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Identifying initial triggering events in neurodegenerative disorders is critical to developing preventive therapies. In Huntington's disease (HD), hyperdopaminergia-probably triggered by the dysfunction of the most affected neurons, indirect pathway spiny projection neurons (iSPNs)-is believed to induce hyperkinesia, an early stage HD symptom. However, how this change arises and contributes to HD pathogenesis is unclear. Here, we demonstrate that genetic disruption of iSPNs function by Ntrk2/Trkb deletion in mice results in increased striatal dopamine and midbrain dopaminergic neurons, preceding hyperkinetic dysfunction. Transcriptomic analysis of iSPNs at the pre-symptomatic stage showed de-regulation of metabolic pathways, including upregulation of Gsto2, encoding glutathione S-transferase omega-2 (GSTO2). Selectively reducing Gsto2 in iSPNs in vivo effectively prevented dopaminergic dysfunction and halted the onset and progression of hyperkinetic symptoms. This study uncovers a functional link between altered iSPN BDNF-TrkB signalling, glutathione-ascorbate metabolism and hyperdopaminergic state, underscoring the vital role of GSTO2 in maintaining dopamine balance., (© 2024. The Author(s).)

In ataxia disorders, motor incoordination (ataxia) is primarily linked to the dysfunction and degeneration of cerebellar Purkinje cells (PCs). In spinocerebellar ataxia 6 (SCA6), for example, decreased BDNF-TrkB signalling appears to contribute to PC dysfunction and ataxia. However, abnormal BDNF-TrkB signalling in granule cells (GCs) may contribute to PC dysfunction and incoordination in ataxia disorders, as TrkB receptors are also present in GCs that provide extensive input to PCs. This study investigated whether dysfunctional BDNF-TrkB signalling restricted to a specific subset of cerebellar GCs can generate ataxia in mice. To address this question, our research focused on Trkb Penk-KO mice, in which the TrkB receptor was removed from enkephalinergic precursor-derived cerebellar GCs. We found that deleting Ntrk2 , encoding the TrkB receptor, eventually interfered with PC function, leading to ataxia symptoms in the Trkb Penk-KO mice without affecting their cerebellar morphology or levels of selected synaptic markers. These findings suggest that dysfunctional BDNF-TrkB signalling in a subset of cerebellar GCs alone is sufficient to trigger ataxia symptoms and may contribute to motor incoordination in disorders like SCA6.

Background: Tribulus terrestris , a plant known for its pharmacological properties, was investigated in this study for its potential anticancer effects against oral cancer cells. The study aimed to explore the phytochemical composition of T. terrestris seed extract and evaluate its cytotoxic, pro-apoptotic, antioxidant, anti-inflammatory, and antimicrobial activities., Materials and Methods: Methanolic seed extracts of T. terrestris were obtained and subjected to phytochemical analysis to identify bioactive compounds. The cytotoxic effect of the extract on oral cancer cells was evaluated using the MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay, while pro-apoptotic effects were assessed through dual fluorescent staining. Antioxidant activity was measured using hydrogen peroxide and erythrocyte aggregation assays, while anti-inflammatory activity was evaluated through inhibition of albumin denaturation., Results: Phytochemical analysis revealed the presence of alkaloids, tannins, saponins, flavonoids, and phenols in T. terrestris seed extract. The extract demonstrated concentration-dependent cytotoxicity against oral cancer cells, with 100 μg/mL showing significant growth inhibition. Pro-apoptotic effects were observed, with characteristic morphological changes in cancer cells treated with the extract. Antioxidant activity was demonstrated by the extract, with methanol fraction of a flower (MFF) exhibiting the highest capacity, followed by total trichome fraction (TTF), and a positive correlation between phenolic content and free radical scavenging effectiveness was noted. Antimicrobial activity against various pathogens, including bacteria and fungi, was also observed, with higher concentrations showing increased efficacy., Conclusion: The study concludes that methanolic extracts of T. terrestris possess significant anticancer, antioxidant, anti-inflammatory, and antimicrobial activities. These findings highlight the potential of T. terrestris as a candidate for further research and clinical applications, either alone or in combination with other agents, for the treatment of oral cancer and associated conditions., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Malik et al.)

Since previous few decays the consideration of non-Newtonian liquids motion due to its immense usages in medicine, biology, industrial procedures, chemistry of catalysts and in environment. Various studies examine the significance of bio-materials flow in physiological procedures to explore the cure of diagnosed symptoms of disease appearing during movement in a human physiological system. To illustrate the characteristics of physiological liquids various non-Newtonian models have been proposed, but yet no such single liquid model is exploited which describes all the properties of nonlinear behaving liquids. Among these several non-Newtonian models, Jeffery liquid model should be reduced to its base fluid case (i.e. viscous liquid) by choosing λ₁ = λ₂ = 0. Various physiological materials which represents both linear and nonlinear characteristics respectively blood is one of these. Jeffery fluid and peristaltic motion have some common properties such as radii, relaxation time and retardation time. Moreover heat and mass transfer is also an important phenomenon which is suitable for various physiological processes such as hemodialysis and oxygenation etc. Thus due to such motivating facts this research is conducted to investigate the peristaltic motion of electrically conducting Jeffery liquid. The peristaltic propagating channel walls are asymmetric and inclined. Joule heating and magnetic field effects are considered by applying magnetic field in transverse direction to the flow. Further conservation laws modelled the flow situation via considering quadric mix convection, thermos diffusion and diffusion-thermos, heat generation and absorption, chemical reaction with activation energy features. Moreover, creeping flow and long wavelength assumptions are used to simplify the mathematical modelling. The reduced system of equation is solved numerically through built-in technique in Mathematica software. This built-in technique is working through ND Solve command and shooting and RK-Felburg numerical schemes are behind this technique. These numerical results are used to discuss the flow quantities i.e., velocity, temperature and concentration against the sundry dimensionless quantities. Examining the results it comes to know that both thermal and concentration nonlinear mix convection have oppositely affecting the axial velocity. Both heat and mass transfer are escalating function of thermo-diffusion/diffusion-thermo aspects., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)

