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OBJECTIVE: Anemia is a pathological condition characterized by reduced oxygen bioavailability and/or changes in hematological parameters. This study investigated the anti-anemic activities of Carica papaya (CP) phytoconstituents in aluminium-chloride-induced anemic rats. METHOD: Twenty-seven rats were randomized into nine groups of three rats as follows; group 1 was the normal (non-induced) group, 2-9 were anemic rats administered 1 mL distilled water, standard drug (3 mg/kg body weight (bw) ferrous sulphate), 100, 300 and 500 mg/kg bw of crude methanolic extract of CP (CMECP) of the leaf and 100, 300 and 500 mg/kg bw of CMECP of the seed respectively in the first stage of the study. In the second stage, thirty-three rats were randomized into eleven groups of three rats as follows; group 1 was the normal group, 2-11 were anemic rats treated with 1 mL distilled water, standard drug, 75 mg/kg bw, 150 mg/kg of alkaloid fraction of CP seed, 75 mg/kg bw, 150 mg/kg bw of flavonoid fraction of CP seed, 75 mg/kg bw and 150 mg/kg of alkaloid fraction of CP leaf, 75 mg/kg bw and 150 mg/kg bw of flavonoid fraction of CP leaf respectively. RESULTS: Treatment of anemic rats with CP extracts and fractions of the seed and leaf significantly reversed the hematological parameters and body weight of anemic rats in a dose independent fashion. The CMECP leaf at 100 and 500 mg/kg gave PCV of 42.50±0.50 and 47.00±0.50, while the seed gave 49.50±0.50 and 42.50±0.50 respectively after 2 weeks of treatment. However, the alkaloid and flavonoid fraction of CP presented better anti-anemic properties probably due to constituents' synergism. CONCLUSION: This study concluded that CP possesses phytoconstituents which potentiates it as a safe anti-anemic drug candidate.
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The continual increase in global diabetic statistics portends decreased productivity and life spans, thus making it a disease of concern requiring more effective and safe therapeutic options. While several reports on antidiabetic plants, including Hura crepitans, are available, there is still a dearth of information on the holistic antidiabetic properties of H. crepitans and its associated complications. This study evaluated the antidiabetic potential of methanolic extract of Hura crepitans using in vitro, in vivo, and in silico approaches. The extract revealed a dose-dependent in vitro effect, with a 47.97â¯% and 65.34â¯% decrease in the fasting blood sugar levels of streptozotocin (STZ) induced diabetic rats at 150 and 300â¯mg/kg BW, respectively. Likewise, the extract increased serum and pancreatic insulin levels, and significantly ameliorated neuronal oxidative stress and inflammation by reducing the expression levels of cholinesterase, NF-κB, and COX-2 in the brain of hyperglycemic rats. Serum dyslipidemia, liver, and kidney biomarker indices, and hematological alterations in diabetic rats were also significantly attenuated by the extract. Several constituents, mainly terpenes, were identified in the extract. To further predict the drug-likeness, pharmacokinetics, and binding properties of the compounds, in silico analysis was conducted. Ergosta-2,24-dien-26-oicacid,18-(acetyloxy)-5,6-epoxy-4, 22-dihydroxy-1-oxo-,delta.-lactone-4.beta., displayed the highest docking scores for acetylcholinesterase, butyrylcholinesterases, alpha-amylase, and nuclear factor-kB with values of -12.4, -10.9, -10.3, and -9.4â¯kcal/mol, while ergost-25-ene-6,12-dione,3,5-dihydroxy-, (3.beta.,5.alpha.) topped for cyclooxygenase-2 (-9.0â¯kcal/mol). The top-ranked compounds also presented significant oral drug-likeness, pharmacokinetics, and safety properties. Altogether, our data provide preclinical evidence of the potential of Hura crepitans in ameliorating diabetes and its associated complications.
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[This corrects the article on p. 2598 in vol. 13, PMID: 37424807.].
