As neuroendocrine neoplasms (NEN) undergo increasing dedifferentiation, CXC chemokine receptor type 4 (CXCR4) becomes upregulated. Higher levels of CXCR4 are associated with invasive growth, metastasis formation, and poor prognosis. CXCR4 is considered a potential diagnostic biomarker and a promising target for precision therapies - e.g., endoradiotherapeutic approaches, monoclonal antibodies, or small-molecule inhibitors. A variety of systemic therapies are used to treat metastatic NEN, which may modulate CXCR4 expression and potentially influence the efficacy of future CXCR4-targeted strategies. In the NEN cell lines BON-1, QGP-1, and MS-18, we applied cisplatin, etoposide, streptozotocin, 5-fluorouracil, temozolomide, and everolimus- all systemic agents used in highly proliferative NEN. Following incubation, CXCR4 expression was quantified by qRT-PCR, Western blot, and immunohistochemistry. The functional receptor activity was determined by measuring uptake of the radioligand [68Ga]Pentixafor. Cisplatin induced a significant reduction in CXCR4 mRNA levels in BON-1 and QGP-1 cells (p < 0.05) and decreased radioligand uptake in QGP-1 and MS-18. Etoposide, 5-FU, and streptozotocin had no significant impact on CXCR4 expression or uptake activity. Temozolomide and Everolimus markedly diminished both CXCR4 mRNA and protein levels with no significant impact on radioligand uptake. In high-grade NEN cell lines, Cisplatin, Everolimus, and Temozolomide substantially diminish CXCR4 expression, with Cisplatin significantly decreasing CXCR4-targeted radioligand uptake. These findings might have an impact on the optimal therapy sequence and patient selection for future CXCR4-targeted approaches. Further, the decreased CXCR4 expression could represent a new mechanism of action of the established drugs Cisplatin, Temozolomide, and Everolimus.

Candidiasis, caused by yeasts of the Candida genus, is increasingly characterized by a high prevalence of clinical isolates resistant to conventional antifungals, rendering the development of novel therapeutic strategies paramount. Drug repurposing has emerged as a key strategy, utilizing established pharmaceuticals for indications beyond their original design; notably, haloperidol (HAL) has shown promising antimicrobial potential. In this context, the present study evaluates the activity of haloperidol, both as a monotherapy and in combination with conventional antifungals, against fluconazole-susceptible and fluconazole-resistant Candida spp. clinical strains. Furthermore, we investigate the underlying mechanisms of its antifungal action. Experimental approaches included broth microdilution assays to determine the Minimum Inhibitory Concentration (MIC), checkerboard assays for synergistic analysis, and cellular assessments via flow cytometry and fluorescence microscopy. Haloperidol displayed MIC values between 26.67 and 256 μg/mL. Synergistic interactions were identified between haloperidol and the azoles fluconazole and itraconazole, alongside a 2.5 % synergy rate with amphotericin B. Additionally, mechanistic assays confirmed that haloperidol induces programmed cell death (apoptosis) in C. albicans and C. auris strains. The oxidative stress caused by haloperidol altered Ca2+ homeostasis, followed by mitochondrial membrane depolarization, reduced ATP production, cytochrome c release into the cytosol and metacaspase activation, reduced viability, phosphatidylserine externalization, promoted fragmentation, damage and methylation of DNA. It also induced expression of genes related to oxidative stress. It reduced mitochondrial depolarization and decreased the reduction of glutathione (GSH), causing morphological alterations. The results suggest the apoptotic pathway as the main antifungal mechanism of haloperidol.

Burkholderia pseudomallei, the causative agent of melioidosis, is a recognised bioterrorism threat. This microorganism produces a key quorum molecule, 3-Hydroxy-C10 homoserine lactone (3-OH-C10 HSL), which has shown to modulate host immune responses. This study investigated the impact of 3-Hydroxy-C10 HSL on A549 cell line, with a focus on organelle stress and inflammatory responses. Treatment with 3-Hydroxy-C10 HSL (100 μM, 2 h) induces a significant elevation of cytosolic calcium and endoplasmic reticulum (ER) stress, evidenced by BiP upregulation and activation of the PERK-CHOP axis, indicating activation of the unfolded protein response (UPR). Mitochondrial function was compromised, as shown by reduced ATP production, loss of mitochondrial membrane potential (MMP), and elevated mitochondrial ROS generation. Furthermore, lysosomal dysfunction was observed through decreased acridine orange puncta, along with TFEB upregulation and LAMP1 downregulation. Gene expression analysis (10 μM, 6 h) revealed activation of the inflammasome pathway, with increased expression of NLRP3, NLRC4, IL-1β, and IL-18, and enhanced secretion of pro-inflammatory cytokines IL-6, TNF- α, and INF- γ. Overall, 3-Hydroxy-C10 HSL disrupts host cellular homeostasis and induces inflammatory stress, providing novel insights into the molecular mechanisms underlying B. pseudomallei mediated pathogenesis.

