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Prohibitin regulates mTOR pathway via interaction with FKBP8.

Jiahui ZHANG ; Yanan YIN ; Jiahui WANG ; Jingjing ZHANG ; Hua LIU ; Weiwei FENG ; Wen YANG ; Bruce ZETTER ; Yingjie XU

Frontiers of Medicine.2021;15(3):448-459. doi:10.1007/s11684-020-0805-6

The ability of tumor cells to sustain continuous proliferation is one of the major characteristics of cancer. The activation of oncogenes and the mutation or inactivation of tumor suppressor genes ensure the rapid proliferation of tumor cells. The PI3K-Akt-mTOR axis is one of the most frequently modified signaling pathways whose activation sustains cancer growth. Unsurprisingly, it is also one of the most commonly attempted targets for cancer therapy. FK506 binding protein 8 (FKBP8) is an intrinsic inhibitor of mTOR kinase that also exerts an anti-apoptotic function. We aimed to explain these contradictory aspects of FKBP8 in cancer by identifying a "switch" type regulator. We identified through immunoprecipitation-mass spectrometry-based proteomic analysis that the mitochondrial protein prohibitin 1 (PHB1) specifically interacts with FKBP8. Furthermore, the downregulation of PHB1 inhibited the proliferation of ovarian cancer cells and the mTOR signaling pathway, whereas the FKBP8 level in the mitochondria was substantially reduced. Moreover, concomitant with these changes, the interaction between FKBP8 and mTOR substantially increased in the absence of PHB1. Collectively, our finding highlights PHB1 as a potential regulator of FKBP8 because of its subcellular localization and mTOR regulating role.
Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Female ; Humans ; Ovarian Neoplasms ; Phosphatidylinositol 3-Kinases ; Proteomics ; Repressor Proteins ; TOR Serine-Threonine Kinases ; Tacrolimus Binding Proteins

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Resveratrol promotes the survival and neuronal differentiation of hypoxia-conditioned neuronal progenitor cells in rats with cerebral ischemia.

Yao YAO ; Rui ZHOU ; Rui BAI ; Jing WANG ; Mengjiao TU ; Jingjing SHI ; Xiao HE ; Jinyun ZHOU ; Liu FENG ; Yuanxue GAO ; Fahuan SONG ; Feng LAN ; Xingguo LIU ; Mei TIAN ; Hong ZHANG

Frontiers of Medicine.2021;15(3):472-485. doi:10.1007/s11684-021-0832-y

Hypoxia conditioning could increase the survival of transplanted neuronal progenitor cells (NPCs) in rats with cerebral ischemia but could also hinder neuronal differentiation partly by suppressing mitochondrial metabolism. In this work, the mitochondrial metabolism of hypoxia-conditioned NPCs (hcNPCs) was upregulated via the additional administration of resveratrol, an herbal compound, to resolve the limitation of hypoxia conditioning on neuronal differentiation. Resveratrol was first applied during the in vitro neuronal differentiation of hcNPCs and concurrently promoted the differentiation, synaptogenesis, and functional development of neurons derived from hcNPCs and restored the mitochondrial metabolism. Furthermore, this herbal compound was used as an adjuvant during hcNPC transplantation in a photothrombotic stroke rat model. Resveratrol promoted neuronal differentiation and increased the long-term survival of transplanted hcNPCs. 18-fluorine fluorodeoxyglucose positron emission tomography and rotarod test showed that resveratrol and hcNPC transplantation synergistically improved the neurological and metabolic recovery of stroke rats. In conclusion, resveratrol promoted the neuronal differentiation and therapeutic efficiency of hcNPCs in stroke rats via restoring mitochondrial metabolism. This work suggested a novel approach to promote the clinical translation of NPC transplantation therapy.
Animals ; Brain Ischemia/drug therapy* ; Cell Differentiation ; Hypoxia ; Neurons ; Rats ; Resveratrol/pharmacology*

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Innate immune responses in RNA viral infection.

Qian XU ; Yuting TANG ; Gang HUANG

Frontiers of Medicine.2021;15(3):333-346. doi:10.1007/s11684-020-0776-7

RNA viruses cause a multitude of human diseases, including several pandemic events in the past century. Upon viral invasion, the innate immune system responds rapidly and plays a key role in activating the adaptive immune system. In the innate immune system, the interactions between pathogen-associated molecular patterns and host pattern recognition receptors activate multiple signaling pathways in immune cells and induce the production of pro-inflammatory cytokines and interferons to elicit antiviral responses. Macrophages, dendritic cells, and natural killer cells are the principal innate immune components that exert antiviral activities. In this review, the current understanding of innate immunity contributing to the restriction of RNA viral infections was briefly summarized. Besides the main role of immune cells in combating viral infection, the intercellular transfer of pathogen and host-derived materials and their epigenetic and metabolic interactions associated with innate immunity was discussed. This knowledge provides an enhanced understanding of the innate immune response to RNA viral infections in general and aids in the preparation for the existing and next emerging viral infections.
Humans ; Immunity, Innate ; Interferons ; RNA ; RNA Viruses ; Virus Diseases

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Prognostic value of the 21-gene recurrence score in ER-positive, HER2-negative, node-positive breast cancer was similar in node-negative diseases: a single-center study of 800 patients.

