Exploring the potential of Aspergillus wentii: secondary metabolites and biological properties.

Fungi are of considerable importance due to their capacity to biosynthesize various secondary metabolites with bioactive properties that draw high attention in new drug discovery with beneficial uses for improving human well-being and life quality. Aspergillus genus members are widespread and cosmopolitan species with varying economic significance in the fields of industry, medicine, and agriculture. Its species are renowned for their biosynthesis of secondary metabolites, characterized by both potent biological activity and structural novelty, making them a substantial reservoir for the development of new pharmaceuticals. The current work aimed at focusing on one species of this genus, Aspergillus wentii Wehmer, including its reported secondary metabolites in the period from 1951 to November 2023. A total of 97 compounds, including nitro-compounds, terpenoids, anthraquinones, xanthones, benzamides, and glucans. A summary of their bioactivities, as well as their biosynthesis was highlighted. Additionally, the reported applications of this fungus and its enzymes have been discussed. This review offers a useful reference that can direct future research into this fungus and its active metabolites, as well as their possible pharmacological and biotechnological applications.

Assessing the antibacterial potential of 6-gingerol: Combined experimental and computational approaches.

The rise of antibiotic resistance in bacteria is becoming a global concern, particularly due to the dwindling supply of new antibiotics. This situation mandates the discovery of new antimicrobial candidates. Plant-derived natural compounds have historically played a crucial role in the development of antibiotics, serving as a rich source of substances possessing antimicrobial properties. Numerous studies have supported the reputation of 6-gingerol, a prominent compound found in the ginger family, for its antibacterial properties. In this study, the antibacterial activities of 6-gingerol were evaluated against Gram-negative bacteria, Acinetobacter baumannii and Klebsiella pneumoniae, with a particular focus on the clinically significant Gram-negative Pseudomonas aeruginosa and Gram-positive bacteria Staphylococcus aureus. Furthermore, the anti-virulence activities were assessed in vitro, in vivo, and in silico. The current findings showed that 6-gingerol's antibacterial activity is due to its significant effect on the disruption of the bacterial cell membrane and efflux pumps, as it significantly decreased the efflux and disrupted the cell membrane of S. aureus and P. aeruginosa. Furthermore, 6-gingerol significantly decreased the biofilm formation and production of virulence factors in S. aureus and P. aeruginosa in concentrations below MICs. The anti-virulence properties of 6-gingerol could be attributed to its capacity to disrupt bacterial virulence-regulating systems; quorum sensing (QS). 6-Gingerol was found to interact with QS receptors and downregulate the genes responsible for QS. In addition, molecular docking, and molecular dynamics (MD) simulation results indicated that 6-gingerol showed a comparable binding affinity to the co-crystalized ligands of different P. aeruginosa QS targets as well as stable interactions during 100 ns MD simulations. These findings suggest that 6-gingerol holds promise as an anti-virulence agent that can be combined with antibiotics for the treatment of severe infections.

Protective effect of kaempferol glucoside against lipopolysaccharide-caused acute lung injury via targeting Nrf2/NF-κB/NLRP3/GSDMD: Integrating experimental and computational studies.

