M2 microglia-derived exosomes promote vascular remodeling in diabetic retinopathy.

Diabetic retinopathy (DR) is a vision-threatening diabetic complication that is characterized by microvasculature impairment and immune dysfunction. The present study demonstrated that M2 microglia intensively participated in retinal microangiopathy in human diabetic proliferative membranes, mice retinas, retinas of mice with oxygen-induced retinopathy (OIR) mice, and retinas of streptozotocin-induced DR mice. Further in vivo and in vitro experiments showed that exosomes derived from M2 polarized microglia (M2-exo) could reduce pericyte apoptosis and promote endothelial cell proliferation, thereby promoting vascular remodeling and reducing vascular leakage from the diabetic retina. These effects were further enhanced by M2-exo that facilitated M2 polarization of retinal microglia. Collectively, the study demonstrated the capability of M2-exo to induce retinal microvascular remodeling, which may provide a new therapeutic strategy for the treatment of DR.

Central nervous system clear cell meningioma: a systematic literature review.

Clear cell meningiomas are a rare histological subtype of World Health Organization (WHO) grade II meningioma. Despite its relatively low frequency, clear cell meningioma has attracted considerable attention because of its unique pathological characteristics, clinical behavior, and challenging management considerations. The purpose of our systematic review is to provide clinicians with a better understanding of this rare disease. PubMed was searched for articles in the English language published from 1988 to 2023 June. The keywords were as follows: "clear cell meningioma," "clear cell" and "meningioma." We analyzed clinical manifestations, radiological manifestations, pathological features, comprehensive treatment strategies, and prognosis to determine the factors influencing recurrence-free survival (RFS). Recurrence-free survival curves of related factors were calculated by the Kaplan‒Meier method. The log-rank test and Cox univariate analysis were adopted to assess the intergroup differences and seek significant factors influencing prognosis and recurrence. Fifty-seven papers met the eligibility criteria, including 207 cases of clear cell meningioma (CCM), which were confirmed by postoperative pathology. The fifty-seven articles involved 84 (40.6%) males and 123 (59.4%) females. The average age at diagnosis was 27.9 years (range, 14 months to 84 years). Among the symptoms observed, headache, neurologic deficit, and hearing loss were the most commonly reported clinical manifestations. Most tumors (47.8%) were located in the skull base region. Most tumors showed significant enhancement, and homogeneous enhancement was more common. A total of 152 (74.1%) patients underwent gross total resection (GTR), and 53 (25.9%) patients underwent subtotal resection (STR). During the follow-up, the tumor recurred in 80 (39.4%) patients. The log-rank test and the Cox univariate analysis revealed that tumor resection range (GTR vs. STR) and adjuvant treatment (YES vs. NO) were significant predictors of recurrence-free survival (RFS). Clear cell meningioma is a rare type of meningioma with challenging diagnosis and therapy. The prognosis of this disease is different from that of regular meningiomas. Recurrence remains a possibility even after total tumor resection. We found that the surgical resection range and adjuvant treatment affected the recurrence period. This finding provides significant guidance for the treatment of clear cell meningioma.

TAX1BP1 contributes to deoxypodophyllotoxin-induced glioma cell parthanatos via inducing nuclear translocation of AIF by activation of mitochondrial respiratory chain complex I.

