Understanding ureteroscopy complications according to modified Clavien classification system.

OBJECTIVE: To determine the complications of ureteric stone treatment with semi-rigid uretero-renoscopy in accordance with the modified Clavien classification system. METHODS: The descriptive, prospective study was conducted at the Department of Urology, Sindh Institute of Urology and Transplantation, Karachi, from June 30, 2020, to December 29, 2021, and comprised patients of either gender aged 18-70 years having ureteric stones. All patients were subjected to ureterorenoscopy using a semi-rigid ureteroscope under general anaesthesia. The patients were followed up for 2 months. All complications were noted and graded in line with the Modified Clavien Complication System. Ultrasound and X-ray were used to determine the stone-free rate. Data was analysed using SPSS 23. RESULTS: Of the 414 patients, 304(73.4%) were males and 110(26.5%) were females. The overall mean age was 40.22±13.10 years. There were 106(25.6%) proximal, 134(32.3%) middle, and 174(42%) distal ureteric stones. Stent placement was done in 56(13.5%) cases. There were 260(62.8%) patients with no complication, 90(21.7%) with grade I complications, 34(8.2%) with grade II complications, 10(2.4%) with grade IIIa, 8(1.9%) with grade IIIb, and 12 (2.9%) with grade IVa complications. CONCLUSIONS: Uretero-renoscopy was found to be a safe procedure, as it had minimal associated complications with optimal stone clearance and great dexterity. The Modified Clavien classification system was found to be an easy way to classify surgical complications of uretero-renoscopy.

Cymbopogon citratus and Citral Overcome Doxorubicin Resistance in Cancer Cells via Modulating the Drug's Metabolism, Toxicity, and Multidrug Transporters.

Multidrug resistance (MDR) is the major complex mechanism that causes the failure of chemotherapy, especially with drugs of natural origin such as doxorubicin (DOX). Intracellular drug accumulation and detoxification are also involved in cancer resistance by reducing the susceptibility of cancer cells to death. This research aims to identify the volatile composition of Cymbopogon citratus (lemon grass; LG) essential oil and compare the ability of LG and its major compound, citral, to modulate MDR in resistant cell lines. The composition of LG essential oil was identified using gas chromatography mass spectrometry (GC-MS). In addition, a comparison of the modulatory effects of LG and citral, performed on breast (MCF-7/ADR), hepatic (HepG-2/ADR), and ovarian (SKOV-3/ADR) MDR cell lines, were compared to their parent sensitive cells using the MTT assay, ABC transporter function assays, and RT-PCR. Oxygenated monoterpenes (53.69%), sesquiterpene hydrocarbons (19.19%), and oxygenated sesquiterpenes (13.79%) made up the yield of LG essential oil. α-citral (18.50%), ß-citral (10.15%), geranyl acetate (9.65%), ylangene (5.70), δ-elemene (5.38%), and eugenol (4.77) represent the major constituents of LG oil. LG and citral (20 µg/mL) synergistically increased DOX cytotoxicity and lowered DOX dosage by >3-fold and >1.5-fold, respectively. These combinations showed synergism in the isobologram and CI < 1. DOX accumulation or reversal experiment confirmed that LG and citral modulated the efflux pump function. Both substances significantly increased DOX accumulation in resistant cells compared to untreated cells and verapamil (the positive control). RT-PCR confirmed that LG and citral targeted metabolic molecules in resistant cells and significantly downregulated PXR, CYP3A4, GST, MDR1, MRP1, and PCRP genes. Our results suggest a novel dietary and therapeutic strategy combining LG and citral with DOX to overcome multidrug resistance in cancer cells. However, these results should be confirmed by additional animal experiments before being used in human clinical trials.

Isolation, Characterization, Complete Structural Assignment, and Anticancer Activities of the Methoxylated Flavonoids from Rhamnus disperma Roots.

