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Crohn’s disease is an inflammatory bowel disease (IBD) that currently lacks satisfactory treatment options. Therefore, new targets for new drugs are urgently needed to combat this disease. In the present study, we investigated the transcriptomics-based mRNA expression of intestinal biopsies from patients with Crohn’s disease. We compared the mRNA expression profiles of the ileum and colon of patients with those of healthy individuals. A total of 72 genes in the ileum and 33 genes in the colon were differentially regulated. Among these, six genes were overexpressed in both tissues, including IL1B, TCL1A, HCAR3, IGHG1, S100AB, and OSM. We further focused on OSM/oncostatin M. To confirm the responsiveness of intestinal tissues from patients with Crohn’s disease to oncostatin M inhibition, we examined the expression of the oncostatin M using immunohistochemistry in patient biopsies as well as in kindlin-1−/− and kindlin-2−/− knockout mice, which exhibit an inflammatory bowel disease (IBD) phenotype, and found strong oncostatin M expression in all samples examined. Next, we conducted a drug-repurposing study using the supercomputer MOGON and bioinformatic methods. A total of 13 candidate compounds out of 1577 FDA-approved drugs were identified by PyRx-based virtual drug screening and AutoDock-based molecular docking. Their lowest binding energies (LBEs) ranged from −10.46 (±0.08) to −8.77 (±0.08) kcal/mol, and their predicted inhibition constants (pKi) ranged from 21.62 (±2.97) to 373.78 (±36.78) nM. Ecamsule has an interesting stereostructure with two C2-symmetric enantiomers (1S,4R-1′S,4′R and 1R,4S-1′R,4′S) (1a and 1b) and one meso diastereomer (1S,4R-1′R,4′S) (1c). These three stereoisomers showed strong, albeit differing, binding affinities in molecular docking. As examined by nuclear magnetic resonance and polarimetry, the 1S,4R-1′S,4′R isomer was the stereoisomer present in our commercially available preparations used for microscale thermophoresis. Ecamsule (1a) was chosen for in vitro validation using recombinant oncostatin M and microscale thermophoresis. Considerable dissociation constants were obtained for ecamsule after three repetitions with a Kd value of 11.36 ± 2.83 µM. Subsequently, we evaluated, by qRT-PCR, the efficacy of ecamsule (1a) as a potential drug that could prevent oncostatin M activation by inhibiting downstream inflammatory marker genes (IL6, TNFA, and CXCL11). In conclusion, we have identified oncostatin M as a promising new drug target for Crohn’s disease through transcriptomics and ecamsule as a potential new drug candidate for Crohn’s disease through a drug-repurposing approach both in silico and in vitro.

Although a broad variety of classes of bioactive compounds have already been isolated from seaweeds of the genus Dictyota, most different species are still chemically and biologically unexplored. Dictyota species are well-known brown seaweeds belonging to the Dictyotaceae (Phaeophyta). The phytochemical composition within the genus Dictyota has recently received considerable interest, and a vast array of components, including diterpenes, sesquiterepenes, sterols, amino acids, as well as saturated and polyunsaturated fatty acids, have been characterized. The contribution of these valued metabolites to the biological potential, which includes anti-proliferative, anti-microbial, antiviral, antioxidant, anti-inflammatory, and anti-hyperpigmentation activities, of the genus Dictyota has also been explored. Therefore, this is the most comprehensive review, focusing on the published literature relevant to the chemically and pharmacologically diverse biopharmaceuticals isolated from different species of the genus Dictyota during the period from 1976 to now.

: The most abundant flavonoid, quercetin, which is mostly found as glycosides, is widely distributed in plants. Quercetin is rapidly metabolized, having a short half-life in the blood circulation, and forms its conjugates by undergoing ring cleavage of the benzopyranone ring system. Despite its fast clearance in the body, quercetin was demonstrated to have clinically anti-inflammatory, cardioprotective, antidiabetic, and anti-obesity activities. This study aimed to determine whether quercetin itself or its metabolites are responsible for these activities. : We performed molecular docking of 27 metabolites, including quercetin itself, against ten inflammation-related proteins in silico. We then conducted microscale thermophoresis (MST) of selected metabolites towards the NLRP3 inflammasome. : Overall, Phase II metabolites yielded better binding energies compared to the metabolites formed by degradation. MST results revealed that isorhamnetin, the 4- -methylated metabolite of quercetin, gave the best results, with a binding affinity (K value) of 16.12 ± 5.16 µM, even better than quercetin itself, which has a binding affinity of 44.84 ± 4.21 µM. Glucuronide metabolites of quercetin (isorhamnetin 3- -glucuronide, quercetin 7- -glucuronide, and quercetin 3- -glucuronide) were found to bind to the inflammasome protein with low binding affinities, whereas small degradation products (hippuric acid and 3,4-dihydroxytoluene) did not bind at all. : These results suggest that Phase II metabolites, specifically isorhamnetin, may contribute more significantly to the biological activity of quercetin than the parent compound, however, degradation products appear inactive.

