Evolution of neuronal cell classes and types in the vertebrate retina.

The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs1. Retinal cell types may have evolved to accommodate these varied needs, but this has not been systematically studied. Here we generated and integrated single-cell transcriptomic atlases of the retina from 17 species: humans, two non-human primates, four rodents, three ungulates, opossum, ferret, tree shrew, a bird, a reptile, a teleost fish and a lamprey. We found high molecular conservation of the six retinal cell classes (photoreceptors, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells (RGCs) and Müller glia), with transcriptomic variation across species related to evolutionary distance. Major subclasses were also conserved, whereas variation among cell types within classes or subclasses was more pronounced. However, an integrative analysis revealed that numerous cell types are shared across species, based on conserved gene expression programmes that are likely to trace back to an early ancestral vertebrate. The degree of variation among cell types increased from the outer retina (photoreceptors) to the inner retina (RGCs), suggesting that evolution acts preferentially to shape the retinal output. Finally, we identified rodent orthologues of midget RGCs, which comprise more than 80% of RGCs in the human retina, subserve high-acuity vision, and were previously believed to be restricted to primates2. By contrast, the mouse orthologues have large receptive fields and comprise around 2% of mouse RGCs. Projections of both primate and mouse orthologous types are overrepresented in the thalamus, which supplies the primary visual cortex. We suggest that midget RGCs are not primate innovations, but are descendants of evolutionarily ancient types that decreased in size and increased in number as primates evolved, thereby facilitating high visual acuity and increased cortical processing of visual information.

YAP/TAZ-mediated regulation of laminin 332 is enabled by ß4 integrin repression of ZEB1 to promote ferroptosis resistance.

We are interested in the contribution of integrins and the extracellular matrix to epithelial differentiation in carcinomas. This study was motivated by our finding that the Hippo effectors YAP and TAZ can sustain the expression of laminin 332 (LM332), the predominant ECM ligand for the integrin ß4, in breast carcinoma cells with epithelial differentiation. More specifically, we observed that YAP and TAZ regulate the transcription of the LAMC2 subunit of LM332. Given that the ß4-LM332 axis is associated with epithelial differentiation and YAP/TAZ have been implicated in carcinoma de-differentiation, we sought to resolve this paradox. Here, we observed that the ß4 integrin sustains the expression of miR-200s that target the transcription factor ZEB1 and that ZEB1 has a pivotal role in determining the nature of YAP/TAZ-mediated transcription. In the presence of ß4, ZEB1 expression is repressed enabling YAP/TAZ/TEAD-mediated transcription of LAMC2. The absence of ß4, however, induces ZEB1, and ZEB1 binds to the LAMC2 promoter to inhibit LAMC2 transcription. YAP/TAZ-mediated regulation of LAMC2 has important functional consequences because we provide evidence that LM332 enables carcinoma cells to resist ferroptosis in concert with the ß4 integrin.

Salicylic acids and pathogenic bacteria: new perspectives on an old compound.

Salicylic acids have been used in human and veterinary medicine for their anti-pyretic, anti-inflammatory, and analgesic properties for centuries. A key role of salicylic acid-immune modulation in response to microbial infection-was first recognized during studies of their botanical origin. The effects of salicylic acid on bacterial physiology are diverse. In many cases, they impose selective pressures leading to development of cross-resistance to antimicrobial compounds. Initial characterization of these interactions was in Escherichia coli, where salicylic acid activates the multiple antibiotic resistance (mar) operon, resulting in decreased antibiotic susceptibility. Studies suggest that stimulation of the mar phenotype presents similarly in closely related Enterobacteriaceae. Salicylic acids also affect virulence in many opportunistic pathogens by decreasing their ability to form biofilms and increasing persister cell populations. It is imperative to understand the effects of salicylic acid on bacteria of various origins to illuminate potential links between environmental microbes and their clinically relevant antimicrobial-resistant counterparts. This review provides an update on known effects of salicylic acid and key derivatives on a variety of bacterial pathogens, offers insights to possible potentiation of current treatment options, and highlights cellular regulatory networks that have been established during the study of this important class of medicines.

Three novel multiplex PCR assays for rapid detection of virulence, antimicrobial resistance, and toxin genes in Acinetobacter calcoaceticus-baumannii complex species.

