Bone marrow-derived mesenchymal stem cells abate CCl4-induced lung damage via their modulatory effects on inflammation, oxidative stress and apoptosis.

OBJECTIVE: The aim of this study was to assess and compare the therapeutic effects of allogenic and xenogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) on a rat model for treating experimental lung inflammation, oxidative stress, and apoptosis. MATERIALS AND METHODS: Male Wistar rats were randomly divided into four groups. Group 1 received an intraperitoneal injection of olive oil vehicle (2 mL/kg body weight) for 8 weeks. Group 2 received an intraperitoneal injection of carbon tetrachloride (CCl4) (0.5 mL/kg body weight, twice/week) dissolved in olive oil for 8 weeks. Groups 3 and 4 received the CCl4 similar to group 2, followed by the intravenous injection of rat and mouse BM-MSCs (1 × 106 cells/rat twice/week into a lateral tail vein), respectively, for 4 weeks. Subsequently, the rats were sacrificed, and lung tissues were excised for molecular, histological, and ultrastructural investigations. RESULTS: Fibrosis, interstitial bleeding, dilatation and congestion of blood vessels, intra-alveolar edema, damaged alveoli, scattered mononuclear leucocytic infiltrates, and an increased number of apoptotic cells and apoptotic remnants were observed in the lungs of rats exposed to CCl4; the treatment with rat and mouse BM-MSCs attenuated these changes. The effects of CCl4 on the increase in collagen fibers in the lungs and the expression levels of cyclooxygenase-2, tumor necrosis factor-α, and apoptotic protein p53 were considerably reduced following treatment with the BM-MSCs. The higher levels of lipid peroxidation, the lower-level glutathione content, and the activities of superoxide dismutase, glutathione peroxidase, and glutathione-S-transferase in CCl4-injected rats were significantly improved by treatments with rat and mouse BM-MSCs. CONCLUSIONS: These findings indicate that mouse and rat BM-MSCs, which were more potent, can protect against CCl4-induced lung damage and fibrosis by reducing inflammation, apoptosis, and oxidative stress and boosting the antioxidant defense system.

Synthesis of novel pyrazolone candidates with studying some biological activities and in-silico studies.

Pyranopyrazole derivatives have a vital role in the class of organic compounds because of their broad spectrum of biological and pharmacological importance. Our current goal is the [3 + 3] cycloaddition of benzoyl isothiocyanate and pyrazolone 1 to undergo oxidation cyclization, producing pyrazoloxadiazine 3. The diol 5 was obtained as a condensation of two equivalents of 1 with thiophene-2-carboxaldehyde in acetic acid above the sodium acetate mixture. When the condensation was carried out in piperidine under fusion, unsaturated ketone 4 was obtained. The pyrazolo pyran derivative 11 resulted from the [3 + 3] cycloaddition of 1 and cinnamic acid, while the Pyrone derivative was prepared by acylation of 12 with two equivalents of acetic anhydride. Phthalic anhydride undergoes arylation using zinc chloride as a catalyst. The cyclic keto acid 23 was synthesized by the action of succinic anhydride on 12 in the acetic medium, while the latter reacted with cinnamic acid, leading to pyrazole derivative 24. All of these reactions were through the Michael reaction mechanism. All the tested compounds showed good antimicrobial activity against pathogenic microorganisms; newly synthesized compounds were also screened for their antioxidant activity. Rational studies were carried out by the ABTs method to allow a broader choice of activities. In addition, similar off-compounds were conducted. Molecular docking studies with the CB-Dock server and MD simulations were created with the default settings of the Solution Builder on the CHARMM-GUI server at 150 nm. A good correlation was obtained between the experimental results and the theoretical bioavailability predictions using POM theory.

Eco-Friendly Synthesis of 1H-benzo[d]imidazole Derivatives by ZnO NPs Characterization, DFT Studies, Antioxidant and Insilico Studies.

Benzimidazoles are classified as a category of heterocyclic compounds. Molecules having benzimidazole motifs show promising utility in organic and scientific studies. A series of mono-substituted benzimidazoles were synthesized by ZnO-NPs via cyclocondensation between substituted aromatic aldehydes and o-phenylene diamine. The synthesized compounds were characterized and compared with the traditional methods. The nano-catalyzed method displayed a higher yield, shorter time and recyclable catalyst. The DFT study and antioxidant activity were investigated for benzo[d]imidazole derivatives. Compound 2a exhibited the highest antioxidant activity among the tested compounds. We focused on the catalytic activity of ZnO in the synthesis of heterocyclic structures with the goal of stimulating further progress in this field. The superiorities of this procedure are high yield of product, low amounts of catalyst and short reaction time.

