Zn-Doped MnCO3/CS Composite Photocatalyst for Visible-Light-Driven Decomposition of Organic Pollutants.

Zn-doped MnCO3/carbon sphere (Zn-doped MnCO3/CS) composites were synthesized using a simple hydrothermal procedure. Among various samples (ZM-50, ZM-05, and ZMC-0), the ternary Zn-doped MnCO3/CS (ZMC-2) catalyst demonstrated excellent visible light-induced photocatalytic activity. This improvement comes from the Zn addition and the conductive CS, which facilitate electron movement and charge transport. The catalyst exhibited efficient degradation of methylene blue (MB) over a wide pH range, achieving a removal efficiency of 99.6% under visible light. Radical trapping experiments suggested that •OH and •O2- played essential roles in the mechanism of organic pollutant degradation. Moreover, the catalyst maintained good degradation performance after five cycles. This study offers valuable perspectives into the fabrication of carbon-based composites with promising photocatalytic activity.

Development and application of a multi-task oriented deep learning model for quantifying drivers of air pollutant variations: A case study in Taiyuan, China.

Quantitative assessment of the drivers behind the variation of six criteria pollutants, namely fine particulate matter (PM2.5), ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), particulate matter (PM10), and carbon monoxide (CO), in the warming climate will be critical for subsequent decision-making. Here, a novel hybrid model of multi-task oriented CNN-BiLSTM-Attention was proposed and performed in Taiyuan during 2015-2020 to synchronously and quickly quantify the impact of anthropogenic and meteorological factors on the six criteria pollutants variations. Empirical results revealed the residential and transportation sectors distinctly decreased SO2 by 25 % and 22 % and CO by 12 % and 10 %. Gradual downward trends for PM2.5, PM10, and NO2 were mainly ascribed to the stringent measures implemented in transportation and power sectors as part of the Blue Sky Defense War, which were further reinforced by the COVID-19 pandemic. Nevertheless, temperature-dependent adverse meteorological effects (27 %) and anthropogenic intervention (12 %) jointly increased O3 by 39 %. The O3-driven pollution events may be inevitable or even become more prominent under climate warming. The industrial (5 %) and transportation sectors (6 %) were mainly responsible for the anthropogenic-driven increase of O3 and precursor NO2, respectively. Synergistic reduction of precursors (VOCs and NOx) from industrial and transportation sectors requires coordination with climate actions to mitigate the temperature-dependent O3-driven pollution, thereby improving regional air quality. Meanwhile, the proposed model is expected to be applied flexibly in various regions to quantify the drivers of the pollutant variations in a warming climate, with the potential to offer valuable insights for improving regional air quality in near future.

Characteristics of metabolic inflammatory syndrome among inpatients with type 2 diabetes: A cross-sectional study in China.

BACKGROUND: As meta-inflammation is a common feature for obesity, type 2 diabetes (T2D), nonalcoholic fatty liver disease and atherosclerosis, we have proposed a new concept, metabolic inflammatory syndrome (MIS), to cluster such diseases. We aimed to characterize MIS and explore its association with coronary heart disease (CHD) among T2D inpatients in China. METHODS: A total number of 8344 T2D participants were enrolled. Each component of MIS and metabolic syndrome (MS) was analyzed. Their association with the risk of CHD was assessed using a binary logistic analysis. RESULTS: Among the T2D inpatients, the detection rate of MIS was much higher than that of MS (93.6 % vs. 53.2 %). Among all the components of MIS and MS, carotid atherosclerosis (71.9 %) was most commonly detected, which increased with aging in subgroups. Surprisingly, the most common combination of MIS was with all 4 components in T2D patients, with a constituent ratio of 30.9 %. According to the odds ratios (ORs), MIS was a better predictor of CHD than MS, especially after adjustment for age, sex, smoking, and alcohol consumption (adjusted OR for MIS: 3.083; for MS: 1.515). The presence of more components of MIS was associated with a higher detection rate of CHD (P < 0.001). Among all the components of MIS and MS, carotid atherosclerosis best predicted the risk of CHD (adjusted OR: 1.787). CONCLUSIONS: MIS is an independent risk factor for CHD, with a bigger OR value than MS. Carotid atherosclerosis, with the highest detection rate, was the best individual predictor of CHD and thus a critical component of MIS. The concept of MIS represents the understanding of metabolic diseases from the perspective of holistic integrative medicine.