Different chromatographic methods including reversed-phase HPLC led to the isolation and purification of three O-methylated flavonoids; 5,4'-dihydroxy-3,6,7-tri-O-methyl flavone (penduletin) (1), 5,3'-dihydroxy-3,6,7,4',5'-penta-O-methyl flavone (2), and 5-hydroxy-3,6,7,3',4',5'-hexa-O-methyl flavone (3) from Rhamnus disperma roots. Additionlly, four flavonoid glycosides; kampferol 7-O-α-L-rhamnopyranoside (4), isorhamnetin-3-O-ß-D-glucopyranoside (5), quercetin 7-O-α-L-rhamnopyranoside (6), and kampferol 3, 7-di-O-α-L-rhamnopyranoside (7) along with benzyl-O-ß-D-glucopyranoside (8) were successfully isolated. Complete structure characterization of these compounds was assigned based on NMR spectroscopic data, MS analyses, and comparison with the literature. The O-methyl protons and carbons of the three O-methylated flavonoids (1-3) were unambiguously assigned based on 2D NMR data. The occurrence of compounds 1, 4, 5, and 8 in Rhamnus disperma is was reported here for the first time. Compound 3 was acetylated at 5-OH position to give 5-O-acetyl-3,6,7,3',4',5'-hexa-O-methyl flavone (9). Compound 1 exhibited the highest cytotoxic activity against MCF 7, A2780, and HT29 cancer cell lines with IC50 values at 2.17 µM, 0.53 µM, and 2.16 µM, respectively, and was 2-9 folds more selective against tested cancer cell lines compared to the normal human fetal lung fibroblasts (MRC5). It also doubled MCF 7 apoptotic populations and caused G1 cell cycle arrest. The acetylated compound 9 exhibited cytotoxic activity against MCF 7 and HT29 cancer cell lines with IC50 values at 2.19 µM and 3.18 µM, respectively, and was 6-8 folds more cytotoxic to tested cancer cell lines compared to the MRC5 cells.

Proapoptotic Activity of Achillea membranacea Essential Oil and Its Major Constituent 1,8-Cineole against A2780 Ovarian Cancer Cells.

Among the hundreds of reported Achillea species, A. membranacea (Labill.) DC. is one of the six that grow in Jordan. Many species of this genus are used in folk medicine to treat a variety of ailments and several biological and pharmacological activities have been ascribed to their essential oil (EO). For this study, the EO obtained from a specimen of A. membranacea grown in Jordan was analyzed by GC-MS. Ninety-six compounds were detected, of which oxygenated monoterpenes was the predominant class (47.9%), followed by non-terpene derivatives (27.9%), while sesquiterpenes represented 14.2% of the total composition. The most abundant compound in the EO was 1,8-cineole (21.7%). The cytotoxic activity of the EO was evaluated against three cancer cell lines (MCF7, A2780 and HT29), and one normal fibroblast cell line (MRC5) by MTT assay. Significant growth inhibition was observed in EO-exposed A2780 and HT29 cells (IC50 = 12.99 and 14.02 µg/mL, respectively), while MCF7 and MRC5 were less susceptible. The EO induced apoptosis and increased the preG1 events in A2780 cells. 1,8-Cineole, the major constituent of the EO, exhibited submicromolar cytotoxicity against A2780 cells, and was 42 times more selective against MRC5 cells. Its cytotoxicity against A2780 cells was comparable with that of doxorubicin, but 1,8-cineole was more selective for MRC5 normal cells. Interestingly, 1,8-cineole enhanced apoptosis in A2780, and caused a remarkable dose-dependent increase in preG1 events. Thus, 1,8-cineole has demonstrated promising cytotoxic and proapoptotic properties.

Pharmacophores Modeling in Terms of Prediction of Theoretical Physicochemical Properties and Verification by EXPERIMENTAL correlations of Carbacylamidophosphates (CAPh) and Sulfanylamidophosphates (SAPh) Tested as New Carbonic Anhydrase Inhibitors.