Jiayi WU ; Weiqi GAO ; Xiaosong CHEN ; Chunxiao FEI ; Lin LIN ; Weiguo CHEN ; Ou HUANG ; Siji ZHU ; Jianrong HE ; Yafen LI ; Li ZHU ; Kunwei SHEN

Frontiers of Medicine.2021;15(4):621-628. doi:10.1007/s11684-020-0738-0

Multi-gene assays have emerged as crucial tools for risk stratification in early-stage breast cancer. This study aimed to evaluate the prognostic significance of the 21-gene recurrence score (RS) in Chinese patients with pN0-1, estrogen receptor-positive (ER
Biomarkers, Tumor/genetics* ; Breast Neoplasms/pathology* ; Female ; Humans ; Neoplasm Recurrence, Local/pathology* ; Neoplasm Staging ; Prognosis ; Receptor, ErbB-2/genetics* ; Receptors, Estrogen

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Repurposing clinical drugs is a promising strategy to discover drugs against Zika virus infection.

Weibao SONG ; Hongjuan ZHANG ; Yu ZHANG ; Rui LI ; Yanxing HAN ; Yuan LIN ; Jiandong JIANG

Frontiers of Medicine.2021;15(3):404-415. doi:10.1007/s11684-021-0834-9

Zika virus (ZIKV) is an emerging pathogen associated with neurological complications, such as Guillain-Barré syndrome in adults and microcephaly in fetuses and newborns. This mosquito-borne flavivirus causes important social and sanitary problems owing to its rapid dissemination. However, the development of antivirals against ZIKV is lagging. Although various strategies have been used to study anti-ZIKV agents, approved drugs or vaccines for the treatment (or prevention) of ZIKV infections are currently unavailable. Repurposing clinically approved drugs could be an effective approach to quickly respond to an emergency outbreak of ZIKV infections. The well-established safety profiles and optimal dosage of these clinically approved drugs could provide an economical, safe, and efficacious approach to address ZIKV infections. This review focuses on the recent research and development of agents against ZIKV infection by repurposing clinical drugs. Their characteristics, targets, and potential use in anti-ZIKV therapy are presented. This review provides an update and some successful strategies in the search for anti-ZIKV agents are given.
Adult ; Animals ; Drug Repositioning ; Humans ; Infant, Newborn ; Microcephaly ; Pharmaceutical Preparations ; Zika Virus ; Zika Virus Infection/prevention & control*

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Proteins moonlighting in tumor metabolism and epigenetics.

Lei LV ; Qunying LEI

Frontiers of Medicine.2021;15(3):383-403. doi:10.1007/s11684-020-0818-1

Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment. High plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer cells. To respond to nutrient stress and to meet the requirements for rapid cell proliferation, cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for biosynthesis. Such actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic enzymes. The signal - moonlighting protein - metabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.
Energy Metabolism ; Epigenesis, Genetic ; Humans ; Metabolic Networks and Pathways ; Neoplasms/genetics* ; Tumor Microenvironment

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Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia.

Jianfeng LI ; Yuting DAI ; Liang WU ; Ming ZHANG ; Wen OUYANG ; Jinyan HUANG ; Saijuan CHEN

Frontiers of Medicine.2021;15(3):347-371. doi:10.1007/s11684-020-0821-6

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by genetic alterations with high heterogeneity. Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology. Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes, such as DUX4 rearrangements, MEF2D rearrangements, ZNF384/ZNF362 rearrangements, NUTM1 rearrangements, BCL2/MYC and/or BCL6 rearrangements, ETV6-RUNX1-like gene expression, PAX5alt (diverse PAX5 alterations, including rearrangements, intragenic amplifications, or mutations), and hotspot mutations PAX5 (p.Pro80Arg) with biallelic PAX5 alterations, IKZF1 (p.Asn159Tyr), and ZEB2 (p.His1038Arg). These molecular subtypes could be classified by gene expression patterns with RNA-seq technology. Refined molecular classification greatly improved the treatment strategy. Multiagent therapy regimens, including target inhibitors (e.g., imatinib), immunomodulators, monoclonal antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy, are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management. We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.
B-Lymphocytes ; Humans ; Mutation ; Oncogene Proteins, Fusion/genetics* ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; Precursor Cell Lymphoblastic Leukemia-Lymphoma

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The "Traditional Chinese medicine regulating liver regeneration" treatment plan for reducing mortality of patients with hepatitis B-related liver failure based on real-world clinical data.