The Acinetobacter calcoaceticus-baumannii (ACB) complex is an often-overlooked group of nosocomial pathogens with a significant environmental presence. Rapid molecular screening methods for virulence, antimicrobial resistance, and toxin (VAT) genes are required to investigate the potential pathogenicity of environmental isolates. This study aimed to develop and apply novel ACB complex-specific multiplex PCR (mPCR) primers and protocols for the rapid detection of eight VAT genes. We optimized three single-tube mPCR assays using reference DNA from ACB complex and other Acinetobacter species. These assays were then applied to detect VAT genes in cultured ACB complex isolates recovered from clinical and environmental sources. Widespread detection of VAT genes in environmental isolates confirmed the validity, functionality, and applicability of these novel assays. Overall, the three newly developed ACB complex species-specific mPCR assays are rapid and simple tools that can be adopted in diagnostic and clinical lab settings. The detection of VAT genes in environmental isolates suggests that environmental niches could serve as a reservoir for potentially pathogenic ACB complex and warrants further investigation. The newly developed mPCR assays are specific, sensitive, and efficient, making them well-suited for high-throughput screening in epidemiological studies and evaluating the potential pathogenicity of ACB complex recovered from various sources.

A Case Report of Alopecia Areata Treated With Individualized Homoeopathy.

Introduction: Hair is regarded as an essential part of human identity, and losing it has a negative effect on many facets of one's quality of life. Alopecia areata (AA) is a chronic, non-scarring hair loss of the scalp or body hair. It is believed to be an autoimmune disorder where the body cannot recognize its own cells, resulting in the subsequent destruction of the hair follicles. The efficacy of the available treatment is not adequate and remission of hair follicles is unpredictable. However, individualized homoeopathy (iHOM) has shown great results in treating AA. Methods: At the Dermatological Department of D.Y. Patil Homoeopathic Medical College & Research Center, India, an 11-year-old female patient diagnosed with Alopecia areata was treated homeopathically from July 2021 to November 2021. During the follow-up visits, the outcome was assessed. To assess whether the changes were due to homoeopathic medicine, an assessment using the modified Naranjo criteria was performed. Results: Over an observation period of 5 months, beneficial result from iHOM medicine was seen, and so can be used by physicians in treating Alopecia Areata as a complementary health practice. Conclusion: Considering the multi-factorial etiology of Alopecia Areata, iHOM medicine and the auxillary line of treatment are effective in treating Alopecia Areata.

Machine Learning Model for Assessment of Risk Factors and Postoperative Day for Superficial vs Deep/Organ-Space Surgical Site Infections.

Background. Deep and organ space surgical site infections (SSI) require more intensive treatment, may result in more severe clinical disease and may have different risk factors when compared to superficial SSIs. Machine learning (ML) algorithms provide the opportunity to analyze multiple factors to predict of the type and time of development of SSI. Therefore, we developed a ML model to predict type and postoperative week of SSI. Methodology. A case-control study was conducted among patients who developed a SSI after undergoing general surgery procedures at a tertiary care hospital between 2019 to 2020. Patients were followed for 30 days. Six ML algorithms were trained as predictors of type of infection (superficial vs deep/organ space) and time of infection, and tested using area under the receiver operating characteristic curve (AUC-ROC). Results. Data for 113 patients with SSIs was available. Of these 62 (54.8%) had superficial and 51 had (45.2%) deep/organ space infections. Compared with other ML algorithms, the XG boost univariate model had highest AUC-ROC (.84) for prediction of type of SSI and Stochastic gradient boosting univariate, logistic regression univariate, XG boost univariate, and random forest classification univariate model had the highest AUC-ROC (.74) for prediction of week of infection. Conclusions. ML models offer reasonable accuracy in prediction of superficial vs deep SSI and time of developing infection. Follow-up duration and allocation of treatment strategies can be informed by ML predictions.

Comparison of visual SLAM and IMU in tracking head movement outdoors.

Tracking head movement in outdoor activities is more challenging than in controlled indoor lab environments. Large-magnitude head scanning is common under natural conditions. Compensatory gaze (head and eye) scanning while walking may be critical for people with visual field loss. We compared the accuracy of two outdoor head tracking methods: differential inertial measurement units (IMU) and simultaneous localization and mapping (SLAM). At a fixed location experiment, a gaze aiming test showed that SLAM outperforms IMU in terms of error (IMU: 9.6°, SLAM: 4.47°). In an urban street walking experiment conducted with five patients with hemifield loss, the IMU drift, quantified by root-mean-square deviation, was as high as 68.1°, while the drift of SLAM was only 5.3°. However, the SLAM method suffered from data loss due to tracking failure (~10% overall, and ~ 18% when crossing streets). Our results show that the SLAM and IMU methods have complementary properties. Because of no data gaps, the differential IMU method may be desirable as compared to SLAM in settings where the signal drift can be removed in post-processing and small gaze estimation errors can be tolerated.