The current study explored the protective potential of kaempferol 3-sophoroside-7-glucoside (KSG) against acute lung injury (ALI). Pre-treatment with KSG effectively secured mice from ALI and showed similar efficaciousness to dexamethasone. KSG markedly increased the survival rate and alleviated lung pathological lesions induced by lipopolysaccharide (LPS). Furthermore, KSG attenuated differential and total cell counts in BALF (bronchoalveolar lavage fluid) and MPO (myeloperoxidase) activity. KSG counteracted the NF-κB (nuclear factor-κB) activation and significantly ameliorated the downstream inflammatory cytokine, TNF-α (tumor necrosis factor-α). Simultaneously, KSG suppressed the over-expression of NLRP3 (NOD-like receptor protein 3), caspase-1, and pro-inflammatory cytokine interleukin IL-1ß (interleukine-1ß) and prohibited the elevation of the pyroptotic parameter GSDMD-N (N-terminal domain of gasdermin D) induced by LPS challenge. In addition, KSG significantly enhanced Nrf2 (nuclear-factor erythroid-2-related factor) and HO-1 (heme-oxygenase-1) expression. Meanwhile, KSG mitigated lipid peroxidative markers (malondialdehyde, protein carbonyl and 4-hydroxynonenal) and boosted endogenous antioxidants (superoxide dismutase/reduced glutathione/catalase) in lung tissue. In silico analyses revealed that KSG disrupts Keap1-Nrf2 protein-protein interactions by binding to the KEAP1 domain, consequently activating Nrf2. Specifically, molecular docking demonstrated superior binding affinity of KSG to KEAP1 compared to the reference inhibitor, with docking scores of -9.576 and -6.633 Kcal/mol, respectively. Additionally, the MM-GBSA binding free energy of KSG (-67.25 Kcal/mol) surpassed that of the reference inhibitor (-56.36 Kcal/mol). Furthermore, MD simulation analysis revealed that the KSG-KEAP1 complex exhibits substantial and stable binding interactions with various amino acids over a duration of 100 ns. These findings showed the protective anti-inflammatory and anti-oxidative modulatory efficiencies of KSG that effectively counteracted LPS-induced ALI and encouraged future research and clinical applications of KSG as a protective strategy for ALI.

Modulation of the crosstalk between Keap1/Nrf2/HO-1 and NF-κB signaling pathways by Tomatidine protects against inflammation/oxidative stress-driven fulminant hepatic failure in mice.

Fulminant hepatic failure (FHF) is the terminal phase of acute liver injury, which is characterized by massive hepatocyte necrosis and rapid hepatic dysfunction in patients without preexisting liver disease. There are currently no therapeutic options for such a life-threatening hepatic failure except liver transplantation; therefore, the terminal phase of the underlying acute liver injury should be avoided. Tomatidine (TOM), asteroidal alkaloid, may have different biological activities, including antioxidant and anti-inflammatory effects. Herein, the lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced FHF mouse model was established to explore the protective potential of TOM and the underlying mechanisms of action. TOM pretreatment significantly inhibited hepatocyte necrosis and decreased serum aminotransferase activities in LPS/D-GalN-stimulated mice. TOM further increased the level of different antioxidant enzymes while reducing lipid peroxidation biomarkers in the liver. These beneficial effects of TOM were shown to be associated with targeting of NF-κB signaling pathways, where TOM repressed NF-κB activation and decreased LPS/D-GalN-induced TNF-α, IL-6, IL-1ß, and iNOS production. Moreover, TOM prevented LPS/D-GalN-induced upregulation of Keap1 expression and downregulation of Nrf2 and HO-1 expression, leading to increased Nrf2-binding activity and HO-1 levels. Besides, TOM pretreatment repressed LPS/D-GalN-induced upregulation of proliferating cell nuclear antigen (PCNA) expression, which spared the hepatocytes from damage and subsequent repair following the LPS/D-GalN challenge. Collectively, our findings revealed that TOM has a protective effect on LPS/D-GalN-induced FHF in mice, showing powerful antioxidant and anti-inflammatory effects, primarily mediated via modulating Keap1/Nrf2/HO-1 and NF-κB/TNF-α/IL-6/IL-1ß/iNOS signaling pathways.

Biofilm-mediated infections by multidrug-resistant microbes: a comprehensive exploration and forward perspectives.

A biofilm is a collection of microorganisms organized in a matrix of extracellular polymeric material. Biofilms consist of microbial cells that attach to both surfaces and each other, whether they are living or non-living. These microbial biofilms can lead to hospital-acquired infections and are generally detrimental. They possess the ability to resist the human immune system and antibiotics. The National Institute of Health (NIH) states that biofilm formation is associated with 65% of all microbial illnesses and 80% of chronic illnesses. Additionally, non-device-related microbial biofilm infections include conditions like cystic fibrosis, otitis media, infective endocarditis, and chronic inflammatory disorders. This review aims to provide an overview of research on chronic infections caused by microbial biofilms, methods used for biofilm detection, recent approaches to combat biofilms, and future perspectives, including the development of innovative antimicrobial strategies such as antimicrobial peptides, bacteriophages, and agents that disrupt biofilms.

