Case Report: Clinical characteristics and genetic analysis of two patients with hereditary hemorrhagic telangiectasia.

Objective: To analyze the clinical features and genetic characteristics of two patients with hereditary hemorrhagic telangiectasia (HHT) and to review the relevant literature. Methods: The clinical data of two HHT patients admitted to the author's hospital between April 2019 and February 2022 were retrospectively analyzed. Meanwhile, the genetic analysis was performed with their consent. Results: The first patient was a 62-year-old woman who had been complaining of shortness of breath and fever for 20 days. Her previous medical history included brain abscess drainage and video-assisted thoracoscopic surgery for a pulmonary hemangioma. A right heart catheterization revealed no pulmonary arterial hypertension, and an abdominal enhanced magnetic resonance imaging revealed multiple arteriovenous malformations in the liver. Her ACVRL1 heterozygous variants were discovered through whole-exon gene testing. The second case involved a 47-year-old woman who had been experiencing chest tightness for the past 2 years. Several years ago, she underwent brain abscess drainage and embolization of a pulmonary arteriovenous fistula. Ultrasound revealed generalized hepatic vascular dilation, and enhanced computed tomography revealed numerous pulmonary venous fistulas scattered in both lungs as well as multiple arteriovenous malformations in the liver. Her whole-exon gene testing revealed that she, like her son, had heterozygous ENG variants. Conclusion: HHT patients may experience infection, bleeding, dyspnea, and other symptoms. Imaging is important in disease diagnosis and management because early detection and treatment can prevent major complications and disability or even death.

[Effects of acute and chronic exercise on fat PI3K/AKT/GLUT4 signal pathway in type 2 diabetic rats].

OBJECTIVE: To study the effects of acute and chronic exercise on phosphatidylinositol 3-hydroxy kinase(PI3K)/protein kinase B(AKT)/glucose transporter 4(GLUT4)signaling pathway in adipose tissue of rats with type 2 diabetes mellitus (T2DM) induced by high-fat diet and low-dose streptozotocin (STZ). METHODS: A total of 52 SD male rats aged 15 months were randomly divided into normal control group (13) and high-fat group (39), and fed normal and high fat diets. After 8 weeks, the body weight of the high-fat group was higher 20% than that of the normal control group. After a small dose of STZ, the blood glucose level was ＞16.7 mmol/l, and the model was successfully established. The diabetic model group was randomly divided into a diabetic control group (DC, n=13), a diabetic chronic exercise group (DCE, n=13), and a diabetic acute exercise group (DAE, n=13). The DCE group underwent an 8-week swimming exercise and the DAE group performed a one-time swimming exercise. Blood lipids, blood glucose and serum insulin levels were measured, and the contents of fat PI3K, AKT and GLUT4 proteins were determined by Western blot method. RESULTS: The levels of body weight, blood lipids, blood glucose and insulin in the diabetic group were significantly higher than those in the normal control group (P＜0.01); high density liptein cholesterol(HDL-C) levels were decreased (P＜0.05), and the expressions of PI3K, AKT and GLUT4 protein in adipose tissue were decreased (P＜0.01). After 8 weeks of swimming training, the levels of body weight, blood lipids, blood glucose and insulin all were decreased significantly (P＜0.01); while the level of HDL-C was increased (P＜0.05), and the expressions of PI3K, AKT and GLUT4 protein were increased (P＜0.01). After acute exercise, the levels of blood lipids, blood glucose and insulin were decreased (P＜0.05); the level of HDL-C was increased (P＜0.05), and the expression levels of fat PI3K, AKT and GLUT4 were increased significantly (P＜0.05). CONCLUSION: ①High fat diet combined with low-dose STZ induced damage to the PI3K/AKT pathway in adipose tissue of T2DM rats reduced insulin sensitivity. ②Acute and chronic aerobic exercise can improve the disorder of glucose and lipid metabolism through PI3K/AKT pathway, and the chronic exercise is better than acute exercise.

Relationships of OPG Genetic Polymorphisms with Susceptibility to Cardiovascular Disease: A Meta-Analysis.