Unraveling the Impact of Cerebellar Stimulation on Attentional Performance: A Behavioral Study.

Attentional processes play a crucial role in our ability to perceive and respond to relevant stimuli. The cerebellum, traditionally associated with motor control, has recently garnered attention as a potential contributor to attention modulation. This study aimed to investigate the effects of cerebellar intermittent theta-burst stimulation (iTBS) on attentional performance using three behavioral tasks: dot counting, target selection, and multi-tasking. Seventeen healthy participants underwent either real or sham iTBS stimulation over seven days, and their performance on the tasks was assessed. Results revealed that dot counting performance did not significantly differ between the real and sham stimulation groups. However, notable improvements were observed over time, suggesting a learning effect. In contrast, significant effects of iTBS stimulation were found in the target selection task, with participants receiving real stimulation demonstrating enhanced discrimination between targets and distractors. Additionally, the multi-tasking task exhibited significant main effects of both iTBS stimulation and time, indicating improved performance with stimulation and progressive enhancements over the study period. These findings highlight the potential of cerebellar iTBS stimulation to enhance attentional performance in specific task domains. The significant effects observed in the target selection and multi-tasking tasks provide promising evidence for the modulatory role of the cerebellum in attention. Further investigations into the underlying mechanisms and optimal stimulation parameters are warranted to refine our understanding of how cerebellar iTBS stimulation influences attentional processes.

Combination of ultra-micro angiography and sound touch elastography for diagnosis of primary Sjögren's syndrome: a diagnostic test.

Background: Primary Sjogren's syndrome (PSS) is a prevalent systemic autoimmune disease. However, the current gold standard diagnostic method is invasive, increasing the difficulty of patient acceptance and then delaying treatment. Therefore, a non-invasive, convenient, and effective diagnostic method is required. Although salivary gland ultrasonography (SGUS) is a good choice, previous studies have not found suitable parameters to diagnose PSS. Salivary gland involvement in patients with PSS leads to changes in gland stiffness and vascularization, so we combined sound touch elastography (STE) and ultra-microangiography (UMA) to demonstrate the diagnostic effectiveness of ultrasonography in PSS. Methods: This prospective study included 27 patients with PSS and 20 healthy controls, with all participants forming a random series. Major salivary glands were examined with UMA and STE. Color pixel percentage (CPP), shear wave velocity (SWV), and Young's modulus values were investigated, and the combination of these parameters was evaluated by logistic regression analysis. Results: For Young's modulus and SWV in the elasticity index, combined evaluation of both parotid glands and submandibular glands yielded an area under the receiver operating characteristic (ROC) curve (AUC) and confidence interval (CI) of 0.819, 0.699-0.938 and 0.801, 0.677-0.925, respectively. The levels of CPP in the parotid glands were significantly elevated (P<0.003) among patients compared to those in the control group, whereas the CPP values in the submandibular glands were not statistically different (P>0.086). We evaluated the elasticity values of the total 4 glands and the CPP of parotid glands together by logistic regression modeling. The ROC curve yielded an AUC of 0.954 (95% CI: specificity 0.849-0.994) which showed the best accuracy, with 92.6% sensitivity and 85.0% specificity. Conclusions: The use of STE and UMA to examine the salivary glands may aid in the diagnosis of PSS, and their combination may be a promising method. This is good news for patients with PSS who are not suitable or unwilling to undergo labial gland biopsy.

Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation.

Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24-dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti-inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3-Leiden. CETP mice, a well-established translational model that develops diet-induced human-like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRα deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet-induced hepatic steatosis and inflammation in a strictly LXRα-dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH.

