Deficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress.

Liver injury is a core pathological process in the majority of liver diseases, yet the genetic factors predisposing individuals to its initiation and progression remain poorly understood. Here we show that asialoglycoprotein receptor 1 (ASGR1), a lectin specifically expressed in the liver, is downregulated in patients with liver fibrosis or cirrhosis and male mice with liver injury. ASGR1 deficiency exacerbates while its overexpression mitigates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice. Mechanistically, ASGR1 binds to an endoplasmic reticulum stress mediator GP73 and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels and promotes the interaction between GP73 and BIP to activate endoplasmic reticulum stress, leading to liver injury. Neutralization of GP73 not only attenuates ASGR1 deficiency-induced liver injuries but also improves survival in mice received a lethal dose of acetaminophen. Collectively, these findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target for the treatment of liver injury.

GDF15 is a major determinant of ketogenic diet-induced weight loss.

A ketogenic diet (KD) has been promoted as an obesity management diet, yet its underlying mechanism remains elusive. Here we show that KD reduces energy intake and body weight in humans, pigs, and mice, accompanied by elevated circulating growth differentiation factor 15 (GDF15). In GDF15- or its receptor GFRAL-deficient mice, these effects of KD disappeared, demonstrating an essential role of GDF15-GFRAL signaling in KD-mediated weight loss. Gdf15 mRNA level increases in hepatocytes upon KD feeding, and knockdown of Gdf15 by AAV8 abrogated the obesity management effect of KD in mice, corroborating a hepatic origin of GDF15 production. We show that KD activates hepatic PPARγ, which directly binds to the regulatory region of Gdf15, increasing its transcription and production. Hepatic Pparγ-knockout mice show low levels of plasma GDF15 and significantly diminished obesity management effects of KD, which could be restored by either hepatic Gdf15 overexpression or recombinant GDF15 administration. Collectively, our study reveals a previously unexplored GDF15-dependent mechanism underlying KD-mediated obesity management.

The cortical regions and white matter tracts underlying auditory comprehension in patients with primary brain tumor.

The comprehension of spoken language is one of the most essential language functions in humans. However, the neurological underpinnings of auditory comprehension remain under debate. Here we used multi-modal neuroimaging analyses on a group of patients with low-grade gliomas to localize cortical regions and white matter tracts responsible for auditory language comprehension. Region-of-interests and voxel-level whole-brain analyses showed that cortical areas in the posterior temporal lobe are crucial for language comprehension. The fiber integrity assessed with diffusion tensor imaging of the arcuate fasciculus and the inferior longitudinal fasciculus was strongly correlated with both auditory comprehension and the grey matter volume of the inferior temporal and middle temporal gyri. Together, our findings provide direct evidence for an integrated network of auditory comprehension whereby the superior temporal gyrus and sulcus, the posterior parts of the middle and inferior temporal gyri serve as auditory comprehension cortex, and the arcuate fasciculus and the inferior longitudinal fasciculus subserve as crucial structural connectivity. These findings provide critical evidence on the neural underpinnings of language comprehension.

Camptothecin effectively treats obesity in mice through GDF15 induction.

Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight through activation of hindbrain receptor glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) in rodents and nonhuman primates, thus endogenous induction of this peptide holds promise for obesity treatment. Here, through in silico drug-screening methods, we found that small molecule Camptothecin (CPT), a previously identified drug with potential antitumor activity, is a GDF15 inducer. Oral CPT administration increases circulating GDF15 levels in diet-induced obese (DIO) mice and genetic ob/ob mice, with elevated Gdf15 expression predominantly in the liver through activation of integrated stress response. In line with GDF15's anorectic effect, CPT suppresses food intake, thereby reducing body weight, blood glucose, and hepatic fat content in obese mice. Conversely, CPT loses these beneficial effects when Gdf15 is inhibited by a neutralizing antibody or AAV8-mediated liver-specific knockdown. Similarly, CPT failed to reduce food intake and body weight in GDF15's specific receptor GFRAL-deficient mice despite high levels of GDF15. Together, these results indicate that CPT is a promising anti-obesity agent through activation of GDF15-GFRAL pathway.

