Search Results (201)

Background/Objectives: The current need for new antibacterial compounds that target non-classical pathways is highlighted by the emergence of multidrug-resistant Klebsiella pneumoniae. In the development of antibiotics, DNA adenine methyltransferase (Dam), a key regulator of bacterial gene expression and pathogenicity, is still underutilized. Epoxy-functionalized analogues of isatin derivatives have not been adequately investigated for their antibacterial activity, particularly as Dam inhibitors. In the pursuit of antimicrobial agents, this study synthesized an epoxy-functionalized isatin derivative (L3) using a one-pot reaction. The compound was characterized using FT-IR, ¹H-NMR, ¹³C-NMR, HR-MS, and UV–Vis spectroscopy. Methods: In silico evaluation performed by using ADMETlab3 and SwissADME. While molecular docking studies were achieved by AutoDock and Vina to find L3’s interaction with potential antibacterial target (Dam protein in K. pneumoniae). In addition, the antibacterial potential of L3 was evaluated using minimum inhibitory concentration (MIC) assays against Bacillus cereus, Bacillus pumilus, Escherichia coli, and K. pneumoniae. Results: Among these, L3 exhibited potential inhibitory activity against K. pneumoniae, with a MIC value of 93.75 μg/mL. In silico evaluations confirmed L3’s favorable drug-like properties, including potential oral bioavailability, blood–brain barrier (BBB) permeability, and low plasma protein binding (PPB). The compound satisfied Lipinski’s and other drug-likeness rules as well as getting a quantitative estimate of drug-likeness (QED) score of 0.52. Here, a homology model of Dam protein in K. pneumoniae was generated using the SWISS-MODEL server and validated using computational tools. Targeted docking analysis revealed that L3 exhibited significant potential binding affinity against Dam protein, with binding energies of −6.4 kcal/mol and −4.85 kcal/mol, as determined by Vina and AutoDock, respectively. The associated inhibition constant was calculated as 280.35 µM. Further interaction analysis identified the formation of hydrogen bonds with TRP7 and PHE32, along with Van der Waals’ interactions involving GLY9, ASP51, and ASP179. Conclusions: These findings highlight L3 as a promising scaffold for antimicrobial drug development, particularly in targeting Dam protein in K. pneumoniae. Furthermore, the ADMET profiling and physicochemical properties of L3 support its potential as a drug-like candidate. Full article

Background/Objectives: In many societies, especially in highly masculine societies like Japan, being a man, getting older, engaging in knowledge work, and earning a high annual salary are seen as conditions for success. On the other hand, an increasing number of studies have shown that incorporating kawaii-ness into our lives can help maintain and improve happiness and well-being. Methods: Therefore, in this study, we employed a variable expressing the response to kawaii-ness together with four demographic variables (sex, age, income, and knowledge work), happiness, and fractional anisotropy brain healthcare quotient (FA-BHQ) which is derived from magnetic resonance imaging (MRI) images calculations to analyze the relationship between them. Results: The results of a path analysis using data obtained from 182 healthy men and women showed that kawaii-ness mediates the association between demographic variables and happiness, which is in turn associated with FA-BHQ. Furthermore, with the correlation analysis between happiness and individual FA regions, we were able to confirm that FA regions, including the limbic-thalamo-cortical pathway, which is responsible for emotional regulation, are related to happiness. Conclusions: These results indicate the following: Men, older people, people engaged in knowledge work, and people with high annual incomes avoid kawaii-ness; As a result, they are unable to obtain the sense of happiness that they should have; as a result, they are unable to keep their brains healthy, and their brain functions, including emotional regulation, are not functioning properly; This may prevent them from maintaining or improving their performance. This study is the first attempt to clarify the relationship between demographic scales, kawaii-ness, happiness, and brain conditions. Full article