Perinatal exposure to UDCA prevents neonatal cholestasis in Cyp2c70-/- mice with human-like bile acids.

BACKGROUND: Cyp2c70-/- mice with a human-like bile acid (BA) composition display features of neonatal cholestasis. We assessed whether perinatal ursodeoxycholic acid (UDCA) exposure prevents neonatal cholestasis in Cyp2c70-/- mice and reduces cholangiopathy development later in life. METHODS: Cyp2c70+/- males were crossed with Cyp2c70+/- females fed either a regular chow diet or a 0.1% UDCA-containing diet during breeding, gestation, and suckling. Cholestasis and liver function parameters were assessed in their Cyp2c70-/- and wild-type offspring at 3 and 8 weeks of age. RESULTS: Three-week-old Cyp2c70-/- pups showed features of neonatal cholestasis, including elevated plasma BAs and transaminases, which were completely prevented in Cyp2c70-/- pups upon perinatal UDCA exposure. In addition, UDCA administration to the dams corrected altered hepatic gene expression patterns in Cyp2c70-/- pups, reduced markers of fibrogenesis and inflammation, and prevented cholangiocyte proliferation. Yet, these beneficial effects of perinatal UDCA exposure were not retained into adulthood upon discontinuation of treatment. CONCLUSION: Perinatal exposure of Cyp2c70-/- mice to UDCA has beneficial effects on liver function parameters, supporting a direct role of BA hydrophobicity in the development of neonatal cholestasis in these mice. However, prevention of neonatal cholestasis in Cyp2c70-/- mice has no long-lasting effects on liver pathophysiology. IMPACT: This is the first study showing that perinatal UDCA exposure prevents features of neonatal cholestasis that are observed in mice with a human-like bile acid composition, i.e., Cyp2c70-/- mice. Perinatal UDCA exposure of Cyp2c70-/- pups leads to UDCA enrichment in their circulating bile acid pool and, consequently, to a reduced hydrophobicity of biliary bile acids. Perinatal UDCA exposure of Cyp2c70-/- pups has no long-lasting effects on the development of cholangiopathy after discontinuation of treatment. The results in this study expand current knowledge regarding acute and long-lasting effects of UDCA treatment in early life.

A Method for the Study of Cerebellar Cognitive Function-Re-Cognition and Validation of Error-Related Potentials.

The cerebellar region has four times as many brain cells as the brain, but whether the cerebellum functions in cognition, and how it does so, remain unexplored. In order to verify whether the cerebellum is involved in cognition, we chose to investigate whether the cerebellum is involved in the process of error judgment. We designed an experiment in which we could activate the subject's error-related potentials (ErrP). We recruited 26 subjects and asked them to wear EEG caps with cerebellar regions designed by us to participate in the experiment so that we could record their EEG activity throughout the experiment. We successfully mitigated the majority of noise interference after a series of pre-processing of the data collected from each subject. Our analysis of the preprocessed data revealed that our experiment successfully activated ErrP, and that the EEG signals, including the cerebellum, were significantly different when subjects made errors compared to when they made correct judgments. We designed a feature extraction method that requires selecting channels with large differences under different classifications, firstly by extracting the time-frequency features of these channels, and then screening these features with sequence backward feature (SBS) selection. We use the extracted features as the input and different event types in EEG data as the labels for multiple classifiers to classify the data in the executive and feedback segments, where the average accuracy for two-class classification of executive segments can reach 80.5%. The major contribution of our study is the discovery of the presence of ErrP in cerebellar regions and the extraction of an effective feature extraction method for EEG data.

A novel naturally Phe206Tyr mutation confers tolerance to ALS-inhibiting herbicides in Alopecurus myosuroides.