Integrating computational methods guided the discovery of phytochemicals as potential Pin1 inhibitors for cancer: pharmacophore modeling, molecular docking, MM-GBSA calculations and molecular dynamics studies.

Pin1 is a pivotal player in interactions with a diverse array of phosphorylated proteins closely linked to critical processes such as carcinogenesis and tumor suppression. Its axial role in cancer initiation and progression, coupled with its overexpression and activation in various cancers render it a potential candidate for the development of targeted therapeutics. While several known Pin1 inhibitors possess favorable enzymatic profiles, their cellular efficacy often falls short. Consequently, the pursuit of novel Pin1 inhibitors has gained considerable attention in the field of medicinal chemistry. In this study, we employed the Phase tool from Schrödinger to construct a structure-based pharmacophore model. Subsequently, 449,008 natural products (NPs) from the SN3 database underwent screening to identify compounds sharing pharmacophoric features with the native ligand. This resulted in 650 compounds, which then underwent molecular docking and binding free energy calculations. Among them, SN0021307, SN0449787 and SN0079231 showed better docking scores with values of -9.891, -7.579 and -7.097 kcal/mol, respectively than the reference compound (-6.064 kcal/mol). Also, SN0021307, SN0449787 and SN0079231 exhibited lower free binding energies (-57.12, -49.81 and -46.05 kcal/mol, respectively) than the reference ligand (-37.75 kcal/mol). Based on these studies, SN0021307, SN0449787, and SN0079231 showed better binding affinity that the reference compound. Further the validation of these findings, molecular dynamics simulations confirmed the stability of the ligand-receptor complex for 100 ns with RMSD ranging from 0.6 to 1.8 Å. Based on these promising results, these three phytochemicals emerge as promising lead compounds warranting comprehensive biological screening in future investigations. These compounds hold great potential for further exploration regarding their efficacy and safety as Pin1 inhibitors, which could usher in new avenues for combating cancer.

RETRACTED: Alhakamy et al. Fluoxetine Ecofriendly Nanoemulsion Enhances Wound Healing in Diabetic Rats: In Vivo Efficacy Assessment. Pharmaceutics 2022, 14, 1133.

The journal retracts the article, "Fluoxetine Ecofriendly Nanoemulsion Enhances Wound Healing in Diabetic Rats: In Vivo Efficacy Assessment" [...].

Antimicrobial and anti-virulence activities of 4-shogaol from grains of paradise against gram-negative bacteria: Integration of experimental and computational methods.

ETHNOPHARMACOLOGICAL RELEVANCE: Bacterial resistance to antibiotics is a growing global concern, highlighting the urgent need for new antimicrobial candidates. Aframomum melegueta was traditionally used for combating urinary tract and soft tissue infections, which implies its potential as an antimicrobial agent. AIM OF STUDY: This study was designed to explore the antibacterial and anti-virulence capabilities of 4-shogaol isolated from A. melegueta seeds versus gram-negative bacteria: Serratia marcescens, Klebsiella pneumoniae, Acinetobacter baumannii, and the clinically important pathogen Pseudomonas aeruginosa. MATERIALS AND METHODS: 4-Shogeol was isolated from A. melegueta seeds and its MICs were determined for Acinetobacter baumannii (ATCC-17978), Pseudomonas aeruginosa (ATCC-27853), Klebsiella pneumoniae (ATCC-700603), and Serratia marcescens clinical isolate. The anti-efflux activity and effect on the bacterial cell membrane for the compound were evaluated. Furthermore, the anti-virulence activities of the compound were evaluated. The effects of 4-shogeol at sub-MIC on bacterial motility, biofilm formation, and production of virulent enzymes and pigments were assessed. The anti-quorum sensing activities of 4-shogeol were evaluated virtually and by quantification its effect on the expression of quorum sensing encoding genes. The in vivo protection assay was conducted to evaluate the effect of 4-shogaol on the P. aeruginosa capacity to induce pathogenesis in mice. Finally, the effect of shogaol-antibiotics combination was assessed. RESULTS: The research revealed that 4-shogaol's antibacterial action primarily involves disrupting the bacterial cell membrane and efflux pumps. It also exhibited significant anti-virulence effects by reducing biofilm development and repressing virulence factors production, effectively protecting mice against P. aeruginosa infection. Furthermore, when combined with antibiotics, 4-shogaol demonstrated synergistic effects, leading to reduced minimum inhibitory concentrations (MICs) against P. aeruginosa. Its anti-virulence properties were linked to its ability to disrupt bacterial quorum sensing (QS) mechanisms, as evidenced by its interaction with QS receptors and downregulation of QS-related genes. Notably, in silico analysis indicated that 4-shogaol exhibited strong binding affinity to different P. aeruginosa QS targets. CONCLUSION: These findings suggest that 4-shogaol holds promise as an effective anti-virulence agent that can be utilized in combination with antibiotics for treating severe infections caused by gram-positive bacteria.

