Search Results (18,794)

MDM2 and MDM4 are major negative regulators of tumor suppressor p53. Beyond regulating p53, MDM2 possesses p53-independent activity in promoting cell cycle progression and tumorigenesis via its RING domain ubiquitin E3 ligase activity. MDM2 and MDM4 form heterodimer polyubiquitin E3 ligases via their RING domain interaction. Inhibitors disrupting p53 interaction with MDM2/MDM4 are in clinical trials in patients bearing wild-type p53 cancers. However, these inhibitors are not designed to work for p53-null/mutant cancer cells. Owing to the importance of the E3 ligase of MDM2 in its p53-independent oncogenic activity, inhibitors targeting the E3 ligase activity of MDM2-MDM4 are desirable for p53-mutant cancer cells. Here, we report the development of such inhibitors with pro-apoptotic activity in p53-null leukemic cells. Among analogues of MDM2-MDM4 E3 ligase inhibitors, we initially identified MMRi36 as a potent pro-apoptotic compound in p53-null leukemic cells with acquired drug resistance. MMRi36 acts as an activator of MDM2-MDM4 E3 ligase by stabilizing MDM2-MDM4 heterodimers and promotes MDM2/MDM4 degradation in cells. Interestingly, replacement of the sulfur in 1,3,4-thiadiazole MMRi36 with a carbon led to identification of pyrazole MMRi36C that dissociates the MDM2-MDM4 RING heterodimers, inhibits the E3 ligase activity of the complex, and induces p53 protein accumulation, but retains the p53-independent pro-apoptotic activity. A brief SAR study identified a fluorine derivative of MMRi36C with improved pro-apoptotic activity. This study discovered a novel class of compound that targets MDM2-MDM4 ubiquitin E3 ligase activity for apoptosis induction in p53-mutant cancer cells. Full article

Cultivated persimmon (Diosspyros kaki Thunb.) is a hexaploid (mostly) or a nonaploid with high heterozygosity, hindering molecular genetic studies on proanthocyanidin (PA) metabolism, which is a major trait for persimmon astringency. Recently, one of its wild diploid relative species, oily persimmon (Diospyros oleifera), has been assembled with a chromosome-level reference. Thus, oily persimmon is now regarded as a model plant for discovering new genes associated with PA metabolism, which is highly accumulated in the fruits of this genus. In our study, we identified genome-wide microRNAs (miRNAs) and their precursor sequence based on the chromosome-scale genome of oily persimmon and the miRNA database of “Eshi 1” according to the sequence alignment and secondary structure accession. The targets were predicted on the psRNATarget software based on the genome CDS database. The size, conservation, diversity, stem-loop hairpin structures, and genome location of miRNA or the precursor sequence were analyzed by bioinformatics tools. The promoter elements of the miRNA genes were predicted on the promoter-2.0 software, which indicated that the abundant cis-acting elements were light responsiveness, promoter, and enhancer regions. The qRT-PCR assay was performed to elucidate the potential expression patterns of precursor miRNA and their targets during fruit development, and one target gene, DkMYB22, of miR2911 was verified to promote the conversion of soluble tannins into insoluble tannins involved in the deastringency in persimmons. Together, this study provides a robust foundation for further functional verification of these miRNAs associated with the natural deastringency process in persimmon, thereby facilitating advancements in persimmon fruit breeding. Full article

The genus Ziziphus includes numerous species, both cultivated and wild, offering significant genetic variability and economic potential that are often overlooked. Due to their high variability and ecological plasticity, jujube species and genotypes can be utilized in marginal areas and on land where few plants could be efficiently exploited. This study investigated variations in morphological characteristics (qualitative and quantitative), bioactive content (e.g., DPPH radicals), and antioxidant capacity in fruits, leaves, and stones of cultivated Z. jujuba genotypes (‘Hu Ping Zao’ and ‘Jun Zao’) and wild genotypes (Z. acido-jujuba and ‘Jurilovca’), using different solvents (water, ethanol, and methanol). The mass and dimensions of the fruits as well as their parameters (fresh and dry weight, length, width, and pulp-to-stone ratio) and the antioxidant potential of different plant organ types (leaves, fruit pulps, and stones) were determined. The results showed that the cultivated genotypes produced larger and heavier fruits with a higher pulp percentage than the wild forms of the same species. However, the wild forms exhibited higher antioxidant capacities than the cultivated genotypes, depending on the type of plant organ analyzed and the solvent used for extraction. Full article