Herbicide-resistant weeds pose a serious threat to world food production. The rapid and widespread development of target-site based resistance limits the application of herbicides. Alopecurus myosuroides Huds. (blackgrass) has spread rapidly in winter wheat regions in China, and the field recommended dose of ALS herbicides no longer controls blackgrass populations in recent years. A highly resistant population TW18(R) was collected in 2018 from Shandong Province. Dose-response assays showed that the TW18 was resistant to mesosulfuron-methyl, flucarbazone-sodium, and imazethapyr, with resistance index values of 5.96, 6.1, and 4.09, respectively. DNA sequencing of the TW18 population revealed a Phe206Tyr (F206Y) mutation in the ALS, which was not yet reported. Blackgrass ALS gene with the F206Y mutation (R gene) was expressed in Arabidopsis and rice. Transgenic studies have shown that both Arabidopsis and rice expressing this R gene have resistance to imazethapyr. However, it did not confer resistance to tribenuron methyl and florasulam in transgenic Arabidopsis. This study showed that the F206Y substitution caused herbicide resistance in blackgrass. To our knowledge, this is the first-reported F206Y mutation of a weed species in the natural environment. Transgenic plants showed this functional site could be utilized to generate imazethapyr-resistant rice to control herbicide-resistant weed damage.

Short-term obeticholic acid treatment does not impact cholangiopathy in Cyp2c70-deficient mice with a human-like bile acid composition.

Cyp2c70-/- mice with a human-like bile acid (BA) composition, lacking hydrophilic muricholic acids (MCAs), have been reported to display cholangiopathy and biliary fibrosis with female preponderance that can be reversed by ursodeoxycholic acid (UDCA). Obeticholic acid (OCA), a steroidal BA-like FXR agonist, has been shown to improve liver function in patients with primary biliary cholangitis and is approved as second-line treatment for patients with an inadequate response or intolerance to UDCA. Here, we investigated the impact of OCA on BA hydrophobicity and cholangiopathy in Cyp2c70-/- mice. Male and female wild-type (WT) and Cyp2c70-/- mice were fed a chow diet with or without 10 mg/kg/day OCA for 4 weeks. OCA accounted for 1-5% of biliary BAs, with larger enrichments in Cyp2c70-/- than in WT mice. In WT mice, OCA induced a more hydrophilic, MCA-rich BA pool. In Cyp2c70-/- mice, however, BA pool became more hydrophobic with a larger proportion of chenodeoxycholic acid, attributable to a reduction of BA 12α-hydroxylation. OCA treatment reduced fecal BA excretion, indicating repression of hepatic BA synthesis in both WT and Cyp2c70-/- mice. OCA did, however, not impact on markers of liver (dys)function in plasma nor did it ameliorate cholangiopathy and fibrosis in male or female Cyp2c70-/- mice. OCA treatment also did not affect the expression of genes involved in fibrosis, inflammation and cellular senescence. In conclusion, 4 weeks of OCA treatment oppositely modulates the hydrophobicity of the BA pool in WT and Cyp2c70-/- mice, but does not improve or worsen the characteristic sex-dependent liver pathology in Cyp2c70-/- mice.

Correlation of common inflammatory cytokines with cognition impairment, anxiety, and depression in acute ischemic stroke patients.

Inflammatory cytokines are related to cognitive function and psychiatric disorders in patients with several diseases. However, few relevant studies have been performed on acute ischemic stroke (AIS) patients. Hence, this study aimed to investigate the correlation of common inflammatory cytokines with cognition impairment, anxiety, and depression in AIS patients. Common inflammatory cytokines of 176 AIS patients (including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, IL-6, and IL-17) were measured using Human Enzyme Linked Immunosorbent Assay Kits. Cognition impairment (Mini-Mental State Examination (MMSE)), anxiety (Hospital Anxiety and Depression Scale for anxiety (HADS-A)), and depression (HADS-D) were evaluated. The incidence of cognition impairment, anxiety, and depression was 43.2, 39.2, and 31.2%, respectively. TNF-α and IL-6 were negatively associated with MMSE score, and high TNF-α, IL-1ß, and IL-6 were correlated with cognition impairment occurrence. In addition, TNF-α, IL-1ß, and IL-17 were positively associated with HADS-A score, while only high TNF-α was associated with anxiety occurrence. Furthermore, TNF-α, IL-1ß, and IL-17 were positively associated with HADS-D score, while high IL-1ß, IL-6, and IL-17 correlated with depression occurrence. Multivariate logistic regression revealed that TNF-α and National Institutes of Health Stroke Scale (NIHSS) score ≥5 were associated with high risk of cognition impairment; TNF-α, IL-17, unemployed before surgery, hypertension, and chronic kidney disease (CKD) correlated with high anxiety occurrence. Furthermore, IL-17, divorced/widowed/single status, diabetes, and NIHSS score ≥5 were associated with high risk of depression. In conclusion, common inflammatory cytokines including TNF-α, IL-1ß, and IL-17 were related to cognition impairment, anxiety, or depression in AIS patients.

