Gut bacteria alleviate smoking-related NASH by degrading gut nicotine.

Tobacco smoking is positively correlated with non-alcoholic fatty liver disease (NAFLD)1-5, but the underlying mechanism for this association is unclear. Here we report that nicotine accumulates in the intestine during tobacco smoking and activates intestinal AMPKα. We identify the gut bacterium Bacteroides xylanisolvens as an effective nicotine degrader. Colonization of B. xylanisolvens reduces intestinal nicotine concentrations in nicotine-exposed mice, and it improves nicotine-exacerbated NAFLD progression. Mechanistically, AMPKα promotes the phosphorylation of sphingomyelin phosphodiesterase 3 (SMPD3), stabilizing the latter and therefore increasing intestinal ceramide formation, which contributes to NAFLD progression to non-alcoholic steatohepatitis (NASH). Our results establish a role for intestinal nicotine accumulation in NAFLD progression and reveal an endogenous bacterium in the human intestine with the ability to metabolize nicotine. These findings suggest a possible route to reduce tobacco smoking-exacerbated NAFLD progression.

Pan-transcriptomic analysis reveals alternative splicing control of cold tolerance in rice.

Plants have evolved complex mechanisms to adapt to harsh environmental conditions. Rice (Oryza sativa) is a staple food crop that is sensitive to low temperatures. However, its cold stress responses remain poorly understood, thus limiting possibilities for crop engineering to achieve greater cold tolerance. In this study, we constructed a rice pan-transcriptome and characterized its transcriptional regulatory landscape in response to cold stress. We performed Iso-Seq and RNA-Seq of 11 rice cultivars subjected to a time-course cold treatment. Our analyses revealed that alternative splicing-regulated gene expression plays a significant role in the cold stress response. Moreover, we identified CATALASE C (OsCATC) and Os03g0701200 as candidate genes for engineering enhanced cold tolerance. Importantly, we uncovered central roles for the 2 serine-arginine-rich proteins OsRS33 and OsRS2Z38 in cold tolerance. Our analysis of cold tolerance and resequencing data from a diverse collection of 165 rice cultivars suggested that OsRS2Z38 may be a key selection gene in japonica domestication for cold adaptation, associated with the adaptive evolution of rice. This study systematically investigated the distribution, dynamic changes, and regulatory mechanisms of alternative splicing in rice under cold stress. Overall, our work generates a rich resource with broad implications for understanding the genetic basis of cold response mechanisms in plants.

Intestinal peroxisome proliferator-activated receptor α-fatty acid-binding protein 1 axis modulates nonalcoholic steatohepatitis.

BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor α (PPARα) regulates fatty acid transport and catabolism in liver. However, the role of intestinal PPARα in lipid homeostasis is largely unknown. Here, intestinal PPARα was examined for its modulation of obesity and NASH. APPROACH AND RESULTS: Intestinal PPARα was activated and fatty acid-binding protein 1 (FABP1) up-regulated in humans with obesity and high-fat diet (HFD)-fed mice as revealed by using human intestine specimens or HFD/high-fat, high-cholesterol, and high-fructose diet (HFCFD)-fed C57BL/6N mice and PPARA -humanized, peroxisome proliferator response element-luciferase mice. Intestine-specific Ppara or Fabp1 disruption in mice fed a HFD or HFCFD decreased obesity-associated metabolic disorders and NASH. Molecular analyses by luciferase reporter assays and chromatin immunoprecipitation assays in combination with fatty acid uptake assays in primary intestinal organoids revealed that intestinal PPARα induced the expression of FABP1 that in turn mediated the effects of intestinal PPARα in modulating fatty acid uptake. The PPARα antagonist GW6471 improved obesity and NASH, dependent on intestinal PPARα or FABP1. Double-knockout ( Ppara/Fabp1ΔIE ) mice demonstrated that intestinal Ppara disruption failed to further decrease obesity and NASH in the absence of intestinal FABP1. Translationally, GW6471 reduced human PPARA-driven intestinal fatty acid uptake and improved obesity-related metabolic dysfunctions in PPARA -humanized, but not Ppara -null, mice. CONCLUSIONS: Intestinal PPARα signaling promotes NASH progression through regulating dietary fatty acid uptake through modulation of FABP1, which provides a compelling therapeutic target for NASH treatment.

