Polydatin inhibits histone deacetylase 1 and shows an anti-angiogenic action in head and neck squamous cell carcinoma.

Polydatin, a natural derivative of resveratrol, has shown many anticancer properties. However, the underlying mechanisms of its anticancer properties including its effect on the epigenetic landscape are not well understood. Here, we explored the effect of polydatin on histone deacetylase 1 (HDAC1) activity. We used in silico approaches to assess the possible binding of polydatin to the active site pockets of HDAC1 and in vitro approaches to test the potential effects of the interaction on its enzymatic activity. As compared to SAHA, an approved drug, the polydatin showed stronger and stable binding to the HDAC1. The binding energy, conformational changes, formation of extra hydrogen bonding, and other interactions within and outside the active site all favour largely stable and strong polydatin binding to the enzyme. Further, the ADME and toxicity prediction values are encouraging for the evaluation of polydatin as a drug. The laboratory leg of the study substantiated that the polydatin binding was strong and stable enough to inhibit HDAC1 activity in UMS-CC-22B cells as demonstrated by an increase in H3K9 acetylation. In addition, polydatin treated cells showed attenuated proliferation. The in vitro tube formation and migration by HUVEC and UM-SCC-22B cells were inhibited by polydatin. The decreased tube formation due to HDAC1 inhibition is possibly due to up-regulation of the anti-angiogenic gene - TSP1 in UM-SCC-22B cells. As compared to SAHA, more promising results were shown both in its computational calculations and on the cell physiology features. Stronger and stable binding, more anti-proliferative and anti-angiogenic potential were observed with respect to polydatin. Further, the cell death was more pronounced with SAHA treatment. Therefore, polydatin might be a better anticancer drug and can have a potential to replace SAHA in combinational therapeutic regimen.

Recent Advances in the Development of Alpha-Glucosidase and Alpha-Amylase Inhibitors in Type 2 Diabetes Management: Insights from In silico to In vitro Studies.

Diabetes is a metabolic disorder caused by high glucose levels, leading to serious threats such as diabetic neuropathy and cardiovascular diseases. One of the most reliable measures for controlling postprandial hyperglycemia is to reduce the glucose level by inhibiting enzymes in the digestive system, such as Alpha-Glucosidase and Alpha-Amylase. Here, we have investigated the use of inhibitors to inhibit carbohydrate metabolism in order to restrict glucose levels in diabetic patients. Acarbose, Voglibose, and Miglitol are three inhibitors approved by the FDA that efficiently inhibit these two enzymes and thereby minimising hyperglycemia but are al-so significantly helpful in reducing the risk of cardiovascular effects. We also provide insight into the other known inhibitors currently available in the market. The adverse effects associated with other inhibitors emphasise the demand for the latest in silico screening and in vitro validation in the development of potent inhibitors with greater efficacy and safety for the treatment of Type 2 diabetes. The recent findings suggest that Alpha-Glucosidase and Alpha-Amylase play a major role in carbohydrate metabolism and triggering the increase in glucose levels. This review pro-vides the latest scientific literature findings related to these two enzymes as well as the role of primary and secondary inhibitors as potential candidates. Moreover, this review elaborates the framework on the mechanism of action, different plant sources of extraction of these enzymes, as well as kinetic assay of inhibitors and their interaction that can be used in future prospects to de-velop potential leads to combat Type 2 diabetes.

Diabetes Driven Oncogenesis and Anticancer Potential of Repurposed Antidiabetic Drug: A Systemic Review.

