Evaluation of Physicochemical Properties of Ipsapirone Derivatives Based on Chromatographic and Chemometric Approaches.

Drug discovery is a challenging process, with many compounds failing to progress due to unmet pharmacokinetic criteria. Lipophilicity is an important physicochemical parameter that affects various pharmacokinetic processes, including absorption, metabolism, and excretion. This study evaluated the lipophilic properties of a library of ipsapirone derivatives that were previously synthesized to affect dopamine and serotonin receptors. Lipophilicity indices were determined using computational and chromatographic approaches. In addition, the affinity to human serum albumin (HSA) and phospholipids was assessed using biomimetic chromatography protocols. Quantitative Structure-Retention Relationship (QSRR) methodologies were used to determine the impact of theoretical descriptors on experimentally determined properties. A multiple linear regression (MLR) model was calculated to identify the most important features, and genetic algorithms (GAs) were used to assist in the selection of features. The resultant models showed commendable predictive accuracy, minimal error, and good concordance correlation coefficient values of 0.876, 0.149, and 0.930 for the validation group, respectively.

Artificial Intelligence Based Approach for Classification of Human Activities Using MEMS Sensors Data.

The integration of Micro Electronic Mechanical Systems (MEMS) sensor technology in smartphones has greatly improved the capability for Human Activity Recognition (HAR). By utilizing Machine Learning (ML) techniques and data from these sensors, various human motion activities can be classified. This study performed experiments and compiled a large dataset of nine daily activities, including Laying Down, Stationary, Walking, Brisk Walking, Running, Stairs-Up, Stairs-Down, Squatting, and Cycling. Several ML models, such as Decision Tree Classifier, Random Forest Classifier, K Neighbors Classifier, Multinomial Logistic Regression, Gaussian Naive Bayes, and Support Vector Machine, were trained on sensor data collected from accelerometer, gyroscope, and magnetometer embedded in smartphones and wearable devices. The highest test accuracy of 95% was achieved using the random forest algorithm. Additionally, a custom-built Bidirectional Long-Short-Term Memory (Bi-LSTM) model, a type of Recurrent Neural Network (RNN), was proposed and yielded an improved test accuracy of 98.1%. This approach differs from traditional algorithmic-based human activity detection used in current wearable technologies, resulting in improved accuracy.

An Intelligent Bio-Inspired Autonomous Surveillance System Using Underwater Sensor Networks.

Energy efficiency is important for underwater sensor networks. Designing such networks is challenging due to underwater environmental traits that hinder network lifespan extension. Unlike terrestrial protocols, underwater settings require novel protocols due to slower signal propagation. To enhance energy efficiency in underwater sensor networks, ongoing research concentrates on developing innovative solutions. Thus, in this paper, an intelligent bio-inspired autonomous surveillance system using underwater sensor networks is proposed as an efficient method for data communication. The tunicate swarm algorithm is used for the election of the cluster heads by considering different parameters such as energy, distance, and density. Each layer has several clusters, each of which is led by a cluster head that continuously rotates in response to the fitness values of the SNs using the tunicate swarm algorithm. The performance of the proposed protocol is compared with existing methods such as EE-LHCR, EE-DBR, and DBR, and results show the network's lifespan is improved by the proposed work. Due to the effective fitness parameters during cluster head elections, our suggested protocol may more effectively achieve energy balance, resulting in a longer network lifespan.

Tryptamine: A privileged scaffold for the management of Alzheimer's disease.

Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disease associated with aging. It is characterized by the progressive loss of memory and other cognitive functions. Although the exact etiology of AD is not well explored, several factors, such as the deposition of amyloid-ß (Aß) plaques, hyperphosphorylation of tau protein, presence of low levels of acetylcholine, and generation of oxidative stress, are key mediators in the progression of AD. Currently, the clinical treatment options for AD are limited and are based on cholinesterase (ChE) inhibitors (e.g., donepezil, rivastigmine, and galantamine), N-methyl- d-aspartic acid receptor antagonists (e.g., memantine), and the recently approved Aß modulator (e.g., aducanumab). Tryptamine (2-(1H-indol-3-yl)ethan-1-amine) is a small molecule that contains an indole nucleus and an ethylamine side chain. It is also the active metabolite of tryptophan. It possesses a wide range of biological activities related to neurodegenerative disorders, such as ChE inhibition, Aß aggregation inhibition, antioxidant effects, monoamine-oxidase inhibition, and neuroprotection. Several tryptamine-based hybrid analogs are currently being investigated as multifunctional agents for the development of novel hybrids for AD treatment. Thus, this review article aims to provide in-depth insights into the research progress and strategies for designing multifunctional agents used in Alzheimer's therapy.

Carbamate as a potential anti-Alzheimer's pharmacophore: A review.

Alzheimer's disease (AD) is a progressive age-related neurodegenerative brain disorder, which leads to loss of memory and other cognitive dysfunction. The underlying mechanisms of AD pathogenesis are very complex and still not fully explored. Cholinergic neuronal loss, accumulation of amyloid plaque, metal ions dyshomeostasis, tau hyperphosphorylation, oxidative stress, neuroinflammation, and mitochondrial dysfunction are major hallmarks of AD. The current treatment options for AD are acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and NMDA receptor antagonists (memantine). These FDA-approved drugs mainly provide symptomatic relief without addressing the pathological aspects of disease progression. So, there is an urgent need for novel drug development that not only addresses the basic mechanisms of the disease but also shows the neuroprotective property. Various research groups across the globe are working on the development of multifunctional agents for AD amelioration using different core scaffolds for their design, and carbamate is among them. Rivastigmine was the first carbamate drug investigated for AD management. The carbamate fragment, a core scaffold of rivastigmine, act as a potential inhibitor of acetylcholinesterase. In this review, we summarize the last 10 years of research conducted on the modification of carbamate with different substituents which primarily target ChE inhibition, reduce oxidative stress, and modulate Aß aggregation.

Understanding hip pathology in ballet dancers.

PURPOSE: The literature on hip injuries in ballet dancers was systematically evaluated to answer (1) whether the prevalence of morphological abnormalities and pathology of hip injuries in dancers differs from the general population (2) if there are any specific risk factors which contribute to a higher rate of hip injury and (3) what are the outcomes of primary and secondary intervention strategies. METHODS: A systematic literature search of Medline, EMBASE and the Cochrane Library was undertaken for all literature relating to hip injuries in ballet dancers using the PRISMA guidelines. Reference lists were also searched for relevant literature. Clinical outcome studies, prospective/retrospective case series published between 1989 and October 2021 were included. Review articles (non-original data), case reports, studies on animals as well as book chapters were excluded. RESULTS: The search yielded 445 studies, of which 35 were included for final analyses after screening. This included 1655 participants, of which 1131 were females. The analyses revealed that damage at the chondrolabral junction and degenerative disease of the hip may develop at a higher rate in ballet dancers than in the general population (odds ratio > 1 in 15/18 cohorts). The intra-articular lesions were more frequently found in postero-superior region of the hip suggesting an alternative impingement mechanism. Furthermore, numerous risk factors specific for hip injury in ballet were highlighted amidst a wide body of literature which consistently reports risk factors for a more generic 'dancer vulnerability'. CONCLUSION: Ballet dancers may suffer from both higher rates of chondrolabral damage and degenerative disease in their hips. In contrast to other sports, the intra-articular lesions are more frequently found in postero-superior region of the hip. Future research clarifying the prevalence of osseous abnormalities and prevention strategies in dancers may be pivotal in delaying the development of hip disease in this cohort. LEVEL OF EVIDENCE: Level IV.

Further SAR studies on natural template based neuroprotective molecules for the treatment of Alzheimer's disease.