[Influence of Different Soil Conditioner on the Transfer and Transformation of Cadmium and Phthalate Esters in Soil].

This study examines the existing common form of soil pollution, combined organic and inorganic pollution. Cadmium (Cd) is the most important inorganic element in soil pollution. Due to the widespread use of plastic film, phthalates have become the main organic pollutants in soil. Pot experiments were conducted with purple soil from southwest China, and Chinese cabbage was used as a biological indicator. Different concentration gradients of Cd and diethylhexyl phthalate (DEHP) was used as foreign pollutants. The soil was treated with one of the six common soil conditioners, namely potassium feldspar powder, oyster shell powder, biological carbon powder (biochar), calcium, potassium carbonate, and calcium phosphate, to examine the effect of conditioners on cadmium morphology, DEHP content in contaminated soil, and cadmium and DEHP absorption in Chinese cabbage. The results showed that biochar is the optimal soil conditioner for the remediation of cadmium-phthalate composite pollution in purple soil. Subsequently, the effects of soil biochar content on cadmium pollution and phthalate ester migration were studied. Uncontaminated control soil, Cd-contaminated soil, and DEHP-contaminated soil were examined by pot experiments, and biochar treatments with mass fraction of 0%, 0.5%, 1%, 3%, and 5% added to cadmium contaminated soil were used to determine its influence on Cd morphology and DEHP content of contaminated soil.

Glioma surgery with awake language mapping versus generalized anesthesia: a systematic review.

Awake craniotomy with language mapping is being increasingly applied to avoid postoperative language dysfunctions worldwide. However, the effectiveness and reliability of this technique remain unclear due to the paucity of studies comparing the awake craniotomy with general anesthesia. To determine the benefit of awake craniotomy for language, motor, and neurological functions, as well as other clinical outcomes, we searched Medline, Embase, the Cochrane Library, and the Chinese Biomedical Literature Database up to December 2019. Gray literatures were also searched. We included randomized and non-randomized controlled studies comparing awake craniotomy versus general anesthetic resection and reporting the language and neurological outcomes. Ten studies with 833 patients were included in the meta-analysis. The pooled risk ratio (RR) suggested no significant differences in language and neurological outcomes between general anesthesia group and awake craniotomy group without electrical stimulation. Awake craniotomy with electrical stimulation, however, was associated with improved late language and neurological outcomes (≥ 3 months) versus general anesthesia with pooled RR of 0.44 (95% CI = 0.20-0.96) and 0.49 (95% CI = 0.30-0.79), respectively. Awake craniotomy with electrical stimulation was also associated with better extent of resection with the pooled RR of 0.81 (95%CI = 0.71-0.92) and shorter hospital stay duration with the pooled weighted mean difference (WMD) of - 1.14 (95%CI = - 1.80 to - 0.48). This meta-analysis suggested that the application of awake craniotomy with electrical stimulation during glioma resection is associated with lower risks of long-term neurological and language deficits and higher extent of tumor resection, as well as shorter hospital stay duration.

Neohesperidin attenuates obesity by altering the composition of the gut microbiota in high-fat diet-fed mice.

Obesity and related metabolic disorders are associated with intestinal microbiota dysbiosis, disrupted intestinal barrier, and chronic inflammation. Neohesperidin (Neo), a natural polyphenol abundant in citrus fruits, is known for its preventative and therapeutic effects on numerous diseases. Here, we report that Neo administration attenuates weight gain, low-grade inflammation, and insulin resistance in mice fed high-fat diet (HFD). Also, Neo administration substantially restores gut barrier damage, metabolic endotoxemia, and systemic inflammation. Sequencing of 16S rRNA genes in fecal samples revealed that Neo administration reverses HFD-induced intestinal microbiota dysbiosis: an increase in the diversity of gut microbiota and alteration in the composition of intestinal microbiota (particularly in the relative abundances of Bacteroidetes and Firmicutes). Furthermore, systemic antibiotic treatment abolishes the beneficial effects of Neo in body weight control, suggesting that the effect of Neo on obesity attenuation largely depends on the gut microbiota. More importantly, we demonstrate that the impact of Neo on the regulation of obesity could be transferred from Neo-treated mice to HFD-fed mice via fecal microbiota transplantation. Collectively, our data highlight the efficacy of Neo as a prebiotic agent for attenuating obesity, implying a potential mechanism for gut microbiota mediated the beneficial effect of Neo.