Iron Acquisition Mechanisms and Their Role in the Virulence of Acinetobacter baumannii.

Iron is an essential element for survival of most organisms. One mechanism of host defense is to tightly chelate iron to several proteins to limit its extracellular availability. This has forced pathogens such as Acinetobacter baumannii to adapt mechanisms for the acquisition and utilization of iron even in iron-limiting conditions. A. baumannii uses a variety of iron acquisition strategies to meet its iron requirements. It can lyse erythrocytes to harvest the heme molecules, use iron-chelating siderophores, and use outer membrane vesicles to acquire iron. Iron acquisition pathways, in general, have been seen to affect many other virulence factors such as cell adherence, cell motility, and biofilm formation. The knowledge gained from research on iron acquisition led to the synthesis of the antibiotic cefiderocol, which uses iron uptake pathways for entry into the cell with some success as a novel cephalosporin. Understanding the mechanisms of iron acquisition of A. baumannii allows for insight into clinical infections and offer potential targets for novel antibiotics or potentiators of current drugs.

Electrochemical Quantification of Tobramycin Retention in Pseudomonas aeruginosa as Antimicrobial Susceptibility Indicator.

The emergence and spread of bacterial resistance to antibiotics has developed into one of the most challenging threats to public health. Antibiotic susceptibility tests (ASTs) for bacterial infections are now essential, because they provide guidance for physicians in the selection of antibiotics, to which bacteria will respond. Most current AST methods require long periods of time, because of bacterial growth and incubation, leading to a prolonged and overuse of broad-spectrum antibiotics. Thus, there is a growing demand for methods and technologies that enable rapid antibiotic susceptibility assessment. Due to advantages related to cost-effectiveness, rapid response time and high sensitivity, electrochemical detection methods are promising analytical tools that can successfully quantify antibiotic uptake and retention in clinically relevant bacterial strains. This study presents the electroanalytical quantification of tobramycin (TOB) retention in susceptible and resistant bacterial strains of Pseudomonas aeruginosa. The electrochemical behavior of TOB was characterized by voltammetry, identifying redox potentials, the current dependence on pH conditions, and the detection limit at unmodified glassy carbon electrodes. The presented methodology was able to distinguish between susceptible and resistant bacterial strains, and is also capable of identifying varying degrees of resistance against TOB. The presented approach detects the immediate interaction of bacteria with an antibiotic, without the need of complex and cost-intense equipment related to genomic testing methods.

Update on Multidrug Resistance Efflux Pumps in Acinetobacter spp.

Acinetobacter spp. have become of increased clinical importance as studies have shown the antimicrobial resistant potential of these species. Efflux pumps can lead to reduced susceptibility to a variety of antibiotics and are present in large number across Acinetobacter spp. There are six families of efflux pumps that have been shown to be of clinical relevance: the major facilitator superfamily (MFS), small multidrug resistance (SMR) family, ATP-binding cassette (ABC) family, multidrug and toxic compound extrusion (MATE) family, proteobacterial antimicrobial compound efflux (PACE) family, and the resistance-nodulation-division (RND) family. Much work has been done for understanding and characterizing the roles these efflux pumps play in relation to antimicrobial resistance and the physiology of these bacteria. RND efflux pumps, with their expansive substrate profiles, are a major component of Acinetobacter spp. antimicrobial resistance. New discoveries over the last decade have shed light on the complex regulation of these efflux pumps, leading to greater understanding and the potential of slowing the reduced susceptibility seen in these bacterial species.

Reference range of fetal thorax using two-dimensional and three-dimensional ultrasound VOCAL technique and application in fetal thoracic malformations.

