Lysosomes are degradation and signaling organelles that adapt their biogenesis to meet many different cellular demands; however, it is unknown how lysosomes change their numbers for cell division. Here, we report that the cyclin-dependent kinases CDK4/6 regulate lysosome biogenesis during the cell cycle. Chemical or genetic inactivation of CDK4/6 increases lysosomal numbers by activating the lysosome and autophagy transcription factors TFEB and TFE3. CDK4/6 interact with and phosphorylate TFEB/TFE3 in the nucleus, thereby inactivating them by promoting their shuttling to the cytoplasm. During the cell cycle, lysosome numbers increase in S and G2/M phases when cyclin D turnover diminishes CDK4/6 activity. These findings not only uncover the molecular events that direct the nuclear export of TFEB/TFE3, but also suggest a mechanism that controls lysosome biogenesis in the cell cycle. CDK4/6 inhibitors promote autophagy and lysosome-dependent degradation, which has important implications for the therapy of cancer and lysosome-related disorders.
Objective To evaluate the role of CREB-binding protein (CBP) in cyclooxygenase 2 (COX-2) expression in spinal cord in a rat model of neuropathic pain (NP).Methods Forty male SD rats weighing 220-250 g in which intrathecal catheter was successfully implanted were randomly divided into 4 groups (n=10 each):sham operation group (group Sham),group NP,negative control group (group NC) and group CBP.NP was induced by CCI at 5 days after successful implantation of the intrathecal catheter.Normal saline,negative lentivirus vector (RNAi-NC-LV) and CBP shRNA lentivirus vector (CBP RNAi-LV) 20 μl were injected intrathecally at 7 days after CCI in groups NP,NC and CBP,respectively.Paw withdrawal threshold to mechanical stimuli (MWT)and paw withdrawal latency to thermal stimulus (TWL) were measured at 1 day before operation and at 3,5,7,10,12 and 14 days after operation.The rats were sacrificed after the measurement of MWT and TWL at 14 days after operation and the lumbar segment of the spinal cord was then removed for determination of the expression of CBP,acetylated histone H3/H4 (Ac-H3,Ac-H4) and COX-2 protein (by immunohistochemistry),and CBP and COX-2 mRNA (by RF-PCR).Results Compared with group Sham,MWT and TWL were significantly decreased at different time points after operation in groups NP,NCand CBP,and the expression of CBP,Ac-H3,Ac-H4 and COX-2 protein,and CBP and COX-2 mRNA was up-regulated at 14 days after operation in groups NP and NC (P ＜ 0.05).Compared with group NP,MWT and TWL were significantly increased at 10,12 and 14 days after operation and the expression of CBP,Ac-H3,Ac-H4 and COX-2 protein,and CBP and COX-2 mRNA was downregulated at 14 days after operation in group CBP (P ＜ 0.05).Conclusion CBP is involved in the development of NP by up-regulating COX-2 expression and increasing histone H3 and H4 acetylation in spinal cord.
Key words:
Neuralgia; Spinal cord; RNA,small interfering; CREB-binding protein
Abstract Interleukin-15 (IL-15) emerges as a promising immunotherapeutic candidate in oncology because of its pivotal role in modulating both innate and adaptive immunity. However, the therapeutic utility remains concern due to the unexpected toxicity. We propose here that the mRNA lipid nanoparticle (mRNA-LNP) system can balance the issue through targeted delivery to increase IL-15 concentration in the tumor area and reduce leakage into the circulation. Utilizing the Structure-driven TARgeting (STAR) platform, we acquired intellectual property LNP vectors for effective and selective mRNA delivery to local (LNP Local ) and to pulmonary (LNP Lung ). Then the promising IL-15 superagonists mRNAs were obtained through structural optimization and sequence screening, showing better activity compared with benchmarker N-803. Subsequently, the anti-tumor efficacy of IL-15 superagonists mRNAs were evaluated by intratumoural (i.t.) injection and intravenous (i.v.) injection via LNP Local and LNP Lung , respectively. As a result, such superagonists exhibited better anti-tumor activity, less systematic exposure, and less cytokine related risks than N-803. We finally verified the selective delivery and well tolerability of LNP Lung in non-human primates (NHPs), confirming the potential for clinical application. This finding may open up new possibilities for the treatment of lung cancers and lung metastasis cancers.
