Estrogen promotes gonadotropin-releasing hormone expression by regulating tachykinin 3 and prodynorphin systems in chicken.

The "KNDy neurons" located in the hypothalamic arcuate nucleus (ARC) of mammals are known to co-express kisspeptin, neurokinin B (NKB), and dynorphin (DYN), and have been identified as key mediators of the feedback regulation of steroid hormones on gonadotropin-releasing hormone (GnRH). However, in birds, the genes encoding kisspeptin and its receptor GPR54 are genomic lost, leaving unclear mechanisms for feedback regulation of GnRH by steroid hormones. Here, the genes tachykinin 3 (TAC3) and prodynorphin (PDYN) encoding chicken NKB and DYN neuropeptides were successfully cloned. Temporal expression profiling indicated that TAC3, PDYN and their receptor genes (TACR3, OPRK1) were mainly expressed in the hypothalamus, with significantly higher expression at 30W than at 15W. Furthermore, overexpression or interference of TAC3 and PDYN can regulate the GnRH mRNA expression. In addition, in vivo and in vitro assays showed that estrogen (E2) could promote the mRNA expression of TAC3, PDYN, and GnRH, as well as the secretion of GnRH/LH. Mechanistically, E2 could dimerize the nuclear estrogen receptor 1 (ESR1) to regulate the expression of TAC3 and PDYN, which promoted the mRNA and protein expression of GnRH gene as well as the secretion of GnRH. In conclusion, these results revealed that E2 could regulate the GnRH expression through TAC3 and PDYN systems, providing novel insights for reproductive regulation in chickens.

Damage Monitoring of Steel Bars Based on Torsional Guided Waves.

Ultrasonic guided waves represent a new development in the field of non-destructive testing. Longitudinal guided waves are mostly used to monitor the damage of steel bars, but the received signal is usually degraded and noisy owing to its dispersive propagation and multimodal behavior, making its implementation and location challenging. The torsional mode of T (0, 1) is not dispersive in the propagation of a steel bar and only produces circumferential displacement. It was chosen, in this study, to conduct guided wave-based damage monitoring on steel bars to reduce the signal processing complexity. The defects of steel bars, including circular surface defects, internal defects, and uniform damage defects, were thoroughly investigated, respectively, using numerical simulation. The waves were excited and received using the pitch-and-catch technique and the collected monitoring signals were processed using Hilbert transformation to highlight the amplitude and time-of-flight values of the wave signals, which were used for defect identification. In this paper, the reflectivity of guided waves is compared between torsional waves and longitudinal waves, in each case. The impact of defect size changes on damage monitoring is studied and the sensitivity of both the wave frequency and the wave mode (L and T) is also discussed. The results show that the monitoring method based on the torsional wave T (0, 1) is more sensitive to surface defects than the conventional method based on longitudinal waves. The reflectivity of the torsional wave T (0, 1) can be twice that of the longitudinal wave L (0, 1) when the depth of the defect in the circumferential grooves is less than 50% of the diameter of the steel bar. It is more sensitive to shallow surface defects within half of the bar's radius, and it can also effectively identify defects under the conditions of the uniform damage defects of steel bars, even when the measurements are heavily noise-polluted. This proves the superiority of the torsional guided wave T (0, 1) in defect monitoring and provides a theoretical basis for the application of the torsional guided wave T (0, 1) in actual monitoring.

Functional and Transcriptome Analysis Reveal Specific Roles of Dimocarpus longan DlRan3A and DlRan3B in Root Hair Development, Reproductive Growth, and Stress Tolerance.

Ran GTPases play essential roles in plant growth and development. Our previous studies revealed the nuclear localization of DlRan3A and DlRan3B proteins and proposed their functional redundancy and distinction in Dimocarpus longan somatic embryogenesis, hormone, and abiotic stress responses. To further explore the possible roles of DlRan3A and DlRan3B, gene expression analysis by qPCR showed that their transcripts were both more abundant in the early embryo and pulp in longan. Heterologous expression of DlRan3A driven by its own previously cloned promoter led to stunted growth, increased root hair density, abnormal fruits, bigger seeds, and enhanced abiotic stress tolerance. Conversely, constitutive promoter CaMV 35S (35S)-driven expression of DlRan3A, 35S, or DlRan3B promoter-controlled expression of DlRan3B did not induce the alterations in growth phenotype, while they rendered different hypersensitivities to abiotic stresses. Based on the transcriptome profiling of longan Ran overexpression in tobacco plants, we propose new mechanisms of the Ran-mediated regulation of genes associated with cell wall biosynthesis and expansion. Also, the transgenic plants expressing DlRan3A or DlRan3B genes controlled by 35S or by their own promoter all exhibited altered mRNA levels of stress-related and transcription factor genes. Moreover, DlRan3A overexpressors were more tolerant to salinity, osmotic, and heat stresses, accompanied by upregulation of oxidation-related genes, possibly involving the Ran-RBOH-CIPK network. Analysis of a subset of selected genes from the Ran transcriptome identified possible cold stress-related roles of brassinosteroid (BR)-responsive genes. The marked presence of genes related to cell wall biosynthesis and expansion, hormone, and defense responses highlighted their close regulatory association with Ran.