BACKGROUND: To establish the normal reference range of fetal thorax by two-dimensional (2D) and three-dimensional (3D) ultrasound VOCAL technique and evaluate the application in diagnosing fetal thoracic malformations. METHODS: A prospective cross-sectional study was undertaken involving 1077 women who have a normal singleton pregnancy at 13-40 weeks gestational age (GA). 2D ultrasound and 3D ultrasound VOCAL technique were utilized to assess fetal thoracic transverse diameter, thoracic anteroposterior diameter, thoracic circumference, thoracic area, lung volume, thoracic volume and lung-to-thoracic volume ratio. The nomograms of 2D and 3D fetal thoracic measurements were created to GA. 50 cases were randomly selected to calculate intra- and inter-observer reliability and agreement. In addition, the case groups including congenital skeletal dysplasia (SD) (15), congenital diaphragmatic hernia (CDH) (30), pulmonary sequestration (PS) (25) and congenital cystic adenomatoid malformation (CCAM) (36) were assessed by the nomograms and followed up subsequently. RESULTS: Both 2D and 3D fetal thoracic parameters increased with GA using a quadratic regression equation. The intra- and inter-observer reliability and agreement of each thoracic parameter were excellent. 2D fetal thoracic parameters could initially evaluate the fetal thoracic development and diagnose the skeletal thoracic deformity, and lung volume, thoracic volume and lung-to-thorax volume ratio were practical to diagnose and differentiate CDH, PS and CCAM. CONCLUSION: We have established the normal fetal thoracic reference range at 13-40 weeks, which has a high value in diagnosing congenital thoracic malformations.

Role of Hydrogen Sulfide, Substance P and Adhesion Molecules in Acute Pancreatitis.

Inflammation is a natural response to tissue injury. Uncontrolled inflammatory response leads to inflammatory disease. Acute pancreatitis is one of the main reasons for hospitalization amongst gastrointestinal disorders worldwide. It has been demonstrated that endogenous hydrogen sulfide (H2S), a gasotransmitter and substance P, a neuropeptide, are involved in the inflammatory process in acute pancreatitis. Cell adhesion molecules (CAM) are key players in inflammatory disease. Immunoglobulin (Ig) gene superfamily, selectins, and integrins are involved at different steps of leukocyte migration from blood to the site of injury. When the endothelial cells get activated, the CAMs are upregulated which leads to them interacting with leukocytes. This review summarizes our current understanding of the roles H2S, substance P and adhesion molecules play in acute pancreatitis.

MexXY RND pump of Pseudomonas aeruginosa PA7 effluxes bi-anionic ß-lactams carbenicillin and sulbenicillin when it partners with the outer membrane factor OprA but not with OprM.

Antibiotic resistance in Pseudomonas aeruginosa is a serious concern in healthcare systems. Among the determinants of antibiotic resistance in P. aeruginosa, efflux pumps belonging to the resistance-nodulation-division (RND) family confer resistance to a broad range of antibacterial compounds. The MexXY efflux system is widely overexpressed in P. aeruginosa isolates from cystic fibrosis (CF) patients. MexXY can form functional complexes with two different outer membrane factors (OMFs), OprA and OprM. In this study, using state-of-the-art genetic tools, the substrate specificities of MexXY-OprA and MexXY-OprM complexes were determined. Our results show, for the first time, that the substrate profile of the MexXY system from P. aeruginosa PA7 can vary depending on which OM factor (OprM or OprA) it complexes with. While both MexXY-OprA and MexXY-OprM complexes are capable of effluxing aminoglycosides, the bi-anionic ß-lactam molecules carbenicillin and sulbenicillin were found to only be the substrate of MexXY-OprA. Our study therefore shows that by partnering with different OMF proteins MexY can expand its substrate profile.

A response regulator protein with antar domain, AvnR, in Acinetobacter baumannii ATCC 17978 impacts its virulence and amino acid metabolism.