BACKGROUND The aim of this meta-analysis was to determine whether genetic polymorphisms in the osteoprotegerin (OPG) gene contribute to increased risk of cardiovascular disease (CVD). MATERIAL AND METHODS Electronic databases were searched carefully without any language restriction. Analyses of data were conducted using STATA software. Odds ratios (OR) and 95% confidence intervals (95%CI) were also calculated. RESULTS Seven clinical case-control studies that enrolled 1170 CVD patients and 1194 healthy subjects were included. The results indicated that OPG gene polymorphism might be closely associated with susceptibility to CVD, especially for rs2073617 T>C and rs2073618 G>C polymorphisms. Ethnicity-stratified analysis indicated that genetic polymorphism in the OPG were closely related with the pathogenesis of CVD among Asians (all P<0.001), but no obvious relationship was found among Caucasians (all P>0.05). CONCLUSIONS Our meta-analysis provided quantitative evidence that OPG gene polymorphism may be closely related to an increased risk of CVD, especially for rs2073617 T>C and rs2073618 G>C polymorphisms.

Genetic polymorphisms of IL-6 and IL-10 genes correlate with lung cancer in never-smoking Han population in China.

Lung cancer is one of the most common cancers in the world, especially in China. It is believed that genetic polymorphisms played a role in cancer susceptibility. Here we investigated the association of interleukin-6 (IL-6) and interleukin-10 (IL-10) gene polymorphisms with the susceptibility of lung cancer in never-smoking Chinese Han population. In this study, we performed a case-control study including 330 cases of never-smoking lung cancer patients and 336 cancer-free never-smoking controls in Chinese Han population. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to identify gene polymorphisms, and then verified by sequencing method. The results indicated that the four single nucleotide polymorphisms (IL-6 -1363T/G and -572G/C, IL-10 -819T/C and -592A/C) were genotyped by PCR-RFLP and confirmed by sequencing, and we found that the allelic frequencies of G in IL-6 -1363T/G, C in IL-10 -819T/C and C in IL-10 -592A/C were significantly increased in lung cancer patients, by comparing with the control group. However, there was no significant difference in the distribution of the IL-6 572G/C polymorphisms between patients and controls. In conclusion, the IL-6 -1363T/G, IL-10 -819T/C and IL-10 -592A/C polymorphisms are closely related to genetic susceptibility to lung cancer in never-smoking Chinese Han population, and these genetic variants might be used as molecular markers for detecting lung cancer susceptibility.

Characterization of PHB1 and its role in mitochondrial maturation and yolk platelet degradation during development of Artemia embryos.

BACKGROUND: To cope with harsh environments, crustaceans such as Artemia produce diapause gastrula embryos (cysts) with suppressed metabolism. Metabolism and development resume during post-diapause development, but the mechanism behind these cellular events remains largely unknown. PRINCIPAL FINDING: Our study investigated the role of prohibitin 1 (PHB1) in metabolic reinitiation during post-diapause development. We found that PHB1 was developmentally regulated via changes in phosphorylation status and localization. Results from RNA interference experiments demonstrated PHB1 to be critical for mitochondrial maturation and yolk degradation during development. In addition, PHB1 was present in yolk platelets, and it underwent ubiquitin-mediated degradation during the proteolysis of yolk protein. CONCLUSIONS/SIGNIFICANCE: PHB1 has an indispensable role in coordinating mitochondrial maturation and yolk platelet degradation during development in Artemia. This novel function of PHB1 provides new clues to comprehend the roles of PHB1 in metabolism and development.

Identification and characterization of a Ste20-like kinase in Artemia and its role in the developmental regulation and resistance to environmental stress.

BACKGROUND: To adapt to extreme environments, the crustacean Artemia has evolved two alternative reproductive pathways. During ovoviviparous (direct) development, nauplius larvae are produced. In contrast, Artemia females release encysted diapause embryos (cysts) via the oviparous pathway. To date, the cellular mechanisms that regulate stress resistance of Artemia remain largely unknown. Ste20-like kinase (SLK) participates in multiple biological processes, including stress responses, apoptosis, and cell cycle progression. PRINCIPAL FINDING: We isolated and characterized a member of the SLK superfamily termed ArSLK from Artemia parthenogenetica. The ArSLK gene is transcribed throughout both ovoviviparous and oviparous development; however, the protein is located mainly in the nuclei of stress-resistant diapause cysts, unlike the nauplii and nauplius-destined embryos where it is cytoplasmic. Interestingly, exposure of nauplii to heat shock, acidic pH, and UV irradiation induced the translocation of ArSLK from cytoplasm to nucleus. This translocation was reversed following stress removal. Moreover, under physiologically-stressful conditions, the nauplius larvae produced by adults after gene knockdown of endogenous ArSLK by RNAi, lost the ability of free-swimming much earlier than those of control larvae from females injected with GFP dsRNA. CONCLUSIONS/SIGNIFICANCE: Taken together, this study demonstrated that trafficking of ArSLK between the cytoplasm and the nucleus participates in regulating the stress resistance of Artemia. Our findings may provide significant insight into the functions of members of the SLK superfamily.

