Pharmacology
A Comprehensive Review on the Antimicrobial Activities and Structure-Activity Relationships (SARs) of Rhodanine Analogues
Rhodanines are five-member heterocyclics having sulfur nitrogen and oxygen atoms in their ring structure and exhibit potent as well as a broad range of pharmacological activities. They are thiazolidine derivatives and are well-known in medicinal chemistry for their wide spectrum of antimicrobial activities. Various modifications can be made to the structure of the rhodanine ring. Studies in recent years have validated the possibility of the potential of rhodanine derivatives to exhibit antimicrobial activity against both Gram-positive and Gram-negative bacterial strains as well as mycobacterial and fungal strains. In this review the synthesis biological activity and Structure-activity Relationships (SARs) of molecules based on rhodanine against different microbes have been described
Computer-aided Drug Discovery Approaches in the Identification of Anticancer Drugs from Natural Products: A Review
Natural plant sources are essential in the development of several anticancer drugs such as vincristine vinblastine vinorelbine docetaxel paclitaxel camptothecin etoposide and teniposide. However various chemotherapies fail due to adverse reactions drug resistance and target specificity. Researchers are now focusing on developing drugs that use natural compounds to overcome these issues. These drugs can affect multiple targets have reduced adverse effects and are effective against several cancer types. Developing a new drug is a highly complex expensive and time-consuming process. Traditional drug discovery methods take up to 15 years for a new medicine to enter the market and cost more than one billion USD. However recent Computer Aided Drug Discovery (CADD) advancements have changed this situation. This paper aims to comprehensively describe the different CADD approaches in identifying anticancer drugs from natural products. Data from various sources including Science Direct Elsevier NCBI and Web of Science are used in this review. In-silico techniques and optimization algorithms can provide versatile solutions in drug discovery ventures. The structure-based drug design technique is widely used to understand chemical constituents' molecular-level interactions and identify hit leads. This review will discuss the concept of CADD in-silico tools virtual screening in drug discovery and the concept of natural products as anticancer therapies. Representative examples of molecules identified will also be provided.
Comprehensive In Silico Analysis of Uncaria Tomentosa Extract: Chemical Profiling, Antioxidant Assessment, and CLASP Protein Interaction for Drug Design in Neurodegenerative Diseases
Uncaria tomentosa is a traditional medicinal herb renowned for its anti-inflammatory antioxidant and immune-enhancing properties. In the realm of neurodegenerative diseases (NDDS) CLASP proteins responsible for regulating microtubule dynamics in neurons have emerged as critical players. Dysregulation of CLASP proteins is associated with NDDS such as Alzheimer's Parkinson's and Huntington's diseases. Consequently comprehending the role of CLASP proteins in NDDS holds promise for the development of innovative therapeutic interventions.
The objectives of the research were to identify phytoconstituents in the hydroalcoholic extract of Uncaria tomentosa (HEUT) to evaluate its antioxidant potential through in vitro free radical scavenging assays and to explore its potential interaction with CLASP using in silico molecular docking studies.
HPLC and LC-MS techniques were used to identify and quantify phytochemicals in HEUT. The antioxidant potential was assessed through DPPH ferric reducing antioxidant power (FRAP) nitric oxide (NO) and superoxide (SO) free radical scavenging methods. Interactions between conventional quinovic acid chlorogenic acid epicatechin corynoxeine rhynchophylline and syringic acid and CLASP were studied through in silico molecular docking using Auto Dock 4.2.
The HEUT extract demonstrated the highest concentration of quinovic acid derivatives. HEUT exhibited strong free radical-scavenging activity with IC50 values of 0.113 µg/ml (DPPH) and 9.51 µM (FRAP). It also suppressed NO production by 47.1 ± 0.37% at 40 µg/ml and inhibited 77.3 ± 0.69% of SO generation. Additionally molecular docking revealed the potential interaction of quinovic acid with CLASP for NDDS.
The strong antioxidant potential of HEUT and the interaction of quinovic acid with CLASP protein suggest a promising role in treating NDDS linked to CLASP protein dysregulation.
