Complete Growth Inhibition Research Articles

Combining the Powerful Antioxidant and Antimicrobial Activities of Pomegranate Waste Extracts with Whey Protein Coating-Forming Ability for Food Preservation Strategies

Different solvents water, ethanol and ethanol/water (6:4 v/v), were compared in the extraction of pomegranate peels and seeds (PPS) in terms of recovery yields, antioxidant properties, and antimicrobial action against typical spoilage bacterial and fungal species. The best performing extract (ethanol/water (6:4 v/v) was shown to contain mostly ellagic acid and punicalagin as phenolic compounds (5% overall) and hydrolysable tannins (16% as ellagic acid equivalents) and was able to inhibit the growth of the acidophilic Alicyclobacillus acidoterrestris at a concentration as low as 1%. The preservation of the organoleptic profile of A. acidoterrestris-inoculated apple juice with extract at 1% over 20 days was also observed thanks to the complete inhibition of bacterial growth, while the extract at 0.1% warranted a significant (40%) inhibition of the enzymatic browning of apple smoothies over the first 30 min. When incorporated in whey proteins’ isolate (WPI) at 5% w/w, the hydroalcoholic extract conferred well appreciable antioxidant properties to the resulting coating-forming hydrogel, comparable to those expected for the pure extract considering the amount present. The WPI coatings loaded with the hydroalcoholic extract at 5% were able to delay the browning of cut fruit by ca. 33% against a 22% inhibition observed with the sole WPI. In addition, the functionalized coating showed an inhibition of lipid peroxidation of Gouda cheese 2-fold higher with respect to that observed with WPI alone. These results open good perspectives toward sustainable food preservation strategies, highlighting the potential of PPS extract for the implementation of WPI-based active packaging.

EXTH-22. TARGETING MITOCHONDRIAL PROTEASE IN DIFFUSE GLIOMAS

Abstract BACKGROUND Targeting mitochondrial function has emerged as a promising therapeutic strategy in cancer treatment. TR107 is characterized as a specific activator of caseinolytic protease proteolytic subunit (ClpP) in the mitochondria, potentially affecting oncogenic pathways. Here, we investigated the effects of TR107 on adult malignant gliomas, IDH-wildtype and IDH-mutant METHODS We utilized patient-derived glioma cells to determine the efficacy of TR107 with cell viability, proliferation, cell cycle, and apoptosis assays. Immunofluorescent staining and electron microscopy (EM) were employed to uncover organelle morphological changes upon treatment. Mitochondrial function and ATP production were assessed in live cells utilizing Seahorse analysis. Global proteomics and RNA sequencing were performed to identify treatment-induced dysregulated pathways in glioma cells RESULTS Both IDH-wildtype and IDH-mutant glioma cell lines were highly sensitive to TR107, showing at least 100 times lower IC50 compared to the related compound ONC201. Genetic knock out of ClpP revealed that the growth inhibitory effects of TR107 are ClpP-dependent. Interestingly, IDH-mutant cell lines showed a more profound disintegration of mitochondrial morphology and dysregulation of mitochondrial function evidenced by an enhanced suppression of oxidative phosphorylation, mitochondrial complexes expression, mtDNA copy number, complex I activity, and ATP production, compared to IDH-wildtype cells. Six days of treatment with TR107 led to a complete inhibition of cell growth and up to 97% of cell death in IDH-mutant cells, while 50% of IDH-wildtype cells remained viable. Western blot, EM, and RNAsequencing analyses uncovered autophagy as a potential pro-survival mechanism in IDH-wildtype cells. Importantly, multiple metabolic and DNA repair-related pathways were affected by the treatment, suggested by global proteomics and RNA sequencing. Finally, TR107 was not affected by ABC transporters, supporting its potential use in brain tumor patients CONCLUSION TR107 demonstrated potent cytotoxic effects in patient-derived glioma cells by disrupting mitochondrial structural and functional integrity. TR107 efficacy in vivo is under investigation.

