Potent Activity Research Articles

A Diazeniumdiolate Signal in Pseudomonas syringae Upregulates Virulence Factors and Promotes Survival in Plants.

Pseudomonas syringae infects a wide variety of crops. The mangotoxin-generating operon (mgo) is conserved across many P. syringae strains and is responsible for producing an extracellular chemical signal, leudiazen. Disruption of the mgoA gene in P. syringae pv. syringae (Pss) UMAF0158 alleviated tomato chlorosis caused by this bacterium. We showed that deletion of the entire mgo reduced Pss UMAF0158 population in tomato leaflets. Leudiazen restored the signaling activity of the deletion mutant at a concentration as low as 10 nM. Both the diazeniumdiolate and isobutyl groups of leudiazen are critical for this potent signaling activity. Transcriptional analysis showed that mgo and leudiazen induce the expression of mangotoxin biosynthetic operon as well as an uncharacterized gene cluster, RS17235-RS17245. We found that this cluster enhances the survival of Pss UMAF0158 in planta and is widely distributed in P. syringae strains. Our results demonstrate that mgo plays prominent roles in the virulence and growth of P. syringae. The mgo and mgo-like signaling systems in different bacteria likely regulate diverse microbe-host interactions. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Synergistic fermentation of Cordyceps militaris and herbal substrates boosts grower pig antioxidant and immune function

BackgroundPathogenic infections can significantly impact the health of livestock. Traditionally, antibiotic growth promoters (AGPs) have been used in feed to enhance growth performance and disease control. However, concerns regarding antibiotic resistance have led to the exploration of traditional herbal medicine as a natural alternative, guided by the principle of medicine-food homology. The Taguchi method was employed to optimize the culture formula for cordycepin production, an active component of Cordyceps militaris (C. militaris). The influences of C. militaris supplementing solid-state fermentation (CMSSF) in feed on the growth performance and immune responses of grower pigs were evaluated in the present study.ResultsThe C. militaris ethanol extract (CME) displayed potent free radical scavenging activity against 2, 2-Diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) after undergoing fermentation. Additionally, the antibacterial testing revealed that CME effectively inhibits the growth of common pig pathogens such as Glaesserella parasuis, Pasteurella multocida, Staphylococcus hyicus, and Streptococcus suis. In lipopolysaccharide (LPS)-treated intestinal porcine enterocyte cell line (IPEC-J2), CME significantly suppressed the production of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-6. In addition, higher antioxidative activity was detected as indicated by elevated concentration of superoxide dismutase (SOD) in pig serum. The levels of immunoglobulin M (IgM), IgA, and IgG antibodies, as well as classical swine fever virus (CSFV) antibodies (S/P ratio) in serum were all increased. Growth performance of pigs fed with dietary CMSSF supplementation was improved in comparison with the control.ConclusionsResults demonstrated that CMSSF has the potential to be used as a natural growth promoter to enhance immunity, antioxidation, as well as overall health and growth performance of grower pigs.

Hybrid poly(lactide-co-glycolide) membranes incorporated with Doxycycline-loaded copper-based metal–organic nanosheets as antibacterial platforms

The rise of antimicrobial resistance necessitates innovative strategies to combat persistent infections. Metal-organic frameworks (MOFs) have attracted significant attention as antibiotic carriers due to their high drug loading capacity and structural adaptability. In particular, 2D MOF nanosheets are emerging as a notable alternative to their traditional 3D relatives due to their remarkable advantages in enhanced surface area, flexibility and exposed active region properties. Herein, we synthesized 2D copper 1,4-benzendicarboxylate (CuBDC) nanosheets and utilized them as a carrier and controlled release system for Doxycycline (Doxy@CuBDC), for the first time. The Doxy@CuBDC nanosheets were subsequently incorporated into Poly(lactic-co-glycolic acid) (PLGA) electrospun membranes (Doxy@CuBDC/PLGA). The resultant bioactive fibrous membranes exhibited double-barrier controlled release properties, extending the Doxy release up to ∼9 d at pH 7.4 and 5.5. Significant inhibitory effects againstStaphylococcus aureusandEscherichia coliwere observed. The morphological analyses revealed the deformed bacterial cell structures on Doxy@CuBDC/PLGA membranes that indicates potent bactericidal activity. Furthermore, cytotoxicity assays demonstrated the non-toxic nature of the fabricated membranes, underscoring their potential use for biomedical applications. Overall, the hybrid antibacterial PLGA membranes present a promising strategy for combating microbial infections while maintaining biocompatibility and offer a versatile approach for biomedical material design and surface coatings (e.g. wound dressings, implants).