Chronic endometritis (CE) is a common gynecological disorder linked to infertility, but its pathogenesis remains unclear.

Fructose is an abundant monosaccharide in the human diet and an important source of energy in the human body. GLUT5, a member of facilitative glucose transporter family, is the only membrane transporter that specifically transports fructose in the human body, and plays an important role in dietary fructose uptake and metabolism. Previous studies have shown that medium-chain fatty acids (MCFAs) can regulate glucose metabolism via modulating glucose transporters. However, it has not been addressed if MCFAs can regulate GLUT5-mediated fructose metabolism. In the present study, we demonstrated for the first time that MCFAs but not short chain or long chain fatty acids are able to promote fructose uptake in both IEC-18 rat intestinal epithelial cells and human MDA-MB-231 breast cancer cells (a commonly used cell line for fructose metabolism-related study) measured by 1-NBD-Fructose-based assay, which are well correlated with the activation of GLUT5-KHK axis. Moreover, the activation of GLUT5-ketohexokinase (KHK) axis was also achieved in vivo by the treatment with tricapylin, a precursor of octanoic acid (OA), leading to the improvement in fructose-based energy recovery after fasting. The findings of the present study not only provide novel mechanistic support for MCFAs as regulator of carbohydrate metabolism, but also denote that MCFAs could be useable for managing fructose-associated metabolic diseases or as an enhancer for energy recovery after fasting or exercise.

Ovarian cancer remains the deadliest gynecologic malignancy. Erianin, a plant-derived compound with antitumor activity through inducing ferroptosis-an iron-dependent programmed cell death that has been shown in other contexts to enhance tumor sensitivity to chemotherapy-has not yet been fully explored in ovarian cancer. We therefore evaluated its anti-proliferative effects and underlying mechanism.

Enhanced proteasome activity is known to confer resistance to cellular stress in vitro and in vivo, but such effects have largely been achieved through genetic upregulation of proteasome subunits and assembly factors. Here, we investigate whether small-molecule 20S proteasome activators can modulate XBP1 signaling during IRE1-driven unfolded protein response (UPR) activation. We show that pre-treatment with a 20S activator prior to IRE1 induction significantly attenuates XBP1 signaling, whereas treatment after chemical induction of IRE1 produces no detectable effect. These findings indicate that proteasome activators can bolster proteasome activity under endoplasmic reticulum (ER) stress, but their ability to modulate an ongoing UPR is limited. This work highlights a potential temporal window in which proteasome activation may influence stress-adaptive signaling.

Low-density lipoprotein receptor-related protein 5 (LRP5), a co-receptor of frizzled (FZD) in the WNT/β-catenin signaling pathway, recognizes Wnt ligands. This study aimed to assess the anti-cancer effects of silencing LRP5 on glioblastoma (GBM) and brain cancer stem cells (BCSCs). Additionally, the effect of temozolomide (TMZ) was also examined in these cells with suppressed LRP5 expression. LRP5 expression was silenced in U87MG, T98G, and BCSC cells using siRNA. Protein expression levels were determined by Western blotting. Cell viability after LRP5 silencing and/or TMZ treatment was evaluated using the CVDK-8 assay. Flow cytometry was used to examine apoptosis and cell cycle progression. Clonogenic, cell invasion, and wound-healing assays were used to assess colony formation, invasion, and migration, respectively. siRNA-mediated silencing reduced protein expression of LRP5 and Wnt/β-catenin target genes in GBM and BCSC cells. Furthermore, suppression of LRP5 reduced cell viability, and its combination with TMZ enhanced anti-proliferative effects. Silencing LRP5 and/or TMZ treatment caused cell cycle arrest and significantly diminished the aggressive characteristics of GBM and BCSC cells. These findings suggest that LRP5 may serve as a potential therapeutic target for treating GBM. Targeting LRP5 may enhance the effectiveness of the chemotherapy agent TMZ in GBM.