Prevalence of sarcopenic obesity in the older non-hospitalized population: a systematic review and meta-analysis.

BACKGROUND: Sarcopenic obesity emerges as a risk factor for adverse clinical outcomes in non-hospitalized older adults, including physical disabilities, metabolic diseases, and even mortality. In this systematic review and meta-analysis, we investigated the overall SO prevalence in non-hospitalized adults aged ≥ 65 years and assessed the sociodemographic, clinicobiological, and lifestyle factors related to SO. METHODS: We searched the PubMed, Embase, Cochrane Library, and Web of Science databases for studies reporting the prevalence of SO from database inception to October 2023. Two researchers independently screened the literature, evaluated the study quality, and extracted the data. Both fixed- and random-effects models were used in the meta-analysis to estimate the pooled SO prevalence and perform subgroup analyses. Publication and sensitivity bias analyses were performed to test the robustness of the associations. RESULTS: Among 46 studies eligible for review and a total of 71,757 non-hospitalized older adults, the combined prevalence of SO was 14% (95% CI:11-17%, I2 = 99.5%, P < 0.01). Subgroup analysis according to lifestyle factors demonstrated that the SO prevalence was 17% (95% CI: 8-29%, I2 = 99.5%, P < 0.01) in older adults without exercise habits. Regarding clinicobiological factors, older adults with a history of falls (15% [95% CI: 10-22%, I2 = 82%, P < 0.01]), two or more chronic diseases (19% [95% CI: 10-29%, I2 = 97%, P < 0.01]), functional impairment (33% [95% CI: 29-37%, I2 = 0%, P = 0.95]), cognitive impairment (35% [95% CI: 9-65%, I2 = 83%, P = 0.02]), osteoporosis (20% [95% CI: 8-35%, I2 = 96%, P < 0.01]), high fasting glucose level (17% [95% CI: 1-49%, I2 = 98%, P < 0.01]), or the use of antipsychotics (13% [95% CI: 2-28%, I2 = 0%, P = 0.32]) exhibited a higher SO prevalence. CONCLUSION: SO prevalence is high among non-hospitalized older adults, especially those with functional and cognitive impairments. Thus, SO is a potential problem for the aging population; implementation of planned interventions in the community is needed to reduce the prevalence and adverse outcomes of SO.

Manipulating Redox Kinetics using p-n Heterojunction Biservice Matrix as both Cathode Sulfur Immobilizer and Anode Lithium Stabilizer for Practical Lithium-Sulfur Batteries.

As an attractive high-energy-density technology, the practical application of lithium-sulfur (Li-S) batteries is severely limited by the notorious dissolution and shuttle effect of lithium polysulfides (LiPS), resulting in sluggish reaction kinetics and uncontrollable dendritic Li growth. Herein, a p-n typed heterostructure consisting of n-type MoS2 nanoflowers embedded with p-type NiO nanoparticles is designed on carbon nanofibers (denoted as NiO-MoS2 @CNFs) as both cathode sulfur immobilizer and anode Li stabilizer for practical Li-S batteries. Such p-n typed heterostructure is proposed to establish the built-in electric field across the heterointerface for facilitated the positive charge to reach the surface of NiO-MoS2 , meanwhile inherits the excellent LiPS adsorption ability of p-type NiO nanoparticles and catalytic ability of n-type MoS2 . As the anode matrix, the implementation of NiO-MoS2 heterostructure can prevent the growth of Li dendrites by enhancing the lithiophilicity and reducing local current density. The obtained Li-S full battery exhibits an ultra-high areal capacity over 7.3 mAh cm-2 , far exceeding that of current commercial Li-ion batteries. Meanwhile, a stable cycling performance can be achieved under low electrolyte/sulfur ratio of 5.8 µL mg-1 and negative/positive capacity ratio of 1. The corresponding pouch cell maintains high energy density of 305 Wh kg-1 and stable cycling performance under various bending angles.

