Unveiling multifunctional inhibitors: holistic spectral, electronic and molecular characterization, coupled with biological profiling of substituted pyridine derivatives against LD transpeptidase, heme oxygenase and PPAR gamma.

This study delves into the therapeutic potential of a molecule, 3-substituted phenyl-1-(pyridine-4-carbonyl)-1H-pyrazole-4-carboxylic acid (PPP), for antimicrobial, antioxidant and anti-diabetic activities. The research encompasses design, synthesis, molecular docking and biological screening of related pyrazole carboxylic acid derivatives. Spectral studies confirmed the structures and molecular mechanics with DFT calculations provided insights into molecular properties and interactions. Quantum chemical descriptors were employed to assess the stability while NBO analysis predicted reactivity, ELF and LOL methods identified electron density. Non-covalent interactions were characterized using RDG and IRI, while the Multiwfn tool was used to evaluate intra and intermolecular aspects. Docking studies elucidated potential therapeutic efficacy against specific protein targets.

Design, Transport/Molecular Scale Electronics, Electric Properties, and a Conventional Quantum Study of a New Potential Molecular Switch for Nanoelectronic Devices.

In this study, we examined the influence of an external electric field applied in two directions: horizontal (X-axis) and vertical (Y-axis) on the electronic and vibrational properties of a field-effect molecular switch, denoted as M. We employed density functional theory and quantum theory of atoms in molecules for this analysis. The current-voltage (I-V) characteristic curve of molecular switch system M was computed by applying the Landauer formula. The results showed that the switching mechanism depends on the direction of the electric field. When the electric field is applied along the X-axis and its intensity is around 0.01 au, OFF/ON switching mechanisms occur. By utilizing electronic localization functions and localized-orbital locator topological analysis, we observed significant intramolecular electronic charge transfer "back and forth" in Au-M-Au systems when compared to the isolated system. The noncovalent interaction revealed that the Au-M-Au complex is also stabilized by electrostatic interactions. However, if the electric field is applied along the Y-axis, a switching mechanism (OFF/ON) occurs when the electric field intensity reaches 0.008 au. Additionally, the local electronic phenomenological coefficients (Lelec) of this field-effect molecular switch were determined by using the Onsager phenomenological approach. It can also be predicted that the molecular electrical conductance (G) increases as Lelec increases. Finally, the electronic and vibrational properties of the proposed models M and Au-M-Au exhibit a powerful switching mechanism that may potentially be employed in a new generation of electronic devices.

Ternary Mixture of Pentanamide in Solvent Analogy with Halogenated Phenol: Experimental, Theoretical, and In Silico Biological Studies.

This research describes the preparation of mixtures of new halogen-substituted phenol derivatives and their effects due to linkages with a fatty amide (pentanamide). The molecules were optimized using DFT, and the vibrational and electronic analysis was done subsequently. The energies of frontier molecular orbitals (FMOs) were used to estimate the global chemical reactivity parameters as we suggest that hydrogen-bonded networks may have contributed to the stability and reactivity of the compound. In addition to the experimental investigation, dielectric parameters were calculated. Fukui functions were analyzed to study the chemical reactivity. To get insight into interactions of σ → π* orbitals, natural bond orbital calculations were done. Additionally, surface analysis of the MEP and Hirshfeld charges were performed at the equivalent DFT levels. The research also indicated that both (interaction region indicator) IRI and (electron delocalize range) EDR would proficiently identify chemical-bonding and weak interaction regions, providing a significant advantage in exploring diverse chemical systems and reactions. This indicated that compounds could diffuse through noncovalent interactions, including intramolecular hydrogen bonding. Dielectric relaxation studies taken at five distinct molar ratios identified significant dielectric properties such as ε', ε″, ε0, and ε∞. The PA with FP, CP, BP, and IP molecules has potential antiviral and antioxidant benefits for carbonic anhydrase, with favorable drug-like features and diverse biological benefits. Pharmacological effects were forecasted using the PASS server, and these molecules exhibited favorable pharmacokinetic properties.

