Palladium(II) Complexes of 4-Phenyl-3-thiosemicarbazone Ligands: Insights Into Cytotoxic Properties and Mode of Cell Death.

Reactions between sodium tetrachloropalladate and 2- (or 4-) substituted 4-phenyl-3-thiosemicarbazone ligands (HLR), with various electron-donating and electron-withdrawing substituents (R = OCH3, NO2, and Cl), afford square-planar complexes of the general formula [Pd(LR)2]. Ground-state geometry optimization and the vibrational analysis of cis- and trans-isomers of the complexes were carried out to get an insight into the stereochemistry of the complexes. Natural bond orbital analysis was used to analyze how the nature of the substituent affects the natural charge of the metal center, the type of hybridization, and the strength of the M-N and M-S bonds. Using spectrophotometry, the stability of the complexes, and their DNA binding abilities were assessed. The Pd(II) complexes showed moderate cytotoxicity against MCF-7 and Caco-2 cell lines, two of the assessed malignant cell lines, resulting in all known cell death types, including early apoptotic bodies and late apoptotic vacuoles as well as evident necrotic bodies.

Phototriggered cytotoxic properties of tricarbonyl manganese(I) complexes bearing α-diimine ligands towards HepG2.

Reaction between bromo tricarbonyl manganese(I) and N,N'-bis(phenyl)-1,4-diaza-1,3-butadiene ligands, bearing different electron-donating and electron-withdrawing groups R = OCH3, Cl, and NO2 in the ortho- and para-positions on the phenyl substituent, afforded [MnBr(CO)3(N-N)] complexes. The influence of the character and position of the substituent on the dark stability and carbon monoxide releasing kinetics was systematically investigated and correlated with the data of the time-dependent density functional theory calculations. The combined UV/Vis and IR data clearly revealed that the aerated solutions of [MnBr(CO)3(N-N)] in either coordinating or noncoordinating solvents are dark stable and the fluctuations observed during the incubation period especially in the case of the nitro derivatives may be attributed to the exchange of the axial bromo ligand with the coordinating solvent molecules. The free ligands and nitro complexes were non-cytotoxic to HepG2 cells under both the dark and illumination conditions. In the dark, Mn(I) compounds, incorporating o-OCH3 and o-Cl, exhibited excellent cytotoxicity with IC50 values of 18.1 and 11.8 µM, while their para-substituted analogues were inactive in the dark and active upon the irradiation at 365 nm with IC50 values of 5.7 and 6.7 µM, respectively.

Large-scale screening and characterization of enteroviruses and kobuviruses infecting pigs in Vietnam.

A recent survey of pigs in Dong Thap province, Vietnam identified a high frequency of enterovirus species G (EV-G) infection (144/198; 72.7%). Amongst these was a plethora of EV-G types (EV-G1, EV-G6 and four new types EV-G8-EV-G11). To better characterize the genetic diversity of EV-G and investigate the possible existence of further circulating types, we performed a larger-scale study on 484 pig and 45 farm-bred boar faecal samples collected in 2012 and 2014, respectively. All samples from the previous and current studies were also screened for kobuviruses. The overall EV infection frequency remained extremely high (395/484; 81.6%), but with comparable detection rates and viral loads between healthy and diarrhoeic pigs; this contrasted with less frequent detection of EV-G in boars (4/45; 8.9%). EV was most frequently detected in pigs ≤ 14 weeks old (∼ 95%) and declined in older pigs. Infections with EV-G1 and EV-G6 were most frequent, whilst less commonly detected types included EV-G3, EV-G4 and EV-G8-EV-G11, and five new types (EV-G12-EV-G16). In contrast, kobuvirus infection frequency was significantly higher in diarrhoeic pigs (40.9 versus 27.6%; P = 0.01). Kobuviruses also showed contrasting epizootiologies and age associations; a higher prevalence was found in boars (42%) compared with domestic pigs (29%), with the highest infection frequency amongst pigs >52 weeks old. Although genetically diverse, all kobuviruses identified belonged to the species Aichivirus C. In summary, this study confirms infection with EV-G was endemic in Vietnamese domestic pigs and exhibits high genetic diversity and extensive inter-type recombination.

Metal-based carbon monoxide releasing molecules with promising cytotoxic properties.