Ensuring adequate implementation of solar energy for providing environment-friendly energy to the household sector, which can considerably abate pollutants in the environment and make power industry structure sustainable, is necessary for developing countries. Comparison in terms of environmental and cost impacts of renewable energy (hybrid solar system) with non-renewable energy sources, water and planning development authority (WAPDA), and diesel generators (DGs) has been examined in the household sector of Pakistan. Primary data of hybrid solar systems have been obtained from 10 different households segregated them into two categories according to their income as medium-income households (MIHs) and lower income households (LIHs) containing 5 kW and 3 kW of hybrid solar energy systems, respectively. While operating with a hybrid solar energy system instead of a non-renewable energy system, in terms of average generated power and average running load, carbon dioxide (CO 2 ) emissions can be reduced up to 8,446.6 kg CO 2 and 6,131.725 kg CO 2 , respectively, in the next 25 years. Comparison of costs indicated that renewable energy has a comparatively low cost per electric unit. It can pay back its total installation cost in just 8 years and can save a sum of $4,936.4375, along with many more ecological, economic, and societal benefits. Pakistan can efficiently utilize solar energy to relegate CO 2 emissions and general costs as it has distinct geographical features to access sunlight in most days of the year., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The foremost focus of this article was to investigate the entropy generation in hydromagnetic flow of generalized Newtonian Carreau nanofluid through a converging and diverging channel. In addition, a heat transport analysis was performed for Carreau nanofluid using the Buongiorno model in the presence of viscous dissipation and Joule heating. The second law of thermodynamics was employed to model the governing flow transport along with entropy generation arising within the system. Entropy optimization analysis is accentuated as its minimization is the best measure to enhance the efficiency of thermal systems. This irreversibility computation and optimization were carried out in the dimensional form to obtain a better picture of the system's entropy generation. With the help of proper dimensionless transformations, the modeled flow equations were converted into a system of non-linear ordinary differential equations. The numerical solutions were derived using an efficient numerical method, the Runge-Kutta Fehlberg method in conjunction with the shooting technique. The computed results were presented graphically through different profiles of velocity, temperature, concentration, entropy production, and Bejan number. From the acquired results, we perceive that entropy generation is augmented with higher Brinkman and Reynolds numbers. It is significant to mention that the system's entropy production grew near its two walls, where the irreversibility of heat transfer predominates, in contrast to the channel's center, where the irreversibility of frictional force predominates. These results serve as a valuable guide for designing and optimizing channels with diverging-converging profiles required in several heat-transfer applications.

The hydrothermal features of unsteady, incompressible, and laminar hybrid nanofluid motion through a porous capillary are analytically studied in the magnetic field presence. The hybrid nanofluid (GO + ZnO + Blood) is synthesized by blending nanomaterials of graphene oxide and zinc oxide with blood acting as the host fluid. The mathematical model of the flow comprises of a coupled nonlinear set of partial differential equations (PDEs) satisfying appropriate boundary conditions. These equations are reduced to ordinary differential equations (ODEs) by using similarity transformations and then solved with homotopy analysis method (HAM). The impacts of various pertinent physical parameters over the hybrid nanofluid state functions are examined by displaying 2 D graphs. It has been observed that the fluid velocity mitigates with the varying strength of M , A 0 , N 0 , and N 1 . The enhancing buoyancy parameter ϵ augments the fluid velocity. The increasing Prandtl number causes to reduce, while the enhancing A 0 , B , and N 2 augment the hybrid nanofluid temperature. The fluid concentration mitigates with the higher Schmidt number values and A 0 , and augments with the increasing Soret number strength. The augmenting magnetic field strength causes to enhance the fluid friction, whereas the convective heat transfer increases with the Prandtl number rising values. The rising Sherwood number drops the mass transfer rate of the fluid. The achieved results are validated due to the agreement with the published results. The results of this computation will find applications in biomedicine, nanotechnology, and fluid dynamics.

This paper explores the impact of MHD and viscous dissipation with joule heating on convective stretching flow of dusty tangent hyperbolic fluid over a sheet in 3D. A time-dependent magnetic field is applied along the z-axis and the sheet being stretched along the xy-plane. The fluid and dust particles motions are coupled only through drag and heat transfer between them. The effect of viscous dissipation with convection is appreciable when the generated kinetic energy becomes appreciable as compared to the amount of heat transferred. A well known bvp4c method has been used to find the fruitful results. Graphs and tables show the facts and figures for physical properties according to different parameters. The main findings are that Increase in power law index, magnetic field, Weissenberg effect, concentration of dust particles, and unsteadiness parameter reduces the flow of fluid and solid granules., (© 2022. The Author(s).)

In present research manuscript, analysis is presented for the influences of heat transition in a bodewadt flow over a penetrable disk numerically. Estimation parameters in current mathematical flow model include magnetic field parameter [Formula: see text] wall suction [Formula: see text] prandtl number [Formula: see text] heat generation/absorption [Formula: see text] eckert number [Formula: see text] variable viscosity [Formula: see text] and thermal conductivity [Formula: see text] The repercussions of joule heating, wall suction, heat generation & absorption, magnetic field, viscous dissipation accompanying with variable characteristics of the fluid are also examined as well. Kinetics of viscous fluid with variable characteristics of fluid having solid body rotation over a permeable disk (having cylindrical geometry) are analyzed. We transformed the governing equations of heat transfer (accompanied by variable properties) and fluid motion in to self-similar non-dimensional differential equations by using the Von-Karman variables which are then further analyzed numerically by utilizing Adams Bashforth method. For a physical insight, results are manifested to scrutinize the behavior of velocity and temperature profiles for different emerging parameters graphically. Moreover, the values of nusselt number & skin friction co-efficient are also computed and physically explicated for the assorted parameters. Outcomes of current investigations are compared with prior work, to ensure the authenticity of the numerical method, and strong agreement is noted., (© 2022. The Author(s).)

The new coronavirus SARS-CoV-2 pandemic has put the world on lockdown for the first time in decades. This has wreaked havoc on the global economy, put additional burden on local and global public health resources, and, most importantly, jeopardised human health. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats, and the CRISPR associated (Cas) protein (CRISPR/Cas) was identified to have structures in E. coli. The most modern of these systems is CRISPR/Cas. Editing the genomes of plants and animals took several years and cost hundreds of thousands of dollars until the CRISPR approach was discovered in 2012. As a result, CRISPR/Cas has piqued the scientific community's attention, particularly for disease diagnosis and treatment, because it is faster, less expensive, and more precise than previous genome editing technologies. Data from gene mutations in specific patients gathered using CRISPR/Cas can aid in the identification of the best treatment strategy for each patient, as well as other research domains such as coronavirus replication in cell culture, such as SARS-CoV2. The implications of the most prevalent driver mutations, on the other hand, are often unknown, making treatment interpretation difficult. For detecting a wide range of target genes, the CRISPR/Cas categories provide highly sensitive and selective tools. Genome-wide association studies are a relatively new strategy to discovering genes involved in human disease when it comes to the next steps in genomic research. Furthermore, CRISPR/Cas provides a method for modifying non-coding portions of the genome, which will help advance whole genome libraries by speeding up the analysis of these poorly defined parts of the genome., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Published by Elsevier B.V. on behalf of King Saud University.)