Tetraenone A: A New ß-Ionone Derivative from Tetraena aegyptia.

In this study, the chemical investigation of Tetraena aegyptia (Zygophyllaceae) led to the identification of a new megastigmene derivative, tetraenone A ((2S, 5R, 6R, 7E)-2-hydroxy-5,6-dihydro-ß-ionone) (1), along with (3S, 5R, 6S, 7E)-3-hydroxy-5,6-epoxy-5,6-dihydro-ß-ionone- (2), 3,4-dihydroxy-cinnamyl alcohol-4-glucoside (3), 3ß,19α-dihydroxy-ursan-28-oic acid (4), quinovic acid (5), p-coumaric acid (6), and ferulic acid (7), for the first time. The chemical structures of 1-7 were confirmed by analysis of their 1D and 2D NMR and HRESIMS spectra and by their comparison with the relevant literature. The absolute configurations of 1 and 2 were assigned based on NOESY interactions and ECD spectra. Conformational analysis showed that 1 existed exclusively in one of the two theoretically possible chair conformers with a predominant s-trans configuration for the 3-oxobut-1-en-1-yl group with the ring, while the half-chair conformer had a pseudo-axial hydroxy group that was predominant over the other half-chair conformation. Boat conformations were not among the most stable conformations, and the s-trans isomerism was in favor of s-cis configuration. In silico investigation revealed that 1 and 2 had more favorable binding interactions with Mpro rather than with TMPRSS2. Accordingly, molecular dynamic simulations were performed on the complexes of compounds 1 and 2 with Mpro to explore the stability of their interaction with the target protein structure. Compounds 1 and 2 might offer a possible starting point for developing covalent inhibitors of Mpro of SARS-CoV-2.

Acetyl barlerin from Barleria trispinosa induces chemopreventive NQO1 and attenuates LPS-induced inflammation: in vitro and molecular dynamic studies.

Extraction and fractionation of Barleria trispinosa growing in Saudi Arabia yielded four iridoid compounds identified by spectroscopic techniques as acetylbarlerin (1), barlerin (2), shanzhiside methyl ester (3) and 6-⍺-L-rhamnopyranosyl-8-O-acetylshanzihiside methyl ester (4). Preliminary experiments confirmed that compound 1 acts as an inducer of chemopreventive NAD(P)H:Quinone oxidoreductase 1 (NQO1) enzymatic activity in a murine hepatoma (Hepa1c1c7) chemoprevention model. It also demonstrated the ability to inhibit the lipopolysaccharides (LPS)-induced nitric oxide (NO) production in the RAW264.7 macrophage model. Western blotting revealed the ability of compound 1 to up-regulate the protein expression of the NQO1 marker. Furthermore, compound 1 elicited NO suppression in RAW264.7 macrophages by inhibiting iNOS protein expression. Molecular docking and molecular simulation studies of 1 supported its experimental results as an inhibitor of the nuclear factor erythroid 2-Kelch-like ECH-associated protein 1 (Nrf2-KEAP1) complex, resulting in Nrf2-mediated induction of chemopreventive NQO1.Communicated by Ramaswamy H. Sarma.