Acetylation of Chromatin-Associated Histone H3 Lysine 56 Inhibits the Development of Encysted Artemia Embryos.

BACKGROUND: As a response to harsh environments, the crustacean artemia produces diapause gastrula embryos (cysts), in which cell division and embryonic development are totally arrested. This dormant state can last for very long periods but be terminated by specific environmental stimuli. Thus, artemia is an ideal model organism in which to study cell cycle arrest and embryonic development. PRINCIPAL FINDING: Our study focuses on the roles of H3K56ac in the arrest of cell cycle and development during artemia diapause formation and termination. We found that the level of H3K56ac on chromatin increased during diapause formation, and decreased upon diapause termination, remaining basal level throughout subsequent embryonic development. In both HeLa cells and artemia, blocking the deacetylation with nicotinamide, a histone deacetylase inhibitor, increased the level of H3K56ac on chromatin and induced an artificial cell cycle arrest. Furthermore, we found that this arrest of the cell cycle and development was induced by H3K56ac and dephosphorylation of the checkpoint protein, retinoblastoma protein. CONCLUSIONS/SIGNIFICANCE: These results have revealed the dynamic change in H3K56ac on chromatin during artemia diapause formation and termination. Thus, our findings provide insight into the regulation of cell division during arrest of artemia embryonic development and provide further insight into the functions of H3K56ac.

Therapeutic effect of SN50, an inhibitor of nuclear factor-κB, in treatment of TBI in mice.

NF-κB upregulation has been demonstrated in neurons and glial cells in response to experimental injury and neuropathological disorders, where it has been related to both neurodegenerative and neuroprotective activities. It has been generally recognized that NF-κB plays important roles in the regulation of apoptosis and inflammation as well as innate and adaptive immunity. However, the regulatory mechanism of NF-κB in apoptosis remained to be determined. The present study sought to first investigate the effect of a NF-κB inhibitor SN50, which inhibits NF-κB nuclear translocation, on cell death and behavioral deficits in our mice traumatic brain injury (TBI) models. Additionally, we tried to elucidate the possible mechanisms of the therapeutic effect of SN50 through NF-κB regulating apoptotic and inflammatory pathway in vivo. Encouragingly, the results showed that pretreatment with SN50 remarkably attenuated TBI-induced cell death (detected by PI labeling), cumulative loss of cells (detected by lesion volume), and motor and cognitive dysfunction (detected by motor test and Morris water maze). To analyze the mechanism of SN50 on cell apoptotic and inflammatory signaling pathway, we thus assessed expression levels of TNF-α, cathepsin B and caspase-3, Bid cleavage and cytochrome c release in SN50-pretreated groups compared with those in saline vehicle groups. The results imply that through NF-κB/TNF-α/cathepsin networks SN50 may contribute to TBI-induced extrinsic and intrinsic apoptosis, and inflammatory pathways, which partly determined the fate of injured cells in our TBI model.

Cathepsin B contributes to traumatic brain injury-induced cell death through a mitochondria-mediated apoptotic pathway.

It has been reported that lysosomal proteases play important roles in ischemic and excitotoxic neuronal cell death. We have previously reported that cathepsin B expression increased remarkably after traumatic brain injury (TBI). The present study sought to investigate the effects of a selective cathepsin B inhibitor (CBI) [N-L-3-trans-prolcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-proline] on cell death and behavioral deficits in our model. We examined the levels of cathepsin B enzymatic activity and its expression by double labelling damaged cells in the brain slice with propidium iodide (PI) and anticathepsin B. The results showed an elevated enzymatic activity associated with TBI-induced increase in a mature form of cathepsin B, suggesting that cathepsin B may play a role in TBI-induced cell injury. PI was found to label cells positive for the neuronal-specific nuclear marker NeuN, whereas fewer GFAP-positive cells were labelled by PI, suggesting that neurons are more sensitive to cell death induced by TBI. Additionally, we found that pretreatment with CBI remarkably attenuated TBI-induced cell death, lesion volume, and motor and cognitive dysfunction. To analyze the mechanism of action of cathepsin B in the cell death signaling pathway, we assessed DNA fragmentation by electrophoresis, Bcl-2/Bax protein expression levels, Bid cleavage, cytochrome c release, and caspase-3 activation. The results imply that cathepsin B contributes to TBI-induced cell death through the present programmed cell necrosis and mitochondria-mediated apoptotic pathways.