Acinetobacter baumannii, a Gram-negative coccobacillus, is notorious for its involvement in opportunistic infections around the world. Its resistance to antibiotics makes treatment of infections challenging. In this study, we describe a novel response regulator protein, AvnR (A1S_2006) that regulates virulence-related traits in A. baumannii ATCC17978. Sequence analysis suggests that AvnR is a CheY-like response regulator and contains the RNA-binding ANTAR (AmiR and NasR transcription anti-termination regulators) domain. We show that AvnR plays a role in regulating biofilm formation (on glass and plastic surfaces), surface motility, adhesion to A549 cells as well as in nitrogen metabolism in A. baumannii. RNA-Seq analysis revealed that avnR deletion results in altered expression of more than 150 genes (116 upregulated and 42 downregulated). RNA-Seq data suggest that altered biofilm formation and surface motility observed in the avnR deletion mutant is likely mediated by previously unknown pathways. Of note, was the altered expression of genes predicted to be involved in amino acid transport and metabolism in avnR deletion mutant. Biolog phenotypic array showed that deletion of avnR hampered A. baumannii ATCC17978's ability to metabolize various nitrogen sources, particularly that of glutamic acid, serine, histidine, aspartic acid, isoleucine and arginine. Taken together our data show that AvnR, the first ANTAR protein described in A. baumannii, affects virulence phenotypes as well as its ability to metabolize nitrogen sources.

Metabolic Forest: Predicting the Diverse Structures of Drug Metabolites.

Adverse drug metabolism often severely impacts patient morbidity and mortality. Unfortunately, drug metabolism experimental assays are costly, inefficient, and slow. Instead, computational modeling could rapidly flag potentially toxic molecules across thousands of candidates in the early stages of drug development. Most metabolism models focus on predicting sites of metabolism (SOMs): the specific substrate atoms targeted by metabolic enzymes. However, SOMs are merely a proxy for metabolic structures: knowledge of an SOM does not explicitly provide the actual metabolite structure. Without an explicit metabolite structure, computational systems cannot evaluate the new molecule's properties. For example, the metabolite's reactivity cannot be automatically predicted, a crucial limitation because reactive drug metabolites are a key driver of adverse drug reactions (ADRs). Additionally, further metabolic events cannot be forecast, even though the metabolic path of the majority of substrates includes two or more sequential steps. To overcome the myopia of the SOM paradigm, this study constructs a well-defined system-termed the metabolic forest-for generating exact metabolite structures. We validate the metabolic forest with the substrate and product structures from a large, chemically diverse, literature-derived dataset of 20 736 records. The metabolic forest finds a pathway linking each substrate and product for 79.42% of these records. By performing a breadth-first search of depth two or three, we improve performance to 88.43 and 88.77%, respectively. The metabolic forest includes a specialized algorithm for producing accurate quinone structures, the most common type of reactive metabolite. To our knowledge, this quinone structure algorithm is the first of its kind, as the diverse mechanisms of quinone formation are difficult to systematically reproduce. We validate the metabolic forest on a previously published dataset of 576 quinone reactions, predicting their structures with a depth three performance of 91.84%. The metabolic forest accurately enumerates metabolite structures, enabling promising new directions such as joint metabolism and reactivity modeling.

The Anthelmintic Drug Niclosamide Synergizes with Colistin and Reverses Colistin Resistance in Gram-Negative Bacilli.

There is an urgent need for new therapies to overcome antimicrobial resistance especially in Gram-negative bacilli (GNB). Repurposing old U.S. Food and Drug Administration-approved drugs as complementary agents to existing antibiotics in a synergistic combination presents an attractive strategy. Here, we demonstrate that the anthelmintic drug niclosamide selectively synergized with the lipopeptide antibiotic colistin against colistin-susceptible but more importantly against colistin-resistant GNB, including clinical isolates that harbor the mcr-1 gene. Breakpoints for colistin susceptibility in resistant Gram-negative bacilli were reached in the presence of 1 µg/ml (3 µM) niclosamide. Reversal of colistin resistance was also observed in combinations of niclosamide and polymyxin B. Enhanced bacterial killing was evident for the combination, in comparison to colistin monotherapy, against resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae Accumulating evidence in the literature, along with our results, strongly suggests the potential for the combination of niclosamide and colistin to treat colistin-resistant Gram-negative bacillary infections. Our finding is significant since colistin is an antibiotic of last resort for multidrug-resistant Gram-negative bacterial infections that are nonresponsive to conventional treatments. With the recent global dissemination of plasmid-encoded colistin resistance, the addition of niclosamide to colistin therapy may hold the key to overcome colistin resistance.

Next Generation of Tn7-Based Single-Copy Insertion Elements for Use in Multi- and Pan-Drug-Resistant Strains of Acinetobacter baumannii.

