Search Results (30)

Background: The profound heterogeneity of glioblastoma and the often-limited efficacy of conventional treatments, including arsenic trioxide (ATO), underscore the urgent and critical demand for innovative combination strategies specifically designed to overcome treatment resistance. Methods: We evaluated the therapeutic effects of ATO as a single agent and in combination with the MNK1 inhibitor AUM001 across patient-derived xenograft (PDX) models and investigated molecular determinants of sensitivity and synergy. Our results demonstrated that GBM models resistant to ATO, particularly those of the mesenchymal subtype, are more likely to show synergistic cytotoxicity when AUM001 is added. The combination significantly reduces the frequency of glioblastoma stem cells (GSCs) compared to either drug alone, especially in ATO-resistant models. Results: These observations suggest that targeting the MNK1 pathway in conjunction with ATO is a promising strategy to specifically eradicate GSCs, which are major drivers of GBM recurrence and therapeutic failure. Transcriptomic analyses revealed that ATO sensitivity correlated with activated translation-related pathways and cell cycle processes, while synergistic responses to the combination were driven by distinct molecular signatures in different GBM subtypes. Overall, synergistic response to the combination therapy is more associated with cellular organization, amino acid transmembrane transporter activity, ion channels, extracellular matrix organization and collagen formation. Conclusions: Our findings highlight that specific molecular pathways and their activities, including those involving translation, cell cycle and ion transport, appear to modulate the synergistic efficacy of the ATO and AUM001 combination, thereby offering potential biomarkers for improved patient stratification in future GBM clinical trials of such ATO-based treatments. Full article

Background: Urinary tract infections (UTIs) rank among the most prevalent infectious diseases globally, with recurrent UTIs (rUTIs) posing substantial therapeutic challenges due to the lack of durable protective immunity. While trained immunity augments innate immune responses, its induction and functional significance in bladder-resident group 3 innate lymphoid cells (ILC3s) remain unknown. This study investigates whether ILC3s develop trained immunity following uropathogenic Escherichia coli (UPEC) exposure and how they contribute to mucosal defense against rUTIs. Methods: The ILC3 counts were detected in bladder sections from UTI patients and health controls (HC). A recurrent UTI mouse model was established through primary and secondary urethral UPEC inoculation. Bacterial loads in tissues were assessed, and single-cell suspensions were analyzed via flow cytometry. Bladder naïve- and UPEC-trained ILC3s were adoptively transferred, with evaluations of histopathology, epithelial barrier function, inflammation, and antimicrobial peptides. The in vitro ILC3 cell line MNK-3 was detected for IL-17A and IL-22 production following primary and secondary UPEC lysate stimulation. Results: We demonstrate that primary UPEC infection triggers ILC3 expansion in both human and murine bladders. Upon secondary challenge, these ILC3s develop trained immunity, characterized by enhanced proliferation, amplified IL-17A and IL-22 production, and improved pathogen clearance. Mechanistically, trained ILC3s reinforce urothelial barrier integrity through upregulation of antimicrobial peptides (Reg3b/Reg3g) and attenuate inflammatory pathology by suppressing pro-inflammatory cytokines (IL-6, TNF-α). Conclusions: We uncover an endogenous defense mechanism wherein UPEC primes bladder ILC3s via trained immunity, enabling amplified IL-17A- and IL-22-mediated protection against recurrent infections. These findings establish ILC3-trained immunity as a novel conceptual foundation, providing a basis for developing immunotherapies against rUTIs. Full article

Background: Socioeconomic factors may influence maternal nutrition knowledge (MNK), which directly affects the nutritional status of children under five. This study aims to explore the importance of socioeconomic factors associated with MNK and nutritional status. Methods: This cross-sectional study focused on mothers of children aged 36–59 months (n = 657). A structured questionnaire was employed to collect data on socioeconomic factors. Anthropometric measurements were taken to assess nutritional status. The Boruta algorithm, implemented using R Studio version R.4.5.1, was used to identify the most important socioeconomic factors associated with MNK and nutrition status. Results: The analysis revealed that socioeconomic status (SES) emerged as an important factor associated with MNK and nutrition status, particularly stunting and wasting. However, SES was not confirmed as an important factor associated with underweight. This study uncovered a bidirectional relationship between child nutrition outcomes; underweight was found to be an important factor related to stunting and wasting, whereas stunting and wasting were important factors for underweight. Furthermore, infant and young child feeding (IYCF) indicators, such as weaning practices and exclusive breastfeeding (BF), were found to be important factors for stunting and wasting. Conclusions: The interlinkage among forms of undernutrition, where each nutritional outcome is related to other outcomes, underscores the importance of comprehensively addressing child undernutrition, rather than focusing on single outcomes independently. Moreover, the association between SES and MNK, wasting, and stunting supports approaches based on holistic and multi-sectoral strategies to reduce poverty by WASH programs, promote IYCF practices, and improve healthcare access by providing health insurance coverage. Full article