Carbon monoxide, the "silent killer" gas, is increasingly recognised as an important signalling molecule in human physiology, which has beneficial biological properties. A particular way of achieving controlled CO administration is based on the use of biocompatible molecules that only release CO when triggered by internal or external factors. These approaches include the development of pharmacologically effective prodrugs known as CO releasing molecules (CORMs), which can supply biological systems with CO in well-regulated doses. An overview of transition metal-based CORMs with cytotoxic properties is here reported. The mechanisms at the basis of the biological activities of these molecules and their potential therapeutical applications with respect to their stability and CO releasing properties have been discussed. The activation of metal-based CORMs is determined by the type of metal and by the nature and features of the auxiliary ligands, which affect the metal core electronic density and therefore the prodrug resistance towards oxidation and CO release ability. A major role in regulating the cytotoxic properties of these CORMs is played by CO and/or CO-depleted species. However, several mysteries concerning the cytotoxicity of CORMs remain as intriguing questions for scientists.

Role of the auxiliary ligand in determining the genotoxicity and mode of cell death of thiosemicarbazone Pd(II) complexes.

A series of Pd(II) complexes of the general formula [PdX(NNS)] (X = Cl, Br, I, NCS and phenyl-tetrazole-thiolato; NNS = 2-quinolinecarboxyaldehyde-N4-phenylthiosemicarbazone) was tested against four malignant cell lines for their antiproliferative properties and the outcomes were compared to those seen in normal mouse splenocytes. Various auxiliary ligands were substituted in order to investigate the impact of the character of the ligand on the cytotoxicity of this class of Pd(II) complexes. The iodo complex was the most cytotoxic compound towards the Caco-2 cell line in this study. The improved apoptosis and necrosis cell modes were in accordance with the fragmentation results of DNA, which revealed increased fragmentation terminals, especially in isothiocyanate and tetrazole-thiolato complexes. After 24 hours, at half the IC50 of each complex, the complex-treated cells exhibited considerable genotoxicity when compared to the corresponding non-treated control especially in the case of isothiocyanate and tetrazole-thiolato complexes.

Insights into the photoactivatable CO releasing properties of dicarbonyl Ru(II) complex with 8-amino quinoline ligand: Experimental and theoretical studies.

Reaction between the polymeric [RuCl2(CO)2]n and the N,N-bidentate ligand, 8-amino-quinoline (Quin), in methanol, afforded the photoactivated CO releasing molecule with the formula of trans-(Cl,Cl)-[RuCl2(CO)2Quin]. In the presence of biomolecules or in solvents with varying polarity and coordinating abilities, the solvatochromic characteristics and dark stability were investigated. A new board band emerged in the visible spectrum during the illumination, and its position varies according to the type of solvent used, indicating the role of the solvent in controlling the nature of the CO-depleted species. Spectral methods were used in combination with density functional theory simulations to get insight into the local minimum structure and the electronic properties of the Ru(II) complex. The results of the myoglobin assay showed that within the first two hours of illumination, one of the two CO molecules was released. The cytotoxic properties of the Ru(II)-based complex were investigated against normal mice bone marrow stromal cells and malignant human acute monocytic leukaemia cells.

In vitro cytotoxicity of Mn(I) and Ru(II) carbonyls with a diphenyl pyridyl phosphine coligand towards leukaemia.

Human acute monocytic leukaemia cells were tested under both dark and light conditions for their susceptibility to Mn(I) and Ru(II) carbonyl complexes with a diphenyl pyridyl phosphine coligand. The Ru(II) complex (IC50 = 7.13 ± 0.8 µM) displayed higher outstanding potency against leukaemia than the Mn(I) analogue (54.58 ± 4.1 µM) in the dark and both complexes were completely harmless to healthy mouse bone marrow cells.

Evaluating educational service quality among dentistry and nursing students with the SERVQUAL model: A cross-sectional study.

Objectives: This study was aimed at evaluating the quality of educational services among dentistry and nursing students through use of the SERVQUAL model. Additionally, the effects of education sector, country, gender, and academic year on the quality of education services were studied. Methods: A convenience sampling technique was used in this cross-sectional study to recruit 528 dentistry and nursing students in governmental and private sectors from Egypt and KSA. Data were collected through two self-administered questionnaires. The first questionnaire included participants' demographic characteristics, whereas the second questionnaire collected data on educational service quality by using the five-dimension SERVQUAL tool. Results: The total mean score for quality of education was 3.65. The mean reliability score was highest among all quality dimensions (3.79). A significant positive linear association was observed between the quality of education and educational sector, field of study, country, and academic year. Conclusion: Students' perceptions of educational service quality were above average. Field of study had the largest main effect on the quality of educational services. Additionally, academic year, educational sectors, and country significantly influenced the quality of educational services.

A fatal outbreak of neonatal sepsis caused by mcr-10-carrying Enterobacter kobei in a tertiary care hospital in Nepal.