Evaluating the Anti-inflammatory Efficacy of a Novel Bipyrazole Derivative in Alleviating Symptoms of Experimental Colitis.

This aims to assess the efficacy of 2', 3, 3, 5'-Tetramethyl-4'-nitro-2'H-1, 3'-bipyrazole (TMNB), a novel compound, in colitis treatment. Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with limited effective treatments available. The exploration of new therapeutic agents is critical for advancing treatment options. To assess the effect of TMNB in alleviating symptoms of experimental colitis in mice and to compare its effectiveness with that of sulfasalazine, a standard treatment. Experimental colitis was induced in mice, which were subsequently treated with TMNB at dosages of 50, 100, and 150 mg/kg. The outcomes were evaluated based on colitis symptoms, Colon damage, Disease Activity Index (DAI) scores, and inflammation markers, including nitric oxide (NO) and myeloperoxidase (MPO) levels. Additional assessments included spleen cell proliferation, pro-inflammatory cytokine production (TNF-α, IL-6, IL-1β), and inflammatory genes expression (IL-1β, IL-6, TNF-α, COX2, and iNOS). TMNB treatment significantly alleviated colitis symptoms (100 and 150 mg/kg). These higher doses notably reduced colonic damage, inflammation, hyperemia, edema, and ulceration (p<0.01). The treatment also effectively decreased Disease Activity Index (DAI) scores, demonstrating a marked improvement in clinical signs of colitis (100 mg/kg, p<0.05; 150 mg/kg, p<0.01). Additionally, TMNB substantially lowered myeloperoxidase (MPO) levels, indicating reduced neutrophil activity and inflammation (100 mg/kg, p<0.05; 150 mg/kg, p<0.01), and nitric oxide (NO) levels, suggesting diminished oxidative stress (100 mg/kg, p<0.05; 150 mg/kg, p<0.01). The treatment also led to a significant reduction in spleen cell proliferation (100 mg/kg, p<0.05; 150 mg/kg, p<0.01) and pro-inflammatory cytokine levels, with TNF-α, IL-1β, and IL-6 all showing decreases comparable to those observed with sulfasalazine (p<0.01). Moreover, TMNB effectively downregulated IL-1β, IL-6, TNF-α, COX2, and iNOS (p<0.01), affirming its broad-spectrum anti-inflammatory and immunomodulatory effects. TMNB exhibits potent anti-inflammatory and immunomodulatory activities, suggesting that TMNB could be a new therapeutic agent for managing inflammatory bowel disease. This study supports the need for further clinical trials to explore TMNB's efficacy and safety in human subjects.

Design, Synthesis and Bioactivity of Benzyl Propiolates with Broad-Spectrum Inhibition Activity on Phytopathogenic Fungi.

As part of our continuing research on propiolic acid derivatives, a series of benzyl propiolate derivatives and analogues were designed, synthesized, and investigated for inhibition activity in vitro and in vivo on phytopathogenic fungi, structure-activity relationship (SAR) and action mechanism. The results showed that most of the compounds had potent and broad-spectrum antifungal activity in vitro at 50 μg/mL. Among the compounds, 2-bromobenzyl propiolate (3h) displayed the highest comprehensive activity with total activity index (TAI) of 4.57 against all the eight test fungi followed by 3-fluorobenzyl propiolate (3c) (TAI = 4.53), superior to positive fungicides thiabendazole (TAI < 4.12) and/or azoxystrobin (TAI < 2.90). Relative to the other fungi, Fusarium solani and Fusarium graminearum revealed higher total susceptibility indexes (TSI) of 11.1 and 8.98, respectively, for all compounds. 3h and 3g (4-chlorobenzyl propiolate) gave the smallest EC50 values of 0.86 and 0.67 μg/mL against F. solani and F. graminearum, respectively, superior or comparable with thiabendazole and azoxystrobin. As a representative, 3h at 200 μg/mL displayed 100% protection on F. solani infections on potatoes over 7 days and high safety for plant growth. In antifungal mechanism, 3h was able to change mycelial morphology, destroy the structures of both hypha and cell membrane, increase the intracellular ROS level, decrease the intracellular mitochondrial membrane potential level, and change the permeability of the cell membrane. The SAR showed that ethynyl is a key group for the activity, and the presence of halogen atoms at the 2-site of the benzene ring can significantly improve the activity in most cases. Thus, benzyl propiolate can be considered a novel antifungal lead compound, while 3h can be considered a promising fungicide candidate to develop new agricultural fungicides.