Capivasertib augments chemotherapy via Akt inhibition in preclinical small cell lung cancer models.

Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer for which platinum-based chemotherapy is the standard of care. Despite an initial response to this therapy, patients eventually develop resistance to the chemotherapy. To investigate the potential of capivasertib, an approved drug for advanced breast cancer, to enhance the efficacy of cisplatin in preclinical SCLC models and explore the underlying mechanisms. SCLC cell lines were treated with capivasertib and cisplatin, alone or in combination, to assess cell viability, proliferation, colony formation, and apoptosis. Next, capivasertib's effects, alone and combined with cisplatin, were evaluated in an SCLC mouse model. Mechanistic studies focused on Akt and MYC signaling, with constitutively active Akt overexpression used to assess its role. Capivasertib is active against a panel of SCLC cell lines regardless of cellular origin and genetic profiling with IC50 at a clinically achievable range. Particularly, capivasertib inhibits proliferation and anchorage-independent colony formation and induces apoptosis in SCLC cells. It significantly augments cisplatin's inhibitory effects in all tested cell lines. Importantly, capivasertib at a non-toxic dose is effective in delaying SCLC growth in mice and its combination with cisplatin achieves nearly complete tumor growth inhibition. Mechanistic studies confirm that capivasertib inhibits Akt and MYC signaling, and furthermore, that overexpression of constitutively active Akt reversed anti-SCLC activity of capivasertib. Our work is the first to reveal that Akt inhibition can augment chemotherapy in SCLC, and capivasertib is a useful addition to the treatment armamentarium for SCLC.

Chitosan-Zinc-Ligated Hydroxychloroquine: Molecular Docking, Synthesis, Characterization, and Trypanocidal Activity against Trypanosoma evansi

The existing treatments against Trypanosoma evansi are faced with several drawbacks, such as limited drug options, resistance, the relapse of infection, toxicity, etc., which emphasizes the necessity for new alternatives. We synthesized novel metal-based antiparasitic compounds using chitosan, hydroxychloroquine (HC), and ZnO nanoparticles (NPs) and characterized them for size, morphology, chemical interactions, etc. Molecular docking and protein interaction studies were performed in silico to investigate the inhibitory effects of HC, zinc-ligated hydroxychloroquine (HCZnONPs), and chitosan-zinc-ligated hydroxychloroquine (CsHCZnONPs) for two key proteins, i.e., heat shock protein 90 (Hsp90) and trypanothione reductase associated with T. evansi. In vitro trypanocidal activity and the uptake of zinc ions by T. evansi parasites were observed. The formulation was successfully synthesized, as indicated by its size, stability, morphology, elemental analysis, and functional groups. CsHCZnO nanoparticles strongly inhibit both Hsp90 and trypanothione reductase proteins. The inhibition of Hsp90 by these nanoparticles is even stronger than that of trypanothione reductase when compared to HC and HCZnONPs. This suggests that the presence of polymer chitosan enhances the nanoparticles’ effectiveness against the parasite. For the first time, CsHCZnO nanoparticles exhibited trypanocidal activity against T. evansi, with complete growth inhibition being observed at various concentrations after 72 h of treatment. Fluorescent microscopy using FluoZin-3 on T. evansi culture confirmed the presence of zinc on the surface of parasites. This innovative approach has shown promising results in the quest to develop improved antiparasitic compounds against T. evansi with enhanced effectiveness and safety, highlighting their potential as therapeutic agents against trypanosomiasis.