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Pancreatic adenocarcinoma (PAAD), known as one of the deadliest cancers, is characterized by a complex tumor microenvironment, primarily comprised of cancer-associated fibroblasts (CAFs) in the extracellular matrix. These CAFs significantly alter the matrix by interacting with hyaluronic acid (HA) and the enzyme hyaluronidase, which degrades HA - an essential process for cancer progression and spread. Despite the critical role of this interaction, the specific functions of CAFs and hyaluronidase in PAAD development are not fully understood. Our study investigates this interaction and assesses NSC777201, a new anti-cancer compound targeting hyaluronidase. This research utilized computational methods to analyze gene expression data from the Gene Expression Omnibus (GEO) database, specifically GSE172096, comparing gene expression profiles of cancer-associated and normal fibroblasts. We conducted in-house sequencing of pancreatic cancer cells treated with NSC777201 to identify differentially expressed genes (DEGs) and performed functional enrichment and pathway analysis. The identified DEGs were further validated using the TCGA-PAAD and Human Protein Atlas (HPA) databases for their diagnostic, prognostic, and survival implications, accompanied by Ingenuity Pathway Analysis (IPA) and molecular docking of NSC777201, in-vitro, and preclinical in-vivo validations. The result revealed 416 DEGs associated with CAFs and 570 DEGs related to NSC777201 treatment, with nine overlapping DEGs. A key finding was the transmembrane protein TMEM2, which strongly correlated with FAP, a CAF marker, and was associated with higher-risk groups in PAAD. NSC777201 treatment showed inhibition of TMEM2, validated by rescue assay, indicating the importance of targeting TMEM2. Further analyses, including IPA, demonstrated that NSC777201 regulates CAF cell senescence, enhancing its therapeutic potential. Both in-vitro and in-vivo studies confirmed the inhibitory effect of NSC777201 on TMEM2 expression, reinforcing its role in targeting PAAD. Therefore, TMEM2 has been identified as a theragnostic biomarker in PAAD, influenced by CAF activity and HA accumulation. NSC777201 exhibits significant potential in targeting and potentially reversing critical processes in PAAD progression, demonstrating its efficacy as a promising therapeutic agent.
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Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor whose median survival is less than 15 months. The current treatment regimen comprising surgical resectioning, chemotherapy with Temozolomide (TMZ), and adjuvant radiotherapy does not achieve total patient cure. Stem cells' presence and GBM tumor heterogeneity increase their resistance to TMZ, hence the poor overall survival of patients. A dysregulated cell cycle in glioblastoma enhances the rapid progression of GBM by evading senescence or apoptosis through an over-expression of cyclin-dependent kinases and other protein kinases that are the cell cycle's main regulatory proteins. Herein, we identified and validated the biomarker and predictive properties of a chemoradio-resistant oncogenic signature in GBM comprising CDK1, PBK, and CHEK1 through our comprehensive in silico analysis. We found that CDK1/PBK/CHEK1 overexpression drives the cell cycle, subsequently promoting GBM tumor progression. In addition, our Kaplan-Meier survival estimates validated the poor patient survival associated with an overexpression of these genes in GBM. We used in silico molecular docking to analyze and validate our objective to repurpose Dapagliflozin against CDK1/PBK/CHEK1. Our results showed that Dapagliflozin forms putative conventional hydrogen bonds with CDK1, PBK, and CHEK1 and arrests the cell cycle with the lowest energies as Abemaciclib.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Simulación del Acoplamiento Molecular , Línea Celular Tumoral , Temozolomida/farmacología , Temozolomida/uso terapéutico , Biología Computacional , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Antineoplásicos Alquilantes/farmacología , Resistencia a Antineoplásicos/genética , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/genética , Proteína Quinasa CDC2/genéticaRESUMEN
Viola L. is the largest genus of the Violaceae family with more than 500 species across the globe. The present extensive literature survey revealed Viola species to be a group of important nutritional and medicinal plants used for the ethnomedicinal treatment of noncommunicable diseases (NCDs) such as diabetes, asthma, lung diseases, and fatigue. Many plant species of this genus have also received scientific validation of their pharmacological activities including neuroprotective, immunomodulatory, anticancer, antihypertensive, antidyslipidemic, analgesic, antipyretic, diuretic, anti-inflammatory, anthelmintic, and antioxidant. Viola is highly rich in different natural products some of which have been isolated and identified in the past few decades; these include flavonoids terpenoids and phenylpropanoids of different pharmacological activities. The pharmacokinetics and clinical studies on this genus are lacking, and the present review is aimed at summarizing the current understanding of the ethnopharmacology, phytochemistry, nutritional composition, and pharmacological profile of medicinal plants from the Viola genus to reveal its therapeutic potentials, gaps, and subsequently open a new window for future pharmacological research.
