Possible Mechanism Of Action Research Articles

Insulin eye drops improve corneal wound healing in STZ-induced diabetic mice by regulating corneal inflammation and neuropeptide release

IntroductionIn recent years, insulin eye drops have attracted increasing attention from researchers and ophthalmologists. The aim of this study was to investigate the efficacy and possible mechanism of action of insulin eye drops in diabetic mice with corneal wounds.MethodsA type 1 diabetes model was induced, and a corneal epithelial injury model of 2.5 mm was established. We used corneal fluorescein staining, hematoxylin-eosin (H-E) staining and the Cochet-Bonnet esthesiometer to examine the process of wound healing. Subsequently, the expression levels of Ki-67, IL-1β, β3-tubulin and neuropeptides, including substance P (SP) and calcitonin gene-related peptide (CGRP), were examined at 72 h after corneal injury.ResultsFluorescein staining demonstrated an acceleration of the recovery of corneal epithelial injury in diabetic mice compared with the saline treatment, which was further evidenced by the overexpression of Ki-67. Moreover, 72 h of insulin application attenuated the expression of inflammatory cytokines and neutrophil infiltration. Remarkably, the results demonstrated that topical insulin treatment enhanced the density of corneal epithelial nerves, as well as neuropeptide SP and CGRP release, in the healing cornea via immunofluorescence staining.ConclusionsOur results indicated that insulin eye drops may accelerate corneal wound healing and decrease inflammatory responses in diabetic mice by promoting nerve regeneration and increasing levels of neuropeptides SP and CGRP.

Protective Activity of Palm Oil Extracts against Dichlorvos Poisoning in Rats: Biochemical Parameters and Mechanisms of Action

Protective activity on biochemical parameters and possible mechanisms of action of palm oil extracts were investigated in orally Dichlorvos poisoned rats and the efficacy of treatments in the poisoned rats. The safety profile of the extracts was evaluated via acute toxicity studies which was done in two phases. To screen for phytochemicals, present in this extract. This study was carried out in Pharmacy and KIUTH laboratories, Kampala International University, Uganda. Wistar rats of both sexes, weighing 85g and above were used for the study. Selection of rats was done by simple random sampling. At the end of the administration, plasma biochemical parameters were measured as indices of organ toxicity. The red palm oil used in treatment of Dichlorvos poisoned rats caused a reduction in concentration of some of the biochemical parameters of the rats when given simultaneously compared to the kernel oil combinations. Administration of palm oil does not have prophylactic effect against the poison. However, it does seem to have similar protective effects against oxidative stress with ascorbic acid. In summary the administration of palm oil seemed to have limited ameliorative role against Dichlorvos poisoning in rats. Keywords: Dichlorvos, palm oil, palm kernel oil, rats, acute toxicity, oxidative stress.

Molecular Dynamics Simulation of SARS-CoV-2 E Ion Channel: The Study of Lone Protein and its Conformational Changes in Complex with Potential Cage Inhibitors.

The coronavirus E ion channel has previously been studied as a potential target for antiviral therapy, with several compounds found to bind to the channel. However, these compounds have low activity, searching for effective E ion channel inhibitors of great importance. This study aimed to develop a computational approach for designing ligands for the coronaviral E ion channel and identify potential inhibitors based on this approach. The structure of the E-ion channel was refined using molecular dynamics, and the pore responsible for binding cage compounds was selected as the inhibitor-binding site. Potential inhibitor structures were identified using molecular docking, and their binding was confirmed using molecular dynamics simulations. A number of potential SARS E ion channel inhibitors have been identified, and the binding modes and possible mechanisms of action of these inhibitors have been clarified. This study presents a computational approach that can be used to design ligands for E ion channels and identify potential inhibitors, providing valuable insights into the development of new antiviral therapies. The behavior of the E protein pentamer of SARS-CoV-2 in its native environment was investigated using Molecular Dynamics (MD), resulting in an equilibrated structure that could be used to develop new inhibitors through molecular docking. Simulation of the MD of E-channel complexes with amantadine analogues allowed for the identification of the main types of ligand-protein interactions that are responsible for the good binding of ligands within the channel's inner chamber.