Myelocytomatosis-Protein Arginine N-Methyltransferase 5 Axis Defines the Tumorigenesis and Immune Response in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: HCC is a leading cause of cancer-related deaths globally with poor outcome and limited therapeutic options. Although the myelocytomatosis (MYC) oncogene is frequently dysregulated in HCC, it is thought to be undruggable. Thus, the current study aimed to identify the critical downstream metabolic network of MYC and develop therapies for MYC-driven HCC. APPROACH AND RESULTS: Liver cancer was induced in mice with hepatocyte-specific disruption of Myc and control mice by administration of diethylnitrosamine. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses revealed that urinary dimethylarginine, especially symmetric dimethylarginine (SDMA), was increased in the HCC mouse model in an MYC-dependent manner. Analyses of human samples demonstrated a similar induction of SDMA in the urines from patients with HCC. Mechanistically, Prmt5, encoding protein arginine N-methyltransferase 5, which catalyzes SDMA formation from arginine, was highly induced in HCC and identified as a direct MYC target gene. Moreover, GSK3326595, a PRMT5 inhibitor, suppressed the growth of liver tumors in human MYC-overexpressing transgenic mice that spontaneously develop HCC. Inhibition of PRMT5 exhibited antiproliferative activity through up-regulation of the tumor suppressor gene Cdkn1b/p27, encoding cyclin-dependent kinase inhibitor 1B. In addition, GSK3326595 induced lymphocyte infiltration and major histocompatibility complex class II expression, which might contribute to the enhanced antitumor immune response. Combination of GSK3326595 with anti-programed cell death protein 1 (PD-1) immune checkpoint therapy (ICT) improved therapeutic efficacy in HCC. CONCLUSIONS: This study reveals that PRMT5 is an epigenetic executer of MYC, leading to repression of the transcriptional regulation of downstream genes that promote hepatocellular carcinogenesis, highlights a mechanism-based therapeutic strategy for MYC-driven HCC by PRMT5 inhibition through synergistically suppressed proliferation and enhanced antitumor immunity, and finally provides an opportunity to mitigate the resistance of "immune-cold" tumor to ICT.

Bismuth Gadolinium Oxychloride with a Remarkable Visible-Light-Responsive O2 Evolution Activity Promoted by Iodine Doping.

Visible-light-responsive bismuth-based oxyhalide has recently attracted extensive attention, however, the promotion of its charge separation is still challenging. Herein, we introduce iodine into Bi2 GdO4 Cl to synthetize I-doped Bi2 GdO4 Cl (denoted as yI-Bi2 GdO4 Cl, 0≤y≤2). The incorporation of I- ions is found to enhance light absorption and to accelerate charge separation by combining various characterizations such as density functional theory calculation, photoelectrochemical test, electrochemical impedance spectroscopy, photoluminescence spectrum, and open-circuit voltage decay. The O2 -evolving performances of 1I-Bi2 GdO4 Cl with optimized dopant concentration of I- ion and IrO2 loaded 1I-Bi2 GdO4 Cl are tremendously enhanced by ca. 4 and 45 times compared to pristine Bi2 GdO4 Cl. Notably, The O2 evolution rate reaches as high as 154.8 µmol ⋅ h-1 with an apparent quantum efficiency of ∼1.1 % at 420 nm. The synthetic iodine-doped photocatalyst remains stable after long-term photoreaction, demonstrating its potential in the field of photocatalysis.

Manassantin B attenuates obesity by inhibiting adipogenesis and lipogenesis in an AMPK dependent manner.