Enhancing Antibiotic Efficacy with Natural Compounds: Synergistic Activity of Tannic Acid and Nerol with Commercial Antibiotics against Pathogenic Bacteria

The search for synergies between natural products and commercial antibiotics is a promising strategy against bacterial resistance. This study determined the antimicrobial capacity of Nerol (NE) and Tannic Acid (TA) against 14 pathogenic bacteria, including ESKAPE pathogens. TA exhibited the lowest Minimum Inhibitory Concentrations (MICs) at 162.5 µg/mL against Pasteurella aerogenes and 187.5 µg/mL against Acinetobacter baumannii (WHO priority 1). NE showed its lowest MIC of 500 µg/mL against both Pasteurella aerogenes and Salmonella enterica. A total of 35 combinations of NE and 13 of TA with eight commercial antibiotics were analyzed. For NE, combinations with Streptomycin and Gentamicin were effective against Salmonella enterica, Bacillus subtilis, and Streptococcus agalactiae, with antibiotic MIC reductions between 75.0 and 87.5%. TA showed six synergies with Chloramphenicol, Ampicillin, Erythromycin, and Streptomycin against Acinetobacter baumannii, Streptococcus agalactiae, and Pasteurella aerogenes, with MIC reductions between 75.0 and 93.7%. Additionally, 31 additive effects with antibiotics for NE and 8 for TA were found. Kinetic studies on these synergies showed complete inhibition of bacterial growth, suggesting that natural products enhance antibiotics by facilitating their access to targets or preventing resistance. Given their safety profiles recognized by the EPA and FDA, these natural products could be promising candidates as antibiotic enhancers.

Exploring diflunisal as a synergistic agent against Staphylococcus aureus biofilm formation.

Staphylococcus aureus is a bacterial pathogen of considerable significance in public health, capable of inducing a diverse range of infectious diseases. One of the most notorious mechanisms used by S. aureus to survive and colonize the site of infection is its ability to form biofilms. Diflunisal, a non-steroidal anti-inflammatory drug (NSAID), is a known inhibitor of the Agr system in S. aureus, which is key in regulating biofilm formation. This study evaluated the effect of broad-spectrum antibiotics in combination with diflunisal on S. aureus biofilm density. Eight antibiotics were tested independently at different concentrations and in combination with diflunisal to assess their effect on S. aureus biofilm formation. When using the antibiotics alone and with diflunisal, a significant control effect on biofilm formation was observed (p < 0.05), irrespective of diflunisal presence, but did not achieve a complete biofilm growth inhibition. Over time, diflunisal influenced biofilm formation; however, such an effect was correlated with antibiotic concentration and exposure time. With amikacin treatments, biofilm density increased with extended exposure time. In the case of imipenem, doripenem, levofloxacin, and ciprofloxacin, lower doses and absence of diflunisal showed higher control over biofilm growth with longer exposure. However, in all cases, diflunisal did not significantly affect the treatment effect on biofilm formation. In the absence of antibiotics, diflunisal significantly reduced biofilm formation by 53.12% (p < 0.05). This study suggests that diflunisal could be a potential treatment to control S. aureus biofilms, but it does not enhance biofilm inhibition when combined with antibiotics.

In vitro and in vivo evaluation of tedizolid nanoparticle incorporated buccal films for oromucosal infections

A novel tedizolid phosphate (TZP) nanoparticle (NP)-loaded buccal film formulation was developed for the treatment of buccal wounds infected with S. aureus. TZP-loaded chitosan NPs were produced and characterized to prepare this composite system. The optimum NP formulation was then loaded into mucoadhesive buccal films. The antibacterial effects of the obtained buccal films were evaluated by in vitro and in vivo studies. The optimum TZP-NP formulation (F8) had a particle size of 177.40 ± 2.97 nm and PDI and ZP values were 0.437 ± 0.002 and 33.9 ± 0.5, respectively. In antibacterial efficacy tests, the optimum NP containing buccal film formulation was used, which released approximately 90 % of TZP within 5 h. TZP-NP-loaded buccal films achieved a 3 log10 reduction in S. aureus within just 3 h. It was also administered to Wistar albino rats with S. aureus-infected buccal wounds. As a result of in vivo studies, a significant decrease in the number of S. aureus was detected in wound samples treated with TZP-NP-loaded buccal films. In addition, a complete inhibition of growth was observed on the fifth day of the film application. The current work suggested that the TZP-NP-loaded composite films could be promising candidates for effective and long-acting antibacterial treatment of buccal wounds.