Design, Synthesis, and Antifungal Evaluation of Novel Cuminic Acid Derivatives as Potential Laccase Inhibitors.

In search of novel natural product-based fungicides, 49 cuminic acid derivatives were designed, synthesized, and screened for their in vitro antifungal effects toward seven phytopathogenic fungi and oomycetes. Consequently, several derivatives exhibited strong antifungal activities toward Fusarium graminearum, Botryosphaeria dothidea, and Valsa mali. Among them, compound 2b exhibited the most potent antifungal activity toward B. dothidea (EC50 = 0.96 mg/L), more powerful than chlorothalonil. The in vivo assay against B. dothidea found that the protective and curative effects of 2b were comparable to chlorothalonil. Meanwhile, SEM and TEM observations indicated that 2b could ruin the integrity of mycelial morphology and organelles of B. dothidea. Preliminary mechanism research showed that 2b increased the cell membrane permeability and intracellular ROS level, as well as conspicuously decreased the mycelial dry weight and cell wall chitin contents of B. dothidea. The phytotoxicity test revealed that 2b showed good safety on seeds of mung bean and radish. The in vitro laccase inhibitory activity assay and molecular docking study demonstrated that 2b could be a promising laccase inhibitor. This type of cuminic acid hydrazide derivative would provide valuable inspiration for developing novel fungicides against B. dothidea.

Cyclopeptide Avellanins D-O with Antimalarial Activity from the Mariana Trench Anemone-Derived Hamigera ingelheimensis MSC5.

Marine microorganisms are a treasure trove of natural products, especially those in extreme marine environments, which may produce novel natural products. Herein, biosynthetic gene cluster analysis combined with an integrated metabolomic strategy incorporating matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS), nuclear magnetic resonance (NMR), and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) based Global Natural Products Social Molecular Networking (GNPS) was used to discover new compounds from the Mariana trench anemone-derived fungus Hamigera ingelheimensis MSC5. As a result, 12 new cyclic pentapeptides, avellanins D-O (1-12), were isolated, together with a known cyclic pentapeptide avellanin C (13). All the structures and absolute configurations were elucidated using NMR, mass spectrometry, X-ray diffraction analysis, and Marfey's method. A plausible biosynthetic pathway for the avellanins was proposed based on the gene cluster analysis of H. ingelheimensis MSC5. Bioassay revealed that compound 6 exhibited potent antimalarial activity with an IC50 value of 0.19 ± 0.09 μM.

Discovery of Novel Coumarin Pleuromutilin Derivatives as Potent Anti-MRSA Agents.

Treating methicillin-resistant Staphylococcus aureus (MRSA) infection remains one of the most difficult challenges in clinical practice, primarily due to the resistance of MRSA to multiple antibiotics. Therefore, there is an urgent need to develop novel antibiotics with high efficacy and low cross-resistance rates. In this study, a series of novel pleuromutilin derivatives with coumarin structures were synthesized and subsequently assessed for their biological activities. Most of these derivatives showed potent antimicrobial activity against drug-resistant Gram-positive bacterial strains. Compound 14b displayed particularly rapid bactericidal effects, slow resistance development, and low cytotoxicity. Moreover, it decreased bacterial loads in the lung, liver, kidney, spleen, and heart and exhibited better antibacterial efficacy (ED50 = 11.16 mg/kg) than tiamulin (ED50 = 28.93 mg/kg) in a mouse model of systemic MRSA infection. Both in vitro and in vivo analyses suggest that compound 14b is a promising agent for the treatment of MRSA infections.

A generative artificial intelligence approach for antibiotic optimization.

