Exploring the interaction of a potent anti-cancer drug Selumetinib with bovine serum albumin: Spectral and computational attributes.

The binding of drugs to plasma proteins determines its fate within the physiological system, hence profound understanding of its interaction within the bloodstream is important to understand its pharmacodynamics and pharmacokinetics and thereby its therapeutic potential. In this regard, our work delineates the mechanism of interaction of Selumetinib (SEL), a potent anti-cancer drug showing excellent effect against multiple solid tumors, with plasma protein bovine serum albumin (BSA), using methods such as absorption, steady-state fluorescence, time-resolved, fluorescence resonance energy transfer, Fourier transform infrared spectra (FTIR), circular dichroism (CD), synchronous and 3D-fluorescence, salt fluorescence, molecular docking and molecular dynamic simulations. The BSA fluorescence intensity was quenched with increasing concentration of SEL which indicates interactions of SEL with BSA. Stern-Volmer quenching analysis and lifetime studies indicate the involvement of dynamic quenching. However, some contributions from the static quenching mechanism could not be ruled out unambiguously. The association constant was found to be 5.34 × 105 M-1 and it has a single binding site. The Förster distance (r) indicated probable energy transmission between the BSA and SEL. The positive entropy changes and enthalpy change indicate that the main interacting forces are hydrophobic forces, also evidenced by the results of molecular modeling studies. Conformation change in protein framework was revealed from FTIR, synchronous and 3D fluorescence and CD studies. Competitive binding experiments as well as docking studies suggest that SEL attaches itself to site I (subdomain IIA) of BSA where warfarin binds. Molecular dynamic simulations indicate the stability of the SEL-BSA complex. The association energy between BSA and SEL is affected in the presence of different metals differently.

Intravenous Dexmedetomidine-Ketamine Versus Ketamine-Propofol for Procedural Sedation in Adults Undergoing Short Surgical Procedures: A Randomized Controlled Trial.

Background and objective Moderate to deep sedation is a prerequisite during total intravenous anesthesia for short-duration surgeries, and it can be achieved by using individual drugs or in combination. Our study compared dexmedetomidine-ketamine (DK) versus ketamine-propofol (KP) in terms of sedation, procedural interference, hemodynamics, and incidence of side effects in patients undergoing short surgical procedures. Methods A total of 194 patients scheduled for short-duration elective surgeries were randomly allocated into two groups. Group DK received a loading dose of 1 µg/kg of dexmedetomidine and 1 mg/kg of ketamine followed by a maintenance infusion of dexmedetomidine at 0.3 µg/kg/h. Group KP received a loading dose of 1 mg/kg of ketamine and 1 mg/kg of propofol followed by a maintenance infusion of propofol at 25 µg/kg/h. For procedural interference, a rescue ketamine bolus was administered at 0.25 mg/kg. Patients were monitored for the requirement of rescue ketamine bolus, procedural interference, hemodynamics, sedation, recovery time, and adverse effects. Results The procedural interference was higher in group KP than in group DK and the difference was statistically significant (P=0.001). The time to the first rescue bolus was 8.72 ± 4.47 minutes in group KP and 10.82 ± 4.01 minutes in group DK, with a difference of 2.1 minutes (p=0.026). There was no statistically significant difference in the sedation scores between both groups except at time points of six minutes and 15 minutes. Conclusion For short-duration procedures, the DK combination is superior to the KP combination in terms of procedural interference and time to the first rescue bolus, while both groups were comparable with regard to safety and hemodynamics.

Quantum Chemical Investigation on Hydrolysis of Orally Active Organometallic Ruthenium(II) and Osmium(II) Anticancer Drugs and Their Interaction with Histidine.

