In Vitro α-Glucosidase and α-Amylase Inhibition, Cytotoxicity and Free Radical Scavenging Profiling of the 6-Halogeno and Mixed 6,8-Dihalogenated 2-Aryl-4-methyl-1,2-dihydroquinazoline 3-Oxides.

Series of the 6-bromo/iodo substituted 2-aryl-4-methyl-1,2-dihydroquinazoline-3-oxides and their mixed 6,8-dihalogenated (Br/I and I/Br) derivatives were evaluated for inhibitory properties against α-glucosidase and/or α-amylase activities and for cytotoxicity against breast (MCF-7) and lung (A549) cancer cell lines. The 6-bromo-2-phenyl substituted 3a and its corresponding 6-bromo-8-iodo-2-phenyl-substituted derivative 3i exhibited dual activity against α-glucosidase (IC50 = 1.08 ± 0.02 µM and 1.01 ± 0.05 µM, respectively) and α-amylase (IC50 = 5.33 ± 0.01 µM and 1.18 ± 0.06 µM, respectively) compared to acarbose (IC50 = 4.40 ± 0.05 µM and 2.92 ± 0.02 µM, respectively). The 6-iodo-2-(4-fluorophenyl)-substituted derivative 3f, on the other hand, exhibited strong activity against α-amylase and significant inhibitory effect against α-glucosidase with IC50 values of 0.64 ± 0.01 µM and 9.27 ± 0.02 µM, respectively. Compounds 3c, 3l and 3p exhibited the highest activity against α-glucosidase with IC50 values of 1.04 ± 0.03, 0.92 ± 0.01 and 0.78 ± 0.05 µM, respectively. Moderate cytotoxicity against the MCF-7 and A549 cell lines was observed for these compounds compared to the anticancer drugs doxorubicin (IC50 = 0.25 ± 0.05 µM and 0.36 ± 0.07 µM, respectively) and gefitinib (IC50 = 0.19 ± 0.04 µM and 0.25 ± 0.03 µM, respectively), and their IC50 values are in the range of 10.38 ± 0.08-25.48 ± 0.08 µM and 11.39 ± 0.12-20.00 ± 0.05 µM, respectively. The test compounds generally exhibited moderate to strong antioxidant capabilities, as demonstrated via robust free radical scavenging activity assays, viz., DPPH and NO. The potential of selected derivatives to inhibit superoxide dismutase (SOD) was also investigated via enzymatic assay in vitro. Molecular docking revealed the N-O moiety as essential to facilitate electrostatic interactions of the test compounds with the protein residues in the active site of α-glucosidase and α-amylase. The presence of bromine and/or iodine atoms resulted in increased hydrophobic (alkyl and/or π-alkyl) interactions and therefore increased inhibitory effect against both enzymes.

Influence of seasonal and geographic variation on the anti-HSV-1 properties and chlorogenic acids content of Helichrysum aureonitens Sch. Bip.

Pharmacological studies conducted in the past revealed the potential source of medicinal plants in the development of novel medicines. The phenolic contents of medicinal plants containing chlorogenic acids (CGA) have been linked to a variety of therapeutic effects, especially antiviral activity. Helichrysum aureonitens is a medicinal plant which has been reported to contain chlorogenic acids compounds and has also shown antiviral activities against a number of virus species including Herpes Simplex Virus-1 (HSV-1). In this study, the aim was to determine both the influence of seasonal variation and locality on the antiviral properties of H. aureonitens. Since chlorogenic acids have been reported as potent antiviral compounds, these compounds were targeted to determine the effects of locality and seasonal change on the chlorogenic acid profile, and subsequent antiviral activity. The ultra-performance liquid chromatography-quadrupole time-of-flight mass spectroscopy (UPLC-qTOF-MS) was employed to determine the metabolic profile variations of three derivatives of chlorogenic acids-caffeoylquinic acid (CQA), dicaffeoylquinic acid (DCQA) and tricaffeoylquinic acid (TCQA) in the harvested plants growing in two diverse geographical climates and two different seasons (spring and autumn). Using the cytopathic effect (CPE) reduction approach, twenty-six samples of the plants' leaves and stems collected during spring and autumn at Telperion nature reserve in Mpumalanga and Wakefield farm, Midlands in KwaZulu-Natal region of South Africa were evaluated for anti-HSV activity. The MTT assay was used for the cytotoxicity evaluation of the extracts prior to antiviral determination. Seventeen (mostly spring collections) of the twenty-six extracts examined were found to have considerable anti-HSV activity as measured by a reduction in tissue culture infectious dose (TCID50) of less than 105. The UPLC-qTOF-MS result revealed that dicaffeoylquinic acid (DCQA) is the most abundant, with higher concentrations in both regions and seasons. 3-CQA was also shown to be the most abundant isomer of caffeoylquinic acid in this investigation.