In current study, analysis is presented for peristaltic motion of applied magnetic field and entropy generation within couple stress (Cu/H 2 O) nanofluid through an endoscope. An endoscope contains two coaxial cylindrical tubes in which the internal tube is nonflexible while the external tube has sinusoidal wave passing through the boundary. Influences of mixed convection along with applied magnetic field are encountered as well. Formulated governing model is fabricated introducing long wavelength and creeping Stokesian flow approximation which are then analyzed numerically by utilizing Adams Bashforth method. For a physical insight, results are demonstrated to examine the behaviors of flow profiles and entropy generation number for emerging flow parameters with the help of graphs, bar-charts and tables., (© 2022. The Author(s).)

The objective of the present exploration is to examine the nanoliquid flow amid two horizontal infinite plates. The lower plate is stretchable and permeable. The uniqueness of the flow model is assimilated with the Hall effect, variable thermal conductivity, thermal radiation, and irregular heat source/sink. Transmission of mass is enhanced with the impression of chemical reaction incorporated with activation energy. Appropriate similarity transformation is applied to transform the formulated problem into ordinary differential equations (ODEs). The numerical solution is obtained by employing MATLAB software function bvp4c. The dimensionless parameters are graphically illustrated and discussed for the involved profiles. An increasing behavior is exhibited by the temperature field on escalating the Brownian motion, thermophoresis parameter, variable thermal conductivity, and radiation parameter. For larger values of Schmidt number and chemical reaction parameter, the concentration profile deteriorates, while a reverse trend is seen for activation energy. The rate of heat transfer is strengthened at the lower wall on amplifying the Prandtl number. A comparative analysis of the present investigation with already published work is also added to substantiate the envisioned problem., (© 2021. The Author(s).)

The present study analyzes the comparison of the Xue and Yamada-Ota models for a hybrid nanoliquid flow in porous media occurring amidst a rotating channel with surface catalyzed reaction. Here, the hybrid nanofluid flow is studied under the effect of Cattaneo Christov (C-C) heat flux and homogenous heterogeneous (Homo-Hetero) chemical reaction with entropy generation minimization analysis. The assumptions of the viscosity of hybrid nanomaterial fluid and variable thermal conductivity are added characteristics to the inimitability of the flow model. Two kinds of nanoparticles, namely single-wall carbon nanotubes and multi-wall carbon nanotubes with ethylene glycol (EG) as the base fluid are considered. Carbon nanotubes possess diverse applications in daily life including energy storage, drug delivery, cancer treatment, tissue generation, platelet activation, magnetic force microscopy, and microwave absorption, etc. Similarity transformations are utilized to translate the modeled problem into the coupled ordinary differential equations. This system of ordinary differential equations is addressed numerically. The graphical outcomes are scrutinized by utilizing the MATLAB software bvp4c function. The results revealed that the velocity profile decreases for the higher rotation parameter while increases for the escalated slip parameter. Furthermore, the fluid concentration and temperature are on the decline for higher surface catalyzed reaction and thermal relaxation parameters respectively., (© 2021. The Author(s).)

This investigation aims to look at the thermal conductivity of dusty Micropolar nanoliquid with MHD and Cattaneo-Christov heat flux flow over an elongated sheet. The novelty of the envisioned mathematical model is augmented with the added impacts of the heat source/sink, chemical reaction with slip, convective heat, and zero mass flux boundary conditions. The salient feature of the existing problem is to discuss the whole scenario with liquid and dust phases. The graphical depiction is attained for arising pertinent parameters by using bvp4c a built-in MATLAB function. It is noticed that the thermal profile and velocity field increases for greater values of liquid particle interaction parameter in the case of the dust phase. An escalation in the thermal profile of both liquid and dust phases is noticed for the magnetic parameter. The rate of mass transfer amplifies for large estimates of the Schmidt number. The thickness of the boundary layer and the fluid velocity are decreased as the velocity slip parameter is augmented. In both dust and liquid phases, the thermal boundary layer thickness is lessened for growing estimates of thermal relaxation time. The attained results are verified when compared with a published result., (© 2021. The Author(s).)

The nanofluids owing to their alluring attributes like enhanced thermal conductivity and better heat transfer characteristics have a vast variety of applications ranging from space technology to nuclear reactors etc. The present study highlights the Ostwald-de-Waele nanofluid flow past a rotating disk of variable thickness in a porous medium with a melting heat transfer phenomenon. The surface catalyzed reaction is added to the homogeneous-heterogeneous reaction that triggers the rate of the chemical reaction. The added feature of the variable thermal conductivity and the viscosity instead of their constant values also boosts the novelty of the undertaken problem. The modeled problem is erected in the form of a system of partial differential equations. Engaging similarity transformation, the set of ordinary differential equations are obtained. The coupled equations are numerically solved by using the bvp4c built-in MATLAB function. The drag coefficient and Nusselt number are plotted for arising parameters. The results revealed that increasing surface catalyzed parameter causes a decline in thermal profile more efficiently. Further, the power-law index is more influential than the variable thickness disk index. The numerical results show that variations in dimensionless thickness coefficient do not make any effect. However, increasing power-law index causing an upsurge in radial, axial, tangential, velocities, and thermal profile., (© 2021. The Author(s).)

This research concerns the heat transfer and entropy generation analysis in the MHD axisymmetric flow of Al 2 O 3 -Cu/H 2 O hybrid nanofluid. The magnetic induction effect is considered for large magnetic Reynolds number. The influences of thermal radiations, viscous dissipation and convective temperature conditions over flow are studied. The problem is modeled using boundary layer theory, Maxwell's equations and Fourier's conduction law along with defined physical factors. Similarity transformations are utilized for model simplification which is analytically solved with the homotopy analysis method. The h-curves up to 20th order for solutions establishes the stability and convergence of the adopted computational method. Rheological impacts of involved parameters on flow variables and entropy generation number are demonstrated via graphs and tables. The study reveals that entropy in system of hybrid nanofluid affected by magnetic induction declines for β while it enhances for Bi , R and λ. Moreover, heat transfer rate elevates for large Bi with convective conditions at surface.

