Multi-objective home health care routing: a variable neighborhood search method.

Health and convenience are two indispensable indicators of the society promotion. Nowadays, to improve community health levels, the comfort of patients and those in need of health services has received much attention. Providing Home Health Care (HHC) services is one of the critical issues of health care to improve the patient convenience. However, manual nurse planning which is still performed in many HHC institutes results in a waste of time, cost, and ultimately lower efficiency. In this research, a multi-objective mixed-integer model is presented for home health care planning so that in addition to focusing on the financial goals of the institution, other objectives that can help increase productivity and quality of services are highlighted. Therefore, four different objectives of the total cost, environmental emission, workload balance, and service quality are addressed. Taking into account medical staff with different service levels, and the preferences of patients in selecting a service level, as well as different vehicle types, are other aspects discussed in this model. The epsilon-constraint method is implemented in CPLEX to solve small-size instances. Moreover, a Multi-Objective Variable Neighborhood Search (MOVNS) composed of nine local neighborhood moves is developed to solve the practical-size instances. The results of the MOVNS are compared with the epsilon-constraint method, and the strengths and weaknesses of the proposed algorithm are demonstrated by a comprehensive sensitivity analysis. To show the applicability of the algorithm, a real example is designed based on a case study, and the results of the algorithm over real data are evaluated.

Destructive effect of anticancer oxali-palladium on heme degradation through the generation of endogenous hydrogen peroxide.

The interaction between human hemoglobin (Hb) and oxali-palladium was studied using different spectroscopic methods of UV-vis, fluorescence, circular dichroism (CD), and chemiluminescence at two temperatures of 25 and 37°C. The experimental results showed that both dynamic and static quenching is occurred simultaneously when oxali-palladium quenches the fluorescence of Hb. According to the fluorescence quenching method, the binding site number, apparent binding constant, and corresponding thermodynamic parameters were measured at two temperatures. The values of ΔH°, ΔS°, and ΔG° indicate that process of the formation of oxali-palladium-Hb complex is a spontaneous interaction procedure in which electrostatic interaction plays a major role. In addition, UV-vis and CD results showed that the addition of oxali-palladium changes the conformation of Hb. To evaluate the functional changes of Hb via destruction of the heme structure, fluorescence studies were performed. The results demonstrated that two fluorescent heme degradation products are found during the interaction of oxali-palladium with Hb. Also, the amount of hydrogen peroxide produced in the solution of Hb due to the interaction of oxali-palladium with Hb using chemiluminescence method indicated heme degradation in the protein is occurred. Structural and functional changes induced in Hb via heme degradation are considered as side effects of this synthesized anticancer drug.

Inhibitory effects of deferasirox on the structure and function of bovine liver catalase: a spectroscopic and theoretical study.

Deferasirox (DFX), as an oral chelator, is used for treatment of transfusional iron overload. In this study, we have investigated the effects of DFX as an iron chelator, on the function and structure of bovine liver catalase (BLC) by different spectroscopic methods of UV-visible, fluorescence, and circular dichroism (CD) at two temperatures of 25 and 37 °C. In vitro kinetic studies showed that DFX can inhibit the enzymatic activity in a competitive manner. KI value was calculated 39 nM according to the Lineweaver-Burk plot indicating a high rate of inhibition of the enzyme. Intrinsic fluorescence data showed that increasing the drug concentrations leads to a significant decrease in the intrinsic emission of the enzyme indicating a significant change in the three-dimensional environment around the chromophores of the enzyme structure. By analyzing the fluorescence quenching data, it was found that the BLC has two binding sites for DFX and the values of binding constant at 25 and 37 °C were calculated 1.7 × 10(7) and 3 × 10(7) M(-1), respectively. The static type of quenching mechanism is involved in the quenching of intrinsic emission of enzyme. The thermodynamic data suggest that hydrophobic interactions play a major role in the binding reaction. UV-vis spectroscopy results represented the changes in tryptophan (Trp) absorption and Soret band spectra, which indicated changes in Trp and heme group position caused by the drug binding. Also, CD data represented that high concentrations of DFX lead to a significant decreasing in the content of ß-sheet and random coil accompanied an increasing in α-helical content of the protein. The molecular docking results indicate that docking may be an appropriate method for prediction and confirmation of experimental results and also useful for determining the binding mechanism of proteins and drugs. According to above results, it can be concluded that the DFX can chelate the Fe(III) on the enzyme active site leading to changes in the function and structure of catalase which can be considered as a side effect of this drug and consequently has an important role in hepatic complications and fibrosis.

Binding studies of a novel antitumor palladium(II) complex to calf thymus DNA.