Discovery of Novel Pyrimidine Based Small Molecule Inhibitors as VEGFR-2 Inhibitors: Design, Synthesis, and Anti-cancer Studies
Receptor tyrosine kinases (RTKs) are potent oncoproteins in cancer that when mutated or overexpressed can cause uncontrolled growth of cells angiogenesis and metastasis making them significant targets for cancer treatment. Vascular endothelial growth factor receptor 2 (VEGFR2) is a tyrosine kinase receptor that is produced in endothelial cells and is the most crucial regulator of angiogenic factors involved in tumor angiogenesis. So a series of new substituted N-(4-((2-aminopyrimidin-5-yl)oxy)phenyl)-N-phenyl cyclopropane-11-dicarboxamide derivatives as VEGFR-2 inhibitors have been designed and synthesized.
Utilizing H-NMR C13-NMR and mass spectroscopy the proposed derivatives were produced and assessed. HT-29 and COLO-205 cell lines were used for the cytotoxicity tests. The effective compound was investigated further for the Vegfr-2 kinase inhibition assay cell cycle arrest and apoptosis. A molecular docking examination was also carried out with the Maestro-12.5v of Schrodinger.
In comparison to the reference drug Cabozantinib (IC50 = 9.10 and 10.66 μM) compound SP2 revealed promising cytotoxic activity (IC50 = 4.07 and 4.98 μM) against HT-29 and COLO-205 respectively. The synthesized compound SP2 showed VEGFR-2 kinase inhibition activity with (IC50 = 6.82 μM) against the reference drug Cabozantinib (IC50 = 0.045 μM). Moreover compound SP2 strongly induced apoptosis by arresting the cell cycle in the G1 phase. The new compounds' potent VEGFR-2 inhibitory effect was noted with key amino acids Asp1044 and Glu883 and the hydrophobic interaction was also observed in the pocket of the VEGFR-2 active site by using a docking study.
The results demonstrate that at the cellular and enzyme levels the synthetic compounds SP2 are similarly effective as cabozantinib. The cell cycle and apoptosis data demonstrate the effectiveness of the suggested compounds. Based on the findings of docking studies cytotoxic effects in vitro VEGFR-2 inhibition apoptosis and cell cycle arrest this research has given us identical or more effective VEGFR-2 inhibitors.
Exploring the Mechanisms of Sanguinarine in the Treatment of Osteoporosis by Integrating Network Pharmacology Analysis and Deep Learning Technology
Sanguinarine (SAN) has been reported to have antioxidant anti-inflammatory and antimicrobial activities with potential for the treatment of osteoporosis (OP).
This work purposed to unravel the molecular mechanisms of SAN in the treatment of OP.
OP-related genes and SAN-related targets were predicted from public databases. Differential expression analysis and VennDiagram were adopted to detect SAN-related targets against OP. Protein-protein interaction (PPI) network was served for core target identification. Molecular docking and DeepPurpose algorithm were further adopted to investigate the binding ability between core targets and SAN. Gene pathway scoring of these targets was calculated utilizing gene set variation analysis (GSVA). Finally we explored the effect of SAN on the expressions of core targets in preosteoblastic MC3T3-E1 cells.
A total of 21 candidate targets of SAN against OP were acquired. Furthermore six core targets were identified among which CASP3 CTNNB1 and ERBB2 were remarkably differentially expressed in OP and healthy individuals. The binding energies of SAN with CASP3 CTNNB1 and ERBB2 were -6 -6.731 and -7.162 kcal/mol respectively. Moreover the GSVA scores of the Wnt/calcium signaling pathway were significantly lower in OP cases than in healthy individuals. In addition the expression of CASP3 was positively associated with Wnt/calcium signaling pathway. CASP3 and ERBB2 were significantly lower expressed in SAN group than in DMSO group whereas the expression of CTNNB1 was in contrast.
CASP3 CTNNB1 and ERBB2 emerge as potential targets of SAN in OP prevention and treatment.