Assessing the effects of allelopathic properties of organic mulches on liverwort control in container-grown ornamentals

Liverwort (Marchantia polymorpha) is a problematic weed in ornamental crop production. The major limitation of liverwort control is lack of herbicide options inside greenhouses and their potential to cause injury. The current research was undertaken to study the effectiveness of allelopathic properties of six different organic mulches including rice hull (RH), cocoa hull (CH), pine bark (PB), maple leaf (ML), shredded cypress (SC), and red hardwood (HW) for liverwort control. Mulch extracts were prepared and used to impregnate agar media at an increasing dose at 1X (2 mL mulch extract), 2X (4 mL), 3X (6 mL), and 4X (8 mL) rates, in a randomized complete block design. Ten liverwort gemmae were transferred to each petri dish and they were maintained inside a growth chamber. The number of gemmae germinating in each petri dish after 1 week and gemmae surviving at the end of 2 weeks was recorded. In greenhouse study, mulch extracts were applied to containers filled with substrate for assessing liverwort control. The mulch extracts or no extract (control) were applied to the containers uniformly at 1X (15 mL), 2X (30 mL), 3X (45 mL) or 4X (60 mL) rates, in a randomized complete block design. The percentage of substrate surface covered by liverwort thalli was visually estimated bi-weekly for 10 weeks. Fresh biomass of the thalli and gemmae cup counts in each pot were also recorded. After 1 week in the growth chamber, ML followed by SC, PB and RH extracts showed maximum suppression of liverwort gemmae germination. At 2 weeks, ML applied at either of the rates provided complete inhibition of liverwort growth. In greenhouse, all the mulch extracts were able to provide complete liverwort control for the first two weeks. All the mulches and rates of applications were significantly different from the control after 6, 8, and 10 weeks. PB and HW mulches showed excellent liverwort control and minimum fresh biomass of liverwort after 10 weeks as compared to other mulches. The allelopathic potential of the organic mulches can be a promising option for biopesticidal control of liverwort and a component of integrated liverwort management.

Comparative in vitro evaluation of fungicides against collar rot pathogen, Sclerotium rolfsii in elephant foot yam

Amorphophallus or elephant foot yam (Amorphophallus paeoniifolius) popularly known as the ‘King of tubers’ is one of the major tuber crops grown in India and other parts of the world. Collar rot disease, caused by Sclerotium rolfsii is one of the primary obstacles to tuber cultivation which can significantly reduce yield up to 100%. Saprophytic nature, broad host range, and ability to produce resting structures make it difficult to manage. In this experiment, 10 isolates of S. rolfsii were isolated by the surveying Thiruvananthapuram, Kollam and Alappuzha districts of Kerala, proved the pathogenicity by inoculating the pathogen cultured in sand- maize meal media (9:1). The isolate I3 obtained from Thiruvananthapuram district was found to be the most virulent based on the days taken for symptom development (4 days). Six fungicides (copper oxy chloride (50% WP), mancozeb (75% WP), propiconazole (25% EC), carbendazim (50% WP), trifloxystrobin (25%) + tebuconazole (50%) 75 WG, and carbendazim (12%) + mancozeb (63%) WP @ 50, 100, 250, 500, 1000 and 2000 ppm were evaluated in vitro for their efficacy in inhibiting the fungal mycelial growth and sclerotia formation in isolate I3. All fungicides except carbendazim 50% WP and copper oxy chloride 50% WP, considerably reduced the mycelial development of S. rolfsii. Mancozeb 75%WP and trifloxystrobin (25%) + tebuconazole (50%) 75WG, showed complete inhibition of mycelial growth even at a lower concentration of 50 ppm.