Saururus chinensis (S chinensis) has been used as an herb to treat edema, jaundice, and gonorrhea. Manassantin B (MNSB), a dineolignan isolated from S chinensis, was identified as a potent adipogenesis/lipogenesis inhibitor (IC50  = 9.3 nM). To explore the underlying mechanism, both adipogenesis and lipogenesis were measured in differentiated 3T3-L1 preadipocytes, murine primary preadipocytes and adipose tissue explants upon MNSB treatment. Key regulators of adipogenesis/lipogenesis were downregulated by MNSB treatment, mainly resulting from increased phosphorylation of AMPK which was identified as a vital regulator of adipogenesis and lipogenesis. Moreover, MNSB did not increase AMPK phosphorylation in 3T3-L1 cells transfected with Prkaa1 (encoding protein kinase AMP-activated catalytic subunit alpha 1) siRNA or adipose tissue explants isolated from adipose-specific Prkaa1-disrupted mice (Prkaa1Δad ). In diet-induced obese C57BL/6N mice, MNSB displayed preventive and therapeutic effects on obesity accompanied by decreased adipocyte size. MNSB was also found to increase AMPK phosphorylation both in subcutaneous white adipose tissue and brown adipose tissue in vivo. These findings suggest that MNSB can be a new therapeutic agent for the prevention and treatment of obesity and other related metabolic disorders.

St. John's Wort alleviates dextran sodium sulfate-induced colitis through pregnane X receptor-dependent NFκB antagonism.

St. John's wort (SJW), from traditional herbs, activates the pregnane X receptor (PXR), a potential drug target for treating inflammatory bowel disease (IBD). However, how SJW alleviates dextran sodium sulfate (DSS)-induced experimental IBD by activating PXR is unknown. To test this, PXR-humanized, wild-type (WT) and Pxr-null mice, primary intestinal organoids cultures, and the luciferase reporter gene assays were employed. In vivo, a diet supplemented with SJW was found to activate intestinal PXR both in WT and PXR-humanized mice, but not in Pxr-null mice. SJW prevented DSS-induced IBD in PXR-humanized and WT mice, but not in Pxr-null mice. In vitro, hyperforin, a major component of SJW, activated PXR and suppressed tumor necrosis factor (TNF)α-induced nuclear factor (NF) κB translocation in primary intestinal organoids from PXR-humanized mice, but not Pxr-null mice. Luciferase reporter gene assays showed that hyperforin dose-dependently alleviated TNFα-induced NFκB transactivation by activating human PXR in Caco2 cells. Furthermore, SJW therapeutically attenuated DSS-induced IBD in PXR-humanized mice. These data indicate the therapeutic potential of SJW in alleviating DSS-induced IBD in vivo, and TNFα-induced NFκB activation in vitro, dependent on PXR activation, which may have clinical implications for using SJW as a herbal drug anti-IBD treatment.

A bioluminescent probe for NQO1 overexpressing cancer cell imaging in vitro and in vivo.

NAD(P)H quinone oxidoreductase1 (NQO1) is a flavoenzyme that regulates the redox potential level in cells. Overexpression of NQO1 has been proven to be relevant to some malignant tumors. Herein a bioluminescent probe NQO1-Luc equipped with an NQO1-targeting group, trimethyl-locked quinone propionic acid (QPA), was constructed. The reduction of NQO1-Luc could be triggered by NQO1, resulting in the release of free D-luciferin, and concomitantly a bright bioluminescence emission. NQO1-Luc exhibits high selectivity and sensitivity toward NQO1 activity and the capability of distinguishing NQO1-overexpressing cells in vitro and in vivo, which offers a promising tool for investigations of NQO1 related biological processes including tumors in living organisms.

[Recurrence Rate and Risk Factors of Atypical Meningioma:a Meta-analysis].