To reveal the changes in crop yield and contribution rate of black soil productivity under long-term different fertilization conditions in black soil areas and to find the important significance of fertilization for sustainable and stable crop yield, high yield, and improving the contribution rate of black soil nutrients. Based on the long-term experiment of black soil fertility in Harbin, the Ministry of Agriculture and Rural Affairs, under the maize–wheat–soybean rotation system, crop yield, sustainability and stability of yield, the contribution rate of black soil productivity, and natural nutrient supply capacity under 10 fertilization treatments (CK, NP, NK, PK, NPK, M, MNP, MNK, MPK, and MNPK) were analyzed. Results showed that, compared with the treatment of chemical fertilizer, yields of maize, wheat, and soybeans increased under treatment of organic fertilizer combined with chemical fertilizer, among which the yields of maize and wheat changed the most. As the rotation period lengthened, the sustainable yield index (SYI) values of chemical fertilizer treatment and its combination with organic fertilizer treatment gradually decreased. During the rotation period, the SYI value follows: chemical fertilizer combined with organic fertilizer > chemical fertilizer > organic fertilizer. The coefficient of variation (CV) of yield stability showed an overall trend of increasing first and then decreasing, with individual treatments showing a gradual increasing trend (NP and NPK; MNP and MNPK). Under different rotation periods, the overall contribution rate of soil productivity of long-term organic fertilizer combined with chemical fertilizer treatment was higher than that of single chemical fertilizer treatment. With the extension of the rotation period, the contribution rate of soil productivity of NPK treatment was higher and slightly increased, while other treatments showed a downward trend. Although the contribution rate of soil productivity of organic–inorganic fertilizer combined treatment (MNP and MNK) showed a downward trend, it still remained at a high level (97.2% and 95.9%). In addition, the black soil has strong phosphorus and potassium supply capacity; nitrogen was lower than those two elements, with an average natural potassium supply capacity of 94.0–97.1%. Therefore, the combination of organic and inorganic fertilizers is one of the most effective fertilization measures to stabilize crop yield in the black soil region. Nitrogen fertilizer, as a limiting factor for crop growth in the black soil region, should be emphasized in its application. Full article

Specific strains of Vibrio parahaemolyticus can cause Acute Hepatopancreatic Necrosis Disease (AHPND), a critical issue in shrimp aquaculture despite the application of several control strategies. The use of antibiotics is now restricted due to increasing bacterial resistance and overuse. Silver nanoparticles (AgNPs) have shown potential in shrimp aquaculture, with applications in boosting immunity against certain types of pathogens, promoting growth, and improving survival rates. However, an economically viable solution that protects the organisms has not been found, which is why the search for nanoparticles synthesized with plant extracts is necessary to generate environmentally friendly control strategies. In this study, we synthesized AgNPs from Larrea tridentata extract and administered them orally with feed over a 35-day period. Shrimps fed with AgNP-enriched diets showed a significant increase (p < 0.05) in mRNA expression of immune-related genes (CTL-5, MNK, SR, and GILT), particularly within the first 24–48 h. No significant differences were observed in growth rates, but survival rates in a challenge against V. parahaemolyticus exceeded 85%, higher than the control group. Based on our findings and previous literature, L. tridentata can effectively promote the synthesis of AgNPs and shows potential as an antimicrobial agent, without affecting the growth or survival of treated shrimp. Full article

