Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury.

Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.

USP18 enhances the resistance of BRAF-mutated melanoma cells to vemurafenib by stabilizing cGAS expression to induce cell autophagy.

This study aims to discern the possible molecular mechanism of the effect of ubiquitin-specific peptidase 18 (USP18) on the resistance to BRAF inhibitor vemurafenib in BRAF V600E mutant melanoma by regulating cyclic GMP-AMP synthase (cGAS). The cancer tissues of BRAF V600E mutant melanoma patients before and after vemurafenib treatment were collected, in which the protein expression of USP18 and cGAS was determined. A BRAF V600E mutant human melanoma cell line (A2058R) resistant to vemurafenib was constructed with its viability, apoptosis, and autophagy detected following overexpression and depletion assays of USP18 and cGAS. Xenografted tumors were transplanted into nude mice for in vivo validation. Bioinformatics analysis showed that the expression of cGAS was positively correlated with USP18 in melanoma, and USP18 was highly expressed in melanoma. The expression of cGAS and USP18 was up-regulated in cancer tissues of vemurafenib-resistant patients with BRAF V600E mutant melanoma. Knockdown of cGAS inhibited the resistance to vemurafenib in A2058R cells and the protective autophagy induced by vemurafenib in vitro. USP18 could deubiquitinate cGAS to promote its protein stability. In vivo experimentations confirmed that USP18 promoted vemurafenib-induced protective autophagy by stabilizing cGAS protein, which promoted resistance to vemurafenib in BRAF V600E mutant melanoma cells. Collectively, USP18 stabilizes cGAS protein expression through deubiquitination and induces autophagy of melanoma cells, thereby promoting the resistance to vemurafenib in BRAF V600E mutant melanoma.

Cross-sectional study of characteristics of body composition of 24,845 children and adolescents aged 3-17 years in Suzhou.

BACKGROUND: We aimed to analyze the characteristics of the body composition of children and adolescents aged 3-17 in Suzhou, China. METHODS: A cross-sectional study between January 2020 and June 2022 using bioelectrical impedance was conducted to determine the fat mass (FM), fat-free mass (FFM), skeletal muscle mass, and protein and mineral contents of 24,845 children aged 3-17 who attended the Department of Child and Adolescent Healthcare, Children's Hospital of Soochow University, China. Measurement data was presented in tables as mean ± SD, and groups were compared using the independent samples t-test. RESULTS: FM and fat-free mass increased with age in both boys and girls. The fat-free mass of girls aged 14-15 decreased after reaching a peak, and that of boys in the same age group was higher than that of the girls (p < 0.05). There were no significant differences in FM between boys and girls younger than 9- and 10-years old. The percentage body fat (PBF) and FM index of girls increased rapidly between 11 and 15 years of age (p < 0.05), and those of boys aged 11-14 were significantly lower (p < 0.05), suggesting that the increase in body mass index (BMI) was mainly contributed by muscle mass (MM) in boys. CONCLUSIONS: The body composition of children and adolescents varies according to their age and sex. A misdiagnosis of obesity made on the basis of BMI alone can be avoided if BMI is used in combination with FM index, percentage body fat, and other indexes.

The mitochondrial protein TIMM44 is required for angiogenesis in vitro and in vivo.

The mitochondrial integrity and function in endothelial cells are essential for angiogenesis. TIMM44 (translocase of inner mitochondrial membrane 44) is essential for integrity and function of mitochondria. Here we explored the potential function and the possible mechanisms of TIMM44 in angiogenesis. In HUVECs, human retinal microvascular endothelial cells and hCMEC/D3 brain endothelial cells, silence of TIMM44 by targeted shRNA largely inhibited cell proliferation, migration and in vitro capillary tube formation. TIMM44 silencing disrupted mitochondrial functions in endothelial cells, causing mitochondrial protein input arrest, ATP reduction, ROS production, and mitochondrial depolarization, and leading to apoptosis activation. TIMM44 knockout, by Cas9-sgRNA strategy, also disrupted mitochondrial functions and inhibited endothelial cell proliferation, migration and in vitro capillary tube formation. Moreover, treatment with MB-10 ("MitoBloCK-10"), a TIMM44 blocker, similarly induced mitochondrial dysfunction and suppressed angiogenic activity in endothelial cells. Contrarily, ectopic overexpression of TIMM44 increased ATP contents and augmented endothelial cell proliferation, migration and in vitro capillary tube formation. In adult mouse retinas, endothelial knockdown of TIMM44, by intravitreous injection of endothelial specific TIMM44 shRNA adenovirus, inhibited retinal angiogenesis, causing vascular leakage, acellular capillary growth, and retinal ganglion cells degeneration. Significant oxidative stress was detected in TIMM44-silenced retinal tissues. Moreover, intravitreous injection of MB-10 similarly induced oxidative injury and inhibited retinal angiogenesis in vivo. Together, the mitochondrial protein TIMM44 is important for angiogenesis in vitro and in vivo, representing as a novel and promising therapeutic target of diseases with abnormal angiogenesis.

