Lambda-Cyhalothrin (LCT), a potent insecticide, is renowned for its efficacy, rapid onset, and broad-spectrum insecticidal activity. With rising annual demand for LCT, environmental concerns have similarly intensified. Nevertheless, its impact on mammalian reproduction, specifically oocytes, and possible mitigation strategies, remains insufficiently understood. This research evaluated the effects of varying LCT concentrations (25, 50, 100 μM) on the in vitro maturation of porcine oocytes, revealing that LCT exposure markedly hindered oocyte maturation and subsequent developmental potential. Fisetin (FIS), a natural flavonoid found in numerous fruits and vegetables, exhibits robust antioxidant, anti-inflammatory, and neuroprotective properties. Notably, when different concentrations of FIS were incorporated into the culture medium of LCT-exposed oocytes, it mitigated LCT-induced toxicity. FIS supplementation significantly enhanced antioxidant capacity, improved endoplasmic reticulum (ER) and mitochondrial functions, and reduced apoptosis in comparison to the LCT-exposed group. Key markers, including the ER stress protein GRP78 (Control: 1.00 vs. LCT: 1.75 ± 0.08, P < 0.001; vs. LCT + FIS: 1.37 ± 0.07, P < 0.001) and autophagy marker LC3B (Control: 1.00 vs. LCT: 1.50 ± 0.32, P < 0.05; vs. LCT + FIS: 1.18 ± 0.16, P > 0.05), were significantly reduced in the FIS-treated oocytes. These results suggest that LCT compromises mitochondrial and ER function in oocytes through the upregulation of GRP78, while FIS supplementation effectively counteracts this toxicity, providing protection against LCT-induced damage. This study underscores FIS's potential as a protective agent in alleviating LCT-related reproductive toxicity.

Background Gastric cancer is the world's leading tumor disease in terms of morbidity and mortality and is currently treated clinically with a comprehensive approach based on surgery. Studies have demonstrated the antitumor effects of neferine, but the anti-cancer mechanism for gastric cancer is not yet clear. Methods The Pubchem and Swiss TargetPrediction databases were searched to retrieve the targets of action of neferine. Meanwhile, relevant gene expression data were downloaded by means of the Gene Expression Omnibus(GEO) database to screen for differential genes and build a drug-disease network. The selected genes were analysed by bioinformatics analysis. Finally, gastric cancer treatment potential of neferine was determined through molecular docking. The molecular mechanism of neferine in the treatment of gastric cancer was verified by CCK8 assay, monoclonal assay, apoptotic and cycle assay, qRT-PCR and Western Blot. Results The results of network pharmacological analyses illustrate that the core genes are closely related to apoptosis, cell cycle, and cell proliferation. Through molecular docking, it was confirmed that neferine were closely related to key proteins. The results of in vitro experiments indicated that neferine could significantly inhibit the viability of gastric cancer cells, induce apoptosis of gastric cancer cells, and block the cell cycle of gastric cancer cells in the G0/G1 phase. Conclusion In summary, neferine inhibited the proliferation of gastric cancer cells through the CDK4/CDK6/CyclinD1 complex. This study provides a theoretical basis for the treatment of gastric cancer with neferine and an idea for the development of neferine for gastric cancer.