The purpose of this study was to create single-copy gene expression systems for use in genomic manipulations of multidrug-resistant (MDR) and extensively drug-resistant (XDR) clinical isolates of Acinetobacter baumannii In this study, mini-Tn7 vectors with zeocin and apramycin selection markers were created by cloning the ble and aac(3)-IV genes, respectively, enabling either inducible gene expression (pUC18T-mini-Tn7T-Zeo-LAC and pUC18T-mini-Tn7T-Apr-LAC) or expression from native or constitutive promoters (pUC18T-mini-Tn7T-Zeo and pUC18T-mini-Tn7T-Apr). The selection markers of these plasmids are contained within a Flp recombinase target (FRT) cassette, which can be used to obtain unmarked mini-Tn7 insertions upon introduction of a source of Flp recombinase. To this end, site-specific excision vectors pFLP2A and pFLP2Z (containing apramycin and zeocin selection markers, respectively) were created in this study as an accessory to the mini-Tn7 vectors described above. Combinations of these novel mini-Tn7 plasmids and their compatible pFLP2Z or pFLP2A accessory plasmid were used to generate unmarked insertions in MDR clinical isolates of A. baumannii In addition, several fluorescent markers were cloned and inserted into MDR and XDR clinical isolates of A. baumannii via these apramycin and zeocin mini-Tn7 constructs to demonstrate their application.IMPORTANCEAcinetobacter baumannii is a high-priority pathogen for which research on mechanisms of resistance and virulence is a critical need. Commonly used antibiotic selection markers are not suitable for use in MDR and XDR isolates of A. baumannii due to the high antibiotic resistance of these isolates, which poses a barrier to the study of this pathogen. This study demonstrates the practical potential of using apramycin and zeocin mini-Tn7- and Flp recombinase-encoded constructs to carry out genomic manipulations in clinical isolates of A. baumannii displaying MDR and XDR phenotypes.

Two Component Regulatory Systems and Antibiotic Resistance in Gram-Negative Pathogens.

Gram-negative pathogens such as Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are the leading cause of nosocomial infections throughout the world. One commonality shared among these pathogens is their ubiquitous presence, robust host-colonization and most importantly, resistance to antibiotics. A significant number of two-component systems (TCSs) exist in these pathogens, which are involved in regulation of gene expression in response to environmental signals such as antibiotic exposure. While the development of antimicrobial resistance is a complex phenomenon, it has been shown that TCSs are involved in sensing antibiotics and regulating genes associated with antibiotic resistance. In this review, we aim to interpret current knowledge about the signaling mechanisms of TCSs in these three pathogenic bacteria. We further attempt to answer questions about the role of TCSs in antimicrobial resistance. We will also briefly discuss how specific two-component systems present in K. pneumoniae, A. baumannii, and P. aeruginosa may serve as potential therapeutic targets.

Neuromodulatory potential of phenylpropanoids; para-methoxycinnamic acid and ethyl-p-methoxycinnamate on aluminum-induced memory deficit in rats.

Para-methoxycinnamic acid (PMCA) and Ethyl-p-methoxycinnamate (EPMC) are reported to possess neuroprotective effect in reversing an acute memory deficit. However, there is a dearth of evidence for their therapeutic effect in chronic memory deficit. Thus, there is a scope to study these derivatives against the chronic model of cognitive dysfunction. The present study was aimed to determine the cognitive enhancing activity of PMCA and EPMC in aluminum-induced chronic dementia. Cognitive enhancing property of PMCA and EPMC was assessed using Morris water maze by analyzing spatial memory parameters such as escape latency, D-quadrant latency, and island entries. To find a possible mechanism, the effect of test compounds on altered acetylcholinesterase (AChE) activity and oxidative stress was determined in the hippocampus and frontal cortex of rats. Docking interaction of these derivatives with acetylcholinesterase enzyme and glutamate receptors was also studied. Treatment with PMCA and EPMC showed a significant improvement in spatial memory markers and altered hippocampal AChE activity in rats with cognitive dysfunction. The implication of hippocampal and cortical oxidative stress in memory impairment was confirmed with decreased catalase/increased thiobarbituric acid reactive substances (TBARS) in rats. PMCA and EPMC reversed the oxidative stress in the brain by negatively affecting TBARS levels. Against depleted catalase levels, PMCA was more effective than EPMC in raising the depleted catalase levels. In silico analysis revealed poor affinity of EPMC and PMCA with AChE enzyme and glutamate receptor. To conclude, PMCA and EPMC exerted cognitive enhancing property independent of direct AChE and glutamate receptor inhibition.