The suppression of cervical cancer ferroptosis by macrophages: The attenuation of ALOX15 in cancer cells by macrophages-derived exosomes

Induction of cancer cell ferroptosis has been proposed as a potential treatment in several cancer types. Tumor-associated macrophages (TAMs) play a key role in promoting tumor malignant progression and therapy resistance. However, the roles and mechanisms of TAMs in regulating tumor ferroptosis is still unexplored and remains enigmatic. This study shows ferroptosis inducers has shown therapeutic outcomes in cervical cancer in vitro and in vivo. TAMs have been found to suppress cervical cancer cells ferroptosis. Mechanistically, macrophage-derived miRNA-660-5p packaged into exosomes are transported into cancer cells. In cancer cells, miRNA-660-5p attenuates ALOX15 expression to inhibit ferroptosis. Moreover, the upregulation of miRNA-660-5p in macrophages depends on autocrine IL4/IL13-activated STAT6 pathway. Importantly, in clinical cervical cancer cases, ALOX15 is negatively associated with macrophages infiltration, which also raises the possibility that macrophages reduce ALOX15 levels in cervical cancer. Moreover, both univariate and multivariate Cox analyses show ALOX15 expression is independent prognostic factor and positively associated with good prognosis in cervical cancer. Altogether, this study reveals the potential utility of targeting TAMs in ferroptosis-based treatment and ALOX15 as prognosis indicators for cervical cancer.

Prenatal diagnosis and genetic counselling for a pedigree carrying a large fragment deletion of 13q / 中华医学遗传学杂志

OBJECTIVE@#To carry out prenatal diagnosis for a fetus with normal ultrasonographic finding at 20 weeks' gestation but a copy number variant(CNV) of 13q indicated by non-invasive prenatal test (NIPT).@*METHODS@#Karyotyping analysis and chromosomal CNV assay were carried out on the amniotic fluid sample. Parental peripheral blood sample was collected for chromosomal analysis. Detailed fetal ultrasound scan was carried out to rule out structural abnormalities of the fetus.@*RESULTS@#The fetus was detected with a heterozygous 10.14 Mb deletion at 13q21.1q21.32, which has originated from the phenotypically normal mother. No apparent karyotypic abnormality was detected in the fetus and its parents. No ultrasonic abnormality was found in the fetus.@*CONCLUSION@#Both the fetus and its mother have carried a heterozygous 10.14 Mb deletion at 13q21.1q21.32 and presented normal phenotypes.Combined with literature review, the segmental deletion was judged to be a benign variant.

Clinical manifestations and genetic analysis of six different families of Leber's congenital amaurosis / 中华眼底病杂志

Objective:To observe and analyze the pathogenic gene types and clinical phenotypes of Leber congenital amaurosis (LCA).Methods:A retrospective clinical study. Six patients with LCA confirmed by genetic testing and 18 family members were included in the study. The patients came from six unrelated families. The family was investigated with a specific hereditary eye disease enrichment panel which contained 463 known pathogenic genes and based on targeted exome capture technology first to indentify the potential pathogenic genes and mutations. Then the TULP1 , RPGRIP1 , GUCY2D pathogenic mutations were conformed by Sanger sequencing. The pathogenicity of the gene variation was searched through relevant databases and PubMed literature, and its function was explained by protein prediction software. Results:Of the 6 patients, 3 were males and 3 were females; the age was from 3 to 33 years. Nystagmus, finger pressing eyes, photophobia, and night blindness were seen in 5 cases; electroretinogram showed 3 cases of extinction or near extinction; and 4 cases of retinopathy. The results showed patients with compound heterozygous mutation of c.1318C> T and c.1142T> G, homozygous mutation ofc.1318C> T and compound heterozygous mutation of c.1153G> A and c.1561C> T of TULP1 in Family 1, Family 2 and Family 5, respectively. There were compound heterozygous mutations of RPGRIP1 c.391delG and c.1468-2A> G in Family 3 and c.715delA and c.1765C> T in Family 6, respectively. Homozygous mutation of c.3177_3178delAC of GUCY2D was found in Family 4.The parents of all six patients were carriers of corresponding heterozygous mutations. TULP1 gene c.1142T> G, RPGRIP1 gene c.391delG, c.715delA and c.1765C> T and GUCY2D gene c.3177_3178delAC mutations were novel mutations and unreported. The 381th amino acid locus of product protein of TULP1 gene was highly conserved among species. The protein prediction software predicted that the mutation pathogenic. The c.391delG, c.715delA and c.1765C> T mutations of RPGRIP1 gene and c.3177_3178delAC mutation of GUCY2D gene can lead to early translation termination of their product proteins, which are pathogenic variants. Conclusion:The pathogenic mutations of TULP1, RPGRIP1 and GUCY2D genes led to LCA 15, LCA 6 and LCA 1 in six families.