Aspergillus fumigatus (A. fumigatus) is a filamentous fungus that causes invasive aspergillosis in immunocompromised individuals. Regulating fungal growth is crucial for preventing disease development. This study found that deleting the guanine nucleotide exchange factor Sec2p gene led to slower A. fumigatus growth and reduced the fungal burden and mortality of infected mice. However, the mechanism by which this gene affects A. fumigatus growth and pathogenicity remains unclear. Transmission electron microscopy revealed that the vacuoles of the gene knockout strain ΔSec2p accumulated more autophagosomes, indicating inhibition of autophagosome degradation. When phenylmethylsulfonyl fluoride was applied to inhibit autophagosome degradation, the ΔSec2p strain produced fewer autophagosomes; the ΔSec2p autophagy pathway was inhibited, affecting A. fumigatus’ nutrient homeostasis and growth. Unlike the wild type, the ΔSec2p strain showed strong resistance to cell wall stress. When exposed to caspofungin, Sec2p negatively regulated the expression of cell wall integrity (CWI) pathway genes and participated in the cell wall stress response of A. fumigatus. Furthermore, this gene positively regulated the autophagy pathway and enhanced CWI pathway gene expression to respond to rapamycin-induced autophagy. In summary, Sec2p positively regulated the autophagy pathway; it negatively regulated the CWI pathway during cell wall stress, coordinating the growth and pathogenicity of A. fumigatus. Full article

Menin (MEN1) is a well-recognized powerful tumor promoter in acute leukemias (AL) with KMT2A rearrangements (KMT2Ar, also known as MLL) and mutant nucleophosmin 1 (NPM1m) acute myeloid leukemia (AML). MEN1 is essential for sustaining leukemic transformation due to its interaction with wild-type KMT2A and KMT2A fusion proteins, leading to the dysregulation of KMT2A target genes. MEN1 inhibitors (MIs), such as revumenib, ziftomenib, and other active small molecules, represent a promising new class of therapies currently under clinical development. By disrupting the MEN1-KMT2Ar complex, a group of proteins involved in chromatin remodeling, MIs induce apoptosis and differentiation AL expressing KMT2Ar or NPM1m AML. Phase I and II clinical trials have evaluated MIs as standalone treatments and combined them with other synergistic drugs, yielding promising results. These trials have demonstrated notable response rates with manageable toxicities. Among MIs, ziftomenib received orphan drug and breakthrough therapy designations from the European Medicines Agency in January 2024 and the Food and Drug Administration (FDA) in April 2024, respectively, for treating R/R patients with NPM1m AML. Additionally, in November 2024, the FDA approved revumenib for treating R/R patients with KMT2Ar-AL. This review focuses on the pathophysiology of MI-sensitive AL, primarily AML. It illustrates data from clinical trials and discusses the emergence of resistance mechanisms. In addition, we outline future directions for the use of MIs and emphasize the need for further research to fully realize the potential of these novel compounds, especially in the context of specific genetic subtypes of challenging AL. Full article

The PLATZ gene family, known for its pivotal roles in regulating plant growth, development, and stress responses, is of great significance in rice biology and crop improvement efforts. In this study, we undertook a comprehensive identification and analysis of the PLATZ gene family across 10 Oryza genus species, including both cultivated and wild rice varieties. A total of 144 PLATZ genes were identified, demonstrating their widespread distribution. Phylogenetic analysis revealed six distinct groups among these genes, with high sequence similarity among members indicating a common evolutionary origin and potential functional conservation. Further analysis of conserved motifs, domains, and promoter regions provided insights into the transcriptional regulation and potential functions of PLATZ genes. Notably, expression profiling showed differential expression patterns of specific PLATZ genes, such as OsPLATZ7, OsPLATZ9, and OsPLATZ11, under various abiotic stress conditions and hormone treatments, highlighting their important roles in stress adaptation and hormone signaling. Additionally, the consistently high expression of OsPLATZ9 across multiple tissues suggests its involvement in multiple developmental processes. Overall, this study provides a detailed characterization of the PLATZ gene family in rice, laying the foundation for future functional studies and potential applications in agricultural biotechnology. Full article