Mitochondrial aconitase controls adipogenesis through mediation of cellular ATP production.

Mitochondrial aconitase (Aco2) catalyzes the conversion of citrate to isocitrate in the TCA cycle, which produces NADH and FADH2, driving synthesis of ATP through OXPHOS. In this study, to explore the relationship between adipogenesis and mitochondrial energy metabolism, we hypothesize that Aco2 may play a key role in the lipid synthesis. Here, we show that overexpression of Aco2 in 3T3-L1 cells significantly increased lipogenesis and adipogenesis, accompanied by elevated mitochondrial biogenesis and ATP production. However, when ATP is depleted by rotenone, an inhibitor of the respiratory chain, the promotive role of Aco2 in adipogenesis is abolished. In contrast to Aco2 overexpression, deficiency of Aco2 markedly reduced lipogenesis and adipogenesis, along with the decreased mitochondrial biogenesis and ATP production. Supplementation of isocitrate efficiently rescued the inhibitory effect of Aco2 deficiency. Similarly, the restorative effect of isocitrate was abolished in the presence of rotenone. Together, these results show that Aco2 sustains normal adipogenesis through mediating ATP production, revealing a potential mechanistic link between TCA cycle enzyme and lipid synthesis. Our work suggest that regulation of adipose tissue mitochondria function may be a potential way for combating abnormal adipogenesis related diseases such as obesity and lipodystrophy.

A Potential Nutraceutical Candidate Lactucin Inhibits Adipogenesis through Downregulation of JAK2/STAT3 Signaling Pathway-Mediated Mitotic Clonal Expansion.

The prevalence of obesity has increased dramatically worldwide in the past ~50 years. Searching for safe and effective anti-obesity strategies are urgently needed. Lactucin, a plant-derived natural small molecule, is known for anti-malaria and anti-hyperalgesia. The study is to investigate whether lactucin plays a key role in adipogenesis. To this end, in vivo male C57BL/6 mice fed a high-fat diet (HFD) were treated with 20 mg/kg/day of lactucin or vehicle by gavage for seven weeks. Compared with vehicle-treated controls, Lactucin-treated mice showed lower body mass and mass of adipose tissue. Consistently, in vitro 3T3-L1 cells were treated with 20 µM of lactucin. Compared to controls, lactucin-treated cells showed significantly less lipid accumulation during adipocyte differentiation and lower levels of lipid synthesis markers. Mechanistically, we showed the anti-adipogenic property of lactucin was largely limited to the early stage of adipogenesis. Lactucin-treated cells fail to undergo mitotic clonal expansion (MCE). Further studies demonstrate that lactucin-induced MCE arrests might result from reduced phosphorylation of JAK2 and STAT3. We then asked whether activation of JAK2/STAT3 would restore the inhibitory effect of lactucin on adipogenesis with pharmacological STAT3 activator colivelin. Our results revealed similar levels of lipid accumulation between lactucin-treated cells and controls in the presence of colivelin, indicating that inactivation of STAT3 is the limiting factor for the anti-adipogenesis of lactucin in these cells. Together, our results provide the indication that lactucin exerts an anti-adipogenesis effect, which may open new therapeutic options for obesity.

Phthalate esters in biota, air and water in an agricultural area of western China, with emphasis on bioaccumulation and human exposure.