Our study aims to investigate the potential of artesunate (ART) in improving learning and memory function by down-regulating NLRP3 and consequently affecting pyroptosis levels in the brains of rats with cerebral small vessel disease (CSVD). Initially, Sprague-Dawley (SD) rats were randomly assigned to five groups: the solvent sham operation group, solvent model group, low-dose ART (ARTL) group, medium-dose ART (ARTM) group, and high-dose ART group (ARTH). CSVD rat models were established through bilateral common carotid artery occlusion (BCCAO). Subsequently, the rats were further divided into four groups: the empty plasmid control group (shNC) and three groups receiving NLRP3-shRNA interference plasmids (shNLRP3-1, shNLRP3-2, shNLRP3-3). We recorded animal behaviors and stained nerve cell changes. Hippocampal expression levels of Caspase-1, cleaved caspase-1, IL-18, IL-1β, GSDMD-N, β-actin, and NLRP3 were evaluated in each group. Our findings revealed that ART ameliorated cognitive dysfunction and brain tissue injury in CSVD rats. Moreover, expression levels of cleaved caspase-1, IL-18, IL-1β, GSDMD-N, and NLRP3 in the hippocampus were significantly reduced in the shNLRP3 group, resulting in improved cognitive function in these rats. These results suggest that NLRP3 could be a potential therapeutic target in CSVD development in rats, and modulating its expression might mitigate pathological alterations associated with CSVD. Subsequently, lipopolysaccharide (LPS) was injected into the tail vein, and inflammatory factors in peripheral blood of rats were found to be increased, suggesting that the level of intracranial NLRP3 was increased. In addition, MWM experiment showed that after the increase of NLRP3 expression, the repair effect of ART on learning and memory dysfunction was weakened. ART may enhance cognitive impairment in CSVD rats by downregulating NLRP3 expression in the brain, thereby inhibiting neuronal cell pyroptosis in the hippocampus.

Metabotropic glutamate receptor 5 (mGluR5) is a critical regulator of immune responses within the neuroimmune system, influencing cytokine secretion and immune cell function. Although extensively studied in mammals, its role in regulating IL-17 in invertebrate immunity is poorly understood. This study examines CgmGluR5 expression and downstream signaling activation in Pacific oyster (Crassostrea gigas) hemocytes following glutamate (Glu) and Vibrio splendidus treatment. Glu treatment significantly induced the expression of CgmGluR5 and key signaling molecules, including PLC, DAG, IP3, Ca²⁺, and PKC, while enhancing mRNA levels of CgIL17-1, CgIL17-5, and CgCaspase3. Elevated Ca²⁺ content and CgIL17 expression in hemocytes were observed at 12 h post-Glu exposure, indicating CgmGluR5-mediated immune regulation through the phosphoinositide pathway. A 1.14-fold increase in the apoptosis rate was found in the Glu treatment group compared to the control group. Knockdown of CgmGluR5 suppressed CgIL17-1 and CgIL17-5 expression and reduced granulocyte proportions, reflecting its role in immune regulation. This study shows that CgmGluR5 mediates long-term immune regulation in oysters through the phosphoinositide pathway, providing new theoretical insights for aquaculture immune management.

Cuproptosis is a form of copper-dependent non-apoptotic cell death. Cancer cells that prefer to use aerobic glycolysis for energy generation are commonly insensitive to cuproptosis, which hinders its application for cancer treatment. Epigallocatechin gallate (EGCG) possesses diverse pharmacological activities. However, the association between EGCG and cuproptosis has not been studied.

Type 2 diabetes is a risk factor for colorectal cancer (CRC) development and progression. However, metformin-treated diabetic CRC patients tend to have better clinical outcomes than those managed by other means. To better characterize the molecular underpinnings of metformin's protective effects, we performed a targeted transcriptomic analysis of primary CRC tissue samples (n = 272). A supervised learning algorithm pinpointed molecular features that discriminate between metformin-treated and diet-controlled diabetic CRC samples, as well as those that discriminated between non-diabetic samples based on their five-year overall survival status. Our results show downregulation of TMEM132 in metformin-treated samples (p = 0.05) and non-diabetics with good clinical outcomes (p = 0.05) relative to diet-controlled and non-diabetics with poor survival, respectively. Furthermore, upregulation of SCNN1A is observed in metformin-treated samples (p = 0.04) and non-diabetics with good clinical outcomes (p = 0.01) relative to diet-controlled samples and those with poor clinical outcomes, respectively. We also show that the antiapoptotic protein sFas is downregulated in metformin-treated samples relative to diet-controlled samples (p = 0.005). These findings suggest a role for the unfolded protein response in mediating metformin-related CRC-protective effects by enhancing apoptosis and suggest the investigation of these proteins as targets for novel CRC therapies.