Quercetin inhibited mesangial cell proliferation of early diabetic nephropathy through the Hippo pathway.

Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and the leading cause of end-stage renal disease. The proliferation of glomerular mesangial cells (MCs) is a common and prominent pathological change of DN, which takes place at the early stage. Quercetin, a bioflavonoid compound, possesses therapeutic efficacy in cardiovascular and kidney diseases via anti-tumour, anti-oxidation, anti-virus, and anti-proliferation effects. However, the mechanism of quercetin in the proliferation of glomerular MCs in early DN has not been reported. In the present study, we investigated the effect of quercetin on the proliferation of glomerular MCs in high glucose-induced mouse glomerular MCs and in db/db mice. On this basis, we tried to clarify the specific mechanisms underlying these effects. The in vitro results showed that the proliferation of glomerular MCs was induced by high glucose, and the Hippo pathway was highly inactivated in high glucose-cultured MCs. Decreased phosphorylation of MST1 and Lats1 promoted expression and nuclear translocation of Yes-associated protein (YAP) and subsequently increased the combination of YAP and TEA/ATS domain (TEAD), which promoted the expression of the downstream target gene such as cyclinE. Quercetin effectively inhibited the high glucose-induced MC proliferation and reactivated the Hippo pathway. In vivo, the proliferation of glomerular MCs was increased, renal function was decreased, and blood fasting glucose was elevated in db/db mice. Furthermore, the Hippo pathway was inactivated in the renal cortex of db/db mice. Eight-week treatment of quercetin retarded MC proliferation, alleviated the renal function, and reactivated Hippo pathway in the renal cortex of db/db mice at 16 weeks. Our previous study clarified that the Hippo pathway was involved in MC proliferation of DN. The results revealed that quercetin inhibited MC proliferation in high glucose-treated mouse glomerular MCs and in DN via reactivation of the Hippo pathway.

Prenatal diagnosis for two families affected with cleidocranial dysplasia due to novel RUNX2 variants / 中华医学遗传学杂志

Objective@#To analyze variants of RUNX2 gene in two pedigrees affected with cleidocranial dysplasia and provide prenatal diagnosis for them.@*Methods@#For the two probands, the coding sequences of the RUNX2 gene were analyzed with PCR and bidirectional Sanger sequencing. To verify the results, peripheral blood samples were collected from their parents and 100 healthy controls. For family 1, umbilical cord blood was also collected for prenatal genetic diagnosis.@*Results@#In family 1, the proband and the fetus both carried a heterozygous c. 578G>C (p.Arg193Pro) mutation. For family 2, the proband was found to carry a heterozygous c. 909C>A (p.Tyr303X) mutation. The same mutations were not found among their parents and 100 healthy controls. Neither mutation was reported previously.@*Conclusion@#Variants of the RUNX2 gene probably underlie the cleidocranial dysplasia in both pedigrees. The results enabled prenatal diagnosis for the affected family.

Prenatal diagnosis for two families affected with cleidocranial dysplasia due to novel RUNX2 variants / 中华医学遗传学杂志

OBJECTIVE@#To analyze variants of RUNX2 gene in two pedigrees affected with cleidocranial dysplasia and provide prenatal diagnosis for them.@*METHODS@#For the two probands, the coding sequences of the RUNX2 gene were analyzed with PCR and bidirectional Sanger sequencing. To verify the results, peripheral blood samples were collected from their parents and 100 healthy controls. For family 1, umbilical cord blood was also collected for prenatal genetic diagnosis.@*RESULTS@#In family 1, the proband and the fetus both carried a heterozygous c.578G>C (p.Arg193Pro) mutation. For family 2, the proband was found to carry a heterozygous c.909C>A (p.Tyr303X) mutation. The same mutations were not found among their parents and 100 healthy controls. Neither mutation was reported previously.@*CONCLUSION@#Variants of the RUNX2 gene probably underlie the cleidocranial dysplasia in both pedigrees. The results enabled prenatal diagnosis for the affected family.