Sphingolipids are essential components of eukaryotic membranes and play central roles in cellular growth and stress responses. In the budding yeast Saccharomyces cerevisiae, Lcb1 and Lcb2 constitute the serine palmitoyltransferase complex, which catalyzes the initial step of sphingolipid biosynthesis. Repression of LCB1 expression leads to inhibition of sphingolipid biosynthesis, resulting in severe growth defects. Here, we aimed to identify novel genes functionally associated with sphingolipid metabolism by screening for suppressor mutations that confer resistance to sphingolipid biosynthesis inhibition. To conditionally suppress sphingolipid biosynthesis, we employed a tetracycline-repressible promoter to control LCB1 expression. This screen revealed that deletion of SAC7, YTA7, RNR1, RPL23B, or RPL35A confers resistance to LCB1 repression. The suppressive effect of YTA7, RNR1, RPL23B, and RPL35A deletions was also observed under conditions in which growth inhibition was induced by repression of AUR1, a gene involved in the conversion of ceramides to complex sphingolipids. These genes encode proteins related to ribosomal subunits or DNA biosynthesis. Furthermore, sublethal concentrations of cycloheximide (a translation inhibitor), diazaborine (a ribosome maturation inhibitor), hydroxyurea (a DNA biosynthesis inhibitor), and zeocin (a DNA double-strand break inducer) alleviated growth defects caused by LCB1 repression. Diazaborine or hydroxyurea partly suppressed the decrease in complex sphingolipids induced by Lcb1 repression. Additionally, these treatments suppressed the reduction in Lcb1 and Aur1 protein expression levels. These findings reveal a previously unappreciated link between ribosome function, DNA biosynthesis, and sphingolipid metabolism and provide insight into how cells adapt to metabolic stress.

While BRASSINOSTEROID (BR) SIGNALING KINASEs (BSKs) are known to interact with the BR receptor BR-INSENSITIVE 1 (BRI1), the extent of their genetic redundancy and essential contribution to BR signaling remain unclear. This study aimed to systematically investigate the function of BSK family members and uncover novel developmental outputs controlled by BR signaling via BSKs mediated pathway in Arabidopsis. We generated an undecuple bsk knockout/knockdown mutant (bsk-u) in Arabidopsis. Comprehensive phenotypic observation, molecular analyses, and genetic complementation were performed to characterize the mutant. Subsequently, the role of the LATERAL ORGAN BOUNDARIES DOMAIN16 (LBD16) in mediating BR-suppressed adventitious root (AR) development was further examined using genetic and physiological approaches. The bsk-u mutant exhibited severe BR-insensitive phenotypes, including dwarfism, impaired BZR1 dephosphorylation, and attenuated transcriptional responses to BR. We identified LBD16 as a key BZR1 target repressed by BR signaling. BR application inhibited AR formation in wild-type explants, whereas BR-deficient mutants produced more ARs. Overexpression of LBD16 partially alleviated BR-mediated suppression of AR development. This study establishes that BSKs are indispensable for the BR signaling pathway in Arabidopsis. Furthermore, it reveals a novel role for BR in negatively regulating AR development through transcriptional repression of LBD16, expanding our understanding of BR-mediated developmental control.

Polygonatum sibiricum (P. sibiricum), rich in saponins, possesses extremely high medicinal value. However, inconsistent saponin levels in naturally grown P. sibiricum hinder its quality control assessments and industrial progress. In this study, we applied salicylic acid (SA) to P. sibiricum and measured the content changes of 11 saponins. Transcriptome sequencing was used to explore the molecular mechanism of saponin biosynthesis. Key saponin biosynthesis genes were identified and subsequently characterized through phylogenetic and structural analyses. The results showed that saponin contents changed significantly after SA treatment. We characterized six key gene families: SQLEs (squalene epoxidases, EC: 1.14.14.17), DXSs (1-deoxy-D-xylulose-5-phosphate synthases, EC: 2.2.1.7), FDPSs (farnesyl diphosphate synthases, EC: 2.5.1.1/2.5.1.10), CYP710As (cytochrome P450, family 710, subfamily A; sterol 22-desaturase, EC: 1.14.19.41), HMGCSs (3-hydroxy-3-methylglutaryl-CoA synthases, EC: 2.3.3.10), and SMT1s (sterol methyltransferase 1s, EC: 2.1.1.41), whose phylogenetic analysis revealed the unique evolutionary position of saponin biosynthesis genes. Furthermore, structural prediction and molecular docking revealed functional adaptations of SQLEs. In summary, our findings decipher the molecular mechanisms of SA-induced saponin biosynthesis in P. sibiricum, which can boost its medicinal value.