Validity, Reliability and Responsiveness of the Malay Shoulder Pain and Disability Index (M-SPADI) for Patients with Shoulder Pain.

Introduction: The purpose of this study is to determine the validity, reliability, and responsiveness of the Malay Shoulder Pain and Disability Index (M-SPADI) in Malay speakers suffering from shoulder pain. Materials and methods: The M-SPADI, the Numerical Rating Scale (NRS), and measurements of shoulder active range of motion (AROM) were completed by 140 patients with shoulder pain (68 with rotator cuff pathology and 72 with other shoulder pathology). Thirty-four patients were retested for test-retest reliability with M-SPADI after an average of 9.2 days. M-SPADI was performed on twenty-one individuals three months after completing treatment for rotator cuff disorders to assess response. Results: The results of exploratory factor analysis revealed a bidimensional structure for M-SPADI. M-SPADI disability score was significantly greater in patients with rotator cuff pathologies (median = 31.87, IQR 82.50) than in patients with other shoulder pathologies (median = 20.00, IQR 23.84). In multi-group factor analysis, measurement invariance revealed no significant difference between the two groups (p>0.05). There was a significant positive correlation between M-SPADI and NRS (Pain = 0.86, Disability = 0.75, Total = 0.82, p=0.005), and a significant negative correlation between M-SPADI and shoulder AROM (Pain = -0.34 to -0.67, Disability =-0.44 to -0.73, Total =0.43 to -0.72, p=0.005). M-SPADI had a high degree of internal consistency (Cronbach's 0.92 for pain and 0.95 for disability). Test-retest reliability was moderate to excellent (ICC Pain = 0.84, ICC Disability = 0.78, ICC Total = 0.81, p=0.001), and the smallest detectable change ranges (Pain = 8.74, Disability = 3.21, Total = 3.83) were less than the minimal detectable change ranges (Pain = 21.57, Disability = 6.82, Total = 8.79). The area under the receiver operating characteristic curve (AUC) for M-SPADI was greater than 0.90 (Pain = 0.99, Disability = 0.94, Total = 0.96). Conclusion: The M-SPADI has established construct validity, internal consistency, test-retest reliability, and responsiveness. The M-SPADI is a reliable and valid instrument for evaluating shoulder pain among Malay-speaking individuals. In addition, the M-SPADI disability subscale may be useful for monitoring functional score changes in patients with rotator cuff pathology.

Tuning anticancer properties and DNA-binding of Pt(ii) complexes via alteration of nitrogen softness/basicity of tridentate ligands.

Nine tridentate Schiff base ligands of the type (N^N^O) were synthesized from reactions of primary amines {2-picolylamine (Py), N-phenyl-1,2-diaminobenzene (PhN), and N-phenyl-1,2-diaminoethane(EtN)} and salicylaldehyde derivatives {3-ethoxy (OEt), 4-diethylamine (NEt2) and 4-hydroxy (OH)}. Complexes with the general formula Pt(N^N^O)Cl were synthesized by reacting K2PtCl4 with the ligands in DMSO/ethanol mixtures. The ligands and their complexes were characterized by NMR spectroscopy, mass spectrometry and elemental analysis. The DNA-binding behaviours of the platinum(ii) complexes were investigated by two techniques, indicating good binding affinities and a two-stage binding process for seven complexes: intercalation followed by switching to a covalent binding mode over time. The other two complexes covalently bond to ct-DNA without intercalation. Theoretical calculations were used to shed light on the electronic and steric factors that lead to the difference in DNA-binding behavior. The reactions of some platinum complexes with guanine were investigated experimentally and theoretically. The binding of the complexes with bovine serum albumin (BSA) indicated a static interaction with higher binding affinities for the ethoxy-containing complexes. The half maximal inhibitory concentration (IC50) values against MCF-7 and HepG2 cell lines suggest that platinum complexes with tridentate ligands of N-phenyl-o-phenylenediamine or pyridyl with 3-ethoxysalicylimine are good chemotherapeutic candidates. Pt-Py-OEt and Pt-PhN-OEt have IC50 values against MCF-7 of 13.27 and 10.97 µM, respectively, compared to 18.36 µM for cisplatin, while they have IC50 values against HepG2 of 6.99 and 10.15 µM, respectively, compared to 19.73 µM for cisplatin. The cell cycle interference behaviour with HepG2 of selected complexes is similar to that of cisplatin, suggesting apoptotic cell death. The current work highlights the impact of the tridentate ligand on the biological properties of platinum complexes.