Antimicrobial resistance (AMR) poses a critical global health threat, underscoring the urgent need for innovative antibiotic discovery strategies. While recent advances in peptide design have yielded numerous antimicrobial agents, optimizing these molecules experimentally remains challenging due to unpredictable and resource-intensive trial-and-error approaches. Here, we introduce APEX Generative Optimization (APEX GO ), a generative artificial intelligence (AI) framework that integrates a transformer-based variational autoencoder with Bayesian optimization to design and optimize antimicrobial peptides. Unlike traditional supervised learning approaches that screen fixed databases of existing molecules, APEX GO generates entirely novel peptide sequences through arbitrary modifications of template peptides, representing a paradigm shift in peptide design and antibiotic discovery. Our framework introduces a new peptide variational autoencoder with design and diversity constraints to maintain similarity to specific templates while enabling sequence innovation. This work represents the first in vitro and in vivo experimental validation of generative Bayesian optimization in any setting. Using ten de-extinct peptides as templates, APEX GO generated optimized derivatives with enhanced antimicrobial properties. We synthesized 100 of these optimized peptides and conducted comprehensive in vitro characterizations, including assessments of antimicrobial activity, mechanism of action, secondary structure, and cytotoxicity. Notably, APEX GO achieved an outstanding 85% ground-truth experimental hit rate and a 72% success rate in enhancing antimicrobial activity against clinically relevant Gram-negative pathogens, outperforming previously reported methods for antibiotic discovery and optimization. In preclinical mouse models of Acinetobacter baumannii infection, several AI-optimized molecules-most notably derivatives of mammuthusin-3 and mylodonin-2-exhibited potent anti-infective activity comparable to or exceeding that of polymyxin B, a widely used last-resort antibiotic. These findings highlight the potential of APEX GO as a novel generative AI approach for peptide design and antibiotic optimization, offering a powerful tool to accelerate antibiotic discovery and address the escalating challenge of AMR.

Systems biology and molecular modeling assisted exploration of the underlying mechanism of Safflower (Carthamus tinctorius L.) in the treatment of hearing loss

Hearing loss is the incapability to hear sound, either partially or fully. One potential natural remedy for hearing loss is the use of Carthamus tinctorius, commonly known as safflower, contains bioactive compounds, including flavonoids, phenolic acids, and terpenoids, which possess potent antioxidant and anti-inflammatory activities. This study uses network pharmacology to identify the potential therapeutic effects of these compounds on hearing loss. We identified 17 active compounds of C. tinctorius with favorable ADME properties through a litrature search. Potential targets for these compounds were found using databases like STITCH and Swiss Target Prediction, as well as the GeneCards database to retrieve hearing loss-related potential targets. A Venn diagram was drawn to determine shared targets, and GO enrichment and KEGG pathways analysis of 64 key targets were conducted DAVID database. Protein-protein interactions (PPIs) were analyzed via STRING database, and a compound-target-pathway network was created in Cytoscape. Molecular docking studies focused on one hub gene, namely, tumor necrosis factor (TNF) revealing that C. tinctorius’s compounds have high affinity for TNF, suggesting a potential therapeutic link to hearing loss. Finally, molecular dynamics simulations and calculations of binding free energy showed TNF_Beta Sitosterol and TNF_Campesterol were more stable than TNF_Cholesterol. Our findings indicate that C. tinctorius may have therapeutic potential for hearing loss by targeting key genes and pathways. However, further in-vivo and in-vitro studies are needed to confirm these findings and determine optimal treatment parameters.

Dimer-monomer transition defines a hyper-thermostable peptidoglycan hydrolase mined from bacterial proteome by lysin-derived antimicrobial peptide-primed screening.

Phage-derived peptidoglycan hydrolases (i.e. lysins) are considered promising alternatives to conventional antibiotics due to their direct peptidoglycan degradation activity and low risk of resistance development. The discovery of these enzymes is often hampered by the limited availability of phage genomes. Herein, we report a new strategy to mine active peptidoglycan hydrolases from bacterial proteomes by lysin-derived antimicrobial peptide-primed screening. As a proof-of-concept, five peptidoglycan hydrolases from the Acinetobacter baumannii proteome (PHAb7-PHAb11) were identified using PlyF307 lysin-derived peptide as a template. Among them, PHAb10 and PHAb11 showed potent bactericidal activity against multiple pathogens even after treatment at 100°C for 1 hr, while the other three were thermosensitive. We solved the crystal structures of PHAb8, PHAb10, and PHAb11 and unveiled that hyper-thermostable PHAb10 underwent a unique folding-refolding thermodynamic scheme mediated by a dimer-monomer transition, while thermosensitive PHAb8 formed a monomer. Two mouse models of bacterial infection further demonstrated the safety and efficacy of PHAb10. In conclusion, our antimicrobial peptide-primed strategy provides new clues for the discovery of promising antimicrobial drugs.

