Identification of the Shared Gene Signatures and Biological Mechanisms in Hyperplastic Enlarged Lobular Units and Breast Cancer.

Breast cancer is a common cancer worldwide. Hyperplastic enlarged lobular units (HELUs) are common changes in the breasts of adult women. HELUs may be closely related to the occurrence and development of breast cancer. In this study, genes that are commonly contained in the expression profiles of the genomes of the two diseases and have significant differences in expression before and after the respective diseases were identified. Various enrichment analyses were performed according to the expression levels of these differentially expressed genes. Furthermore, LASSO regression analysis was performed on the differentially expressed genes to identify genes significantly related to survival. The optimal risk model for the survival of patients with breast cancer was established, and the accuracy of the model was verified on multiple data sets. A gene combination containing 17 genes was ultimately determined to be an independent prognostic factor. Kaplan‒Meier survival analysis demonstrated the good performance of this risk model. The study found that Shared Gene Signatures and Biological Mechanisms in Hyperplastic Enlarged Lobular Units and Breast Cancer, screened 17 important Shared Gene Signatures of Hyperplastic Enlarged Lobular Units which are closely related to the survival of breast cancer patients through machine learning, and established a prognosis model with high-accuracy, which is worthy of further exploration.

Pharmacological Activation of GPR55 Improved Cognitive Impairment Induced by Lipopolysaccharide in Mice.

Our previous research found that activation of GPR55 can alleviate cognitive impairment induced by amyloid-beta 1-42 (Aß1-42) and streptozotocin in mice, but the role of GPR55 in the pathogenesis of cognitive impairment remains unknown. Here, we used a lipopolysaccharide (LPS) mouse model to further investigate the role and mechanism of O-1602, a GPR55 agonist, on cognitive dysfunction. ICR mice were treated with an intracerebroventricular (i.c.v.) injection of LPS, followed by cognitive function tests. The expression of GPR55, NF-κB p65, caspase-3, Bax, and Bcl-2 in the hippocampus was examined by Western blotting. Inflammatory cytokines and microglia were detected by ELISA kit and immunohistochemical analyses, respectively. The levels of MDA, GSH, SOD, and CAT were examined by assay kits. Furthermore, TUNEL-staining was used to detect neuronal apoptosis. Our results showed that i.c.v. injection of LPS in mice exhibited impaired performance in the behavior tests, which were ameliorated by O-1602 treatment (2.0 or 4.0 µg/mouse, i.c.v.). Importantly, we found that O-1602 treatment reversed GPR55 downregulation, decreased the expression of NF-κB p65, suppressed the accumulation of proinflammatory cytokines and microglia activation, increased the anti-inflammatory cytokines, and reduced the levels of MDA, increased the levels of GSH, SOD, and CAT in the hippocampus. In addition, O-1602 treatment also significantly reduced Bax and increased Bcl-2 expression as well as decreased caspase-3 activity and TUNEL-positive cells in the hippocampus. These observations indicate that O-1602 may ameliorate LPS-induced cognition deficits via inhibiting neuroinflammation, oxidative stress, and apoptosis mediated by the NF-κB pathway in mice.

Inhibition of GPR17 with cangrelor improves cognitive impairment and synaptic deficits induced by Aß1-42 through Nrf2/HO-1 and NF-κB signaling pathway in mice.

The accumulation of amyloid beta (Aß) in the brain is thought to be associated with cognitive deficits in Alzheimer's disease (AD). However, current methods to combat Aß neurotoxicity are still lacking. G protein-coupled receptor 17 (GPR17) has become a target for treating inflammation in brain diseases, but it is unclear whether it has a role in AD. Here, we investigated the effects of cangrelor, a GPR17 antagonist, on neurotoxicity and memory impairment induced by intracerebroventricular (i.c.v.) injection of Aß1-42 in mice. The behavior results showed that cangrelor (2.0 or 4.0 µg/mouse, i.c.v.) treatment reversed the deficits in memory and learning ability induced by Aß1-42 in mice. Importantly, we demonstrated for the first time that GPR17 expression in the hippocampus and frontal cortex is increased in response to Aß1-42 exposures. We also found that cangrelor treatment reduced the activity of ß-secretase 1 (BACE1) and the levels of soluble Aß1-42 in the hippocampus and frontal cortex. Meanwhile, cangrelor treatment suppressed oxidative stress induced by Aß1-42, as proved by reduced production of malondialdehyde (MDA), and increased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), and promoted the expression of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). Furthermore, cangrelor also suppressed Aß1-42-induced neuroinflammation, characterized by suppressed activation of microglia, decreased the levels of pro-inflammatory cytokines, and nuclear translocation of NF-κB p65, as well as ameliorated synaptic deficits by promoting the upregulation of synaptic proteins, and increasing the number of Golgi-Cox stained dendritic spines. These results suggest that cangrelor may reverse Aß1-42-induced cognition deficits via inhibiting oxidative stress, neuroinflammation, and synaptic dysfunction mediated by Nrf2/HO-1 and NF-κB signaling.

cGAS-STING Signaling Pathway and Liver Disease: From Basic Research to Clinical Practice.