Objective To systematically review the overall status of postoperative recurrence in patients with atypical meningiomas. Methods China National Knowledge Infrastructure,Wanfang Database,Chinese Biomedical Literature Database,VIP Database,PubMed,Embase,Web of Science,and Cochrane Library were searched for collection of the relevant literature on the recurrence of atypical meningioma from database establishment to July 2021.Two investigators independently screened the literature,extracted data,and assessed the risk of bias of the included studies,and then performed a meta-analysis by using R 5.0. Results A total of 29 studies involving 3122 patients were included in this study.The meta-analysis showed that the overall postoperative recurrence rate of atypical meningioma was 38%.The subgroup analysis showed that the tumor recurrence rate of patients ≥60 years old and<60 years old was 51% and 40%,respectively,with no significant difference.The tumor recurrence rates in male and female patients were 42% and 44%,respectively,which showed no significant difference.The recurrence rates of the patients with parasagittal meningiomas,brain tissue infiltration,Ki-67>8%,mitotic count ≥6/10 high-power fields,and tissue necrosis were 52%,47%,63%,53%,and 69%,respectively.The recurrence rate after subtotal tumor resection was as high as 58%,and the patients who received radiotherapy had higher tumor recurrence rate than that those who did not receive radiotherapy (38% vs.29%,P=0.007). Conclusions The current evidence demonstrates that atypical meningioma has a high recurrence rate after surgery.It is essential to pay more attention and take corresponding measures to improve the tumor-free survival rate of the patients.

Spatial distribution, risk assessment, and source identification of heavy metals in water from the Xiangxi River, Three Gorges Reservoir Region, China.

Heavy metals (HMs) contamination in rivers has attracted wide concern due to its persistence and potential risks to the natural environment and human health. In this study, eight HMs (As, Hg, Cu, Pb, Ca, Zn, Mn, and Ni) were measured by inductively coupled plasma mass spectrometry in 24 water samples to investigate HMs contamination levels in the Xiangxi River of the Yangtze River basin. A geographic information systems kriging interpolation method was used to reveal the spatial distribution of HMs contamination. The results indicate that most HMs occurred at acceptable levels below the Surface Water Quality Standard (GB 3838-2002), with the highest concentration (23.23 mg kg-1) of Mn being observed at sampling site X20. The values of the potential ecological risk index (RI) suggest that high potential ecological risks were present at sampling sites X1, X3, X4, X14, X16, X17, and X24, which reached moderate risk level. The highest value of RI (279.56) was observed at site X17. HM spatial distributions show that upstream pollution is more severe than downstream. The hazard index was below 1 for all HMs except for Mn, indicating that HMs in Xiangxi River pose a low risk to human health. HM source identification was accomplished using principal component analysis and Pearson's correlation. Cu, Cd, Ni, and Hg originate primarily from agriculture, while Pb, Zn, and As originate primarily from transportation and mining. This research provides a reference on the risks posed by HMs in Xiangxi River and will support efforts to protect and improve water quality in Xiangxi River.

Intestinal PPARα Protects Against Colon Carcinogenesis via Regulation of Methyltransferases DNMT1 and PRMT6.

BACKGROUND & AIMS: Many genetic and environmental factors, including family history, dietary fat, and inflammation, increase risk for colon cancer development. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that regulates systemic lipid homeostasis. We explored the role of intestinal PPARα in colon carcinogenesis. METHODS: Colon cancer was induced in mice with intestine-specific disruption of Ppara (PparaΔIE), Pparafl/fl (control), and mice with disruption of Ppara that express human PPARA (human PPARA transgenic mice), by administration of azoxymethane with or without dextran sulfate sodium (DSS). Colons were collected from mice and analyzed by immunoblots, quantitative polymerase chain reaction, and histopathology. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses were performed on urine and colons. We used molecular biology and biochemical approaches to study mechanisms in mouse colons, primary intestinal epithelial cells, and colon cancer cell lines. Gene expression data and clinical features of patients with colorectal tumors were obtained from Oncomine, and human colorectal-tumor specimens and adjacent normal tissues were collected and analyzed by immunohistochemistry. RESULTS: Levels of Ppara messenger RNA were reduced in colon tumors from mice. PparaΔIE mice developed more and larger colon tumors than control mice following administration of azoxymethane, with or without DSS. Metabolomic analyses revealed increases in methylation-related metabolites in urine and colons from PparaΔIE mice, compared with control mice, following administration of azoxymethane, with or without DSS. Levels of DNA methyltransferase 1 (DNMT1) and protein arginine methyltransferase 6 (PRMT6) were increased in colon tumors from PparaΔIE mice, compared with colon tumors from control mice. Depletion of PPARα reduced the expression of retinoblastoma protein, resulting in increased expression of DNMT1 and PRMT6. DNMT1 and PRMT6 decreased expression of the tumor suppressor genes Cdkn1a (P21) and Cdkn1b (p27) via DNA methylation and histone H3R2 dimethylation-mediated repression of transcription, respectively. Fenofibrate protected human PPARA transgenic mice from azoxymethane and DSS-induced colon cancer. Human colon adenocarcinoma specimens had lower levels of PPARA and retinoblastoma protein and higher levels of DNMT1 and PRMT6 than normal colon tissues. CONCLUSIONS: Loss of PPARα from the intestine promotes colon carcinogenesis by increasing DNMT1-mediated methylation of P21 and PRMT6-mediated methylation of p27 in mice. Human colorectal tumors have lower levels of PPARA messenger RNA and protein than nontumor tissues. Agents that activate PPARα might be developed for chemoprevention or treatment of colon cancer.