Parthanatos is a type of programmed cell death initiated by over-activated poly (ADP-ribose) polymerase 1 (PARP1). Nuclear translocation of apoptosis inducing factor (AIF) is a prominent feature of parthanatos. But it remains unclear how activated nuclear PARP1 induces mitochondrial AIF translocation into nuclei. Evidence has shown that deoxypodophyllotoxin (DPT) induces parthanatos in glioma cells via induction of excessive ROS. In this study we explored the downstream signal of activated PARP1 to induce nuclear translocation of AIF in DPT-triggered glioma cell parthanatos. We showed that treatment with DPT (450 nM) induced PARP1 over-activation and Tax1 binding protein 1 (TAX1BP1) distribution to mitochondria in human U87, U251 and U118 glioma cells. PARP1 activation promoted TAX1BP1 distribution to mitochondria by depleting nicotinamide adenine dinucleotide (NAD+). Knockdown of TAX1BP1 with siRNA not only inhibited TAX1BP1 accumulation in mitochondria, but also alleviated nuclear translocation of AIF and glioma cell death. We demonstrated that TAX1BP1 enhanced the activity of respiratory chain complex I not only by upregulating the expression of ND1, ND2, NDUFS2 and NDUFS4, but also promoting their assemblies into complex I. The activated respiratory complex I generated more superoxide to cause mitochondrial depolarization and nuclear translocation of AIF, while the increased mitochondrial superoxide reversely reinforced PARP1 activation by inducing ROS-dependent DNA double strand breaks. In mice bearing human U87 tumor xenograft, administration of DPT (10 mg· kg-1 ·d-1, i.p., for 8 days) markedly inhibited the tumor growth accompanied by NAD+ depletion, TAX1BP1 distribution to mitochondria, AIF distribution to nuclei as well as DNA DSBs and PARP1 activation in tumor tissues. Taken together, these data suggest that TAX1BP1 acts as a downstream signal of activated PARP1 to trigger nuclear translocation of AIF by activation of mitochondrial respiratory chain complex I.

Activated SIRT1 contributes to DPT-induced glioma cell parthanatos by upregulation of NOX2 and NAT10.

Parthanatos is a type of programmed cell death dependent on hyper-activation of poly (ADP-ribose) polymerase 1 (PARP-1). SIRT1 is a highly conserved nuclear deacetylase and often acts as an inhibitor of parthanatos by deacetylation of PARP1. Our previous study showed that deoxypodophyllotoxin (DPT), a natural compound isolated from the traditional herb Anthriscus sylvestris, triggered glioma cell death via parthanatos. In this study, we investigated the role of SIRT1 in DPT-induced human glioma cell parthanatos. We showed that DPT (450 nmol/L) activated both PARP1 and SIRT1, and induced parthanatos in U87 and U251 glioma cells. Activation of SIRT1 with SRT2183 (10 µmol/L) enhanced, while inhibition of SIRT1 with EX527 (200 µmol/L) or knockdown of SIRT1 attenuated DPT-induced PARP1 activation and glioma cell death. We demonstrated that DPT (450 nmol/L) significantly decreased intracellular NAD+ levels in U87 and U251 cells. Further decrease of NAD+ levels with FK866 (100 µmol/L) aggravated, but supplement of NAD+ (0.5, 2 mmol/L) attenuated DPT-induced PARP1 activation. We found that NAD+ depletion enhanced PARP1 activation via two ways: one was aggravating ROS-dependent DNA DSBs by upregulation of NADPH oxidase 2 (NOX2); the other was reinforcing PARP1 acetylation via increase of N-acetyltransferase 10 (NAT10) expression. We found that SIRT1 activity was improved when being phosphorylated by JNK at Ser27, the activated SIRT1 in reverse aggravated JNK activation via upregulating ROS-related ASK1 signaling, thus forming a positive feedback between JNK and SIRT1. Taken together, SIRT1 activated by JNK contributed to DPT-induced human glioma cell parthanatos via initiation of NAD+ depletion-dependent upregulation of NOX2 and NAT10.

Erratum: Trehalose inhibits H2O2-induced autophagic death in dopaminergic SH-SY5Y cells via mitigation of ROS-dependent endoplasmic reticulum stress and AMPK activation: Erratum.

[This corrects the article DOI: 10.7150/ijms.25656.].

The effects and drivers of green financial reform in promoting environmentally-biased technological progress.