Blood Glucose Regulation for Post-Operative Patients with Diabetics and Hypertension Continuum: A Cascade Control-Based Approach.

Management of glycemic level in post-operative condition is critical for hypertensive patients and the post-operative stress may results in hyperglycemia, hyper insulin and osmotic diuresis. Recent medical research shows that diabetic and hypertension hands together in a significant overlap in its etiology and its disease mechanism. It is clear that there is a call for monitoring in the parameter and controlling the glucose level particularly in the presence of hypertension. This paper proposes the novel complex (cascade) control system to control the insulin infusion level particularly in the presence of hypertension. Based on the requirements the structure has been designed and the simulation results indicates that the proposed control strategy shows better results and may achieve potentially better glycemic control to the hypersensitive diabetic patients.

Evolution of blood pressure control identification in lieu of post-surgery diabetic patients: a review.

The blood pressure disparity is the major problem in post-operative surgery especially diabetic patients, because there is substantial interrelation between diabetic and hypertension and this abnormality creates complicated problems and needs to be controlled by continuous monitoring based on the severity. To overcome this problem, implementation of automatic drug infusion is required for critical patients, by which workload of the clinical staffs are reduced. Most commonly the sodium nitroprusside (SNP) is used to reduce the blood pressure in fast action based on the prescribed level. In this paper three different types of estimation techniques (PID, IMC and MPC) are uses to identify the valuation. The strength of the projected controller performance is evaluated under different types of patients such as sensitive, and normal along with insensitive patients. Therefore, this paper review the validation results based on the optimized SNP infusion rate for persistent Blood pressure control compare then the reviewed methods. The MATLAB simulation is used to evaluate the efficiency of the proposed work and obtain the results based on the projected values.

Delivery of viral recombinant VP28 protein using chitosan tripolyphosphate nanoparticles to protect the whiteleg shrimp, Litopenaeus vannamei from white spot syndrome virus infection.

The VP28 gene of white spot syndrome virus was amplified by PCR using gene specific primer set and cloned into pRSET B vector to produce recombinant VP28 (r-VP28) in E. coli GJ1158. The chitosan tripolyphosphate nanoparticles (CS/TPP) were prepared by ionic gelation process and characterized. The purified r-VP28 protein was encapsulated by CS/TPP nanoparticles. The encapsulation efficiency of CS/TPP nanoparticles was found to be 84.8% for r-VP28 protein binding with CS/TPP nanoparticles. The in vitro release profile of encapsulated r-VP28 was determined after treating with protease and chitosanase. The different types of feed were formulated and named as normal feed with PBS, Feed A coated with crude r-VP28, Feed B with purified r-VP28 and Feed C with CS/TPP encapsulated r-VP28 (Purified). Tissue distribution and clearance of r-VP28 at different time intervals were examined in shrimp fed with different types of feed by ELISA and the results showed the presence of r-VP28 protein in different organs. Various immunological parameters were assessed in experimental shrimp. The mRNA expression of five immune-related genes was analysed by qPCR in order to investigate their response to all types of feed in shrimp. A cumulative percentage mortality was also recorded in treated shrimp challenged with WSSV.

The deconvolution of thermoluminescence glow-curves using general expressions derived from the one trap-one recombination (OTOR) level model.

The new developed thermoluminescence (TL) glow-peak expressions derived from the one trap-one recombination (OTOR) level model were used to analyze the TL glow-curves recorded with linear and exponential heating function profiles under various experimental conditions. The results showed that these expressions can, accurately, analyze the TL glow-curves even with the overlapped glow-peaks. Low values of R=An/Am were reported for glow-peaks in different TL materials. A glow-peak with the possibility of An>Am was also pointed out.

Organo-functionalized metal-oxide clusters: synthesis and characterization of the reduced cationic species [NaV(IV)6O6{(OCH2CH2)2NH}6]+.