Sex-based differences in innate immunity may play a crucial role in susceptibility to and progression of tuberculosis (TB), a disease that disproportionately affects men. This study aimed to examine whether early host–pathogen interactions contribute to the heightened vulnerability of males to Mycobacterium tuberculosis (Mtb) infection. Using recombination activating gene 2 knockout (RAG2 KO) mice, which lack adaptive immunity, we were able to isolate and analyze innate immune responses to Mtb without the influence of T and B cells. Surprisingly, and in stark contrast to wild-type mice that reflect the male bias as observed in humans, female RAG2 KO mice were more susceptible to Mtb than their male counterparts. Increased lung CFU in females was accompanied by a significant rise in inflammation, indicated by elevated levels of inflammatory cytokines and chemokines, as well as a massive influx of neutrophils into the lungs. In contrast, male mice exhibited higher levels of IFN-γ and CCL5, along with a greater presence of NK cells in their lungs, suggesting that, in the absence of adaptive immunity, males benefit from a more robust NK cell response, potentially offering greater protection by better controlling inflammation and slowing disease progression. Full article

Physalis peruviana Linnaeus, also called Cape gooseberry, has been used extensively as a medicinal herb since ancient times. The current study is the very first investigation into the nutrient characteristics of Physalis peruviana L. fruits found in Ethiopia. Its main objective is to investigate the nutritional, antinutritional, and antioxidant capacity of the edible fruit of Physalis peruviana L. Three different drying conditions (shade, sun, and oven drying) were investigated to observe their effects on the chemical composition of the fruit. The antioxidant activities were quantified using DPPH (2,2-diphenylpicrylhydrazyl) and FRAP (ferric reducing antioxidant power) assays. Total flavonoid and total phenol contents were also determined for all dried samples. The shade-dried sample exhibited a better composition with regard to most of the characterized constituents than the other dried samples. From all of the results obtained, the shade-dried sample showed higher antioxidant activity, and, among the investigated minerals, its K content was found to be the highest (313.66 ± 0.05 g/100 g). However, the Fe content (in the oven-dried sample) was found to be the lowest (0.06 ± 0.10 g/100 g) of the investigated minerals. Through fermentation using Saccharomyces cerevisiae, the alcoholic content of the fruit was 9.11%, 9.90%, and 12.34% after 24, 48, and 72 h of fermentation time, respectively. It was also observed that the high temperature used in the drying process led to content loss in the fruit samples. This was evident in the oven-dried samples. It is expected that the analysis of the effects of drying on fruit composition can contribute to a better understanding of fruit storage/preparation and provide useful information on fruit product formulations. Full article

Purslane (Portulaca oleracea L.) is an herbaceous species that is traditionally consumed across the world due to its nutraceutical quality, boasting anticancer, anti-inflammatory and antidiabetic properties. These traits render purslane an attractive wild edible species for research and commercial exploitation. The current study examined the effect of different nitrogen (N) concentrations (100–200 mg L⁻¹; as N100, N200) in combination with different levels (decreased 0.66-fold: dec, recommended 1-fold: rec, or increased 1.5-fold: inc) of phosphorus (P; 47–70–105 mg L⁻¹) and potassium (K; 250–350–525 mg L⁻¹) in the nutrient solution (NS) used in hydroponic nutrient film technique (NFT) cultivation. The N200_PKinc NS resulted in improved crop growth compared to N200_PKrec NS, suggesting a positive correlation between optimal N levels (i.e., 200 mg L⁻¹) and increased P and K levels (105 and 525 mg L⁻¹, respectively). Plants grown in N200_PKinc revealed decreased antioxidant activity (e.g., DPPH, FRAP, and ABTS), phenols and flavonoids, while simultaneously increased total soluble solids levels. The recommended levels of P and K mirrored low levels in lipid peroxidation, mainly due to the increase in catalase enzymatic activity. Higher nutrient use efficiency was observed when both N100_PKinc and N200_PKinc were applied, resulting in higher yield and enhanced plant growth, while N100_PKinc produced plants with increased antioxidant activity. These findings suggest that both (N200_PKinc and N100_PKinc) NS have potential benefits for the hydroponic cultivation of purslane, with the latter NS offering additional advantages in terms of higher produce quality. Full article