Promoting green financial reform is an important measure to support environmentally-biased technological progress (EBTP) and achieve sustainable economic and social development. Although China launched a green finance reform and innovation pilot zone (GFRIPZ) policy in 2017, little is known about whether and how such a policy affects EBTP. Based on mathematical deduction, this paper studies the mechanism through which green financial reform influences EBTP. The analysis employs panel data of Chinese prefecture-level cities and a generalized synthetic control method to examine the policy effect of the establishment of GFRIPZ in EBTP. It is found that establishing GFRIPZ significantly promotes EBTP, and that the policy effect shows "ahead-of-policy" and dynamically increasing features. Potential mechanisms reside in the pilot policy's easing of financing constraints and upgrading of industrial structure. Further heterogeneity analyses reveal that great disparities exist in the policy effects of different pilot zones, with a steadily increasing policy effect in Zhejiang and Guangdong, a lagging policy effect in Jiangxi and Guizhou, and an inverse U-shaped policy effect in Xinjiang. Policy effects are much stronger in regions with a higher degree of marketization and a higher level of attention to education. Additional tests of economic performance indicate that the pilot policy, interweaved with its driving effect on EBTP, is conducive to promoting an energy-conservation and low-carbon-energy transition. The findings shed light on applying green financial reform to encourage environment-friendly technological research and development.

BNIP3 contributes to silibinin-induced DNA double strand breaks in glioma cells via inhibition of mTOR.

BNIP3 is found to eliminate cancer cells via causing mitochondrial damage and endoplasmic reticulum stress, but it remains elusive of its role in regulating DNA double strand breaks (DSBs). In this study, we find that silibinin triggers DNA DSBs, ROS accumulation and expressional upregulation of BNIP3 in glioma cells. Mitigation of ROS with antioxidant GSH significantly inhibits silibinin-induced DNA DSBs and glioma cell death. Then, we find knockdown of BNIP3 with SiRNA obviously prevents silibinin-induced DNA DSBs and ROS accumulation. Mechanistically, BNIP3 knockdown not only reverses silibinin-triggered depletion of cysteine and GSH via maintaining xCT level, but also abrogates catalase decrease. Notably, silibinin-induced dephosphorylation of mTOR is also prevented when BNIP3 is knocked down. Given that activated mTOR could promote xCT expression and inhibit autophagic degradation of catalase, our data suggest that BNIP3 contributes to silibinin-induced DNA DSBs via improving intracellular ROS by inhibition of mTOR.

Inactivation of Shigella flexneri by 405-nm Light-Emitting Diode Treatment and Possible Mechanism of Action.

Shigella flexneri, a common Gram-negative foodborne pathogen, is widely distributed in fresh-cut fruits and vegetables, unpasteurized milk, and food processing environments. The aims of this study were to evaluate the antibacterial effects of 405-nm light-emitting diode (LED) treatment on S. flexneri and to investigate the possible mechanism. The results showed that LED irradiation (360 min) reduced the number of S. flexneri in phosphate-buffered saline by 3.29 log colony-forming unit (CFU)/mL (initial bacterial count: 6.81 log CFU/mL). The cells in reconstituted infant formula, cells on fresh-cut carrot slices, and biofilm-associated cells on stainless steel surfaces were reduced by 1.83 log CFU/mL, 7.00 log CFU/cm2, and 4.35 log CFU/cm2 following LED treatment for 360, 120, and 120 min, respectively. LED treatment damaged both DNA and cell wall of S. flexneri and changed cell morphology and cell membrane permeability. In addition, LED treatment decreased total cell protein concentration of S. flexneri. These results indicated that 405-nm LED treatment effectively controlled S. flexneri contamination of foods and food contact surfaces and that the bacterial inactivation may be the result of damage to multiple cellular components. These findings highlight the potential of LED technology in controlling S. flexneri during food processing, storage, and preparation.

ATF3 contributes to brucine-triggered glioma cell ferroptosis via promotion of hydrogen peroxide and iron.