A new heteropolyoxovanadium compound, [NaV6O6{(OCH2CH2)2NH}6]·(OH)0.5Cl0.5·3(H2O), was synthesized and characterized by single-crystal X-ray diffraction analysis, cyclic voltammetry, FTIR and UV-vis spectroscopy, and TGA. [NaV6O6{(OCH2CH2)2NH}6]·(OH)0.5Cl0.5·3(H2O) contains the diethanolamine functionalized oxovanadium cationic cluster, [NaV(IV)6O6{(OCH2CH2)2NH}6](+). The cluster cation is composed of a fully reduced cyclic {NaV6N6O18} framework which adopts an Anderson-like structure and is comprised of a ring of six edge-sharing {VO5N} octahedra linked to a central {NaO6} unit. Two (OCH2CH2-) arms of each of the six diethanolamine ligands are incorporated into the oxometalate core. FTIR spectra are consistent with the presence of expected V=Ot stretching modes and functionalization with diethanolamine. Electrochemical and UV-vis absorption properties are consistent with two distinct MLCT processes: the characteristic V=Ot dπ-pπ interaction, and a second process occurring through the hydrogen-terminated nitrogen atoms (V-N-H) of the octahedra forming the cyclic {NaV6N6O18} core.

Protective effect of light emitting diode phototherapy on fluorescent light induced retinal damage in Wistar strain albino rats.

BACKGROUND: Artificial light at night alters retinal physiology. Several studies have shown that light emitting diode phototherapy protects the retina from the damaging effects of acute light exposure. OBJECTIVE: The aim of this study has been to elucidate the protective effects of 670 nm LED light on retinal damage induced by chronic fluorescent light in Wistar rats. METHODS: Male Wistar albino rats were divided into four groups: group 1 were control (CL), group 2, 3 and 4 were exposed to fluorescent light (FL), LED preexposure+fluorescent light exposure (LL) and only LED light exposure (OL) respectively. All animals were maintained in their specific exposure regime for 30 days. Fluorescent light of 1800 lx was exposed between 8 pm to 8 am. Rats were exposed to therapeutic LED light of 670 nm of 9 J/cm2 at 25 mW/cm2 for 6 min duration. Histopathological changes in the retina were studied. RESULTS: Animals of the FL group showed a significant reduction in the outer nuclear layer thickness and cell count in addition to the total thickness of the retina. LL group which were exposed to 670 nm LED prior to exposure to fluorescent light showed a significant decrease in the degree of damage. CONCLUSIONS: 670 nm LED light preexposure is protective to retinal cells against fluorescent light-induced damage.

Neutralization of cobra venom by cocktail antiserum against venom proteins of cobra (Naja naja naja).

Naja naja venom was characterized by its immunochemical properties and electrophoretic pattern which revealed eight protein bands (14 kDa, 24 kDa, 29 kDa, 45 kDa, 48 kDa, 65 kDa, 72 kDa and 99 kDa) by SDS-PAGE in reducing condition after staining with Coomassie Brilliant Blue. The results showed that Naja venom presented high lethal activity. Whole venom antiserum or individual venom protein antiserum (14 kDa, 29 kDa, 65 kDa, 72 kDa and 99 kDa) of venom could recognize N. naja venom by Western blotting and ELISA, and N. naja venom presented antibody titer when assayed by ELISA. The neutralization tests showed that the polyvalent antiserum neutralized lethal activities by both in vivo and in vitro studies using mice and Vero cells. The antiserum could neutralize the lethal activities in in-vivo and antivenom administered after injection of cobra venom through intraperitoneal route in mice. The cocktail antiserum also could neutralize the cytotoxic activities in Vero cell line by MTT and Neutral red assays. The results of the present study suggest that cocktail antiserum neutralizes the lethal activities in both in vitro and in vivo models using the antiserum against cobra venom and its individual venom proteins serum produced in rabbits.

Clearance of Macrobrachium rosenbergii nodavirus (MrNV) and extra small virus (XSV) and immunological changes in experimentally injected Macrobrachium rosenbergii.