Blockade of V-domain immunoglobulin suppressor of T-cell activation reprograms tumour-associated macrophages and improves efficacy of PD-1 inhibitor in gastric cancer.

BACKGROUND AND AIMS: In gastric cancer, the response rate of programmed cell death protein-1 (PD-1) inhibitor is far from satisfactory, indicating additional nonredundant pathways might hamper antitumour immunity. V-domain immunoglobulin suppressor of T-cell activation (VISTA) has been reported in several malignancies as a novel immune-checkpoint. Nevertheless, the role of VISTA in gastric cancer still remains obscure. Our purpose is to explore the clinical significance and potential mechanism of VISTA in affecting gastric cancer patients' survival and immunotherapeutic responsiveness. METHODS: Our study recruited eight independent cohorts with a total of 1403 gastric cancer patients. Immunohistochemistry, multiplex immunofluorescence, flow cytometry or intracellular flow cytometry, quantitative polymerase chain reaction, western blotting, fluorescence-activated cell sorting, magnetic-activated cell sorting, smart-seq2, in vitro cell co-culture and ex vivo tumour inhibition assays were applied to investigate the clinical significance and potential mechanism of VISTA in gastric cancer. RESULTS: VISTA was predominantly expressed on tumour-associated macrophages (TAMs), and indicated poor clinical outcomes and inferior immunotherapeutic responsiveness. VISTA+ TAMs showed a mixed phenotype. Co-culture of TAMs and CD8+ T cells indicated that VISTA+ TAMs attenuated effective function of CD8+ T cells. Blockade of VISTA reprogrammed TAMs to a proinflammatory phenotype, reactivated CD8+ T cells and promoted apoptosis of tumour cells. Moreover, blockade of VISTA could also enhance the efficacy of PD-1 inhibitor, suggesting that blockade of VISTA might synergise with PD-1 inhibitor in gastric cancer. CONCLUSIONS: Our data revealed that VISTA was an immune-checkpoint associated with immunotherapeutic resistance. Blockade of VISTA reprogrammed TAMs, promoted T-cell-mediated antitumour immunity, and enhanced efficacy of PD-1 inhibitor, which might have implications in the treatment of gastric cancer.

Significance of Volatile Organic Compounds to Secondary Pollution Formation and Health Risks Observed during a Summer Campaign in an Industrial Urban Area.

The chemical complexity and toxicity of volatile organic compounds (VOCs) are primarily encountered through intensive anthropogenic emissions in suburban areas. Here, pollution characteristics, impacts on secondary pollution formation, and health risks were investigated through continuous in-field measurements from 1-30 June 2020 in suburban Nanjing, adjacent to national petrochemical industrial parks in China. On average, the total VOCs concentration was 34.47 ± 16.08 ppb, which was comprised mostly by alkanes (41.8%) and halogenated hydrocarbons (29.4%). In contrast, aromatics (17.4%) dominated the ozone formation potential (OFP) and secondary organic aerosol formation potential (SOAFP) with 59.6% and 58.3%, respectively. Approximately 63.5% of VOCs were emitted from the petrochemical industry and from solvent usage based on source apportionment results, followed by biogenic emissions of 22.3% and vehicle emissions of 14.2%. Of the observed 46 VOC species, hexachlorobutadiene, dibromoethane, butadiene, tetrachloroethane, and vinyl chloride contributed as high as 98.8% of total carcinogenic risk, a large fraction of which was ascribed to the high-level emissions during ozone pollution episodes and nighttime. Therefore, the mitigation of VOC emissions from petrochemical industries would be an effective way to reduce secondary pollution and potential health risks in conurbation areas.