The interaction of new 1, 10-phenanthrolineoctyldithiocarbamatopalladium (II) nitrate with DNA from calf thymus was investigated at 300 and 310 K in a Tris-HCl buffer of pH 7.0 medium containing 20 mM sodium chloride. This water soluble, square planar Pd(II) complex has been synthesized and spectroscopic (electronic, infrared, and nuclear magnetic resonance) and elemental analysis of the complex are discussed. This complex shows greater growth inhibitory activity against human tumor cell line K562 than cisplatin. Results of UV-visible studies show that the complex exhibits cooperative binding with DNA and denatures the DNA at an extremely low concentration (∼11.98 µM). Fluorescence studies reveal that the mode of binding of this complex with DNA seems to be intercalation. The results of sephadex G-25 column show that the binding of metal complex with DNA is so strong that it does not readily break. Several binding and thermodynamic parameters are also described. They may shed light on the mechanisms of interaction of this agent with DNA, which should be quite different from that of cisplatin.

Study on interaction of DNA from calf thymus with 1,10-phenanthrolinehexyldithiocarbamatopalladium(II) nitrate as potential antitumor agent.

A novel palladium(II) complex has been synthesized with hexyldithiocarbamate (Hex-dtc) and 1,10-phenanthroline (phen) by the reaction of [Pd(phen)(H(2)O)(2)](NO(3))(2) with sodium salt of hexyldithiocarbamate and a complex of type [Pd(Hex-dtc) (phen)]NO(3) has been obtained. The complex has been characterized by elemental analysis, molar conductance, (1)H NMR, IR and electronic spectroscopic studies. The dithiocarbamate ligand acts in bidentate fashion. This water-soluble complex was screened against chronic myelogenous leukemia cell line, K562, for cytotoxic effects and showed significant antitumor activity much lower than that of cisplatin. The interaction of this complex with calf thymus DNA (ctDNA) was extensively investigated by a variety of spectroscopic techniques. Absorbance titration experiments imply the interaction of 4 Pd(II) complex molecules per 1000 nucleotides on DNA with positive cooperativity in the binding process and the complex denature the DNA at very low concentration (~14.3 µM). Fluorescence titration spectra and fluorescence Scatchard plots suggest that the Pd(II) complex intercalate in DNA. The gel chromatograms obtained from Sephadex G-25 column experiments showed that the binding of metal complex with DNA is so strong that it does not readily break. Furthermore, some thermodynamic and binding parameters found in the process of UV-Visible studies are described. They may provide specificity of the compound with ctDNA.

The effects of deferiprone and deferasirox on the structure and function of beta-thalassemia hemoglobin.

Transfusional iron overload is a major cause of morbidity and mortality in thalassemia, sickle-cell disease and other chronic anemias. To overcome these problems, orally bio available iron chelators, deferiprone and deferasirox, were used for the treatment of patients suffering from thalassemia. The interactions between deferiprone and deferasirox with the carrier protein, beta-thalassemia hemoglobin (Hb), were investigated using fluorescence, circular dichroism (CD) and UV-visible measurements at physiological condition. Strong fluorescence quenching on interactions of the above drugs with beta-thalassemia Hb were observed. Fluorescence quenching data of thalassemia Hb in the presence of deferasirox have shown greater affinity of binding. The number of binding sites to Hb for deferasirox was found to be more relative to those of the deferiprone. The effects of these drugs on the oxygen affinity of the thalassemia Hb were studied by spectroscopic methods using sodium dithionite. Results indicated that deferiprone reduces oxygen affinity (increases oxygen releasing ability) of Hb, while in the presence of deferasirox, oxygen affinity of Hb has significantly increased by dose-dependent manner. As such, deferasirox exhibited opposite effect relative to deferiprone on the function of thalassemia Hb. In clinical dose of deferiprone, CD results showed that, the alpha-helical content of thalassemia Hb significantly increased. By use of the clinical dose of deferasirox, however, a decrease in alpha-helical content of protein was observed, which resulted in decreasing stability of thalassemia Hb. Our study showed that reduction in stability of thalassemia Hb in the presence of deferasirox induced higher conformational changes in protein.

Diimine platinum(II) and palladium(II) complexes of dithiocarbamate derivative as potential antitumor agents: synthesis, characterization, cytotoxicity, and detail dna-binding studies.

The synthesis and chemical characterization of two structurally related platinum(II) and palladium(II) complexes, [M(2,2'-bipyridine)(morpholinedithiocarbamate)]NO(3) or [M(bpy)(mor-dtc)]NO(3), where M = Pt(II) or Pd(II), are described. Studies of anti-tumor activities of these complexes against human cell tumor lines (K(562)) have been carried out. They show 50% cytotoxic concentration (Cc(50)) values much lower than that of cisplatin. Both of these water soluble complexes have been shown to interact with calf thymus DNA (ct-DNA) using difference absorption-, fluorescence-, and circular dichroism-titration techniques. These studies showed that both complexes exhibit cooperative binding and presumably intercalate in DNA. These complexes unexpectedly denature DNA at very low concentrations (50-100 microM). Several binding and thermodynamic parameters are also described.