Macrobrachium rosenbergii was experimentally challenged with Macrobrachium rosenbergii nodavirus (MrNV) and extra small virus (XSV) to study the clearance of these viruses and consequent changes in various immunological parameters. The healthy animals were injected MrNV and XSV intramuscularly and various organ samples such as gill tissue, head soft tissue, pleopods and intestine were collected at different time intervals of 3, 5, 10, 15, 25, 50, 75 and 100d post-infection (p.i.) to study the viral clearance. Tissue tropism and clearing of MrNV and XSV were confirmed by RT-PCR, nested RT-PCR and bioassay. These 2 viruses failed to cause mortality or clinical signs of disease in injected adult prawns during the experimental period of 100 days. The result of RT-PCR analysis revealed that all the organs showed positive for both viruses by single step RT-PCR on 3, 5 and 10 d p.i., positive by nested RT-PCR on 15 and 20 d p.i. and all the organs became negative at 25 d p.i. onwards. The viral inoculum prepared from the tissue of MrNV and XSV-injected M. rosenbergii at 3, 5, 10, 15 and 20 d p.i. caused 100% mortality in post-larvae of M. rosenbergii at 9, 8, 7, 10 and 10 d p.i., respectively whereas the inoculum prepared at 25, 50 and 100 d p.i. failed to cause significant mortality in post-larvae of prawn. Immunological parameters such as proPO, superoxide anion, SOD, THC, clotting time and oxyhemocyanin were determined in MrNV and XSV-injected prawns and significant differences in some of the immunological parameters were found in the early days p.i. and became insignificant in the later days p.i.

Clearance of white spot syndrome virus (WSSV) and immunological changes in experimentally WSSV-injected Macrobrachium rosenbergii.

A time course experimental challenge of WSSV was carried out to examine the clearance of WSSV in Macrobrachium rosenbergii and the consequent immunological changes. The experimental animals were injected with WSSV and the samples of gills, pleopods, head soft tissue and hemolymph were collected at different intervals of 1, 3, 5, 10, 25, 50, 75 and 100 days post infection (p.i.). WSSV infection and clearing were confirmed by single step PCR, nested PCR and bioassay. At 3 days p.i., M. rosenbergii became lethargic and stopped feeding in contrast to the control prawns that behaved and fed normally. However, the WSSV-injected prawns suffered no mortality during the experimental period and recovered without any further gross signs of disease or any mortality over a period of 100 days p.i. The single step PCR analysis showed positive at 1, 3 and 5 days p.i. in gills, head soft tissue, pleopods and hemolymph, and all the organs showed negative at 10 days p.i. onwards. The nested PCR results showed that all organs were positive for WSSV from 3 days p.i. and extended up to 25 days p.i. At 50 days p.i, head soft tissue sample alone showed WSSV-positive while all other organs were negative by nested PCR. All the organs at 75 and 100 days p.i. showed nested PCR negative for WSSV as observed in the control prawn. The hemolymph collected from experimentally infected M. rosenbergii at 1, 3 and 5 days p.i. caused 100% mortality at 40 h p.i., 55 h p.i. and 72 h p.i, respectively in Penaeus monodon whereas hemolymph collected at 10, 25, 50, 75 and 100 days p.i. failed to cause mortality in shrimp. The moribund shrimp showed WSSV-positive and surviving shrimp showed negative by PCR. Immunological parameters such as proPO, O(2)(-) and clotting time in WSSV-injected M. rosenbergii were found to be significantly higher than those of the control groups, whereas THC and superoxide dismutase were significantly lower when compared to control groups.

Immunological responses of Penaeus monodon to DNA vaccine and its efficacy to protect shrimp against white spot syndrome virus (WSSV).