The urgent global health challenge posed by methicillin-resistant Staphylococcus aureus (MRSA) infections demands effective solutions. Antimicrobial peptides (AMPs) represent promising tools of research of new antibacterial agents and LyeTx I mn∆K, a short synthetic peptide based on the Lycosa erythrognatha spider venom, is a good representative. This study focused on analyzing the antimicrobial activities of LyeTx I mn∆K, including minimum inhibitory and bactericidal concentrations, synergy and resensitization assays, lysis activity, the effect on biofilm, and the bacterial death curve in MRSA. Additionally, its characterization was conducted through isothermal titration calorimetry, dynamic light scattering, calcein release, and finally, efficacy in a mice wound model. The peptide demonstrates remarkable efficacy against planktonic cells (MIC 8–16 µM) and biofilms (>30% of inhibition) of MRSA, and outperforms vancomycin in terms of rapid bactericidal action and anti-biofilm effects. The mechanism involves significant membrane damage. Interactions with bacterial model membranes, including those with lysylphosphatidylglycerol (LysylPOPG) modifications, highlight the versatility and selectivity of this compound. Also, the peptide has the ability to sensitize resistant bacteria to conventional antibiotics, showing potential for combinatory therapy. Furthermore, using an in vivo model, this study showed that a formulated gel containing the peptide proved superior to vancomycin in treating MRSA-induced wounds in mice. Together, the results highlight LyeTx I mnΔK as a promising prototype for the development of effective therapeutic strategies against superficial MRSA infections. Full article

Lung cancer is the leading cause of cancer-related death worldwide. Its late diagnosis and consequently poor survival make necessary the search for new therapeutic targets. The mitogen-activated protein kinase (MAPK)-interacting kinase 1 (MNK1) is overexpressed in lung cancer and correlates with poor overall survival in non-small cell lung cancer (NSCLC) patients. The previously identified and optimized aptamer from our laboratory against MNK1, apMNKQ2, showed promising results as an antitumor drug in breast cancer in vitro and in vivo. Thus, the present study shows the antitumor potential of apMNKQ2 in another type of cancer where MNK1 plays a significant role, such as NSCLC. The effect of apMNKQ2 in lung cancer was studied with viability, toxicity, clonogenic, migration, invasion, and in vivo efficacy assays. Our results show that apMNKQ2 arrests the cell cycle and reduces viability, colony formation, migration, invasion, and epithelial-mesenchymal transition (EMT) processes in NSCLC cells. In addition, apMNKQ2 reduces tumor growth in an A549-cell line NSCLC xenograft model. In summary, targeting MNK1 with a specific aptamer may provide an innovative strategy for lung cancer treatment. Full article

Anthocyanins, soluble sugars, and organic acids play a vital role in the color and flavor of grape berries. N and KH₂PO₄ are essential nutrients for grape growth and development. However, the research on the effects of foliar spraying of KH₂PO₄ on the skin color and flavor of grapes under different N levels were not systematic. In this study, “Flame seedless” grapes were used as the test material. There were six treatments in this experiment, including low nitrogen (LN), low nitrogen + KH₂PO₄ (LNK), moderate nitrogen (MN), moderate nitrogen + KH₂PO₄ (MNK), high nitrogen (HN), and high nitrogen + KH₂PO₄ (HNK). Foliar spraying of KH₂PO₄ on grapes significantly increased total K, anthocyanin contents, and the color index of red grapes (CIRG) in LN, MN, and HN. In the N and KH₂PO₄ treatments, foliar spraying of KH₂PO₄ significantly increased the content of methylated, acetylated, and coumarylated anthocyanins under MN treatment. The glucose and fructose contents of MNK were the highest compared to other treatments. The sole use of N showed the highest glucose and fructose contents with MN application. Anthocyanin had a significant positive correlation with soluble sugars; and showed a significant negative correlation with organic acids. Overall, foliar spraying of 0.5% KH₂PO₄ improved the color and flavor of “Flame seedless” grapes under all N levels, with the most significant effect at MN. Full article

Background: Previous studies indicate that dihydromyricetin (DHM) could alleviate intestinal inflammation and improve intestinal barrier integrity, yet the underlying mechanism remains obscure. Methods: C57BL/6 male mice were fed with a control diet, high-fat diet (HFD), or HFD + DHM diet for 12 weeks. The intestinal permeability and expression of intestinal tight junction (TJ) protein were detected to evaluate the effects of DHM on intestinal barrier integrity. The interleukin 22 (IL-22) production of group 3 innate lymphoid cells (ILC3s) in small intestine lamina propria was tested to clarify the effects of DHM on ILC3s. In addition, an MNK3 cell line, which expresses the same transcription factors and cytokines as ILC3, was used to investigate the molecular mechanism under DHM-induced IL-22 expression. Results: DHM effectively protected HFD-fed mice against intestinal barrier destruction by promoting ILC3 activation and IL-22 secretion, and IL-22 expression increased the expression levels of TJ molecules to protect intestinal barrier integrity. Moreover, DHM increased activation of the AMPK/SIRT3/STAT3 pathway, which in turn promoted IL-22 expression in MNK3 cells. Conclusions: DHM improved IL-22 production in ILC3 cells to alleviate HFD-induced intestinal barrier destruction via the AMPK/SIRT3/STAT3 pathway. Full article