In our earlier paper, we described ferulic acid (FA) template based novel series of multifunctional cholinesterase (ChE) inhibitors for the management of AD. This report has further extended the structure-activity relationship (SAR) studies of this series of molecules in a calibrated manner to improve upon the ChEs inhibition and antioxidant property to identify the novel potent multifunctional molecules. To investigate the effect of replacement of phenylpiperazine ring with benzylpiperazine, increase in the linker length between FA and substituted phenyl ring, and replacement of indole moiety with tryptamine on this molecular template, three series of novel molecules were developed. All synthesized compounds were tested for their acetyl and butyryl cholinestrases (AChE and BChE) inhibitory properties. Enzyme inhibition and PAS binding studies identified compound 13b as a lead molecule with potent inhibitor property towards AChE/BChE (AChE IC50 = 0.96 ± 0.14 µM, BChE IC50 = 1.23 ± 0.23 µM) compared to earlier identified lead molecule EJMC-G (AChE IC50 = 5.74 ± 0.13 µM, BChE IC50 = 14.05 ± 0.10 µM, respectively). Molecular docking and dynamics studies revealed that 13b fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Trp86, Ser125, Glu202, Trp 286, Phe295, Tyr 337 in AChE, and with Trp 82, Gly115, Tyr128, and Ser287 in BChE. The compound, 13b was found to be three times more potent antioxidant in a DPPH assay (IC50 = 20.25 ± 0.26 µM) over the earlier identified EJMC-B (IC50 = 61.98 ± 0.30 µM) and it also was able to chelate iron. Co-treatment of 13b with H2O2, significantly attenuated and reversed H2O2-induced toxicity in the SH-SY5Y cells. The parallel artificial membrane permeability assay-blood brain barrier (PAMPA-BBB) revealed that 13b could cross BBB efficiently. Finally, the in-vivo efficacy of 13b at dose of 10 mg/kg in scopolamine AD model has been demonstrated. The present study strongly suggests that the naturally inspired multifunctional molecule 13b may behave as a potential novel therapeutic agent for AD management.

Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: an effort toward drug repurposing to combat COVID-19.

The importance of the main protease (Mpro) enzyme of SARS-CoV-2 in the digestion of viral polyproteins introduces Mpro as an attractive drug target for antiviral drug design. This study aims to carry out the molecular docking, molecular dynamics studies, and prediction of ADMET properties of selected potential antiviral molecules. The study provides an insight into biomolecular interactions to understand the inhibitory mechanism and the spatial orientation of the tested ligands and further, identification of key amino acid residues within the substrate-binding pocket that can be applied for structure-based drug design. In this regard, we carried out molecular docking studies of chloroquine (CQ), hydroxychloroquine (HCQ), remdesivir (RDV), GS441524, arbidol (ARB), and natural product glycyrrhizin (GA) using AutoDock 4.2 tool. To study the drug-receptor complex's stability, selected docking possesses were further subjected to molecular dynamics studies with Schrodinger software. The prediction of ADMET/toxicity properties was carried out on ADMET Prediction™. The docking studies suggested a potential role played by CYS145, HIS163, and GLU166 in the interaction of molecules within the active site of COVID-19 Mpro. In the docking studies, RDV and GA exhibited superiority in binding with the crystal structure of Mpro over the other selected molecules in this study. Spatial orientations of the molecules at the active site of Mpro exposed the significance of S1-S4 subsites and surrounding amino acid residues. Among GA and RDV, RDV showed better and stable interactions with the protein, which is the reason for the lesser RMSD values for RDV. Overall, the present in silico study indicated the direction to combat COVID-19 using FDA-approved drugs as promising agents, which do not need much toxicity studies and could also serve as starting points for lead optimization in drug discovery.

Combined fluorescence-guided surgery and photodynamic therapy for glioblastoma multiforme using cyanine and chlorin nanocluster.