BACKGROUND: The function of Carbonic anhydrase is to facilitate the physiological process i.e. interconversion of CO2 to HCO3 - by hydration. Carbonic anhydrase enzyme plays a vital role in different physiological processes to regulate pH as well as regulate the inner environment of CO2 and secretion of electrolytes. METHODS: Six representatives of amidophosphate derivatives (L1-L6) were synthesized and evaluated for their biological activities against carbonic anhydrase enzyme. RESULTS: Out of six derivatives, L1 (IC50 = 12.5 ± 1.35 µM), and L2 (IC50 = 3.12 ± 0.45 µM) showed potent activity against BCA-II. While (L3, L4 and L5) showed weak inhibitory activity with IC50 values of 24.5 ± 2.25, 55.5± 1.60, and 75.5 ± 1.25 µM, respectively and were found to be weak inhibitors of carbonic anhydrase as compared to acetazolamide (IC50 =0.12± 0.03µM), used as standard inhibitor. A computational Petra/Osiris/Molinspiration/DFT (POM/DFT) based model has been expanded for the determination of physicochemical parameters governing the bioactivity amidophosphate derivatives (L1-L6) containing (O1 --- O2) pharmacophore site. The six compounds (L1-L6) analyzed here were previously experimentally and now virtually screened for their anti-carbonic anhydrase activity. CONCLUSION: The highest anti-carbonic anhydrase activity was obtained for compound L2, which exhibited excellent bioactivity (% of inhibition = 95%), comparable to acetazolamide (% of inhibition = 89%). The compound L3 represents increased activity as compared to its analogues (L4-L6). The increase of bioactivity from L3 to L4-L6 could be attributed to the presence of a minimum of steric effect of substituents of P=O moiety which plays a decisive template part in the organization of anti-carbonic anhydrase (O1---O2) phramacophore site. Moreover, it is inexpensive, has little side effects and possible inclusions in selective anti-carbonic anhydrase agents design.

Muscle relaxant activities of pistagremic acid isolated from Pistacia integerrima.

The aim of the current work was to explore the muscle relaxant effect of pistagremic acid (PA) isolated from Pistacia integerrima in various animal paradigms. In a rotarod test, PA caused a significant (p<0.05) muscle relaxant potential in a dose-dependent manner. When studied in the inclined plane test, pretreatment with PA (5 and 10 mg/kg) caused promising activity (p<0.05) after treatment for 30, 60 and 90 min. The muscle relaxant potential of PA was strongly complimented by the traction and chimney tests, showing a dominant effect after 60 min of treatment. In conclusion, PA possesses strong muscle relaxant activity in various animal-based models.

Multidrug resistance reversal activity of extract and a rare dimeric naphthoquinone from Diospyros lotus.

A dimeric naphthoquinone namely dihydrodyspyrole R (1) was purified once more from Diospyros lotus. Dihydrodyspyrole R and chloroform fractions were evaluated for their effects on the reversion of multidrug resistance (MDR). The compounds (1) and extract exhibited promising MDR reversing effect in a dose-dependent manner against mouse T-lymphoma cell line. Molecular docking of compound 1 revealed the correlation between in-silico with in-vitro results. The molecular docking results showed that compound 1 is bind closely where co-crystal ligand of P-gp is present. But usually, computational investigation predicts that, if a compound gives lesser score then compound will exhibit good activity. Hence, the docking scores of compound 1 are the near to the Rhodamine. It is conclude that there are certain important structural features of compound 1which are responsible for the inhibiting potency of P-gp from mice. The computational Petra/Osiris/Molinspiration (POM) analysis confirms the possibility of use of compound 1 without side effect or less toxicity risks.

Triterpenoidal saponins from the fruits of Gleditsia caspica with proapoptotic properties.

Three previously undescribed oleanane-type triterpenoidal saponins named caspicaosides L-N were isolated from the fruits of Gleditsia caspica Desf. The aglycons of these saponins were echinocystic acid, erythrodiol and 12-oleanene-3,28,30-triol. Caspicaoside L is a bisdesmosidic saponin acylated with two monoterpenic acids. It has a disaccharide moiety made up of glucose and arabinose attached to C-3 and pentasaccharide moiety linked to C-28 made up of one glucose, 2 xyloses, one inner rhamnose and one terminal rhamnose which was acylated with two identical monoterpenic acids. Caspicaoside M is a monodesmosidic saponin with a trisaccharide moiety at C-3 made up of glucose, xylose and arabinose, while caspicaoside N has a disaccharide moiety at C-3 made up of glucose and arabinose. Their structures were determined by extensive 1D and 2D (DQF-COSY, HSQC, TOCSY, 1H-13C-HSQC-TOCSY, HMBC, ROESY, NOESY) NMR, HRESIMS analyses and chemical degradation. The cytotoxicity MTT-based assay showed that caspicaosides M, N and L, respectively, exhibited high cytotoxic activity with IC50 ≤ 10 µM (72 h) at least against one of the three used cancer cell lines, MCF 7, A2780 and HT 29; and were 2-34 folds selective against the normal fibroblasts (MRC 5). All compounds also induced apoptosis and caused G2/M arrest in MCF 7 cells (24 h); thus showing pro-apoptotic properties.