Anthracyclines have been clinically well established in cancer chemotherapy for decades. The main limitations of this drug class are the development of resistance and severe side effects. In the present investigation, we analyzed 30 anthracyclines in a panel of 59 cell lines of the National Cancer Institute, USA. The log10IC50 values varied from −10.49 M (3′-deamino-3′-(4″-(3″-cyano)morpholinyl)-doxorubicin, 1) to −4.93 M (N,N-dibenzyldaunorubicin hydrochloride, 30). Multidrug-resistant NCI-ADR-Res ovarian cancer cells revealed a high degree of resistance to established anthracyclines (between 18-fold to idarubicin (4) and 166-fold to doxorubicin (13) compared to parental, drug-sensitive OVCAR8 cells). The resistant cells displayed only low degrees of resistance (1- to 5-fold) to four other anthracyclines (7, 18, 28, 30) and were even hypersensitive (collaterally sensitive) to two compounds (1, 26). Live cell time-lapse microscopy proved the cross-resistance of the three chosen anthracyclines (4, 7, 9) on sensitive CCRF/CEM and multidrug-resistant CEM/ADR5000 cells. Structure–activity relationships showed that the presence of tertiary amino functions is helpful in avoiding resistance, while primary amines rather increased resistance development. An α-aminonitrile function as in compound 1 was favorable. Investigating the mRNA expression of 49 ATP-binding cassette (ABC) transporter genes showed that ABCB1/MDR1 encoding P-glycoprotein was the most important one for acquired and inherent resistance to anthracyclines. Molecular docking demonstrated that all anthracyclines bound to the same binding domain at the inner efflux channel side of P-glycoprotein with high binding affinities. Kaplan–Meier statistics of RNA sequencing data of more than 8000 tumor biopsies of TCGA database revealed that out of 23 tumor entities high ABCB1 expression was significantly correlated with worse survival times for acute myeloid leukemia, multiple myeloma, and hepatocellular carcinoma patients. This indicates that ABCB1 may serve as a prognostic marker in anthracycline-based chemotherapy regimens in these tumor types and a target for the development of novel anthracycline derivatives.

Marine organisms and their associated microbes are rich in diverse chemical leads. With the development of marine biotechnology, a considerable number of research activities are focused on marine bacteria and fungi-derived bioactive compounds. Marine bacteria and fungi are ranked on the top of the hierarchy of all organisms, as they are responsible for producing a wide range of bioactive secondary metabolites with possible pharmaceutical applications. Thus, they have the potential to provide future drugs against challenging diseases, such as cancer, a range of viral diseases, malaria, and inflammation. This review aims at describing the literature on secondary metabolites that have been obtained from Scleractinian-associated organisms including bacteria, fungi, and zooxanthellae, with full coverage of the period from 1982 to 2020, as well as illustrating their biological activities and structure activity relationship (SAR). Moreover, all these compounds were filtered based on ADME analysis to determine their physicochemical properties, and 15 compounds were selected. The selected compounds were virtually investigated for potential inhibition for SARS-CoV-2 targets using molecular docking studies. Promising potential results against SARS-CoV-2 RNA dependent RNA polymerase (RdRp) and methyltransferase (nsp16) are presented.