New Alk(en)ylhydroxycyclohexanes with Tyrosinase Inhibition Potential from Harpephyllum caffrum Bernh. Gum Exudate.

This work presents the first report on the phytochemical investigation of Harpephyllum caffrum Bernh. gum exudate. A known cardanol, 3-heptadec-12'-Z-enyl phenol (1) and three new alk(en)ylhydroxycyclohexanes, namely, (1R,3R)-1,3-dihydroxy-3-[heptadec-12'(Z)-enyl]cyclohexane (2) (1S,2S,3S,4S,5R)-1,2,3,4,5-pentahydroxy-5-[octadec-13'(Z)-enyl]cyclohexane (3) and (1R,2S,4R)-1,2,4-trihydroxy-4-[heptadec-12'(Z)-enyl]cyclohexane (4) were isolated from the gum. The structures of the compounds were determined by extensive 1D and 2D NMR spectroscopy and HR-ESI-MS data. The ethanolic extract of the gum was found to be the most potent tyrosinase inhibitor with IC50 of 11.32 µg/mL while compounds 2 and 3, with IC50 values of 24.90 and 26.99 µg/mL, respectively, were found to be potential anti-tyrosinase candidates from the gum. Gum exudate may be a potential source for non-destructive harvesting of selective pharmacologically active compounds from plants. The results also provide evidence that H. caffrum gum may find application in cosmetics as a potential anti-tyrosinase agent.

In Vitro Enzymatic and Kinetic Studies, and In Silico Drug-Receptor Interactions, and Drug-Like Profiling of the 5-Styrylbenzamide Derivatives as Potential Cholinesterase and ß-Secretase Inhibitors with Antioxidant Properties.

The 5-(styryl)anthranilamides were transformed into the corresponding 5-styryl-2-(p-tolylsulfonamido)benzamide derivatives. These 5-styrylbenzamide derivatives were evaluated through enzymatic assays in vitro for their capability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-secretase (BACE-1) activities as well as for antioxidant potential. An in vitro cell-based antioxidant activity assay involving lipopolysaccharides (LPS)-induced reactive oxygen species (ROS) production revealed that compounds 2a and 3b have the capability of scavenging free radicals. The potential of the most active compound, 5-styrylbenzamide (2a), to bind copper (II) or zinc (II) ions has also been evaluated spectrophotometrically. Kinetic studies of the most active derivatives from each series against the AChE, BChE, and ß-secretase activities have been performed. The experimental results are complemented with molecular docking studies into the active sites of these enzymes to predict the hypothetical protein-ligand binding modes. Their drug likeness properties have also been predicted.

In Vitro Evaluation of Anti-Rift Valley Fever Virus, Antioxidant and Anti-Inflammatory Activity of South African Medicinal Plant Extracts.

