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Bone cancer pain is a common symptom in cancer patients with bone metastases and the underlying mechanisms are largely unknown. The aim of this study is to explore the endogenous analgesic mechanisms to develop new therapeutic strategies for bone‐cancer induced pain (BCIP) as a result of metastases. MRMT‐1 tumor cells were injected into bilateral tibia of rats and X‐rays showed that the area suffered from bone destruction, accompanied by an increase in osteoclast numbers. In addition, rats with bone cancer showed apparent mechanical and thermal hyperalgesia at day 28 after intratibial MRMT‐1 inoculation. However, intrathecal injection of morphine or lentivirus‐mediated glial cell line‐derived neurotrophic factor RNAi (Lvs‐siGDNF) significantly attenuated mechanical and thermal hyperalgesia, as shown by increases in paw withdrawal thresholds and tail‐flick latencies, respectively. Furthermore, Lvs‐siGDNF interference not only substantially downregulated GDNF protein levels, but also reduced substance P immunoreactivity and downregulated the ratio of pERK/ERK, where its activation is crucial for pain signaling, in the spinal dorsal horn of this model of bone‐cancer induced pain. In this study, Lvs‐siGDNF gene therapy appeared to be a beneficial method for the treatment of bone cancer pain. As the effect of Lvs‐siGDNF to relieve pain was similar to morphine, but it is not a narcotic, the use of GDNF RNA interference may be considered as a new therapeutic strategy for the treatment of bone cancer pain in the future. The aim of this study is to explore the endogenous analgesic mechanisms to develop new therapeutic strategy for bone cancer pain induced by metastases. The effect of Lvs‐siGDNF to relief pain was similar the effect from morphine administration. GDNF RNAi therefor might be considered as a new therapeutic strategy for bone cancer pain treatment in the future.

The aim of this study was to prepare a liposomal delivery system for rapamycin and study its in vitro release characteristics. The results may provide a foundation for the further development of a liposomal delivery system for rapamycin and the establishment of a new active treatment method targeted towards the cellular components of atherosclerotic plaques. The ethanol injection method was used to prepare rapamycin-containing liposomes. The formulation was optimized by orthogonal design, and the degree of rapamycin release by the liposomes was measured by the reverse dialysis method. Orthogonal testing showed that the optimum formulation had a phospholipid concentration of 4%, a phospholipid-cholesterol mass ratio of 8:1, a drug-lipid mass ratio of 1:20 and an aqueous phase pH of 7.4. Rapamycin-containing liposomes with an encapsulation efficiency of 82.11±2.13% were prepared, and the in vitro release of rapamycin from the liposomes complied with a first-order kinetic equation. In conclusion, the formulation was optimized, the prepared liposomes had a high rapamycin encapsulation rate and good reproducibility, and their in vitro release had a certain delayed-release effect.

Our previous studies demonstrated that interferon gamma increases the human (h) growth hormone (GH) gene promoter activity in rat pituitary GH3 cells, and its regulatory mechanism may be different from the classical GH-releasing hormone-induced regulatory mechanism. Interleukin-1β (IL-1β) is thought to induce the release of GH by pituitary cells, but whether or not and by which mechanisms IL-1β regulates GH synthesis remains unclear. The purpose of our study was thus to investigate the effect of IL-1β on the hGH gene expression in GH3 rat pituitary tumor cells using stable transfection of the hGH promoter fused to a luciferase reporter gene. Our results showed that IL-1β (10–10 4 U/ml) increased GH secretion and synthesis and that 10 2 to 10 4 U/ml IL-1β promoted the luciferase expression in stable GH3 cells, with a maximal action of 1.61 times over that of controls. Among inhibitors of intracellular signaling transduction pathways, mitogen-activated protein kinase kinase (MAPKK/MEK) inhibitor PD98059 (40 µM) and p38 MAPK inhibitor SB203580 (5 µM)blocked completely the stimulatory effect of IL-1β, and the phosphoinositide 3-kinase inhibitor LY294002 (10 µM) blocked partially the induction of IL-1β. Western blot analysis demonstrated that IL-1β increased the activation of phosphorylated MEK and p38 MAPK in GH3 cells. Neither overexpression of Pit-1 nor inhibiting Pit-1 expression affected IL-1β induction of hGH promoter activity. To identify the DNA sequence that mediated the effect of IL-1β, six deletion constructs of hGH promoter were created. The stimulatory effect of IL-1β was abolished following deletion of the –196- to –132-bp fragment. In conclusion, our data show that IL-1β promotes GH secretion and synthesis by rat pituitary GH3 cells. The stimulatory effect of IL-1β on the hGH gene promoter appears to require the activation of MEK, p38 MAPK, and phosphoinositide 3-kinase and a fragment of promoter sequence that spans the –196- to –132-bp fragment of the gene, but is unrelated to the Pit-1 protein.