BACKGROUND: Enterobacter kobei is an emerging cause of outbreak of nosocomial infections in neonatal intensive care units (NICUs). Between July and September 2016, a NICU in a tertiary care hospital of Nepal observed an abrupt increase in the number of neonatal sepsis cases caused by Enterobacter spp. infecting 11 out of 23 admitted neonates, five of whom died of an exacerbated sepsis. AIM: To confirm the suspected outbreak, identify environmental source of infection, and characterize genetic determinants of antimicrobial resistance (AMR) and virulence of the pathogen. METHODS: Whole-genome sequencing of all Enterobacter spp. isolated from blood cultures of septic neonates admitted to NICU between May 2016 and December 2017 was performed. Also, an environmental sampling was intensified from fortnightly to weekly during the outbreak. FINDINGS: The genomic analysis revealed that 10 out of 11 non-duplicated E. kobei isolated from neonatal blood cultures between July and September 2016 were clonal, confirming the outbreak. The isolates carried AMR genes including blaAmpC and mcr-10 conferring reduced susceptibility to carbapenem and colistin respectively. The environmental sampling, however, failed to isolate any Enterobacter spp. Reinforcement of aseptic protocols in invasive procedures, hand hygiene, environmental decontamination, fumigation, and secluded care of culture-positive cases successfully terminated the outbreak. CONCLUSION: Our study underscored the need to implement stringent infection control measures to prevent infection outbreaks. For the first time, we report the emergence of carbapenem and colistin non-susceptible E. kobei carrying mcr-10 gene as a cause of nosocomial neonatal sepsis in a NICU.

Ruthenium(II) carbon monoxide releasing molecules: Structural perspective, antimicrobial and anti-inflammatory properties.

Carbon monoxide has recently emerged to promote tissue regeneration, enhance the innate immune system, and have anti-inflammatory and antibacterial properties. While the first generation Ru(II) carbonyl prodrugs (CORM-2 and CORM-3) displayed several beneficial biological effects, a search in the literature shows that little work has been done to address the drawbacks of CORM-2/-3, exploring other CO triggered methods for the next generation Ru(CO)2II based compounds and examining their valuable biological impact. We present a summary of most work related to Ru(II) carbon monoxide-releasing molecules, protein bioconjugation, and antibacterial and anti-inflammatory properties.

Cytotoxicity of fac-Mn(CO)3 complexes with a bidentate quinoline ligand towards triple negative breast cancer.

The cytotoxicity of two tricarbonyl Mn(I) complexes of the general formula fac-[MnBr(CO)3L] (L = quinoline-2-carboxaldehyde (A) and 8-amino quinoline (B)) towards triple negative breast cancer (MDA-MB-231) was reported. Complexes A and B released CO when exposed to 468 nm light. Compound B has a dose-dependent cytotoxicity, with half maximal inhibitory concentration values of 19.62 µM and 11.43 µM before and after illumination, respectively. Co-treatment of MDA-MB-231 with paclitaxel (30 nM) and complex B (10 µM) resulted in a 50% reduction in cell viability.

Light-activated cytotoxicity of dicarbonyl Ru(II) complexes with a benzimidazole coligand towards breast cancer.

Reaction between [RuCl2(CO)2]n and 1H-benzimidazol-2-ylmethyl-(N-phenyl)amine ligands (LR) functionalized with various electron-donating and electron-withdrawing substituents on the phenyl ring (R = H, 4-CH3, 4-Cl, 4-COOCH3, and 3-COOCH3) afforded the dark-stable photoactivatable carbon monoxide prodrugs of the general formula [RuCl2(CO)2LR]. Release of the CO molecules from the Ru(II) compounds was examined by monitoring the electronic and IR spectra upon illumination at 365 nm. A noticeable decrease in the intensities of the two characteristic ν(CO) modes for Ru(CO)II2 species, and the growth of two new bands for the mono-carbonyl species and free CO, were the main features of the photolysis profiles. The cytotoxicity of the complexes towards breast cancer (MCF-7) cells was assessed with and without illumination at 365 nm. All the complexes except that with a 4-COOCH3 group (IC50 = 45.08 ± 3.5 µM) are nontoxic under dark conditions. Upon illumination, all the compounds acquired cytotoxicity in the following order: H > 4-COOCH3 > 4-CH3 > 4-Cl > 3-COOCH3. Investigation of the cytotoxicity of the CO-depleted fragments showed that the light-induced cytotoxicity can be attributed to the liberated CO and CO-depleted metal fragments, including the liberated benzimidazole ligands.

Cytotoxicity of photoactivatable bromo tricarbonyl manganese(i) compounds against human liver carcinoma cells.

