Targeting ferroptosis and ferritinophagy: new targets for cardiovascular diseases / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Cardiovascular diseases (CVDs) are a leading factor driving mortality worldwide. Iron, an essential trace mineral, is important in numerous biological processes, and its role in CVDs has raised broad discussion for decades. Iron-mediated cell death, namely ferroptosis, has attracted much attention due to its critical role in cardiomyocyte damage and CVDs. Furthermore, ferritinophagy is the upstream mechanism that induces ferroptosis, and is closely related to CVDs. This review aims to delineate the processes and mechanisms of ferroptosis and ferritinophagy, and the regulatory pathways and molecular targets involved in ferritinophagy, and to determine their roles in CVDs. Furthermore, we discuss the possibility of targeting ferritinophagy-induced ferroptosis modulators for treating CVDs. Collectively, this review offers some new insights into the pathology of CVDs and identifies possible therapeutic targets.

A family of Alport syndrome with a novel dominant hereditary hematuria and a mutation in the COL4A4 gene / 中华检验医学杂志

Objective@#Alport syndrome was an inherited kidney disease caused by the mutation of COL4A3, COL4A4, or COL4A5. Whole-exome sequencing was used to detect the mutations on these genes for the molecular diagnosis of Alport syndrome.@*Methods@#A 6-year-old girl found accidentally with microscopic hematuria at the age of 4. The clinical data and blood sample of the family including proband, parents, brothers, and sisters were collected. Whole exome sequencing was conducted using their genomic DNAs.@*Results@#A novel heterozygous frameshift mutation c.1826delC (p.Pro609Glnfs*44) was found in the exon 25 of the COL4A4 (NM_000092) in the proband, the father, and the sister, showing an autosomal dominant inheritance pattern of Alport syndrome. This mutation of COL4A4 was confirmed by mutation analysis, and the mutation of c.1826delC was verified by Sanger sequencing. No mutations on COL4A3 and COL4A5 were detected in this family. And the mother and brother are normal wide-type.@*Conclusions@#This novel mutation is a valuable addition to the current genetic profile of Alport syndrome, and provide us a better understanding of the disease. Whole-exome sequencing is a power tool to identify the novel mutations of inherited disease and contribute to the molecular diagnosis of disease.

A family of Alport syndrome with a novel dominant hereditary hematuria and a mutation in the COL4A4 gene / 中华检验医学杂志

Objective Alport syndrome was an inherited kidney disease caused by the mutation of COL4A3,COL4A4, or COL4A5. Whole-exome sequencing was used to detect the mutations on these genes for the molecular diagnosis of Alport syndrome. Methods A 6-year-old girl found accidentally with microscopic hematuria at the age of 4. The clinical data and blood sample of the family including proband, parents, brothers, and sisters were collected. Whole exome sequencing was conducted using their genomic DNAs. Results A novel heterozygous frameshift mutation c.1826delC (p.Pro609Glnfs*44) was found in the exon 25 of the COL4A4(NM_000092) in the proband, the father, and the sister, showing an autosomal dominant inheritance pattern of Alport syndrome. This mutation of COL4A4 was confirmed by mutation analysis, and the mutation of c.1826delC was verified by Sanger sequencing. No mutations on COL4A3 and COL4A5 were detected in this family. And the mother and brother are normal wide-type. Conclusions This novel mutation is a valuable addition to the current genetic profile of Alport syndrome, and provide us a better understanding of the disease. Whole-exome sequencing is a power tool to identify the novel mutations of inherited disease and contribute to the molecular diagnosis of disease.

Mechanism of immune regulatory dysfunction in surgical sepsis / 医学研究生学报

Surgical sepsis induced by major trauma, burns and hemorrhage remains a main cause of death of the patients in intensive care units, and may result in both the widespread activation and dysfunction of the innate and adaptive responses in the host immune system. A large amount of information concerning the subsets of innate and adaptive immune cells in sepsis has implicated that these cells, including neutrophils, macrophages, dendritic cells, T lymphocytes, regulatory T cells, and natural killer cells, have significant effects on immunoreactivity during acute insults or sepsis through modulating multiple receptor expressions or cytokine release, in turn contributing to the development and outcome of sepsis. Therefore, a deeper insight into the mechanism of immune regulatory dysfunction in surgical sepsis is of great significance in helping assess the prognosis of sepsis and guide the treatment of its complications.

Clinical features and prognosis of patients with acute ST-segment elevation myocardial infarction comorbid with diabetes mellitus / 中国介入心脏病学杂志

Objective To investigate the clinical features of patients with acute ST-segment elevation myocardial infarction (STEMI) comorbid with diabetes mellitus (DM) and to analyze the prognosis within 12 months after primary percutaneous coronary intervention (pre-PCI). Methods A total of 375 STEMI patients were divided into the diabetes group (n=140) and the normal blood glucose group(n=235) according to whether they met the diagnostic criteria of DH. The clinical data,characteristics of coronary artery lesions,type of stent implant,rate of coronary slow flow or no-reflow after pre-PCI, and the prognosis within 12 months after PCI of the two groups were investigated.Results Patient in the diabetes group presented with higher mean age ,higher comorbid rates of hypertension , hyperlipidemia and heart function of Killip class Ш and above than patients in the normal blood glucose group (all P<0.05). patients in the diabetes group had higher rates of slow reflow /no-reflow after PCI(12.9% vs.5.5%,P=0.013),higher percentages of 3-ressel disease(40.7% vs. 28.9%,P=0.019)and lef t main lesions(13.6% vs. 7.2%,P=0.044). The in-hospital mortality rates(6.4% vs.1.7%,P=0.020),revascularization rates within 12 months(7.9% vs.0.9%,P=0.001)and incidence of heart failure(7.9% vs. 2.6%,P=0.017)were all higher in the diabetes group. Conclusions STEMI patients comorbid with DM were relatively older, had higher comorbidities of hypertension,hyperlipidemia, three-vessel disease, left main coronary lesions and higher mortality during hospitalization. No significant increase in cardiac death and recurrent myocardial infarction were deserved during the follow-up period. These patients may benefit more from early intervention.