Diabetes and cancer are two prevalent disorders, pose significant public health challenges and contribute substantially to global mortality rates, with solely 10 million reported cancer-related deaths in 2020. This review explores the pathological association between diabetes and diverse cancer progressions, examining molecular mechanisms and potential therapeutic intersections. From altered metabolic landscapes to dysregulated signaling pathways, the intricate links are delineated, offering a comprehensive understanding of diabetes as a modulator of tumorigenesis. Cancer cells develop drug resistance through mechanisms like enhanced drug efflux, genetic mutations, and altered drug metabolism, allowing them to survive despite chemotherapeutic agent. Glucose emerges as a pivotal player in diabetes progression, and serving as a crucial energy source for cancer cells, supporting their biosynthetic needs and adaptation to diverse microenvironments. Glycation, a non-enzymatic process that produces advanced glycation end products (AGEs), has been linked to the etiology of cancer and has been shown in a number of tumor forms, such as leiomyosarcomas, adenocarcinomas, and squamous cell carcinomas. Furthermore, in aggressive and metastatic breast cancer, the receptor for AGEs (RAGE) is increased, which may increase the malignancy of the tumor. Reprogramming glucose metabolism manifests as hallmark cancer features, including accelerated cell proliferation, angiogenesis, metastasis, and evasion of apoptosis. This manuscript encapsulates the dual narrative of diabetes as a driver of cancer progression and the potential of repurposed antidiabetic drugs as formidable countermeasures. The amalgamation of mechanistic understanding and clinical trial outcomes establishes a robust foundation for further translational research and therapeutic advancements in the dynamic intersection of diabetes and cancer.

In Silico Investigation against Inhibitors of Alpha-Amylase Using Structure-based Screening, Molecular Docking, and Molecular Simulations Studies.

Type-II diabetes mellitus is a chronic disorder that results from fluctuations in the glucose level leading to hyperglycemia with severe adverse effects increasing worldwide. Alpha-Amylase is the key enzyme involved in the mechanism of glucose formation therefore Alpha-Amylase inhibitors have become a therapeutic target in the development of new leads as they have the potential to suppress glucose levels. Existing drugs targeting Alpha-Amylase highlight major drawbacks in terms of poor absorption rate that causes several gastrointestinal issues. So, this research is aimed to develop novel inhibitors interacting with Alpha-Amylase's active site using structural-based screening, binding pattern analysis, and molecular dynamic simulation. Hence, to search for a potential lead, we analyzed a total of 133 valiolamine derivatives and 535 desoxynojirimycin derivatives that exhibited drug-like properties screened through Lipinski filters. Virtual screening followed by binding interaction analysis we identified ten compounds that exhibited better binding energy scores compared to the standard drugs voglibose and miglitol, used in our study. The docking analysis, ADMET and metabolic site prediction estimated the best top two compounds with good drug profiles. Further, top compounds VG9 and VG15 were promoted to simulation study using the Biovia Discovery study to access the stability at a time interval of 100 ns. MD simulation results revealed that our compound VG9 possesses better conformational stability in the complex to the active site residues of Alpha-Amylase target protein than standard drug voglibose. Thus, our investigation revealed that compound VG9 also exhibits the best pharmacokinetic as well as binding affinity results and could act as a potential lead compound targeting Alpha-Amylase for Type II diabetes.

Soft diamonds: poetic sentiment, poetic speech, and poetic specimen in the clinical hour.

Three links between poetry and psychoanalysis are highlighted in this paper. These refer to the presence, in the clinical hour, of (i) poetic sentiment, (ii) poetic speech, and (iii) poetic specimen. Each is elucidated in detail and with the help of socio-clinical vignettes. The aim of the paper is to demonstrate that, through the affirmative holding and partial unmasking of the instinctual-epistemic conflation in verse and free-association, both poetry and psychoanalysis seek to transform the private into shared, the hideous into elegant, and the unfathomable into accessible.

Computational fluid dynamics analysis on endoscopy of main left coronary artery: An application of applied mathematics.

The endoscopy of a coronary arterial segment having a symmetric emergence of plaque at its innermost region is numerically modeled via computational fluid dynamics toolbox Open-FOAM. The considered left coronary artery for this model has a radius of 2 mm and span of 10 mm. The formation of plaque inside the artery that is a stenosis has length 2 mm and height 0.82 mm. The catheter used for this analysis has a diameter of 1 mm with a balloon over it with a height of 0.53 mm. The blood flow rate considered for this analysis has a range 2.00 ml/s to 2.50 ml/s. The fluid under consideration for this endoscopy review is the non-Newtonian Casson model. The mesh illustrations are arranged for the proposed model with numerical simulations of velocity, pressure profile and streamlines. The narrow channel formed due to assembly of stenosis and balloon over catheter inside this arterial segment has developed some swirling flow profile with turbulence effects just after the flow leaves the stenosis plus balloon region. Although this disturbance caused due to narrowing of channel has made the flow slightly turbulent, the flow eventually leaves the arterial segment again as a laminar flow. To cure coronary artery disease, catheterization, and balloon dilation of stenosed arteries is performed to locate the position and shape of stenosis. A catheter is inserted inside the body through a minor cut and then it is moved inside arteries to place it exactly at the stenosis location. A balloon is placed at front of that catheter and the stenosed region can be opened wide by using balloon dilation.