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OBJECTIVES: Digital sphygmomanometers have been used for more than 40 years in Western medicine for accurately measuring systolic and diastolic blood pressures, which are vital signs observed for the diagnosis of different diseases. Similarly, traditional Chinese medicine (TCM) has been using wrist pulse diagnosis for thousands of years. Some studies have combined digital wrist pulse signals and the diagnosis method of TCM to quantify pulse waves and identify diseases. However, the effectiveness of this approach is limited because of scattered methods and complex pathological features. Moreover, the literature on TCM does not provide quantitative data or objective indicators. METHODS: In this prospective study, we developed a diagnostic system that contains a modified sphygmomanometer. In addition, we designed a procedure for analyzing pulse waves with 156 features of harmonic modes and a decision tree method for diagnosing kidney insufficiency. RESULTS: In the decision tree method, at least three features of harmonic modes can achieve an accuracy of 0.86, a specificity of 0.91, and a Cohen's kappa coefficient of 0.72. By comparison, the random forest method can achieve an accuracy of 0.99, a specificity of 0.99, and a Cohen's kappa coefficient of 0.94 within 200 trees. The results of this study indicated that even in patients with kidney insufficiency and complex etiology, common features can be distinguished by identifying changes in pulse waveforms. CONCLUSION: By using the modified sphygmomanometer to measure blood pressure, people can monitor their health status and take care of it in advance by simply measuring their blood pressure.
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OBJECTIVES: The use of medicinal plants for diabetes treatment is increasing owing to their effectiveness and safety compared to synthetic drugs. Thus, the ameliorative effects of Azanza garckeana (F. Hoffm.) fractions in diabetes-induced dyslipidemia, hepatopathy, and nephropathy in rats were evaluated in this study. METHODS: Rats with alloxan (120 mg/kg body weight (BW))-induced diabetes were randomized into different groups (n=5) and treated with the crude methanolic extract, and fractions (n-hexane, ethyl acetate, and aqueous fractions) of A. garckeana each at 100, 200, and 400 mg/kg BW. Glibenclamide (5 mg/kg BW) was used as a reference drug, and all treatments were administered orally daily for 6 weeks. RESULTS: Our data revealed that treatment with the crude extract caused a dose-dependent hypoglycemic effect of 61.32±3.45%, 76.05±3.05%, and 78.59±5.90% at 100, 200, and 400 mg/kg BW, respectively and improved the BW of the animals. The extract also ameliorated the elevated cholesterol, triglyceride, low-density lipoprotein cholesterol, and increased serum levels of high-density lipoprotein cholesterol compared with untreated control animals. The extract also reversed serum biochemical alterations in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine, total and direct bilirubin, urea, and uric acid that were observed in untreated diabetic rats. Interestingly, the A. garckeana fraction also exhibited significant protection against diabetes-induced dyslipidemia, hepatopathy, and nephropathy in rats, with the ethyl acetate fraction exhibiting a remarkable protective effect. The LC-MS characterisation of the active fraction identified the presence of various phenolic and flavonoid compounds that could be responsible for the bioactivity of the fraction. CONCLUSION: Collectively, this study suggests the potential application of A. garckeana for effective treatment of diabetic nephropathy, with the ethyl acetate fraction of this plant representing a reserve of potential candidates for developing new drugs.