Thermodynamic study of the binding of calcium and magnesium ions with myelin basic protein using the extended solvation theory.

The interaction of myelin basic protein (MBP) from the bovine central nervous system with Ca2+ and Mg2+ ions, named as M2+, was studied by isothermal titration calorimetry at 27 degrees C in aqueous solution. The extended solvation model was used to reproduce the enthalpies of MBP+M2+ interactions. The solvation parameters recovered from the extended solvation model were attributed to the structural change of MBP due to the metal ion interaction. It was found that there is a set of two identical and noninteracting binding sites for Ca2+ and Mg2+ ions.

Interaction of bovine serum albumin with some novel PEG-containing diblock copolymers.

A comparative study on the interaction of different PEG-containing diblock copolymers including SA400, SA600, SA1500 and OA1500 (stearyl and oleyl esters of polyethylene glycol with 400, 600 and 1500 molecular weights, respectively) with bovine serum albumin (BSA) was carried out using isothermal titration calorimetry (ITC), attenuated total reflectance Fourier transform infrared (ATR-FTIR), circular dichroism (CD), and fluorescence spectroscopies. ITC data show that SA400, SA600, SA1500 and OA1500 bind to BSA, with association constants of (14.5, 3.16, 50.7 and 17.6)x10(3) M(-1), respectively. Results also show that the binding is enthalpically driven, disfavored by conformational entropy. Quantitative analysis of the FTIR absorbance spectra at amide I' (1600-1700 cm(-1)) as well as far UV circular dichroism data show that these polymers do not disturb the BSA structure and only cause a slight increment in helicity along with a slight decrease in the beta-structure. Only stearyl esters SA400 and SA1500 slightly decreased the random structure content of the BSA. The diblock copolymers inhibit protein aggregation and bind to BSA better than their constituent PEGs causing an increment in its Tm; SA1500 is showing the strongest effect.

Binding properties of a new anti-tumor component (2,2'-bipyridin octylglycinato Pd(II) nitrate) with bovine beta-lactoglobulin-A and -B.

An new water soluble palladium (II) complex of formula [Pd(bpy)(Oct-Gly)]NO(3), (where bpy is 2,2'-bipyridine and Oct-Gly is octylglycine) have been synthesised. The Pd(II) complex has been characterized by elemental analysis and conductivity measurements as well as spectroscopic methods such as infrared, (1)H NMR, and ultraviolet-visible. The interaction between the new Pd(II)-complex (2,2'-bipyridin octylglycinato Pd(II) nitrate), an anti-tumor component, with beta-lactoglobulin-A and -B (BLG-A and -B) was studied by fluorescence spectroscopy and far and near-UV circular dichroism (CD) spectrophotometric techniques. A strong fluorescence quenching interaction of Pd(II) complex with BLG-A and -B was observed. The quenching constant was determined using the modified Stern-Volmer equation. The calculated binding constants of Pd(II) complex with BLG-A and -B were 0.51 and 0.28 (x 10(6) M(-1)) and the corresponding average number of binding sites were 2.8 and 1.5, respectively. Far-UV CD studies showed that the Pd(II) complex can significantly change the secondary structure of BLG-A and -B via an increase in the content of alpha-helix structure, which stabilizes the secondary structure of the proteins. Near-UV CD data clearly indicate the alteration in the tertiary structure of BLG-A and -B due to the interaction with Pd(II) complex. Pd(II) complex can change and stabilize both the secondary and tertiary structures of BLG-A more than BLG-B. These conformational changes may be considered to be a deleterious effect of the designed ligand on the protein structures. The difference in the interaction properties observed for BLG-A and -B with Pd(II) complex is due to the difference in the amino acid sequences between these two variants.

Spectroscopic and cytotoxic studies of the novel designed palladium(II) complexes: beta-lactoglobulin and K562 as the targets.