Dodonaea viscosa L.Jacq. is an evergreen shrub and native to Asia, Africa, and Australia. It has been used as traditional medicine in different countries. The foremost objective of the current study was to discover the protective potential of D. viscosa flowers Methanol (DVM) and Chloroform (DVC) extracts against CCL 4 induced toxicity in mice. This study was intended to identify phytochemicals through HPLC, GCMS, and FT-IR, as well as in vitro antioxidant and in vitro anti-tuberculosis activity. Our comprehensive findings indicate that Dodonaea viscosa is valuable and widespread herbal medicine through therapeutic potentials for curing various ailments. Dodonaeaviscosa flowersare found to have a protective effect against oxidative stress produced by CCL 4 in the liver, kidney, and spleen. The intake of DV extracts restored the level of hepatic enzymes (ALP, AST ALT, and Direct bilirubin), hematological parameters (RBCs, WBCs, and Platelets), total protein, and liver antioxidant enzymes (SOD, GPx, and CAT) after a decline in levels by CCL 4 . Histopathological results discovered the defensive effect of 300 mg/kg of DVM extract against CCL 4 induced damage, thus having an improved protective effect compared to DVC and control. As a result of metabolite screening, the total flavonoids and total phenolics were present in abundance. A phytochemical investigation by HPLC identified gallic acid, epicatechin, cumeric acid, flavonoids, while GCMS estimated oleic acid (Octadecenoic acid) (C 18 H 34 O 2 ), Stearic acid (C 18 H 36 O 2 ), Ricinoleic acid (C 18 H 34 O 3 ), and Cedrol (C 15 H 26 O). DVM extract exhibited resistance against in vitro Mycobacterium tuberculosis strains. So this study proposed that the protective effect of DV against oxidative damage induced in the liver, kidney, and spleen can be correlated to the antioxidant compounds.

Matrix nanocomposites are high performance materials possessing unusual features along with unique design possibilities. Due to extraordinary thermophysical characteristic contained by these matrix nanocomposites materials they are useful in several areas ranging from packaging to biomedical applications. Being an environment friendly, utilization of nanocomposites offer new technological opportunities for several sectors of aerospace, automotive, electronics and biotechnology. In this regards, current pagination is devoted to analyze thermal features of viscous fluid flow between orthogonally rotating disks with inclusion of metallic matrix nanocomposite (MMNC) and ceramic matrix nanocomposites (CMNC) materials. Morphological aspects of these nanomaterials on flow and heat transfer characteristics has been investigated on hybrid viscous fluid flow. Mathematical structuring of problem along with empirical relations for nanocomposites materials are formulated in the form of partial differential equations and later on converted into ordinary differential expressions by using suitable variables. Solution of constructed coupled differential system is found by collaboration of Runge-Kutta and shooting methods. Variation in skin friction coefficient at lower and upper walls of disks along with measurement about heat transfer rate are calculated against governing physical parameters. Impact of flow concerning variables on axial, radial components of velocity and temperature distribution are also evaluated. Contour plots are also drawn to explore heat and thermal profiles. Comparison and critical analysis of MMNc and CMNc have been presented at lower and upper porous disks. Our computed analysis indicates that hybrid nanofluids show significant influence as compared to simple nanofluids with the permutation of the different shape factors.

Studies accentuating nanomaterials suspensions and flow traits in the view of their applications are the focus of the present study. Especially, the usage of such materials in biomedical rheological models has achieved great importance. The nanofluids' role is essential in the cooling of small electronic gizmos like microchips and akin devices. Having such exciting and practical applications of nanofluids our goal is to scrutinize the Maxwell MHD nanofluid flow over an extended cylinder with nonlinear thermal radiation amalgamated with chemical reaction in a Darcy-Forchheimer spongy media. The presence of gyrotactic microorganisms is engaged to stabilize the nanoparticles in the fluid. The partial slip condition is considered at the boundary of the stretching cylinder. The Buongiorno nanofluid model is betrothed with impacts of the Brownian motion and thermophoresis. The analysis of entropy generation is also added to the problem. The highly nonlinear system is tackled numerically is addressed by the bvp4c built-in function of the MATLAB procedure. The outcomes of the prominent parameters versus embroiled profiles are portrayed and conversed deeming their physical significance. It is perceived that fluid temperature is augmented for large estimates of the radiation and Darcy parameters. Moreover, it is noticed that the magnetic and wall roughness parameters lower the fluid velocity. To corroborate the presented results, a comparison of the current study with a previously published paper is also executed. An outstanding correlation in this regard is attained.

This study investigates the role of natural resources rent, green investment, financial development and energy consumption in mitigation of carbon emissions to achieve sustainable development goal of a clean environment by using the panel data of 30 provinces of China from 1995 to 2017. This study employs novel cross-sectionally augmented autoregressive distributed lags (CS-ARDL) methodology to find the long and short-run impact of the variables of the study on carbon emission, where CS-ARDL estimates confirm the positive impact of energy consumption and financial development on carbon emissions (CO 2 ). Moreover, green investment is negatively linked to CO 2 , whereas national natural resources rent is positively associated with carbon emissions. Similarly, augmented mean group and common correlated effect mean group methods provide supportive results for CS-ARDL estimates. This study recommends strengthening of national natural tax law, promotion of green investment and environmental-friendly policies to control carbon emissions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Several studies have examined the impact of economic growth on carbon emission; however, the symmetric and asymmetric impact of oil price along with FDI on carbon emission has not studied in the case of Pakistan. For this purpose, the long and short-run impact of per capita income, FDI, and oil price on carbon emissions investigated by employing the ARDL and non-linear ARDL cointegration methodology, along with Granger causality in the context of Pakistan for 1971-2014. This study confirms the EKC hypothesis for Pakistan under both methodologies, whereas symmetric results show that economic growth and FDI intensify carbon emission in both the long and short-run, while oil price increase emission in the short-run and reduces emission in the long-run. Whereas asymmetric results in the long-run show that an increase in oil price reduces emissions and decrease in oil price intensify emissions. The causality analysis also supports the above findings and suggests a feedback effect between economic growth and carbon emission in Pakistan. This study provides implications for policymakers, where the descending flow of FDI allows limited space to Pakistan in FDI selection; however, the presence of emission convergence and adoption of carbon pricing may facilitate Pakistan in achieving its environmental targets. While diversifying the overall energy mix towards more renewable/clean energy along with formulating favorable policies for the adoption of renewable energy like solar by the industrial and residential consumers can further reduce the overall emission levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: Metronidazole, a nitroimidazole derived antibiotic used to treat many bacterial infections, is reported to penetrate the blood brain barrier after long term administration resulting into neuronal toxicity. Further, quercetin, a polyphenol flavonoid is reported to exhibit neuroprotective activity but its pharmacodynamics interaction against metronidazole induced neurotoxicity. Therefore, the present study was designed to evaluate the postulated mechanism of metronidazole induced neurotoxicity and potential neuroprotective role of quercetin., Main Methods: Animals (Sprague Dawley) rats were randomly divided into five groups such as control, metronidazole (135 mg/kg), quercetin (100 mg/kg), metronidazole (135 mg/kg) + quercetin (50 mg/kg), and metronidazole (135 mg/kg) + quercetin (100 mg/kg). The brain tissues were evaluated for tissue cyclo-oxygenase, lipoxygenase, nitrite levels, inflammatory and antioxidant biomarkers. The brain tissues were further scrutinized histopathologically for neuronal degeneration. Western blotting analysis was performed for the localization of protein expression for Bax, Bcl 2 , iNOS, eNOS and caspase-3., Key Findings: The metronidazole significantly alters the antioxidant levels, inflammatory mediators and morphological changes in the brain tissue. Metronidazole also induces iNOS, Bax and caspase 3 protein expressions whilst decreases the expression of Bcl 2 and eNOS in the brain tissue. Metronidazole administration causes a momentous increase in tissue inflammatory markers., Significance: The metronidazole (oral) administration causes remarkably neurotoxicity effects and the same could be attributed to the fact that metronidazole has the ability to cross the blood brain barrier and transforms the enzymatic activity of various biomarkers present in the brain. From the results, it could be hypothesized that metronidazole causes neurotoxicity by hindering the proportion of antioxidants in the brain tissue and inducing nitric oxide synthesis along with apoptosis. However, quercetin demonstrated a significant protective effect on neuronal toxicity precipitated through metronidazole., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: In this work the theoretical analysis is presented for a electroosmotic flow of Bingham nanofluid induced by applied electrostatic potential. The linearized Poisson-Boltzmann equation is considered in the presence of Electric double layer (EDL). A Bingham fluid model is employed to describe the rheological behavior of the non-Newtonian fluid. Mathematical formulation is presented under the assumption of long wavelength and small Reynolds number. Flow characteristics are investigated by employing Debye-Huckel linearization principle. Such preferences have not been reported previously for non-Newtonian Bingham nanofluid to the best of author's knowledge., Method: The transformed equations for electroosmotic flow are solved to seek values for the nanofluid velocity, concentration and temperature along the channel length., Results: The effects of key parameters like Brinkmann number, Prandtl number, Debey Huckel parameter, thermophoresis parameter, Brownian motion parameter are plotted on velocity, temperature and concentration profiles. Graphical results for the flow phenomenon are discussed briefly., Conclusions: Non-uniformity in channel as well as yield stress τ 0 cause velocity declaration for both positive and negative values of U. Nanofluid temperature is found an increasing function of electro osmotic parameter κ if U is positive while it is a decreasing function if U is negative. A completely reverse response is seen in case of concentration profile. The thermophoresis parameter Nt, the Brow nian motion parameter Nb and Brinkman number Br cause an enhancement in temperature. The results are new in case of U., Competing Interests: Declaration of Competing Interest The corresponding author on behalf of all authors declares “no conflict of interest” with anyone exists., (Copyright © 2019. Published by Elsevier B.V.)

