[摘 要] 目的：探究银杏内酯B（GKB）调控蛋白激酶R样内质网激酶（PERK）/转录激活子4（ATF4）/C/EBP同源蛋白（CHOP）信号通路对肝癌细胞增殖、迁移、凋亡和上皮间质转化（EMT）的影响。方法：将人肝癌细胞MHCC-97H随机分为对照组、GKB组、GSK2656157（PERK抑制剂）组和GKB + GSK2656157组，以GKB和GSK2656157分别干预后，采用MTT法和EdU染色检测各组细胞的增殖活性及增殖率，划痕愈合实验、流式细胞术分别检测各组细胞的迁移及凋亡水平，WB法检测各组细胞中EMT和PERK/ATF4/CHOP信号通路相关蛋白的表达水平。构建MHCC-97H细胞裸鼠移植瘤模型，以同法分组及药物干预后测定各组移植瘤体积，采用免疫组化、TUNEL染色分别检测各组肿瘤细胞增殖、凋亡水平，WB法检测各组移植瘤组织中EMT和PERK/ATF4/CHOP信号通路相关蛋白的表达水平。结果：与对照组比较，GKB组细胞活性、增殖率、迁移率、移植瘤体积、Ki-67阳性细胞率、MMP2、N-cadherin与MMP9蛋白表达均显著降低（均P < 0.05），细胞凋亡率、TUNEL阳性细胞率、p-PERK/PERK与E-cadherin、ATF4、CHOP蛋白表达均显著升高（均P < 0.05）；GSK2656157组各指标变化与GKB组相反（均P < 0.05）。与GKB组比较，GKB + GSK2656157组细胞活性、增殖率、迁移率、移植瘤体积、Ki-67阳性细胞率、MMP2、N-cadherin与MMP9蛋白表达均显著升高（均P < 0.05），细胞凋亡率、TUNEL阳性细胞率、p-PERK/PERK与E-cadherin、ATF4、CHOP蛋白表达均显著降低（均P < 0.05）。结论：GKB可通过激活PERK/ATF4/CHOP信号通路抑制肝癌MHCC-97H细胞增殖、迁移和EMT并促进其凋亡。

Objective To investigate the risk factors for postoperative recurrence and metastasis in patients with T1 stageⅢ/Ⅳ clear cell renal cell carcinoma(ccRCC), and to analyze the influence of surgical methods on prognosis, so as to provide prognostic evaluation and treatment guidance for clinical practice. Methods A retrospective analysis was conducted on 398 patients diagnosed with T1 stage Ⅲ/Ⅳ ccRCC who underwent either partial nephrectomy(PN)or radical nephrectomy(RN)at Jiangsu Province Hospital during Jan. 2008 and Sep. 2022. The patients were divided into recurrence group(n=49)and non-recurrence group(n=349)according to whether the tumor recurred during the follow-up period. The general, clinical data and prognosis were compared between the two groups. Univariate and multivariate Cox regression analyses were used to explore the factors influencing disease-free survival(DFS)and overall survival(OS)after surgery. Subgroup analysis using Kaplan-Meier curves was performed for T1a and T1b patients. Results During the median follow-up of 67(42, 98)months, the recurrence group was characterized by older age, larger tumor diameter, higher proportion of T1b stage, and more complex tumor anatomy. Univariate and multivariate Cox regression analyses showed that age ≥55 years and R.E.N.A.L. score ≥7 were independent risk factors for poorer DFS and OS(P＜0.05). Subgroup analysis revealed that PN or RN did not significantly affect DFS or OS in T1a patients and OS in T1b patients, while RN significantly improved DFS in T1b patients(P＜0.05). Conclusion Age ≥55 years and R.E.N.A.L. score ≥7 are independent risk factors for poor DFS and OS in highgrade T1 ccRCC patients. For T1b patients, RN may improve DFS.