1-Deoxynojirimycin containing Morus alba leaf-based food modulates the gut microbiome and expression of genes related to obesity

BackgroundObesity is a serious disease with an alarmingly high incidence that can lead to other complications in both humans and dogs. Similar to humans, obesity can cause metabolic diseases such as diabetes in dogs. Natural products may be the preferred intervention for metabolic diseases such as obesity. The compound 1-deoxynojirimycin, present in Morus leaves and other sources has antiobesity effects. The possible antiobesity effect of 1-deoxynojirimycin containing Morus alba leaf-based food was studied in healthy companion dogs (n = 46) visiting the veterinary clinic without a history of diseases. Body weight, body condition score (BCS), blood-related parameters, and other vital parameters of the dogs were studied. Whole-transcriptome of blood and gut microbiome analysis was also carried out to investigate the possible mechanisms of action and role of changes in the gut microbiome due to treatment.ResultsAfter 90 days of treatment, a significant antiobesity effect of the treatment food was observed through the reduction of weight, BCS, and blood-related parameters. A whole-transcriptome study revealed differentially expressed target genes important in obesity and diabetes-related pathways such as MLXIPL, CREB3L1, EGR1, ACTA2, SERPINE1, NOTCH3, and CXCL8. Gut microbiome analysis also revealed a significant difference in alpha and beta-diversity parameters in the treatment group. Similarly, the microbiota known for their health-promoting effects such as Lactobacillus ruminis, and Weissella hellenica were abundant (increased) in the treatment group. The predicted functional pathways related to obesity were also differentially abundant between groups.Conclusions1-Deoxynojirimycin-containing treatment food have been shown to significantly improve obesity. The identified genes, pathways, and gut microbiome-related results may be pursued in further studies to develop 1-deoxynojirimycin-based products as candidates against obesity.

Omega-3 and omega-6 polyunsaturated fatty acids and their potential therapeutic role in protozoan infections.

Protozoa exert a serious global threat of growing concern to human, and animal, and there is a need for the advancement of novel therapeutic strategies to effectively treat or mitigate the impact of associated diseases. Omega polyunsaturated fatty acids (ω-PUFAs), including Omega-3 (ω-3) and omega-6 (ω-6), are constituents derived from various natural sources, have gained significant attention for their therapeutic role in parasitic infections and a variety of essential structural and regulatory functions in animals and humans. Both ω-3 and ω-6 decrease the growth and survival rate of parasites through metabolized anti-inflammatory mediators, such as lipoxins, resolvins, and protectins, and have both in vivo and in vitro protective effects against various protozoan infections. The ω-PUFAs have been shown to modulate the host immune response by a commonly known mechanism such as (inhibition of arachidonic acid (AA) metabolic process, production of anti-inflammatory mediators, modification of intracellular lipids, and activation of the nuclear receptor), and promotion of a shift towards a more effective immune defense against parasitic invaders by regulation the inflammation like prostaglandins, leukotrienes, thromboxane, are involved in controlling the inflammatory reaction. The immune modulation may involve reducing inflammation, enhancing phagocytosis, and suppressing parasitic virulence factors. The unique properties of ω-PUFAs could prevent protozoan infections, representing an important area of study. This review explores the clinical impact of ω-PUFAs against some protozoan infections, elucidating possible mechanisms of action and supportive therapy for preventing various parasitic infections in humans and animals, such as toxoplasmosis, malaria, coccidiosis, and chagas disease. ω-PUFAs show promise as a therapeutic approach for parasitic infections due to their direct anti-parasitic effects and their ability to modulate the host immune response. Additionally, we discuss current treatment options and suggest perspectives for future studies. This could potentially provide an alternative or supplementary treatment option for these complex global health problems.

Esters of Quinoxaline-7-Carboxylate 1,4-di-N-Oxide as Potential Inhibitors of Glycolytic Enzymes of Entamoeba histolytica: In silico Approach.

Esters of quinoxaline-7-carboxylate 1,4-di-N-oxide (7-carboxylate QdNOs) derivatives are compounds that inhibit the growth of Entamoeba histolytica</i>, the causative agent of amebiasis. Although these compounds cause changes in the redistribution of glycogen deposits within the parasite, it is unknown whether these compounds interact with enzymes of the glycolytic pathway. The aim of this study was to test the binding affinity of these compounds to pyrophosphate- dependent phosphofructokinase (PPi-PFK), triosephosphate isomerase (TIM), and pyruvate phosphate dikinase (PPDK) from E. histolytica</i> as a possible mechanism of action. The molecular docking study of the 7-carboxylate QdNOs derivatives and the proteins was performed using AutoDock/Vina software. Molecular dynamics simulation was performed for 100 ns. Among all the selected compounds, T-072 exhibited the best binding affinity to EhPPi- PFK and EhTIM proteins, while T-006 interacted best with EhPPDK. ADMET analysis revealed that T-072 was non-toxic, while T-006 could become harmful to the host. In addition, molecular dynamics showed that T-072 has stable interaction with EhPPi-PFK and EhTIM. Including all aspects, these data indicated that these compounds might inhibit the activity of key enzymes in energy metabolism leading to parasite death. Furthermore, these compounds may be a good starting point for the future development of new potent antiamebic agents.