Design of new Mcl-1 inhibitors for cancer using fragments hybridization, molecular docking, and molecular dynamics studies.

Apoptosis is a critical process that regulates cell survival and death and plays an essential role in cancer development. The Bcl-2 protein family, including myeloid leukemia 1 (Mcl-1), is a key regulator of the intrinsic apoptosis pathway, and its overexpression in many human cancers has prompted efforts to develop Mcl-1 inhibitors as potential anticancer agents. In this study, we aimed to design new Mcl-1 inhibitors using various computational techniques. First, we used the Mcl-1 receptor-ligand complex to build an e-pharmacophore hypothesis and screened a library of 567,000 fragments from the Enamine database. We obtained 410 fragments and used them to design 92,384 novel compounds, which we then docked into the Mcl-1 binding cavity using HTVS, SP, and XP docking modes of Glide. To assess their suitability as drug candidates, we conducted MM-GBSA calculations and ADME prediction, leading to the identification of 10 compounds with excellent binding affinity and favorable pharmacokinetic properties. To further investigate the interaction strength, we performed molecular dynamics simulations on the top three Mcl-1 receptor-ligand complexes to study their interaction stability. Overall, our findings suggest that these compounds have promising potential as anticancer agents, pending further experimental validation such as Mcl-1 apoptosis Assay. By combining experimental methods with various in silico approaches, these techniques prove to be invaluable for identifying novel drug candidates with distinct therapeutic applications using fragment-based drug design. This methodology has the potential to expedite the drug discovery process while also reducing its costs.Communicated by Ramaswamy H. Sarma.

Marine-Derived Compounds for CDK5 Inhibition in Cancer: Integrating Multi-Stage Virtual Screening, MM/GBSA Analysis and Molecular Dynamics Investigations.

Cyclin-dependent kinase 5 (CDK5) plays a crucial role in various biological processes, including immune response, insulin secretion regulation, apoptosis, DNA (deoxyribonucleic acid) damage response, epithelial-mesenchymal transition (EMT), cell migration and invasion, angiogenesis, and myogenesis. Overactivation of CDK5 is associated with the initiation and progression of cancer. Inhibiting CDK5 has shown potential in suppressing cancer development. Despite advancements in CDK5-targeted inhibitor research, the range of compounds available for clinical and preclinical trials remains limited. The marine environment has emerged as a prolific source of diverse natural products with noteworthy biological activities, including anti-cancer properties. In this study, we screened a library of 47,450 marine natural compounds from the comprehensive marine natural product database (CMNPD) to assess their binding affinity with CDK5. Marine compounds demonstrating superior binding affinity compared to a reference compound were identified through high-throughput virtual screening, standard precision and extra-precision Glide docking modes. Refinement of the selected molecules involved evaluating molecular mechanics-generalized born surface area (MM/GBSA) free binding energy. The three most promising compounds, (excoecariphenol B, excoecariphenol A, and zyzzyanone B), along with the reference, exhibiting favorable binding characteristics were chosen for molecular dynamics (MD) simulations for 200 nanoseconds. These compounds demonstrated interaction stability with the target during MD simulations. The marine compounds identified in this study hold potential as effective CDK5 inhibitors and warrant subsequent experimental validation.

Optimized bilosome-based nanoparticles enhance cytotoxic and pro-apoptotic activity of costunolide in LS174T colon cancer cells.