In recent years, there has been an increasing number of publications on Meniere's disease. However, there are no bibliometric research on Meniere's disease. The purpose of this study was to find the focus and trends of Meniere's disease research through bibliometric approach.Publications related to Meniere's disease in the Web of Science Core Collection (WOSCC) from 2002 to 2021 were collected. The bibliometric approach was used to estimate the searched data. Research foci of the studies were identified using VOSviewer and CiteSpace software.A total of 1,987 articles meet the inclusion criteria and are included in the study. In the past 20 years, the number of Meniere's disease publications is gradually increasing, especially in the past 3 years. The country with the largest contribution to Meniere's disease research is the United States, followed by Europe and Japan. High-frequency keywords included Meniere's disease, endolymphaic hydrops, vertigo, meniere-disease, inner ear, dizziness, symptoms, hearing, diagnosis, and tentamicin. The analyses of keyword burst direction indicate that evoked myogenic potential, MRI, and committee are emerging research hotspots.This study provides an objective, systematic, and comprehensive analysis of Meniere's disease-related literature. In addition, we find a dramatic increase in studies in this field over the past 3 years. Evoked myogenic potentials and MRI may become the research hotspots of Meniere's disease in future. This study will help otolaryngologists, neurologists, and audiologists to clarify the research direction and potential hotspots of Meniere's disease and further help clinicians improve patients' prognosis.
e15040 Background: The molecular classification of hepatocellular carcinoma (HCC) plays a vital role in the management of precision therapy. Several molecular classification systems, mainly focusing on the tumor cells, were developed according to distinct omics features of HCC. Heterogeneous tumor microenvironment (TME) in HCC is recognized as a crucial part of inter-tumor heterogeneity. Few molecular classifications of HCC have so far taken into account both the related molecules of tumor cells and TME. Methods: Wefirstly identified the tumor purity (TP)-related and TME-related genes in the differentially expressed genes in HCC using GSE14520 data set, and separately constructed the TP-related and TME-related polygenic risk score (PRS). Secondly, according to the TP-related and TME-related PRSs, we proposed the TP-TME risk classification which was validated in two external data sets from The Cancer Genome Atlas Program and International Cancer Genome Consortium database. We also performed functional enrichment and drug repositioning analysis to reveal the potential biological heterogeneity among different subtypes. Results: The three TP-TME risk subtypes of HCC had significantly different prognosis and biological characteristics. The TP-TME low risk subtype had the best prognosis and was characterized by well-differentiated, the TP-TME high risk subtype had the worst prognosis and was characterized by aberrant activation of TGFβ and WNT pathways, and the TP-TME high risk subtype had the moderate prognosis and was characterized by exhibited activated MYC targets and proliferation-related gene sets. We also found that these three TP-TME risk subtypes may respond differently to immunotherapy (e.g., immune checkpoint inhibitors and chimeric antigen receptor-modified T cells) or other drug therapies. Conclusions: By combining separately constructed TP-related PRS and TME-related PRS, we proposed and validated a novel molecular classification system, the TP-TME risk subtyping system, to divide patients with HCC into three subtypes with distinct biological characteristics and prognosis. These findings highlight the significant clinical implications of the TP-TME risk subtyping system and provide potential personalized immunotherapy strategies for patients with HCC.
Although intracerebral hemorrhage (ICH) is a devastating disease worldwide, the pathologic changes in ultrastructure during the acute and chronic phases of ICH are poorly described. In this study, transmission electron microscopy was used to examine the ultrastructure of ICH-induced pathology. ICH was induced in mice by an intrastriatal injection of collagenase. Pathologic changes were observed in the acute (3 days), subacute (6 days), and chronic (28 days) phases. Compared with sham animals, we observed various types of cell death in the injured striatum during the acute phase of ICH, including necrosis, ferroptosis, and autophagy. Different degrees of axon degeneration in the striatum were seen in the acute phase, and axonal demyelination was observed in the ipsilateral striatum and corpus callosum at late time points. In addition, phagocytes, resident microglia, and infiltrating monocyte-macrophages were present around red blood cells and degenerating neurons and were observed to engulf red blood cells and other debris. Many synapses appeared abnormal or were lost. This systematic analysis of the pathologic changes in ultrastructure after ICH in mice provides information that will be valuable for future ICH pathology studies.
Diabetic neuropathy is one of the clinical syndromes characterized by pain and substantial morbidity primarily due to a lesion of the somatosensory nervous system . The burden of diabetic neuropathy is related not only to the complexity of diabetes but also to the poor outcomes and difficult treatment options. There is no specific treatment for diabetic neuropathy other than glycemic control and diligent foot care. Although various metabolic pathways are impaired in diabetic neuropathy, enhanced cellular oxidative stress is proposed as a common initiator. A mechanism-based treatment of diabetic neuropathy is challenging; a better understanding of the pathophysiology of diabetic neuropathy will help to develop strategies for the new and correct diagnostic procedures and personalized interventions. Thus, we review the current knowledge of the pathophysiology in diabetic neuropathy. We focus on discussing how the defects in metabolic and vascular pathways converge to enhance oxidative stress and how they produce the onset and progression of nerve injury present in diabetic neuropathy. We discuss if the mechanisms underlying neuropathy are similarly operated in type I and type II diabetes and the progression of antioxidants in treating diabetic neuropathy.
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