Exploring the potential of EphA2 receptor signaling pathway: a comprehensive review in cancer treatment.

The protein encoded by the ephrin type-A receptor 2 (EphA2) gene is a member of the ephrin receptor subfamily of the receptor tyrosine kinase family (RTKs). Eph receptors play a significant role in various biological processes, particularly cancer progression, development, and pathogenesis. They have been observed to regulate cancer cell growth, migration, invasion, tumor development, invasiveness, angiogenesis, and metastasis. To target EphA2 activity, various molecular, genetic, biochemical, and pharmacological strategies have been extensively tested in laboratory cultures and animal models. Notably, drugs, such as dasatinib, initially designed to target the kinase family, have demonstrated an additional capability to target EphA2 activity. Additionally, a novel monoclonal antibody named EA5 has emerged as a promising option to counteract the effects of EphA2 overexpression and restore tamoxifen sensitivity in EphA2-transfected MCF-7 cells during in vitro experiments. This antibody mimicked the binding of Ephrin A to EphA2. These methods offer potential avenues for inhibiting EphA2 activity, which could significantly decelerate breast cancer progression and restore sensitivity to certain drugs. This review article comprehensively covers EphA2's involvement in multiple malignancies, including ovarian, colorectal, breast, lung, glioma, and melanoma. Furthermore, we discuss the structure of EphA2, the Eph-Ephrin signaling pathway, various EphA2 inhibitors, and the mechanisms of EphA2 degradation. This article provides an extensive overview of EphA2's vital role in different types of cancers and outlines potential therapeutic approaches to target EphA2, shedding light on the underlying molecular mechanisms that make it an attractive target for cancer treatment.

Molecular modeling, dynamic simulation, and metabolic reactivity studies of quinazoline derivatives to investigate their anti-angiogenic potential by targeting wild EGFRwt and mutant EGFRT790M receptor tyrosine kinases.

Non-small cell lung cancer, head and neck cancer, glioblastoma, and various other cancer types often demonstrate persistent elevation in EGFR tyrosine kinase activity due to acquired mutations in its kinase domain. Any alteration in the EGFR is responsible for triggering the upregulation of tumor angiogenic pathways, such as the PI3k-AKT-mTOR pathway, MAPK-ERK pathway and PLC-Ƴ pathway, which are critically involved in promoting tumor angiogenesis in cancer cells. The emergence of frequently occurring EGFR kinase domain mutations (L858R/T790M/C797S) that confer resistance to approved therapeutic agents has presented a significant challenge for researchers aiming to develop effective and well-tolerated treatments against tumor angiogenesis. In this study, we directed our efforts towards the rational design and development of novel quinazoline derivatives with the potential to act as antagonists against both wild-type and mutant EGFR. Our approach encompasing the application of advanced drug design strategies, including structure-based virtual screening, molecular docking, molecular dynamics, metabolic reactivity and cardiotoxicity prediction studies led to the identification of two prominent lead compounds: QU648, for EGFRwt inhibition and QU351, for EGFRmt antagonism. The computed binding energies of selected leads and their molecular dynamics simulations exhibited enhanced conformational stability of QU648 and QU351 when compared to standard drugs Erlotinib and Afatinib. Notably, the lead compounds also demonstrated promising pharmacokinetic properties, metabolic reactivity, and cardiotoxicity profiles. Collectively, the outcomes of our study provide compelling evidence supporting the potential of QU648 and QU351 as prominent anti-angiogenic agents, effectively inhibiting EGFR activity across various cancer types harboring diverse EGFR mutations.Communicated by Ramaswamy H. Sarma.

Oblique stagnation point flow of magnetized Maxwell fluid over a stretchable Riga plate with Cattaneo-Christov heat flux and convective conditions.