Fluctuation in Cry1Ac endotoxin levels expressed in transgenic Bacillus thuringiensis (Bt) cotton (Gossypium hirsutum L.) can result in a variation in efficacy throughout the growing season. Here, a green tissue-specific strong promoter of the cotton leaf curl Kokhran virus-Burewala (CLCuKoV-Bu) C1 gene is reported that can direct consistently high levels of Cry1Ac endotoxin expression in transformed cotton plants. The objective of this study was to investigate the capacities of the CLCuKoV-BuC1 promoter to drive transcription of Cry1Ac and stably express endotoxin in mature leaves and bolls of transgenic cotton plants, compared to the traditional CaMV35S promoter. The Cry1Ac gene expression cassettes were constructed under the control of a bidirectional promoter and transformed into cotton ‘MNK-786′. The expression of Cry1Ac constructs was evaluated in transient and stable expression systems using Nicotiana tabacum ‘Rustica’ and cotton plants, respectively. Accumulation of the Cry1Ac expressed in two resultant transgenic cotton plants harboring the constructs driven by the CLCuKoV-BuC1 and CaMV35S promoter, respectively, was analyzed using a commercially available enzyme-linked immunosorbent assay. In leaves and bolls of two cotton plants shown to express CLCuKoV-BuC1-Cry1Ac (CLCuV-Ac), the Cry1Ac protein accumulated at 400 and 300 ng g⁻¹ per fresh tissue weight, respectively, whereas no toxin was detectable in the roots. In contrast, CaMV35S-Cry1Ac transgenic cotton plants accumulated three times less Cry1Ac protein than those transformed with CLCuV-Ac. Results indicate that the greatest amount of Cry1Ac endotoxin accumulated in transgenic cotton when expression was driven by the CLCuKoV-BuC1 compared to the CaMV35S promoter. Thus, the CLCuKoV-BuC1 promoter offered more robust transgene expression in cotton plants than the traditional CaMV35S promoter. The newly validated CLCuV-Ac promoter of begomoviral origin offers an exciting alternative as a robust promoter for genetic engineering of cotton and other plants. Full article

Prostate cancer (PCa) relies in part on AR-signaling for disease development and progression. Earlier, we developed drug candidate galeterone, which advanced through phase 2-clinical trials in treating castration-resistant PCa (CRPC). Subsequently, we designed, synthesized, and evaluated next-generation galeterone-analogs including VNPP433-3β which is potently efficacious against pre-clinical models of PCa. This study describes the mechanism of action of VNPP433-3β that promotes degradation of full-length AR (fAR) and its splice variant AR-V7 besides depleting MNK1/2 in in vitro and in vivo CRPC models that stably overexpresses fAR. VNPP433-3β directly engages AR within the cell and promotes proteasomal degradation of fAR and its splice variant AR-V7 by enhancing the interaction of AR with E3 ligases MDM2/CHIP but disrupting AR-HSP90 binding. Next, VNPP433-3β decreases phosphorylation of 4EBP1 and abates binding of eIF4E and eIF4G to 5′ cap of mRNA by depleting MNK1/2 with consequent depletion of phosphorylated eIF4E. Finally, RNA-seq demonstrates modulation of multiple pathways that synergistically contribute to PCa inhibition. Therefore, VNPP433-3β exerts its antitumor effect by imposing 1) transcriptional regulation of AR and AR-responsive oncogenes 2) translational regulation by disrupting mRNA-5′cap-dependent translation initiation, 3) reducing AR half-life through enhanced proteasomal degradation in vitro and AR-overexpressing tumor xenografts in vivo. Full article