Influence of the metal center on hydrolysis of organometallic anticancer complexes containing an N-phenyl-2-pyridinecarbothioamide (PCA) ligand, [M(η6-p-cymene)(N-phenyl-2-pyridinecarbothioamide)Cl]+ (M = RuII, 1A, and OsII, 2A), as well as their N-fluorophenyl derivatives [M(η6-p-cymene)(N-fluorophenyl-2-pyridinecarbothioamide)Cl]+ (M = RuII, 1B, and OsII, 2B) have been investigated using the DFT method in aqueous medium. The activation energy barriers for the hydrolysis of 1A (21.5 kcal/mol) and 1B (20.7 kcal/mol) are found to be significantly lower than those of their corresponding osmium analogs 2A (28.6 kcal/mol) and 2B (27.5 kcal/mol). DFT evaluated results reveal the inertness of Os(II)-PCA complex toward the hydrolysis that rationalizes the experimental observations. However, the incorporation of fluoride substituent slightly decreases the activation energy for the hydrolysis of Ru(II)- and Os(II)-PCA. In addition, the interaction of hydrolyzed Ru(II)-PCAs (1AH and 1BH) and Os(II)-PCAs (2AH and 2BH) complexes with the histidine (Hist) have also been investigated. The aquated 1BH and 2BH show an enhanced propensity toward the interaction with histidine, and their activation Gibbs free energies are calculated to be 15.9 and 18.9 kcal/mol, respectively. ONIOM (QM/MM) study of the resulting aquated complexes inside histone protein shows the maximum stability of the 2BH complex having a binding energy of -43.6 kcal/mol.

Perfusion Index and Its Correlation With Intraoperative Hypotension in Lower-Segment Cesarean Section Under Spinal Anesthesia: A Prospective Observational Study in a Tertiary Care Hospital in Eastern India.

Background Hypotension is commonly encountered in patients undergoing lower-segment cesarean section (LSCS) under the subarachnoid block (SAB) owing to decreased vascular resistance caused by the sympathetic blockade and decreased cardiac output because of blood pooling in blocked areas of the body. Perfusion index (PI) is a good indicator of systemic vascular resistance and can foretell hypotension. This study aimed to associate baseline PI with intraoperative hypotension after SAB in LSCS. Methodology This was a prospective observational study with a sample size of 50. The baseline PI was recorded every 10 seconds for one minute in a supine position on the right index finger at room temperature of 26°C to 28°C. The blood pressure (BP) and heart rate (HR) were recorded at an interval of one minute for three minutes. The mean of PI, BP, and HR were taken as the preoperative value. Spinal anesthesia was administered as per institutional protocol. Hypotension, defined as mean arterial pressure (MAP) <20% of baseline or MAP <60 mmHg was treated with vasopressors. Regression analysis with the Spearman correlation coefficient was done to correlate PI and hypotension. Results The incidence of hypotension in parturients with PI <2.85 was 28.6% (5/20) and in parturients with PI >2.85 was 82.8% (p < 0.001). The requirement of sympathomimetics was higher in parturients with PI >2.85.The area under the receiver operating characteristic curve was 0.8883. A cut-off PI value of 2.85 can identify parturients at risk for central neuraxial block-induced hypotension with a sensitivity of 80% and a specificity of 75% (p < 0.001). Conclusions The PI is a useful tool for predicting hypotension in healthy parturients undergoing elective cesarean section under SAB.

Adipic acid directed self-healable supramolecular metallogels of Co(II) and Ni(II): intriguing scaffolds for comparative optical-phenomenon in terms of third-order optical non-linearity.

Two brilliant outcomes of supramolecular self-assembly directed, low molecular weight organic gelator based self-healable Co(II) and Ni(II) metallogels were achieved. Adipic acid as the low molecular weight organic gelator and dimethylformamide (DMF) solvent are employed for the metallogelation process. Rheological analyses of both gel-scaffolds reveal mechanical toughness as well as visco-elasticity. Thixotropic behaviours of both the gels were scrutinized. Morphological variations due to the presence of two different metal ions with diverse metal-ligand coordinating interactions were established. The mechanistic pathways for forming stable metallogels of Co(II)-adipic acid (Co-AA) and Ni(II)-adipic acid (Ni-AA) were judiciously developed through infrared absorption spectral analysis. The nonlinear optical properties, such as the third-order process, of these synthesized metallogels were scrutinized by means of the Z-scan method at a beam excitation wavelength of 750 nm by a femtosecond laser with different excitation intensities ranging from 64 to 140 GW cm-2. The third-order nonlinear optical susceptibility (χ(3)) of the order of 10-14 esu was obtained from the measured Z-scan data. Both the metallogels exhibit positive nonlinear refraction and reverse saturable (RSA) absorption at high-intensity excitation. Co(II) and Ni(II) metallogels show nonlinear refractive indices (n2I) of (3.619 ± 0.146) × 10-6 cm2 GW-1 and (3.472 ± 0.102) × 10-6 cm2 GW-1, respectively, and two photon absorption coefficients (ß) of (1.503 ± 0.045) × 10-1 cm GW-1 and (1.381 ± 0.029) × 10-1 cm GW-1 at an excitation intensity of 140 GW cm-2. We also studied the optical limiting properties with a limiting threshold of 9.57 mJ cm-2. Therefore, both metallogels can be considered promising materials for photonic devices: for instance, for optical switching and optical limiting.