Objective·To identify relevant biomarkers for patients with coronavirus disease 2019-associated kidney injury(COVID-19-associated KI)and explore the mechanisms underlying the involvement of severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)proteins in infection-related KI by affecting the interactions between renal cells and macrophages.Methods·A retrospective analysis was conducted on the clinical characteristics of COVID-19 patients with KI treated in Shanghai Ninth,People's,hospital from December 2022 to February 2023.Serum levels of inflammatory factors and chemokines were measured by using enzyme-linked immunosorbent assay(ELISA).In vitro,human macrophage cell line THP-1 cells were stimulated with recombinant S1 subunit protein derived from SARS-CoV-2 spike protein.The cells and culture supernatants were collected to detect the levels of inflammatory factors and chemokines by using quantitative real-time PCR(qRT-PCR)and ELISA.Conditioned medium was prepared from the cell culture supernatants of S1-stimulated THP-1 cells and used to stimulate human renal epithelial cells(HK-2)in vitro to assess cytokine secretion.Antibody blocking experiments were performed to analyze the effects of the conditioned medium on the production of cytokines in HK-2 cells.Results·Among 39 patients with COVID-19,8(20.50%)had creatinine levels above the reference interval,which indicated the occurrence of KI.The levels of peripheral tumor necrosis factor-α(TNF-α)in the COVID-19 patient with KI group[(18.33±8.20)pg/mL]were significantly higher than those in the non-KI group[(11.88±6.50)pg/mL](P=0.015).In vitro assay has shown that S1-spike protein stimulation promoted the level of gene transcription and production of TNF-α,interleukin-1β(IL-1β)and chemokine C-X-C motif ligand 10(CXCL10)in THP-1 macrophage cells(P＜0.001).Furthermore,the conditioned medium from S1-stimulated THP-1 cells promoted the secretion of TNF-α,IL-1β and CXCL10 by HK-2 cells(P=0.005).When anti-TNF-α antibody(Infliximab)was used to block TNF-α in the culture supernatants from S1-stimulated THP-1 cells,the secretion level of TNF-α by HK-2 cells decreased dramatically(P＜0.001).Conclusion·TNF-α levels increase significantly in COVID-19 patients with KI,implying the significance of TNF-α in the occurrence of COVID-19-associated KI.In vitro experiments confirm that the S1 protein induces TNF-α secretion from THP-1 cells,leading to increased inflammatory responses in renal cells,which may contribute to the development of COVID-19-associated KI.Therefore,targeting TNF-α may become an alternative strategy to reduce the occurrence of COVID-19-associated KI.

Growth arrest DNA damage-inducible protein 45 β (GADD45B) has been reported to be a regulatory factor for active DNA demethylation and is implicated in the modulation of synaptic plasticity and chronic stress-related psychopathological processes. However, its precise role and mechanism of action in stress susceptibility remain elusive. In this study, we found a significant reduction in GADD45B expression specifically in the ventral, but not the dorsal hippocampal CA1 (dCA1) of stress-susceptible mice. Furthermore, we demonstrated that GADD45B negatively regulates susceptibility to social stress and NMDA receptor-dependent long-term potentiation (LTP) in the ventral hippocampal CA1 (vCA1). Importantly, through pharmacological inhibition using the NMDA receptor antagonist MK801, we provided further evidence supporting the hypothesis that GADD45B potentially modulates susceptibility to social stress by influencing NMDA receptor-mediated LTP. Collectively, these results suggested that modulation of NMDA receptor-mediated synaptic plasticity is a pivotal mechanism underlying the regulation of susceptibility to social stress by GADD45B.
Animals ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors* ; CA1 Region, Hippocampal/drug effects* ; Male ; Stress, Psychological/physiopathology* ; Mice ; Neuronal Plasticity/drug effects* ; Long-Term Potentiation/drug effects* ; Mice, Inbred C57BL ; Antigens, Differentiation/metabolism* ; Dizocilpine Maleate/pharmacology* ; Excitatory Amino Acid Antagonists/pharmacology* ; GADD45 Proteins

This study investigates the mechanism by which Xintong Granules improve myocardial ischemia-reperfusion injury(MIRI) through the regulation of gut microbiota and their metabolites, specifically short-chain fatty acids(SCFAs). Rats were randomly divided based on body weight into the sham operation group, model group, low-dose Xintong Granules group(1.43 g·kg~(-1)·d~(-1)), medium-dose Xintong Granules group(2.86 g·kg~(-1)·d~(-1)), high-dose Xintong Granules group(5.72 g·kg~(-1)·d~(-1)), and metoprolol group(10 mg·kg~(-1)·d~(-1)). After 14 days of pre-administration, the MIRI rat model was established by ligating the left anterior descending coronary artery. The myocardial infarction area was assessed using the 2,3,5-triphenyltetrazolium chloride(TTC) staining method. Apoptosis in tissue cells was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL) assay. Pathological changes in myocardial cells and colonic tissue were observed using hematoxylin-eosin(HE) staining. The levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6), creatine kinase MB isoenzyme(CK-MB), and cardiac troponin T(cTnT) in rat serum were quantitatively measured using enzyme-linked immunosorbent assay(ELISA) kits. The activities of lactate dehydrogenase(LDH), creatine kinase(CK), and superoxide dismutase(SOD) in myocardial tissue, as well as the level of malondialdehyde(MDA), were determined using colorimetric assays. Gut microbiota composition was analyzed by 16S rDNA sequencing, and fecal SCFAs were quantified using gas chromatography-mass spectrometry(GC-MS). The results show that Xintong Granules significantly reduced the myocardial infarction area, suppressed cardiomyocyte apoptosis, and decreased serum levels of pro-inflammatory cytokines(TNF-α, IL-1β, and IL-6), myocardial injury markers(CK-MB, cTnT, LDH, and CK), and oxidative stress marker MDA. Additionally, Xintong Granules significantly improved intestinal inflammation in MIRI rats, regulated gut microbiota composition and diversity, and increased the levels of SCFAs(acetate, propionate, isobutyrate, etc.). In summary, Xintong Granules effectively alleviate MIRI symptoms. This study preliminarily confirms that Xintong Granules exert their inhibitory effects on MIRI by regulating gut microbiota imbalance and increasing SCFA levels.
Animals ; Gastrointestinal Microbiome/drug effects* ; Rats ; Male ; Myocardial Reperfusion Injury/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Rats, Sprague-Dawley ; Apoptosis/drug effects* ; Humans ; Tumor Necrosis Factor-alpha/metabolism* ; Interleukin-6/genetics* ; Malondialdehyde/metabolism*