Prescription Data Mining and Network Pharmacology Study of 1152 Patients with Rectal Prolapse using Traditional Chinese Medicine
In recent years the incidence of rectal prolapse has increased significantly due to the sedentary lifestyle and irregular eating habits of modern life. However there is a lack of clinical studies on the treatment of rectal prolapse with traditional Chinese medicine (TCM) with a large sample size. Therefore this study investigated the characteristics of rectal prolapse treatment formulas and then studied the network pharmacology of their core therapeutic drugs which can help to provide a reference for the treatment and postoperative care of rectal prolapse patients.
This study aimed to explore the prescription characteristics and the mechanism of action of core drugs in the treatment of rectal prolapse in Chinese medicine through data mining and bioinformatics techniques.
We collected the diagnosis and treatment information of patients with rectal prolapse from January 2014 to September 2021 in the electronic case database of Nanjing Hospital of TCM mined the patient information and prescription features using R screened the active ingredients of the core pairs of drugs and disease drug intersection targets using TCMSP and GnenCard databases and constructed a Protein-protein interaction (PPI) network using STRING and Cytoscape and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the intersecting targets were performed using Metascape and R.
We found that prolapse is easy to occur in people over 50 years old preferably in autumn and winter. Commonly used therapeutic Chinese medicines include Glycyrrhiza glabra Radix angelicae sinensis Radix astragali Atractylodes macrocephala and Pericarpium citri reticulatae which are mostly deficiency tonic medicines warm in nature and belong to spleen meridian. The core therapeutic medicinal pair was “Bupleuri radix-Cimicifugae rhizoma”. There were 190 common targets of Bupleuri radix and Cimicifugae rhizoma and 71 intersection targets of the drug pair and prolapse. The main components of the core drugs for the treatment of prolapse may be quercetin kaempferol Stigmasterol etc and the core targets may be CASP3 AKT1 HIF1A etc. The total number of GO entries for the intersection targets of “Bupleuri radix-Cimicifugae rhizoma” and diseases was 3495 among which the molecular functions accounted for the largest proportion mainly Pathways in cancer IL-18 signaling pathway etc. KEGG enriched pathway analysis yielded 168 results and the major pathways were pathways in cancer lipid and atherosclerosis IL-17 signaling pathway etc.
This study adopted real-world research methodology and used data mining and bioinformatics technology to mine the medication law of rectal prolapse and its core drug action mechanism from the clinical information of Chinese medicine.
DeepTransformer: Node Classification Research of a Deep Graph Network on an Osteoporosis Graph based on GraphTransformer
Osteoporosis (OP) is one of the most common diseases in the elderly population. It is mostly treated with medication but drug research and development have the disadvantage of taking a long time and having a high cost.
Therefore we developed a graph neural network with the help of artificial intelligence to provide new ideas for drug research and development for OP.
In this study we built a new osteoporosis graph (called OPGraph) and proposed a deep graph neural network (called DeepTransformer) to predict new drugs for OP. OPGraph is a graph data model established by gathering features and their interrelationships from a vast amount of OP data. DeepTransformer uses GraphTransformer as its foundational network and applies residual connections for deep layering.
The analysis and results showed that DeepTransformer outperformed numerous models on OPGraph with area under the curve (AUC) and area under the precision-recall curve (AUPR) reaching 0.9916 and 0.9911 respectively. In addition we conducted an in vitro validation experiment on two of the seven predicted compounds (Puerarin and Aucubin) and the results corroborated the predictions of our model.
The model we developed with the help of artificial intelligence can effectively reduce the time and cost of OP drug development and reduce the heavy economic burden brought to patient's family by complications caused by osteoporosis.
Insights into the Molecular Mechanisms of Bushen Huoxue Decoction in Breast Cancer via Network Pharmacology and In vitro experiments
Breast cancer (BC) is by far seen as the most common malignancy globally with 2.261 million patients newly diagnosed accounting for 11.7% of all cancer patients according to the Global Cancer Statistics Report (2020). The luminal A subtype accounts for at least half of all BC diagnoses. According to TCM theory Bushen Huoxue Decoction (BSHXD) is a prescription used for cancer treatment that may influence luminal A subtype breast cancer (LASBC).