Effects of fentanyl and dexmedetomidine as adjuvants to bupivacaine in paravertebral block for postoperative analgesia in patients undergoing modified radical mastectomy: A prospective randomised double-blind study.

Background and Aims: Paravertebral block (PVB) is an established method, indicated for postoperative analgesia after modified radical mastectomy (MRM). Although many additives to bupivacaine in PVB have been tried to prolong the analgesia in postoperative period, no additive has been found without any adverse effects. We have compared the duration of analgesia in PVB using adjuvants like dexmedetomidine and fentanyl with bupivacaine after MRM. Methods: A total of 60 female patients enroled for MRM were divided into two groups of 30 patients each. Group BF received PVB with 20 ml bupivacaine 0.25% with fentanyl 1 mg/kg and group BD received 20 ml bupivacaine 0.25% with dexmedetomidine 1 mg/kg for PVB. After confirming successful PVB, surgery was done under general anaesthesia. Time for first rescue analgesic request was the primary outcome of the study. The secondary outcome was comparison of visual analogue scale scores for pain and total analgesic consumption. Side effects like sedation, nausea, vomiting, bradycardia and hypotension in the postoperative period till 24 h were also assessed. Results: The time for first rescue analgesic request was 6.32 ± 1.75 h in the BD group contrary to 3.94 ± 2.12 h in group BF (P < 0.05). Total paracetamol consumed as rescue analgesia in the first 24 h of postoperative period was remarkably reduced in group BD (1.7 ± 0.94 gm) in contrary to group BF (2.6 ± 0.98 gm) (P < 0.05). There was no significant difference in the incidence of complications between the groups. Conclusion: Dexmedetomidine provides prolonged postoperative analgesia compared with fentanyl when used as an adjuvant to bupivacaine in PVB after MRM.

Transcriptomic Analysis Revealed Reactive Oxygen Species Scavenging Mechanisms Associated With Ferrous Iron Toxicity in Aromatic Keteki Joha Rice.

Lowland acidic soils with water-logged regions are often affected by ferrous iron (Fe2+) toxicity, a major yield-limiting factor of rice production. Under severe Fe2+ toxicity, reactive oxygen species (ROS) are crucial, although molecular mechanisms and associated ROS homeostasis genes are still unknown. In this study, a comparative RNA-Seq based transcriptome analysis was conducted to understand the Fe2+ toxicity tolerance mechanism in aromatic Keteki Joha. About 69 Fe homeostasis related genes and their homologs were identified, where most of the genes were downregulated. Under severe Fe2+ toxicity, the biosynthesis of amino acids, RNA degradation, and glutathione metabolism were induced, whereas phenylpropanoid biosynthesis, photosynthesis, and fatty acid elongation were inhibited. The mitochondrial iron transporter (OsMIT), vacuolar iron transporter 2 (OsVIT2), ferritin (OsFER), vacuolar mugineic acid transporter (OsVMT), phenolic efflux zero1 (OsPEZ1), root meander curling (OsRMC), and nicotianamine synthase (OsNAS3) were upregulated in different tissues, suggesting the importance of Fe retention and sequestration for detoxification. However, several antioxidants, ROS scavenging genes and abiotic stress-responsive transcription factors indicate ROS homeostasis as one of the most important defense mechanisms under severe Fe2+ toxicity. Catalase (CAT), glutathione (GSH), ascorbate peroxidase (APX), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), and glutathione reductase (GR) were upregulated. Moreover, abiotic stress-responsive transcription factors, no apical meristem (NAC), myeloblastosis (MYB), auxin response factor (ARF), basic helix-loop-helix (bZIP), WRKY, and C2H2-zinc finger protein (C2H2-ZFP) were also upregulated. Accordingly, ROS homeostasis has been proposed as an essential defense mechanism under such conditions. Thus, the current study may enrich the understanding of Fe-homeostasis in rice.