Phospholysine phosphohistidine inorganic pyrophosphate phosphatase suppresses insulin-like growth factor 1 receptor expression to inhibit cell adhesion and proliferation in gastric cancer.

Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) has recently emerged as a novel tumor suppressor. Researchers have observed that LHPP plays a crucial role in inhibiting proliferation, growth, migration, invasion, and cell metabolism across various cancers. Nevertheless, the specific functions and underlying mechanisms of LHPP as a tumor suppressor in gastric cancer (GC) require further exploration. The expression of LHPP was assessed in human GC specimens and cell lines. Various assays were employed to evaluate the impact of LHPP on GC cells. RNA sequencing and Gene Set Enrichment Analysis were conducted to unravel the mechanism through which LHPP regulates GC cell behavior. Additionally, xenograft nude mouse models were utilized to investigate the in vivo effects of LHPP. The findings indicate that LHPP, functioning as a tumor suppressor, is downregulated in both GC tissues and cells. LHPP emerges as an independent risk factor for GC patients, and its expression level exhibits a positive correlation with patient prognosis. LHPP exerts inhibitory effects on the adhesion and proliferation of GC cells by suppressing the expression of insulin-like growth factor 1 receptor (IGF1R) and modulating downstream signaling pathways. Consequently, LHPP holds potential as a biomarker for targeted therapy involving IGF1R inhibition in GC patients.

Octanoic acid-rich enteral nutrition attenuated hypercatabolism through the acylated ghrelin-POMC pathway in endotoxemic rats.

OBJECTIVES: Metabolic disorders and no response to intravenous nutrition because of sepsis have been urgent problems for clinical nutrition support. Enteral nutrition (EN) has been an important clinical therapeutic measure in septic patients; however, simple EN has not demonstrated good performance. This study aimed to investigate the effects of different concentrations of octanoic acid (OA)-rich EN on hypercatabolism in endotoxemic rats and test whether OA-rich EN could attenuate hypercatabolism through the acylated ghrelin-proopiomelanocortin (POMC) pathway. METHODS: Rats were randomly divided into six groups: sham, lipopolysaccharide (LPS), LPS + EN and LPS + EN + OA (0.25, 0.5, and 1 g/kg, respectively) groups to investigate the effects of different concentrations of OA-rich EN on hypercatabolism in endotoxemic rats. The rats were then randomly divided into four groups: sham, LPS, LPS + OA, and LPS + OA + Go-CoA-Tat, to test whether OA-rich EN attenuated hypercatabolism through the acylated ghrelin-POMC pathway. Rats received nutrition support via a gastric tube for 3 d (100 kcal/kg daily). Insulin resistance, muscle protein synthesis and atrophy, inflammatory cytokines, ghrelin in circulation and hypothalamus, ghrelin O-acyltransferase (GOAT), and the adenosine 5'-monophosphate-activated protein kinase (AMPK)-autophagy-POMC pathway were measured. RESULTS: Compared with simple EN, OA-rich EN promoted the acylation of ghrelin in a dose-dependent manner and attenuated POMC-mediated hypercatabolism in endotoxemic rats. Inhibition of GOAT activity decreased the level of acylated ghrelin and aggravated POMC-mediated hypercatabolism conferred by OA-rich EN. CONCLUSIONS: OA-rich EN could increase the level of acylated ghrelin and attenuate hypercatabolism through the acylated ghrelin-POMC pathway compared with simple EN in endotoxemic rats.

Chicken muscle antibody array reveals the regulations of LDHA on myoblast differentiation through energy metabolism.

Myoblast proliferation and differentiation are highly dynamic and regulated processes in skeletal muscle development. Given that proteins serve as the executors for the majority of biological processes, exploring key regulatory factors and mechanisms at the protein level offers substantial opportunities for understanding the skeletal muscle development. In this study, a total of 607 differentially expressed proteins between proliferation and differentiation in myoblasts were screened out using our chicken muscle antibody array. Biological function analysis revealed the importance of energy production processes and compound metabolic processes in myogenesis. Our antibody array specifically identified an upregulation of LDHA during differentiation, which was associated with the energy metabolism. Subsequent investigation demonstrated that LDHA promoted the glycolysis and TCA cycle, thereby enhancing myoblasts differentiation. Mechanistically, LDHA promotes the glycolysis and TCA cycle but inhibits the ETC oxidative phosphorylation through enhancing the NADH cycle, providing the intermediate metabolites that improve the myoblasts differentiation. Additionally, increased glycolytic ATP by LDHA induces Akt phosphorylation and activate the PI3K-Akt pathway, which might also contribute to the promotion of myoblasts differentiation. Our studies not only present a powerful tool for exploring myogenic regulatory factors in chicken muscle, but also identify a novel role for LDHA in modulating myoblast differentiation through its regulation of cellular NAD+ levels and subsequent downstream effects on mitochondrial function.