GC-MS Assisted Determination of 26 Compounds in Phlomis Stewartii Extract Exhibiting Antioxidant, Antifungal, and Antibacterial Properties.

Medicinal plants have long been studied for their therapeutic benifits. The present research aims to unveil complex phytochemical profile and therapeutic properties of ethyl acetate fraction of Phlomis stewartii, an important medicinal plant. In this context, the Gas Chromatography-Mass Spectrometry (GC-MS) analysis of the fraction identified 26 compounds. Additionally, the fraction exhibited concentration dependent antioxidant activity with an IC50 value lower than the standard antioxidant butylated hydroxytoluene. The antifungal activity of the fraction examined against F. oxysporum, A. alternate, and R. solani resulted in almost complete inhibition (>90 %) of fungal growth. Furthermore, the fraction exhibited significant antibacterial potential against B. subtilus, S. aureus, E. coli, and S. dysenteriae, with inhibition zones of 18±0.22, 17±0.22, 12±0.11, and 10±0.12, respectively. Briefly, the plant extract was found to be highly potent, particularly in its antifungal action. Further studies, including natural products isolation coupled with bioassays, are recommended for promising drug candidates discovery.

Two-Stage Screening of Metschnikowia spp. Bioprotective Properties: From Grape Juice to Fermented Must by Saccharomyces cerevisiae.

Gluconobacter oxydans (Go) and Brettanomyces bruxellensis (Bb) are detrimental micro-organisms compromising wine quality through the production of acetic acid and undesirable aromas. Non-Saccharomyces yeasts, like Metschnikowia species, offer a bioprotective approach to control spoilage micro-organisms growth. Antagonist effects of forty-six Metschnikowia strains in a co-culture with Go or Bb in commercial grape juice were assessed. Three profiles were observed against Go: no effect, complete growth inhibition, and intermediate bioprotection. In contrast, Metschnikowia strains exhibited two profiles against Bb: no effect and moderate inhibition. These findings indicate a stronger antagonistic capacity against Go compared to Bb. Four promising Metschnikowia strains were selected and their bioprotective impact was investigated at lower temperatures in Chardonnay must. The antagonistic effect against Go was stronger at 16 °C compared to 20 °C, while no significant impact on Bb growth was observed. The bioprotection impact on Saccharomyces cerevisiae fermentation has been assessed. Metschnikowia strains' presence did not affect the fermentation time, but lowered the fermentation rate of S. cerevisiae. An analysis of central carbon metabolism and volatile organic compounds revealed a strain-dependent enhancement in the production of metabolites, including glycerol, acetate esters, medium-chain fatty acids, and ethyl esters. These findings suggest Metschnikowia species' potential for bioprotection in winemaking and wine quality through targeted strain selection.

Synergistic effects of chitosan and gamma irradiation on enhanced fungal growth inhibition and biodegradability of natural rubber latex film

Developing novel formulations and processes to improve the fungal growth inhibition and biodegradability of NR products has become a major challenge for the scientific community, given the health risks associated with fungi in natural rubber (NR) products and the environmental concerns regarding NR waste. Consequently, this study comprehensively investigated the synergistic effects of chitosan and gamma irradiation on enhancing fungal growth inhibition and biodegradability in natural rubber latex (NRL) films. The research involved incorporating varying chitosan contents (0, 3, 6, or 9 phr) into NRL composites and exposing them to different gamma doses (0, 5, 10, or 15 kGy). The results showed that increasing the chitosan content and the gamma dose improved the ability of the NRL samples to inhibit fungal growth on their surfaces. This was evidenced by the absence of fungal colonies after 7 days of incubation on potato dextrose agar (PDA) plates for NRL samples irradiated at 5–15 kGy with 9 phr of chitosan. This determination was based on isolating fungi from the film surfaces, followed by serial dilution and a viable plate count. The biodegradability tests also revealed that the NRL films irradiated at 15 kGy with 9 phr of chitosan had the highest weight loss, reaching as high as 10.42 ± 0.62 % after soil burial for 8 weeks. However, the results indicated that gamma irradiation on the pristine NRL and chitosan/NRL films did not substantially alter the thermal stabilities, density, morphology, and functional groups of the samples. Lastly, by comparing the tensile properties of all the NRL films to the ASTM D3578-01a standard for examination gloves, the optimum conditions for the NRL films were 5 kGy of gamma irradiation with 9 phr of chitosan. This combination resulted in gloves with sufficient tensile strength and complete fungal growth inhibition.