Correlation of common inflammatory cytokines with cognition impairment, anxiety, and depression in acute ischemic stroke patients

Abstract Inflammatory cytokines are related to cognitive function and psychiatric disorders in patients with several diseases. However, few relevant studies have been performed on acute ischemic stroke (AIS) patients. Hence, this study aimed to investigate the correlation of common inflammatory cytokines with cognition impairment, anxiety, and depression in AIS patients. Common inflammatory cytokines of 176 AIS patients (including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, and IL-17) were measured using Human Enzyme Linked Immunosorbent Assay Kits. Cognition impairment (Mini-Mental State Examination (MMSE)), anxiety (Hospital Anxiety and Depression Scale for anxiety (HADS-A)), and depression (HADS-D) were evaluated. The incidence of cognition impairment, anxiety, and depression was 43.2, 39.2, and 31.2%, respectively. TNF-α and IL-6 were negatively associated with MMSE score, and high TNF-α, IL-1β, and IL-6 were correlated with cognition impairment occurrence. In addition, TNF-α, IL-1β, and IL-17 were positively associated with HADS-A score, while only high TNF-α was associated with anxiety occurrence. Furthermore, TNF-α, IL-1β, and IL-17 were positively associated with HADS-D score, while high IL-1β, IL-6, and IL-17 correlated with depression occurrence. Multivariate logistic regression revealed that TNF-α and National Institutes of Health Stroke Scale (NIHSS) score ≥5 were associated with high risk of cognition impairment; TNF-α, IL-17, unemployed before surgery, hypertension, and chronic kidney disease (CKD) correlated with high anxiety occurrence. Furthermore, IL-17, divorced/widowed/single status, diabetes, and NIHSS score ≥5 were associated with high risk of depression. In conclusion, common inflammatory cytokines including TNF-α, IL-1β, and IL-17 were related to cognition impairment, anxiety, or depression in AIS patients.

Low production of 12α-hydroxylated bile acids prevents hepatic steatosis in Cyp2c70-/- mice by reducing fat absorption.

Bile acids (BAs) play important roles in lipid homeostasis, and BA signaling pathways serve as therapeutic targets for nonalcoholic fatty liver disease (NAFLD). Recently, we generated cytochrome P450, family 2, subfamily C, polypeptide 70 (Cyp2c70-/-) mice with a human-like BA composition lacking mouse-/rat-specific muricholic acids to accelerate translation from mice to humans. We employed this model to assess the consequences of a human-like BA pool on diet-induced obesity and NAFLD development. Male and female Cyp2c70-/- mice and WT littermates were challenged with a 12-week high-fat Western-type diet (WTD) supplemented with 0.25% cholesterol. Cyp2c70 deficiency induced a hydrophobic BA pool with high abundances of chenodeoxycholic acid, particularly in females, because of sex-dependent suppression of sterol 12α-hydroxylase (Cyp8b1). Plasma transaminases were elevated, and hepatic fibrosis was present in Cyp2c70-/- mice, especially in females. Surprisingly, female Cyp2c70-/- mice were resistant to WTD-induced obesity and hepatic steatosis, whereas male Cyp2c70-/- mice showed similar adiposity and moderately reduced steatosis compared with WT controls. Both intestinal cholesterol and FA absorption were reduced in Cyp2c70-/- mice, the latter more strongly in females, despite unaffected biliary BA secretion rates. Intriguingly, the biliary ratio 12α-/non-12α-hydroxylated BAs significantly correlated with FA absorption and hepatic triglyceride content as well as with specific changes in gut microbiome composition. The hydrophobic human-like BA pool in Cyp2c70-/- mice prevents WTD-induced obesity in female mice and NAFLD development in both genders, primarily because of impaired intestinal fat absorption. Our data point to a key role for 12α-hydroxylated BAs in control of intestinal fat absorption and modulation of gut microbiome composition.