To study the effect(s) of interferon gamma (IFN-gamma) on the activity of human growth hormone (hGH) gene promoter in rat pituitary GH3 cells and the molecular mechanism underlying the effect(s). Cell transfection and luciferase reporter gene were used. IFN-gamma (10(2) and 10(3) U/ml) increased the activity of hGH in GH3 cells. The addition of the mitogen-activated protein kinase inhibitor PD98059 (40 micromol/l) to the cells blocked the stimulatory effect of IFN-gamma. Neither overexpression of Pit-1 nor inhibiting Pit-1 expression affected IFN-gamma induction of hGH promoter activity. To identify the DNA sequence that mediated the effect of IFN-gamma, four deletion constructs of hGH gene promoter were created. The stimulatory effect of IFN-gamma was abolished following deletion of the -250 to -132 fragment. IFN-gamma increases the activity of hGH gene promoter in rat pituitary GH3 cells. This stimulatory effect of IFN-gamma appears to require the intracellular mitogen-activated protein kinase-dependent signaling pathway. The effect of IFN-gamma requires the promoter sequence that spans the -250 to -132 fragment of the gene, but is unrelated to Pit-1 protein.

Our previous studies demonstrated that interferon gamma increases the human (h) growth hormone (GH) gene promoter activity in rat pituitary GH3 cells, and its regulatory mechanism may be different from the classical GH-releasing hormone-induced regulatory mechanism. Interleukin-1[beta] (IL-1[beta]) is thought to induce the release of GH by pituitary cells, but whether or not and by which mechanisms IL-1[beta] regulates GH synthesis remains unclear. The purpose of our study was thus to investigate the effect of IL-1[beta] on the hGH gene expression in GH3 rat pituitary tumor cells using stable transfection of the hGH promoter fused to a luciferase reporter gene. Our results showed that IL-1[beta] (10-104 U/ml) increased GH secretion and synthesis and that 102 to 104 U/ml IL-1[beta] promoted the luciferase expression in stable GH3 cells, with a maximal action of 1.61 times over that of controls. Among inhibitors of intracellular signaling transduction pathways, mitogen-activated protein kinase kinase (MAPKK/MEK) inhibitor PD98059 (40 μM) and p38 MAPK inhibitor SB203580 (5 μM)blocked completely the stimulatory effect of IL-1[beta], and the phosphoinositide 3-kinase inhibitor LY294002 (10 μM) blocked partially the induction of IL-1[beta]. Western blot analysis demonstrated that IL-1[beta] increased the activation of phosphorylated MEK and p38 MAPK in GH3 cells. Neither overexpression of Pit-1 nor inhibiting Pit-1 expression affected IL-1[beta] induction of hGH promoter activity. To identify the DNA sequence that mediated the effect of IL-1[beta], six deletion constructs of hGH promoter were created. The stimulatory effect of IL-1[beta] was abolished following deletion of the -196- to -132-bp fragment. In conclusion, our data show that IL-1[beta] promotes GH secretion and synthesis by rat pituitary GH3 cells. The stimulatory effect of IL-1[beta] on the hGH gene promoter appears to require the activation of MEK, p38 MAPK, and phosphoinositide 3-kinase and a fragment of promoter sequence that spans the -196- to -132-bp fragment of the gene, but is unrelated to the Pit-1 protein. Copyright © 2005 S. Karger AG, Basel

Our previous studies demonstrated that interferon gamma increases the human (h) growth hormone (GH) gene promoter activity in rat pituitary GH3 cells, and its regulatory mechanism may be different from the classical GH-releasing hormone-induced regulatory mechanism. Interleukin-1beta (IL-1beta) is thought to induce the release of GH by pituitary cells, but whether or not and by which mechanisms IL-1beta regulates GH synthesis remains unclear. The purpose of our study was thus to investigate the effect of IL-1beta on the hGH gene expression in GH3 rat pituitary tumor cells using stable transfection of the hGH promoter fused to a luciferase reporter gene. Our results showed that IL-1beta (10-10(4) U/ml) increased GH secretion and synthesis and that 10(2) to 10(4) U/ml IL-1beta promoted the luciferase expression in stable GH3 cells, with a maximal action of 1.61 times over that of controls. Among inhibitors of intracellular signaling transduction pathways, mitogen-activated protein kinase kinase (MAPKK/MEK) inhibitor PD98059 (40 microM) and p38 MAPK inhibitor SB203580 (5 microM)blocked completely the stimulatory effect of IL-1beta, and the phosphoinositide 3-kinase inhibitor LY294002 (10 microM) blocked partially the induction of IL-1beta. Western blot analysis demonstrated that IL-1beta increased the activation of phosphorylated MEK and p38 MAPK in GH3 cells. Neither overexpression of Pit-1 nor inhibiting Pit-1 expression affected IL-1beta induction of hGH promoter activity. To identify the DNA sequence that mediated the effect of IL-1beta, six deletion constructs of hGH promoter were created. The stimulatory effect of IL-1beta was abolished following deletion of the -196- to -132-bp fragment. In conclusion, our data show that IL-1beta promotes GH secretion and synthesis by rat pituitary GH3 cells. The stimulatory effect of IL-1beta on the hGH gene promoter appears to require the activation of MEK, p38 MAPK, and phosphoinositide 3-kinase and a fragment of promoter sequence that spans the -196- to -132-bp fragment of the gene, but is unrelated to the Pit-1 protein.