Background: In this paper, we discussed the Cu - Al 2 O 3 /H 2 O (Hybrid nanofluid) flow over permeable exponentially stretching channel. The hybrid nanofluid involves two kinds of nanoparticles along with base fluid (pure water). Our research objective is to evaluate the heat transfer rate of hybrid nanofluid., Method: The resulting system is numerically tackled via shooting method (bvp4c)., Results: The hybrid nanofluid gains larger rate of heat transfer as compared to simple nanofluid. The impact of non-dimension parameter on temperature profile, boundary layer will be analyzed for enormous values of dimensionless parameter. Also, boundary layer thickness when γ < 0 (injection) and when γ > 0 (suction) will be compared. The present results with the existence literature will be compared for justification/validation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: In this article, the nanomaterial flow of micropolar fluid in rotating frame is considered. The SWCNT and MWCNT with base fluid namely pure water is also taken into account to analyze the flow behavior over stretching surface. Mathematical model have been constructed under the nanomaterial of micropolar fluid., Method: The governing equations have been developed in the form of system of partial differential equations. The partial differential equations are transformed into ordinary differential equations using similarity transformations. The transformed system has been solved through MAPLE software., Results: The physical parameters like as thermal slip effects, velocity slip effects and magnetic hydrodynamics on the micropolar nanofluid are presented by tables and graphs. Surprisingly in the rotating parameter, F''(0) and - θ'(0) increases for higher values of the rotating parameter while opposite to be noted for G''(0). The Nusselt number and skin friction increases for higher values of micropolar parameter but MWCNT achieves higher heat transfer as associated to SWCNT., Competing Interests: Declaration of Competing Interest The authors have declared no conflict of interest, (Copyright © 2019. Published by Elsevier B.V.)

Objective: The flow kinetics generated with a pulsatile wave that travel along the channel has prime relevance in various processes in physiology and industry. The aim here is to investigate such phenomenon with Bingham fluid with chemically reacting species in terms of their homogeneous and heterogeneous characteristics., Method: To formulate the mathematical descriptions Bingham fluid with heat and mass equations is accounted. Using the similarity solutions, the proposed leading partial differential equations of the flow phenomena transferred into the nonlinear ordinary differential equations and boundary conditions are solved analytically. Such considerations perceive prime importance in medicine and genetics where heterogeneity in a cell makes several diseases difficult to execute., Results: Further the physical aspect of human tabular organs i.e., porosity in a medium is retained in the analysis. The utility of magnetic field in reference to medicine is employed. The walls are considered flexible. The whole problem is set to lubrication approach for simplification of resulting system. The attained results are tested on physical grounds by plotting graphs., Conclusion: It is analyzed that the Hartman number and porosity parameter reduce the velocity and temperature profiles. The elastic wall parameters E 1 and E 2 enhances both the velocity and temperature fields while E 3 enrolls an adverse effect., (Copyright © 2019. Published by Elsevier B.V.)

We deliberated the flow of magnetized micropolar hybrid nanoparticles fluid flow over the Riga curved surface. Exponentially stretching and slip effects are also considered in this analysis. Mathematical model has been established on the base of assumptions in the form of partial differential equations. Such equations are renewed into ordinary differential equations utilizing similarity transformations. Reduced model has been elucidated by means of bvp4c scheme. Impacts of physical parameters namely as stretching parameter R 0 , curvature parameter K, solid nanoparticle volume fraction Φ 2 , micropolar parameter K 1 , microgyration parameter n, thermal slip parameter M, partial slip parameter γ, modified Harman number ∅ and dimensionless parameter ω. Magnetic parameter β and reciprocal magnetic Prandtl number λ are depicted by means of numerically and graphically. Our results help in the field of engineering and industrial. This model is presented in the first time through literatures. Our interest of study is to be analyzed about the heat transfer rate of magnetized micropolar hybrid nanomaterial fluid over a Riga curved surface. Comparison with the literature has been worked out and excellent agreement is found., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019. Published by Elsevier B.V.)