Pseudomonas aeruginosa is an opportunistic pathogen that uses several mechanisms to survive in the iron-limiting host environment. The innate immune protein calprotectin (CP) sequesters ferrous iron [Fe(II)], among other divalent transition metal ions, to limit its availability to pathogens. CP levels are increased in individuals with cystic fibrosis (CF), a hereditary disease that leads to chronic pulmonary infection by P. aeruginosa. We previously showed that aerobic CP treatment of P. aeruginosa induces a multi-metal starvation response that alters expression of several virulence properties. However, the CF lung is a hypoxic environment due to the growth of P. aeruginosa in dense biofilms. Here, we report that anaerobic CP treatment of P. aeruginosa induces many processes associated with an aerobic iron starvation response, including decreased phenazine production and increased expression of the PrrF small regulatory RNAs (sRNAs). However, the iron starvation response elicited by CP in anaerobic conditions shows characteristics that are distinct from responses observed in aerobic growth, including a lack of siderophore production and increased induction of genes for the FeoAB Fe(II) and Phu heme uptake systems. Also distinct from aerobic conditions, CP treatment induces expression of genes for predicted manganese transporters MntH1 and MntH2 during anaerobic growth while eliciting a less robust zinc starvation response compared to aerobic conditions. Induction of mntH2 is dependent on the PrrF sRNAs, suggesting a novel example of metal regulatory cross-talk. Thus, anaerobic CP treatment results in a multi-metal starvation response with key distinctions from aerobic conditions, revealing differences in P. aeruginosa metal homeostasis during anaerobic growth.IMPORTANCEIron is critical for most microbial pathogens, and the innate immune system sequesters this metal to limit microbial growth. Pathogens must overcome iron sequestration to survive during infection. For many pathogens, iron homeostasis has primarily been studied in aerobic conditions. Nevertheless, some host environments are hypoxic, including chronic lung infection sites in individuals with cystic fibrosis (CF). Here, we use the innate immune protein calprotectin, which sequesters divalent metal ions including Fe(II), to study the anaerobic iron starvation response of a common CF lung pathogen, Pseudomonas aeruginosa. We report several distinctions of this response during anaerobiosis, highlighting the importance of carefully considering the host environment when investigating the role of nutritional immunity in host-pathogen interactions.

Targeted therapies for melanoma MEK and BRAF inhibitors fail due to the development of chemoresistance. As Hsp90 inhibitors target client proteins of resistant pathways, we hypothesised that C-terminal Hsp90 inhibitors will target BRAF/MEK inhibitor resistant melanoma cells by overcoming the resistant pathways. Two melanoma cell lines, A375 and A375 MEK/BRAF inhibitor resistant (A375MEKi) were utilised. The inhibitory concentrations (IC50) of two C-terminal Hsp90 inhibitors, KU757 and KU758, were determined by CellTiter Glo. RNA sequencing was performed after treatment with KU757. Pathways targeted by differentially expressed genes were evaluated by David, IPA, GSEA, and by evaluating the cell cycle, apoptosis and oxidative phosphorylation. Expression levels of hub genes were evaluated using Xena and validated by RT-PCR. The survival analysis was performed using UALCAN. A375MEKi was not resistant to the C-terminal Hsp90 inhibitor with a KU757 IC50 of 0.59 μM versus 0.64 μM and a KU758 IC50 of 0.89 μM versus 0.93 μM in A375 versus A375MEKi, respectively. RNA sequencing analysis revealed KU757 upregulates cell cycle checkpoint regulation and apoptosis and downregulates genes involved in the peroxisome, AKT/PI3K/MTOR, EIF2, fatty acid metabolism and oxidative phosphorylation. These pathways were further validated through survival analysis that demonstrated potential survival benefit in patients with dysregulated NDUFA7, CDC20, CDC25C, CDK1, VDAC2, HEATR5a, COL4A4, FLT3LG, BMP2, PRKCH and ADMST9. Melanomas often develop concurrent resistance to BRAF and MEK inhibitors. C-terminal Hsp90 inhibition with KU757 appears to overcome these chemo-resistance pathways in vitro, downregulating metabolic pathways including oxidative phosphorylation and the cell cycle, warranting further in vivo translation. The novel C-terminal HSP90 inhibitor KU757 effectively targets primary and BRAF and MEK inhibitor-resistant melanoma cells equally by affecting oxidative phosphorylation and the cell cycle.