New insights into the interactions between the gut microbiota and the inflammatory response to ulcerative colitisin a mouse model of dextran sodium sulfate and possible mechanisms of action for treatment with PE&AFWE.

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation. Intestinal innate immunity, including innate immune cells, defends against pathogens and excessive entry of gut microbiota, while preserving immune tolerance to resident intestinal microbiota, and may be characterized by its capacity to produce a rapid and nonspecific reaction. The association between microbiota dysbiosis and the pathogenesis of IBD is complex and dynamic. When the intestinal ecosystem is in dysbiosis, the reduced abundance and diversity of intestinal gut microbiota make the host more vulnerable to the attack of exogenous and endogenous pathogenic gut microbiota. The aim of our study was to comprehensively assess the relationship between microbial populations within UC, the signaling pathways of pathogenic gut microbe therein and the inflammatory response, as well as to understand the effects of using PE&AFWE (poppy extract [Papaver nudicaule L.] and Artemisia frigida Willd. extract) on UC modulation. A UC mouse model was established by inducing SPF-grade C57BL/6 mice using dextrose sodium sulfate (DSS). Based on metagenomic sequencing to characterize the gut microbiome, the relationship between gut microbiota dysbiosis and gut microbiota was further studied using random forest and Bayesian network analysis methods, as well as histopathological analysis. (1) We found that the 5 gut microbiota with the highest relative abundance of inflammatory bowel disease UC model gut microbiota were consistent with the top 5 ranked natural bacteria. There were three types of abundance changes in the model groups: increases (Chlamydiae/Proteobacteria and Deferribacteres), decreases (Firmicutes), and no significant changes (Bacteroidetes). The UC model group was significantly different from the control group, with 1308 differentially expressed species with abundance changes greater than or equal to 2-fold. (2) The proportion of the fecal flora in the UC group decreased by 37.5% in the Firmicutes and increased by 14.29% in the proportion of Proteobacteria compared to the control group before treatment. (3) The significantly enriched and increased signaling pathways screened were the 'arachidonic acid metabolic pathway' and the 'phagosomal pathway', which both showed a decreasing trend after drug administration. (4) Based on the causal relationship between different OTUs and the UC model/PE&AFWE administration, screening for directly relevant OTU networks, the UC group was found to directly affect OTU69, followed by a cascade of effects on OTU12, OTU121, OTU93, and OTU7, which may be the pathway of action that initiated the pathological changes in normal mice. (5) We identified a causal relationship between common differentially expressed OTUs and PE&AFWE and UC in the pre- and post-PE&AFWE-treated groups. Thereby, we learned that PE&AFWE can directly affect OTU90, after which it inhibits UC, inhibiting the activity of arachidonic acid metabolic pathway by affecting OTU118, which in turn inhibits the colonization of gut microbiota by OTU93 and OTU7. (6) Histopathological observation and scoring (HS) of the colon showed that there was a significant difference between the model group and the control group (p < 0.001), and that there was a significant recovery in both the sulfasalazine (SASP)and the PE&AFWE groups after the administration of the drug (p < 0.0001). We demonstrated causal effects and inflammatory metabolic pathways in gut microbiota dysbiosis and IBD, with five opportunistic pathogens directly contributing to IBD. PE&AFWE reduced the abundance of proteobacteria in the gut microbiota, and histopathology showed significant improvement.