INTRODUCTION: Glioblastoma multiforme (GBM) is the most common primary intracranial malignancy; survival can be improved by maximizing the extent-of-resection. METHODS: A near-infrared fluorophore (Indocyanine-Green, ICG) was combined with a photosensitizer (Chlorin-e6, Ce6) on the surface of superparamagnetic-iron-oxide-nanoparticles (SPIONs), all FDA-approved for clinical use, yielding a nanocluster (ICS) using a microemulsion. The physical-chemical properties of the ICS were systematically evaluated. Efficacy of photodynamic therapy (PDT) was evaluated in vitro with GL261 cells and in vivo in a subtotal resection trial using a syngeneic flank tumor model. NIR imaging properties of ICS were evaluated in both a flank and an intracranial GBM model. RESULTS: ICS demonstrated high ICG and Ce6 encapsulation efficiency, high payload capacity, and chemical stability in physiologic conditions. In vitro cell studies demonstrated significant PDT-induced cytotoxicity using ICS. Preclinical animal studies demonstrated that the nanoclusters can be detected through NIR imaging in both flank and intracranial GBM tumors (ex: 745 nm, em: 800 nm; mean signal-to-background 8.5 ± 0.6). In the flank residual tumor PDT trial, subjects treated with PDT demonstrated significantly enhanced local control of recurrent neoplasm starting on postoperative day 8 (23.1 mm3 vs 150.5 mm3, p = 0.045), and the treatment effect amplified to final mean volumes of 220.4 mm3 vs 806.1 mm3 on day 23 (p = 0.0055). CONCLUSION: A multimodal theragnostic agent comprised solely of FDA-approved components was developed to couple optical imaging and PDT. The findings demonstrated evidence for the potential theragnostic benefit of ICS in surgical oncology that is conducive to clinical integration.

A review on iron chelators as potential therapeutic agents for the treatment of Alzheimer's and Parkinson's diseases.

Iron plays a vital role in several cellular functions due to its unique physiochemical properties. Iron concentration increases in the brain with age due to multiple factors. Excessive amount of iron can lead to formation of reactive oxygen species. Neurodegenerative disorders are characterized by iron supplemented increase in oxidative stress and cellular damage. There is an urgent need of novel therapies which should not only provide symptomatic relief but also be able to modulate iron accumulation in the brain. Therefore, the development of novel iron chelators as neuroprotective agents for the treatment of neurodegeneration is an emerging trend. Several iron chelators including 8-hydroxyquinoline derivatives, dopaminergic agonists and natural products are under preclinical and clinical investigations for the treatment of neurodegenerative disorders.

Pediatric Maxillofacial Trauma: A Review of 156 Patients.

PURPOSE: To review the epidemiology and management of facial fractures in a pediatric population. MATERIALS AND METHODS: This study was a retrospective review of patients younger than 18 years who presented to a pediatric emergency department during a 5-year period in an urban, academic, level 1 designated trauma center. RESULTS: Of the 156 patients identified, most were boys (87%) and the mean age was 13.5 years (standard deviation, 4.9 yr; interquartile range, 12 to 17 yr). The most common mechanism of injury was assault (48.1%). Mandibular fractures (40.7%) were most common. Multiple fractures occurred in 26.9% of patients. Concomitant injuries occurred in 73.7% of patients, most commonly concussions (39.1%). Intracranial hemorrhages were associated with panfacial (P = .005), frontal (P = .001), and orbital (P = .04) fractures. Most patients (91.7%) were admitted, and nonoperative repair was undertaken in 57.1%. There was an independent association of surgical intervention with age older than 14 years and with mandibular fractures (P < .01). CONCLUSIONS: Assault was the most common mechanism of injury and mandibular fracture was the most commonly encountered. Concomitant nonfacial injuries occurred in most patients. Patients sustaining panfacial, frontal, and orbital fractures should provoke an evaluation for other intracranial injuries. Children older than 14 years and those with mandibular fractures should prompt mobilization of resources for operative repair.

An Ectopic Pelvic Kidney.