Rift valley fever virus (RVFV) is a mosquito-borne virus endemic to sub-Saharan African countries, and the first sporadic outbreaks outside Africa were reported in the Asia-Pacific region. There are no approved therapeutic agents available for RVFV; however, finding an effective antiviral agent against RVFV is important. This study aimed to evaluate the antiviral, antioxidant and anti-inflammatory activity of medicinal plant extracts. Twenty medicinal plants were screened for their anti-RVFV activity using the cytopathic effect (CPE) reduction method. The cytotoxicity assessment of the extracts was done before antiviral screening using the MTT assay. Antioxidant and reactive oxygen/nitrogen species' (ROS/RNS) inhibitory activity by the extracts was investigated using non-cell-based and cell-based assays. Out of twenty plant extracts tested, eight showed significant potency against RVFV indicated by a decrease in tissue culture infectious dose (TCID50) < 105. The cytotoxicity of extracts showed inhibitory concentrations values (IC50) > 200 µg/mL for most of the extracts. The antioxidant activity and anti-inflammatory results revealed that extracts scavenged free radicals exhibiting an IC50 range of 4.12-20.41 µg/mL and suppressed the production of pro-inflammatory mediators by 60-80% in Vero cells. This study demonstrated the ability of the extracts to lower RVFV viral load and their potency to reduce free radicals.

Antimicrobial, Cytotoxic and Oxidative Stress Inhibitory Activities of Terpenoids and Flavonols from Senegalia nigrescens (Oliv.) P.J.H. Hurter.

Senegalia nigrescens (knob thorn) is a deciduous tree distributed in savannah regions from Tanzania to South Africa used for timber but also medicinally for the treatment of convulsions, wounds, and skin problems. In this study, the biological activities of six phytocompounds, namely: 3 ß -hydroxy-20(29)-en-lupan-30-al (1), 30-hydroxylup-20(29)-en-3 ß -ol (2), ent-kaur-15-en-18,20-diol (3), melanoxetin (4), quercetin (5) and quercetin-3-O-methyl ether (6), isolated from S. nigrescens were investigated. The compounds were screened against two bacterial (Escherichia coli and Staphylococcus aureus) and one fungal (Candida albicans) strain and were also tested for their cytotoxicity on breast cancer (MDA-MB-231) and normal murine macrophage (RAW 264.7) cell line. Effects of the compounds on attenuating the lipopolysaccharide (LPS)-induced intracellular reactive oxygen species (ROS) production in RAW 264.7 cells were quantified with the H2DCF-DA assay. This study revealed that flavonols (5 and 6) had the strongest antibacterial and antifungal effects, both having MIC values of 62.5, 31.25 and 31.25 µg/mL on E. coli, S. aureus and C. albicans, respectively. Compounds 2, 3 and 6 were the most cytotoxic against the breast cancer cells with IC50 values of 11.86, 12.62 and 14.03 µg/mL, respectively, while the least toxicity towards normal cells were observed in compounds 2, 5 and 6. All compounds (1-6) significantly lowered ROS production in RAW264.7 cells. In conclusion, tested compounds represent potential promising candidates as antimicrobial, anticancer and antidotes for LPS-induced oxidative stress. This is the first report on the antifungal, cytotoxicity and antioxidative activities of the ent-kaurene diterpenoid, ent-kaur-15-en-18,20-diol (3).

Synthesis of furocoumarin-stilbene hybrids as potential multifunctional drugs against multiple biochemical targets associated with Alzheimer's disease.

A series of furocoumarin-stilbene hybrids has been synthesized and evaluated in vitro for inhibitory effect against acetylcholinesterase (AChE), butyrylcholinestarase (BChE), ß-secretase, cyclooxygenase-2 (COX-2), and lipoxygenase-5 (LOX-5) activities including free radical-scavenging properties. Among these hybrids, 8-(3,5-dimethoxyphenyl)-4-(3,5-dimethoxystyryl)furochromen-2-one 4h exhibited significant anticholinesterase activity and inhibitory effect against ß-secretase, COX-2 and LOX-5 activities. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and an in vitro cell-based antioxidant activity assay involving lipopolysaccharide induced reactive oxygen species production revealed that 4h has capability of scavenging free radicals. Molecular docking into AChE, BChE, ß-secretase, COX-2 and LOX-5 active sites has also been performed.

In-vitro analysis of free radical scavenging activities and suppression of LPS-induced ROS production in macrophage cells by Solanum sisymbriifolium extracts.