Circumferential Damage Monitoring of Steel Pipe Using a Radar Map Based on Torsional Guided Waves.

Ultrasonic guided wave technology has been successfully applied to detect multiple types of defects in pipes. However, the circumferential location and coverage of a defect are less studied because it is difficult to determine. In this study, the fundamental torsional mode T (0, 1) is selected to conduct monitoring of the circumferential defect in pipelines because of its almost non-dispersive property. A radar map of the peak wave signals at 30 circumferential positions is proposed to detect the damage. The circumferential defect of a steel pipe is thoroughly investigated using numerical simulation. First, the circumferential positioning of defects in various areas of the pipe is studied. Second, the results are compared to those based on longitudinal guide waves. Finally, the circumferential coverage of a defect in the pipeline is determined. The waves are excited and received using the pitch-catch approach, and the collected monitoring signals are processed using the Hilbert transformation. According to the findings, the circumferential defect in the pipe can be effectively identified from a 'T' shape in the radar image, and the monitoring method by the torsional guided wave is superior to the longitudinal wave method. The results clearly demonstrate the advantages of torsional guided waves in defect monitoring. The proposed method is expected to provide a promising solution to circumferential damage identification in pipelines.

Alpha-lipoic acid supplementation reverses the declining quality of oocytes exposed to cyclophosphamide.

Cyclophosphamide (CY) is a chemotherapeutic drug that is commonly used to treat malignancies of the ovary, breast, and hematology, as well as autoimmune disorders. As a cofactor of mitochondrial multienzyme complexes, alpha lipoic acid (ALA) is well known for its antioxidant characteristics, which operate directly on the scavenging of reactive oxygen species (ROS) and indirectly on the intracellular recycling of other antioxidants. However, the underlying mechanisms through which CY exerts its toxic effects on meiosis and oocyte quality, as well as a viable approach for protecting oocyte quality and preserving fertility, remain unknown. In present study, immunostaining and fluorescence intensity quantification were applied to assess the effects of CY and ALA supplementation on the key processes during the oocyte meiotic maturation. Our results show that supplementing oocytes with ALA, a well-known antioxidant and free radical scavenger, can reverse CY-induced oocyte meiotic maturation failure. Specifically, we found that CY exposure caused oocyte meiotic failure by disrupting meiotic organelle dynamics and arrangement, as well as a prominently impaired cytoskeleton assembly. In addition, CY caused an abnormal distribution of mitochondrion and cortical granules, two indicators of oocyte cytoplasmic maturation. More importantly, we show that ALA supplementation effectively reverses CY-induced meiotic failure and oocyte quality decline by suppressing oxidative stress-induced DNA damage and apoptosis in oocytes. Collectively, our data reveal that ALA supplementation is a feasible approach to protect oocytes from CY-exposed deterioration, providing a better understanding of the mechanisms involved in chemotherapy-induced meiotic failure.

Transcriptome analysis provides insight into the regulatory mechanisms underlying pollen germination recovery at normal high ambient temperature in wild banana (Musa itinerans).