Isoformononetin (methoxy isoflavone) is a potent osteogenic isoflavone abundantly present in Butea monosperma, Pisum sativum, Mung bean, Machaerium villosum, Medicago sativa, and Glycine max. In the current study, an LC-ESI-MS/MS method for the simultaneous evaluation of isoformononetin (IFN), daidzein (DZN) and equol (EQL) was developed and validated in rat plasma using biochanin A as an internal standard. IFN, DZN, and EQL separation was achieved by using acetonitrile and acetic acid (0.1%) in the ratio of 90:10 (% v/v) as mobile phase under isocratic conditions at a flow rate of 0.6 mL/min on Atlantis C 18 (4.6 × 250 mm, 5.0 μm) column. The achieved method was linear within the concentration range of 0.5-500 ng/mL. The method was effectively applied to investigate the permeability, protein binding estimation and pharmacokinetics studies of IFN in rats. The PAMPA permeability of IFN was found to be high at pH 4.0 and 7.0. The protein binding was found to be about 91% of IFN. The oral bioavailability of IFN was found to be poor (21.6%). IFN was found to have a moderate clearance (2.9 L/h/kg) and a large apparent volume of distribution (12.1 L/kg). The plasma half-life (t 1/2 ) and maximum attainable concentration (C max ) of IFN at systemic circulation was found to be 1.9 ± 0.6 h and 269.3 ± 0.4 after oral administration., (Copyright © 2019. Published by Elsevier B.V.)

The effects of slip condition and Joule heating on the peristaltic flow of Bingham nanofluid are investigated. The flow is taken in a porous channel with elastic walls. Mathematical formulation is presented under the assumption of long wavelength and small Reynolds number. The transformed equations for the flow are solved to seek values for the nanoparticles velocity, concentration and temperature along the channel length. Graphs are plotted to evaluate the behavior of various physical parameters on flow quantities in both slip and no-slip cases. The main features of the physical parameters are highlighted on the inclined non uniform channel. The results show an increment in velocity with rise in inclination and porosity while it reduces with magnetic field. Moreover, nanofluid favors the heat transfer and decline the concentration., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Pentoxifylline (PTX) is a non-selective phosphodiesterase inhibitor and is used for the management of intermittent claudication. We tested whether PTX has oral efficacy in stimulating new bone formation. Rat calvarial osteoblasts (RCO) were used to study the effect of PTX on osteoblast differentiation and angiogenesis. Pharmacokinetic and pharmacodynamic studies were carried out in rats to determine an oral dose of PTX. In ovariectomized (OVX) rats with osteopenia, the effect of PTX on various skeletal parameters was studied, and compared with teriparatide. Effect of PTX on angiogenic signaling was studied by immunoblotting and relevant pharmacologic inhibitors. Bone vascularity was measured by intravenous injection of polystyrene fluorospheres followed by in vivo imaging, and angiogenesis was studied in vitro by tubulogenesis of endothelial cells and in vivo by Matrigel plug assay. Effective concentration (EC 50 ) of PTX in RCO was 8.2 nM and plasma PTX level was 7 nM/mL after single oral dosing of 25 mg/kg, which was 1/6th the clinically used dose. At this dose, PTX enhanced bone regeneration at femur osteotomy site and completely restored bone mass, microarchitecture, and strength in OVX rats. Furthermore, PTX increased surface referent bone formation parameters and serum bone formation marker (PINP) without affecting the resorption marker (CTX-1). PTX increased the expression of vascular endothelial growth factor and its receptor in bones and osteoblasts. PTX also increased skeletal vascularity, tubulogenesis of endothelial cells and in vivo angiogenesis. Taken together, our study suggested that PTX at 16% of adult human oral dose completely reversed osteopenia in OVX rats by osteogenic and osteo-angiogenic mechanisms.

The non-selective phosphodiesterase inhibitor pentoxifylline (PTX) is used for the treatment of intermittent claudication due to artery occlusion. Previous studies in rodents have reported salutary effects of the intraperitoneal administration of PTX in segmental bone defect and fracture healing, as well as stimulation of bone formation. We determined the effect of orally dosed PTX in skeletally mature ovariectomized (OVX) rabbits with osteopenia. The half-maximal effective concentration (EC 50 ) of PTX in rabbit bone marrow stromal cells was 3.07 ± 1.37 nM. The plasma PTX level was 2.05 ± 0.522 nM after a single oral dose of 12.5mg/kg, which was one-sixth of the adult human dose of PTX. Four months of daily oral dosing of PTX at 12.5 mg/kg to osteopenic rabbits completely restored bone mineral density, bone mineral content (BMC), microarchitecture and bone strength to the level of the sham-operated (ovary intact) group. The bone strength to BMC relationship between PTX and sham was similar. The bone restorative effect of PTX was observed in both axial and appendicular bones. In osteopenic rabbits, PTX increased serum amino-terminal propeptide, mineralized nodule formation by stromal cells and osteogenic gene expression in bone. PTX reversed decreased calcium weight percentage and poor crystal packing found in osteopenic rabbits. Furthermore, similar to parathyroid hormone (PTH), PTX had no effect on bone resorption. Taken together, our data show that PTX completely restored bone mass, bone strength and bone mineral properties by an anabolic mechanism. PTX has the potential to become an oral osteogenic drug for the treatment of post-menopausal osteoporosis., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

WHO classified neurological disorders to be among 6.3% of the global disease burden. Among the most central aspects of CNS drug development is the ability of novel molecules to cross the blood-brain barrier (BBB) to reach the target site over a desired time period for therapeutic action. Based on various aspects, brain pharmacokinetics is considered to be one of the foremost perspectives for the higher attrition rate of CNS biologics. Although drug traits are important, the BBB and blood-cerebrospinal fluid barrier together with transporters become the mechanistic approach behind CNS drug delivery. The present review emphasizes neuropharmacokinetic parameters, their importance, an assessment approach and the vast effect of transporters to brain drug distribution for CNS drug discovery., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The major concern of current pagination is to report the doubly stratified medium subject to both magnetized and non-magnetized flow fields. For this purpose both the Newtonian and non-Newtonian liquids are considered in a double stratified medium having magnetic field interaction. To be more specific, a generally accepted rheological liquid around a cylindrical surface having constant radius embedded in magnetized doubly stratified media is taken into account. Additionally, flow field is manifested with various pertinent physical effects. The flow problem statement is defended through generalized formulation via fundamental laws. A computational scheme is executed and stream lines topologies are constructed for the both magnetized and non-magnetized stratified medium to explore the interesting features. It is observed that the Casson fluid velocity towards cylindrical surface is higher in magnitude as compared to flat surface. Such observation is same for the both the magnetized and non-magnetized flow fields. Our general formulation yields some existing attempts in the literature. The variations in local skin friction coefficient (LSFC), local Nusselt number (LNN) and local Sherwood number (LSN) are provided with the aid of tabular forms. It is trusted that the obtain observations via stream lines topologies will serve a clear insight to the said flow problem.