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OBJECTIVES: Diabetic nephropathy (DN) is one of the most prevalent secondary complications associated with diabetes mellitus. Decades of research have implicated multiple pathways in the etiology and pathophysiology of diabetic nephropathy. There has been no reliable predictive biomarkers for the onset or progression of DN and no successful treatments are available. METHODS: In the present study, we explored the datasets of RNA sequencing data from patients with Type II diabetes mellitus (T2DM)-induced nephropathy to identify a novel gene signature. We explored the target bioactive compounds identified from Azanza garckeana, a medicinal plant commonly used by the traditional treatment of diabetes nephropathy. RESULTS: Our analysis identified lymphotoxin beta (LTB), SRY-box transcription factor 4 (SOX4), SOX9, and WAP four-disulfide core domain protein 2 (WFDC2) as novel signatures of T2DM-induced nephropathy. Additional analysis revealed the pathological involvement of the signature in cell-cell adhesion, immune, and inflammatory responses during diabetic nephropathy. Molecular docking and dynamic simulation at 100 ns conducted studies revealed that among the three compounds, Terpinen-4-ol exhibited higher binding efficacies (binding energies (ΔG) = -3.9~5.5 kcal/mol) against the targets. The targets, SOX4, and SOX9 demonstrated higher druggability towards the three compounds. WFDC2 was the least attractive target for the compounds. CONCLUSION: The present study was relevant in the diagnosis, prognosis, and treatment follow up of patients with diabetes induced nephropathy. The study provided an insight into the therapeutic application of the bioactive principles from Azanza garckeana. Continued follow-up invitro validations study are ongoing in our laboratory.
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Glucokinase plays an important role in regulating the blood glucose level and serves as an essential therapeutic target in type 2 diabetes management. Entada africana is a medicinal plant and highly rich source of bioactive ligands with the potency to develop new target drugs for glucokinase such as diabetes and obesity. Therefore, the study explored a computational approach to predict identified compounds from Entada africana following its intermolecular interactions with the allosteric binding site of the enzymes. We retrieved the three-dimensional (3D) crystal structure of glucokinase (PDB ID: 4L3Q) from the online protein data bank and prepared it using the Maestro 13.5, Schrödinger Suite 2022-3. The compounds identified were subjected to ADME, docking analysis, pharmacophore modeling, and molecular simulation. The results show the binding potential of the identified ligands to the amino acid residues, thereby suggesting an interaction of the amino acids with the ligand at the binding site of the glucokinase activator through conventional chemical bonds such as hydrogen bonds and hydrophobic interactions. The compatibility of the molecules was highly observed when compared with the standard ligand, thereby leading to structural and functional changes. Therefore, the bioactive components from Entada africana could be a good driver of glucokinase, thereby paving the way for the discovery of therapeutic drugs for the treatment of diabetes and its related complications.
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Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Simulación del Acoplamiento Molecular , Glucoquinasa/metabolismo , Ligandos , Diabetes Mellitus Tipo 2/tratamiento farmacológicoRESUMEN
Despite the therapeutic advancement with chemotherapy and targeted therapy against non-small-cell lung cancer (NSCLC), most patients ultimately develop resistance to these drugs, exhibiting disease progression, metastasis, and worse prognosis. There is, therefore, a need for the development of novel multi-targeted therapies that can offer a high therapeutic index with lesser chances of drug resistance against NSCLC. In the present study, we evaluated the therapeutic potential of a novel multi-target small molecule NLOC-015A for targeted treatment of NSCLC. Our in vitro studies revealed that NLOC-015A exhibited a broad spectrum of anticancer activities against lung cancer cell line. NLOC-015A decreased the viability of H1975 and H1299 cells with respective IC50 values of 2.07±0.19 and 1.90±0.23 µm. In addition, NLOC-015A attenuated the oncogenic properties (colony formation, migratory ability, and spheroid formation) with concomitant downregulation of expression levels of epidermal growth factor receptor (EGFR)/mammalian target of rapamycin (mTOR)/AKT, nuclear factor (NF)-κB, signaling network. In addition, the stemness inhibitory effect of NLOC0-15A was accompanied by decreased expression levels of aldehyde dehydrogenase (ALDH), MYC Proto-Oncogene (C-Myc), and (sex-determining region Y)-box 2 (SOX2) in both H1975 and H1299 cell lines. Furthermore, NLOC-015A suppressed the tumor burden and increased the body weight and survival of H1975 xenograft-bearing mice. Treatment with NLOC-015A also attenuated biochemical and hematological alterations in the tumor bearing mice. Interestingly, NLOC-015A synergistically enhanced the in vitro efficacy, and therapeutic outcome of osimertinib in vivo. In addition, the toxicity of osimertinib was significantly attenuated by combination with NLOC-015A. Altogether, our findings suggested that combining osimertinib with NLOC-015 appears to be a promising way to improve osimertinib's efficacy and achieve better therapeutic results against NSCLC. We therefore suggest that NLOC-015A might represent a new candidate for treating NSCLC via acting as a multitarget inhibitor of EGFR/mTOR/NF-Κb signaling networks and efficiently compromising the oncogenic phenotype of NSCLC.