The current work deals with the oblique stagnation point flow phenomenon of a rate-type Maxwell fluid with the significance of the Cattaneo-Christov double diffusion theory. The Cattaneo-Christov theory is illustrated through the modified form of Fourier's and Fick's laws. The steady magnetized flow mechanism is observed in two dimensions through a stretchable convective Riga plate. In the mass and heat transfer analysis, the consequences of chemical reactions and thermal radiation are also incorporated. With the contribution of relevant dimensionless quantities, the setup of dimensionless equations is acquired which further takes the form of nonlinear equations. The physical significance of the numerous parameters on different features of the flow phenomenon is graphically exhibited. The interesting physical quantities are computed and numerically evaluated relative to the pertinent parameters. This study reveals that the thermal relaxation time parameter lowers the rate of heat transfer, and the thermal Biot number enhances the rate of heat transport. Moreover, the Deborah number minimizes the flow field of both tangential and axial velocities.

CFD analysis on blood flow inside a symmetric stenosed artery: Physiology of a coronary artery disease.

This research article interprets the computational fluid dynamics analysis on blood flow inside a symmetric stenosed artery. The current problem models the blood flow inside the left coronary artery as having a symmetric stenosis in the central region. A comprehensive physiological examination of coronary artery disease is numerically evaluated by using the computational fluid dynamics toolbox Open-Field Operation And Manipulation. There are no assumptions of mild stenosis taken into account since the considered stenosis has an exactly measured length, height and position, etc. The blood flow problem is modeled for the non-Newtonian Casson fluid with unsteady, laminar, and incompressible flow assumptions. The underlying problem is solved numerically in its dimensional form. A thorough graphical analysis is provided on the blood flow simulations, pressure profile, velocity line graphs, pressure line graphs, and streamlines for the left coronary artery having a symmetric stenosis formation. The considered artery is divided into three sections, i.e. pre-stenosis, post-stenosis, and stenosis region, and the velocity and pressure line graphs are plotted for these considered regions. The graphical illustrations provide a detailed analysis of how the blood flow is affected inside the left coronary artery due to coronary artery disease. These pre- and post-stenosis velocity line graphs reveal two intriguing results: In the pre-stenosis zone, the velocity increases with increasing axial coordinate length, whereas in the post-stenosis region, the velocity decreases with rising axial coordinate length. It is evident that as the flow moves toward the stenosis region, the flow profile rises; yet, after passing through the stenosis zone, the flow profile begins to fall as the flow moves away from the stenosis region.

Entropy analysis for a novel peristaltic flow in a curved heated endoscope: an application of applied sciences.

Entropy interpretation with a descriptive heat generation analysis is carried out for the heated flow between two homocentric and sinusoidally fluctuating curved tubes. A novel peristaltic endoscope is considered for the first time inside a curved tube with evaluation of heat transfer and entropy. This flexible and novel endoscope with peristaltic locomotion is more efficient for endoscopy of complex mechanical structures and it is more comfortable for patients undergoing the endoscopy of a human organs. A comprehensive mathematical model is developed that also completely evaluates the heat transfer analysis for this novel endoscope. Certain and systematic computations are performed with the help of Mathematica software and exact mathematical as well as graphical solutions are obtained. Entropy has a lower rate that is almost zero entropy in the central region of these two curved tubes, but maximum entropy is noted near the sinusoidally deformable walls of both the endoscope and channel.

Nanoinformatics and Personalized Medicine: An Advanced Cumulative Approach for Cancer Management.

BACKGROUND: Even though the battle against one of the deadliest diseases, cancer, has advanced remarkably in the last few decades and the survival rate has improved significantly; the search for an ultimate cure remains a utopia. Nanoinformatics, which is bioinformatics coupled with nanotechnology, endows many novel research opportunities in the preclinical and clinical development of personalized nanosized drug carriers in cancer therapy. Personalized nanomedicines serve as a promising treatment option for cancer owing to their noninvasiveness and their novel approach. Explicitly, the field of personalized medicine is expected to have an enormous impact soon because of its many advantages, namely its versatility to adapt a drug to a cohort of patients. OBJECTIVE: The current review explains the application of this newly emerging field called nanoinformatics to the field of precision medicine. This review also recapitulates how nanoinformatics could hasten the development of personalized nanomedicine for cancer, which is undoubtedly the need of the hour. CONCLUSION: This approach has been facilitated by a humongous impending field named Nanoinformatics. These breakthroughs and advances have provided insight into the future of personalized medicine. Imperatively, they have been enabling landmark research to merge all advances, creating nanosized particles that contain drugs targeting cell surface receptors and other potent molecules designed to kill cancerous cells. Nanoparticle- based medicine has been developing and has become a center of attention in recent years, focusing primely on proficient delivery systems for various chemotherapy drugs.

