To establish and identify induced pluripotent stem cells (iPSCs) derived from patients with Aicardi-Goutières syndrome (AGS) with TREX1 gene 667G>A mutation, and obtain a specific induced pluripotent stem cell model for Aicardi-Goutières syndrome (AGS-iPSCs). A 3-year-old male child with Aicardi-Goutieres syndrome was admitted to Zhongshan People's Hospital in December 2020. After obtaining the informed consent of the patient's family members, 5 ml peripheral blood samples from the patient were collected, and mononuclear cells were isolated. Then,the peripheral blood mononuclear cells(PBMCs) were transduced with OCT3/4, SOX2, c-Myc and Klf4 by using Sendai virus, and PBMCs were reprogrammed into iPSCs. The pluripotency and differentiation ability of the cells were identified by cellular morphological analysis, real-time PCR, alkaline phosphatase staining (AP), immunofluorescence, teratoma formation experiments in mice. The results showed that the induced pluripotent stem cell line of Aicardi-Goutieres syndrome was successfully constructed and showed typical embryonic stem-like morphology after stable passage, RT-PCR showed mRNA expression of stem cell markers, AP staining was positive, OCT4, SOX2, NANOG, SSEA4, TRA-1-81 and TRA-1-60 pluripotency marker proteins were strongly expressed. In vivo teratoma formation experiments showed that iPSCs differentiate into the ectoderm (neural tube like tissue), mesoderm (vascular wall tissue) and endoderm (glandular tissue). Karyotype analysis also confirmed that iPSCs still maintained the original karyotype (46, XY). In conclusion, induced pluripotent stem cell line for Aicardi-Goutières syndrome was successfully established using Sendai virus, which provided an important model platform for studying the pathogenesis of the disease and for drug screening.
Animals ; Male ; Mice ; Cell Differentiation ; Induced Pluripotent Stem Cells/pathology* ; Leukocytes, Mononuclear ; Teratoma/pathology* ; Child, Preschool

This project was aimed to investigate the role and the underlying mechanism of microglia polarization on blood-brain barrier (BBB) during cerebral ischemia-reperfusion. After construction of the mouse model of cerebral ischemia-reperfusion, upregulated IL-6 and TNF-α in peripheral blood and increased IL-6 and iNOS in ischemia tissues were confirmed. The supernatant expression of TNF-α and IL-6, as well as IL-6, iNOS and CD86 mRNA, was significantly increased in the of Bv-2 cells after oxygen-glucose deprivation/reoxygenation (OGD/R) model was constructed in vitro. For further understanding the expression pattern of RNAs, the next-generation RNA sequencing was performed and upregulation of Robo4 (roundabout guidance receptor 4) was found both in M1-polarized and OGD/R treated Bv-2 cells, which was also confirmed by RT-qPCR. Extracellular soluble Robo4 (sRobo4) protein also increased in the supernatant of M1-polarized and OGD/R treated Bv-2 cells. Treating bEND3 cells with the Robo4 recombinant protein, M1-polarized Bv-2 cell supernatant or OGD/R Bv-2 cell supernatant decreased trans-endothelial electrical resistance (TEER), suggesting the injury of BBB. In addition, Robo4 was also highly expressed in the serum of patients who experienced acute ischemia stroke and mechanical thrombectomy operation. All the results suggest that increased secretion of Robo4 by M1-polarized-microglia during cerebral ischemia-reperfusion is most likely one of the causes of BBB injury, and Robo4 may be one of the therapeutic targets for BBB functional protection.
Animals ; Blood-Brain Barrier/metabolism* ; Brain Ischemia/drug therapy* ; Glucose/metabolism* ; Interleukin-6/metabolism* ; Mice ; Microglia/metabolism* ; Oxygen/metabolism* ; Receptors, Cell Surface/metabolism* ; Reperfusion ; Reperfusion Injury/drug therapy* ; Tumor Necrosis Factor-alpha/metabolism*