Tuning the anticancer properties of Pt(ii) complexes via structurally flexible N-(2-picolyl)salicylimine ligands.

Three tridentate Schiff base ligands were synthesized from the reactions between 2-picolylamine and salicylaldehyde derivatives (3-ethoxy (OEt), 4-diethylamino (NEt2) and 4-hydroxy (OH)). Complexes with the general formula Pt(N^N^O)Cl were obtained from reactions between the ligands and K2PtCl4. The ligands and their complexes were characterized by NMR spectroscopy, mass spectrometry and elemental analysis. Further confirmation of the structure of Pt-OEt was achieved by single-crystal X-ray diffraction. The DMSO/chlorido exchange process at Pt-OEt was investigated by monitoring the change in conductivity, revealing very slow dissociation in DMSO. Moreover, solvent/chlorido exchange for Pt-OEt and Pt-NEt2 were investigated by NMR spectroscopy in DMSO and DMSO/D2O; Pt-NEt2 forms an adduct with DMSO while Pt-OEt forms adducts with DMSO and water. The DNA-binding behaviour of the platinum(ii) complexes was investigated by two techniques. Pt-NEt2 has the best apparent binding constant. The intercalation mode of interaction with ct-DNA was suggested by molecular docking studies and the increase in the relative viscosity of ct-DNA with increasing concentrations of the platinum(ii) complexes. However, the gradual decrease in the relative viscosity over time at constant concentration of platinum(ii) complexes indicated a shift from intercalation to a covalent binding mode. Anticancer activities of the ligands and their platinum(ii) complexes were examined against two cell lines. The platinum(ii) complexes exhibit superior cytotoxicity to that of their ligands. Among the platinum(ii) complexes, Pt-OEt possesses the best IC50 against both cell lines, its cytotoxicity being comparable to that observed for cisplatin. Cell cycle arrest in the HepG2 cell line upon treatment with Pt-OEt and Pt-NEt2 was investigated and compared to that of cisplatin; the change in the cell accumulation patterns supports the presumption of an apoptotic cell death pathway. The optimized structures of the B-DNA trimer adducts with the platinum complexes showed hydrogen-bonding interactions between the ligands and nucleobases, affecting the inter-strand hydrogen bonding within the DNA, and highlighting the strong ability of the complexes to induce conformational changes in the DNA, leading to the activation of apoptotic cell death. In summary, the current study demonstrates promising new anticancer platinum(ii) complexes with highly flexible tridentate ligands; the functional groups on the ligands are important in tuning their DNA binding/anticancer properties.

You Are What You Eat: Application of Metabolomics Approaches to Advance Nutrition Research.

A healthy condition is defined by complex human metabolic pathways that only function properly when fully satisfied by nutritional inputs. Poor nutritional intakes are associated with a number of metabolic diseases, such as diabetes, obesity, atherosclerosis, hypertension, and osteoporosis. In recent years, nutrition science has undergone an extraordinary transformation driven by the development of innovative software and analytical platforms. However, the complexity and variety of the chemical components present in different food types, and the diversity of interactions in the biochemical networks and biological systems, makes nutrition research a complicated field. Metabolomics science is an "-omic", joining proteomics, transcriptomics, and genomics in affording a global understanding of biological systems. In this review, we present the main metabolomics approaches, and highlight the applications and the potential for metabolomics approaches in advancing nutritional food research.

DNA-Binding and Cytotoxicity of Copper(I) Complexes Containing Functionalized Dipyridylphenazine Ligands.

A set of copper(I) coordination compounds with general formula [CuBr(PPh3)(dppz-R)] (dppz-R = dipyrido[3,2-a:2',3'-c]phenazine (Cu-1), 11-nitrodipyrido[3,2-a:2',3'-c]phenazine (Cu-2), 11-cyanodipyrido[3,2-a:2',3'-c]phenazine (Cu-3), dipyrido[3,2-a:2',3'-c]phenazine-11-phenone (Cu-4), 11,12-dimethyldipyrido[3,2-a:2',3'-c]phenazine (Cu-5)) have been prepared and characterized by elemental analysis, 1H-NMR and 31P-NMR spectroscopies as well as mass spectrometry. The structure of Cu-1 was confirmed by X-ray crystallography. The effect of incorporating different functional groups on the dppz ligand on the binding into CT-DNA was evaluated by absorption spectroscopy, fluorescence quenching of EtBr-DNA adducts, and viscosity measurements. The functional groups affected the binding modes and hence the strength of binding affinities, as suggested by the changes in the relative viscosity. The differences in the quenching constants (Ksv) obtained from the fluorescence quenching assay highlight the importance of the functional groups in altering the binding sites on the DNA. The molecular docking data support the DNA-binding studies, with the sites and mode of interactions against B-DNA changing with the different functional groups. Evaluation of the anticancer activities of the five copper compounds against two different cancer cell lines (M-14 and MCF-7) indicated the importance of the functional groups on the dppz ligand on the anticancer activities. Among the five copper complexes, the cyano-containing complex (Cu-3) has the best anticancer activities.