Role of ammonia in secondary inorganic aerosols formation at an ammonia-rich city in winter in north China: A comparative study among industry, urban, and rural sites.

Ammonia is essential for the generation of secondary inorganic aerosols (SIA) in particulate matter, which affects severely the air quality in north China. In this study, PM2.5 sampling was conducted as well as gaseous pollutant concentration and meteorological parameters were measured from November 2017 to January 2018. PM2.5 concentration was highest in the industrial site (94.8 ± 41.7 µg m-3), followed by urban (40.9 ± 24.1 µg m-3) and rural (35.6 ± 20.3 µg m-3) sites. The mass ratio of NO3-/SO42- exhibited clear site variations, with the highest average value of 1.2 was found at the urban site, likely due to the dense traffic volume resulting in higher emissions of NO2, and the lowest value of 0.9 at the industry site. The presence of Excess-NHx (E-NHx), raising the pH 24 by 1.4, 1.3, and 1.4 units in industry, urban, and rural sites, respectively, might be vital for raising the aerosol pH. Correlation coefficients of Nitrogen oxidation rate (NOR, NOR = [NO3-]/[NO3-] + [NO2]) vs. Photochemical oxidants (Ox, NO2 +O3 in our study) and NOR vs. aerosol water content (AWC) at three sites were implied that both homogeneous and heterogeneous reactions occurred for nitrate formation in industry site, while heterogeneous reactions were dominant in urban and rural sites. Oxidation rates were most sensitive to the variation of E-NHx concentration at rural site, followed by the urban and industry sites, which was shown by the fact that the increase in E-NHx concentration by 1.0 µg m-3 increased the SIA concentration by 1.21, 1.02, and 0.37 µg m-3 at rural, urban, and industry sites, respectively. With the increase in NHx emissions at present, the role of NHx in SIA formation at ammonia-rich atmosphere requires more attention, especially in the less-noticed rural areas.

CNN1 regulates the DKK1/Wnt/ß-catenin/c-myc signaling pathway by activating TIMP2 to inhibit the invasion, migration and EMT of lung squamous cell carcinoma cells.

The present study aimed to investigate the effect of calponin 1 (CNN1) on the invasion and migration of lung squamous cell carcinoma (LUSC) cells and the associations between CNN1, tissue inhibitor of metalloproteinases 2 (TIMP2), Dickkopf-1 (DKK1) and the Wnt/ß-catenin/c-myc signaling pathway. The expression levels of CNN1 and TIMP2 in LUSC cells and the association between CNN1 and TIMP2 were predicted using the GEPIA database. The cells were transiently transfected to overexpress CNN1, which resulted in inhibition of DKK1 and TIMP2 expression levels. Wound healing and Transwell assays were used to detect the invasive and migratory abilities of LUSC cells. Reverse transcription-quantitative PCR and western blotting were used to investigate the expression levels of CNN1, MMP2, MMP9, E-cadherin, N-cadherin (N-cad), SLUG, DKK1, ß-catenin and c-myc. The expression levels of N-cad were detected using immunofluorescence staining. The results indicated that overexpression of CNN1 inhibited the invasion and migration of NCI-H2170 cells. Inhibition of DKK1 reversed this change and the expression levels of ß-catenin and c-myc were upregulated, whereas the expression levels of DKK1 were downregulated with a concomitant inhibition of TIMP2. In summary, these results demonstrated that CNN1 regulated the DKK1/Wnt/ß-catenin/c-myc signaling pathway by activating TIMP2 to inhibit the invasion, migration and epithelial-to-mesenchymal transition of LUSC cells.