Getting through the cell membrane is challenging, and transporting a therapeutic agent while entering the cell is even more complicated. Cell-penetrating peptides (CPPs) are valuable tools for solving this problem, although they have drawbacks. In this work, the synthesis and investigation of efficient CPPs are described. We used an aromatic group, 1-pyrene carboxylic acid (PCA), to enhance internalization. We designed oligoarginines to investigate the effect of PCA in different positions at the N-terminus or in the side chain. Our novel peptide derivatives showed remarkable internalization on tumor cell lines, and more than one endocytic pathway plays a role in their internalization mechanism. With this modification, there is an opportunity to design short oligoarginines that can rival well-known CPPs like octaarginine in internalization. Full article

Peroxisome proliferator-activated receptors (PPARs) are considered good drug targets for breast cancer because of their involvement in fatty acid metabolism that induces cell proliferation. In this study, we used the KAIMRC1 breast cancer cell line. We showed that the PPARE-Luciferase reporter gets highly activated without adding any exogenous ligand when PPAR alpha is co-transfected, and the antagonist GW6471 can inhibit the activity. Using this reporter system, we screened 240 compounds representing kinase inhibitors, epigenetic modulators, and stem cell differentiators and identified compounds that inhibit the PPARα-activated PPARE-Luciferase reporter in the KAIMRC1 cell. We selected 11 compounds (five epigenetic modulators, two stem cell differentiators, and four kinase inhibitors) that inhibited the reporter by at least 40% compared to the controls (DMSO-treated cells). We tested them in a dose-dependent manner and measured the KAIMRC1 cell viability after 48 h. All 11 compounds induced the cell killing at different IC50 values. We selected two compounds, PHA665752 and NSC3852, to dissect how they kill KAIMRC1 cells compared to the antagonist GW6741. First, molecular docking and a TR-FRET PPARα binding assay showed that compared to GW6471, these two compounds could not bind to PPARα. This means they inhibit the PPARα pathway independently rather than binding to the receptor. We further confirmed that PHA665752 and NSC3852 induce cell killing depending on the level of PPARα expression, and as such, their potency for killing the SW620 colon cancer cell line that expresses the lowest level of PPARα was less potent than for the KAIMRC1 and MDA-MB-231 cell lines. Further, using an apoptosis array and fatty acid gene expression panel, we found that both compounds regulate the PPARα pathway by controlling the genes involved in the fatty acid oxidation process. Our findings suggest that these two compounds have opposite effects involving fatty acid oxidation in the KAIMRC1 breast cancer cell line. Although we do not fully understand their mechanism of action, our data provide new insights into the potential role of these compounds in targeting breast cancer cells. Full article

Graphene and its derivatives (GDs) have been applied in many fields, like photocatalysts, sensors, and biomedical delivery, due to its excellent physicochemical properties. However, the widespread use of GDs has significantly increased human exposure to these materials. Some health risks of exposure to GDs have been identified, including organ fibrosis, inflammation, DNA damage, etc. Given that graphene is a novel concern, we especially emphasized the various exposure pathways and potential health risks of exposure to GDs. People get exposed to GDs mainly through inhalation, ingestion, dermal contact, etc. GDs could transfer to the circular system of people and accumulate in blood, cells, and major organs. GDs exposure could induce organ and cell inflammatory responses and damage, such as disrupted kidney function, declined cell vitality, cytotoxicity, etc. These changes at the organ and cell levels might lead to adverse tangible influences on people, like decreased locomotor activity, the accelerated aging process, and even abnormal offspring development. We also summarized the characterization and detection methods of GDs. In addition, we compared the studies of exposure to dust and GDs in the aspects of health risks and study methods. This review could offer a comprehensive summary related to GDs and provide helpful references for further graphene-related studies. Full article