Background: Berberine, a benzylisoquinoline alkaloid, has been traditionally used in Ayurvedic and Chinese medicine. We examined the resistance mechanisms to berberine in a panel of different cancer cells and focused on understanding its molecular mechanisms. Methods: Resazurin assay determined berberine’s cytotoxicity. Molecular docking unraveled the interaction of berberine with the BCRP transporter. Fluorescence microscopy evaluated its effect on microtubules. Further, proteomic profiling identified novel determinants of cellular response to berberine and its derivatives. Results: Cell lines overexpressing ABC transporters displayed cross-resistance to berberine compared to their counterparts. While cells over-expressing EGFR were 3.57-fold resistant, wild-type and p53 knockout cells showed similar sensitivity to berberine. P-glycoprotein/ABCB1, EGFR, and WT1 expression correlated with the log10IC50 values for berberine in the NCI cell line panel. Berberine was bound to the same pharmacophore of BCRP as BWQ, and live cell microscopy showed that BCRP-transfected cells did not uptake considerable amounts of berberine in contrast to wild-type cells. Berberine altered the microtubule cytoskeleton similarly to vincristine. The sensitivity of berberine and its derivatives could be predicted by 40 out of 3171 proteins. Of them, 29 proteins have been previously involved in drug resistance. Their relationship to berberine and its derivatives is novel. Conclusions: Berberine-type compounds may be new candidates against cancer; however, they may develop drug resistance.

Background: Acute lung injury (ALI) is a major complication of sepsis, driven by oxidative stress, inflammation, and apoptosis. Paeoniflorin, a monoterpenoid glycoside, has demonstrated notable antioxidant and anti-inflammatory properties, suggesting potential therapeutic value in ALI. Methods: Sepsis-induced ALI was established in mice using the cecal ligation and puncture (CLP) model. The protective effects of paeoniflorin were evaluated by measuring oxidative stress markers (SOD, GSH, and MDA) and pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) using biochemical assays and RT-PCR. Histopathological examination and apoptosis assessment (Bax and Bcl-2 expression) were performed. Western blot analysis was conducted to investigate the involvement of the JAK2/STAT3 signaling pathway. Network pharmacology analysis was used to identify potential molecular targets, and molecular docking was performed to explore binding interactions. Results: CLP-induced ALI resulted in increased oxidative stress and inflammatory responses, as evidenced by elevated MDA and cytokine levels, along with reduced SOD and GSH levels. Paeoniflorin treatment significantly ameliorated these alterations. Histological damage and apoptosis were markedly reduced, accompanied by the downregulation of Bax and upregulation of Bcl-2. Additionally, paeoniflorin inhibited activation of the JAK2/STAT3 pathway. Network pharmacology identified key ALI-related targets, including IL6, TNF, IL1B, HIF1A, STAT3, NFKB1, CCL2, CYBB, CXCL8, and NOX4. Molecular docking revealed strong binding affinity of paeoniflorin toward HIF-1 and JUN, and moderate interactions with IL-1β, TNF-α, and Bax. Conclusions: Paeoniflorin exerts protective effects against sepsis-induced ALI by attenuating oxidative stress, inflammation, and apoptosis, partly through inhibition of the JAK2/STAT3 signaling pathway. These findings highlight its potential as a promising therapeutic candidate for ALI management.

Wound healing, one of the most intricate and dynamic processes of the body, maintains skin integrity following trauma. One of the main issues that still exists is impaired wound healing, particularly for immunosuppressed patients. Recently, natural products from marine environments have been employed in wound-repairing activities. This work investigates the mesenchymal stem cells in the combined capacity of the bone marrow (BMMSC) for wound healing and Cystoseira sp. Algae extract in immunosuppressed rats. High-resolution liquid chromatography / MS investigation of Cystoseira extract revealed the prevalence of fatty acids that have wound-soothing potential. From constructed PPI network for wound healing and further analysis through molecular docking and molecular dynamics (MD) simulation experiments suggested that cystalgerone metabolite may be responsible for the wound healing-promoting effect of Cystoseira extract. According to the CD marker characterization of the BMMSC, 98.21% of them expressed CD90, and 97.1% expressed CD105. Sixteen d after immunity suppression (by 40 mg/kg hydrocortisone daily), an incision was made in the dorsal skin of the rat. The treatments were applied for 16 d and samples were taken from the tested groups on the 8 th , 14 th , and 16 th days. The BMMSCs / Cystoseira group showed significantly improved wound closure, thickness, density of new layers, and skin elasticity than the control group (p < 0.001). The BMMSCs / Cystoseira combination significantly reduced the oxidative indicators, pro-inflammatory cytokines, and immune markers, according to the RT-PCR gene expression study. In order to delve deeper into the complex interconnections among wound healing-related biological targets and pinpoint key factors in this complex process, we engaged in network pharmacology and computational research. Subsequently, we conducted a comprehensive computational analysis, including reverse docking, free energy (ΔG) computation, and molecular dynamics simulations, on the molecular structures of the annotated compounds. The purpose of this investigation was to identify potential new targets for these chemicals as well as any potential interactions they may have with different signaling pathways related to the wound healing process. Our research indicates that the primary compounds of Cystoseira holds potential wound healing therapeutic activity. Although more safety testing and clinical studies are required, the combination has great potential for regenerative medicine and could be a revolutionary advance in the healing of the wounds of immunosuppressed patients.