Analytical solutions of PDEs by unique polynomials for peristaltic flow of heated Rabinowitsch fluid through an elliptic duct.

In this research, we have considered the convective heat transfer analysis on peristaltic flow of Rabinowitsch fluid through an elliptical cross section duct. The Pseudoplastic and Dilatant characteristics of non-Newtonian fluid flow are analyzed in detail. The Rabinowitsch fluid model shows Pseudoplastic fluid nature for [Formula: see text] and Dilatant fluid behaviour for [Formula: see text] The governing equations are transformed to dimensionless form after substituting pertinent parameters and by applying the long wavelength approximation. The non-dimensional momentum and energy equations are solved analytically to obtain the exact velocity and exact temperature solutions of the flow. A novel polynomial of order six having ten constants is introduced first time in this study to solve the energy equation exactly for Rabinowitsch fluid flow through an elliptic domain. The analytically acquired solutions are studied graphically for the effective analysis of the flow. The flow is found to diminish quickly in the surrounding conduit boundary for Dilatant fluid as compared to the Pseudoplastic fluid. The temperature depicted the opposite nature for Pseudoplastic and Dilatant fluids. The flow is examined to plot the streamlines for both Pseudoplastic and Dilatant fluids by rising the flow rate.

Entropy and stability analysis on blood flow with nanoparticles through a stenosed artery having permeable walls.

In this research, the electro-osmotic effects are highlighted for a blood-based hybrid nanofluid flow across an artery infected with multiple stenosis. The artery has permeable walls together with slip boundary effects. The slip and permeable boundary conditions model the more realistic blood flow problems. The governing equations of the problem are converted into non-dimensional form by introducing adequate dimensionless variables and acquired the exact solutions. The detailed study of heat transfer is given by Joule heating and viscous dissipation effects. The disorder of fluid flow is investigated by the mathematical study of entropy generation. Analytically attained solutions are examined graphically for both symmetric and non-symmetric shapes of stenosis. Streamlines are analyzed for varying values of flow rate Q and electro-osmotic parameter m. The flow velocity has smallest values on the axis of channel and gets higher value near the boundary walls. The temperature profile delineates opposite behavior to the velocity, and it is parabolic in nature. The velocity reduces towards the non-uniform stenosis except for electroosmotic parameter m. The temperature has larger magnitude in the case of anti-symmetric stenosis. Moreover, the stability of velocity solution is also analyzed.

Effect of Cardiac Catheterization Personnel On Time to Treatment for Myocardial Infarction.

PURPOSE: To evaluate the effect of physician and nonphysician cardiac catherization laboratory personnel on the treatment of myocardial infarction. METHODS: Admissions data from 4 Las Vegas, Nevada hospitals were analyzed via multivariate regression analysis to determine predictors of reperfusion times. The goal for reperfusion is a door-to-balloon time of less than 90 minutes. RESULTS: Prehospital ST-segment elevation myocardial infarction (STEMI) activation, cardiologist arrival time, lifesaving measures, door-to-electrocardiogram (ECG) time, time and day, critical diagnostic examinations, and door-to-first-medical-doctor time all significantly affected door-to-balloon time. However, cardiac catheterization laboratory (CCL) staff arrival time did not affect door-to-balloon time. DISCUSSION: This study confirms the well-established importance of prehospital ECG and STEMI protocol activation. The results also indicate the importance of cardiologist arrival time on reperfusion times as this explained a significant amount of the explained variance in door-to-balloon time. CCL team arrival time did not affect door-to-balloon time, dispelling a long-held belief that reducing the response time of the CCL team significantly reduced reperfusion times. CONCLUSION: Although cardiologist arrival time influenced door-to-balloon time, CCL staff arrival time did not. Programs to provide greater laboratory coverage might help improve reperfusion times as well as assist STEMI program coordinators in developing more efficient protocols.

Structure-based pharmacophore modeling, virtual screening and simulation studies for the identification of potent anticancerous phytochemical lead targeting cyclin-dependent kinase 2.