Two series of photoinduced tricarbonyl manganese(i) compounds were prepared from the reaction of [MnBr(CO)3(2-C(H)[double bond, length as m-dash]O)] (2-C(H)[double bond, length as m-dash]O: quinoline-2-carboxaldehyde and pyridine-2-carboxaldehyde) and para-substituted aniline derivatives (X = OH, OCH3, Cl and NO2). Different electron-donating and electron-withdrawing substituents were introduced in the para-position of the phenyl ring to investigate their influence on the stability of the compounds in the dark and the photophysical properties upon illumination at 525 nm. When kept in the dark, the aerated solutions of the complexes in dimethyl sulfoxide (DMSO) and CH2Cl2 were stable. In the solution, the complexes bearing electron-withdrawing substituents, exchange their bromo ligands with DMSO solvent molecules, as evidenced from infrared and UV/Vis studies as well as time-dependent density functional theory (TDDFT) calculations. The complexes were assessed for their cytotoxicity, both in the dark and upon exposure to a 525 nm LED, against the human hepatocarcinoma cell line (HepG2). A marked reduction in the viability of HepG2 cells treated with the complex functionalized with quinoline and methoxy substituent was observed after illumination in a dose-dependent manner, with an IC50 value of 7.1 µM, making it the most phototoxic compound in our study.

Deferasirox removes cardiac iron and attenuates oxidative stress in the iron-overloaded gerbil.

Iron-induced cardiovascular disease is the leading cause of death in iron-overloaded patients. Deferasirox is a novel, once daily oral iron chelator that was recently approved for the treatment of transfusional iron overload. Here, we investigate whether deferasirox is capable of removing cardiac iron and improving iron-induced pathogenesis of the heart using the iron overload gerbil model. Animals were randomly divided into three groups: control, iron overload, and iron overload + deferasirox treatment. Iron-dextran was given 100 mg/kg per 5 days i.p for 10 weeks. Deferasirox treatment was taken post iron loading and was given at 100 mg/kg/day p.o for 1 or 3 months. Cardiac iron concentration was determined by inductively coupled plasma atomic emission spectroscopy. Compared with the untreated group, deferasirox treatment for 1 and 3 months decreased cardiac iron concentration 17.1% (P = 0.159) and 23.5% (P < 0.05), respectively. These treatment-associated reductions in cardiac iron were paralleled by decreases in tissue ferritin expression of 20% and 38% at 1 and 3 months, respectively (P < 0.05). Using oxyblot analysis and hydroethidine fluorescence, we showed that deferasirox significantly reduces cardiac protein oxidation and superoxide abundance by 36 and 47.1%, respectively (P < 0.05). Iron-induced increase in oxidative stress was also associated with increased phosphorylation of ERK-, p38-, and JNK-mitogen-activated protein kinase (MAPK). Interestingly, deferasirox treatment significantly diminished the phosphorylation of all three MAPK subfamilies. These results suggest that deferasirox may confer a cardioprotective effect against iron induced injury.

Physician attitudes toward collaborative agreements with pharmacists and their expectations of community pharmacists' responsibilities in West Virginia.

OBJECTIVES: To (1) investigate physicians' expectations about community pharmacist's roles and physician attitudes toward collaborative agreements with community pharmacists in West Virginia and (2) determine physicians' perceptions of pharmacists providing medication therapy management (MTM) services. METHODS: A mail survey was conducted for a random sample of 500 physicians practicing in West Virginia. Survey items measured the physicians' perceptions about the roles of pharmacists, their level of comfort with pharmacists providing certain MTM services, and their attitudes toward a collaborative agreement with pharmacists. RESULTS: 102 responses were received, yielding a response rate of 22.1%; 60% of the physicians had a favorable attitude toward supporting collaborative agreement with pharmacists. Physicians were more comfortable with certain areas of MTM services, such as general drug education and the Medicare Part D prescription drug benefit, and they expected pharmacists to identify medication errors and educate the patients about the safe and appropriate use of medications. CONCLUSION: Of the physician respondents, 60% reported a favorable attitude toward collaborative practice agreements, but their attitude toward pharmacists' role in collaborative drug therapy management and pharmacists providing MTM services were not that favorable. Participating physicians may not have consistent expectations regarding pharmacists providing patient care.

Folic acid awareness among female college students: neural tube defects prevention.