GET3 is an ATPase protein that plays a pivotal role in the guided entry of the tail-anchored (GET) pathway. The protein facilitates the targeting and inserting of tail-anchored (TA) proteins into the endoplasmic reticulum (ER) by interacting with a receptor protein complex on the ER. The role of GET3 in various biological processes has been established in yeast, plants, and mammals but not in filamentous fungi. Fusarium graminearum is the major causal agent of Fusarium head blight (FHB), posing a threat to the yield and quality of wheat. In this study, we found that FgGET3 exhibits a high degree of sequence and structural conservation with its homologs across a wide range of organisms. Ectopic expression of FgGET3 in yeast restored the growth defects of the Saccharomyces cerevisiae ScGET3 knock-out mutant. Furthermore, FgGET3 was found to dimerize and localize to the cytoplasm, similar to its homologs in other species. Deletion of FgGET3 in F. graminearum results in decreased fungal growth, fragmented vacuoles, altered abiotic stress responses, reduced conidia production, delayed conidial germination, weakened virulence on wheat spikes and reduced DON production. Collectively, these findings underscore the critical role of FgGET3 in regulating diverse cellular and biological functions essential for the growth and virulence of F. graminearum. Full article

Podosphaera xanthii is the main causal agent of powdery mildew (PM) disease for Cucurbita pepo. Disease control is attained principally by applications of chemical fungicides, along with parallel use of tolerant crop varieties and alternate application of elicitors to control development of disease resistance. To get insight into C. pepo molecular responses to P. xanthii infection and elicitor treatment we studied the proteomic profile differences at the phyllosphere of a zucchini cultivar susceptible to PM, at the onset of P. xanthii (PX) infection and after application of Reynoutria sachalinensis (RS) plant extract, respectively, using a nano-LC-HRMS/MS, Q-Exactive-Orbitrap approach. Analysis of peptide sequences regarding four treatment groups (Control; PX; RS; and RSPX (PX-infected priorly treated with RS)) resulted in 2070 CuGenDB annotations. Three comparisons (treatments vs. Control) encompassed most of the Differentially Expressed Proteins (DEPs). In these three comparisons, KEGG and Gene Ontology functional analyses highlighted unique differentially enriched pathways—some of which included highly expressed proteins—in PX-related (proteasome, pentose phosphate pathway, and carbon fixation), RS-related (biosynthesis of secondary metabolites, flavonoids, and starch and sucrose metabolism), and RSPX-related (pyruvate metabolism and polycomb repressive complex) comparisons, respectively, suggesting distinct mechanisms of early plant responses modulated by PX and RS. Furthermore, in four out of six comparisons the thiamine metabolism pathway was found to be enriched, suggesting a pivotal role in PX-induced responses. Full article

The rise of artificial intelligence is fundamentally transforming the competitive landscape across various sectors, offering visionary enterprises new pathways to innovation development and to get a competitive edge. AI leverages data, analysis, and observations to perform tasks without hard coding, and benefits from self-learning and continuous improvement. We use Systems Thinking to frame how managers may adopt and integrate AI in business activities. We also investigate the motivations driving entrepreneurs to adopt AI solutions, and how they may impact on sustainable business model innovation, by administering a questionnaire to a sample of innovative Italian SMEs to get a comprehensive overview of the dynamics influencing AI adoption in business. This study sheds light on the intricate relationship between technology, sustainability, and corporate innovation. It offers both valuable insights for future research and for strategic managerial decisions on AI integration. Furthermore, it helps the development of innovative, sustainable business models in the evolving landscape of the Great Reset. Full article

Ischemic stroke is one of the leading causes of death and disability. As the currently used neurorehabilitation methods present several limitations, the ongoing research focuses on the use of non-invasive brain stimulation (NIBS) techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). NIBS methods were demonstrated to modulate neural excitability and improve motor and cognitive functioning in neurodegenerative diseases. However, their mechanisms of action are not fully elucidated, and the clinical outcomes are often unpredictable. This review explores the molecular processes underlying the effects of TMS and tDCS in stroke rehabilitation, including oxidative stress reduction, cell death, stimulation of neurogenesis, and neuroprotective phenotypes of glial cells. A highlight is put on the newly emerging therapeutic targets, such as ferroptotic and pyroptotic pathways. In addition, the issue of interindividual variability is discussed, and the role of neuroimaging techniques is investigated to get closer to personalized medicine. Furthermore, translational challenges of NIBS techniques are analyzed, and limitations of current clinical trials are investigated. The paper concludes with suggestions for further neurorehabilitation stroke treatment, putting the focus on combination and personalized therapies, as well as novel protocols of brain stimulation techniques. Full article