Introduction: Cultivated banana are polyploid, with low pollen fertility, and most cultivars are male sterile, which leads to difficulties in banana breeding research. The selection of male parent with excellent resistance and pollen fertility is therefore essential for banana breeding. Wild banana (Musa itinerans) have developed many good characteristics during natural selection and constitute an excellent gene pool for breeding. Therefore, research on wild banana breeding is very important for banana breeding. Results: In the current analysis, we examined the changes in viability of wild banana pollens at different temperatures by in vitro germination, and found that the germination ability of wild banana pollens cultured at 28°C for 2 days was higher than that of pollens cultured at 23°C (pollens that could not germinate normally under low temperature stress), 24°C (cultured at a constant temperature for 2 days) and 32°C (cultured at a constant temperature for 2 days). To elucidate the molecular mechanisms underlying the germination restoration process in wild banana pollens, we selected the wild banana pollens that had lost its germination ability under low temperature stress (23°C) as the control group (CK) and the wild banana pollens that had recovered its germination ability under constant temperature incubation of 28°C for 2 days as the treatment group (T) for transcriptome sequencing. A total of 921 differentially expressed genes (DEGs) were detected in CK vs T, of which 265 were up-regulated and 656 were down-regulated. The combined analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that the activation, metabolism of various substances (lipids, sugars, amino acids) play a major role in restoring pollen germination capacity. TCA cycle and the sesquiterpenoid and triterpenoid biosynthetic pathways were also significantly enriched in the KEGG pathway. And we found that some DEGs may be associated with pollen wall formation, DNA methylation and DNA repair. The cysteine content, free fatty acid (FFA) content, H2O2 content, fructose content, and sucrose content of pollen were increased at treatment of 28°C, while D-Golactose content was decreased. Finally, the GO pathway was enriched for a total of 24 DEGs related to pollen germination, of which 16 DEGs received targeted regulation by 14 MYBs. Discussions: Our study suggests that the balance between various metabolic processes, pollen wall remodelling, DNA methylation, DNA repairs and regulation of MYBs are essential for germination of wild banana pollens.

Adiponectin inhibits GnRH secretion via activating AMPK and PI3K signaling pathways in chicken hypothalamic neuron cells.

It has been reported that adiponectin (AdipoQ), an adipokine secreted by white adipose tissue, plays an important role in the control of animal reproduction in addition to its function in energy homeostasis by binding to its receptors AdipoR1/2. However, the molecular mechanisms of AdipoQ in the regulation of animal reproduction remain elusive. In this study, we investigated the effects of AdipoQ on hypothalamic reproductive hormone (GnRH) secretion and reproduction-related receptor gene (estrogen receptor [ER] and progesterone receptor [PR]) expression in hypothalamic neuronal cells (HNCs) of chickens by using real-time fluorescent quantitative PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), Western blot (WB) and cell counting kit-8 (CCK-8) assays and found that overexpression of AdipoQ could increase the expression levels of AdipoR1/2 and reproduction-related receptor genes (P < 0.05) while decreasing the expression level of GnRH. In contrast, interference with AdipoQ mRNA showed the opposite results in HNCs. Furthermore, we demonstrated that AdipoQ exerts its functions through the AMPK and PI3K signaling pathways. Finally, our in vitro experiments found that AdipoRon (a synthetic substitute for AdipoQ) treatment and AdipoR1/2 RNAi interference co-treatment resulted in no effect on GnRH secretion, suggesting that the inhibition of GnRH secretion by AdipoQ is mediated by the AdipoR1/2 signaling axis. In summary, we uncovered, for the first time, the molecular mechanism of AdipoQ in the regulation of reproductive hormone secretion in hypothalamic neurons in chickens.

Suppression of tumorigenesis in LUAD by LRP1B through regulation of the IL-6-JAK-STAT3 pathway.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer. LRP1B was initially identified as a cancer suppressor in several cancers. However, the potential biological phenotypes and molecular mechanisms of LRP1B in LUAD have not been fully investigated. In our study, we showed that the expression of LRP1B in LUAD tissues was lower than that in normal tissues. Knockdown of LRP1B markedly enhanced malignancy of LUAD cells. Genomic analysis indicated that the population expressing low-levels of LRP1B had higher genomic instability, which accounted for a larger proportion of aneuploidy and inflammation subtyping. Enrichment analysis of bulk and cell-line transcriptomic data both showed that the low expression of LRP1B could induce the activation of IL-6-JAK-STAT3, chemokine, cytokine, and other inflammation signaling pathways. Moreover, our findings revealed that knockdown LRP1B enhanced the secretion of IL-6 and IL-8, as confirmed by ELISA assays. Further validation using PCR and WB confirmed that downregulation of LRP1B mRNA significantly upregulated the activity of the IL-6-JAK-STAT3 pathway. Collectively, this study highlights LRP1B as a tumor suppressor gene and reveals that LRP1B knockdown promotes malignant progression in LUAD by inducing inflammation through the IL-6-JAK-STAT3 pathway.

Detection of trace chlorine pollutants in recycled pulp using gas chromatography-tandem mass spectrometry with response surface-optimized carbon structure online catalysis.