Phthalate esters (PAEs) have been shown to be ubiquitous in abiotic and biotic environmental compartments; however, information about bioaccumulation behavior and human exposure, both via environmental exposure and the diet, are limited. Herein, we report the concentrations and composition profiles of phthalate esters (PAEs) in biological samples, river water, indoor air, and outdoor air samples collected from an agricultural site in western China. Dibutyl phthalate (DNBP) occupied a relatively high abundance in biological samples, discrepant with the environmental samples in which di-(2-ethylhexyl) phthalate (DEHP) was the dominant congener. Significant correlations (P < 0.05) were observed between the biota and river water samples, indicating that river water heavily influenced PAE accumulation in biological samples. The mean log Bioaccumulation Factors (BAFs) varied from 0.91 to 2.96, which implies that most PAE congeners are not likely to accumulate in organisms. No obvious trends were observed between log octanol-water partition coefficient (KOW) and log BAF values, nor between log octanol-air partition coefficient (KOW) and biota-air accumulation factors (BAAFs). Nevertheless, the calculated log air-water partitioning factors (AWPFs) of diethyl phthalate (DEP), dimethyl phthalate (DMP), and butyl benzyl phthalate (BBP) were similar to predicted values whereas those for diisobutyl phthalate (DIBP), DNBP and DEHP were significantly higher. The estimated daily intakes of PAEs via food ingestion and environmental exposure were 15, 9.4 and 1.2 ng/kg-bw/day in toddlers, children and adults, respectively, laying at the low end of the reported data and well below the reference dose.

Organophosphate esters in biota, water, and air from an agricultural area of Chongqing, western China: Concentrations, composition profiles, partition and human exposure.

We measured the concentrations of organophosphate esters (OPEs) in some biotic samples which can serve as human foodstuffs and ambient environments including air and river water from an agricultural area of Chongqing, western China. Fish samples exhibited highest OPEs levels (960 ng/g lipid weight) among the biota, followed by chicken (676 ng/g lw), cattle (545 ng/g lw) and pigs (535 ng/g lw). Tributyl phosphate (TNBP), tris (2-methylpropyl) (TIBP) and chlorinated OPEs were the major analogs in biotic samples, which appeared similar with the patterns from river water and outdoor air, but apparently different from indoor air. To further investigate the influence of ambient environment on the distribution of OPEs in biota, we analyzed the correlation between OPEs concentrations in ambient environment and biological samples, and the results revealed that most of the samples (except for pig samples) heavily correlated with outdoor air, whereas only fish and cattle samples were strongly correlated with river water. The partitioning behaviors of OPEs among biota, air and river water were also studied through calculating the biota-water accumulation factors (BWAFs), biota-air accumulation factors (BAAFs) and air-water partitioning factor (AWPFs). Significantly linear correlations (P < 0.05) were observed between log (BWAFs) and log (KOW) values, and between log (AWPFs) and log H (Henry's law constants), nevertheless log (BAAFs) was increasing along with the log (KOA) values. The daily intake (DI) values were estimated via foodstuffs ingestion and environmental exposure. The estimated DI values of OPEs from food and ambient environments were 1.78 ng/kg-bw/day, 1.23 ng/kg-bw/day and 1.42 ng/kg-bw/day in toddlers, children and adults, respectively, which lay at the low end of the reported data and well below the reference dose (RfD).

[Occurrence and Distribution of Phthalate Esters in Urban Soils of Chongqing City].

In total, 66 soil samples were collected from five different urban functional areas in Chongqing, and the concentration levels of phthalate esters (PAEs) were analyzed using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Meanwhile, the composition and characteristics of PAEs were discussed, along with their possible sources, through correlation analysis and principal component analysis. The results showed that the concentrations of ∑PAEs ranged from 93.1-312 ng·g-1 dry weight, which is at the low end of the worldwide figure. DEHP, DBP, and DIBP were the dominant compounds, contributing 87.4%-92.9% of the total ∑PAEs. DEHP was the most abundant PAE congener, responsible for 52.4% of the total ∑PAEs. Through correlation analysis, it was noted that PAEs with similar molecular weight were more likely to show a significant relationship with each other, which suggested that these PAEs may share a similar source. According to the principal component analysis, DBP, DIBP, and DEHP had a similar source, while BBP and DnOP strongly correlated with each other. Compared to other studies, relatively low PAE concentrations were apparently observed in this study, but the potential human risk via exposure to these compounds should also been considered.

Occurrence of tetrabromobisphenol a (TBBPA) and hexabromocyclododecane (HBCD) in soil and road dust in Chongqing, western China, with emphasis on diastereoisomer profiles, particle size distribution, and human exposure.