Background: Bioavailability, one of the prime pharmacokinetic properties of a drug, is defined as the fraction of an administered dose of unchanged drug that reaches the systemic circulation and is used to describe the systemic availability of a drug. Bioavailability assessment is imperative in order to demonstrate whether the drug attains the desirable systemic exposure for effective therapy. In recent years, bioavailability has become the subject of importance in drug discovery and development studies., Methods: A systematic literature review in the field of bioavailability and the approaches towards its enhancement have been comprehensively done, purely focusing upon recent papers. The data mining was performed using databases like PubMed, Science Direct and general Google searches and the collected data was exhaustively studied and summarized in a generalized manner., Results: The main prospect of this review was to generate a comprehensive one-stop summary of the numerous available approaches and their pharmaceutical applications in improving the stability concerns, physicochemical and mechanical properties of the poorly water-soluble drugs which directly or indirectly augment their bioavailability., Conclusion: The use of novel methods, including but not limited to, nano-based formulations, bio-enhancers, solid dispersions, lipid-and polymer-based formulations which provide a wide range of applications not only increases the solubility and permeability of the poorly bioavailable drugs but also improves their stability, and targeting efficacy. Although, these methods have drastically changed the pharmaceutical industry demand for the newer potential methods with better outcomes in the field of pharmaceutical science to formulate various dosage forms with adequate systemic availability and improved patient compliance, further research is required., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: Ritonavir (RIT) is a human immune deficiency virus (HIV) protease inhibitor (PI) active against HIV-1 and HIV-2. Among various adverse effects of PIs, hepatotoxicity is a very common adverse reaction of RIT which is concentration dependent. Red clover isoflavones are found to possess anti-inflammatory, antioxidant and anti-apoptosis activity. Furthermore, recent studies have demonstrated that these isoflavones can be used to alleviate the side-effects of drugs. Hence, the present study was inquested to ascertain the effect of Formononetin (FMN) and Biochanin A (BCA) on RIT induced hepatotoxicity., Main Methods: Five groups of animals were subjected to treatment as control, toxic control (RIT), third group (RIT + FMN), fourth group (RIT + BCA), the fifth group (RIT + FMN + BCA) and sixth group (FMN + BCA) for 14 days. The animals were evaluated for estimation of liver toxicity markers, inflammatory biomarkers, in-vivo biochemical antioxidant parameters. The liver tissues were further evaluated histopathologically and western blotting examination for localization of apoptotic gene expression that plays a pivotal role in hepatotoxicity., Key Findings: FMN and BCA ameliorated the increased levels of biochemical markers of liver, attenuated the RIT induced Bax, caspase-3, NFκB and eNOS activation and persuaded the Bcl 2 and pAkt level. Alteration in the levels of inflammatory markers was also observed in both hepatic tissue and serum., Significance: FMN and BCA exerts hepatoprotective effect through modulating the oxidative stress, inflammation, apoptosis and reversing the tissue degeneration suggesting its therapeutic role in hepatotoxicity and other hepatocellular diseases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cladrin, an isoflavone is a major bioactive constituent found in stem bark of Butea monosperma with remarkable osteogenic activity. A speedy and sensitive UPLC coupled tandem mass spectrometry (UPLC-MS/MS) method was developed, validated and successfully applied to bioavailability, blood partitioning, plasma protein binding, intravenous and multiple-dose oral pharmacokinetics of cladrin in rats. Separation was done on C18 column (5.0 μm, 4.6 × 50 mm) using mobile phase containing acetonitrile and 0.10% formic acid in the ratio of 65:35 (v/v) with 0.60 mL/min flow rate. The method was highly sensitive and has a short run time of 2.50 min with an excellent linearity (R 2  > 0.99) in the range of 0.20-200 μg/L. Absolute bioavailability was found to be 16.58, 19.04 and 6.76% at oral doses of 5, 10, and 20 mg/Kg, respectively. Cladrin was rapidly absorbed (T max 3.0 h) with a high apparent volume of distribution (15.03 ± 1.79L/Kg), high clearance (2.27 ± 0.30L/h/Kg) and high plasma protein binding. The present study is a first comprehensive in-vitro as well as the in-vivo preclinical pharmacokinetic report of cladrin giving insights about its drug-likeness and further development as a potential therapeutic agent., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The current paper contains the simultaneous analysis of both Newtonian and non-Newtonian nanofluid models. The fluid flow is achieved by considering the no-slip condition subject to a stretched cylindrical surface. The flow regime manifests with pertinent physical effects, namely temperature stratification, concentration stratification, thermal radiation, heat generation, magnetic field, dual convection and chemical reaction. The strength of fluid temperature and nanoparticles concentration adjacent to an inclined cylindrical surface is assumed to be higher than the ambient flow field. A mathematical model is developed in terms of differential equations. A self-constructed numerical algorithm is executed to report the numerical solution. The resultant annotations are illustrated through both tables and graphs. It is noticed that the Casson fluid shows significant variations with respect to the involved physical parameters as compared to the Newtonian fluid model. Moreover, the analysis is certified through comparison with the existing values in a limiting sense.

Two-dimensional flow of Casson fluid toward an exponentially stretched surface in view of Cattaneo-Christove flux theory is discoursed in current communication. Flow pattern within boundary layer under the effectiveness of magnetic field is also contemplated in the communication. Non-dimensionalized governing expressions are attained through transformation procedure. To anticipate the fascinating features of present work, solution of resulted nonlinear differential system is computed with the collaborated help of shooting scheme and Runge-Kutta method. The influence of involved variables on velocity and temperature fields is scrutinized. Contribution of thermal relaxation is explicitly pointed out. Evaluation of convective heat transfer and friction factor in the fluid flow is visualized through graphs and tables. Additionally, the assurance of present work is affirmed by developing comparison with previous findings in the literature which sets a trade mark for the implementation of numerical approach. It is inferred from the thorough examination of the analysis that present formulation reduces to classical Fourier's problem by considering Λ = 0 . Furthermore, decreasing pattern in temperature distribution is depicted in the presence of Cattaneo-Christove flux law as compared to heat transfer due to the Fourier's law.

This article addresses the effects of homogenous-heterogeneous reactions on electrically conducting boundary layer fluid flow and heat transfer characteristics over a stretching sheet with Newtonian heating are examined. Using similarity transformations, the governing equations are transformed into nonlinear ordinary differential equations. The constricted ordinary differential equations are solved computationally by shooting technique. The impact of pertinent physical parameters on the velocity, concentration and temperature profiles is discussed and explored via figures and tables. It is clear from figures that the velocity profile reduces for large values of fluid parameter B and Hartmann number H . Skin friction coefficient decreases for large values of Hartmann number H and fluid parameter B . Also, heat transfer rate monotonically enhances with conjugate parameter of Newtonian heating γ and Prandtl number Pr ., Competing Interests: Compliance with ethical standardsIn the present work, we have not used any material from previously published. So we have no conflict of interest.