Ferroptotic cell death is characterized by iron-dependent lipid peroxidation that is initiated by ferrous iron and H2O2 via Fenton reaction, in which the role of activating transcription factor 3 (ATF3) remains elusive. Brucine is a weak alkaline indole alkaloid extracted from the seeds of Strychnos nux-vomica, which has shown potent antitumor activity against various tumors, including glioma. In this study, we showed that brucine inhibited glioma cell growth in vitro and in vivo, which was paralleled by nuclear translocation of ATF3, lipid peroxidation, and increases of iron and H2O2. Furthermore, brucine-induced lipid peroxidation was inhibited or exacerbated when intracellular iron was chelated by deferoxamine (500 µM) or improved by ferric ammonium citrate (500 µM). Suppression of lipid peroxidation with lipophilic antioxidants ferrostatin-1 (50 µM) or liproxstatin-1 (30 µM) rescued brucine-induced glioma cell death. Moreover, knockdown of ATF3 prevented brucine-induced accumulation of iron and H2O2 and glioma cell death. We revealed that brucine induced ATF3 upregulation and translocation into nuclei via activation of ER stress. ATF3 promoted brucine-induced H2O2 accumulation via upregulating NOX4 and SOD1 to generate H2O2 on one hand, and downregulating catalase and xCT to prevent H2O2 degradation on the other hand. H2O2 then contributed to brucine-triggered iron increase and transferrin receptor upregulation, as well as lipid peroxidation. This was further verified by treating glioma cells with exogenous H2O2 alone. Moreover, H2O2 reversely exacerbated brucine-induced ER stress. Taken together, ATF3 contributes to brucine-induced glioma cell ferroptosis via increasing H2O2 and iron.

FOXO3a protects glioma cells against temozolomide-induced DNA double strand breaks via promotion of BNIP3-mediated mitophagy.

FOXO3a (forkhead box transcription factor 3a) is involved in regulating multiple biological processes in cancer cells. BNIP3 (Bcl-2/adenovirus E1B 19-kDa-interacting protein 3) is a receptor accounting for priming damaged mitochondria for autophagic removal. In this study we investigated the role of FOXO3a in regulating the sensitivity of glioma cells to temozolomide (TMZ) and its relationship with BNIP3-mediated mitophagy. We showed that TMZ dosage-dependently inhibited the viability of human U87, U251, T98G, LN18 and rat C6 glioma cells with IC50 values of 135.75, 128.26, 142.65, 155.73 and 111.60 µM, respectively. In U87 and U251 cells, TMZ (200 µM) induced DNA double strand breaks (DSBs) and nuclear translocation of apoptosis inducing factor (AIF), which was accompanied by BNIP3-mediated mitophagy and FOXO3a accumulation in nucleus. TMZ treatment induced intracellular ROS accumulation in U87 and U251 cells via enhancing mitochondrial superoxide, which not only contributed to DNA DSBs and exacerbated mitochondrial dysfunction, but also upregulated FOXO3a expression. Knockdown of FOXO3a aggravated TMZ-induced DNA DSBs and mitochondrial damage, as well as glioma cell death. TMZ treatment not only upregulated BNIP3 and activated autophagy, but also triggered mitophagy by prompting BNIP3 translocation to mitochondria and reinforcing BNIP3 interaction with LC3BII. Inhibition of mitophagy by knocking down BNIP3 with SiRNA or blocking autophagy with 3MA or bafilomycin A1 exacerbated mitochondrial superoxide and intracellular ROS accumulation. Moreover, FOXO3a knockdown inhibited TMZ-induced BNIP3 upregulation and autophagy activation. In addition, we showed that treatment with TMZ (100 mg·kg-1·d-1, ip) for 12 days in C6 cell xenograft mice markedly inhibited tumor growth accompanied by inducing FOXO3a upregulation, oxidative stress and BNIP3-mediated mitophagy in tumor tissues. These results demonstrate that FOXO3a attenuates temozolomide-induced DNA double strand breaks in human glioma cells via promoting BNIP3-mediated mitophagy.

Optimal DCO-OFDM signal shaping with double-sided clipping in visible light communications.

