI management are catheter removal (CR) and guidewire exchange (GE) of the catheter. The aim of this study was to compare the clinical outcome of CRBSI treated with two different strategies: GE vs CR with new catheter insertion 3 to 7 days later. METHODS: This prospective randomized study analyzed the outcomes of all cases of long-term hemodialysis CRBSI during a 5-year period. The catheter infection-free survival time was analyzed in the two groups of patients (GE group, 339 patients; CR group, 339 patients). Three weeks of systemic antibiotic therapy was used according to culture in both groups. The catheter infection-free survival was analyzed using Kaplan-Meier analysis. RESULTS: No statistically significant difference was found in catheter infection-free survival time for GE and CR groups (P = .69), which is not affected by age, sex, presence of diabetes mellitus, or type of causative organism. CONCLUSIONS: Our study did not demonstrate a difference in the clinical outcome of CRBSI treated with GE or CR with new catheter insertion 3 to 7 days later. However, guidewire catheter exchange saves veins for future access, reduces the cost and number of procedures, and avoids complications of new venipuncture.

Characterisation of three alpha-helical antimicrobial peptides from the venom of Scorpio maurus palmatus.

Scorpion venoms provide a rich source of anti-microbial peptides. Here we characterise three from the venom of Scorpion maurus palmatus. Smp13 is biologically inactive, despite sharing homology with other antimicrobial peptides, probably because it lacks a typically charged structure. Both Smp-24 and Smp-43 have broad spectrum antimicrobial activity, disrupting bacterial membranes. In addition, there is evidence that Smp24 may inhibit DNA synthesis in Bacillus subtilis. Smp24 haemolysed red blood cells but in contrast, Smp43 was non-haemolytic. The introduction of a flexible Gly-Val-Gly hinge into the middle of Smp24 did not alter the haemolytic activity of Smp24 (as might have been predicted from earlier studies with Pandinin2 (Pin2), although C-terminal truncation of Smp-24 reduced its haemolytic activity, in agreement with earlier Pin 2 studies. Smp24 and its derivatives, as well as Smp-43, were all cytotoxic (ATP release assay) toward mammalian HepG2 liver cells. Our results highlight the beneficial effect of helical-hinge-helical conformation on promoting prokaryotic selectivity of long chain scorpion AMPs, as well as the importance of examining a wide range of mammalian cell types in cytotoxicity testing.

Ultrasound-guided spinal anesthesia for cesarean section in a parturient with spinal metastases.

Preprocedural spinal ultrasound appears to decrease the failure rate and complications of neuraxial anesthesia compared to the conventional landmark technique. It is especially beneficial in difficult cases where conventional palpation technique may fail. We recently encountered a parturient with multiple lumbar and cervical spinal metastatic lesions presenting for cesarean section in the third trimester. We used spinal ultrasound to define the appropriate intervertebral space and measure the distance to the ligamentum flavum-dura mater complex. This greatly helped in administering a safe spinal anesthetic and avoiding general anesthesia which might have been hazardous in this patient.

Prospective, randomized study of cutting balloon angioplasty versus conventional balloon angioplasty for the treatment of hemodialysis access stenoses.

OBJECTIVE: The aim of this trial was to compare the rates of patency achieved by cutting and conventional balloon angioplasty to treat hemodialysis access stenoses. METHODS: End-stage renal failure patients (at three tertiary referral centers) with significant hemodialysis access stenoses were prospectively randomized to have percutaneous transluminal angioplasty (PTA) by either cutting or conventional balloons. Patients with more than one hemodynamically significant stenosis were excluded. Kaplan-Meier method was used to compare the primary assisted patency rates for the two groups. RESULTS: The study randomized 623 patients into two groups, and the duration of follow-up was 15 ± 3 months. In the cutting balloon angioplasty group, the clinical success rate was 89% (282 of 316 stenoses). In the conventional balloon angioplasty group, the clinical success rate was 86% (265 of 307 stenoses; P = .637). Assisted primary patency for cutting PTA was statistically significantly higher at 6 months and 1 year (86% and 63%) than that for conventional PTA (56% and 37%, respectively; P = .037) in the treatment of stenosis of the graft-to-vein anastomosis. In the venous stenosis subgroup, equivalent primary assisted patency at 6 months and 1 year was observed for cutting PTA (84% and 55%) and conventional PTA (70% and 46%, respectively; P = .360). In the intragraft stenosis subgroup, primary assisted patency was equivalent at 6 months and 1 year for cutting PTA (67% and 39%) and conventional PTA (62% and 49%, respectively; P = .371). In the arterial anastomotic stenosis subgroup, assisted primary patency at 6 months and 1 year was equivalent for cutting PTA (70% and 30%) and conventional PTA (75% and 33%, respectively; P = .921). CONCLUSIONS: Cutting balloon angioplasty proved to be a safe and effective treatment of graft-to-vein anastomotic stenosis, with significantly higher patency than that of conventional balloon angioplasty.