Aim: To study the effect(s) of interferon gamma (IFN-[gamma]) on the activity of human growth hormone (hGH) gene promoter in rat pituitary GH3 cells and the molecular mechanism underlying the effect(s). Methods: Cell transfection and luciferase reporter gene were used. Results: IFN-[gamma] (102 and 103 U/ml) increased the activity of hGH in GH3 cells. The addition of the mitogen-activated protein kinase inhibitor PD98059 (40 μmol/l) to the cells blocked the stimulatory effect of IFN-[gamma]. Neither overexpression of Pit-1 nor inhibiting Pit-1 expression affected IFN-[gamma] induction of hGH promoter activity. To identify the DNA sequence that mediated the effect of IFN-[gamma], four deletion constructs of hGH gene promoter were created. The stimulatory effect of IFN-[gamma] was abolished following deletion of the -250 to -132 fragment. Conclusions: IFN-[gamma] increases the activity of hGH gene promoter in rat pituitary GH3 cells. This stimulatory effect of IFN-[gamma] appears to require the intracellular mitogen-activated protein kinase-dependent signaling pathway. The effect of IFN-[gamma] requires the promoter sequence that spans the -250 to -132 fragment of the gene, but is unrelated to Pit-1 protein. Copyright © 2003 S. Karger AG, Basel [PUBLICATION ABSTRACT]

Background Histone chaperones (HCs) are crucial for governing genome stability and gene expression in multiple cancers. However, the functioning of HCs in the tumor microenvironment (TME) is still not clearly understood. Methods Self-tested single-cell RNA-seq data derived from 6 breast cancer (BC) patients with brain and liver metastases were reanalyzed by nonnegative matrix factorization (NMF) algorithm for 36 HCs. TME subclusters were observed with BC and immunotherapy public cohorts to assess their prognosis and immune response. The biological effect of HSPA8, one of the HCs, was verified by transwell assay and wound-healing assays. Results Cells including fibroblasts, macrophages, B cells, and T cells, were classified into various subclusters based on marker genes. Additionally, it showed that HCs might be strongly associated with biological and clinical features of BC metastases, along with the pseudotime trajectory of each TME cell type. Besides, the results of bulk-seq analysis revealed that TME cell subclusters mediated by HCs distinguished significant prognostic value for BC patients and were relevant to patients’ immunotherapy responses, especially for B cells and macrophages. In particular, CellChat analysis exhibited that HCs-related TME cell subclusters revealed extensive and diverse interactions with malignant cells. Finally, transwell and wound-healing assays exhibited that HSPA8 deficiency inhibited BC cell migration and invasion. Conclusions Collectively, our study first dissected HCs-guided intercellular communication of TME that contribute to BC metastases.

Methamphetamine (METH) is a highly addictive psychostimulant, yet its addiction mechanisms remain unclear. Oxytocin (OXT), a neuropeptide, shows promise in reducing METH addiction, but how OXT exerts its effects is poorly understood. Using conditioned place preference (CPP), we first found that intranasal OXT other than Arginine Vasopressin (AVP) administration suppressed METH-CPP in mice, which could be reversed by OXT receptors (OXTRs) blockade in the nucleus accumbens (NAc) core. Activating OXTRs in the NAc core similarly reduced METH-CPP. Then, we found repeated METH exposure inhibited oxytocinergic neurons within the paraventricular nucleus (PVN) and lowered PVN OXT protein level. Chemogenetic activation of PVN oxytocinergic neurons (PVN OXT ) blocked METH-CPP. Furthermore, METH inhibited PVN OXT -NAc core circuit other than PVN OXT -NAc shell circuit. Activation of PVN OXT -NAc core circuit significantly inhibited METH-CPP. This study reveals METH may impair the endogenous OXT system, especially the PVN OXT -NAc core circuit, highlighting OXT’s therapeutic potential for METH use disorder (MUD). The mechanisms whereby METH yields strong addiction potential is not fully understood. Here, authors show that METH may impair the function of the endogenous OXT system, particularly the PVN OXT -NAc core pathway, suggesting OXT-based therapies for METH use disorder (MUD).