Treatment of hemorrhagic transformation in patients with ischemic stroke / 国际脑血管病杂志

10% to 15% of patients with ischemic stroke may have hemorrhagic transformation.Its treatment is more complex,mainly includes blood pressure management,reversing coagulopathy,and treatment of complications (including increased intracranial pressure).The current research is mainly to find the therapeutic regimen of hemorrhagic transformation after anticoagulation and thrombolytic therapy in order to improve the prognosis in patients with stroke.

Effect of cocaine and amphetamine-regulated transcript peptides on cortical synaptic plasticity in the model mice of ischemia-reperfusion injury / 中国脑血管病杂志

Objective To investigate the effect of cocaine and amphetamine-regulated transcript (CART ) peptides on cortical synaptic plasticity in ischemia-reperfusion (I/R ) injury mice. Methods A total of 288 healthy male specific pathogen free(SPF)grade Kunming mice aged 0 to 12 weeks were selected. They were divided into four groups:I/R group (n =81 ),I/R +CART group (n =81),sham operation group (n=63),and sham operation+CART group (n=63)according to the random number table method. A model of middle cerebral artery occlusion (MCAO)for 2 h and reperfusion was induced. Before reperfusion,the mice of the I/R+CART group were injected CART via tail vein (0. 5μg, 200μl)and the those of the sham operation+CART group were injected equal CART;repeated administration once every 24 hours. 2,3,5-Triphenyl tetrazolium chloride assay was used to detect cerebral infarction volume of the I/R group and the I/R+CART group at different time points (24 h,72 h,and day 7 )after achieving reperfusion. The transmission electron microscope was used to observe the ultrastructural changes of synapses at different time points,and the synaptic morphological parameters were analyzed quantitatively. Western blot was used to observe the expression level of postsynaptic density 95 (PSD-95)proteins in the surrounding area of cortical infarct at 72 h after reperfusion. Results (1 )Compared with the sham operation group,the number of synapses was significantly decreased in the cortical slices in the I/R group (3. 37 ± 0. 38μm2 vs. 7. 04 ± 0. 55μm2 ,2. 89 ± 0. 22μm2 vs. 6. 89 ± 0. 04μm2 ,3. 25 ± 0. 18μm2 vs. 6. 78 ± 0. 42μm2;all P0.05).Conclusion CART can reduce cerebral infarct volume of I/R in mice and improve synaptic plasticity of cortical neurons in mice after ischemic injury.

Mechanism of ultrasound-mediated microbubbles enhancing homing effect of transplanted mesenchymal stem cells / 中国组织工程研究

BACKGROUND:Animal studies have indicated ultrasound-mediated microbubbles can significantly enhance the effect of stem cel transplantation to treat ischemic diseases. But its mechanism is stil unknown. OBJECTIVE:To explore the mechanism of ultrasound-mediated microbubbles to significantly enhance the effect of stem cel transplantation in the treatment of ischemic diseases. METHODS:Bone marrow mesenchymal stem cel s and vascular endothelial cel s of rats were cultured in vitro, and then randomized to three groups:control group with no intervention, ultrasound group exposed to ultrasound at 1 MHz, 1 W/cm2 for 90 seconds, and ultrasound-mediated microbubble group treated with 5μL liposomes ultrasound microbubbles containing fluorocarbon gases (about 2×1011/L) and ultrasound exposure at 1 MHz, 1 W/cm2 for 90 seconds. RESULTS AND CONCLUSION:Compared to the control group, ultrasound-mediated microbubbles significantly increased expressions of vascular endothelial growth factor and stromal cel-derived factor 1 in the supernatant of vascular endothelial cel s (P0.05). These findings suggest that 1 W/cm2 ultrasound-mediated microbubbles can promote vascular endothelial growth factor and stromal cel-derived factor 1 secretion by vascular endothelia cel s, and meanwhile promote CXCR4 gene expression in bone marrow mesenchymal stem cel s. This may be the mechanism of the ultrasound-mediated microbubbles enhancing homing effect of transplanted stem cel s.