Flavonoidal Constituents, Antioxidant, Antimicrobial, and Cytotoxic Activities of Dipterygium glaucum Grown in Kingdom of Saudi Arabia.

BACKGROUND: Dipterygium glaucum Decne. herb is one of the common traditional plants with multiple medicinal uses. OBJECTIVE: To isolate the major constituents and to investigate the antioxidant, antimicrobial, and cytotoxic activities of this herb. MATERIALS AND METHODS: Methanolic extract of D. glaucum herb was fractionated using n-hexane, dichloromethane, and n-butanol. Butanol fraction was chromatographed using column chromatography and preparative thin layer chromatography to isolate the major constituents. Isolated compounds were elucidated by means of spectroscopic methods, including 1D, 2D NMR (1H, 13C, DEPT, COSY, HSQC, HMBC, NEOSY) and MS analysis. Total phenolic content using Folin-Ciocalteu reagent and antioxidant activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay of the total methanolic extract were evaluated. Cytotoxic potential of both methanolic extract and butanol fraction was tested using a crystal violet viability assay. Antimicrobial activities of both extracts were investigated using diffusion agar technique. RESULTS: Apigenin 6, 8-di-C-glucopyranoside (vicenin-2), quercetin-3`-O-methyl-3-O-glucopyranoside, quercetin-3`-O-methyl-3-O-galactopyranoside, quercetin-3-O-ß-D-glucopyranoside, and quercetin-3-O-ß-D-galactopyranoside were isolated and elucidated. Total phenolic content was (83.89 mg gallic acid equivalent/g extract). The EC50 value of scavenging DPPH radical was 152.0 ± 2 mg/mL. Butanol fraction showed the highest cytotoxic activity against cervical and breast carcinoma cells (IC50 3.6 and 6.1 mg/mL, respectively). Both methanolic extract and butanol fraction showed wide spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria and some fungi. The highest activity was from methanolic extract against Enterococcus faecalis (83.25%) and against Candida tropicalis (77.03%) as compared to reference antibiotics. CONCLUSION: Data obtained from this study demonstrate that D. glaucum possesses significant antioxidant, cytotoxic, and antimicrobial activities which could be ascribed to its flavonoidal content. SUMMARY: Dipterygium glaucum Decne. herb is one of the common traditional plants with multiple medicinal uses in KSAFive flvonidal glycosides were isolated and elucidatedThis study demonstrated that D. glaucum possesses significant antioxidant, cytotoxic, and antimicrobial activities. Abbreviations used: KSA: Kingdom of Saudi Arabia; TLC: Thin Layer Chromatography; DPPH: 2,2`-diphenyl-1-picrylhydrazyl; EC50: Half maximal effective concentration; IC50: Half maximal inhibitory concentration; DMSO: dimethyl sulfoxide; NMR: Nuclear Magnetic Resonance; ESIMS: Electrospray ionization mass spectrometry; MeOH: Methyl alcohol.

Antihypertensive and vasodilator effects of methanolic extract of Inula viscosa: Biological evaluation and POM analysis of cynarin, chlorogenic acid as potential hypertensive.