Parkinson’s disease (PD) presents as a progressive deterioration of dopaminergic neurons, a process closely associated with increased oxidative damage due to accumulated reactive oxygen species, leading to weakened antioxidant defenses and ultimately neuronal dysfunction. Currently, no definitive approach exists to counteract the degeneration of dopaminergic neurons in PD. The use of Tamarix aphylla as a protective agent against Parkinson’s disease is not well studied yet. In this study, a rotenone-induced rodent model was utilized to examine the neuroprotective potential of T. aphylla extract. The chemical composition of T. aphylla leaves was analyzed through LC-HR-ESI-MS profiling, identifying 13 metabolites from various chemical categories. Furthermore, the research incorporated the STRING database and Cytoscape software to perform a protein-protein interaction (PPI) analysis, pinpointing essential hub proteins involved in neuroprotection and inflammation in PD. Molecular docking and a 150 ns molecular dynamics simulation were performed to assess the interaction of plant-derived compounds with the Sirt-1 catalytic domain. Compound 12 , one of the bioactive compounds found in T. aphylla , exhibited strong binding affinity and stability throughout the 150 ns simulation, highlighting its role as a neuroprotective agent. This study underscores the fusion of computational and experimental techniques to investigate natural neuroprotective compounds, providing potential therapeutic strategies for PD treatment by influencing key pathways linked to oxidative damage and neuroinflammation.

The incidence of methicillin-resistant Staphylococcus aureus (MRSA) has been steadily increasing in Ethiopia over the past few decades. As a result, the need for new antibiotic classes has become imperative to combat the growing threat of multidrug-resistant bacteria, including MRSA. Phytochemical investigation of the aerial parts extract of the edible plant Solanum muricatum Aiton (F. Solanaceae) afforded eight known metabolites: kaempferol 3- O -gentiobioside ( 1 ), kaempferol 3- O -sambubioside ( 2 ), quercetin 3- O -rhamnoside ( 3 ), procyanidin A2 ( 4 ), procyanidin A2 3- O -glucoside ( 5 ), (2 S )-2-hydroxy-3-[(9 Z ,12 Z )-1-oxo-9,12-octadecadien-1-yl]oxy]propyl- O-β -D-galactopyranoside ( 6 ), palmitic acid ( 7 ), and linoleic acid ( 8 ). The structures of the isolated compounds were assigned by 1D and 2D NMR. The crude extract exhibited moderate anti- Staphylococcus activity (MIC = 196.8 µg/mL), while compound 1 (kaempferol 3- O -gentiobioside) showed the strongest inhibitory effect (MIC = 8.3 µM), followed by compounds 2 and 3 (MIC = 10.2 and 11.2 µM, respectively). These compounds significantly reduced MRSA biofilm formation by up to 75.09% at sub-MIC concentrations ( p < 0.05). Checkerboard assays revealed synergistic interactions among compounds 1 , 2 , and 3 and between these compounds and gentamicin (FICI < 0.5), suggesting enhanced therapeutic potential when combined. An integrated computational approach combining protein-protein interaction (PPI) network analysis, molecular docking, and molecular dynamics (MD) simulations was employed. The PPI network analysis, constructed using the STRING and STITCH databases, revealed critical MRSA-associated targets and their interactions with bioactive compounds from S. muricatum . Network hub analysis identified key immune-regulatory and antibacterial resistance-related proteins, suggesting potential intervention points. Molecular docking results identified kaempferol 3-gentiobioside (compound 1 ) as the most potent inhibitor of APH(3’)-IIIa, with strong binding energy and interactions with key catalytic residues. Further 150 ns MD simulations confirmed the stability of the compound 1 -APH(3’)-IIIa complex, as evidenced by minimal RMSD fluctuations, sustained hydrogen bonding, stable protein compactness (Rg), and favorable potential energy values.