Currently, the HBCDs were listed in Annex A by the Stockholm Convention, and the knowledge on the contamination of TBBPA and HBCDs in soil and road dust in China is still limited, and it is unclear what role is played by dust particle size distribution. In this study, a total of 81 soil and 43 road dust samples were analyzed with TBBPA and ΣHBCDs concentrations ranging from < LOQ to 33.8 ng/g dw (dry weight) and 0.43-15.2 ng/g dw in soil, and from < LOQ to 74.1 ng/g dw and 7.25-14.0 ng/g dw in road dust, respectively. TBBPA and HBCDs exhibited different spatial distribution patterns in soil, where relatively high levels of HBCDs were found in industrial area and commercial area, while high levels of TBBPA were detceted in residential area. However, no distinct variation in spatial distribution of these two compounds was observed in road dust. Different diastereoisomer profiles of HBCDs were also found with γ-HBCD predominating in soil and α-HBCD occupying a large proportion in road dust. The α-/γ-HBCD values in road dust were significantly greater (T-test, P < 0.05) than those in soil, which suggested that γ-HBCD in road dust were likely to transform into α-HBCD compared with soil. The distribution of dust particle size showed that HBCDs levels were increasing with the decreasing in particle sizes, while the TBBPA showed some "accidental" peak values in specific diameter ranges. The estimated daily intakes (EDIs) of TBBPA and HBCDs were assessed through dust ingestion, dermal absorption and inhalation via road dust, and all the exposure estimates were well below the reference dose (RfD), but the toddlers were more vulnerable to TBBPA and HBCDs intakes, which should be paid more attention.

Organophosphate esters and phthalate esters in human hair from rural and urban areas, Chongqing, China: Concentrations, composition profiles and sources in comparison to street dust.

Human hair and street dust from rural and urban areas in Chongqing were collected to analyze Organophosphate esters (OPEs) and phthalate esters (PAEs). Concentrations of OPEs in urban hair were significantly higher than those in rural hair, whereas PAEs concentrations in rural hair were significantly higher than those in urban hair. Different composition patterns of OPEs were observed in rural and urban hair, where tris (2-chloroisopropyl) phosphate (TCIPP), tris (butyl) phosphate (TNBP) and triphenyl phosphate (TPHP) were the dominating analogues in rural hair, accounting for 62.1% of the OPEs burden, and tris (methylphenyl) phosphate (TMPP) exhibited a high contribution in urban hair, responsible for 51.3% of total OPEs, which differed from the composition profiles in corresponding street dust. Analogous composition patterns of PAEs were found in hair of both areas. Di-(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DNBP), diisobutyl phthalate (DIBP) and diethyl phthalate (DEP) were the most abundant analogues in hair samples, while DEHP was the predominant analogue in dust samples. No clear tendency was obtained between the increasing ages and the concentrations of both compounds. Most OPEs and PAEs congeners showed significantly positive correlation with one another in rural hair. On the contrary, different correlation patterns were observed in urban hair for OPEs and PAEs, indicating multiple or additional sources existed in urban areas. Significant correlations of OPEs and PAEs were found between hair and corresponding street dust samples, but poor correlations of OPEs and PAEs were observed between rural hair and rural indoor dust, suggesting that street dust may be a predominant exogenous source for human exposure to OPEs and PAEs in this area.

[Occurrence and Distribution of the Organophosphate Esters in Soils of Mixed-land Use Area in Chongqing City].