Cyclin-dependent kinases are of critical importance in directing various cell cycle phases making them as potential tumor targets. Cyclin-dependent kinase 2 (CDK2) in particular plays a significant part during cell cycle events and its imbalance roots out tumorogenic environment. Herein, we built a structure-based pharmacophore model complementing the ATP pocket site of CDK2 with four pharmacophoric features, using a series of structures obtained from cluster analysis during MD simulation assessment. This was followed by its validation and further database screening against Taiwan indigenous plants database (5284 compounds). The screened compounds were subjected toward Lipinski's rule (RO5) and ADMET filter followed by docking analysis and simulation study. In filtering hits (10 compounds) via molecular docking against CDK2, Schinilenol with -8.1 kcal/mol fetched out as a best lead phytoinhibitor in the presence of standard drug (Dinaciclib). Additionally, pharmacophore mapping analysis also indicated relative fit values of dinaciclib and schinilenol as 2.37 and 2.31, respectively. Optimization, flexibility prediction and the stability of CDK2 in complex with the ligands were also ascertained by means of molecular dynamics for 50 ns, which further proposed schinilenol having better binding stability than dinaciclib with RMSD values ranging from 0.31 to 0.34 nm. Reactivity site, biological activity detection and cardiotoxicity assessment also proposed schinilenol as a better phytolead inhibitor than the existing dinaciclib. Abbreviations: CDK2: Cyclin dependent kinase2; ATP: Adenosine triphosphate; MD: Molecular dynamics, RO5: Rule of five; ADMET: Absorption, distribution, metabolism, and excretion; RMSD: Root mean square deviation; DS: Discovery Studio; SOM: Site of metabolism; RBPM: receptor based pharmacophore model; TIP: Schinilenol; hERG: human Ether-à-go-go - Related GeneCommunicated by Ramaswamy H. Sarma.

Eigenfunction expansion method for peristaltic flow of hybrid nanofluid flow having single-walled carbon nanotube and multi-walled carbon nanotube in a wavy rectangular duct.

In this study, "peristaltic transport of hybrid nanofluid" inside a rectangular duct is examined. Water (base fluid) is used with two types of nanoparticles, namely, single-walled carbon nanotube (SWCNT) and multi-walled carbon nanotube (MWCNT). The viscous dissipation effect comes out as the prime heat generation source as compared to the conduction of molecules. After using some suitable dimensionless quantities, we obtained the nonlinear partial differential equations in a coupled form which are then solved exactly by the Eigenfunction expansion method. Velocity distribution, pressure gradient, and pressure rise phenomena are also discussed graphically through effective physical parameters. The heat transfer rate is high for the phase flow (single-walled carbon nanotube/water) model as compared to the hybrid (single-walled carbon nanotube + multi-walled carbon nanotube/water) model due to the enhanced thermal conductivity of the hybrid model.

Nanomaterials in Alzheimer's disease treatment: a comprehensive review.

Alzheimer's, a progressive neurodegenerative disease affects brain and neurons through enormous reduction in nerve cell regenerative capacity. Dementia and impairment of cognitive functions are more prevalent in Alzheimer's disease (AD) patients in both industrialized and non-industrialized countries. Various factors play significant role in molecular cascades that leads to neuronal inflammation, dementia and thereby AD progression. Current medications are symptomatic that alleviates pain while lack in absolute cure, urging researchers to explore targets and therapeutics. Interestingly, nanomedicines developed due to the onset of nanotechnology, are being extensively investigated for the treatment of AD. This review presents the advancement in nanotherapeutic strategies, involving the emergence of nanomaterials that offers advantage to pass through the blood-brain barrier and acts as a therapeutic modality against AD.

Entropy Analysis of the Peristaltic Flow of Hybrid Nanofluid Inside an Elliptic Duct with Sinusoidally Advancing Boundaries.

Peristaltic flow of hybrid nanofluid inside a duct having sinusoidally advancing boundaries and elliptic cross-section is mathematically investigated. The notable irreversibility effects are also examined in this mathematical research by considering a descriptive entropy analysis. In addition, this work provides a comparison analysis for two distinct nanofluid models: a hybrid model (Cu-Ag/water) and a phase flow model (Cu/water). A comprehensive graphical description is also provided to interpret the physical aspects of this mathematical analysis.