Due to its lack of the L-gulonolactone oxidase (GULO) enzyme, Nile tilapia is unable to synthesize vitamin C; thus, it requires an adequate level of exogenous vitamin C in its diet. To enhance antioxidant properties and vitamin C-related effects, we employed recombinant technology to integrate the GULO-encoding gene into the Bacillus subtilis chromosome. In this study, fish were divided into four groups: those fed with a basal diet (CON), a basal diet + vitamin C (VC), a basal diet + wild-type B. subtilis (BS), and a basal diet + recombinant B. subtilis (BS+GULO). After 90 days of the feeding trial, the BS+GULO groups showed the highest improvements in final weight, weight gain, specific growth rate, average daily gain, and relative growth rate. The VC, BS, and BS+GULO groups exhibited increased total immunoglobulin and lysozyme activity; however, only the VC and BS+GULO groups showed elevated alternative complement 50 levels, phagocytic activity and improved antioxidant parameters compared to the control. HPLC and qRT-PCR analyses revealed elevated serum vitamin C and intestinal GULO mRNA levels in the BS+GULO group. A challenge test showed increased pro-inflammatory gene expression and immune response against S. agalactiae in the BS+GULO group, indicating improved antagonistic activity over wild-type B. subtilis. Full article

Background/Objectives: According to the One Health concept, wild birds can be indicators of ecosystem pollution and disease incidence. Escherichia coli strains are widespread worldwide, but there are still few reports on the association of human infections with a potential reservoir of highly pathogenic human strains in wild birds. Fecal E. coli with uropathogenic potential (UPEC) can be transmitted between birds and humans and may be a risk factor for urinary tract infections (UTIs). Results: The results showed that above 50% of the isolates were grouped as highly pathogenic, according to Clermont phylogroup classification. Such strains were found to be stronger biofilm producers, with a higher adherence of monocytes than low pathogenic. However, the highest cytotoxicity was observed for strains described as aquatic environmental. Convergence of the results of the analysis of monocyte activation by E. coli strains and the ability to form biofilm by individual phylogroups of the strains tested was demonstrated. Genetic determinants of the uropathogenicity of E. coli (UPEC) correlate with the evidence of strain pathogenicity during monocyte activation in in vitro assays. Methods: In this study, we assessed the virulence potential of environmental strains isolated from wild waterfowl using genetic analysis (Clermont phylogroup classification) and phenotypic methods, including analysis of the human monocyte response to biofilm formation. The estimation of the ability to form biofilms was tested using crystal violet, and the pathogenic potential of strains by monocyte activation assay including changes in morphology, adhesion and cytotoxicity. Conclusions: In conclusion, the virulence of E. coli strains isolated from free-living birds is significant, and they can be considered environmental reservoirs of pathogenic strains. According to our observations, they can be responsible for the dissemination of uropathogenic strains among humans. Full article

Scrub typhus is caused by intracellular bacteria belonging to the genus Orientia. Until 2010, the endemic region was thought to be restricted to the Asia–Pacific region. Orientia species have recently been discovered in South America, Africa, Europe, and North America. In accordance with these circumstances, we tried to find new or novel bacterial strains in the Republic of Korea (ROK). We found that a new strain of O. tsutsugamushi formed a unique clade based on a 56-kDa type-specific antigen gene and showed 63.2–77.8% similarity to other strains of the same species. Additionally, we identified another sequence with 99.8% similarity to the O3 strain, which has not been recorded in the ROK and whose pathogenicity remains unknown. These findings confirm the diversity of O. tsutsugamushi strains in the ROK, and highlight the need for continued surveillance and further studies to characterize the pathogenicity of this novel bacterial strain. Full article