PS-341 alleviates chronic low-grade inflammation and improves insulin sensitivity through the inhibition of TM4 (UBAC2) degradation.

BACKGROUND: The TM4 (UBAC2) protein, which contains 4 transmembrane domains and one ubiquitin binding domain, is mainly expressed in cell and nuclear membranes. The current research aimed to explore the role of TM4 in metabolic inflammation and to examine whether the ubiquitin-proteasome inhibitor PS-341 could regulate the function of TM4. METHODS: The metabolic phenotypes of TM4 knockout (KO) mice were studied. We next explored the association between the polymorphisms of TM4 and obesity in a Chinese Han population. TM4 expression in the visceral fat of obese patients who underwent laparoscopic cholecystectomy was also analysed. Finally, the effect of PS-341 on the degradation and function of the TM4 protein was investigated in vivo and in vitro. RESULTS: TM4 KO mice developed obesity, hepatosteatosis, hypertension, and glucose intolerance under a high-fat diet. TM4 counterregulated Nur77, IKKß, and NF-kB both in vivo and in vitro. The TM4 SNP rs147851454 is significantly associated with obesity after adjusting for age and sex (OR 1.606, 95% CI 1.065-2.422 P = 0.023) in 3394 non-diabetic and 1862 type 2 diabetic adults of Han Chinese. TM4 was significantly downregulated in the visceral fat of obese patients. PS-341 induced TM4 expression through inhibition of TM4 degradation in vitro. In db/db mice, PS-341 administration led to downregulation of Nur77/IKKß/NF-κB expression in visceral fat and liver, and alleviation of hyperglycaemia, hypertension, and glucose intolerance. The hyperinsulinaemic-euglycaemic clamp demonstrated that PS-341 improved the glucose infusion rate and alleviated insulin resistance in db/db mice. CONCLUSIONS: PS-341 alleviates chronic low-grade inflammation and improves insulin sensitivity through inhibition of TM4 degradation.

Liver fibrosis is independently associated with diabetic peripheral neuropathy in type 2 diabetes mellitus.

AIMS/INTRODUCTION: Non-alcoholic fatty liver disease and type 2 diabetes mellitus are closely related, and often occur simultaneously in patients. Type 2 diabetes increases the risk of diabetic peripheral neuropathy, resulting in intolerable pain and extremity amputation that reduces the quality of life. However, the role of non-alcoholic fatty liver disease in the pathogenesis of diabetic peripheral neuropathy remains unclear. Thus, we evaluated the correlation of liver fibrosis and steatosis, which are representative histological morphologies of non-alcoholic fatty liver disease, with diabetic peripheral neuropathy in type 2 diabetes patients. MATERIALS AND METHODS: Five hundred twenty individuals with type 2 diabetes were recruited. All the patients were detected nerve conduction study for diabetic peripheral neuropathy and fibro touch for liver steatosis and fibrosis. Correlation of DPN with liver steatosis and fibrosis were analysed with binary logistic analysis. RESULTS: Among the 520 patients, the prevalence of liver steatosis, fibrosis and diabetic peripheral neuropathy was 63.0% (n = 328), 18.1% (n = 94) and 52.1% (n = 271), respectively. The prevalence of diabetic peripheral neuropathy was significantly elevated in patients with liver steatosis (55.7 vs 44.9%, P = 0.03) and fibrosis (61.5 vs 50%, P = 0.04), and it increased as liver stiffness measurement increased. Additionally, both hepatic steatosis (odds ratio 1.48, 95% confidence interval 1.04-2.11, P = 0.03) and fibrosis (odds ratio 1.60, 95% confidence interval 1.02-2.51, P = 0.04) were correlated with diabetic peripheral neuropathy. After adjusting for age, sex, weight, height, body mass index, waist hip ratio, duration of type 2 diabetes, blood glucose, homeostatic model assessment of insulin resistance, blood pressure, serum lipid, liver enzyme, urea, uric acid, creatinine and inflammatory factors, liver fibrosis remained associated with diabetic peripheral neuropathy (odds ratio 2.24, 95% confidence interval 1.11-4.53, P = 0.02). CONCLUSIONS: The prevalence of diabetic peripheral neuropathy was elevated in patients with liver steatosis and fibrosis. Liver fibrosis was also independently associated with an increased risk of diabetic peripheral neuropathy.