Discovery of novel analogs of KHS101 as transforming acidic coiled coil containing protein 3 (TACC3) inhibitors for the treatment of glioblastoma.

Transforming acidic coiled coil containing protein 3 (TACC3) is emerging as an attractive anticancer target in recent years, however, few TACC3 small-molecular inhibitors have been reported up to now. In this study, fifteen compounds were designed and synthesized based on the lead compound KHS101 to find more potent TACC3 inhibitors. Among them, the most potent compound 7g exhibited about 10-folds more potent antiproliferative activities than KHS101 in various cancer cell lines. Two different protein-drug binding assays including DARTS, and CETSA revealed TACC3 as a biologically relevant target of compound 7g. In addition, compound 7g induced cell cycle arrest at the G2/M phase and induced cell apoptosis. Furthermore, compound 7g depolarized the MMP and induced ROS generation in a dose-dependent manner in U87 cells. More importantly, 7g reduced tumor weight by 72.7% in U87 xenograft model at a dose of 20 mg/kg/day without obvious toxicity. Altogether, compound 7g deserved further investigations as a novel, safe and efficacious TACC3 inhibitor for the treatment of GBM.

Body composition in preschool children with short stature: a case-control study.

BACKGROUND: Short stature is defined as height below 2 standard deviations of the population with the same age, gender. This study is aimed to assess the characteristics of body composition in preschool children with short stature. METHODS: Anthropometric measurements and body composition were assessed in 68 preschool children aged 3 to 6 years old with short stature and 68 normal controls matched on age and gender. Height, weight and body composition (total body water, protein, minerals, body fat mass, fat-free mass, soft lean mass, skeletal muscle mass, and bone mineral contents) in the two groups were measured and compared. RESULTS: The total body water, protein, minerals, body fat mass, fat-free mass, soft lean mass, skeletal muscle mass, and bone mineral contents were lower in preschool children with short stature than controls (P < 0.05). Body mass index and fat mass index did not differ between groups. Fat-free mass index was significantly lower in short stature group than controls (t = 2.17, P = 0.03). Linear regression analysis showed that there was a positive correlation between height and fat-free mass index [ß, 1.99 (0.59, 3.39), P = 0.01], a negative correlation between height and body fat percentage [ß, - 0.20 (- 0.38, - 0.01), P = 0.04]. The proportions of fat-free mass in the upper limbs were significantly lower (Right,t = - 2.78,Left t = - 2.76, P < 0.05, respectively) in short stature, although body fat distribution was not. CONCLUSIONS: The fat-free mass such as protein and bone minerals is lower in preschool children with short stature, suggesting the monitoring of fat-free mass for early identification and intervention.

Ginsenoside Rg1 Attenuates Premature Ovarian Failure of D-gal Induced POF Mice Through Downregulating p16INK4a and Upregulating SIRT1 Expression.