Terpenoids and Triterpenoid Saponins: Future Treatment for Depression

Background: Depression is a crippling mental disorder with high prevalence around the world. The available clinical antidepressants have been effective to a certain degree, and different side effects have limited their application. This leads to the necessity of finding new treatments. Herbal plants are a substantial source of new drug leads. Terpenoid compounds are secondary metabolites representing an enormous category of structures found commonly in plants either as aglycones or attached to sugar moieties. These phytochemicals have been extensively studied for their various biological effects, and several have been investigated for potential therapeutic effects in the treatment of depression. Aim: This review aims to highlight the current knowledge on some terpenoids and triterpenoid saponins as potential antidepressant agents and their mechanisms of action, which may provide a better understanding of the potential antidepressant-like effects of these compounds and lead to the development of auspicious molecules with high efficiency and low side effects for depressive disorders treatment. Methods: A total of 16 plants containing antidepressant agents are reviewed in this article. 9 terpenoids and 23 triterpenoid saponins compounds have been reported to becommonly found in plant extracts, indicating potential use for depression. To enhance the datum of this review, the mechanism of action for the candidate compounds has been predicted via functional enrichment analysis. Results: The behavioural and neurochemical effects, as well as the possible mechanisms of action, have been evaluated in rodents by different predictive models of depression, mainly the acute stress models of the forced swimming test (FST) and tail suspension test (TST). The involved mechanisms include enhancing monoamine neurotransmitters, ameliorating brain-derived neurotrophic factor (BDNF), and normalizing the hypothalamus-pituitary-adrenal (HPA) axis. Preclinical studies support the potential antidepressant activities of some terpenoid compounds. Furthermore, the functional enrichment analysis has confirmed the previous pre-clinical findings and predicted further mechanisms of action, including cellular calcium ion homeostasis, cellular response to dopamine, endocrine resistance, and regulating GABAergic, serotonergic, glutamatergic, and dopaminergic synapse, bedsides neurotransmitter reuptake. Conclusion: Terpenoids and triterpenoid saponins provide a large number of natural compounds. This review sheds light on terpenoids and triterpenoid saponins compounds with antidepressantlike activity and their potential mechanisms of action. However, more evaluations are required to confirm that these compounds are promising for discovering antidepressant drugs.

Novel N-(3-ethynyl Phenyl)-6,7-bis(2-methoxyethoxy)Quinazoline-4-amine Derivatives: Synthesis, Characterization, Anti-cancer Activity, In-silico and DFT Studies.

Cancer is one of the most common reasons for mortality in the world. A continuous effort to develop effective anti-cancer drugs with minimum side effects has become necessary. The use of small-molecule drugs has revolutionized cancer research by inhibiting cancer cell survival and proliferation. Quinazolines are a class of bioactive heterocyclic compounds with active pharmacophores in several anti-cancer drugs. Such small molecule inhibitors obstruct the significant signals responsible for cancer cell development, thus blocking these cell signals to prevent cancer development and spread. In the current study, novel quinazoline derivatives structurally similar to erlotinib were synthesized and explored as novel anti-cancer agents. All the synthesized molecules were confirmed by spectroscopic techniques like 1H NMR, 13C NMR, and ESI-MS. Various techniques were applied to study the protein-drug interaction, DFT analysis, Hirshfeld surface, and target prediction. The molecules were screened in vitro for their anti-cancer properties against 60 human tumor cell lines. The growth inhibitory properties of a few compounds were studied against the MCF7 breast cancer cell line. The activity of compounds 9f, 9o, and 9s were found to be active. However, compound 9f is more active when compared with other compounds. Some synthesized compounds were active against different cancer cell lines. The in-vitro study results were found to be in agreement with the predictions from in-silico data. The selected molecules were further subjected to get the possible mechanism of action against different cancer cells.

The Role of the NLRP3 Inflammasome in the Molecular and Biochemical Mechanisms of Cervical Ripening: A Comprehensive Review.

The uterine cervix is one of the key factors involved in ensuring a proper track of gestation and labor. At the end of the gestational period, the cervix undergoes extensive changes, which can be summarized as a transformation from a non-favorable cervix to one that is soft and prone to dilation. During a process called cervical ripening, fundamental remodeling of the cervical extracellular matrix (ECM) occurs. The cervical ripening process is a derivative of many interlocking and mutually driving biochemical and molecular pathways under the strict control of mediators such as inflammatory cytokines, nitric oxide, prostaglandins, and reactive oxygen species. A thorough understanding of all these pathways and learning about possible triggering factors will allow us to develop new, better treatment algorithms and therapeutic goals that could protect women from both dysfunctional childbirth and premature birth. This review aims to present the possible role of the NLRP3 inflammasome in the cervical ripening process, emphasizing possible mechanisms of action and regulatory factors.

Metabolomics combined with chemometric analysis to identify α-glucosidase inhibitors in Phaleria macrocarpa fruit extracts and its molecular docking simulation