Alteration of Anticancer and Protein-Binding Properties of Gold(I) Alkynyl by Phenolic Schiff Bases Moieties.

A set of five gold complexes with the general formula Au(PR3)(C≡C-C6H4-4-R') (R = PPh3, R' = -CHO (1), R = PCy3, R' = -CHO (2), R = PPh3, R' = -N=CH-C6H4-2-OH (3), R = PPh3, R' = -N=CH-C6H4-4-OH (4), R = PCy3, R' = -N=CH-C6H4-2-OH (5)) were synthesized and characterized by elemental analysis, 1H-NMR spectroscopy, 31P-NMR spectroscopy, and mass spectrometry. The structures of complexes 2 and 5 were determined by X-ray crystallography. The effects of the structural modifications on the protein binding affinities and anticancer activities of the five gold complexes were assessed. Fluorescence quenching experiments to assess binding to human serum albumin (HSA) revealed that the Schiff base complexes (3, 4, and 5) had binding constants that were superior to their parent aldehyde complexes and highlighted the position of the hydroxy group because complex 4 (4-hydroxy) had a binding constant 6400 times higher than complex 3 (2-hydroxy). The anticancer activities of the complexes against the OVCAR-3 (ovarian carcinoma) and HOP-62 (non-small-cell lung) cancer cell lines showed that the Schiff bases (3-5) were more cytotoxic than the aldehyde-containing complexes (1 and 2). Notably, compound 4 had cytotoxic activity comparable to that of cisplatin against OVCAR-3, demonstrating the significance of the para position for the hydroxy group. Molecular docking studies against the enzyme thioredoxin reductase (TrxR) and human serum albumin were conducted, with docking scores in good agreement with the experimental data. The current study highlights how small structural modifications can alter physiochemical and anticancer properties. Moreover, this simple design strategy using the aldehyde group can generate extensive opportunities to explore new gold(I)-based anticancer drugs via condensation, cyclization, or nucleophilic addition reactions of the aldehyde.

Extraction, Characterization, and Anticoagulant Activity of a Sulfated Polysaccharide from Bursatella leachii Viscera.

Bioactive compounds for drug discovery are increasingly extracted and purified from natural sources including marine organisms. Heparin is a therapeutic agent that has been used for several decades as an anticoagulant. However, heparin is known to cause many undesirable complications such as thrombocytopenia and risk of hemorrhage. Hence, there is a need to find alternatives to current widely used anticoagulant drugs. Here, we extract a sulfated polysaccharide from sea hare, that is, Bursatella leachii viscera, by enzymatic digestion. Several analytical approaches including elemental analysis, Fourier-transform infrared spectroscopy, nuclear magnetic resonance, and high-performance liquid chromatography-mass spectrometry analysis show that B. leachii polysaccharides have chemical structures similar to glycosaminoglycans. We explore the anticoagulant activity of the B. leachii extract using the activated partial thromboplastin time and the thrombin time. Our results demonstrate that the extracted sulfated polysaccharide has heparin-like anticoagulant activity, thus showing great promise as an alternative anticoagulant therapy.

WMSS: A Web-Based Multitiered Surveillance System for Predicting CLABSI.

Central-line-associated bloodstream infection (CLABSI) rates are a key quality metric for comparing hospital quality and safety. Manual surveillance systems for CLABSIs are time-consuming and often limited to intensive care units (ICUs). A computer-automated method of CLABSI detection can improve the validity of surveillance. A new web-based, multitiered surveillance system for predicting and reducing CLABSI is proposed. The system has the capability to collect patient-related data from hospital databases and hence predict the patient infection automatically based on knowledge discovery rules and CLABSI decision standard algorithms. In addition, the system has a built-in simulator for generating patients' data records, when needed, offering the capability to train nurses and medical staff for enhancing their qualifications. Applying the proposed system, both CLABSI rates and patient treatment costs can be reduced significantly. The system has many benefits, among which there is the following: it is a web-based system that can collect real patients' data from many IT resources using iPhone, iPad, laptops, Internet, scanners, and hospital databases. These facilities help to collect patients' actual data quickly and safely in electronic format and hence predict CLABSI efficiently. Automation of the patients' data diagnosis process helps in reducing CLABSI detection times. The system is multimedia-based; it uses text, colors, and graphics to enhance patient healthcare report generation and charts. It helps healthcare decision makers to review and approve policies and surveillance plans to reduce and prevent CLABSI.