Effectiveness of prophylactic iron supplementation in the reduction of recurrence of febrile seizures in children: A prospective study with comparison with historical controls.

Objectives: The primary objective of the study was to compare the number of patients with febrile seizure recurrence within 1 year of presenting to our institute, among patients who received and didn't receive oral iron supplementation. Materials and Methods: This prospective intervention study with historical controls was conducted to compare the number of patients with febrile seizure recurrence within 1 year, among patients who received and did not receive oral iron supplementation. The intervention group additionally received prophylactic iron supplementation of 20 mg biweekly for 1 year. Results: A total of 53 patients each were enrolled in both the groups, with comparable baseline characteristics. Although there was a trend toward a lower rate of recurrence of febrile seizures in the interventional group, as compared to the control group, it did not reach the point of statistical significance (P = 0.35). Both in the worst-case scenario and best-case scenario, there was a trend toward less risk of recurrence of febrile seizure in the intervention group, but it did not reach the point of statistical significance (P = 0.43 and 0.52). For the original scenario, worst-case scenario, and best-case scenario, the absolute risk reduction was 6.5%, 7%, and 6%, respectively, with corresponding number needed to treat (NNT) being 15, 14, and 16, respectively. The trend for absolute risk reduction was more pronounced in those with complex febrile seizures with an NNT of 6.5, but it still did not reach the point of statistical significance (P = 0.16). Moderate/severe IDA was also found to be an independent risk factor for recurrence of febrile seizure in the intervention group (P = 0.03). Conclusion: Oral serum iron supplementation does not significantly reduce the recurrence rate of febrile seizures in children aged 6-60 months. However, there is a trend toward reduction in the frequency of recurrence of febrile seizures, which is more pronounced in the subset with complex febrile seizures.

Quantum Chemical Investigations on the Hydrolysis of Gold(III)-Based Anticancer Drugs and Their Interaction with Amino Acid Residues.

A comprehensive hydrolysis mechanism of the promising class of Au(III) anticancer drugs [Au(DMDT)Cl2] (DMDT = N,N-dimethyldithiocarbamate) (R) and [Au(damp)Cl2] (damp = 2-[(dimethylamino)methyl]phenyl) (R') was done by means of density functional theory (DFT) in combination with the CPCM solvation model to explore the solution behavior and stability under physiological conditions. The activation free energies (ΔG) for the second hydrolysis, R (13.7 kcal/mol) and R' (10.0 kcal/mol) are found to be relatively lower in comparison to the first hydrolysis, and their rate constant values are computed to be 5.62 × 102 and 2.90 × 105 s-1, respectively. Besides these, the interaction mechanisms of aquated R and R' with the potential protein-binding sites cysteine (Cys) and selenocysteine (Sec) were also investigated in detail. The kinetic study and activation Gibbs free energy profiles reveal that the aquated complexes of R and R' bind more effectively to the Se site of Sec than to the S site of Cys. Intra- and intermolecular hydrogen bonding play a pivotal role in stabilizing the intermediates and transition states involved in the ligand substitution reactions of R and R'. Natural population analysis (NPA) was done to determine the charge distributions on important atoms during the hydrolysis and ligand substitution reactions.

A Density Functional Theory Study on Et-BAC-Catalyzed 1,6-Conjugate Addition of p-Chlorobenzaldehyde to p-Quinone Methide for the Synthesis of α,α'-Diarylated Ketones.