The development of new nanotechnologies and their use in everyday life always carries the risk of environmental hazards and consequences for human health. Among them, graphene oxide (GO) is a promising material. Due to its excellent physicochemical properties, GO is attractive not only for industrial applications but also in medicine. There is still a lack of sufficient reports on the long-term effects of GO on organisms, including studies of a multigenerational nature. We investigated the health status of two strains of Acheta domesticus: the wild type and the long-lived. The strains were exposed to GO for five generations and a sixth recovery generation. We investigated parameters that may indirectly explain the mechanisms involved in transmitting the informational pattern of the stress response to subsequent generations: DNA stability, mitochondrial potential, apoptosis, and autophagy. GO intoxication induced multilevel cellular responses in five subsequent generations. GO cessation in recovery F5 acted as a new stressor. Across five generations, variation in the response to GO was observed. GO is most likely responsible for changes that persist over generations. We believe that epigenetic inheritance is a likely mechanism underlying the multigenerational adaptation observed in GO-exposed insects, and future research should aim to elucidate this phenomenon in more detail.

There is significant interest in the development of comprehensive strategies to combat obesity. One such approach involves the combination of exercise training with pharmacological interventions. Recently, the injection of adenosine (Ade) has garnered attention as a potential adjunctive treatment. Forty-two male rats were assigned to two dietary groups for 25 weeks: normal diet and high-fat diet (HFD). After 13 weeks, the HFD group was randomly divided into 4 subgroups for a 12-week intervention: HFD + HIIT + Ade, HFD + HIIT, HFD + Ade and HFD control. The study comprised 4 phases:1) initiation and baseline weighing, 2) fattening, 3) first intervention (Ade 0.2 mg/kg + HIIT), and 4) second intervention (Ade 0.4 mg/kg + HIIT). The HFD + HIIT + Ade group exhibited a significant increase in the expression of AMPK, HSL and A2A receptor genes and proteins compared to other groups. The highest expression of the CGI-58 gene and protein was significantly observed in the HFD + HIIT group. The ACC gene expression was significantly higher in the HFD group, while the lowest expression was observed in the HFD + HIIT group. The most significant weight loss occurred in the HFD + HIIT + Ade group. HIIT activates lipolytic pathways while concurrently suppressing lipogenic pathways, effects that are enhanced by Ade administration. Moreover, HIIT alone can stimulate Ade-mediated lipolytic receptors, with these effects further augmented by optimal doses of Ade.

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Among its genetic subtypes, KMT2A (formerly MLL)-rearranged ALL (KMT2Ar-ALL) is associated with poor outcomes. Immunotherapy approaches are being studied and used in KMT2Ar-ALL; however, there is evidence that leukemic cells can escape immune control. Our previous study identified Galectin-1, an immune checkpoint protein, as highly expressed in KMT2Ar-ALL, suggesting it as a potential therapeutic target. To date, the exact mechanism of Galectin-1 regulation in KMT2Ar-ALL is unknown. Therefore, the present study aimed to investigate the potential involvement of the mTOR signaling pathway in the regulation of Galectin-1 expression in KMT2Ar-ALL.

The Hevea brasiliensis is the only commercial source of natural rubber. In natural rubber production, exogenous ethylene is widely used as a stimulant for increasing rubber latex yield. To reveal the potential regulation mechanisms for ethylene stimulation of natural rubber production in H. brasiliensis, we performed an integrative analysis of transcriptomics and proteomics for ethylene-stimulated rubber latex. A total of 35,306 genes and 3620 proteins were successfully identified from the different latex samples upon ethylene stimulation. Gene Ontology analysis revealed that these genes are mainly involved in cytoplasm and cytoplasmic and catalytic activity. Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that their pathways are mainly enriched in alanine and glutamate metabolism, carbon metabolism, and carbon fixation. Ethylene stimulation played a key regulatory role at the translational/post-translational modification level to promote natural rubber synthesis. Notably, 64 genes and 35 proteins are directly involved in natural rubber biosynthesis. Among them, several family members of 3-hydroxy-3-methylglutaryl coenzyme A reductase, small rubber particle protein, and cis-prenyl transferase (CPT) are ethylene-responsive ones. It is noteworthy that accumulation of CPT7 was significantly increased after ethylene application. Overexpression of HbCPT7 in a rubber-producing model plant, Taraxacum Kok-saghyz, resulted in a significant increase in rubber content in the transgenic Taraxacum Kok-saghyz roots.

Traditional Chinese medicine (TCM) has demonstrated multiple therapeutic advantages in colorectal cancer (CRC) management. The herbal formula Fuzheng Shengbai Decoction (FZSB) has been widely used in clinical practice with well-documented therapeutic efficacy; nevertheless, the mechanisms underlying its anti-CRC effects remain largely unexplored.