To analyze the clinical efficacy and underlying mechanisms of BSHXD in LASBC.
Network pharmacology and in vitro experiments were utilized to foresee the underlying mechanism of BSHXD for LASBC.
According to the bioinformatics analysis BSHXD induced several proliferation and apoptosis processes against LASBC and the presumed targets of active components in BSHXD were mainly enriched in the HIF-1 and PI3K/AKT pathways. Flow cytometry assay and western blotting results revealed that the rate of apoptosis enhanced in a dose-dependent manner with BSHXD concentration increasing respectively. BSHXD notably downregulated the expressions of HIF-1α P-PI3K PI3K P-AKT and AKT proteins. However adding an HIF-1α agonist restored those protein levels.
The study proved that the mechanism of BSHXD in LASBC may be connected to suppressing proliferation by inhibiting the activity of the HIF-1α/PI3K/AKT signaling pathway and promoting apoptosis via the Caspase cascade in LASBC cells.
Insights to Design New Drugs against Human African Trypanosomiasis Targeting Rhodesain using Covalent Docking, Molecular Dynamics Simulations, and MM-PBSA Calculations
Neglected tropical diseases (NTDs) are parasitic and bacterial diseases that affect approximately 149 countries mainly the poor population without basic sanitation. Among these Human African Trypanosomiasis (HAT) known as sleeping sickness shows alarming data with treatment based on suramin and pentamidine in the initial phase and melarsoprol and eflornithine in the chronic phase. Thus to discover new drugs several studies point to rhodesain as a promising drug target due to the function of protein degradation and intracellular transport of proteins between the insect and host cells and is present in all cycle phases of the parasite.
Here based on the previous studies by Nascimento et al. (2021) [5] that show the main rhodesain inhibitors development in the last decade molecular docking and dynamics were applied in these inhibitors datasets to reveal crucial information that can be into drug design.
Also our findings using MD simulations and MM-PBSA calculations confirmed Gly19 Gly23 Gly65 Asp161 and Trp184 showing high binding energy (ΔGbind between -72.782 to -124.477 kJ.mol-1). In addition Van der Waals interactions have a better contribution (-140930 to -96988 kJ.mol-1) than electrostatic forces (-43270 to -6854 kJ.mol-1) indicating Van der Waals interactions are the leading forces in forming and maintaining ligand-rhodesain complexes. Thus conventional and covalent docking was employed and highlighted the presence of Michael acceptors in the ligands in a peptidomimetics scaffold and interaction with Gly19 Gly23 Gly65 Asp161 and Trp184 is essential to the inhibiting activity. Furthermore the Dynamic Cross-Correlation Maps (DCCM) show more correlated movements for all complexes than the free rhodesain and strong interactions in the regions of the aforementioned residues. Principal Component Analysis (PCA) demonstrates complex stability corroborating with RMSF and RMSD.
This study can provide valuable insights that can guide researchers worldwide to discover a new promising drug against HAT.
Detection of Brain Tumor Employing Residual Network-based Optimized Deep Learning
Diagnosis and treatment planning play a very vital role in improving the survival of oncological patients. However there is high variability in the shape size and structure of the tumor making automatic segmentation difficult. The automatic and accurate detection and segmentation methods for brain tumors are proposed in this paper.
A modified ResNet50 model was used for tumor detection and a ResUNetmodel-based convolutional neural network for segmentation is proposed in this paper. The detection and segmentation were performed on the same dataset consisting of pre-contrast FLAIR and post-contrast MRI images of 110 patients collected from the cancer imaging archive. Due to the use of residual networks the authors observed improvement in evaluation parameters such as accuracy for tumor detection and dice similarity coefficient for tumor segmentation.