The development of growth hormone-releasing hormone analogs: Therapeutic advances in cancer, regenerative medicine, and metabolic disorders.

Growth Hormone-Releasing Hormone (GHRH) and its analogs have gained significant attention for their therapeutic potential across various domains, including oncology, regenerative medicine, and metabolic disorders. Originally recognized for its role in regulating growth hormone (GH) secretion, GHRH has since been discovered to exert broader physiological effects beyond the pituitary gland, with GHRH receptors identified in multiple extrahypothalamic tissues, including tumor cells. This review explores the development of both GHRH agonists and antagonists, focusing on their mechanisms of action, therapeutic applications, and future potential. GHRH agonists have shown promise in promoting tissue regeneration, improving cardiac function, and enhancing islet survival in diabetes. Meanwhile, GHRH antagonists, particularly those in the MIA and AVR series, demonstrate potent antitumor activity by inhibiting cancer cell proliferation and downregulating growth factor pathways, while also exhibiting anti-inflammatory properties. Preclinical studies in models of lung, prostate, breast, and gastrointestinal cancers indicate that GHRH analogs could offer a novel therapeutic approach with minimal toxicity. Additionally, GHRH antagonists are being investigated for their potential in treating neurodegenerative diseases and inflammatory conditions. This review highlights the versatility of GHRH analogs as a promising class of therapeutic agents, poised to impact multiple fields of medicine.

Protocatechuic acid relieves ferroptosis in hepatic lipotoxicity and steatosis via regulating NRF2 signaling pathway

Ferroptosis represents a newly programmed cell death, and the process is usually accompanied with iron-dependent lipid peroxidation. Importantly, ferroptosis is implicated in a myriad of diseases. Recent literature suggests a potential position of ferroptosis in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD), the most widespread liver ailment worldwide. Intriguingly, several functional genes and metabolic pathways central to ferroptosis are regulated by nuclear factor erythroid-derived 2-like 2 (NRF2). In current work, we aim to identify protocatechuic acid (PCA), a primary metabolite of antioxidant polyphenols, as a potent NRF2 activator and ferroptosis inhibitor in the hepatic lipotoxicity and steatosis models. Herein, both NRF2+/+ and NRF2−/− cell lines and mice were used to analyze the importance of NRF2 in PCA function, and hepatic lipotoxicity and steatosis models were induced by palmitic acid and high-fat diet respectively. Our results indicated that ferroptosis was mitigated by PCA intervention in hepatic cells. Furthermore, PCA exhibited therapeutic efficacy against ferroptosis, as well as hepatic lipotoxicity and steatosis. The protective role of PCA was predominantly mediated through NRF2 activation, potentially elucidating a pivotal mechanism underlying PCA's therapeutic impact on MAFLD. Additionally, the augmented mitochondrial TCA cycle activity observed in hepatic lipotoxicity and steatosis models was ameliorated by PCA, in part via NRF2-dependent pathways, further bolstering PCA's anti-ferroptosis properties. Collectively, our findings underscore PCA’s potential in alleviating hepatic ferroptosis, lipotoxicity and steatosis via inducing activation of NRF2 signaling pathway, offering a promising strategy for the therapy of MAFLD as well as related lipid metabolic disorders.

Therapeutic Potential of Rare Sesterterpenoids from Aspergillus Variecolor Strain SDG and Docking Studies.