Recent research has highlighted associations between sleep and microbial taxa and pathways. However, the causal effect of these associations remains unknown. To investigate this, we performed a bidirectional two-sample Mendelian randomization (MR) analysis using summary statistics of genome-wide association studies (GWAS) from 412 gut microbiome traits (N = 7738) and GWAS studies from seven sleep-associated traits (N = 345,552 to 386,577). We employed multiple MR methods to assess causality, with Inverse Variance Weighted (IVW) as the primary method, alongside a Bonferroni correction ((p < 2.4 × 10⁻⁴) to determine significant causal associations. We further applied Cochran’s Q statistical analysis, MR-Egger intercept, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) for heterogeneity and pleiotropy assessment. IVW estimates revealed 79 potential causal effects of microbial taxa and pathways on sleep-related traits and 45 inverse causal relationships, with over half related to pathways, emphasizing their significance. The results revealed two significant causal associations: genetically determined relative abundance of pentose phosphate decreased sleep duration (p = 9.00 × 10⁻⁵), and genetically determined increase in fatty acid level increased the ease of getting up in the morning (p = 8.06 × 10⁻⁵). Sensitivity analyses, including heterogeneity and pleiotropy tests, as well as a leave-one-out analysis of single nucleotide polymorphisms, confirmed the robustness of these relationships. This study explores the potential causal relationships between sleep and microbial taxa and pathways, offering novel insights into their complex interplay. Full article

The current study deals with an examination of strategies for the sequential treatment of corn stalks (CSs) in an integrated manner aiming to obtain papermaking fibers and to recover both lignin and hemicelluloses (HCs). Several pathways of valorization were experimentally trialed, focusing on getting information from mass balance analysis in an attempt to reveal the potential outcomes in terms of pulp yield, chemical composition, and papermaking properties such as tensile and burst strength. The raw lignin amounts and purity as well as separated hemicelluloses were also characterized. In this work, pulp yields in the range of 44–50% were obtained from CSs, while lignin and hemicelluloses yielded maximum values of 10 g/100 g of CS and 6.2 g/100 g of CS, respectively. Other findings of mass balance analysis evidenced that besides the papermaking pulp, the lignin and HCs also have interesting output values. The recovered lignin yield values were shown to be less than 50% in general, meaning that even if 67 to 90% of it is removed from CSs, only about half is recovered. The removal rates of hemicelluloses were found to be in the range of approx. 30 to 60%. About 15 to 25% of the original HCs could be recovered, and polysaccharides-based products with 67 to 75% xylan content could be obtained. Some key opinions were developed regarding how the mass balance could turn as a result of the chosen CS valorization set-up. The determined antioxidant activity showed that both lignin and hemicelluloses had interesting values for IC₅₀. Full article

Psoriasis is a chronic recurrent inflammatory autoimmune pathology with a significant genetic component and several interferences of immunological cells and their cytokines. The complex orchestration of psoriasis pathogenesis is related to the synergic effect of immune cells, polygenic alterations, autoantigens, and several other external factors. The major act of the IL-23/IL-17 axis, strongly influencing the inflammatory pattern established during the disease activity, is visible as a continuous perpetuation of the pro-inflammatory response and keratinocyte activation and proliferation, leading to the development of psoriatic lesions. Genome-wide association studies (GWASs) offer a better view of psoriasis pathogenic pathways, with approximately one-third of psoriasis’s genetic impact on psoriasis development associated with the MHC region, with genetic loci located on chromosome 6. The most eloquent genetic factor of psoriasis, PSORS1, was identified in the MHC I site. Among the several factors involved in its complex etiology, dysbiosis, due to genetic or external stimulus, induces a burst of pro-inflammatory consequences; both the cutaneous and gut microbiome get involved in the psoriasis pathogenic process. Cutting-edge research studies and comprehensive insights into psoriasis pathogenesis, fostering novel genetic, epigenetic, and immunological factors, have generated a spectacular improvement over the past decades, securing the path toward a specific and targeted immunotherapeutic approach and delayed progression to inflammatory arthritis. This review aimed to offer insight into various domains that underline the pathogenesis of psoriasis and how they influence disease development and evolution. The pathogenesis mechanism of psoriasis is multifaceted and involves an interplay of cellular and humoral immunity, which affects susceptible microbiota and the genetic background. An in-depth understanding of the role of pathogenic factors forms the basis for developing novel and individualized therapeutic targets that can improve disease management. Full article