Gut microbiome and bile acids in obesity-related diseases.

Dysbiosis has been implemented in the etiologies of obesity-related chronic diseases such as type 2 diabetes, NAFLD and cardiovascular diseases. Bile acids, a class of amphipathic steroids produced in the liver and extensively modified by the microbiome, are increasingly recognized as actors in onset and progression of these diseases. Indeed, human obesity is associated with altered bile acid metabolism. Bile acids facilitate intestinal fat absorption but also exert hormone-like functions through activation of nuclear and membrane-bound receptors and thereby modulate glucose, lipid and energy metabolism, intestinal integrity and immunity. Bile acid-signaling pathways have thus been identified as potential pharmacological targets for obesity-related diseases. Interfering with microbiome composition may also be considered, as liver- and microbiome-derived bile acid species have different signaling functions. This review summarizes recent developments in this rapidly expanding field of research and addresses potential clinical prospects of interference with bile acid signaling pathways in human diseases.

Retroperitoneal parasitic fetus: A case report.

BACKGROUND: Fetus-in-fetu (FIF) is an extremely rare congenital abnormal mass, in which a normal fetus's vertebral axis frequently connected with malformed fetus around this axis. Here, we report the case of a male infant aged 26 d presenting with retroperitoneal parasitic fetus. CASE SUMMARY: In a prenatal examination, we first detected an abdominal mass measuring 7.8 cm × 5.1 cm × 6.8 cm in a mother's abdomen at 25 gestational weeks and teratoma was suspected. After the fetal was born, we did a magnetic resonance imaging (MRI) and ultrasonography on him and saw a distinctive limb with five-toes. According to the result of MRI, ultrasonography and postoperative pathology, he finally was diagnosed with FIF. CONCLUSION: A laparotomy was performed at 26 d of age with excision of the retroperitoneal cystic tumor, which measured about 10 cm in diameter. According to the result of imaging and histological test, FIF was confirmed.

Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic Acid.

BACKGROUND AND AIMS: Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for liver diseases. Yet, differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes. Cyp2c70-ablation in mice prevents synthesis of mouse/rat-specific muricholic acids (MCAs), but potential (patho)physiological consequences of their absence are unknown. We therefore assessed age- and gender-dependent effects of Cyp2c70-deficiency in mice. METHODS: The consequences of Cyp2c70-deficiency were assessed in male and female mice at different ages. RESULTS: Cyp2c70-/- mice were devoid of MCAs and showed high abundances of chenodeoxycholic and lithocholic acids. Cyp2c70-deficiency profoundly impacted microbiome composition. Bile flow and biliary BA secretion were normal in Cyp2c70-/- mice of both sexes. Yet, the pathophysiological consequences of Cyp2c70-deficiency differed considerably between sexes. Three-week old male Cyp2c70-/- mice showed high plasma BAs and transaminases, which spontaneously decreased thereafter to near-normal levels. Only mild ductular reactions were observed in male Cyp2c70-/- mice up to 8 months of age. In female Cyp2c70-/- mice, plasma BAs and transaminases remained substantially elevated with age, gut barrier function was impaired and bridging fibrosis was observed at advanced age. Addition of 0.1% ursodeoxycholic acid to the diet fully normalized hepatic and intestinal functions in female Cyp2c70-/- mice. CONCLUSION: Cyp2c70-/- mice show transient neonatal cholestasis and develop cholangiopathic features that progress to bridging fibrosis in females only. These consequences of Cyp2c70-deficiency are restored by treatment with UDCA, indicating a role of BA hydrophobicity in disease development.