Exploring the Antifungal Efficacy of Essential Oils against Alternaria solani, the Causative Pathogen of Early Leaf Blight in Tomato Plants

Alternaria solani is an important necrotrophic fungus that is responsible for the early blight disease which is a common disease in tomato fields. In this research, the antifungal activity of essential oils extracted from Satureja hortensis, Thymbra spicata, Thymus sipyleus, Origanum majorana, O. syriacium, O. onites, O. vulgar, Artemisia absinthium, A. santonicum and A. spicigera were tested against Alternaria solani the causative agent of Tomato early blight disease. The study was carried out in two different ways, in vitro and in vivo. In vitro studies were conducted on media mixed with essential oils, and different concentrations of oils were examined on fungal growth in petri dishes. In in vivo studies, the effects of essential oils on the development of disease lesions were evaluated by infecting healthy tomato fruits. The concentrations used in the study were 140, 280, 560 and 1000 µl/L in the in vitro and 2.5, 5, 10 and 20 µl/fruit under in vivo conditions. Among the in vitro trials, the essential oils extracted from Thymus sipyleus and O. onites exhibited the most pronounced antifungal efficacy, achieving complete growth inhibition of the fungal pathogen across all concentrations whereas the essential oils from Artemisia spicigera and A. santonicum displayed relatively lower efficacy compared to the other oils. Conversely, under in vivo conditions, the essential oils derived from O. majorana and A. absinthium demonstrated the greatest capacity to impede the development of disease lesions on the fruit, yielding inhibition rates of 84% and 64% at 2.5 µl per fruit concentrations, respectively. In contrast the essential oils from Artemisia spicigera and A. santonicum had the least effect on the development of the disease, as there was disease lesions appeared even on the fruits that were applied at 20µl/fruit doses. Although most of the essential oils had some degree of antifungal action, still much effort is needed to put on both in vitro and in vivo trials to strength the reliability and consistency of the future related researches.

Repolarizing neutrophils via MnO2 nanoparticle-activated STING pathway enhances Salmonella-mediated tumor immunotherapy

Engineered Salmonella has emerged as a promising microbial immunotherapy against tumors; however, its clinical effectiveness has encountered limitations. In our investigation, we unveil a non-dose-dependent type of behavior regarding Salmonella’s therapeutic impact and reveal the regulatory role of neutrophils in diminishing the efficacy of this. While Salmonella colonization within tumors recruits a substantial neutrophil population, these neutrophils predominantly polarize into the pro-tumor N2 phenotype, elevating PD-L1 expression and fostering an immunosuppressive milieu within the tumor microenvironment. In order to bypass this challenge, we introduce MnO2 nanoparticles engineered to activate the STING pathway. Harnessing the STING pathway to stimulate IFN-β secretion prompts a shift in neutrophil polarization from the N2 to the N1 phenotype. This strategic repolarization remodels the tumor immune microenvironment, making the infiltration and activation of CD8+ T cells possible. Through these orchestrated mechanisms, the combined employment of Salmonella and MnO2 attains the synergistic enhancement of anti-tumor efficacy, achieving the complete inhibition of tumor growth within 20 days and an impressive 80% survival rate within 40 days, with no discernible signs of significant adverse effects. Our study not only unveils the crucial in vivo constraints obstructing microbial immune therapy but also sets out an innovative strategy to augment its efficacy. These findings pave the way for advancements in cell-based immunotherapy centered on leveraging the potential of neutrophils.Graphical