White spot disease is an important viral disease caused by white spot syndrome virus (WSSV) and is responsible for huge economic losses in the shrimp culture industry worldwide. The VP28 gene encoding the most dominant envelope protein of WSSV was used to construct a DNA vaccine. The VP28 gene was cloned in the eukaryotic expression vector pcDNA3.1 and the construct was named as pVP28. The protective efficiency of pVP28 against WSSV was evaluated in Penaeus monodon by intramuscular challenge. In vitro expression of VP28 gene was confirmed in sea bass kidney cell line (SISK) by fluorescence microscopy before administering to shrimp. The distribution of injected pVP28 in different tissues of shrimp was studied and the results revealed the presence of pVP28 in gill, head soft tissue, abdominal muscle, hemolymph, pleopods, hepatopancreas and gut. RT-PCR and fluorescence microscopy analyses showed the expression of pVP28 in all these tissues examined. The results of vaccination trials showed a significantly higher survival rate in shrimp vaccinated with pVP28 (56.6-90%) when compared to control groups (100% mortality). The immunological parameters analyzed in the vaccinated and control groups revealed that the vaccinated shrimp showed significantly high level of prophenoloxidase and superoxide dismutase (SOD) when compared to the control groups. The high levels of prophenoloxidase and superoxide dismutase (SOD) might be responsible for developing resistance against WSSV in DNA vaccinated shrimp.

Kidney dimensions at sonography are correlated with glomerular filtration rate in renal transplant recipients and in kidney donors.

The gold standard to assess renal function is the measurement of glomerular filtration rate (GFR). For practical reasons, renal function is often evaluated from serum creatinine (S Cr) or cystatin C (S Cys), and GFR is predicted from SCr. Ultrasound scanning of the kidneys is used only to evaluate renal morphology. The aim of this study was to evaluate the relationship between sonographic renal dimensions and GFR in renal transplant recipients and in kidney donors. GFR (urinary clearance of (99m)Tc-DTPA), S Cr, and S Cys were measured in 33 donors (28 females [F], 5 males [M]; SCr, 0.81-1.90 mg/dL) and 30 recipients (8 F, 22 M; SCr, 0.96-2.42 mg/dL). GFR was also predicted using the Cockcroft and Gault (CG) formula and with the simplified Modification of Diet in Renal Disease (MDRD) formula. Length, width, and depth of kidneys and renal sinus were measured using renal sonography. Among sonographic measurements, kidney length showed the best correlation with GFR. A closer correlation with GFR was found in donors (r = 0.639; P < .00007) than in recipients (r = 0.511; P < .005). In either case, the correlation of kidney length with GFR was greater than that of S Cr or S Cys, and similar to that of CG or MDRD GFR. Accuracy of kidney length as an indicator of GFR impairment was not statistically different from laboratory tests. Only in donors did CG show better accuracy. In conclusion, renal dimensions at sonography closely correlated with GFR. Thus, renal sonography can give information also on the function of the renal graft and of the remaining kidney of living donors.

Symmetrical bis(heteroarylmethoxyphenyl)alkylcarboxylic acids as inhibitors of leukotriene biosynthesis.

Symmetrical bis(quinolylmethoxyphenyl)alkylcarboxylic acids were investigated as inhibitors of leukotriene biosynthesis and 4, 4-bis(4-(2-quinolylmethoxy)phenyl)pentanoic acid sodium salt (47.Na) met our design parameters for a drug candidate (ABT-080). This compound was readily synthesized in three steps from commercially available diphenolic acid. Against intact human neutrophils, 47.Na inhibited ionophore-stimulated LTB(4) formation with an IC(50) = 20 nM. In zymosan-stimulated mouse peritoneal macrophages producing both LTC(4) and PGE(2), 47.Na showed 9000-fold selectivity for inhibition of LTC(4) (IC(50) = 0.16 nM) over PGE(2) (IC(50) = 1500 nM). Preliminary pharmacokinetic evaluation in rat and cynomolgus monkey demonstrated good oral bioavailability and elimination half-lives of 9 and 5 h, respectively. Pharmacological evaluation of leukotriene inhibition with oral dosing was demonstrated in a rat pleural inflammation model (ED(50) = 3 mg/kg) and a rat peritoneal passive anaphylaxis model (LTB(4), ED(50) = 2.5 mg/kg; LTE(4), ED(50) = 1.0 mg/kg). In a model of airway constriction induced by antigen challenge in actively sensitized guinea pigs, 47.Na dosed orally blocked bronchoconstriction with an ED(50) = 0.4 mg/kg, the most potent activity we have observed for any leukotriene inhibitor in this model. The mode of inhibitory action of 47.Na occurs at the stage of 5-lipoxygenase biosynthesis as it blocks both leukotriene pathways leading to LTB(4) and LTC(4) but not PGH(2) biosynthesis. However, 47.Na does not inhibit 5-lipoxygenase catalysis in a broken cell enzyme assay; therefore it is likely that 47.Na acts as a FLAP inhibitor.