Direct-current-biased optical orthogonal frequency-division multiplexing (DCO-OFDM) is widely used in high-speed visible light communication (VLC). Due to the limited dynamic range of light-emitting diode (LED) and the unipolarity for the intensity modulation (IM), double-sided clipping is inevitably imposed on the time-domain signal in VLC OFDM systems. Consequently, it calls for proper DCO-OFDM signal shaping by selecting an appropriate bias and time-domain signal power to reduce the clipping distortion and achieve a higher transmission rate. In this paper, we deep dive into the signal shaping design problem for double-sided clipping DCO-OFDM over both flat and dispersive channels. We derive the optimal bias for flat and dispersive channels, and explain its optimality from the perspectives of effective signal-to-noise ratio (SNR) and information theory. We then analytically characterize the optimal power for flat channels and propose a useful algorithm for dispersive channels enlightened by the optimal solution to the flat case. Furthermore, we uncover an inherent relationship between the considered double-sided clipping and the downside-clipping only DCO-OFDM regarding signal shaping optimization, and develop an in-depth understanding of the impact of top clipping based on the established connection. Practical simulations are provided to validate the superiority of our proposed signal shaping over the existing shaping schemes.

RSL3 induced autophagic death in glioma cells via causing glycolysis dysfunction.

RSL3 is a type of small molecular compound which can inactivate glutathione peroxidase 4 (GPX4) and induce ferroptosis, but its role in glioma cell death remains unclear. In this study, we found RSL3 inhibited the viabilities of glioma cells and induced glioma cell death in a dose-dependent manner. In vitro studies revealed that RSL3-induced cell death was accompanied with the changes of autophagy-associated protein levels and was alleviated by pretreatment of 3-Methyladenine, bafilomycin A1 and knockdown of ATG5 with siRNA. The ATP and pyruvate content as well as the protein levels of HKII, PFKP, PKM2 were decreased in cells treated by RSL3, indicating that RSL3 induced glycolysis dysfunction in glioma cells. Moreover, supplement of exterior sodium pyruvate, which was a final product of glycolysis, not only inhibited the changes of autophagy-associated protein levels caused by RSL3, but also prevented RSL3-induced cell death. In vivo data suggested that the inhibitory effect of RSL3 on the growth of glioma cells was associated with glycolysis dysfunction and autophagy activation. Taken together, RSL3 induced autophagic cell death in glioma cells via causing glycolysis dysfunction.

[Epidemic characteristics of central obesity among adults in Gansu Province in 2013-2014].

OBJECTIVE: To analyze waist circumference level and the prevalence of central obesity among adults aged 18 years and above in Gansu Province. METHODS: The data from Chinese adult chronic diseases and their risk factors monitoring in 2013 was obtained by multi-stage stratified cluster random sampling method. The waist circumference level and epidemiologic characteristics of central obesity of 7607 adults aged 18 years and above in Gansu Province were analyzed. RESULTS: The waist circumference was(84.7±10.3)cm and(81.3±9.5)cm for adult men and women in Gansu Province, respectively. With the increase of age, waist circumference level of women showed a gradual increase trend from 78.6 cm in the group of 18-44 years to 83.5 cm in the group above 60 years; with improvement of education level, the average waist circumference of men gradually increased from 82.7 cm in illiterate/semi-literate group to 87.6 cm in group of junior college and above(P<0.001), but the value of women gradually reduced from 81.9 cm in illiterate/semi-literate group to 77.6 cm in group of junior college and above group(P<0.001); the higher the average annual income of family, the higher the waist circumference of the men from 83.0 cm in the group below 5000 yuan to 85.9 cm in the group above 18 000 yuan; among the occupational group, the highest waist circumference(88.9 cm) was the men engaged in enterprises and institutions and in contrast the women were the lowest in this occupation(79.0 cm). The prevalence of central obesity was 32.6%(standardized rate 28.8%) and men(33.9%)(standardized rate 28.8%) was higher than women(30.9%)(standardize rate 28.8%). The pre-obesity rate was 18.1%(standardized rate 17.6%), and that of women and men was 19.5%(standardized rate 18.5%) and 16.2%(standardized rate 16.0%), respectively. With the age increase, the central obesity rate of women showed a gradually increasing trend from 22.6% in the group of 18-44 years to 45.3% in the group above 60 years. With the increase of education level, the prevalence of central obesity showed increasing trend from 23.0% in illiterate/semi-literate group to 42.5% in group of college and above in men(P<0.001), but the prevalence of women gradually reduced from 36.1% in illiterate/semi-literate group to 20.1% in group of college and above group(P<0.001); with the increase in per capita annual income of the family, the prevalence of male central obesity increased from 23.8% in the group below 5000 yuan to 35.5% in the group above 18 000 yuan; among the professional groups, men predisposed central obesity(48.5%, P<0.001) and women had lowest prevalence(25.8%, P<0.001) in enterprises and institutions. Among the groups of overweight and obesity, the waist circumference was(88.3±7.4) cm and(98.8±8.3) cm in men, respectively, while the waist was(84.4±6.7)cm and(94.5±8.1)cm in women, respectively; the prevalence of central obesity was 43.3% and 87.7% in men and 47.3% and 93.9% in women between overweight and obese groups. However, the rate of central obesity in the groups without overweight/obesity(BMI<24.0) was only 6.0% in men and 9.8% in women. CONCLUSION: The central obesity is widely prevalence in adults of Gansu Province, and the averaged waist circumference level in men and women is close to or more than the cut-off point predicating pre-central obesity and the prevalence for this type of obesity is higher than that of the national level which indicates that using cut-off point of waist circumference. The subjects with obesity are more likely susceptible to central obesity.