Before the Bronze age, when agricultural practices spread throughout the Iberian Peninsula, the diet of the native people was based on hunting, fishing, and gathering wild plants. In spite of modern agriculture, the popular gathering of wild species for medical use, food, craftwork, etc., for centuries has left a detailed knowledge on the use of many of these species. Of the 6176 Angiosperms native to the Iberian Peninsula and the Balearic Islands, over 200 species were introduced into cultivation during the Neolithic period outside the Iberian Peninsula. The names of 30 of the progenitors still popularly used as food are listed in this paper, together with the names of their derived crops. This review focuses on five wild species collected as food from ancient times, namely Borago officinalis L. Prunus spinosa L., Silene vulgaris (Moench) Garke subsp. vulgaris, Scolymus hispanicus L., and Asparagus acutifolius L. In response to great demand, they have been recently introduced into cultivation in Spain and are now harvested and commercialized as new crops. Special attention is paid to their basic bioactive compounds and pharmacological properties. The limitation of this study is that the published information about the bioactive compounds of these five plants originates from different parts of the world where they grow wild or are cultivated. Therefore, further research is needed to trace the metabolomic dynamics of these plants regarding geographical and ecological principles, as well as wild versus cultivated origins. Full article

Background/Objectives: The diagnosis and treatment of endometriosis should be based on the best available evidence. Emphasising the risk of bias, the pyramid of evidence has the double-blind, randomised controlled trial and its meta-analyses on top. After the grading of all evidence by a group of experts, clinical guidelines are formulated using well-defined rules. Unfortunately, the impact of evidence-based medicine (EBM) on the management of endometriosis has been limited and, possibly, occasionally harmful. Methods: For this research, the inherent problems of diagnosis and treatment were discussed by a working group of endometriosis and EBM specialists, and the relevant literature was reviewed. Results: Most clinical decisions are multivariable, but randomized controlled trials (RCTs) cannot handle multivariability because adopting a factorial design would require prohibitively large cohorts and create randomization problems. Single-factor RCTs represent a simplification of the clinical reality. Heuristics and intuition are both important for training and decision-making in surgery; experience, Bayesian thinking, and learning from the past are seldom considered. Black swan events or severe complications and accidents are marginally discussed in EBM since trial evidence is limited for rare medical events. Conclusions: The limitations of EBM for managing endometriosis and the complementarity of multivariability, heuristics, Bayesian thinking, and experience should be recognized. Especially in surgery, the value of training and heuristics, as well as the importance of documenting the collective experience and of the prevention of complications, are fundamental. These additions to EBM and guidelines will be useful in changing the Wild West mentality of surgery resulting from the limited scope of EBM data because of the inherent multivariability, combined with the low number of similar interventions. Full article

This ethnobotanical study examines the traditional knowledge and usage patterns of wild plants in the western Alps, specifically within the Ubaye and Bellino Valleys, through a comparative analysis of data collected from 1983 (published in 1990) to 2024. Our study aims to assess the change in plant usage, species diversity, and the changing roles of plants in local traditions in the western Alpine mountain ecosystems. While the 1983 survey documented medicinal uses centered around pastoralist practices, the 2024 data highlight a notable increase in the use of synanthropic plants, now utilized both medicinally and as food. Several species such as Allium sativum, Artemisia absinthium, and Urtica dioica have shown resilience and continuity in local cultural practices, maintaining medicinal, culinary, and ritual significance across the four decades. The 1983 survey documented the greatest variety of species (101), a number that decreased in subsequent studies. The 2009 survey identified 36 species not previously recorded in 1983, and the 2024 field study noted an additional 20 species. The study highlights the economic potential of several wild species in these alpine areas, such as Achillea, Artemisia, Verbascum, Veronica, Viola, Polygonum, Bunium, and Sorbus spp., which could be utilized for creating new herbal teas, artisanal beers, liqueurs, ice creams, sweets, and seasoned food products. Expanding the uses of these plants could not only preserve ethnobotanical knowledge but also stimulate local economies and support sustainable development in alpine communities. The documented temporal shifts in plant usage reflect broader cultural, ecological, and socio-economic changes, underscoring the importance of preserving biodiversity and traditional knowledge amidst ongoing environmental and societal shifts. This study underscores the need to conserve ethnobotanical heritage while adapting to the evolving landscape of the region. Future research could focus on exploring the role of these species in broader sustainability initiatives, including conservation strategies, ecosystem services, and community-based tourism while continuing to document the cultural dynamics influencing plant usage. Full article