Ethyl acetate extract of the cultures of the soil-derived filamentous fungus, Aspergillus variecolor SDG strain from Nallamala forest resulted in the isolation of extremely rare sesterterpenoids, stellatic acid (1) and andilesin C (2). We report a thorough chemical characterization of these compounds using various spectroscopic techniques and evaluation of their in vitro preclinical therapeutic potential. Stellatic acid exhibits potent antioxidant activity with an IC50 of 38 μg/mL and significant anticancer activity against HeLa, HepG2, MCF7, and A549 cancer cell lines with an IC50 of 7-12 μM. On the other hand, andilesin C displayed moderate cytotoxicity against DU145 and B16F10 cancer cell lines but lacked antioxidant activity. Furthermore, the potential hypoglycemic property of stellatic acid was evaluated by measuring its inhibitory effect against α-glucosidase. It exhibited tenfold potency against yeast α-glucosidase (IC50 101.73 μg/mL) than mammalian α-glucosidase (IC50 1000.00 μg/mL). Docking studies were also performed to suggest the interaction mode of stellatic acid in the α-glucosidase enzyme active site. Notably, yeast α-glucosidase shows a higher affinity towards stellatic acid than mammalian α-glucosidase (3TOP). Thus, the in vitro preclinical study of stellatic acid suggests its potential efficacy in therapeutic drug development.

Design and synthesis of camphor-thiazole derivatives as potent antifungal agents: structure-activity relationship and preliminary mechanistic study.

Plant pathogenic fungi pose a severe threat to crop yield and food security. This study aims to investigate the potential antifungal activity and mechanism of action of camphor-thiazole derivatives against six plant pathogenic fungi. A novel series of camphor-thiazole derivatives were designed, synthesized and evaluated for their antifungal effects against Rhizoctonia solani, Fusarium graminearum, Valsa mali, Alternaria solani, Colletotrichum orbiculare and Botryitis cinerea. Most of the synthesized camphor-thiazole derivatives exhibited notable antifungal activity. Amongst them, compounds C5, C10 and C17 showed significant activity against R. solani with median effective concentrations (EC50) values in the range 3-4 μg mL-1, demonstrating superior antifungal efficacy to the control drug boscalid (EC50 = 1.23 μg mL-1). Structure-activity relationship and density functional theory analysis emphasized the critical role of substituent selection in optimizing the biological activity of these compounds. Moreover, preliminary mechanistic studies revealed that compound C5 induced abnormal mycelial and cellular morphology in R. solani as observed using scanning and transmission electron microscopy, and triggered the production and accumulation of reactive oxygen species. Additionally, the increased concentration of C5 resulted in enhanced cell membrane permeability. In this study, the designed and optimized compound C5 emerged as a promising candidate for potent antifungal agents. The results demonstrate that synthesized camphor-thiazole derivatives possess potent antifungal activity and can serve as lead compounds for further optimization in antifungal agent development. © 2024 Society of Chemical Industry.

Antioxidant and neuroprotective potential of extracts from Hass avocado peel obtained through a biorefinery process: A sustainable strategy for the valorization of agro-food waste

This study presents a novel three-step biorefinery approach for extracting bioactive compounds from Hass avocado (Persea americana, Mill.) epicarp. By sequentially using supercritical CO2, CO2-expanded ethanol, and subcritical water, we efficiently recovered a diverse range of extracts with distinct phytochemical profiles and potent biological activities. Our innovative extraction strategy outperformed conventional methods, demonstrating the potential of biorefinery for sustainable valorization of agricultural byproducts. Medium and high extracts exhibited strong antioxidant and anticholinesterase activity. For example, the CO2-expanded ethanol extracts demonstrated an ABTS radical cation scavenging capacity of 3.01 ± 0.06 mmol Trolox equivalents/g and an SC50 value of 53.4 ± 1.2 μg/mL for anticholinesterase activity. These findings highlight the feasibility of integrating biorefinery processes into circular economy initiatives to create high-value bioproducts while minimizing waste.

Unlocking the wound-healing potential: An integrative in silico proteomics and in vivo analysis of Tacorin, a bioactive protein fraction from Ananas comosus (L.) Merr. Stem