RATIONALE: Chlorinated aromatics and alkanes are widely used for their flame retardancy, but they need to be monitored when used in recycled pulp. This paper reports the use of palladium acetate/activated carbon (Pa/Ac) activated by nitric acid as an online catalyst to determine chlorinated aromatics and chlorinated alkanes in recycled paper products using gas chromatography-tandem mass spectrometry (GC-MS/MS), which significantly improves the sensitivity of the method and remarkably lowers the detection limits. METHODS: The Pa/Ac catalyst was prepared using a self-made catalytic device and used as key to the online catalytic conversion of target chlorinated aromatic hydrocarbons and chlorinated alkanes for GC-MS/MS analysis. The response surface model was used to optimize catalytic conditions. Then GC-MS/MS in the multireaction monitoring mode with online catalysis was applied for the analysis of polychlorinated biphenyls, polychlorinated terphenyls, polychlorinated naphthalene, and chlorinated paraffins (CP) in recycled paper products. RESULTS: Compared with traditional methods, the Pa/Ac catalyst can transform chlorinated aromatic hydrocarbons into aromatic hydrocarbons through dechlorination hydrogenation, thus lowering the detection limit of the GC-MS/MS method significantly. It can transform paraffin chloride into the corresponding alkane to better distinguish short-chain, medium-chain, or long-chain CPs. Online catalytic conversion significantly improved the sensitivity and reproducibility (88.7%-113.1%) of the method. Tissue samples with various concentration levels of chlorinated aromatics and chlorinated alkanes were tested. The linearity range of the reduced target compounds in the reduction product solution was 0.02-1.00 µg/ml (R2  > 0.995). The quantitative detection limit was 0.03-0.05 µg/kg, and relative standard deviation was less than 6.9%. CONCLUSION: This study was the first to introduce the Pa/Ac catalytic device as an online catalytic unit in the determination of chlorinated aromatics and chlorinated alkanes using the GC-MS/MS method. The target compounds were converted into alkanes and aromatic hydrocarbons with unchanged carbon structures, and the method could achieve a low detection limit with no need for high-end methods such as GC-chemical ionization ion source (CI)-MS or high-resolution mass spectrometry. These methods are suitable for the determination of chlorine pollutants in recycled paper and its raw materials.

Mediating immunosuppressive functions: a new perspective on the complex immunological properties of SEMA4D in the tumor microenvironment.

Semaphorin 4D (SEMA4D) is considered a new antitumor target closely related to immune cells. However, understanding the role of SEMA4D in the tumor microenvironment (TME) is limited. In this study, we explored the expression and immune cell infiltration patterns of SEMA4D using multiple bioinformatics datasets and analyzed the relationship between SEMA4D expression with immune checkpoints, tumor mutational load (TMB), microsatellite instability (MSI) and immune function. We detected that SEMA4D is overexpressed in many tumors types, widely enriched in immune cells, and closely associated with TILs, MSI, TMB, as well as T-cell exhaustion-associated immune checkpoints, and thus can broadly affect the immune microenvironment. We further verified the overexpression of SEMA4D in tumor and its distribution in TME by immunohistochemistry, RT-qPCR and flow cytometry, and confirmed that decreased expression of SEMA4D can lead to recovery of T cell exhaustion. In conlusion, this study provides a more comprehensive perspective of SEMA4D regulation of tumor immunity, which provide a new option for cancer immunotherapy.

Paris saponins â ¦ inhibits glycolysis of ovarian cancer via the RORC/ACK1 signaling pathway.

Rhizoma Paridis is a traditional Chinese medicine commonly used for treatment of malignant tumors. Paris saponins Ⅶ (PSⅦ) is one of the components of Rhizoma Paridis, but the role of PSⅦ in glucose metabolism in ovarian cancer remains elucidated. A series of experiments in the current study demonstrated that PSⅦ inhibites glycolysis and promotes cell apoptosis in ovarian cancer cells. Expression levels of glycolysis-related proteins and apoptosis-related proteins were significantly altered by upon treatment with PSⅦ, as determined from western blot analyses. Mechanistically, PSⅦ exerted its anti-tumor effects by targeting the RORC/ACK1 signaling pathway. These findings indicate that PSⅦ inhibits glycolysis-induced cell proliferation and apoptosis through the RORC/ACK1 pathway, supporting its potential development as a candidate chemotherapeutic agent for ovarian cancer.

ITGB1-mediated molecular landscape and cuproptosis phenotype induced the worse prognosis in diffuse gastric cancer.