Umpolung-based organocatalysis has made a remarkable breakthrough in the field of synthetic organic chemistry. Among a plethora of umpolung catalysts, bis(amino)cyclopropenylidenes (BACs) have emerged as efficient organocatalysts with potential applications in synthesizing numerous essential organic moieties. In this study, a plausible mechanism for bis(diethylamino)cyclopropenylidene (Et-BAC)-catalyzed synthesis of α,α'-diarylated ketones has been established using the density functional theory (DFT) method. The proposed catalytic cycle of the studied reaction initiates with the nucleophilic interaction of Et-BAC with p-chlorobenzaldehyde to form a zwitterionic intermediate, which is then transformed to a reactive Breslow intermediate. The Breslow intermediate further undergoes a chemoselective and stereoselective 1,6-conjugate addition reaction with p-quinone methide to form a new C-C bond connection. Finally, the generated adduct undergoes a proton shift reaction with the assistance of both 8-diazabicyclo(5.4.0)undec-7-ene (DBU) and protonated DBU to yield the desired product. Conceptual DFT-derived reactivity indices and frontier molecular orbital theory analysis have been successfully utilized to unravel the role of Et-BAC in this studied reaction. In addition to Et-BAC, DBU and protonated DBU also play a very important role in lowering the activation energy barrier of proton transfer steps. This investigation will help in the rational designing of simple nonheterocyclic carbene-mediated novel organic transformations.

Post-operative analgesia for shoulder arthroscopic surgeries: A comparison between inter-scalene block and shoulder block.

BACKGROUND AND AIMS: Shoulder arthroscopic surgeries can produce intense post-operative pain. Inter-scalene block (ISB) provides good analgesia after shoulder surgery, but concerns over its associated risks have prompted the search for alternatives. Shoulder block (SHB), which includes suprascapular block along with axillary nerve (AN) block, was recently proposed as an alternative to ISB, but evidence of its efficacy is conflicting. The aim of our study was to compare SHB with ISB in shoulder surgery for post-operative analgesia. METHODS: A total of 76 patients scheduled for shoulder arthroscopic surgery were equally divided into 2 groups of 38 patients each: ISB group and SHB group. Both the nerve blocks were achieved by using ultrasound and a nerve stimulator. Visual analogue scale (VAS) scores were evaluated at 1, 4, 6, 12 and 24 h post-operatively. The time to first analgesia request, total analgesic requirement for 24 h post-operatively, patient satisfaction and any complications were recorded. RESULTS: SHB provided equivalent analgesia to ISB in terms of post-operative VAS scores. Time to first analgesic request was 6.2 ± 1.3 h in ISB group and 5.9 ± 1.2 h in SHB group, which was not statistically significant. Complications like subjective dyspnoea and weakness of arm were significantly higher in ISB group compared to SHB group. Patient satisfaction scores were also significantly higher in SHB group compared to ISB group. CONCLUSION: SHB is as effective as ISB for post-operative pain relief and with fewer complications due to selective blockade of suprascapular and axillary nerves.

Comparison of Intrathecal Clonidine and Fentanyl as Adjuvant to Hyperbaric Bupivacaine in Subarachnoid Block for Lower Limb Orthopedic Surgery.

BACKGROUND: Many studies are there using adjuvants such as clonidine and fentanyl with bupivacaine in the subarachnoid block for prolonging postoperative analgesia. However, literature is divided regarding the dosage and efficacy of both intrathecal adjuvants. Furthermore, these adjuvants have their own side effects. Hence, search for ideal intrathecal adjuvant between clonidine and fentanyl to bupivacaine goes on. AIM: The aim of the present study was to compare the effect of intrathecal clonidine and fentanyl as adjuvant to bupivacaine in the subarachnoid block for lower limb orthopedic surgery. MATERIALS AND METHODS: It was a prospective randomized study in which eighty patients posted for lower limb orthopedic surgery were divided into two groups of forty each. Group C - Received intrathecal hyperbaric bupivacaine (2.5 ml) +50 µg clonidine (diluted to 0.5 ml). Group F - Received intrathecal hyperbaric bupivacaine (2.5 ml) + fentanyl 25 µg (diluted to 0.5 ml). Duration of postoperative analgesia, sensory and motor block characteristics, hemodynamic parameters, and side effects were recorded and analyzed. RESULTS: Time for first dose of rescue analgesic was delayed in Group C (510.84 ± 24.10 min) in comparison to Group F (434.95 ± 19.16 min) which was statistically significant (P < 0.001). Duration of sensory and motor block was significantly prolonged in Group C compared to Group F (P < 0.001). Sedation was more in Group C than Group F (P < 0.001). Other block characteristics, hemodynamic, and side effects were comparable in both groups. CONCLUSION: Intrathecal clonidine as adjuvant to hyperbaric bupivacaine provided prolonged postoperative analgesia with more sedation in comparison to intrathecal fentanyl.