Tacorin, a bioactive protein fraction derived from pineapple stem (Ananas comosus), has emerged as a promising therapeutic agent for wound healing. This study employs an integrated approach, combining in silico proteomics and in vivo investigations, to unravel the molecular mechanisms underlying Tacorin's wound healing properties. In the domain of in silico proteomics, the composition of Tacorin is elucidated through LC/MS-MS protein sequencing, revealing ananain (23.77 kDa) and Jacalin-like lectin (14.99 kDa) as its predominant constituents. Molecular protein-protein docking simulations unveil favorable interactions between Tacorin's components and key regulators of wound healing, including TGF-β, TNF-α, and MMP-2. The calculated free binding energies indicate strong binding affinities between Tacorin proteins and their target receptors. Specifically, ananain demonstrates a binding affinity of −12.2 kcal/mol with TGF-β, suggesting its potential as a potent activator of TGF-β-mediated signaling, while Jacalin-like lectin exhibits the most favorable binding affinity of −8.7 kcal/mol with TNF-α. Subsequent 100 ns molecular dynamics (MD) simulations provide insights into the dynamic behavior and stability of Tacorin-receptor complexes, shedding light on the molecular determinants of Tacorin's therapeutic effects. Complementing the in silico analyses, in vivo studies evaluate Tacorin's efficacy in wound healing using skin and uterine incision models. Tacorin treatment accelerates wound closure and promotes tissue repair in both models, as evidenced by macroscopic observations and histological assessments. Overall, this study provides compelling evidence of Tacorin's therapeutic potential in wound healing and underscores the importance of elucidating its molecular mechanisms for further development and clinical translation.

Evaluation of Fifteen 5,6-Dihydrotetrazolo[1,5-c]quinazolines Against Nakaseomyces glabrata: Integrating In Vitro Studies, Molecular Docking, QSAR, and In Silico Toxicity Assessments

Nakaseomyces glabrata (Candida glabrata), the second most prevalent Candida pathogen globally, has emerged as a major clinical threat due to its ability to develop high-level azole resistance. In this study, two new 5,6-dihydrotetrazolo[1,5-c]quinazoline derivatives (c11 and c12) were synthesized and characterized using IR, LC-MS, 1H, and 13C NMR spectra. Along with 13 previously reported analogues, these compounds underwent in vitro antifungal testing against clinical N. glabrata isolates using a serial dilution method (0.125–64 mg/L). Remarkably, compounds c5 and c1 exhibited potent antifungal activity, with minimum inhibitory concentrations of 0.37 μM and 0.47 μM, respectively—about a 20-fold improvement in μM concentration over standard drugs like amphotericin B, caspofungin, and micafungin. A detailed structure–activity relationship analysis revealed crucial molecular features enhancing antifungal potency. Extensive molecular docking studies across 18 protein targets explored potential binding pockets and affinities of the lead compounds. A robust 3D-QSAR model, incorporating molecular descriptors Mor26m and Mor29e, displayed good predictive ability for antifungal activity. In silico predictions indicated an absence of herbicidal effect, negligible environmental toxicity (to honeybees, avian species, and aquatic organisms), and mild human toxicity concerns for these compounds. This comprehensive approach aims to develop novel and effective antifungal compounds against the clinically relevant pathogen N. glabrata.

Novel conditioning and prophylaxis regimens for relapse prevention.

The last 20 years witnessed relevant clinical advancements in the field of hematopoietic cell transplantation (HCT) for leukemia patients. The introduction of novel conditioning regimens, a better prophylaxis and management of graft- versus-host disease, and an ameliorated posttransplant support system improved safety and, therefore, outcomes. On the other hand, leukemia relapse remains the major cause of allogeneic HCT failure. Efforts have been made to understand the mechanisms of leukemia relapse, and new insights that clarify how donor immunity exerts graft-versus- leukemia (GVL) activity are available. Such studies set the base to design novel transplant strategies that can improve disease control. In our review we begin by discussing the most relevant criteria to choose a donor that provides a strong GVL effect. We also report some of the novel conditioning regimens that aim to deliver and extend myeloablation in order to reduce the disease burden at time of graft infusion. Finally, we discuss how the graft can be manipulated to limit the use of immune suppression and ensure potent antileukemic activity.

Structure-Activity Relationship Study of Splicing Modulators on Hsh155/SF3B1 through Chemical Synthesis and Yeast Genetics.

Meayamycins are synthetic analogs of the natural product FR901464 and exhibit potent anticancer activity against human cancers. They bind SF3B1 and PHF5A, components of the human spliceosome, and they alter pre-mRNA splicing. Detailed analysis of the active site led us to investigate a narrow pocket within the binding site that surrounds the α,β-unsaturated amide portion of meayamycin. We describe the synthesis and biological activity of two new analogs bearing a methyl substituent on the α or β position of the amide. With these analogs, we investigated the discrete interactions within the narrow region of SF3B1 using a human/yeast chimeric SF3B1 protein and found that the V1078 residue of SF3B1 affects compound binding at the amide moiety.