BACKGROUND: Premature ovarian failure (POF) refers to pathological amenorrhea before 40 years. OBJECTIVE: To explore the regulatory effect of Rg1 on POF and clarify associated mechanisms. MATERIALS AND METHODS: POF mice were induced by injecting with D-galactose (D-gal, 200 mg/kg/- day). Mice were divided into phosphate buffered saline (PBS), D-gal (POF mice), D-gal/Rg1 group (POF mice administrating D-gal/Rg1). Weight growth rate and ovarian weight coefficient were measured. Serum estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH), superoxide dismutase (SOD), catalase (CAT) levels were examined using ELISA. The status of follicle and corpus luteum was determined using hematoxylin-eosin (HE) staining. P16INK4a and silent- mating type information regulation-2 homolog-1 (SIRT1) were determined using western blotting and RT-PCR. RESULTS: Weight growth rate and ovarian weight coefficient of mice in D-gal group were significantly decreased than PBS group (p<0.05). Serum E2, LH, SOD, CAT levels were significantly decreased, FSH levels were remarkably increased in D-gal group than PBS group (p<0.05). Rg1 (D-- gal/Rg1 group) significantly increased weight growth rate and ovarian weight coefficient, enhanced E2, LH, SOD, CAT levels and decreased FSH levels than D-gal group (p<0.05). HE staining demonstrated normal follicle morphology/structure of mice in PBS group and decreased the number of follicles, obvious vacuolation of corpus luteum and increased atretic follicles of mice in D-gal group. Compared with D-gal group, the number of follicles was increased, luteal follicles were decreased in mice in D-gal/Rg1 group (p<0.05). Rg1 significantly (D-gal/Rg1) downregulated p16INK4a and upregulated SIRT1 expression in ovarian tissues of mice compared to the D-gal group (p<0.05). CONCLUSION: Rg1 could delay premature ovarian failure in D-gal induced POF mouse model through downregulating p16INK4a and upregulating SIRT1 expression.

ß-Elemene Triggers ROS-dependent Apoptosis in Glioblastoma Cells Through Suppressing STAT3 Signaling Pathway.

Glioblastoma is one of the most aggressive primary brain tumors with few treatment strategies. ß-Elemene is a sesquiterpene known to have broad spectrum antitumor activity against various cancers. However, the signaling pathways involved in ß-elemene induced apoptosis of glioblastoma cells remains poorly understood. In this study, we reported that ß-elemene exhibited antiproliferative activity on U87 and SHG-44 cells, and induced cell death through induction of apoptosis. Incubation of these cells with ß-elemene led to the activation of caspase-3 and generation of reactive oxygen species (ROS). Western blot assay showed that ß-elemene suppressed phosphorylation of STAT3, and subsequently down-regulated the activation of p-JAK2 and p-Src. Moreover, pre-incubation of cells with ROS inhibitor N-acetyl-L-cysteine (NAC) significantly reversed ß-elemene-mediated apoptosis effect and down-regulation of JAK2/Src-STAT3 signaling pathway. Overall, our findings implied that generation of ROS and suppression of STAT3 signaling pathway is critical for the apoptotic activity of ß-elemene in glioblastoma cells.

A novel selective mitochondrial-targeted curcumin analog with remarkable cytotoxicity in glioma cells.

Naturally occurring polyphenol curcumin (4) or demethoxycurcumin (5) and their synthetic derivatives display promising anticancer activities. However, their further development is limited by low bioavailability and poor selectivity. Thus, a mitochondria-targeted compound 14 (DMC-TPP) was prepared in the present study by conjugating a triphenylphosphine moiety to the phenolic hydroxyl group of demethoxycurcumin to enhance its bioavailability and treatment efficacy. The in vitro biological experiments of DMC-TPP showed that it not only displayed higher cytotoxicity as compared with its parent compound 5, but also exhibited superior mitochondria accumulation ability. Glioma cells were more sensitive to DMC-TPP, which inhibited the proliferation of U251 cells with an IC50 of 0.42 µM. The mechanism studies showed that DMC-TPP triggers mitochondria-dependent apoptosis, caused by caspase activation, production of reactive oxygen species (ROS) and decrease of mitochondrial membrane potential (MMP). In addition, DMC-TPP efficiently inhibited cellular thioredoxin reductase, which contributed to its cytotoxicity. Significantly, DMC-TPP delayed tumor progression in a mouse xenograft model of human glioma cancer. Taken together, the potent in vitro and in vivo antitumor activity of DMC-TPP warrant further comprehensive evaluation as a novel anti-glioma agent.

Anxiety in Chinese pediatric medical staff during the outbreak of Coronavirus Disease 2019: a cross-sectional study.

BACKGROUND: Our study aimed to explore the anxiety levels and possible associated factors in the pediatric medical staff in Jiangsu province during an outbreak of Coronavirus Disease 2019 (COVID-19). METHODS: Pediatric medical staff (n=534) from nine hospitals in Jiangsu province were enrolled. Their anxiety levels and quality of sleep were assessed using the online SAS and PSQI questionnaires. RESULTS: The prevalence of anxiety was 14.0% among the medical staff. In children's hospital staff, anxiety levels in outpatient and emergency departments were significantly higher than those in inpatient departments, except for the intensive care unit. The SAS scores were significantly associated with educational background, professional title, lifestyle, and physical condition. Stepwise multiple linear regression showed that physical condition, lifestyle, attention to the epidemic, professional title, and educational background all had a linear relationship with the individual's anxiety levels. Pearson correlation analysis showed that sleep quality was moderately associated with anxiety levels. CONCLUSIONS: The prevalence of anxiety was 14.0% in pediatric medical staff in Jiangsu province during an outbreak of COVID-19. Department, professional title, and educational background were associated with anxiety levels in these workers. More attention should be paid to staff who are in poor health, and this anxiety can also be accompanied by poor sleep quality. Peer support can assist with anxiety relief.