The accuracy of tumor detection and dice similarity coefficient achieved by the segmentation model were 96.77% and 0.893 respectively for the TCIA dataset. The results were compared based on manual segmentation and existing segmentation techniques. The tumor mask was also individually compared to the ground truth using the SSIM value. The proposed detection and segmentation models were validated on BraTS2015 and BraTS2017 datasets and the results were consensus.
The use of residual networks in both the detection and the segmentation model resulted in improved accuracy and DSC score. DSC score was increased by 5.9% compared to the UNet model and the accuracy of the model was increased from 92% to 96.77% for the test set.
A Snapshot of Biomarkers in Psoriasis
A persistent long-standing inflammatory skin condition that is brought on by a variety of factors is psoriasis. It is distinguished by itchy scaly reddish plaques particularly on areas of the body that are frequently chafed including the extensor sites of the limbs. Recent developments in molecular-targeted therapy that use biologics or small-molecule inhibitors can effectively cure even the worst psoriatic indications. The outstanding clinical outcomes of treatment help to clarify the disease's detrimental consequences on quality of life. Biomarkers that identify deep remission are essential for developing uniform treatment plans. Blood protein markers such as AMPs that are consistently quantifiable can be very helpful in routine clinical practice. The metabolic pathways involve biomarkers that can not only help diagnose psoriasis in a clinical setting but also indicate its severity based on the levels present in the body. Machine learning and AI have made a diagnosis of the expression of genes as biomarkers more accessible. In this article biomarkers as well as their key role in psoriasis are discussed.
Harnessing the Therapeutic Potential of Dillenia indica: An Overview of Recent Dosage Form Developments
Dillenia indica commonly known as Elephant Apple is a significant medicinal plant found in Assam North-East India. This evergreen shrub or small to medium-sized tree possesses not only tasty components but also a plethora of beneficial therapeutic characteristics. This review article aims to explore the potential use of Dillenia indica in the treatment of diabetes and other diseases as well as discuss various patents associated with this plant. The study focuses on identifying different formulations derived from various parts of Dillenia indica. These formulations encompass a range of dosage forms including mucoadhesive buccal dosage forms buccal patches microbeads emulgel and mucoadhesive nasal gel. Each of these dosage forms offers unique advantages and applications. Mucoadhesive buccal dosage forms are designed to adhere to the oral mucosa allowing for controlled drug release and enhanced absorption. Buccal patches provide a convenient and localized delivery system for specific therapeutic agents. Microbeads offer a versatile approach for encapsulating drugs and facilitating their controlled release. Emulgels combine the benefits of both emulsions and gels providing improved drug delivery and stability. Mucoadhesive nasal gels offer a non-invasive route for drug administration allowing for rapid absorption through the nasal mucosa. By exploring these different formulations researchers aim to harness the therapeutic potential of Dillenia indica in a variety of diseases including diabetes. The study also highlights the importance of patents associated with Dillenia indica indicating the growing interest in its medicinal properties and potential commercial applications. Dillenia indica holds promise as a valuable medicinal plant with its diverse therapeutic characteristics and tasty components. The study discussed various formulations derived from different parts of the plant showcasing their potential applications in the treatment of diseases. Further research and development in this field may lead to the discovery of novel treatments and contribute to the advancement of pharmaceutical science.
Repurposing Phytochemicals against Breast Cancer (MCF-7) using Classical Structure-Based Drug Design
The significant public health effect of breast cancer is demonstrated by its high global prevalence and the potential for severe health consequences. The suppression of the proliferative effects facilitated by the estrogen receptor alpha (ERα) in the MCF-7 cell line is significant for breast cancer therapy.
The current work involves in-silico techniques for identifying potential inhibitors of ERα.
The method combines QSAR models based on machine learning with molecular docking to identify potential binders for the ERα. Further molecular dynamics simulation studied the stability of the complexes and ADMET analysis validated the compound’s properties.