Trehalose inhibits H2O2-induced autophagic death in dopaminergic SH-SY5Y cells via mitigation of ROS-dependent endoplasmic reticulum stress and AMPK activation.

Autophagy is a catabolic process to maintain intracellular homeostasis via removal of cytoplasmic macromolecules and damaged cellular organelles through lysosome-mediated degradation. Trehalose is often regarded as an autophagy inducer, but we reported previously that it could prevent ischemic insults-induced autophagic death in neurons. Thus, we further investigated in this study whether trehalose could protect human dopaminergic SH-SY5Y cells against H2O2-induced lethal autophagy. We found pretreatment with trehalose not only prevented H2O2-induced death in SH-SY5Y cells, but also reversed H2O2-induced upregulation of LC3II, Beclin1 and ATG5 and downregulation of p62. Then, we proved that either autophagy inhibitor 3MA or genetic knockdown of ATG5 prevented H2O2-triggered death in SH-SY5Y cells. These indicated that trehalose could inhibit H2O2-induced autophagic death in SH-SY5Y cells. Further, we found that trehalose inhibited H2O2-induced AMPK activation and endoplasmic reticulum (ER) stress. Moreover, inhibition of AMPK activation with compound C or alleviation of ER stress with chemical chaperone 4-PBA obviously attenuated H2O2-induced changes in autophagy-related proteins. Notably, we found that trehalose inhibited H2O2-induced increase of intracellular ROS and reduction in the activities of CAT and SOD. Consistently, our data revealed as well that mitigation of intracellular ROS levels with antioxidant NAC markedly attenuated H2O2-induced AMPK activation and ER stress. Therefore, we demonstrated in this study that trehalose prevented H2O2-induced autophagic death in SH-SY5Y cells via mitigation of ROS-dependent endoplasmic reticulum stress and AMPK activation.

A prediction model for lymph node metastases using pathologic features in patients intraoperatively diagnosed as stage I non-small cell lung cancer.