3,5-Bis(trifluoromethyl)pyrazoles: a novel class of NFAT transcription factor regulator.

A series of bis(trifluoromethyl)pyrazoles (BTPs) has been found to be a novel inhibitor of cytokine production. Identified initially as inhibitors of IL-2 synthesis, the BTPs have been optimized in this regard and even inhibit IL-2 production with a 10-fold enhancement over cyclosporine in an ex vivo assay. Additionally, the BTPs show inhibition of IL-4, IL-5, IL-8, and eotaxin production. Unlike the IL-2 inhibitors, cyclosporine and FK506, the BTPs do not directly inhibit the dephosphorylation of NFAT by calcineurin.

5-Lipoxygenase inhibitors: synthesis and structure-activity relationships of a series of 1-aryl-2H,4H-tetrahydro-1,2,4-triazin-3-ones.

Synthetic routes were developed to access a variety of novel 1-aryl-2H,4H-tetrahydro-1,2,4-triazin-3-one analogs which were evaluated as 5-lipoxygenase (5-LO) inhibitors. The parent structure, 1-phenylperhydro-1,2,4-triazin-3-one (4), was found to be a selective inhibitor of 5-LO in broken cell, intact cell, and human blood assays with IC50 values of 5-21 microM. In a rat anaphylaxis model, 4 blocked leukotriene formation with an ED50 = 7 mg/kg when administered orally. Compound 4 exhibited selectivity for inhibition of 5-LO with little activity against related enzymes: 12-LO from human platelets, 15-LO from soybean, and cyclooxygenase (COX) from sheep seminal vesicle. In pilot subacute toxicity testing, 4 did not produce methemoglobinemia in rats (400 mg/kg po daily for 9 days) or in dogs (200 mg/kg po daily for 28 days). These results indicated that the triazinone structure provided a 5-LO inhibitor template devoid of the toxicity problems observed in the related phenidone (1) and pyridazinone (3) classes of 5-LO inhibitors. The parent compound 4 is a selective, orally bioavailable 5-LO inhibitor which can serve as a useful reference standard for in vivo pharmacological studies involving leukotriene-mediated phenonmena.

(R)-(+)-N-[3-[5-[(4-fluorophenyl)methyl]-2-thienyl]-1-methyl- 2-propynyl]-N-hydroxyurea (ABT-761), a second-generation 5-lipoxygenase inhibitor.

Structure-activity optimization of inhibitory potency and duration of action of N-hydroxyurea containing 5-lipoxygenase inhibitors was conducted. The lipophilic heteroaryl template and the link group connecting the template to the N-hydroxyurea pharmacophore were modified. Inhibition of 5-lipoxygenase was evaluated in vitro in a human whole blood assay. An in vitro assay using liver microsomes from monkey was used to evaluate congeners for comparative rates of glucuronidation. (3-Heteroaryl-1-methyl-2-propynyl)-N-hydroxyureas were found to be more resistant to in vitro glucuronidation. The promising inhibitor N-[3-[5-(4-fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]-N- hydroxyurea (6) was found to have stereoselective glucuronidation in monkey and man. The R enantiomer 7 provided longer duration of inhibition as evaluated by an ex vivo whole blood assay. Further optimization of the lipophilic template led to the discovery of (R)-(+)-N-[3-[5-[(4-fluorophenyl)methyl]-2- thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (11) with more effective and prolonged inhibition of leukotriene biosynthesis than zileuton (1) and 7 in monkey and man. The optimized 5-lipoxygenase inhibitor 11 was selected for development as an investigational drug for leukotriene-mediated disorders.