The developmental origins of health and disease hypothesis suggests that environmental exposures during early immune development may trigger long-term immune pathologies. However, the timing of sensitive developmental windows in the innate immune system of vertebrates remains poorly defined. Here, we propose the marine medaka fish (Oryzias melastigma) as a model organism to define a molecular timeline for innate immune system maturation. To identify critical windows of immune development, we assessed both organismal resistance to bacterial infection and molecular markers of immune gene expression across developmental stages. Immune competence evaluation in embryos and larvae revealed distinct windows of vulnerability to bacterial challenge, suggesting dynamic immune regulation. 17α-Ethinylestradiol (EE2), a potent synthetic estrogen is known to affect both reproductive and immune function. Embryos and larvae were exposed to EE2 during three key periods (7-11 days post fertilization (dpf), 3-5 days post hatching (dph), and 12-19 dph) and subsequently challenged with a bacterial pathogen. EE2 exposure during the embryonic (7-11 dpf) and later larval (12-19 dph) periods significantly reduced pathogen resistance in a non-monotonic dose response manner, altered the expression of immune-related genes involved in protein synthesis and ribosome biogenesis and modified energy and amino acid metabolism. Altogether, this study underscores the importance of identifying sensitive periods in immune development when evaluating environmental risks and support the use of marine medaka as a relevant model for developmental immunotoxicity.

Follicle maturation is critical for egg quality and fry production, yet its transcriptional regulation remains poorly defined. In this study, we employed comparative transcriptomics across five developmental stages (SCS1-SCS5) following HCG induction to resolve stage-specific transcriptional dynamics in mandarin fish (Siniperca chuatsi) follicle. A total of 15 libraries yielded high-quality data with mapping rates of 92.50-96.79 %, identifying 17,320 differentially expressed genes (DEGs), with a pronounced increase in later maturation stages. Functional enrichment highlighted stage-specific activation of key biological processes, including oocyte maturation, steroid biosynthesis, meiotic regulation, lysosomal proteolysis, fatty acid degradation, and immune responses. Notably, core cell-cycle regulators (CDC20, BUB1Bb, PKMYT1, YWHAE1) exhibited dynamic patterns consistent with meiotic resumption, indicating activation of the maturation-promoting factor (MPF) and APC/C pathways. Yolk hydrolysis was mediated by lysosomal proteases (CTSBa, CTSC) and ubiquitin-proteasome system genes (CDC34a), while lipid metabolism supported lipid droplet formation. Stage-specific immune activation further suggested complex immune-reproductive crosstalk. Co-expression network analysis further identified key hub genes positively (e.g., CDC20, BUB1Bb, SETD2) or negatively (e.g., MRPL4, RPS3) associated with maturation. Collectively, this study provides a comprehensive transcriptomic resource and reveals critical pathways and regulators, offering molecular insights to refine hormonal induction and selective breeding strategies in aquaculture.

Given the high recurrence rate of bladder cancer (BCa) and the significant adverse effects associated with conventional treatments, it is urgent to search for new clinical therapeutic targets and safer natural-derived compounds. Resveratrol (Res) has been demonstrated to exhibit cytotoxicity against various tumors. However, the signaling pathways and targets involved in inhibition of BCa cells still need further exploration. This study aims to investigate the mechanism of Res in Bca via suppression of the AURKA/STAT3 axis, providing important theoretical basis for subsequent further researches on Res for treating BCa.

The transition period around parturition in dromedary camels is characterized by profound metabolic and oxidative challenges that can compromise animal health and productivity. This study aimed to evaluate the effects of targeted nutritional strategies on systemic oxidative stress, hepatic antioxidant gene expression, and milk production in multiparous dromedary camels during the transition period. Twenty-four camels were assigned to three dietary groups: control (basal diet), antioxidant-enriched (AOX; vitamin E, selenium, polyphenols derived from pomegranate peel (standardized to punicalagins and ellagitannins)), and energy-enriched (ENE; bypass fats and barley grain). Blood samples were collected weekly from - 45 to + 45 days relative to parturition, and liver biopsies were obtained at days - 30, 0, and + 30 for gene expression analysis. Results showed that AOX and ENE significantly reduced serum malondialdehyde (MDA) levels (P < 0.001) and enhanced activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), particularly at parturition (P < 0.01). Hepatic expression of antioxidant genes (CAT, GPX3, GCLC, GSR) was significantly upregulated in both supplemented groups compared to control (P < 0.05). Furthermore, both AOX and ENE groups exhibited higher milk yields without altering milk composition. Strong correlations (R² = 0.42-0.61) were observed between hepatic gene expression, systemic antioxidant markers, and milk output. These findings demonstrate that nutritional modulation can effectively enhance oxidative resilience and productive performance in transition camels and underscore the value of nutrigenomic approaches in optimizing camel health and management.