Phaleria macrocarpa is a medicinal plant widely available in Malaysia. The plant parts have been traditionally used as an antidiabetic remedy. This study aimed to identify the putative inhibitors of the α-glucosidase enzyme from P. macrocarpa using a gas chromatography-mass spectrometry (GC–MS)-based metabolomics approach and further subjected them to in silico molecular docking analysis to elucidate the possible mechanism of action. This study assessed the inhibitory potential of P. macrocarpa fruit extracts (aqueous, 20 %, 40 %, 60 %, 80 %, and 100 % ethanol) against the α-glucosidase enzyme using GC–MS and chemometric analysis. Orthogonal partial least squares (OPLS) combined with GC–MS analysis were applied to correlate the inhibition of enzyme activity to the metabolites profile of P. macrocarpa. All the potential inhibitors identified were further docked to the yeast (Saccharomyces cerevisiae) protein crystal structure (PDB3A4A). The generated score scatter plot of OPLS showed a recognizable separation of all the extracts into six different clusters. GC–MS, incorporated with multivariate data analysis techniques, was used to identify significant chemical markers. Methyl α-d-glucopyranoside, squalene, palmitic acid, myo-inositol and isoquinoline metabolites were identified as putative inhibitors against α-glucosidase activity from P. macrocarpa. In conclusion, the GC–MS-based metabolomics approach identified potential chemical markers of P. macrocarpa that could be utilized in the development of herbal based medicine.

Network Pharmacology and Molecular Docking Technology-based Strategy to Explore the Potential Mechanism of Diabecon Formulation Botanicals

This study presents network pharmacology and a molecular docking-centered approach to elucidate the possible mechanism of action underlying the therapeutic effects of diabecon, a formulation containing Gymnema sylvestre, Pterocarpus marsupium, and Asphaltum punjabinum botanicals. Through comprehensive bioinformatics analysis, a collection of bioactive compounds present in these botanicals was identified, and their potential targets were forecasted using Swiss Target Prediction and STITCH. Disease-related genes were retrieved from Genecards and OMIM, and common genes between potential targets and disease-related genes were determined. Pathway analysis using the DAVID database revealed significant enrichment in pathways related to metabolic processes, xenobiotic metabolism, and signaling pathways, such as the insulin signaling pathway and pathways in cancer. Network construction using cytoscape highlighted interactions among identified genes, providing insights into the molecular pathways modulated by diabecon. Molecular docking analysis further elucidated the possible connections amongst biologically active compounds and target proteins, with (2S)-7-hydroxyflavanone exhibiting strong binding affinity with DPP-IV enzyme. Overall, this integrated approach offers valuable insights into the potential mechanisms of action of diabecon, contributing to our understanding of its therapeutic effects in the management of diabetes mellitus

2-aryloxazolines inhibit Candida clinical isolates growth and morphogenesis of Candida albicans and Candida tropicalis

New antifungal molecules are being researched addressing new targets and mechanisms of action. Therefore, the present study aimed to evaluate the antifungal activity of 2-aryloxazoline derivatives (4i and 9i) on Candida clinical isolates and on morphogenesis of competent-filament species. Both compounds inhibited Candida spp. growth at concentrations ≤0.03–2 μg/mL, including less susceptible and resistant isolates to standard antifungals. However, neither fungicidal effect of compounds nor synergistic/antagonistic interactions in combination with antifungals were observed. On the other hand, C. albicans treated with 2-aryloxazoline exhibited some ultrastructural changes such as the integrity loss of the plasma membrane and cell wall. In C. albicans, the proteinase activity was reduced after treatment with high concentrations of 2-aryloxazoline, but this inhibition was not observed in C. tropicalis. The compounds inhibited up to 50% of the total biomass of C. albicans and C. tropicalis biofilms but did not inhibit the metabolic activity. Additionally, 2-aryloxazolines caused a dose-dependent reduction in the pseudohyphae/hyphae formation of both Candida species (C. albicans and C. tropicalis) in RPMI medium and other filament-inducing media. Notably, the compounds caused a total inhibition of pseudohyphae/hyphae formation in Spider broth, a partial inhibition in Lee medium, and no inhibition in SM supplemented with N-acetylglucosamine. This effect on the yeast-hyphae transition was associated with blockage of cAMP and MAPK pathways due to the gene downregulation of the transcription factors TEC1, EFG1, and CEK1 in 4i-treated C. albicans cells. In this regard, the adhesins (HWP1 and ALS3) and candidalysin (ECE1) genes were also downregulated as a result of the interference of compounds on the filamentation signaling pathways. Therefore, 2-aryloxazolines showed promising results inhibiting Candida growth and morphogenesis; however, other approaches should be carried out to better elucidate other possible mechanisms of action.