OBJECTIVE: To investigate the level of awareness among female college students on the importance of preconception folic acid supplementation in preventing neural tube defects (NTDs). We have also studied their response after educating them. METHODS: This is a questionnaire-based study. Five hundreds questionnaires were distributed to the female students of the 3 colleges, namely, Humanities, Sciences, and Health in Jeddah, Kingdom of Saudi Arabia in April 2008. The questions included an enquiry on their knowledge regarding the importance of folic acid preconception, and if they will implement what they learned after listening to lectures, delivered by the 4th year medical students, who were trained and supervised by the faculty members of the King Abdul-Aziz University. RESULTS: Two hundred and seventeen questionnaires were filled, and returned (43.4%). Mean age +/- SD was 20.96 +/- 2.25 years. Almost 88% were not aware of the importance of folic acid in preventing NTDs. After listening to the lecture, 82.9% thought that they will surely use folic acid preconception, and 98.6% will relay the important message about the importance of folic acid to others. CONCLUSION: There is a need to increase the awareness of the importance of folic acid among females' childbearing age. Medical students' involvement in educating college students was an effective way to increase their awareness. Similar educating programs are required, in order to reduce the high incidence of NTDs.

Detection of potentially novel paramyxovirus and coronavirus viral RNA in bats and rats in the Mekong Delta region of southern Viet Nam.

Bats and rodents are being increasingly recognized as reservoirs of emerging zoonotic viruses. Various studies have investigated bat viruses in tropical regions, but to date there are no data regarding viruses with zoonotic potential that circulate in bat and rat populations in Viet Nam. To address this paucity of data, we sampled three bat farms and three wet markets trading in rat meat in the Mekong Delta region of southern Viet Nam. Faecal and urine samples were screened for the presence of RNA from paramyxoviruses, coronaviruses and filoviruses. Paramyxovirus RNA was detected in 4 of 248 (1%) and 11 of 222 (4.9%) bat faecal and urine samples, respectively. Coronavirus RNA was detected in 55 of 248 (22%) of bat faecal samples; filovirus RNA was not detected in any of the bat samples. Further, coronavirus RNA was detected in 12 of 270 (4.4%) of rat faecal samples; all samples tested negative for paramyxovirus. Phylogenetic analysis revealed that the bat paramyxoviruses and bat and rat coronaviruses were related to viruses circulating in bat and rodent populations globally, but showed no cross-species mixing of viruses between bat and rat populations within Viet Nam. Our study shows that potentially novel variants of paramyxoviruses and coronaviruses commonly circulate in bat and rat populations in Viet Nam. Further characterization of the viruses and additional human and animal surveillance is required to evaluate the likelihood of viral spillover and to assess whether these viruses pose a risk to human health.

Long-term efficacy of deferasirox in preventing cardiovascular complications in the iron-overloaded gerbil.

Iron-induced cardiovascular disease is the leading cause of death in iron-overloaded patients. Deferasirox is a novel tridentate oral chelator that exhibits a half-life suitable for once-daily dosing; however, little is known regarding the effectiveness of this agent in preventing iron-induced cardiovascular disease. Adult male Mongolian gerbils were randomly divided into 3 groups: control, iron overload, and iron overload followed by deferasirox treatment. Iron-overloaded animals received iron dextran 100 mg/kg intraperitoneally (ip)/5 days for 10 weeks, while deferasirox was given 100 mg/kg per d orally (po) for 9 months post iron loading. Cardiac and aortic iron levels were determined by inductively coupled plasma atomic emission spectrometry. Gerbil electro- and echocardiograms were obtained in anesthetized animals at regular intervals. Compared to control animals, iron concentration was 3.3- and 2.4-fold higher in iron-overloaded heart and aorta, respectively (P < .05). Deferasirox treatment reduced cardiac and aortic iron levels by 32% and 35%, respectively (P < .05). These results were consistent with the decrease in cellular iron deposition observed with Prussian Blue iron staining. Iron-overloaded gerbils were found to exhibit frequent arrhythmias including premature ventricular contractions, supraventricular tachycardia, and recurrent ventricular tachycardia. In addition, echocardiographic assessment demonstrated iron overload-associated increase in left ventricular dimensions including left ventricular posterior wall dimension (LVPWd: 49%), left ventricular internal dimension (LVIDd: 26%), and left ventricular septum thickness (LVSd: 42%). These parameters were significantly reduced with deferasirox treatment (LVPWd: 23%, LVIDd: 24%, and LVSd: 27%). Iron overload was also associated with reduced ejection fraction (EF: by 30%) and fractional shortening (FS: by 23%) in comparison with controls (P < .05). With deferasirox treatment, these values were higher (EF: by 30%, FS: by 28%) compared to iron-overloaded group. These findings suggest that deferasirox may be useful for attenuating iron-induced changes in cardiac structure and function.