Organophosphate esters (OPEs) in surface soil of four different functional areas in Chongqing were identified and quantified using ultra-high performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-Q-TOF-MS). The composition and characteristics of OPEs were discussed along with the relationships between soil organic matter (SOM) and OPEs through correlation analysis, and possible sources of OPEs were simultaneously investigated through principal component analysis (PCA). The results showed that the concentrations of ∑OPEs ranged from 10.7 to 108 ng·g-1 dry weight, with a mean concentration of 46.4 ng·g-1, which was at the low-level end of the global figure. The average concentration was 55.6 ng·g-1 in the industrial area, 55.5 ng·g-1 in the residential area, 41.8 ng·g-1 in the commercial area, and 34.1 ng·g-1 in the city park. Tris (1-chloro-2-propyl) phosphate (TCPP) and 2-ethylhexyl diphenyl phosphate (EHDPP) were dominant compounds, contributing up to 31.5% in the industrial area for TCPP and 23.4% and 24.7% in the commercial area and city park, respectively, for EHDPP. Significant relationships between concentrations of SOM and ∑OPEs (P<0.05) and tricresyl phosphate (TCP) (P<0.01), respectively, indicated that SOM was a factor affecting the concentration and distribution of the OPEs. The PCA suggested that there were multiple sources of OPEs in urban soil. Sewage irrigation, road runoff, indoor source pollution, and sludge reuse could be potential sources of soil OPEs.

Intraoperative Multi-Information-Guided Resection of Dominant-Sided Insular Gliomas in a 3-T Intraoperative Magnetic Resonance Imaging Integrated Neurosurgical Suite.

OBJECTIVE: To evaluate the clinical application of 3-T intraoperative magnetic resonance imaging (iMRI), awake craniotomy, multimodal functional mapping, and intraoperative neurophysiologic monitoring (IONM) for resection of dominant-sided insular gliomas. METHODS: From March 2011 to June 2013, 30 gliomas involving the dominant insular lobe were resected in the IMRIS 3.0-T iMRI integrated neurosurgical suite. For 20 patients, awake craniotomy with cortical electrical stimulation mapping was performed to locate the language areas. For 10 patients who were not suitable for awake surgery, general anesthesia and functional navigation were performed. Diffusion tensor imaging tractography-based navigation, continuous motor evoked potential monitoring, and subcortical electrical stimulation mapping were applied to localize and monitor the motor pathway in all cases. iMRI was used to assess the extent of resection. The results of intraoperative imaging, IONM, and the surgical consequences were analyzed. RESULTS: Intraoperative imaging revealed residual tumor in 26 cases and led to further resection in 9 cases. As a result, the median extent of resection was increased from 90% to 93% (P = 0.008) in all cases, and from 88% to 92% (P = 0.018) in low-grade gliomas. The use of iMRI also resulted in an increase in the percentage of gross and near total resection from 53% to 77% (P = 0.016). The rates of permanent language and motor deficits resulting from tumor removal were 11% and 7.1%, respectively. CONCLUSIONS: The combination of iMRI, awake craniotomy, multimodal brain mapping, and IONM tailored for each patient permits the maximal safe resection of dominant-sided insular glioma.

[Efficacy of combination antiviral therapy following childbirth in pregnant HBV carriers receiving telbivudine for prevention of mother-to-child transmission].

OBJECTIVE: To observe the clinical efficacy of combination therapy with peg-IFNalpha and adefovir (CPIA) in women who were hepatfis B virus (HBV) carriers and had just given birth and received telbivudine (LdT) during pregnancy for prevention of mother-to-child transmission. METHODS: One-hundred-and-fifty third trimester-pregnant women who were HBV carriers with highly-viremic were treated with LdT until time of birth. After delivery, those women with alanine aminotransferase (ALT) level exceeding two times the upper limit of normal and HBV DNA level that had decreased more than 31 gIU/mL or hepatitis B e antigen (HBeAg) titer that had decreased more than 50% were switched to CPIA for 96 weeks. RESULTS: Following delivery, 45 of the women were switched to the CPIA treatment, of which 91.1% (41/45) achieved virological response, 55.6% (25/45) achieved HBeAg clearance or seroconversion, and 26.7% (12/45) achieved hepatitis B surface antigen (HBsAg) clearance or seroconversion.The immediate post-delivery (and pre-CPIA) levels of HBeAg and HBV DNA were negatively associated with HBeAg clearance. Ninety-eight of the total study participants stopped the LdT treatment and there were no cases of significant deterioration of liver function. CONCLUSION: Pregnant women who are HBV carriers and receive LdT for protection against mother-to-child transmission, and who show significant ALT elevation and decreased HBeAg titer and/or reduced HBV DNA after delivery, may be good candidates for the CPIA therapy following delivery.