Abstract 1987: PARP inhibitor (PARPi) rechallenge shows differential sensitivity in PARPi olaparib-resistant BRCA1-mutated (BRCA1m) high-grade serous ovarian cancer (HGSC)

Abstract Background: PARPis have changed the treatment paradigm in HGSC, particularly for women with BRCA mutations. PARPi, olaparib (O), is a standard of care maintenance therapy following platinum-based chemotherapy in newly diagnosed BRCA-mutated (BRCAm) HGSC. But patients ultimately develop resistance to O. We investigated whether rechallenge with different PARPi monotherapy could cause cytotoxicity in BRCAm HGSC after becoming O-resistant. We also aimed to identify possible mechanisms of actions of PARPi’s differential sensitivity. Methods: We developed a PARPi-resistant line (UWB-OlaJR) from BRCA1m PARPi-sensitive cells (UWB1.289) by gradient exposure of O with initial lower doses to a final concentration of 20 μM over 10 months. Four PARPis including O, niraparib (N), talazoparib (T), and veliparib (V) were tested. Cell growth was assessed using 5-day XTT and 10-day clonogenic assays. DNA damage and homologous recombination (HR) repair activity were evaluated using immunofluorescence (IF) staining of γH2AX and RAD51 foci, respectively. Replication fork (RF) dynamics was measured by DNA fiber assay. All data were repeated in triplicate and analyzed using t-test or one-way ANOVA. Data were shown as mean ± SD and P &amp;lt; 0.05 was considered statistically significant. Results: 5-day XTT assay shows a 53.7-fold increase in resistance to O in UWB-OlaJR relative to UWB1.289 (IC50 2.2 μM vs. 118.1 μM). Cross-resistance was observed with other 3 PARPis, showing increased IC50 values compared to its parental line (V: 23.4-fold, N: 160.5-fold, T: 229.6-fold). However, 10-day clonogenic assay showed no resistance against N (1.09-fold) and T (0.51-fold) in UWB-OlaJR, indicating differential sensitivity to different PARPis by a long-term cytotoxicity measure. Surprisingly, γH2AX foci did not increase in response to PARPis in UWB-OlaJR compared to UWB1.289 (O: 2.58-fold, V: 2.33-fold; N: 2.89-fold, T: 2.58-fold; all P &amp;lt; 0.05), suggesting possible restored DNA repair function. All four PARPis induced replication stress in both O-sensitive and -resistant cell lines as evidenced by decreased RF speed compared to untreated group (O: 0.57- and 0.7-fold, V: 0.68- and 0.74-fold, N: 0.47- and 0.47-fold, T: 0.47- and 0.52-fold; all P &amp;lt; 0.001). Notably, N and T treatments reduced fork speed to a greater extent than O and V in UWB-OlaJR. However, RF protection was not affected when UWB-OlaJR treated with different PARPis compared to UWB1.289 (O: 0.89-fold, V: 0.87-fold, N: 0.71-fold, T: 0.83-fold; all P &amp;lt; 0.05), suggesting that differential sensitivity to different PARPis was unlikely due to modulation of RF stabilization. Conclusions: Our findings demonstrate different PARPis may induce varied levels of cytotoxicity and replication stress in O-resistant BRCA1m HGSC, possibly via modulating alternative RF dynamics besides RF protection. Citation Format: Chi-Ting Shih, Tzu-Ting Huang, Jayakumar R. Nair, Jung-Min Lee. PARP inhibitor (PARPi) rechallenge shows differential sensitivity in PARPi olaparib-resistant BRCA1-mutated (BRCA1m) high-grade serous ovarian cancer (HGSC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1987.

Abstract 7140: A new series of flavonoid derivatives with anti-cancer activity includes SDN207, SND210, SND524, and SND562 as potent microtubule-targeting agents