We have found that few attempts are reported on Williamson fluid flow yields by an inclined cylindrical surface. To be more specific, Williamson fluid flow regime characteristics under stagnation point region especially when it is manifested with mutual interaction of double stratification and mixed convection effects are not proposed as yet. Therefore, we have considered stagnation point mixed convection Williamson fluid flow brought by an inclined cylinder in the presence of temperature and concentration stratification phenomena. Further, the fluid flow is entertained through no slip condition i-e the velocity of particles is directly related to velocity of cylindrical surface due to stretching. The physical situation within the real concerned constraints is translated in terms of differential equations as a boundary value problem. To make implementation of computational algorithm possible, following steps are taken into account •The PDE's are transformed into ODE's by using suitable transformation.•The resulting boundary value problem is converted into an initial value problem.•These constructed ordinary differential equations are solved computationally by shooting technique charted with Runge-Kutta scheme.•The effect logs of an involved physical flow parameters are explored by way of graphical outcomes and tabular values.

Cardamonin (CRD), a chalconoid obtained from several medicinal plants of Zingiberaceae family, had shown promising potential in cancer prevention and therapy. For further development and better pharmacological elucidation, we performed a series of in vitro and in vivo studies to characterize its preclinical pharmacokinetics. The study samples were analyzed using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high performance liquid chromatography-ultra violet (HPLC-UV) methods. CRD is partially soluble (<10 μM) and possess high permeability (>0.2 × 10-4 cm/sec). It is moderately bound to plasma proteins (<50%). It shows partitioning in red blood cell (RBC) compartment with the partition coefficient between RBCs and plasma (K RBC/P ) of 0.95 at 0 min to 1.39 at 60 min, indicating significant but slow RBC uptake. In mice, CRD is poorly absorbed after oral administration with 18% oral bioavailability. It possesses high clearance, short mean residence time, and high volume of distribution in mice. It exhibited multiple peak phenomena both after oral and intravenous administration and is excreted both as conjugated and unchanged CRD in bile. It is majorly excreted in faeces and negligibly in urine. The preclinical absorption, distribution, metabolism, and excretion data are expected to succour the future clinical investigations of CRD as a promising anticancer agent. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Tuberculosis is a life threatening disease and second to HIV in terms of deaths due to infectious diseases. Drug resistance development of the first-line drugs is a major concern in the treatment of this disease. There is no comprehensive and critical review in the literature of the bioanalytical methods for the determination of anti-tubercular agents from last two decades. This work offers a detailed account on the liquid chromatographic methods reported in the literature for the estimation of various anti-tubercular drugs. Major emphasis is given to sample preparation process, sensitivity of method, chromatographic separation conditions and detection systems used in their bioanalysis., (Copyright © 2016. Published by Elsevier B.V.)

The concepts, importance, and application of bioanalytical method validation have been discussed for a long time and validation of bioanalytical methods is widely accepted as pivotal before they are taken into routine use. United States Food and Drug Administration (USFDA) guidelines issued in 2001 have been referred for every guideline released ever since; may it be European Medical Agency (EMA) Europe, National Health Surveillance Agency (ANVISA) Brazil, Ministry of Health and Labour Welfare (MHLW) Japan or any other guideline in reference to bioanalytical method validation. After 12 years, USFDA released its new draft guideline for comments in 2013, which covers the latest parameters or topics encountered in bioanalytical method validation and approached towards the harmonization of bioanalytical method validation across the globe. Even though the regulatory agencies have general agreement, significant variations exist in acceptance criteria and methodology. The present review highlights the variations, similarities and comparison between bioanalytical method validation guidelines issued by major regulatory authorities worldwide. Additionally, other evaluation parameters such as matrix effect, incurred sample reanalysis including other stability aspects have been discussed to provide an ease of access for designing a bioanalytical method and its validation complying with the majority of drug authority guidelines., (Copyright © 2016. Published by Elsevier B.V.)

Enterohepatic recirculation (EHC) concerns many physiological processes and notably affects pharmacokinetic parameters such as plasma half-life and AUC as well as estimates of bioavailability of drugs. Also, EHC plays a detrimental role as the compounds/drugs are allowed to recycle. An in-depth comprehension of this phenomenon and its consequences on the pharmacological effects of affected drugs is important and decisive in the design and development of new candidate drugs. EHC of a compound/drug occurs by biliary excretion and intestinal reabsorption, sometimes with hepatic conjugation and intestinal deconjugation. EHC leads to prolonged elimination half-life of the drugs, altered pharmacokinetics and pharmacodynamics. Study of the EHC of any drug is complicated due to unavailability of the apposite model, sophisticated procedures and ethical concerns. Different in vitro and in vivo methods for studies in experimental animals and humans have been devised, each having its own merits and demerits. Involvement of the different transporters in biliary excretion, intra- and inter-species, pathological and biochemical variabilities obscure the study of the phenomenon. Modeling of drugs undergoing EHC has always been intricate and exigent models have been exploited to interpret the pharmacokinetic profiles of drugs witnessing multiple peaks due to EHC. Here, we critically appraise the mechanisms of bile formation, factors affecting biliary drug elimination, methods to estimate biliary excretion of drugs, EHC, multiple peak phenomenon and its modeling.

Ormeloxifene (ORM) is a non-steroidal, selective estrogen receptor modulator used as a once a week oral contraceptive and is intended for long-term clinical use by females. Therefore, a simple, sensitive and rapid LC-MS/MS method was developed and validated for simultaneous quantification of ORM and its active metabolite (7-desmethyl ormeloxifene, 7-DMO) in rat plasma. Also, the method was partially validated in human plasma. Chromatographic separation was achieved on Discovery HS C-18 column (5μm, 50×4.6mm) with mobile phase [acetonitrile: aqueous ammonium acetate (0.01M) buffer (85: 15, %v/v)] at a flow rate of 0.8mL/min. The calibration curve was linear (r≥0.99) for a concentration range of 0.78-100ng/mL for both the analytes. The precision (%RSD; ORM, 1.3 to 13.4; 7-DMO, 3.1 to 15.0) and accuracy (%bias; ORM, -13.8 to 12.5; 7-DMO, -10.6 to 6.8) in both rat and human plasma were within the acceptable limits. The recovery for ORM and 7-DMO was always >79.1% and >72.9%, respectively. Both the analytes were found stable in rat plasma even after 30 days of storage at -80°C and on being subjected to three freeze-thaw cycles. The method has not only short run time (3.5min) but requires a low plasma sample volume (20μL) and is the first reported LC-MS/MS method for simultaneous quantification of the marketed drug known as centchroman (INN: ormeloxifene) and the metabolite 7-DMO in plasma. The method was applied to evaluate drug-drug interaction of ORM with the commonly prescribed antidepressant drug sertraline using serial sampling in rats., (Copyright © 2015 Elsevier B.V. All rights reserved.)