[Relationship between long non-coding RNA MALAT1 and prostate cancer].

Prostate cancer (PCa), as a malignant tumor originating in the prostate glandular epithelium, has become a global "killer" that threatens the health of elderly men. PCa-related studies have been focusing on the progression mechanisms and treatment strategies of the malignancy, particularly on the role of long non-coding RNA (lncRNA) in recent years. The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a key role in the progression and treatment of PCa, as well as in its metastasis and invasion and cell proliferation. lncRNA MALAT1 not only influences the biological characteristics of PCa, but also has a regulatory effect on the medicinal treatment of the disease, its action mechanisms involving ceRNA and AR signaling pathways. This review focuses on the relationship between lncRNA MALAT1 and PCa, aiming to provide a new research direction for the diagnosis and treatment of the malignancy.

NSun2 Deficiency Protects Endothelium From Inflammation via mRNA Methylation of ICAM-1.

RATIONALE: Vascular endothelial inflammation, including the expression of intercellular adhesion molecule 1 (ICAM-1), is a key event in vascular diseases. However, the mechanisms underlying the regulation of ICAM-1 are largely unknown. OBJECTIVE: To investigate the mechanisms on the regulation of ICAM-1 by NOP2/Sun domain family, member 2 (NSun2)-mediated mRNA methylation and the impact of NSun2-ICAM-1 regulatory process in vascular inflammation and allograft arteriosclerosis. METHODS AND RESULTS: By using in vitro, in cells, and in vivo methylation assays, we showed that the tRNA methyltransferase NSun2 methylated the ICAM-1 mRNA. Methylation by NSun2 promoted the translation of ICAM-1, thereby increasing the adhesion of leukocytes to endothelial cells. Tumor necrosis factor-α or homocysteine activated the methyltransferase activity of NSun2 by repressing the phosphorylation of NSun2 by Aurora-B. The levels of ICAM-1 induction and of leukocyte adhesion to vascular endothelium observed with homocysteine treatment in wild-type rats were markedly decreased in NSun2(-/-) rats. In a rat model of aortic allograft, the lack of donor NSun2 impaired the formation of allograft arteriosclerosis. CONCLUSIONS: NSun2 upregulates the expression of ICAM-1 by methylating ICAM-1 mRNA. This regulatory process impacts on vascular inflammation and allograft arteriosclerosis.