Lactobacillus salivarius serves as a probiotic potentially capable of preventing dental caries both in vitro and in vivo. This study focused on understanding the key antibiofilm agents and the mechanisms of action of the Lactobacilli supernatant against Streptococcus mutans.

Triple-negative breast cancer (TNBC) is a highly malignant tumor that requires effective therapeutic targets and drugs. Oxidative phosphorylation (OXPHOS) is a metabolic vulnerability of TNBC, but the molecular mechanism responsible for the enhanced OXPHOS remains unclear. The current strategies that target the electronic transfer function of OXPHOS cannot distinguish tumor cells from normal cells. Investigating the mechanism underlying OXPHOS regulation and developing corresponding therapy strategies for TNBC is of great significance.

Chemotherapy resistance is a major challenge in the treatment of intermediate and advanced gastric cancer (GC). This study aimed to recognize oxaliplatin resistance-related genes (OXARGs) in GC and to explore their role and mechanism in oxaliplatin resistance of GC.

The anti-HER2 monoclonal antibody trastuzumab and new derivative formulations are the standard treatment for HER2-positive breast cancer. However, after 1 to 5 years of treatment, some patients acquire resistance to therapy, leading to relapse. The microRNA-449 family members were downregulated in HER2-positive breast cancer cell lines and low levels were associated with patients' worse prognosis. Moreover, trastuzumab-resistant HER2-positive breast cancer cell lines showed lower microRNAs-449 and higher Fatty Acid Synthase (FASN) expression, compared to sensitive cell lines. The direct regulation of FASN by microRNA-449a and microRNA-449b-5p was demonstrated. Moreover, microRNAs-449 overexpression and FASN inhibition decreased cell proliferation and sensitized cells to trastuzumab treatment by inhibiting the PI3K/AKT signaling pathway. Together, these results suggest the microRNAs-449/FASN axis as a potential therapeutic target in combination with anti-HER2 agents to overcome trastuzumab resistance and to improve treatment response in HER2-positive breast cancer patients.

Insect development is primarily controlled by juvenile hormone (JH) and 20-hydroxyecdysone (20E), which regulate gene cascades leading to changes in phenotype, physiology, and behavior. Besides these hormones, microRNAs play a crucial role in insect development by regulating gene expression at the post-transcriptional level. To advance the molecular understanding of holometabolous developmental events, we investigate the pupal phase in the honeybee, Apis mellifera. In this study, we assessed the expression profiles of genes components of JH and 20E cascades - Usp, ftz-f1, EcR, Met, Chd64, InR-2, Kr-h1 and Tai - as well as the microRNAs miRNA-34 and miRNA-281 during pupal development of A. mellifera. We then analyzed the impact of JH and 20E treatments on the expression of these developmental genes and their putative regulators, the microRNAs. Overall, the selected genes and miRNAs remained stable or were downregulated following 20E treatment, while treatments with JH, upregulated most of our candidate developmental genes and microRNAs. Notably, the expression profile of Met, an intracellular receptor of JH, showed a strong correlation with fluctuations in 20E titers during pupal development. Furthermore, a computational analysis, followed by experimental assays, points to both miR-34 and miR-281 as potential regulators of pupal development in A. mellifera. This study paves the way for a better understanding of how JH and 20E hormones interact with developmental genes and microRNAs (miR-34 and miR-281) to regulate pupal development in honeybees, elucidating a piece of this complex network of interactions.