Costunolide (COST) is a sesquiterpene lactone that belongs to the germacranolide group, and occurs mainly in Saussurea lappa Clarke. Although COST inhibits the proliferation and metastasis of cancer cells and induces their apoptosis, it suffers poor water solubility and cellular permeability. Therefore, this study aimed to enhance the anti-proliferative activity of COST in LS174T colon cancer cells through its inclusion in bilosomal nanoformulation (COST-BILs). The optimized BIL formula contained cholesterol and Span-85 in a molar ratio of 1:5 as well as bile salt at a molar concentration of 0.5 mM, with entrapment efficiency of 63.4 ± 3.59 % and particle size of 119.7 ± 3.63 nm. The optimized COST-BILs showed a potent cytotoxic effect against LS174T cells with an IC50 of 6.20 µM; meanwhile, raw COST had an IC50 of 15.78 µM. Safety and relative selectivity were confirmed in the normal human colonic epithelial cells (HCoEpC). Cell cycle analysis indicated that both raw COST and COST-BILs significantly increased the fraction of LS174T cells in the sub-G1 phase. This was accompanied by a significant enhancement of early, late, and total apoptosis, as indicated by annexin-V staining. In addition, COST-BILs exhibited more potent activity in up-regulating CASP3, TP53, and BAX, and in down-regulating the expression of BCL2 mRNA as compared to raw COST. Further, the prepared formula enhanced the release of cytochrome C as well as the generation of reactive oxygen species (ROS) and reduced the integrity of mitochondrial membranes. In conclusion, the loading of COST on BILs significantly enhances its pro-apoptotic activity in LS174T cells.

Taif Rose Oil Ameliorates UVB-Induced Oxidative Damage and Skin Photoaging in Rats via Modulation of MAPK and MMP Signaling Pathways.

Short-wave UVB (ultraviolet B) causes rapid oxidative damage to the skin. Rose water is obtained mainly from the petals of Rosa damascena Mill. (Rosaceae) and used traditionally to hydrate dry skin and reduce signs of aging. This work aimed at evaluating the possible protective potential of the prepared eco-friendly Taif rose oil nanoemulsion (ROSE-NANO) against UVB-induced photoaging in adult male Wistar rats. Taif rose oil (ROSE) was obtained from R. damascene by classical steam distillation and formulated in emulgel (100 mg/g). In addition, the oil was formulated in ROSE-NANO-loaded emulgel (50 and 100 mg/g) to enhance the effect of ROSE. All prepared formulas were tested topically for their potential protective effect in UV-induced skin photoaging. The obtained results demonstrated that application of ROSE-NANO-loaded emulgel resulted in superior antiaging potency over ROSE emulgel based on histological studies as well as biochemical evaluations via amendment in CAT and SOD activities, decreasing the concentration of the inflammatory markers and preventing collagen fragmentation through reduction of MMP-9 content in fibroblasts. Moreover, a significant decrease in mRNA expression of NF-KB, JNK, ERK1/2, and p38 MAPK genes was observed. In conclusion, the current study provides scientific evidence for the traditional use of rose oil in skin aging. Moreover, the NANO formula showed promising efficacy as a skin photoprotector against UV-induced oxidative damage and skin aging.

Molecular Docking and Molecular Dynamics Studies Reveal the Anticancer Potential of Medicinal-Plant-Derived Lignans as MDM2-P53 Interaction Inhibitors.

The interaction between the tumor suppressor protein p53 and its negative regulator, the MDM2 oncogenic protein, has gained significant attention in cancer drug discovery. In this study, 120 lignans reported from Ferula sinkiangensis and Justicia procumbens were assessed for docking simulations on the active pocket of the MDM2 crystal structure bound to Nutlin-3a. The docking analysis identified nine compounds with higher docking scores than the co-crystallized reference. Subsequent AMDET profiling revealed satisfactory pharmacokinetic and safety parameters for these natural products. Three compounds, namely, justin A, 6-hydroxy justicidin A, and 6'-hydroxy justicidin B, were selected for further investigation due to their strong binding affinities of -7.526 kcal/mol, -7.438 kcal/mol, and -7.240 kcal/mol, respectively, which surpassed the binding affinity of the reference inhibitor Nutlin-3a (-6.830 kcal/mol). To assess the stability and reliability of the binding of the candidate hits, a molecular dynamics simulation was performed over a duration of 100 ns. Remarkably, the thorough analysis demonstrated that all the hits exhibited stable molecular dynamics profiles. Based on their effective binding to MDM2, favorable pharmacokinetic properties, and molecular dynamics behavior, these compounds represent a promising starting point for further refinement. Nevertheless, it is essential to synthesize the suggested compounds and evaluate their activity through in vitro and in vivo experiments.