Two compounds (162412 and 443440) showed significant binding affinities with ERα with binding energies comparable to the established binder RL4. The ADMET qualities showed advantageous characteristics resembling pharmaceutical drugs. The stable binding of these ligands in the active region of ERα during dynamic conditions was confirmed by molecular dynamics simulations. RMSD plots and conformational stability supported the ligands' persistent occupancy in the protein's binding site. After simulation two hydrogen bonds were found within the protein-ligand complexes of 162412 and 443440 with binding free energy values of -27.32 kcal/mol and -25.00 kcal/mol.
The study suggests that compounds 162412 and 443440 could be useful for developing innovative anti-ERα medicines. However more research is needed to prove the compounds' breast cancer treatment efficacy. This will help develop new treatments for ERα-associated breast cancer.
Effects of Mesenchymal Stem Cell-conditioned Media with Natural Immunomodulatory Agent Resveratrol on Type 1 Diabetes
Type 1 diabetes mellitus (T1DM) is a condition marked by elevated blood sugar levels and primarily recognized by the destruction of beta cells caused by an autoimmune attack which is a significant characteristic of T1DM. Recent studies have demonstrated the regenerative potential of conditioned medium therapy. In light of this the current research sought to assess the impact of Mesenchymal Stem Cell conditioned media (CM) and CM with resveratrol (CM+ Resveratrol) on the management of T1DM in Swiss albino mice. By leveraging and modifying existing conditioned medium therapy this study aims to evaluate its effectiveness in treating T1DM.
Diabetes was induced in animals using the diabetes-inducing agent streptozotocin (STZ). The animals were then divided into five groups: Normal control Disease Control Resveratrol Condition Media and CM + Resveratrol. Treatments were given to the animals accordingly. The study period was 28 days. During this time the animals were monitored for food-water intake twice a week blood glucose levels and body weight. At the conclusion of the 28-day study period biochemical estimations were performed for serum insulin levels C-peptide levels anti-inflammatory cytokines levels and pro-inflammatory cytokines levels. Additionally histopathology of the pancreas was performed.
The test groups showed a significant decrease in blood glucose levels an increase in C-peptide levels and a decrease in pro-inflammatory cytokine levels compared to the disease group. However no statistically significant change within groups was observed in terms of serum insulin and anti-inflammatory cytokine levels. The improvement in diabetic symptoms such as polyphagia polydipsia and weight loss was observed in the treatment group along with pancreatic regeneration which indicated improved insulin secretion.
In the current investigation we concluded that CM and CM+ Resveratrol as natural immunomodulators have the capacity to regenerate injured pancreatic beta cells and have antidiabetic action together with immunomodulating impact. Nonetheless future studies on this therapy appear to be promising.
A Combination of Pharmacophore Generation, Ligand-based Virtual Screening, Atom-based 3D-QSAR, and Molecular Docking Studies on Febuxostat-based Amides Analogues as Anti-inflammatory Agents
A defence mechanism of the body includes inflammation. It is a process through which the immune system identifies rejects and starts to repair foreign and damaging stimuli. In the world chronic inflammatory disorders are the leading cause of death.
To obtain optimized pharmacophore previously reported febuxostat-based anti-inflammatory amide derivatives series were subjected to pharmacophore hypothesis ligand-based virtual screening and 3D-QSAR studies in the present work using Schrodinger suite 2022-4. QuikProp module of Schrodinger was used for ADMET prediction and HTVS SP and XP protocols of GLIDE modules were used for molecular docking on target protein (PDB ID:3LN1).
Utilising 29 compounds a five-point model of common pharmacophore hypotheses was created having pIC50 ranging between 5.34 and 4.871. The top pharmacophore hypothesis AHHRR_1 model consists of one hydrogen bond acceptor two hydrophobic groups and two ring substitution features. The hypothesis model AHHRR_1 underwent ligand-based virtual screening using the molecules from Asinex. Additionally a 3D-QSAR study based on individual atoms was performed to assess their contributions to model development. The top QSAR model was chosen based on the values of R2 (0.9531) and Q2 (0.9424). Finally four potential hits were obtained by molecular docking based on virtual screening.