BACKGROUND: There is little information on which pattern should be chosen to perform lymph node dissection for stage I non-small-cell lung cancer. This study aimed to develop a model for predicting lymph node metastasis using pathologic features of patients intraoperatively diagnosed as stage I non-small-cell lung cancer. METHODS: We collected pathology data from 284 patients intraoperatively diagnosed as stage I non-small-cell lung cancer who underwent lobectomy with complete lymph node dissection from 2013 through 2014, assessing various factors for an association with metastasis to lymph nodes (age, gender, pathology, tumour location, tumour differentiation, tumour size, pleural invasion, bronchus invasion, multicentric invasion and angiolymphatic invasion). After analysing these variables, we developed a multivariable logistic model to estimate risk of metastasis to lymph nodes. RESULTS: Univariate logistic regression identified tumour size >2.65 cm (p < 0.001), tumour differentiation (p < 0.001), pleural invasion (p = 0.034) and bronchus invasion (p < 0.001) to be risk factors significantly associated with the presence of metastatic lymph nodes. On multivariable analysis, only tumour size >2.65 cm (p < 0.001), tumour differentiation (p = 0.006) and bronchus invasion (p = 0.017) were independent predictors for lymph node metastasis. We developed a model based on these three pathologic factors that determined that the risk of metastasis ranged from 3% to 44% for patients intraoperatively diagnosed as stage I non-small-cell lung cancer. By applying the model, we found that the values y > 0.80, 0.43 < y ≤ 0.80, y ≤ 0.43 plus tumour size >2 cm and y ≤0.43 plus tumour size ≤2 cm yielded positive lymph node metastasis predictive values of 44%, 18%, 14% and 0%, respectively. CONCLUSIONS: A non-invasive prediction model including tumour size, tumour differentiation and bronchus invasion may be useful to give thoracic surgeons recommendations on lymph node dissection for patients intraoperatively diagnosed as Stage I non-small cell lung cancer.

Shikonin induces glioma cell necroptosis in vitro by ROS overproduction and promoting RIP1/RIP3 necrosome formation.

Necroptosis is a type of programmed necrosis regulated by receptor interacting protein kinase 1 (RIP1) and RIP3. Necroptosis is found to be accompanied by an overproduction of reactive oxygen species (ROS), but the role of ROS in regulation of necroptosis remains elusive. In this study, we investigated how shikonin, a necroptosis inducer for cancer cells, regulated the signaling leading to necroptosis in glinoma cells in vitro. Treatment with shikonin (2-10 µmol/L) dose-dependently triggered necrosis and induced overproduction of intracellular ROS in rat C6 and human SHG-44, U87 and U251 glioma cell lines. Moreover, shikonin treatment dose-dependently upregulated the levels of RIP1 and RIP3 and reinforced their interaction in the glioma cells. Pretreatment with the specific RIP1 inhibitor Nec-1 (100 µmol/L) or the specific RIP3 inhibitor GSK-872 (5 µmol/L) not only prevented shikonin-induced glioma cell necrosis but also significantly mitigated the levels of intracellular ROS and mitochondrial superoxide. Mitigation of ROS with MnTBAP (40 µmol/L), which was a cleaner of mitochondrial superoxide, attenuated shikonin-induced glioma cell necrosis, whereas increasing ROS levels with rotenone, which improved the mitochondrial generation of superoxide, significantly augmented shikonin-caused glioma cell necrosis. Furthermore, pretreatment with MnTBAP prevented the shikonin-induced upregulation of RIP1 and RIP3 expression and their interaction while pretreatment with rotenone reinforced these effects. These findings suggest that ROS is not only an executioner of shikonin-induced glioma cell necrosis but also a regulator of RIP1 and RIP3 expression and necrosome assembly.

[Physiologically based toxicokinetic model for nickel].

OBJECTIVE: To estimate the metabolic parameters in different tissues and organs, build the physiologically based pharmacokinetic( PBPK) model of rat and occupational population, and predict the toxic dynamic characteristics exposure to nickel. METHODS: The partition coefficients in different tissues and organs were estimated using vector datas of nickel by the optimization and statistics files of acslx software. The PBTK model of occupational population exposure to nickel was built according to the metabolic parameters by acslx software. RESULTS: The evaluated partition coefficient of nickel were kidney blood( 0. 668), lung blood( 0. 102), spleen blood( 0. 037), liver blood( 0. 028), heart blood( 0. 022), and brain blood( 0. 006). The constructed successful PBPK model of occupational population exposed to 0. 1 mg/m~3 nickel for 8 hours showed that the nickel concentration is higher in kidney reached at 3. 328 µg/kg, followed by the spleen( 0. 185 µg/kg), liver( 0. 140 µg/kg) and heart( 0. 110 µg/kg). The content of nickel is lower in the brain( 0. 030 µg/kg). The kidneys is the major metabolic organs for nickel. CONCLUSION: The PBPK model can be used to convert the nickel levels from external exposure to internal exposure for each organ and to evaluate the time-dose relationship exposure to nickel in both rat and occupational population studies.