Modulation of NRF2/KEAP1-Mediated Oxidative Stress for Cancer Treatment by Natural Products Using Pharmacophore-Based Screening, Molecular Docking, and Molecular Dynamics Studies.

Oxidative stress plays a significant role in the development of cancer. Inhibiting the protein-protein interaction (PPI) between Keap1 and Nrf2 offers a promising strategy to activate the Nrf2 antioxidant pathway, which is normally suppressed by the binding of Keap1 to Nrf2. This study aimed to identify natural compounds capable of targeting the kelch domain of KEAP1 using structure-based drug design methods. A pharmacophore model was constructed based on the KEAP1-inhibitor complex, leading to the selection of 6178 compounds that matched the model. Subsequently, docking and MM/GBSA analyses were conducted, resulting in the identification of 10 compounds with superior binding energies compared to the reference compound. From these, three compounds (ZINC000002123788, ZINC000002111341, and ZINC000002125904) were chosen for further investigation. Ligand-residue interaction analysis revealed specific interactions between these compounds and key residues, indicating their stability within the binding site. ADMET analysis confirmed that the selected compounds possessed desirable drug-like properties. Furthermore, molecular dynamics simulations were performed, demonstrating the stability of the ligand-protein complexes over a 100 ns duration. These findings underscore the potential of the selected natural compounds as agents targeting KEAP1 and provide valuable insights for future experimental studies.

Secondary Metabolites, Biological Activities, and Industrial and Biotechnological Importance of Aspergillus sydowii.

Marine-derived fungi are renowned as a source of astonishingly significant and synthetically appealing metabolites that are proven as new lead chemicals for chemical, pharmaceutical, and agricultural fields. Aspergillus sydowii is a saprotrophic, ubiquitous, and halophilic fungus that is commonly found in different marine ecosystems. This fungus can cause aspergillosis in sea fan corals leading to sea fan mortality with subsequent changes in coral community structure. Interestingly, A. sydowi is a prolific source of distinct and structurally varied metabolites such as alkaloids, xanthones, terpenes, anthraquinones, sterols, diphenyl ethers, pyrones, cyclopentenones, and polyketides with a range of bioactivities. A. sydowii has capacity to produce various enzymes with marked industrial and biotechnological potential, including α-amylases, lipases, xylanases, cellulases, keratinases, and tannases. Also, this fungus has the capacity for bioremediation as well as the biocatalysis of various chemical reactions. The current work aimed at focusing on the bright side of this fungus. In this review, published studies on isolated metabolites from A. sydowii, including their structures, biological functions, and biosynthesis, as well as the biotechnological and industrial significance of this fungus, were highlighted. More than 245 compounds were described in the current review with 134 references published within the period from 1975 to June 2023.

Benzophenones-natural metabolites with great Hopes in drug discovery: structures, occurrence, bioactivities, and biosynthesis.

Fungi have protruded with enormous development in the repository of drug discovery, making them some of the most attractive sources for the synthesis of bio-significant and structural novel metabolites. Benzophenones are structurally unique metabolites with phenol/carbonyl/phenol frameworks, that are separated from microbial and plant sources. They have drawn considerable interest from researchers due to their versatile building blocks and diversified bio-activities. The current work aimed to highlight the reported data on fungal benzophenones, including their structures, occurrence, and bioactivities in the period from 1963 to April 2023. Overall, 147 benzophenones derived from fungal source were listed in this work. Structure activity relationships of the benzophenones derivatives have been discussed. Also, in this review, a brief insight into their biosynthetic routes was presented. This work could shed light on the future research of benzophenones.

Exploring the potential of approved drugs for triple-negative breast cancer treatment by targeting casein kinase 2: Insights from computational studies.