Poly (I:C) can work as an immunostimulant and a viral vaccine; however, its functional mechanism in aquatic animals needs to be further investigated. In this study, comparative transcriptomic analyses were performed to investigate the effects of poly (I:C) on Argyrosomus japonicus at 12 h and 48 h postinjection. A total of 194 and 294 differentially expressed genes were obtained in the liver and spleen, respectively. At 12 h, poly (I:C) injection could significantly influence the function of the metabolism-related pathways and immune-related pathways in the liver through the upregulation of the genes GST, LPIN, FOXO1, CYP24A1, ECM1, and SGK1, and the downregulation of the genes IL-1β, CXC19, TNFAIP3, and IRF1. At 48 h, poly (I:C) could enhance the liver energy metabolism by upregulating the genes TXNRD and ECM1, while it also induced some injury in the cells with the downregulation of the genes HBA and CYP24A1. In the spleen, poly (I:C) could regulate the fish immunity and inflammatory response by upregulating the genes DDIT4, C3, EFNA, and MNK, and by downregulating the genes ABCA1, SORT1, TNF, TLR2, IL8, and MHCII at 12 h, and at 48 h, the poly (I:C) had a similar influence as that in the liver. Intersection analyses demonstrated that CYP24A1 and ECM1 were the main functional genes that contributed to the health of the liver. Ten and four genes participated in maintaining the health of the two tissues after 12 h and 48 h, respectively. In summary, our results provided a new insight into ploy (I:C) application in A. japonicus, and it also helped us to better understand the fish response mechanism to the viral vaccine injection. Full article

Allobetulin is structurally similar tobetulinic acid, inducing the apoptosis of cancer cells with low toxicity. However, both of them exhibited weak antiproliferation against several tumor cell lines. Therefore, the new series of allobetulon/allobetulin–nucleoside conjugates 9a–10i were designed and synthesized for potency improvement. Compounds 9b, 9e, 10a, and 10d showed promising antiproliferative activity toward six tested cell lines, compared to zidovudine, cisplatin, and oxaliplatin based on their antitumor activity results. Among them, compound 10d exhibited much more potent antiproliferative activity against SMMC-7721, HepG2, MNK-45, SW620, and A549 human cancer cell lines than cisplatin and oxaliplatin. In the preliminary study for the mechanism of action, compound 10d induced cell apoptosis and autophagy in SMMC cells, resulting in antiproliferation and G0/G1 cell cycle arrest by regulating protein expression levels of Bax, Bcl-2, and LC3. Consequently, the nucleoside-conjugated allobetulin (10d) evidenced that nucleoside substitution was a viable strategy to improve allobetulin/allobetulon’s antitumor activity based on our present study. Full article

MNKs (mitogen-activated protein kinase-interacting protein kinases) phosphorylate eIF4E at Ser209 to control the translation of certain mRNAs and regulate the process of cell proliferation, cell migration and invasion, etc. Development of MNK inhibitors would be an effective treatment for related diseases. We used the MarineChem3D database to identify hit compounds targeting the protein MNK1 and MNK2 through high-throughput screening. Compounds from the phorbazole family showed good interactions with MNK1, and phorbazole C was selected as our hit compound. By analyzing the binding mode, we designed and synthesized 29 derivatives and evaluated their activity against MNKs, of which, six compounds showed good inhibition to MNKs. We also confirmed three interactions between this kind of compound and MNK1, which are vital for the activity. In conclusion, we report series of novel MNK inhibitors inspired from marine natural products and their relative structure–activity relationship. This will provide important information for further developing MNK inhibitors based on this kind of structure. Full article

Social behavior is a basic domain affected by several neurodevelopmental disorders, including ASD and a heterogeneous set of neuropsychiatric disorders. The SCRIB gene that codes for the polarity protein SCRIBBLE has been identified as a risk gene for spina bifida, the most common type of neural tube defect, found at high frequencies in autistic patients, as well as other congenital anomalies. The deletions and mutations of the 8q24.3 region encompassing SCRIB are also associated with multisyndromic and rare disorders. Nonetheless, the potential link between SCRIB and relevant social phenotypes has not been fully investigated. Hence, we show that Scrib^crc/+ mice, carrying a mutated version of Scrib, displayed reduced social motivation behavior and social habituation, while other behavioral domains were unaltered. Social deficits were associated with the upregulation of ERK phosphorylation, together with increased c-Fos activity. Importantly, the social alterations were rescued by both direct and indirect pERK inhibition. These results support a link between polarity genes, social behaviors and hippocampal functionality and suggest a role for SCRIB in the etiopathology of neurodevelopmental disorders. Furthermore, our data demonstrate the crucial role of the MAPK/ERK signaling pathway in underlying social motivation behavior, thus supporting its relevance as a therapeutic target. Full article