The current study aims to evaluate the antioxidant, cytotoxicity activities and suppression of LPS-induced oxidative stress production and characterization of phytochemicals in Solanum sisymbriifolium leaf extracts. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis3-ethylbenzothiazoline-6-sulphonic acid (ABTS) radical scavenging activity of the leaves of S. sisymbriifolium extracted with solvents of various polarities viz. water: ethanol, ratio 50: 50; ethyl acetate and dichloromethane, was assessed. The cytotoxicity of the extracts was determined using the [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] (MTT) assay on RAW 264.7 macrophage (Murine) cells and real-time cell analysis (RTCA) xCELLigence system was used for determining cell viability. Cell-based detection of reactive oxygen species (ROS) was investigated utilizing a 2',7'-Dichlorodihydrofluorescein diacetate (H2DCF-DA) assay. The DPPH and ABTS scavenging activity results of extracts revealed a dose-dependent response with significantly lower activity in both DPPH and ABTS. The superoxide dismutase (SOD) enzyme activity was then evaluated and extracts displayed a high SOD enzyme activity with 90-50% activity. Cytotoxicity results revealed that S. sisymbriifolium extracts were not toxic to RAW 264.7 macrophage cells at the tested concentrations. All three extracts decreased the production of ROS in macrophage cells. Phytochemical analysis using Fourier-transform infrared spectroscopy (FTIR) indicated the presence of metabolite functional groups which may be responsible for the antioxidant activity. The current study indicates that S. sisymbriifolium contains phytochemicals that scavenge free radicals, with less toxicity, and suppresses the LPS-induced ROS production in RAW 264.7 macrophage cells.

Active surveillance for antenatally detected ureteroceles: Predictors of success.

INTRODUCTION: Historically, ureteroceles were surgically treated, as patients were diagnosed after developing symptoms. However, with the advance of fetal medicine, antenatal detection has provided an opportunity to look at the natural history of ureteroceles. OBJECTIVES: With data derived from a retrospective chart review of patients with ureteroceles that were detected antenatally, the current study aimed to determine which group of children would be at risk for failure on active surveillance. It was hypothesized that single system ureteroceles (SSU) and male patients with duplex system ureteroceles (DSU) would be ideal for observation. METHODS: Outcomes were assessed by descriptive statistics. Kaplan-Meier curves were utilized to estimate median duration on active surveillance in both single and duplex cohorts. Breakthrough febrile urinary tract infection (fUTI) and surgery were determined by Cox regression in the duplex system cohort. Surgery was considered surveillance failure. RESULTS: A total of 102 patients (64 females/38 males) met the criteria: 78 (76.5%) had DSU and 24 (23.5%) SSU. The overall median observation was 1.2 years (range 0.7-3.1). Follow-up ranged from 0.3 to 11.7 years for SSU, and from 0.02 to 17.3 years for DSU. The predictors of failure of active surveillance (AS) in DSU (surgical intervention) were male gender (HR 1.8, 1.0-3.3, P = 0.037), or fUTI (HR 3.1, 1.7-5.8, P = 0.002). Predictors of fUTI were contralateral hydroureter or ipsilateral hydronephrosis ± hydroureter (OR 9.5, 1.2-71.7, P = 0.028). Interestingly, vesicoureteral reflux (VUR) was not a predictor of fUTI. The SSU patients were ideal for AS, while in DSU, surveillance was successful in 30% of patients who were primarily females without contralateral hydroureter or ipsilateral hydronephrosis ± hydroureter. However, in contradiction to the hypothesis, males were at higher risk for surgical intervention in the DSU cohort. CONCLUSION: Active surveillance is an option for patients with antenatally detected ureteroceles, but careful long term follow up is mandatory. Parents should be advised that surgical intervention may still be necessary, particularly in males with DSU.

Outcomes of Trabecular Metal-backed glenoid components in anatomic total shoulder arthroplasty.