Analysis on the clinical characters of optic neuritis caused by antituberculosis drugs / 国际眼科杂志(Guoji Yanke Zazhi)

To summarize the clinical characters of optic neuritis caused by antituberculosis drugs, and to discuss the prevention countermeasures. ● METHODS: The clinical characters of optic neuritis caused by antituberculosis drugs among those outpatients and ward patients from January 2003 to January 2013 were reviewed and analyzed. ● RESULTS: Optic neuritis caused by antituberculosis drugs was rare ( 17 / 60000 ), while retrobulbar neuritis was common. The drugs inducing optical neuritis were mainly ethambutol, followed by isoniazid and streptomycin. The vision of patients would have different degrees of improvement via the following treatment after specific diagnosis, i. e. , timely stopping the tuberculosis medicine associated with optic neuritis, and taking vitamin supplements, dilating blood vessels and applying hormone therapy according to the illness. ●CONCLUSlON: We should pay attention to the change of the vision of patients during the usage of antituberculosis drugs. ln the case of sudden eyesight deterioration, ophthalmology examination and timely treatment are advised preventing blindness.

Effect of high mobility group box-1 protein on immune cells and its regulatory mechanism / 中国应用生理学杂志

High mobility group box-1 protein (HMGB1), which is a nuclear protein, participates in chromatin architecture and transcriptional regulation. When released from cells, HMGB1 also plays a well-established role as a pro-inflammatory mediator during innate immune responses to injury. In the initial stage of injury, there is a release of large quantities of early pro-inflammatory mediators to initiate or perpetuate immune responses against pathogens, but this pro-inflammatory period is transient, and it is followed by a prolonged period of immune suppression. At present, several lines of evidences have suggested that HMGB1 is a late cytokine provoking delayed endotoxin morbidity, which may enhance the production of early proinflammatory mediators, and it can contribute potently to the activation of different immune cells and play a role in the development of host cell-mediated immunity. The biology of HMGB1 has been extensively studied as a pro-inflammatory cytokine of systemic inflammation, however, this review will attempt to provide a summary of the effects of HMGB1 on different immune cells and its regulatory mechanism in acute insults.

The construction of SCID-Hu IC mice model and application in rAd5HPV16L1-E7 vaccine / 中华实验和临床病毒学杂志

<p><b>OBJECTIVE</b>To construct human-SCID chimeric mice through implantation of mononuclear cells from human cord blood and study the immunoreaction of SCID-Hu IC mice immunized with rAd5HPV16L1-E7 vaccine.</p><p><b>METHODS</b>(1) Experiment groups were injected with the suspension of mononuclear cells from human cord blood through a tail vein; the control ones were injected with non serum RPMI 1640 medium. Eight weeks after implantation, blood was collected and human serum IgG level in the mice were tested, and human CD45, CD3 and CD19 were determined. (2) SCID-Hu IC mice were divided into two groups: in group A the mice were immunized intraperitoneally with rAd5HPV16L1-E7 virus and in group B the mice were immunized through nasal drip with rAd5HPV16L1-E7 virus. At the end of fourth week, the serum specific IgG antibody to rAd5HPV16L1-E7 virus, IFN-gamma in culture medium of spleen lymphocyte and T-lymphocyte propagation were tested.</p><p><b>RESULTS</b>(1) In the experiment groups, the number of mice positive for human IgG was 10/15, the average values of CD45, CD3 and CD19 were (9.39+/-4.21), (3.25+/-3.99) and (1.69+/-0.75), respectively. In the control ones, the human IgG, CD45, CD3 and CD19 were negative. (2) The results in the experiment groups showed that the IFN-gamma and T-lymphocyte stimulated by HPV16 protein were higher than those in the non-stimulated group (P less than 0.05).</p><p><b>CONCLUSION</b>(1) The results indicated that the construction of human-SCID chimaera through the implantation of mononuclear cells from human cord blood into SCID mice was successful. They also indicated that the reconstructed SCID-Hu IC mice has the ability to produce immune response against rAd5HPV16L1-E7 recombinant virus.</p>

Optimized codon usage enhances the expression and immunogenicity of DNA vaccine encoding the HPV 6b E7 gene / 中华实验和临床病毒学杂志

<p><b>OBJECTIVE</b>To analyze the influence of optimal codon usage on the expression levels and immunogenicity of DNA vaccines, encoding the human papillomavirus type 6b (HPV 6b) E7 gene.</p><p><b>METHODS</b>The full length E7 gene of HPV 6b was modified to substitute human preferred codon for rarely used codon, and three mutations were introduced into the pRB binding site of HPV 6b E7 to eliminate its transformation potential. The codon optimized and mutated E7 gene (hu-mE7) were cloned into the Kpn I and EcoR I site of the pcDNA3 mammalian expression vector, the in vitro expression of the hu-mE7 gene and the immunogenicity of hu-mE7 DNA vaccine were compared with the wt-E7gene.</p><p><b>RESULTS</b>The in vitro expression of pcDNA3-hu-mE7 was much higher than the classical wt-E7 plasmid in monkey COS-1 cell line. Mice immunized intramuscularly with the pcDNA3-hu-mE7 showed that the codon modified E7 gene induced a stronger IFN-gamma ratios than the wt-E7 gene.</p><p><b>CONCLUSIONS</b>These results suggest that the optimized codon usage contributes to the enhancement of gene expression and immunogenicity of HPV 6b E7 gene.</p>