Female urothelial cell carcinoma in a failed kidney graft of a male recipient.

We present a case of a male kidney transplant patient harbouring two kidney grafts of which one is functional. In the failed graft, he developed urothelial cell carcinoma with cells containing XX-chromosome, and female tumour cells were also found in the bladder. The patient underwent donor nephrectomy, was treated with epirubicin bladder instillations, and immunosuppression was tapered. Less than a year before re-transplantation a CT scan showed no abnormalities of the first graft. Transplantectomy before a second kidney transplantation is debated.

Improving Prediction Accuracy of "Central Line-Associated Blood Stream Infections" Using Data Mining Models.

Prediction of nosocomial infections among patients is an important part of clinical surveillance programs to enable the related personnel to take preventive actions in advance. Designing a clinical surveillance program with capability of predicting nosocomial infections is a challenging task due to several reasons, including high dimensionality of medical data, heterogenous data representation, and special knowledge required to extract patterns for prediction. In this paper, we present details of six data mining methods implemented using cross industry standard process for data mining to predict central line-associated blood stream infections. For our study, we selected datasets of healthcare-associated infections from US National Healthcare Safety Network and consumer survey data from Hospital Consumer Assessment of Healthcare Providers and Systems. Our experiments show that central line-associated blood stream infections (CLABSIs) can be successfully predicted using AdaBoost method with an accuracy up to 89.7%. This will help in implementing effective clinical surveillance programs for infection control, as well as improving the accuracy detection of CLABSIs. Also, this reduces patients' hospital stay cost and maintains patients' safety.

Sample collection and preparation of biofluids and extracts for gas chromatography-mass spectrometry.

To maximize the utility of gas chromatography-mass spectrometry (GC-MS) in metabonomics research, all stages of the experimental design should be standardized, including sample collection, storage, preparation, and sample separation. Moreover, the prerequisite for any GC-MS analysis is that a compound must be volatile and thermally stable if it is to be analyzed using this technique. Since many metabolites are nonvolatile and polar in nature, they are not readily amenable to analysis by GC-MS and require initial chemical derivatization of the polar functional groups in order to reduce the polarity and to increase the thermal stability and volatility of the analytes. In this chapter, an overview is presented of the optimum approach to sample collection, storage, and preparation for gas chromatography-mass spectrometry-based metabonomics with particular focus on urine samples as example of biofluids.

Gas chromatography-mass spectrometry of biofluids and extracts.

Gas chromatography-mass spectrometry (GC-MS) has been widely used in metabonomics analyses of biofluid samples. Biofluids provide a wealth of information about the metabolism of the whole body and from multiple regions of the body that can be used to study general health status and organ function. Blood serum and blood plasma, for example, can provide a comprehensive picture of the whole body, while urine can be used to monitor the function of the kidneys, and cerebrospinal fluid (CSF) will provide information about the status of the brain and central nervous system (CNS). Different methods have been developed for the extraction of metabolites from biofluids, these ranging from solvent extracts, acids, heat denaturation, and filtration. These methods vary widely in terms of efficiency of protein removal and in the number of metabolites extracted. Consequently, for all biofluid-based metabonomics studies, it is vital to optimize and standardize all steps of sample preparation, including initial extraction of metabolites. In this chapter, recommendations are made of the optimum experimental conditions for biofluid samples for GC-MS, with a particular focus on blood serum and plasma samples.

The strengths and weaknesses of NMR spectroscopy and mass spectrometry with particular focus on metabolomics research.

Mass spectrometry (MS) and nuclear magnetic resonance (NMR) have evolved as the most common techniques in metabolomics studies, and each brings its own advantages and limitations. Unlike MS spectrometry, NMR spectroscopy is quantitative and does not require extra steps for sample preparation, such as separation or derivatization. Although the sensitivity of NMR spectroscopy has increased enormously and improvements continue to emerge steadily, this remains a weak point for NMR compared with MS. MS-based metabolomics provides an excellent approach that can offer a combined sensitivity and selectivity platform for metabolomics research. Moreover, different MS approaches such as different ionization techniques and mass analyzer technology can be used in order to increase the number of metabolites that can be detected. In this chapter, the advantages, limitations, strengths, and weaknesses of NMR and MS as tools applicable to metabolomics research are highlighted.