The cGAS-STING signaling pathway is an autoimmune inflammatory pathway that can trigger the expression of a series of inflammatory factors represented by type 1 interferon. Recent studies have found that the cGAS-STING signaling pathway played a significant role in liver physiology and was closely related to the progress of liver diseases. For example, activating the cGAS-STING signaling pathway could significantly inhibit hepatitis B virus (HBV) replication in vivo. Moreover, the cGAS-STING signaling pathway was also closely associated with tumor immunity in hepatocellular carcinoma (HCC). This review summarized the role of the cGAS-STING signaling pathway in several common liver diseases, especially the current application of the cGAS-STING signaling pathway in liver disease treatment, and prospected its future research, which provided a new idea for understanding and treating liver diseases.

Biological applications of copper-containing materials.

Copper is an indispensable trace metal element in the human body, which is mainly absorbed in the stomach and small intestine and excreted into the bile. Copper is an important component and catalytic agent of many enzymes and proteins in the body, so it can influence human health through multiple mechanisms. Based on the biological functions and benefits of copper, an increasing number of researchers in the field of biomaterials have focused on developing novel copper-containing biomaterials, which exhibit unique properties in protecting the cardiovascular system, promoting bone fracture healing, and exerting antibacterial effects. Copper can also be used in promoting incisional wounds healing, killing cancer cells, Positron Emission Tomography (PET) imaging, radioimmunological tracing and radiotherapy of cancer. In the present review, the biological functions of copper in the human body are presented, along with an overview of recent progress in our understanding of the biological applications and development of copper-containing materials. Furthermore, this review also provides the prospective on the challenges of those novel biomaterials for future clinical applications.

Discovery of novel Ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors.

FGF receptors (FGFRs) are tyrosine kinases that are overexpressed in diverse tumors by genetic alterations such as gene amplifications, somatic mutations and translocations. Owing to this characteristic, FGFRs are attractive targets for cancer treatment. It has been demonstrated that most multi-targeted, ATP competitive tyrosine kinase inhibitors are active against FGFRs as well as other kinases. The design of new and more selective inhibitors of FGFRs, which might be reduced off-target and side effects, is a difficult yet significant challenge. The results of the current investigation, show that novel Ponatinib analogues are highly active as FGFR inhibitors and that they possess reduced kinase insert domain receptor (KDR) activities. Observations made in a structure and activity relationship (SAR) investigation led to the development of a promising, orally available lead compound 4, which displays a 50-100 fold in vitro selectivity for inhibition of FGFR1-3 over KDR. In addition, biological evaluation of compound 4 showed that it displays significant antitumor activities in FGFR1-amplificated H1581 and FGFR2-amplificated SNU-16 xenograft models.

Pyridazinone derivatives displaying highly potent and selective inhibitory activities against c-Met tyrosine kinase.

Over activation of c-Met tyrosine kinase is known to promote tumorigenesis and metastasis, as well as to cause therapeutic resistance. Herein we describe the design, synthesis and biological activities of novel, ATP-competitive, c-Met tyrosine kinase inhibitors that are members of the 6-aryl-2-(3-(heteroarylamino)benzyl)pyridazinone family. A structure-activity relationship (SAR) study of these substances led to identification of pyridazinone 19 as a highly selective and potent c-Met tyrosine inhibitor, which displays favorable pharmacokinetic properties in mice and significant antitumor activity against a c-Met driven EBC-1 tumor xenograft.

Enhancing the cellular anti-proliferation activity of pyridazinones as c-met inhibitors using docking analysis.

A series of 2, 6-disubstituted pyridazinone derivatives were evaluated and optimized for their c-Met inhibitory activity in enzyme and cellular assay. An analysis of the SAR results arising from computer modeling analysis of members of the library led to the proposal that in order to obtain optimal inhibitory activity in cellular systems the lipophilic/hydrophilic properties of individual structural fragments in the inhibitors need to match those of corresponding binding pockets in the enzyme. Guided by this proposal, the quinoline-pyridazinone 8a, containing hydrophobic 6-indolyl pyridazinone and quinoline moieties along with a hydrophilic morpholine terminal group, was designed and synthesized. The results of studies with this substance showed that it is a selective c-Met inhibitor with both a high enzyme inhibition IC50 value of 4.2 nM and a high EBC-1 cell proliferation inhibition IC50 value of 17 nM.

Microwave assisted tandem Heck-Sonogashira reactions of N,N-di-Boc-protected 6-amino-5-iodo-2-methyl pyrimidin-4-ol in an efficient approach to functionalized pyrido[2,3-d]pyrimidines.

A microwave assisted tandem Heck-Sonogashira cross-coupling reaction between 6-N,N-di-Boc-amino-5-iodo-2-methyl pyrimidin-4-ol and various aryl alkynyl substrates has been developed. This process generates novel 5-enynyl substituted pyrimidines, which can be transformed to novel functionalized pyrido[2,3-d]pyrimidines by way of a silver catalyzed cyclization reaction.

Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo.

The transcription factor, signal transducer and activator of transcription-3 (STAT-3) contributes to various physiological processes. Here we show that mice with liver-specific deficiency in STAT-3, achieved using the Cre-loxP system, show insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT-3 expression in these mice, using adenovirus-mediated gene transfer, corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Overexpression of STAT-3 in cultured hepatocytes inhibited gluconeogenic gene expression independently of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), an upstream regulator of gluconeogenic genes. Liver-specific expression of a constitutively active form of STAT-3, achieved by infection with an adenovirus vector, markedly reduced blood glucose, plasma insulin concentrations and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT-3 signaling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes mellitus.