BACKGROUND: If a kidney does not ascend as it should in normal fetal development, it remains in the pelvic area and is called a pelvic kidney. Often a person with a pelvic kidney will go through his/her whole life unaware of this condition, unless it is discovered during neonatal kidney ultrasound screening or if complications arise later in life due to this or a completely different reason and the condition is noted during investigations. Generally, this is not a harmful condition but it can lead to complications like in our case. With appropriate testing and treatment, if needed, an ectopic kidney should cause no serious long-term health complications and all that may be required for the patient is reassurance with advice to follow up at regular intervals. CASE REPORT: A 28-year-old male presented with recurrent pain in his lower left abdomen for one month and an episode of hematuria 3 days earlier accompanied by an attack of acute pain lasting for 3-4 hours. He gave a history of passing 2 small (about 5 mm each) calculi in his urine after the occurrence of hematuria, following which pain decreased in intensity. No history of fever was present. CONCLUSIONS: Although a simple ectopic kidney seldom causes symptoms, the association of malrotation of the renal pelvis with calculus increases the risk of hematuria and/or hydronephrosis, presenting with colicky pain as in the present case. The clinician should be aware of these in such a case. If asymptomatic, no treatment is required. However, the patient should be advised to have follow-up ultrasounds at regular intervals to detect complications like calculus, hydronephrosis, etc. With appropriate testing and treatment, if required, an ectopic kidney should not cause serious long-term health complications.

Transcervical removal of an impacted third molar: an uncommon indication.

This article presents a case of and reviews the literature involving the extraoral approach for surgical removal of an ectopic mandibular third molar tooth. Case reports describing extraction of the mandibular third molar using the extraoral approach are very limited. This article describes an unusual case of an impacted, infected, ectopic right mandibular third molar that was positioned at the inferior border and had caused an extraoral draining sinus. Furthermore, the roots were intimately involved with the inferior alveolar nerve (IAN) and had perforated the buccal cortex of the mandible. Surgical removal using a transcervical submandibular approach was deemed necessary to try to preserve the IAN and avoid fracture of the mandible in this 74-year-old patient.

Recent Advances in Medicinal Chemistry of Memantine Against Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic progressive, age-related neurodegenerative brain disorder characterized by the irreversible decline of memory and other cognitive functions. It is one of the major health threat of the 21st century, which affects around 60% of the population over the age of 60 years. The problem of this disease is even more major because the existing pharmacotherapies only provide symptomatic relief without addressing the basic factors of the disease. It is characterized by the extracellular deposition of amyloid ß (Aß) to form senile plaques, and the intracellular hyperphosphorylation of tau to form neurofibrillary tangles (NFTs). Due to the complex pathophysiology of this disease, various hypotheses have been proposed, including the cholinergic, Aß, tau, oxidative stress, and the metal-ion hypothesis. Among these, the cholinergic and Aß hypotheses are the primary targets for addressing AD. Therefore, continuous advances have been made in developing potential cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists to delay disease progression and restore cholinergic neurotransmission. In this review article, we tried to comprehensively summarize the recent advancement in NMDA receptor antagonist (memantine) and their hybrid analogs as potential disease-modifying agents for the treatment of AD. Furthermore, we also depicted the design, rationale, and SAR analysis of the memantine-based hybrids used in the last decade for the treatment of AD.

A Comprehensive Analysis on Galantamine Based Hybrids for the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive chronic age-related neurodegenerative brain disorder characterized by the loss of memory and other cognitive functions. The exact etiology of AD is still under investigation, however several factors such as low level of neurotransmitter acetylcholine (ACh), aggregation of amyloid beta (Aß) in the form of Aß plaques, hyperphosphorylation of tau protein into neurofibrillary tangles (NFTs), oxidative stress, and metal ion imbalance are the major hallmarks of this disease. Of the multiple hypotheses for AD, the amyloid-ß (Aß) and cholinergic hypothesis are the main targeting hypotheses for AD. Some researchers hypothesized that the primary event associated with the cholinergic neurotransmitter (acetylcholine) is memory loss and cognitive impairment. Due to the disease's complicated pathogenesis, long-term therapy with a single target candidate is futile. As a result, multitargeted and multifunctional therapies have emerged. Various research teams are concentrating on addressing multiple disease factors through hybridization techniques. Consequently, this hybridization approach has been applied to all core scaffolds, including galantamine. In this article, we tried to provide a thorough overview of the most recent developments on galantamine, a prospective AChE inhibitor, and its hybrid analogs as possible therapeutic agents for treating AD. Furthermore, we also provided the design, synthesis, and SAR analysis of the galantamine-based compounds used in the last decades for the management of AD.