Cisplatin (CDDP) based chemotherapy has emerged as the predominant therapeutic regimen for patients with advanced gastric cancer (GC). However, its efficacy is dampened by the development of chemoresistance, which results in poor prognosis of patients. GLI2, a key transcription factor in the Hedgehog (Hh) signaling pathway, is regarded as a target for cancer therapy. However, the significance of GLI2 for CDDP resistance in GC has not been well established. Here, we show that GLI2 expression was upregulated in EMT-type GC and associated with poor prognosis. GLI2 promotes proliferation, migration, and CDDP resistance of GC cells by inducing EMT. In terms of mechanism, GLI2 binds to the promoter region of DEC1 and enhances its expression, thereby co-transcriptionally regulating ZEB1 expression. Animal experiments have demonstrated that both GLI2 knockdown and GLI2 inhibitor significantly enhance CDDP sensitivity in GC. Our data not only identify a novel GLI2/DEC1/ZEB1/EMT pathway in GC CDDP resistance but also provide novel strategies to treat GC in the future.

Cervical cancer (CC) remains a major health challenge with high mortality rates due to chemoresistance and immune escape. However, the underlying mechanisms remain unclear. We investigated the role of TAB2 in CC using cisplatin-resistant and parental cell lines. Cell proliferation, migration, sphere formation and T cell-mediated killing assays were performed. Western blot and qRT-PCR analysed protein and mRNA expression. NF-κB pathway involvement was examined using the BAY 11-7082 inhibitor. TAB2 expression was significantly elevated in cisplatin-resistant CC cells. TAB2 overexpression promoted chemoresistance and immune escape through NF-κB pathway activation. Conversely, TAB2 knockdown or NF-κB inhibition sensitised resistant cells to cisplatin and enhanced T cell-mediated killing. The resistant phenotype could be rescued by restoring PD-L1 expression. Our findings reveal TAB2 as a critical regulator of both chemoresistance and immune escape in CC through NF-κB pathway activation. This suggests TAB2 as a potential therapeutic target for overcoming treatment resistance in CC.

Breast cancer (BC) is one of the most common types of cancer and is caused by the complex interplay of genetic and environmental factors, such as an unhealthy lifestyle, family history of illness, reproductive factors, and ageing. However, increasing evidence has revealed that manufactured organic pollutants such as bisphenols are closely related to BC. Bisphenols exposure can promote the progression of BC through multiple complicated and variable molecular mechanisms. Reanalysis of existing data on this topic may reveal molecular markers with clinical value. In this study, we identified four key genes [keratin 14 (KRT14), keratin 5 (KRT5), acyl-CoA synthetase long chain family member 1 (ACSL1) and matrix metallopeptidase 1 (MMP1)] related to both bisphenols exposure and BC by employing the Comparative Toxicogenomics Database (CTD) and The Cancer Genome Atlas Cervical Cancer (TCGA-CESC) dataset; notably, KRT14 expression exhibited the most significant difference between tumour and normal tissues. Further analysis of the functions and biological processes associated with KRT14 and related regulatory molecules revealed that bisphenols exposure induces BC-promoting characteristics and aggressive behaviour-related signaling pathways, such as the steroid biosynthesis, Forkhead box (FOXO) and prolactin signaling pathways. To confirm the expression and biological effects of KRT14, we conducted relevant experiments. In vitro studies revealed that bisphenols such as bisphenol A (BPA) exposure significantly affected the proliferation, migration, and invasion of MCF-7 cells by inhibiting KRT14 expression. Similarly, we also observed a decrease in KRT14 expression in BPA induced abnormal breast tissue in mice. In summary, our study revealed potential genes and pathways associated with bisphenols exposure in BC.