Nonalcoholic fatty liver disease (NAFLD) is a multisystem disease involving metabolic disorder and is more common in patients with obesity and type 2 diabetes mellitus (T2DM), with similar adverse outcomes to these two comorbidities. For a long time, NAFLD has emphasized liver lesions and outcomes of liver diseases, and when treating T2DM according to the current clinical guidelines for diabetes, endocrinologists often neglect the screening, diagnosis, and treatment of liver lesions. Therefore, in clinical practice, NAFLD renamed as metabolic-associated fatty liver disease has important practical significance. Strategies for T2DM prevention and treatment aiming at reducing liver lipid content require multidisciplinary cooperation, and prevention and treatment of obesity, fatty liver disease, and diabetes with the same concepts can help to implement the prevention and treatment of the most common chronic diseases.

Although nonalcoholic fatty liver disease (NAFLD) is a liver disease, it has attracted more and more attention among endocrinologists. There are complex interactions between the metabolic status of diabetes and the pathology of NAFLD, and they promote the development of each other. In the population with type 2 diabetes mellitus (T2DM), the incidence rate of NAFLD is as high as 57%-80%, and NAFLD patients with diabetes are more likely to develop progressive liver diseases such as nonalcoholic steatohepatitis (NASH) and liver fibrosis. NAFLD also leads to the deterioration of glucose and lipid metabolism disorder in diabetes patients, as well as the development and progression of chronic macrovascular and microvascular complications in diabetes. The above evidence supports the view that NASH should be considered a complication of T2DM. Once a definite diagnosis of T2DM is made in clinical practice, the risk of NASH or progressive fibrosis should be evaluated and intervention should be given as early as possible.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumors in the gastrointestinal tract. Though surgical resection is the only radical treatment, postoperative recurrence and metastasis often occur. The first-line therapy for the treatment of recurrent, metastatic and unresectable GIST is imatinib. More than 80% of patients can benefit from imatinib treatment, but half of patients will still have recurrence or metastasis within 2 years after treatment initiation, and secondary drug resistance is a major cause of disease progression. Therefore, adeep understanding of the mechanisms of secondary drug resistance will guide us to develop personalized therapeutic schedule in the future. This article describes the mechanism of IM secondary resistance from the aspects of gene alteration, abnormal activation of signal transduction pathway, autophagy, apoptosis and drug concentration. It is found that single drug therapy has certain limitations in patients with secondary resistance to IM. Using IM combined with downstream signaling molecule inhibitors, autophagy inhibitors, insulin-like growth factor 1 receptor (IGF-1R) inhibitors, heat shock protein 90 (HSP90) inhibitors, cytotoxic T lymphocyte - associated antigen - 4 (CTLA - 4) antibodies and mitochondrial inhibitors provide us new therapeutic ideas. However, these combination treatments are still in the research phase, and further trials are needed to confirm the safety and efficacy. With the gradual deepening of research on drug resistance mechanisms, it will provide more solutions to the current serious drug resistance problem.

Iron is an important nutrient element which is involved in a variety of physiological processes. The potential toxicity of excess iron requires that cells should evolve a robust, tightly regulated mechanism for maintaining iron homeostasis. At the same time, iron plays an indispensable role in the process of tumorigenesis and progression. The mechanism involved in iron homeostasis can make changes to adapt to its metabolic level and to maintain the activity of the tumor cells. This paper reviews iron metabolism and its role in the maintaining of iron homeostasis, as well as the importance of iron metabolism in solid cancers.

Hepatocellular carcinoma (HCC), a highly prevalent malignancy and one of the leading cause of cancer death in China, remains a major public health problem in the next decades. Owing to the tremendous achievements in early diagnosis, precision liver surgery, molecular targeted therapy and immunotherapy, we have witnessed significant improvements in the long-time survival of HCC patients, if properly treated. However, HCC is a highly heterogeneous disease. Even for patients within the same clinical stage, their clinical outcome and treatment efficacy vary significantly. Great efforts to improve the molecular classification of HCC patients are needed to foster precision medicine, paving the way for novel therapeutic strategies. Advances in multi-omics, single-cell analysis, molecular imaging and artificial intelligence will lead to better understanding of the molecular classification and refine precision treatment in HCC, ultimately excluding this neoplasm from the risk list of our Healthy China.