Zeolite-based nanoparticles drug delivery systems in modern pharmaceutical research and environmental remediation.

This review explores the potential of zeolite-based nanoparticles in modern pharmaceutical research, focusing on their role in advanced drug delivery systems. Zeolites, integrated into polymeric materials, offer precise drug delivery capabilities due to their unique structural features, biocompatibility, and controllable properties. Additionally, zeolites demonstrate environmental remediation potential through ion exchange processes. Synthetic zeolites, with modified release mechanisms, possess distinctive optical and electronic properties, expanding their applications in various fields. The study details zeolites' significance across industrial and scientific domains, outlining synthesis methods and size control techniques. The review emphasizes successful encapsulation and functionalization strategies for drug delivery, highlighting their role in enhancing drug stability and enabling targeted delivery. Advanced characterization techniques contribute to a comprehensive understanding of zeolite-based drug delivery systems. Addressing potential carcinogenicity, the review discusses environmental impact and risk assessment, stressing the importance of safety considerations in nanoparticle research. In biomedical applications, zeolites play vital roles in antidiarrheal, antitumor, antibacterial, and MRI contrast agents. Clinical trials featuring zeolite-based interventions underscore zeolite's potential in addressing diverse medical challenges. In conclusion, zeolite-based nanoparticles emerge as promising tools for targeted drug delivery, showcasing diverse applications and therapeutic potentials. Despite challenges, their unique advantages position zeolites at the forefront of innovative drug delivery systems.

Dose optimization of second window indocyanine green in meningioma patients.

OBJECTIVE: Surgery remains the first line treatment for meningiomas and can benefit from fluorescence-guided surgical techniques such as second-window indocyanine green (SWIG). In the current study, we compared the use of the standard SWIG dose of 5.0 mg/kg relative to 2.5 mg/kg indocyanine green (ICG) in meningioma patients. METHODS: Patients were prospectively enrolled in an IRB-approved study of SWIG and received either the standard dose of 5.0 mg/kg or a reduced dose of 2.5 mg/kg of ICG around 24 h prior to their surgery. Intraoperative near-infrared fluorescence imaging was performed with exo- and endoscopic systems. Signal-to-background ratio (SBR) was calculated to quantify fluorescence and was compared between 5.0 mg/kg and 2.5 mg/kg ICG. All patients received pre-operative MRI and, in select cases, the pre-operative MRI was correlated to intraoperative fluorescence imaging. RESULTS/DISCUSSION: In the current study, we found no significant difference in the SBR of meningiomas in patients that were administered with either 5.0 mg/kg or 2.5 mg/kg ICG. However, in five patients that received the standard-dose SWIG regimen of 5.0 mg/kg ICG we observed dose-related fluorescence quenching - referred to as "inversion" - that interfered with tumor visualization during fluorescence-guided surgery (FGS). When correlated to pre-operative MRI, a similar rim pattern was observed around the primary tumor on T2 FLAIR, which, in retrospect, could be used as a predictor for inversion during FGS in meningioma patients receiving standard-dose ICG. CONCLUSION: This study demonstrated that a reduced ICG dose was as effective as standard-dose SWIG in meningioma patients. We therefore recommend to adjust the standard ICG dose for meningioma patients to 2.5 mg/kg particularly when rim enhancement is observed on pre-operative T2 FLAIR.