Serotonin acts in an autocrine/paracrine manner within the mammary epithelium regulating cell homeostasis during lactation and cell turnover during involution after milk stasis. However, the presence and role of mammary serotonin during the pubertal developmental stage is unknown in the bovine. Here, we characterized the serotonin receptor profile and serotonin immunolocalization in bovine mammary tissue at eight developmental stages (i.e., birth, weaning, puberty, six months gestation, early lactation, mid-lactation, early dry and late dry, n = 6/stage). Further, we investigated the effects of 5-HTP (serotonin precursor), 17β-estradiol (E2), and ICI 182780 (ERα antagonist) either alone or in various combinations (i.e., 5-HTP +  E2, 5-HTP + ICI, E2 + ICI or 5-HTP + E2 +  ICI) on cultured bovine mammary epithelial cells (MAC-T). Serotonin receptor gene expression is highly dynamic throughout mammary development, particularly highly expressed in the puberty stage expressing 12 out of the 13 serotonin receptors evaluated (5-HTR1A, -1B, -1D, -1F, -2A, -2B, -2C, -3B, -4, -5a, -6, and -7), relative to the birth stage. Following a 24-hour incubation, all treatments except ICI increased MAC-T cell proliferation. Incubation with 5-HTP +  ICI resulted in a downregulation of ESR1, ESR2, GPER1 and AREG, relative to CON. Incubation with 5-HTP and E2 alone downregulated the expression of TPH1, 5-HTR1A and 5-HTR1B, relative to CON. Overall, our data indicates serotonin is present in the juvenile developing mammary tissue and the expression of various receptors is observed suggesting an active involvement at this early stage. Additionally, serotonin might indirectly regulate mammary epithelial cell proliferation alone and concurrently with E2 during puberty through the modulation of E2 signaling genes and 5-HTR1A and -1B.

This study aimed to investigate the relationship between tumor necrosis factor alpha-induced protein (TNFAIP6/TSG-6) and astrocytes in cerebral ischemia/reperfusion (I/R) injury.

This study aims to investigate the effect and mechanism of photodynamic therapy (PDT) combined with cisplatin on human lung adenocarcinoma A549 cells transplanted tumors in nude mice, and to provide a theoretical basis for clinical PDT. Construction of a nude mouse lung cancer transplantation tumor model using the human lung adenocarcinoma A549 cell line, and the mice were randomly divided into four groups: the control group, the cisplatin alone group, the PDT alone group, and the cisplatin combined PDT group. The apoptosis of tumor cells in the four groups was observed and compared by the TUNEL method, and the mRNA expression levels of apoptosis-related genes Bax, caspase-3 and Survivin, as well as the expression levels of the corresponding proteins, were detected by the real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and the protein immunoblotting technique (Western blot) respectively. The results showed that photodynamic force combined with cisplatin was effective in inhibiting tumor growth, and its effect was superior to that of cisplatin or PDT alone. This may be related to the promotion of apoptosis, specifically through the up-regulation of Bax and caspase-3, and the down-regulation of Survivin gene expression, thus inhibiting cell proliferation.

Inadequate angiogenesis of endometriotic implants stimulated by the inflammatory microenvironment in the uterine region leads to the development of gynecological diseases, which significantly reduce the fertility and vitality of young women. Angiogenic processes are controlled by factors whose activities are regulated at the gene level by reactive oxygen species (ROS), hypoxia-induced factors (HIFs), and zinc-finger proteins (ZnFs) or posttranscriptionally via non-coding RNAs. The cooperation of these factors is responsible for the manifestation of pathological stimuli in the form of endometriosis of the body of the uterus, ovaries, or peritoneum, from which endometrioid carcinoma can develop. Molecules that can control gene expression by their intercalation to target DNA sequence, such as [Zn(neo)(nif)2], could prevent the hyperactivation of pro-angiogenic pathways (decrease HIF-1α, VEGF-A, TGF-β1, COX2, and ANG2/ANG1), reduce the formation of ROS, and reduce the risk of uterine neoplasticity. The NSAID-metal complex [Zn(neo)(nif)2] shows an ability to intercalate into ZNF3-7 target DNA sequence at a higher rate, which could explain its effect on genes regulated by this transcription factor. In addition, [Zn(neo)(nif)2] affects ROS production and Ca2+ level, possibly pointing to mitochondrial dysfunction as a potential cause for the described apoptosis.