Abstract Background: Plant-derived compounds, including flavonoids, can be potent anti-cancer agents, but low bioavailability, lack of specificity, and complexity in their synthesis can hamper their clinical development. Here, we present seven novel flavonoid derivatives, and test them for their anti-tumor activity in various models derived from hematological cancers and solid tumors. Methods: MTT assessed anti-proliferative activity after 72h of exposure to increasing concentrations of drugs. Tubulin Polymerization Assay was performed with 3-fold dilutions (15-0.02 μM), compared to paclitaxel (1-3 μM) or vinblastine (3 μM) as references. The OncolinesProfiler analysis was used to compare IC50 fingerprints determined on the Oncolines cell line panel to the IC50 fingerprints of 213 pre-profiled reference drugs. Results: SDN207, SND210, SND216, SND462, SND504, SND524, and SND562 were designed and synthesized using a flavonoid polyphenol scaffold selectively modified to markedly increase cytotoxicity towards cancer cells. All seven compounds showed dose-dependent anti-proliferative activity across 15 lymphoma cell lines derived from germinal center B-cell-like (GCB) diffuse large B cell lymphoma (DLBCL) (n=6), activated B cell-like (ABC) DLBCL (n=2), mantle cell lymphoma (n=4), and marginal zone lymphoma (MZL) (n=3). Activity in the nM range was seen with five compounds: SDN207 (median IC50 1.6 nM; 95%CI, 1.3-3.2), SND210 (1.4 nM; 95%CI, 0.9-3.3), SND216 (19.5 nM; 95%CI, 10-38 nM), SND562 (28.9 nM; 95%CI, 15.4-57.7), and SND524 (46.7 nM; 95%CI, 32-133.3). Both other compounds had a median IC50 of 2 μΜ (SND462, 95%CI, 1.1-4.5 μM; SND504, 95%CI, 0.5-3.9 μM). There were no differences based on lymphoma histology. The anti-tumor activity was maintained in MZL cell lines with acquired resistance to BTK and PI3K inhibitors (n=3). Six compounds were also assessed for their anti-tumor activity in models other than lymphomas (SDN207, n=31; SND210, n=20; SND462, n=4; SND504, n=4; SND524, n=9; SND562, n=35), confirming the higher activity for SDN207, SND210, SND562, and SND524. Regarding the mechanism of action, up to now, a tubulin polymerization assay was performed for three compounds. Microtubule depolymerization (SND207), and microtubule polymerization (SND524, SND562) were observed at concentrations as low as 20 nM. The OncolinesProfiler identified the tubulin-targeting agents vinblastine, vincristine, paclitaxel, and docetaxel among the top reference compounds most correlated with SND207 and SND210 (i.e., Pearson correlation &amp;gt; 0.5). Conclusions: Novel compounds developed using plant-derived skeletons have shown in vitro anti-tumor activity in lymphomas, leukemias, and solid tumors, including models of resistance to targeted agents. Microtubule targeting appeared as a possible mechanism of action for at least four of them. Citation Format: Alberto J. Arribas, Eleonora Cannas, Eugenio Gaudio, Paulina Biniecka, Dan Stoicescu, Francesco Bertoni. A new series of flavonoid derivatives with anti-cancer activity includes SDN207, SND210, SND524, and SND562 as potent microtubule-targeting agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7140.

Phytochemical Evaluation of Terminalia canescens DC. Radlk. Extracts with Antibacterial and Antibiotic Potentiation Activities against Selected β-Lactam Drug-Resistant Bacteria.

Terminalia canescens DC. Radlk. (family: Combretaceae) is native to northern Australia. Species of the genus Terminalia are widely used as traditional medicines to treat diverse ailments, including bacterial infections. However, we were unable to find any studies that had examined the antimicrobial activity of T. canescens. In this study, T. canescens was screened against a panel of bacterial pathogens, including multi-antibiotic-resistant strains. Solvents with different polarities were used to extract different complements of phytochemicals from T. canescens leaves. Methanolic and aqueous extracts exhibited substantial antimicrobial activity against various pathogens, including those that are multidrug-resistant strains. When combined with some selected clinical antibiotics, some extracts potentiated the antibacterial inhibitory activity. This study identified two synergistic, eleven additive, eleven non-interactive and eight antagonistic interactions. The toxicities of the plant extracts were examined in the Artemia franciscana nauplii assay and were found to be non-toxic, except the aqueous extract, which showed toxicity. Metabolomic liquid chromatography-mass spectrometry (LC-MS) analyses highlighted and identified several flavonoids, including vitexin, quercetin, orientin and kaempferol, as well as the tannins ellagic acid and pyrogallol, which may contribute to the antibacterial activities observed herein. The possible mechanism of action of these extracts was further explored in this study.

Serum metabolomics analysis combined with network pharmacology reveals possible mechanisms of postoperative cognitive dysfunction in the treatment of Mongolian medicine Eerdun Wurile basic formula.

This study analyzed the endogenous metabolites and metabolic pathways in the serum of Sprague-Dawley (SD) rats gavaged with the Eerdun Wurile basic formula (EWB) using metabolomics methods and network pharmacology to explore the possible mechanism of action of the EWB in improving postoperative cognitive dysfunction (POCD). SD rats were divided into the basic formula group, which received the EWB, and the control group, which received equal amounts of distilled water. The blood was collected from the abdominal aorta and analyzed for metabolite profiles using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). Network pharmacology predicts the targets of the differential metabolites and disease targets; takes the intersection and constructs a "metabolite-disease-target" network; and performs protein-protein interaction, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses. A total of 56 metabolites were selected for significant differences between the groups, mainly affecting amphetamine addiction, alcoholism, and regulation of lipolysis in adipocytes. A total of 177 potential targets for differential metabolite action in POCD were selected. The PI3K-Akt pathway, the HIF-1 pathway, and the FoxO pathway were in key positions. The studies have shown that EWB could improve POCD through multicomponents, multitargets, and multipathways, providing new possibilities and reference values for the treatment of POCD.