Design, Synthesis, and Biological Evaluation of Ferulic Acid-Piperazine Derivatives Targeting Pathological Hallmarks of Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent cause of dementia and is characterized by low levels of acetyl and butyrylcholine, increased oxidative stress, inflammation, accumulation of metals, and aggregations of Aß and tau proteins. Current treatments for AD provide only symptomatic relief without impacting the pathological hallmarks of the disease. In our ongoing efforts to develop naturally inspired novel multitarget molecules for AD, through extensive medicinal chemistry efforts, we have developed 13a, harboring the key functional groups to provide not only symptomatic relief but also targeting oxidative stress, able to chelate iron, inhibiting NLRP3, and Aß1-42 aggregation in various AD models. 13a exhibited promising anticholinesterase activity against AChE (IC50 = 0.59 ± 0.19 µM) and BChE (IC50 = 5.02 ± 0.14 µM) with excellent antioxidant properties in DPPH assay (IC50 = 5.88 ± 0.21 µM) over ferulic acid (56.49 ± 0.62 µM). The molecular docking and dynamic simulations further corroborated the enzyme inhibition studies and confirmed the stability of these complexes. Importantly, in the PAMPA-BBB assay, 13a turned out to be a promising molecule that can efficiently cross the blood-brain barrier. Notably, 13a also exhibited iron-chelating properties. Furthermore, 13a effectively inhibited self- and metal-induced Aß1-42 aggregation. It is worth mentioning that 13a demonstrated no symptom of cytotoxicity up to 30 µM concentration in PC-12 cells. Additionally, 13a inhibited the NLRP3 inflammasome and mitigated mitochondrial-induced reactive oxygen species and mitochondrial membrane potential damage triggered by LPS and ATP in HMC-3 cells. 13a could effectively reduce mitochondrial and cellular reactive oxygen species (ROS) in the Drosophila model of AD. Finally, 13a was found to be efficacious in reversing memory impairment in a scopolamine-induced AD mouse model in the in vivo studies. In ex vivo assessments, 13a notably modulates the levels of superoxide, catalase, and malondialdehyde along with AChE and BChE. These findings revealed that 13a holds promise as a potential candidate for further development in AD management.

Berberine derivatives as inhibitors of acetylcholinesterase: A systematic review.

Alzheimer's disease (AD) is a chronic age-related neurodegenerative brain disorder characterized by the impairment of memory accompanied by worsening of thinking ability of an individual. The exact pathophysiology of AD is not fully understood. However low level of the neurotransmitter named acetylcholine (ACh), aggregation of Aß peptide into toxic Aß plaque, hyperphosphorylation of tau, bio-metal imbalance, and oxidative stress are the main hallmarks of this disease. Due to the complex pathophysiology of AD, no specific treatment is available in the market, and treatment is only limited to the symptomatic relief. So, there is an urgent need for the development of new drug candidate, which can have disease-modifying effect and improve learning and memory in AD patient. Therefore, berberine-based multifunction compounds with potential cholinesterase inhibitory properties were reviewed in this article. Structure-activity relationship (SAR) and biological activity provide highlights on the new derivatives used for the management of AD.

Aortic stenosis: a review on acquired pathogenesis and ominous combination with diabetes mellitus.

BACKGROUND: Aortic stenosis (AS) is a progressive disease, with no pharmacological treatment. The prevalence of diabetes mellitus (DM) among AS patients is higher than in the general population. DM significantly increases the risk of AS development and progression from mild to severe. The interplay between AS and DM's mechanism is not entirely known yet. MAIN BODY: The increased accumulation of advanced glycation end products (AGEs) was linked to increased valvular oxidative stress, inflammation, expression of coagulation factors, and signs of calcification, according to an analysis of aortic stenotic valves. It is interesting to note that in diabetic AS patients, valvular inflammation did not correlate with serum glucose levels but rather only with long-term glycemic management markers like glycated haemoglobin and fructosamine. Transcatheter aortic valve replacement, which has been shown to be safer than surgical aortic valve replacement, is advantageous for AS patients who also have concurrent diabetes. Additionally, novel anti-diabetic medications have been proposed to lower the risk of AS development in DM patients, including sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonist that target reduction of AGEs-mediated oxidative stress. CONCLUSIONS: There are little data on the effects of hyperglycemia on valvular calcification, but understanding the interactions between them is essential to develop a successful treatment strategy to stop or at least slow the progression of AS in DM patients. There is a link among AS and DM and that DM negatively impacts the quality of life and longevity of AS patients. The sole successful treatment, despite ongoing efforts to find new therapeutic modalities, involves aortic valve replacement. More research is required to find methods that can slow the advancement of these conditions, enhancing the prognosis and course of people with AS and DM.