BACKGROUND: As glenoid failure is one of the primary causes of failure of anatomic total shoulder arthroplasty (TSA), Trabecular Metal-backed glenoid components have become popular. This study reports implant survival and clinical outcomes of patients who received a Trabecular Metal-backed glenoid component during primary anatomic TSA. METHODS: Patients who underwent TSA with a Trabecular Metal-backed glenoid component by a single surgeon were identified and reviewed for clinical, radiographic, and patient-reported outcome measures with a minimum of 2 years' follow-up. RESULTS: Of 47 patients identified, radiographic and clinical follow-up was available on 36 patients (77%). Average age was 66.36 years (range, 50-85 years), and the average follow-up 41 months (range, 24-66 months). Three patients showed signs of osteolysis, 4 had radiographic evidence of metal debris, and 1 patient had a catastrophic failure after a fall. Of the 47 TSAs, 5 (11%) were revised to a reverse TSA for subscapularis failure and pain. Visual analog scale for pain scores improved by an average of 4.4. At final follow-up, the average Single Assessment Numeric Evaluation score was 72.4; Penn satisfaction score, 7.5; Penn score, 70.35; and American Shoulder and Elbow Surgeons score, 69.23. Outcome scores were similar in the 7 patients with osteolysis or metal debris compared to those without. CONCLUSION: Trabecular Metal-backed glenoids had a 25% rate of radiographic metal debris and osteolysis at a minimum 2-year follow-up in this series with one catastrophic failure. This implant should be used with caution, and patients followed closely.

Hylan G-F 20 improves hip osteoarthritis: a prospective, randomized study.

We compared the efficacy and safety of intra-articular hylan G-F 20 with methylprednisolone acetate (MPA) for treating symptomatic Kellgren-Lawrence grade (KLG) 2 or 3 hip osteoarthritis in a prospective, randomized, multicenter, double-blind trial (N = 313). Two injections of hylan G-F 20 were administered 2 weeks apart (n = 150), or 1 injection of 40 mg MPA and 1 sham injection 2 weeks later (n = 155). The Western Ontario and McMaster Universities Arthritis Index (WOMAC) (total and subscale), clinician observations, and patient global assessments were collected at baseline and at weeks 4, 8, 12, 16, 20, and 26 (intent-to-treat population was analyzed; n = 305). Responder rates were assessed by WOMAC domain A, and criteria were established by the Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI). At week 26, WOMAC A improved by 16.6 mm for hylan G-F 20 versus 13.6 mm for MPA. Response rates were higher with hylan G-F 20 versus MPA in patients with more advanced disease (KLG 3) and were similar between hylan G-F 20 and MPA in patients with less advanced disease (KLG 2). Adverse events were similar between groups and between patients with KLG 2 or 3. Hylan G-F 20 provided clinically meaningful improvements in pain and function, comparable with those of MPA, with good safety and tolerability. Thus, we conclude it is an appropriate option for treating hip osteoarthritis.

Desert hedgehog (Dhh) gene is required in the mouse testis for formation of adult-type Leydig cells and normal development of peritubular cells and seminiferous tubules.

Testes from adult and prepubertal mice lacking the Desert hedgehog (DHH:) gene were examined in order to describe further the role of Dhh in spermatogenesis because, in a previous report, DHH:-null male mice were shown to be sterile. Dhh is a signaling molecule expressed by Sertoli cells. Its receptor, patched (Ptc), has been previously localized to Leydig cells and is herein described as being localized also to peritubular cells. Two phenotypes of the mice were observed: masculinized (7.5% of DHH:-null males) and feminized (92.5%), both of which displayed abnormal peritubular tissue and severely restricted spermatogenesis. Testes from adult feminized animals lacked adult-type Leydig cells and displayed numerous undifferentiated fibroblastic cells in the interstitium that produced abundant collagen. The basal lamina, normally present between the myoid cells and Sertoli cells, was focally absent. We speculate that the abnormal basal lamina contributed to other characteristics, such as extracordal gonocytes, apolar Sertoli cells, and anastomotic seminiferous tubules. The two DHH:-null phenotypes described have common peritubular cell defects that may be indicative of the essential role of peritubular cells in development of tubular morphology, the differentiation of Leydig cells, and the ultimate support of spermatogenesis.

[Effect of the ototoxicity of gentamycin on the vestibulo-ocular reflexes in the cat]. / Efecto de la ototoxicidad de la gentamicina sobre los reflejos vestibulooculares en el gato.

In this paper we show the effect of gentamicin upon the VOR and ViVOR gain and phase in pendular and impulse rotatory tests. We show the early effect of gentamicin upon the gain in low frequency tests, and the small effect upon the phase of the response.