Morpho-physiological analysis of tolerance to aluminum toxicity in rice varieties of North East India.

Aluminum (Al) is the third most abundant metal in earth crust, whose chemical form is mainly dependent on soil pH. The most toxic form of Al with respect to plants is Al3+, which exists in soil pH <5. Acidic soil significantly limits crop production mainly due to Al3+ toxicity worldwide, impacting approximately 50% of the world's arable land (in North-Eastern India 80% soil are acidic). Al3+ toxicity in plants ensues root growth inhibition leading to less nutrient and water uptake impacting crop productivity as a whole. Rice is one of the chief grains which constitutes the staple food of two-third of the world population including India and is not untouched by Al3+ toxicity. Al contamination is a critical constraint to plant production in agricultural soils of North East India. 24 indigenous Indica rice varieties (including Badshahbhog as tolerant check and Mashuri as sensitive check) were screened for Al stress tolerance in hydroponic plant growth system. Results show marked difference in growth parameters (relative growth rate, Root tolerance index, fresh and dry weight of root) of rice seedlings due to Al (100 µM) toxicity. Al3+ uptake and lipid peroxidation level also increased concomitantly under Al treatment. Histochemical assay were also performed to elucidate uptake of aluminum, loss of membrane integrity and lipid peroxidation, which were found to be more in sensitive genotypes at higher Al concentration. This study revealed that aluminum toxicity is a serious harmful problem for rice crop productivity in acid soil. Based on various parameters studied it's concluded that Disang is a comparatively tolerant variety whereas Joymati a sensitive variety. Western blot hybridization further strengthened the claim, as it demonstrated more accumulation of Glutathione reductase (GR) protein in Disang rice variety than Joymati under stressed condition. This study also observed that the emergence of lethal toxic symptoms occurs only after 48h irrespective of the dose used in the study.

Mathematical model of flagella gene expression dynamics in Salmonella enterica serovar typhimurium.

Flagellar assembly in Salmonella is controlled by an intricate genetic and biochemical network. This network comprises of a number of inter-connected feedback loops, which control the assembly process dynamically. Critical among these are the FliA-FlgM feedback, FliZ-mediated positive feedback, and FliT-mediated negative feedback. In this work, we develop a mathematical model to track the dynamics of flagellar gene expression in Salmonella. Analysis of our model demonstrates that the network is wired to not only control the transition of the cell from a non-flagellated to a flagellated state, but to also control dynamics of gene expression during cell division. Further, we predict that FliZ encoded in the flagellar regulon acts as a critical secretion-dependent molecular link between flagella and Salmonella Pathogenicity Island 1 gene expression. Sensitivity analysis of the model demonstrates that the flagellar regulatory network architecture is extremely robust to mutations.

The effect of providing patient-specific electronically monitored antipsychotic medication adherence results on the treatment planning of prescribers of outpatients with schizophrenia.

Adherence to antipsychotic medication was assessed monthly over a 6-month study period using patient-specific electronic monitoring (EM) of medication bottle opening in 23 outpatients with schizophrenia or schizoaffective disorder. Patient-specific EM adherence results were then shared with the seven participating prescribers, who were surveyed concerning the treatment changes, if any, that they would recommend based on the EM adherence results. Prescribers indicated that they would recommend adherence-related treatment plan changes in 61% of patients, all of whom were ≤80% adherent. The strength of this effect was significantly stronger for psychosocial intervention treatment plan change recommendations than for medication treatment plan change recommendations. Of the psychosocial intervention recommendations, an increase in case management intensity was most often recommended. Of the medication treatment plan recommendations, initiation of a long-acting injectable medication and an increase in dosage of current oral antipsychotic medication were each recommended in only one case. Prescriber recommendations of adherence interventions in this study were not necessarily consistent with major guideline recommendations. Findings suggest the need for further study and dissemination of findings regarding evidence-based adherence assessment and interventions.