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Background: Glioblastoma multiforme (GBM) is the most lethal malignancy in brain, which is surrounded by the blood-brain barrier (BBB), which limits the efficacy of standard treatments. Developing an effective drug that can penetrate the blood-brain barrier (BBB) remains a critical challenge in the fight against GBM. CC12 (NSC749232) is an anthraquinone tetraheterocyclic homolog with a lipophilic structure that may facilitate penetration of the brain area. Methods: We used temozolomide sensitive and resistance GBM cells and animal model to identify the CC12 delivery, anti-tumor potential and its underlying mechanism. Results: Importantly, toxicity triggered by CC12 was not associated with the methyl guanine-DNA methyl transferase (MGMT) methylation status which revealed a greater application potential compared to temozolomide. Alexa F488 cadaverine-labelled CC12 successfully infiltrated into the GBM sphere; in addition, 68Ga-labeled CC12 was also found in the orthotopic GBM area. After passing BBB, CC12 initiated both caspase-dependent intrinsic/extrinsic apoptosis pathways and apoptosis-inducing factor, EndoG-related caspase-independent apoptosis signaling in GBM. RNA sequence analysis from The Cancer Genome Atlas indicated that LYN was overexpressed in GBM is associated with poorer overall survival. We proved that targeting of LYN by CC12 may diminish GBM progression and suppress it downstream factors such as signal transduction and activator of extracellular signal-regulated kinases (ERK)/transcription 3 (STAT3)/nuclear factor (NF)-κB. CC12 was also found to participate in suppressing GBM metastasis and dysregulation of the epithelial-mesenchymal transition (EMT) through inactivation of the LYN axis. Conclusion: CC12, a newly developed BBB-penetrating drug, was found to possess an anti-GBM capacity via initiating an apoptotic mechanism and disrupting LYN/ERK/STAT3/NF-κB-regulated GBM progression.
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Neoplasias Encefálicas , Glioblastoma , Animales , Temozolomida/farmacología , Línea Celular Tumoral , Neoplasias Encefálicas/genética , Glioblastoma/metabolismo , FN-kappa B/metabolismo , Apoptosis , CaspasasRESUMEN
Silver nanoparticles (AgNPs) have been generally used due to their strong antibacterial, antiviral and antifungal and antimicrobial properties. However, their toxicity is a subject of sustained debate, thus requiring further studies. Hence, this study examines the adverse effects of the sub-dermal administered dose of AgNPs (200 nm) on the liver, kidney and heart of male Wistar rats. Thirty male rats were randomly distributed into six groups of five animals per group. Group A and D served as the control and received distilled water for 14 and 28 days respectively. Groups B and C were sub-dermally exposed to AgNPs at 10 and 50 mg/kg daily for 14 days while E and F were sub-dermally exposed to AgNPs at 10 and 50 mg/kg daily for 28 days. The liver, kidney and heart of the animals were collected, processed and used for biochemical and histological analysis. Our results revealed that the subdermal administration of AgNPs induced significant increased (p < 0.05) activities of aspartate aminotransferase (AST), alanine transferase (ALT), alkaline phosphatase (ALP), urea, creatinine, and malondialdehyde (MDA) while decreasing the levels of glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and total thiol groups in the rat tissues. Our findings suggest that the subdermal administration of AgNPs induced oxidative stress and impaired the hepatic, renal and cardiac functions of male Wistar rats.