In 2040, neurodegenerative diseases (NDD) will overtake cancer as the second leading cause of death after cardiovascular and cerebrovascular diseases. Therefore, the search for effective intervention measures has become the top priority to deal with this difficult burden. Hyperbaric oxygen therapy (HBOT) has been used for the past 50 years to treat conditions such as decompression sickness, carbon monoxide poisoning and radiation damage. In recent years, studies have confirmed that HBOT has good effects in improving cognitive impairment after brain injury and stroke, and alleviating neurodegeneration and dysfunction related to NDD. Here we reviewed the pathogenesis and treatment state of NDD, introduced the application of HBOT in animal models and clinical studies of NDD, and expounded the application potential of HBOT in the treatment of NDD from the perspective of mitochondrial function, neuroinflammation, neurogenesis and angiogenesis, oxidative stress, apoptosis, microcirculation and epigenetics.
Hyperbaric Oxygenation ; Humans ; Neurodegenerative Diseases/physiopathology* ; Animals ; Oxidative Stress ; Apoptosis ; Mitochondria/physiology* ; Neurogenesis ; Epigenesis, Genetic

Linxian County in Henan Province, Northern China is known as the region with the highest incidence and mortality rate of esophageal cancer worldwide. Since 1959, the Henan medical team has conducted field work on esophageal cancer prevention and treatment in Linxian. Through three generations of effort exerted by oncologists over 65 years of research on esophageal cancer prevention and treatment in Linxian, the incidence rate of esophageal squamous cell carcinoma in this area has dropped by nearly 50%, and the 5-year survival rate has increased to 40%, reaching the international leading level. This article aims to summarize the history, present opportunities and new challenges, and explore the experience of esophageal cancer prevention and treatment in Linxian (referred to as the “Linxian experience”), providing reference and guidance to cancer prevention and treatment research in China.

Objective·To identify relevant biomarkers for patients with coronavirus disease 2019-associated kidney injury(COVID-19-associated KI)and explore the mechanisms underlying the involvement of severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)proteins in infection-related KI by affecting the interactions between renal cells and macrophages.Methods·A retrospective analysis was conducted on the clinical characteristics of COVID-19 patients with KI treated in Shanghai Ninth,People's,hospital from December 2022 to February 2023.Serum levels of inflammatory factors and chemokines were measured by using enzyme-linked immunosorbent assay(ELISA).In vitro,human macrophage cell line THP-1 cells were stimulated with recombinant S1 subunit protein derived from SARS-CoV-2 spike protein.The cells and culture supernatants were collected to detect the levels of inflammatory factors and chemokines by using quantitative real-time PCR(qRT-PCR)and ELISA.Conditioned medium was prepared from the cell culture supernatants of S1-stimulated THP-1 cells and used to stimulate human renal epithelial cells(HK-2)in vitro to assess cytokine secretion.Antibody blocking experiments were performed to analyze the effects of the conditioned medium on the production of cytokines in HK-2 cells.Results·Among 39 patients with COVID-19,8(20.50%)had creatinine levels above the reference interval,which indicated the occurrence of KI.The levels of peripheral tumor necrosis factor-α(TNF-α)in the COVID-19 patient with KI group[(18.33±8.20)pg/mL]were significantly higher than those in the non-KI group[(11.88±6.50)pg/mL](P=0.015).In vitro assay has shown that S1-spike protein stimulation promoted the level of gene transcription and production of TNF-α,interleukin-1β(IL-1β)and chemokine C-X-C motif ligand 10(CXCL10)in THP-1 macrophage cells(P＜0.001).Furthermore,the conditioned medium from S1-stimulated THP-1 cells promoted the secretion of TNF-α,IL-1β and CXCL10 by HK-2 cells(P=0.005).When anti-TNF-α antibody(Infliximab)was used to block TNF-α in the culture supernatants from S1-stimulated THP-1 cells,the secretion level of TNF-α by HK-2 cells decreased dramatically(P＜0.001).Conclusion·TNF-α levels increase significantly in COVID-19 patients with KI,implying the significance of TNF-α in the occurrence of COVID-19-associated KI.In vitro experiments confirm that the S1 protein induces TNF-α secretion from THP-1 cells,leading to increased inflammatory responses in renal cells,which may contribute to the development of COVID-19-associated KI.Therefore,targeting TNF-α may become an alternative strategy to reduce the occurrence of COVID-19-associated KI.