The Antifungal and Inhibitory Effects of Massoia Essential Oil and C10 Massoia Lactone on Mycotoxin Production in Fusarium graminearum KACC 41047

In wheat and barley, Fusarium head blight is mainly caused by Fusarium graminearum, and its control is based on the agricultural practices of not leaving crop residues in the field, growing phytopathogenic fungi-resistant varieties, biological control, and chemical treatment, including using fungicides. Here, we investigated the antifungal and antimycotoxigenic activities of Massoia essential oil (MEO) and C10 Massoia lactone (C10) on Fusarium graminearum KACC 41047. Because DMSO, which was used as a solvent in this study, exhibited antifungal activity at 5% in a fungal growth medium, it was used in the antifungal and antimycotoxigenic experiments at 0.05%. Three assays were used to investigate the antifungal activities of MEO and C10, which exhibited potent antifungal activity in the agar dilution assay, with complete fungal growth inhibition at 100 mg/L. At 5–50 mg/L, MEO and C10 suppressed deoxynivalenol and 15-acetyl-deoxynivalenol production by &gt;50% by downregulating the Tri10 gene, which expresses trichodiene synthase. MEO and C10 might be potent antifungal agents for F. graminearum control with less toxicological concerns because they are GRAS chemicals.

Antimicrobial isoflavans and other metabolites of Dalea nana

The phytochemical investigation of extracts from Dalea nana roots and aerial parts led to the isolation of thirteen phenolic compounds. Three previously undescribed isoflavans, named verdeans A-C (1, 3, and 7), were characterized. Two additional isoflavans (2 and 5) were previously undescribed enantiomers of known compounds. A previously undescribed isoflavone (verdean D, 10) was found, and the known specialized metabolites, isoflavans 4, 6, 8, and 9, isoflavone 11, flavone 12, and a 2-arylbenzofuran 13, were also isolated. All but one (7) of the isoflavans were prenylated. The structures of the previously undescribed compounds were deduced by NMR spectroscopy, supported by HRESI mass spectrometry. The absolute configurations of 1–3, 5, and 7–9 were determined by ECD. Compounds 1, 3, 4, 6, and 8 exhibited in vitro antimicrobial activities, causing complete growth inhibition (MIC) at concentrations between 6.7 and 37.0 μM against Cryptococcus neoformans and between 8.9 and 25.0 μM against methicillin resistant Staphylococcus aureus (MRSA). The most broadly active previously undescribed compound was verdean A (1), with MIC values of 6.7 and 12.9 μM toward C. neoformans and MRSA, respectively, and an MIC of 10.0 μM against the often-intractable C. albicans.

Potent and specific antibiotic combination therapy against Clostridioides difficile.

Keratinicyclins and keratinimicins are recently discovered glycopeptide antibiotics. Keratinimicins show broad-spectrum activity against Gram-positive bacteria, while keratinicyclins form a new chemotype by virtue of an unusual oxazolidinone moiety and exhibit specific antibiosis against Clostridioides difficile. Here we report the mechanism of action of keratinicyclin B (KCB). We find that steric constraints preclude KCB from binding peptidoglycan termini. Instead, KCB inhibits C. difficile growth by binding wall teichoic acids (WTAs) and interfering with cell wall remodeling. A computational model, guided by biochemical studies, provides an image of the interaction of KCB with C. difficile WTAs and shows that the same H-bonding framework used by glycopeptide antibiotics to bind peptidoglycan termini is used by KCB for interacting with WTAs. Analysis of KCB in combination with vancomycin (VAN) shows highly synergistic and specific antimicrobial activity, and that nanomolar combinations of the two drugs are sufficient for complete growth inhibition of C. difficile, while leaving common commensal strains unaffected.

Small Cell Lung Carcinoma Cells Depend on KIF11 for Survival.