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Nanopartículas del Metal , Plata , Masculino , Ratas , Animales , Ratas Wistar , Plata/toxicidad , Nanopartículas del Metal/toxicidad , Hígado , Riñón , Estrés OxidativoRESUMEN
Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer characterized by drug resistance and distant metastasis. Cancer stem cells (CSCs) are considered a major contributor to TNBC's drug resistance. Thus targeting and eliminating CSCs have been vigorously researched. However, the precise targetable molecular networks responsible for CSC genesis remain unclear; this conundrum is mainly due to the high heterogeneity of the TNBC tumor microenvironment (TME). The cancer-associated fibroblasts (CAFs) are one of the most abundant cellular components of the TME. Emerging studies indicate that CAFs facilitate TNBC's progression by establishing a pro-tumor TME. Hence, identifying the molecular networks involved in CAF transformation and CAF-associated oncogenesis are essential areas to be explored. Through a bioinformatics approach, we identified INFG/STAT1/NOTCH3 as a molecular link between CSCs and CAF. DOX-resistant TNBC cell lines showed increased expression of INFG/STAT1/NOTCH3 and CD44 and were associated with increased self-renewal ability and CAF-transformative ability. Downregulation of STAT1 significantly reduced the tumorigenic properties of MDA-MB-231 and -468 cells and their CAF-transforming potential. Our molecular docking analysis suggested that gamma mangostin (gMG), a xanthone, formed complexes with INFG/STAT1/NOTCH3 better than celecoxib. We then demonstrated that gMG treatment reduced the tumorigenic properties similarly observed in STAT1-knocked down conditions. Finally, we utilized a DOX-resistant TNBC tumoroid-bearing mouse model to demonstrate that gMG treatment significantly delayed tumor growth, reduced CAF generation, and improved DOX sensitivity. Further investigations are warranted for clinical translation.
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Fibroblastos Asociados al Cáncer , Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Fibroblastos Asociados al Cáncer/metabolismo , Simulación del Acoplamiento Molecular , Doxorrubicina/uso terapéutico , Línea Celular Tumoral , Microambiente Tumoral , Factor de Transcripción STAT1/metabolismo , Receptor Notch3/genética , Receptor Notch3/metabolismoRESUMEN
Head and neck squamous carcinoma (HNSCC) affects more than half a million individuals and ranks the ninth leading cause of death globally each year. Many patients develop treatment resistance leading to poor clinical outcomes. The poor treatment responses are in part due to the heterogeneity of HNSCC tumor and tumor microenvironment (TME). The interaction of tumor cells with their TME has been studied vigorously in recent years because of their pivotal roles in tumorigenesis and determining the treatment response. Cancer-associated fibroblasts (CAFs) are one of the most abundant tumor-infiltrating cells, which have been shown to associate with the aggressive behavior of HNSCC. Hence, targeting and disrupting the tumor-CAFs interactions represents a rational therapeutic approach. To develop targeted therapeutic drugs against CAFs, the identification of CAF-associated gene signature is essential. Here, we analyzed multiple sequencing databases including microarrays and single-cell RNA-sequencing databases and identified SPARC/MMP9/CD44 as HNSCC targetable gene signatures encompassing cancer-associated fibroblasts (CAFs). We found SPARC/MMP9CD44 signature was highly expressed in HNSC tissues compared to adjacent normal tissues. Increased SPARC/MMP9/CD44 signature levels strongly correlated with tumor-infiltrating CAFs, suggesting the functional importance of this signature for HNSCC-CAFs interaction and progression. Subsequently, we utilized a genomics approach and identified midostaurin as the top-ranking drug candidate for targeting SPARC/MMP9/CD44 signature. For validation, we performed molecular docking of midostaurin in complex with SPARC/MMP9/CD44 and demonstrated midostaurin's high binding affinities compared to their respective standard inhibitors. In summary, our study provided a rapid genomics approach for identifying targetable gene signature and drug candidate for HNSCC.