Effects of gossypin on acetaminophen-induced hepatotoxicity in mice

Liver injury from paracetamol (acetaminophen) (APAP) is common worldwide. To prevent intoxication with a drug with high poisoning, treatment can be made possible with an easily accessible and harmless substance. This study aimed to investigate the hepatoprotective ef-fects of Gossypin (GOS) in mice exposed to an overdose of APAP -the possible mechanism of action. Specifically, serum [alanine aminotransferase (ALT), aspartate transaminase (AST), and hepatic biochemical parameters (glutathione (GSH), malondialdehyde (MDA) and super-oxide dismutase (SOD)] were evaluated. Protein and mRNA levels of inflammatory, apoptot-ic, and cytochrome factors, including TNF-α, IL-1β, IL-6, NF-kB, and CYP2E1, were ana-lyzed using real-time PCR. Pretreatment with GOS significantly reduced APAP-induced he-patic injury via oxidative stress. Along with potent antioxidant activity, GOS promoted APAP hepatic detoxification by regulating AST, ALT, GSH, MDA, and SOD activities and mRNA levels of the cytochrome CYP2E1 gene. The anti-inflammatory activity of GOS in-creases its production. TNF-α, IL-1β and IL-6, through possible NF-kB blockade, are also responsible for its hepatoprotective effect. Taken together, GOS has the potential to be devel-oped as a preventive agent to be administered to patients suffering from APAP overdose.

Immunosuppressive effects of the mycotoxin patulin in macrophages.

Patulin (PAT) is a fungi-derived secondary metabolite produced by numerous fungal species, especially within Aspergillus, Byssochlamys, and Penicillium genera, amongst which P. expansum is the foremost producer. Similar to other fungi-derived metabolites, PAT has been shown to have diverse biological features. Initially, PAT was used as an effective antimicrobial agent against Gram-negative and Gram-positive bacteria. Then, PAT has been shown to possess immunosuppressive properties encompassing humoral and cellular immune response, immune cell function and activation, phagocytosis, nitric oxide and reactive oxygen species production, cytokine release, and nuclear factor-κB and mitogen-activated protein kinases activation. Macrophages are a heterogeneous population of immune cells widely distributed throughout organs and connective tissue. The chief function of macrophages is to engulf and destroy foreign bodies through phagocytosis; this ability was fundamental to his discovery. However, macrophages play other well-established roles in immunity. Thus, considering the central role of macrophages in the immune response, we review the immunosuppressive effects of PAT in macrophages and provide the possible mechanisms of action.

Antimalarial Activity of Mangrove Plants and Possible Mechanisms of Action: A Scoping Review

Malaria is one of life threatening-infectious diseases with high mortality rate in African regions. Malaria is also one of public health problem in most of Southeast Asia (SEA) regions. This disease is caused by a Apicomplexan parasite; Plasmodium sp., which can be transmitted from humans to humans via Anopheles sp. To date, the need of a new antimalarial drug is still high, due to the rapid increase of drug resistance. Natural-derived drug candidates are still being used by researchers to develop new antimalarials. One of the natural resources which could potentially be a source of antimalarial agents are mangrove plants. Traditionally, mangrove plants have been employed as antibacterial, antioxidant, anticancer, and antidiabetic. Therefore, we conducted a scoping review to identify, evaluate and summarize findings of newly found antimalarial drug activity from mangrove plants and elaborate the possible mechanism of actions in killing the parasites. From several databases, we found six mangrove species which have been suggested as potential antimalarial sources. Various phytochemical compounds in extracts made from those plants were revealed to exert antimalarial activity. These include alkaloids, flavonoids, tannins, phenols, terpenoids, saponins, coumarins, triterpenes, glycosides, and anthraquinones which were indicated to have antimalarial activity against Plasmodium. From eight studies investigating mangrove plant extracts, no toxic effects were shown. Therefore, considering the available evidences, we suggested that mangrove plants can be used as a source for the discovery of antimalarial compounds with promising activities against Plasmodium sp. However, deeper understanding on the exact mechanisms of their actions still requires further elucidation.&#x0D; &#x0D; Keywords: Antimalaria, Anthraquinone, Mangrove, Plasmodium sp., Protozoa