Ling DAI ; Xiang GAO ; Zhihua YE ; Hanmin LI ; Xin YAO ; Dingbo LU ; Na WU

Frontiers of Medicine.2021;15(3):495-505. doi:10.1007/s11684-020-0790-9

On the basis of real-world clinical data, the study aimed to explore the effect and mechanisms of the treatment plan of "traditional Chinese medicine (TCM) regulating liver regeneration." A total of 457 patients with HBV-related liver failure were retrospectively collected. The patients were divided into three groups: the modern medicine control group (MMC group), patients treated with routine medical treatment; the control group combining traditional Chinese and Western medicine (CTW), patients treated with routine medical treatment plus the common TCM formula; and the treatment group of "TCM regulating liver regeneration" (RLR), patients treated with both routine medical treatment and the special TCM formula of RLR. After 8 weeks of treatment, the mortality of patients in the RLR group (12.31%) was significantly lower than those in the MMC (50%) and CTW (29.11%) groups. Total bilirubin level significantly decreased and albumin increased in the RLR group when compared with the MMC and CTW groups (P < 0.05). In addition, there were significant differences in the expression of several cytokines related to liver regeneration in the RLR group compared with the MMC group. RLR treatment can decrease jaundice, improve liver function, and significantly reduce the mortality in patients with HBV-related liver failure. The mechanism may be related to the role of RLR treatment in influencing cytokines related to liver regeneration.
Drugs, Chinese Herbal/therapeutic use* ; Hepatitis B/drug therapy* ; Humans ; Liver Failure ; Liver Regeneration ; Medicine, Chinese Traditional ; Retrospective Studies

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Translational application of neuroimaging in major depressive disorder: a review of psychoradiological studies.

Ziqi CHEN ; Xiaoqi HUANG ; Qiyong GONG ; Bharat B BISWAL

Frontiers of Medicine.2021;15(4):528-540. doi:10.1007/s11684-020-0798-1

Major depressive disorder (MDD) causes great decrements in health and quality of life with increments in healthcare costs, but the causes and pathogenesis of depression remain largely unknown, which greatly prevent its early detection and effective treatment. With the advancement of neuroimaging approaches, numerous functional and structural alterations in the brain have been detected in MDD and more recently attempts have been made to apply these findings to clinical practice. In this review, we provide an updated summary of the progress in translational application of psychoradiological findings in MDD with a specified focus on potential clinical usage. The foreseeable clinical applications for different MRI modalities were introduced according to their role in disorder classification, subtyping, and prediction. While evidence of cerebral structural and functional changes associated with MDD classification and subtyping was heterogeneous and/or sparse, the ACC and hippocampus have been consistently suggested to be important biomarkers in predicting treatment selection and treatment response. These findings underlined the potential utility of brain biomarkers for clinical practice.
Brain/diagnostic imaging* ; Depressive Disorder, Major/diagnostic imaging* ; Humans ; Magnetic Resonance Imaging ; Neuroimaging ; Quality of Life

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Cohort study of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis in China: evaluation of risk models and new predictor of pulmonary consolidation on computed tomography.

Yanhong SHOU ; Lu YANG ; Yongsheng YANG ; Xiaohua ZHU ; Feng LI ; Bo YIN ; Yingyan ZHENG ; Jinhua XU

Frontiers of Medicine.2021;15(4):585-593. doi:10.1007/s11684-020-0817-2

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe diseases. This study aimed to validate the predictive ability of risk models in patients with SJS/TEN and propose possible refinement in China. Patients in the Department of Dermatology of Huashan Hospital from January 2008 to January 2019 were included. Results showed that the severity-of-illness score for TEN (SCORTEN) had a good discrimination (area under the receiver operating characteristic curve (AUC), 0.78), and it was superior to auxiliary score (AS) and ABCD-10, which indicates age, bicarbonate level, cancer, dialysis, and 10% involved body surface area (AUC, 0.69 and 0.68, respectively). The calibration of SCORTEN (Hosmer-Lemeshow goodness-of-fit test, P = 0.69) was also better than that of AS (P = 0.25) and ABCD-10 (P = 0.55). SCORTEN and ABCD-10 were similar (Brier score (BS), 0.04 and 0.04) in terms of accuracy of predictions. In addition, the imaging appearance of pulmonary consolidation on computed tomography was associated with high mortality. Refined models were formed using the variables and this imaging appearance. The refined AS and ABCD-10 models were similar in discrimination compared with the original SCORTEN (0.74 vs. 0.78, P = 0.23; 0.74 vs. 0.78, P = 0.30, respectively). Therefore, SCORTEN showed good discrimination performance, calibration, and accuracy, and refined AS or ABCD-10 model may be an option when SCORTEN variables are not available.
Cohort Studies ; Humans ; Retrospective Studies ; Severity of Illness Index ; Stevens-Johnson Syndrome/diagnostic imaging* ; Tomography

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