Contemporary blood lead levels of children aged 0-84 months in China: A national cross-sectional study.

Despite the global abundance of studies on children's lead (Pb) exposure, the magnitude of Pb exposure among children across China remains unclear, especially for rural areas. In 2000, Pb was removed from petrol, marking a change in the sources of Pb exposure in China. To better understand children's Pb exposure and inform potential approaches to exposure reduction, we conducted a national blood Pb survey of 31,373 children (0-84 months old) from May 2013 to March 2015, using a multi-stage and multi-strata sampling method. Blood lead levels (BLLs) were tested using graphite furnace atomic absorption spectrometry with a detection limit of 1 µg/L. The results show that Chinese children had a contemporary geometric mean (GM) BLL of 26.7 µg/L, with 8.6% of BLLs exceeding 50 µg/L. Boys had higher BLLs (GM 27.2 µg/L) compared to girls (GM: 25.9 µg/L) (p < 0.001). Children at the age of 0-36 months had a lower PbB (GM 25.7 µg/L) level compared with those aged 36-84 months (GM 27.9 µg/L) (p < 0.001). When taking into account sociodemographic factors, a multivariate logistic regression analysis shows that the odds ratios (OR) of having a BLL of 27 µg/dL (i.e., median BLL of this study) or higher were 1.88 (95% CI: 1.76, 2.02) and 1.35 (95% CI: 1.22, 1.49) for homes using coal and biomass fuels, respectively, compared to those using gas or electricity. Meanwhile, children in homes close to roads were more likely to have BLLs exceeding 27 µg/dL (OR: 1.11, 95% CI: 1.03, 1.20). In China, rural children had higher BLLs compared to urban children. As a result of pediatric exposure to Pb, there were approximately 144 million and 36 million IQ points lost for rural children and urban children, respectively, revealing a disparity of Pb exposure between rural and urban areas in China. Cleaner domestic fuels and improved cooking/heating equipment will reduce contemporary Pb exposure in rural areas. In addition, the association between contemporary BLLs and distance away from roads further suggests that resuspension of legacy soil/dust Pb should not be neglected in future remediation programs and household interventions. As a large scale survey, this study provides evidence for revising the reference value of BLL, improving the guideline for clinical and public health management, and implementing interventions to prevent adverse health outcomes associated with low-level Pb exposure in children.

Allicin alleviates lead-induced hematopoietic stem cell aging by up-regulating PKM2.

Hematopoietic stem cells (HSCs) aging is associated with hematopoietic dysfunction and diseases. Our previous study showed that lead exposure induced a functional decline in HSCs. Allicin, a chemical extracted from the garlic (Allium sativum L.), has been reported to have antioxidative and anti-inflammatory effects. However, the biological activities of allicin on lead-induced toxicity, especially in the hematopoietic system, remain unclear. Here, we found that lead exposure elicited aging phenotypes in HSCs, including perturbed cell quiescence, disabled self-renewal function and colony-forming ability, and myeloid-biased differentiation, all of which contributed to significant hematopoietic disorders in mice. Intragastric administration of allicin substantially ameliorated lead-induced HSCs aging phenotypes in vivo Lead exposure induced a peroxide condition in HSCs leading to DNA damage, which reduced expression of the glycolytic enzyme pyruvate kinase M2 isoform (PKM2), a phenotype which was significantly ameliorated by allicin treatment. These findings suggested that allicin alleviated lead-induced HSCs aging by up-regulating PKM2 expression; thus, it could be a natural herb for preventing lead toxicity.

Chronic Lead Exposure Results in Auditory Deficits and Disruption of Hair Cells in Postweaning Rats.