BACKGROUND: Inula viscosa L. (Asteraceae) is a medicinal plant widely used as a folk medicine in oriental Morocco, to treat hypertension. The antihypertensive effect of the methanolic extract obtained from I. viscosa leaves was evaluated in hypertensive L-NAME rats. Systolic blood pressure (SBP) was measured using a non-invasive indirect tail-cuff plethysmographic method. Four groups of rats were used: a control group; a hypertensive group treated with L-NAME (32mg/kg/day); a positive control group treated with L-NAME plus enalapril (15mg/kg/day) as a reference antihypertensive agent; and a group treated with L-NAME plus MeOH-extract (40mg/kg/day). METHODS: Treatment with L-NAME alone caused a progressive increase in SBP. After 4 weeks, the value of SBP reached 160±2mmHg which shows the installation of hypertension. Enalapril prevented the increase in SBP, which remained normal at 123±1mmHg after 4 weeks of treatment. The administration of MeOH-extract along with L-NAME prevented the increase in SBP as well, which remained constant at 115±1mmHg after 4 weeks of treatment. In ex-vivo models, MeOH-extract produced a relaxation of pre-contracted ring aorta (54 ± 2% of relaxation at 3g/L). But, when the rings were denuded, MeOH-extract failed to relax pre-contracted rings of aorta. Phytochemical study of I. viscosa MeOH-extract revealed the presence of phenolic compounds, such as cynarin and chlorogenic acid. RESULTS: The present results suggest that I. viscosa MeOH-extract has an antihypertensive, predominantly mediated by an endothelium-dependent vasodilatory effect. Cynarin and chlorogenic acid, which have a strong vasorelaxant effect may be involved in the antihypertensive effect of the plant extract. The bioinformatic POM analysis confirms the therapeutic potential of cynarin and chlorogenic acids as inhibitors of various biotargets. Based on the results, the coordination of these phytochemicals with calcium and transition metals should be studied, for better scope at antihypertensive drug development.

A New Sucrase Enzyme Inhibitor from Azadirachta indica.

BACKGROUND: Sucrase enzyme inhibitor considered as an oral anti-diabetic therapy that delays the absorption of eaten carbohydrates, reducing the postprandial glucose and insulin peaks to reach normoglycemia. MATERIALS AND METHODS: Chromatographic fractionation of the hydroalcoholic extract of leaves of Azadirachta indica growing in KSA, followed by in-vitro assay of sucrase enzyme inhibition activity. RESULTS: This investigation led to the isolation of a new remarkable sucrase enzyme inhibitor; 4'-methyl Quercetin-7-O-ß-D-glucuronopyranoside (1) alongside with four known compounds; 2,3-hexahydroxydiphenoyl-(α/ß)-D-(4)C1-glucopyranose (2), Avicularin (3), Castalagin (4) and Quercetin-3-O-glucoside (5). The structure of the new compound (1) was elucidated on the basis of its spectral data, including ESI-MS, UV, (1)H NMR, (13)C NMR, (1)H-(1)H COSY, HSQC, NOESY and HMBC. CONCLUSION: Under the assay conditions, hydroalcoholic extract of A. indica and compounds 1-5 exhibited significant sucrase enzyme inhibitory activity. SUMMARY: Chromatographic fractionation of the hydroalcoholic extract of leaves of Azadirachta indica, led to the Isolation of a new flavonoid glycoside named 4'-methyl Quercetin-7-O-ß-D-glucuronopyranoside, alongside to other 4 known polyphenols. The hydroalcoholic extract as well as the isolated compounds exhibited significant sucrase enzyme inhibitory activity. Abbreviations used: ESI-MS; electrospray ionization-mass spectrometry, UV; ultraviolet, NMR; nuclear magnetic resonance, 1H-1H COSY; 1H-1H correlation spectroscopy, NOESY; nuclear overhauser effect spectroscopy, and HSQC; heteronuclear multiple bond correlation. A. indica; Azadirachta indica.

Synthesis, characterization, crystal structure determination and biological screening of novel N-1 and C5 alkyl substituted scaffolds of pyrimidine.

The novel N-1 and C5 alkyl substituted derivatives of pyrimidine were synthesized by using tetrabutyl ammonium bromide (TBAB) as phase transfer catalyst at 20-25 °C with excellent productivity (85-95%). The new compounds were evaluated for their antibacterial activities by screening them against Gram-positive and Gram-negative bacterial strain: Staphylococcus aureus ATCC 6538P, Salmonella abony NCTC 6017: Escherichia coli ATCC 8739, Staphylococcus epidermidis ATCC 12228. Among all compounds evaluated the molecule 2c and (2g-j) exhibit the most pronounced antibacterial activity against E. coli, S. aureus and S. abony with MICs value 25 µg/mL.