The virtual screen compounds have shown similar docking interaction with amino acid residues as shown by standard diclofenac sodium drugs. Therefore the findings in the present study can be explored in the development of potent anti-inflammatory agents.
New 1,3,4‒oxadiazole Quinazolines as Potential Anticancer Agents: Design, Synthesis, Biological Evaluation, and In silico Studies
A novel series of 134‒oxadiazole connected to derivatives of quinazolinone (7a–e and 8a–f) was synthesized in the current investigation and its anticancer and Topoisomerase‒II inhibitory activity was evaluated.
These findings inspired the design synthesis and biological analysis of these 134‒oxadiazole-quinazolinone analogues as antiproliferative Topo‒II inhibitors.
The novel compound structures were determined using mass spectrometry and spectral methods (IR NMR: 1H & 13C). The 3-(45-dimethylthiazol-2-yl)-25-diphenyltetrazolium bromide colourimetric assay has been used to evaluate the anticancer efficacy of these drugs and Autodock 4.2 provides a description of the docking results. For the more active members additional biological tests such as the Topo‒II inhibition experiment were performed. These compounds' physicochemical and ADMET characteristics were examined in more detail.
In the experiment for antiproliferative activity compounds 7d 7e 8c 8e and 8f demonstrated encouraging cytotoxicity findings against HCT‒116 and HepG2 cancer cell lines with IC50 values ranging from 3.85 to 19.43 μM. Compounds 7d 7e and 8e were the most potent inhibitors of Topo II with IC50 values of 15.18 17.55 and 12.59 μM respectively. Additionally the docked compound 8c showed the strongest conventional hydrogen bonds among the residues Leu507(B) Asn508(B) Asn520(B) and Glu522(B) in the Human topoisomerase‒IIβ active site in the DNA complex (4G0U) when compared to the findings of docking experiments.
New findings have discovered the fact that fused 134‒oxadiazole bearing quinazolinone contributed great significance in the field of medicinal chemistry due to their diverse biological properties. Finally the in silico pharmacokinetic profile of all the synthesized derivatives was estimated using SwissADME where some of the compounds followed Lipinski Veber Egan and Muegge rules without deviation. The result of this activity advises that with a simple modification in structure a potent anticancer agent can be generated with good efficacy.
Role of Metalloproteinases in Diabetes-associated Mild Cognitive Impairment
Diabetes has been linked to an increased risk of mild cognitive impairment (MCI) a condition characterized by a subtle cognitive decline that may precede the development of dementia. The underlying mechanisms connecting diabetes and MCI involve complex interactions between metabolic dysregulation inflammation and neurodegeneration. A critical mechanism implicated in diabetes and MCI is the activation of inflammatory pathways. Chronic low-grade inflammation as observed in diabetes can lead to the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) interleukin-6 (IL-6) interleukin-1 beta (IL-1β) and interferon-gamma (IFNγ) each of which can exacerbate neuroinflammation and contribute to cognitive decline. A crucial enzyme involved in regulating inflammation is ADAM17 a disintegrin and metalloproteinase which can cleave and release TNF-α from its membrane-bound precursor and cause it to become activated. These processes in turn activate additional inflammation-related pathways such as AKT NF-κB NLP3 MAPK and JAK-STAT pathways. Recent research has provided novel insights into the role of ADAM17 in diabetes and neurodegenerative diseases. ADAM17 is upregulated in both diabetes and Alzheimer's disease suggesting a shared mechanism and implicating inflammation as a possible contributor to much broader forms of pathology and pointing to a possible link between inflammation and the emergence of MCI. This review provides an overview of the different roles of ADAM17 in diabetes-associated mild cognitive impairment diseases. It identifies mechanistic connections through which ADAM17 and associated pathways may influence the emergence of mild cognitive impairment.