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In the present study, in vitro, in vivo, and in silico models were used to evaluate the therapeutic potential of Pulmeria alba methanolic (PAm) extract, and we identified the major phytocompound, apigetrin. Our in vitro studies revealed dose-dependent increased glucose uptake and inhibition of α-amylase (50% inhibitory concentration (IC50)= 217.19 µg/mL), antioxidant (DPPH, ferric-reducing activity of plasma (FRAP), and lipid peroxidation (LPO) [IC50 = 103.23, 58.72, and 114.16 µg/mL respectively]), and anti-inflammatory potential (stabilizes human red blood cell (HRBC) membranes, and inhibits proteinase and protein denaturation [IC50 = 143.73, 131.63, and 198.57 µg/mL]) by the PAm extract. In an in vivo model, PAm treatment reversed hyperglycemia and attenuated insulin deficiency in rats with streptozotocin (STZ)-induced diabetes. A post-treatment tissue analysis revealed that PAm attenuated neuronal oxidative stress, neuronal inflammation, and neuro-cognitive deficiencies. This was evidenced by increased levels of antioxidants enzymes (superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH)), and decreased malondialdehyde (MDA), proinflammatory markers (cyclooxygenase 2 (COX2), nuclear factor (NF)-κB and nitric oxide (NOx)), and acetylcholinesterase (AChE) activities in the brain of PAm-treated rats compared to the STZ-induced diabetic controls. However, no treatment-related changes were observed in levels of neurotransmitters, including serotonin and dopamine. Furthermore, STZ-induced dyslipidemia and alterations in serum biochemical markers of hepatorenal dysfunction were also reversed by PAm treatment. Extract characterization identified apigetrin (retention time: 21,227 s, 30.48%, m/z: 433.15) as the major bioactive compound in the PAm extract. Consequently, we provide in silico insights into the potential of apigetrin to target AChE/COX-2/NOX/NF-κB Altogether the present study provides preclinical evidence of the therapeutic potential of the apigetrin-enriched PAm extract for treating oxidative stress and neuro-inflammation associated with diabetes.
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Diabetes Mellitus Experimental , Ratas , Humanos , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Acetilcolinesterasa/metabolismo , Ratas Wistar , Glucemia/metabolismo , Estrés Oxidativo , Antioxidantes/farmacología , Encéfalo/metabolismo , Inflamación/tratamiento farmacológico , Estreptozocina/uso terapéutico , Extractos Vegetales/farmacologíaRESUMEN
The African nutmeg (Monodora myristica) is a medically useful plant. We, herein, aimed to critically examine whether bioactive compounds identified in the extracted oil of Monodora myristica could act as antimicrobial agents. To this end, we employed the Schrödinger platform as the computational tool to screen bioactive compounds identified in the oil of Monodora myristica. Our lead compound displayed the highest potency when compared with levofloxacin based on its binding affinity. The hit molecule was further subjected to an Absorption, Distribution, Metabolism, Excretion (ADME) prediction, and a Molecular Dynamics (MD) simulation was carried out on molecules with PubChem IDs 529885 and 175002 and on three standards (levofloxacin, cephalexin, and novobiocin). The MD analysis results demonstrated that two molecules are highly compact when compared to the native protein; thereby, this suggests that they could affect the protein on a structural and a functional level. The employed computational approach demonstrates that conformational changes occur in DNA gyrase after the binding of inhibitors; thereby, this resulted in structural and functional changes. These findings expand our knowledge on the inhibition of bacterial DNA gyrase and could pave the way for the discovery of new drugs for the treatment of multi-resistant bacterial infections.