OBJECTIVE: The effects of lead exposure on cognitive function have been studied intensively over the past decade, but less attention has focused on its impact on auditory function. This study is aimed at investigating the effect of lead on the cochlea and the molecular mechanisms responsible for its actions. METHODS: 0.2% lead acetate was administered to rats in drinking water for 30, 60, and 90 days. Brainstem auditory evoked responses (ABR) were recorded, and morphological changes in the hair cells were observed. We also measured glutathione (GSH) and malondialdehyde (MDA) concentrations and antioxidant enzyme activities such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activities in the cochlea. RESULTS: Lead exposure increased the ABR threshold and slightly prolonged the latencies of wave II and wave IV in rats. Abnormally shaped hair cells and loss of hair cells were found in the cochlea basilar membrane, together with degenerative changes in spiral ganglion neurons following lead exposure. The activities of some antioxidant enzymes were also reduced in association with upregulation of MDA expression. These effects may be caused by impaired catalytic function of the enzymes as a result of lead interaction. CONCLUSION: The antioxidant system of the cochlea in the immature rat brain is highly vulnerable to developmental lead exposure. Oxidative stress may therefore represent a possible mechanism for lead-induced auditory deficits.

Alleviation of ginsenoside Rg1 on hematopoietic homeostasis defects caused by lead-acetate.

The hematopoietic system is one of the potential targets of lead intoxication. Recognition of the lead-related deleterious outcomes promotes us to explore the potential therapeutic intervention. Here, we show that ginsenoside Rg1 (Rg1), extracted from the Chinese herb Panax ginseng, remarkably ameliorates the lead acetate-caused hematological index distortion as well as advanced hematopoietic stem cells (HSCs) aging and aging associated inflammation response. Specifically, Rg1 administration alleviated the increment of aging associated p53-p21-Rb signaling in aged HSCs induced by lead acetate. It also led a reduction of the lead acetate-induced increased inflammation level in blood plasma, which also partly contribute the aged HSCs rejuvenation. In conclusion, our results indicate that ginsenoside Rg1 therapeutically alleviated the essential blood deficits and advanced HSCs aging by lead acetate exposure, by which it could be viewed as a potential candidate for lead acetate-caused blood toxicity treatment.

Autophagy plays a protective role in cell death of osteoblasts exposure to lead chloride.

Lead (Pb) is a toxic heavy metal widespreadly used in industrial field. Prior studies showed that Pb exposure had detrimental effects on osteoblasts. The mechanisms underlying Pb-induced damage are complex. Autophagy can protect cells from various cytotoxic stimuli. In the present study, the aim of our research was to investigate whether Pb could activate autophagy to play a protective role against osteoblasts apoptosis. Our results indicated that PbCl2 induced autophagy and autophagic flux in MC3T3-E1 murine osteoblastic cell by RT-PCR, western blot, as well as fluorescence microscopy analysis of GFP-LC3, AO and MDC staining. Pb increased the apoptosis of osteoblasts, evidenced by western blot and Hoechst 33258 staining assessment. In addition, inhibiting autophagy by 3-MA further increased the osteoblasts apoptosis after Pb exposure, showed by flow cytometry and Hoechst 33258 staining. Furthermore, phosphorylation of mTOR and p70S6K was inhibited by Pb exposure, indicating that Pb might induce autophagy in osteoblasts via inhibiting mTOR pathway. Altogether, these evidence suggested that Pb exporsure promoted autophagy flux in osteoblasts. The activation of autophagy by Pb played a protective role in osteoblasts apoptosis, which might be mediated through the mTOR pathway.

Mitochondria defects are involved in lead-acetate-induced adult hematopoietic stem cell decline.

Occupational high-grade lead exposure has been reduced in recent decades as a result of increased regulation. However, environmental lead exposure remains widespread, and is associated with severe toxicity implicated in human diseases. We performed oral intragastric administration of various dose lead acetate to adult Sprague Dawley rats to define the role of lead exposure in hematopoietic stem cells (HSCs) function, and to clarify its underlying mechanism. Lead acetate-exposed rats exhibited developmental abnormalities in myeloid and lymphoid lineages, and a significant decline in immune functions. It also showed HSCs functional decline associated with senescent phenotype with low grade lead acetate exposure or apoptotic phenotype with relative higher grade dose exposure. Mechanistic exploration showed a significant increase in reactive oxygen species (ROS) in the lead acetate-exposed CD90(+)CD45(-) compartment, which correlated with functional defects in cellular mitochondria. Furthermore, in vivo treatment with the antioxidant vitamin C led to reversion of the CD90(+)CD45(-) compartment functional decline. These results indicate that lead acetate perturbs the hematopoietic balance of adult HSCs, associated with cellular mitochondria defects, increased intracellular ROS generation.