Myeloid-derived Suppressor Cells and Multiple Sclerosis
Myeloid-Derived Suppressor Cells (MDSCs) are a heterogeneous population of immature myeloid cells that play important roles in maintaining immune homeostasis and regulating immune responses. MDSCs can be divided into two main subsets based on their surface markers and functional properties: granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs). Recently greatest attention has been paid to innate immunity in Multiple Sclerosis (MS) so the aim of our review is to provide an overview of the main characteristics of MDSCs in MS and its preclinical model by discussing the most recent data available. The immunosuppressive functions of MDSCs can be dysregulated in MS leading to an exacerbation of the autoimmune response and disease progression. Antigen-specific peptide immunotherapy which aims to restore tolerance while avoiding the use of non-specific immunosuppressive drugs is a promising approach for autoimmune diseases but the cellular mechanisms behind successful therapy remain poorly understood. Therefore targeting MDSCs could be a promising therapeutic approach for MS. Various strategies for modulating MDSCs have been investigated including the use of pharmacological agents biological agents and adoptive transfer of exogenous MDSCs. However it remained unclear whether MDSCs display any therapeutic potential in MS and how this therapy could modulate different aspects of the disease. Collectively all the described studies revealed a pivotal role for MDSCs in the regulation of MS.
Bibliometric Analysis of Alzheimer's Disease and Depression
The link between Alzheimer's disease and depression has been confirmed by clinical and epidemiological research. Therefore our study examined the literary landscape and prevalent themes in depression-related research works on Alzheimer's disease through bibliometric analysis.
Relevant literature was identified from the Web of Science core collection. Bibliometric parameters were extracted and the major contributors were defined in terms of countries institutions authors and articles using Microsoft Excel 2019 and VOSviewer. VOSviewer and CiteSpace were employed to visualize the scientific networks and seminal topics.
The analysis of literature utilised 10553 articles published from 1991 until 2023. The three countries or regions with the most publications were spread across the United States China and England. The University of Toronto and the University of Pittsburgh were the major contributors to the institutions. Lyketsos Constantine G. Cummings JL were found to make outstanding contributions. Journal of Alzheimer's Disease was identified as the most productive journal. Furthermore “Alzheimer’s” “depression” “dementia” and “mild cognitive decline” were the main topics of discussion during this period.
Data were searched from a single database to become compatible with VOSviewer and CiteSpace leading to a selection bias. Manuscripts in English were considered leading to a language bias.
Articles on “Alzheimer’s” and “depression” displayed an upward trend. The prevalent themes addressed were the mechanisms of depression-associated Alzheimer's disease the identification of depression and cognitive decline in the early stages of Alzheimer's alleviating depression and improving life quality in Alzheimer's patients and their caregivers and diagnosing and treating neuropsychiatric symptoms in Alzheimer. Future research on these hot topics would promote understanding in this field.
Notch Signaling in Central Nervous System: From Cellular Development to Multiple Sclerosis Disease
Multiple sclerosis (MS) is characterized by autoimmune-driven neuroinflammation axonal degeneration and demyelination. This study aimed to explore the therapeutic potential of targeting Notch signaling within the central nervous system (CNS) in the context of MS. Understanding the intricate roles of Notch signaling could pave the way for targeted interventions to mitigate MS progression.
A comprehensive literature review was conducted using databases such as PubMed Web of Science and Scopus. Keywords such as “Notch signaling” “neuroglial interactions” and “MS” were used. The selection criteria included relevance to neuroglial interactions peer-reviewed publications and studies involving animal models of MS.
This review highlights the diverse functions of Notch signaling in CNS development including its regulation of neural stem cell differentiation into neurons astrocytes and oligodendrocytes. In the context of MS Notch signaling has emerged as a promising therapeutic target exhibiting positive impacts on neuroprotection and remyelination. However its intricate nature within the CNS necessitates precise modulation for therapeutic efficacy.
This study provides a comprehensive overview of the potential therapeutic role of Notch signaling in MS. The findings underscore the significance of Notch modulation for neuroprotection and remyelination emphasizing the need for precision in therapeutic interventions. Further research is imperative to elucidate the specific underlying mechanisms involved which will provide a foundation for targeted therapeutic strategies for the management of MS and related neurodegenerative disorders.