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Annonaceae , Antiinfecciosos , Inhibidores de Topoisomerasa II , Annonaceae/química , Antiinfecciosos/farmacología , Girasa de ADN , Levofloxacino , Inhibidores de Topoisomerasa II/farmacologíaRESUMEN
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated coronavirus disease 2019 (COVID-19) infection remains a global pandemic and health emergency with overwhelming social and economic impacts throughout the world. Therapeutics for COVID-19 are limited to only remdesivir; therefore, there is a need for combined, multidisciplinary efforts to develop new therapeutic molecules and explore the effectiveness of existing drugs against SARS-CoV-2. In the present study, we reported eight (SCOV-L-02, SCOV-L-09, SCOV-L-10, SCOV-L-11, SCOV-L-15, SCOV-L-18, SCOV-L-22, and SCOV-L-23) novel structurally related small-molecule derivatives of niclosamide (SCOV-L series) for their targeting potential against angiotensin-converting enzyme-2 (ACE2), type II transmembrane serine protease (TMPRSS2), and SARS-COV-2 nonstructural proteins (NSPs) including NSP5 (3CLpro), NSP3 (PLpro), and RdRp. Our correlation analysis suggested that ACE2 and TMPRSS2 modulate host immune response via regulation of immune-infiltrating cells at the site of tissue/organs entries. In addition, we identified some TMPRSS2 and ACE2 microRNAs target regulatory networks in SARS-CoV-2 infection and thus open up a new window for microRNAs-based therapy for the treatment of SARS-CoV-2 infection. Our in vitro study revealed that with the exception of SCOV-L-11 and SCOV-L-23 which were non-active, the SCOV-L series exhibited strict antiproliferative activities and non-cytotoxic effects against ACE2- and TMPRSS2-expressing cells. Our molecular docking for the analysis of receptor-ligand interactions revealed that SCOV-L series demonstrated high ligand binding efficacies (at higher levels than clinical drugs) against the ACE2, TMPRSS2, and SARS-COV-2 NSPs. SCOV-L-18, SCOV-L-15, and SCOV-L-09 were particularly found to exhibit strong binding affinities with three key SARS-CoV-2's proteins: 3CLpro, PLpro, and RdRp. These compounds bind to the several catalytic residues of the proteins, and satisfied the criteria of drug-like candidates, having good adsorption, distribution, metabolism, excretion, and toxicity (ADMET) pharmacokinetic profile. Altogether, the present study suggests the therapeutic potential of SCOV-L series for preventing and managing SARs-COV-2 infection and are currently under detailed investigation in our lab.
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Our previous study found that 2-phenyl-4-quinolone (2-PQ) derivatives are antimitotic agents, and we adopted the drug design concept of scaffold hopping to replace the 2-aromatic ring of 2-PQs with a 4-aromatic ring, representing 4-phenyl-2-quinolones (4-PQs). The 4-PQ compounds, whose structural backbones also mimic analogs of podophyllotoxin (PPT), maybe a new class of anticancer drugs with simplified PPT structures. In addition, 4-PQs are a new generation of anticancer lead compounds as apoptosis stimulators. On the other hand, previous studies showed that 4-arylcoumarin derivatives with 5-, 6-, and 7-methoxy substitutions displayed remarkable anticancer activities. Therefore, we further synthesized a series of 5-, 6-, and 7-methoxy-substituted 4-PQ derivatives (19-32) by Knorr quinoline cyclization, and examined their anticancer effectiveness. Among these 4-PQs, compound 22 demonstrated excellent antiproliferative activities against the COLO205 cell line (50% inhibitory concentration (IC50) = 0.32 µM) and H460 cell line (IC50 = 0.89 µM). Furthermore, we utilized molecular docking studies to explain the possible anticancer mechanisms of these 4-PQs by the docking mode in the colchicine-binding pocket of the tubulin receptor. Consequently, we selected the candidate compounds 19, 20, 21, 22, 25, 27, and 28 to predict their absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. Pharmacokinetics (PKs) indicated that these 4-PQs displayed good drug-likeness and bioavailability, and had no cardiotoxic side effects or carcinogenicity, but we detected risks of drug-drug interactions and AMES toxicity (mutagenic). However, structural modifications of these 4-PQs could improve their PK properties and reduce their side effects, and their promising anticancer activities attracted our attention for further studies.