Objective:To introduce the research and innovations around the application of aquatic rehabilitation techniques in the treatment of lumbago, and to summarize specific methods and applications in aeromedicine. Literature resource and selection Literature on the prevention and treatment of lumbago using aquatic rehabilitation techniques as well as on the rehabilitation of lumbago in pilots was retrieved and selected. Literature quotation Sixty-one references were cited. Literature synthesis Aquatic rehabilitation techniques can be classified into shower therapy, immersion therapy, and aquatic exercise therapy according to treatment regimens. Among them, immersion therapy and aquatic exercise therapy are commonly used in the treatment of lumbago. Aquatic rehabilitation techniques can effectively alleviate patients′ lumbago, improve their functional disorders, and enhance their quality of life. Prior to aquatic therapy, patients with lumbago need to have their motor function assessed to tailor the treatment protocol based on diagnostic findings and specific therapeutic objectives. Aquatic rehabilitation techniques, when used to prevent and treat lumbago in pilots under convalescence, are not only more effective than land-based training, but also more accessible to pilots due to their comfort and compliance. Many of our military rehabilitation and convalescent centers in China have integrated modern aquatic rehabilitation techniques into rehabilitation treatment by drawing on their rich water resources so as to improve the physical and mental health, social adaptability and military adaptability of pilots. Conclusions:When used for the prevention and treatment of lumbago, aquatic rehabilitation techniques are highly effective, safe and enjoyable, so they should be made more accessible to pilots during convalescence.

AIM To investigate the effects of Wenyang Jiedu Tongluo Recipe(WYJDTLR)on macrophage recruitment and polarization function in a mouse model of diabetic kidney disease(DKD).METHODS 50 db/db mice were randomly divided into the model group,the valsartan group(10.29 mg/kg)and the high-dose,medium-dose and low-dose WYJDTLR groups(26.52,13.26 and 6.63 g/kg),with 10 mice in each group,in contrast to another 10 db/m mice of the blank group.After 8 weeks of administration,the mice had their levels of fasting blood glucose,24-hour urinary protein quantity(24h-UTP),serum creatinine(Scr)and blood urea nitrogen(BUN)observed;their morphological changes of renal tissues observed by HE staining;their degree of renal glycogen deposition observed by PAS staining;their degree of renal fibrosis observed by Masson staining;their levels of MCP-1 and MCF-1 in serum and TNF-α and IL-1 β in renal tissue detected by ELISA;their renal protein expressions of VCAM-1 and ICAM-1 detected by IHC and Western blot;and their renal expressions of CD86 and CD206 detected by IF.RESULTS Compared with the model group,the WYJDTLR groups displayed decreased levels of fasting blood glucose,24h-UTP,Scr and BUN(P＜0.05,P＜0.01);improved degree of glomerular hypertrophy,mild proliferation of mesangial cells,dilatation of renal tubular,vacuolar degeneration of renal tubular epithelial cells,deposition of glomerular glycogen,and fibrosis of renal tissues(P＜0.01);decreased levels of MCP-1 and MCF-1 in serum and TNF-α and IL-1β in renal tissue(P＜0.05,P＜0.01);decreased renal protein expressions of VCAM-1 and ICAM-1(P＜0.05,P＜0.01),thus reduced the recruitment of macrophages to the kidney;decreased renal CD86 protein expression(P＜0.01);and increased CD206 protein expression(P＜0.01),thus inhibited M1-type polarization of macrophages and promoted M2-type polarization of macrophages.CONCLUSION WYJDTLR can delay the DKD progression in mice by reducing the occurrence of inflammatory reactions through reducing the level of macrophage recruitment factor,inhibiting the M1-type polarization,and promoting the M2-type polarization.