Few efficacious treatment options are available for patients with small cell lung carcinoma (SCLC), indicating the need to develop novel therapeutic approaches. In this study, we explored kinesin family member 11 (KIF11), a potential therapeutic target in SCLC. An analysis of publicly available data suggested that KIF11 mRNA expression levels are significantly higher in SCLC tissues than in normal lung tissues. When KIF11 was targeted by RNA interference or a small-molecule inhibitor (SB743921) in two SCLC cell lines, Lu-135 and NCI-H69, cell cycle progression was arrested at the G2/M phase with complete growth suppression. Further work suggested that the two cell lines were more significantly affected when both KIF11 and BCL2L1, an anti-apoptotic BCL2 family member, were inhibited. This dual inhibition resulted in markedly decreased cell viability. These findings collectively indicate that SCLC cells are critically dependent on KIF11 activity for survival and/or proliferation, as well as that KIF11 inhibition could be a new strategy for SCLC treatment.

A bi-adjuvant nanovaccine amplifying STING activation for cancer immunotherapy

The insufficient immune activation and immunosuppressive microenvironment restrict the therapeutic efficacy of cancer vaccines. Herein, we exploited a bi-adjuvant nanovaccine to amplify the activation of the stimulator of interferon genes (STING) for potent and durable anti-tumor immunity. STING agonist (MnO2 nanoparticles), toll-like receptor 9 agonist (CpG), and antigenic proteins or peptides were strategically formulated into nanovaccines (MnC NVs) by a one-step biomineralization method. The nanovaccine efficiently targeted dendritic cells of draining lymph nodes, in which CpG-mediated the stimulation of nuclear factor-kappa B pathway augmented STING signaling. RNA sequencing analysis validated the enhanced expression of relevant genes of type-I interferon signaling pathways. The priming of antigen-specific CD8+ T cells and humoral immune responses led to potent tumor growth inhibition and prolonged survival time in melanoma and human papilloma virus-derived tumor models. MnC NVs were able to synergize with immune checkpoint blockade therapy, with 80 % survival over 40 days in TC-1 tumor model. Moreover, rechallenging of tumor-free mice with homotypic cells resulted in complete tumor growth inhibition, suggesting the generation of a long-term memory effect. The simplified nanovaccine platform provides a safe and robust strategy to boost STING-mediated anti-tumor immunity for personalized cancer immunotherapy, showing significant potential for clinical translation.

Amylolytic Capability and Performance of Probiotic Strains in a Controlled Sorghum Fermentation System

This study aimed to explore the fermentative performance of nine lactic acid bacterial strains with probiotic potential during sorghum fermentation. The strain’s attributes including proliferation counts, pH levels, production of organic acid antibacterial activity, and their ability to break down starch were evaluated during the fermentation period in the presence and absence of glucose as a carbon source. In addition, the inhibitory activity of these potential probiotic strains against pathogenic bacteria (Salmonella typhimurium, Escherichia coli, and Staphylococcus aureus) was examined through a co-culturing technique. The results demonstrated that all 4 Lactobacillus strains exhibited robust growth in both glucose and glucose-free fermentation experiments. Glucose supplementation significantly enhanced lactic acid yield which ranged from 0.19 to 0.44% compared to fermentation without glucose which ranged from 0.04 to 0.29%. The selected Lactobacillus strains effectively lowered the media pH below 4.0 after 24 h, producing substantial lactic acid. Notably, in the absence of glucose, only Lb. helveticus D7 and Lb. amylolyticus D12 achieved pH levels below 4 after 8 h, producing the highest lactic acid amounts of 0.27 and 0.29% after 24 h, respectively. Amylase activity was detected on two strains, D7 and D12. Furthermore, most of the tested Lactobacillus strains demonstrated complete inhibition (6 log to 0 Log CFU/mL) of pathogen growth after 24 h of co-culturing, suggesting their potential for enhancing the safety quality of sorghum-based fermented products.