Triple-negative breast cancer (TNBC) is an aggressive malignancy that requires effective targeted drug therapy. In this study, we employed in silico methods to evaluate the efficacy of seven approved drugs against human ck2 alpha kinase, a significant modulator of TNBC metastasis and invasiveness. Molecular docking revealed that the co-crystallized reference inhibitor 108600 achieved a docking score of (-7.390 kcal/mol). Notably, among the seven approved drugs tested, sunitinib, bazedoxifene, and etravirine exhibited superior docking scores compared to the reference inhibitor. Specifically, their respective docking scores were -10.401, -7.937, and -7.743 kcal/mol. Further analysis using MM/GBSA demonstrated that these three top-ranked drugs possessed better binding energies than the reference ligand. Subsequent molecular dynamics simulations identified etravirine, an FDA-approved antiviral drug, as the only repurposed drug that demonstrated a stable and reliable binding mode with the human ck2 alpha protein, based on various analysis measures including RMSD, RMSF, and radius of gyration. Principal component analysis indicated that etravirine exhibited comparable stability of motion as a complex with human ck2 alpha protein, similar to the co-crystallized inhibitor. Additionally, Density functional theory (DFT) calculations were performed on a complex of etravirine and a representative gold atom positioned at different sites relative to the heteroatoms of etravirine. The results of the DFT calculations revealed low-energy complexes that could potentially serve as guides for experimental trials involving gold nanocarriers of etravirine, enhancing its delivery to malignant cells and introducing a new drug delivery route. Based on the results obtained in this research study, etravirine shows promise as a potential antitumor agent targeting TNBC, warranting further investigation through experimental and clinical assessments.

SIRT1/Nrf2/NF-κB Signaling Mediates Anti-Inflammatory and Anti-Apoptotic Activities of Oleanolic Acid in a Mouse Model of Acute Hepatorenal Damage.

Background and objectives: Oleanolic acid (OA) is a penta-cyclic triterpene with diverse bioactivities such as anticarcinogenic, antiviral, antimicrobial, hepatoprotective, anti-atherosclerotic, hypolipidemic, and gastroprotective. However, its effects on hepatorenal damage remain unclear. The protective activity of OA, separated from Viscum schimperi (Loranthaceae), against TAA (thioacetamide)-produced acute hepatic and renal damage was explored. Materials and Methods: Mice were treated with OA for 7 days before TAA (200 mg/kg, i.p.). Serum indices of hepatorenal injury, pathological lesions, molecular biological indexes, and inflammatory/apoptotic genes were estimated. Results: The tissues of both organs were greatly affected by the TAA injection. That was evident through increased serum markers of hepato-renal injury as well as remarkable histopathological lesions. TAA-induced injury was associated with oxidative and inflammatory responses in both organs as there was an elevation of oxidative stress parameters (4-HNE (4-hydroxy-nonenal), MDA (malondialdehyde), NOx (nitric oxide)), decline of antioxidants (reduced glutathione (GSH), superoxide dismutase (SOD), and total antioxidant capacity (TAC)), and an increase in the gene expression/level of inflammatory mediators (interleukins (1ß&6)). The inflammatory response was linked to a significant activation of NF-κB (nuclear-factor kappa-B)/TNF-α (tumor-necrosis factor-alpha) signaling. The inflammatory response in both organs was accompanied by apoptotic changes, including a rise in the gene expression and level of apoptotic parameters (caspase-3 and Bax) along with a decline in Bcl-2 (anti-apoptotic parameter) gene expression and level. These pathogenic events were found to be closely related to the suppression of the antioxidant signaling pathway, Nrf2 (nuclear-factor erythroid 2-related factor-2)/SIRT1 (sirtuin-1)/HO-1 (heme-oxygenase 1). On the other hand, OA significantly ameliorated TAA-induced injury in both organs. On the other hand, OA counterpoised the inflammatory response as it ameliorated NF-κB/TNF-α signaling and cytokine release. OA enhanced Nrf2/SIRT1/HO-1 signaling and counteracted apoptotic damage. Conclusions: OA showed anti-inflammation and antiapoptotic capacities that effectively suppressed TAA-induced acute hepatorenal damage.