The national trend of blood lead levels among Chinese children aged 0-18 years old, 1990-2012.

We analyzed the epidemiological data during 1990-2012 that investigated the blood lead level (BLL) in the population aged 0-18 years old in China mainland and provided evidence of the benefits of implementing policies to prevent lead pollution based on the dynamic changes of BLL. Data were collected through databases including China Knowledge Resource Integrated Database (CNKI), CBM disc, Wanfang Data, Pubmed and Medline. The inclusion criteria were: 1. Epidemiological study in healthy population not included studies limited to specific patient; 2. Study subject was not the specific lead exposure population; 3. Sample size should be no less than 100 (for neonatal, no less than 50); 4. BLL detection was under strict quality control; and 5. Results should be presented as BLL (arithmetic mean level or geometric mean level). 62 articles were included in this study. All the surveys in these articles contained 189,352 subjects in 19 provinces, autonomous regions and municipalities. Linear regression analysis showed a significant decrease between 1990 and 2012 with an estimated regression coefficient of 3.05/year (SE=0.01, p<0.001). BLL gradually declined since early 21st century. Median levels of BLL among the three economic zones were 51.4 µg/L in the eastern zone, 52.72 µg/L in the central zone and 46.2 µg/L in the western zone respectively. Median BLLs in male and female population aged 0-18 years old of China were 48.8 µg/L and 46.1µg/L. Median levels of BLL among the different age ranges were 74.9 µg/L in newborn, 46.4 µg/L in 0 to 3 years old, 57.6 µg/L in 3 to 7 years old and 55.6 µg/L in above 7 years old respectively. In conclusion, the BLL in the Chinese population of 0-18 years old has gradually dropped in the past 10 years. The decline in temporal trend still remains under potential impacts of several factors such as economical level, gender and age difference. Although, China has made significant achievements in the control prevention of lead pollution, concerted efforts are still warranted to reduce children lead poisoning.

Senescence effects of Angelica sinensis polysaccharides on human acute myelogenous leukemia stem and progenitor cells.

Leukemia stem cells (LSCs) play important roles in leukemia initiation, progression and relapse, and thus represent a critical target for therapeutic intervention. Hence, it is extremely urgent to explore new therapeutic strategies directly targeting LSCs for acute myelogenous leukemia (AML) therapy. We show here that Angelica sinensis polysaccharide (ASP), a major active component in Dong quai (Chinese Angelica sinensis), effectively inhibited human AML CD34+CD38? cell proliferation in vitro culture in a dose-dependent manner while sparing normal hematopoietic stem and progenitor cells at physiologically achievable concentrations. Furthermore, ASP exerted cytotoxic effects on AML K562 cells, especially LSC-enriched CD34+CD38? cells. Colony formation assays further showed that ASP significantly suppressed the formation of colonies derived from AML CD34+CD38? cells but not those from normal CD34+CD38? cells. Examination of the underlying mechanisms revealed that ASP induced CD34+CD38? cell senescence, which was strongly associated with a series of characteristic events, including up-regulation of p53, p16, p21, and Rb genes and changes of related cell cycle regulation proteins P16, P21, cyclin E and CDK4, telomere end attrition as well as repression of telomerase activity. On the basis of these findings, we propose that ASP represents a potentially important agent for leukemia stem cell-targeted therapy.

Levels of prenatal mercury exposure and their relationships to neonatal anthropometry in Wujiang City, China.

We determined the levels of prenatal Hg exposure in Wujiang City, located in the southeast of Taihu Lake in China's Jiangsu Province, and analyze the relationship between prenatal exposure to Hg and neonatal anthropometry, including birth weight, body length, and head circumference. From June 2009 to July 2010, a total of 213 mother-infant pairs were enrolled. The geometric means of Hg levels in maternal hair, fetal hair, placentas, and cord blood were 496.76 µg/kg, 233.94 µg/kg, 3.58 µg/kg, and 1.54 µg/L, respectively. The Hg levels detected in our study were significantly lower than those reported by previous studies. In addition, no significant correlations were found between Hg levels in maternal hair, fetal hair, placenta, or cord blood and neonatal anthropometrics. Together, our findings may be important for understanding the effects of prenatal exposure to Hg on newborns' development and have implications concerning the recommended dose for Hg.