Diffuse type gastric cancer was identified with relatively worse prognosis than other Lauren's histological classification. Integrin ß1 (ITGB1) was a member of integrin family which played a markedly important role in tumorigenesis and progression. However, the influence of ITGB1 in diffuse gastric cancer (DGC) remains uncertain. Here, we leveraged the transcriptomic and proteomic data to explore the association between ITGB1 expression and clinicopathologic information and biological process in DGC. Cell phenotype experiments combined with quantitative-PCR (q-PCR) and western blotting were utilized to identify the potential molecular mechanism underling ITGB1.Transcriptomics and proteomics both revealed that the higher ITGB1 expression was significantly associated with worse prognosis in DGC, but not in intestinal GC. Genomic analysis indicated that the mutation frequency of significantly mutated genes of ARID1A and COL11A1, and mutational signatures of SBS6 and SBS15 were markedly increased in the ITGB1 low expression subgroup. The enrichment analysis revealed diverse pathways related to dysregulation of ITGB1 in DGC, especially in cell adhesion, proliferation, metabolism reprogramming, and immune regulation alterations. Elevated activities of kinase-ROCK1, PKACA/PRKACA and AKT1 were observed in the ITGB1 high-expression subgroup. The ssGSEA analysis also found that ITGB1 low-expression had a higher cuproptosis score and was negatively correlated with key regulators of cuproptosis, including FDX1, DLAT, and DLST. We further observed that the upregulated expression of mitochondrial tricarboxylic acid (TCA) cycle in the ITGB1 low-expression group. Reduced expression of ITGB1 inhibited the ability of cell proliferation and motility and also potentiated the cell sensitive to copper ionophores via western blotting assay. Overall, this study revealed that ITGB1 was a protumorigenic gene and regulated tumor metabolism and cuproptosis in DGC.

Oxymatrine boosts hematopoietic regeneration by modulating MAPK/ERK phosphorylation after irradiation-induced hematopoietic injury.

Hematopoietic toxicity due to ionizing radiation (IR) is a leading cause of death in nuclear incidents, occupational hazards, and cancer therapy. Oxymatrine (OM), an extract originating from the root of Sophora flavescens (Kushen), possesses extensive pharmacological properties. In this study, we demonstrate that OM treatment accelerates hematological recovery and increases the survival rate of mice subjected to irradiation. This outcome is accompanied by an increase in functional hematopoietic stem cells (HSCs), resulting in enhanced hematopoietic reconstitution abilities. Mechanistically, we observed significant activation of the MAPK signaling pathway, accelerated cellular proliferation, and decreased cell apoptosis. Notably, we identified marked increases in the cell cycle transcriptional regulator Cyclin D1 (Ccnd1) and the anti-apoptotic protein BCL2 in HSCs after OM treatment. Further investigation revealed that the expression of Ccnd1 transcript and BCL2 levels were reversed upon specific inhibition of ERK1/2 phosphorylation, effectively negating the rescuing effect of OM. Moreover, we determined that targeted inhibition of ERK1/2 activation significantly counteracted the regenerative effect of OM on human HSCs. Taken together, our results suggest a crucial role for OM in hematopoietic reconstitution following IR via MAPK signaling pathway-mediated mechanisms, providing theoretical support for innovative therapeutic applications of OM in addressing IR-induced injuries in humans.

Reprogrammed siTNFα/neutrophil cytopharmaceuticals targeting inflamed joints for rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe synovial inflammation and cartilage damage. Despite great progress in RA therapy, there still lacks the drugs to completely cure RA patients. Herein, we propose a reprogrammed neutrophil cytopharmaceuticals loading with TNFα-targeting-siRNA (siTNFα) as an alternative anti-inflammatory approach for RA treatment. The loaded siTNFα act as not only the gene therapeutics to inhibit TNFα production by macrophages in inflamed synovium, but also the editors to reprogram neutrophils to anti-inflammatory phenotypes. Leveraging the active tendency of neutrophils to inflammation, the reprogrammed siTNFα/neutrophil cytopharmaceuticals (siTNFα/TP/NEs) can rapidly migrate to the inflamed synovium, transfer the loaded siTNFα to macrophages followed by the significant reduction of TNFα expression, and circumvent the pro-inflammatory activity of neutrophils, thus leading to the alleviated synovial inflammation and improved cartilage protection. Our work provides a promising cytopharmaceutical for RA treatment, and puts forward a living neutrophil-based gene delivery platform.