Since palladium complexes have been reported to show fewer side effects relative to other heavy metal anticancer compounds, in this study a new class of four structurally related anticancer Pd(II) complexes including 2,2'-bipyridin-n-butyl dithiocarbamato Pd(II) nitrate (Com-1), 2,2'-bipyridin-n-hexyl dithiocarbamato Pd(II) nitrate (Com-2), 2,2'-bipyridin glycinato Pd(II) nitrate (Com-3) and 2,2'-bipyridin octylglycinato Pd(II) nitrate (Com-4) was designed. The effect of four synthesized ligands on the protein structure and cell proliferation were investigated. Whey carrier proteins beta-lactoglobulin-A and-B (BLG-A and-B) and chronic myelogenous leukemia cell line K562 were the targets. Fluorescence and CD instruments were used to assess effect of the ligands on the protein structure. Growth inhibitory effect of the Pd(II) complexes towards the cancer cells was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Results of fluorescence studies revealed that the complexes had no dithiocarbamate moiety (compounds 3 and 4) could quench the intrinsic fluorescence emission of the proteins at lower concentrations than those had such moiety (compounds 1 and 2). The far-UV-CD studies revealed that the regular secondary structure of BLG-A and -B did not show any noticeable alteration upon interaction with different of Pd(II)-complexes. The results of cell proliferation assay also displayed that Com-1 and Com-2 had more growth inhibitory activity against K562, than Com-3 and Com-4. Our results suggested that addition of dithiocarbamate moiety to structure of Pd(II) complexes probably has important role to improve the antiproliferative properties of the anticancer ligands and fewer effects on the carrier protein structure.

Conformational and structural analysis of bovine beta lactoglobulin-A upon interaction with Cr+3.

Thermodynamic studies have been made on the effect of Cr(+3) on the conformation and structure of bovine beta lactoglobulin-A, (Blg-A) in 50 mM sodium chloride solution at 27 degrees C using isothermal titration calorimetry (ITC), circular dichroism (CD) and fluorescence spectroscopy. There is a set of six identical and independent binding sites for Cr(+3) by a dissociation binding constant of 124 microM and the molar enthalpy of binding -17.8 kJ/mol. Circular dichroism studies do not show any significant change in the secondary structure of the protein after the binding of chromium ion on the Blg-A. Fluorescence spectroscopy studies do not show any considerable change in the tertiary structure of Blg-A due to the increasing of Cr(+3) in low concentration. However, occupation of fourth and fifth binding sites for chromium ions induce partially unfolding in the tertiary structure of the protein resulted from solvent - exposed hydrophobic patches on BLG-A.

Comparative analysis of refolding of chemically denatured beta-lactoglobulin types A and B using the dilution additive mode.

The kinetic refolding of beta-lactoglobulin (BLG), types A and B, by beta-cyclodextrin, glucose and sorbitol has been investigated in aqueous solution using fluorescence, far UV-CD and UV-spectrophotometric techniques. A new Pd-complex has been used to denature the protein. CD and fluorescence studies indicated that when incubated with sugar, the denatured BLG is refolded into the native-like structure through the dilution additive mode resulting in a higher yield of active protein than without sugar. CD studies show that these sugars can induce a non-native alpha-helical structure in denatured BLG-A and -B, then aid in the refolding of the protein. Based on the present study, these sugars have a different effect on BLG-A than BLG-B because of their differences in protein thermal stability. BLG-A has a higher thermal stability than BLG-B due to differences in the amino acid sequences.

Kinetic and structural analysis of the inhibition of adenosine deaminase by acetaminophen.

Kinetic and thermodynamic studies have been made on the effect of acetaminophen on the activity and structure of adenosine deaminase in 50 mM sodium phosphate buffer pH 7.5, at two temperatures of 27 and 37 degrees C using UV spectrophotometry, circular dichroism (CD) and fluorescence spectroscopy. Acetaminophen acts as a competitive inhibitor at 27 degrees C (Ki = 126 microM) and an uncompetitive inhibitor at 37 degrees C (Ki = 214 microM). Circular dichroism studies do not show any considerable effect on the secondary structure of adenosine deaminase by increasing the temperature from 27 to 37 degrees C. However, the secondary structure of the protein becomes more compact at 37 degrees C in the presence of acetaminophen. Fluorescence spectroscopy studies show considerable change in the tertiary structure of the protein by increasing the temperature from 27 to 37 degrees C. Also, the fluorescence spectrum of the protein incubated with different concentrations of acetaminophen show different inhibition behaviors by the effector at the two temperatures.

Inhibition study of adenosine deaminase by caffeine using spectroscopy and isothermal titration calorimetry.

Kinetic and thermodynamic studies were made on the effect of caffeine on the activity of adenosine deaminase in 50 mM sodium phosphate buffer, pH 7.5, using UV spectrophotometry and isothermal titration calorimetry (ITC). An uncompetitive inhibition was observed for caffeine. A graphical fitting method was used for determination of binding constant and enthalpy of inhibitor binding by using isothermal titration microcalorimetry data. The dissociation-binding constant is equal to 350 microM by the microcalorimetry method, which agrees well with the value of 342 microM for the inhibition constant that was obtained from the spectroscopy method. Positive dependence of caffeine binding on temperature indicates a hydrophobic interaction.