Nonalcoholic fatty liver disease (NAFLD) is the manifestation of metabolic syndrome in the liver and is closely associated with glucose and lipid metabolism disorders, and they interact as both cause and effect of each other, with insulin resistance as the common pathogenesis. About three quarters of patients with obesity and type 2 diabetes mellitus have NAFLD, and current guidelines recommend reducing metabolic risk factors and treating metabolic syndrome as the primary treatment goals for patients with NAFLD. Although there are no approved drugs for the treatment of NASH at present, the hypoglycemic drugs on the market can bring varying degrees of benefits to NAFLD patients while lowering blood glucose. This article reviews the prospects of three types of hypoglycemic drugs on the market (thiazolidinediones, GLP-1 receptor agonists, and SGLT-2 inhibitors) in the treatment of NAFLD.

OBJECTIVESTo explore the changes of multifocal electroretinograms (mfERG) before and after retinal detachment surgery and to evaluate its clinical significance.

METHODSTwenty-three patients (23 eyes) with rhegmatogenous retinal detachment underwent mfERG before and after surgery. The latencies and average response densities of N(1)-wave and P(1)-wave of mfERGs in detached areas, attached areas, fovea and the entire tested area were compared before and after surgery.

RESULTSPreoperatively, the average response densities of N(1)-wave and P(1)-wave in the detached area were significantly smaller than those in attached areas (t = 3.68, t = 4.26, P < 0.01), and the latencies of N(1)-wave and P(1)-wave in detached areas were significantly longer than those in attached areas (t = 3.07, t = 3.89, P < 0.01). Postoperatively, the average response densities of N(1)-wave and P(1)-wave in detached areas, fovea and the entire tested area increased, and there were significant differences pre- and postoperatively (P < 0.05). However, the latencies of N(1)-wave and P(1)-wave before and after surgery showed no significant differences (P > 0.05).

CONCLUSIONSThe mfERG is a useful tool to evaluate the recovery of posterior retinal function after retinal detachment surgery. The response density is a more sensitive index than latency to evaluate retinal function of retinal detachment.

Adult ; Aged ; Electroretinography ; Female ; Humans ; Male ; Middle Aged ; Retinal Detachment ; physiopathology ; surgery ; Visual Acuity

OBJECTIVETo identify the characteristics of and evaluate surgical impact on idiopathic macular hole (IMH) by using an optical coherence tomography (OCT) scanner.

METHODSSixty-five cases (70 eyes) experiencing IMH were examined using OCT, then graded by their clinical characteristics. Nineteen cases (19 eyes) were scanned and measured using OCT before and after surgery.

RESULTSOf the 70 eyes,the number of stage I-IV macular holes were 11, 12, 36 and 11, respectively. For stage I holes, the OCT images revealed flattened or nonexistent fovea and minimally reflective space within or beneath the neurosensory retina; stage II holes appeared to be full-sized with attached operculum and surrounding edema; stage III holes were also full-sized with surrounding edema; finally, stage IV holes were full-sized and completely separated the posterior hyaloid membrane from the retina. Through quantitative measurements, OCT determined that the values for mean hole diameter, mean halo diameter and mean thickness of the hole's edge were reduced from 570.95 +/- 265.59 to 337.05 +/- 335.95 microm, 1043.53 +/- 278.8 to 695.00 +/- 483.00 microm and 389.78 +/- 60.58 to 298.78 +/- 109.80 microm, respectively in 19 IMH cases after surgery. In 17 eyes, the holes or halos eventually closed or were reduced in size, or the edges of the holes thinned out. The anatomic successful rate of the surgery was 89%.

CONCLUSIONOCT can exhibit the characteristics of IMH and measure the diameter of holes quantitatively. This method can also judge the surgical impacts of IMH objectively, accurately and effectively.

Adult ; Aged ; Female ; Humans ; Macula Lutea ; pathology ; Male ; Middle Aged ; Retinal Perforations ; pathology ; surgery ; Tomography ; methods