Numerous fungicides are essential for controlling phytopathogens, enabling modern industrial agriculture to maximize productivity and profitability. However, the extensive use of widely employed fungicides, such as tebuconazole and carbendazim, has led to reduced efficacy due to the emergence of resistant plant-pathogenic fungi. Accordingly, in this study, we synthesized a 2‑pyrone chemotype bearing a ynone substituent, designated as ynone 6 and evaluated its potential as an antifungal scaffold. This representative lead compound exhibited broad-spectrum antifungal activity against five major phytopathogens, including Fusarium graminearum and Botrytis cinerea. Ynone 6 demonstrated potent in planta control efficacy across various host tissues, including wheat spikes, fruits, and leaves, with inhibitory effects comparable to those of tebuconazole. Sensitivity screening using six knockout mutants targeting well-established antifungal pathways revealed that the sensitivity profiles of the mutants differed significantly between conidial germination and hyphal growth, suggesting that the mode of action of ynone 6 is stage-dependent and may involve multiple targets. Collectively, the potent in vitro activity of ynone 6 and its consistent in planta efficacy across multiple host-pathogen systems highlight the ynone-tethered 2-pyrone scaffold as a promising lead scaffold for the development of effective antifungal agents.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that begins with motor neuron death in the spinal cord and cerebral cortex, ultimately resulting in death from respiratory distress (breathing failure). About 90

Alternative splicing products of AIMP2 and AIMP2-DX2 (DX2) have been reported to be associated with human lung cancer. In fact, DX2 expression is elevated in human lung cancers, and DX2 transgenic mice also develop lung cancer, in particular small cell lung cancer (SCLC). However, the mechanism by which DX2 is induced during cancer progression has not been clearly elucidated. Here, we show that DX2 is induced by nicotine, the main component of smoking-related chemicals, which can stabilize the human epidermal growth factor receptor 2 (HER2) protein and transcriptionally increase sonic hedgehog (Shh). Indeed, nicotine showed tumorigenicity via DX2 by promoting spheroid formation and in vivo lung and kidney cancer progression. Moreover, the elimination of DX2 using small interfering RNA (siRNA) or an optimized inhibitor (SNU-14) blocked the induction of HER2 and Shh and completely suppressed tumor sphere formation in response to nicotine. These results indicate that DX2 is critical for lung cancer progression, and a specific DX2 inhibitor would be useful for the treatment of human cancers, including SCLC and non-SCLC (NSCLC).

Lewis acid catalyzed 4 pi-electrocyclization of Donor-Acceptor Stenhouse Adducts (DASAs) has been developed. By employing catalytic quantities of Dy(OTf)(3), a highly efficient transformation of acyclic DASAs into the corresponding cyclized isomers was achieved. Notably, this transformation exhibited exceptional yields, particularly in the case of first generation DASAs. In addition, Lewis acid catalysis enabled one pot synthesis of the cyclopentenone product from the 'donor' and 'acceptor' components.

Staphylococcus aureus is a gram-positive bacteria known for its multidrug resistance and persistent survival. H2S increased drug resistance and persistent survival in S. aureus, which produces H2S through the PLP-dependent enzyme MccB. In this study, we investigated the catalytic activities of S. aureus MccB in H2S production and explored its inhibitory effects of natural compounds. We found that the natural compound EGCG strongly inhibited MccB enzyme activity in H2S production via an unexpected mechanism. The mass and NMR analysis revealed that EGCG formed a hemiacetal compound with free PLP, resulting in the depletion of the cytosolic pool of PLP. EGCG enhanced the antibiotic effect of antibiotics retarded by MccB. Our results shed light on a novel pathway through which EGCG regulates bacterial H2S production, and this finding may have potential applications in diets aimed at suppressing the pathogenesis of S. aureus in the gut using the edible compound EGCG.

The escalating demand for effective and sustainable weed management strategies, driven by urbanization expansion, is a critical challenge. Herbicides are pivotal tools in modern agriculture, addressing this challenge. Developing novel herbicides with enhanced efficacy and minimal environmental impact is crucial for food security and ecological balance. While numerous herbicides have been developed with varying availability over time and regions, there's a continuous need for innovation. In this study, we explored relatively understudied sulfoxide-containing herbicides and synthesized a smaller yet substantial sulfoxide scaffold for herbicide development. Through screening Digitaria ciliaris (Retz.) Koeler, Amaranthus lividus L . , and Solanum nigrum L . , we observed promising herbicidal efficacy, especially against Wild Amaranth. Encouraged by preliminary findings, we recognize the potential for refining the core structure. In summary, we fashioned a structurally simple sulfoxide scaffold showcasing discernible herbicidal impact on broadleaf weeds.

Escherichia coli RclA and Staphylococcus aureus MerA are part of the Group I flavoprotein disulfide reductase (FDR) family and have been implicated in the contribution to bacterial pathogenesis by defending against the host immune response. Fusobacterium nucleatum is a pathogenic, anaerobic Gram-negative bacterial species commonly found in the human oral cavity and gastrointestinal tract. In this study, we discovered that the F. nucleatum protein FN0820, belonging to the Group I FDR family, exhibited a higher activity of a Cu2+-dependent NADH oxidase than E. coli RclA. Moreover, FN0820 decreased the dissolved oxygen level in the solution with higher NADH oxidase activity. We found that L-tryptophan and its analog 5-hydroxytryptophan inhibit the FN0820 activities of NADH oxidase and the concomitant reduction of oxygen. Our results have implications for developing new treatment strategies against pathogens that defend the host immune response with Group I FDRs.