Globally, cancer is one of the primary causes of both morbidity and mortality. To prevent cancer from getting worse, more targeted and efficient treatment plans must be developed immediately. Recent research has demonstrated the benefits of natural products for several illnesses, and these products have played a significant role in the development of novel treatments whose bioactive components serve as both chemotherapeutic and chemo-preventive agents. Phytochemicals are naturally occurring molecules obtained from plants that have potential applications in both cancer therapy and the development of new medications. These phytochemicals function by regulating the molecular pathways connected to the onset and progression of cancer. Among the specific methods are immune system control, inducing cell cycle arrest and apoptosis, preventing proliferation, raising antioxidant status, and inactivating carcinogens. A thorough literature review was conducted using Google Scholar, PubMed, Scopus, Google Patent, Patent Scope, and US Patent to obtain the data. To provide an overview of the anticancer effects of several medicinal plants, including Annona muricata, Arctium lappa, Arum palaestinum, Cannabis sativa, Catharanthus roseus, Curcuma longa, Glycyrrhiza glabra, Hibiscus, Kalanchoe blossfeldiana, Moringa oleifera, Nerium oleander, Silybum marianum, Taraxacum officinale, Urtica dioica, Withania somnifera L., their availability, classification, active components, pharmacological activities, signaling mechanisms, and potential side effects against the most common cancer types were explored. Full article

Removing the panicle encourages the growth of buds on the elongated node by getting rid of apical dominance. Strigolactones (SLs) are plant hormones that suppress tillering in rice. The present study employed panicle removal (RP) and external application of synthesized strigolactones (GR) to modulate rice bud growth at node 2. We focused on the full-heading stage to investigate proteomic changes related to bud germination (RP-Co) and suppression (GR-RP). A total of 434 represented differentially abundant proteins (DAPs) were detected, with 272 DAPs explicitly specified in the bud germination process, 106 in the bud suppression process, and 28 in both. DAPs in the germination process were most associated with protein processing in the endoplasmic reticulum and ribosome biogenesis. DAPs were most associated with metabolic pathways and glycolysis/gluconeogenesis in the bud suppression process. Sucrose content and two enzymes of sucrose degradation in buds were also determined. Comparisons of DAPs between the two reversed processes revealed that sucrose metabolism might be a key to modulating rice bud growth. Moreover, sucrose or its metabolites should be a signal downstream of the SLs signal transduction that modulates rice bud outgrowth. Contemplating the result so far, it is possible to open new vistas of research to reveal the interaction between SLs and sucrose signaling in the control of tillering in rice. Full article

The p21-activated kinases (PAKs) are important signaling proteins. They contribute to a surprisingly wide range of cellular processes and play critical roles in a number of human diseases including cancer, neurological disorders and cardiac diseases. To get a better understanding of PAK functions, mechanisms and integration of various cellular activities, we screened for proteins that bind to the budding yeast PAK Ste20 as an example, using the split-ubiquitin technique. We identified 56 proteins, most of them not described previously as Ste20 interactors. The proteins fall into a small number of functional categories such as vesicle transport and translation. We analyzed the roles of Ste20 in glucose metabolism and gene expression further. Ste20 has a well-established role in the adaptation to changing environmental conditions through the stimulation of mitogen-activated protein kinase (MAPK) pathways which eventually leads to transcription factor activation. This includes filamentous growth, an adaptation to nutrient depletion. Here we show that Ste20 also induces filamentous growth through interaction with nuclear proteins such as Sac3, Ctk1 and Hmt1, key regulators of gene expression. Combining our observations and the data published by others, we suggest that Ste20 has several new and unexpected functions. Full article