Parenthood and the risk of diabetes in men and women: a 7 year prospective study of 0.5 million individuals.

AIMS/HYPOTHESIS: In women, higher parity has been associated with increased risk of diabetes later in life. It is unclear, however, whether this association is mainly due to biological effects of childbearing, or to socioeconomic and lifestyle factors associated with childrearing. We assessed the association between number of children and diabetes risk separately in women and men. METHODS: Between 2004 and 2008, the nationwide China Kadoorie Biobank recruited 0.5 million individuals aged 30-79 (mean 51 years) from ten diverse regions across China. During 7 years of follow-up, 8,840 incident cases of diabetes were recorded among 463,347 participants without prior cardiovascular diseases or diabetes. Multivariable Cox regression yielded sex-specific HRs and 95% CIs for incident diabetes by number of children. RESULTS: Overall, ∼98% of all participants had children. In women, there was a J-shaped association between number of children and risk of diabetes. Compared with women with one child, the adjusted HRs for diabetes were 1.39 (95% CI 1.11, 1.73) for childless women, 1.12 (95% CI 1.07, 1.18) for those with two children, 1.23 (95% CI 1.16, 1.31) for those with three children, and 1.32 (95% CI 1.21, 1.44) for those with four or more children. In men, there was a similar association with risk of diabetes; the corresponding HRs were 1.28 (95% CI 1.02, 1.60), 1.19 (95% CI 1.12, 1.26), 1.32 (95% CI 1.21, 1.44) and 1.41 (95% CI 1.24, 1.60), respectively. In both sexes, the findings were broadly similar in different population subgroups. CONCLUSIONS/INTERPRETATION: The similarity between women and men in the association between number of children and risk of diabetes suggests that parenthood is most likely to affect diabetes risk through factors associated with childrearing rather than via biological effects of childbearing.

[A Retrospective Analysis on the Prevalence of Visceral Leishmaniasis in Gansu Province during 2005-2014].

OBJECTIVE: To review the prevalence of visceral leishmaniasis in Gansu Province during 2005-2014. METHODS: The data of visceral leishmaniasis cases in Gansu Province during 2005-2014 were collected and descriptive statistical analysis was performed. RESULTS: During 2005-2014, 1,260 cases of visceral leishmaniasis were reported in Gansu Province. The incidence showed a trend of annual increase from 2005 (90 cases, 7.14%) onwards, peaked in 2011 (168 cases, 13.33%), and decreased afterwards. In 2014, 85 cases (6.75%) were reported. Most of the cases were from the Longnan region and some areas in Gannan Tibetan Autonomous Prefecture. Specifically, the case number was highest in Wudu District of the Longnan region (506/1,260, 40.16%), followed by Wenxian County (302/1,260, 23.97%) and Zhouqu County (202/1,260, 16.03%). In total, the cases had a male-to-female ratio of 1.46:1, and concentrated in age group of 0-5 years (665/1,260, 52.78%), showing a trend of decrease with age increase. In addition, visceral leishmaniasis occured throughout the year, with a higher cumulative incidence from March to June [10.48% (132/1,260), 13.33% (168/1,260), 12.86% (162/1,260) and 11.67% (147/1,260), respectively]. CONCLUSION: From 2005 to 2014, the Longnan region and some areas of Gannan Prefecture are the major endemic areas of visceral leishmaniasis, with more cases in children under 5 and higher incidence from March to June.