Eukaryotic Cu, Zn-superoxide dismutase (SOD1) is primarily responsible for cytotoxic filament formation in amyotrophic lateral sclerosis (ALS) neurons. Two cysteine residues in SOD1 form an intramolecular disulfide bond. This study aims to explore the molecular mechanism of SOD1 filament formation by cysteine overoxidation in sporadic ALS (sALS). In this study, we determined the crystal structure of the double mutant (C57D/C146D) SOD1 that mimics the overoxidation of the disulfide-forming cysteine residues. The structure revealed the open and relaxed conformation of loop IV containing the mutated Asp57. The double mutant SOD1 produced more contagious filaments than wild-type protein, promoting filament formation of the wild-type SOD1 proteins. Importantly, we further found that HOCl treatment to the wild-type SOD1 proteins facilitated their filament formation. We propose a feasible mechanism for SOD1 filament formation in ALS from the wild-type SOD1, suggesting that overoxidized SOD1 is a triggering factor of sALS. Our findings extend our understanding of other neurodegenerative disorders associated with ROS stresses at the molecular level.

Natural products decursin and decursinol angelate were recently reported as benign fungicides for controlling rice blast. Inspired by the structural similarity of the cumarin compounds and gained hint from the skeletal motifs, we designed and prepared synthetic compounds to increase the natural product efficacy and evaluated their antifungal activities against various plant disease pathogens in vitro. Synthetically prepared compound 4 and 5 indeed suppressed the mycelial growth of B. cinerea , F. oxysporum , P. italicum , and R. quercus-mongolicae . Additionally, compound 5 effectively prevents the growth of C. coccodes and C. parasitica . Furthermore, both 4 and 5 possess better inhibitory activities on spore germination of F. oxysporum and M. oryzae than the natural product decursin and commercial pesticide Iprodione. These results suggest that the effect of the lead compound for plant disease protection can be improved by tuning the structure of the original natural product and decursinol chloroacrylates 4 and 5 are candidates for the control of F. oxysporum and M. oryzae .

We report the first total synthesis of micrococcin P2 (MP2, 1) by a diversity-oriented route that incorporates a number of refinements relative to earlier syntheses. Biological data regarding the activity of 1 against a range of human pathogens are also provided. Furthermore, we disclose a chemical property of MP2 that greatly facilitates medicinal chemistry work in the micrococcin area and describe a method to obtain MP2 by fermentation in B. subtilis.

Abstract Loss of NF2 (merlin) has been suggested as a genetic cause of neurofibromatosis type 2 and malignant peripheral nerve sheath tumor (MPNST). Previously, we demonstrated that NF2 sustained TGFβ receptor 2 (TβR2) expression and reduction or loss of NF2 activated non-canonical TGFβ signaling, which reduced Raf kinase inhibitor protein (RKIP) expression via TβR1 kinase activity. Here, we show that a selective RKIP inducer (novel chemical, Nf18001) inhibits tumor growth and promotes schwannoma cell differentiation into mature Schwann cells under NF2-deficient conditions. In addition, Nf18001 is not cytotoxic to cells expressing NF2 and is not disturb canonical TGFβ signaling. Moreover, the novel chemical induces expression of SOX10, a marker of differentiated Schwann cells, and promotes nuclear export and degradation of SOX2, a stem cell factor. Treatment with Nf18001 inhibited tumor growth in an allograft model with mouse schwannoma cells. These results strongly suggest that selective RKIP inducers could be useful for the treatment of neurofibromatosis type 2 as well as NF2-deficient MPNST. Implications: This study identifies that a selective RKIP inducer inhibits tumor growth and promotes schwannoma cell differentiation under NF2-deficient conditions by reducing SOX2 and increasing SOX10 expression.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective death of motor neurons. Mutations in Cu, Zn-superoxide dismutase (SOD1) causing the gain of its toxic property are the major culprit of familial ALS (fALS). The abnormal SOD1 aggregation in the motor neurons has been suggested as the major pathological hallmark of ALS patients. However, the development of pharmacological interventions against SOD1 still needs further investigation. In this study, using ELISA-based chemical screening with wild and mutant SOD1 proteins, we screened a new small molecule, PRG-A01, which could block the misfolding/aggregation of SOD1 or TDP-43. The drug rescued the cell death induced by mutant SOD1 in human neuroblastoma cell line. Administration of PRG-A01 into the ALS model mouse resulted in significant improvement of muscle strength, motor neuron viability and mobility with extended lifespan. These results suggest that SOD1 misfolding/aggregation is a potent therapeutic target for SOD1 related ALS.

SARS-CoV-2, the coronavirus strain that initiated the COVID-19 pandemic, and its subsequent variants present challenges to vaccine development and treatment. As the coronavirus evades the host innate immune response at the initial stage of infection, the disease can have a long nonsymptomatic period. The uridylate-specific endoribonuclease Nsp15 processes the viral genome for replication and cleaves the polyU sequence in the viral RNA to interfere with the host immune system. This study screened natural compounds in vitro to identify inhibitors against Nsp15 from SARS-CoV-2. Three natural compounds, epigallocatechin gallate (EGCG), baicalin, and quercetin, were identified as potential inhibitors. Potent antiviral activity of EGCG was confirmed in plaque reduction neutralization tests with a SARS-CoV-2 strain (PRNT50 = 0.20 μM). Because the compound has been used as a functional food ingredient due to its beneficial health effects, we theorize that this natural compound may help inhibit viral replication while minimizing safety issues.