Hepatitis B virus X protein promotes P3 transcript expression of the insulin-like growth factor 2 gene via inducing hypomethylation of P3 promoter in hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatitis B virus (HBV) X protein (HBx) contributes to hepatocarcinogenesis. The overexpression of transcripts from P3 and P4 promoters of the insulin-like growth factor 2 (IGF2) gene is observed in hepatocellular carcinoma (HCC). Here, we aimed to explore the involvement of HBx in P3-driven mRNA overexpression and underlying epigenetic mechanism. METHODS: P3 mRNA, P3 methylation status, HBx mRNA and HBx protein were analysed in human HCC samples with and without HBV infection using quantitative RT-PCR, bisulphite sequencing and Western blotting. The effects of HBx on P3 mRNA expression, and P3 transcriptional activity and methylation were further evaluated in HCC cell lines. RESULTS: P3 mRNA level was higher and P3 methylation level was lower in HBV-positive HCC specimens compared with those of HBV-negative HCC specimens. P3 transcript abundance was positively correlated with HBx expression and negatively correlated with P3 methylation in HCC specimens. The stable expression of HBx upregulated P3 mRNA expression and reduced P3 methylation level in HepG2-HBx cells. The transient expression of HBx stimulated P3 promoter activity and decreased P3 methylation level of P3 promoter-luciferase construct in a dose-dependent manner in HepG2 and Huh-7 cells. Furthermore, HBx mRNA expression was found to be independent predictive factors for both shorter disease-free survival time and shorter overall survival time of HCC patients. CONCLUSION: HBx may promote IGF2-P3 transcript expression by inducing hypomethylation of P3 promoter and may be associated with an inferior clinical outcome of HBV-related HCC patients. This study provides useful information for understanding the mechanism of HBx-mediated HCC.

Intercellular adhesion molecular-1, Fas, and Fas ligand as diagnostic biomarkers for acute allograft rejection of pancreaticoduodenal transplantation in pigs.

BACKGROUND: The early diagnosis of pancreas allograft dysfunction is crucial for the management and long-term survival of transplanted pancreases. We investigated whether intercellular adhesion molecular-1 (ICAM-1), Fas, and Fas ligand (FasL) can be used as novel biomarkers of acute pancreaticoduodenal allograft dysfunction in pigs. METHODS: Forty outbred landraces were randomly divided into three groups. In the control group (8 pigs), a sham operation was performed but no drugs were administered. In groups 1 and 2 (8 pairs each), pancreaticoduodenal transplantation was performed, with the latter administered immunosuppressive drugs and the former not administered drugs. The expression of ICAM-1, Fas, and FasL mRNA in the peripheral vein blood was assessed by flow cytometry and RT-PCR, pre-transplant and on days 1, 3, 5, and 7 after transplantation. Simultaneously, the levels of glucose, insulin, and glucagon in the serum of the recipients were evaluated. The allograft pancreas tissue was obtained to assess the pathological damage and the expression of Fas and FasL by immunohistochemistry. RESULTS: On the first 7 days after transplantation, ICAM-1, Fas, and FasL mRNA expression in the blood leukocytes of the recipient increased significantly in groups 1 and 2 compared with the control group (P < 0.01). However, the levels in group 2 were significantly lower than those in group 1 (P < 0.05). Interestingly, the FasL expression increased but the Fas expression decreased gradually in the graft pancreas tissue during the first week after transplantation in both groups 1 and 2 compared with the control group (P < 0.05). The levels of serous glucose, insulin, and glucagon in groups 1 and 2 obviously changed on day 1 after transplantation but returned to normal on day 2. The recipient's pancreas pathological sections did not exhibit any rejection changes on days 1 and 3 after transplantation but showed rejection damage on days 5 and 7. CONCLUSION: ICAM-1, Fas, and FasL were found to be sensitive biomarkers of acute pancreas allograft dysfunction after pancreaticoduodenal transplantation in pigs, and their monitoring could be used to evaluate the effectiveness of the immunosuppression therapy.

[Hepatitis B virus X protein promotes insulin-like growth factor II gene expression by inducing hypomethylation of the P3 promoter in hepatocellular carcinoma].

OBJECTIVE: To explore the involvement of hepatitis B X protein (HBx) in promoter 3 (P3)-driven mRNA overexpression of the insulin-like growth factor II gene (IGF-II) and investigate the underlying epigenetic mechanism. METHODS: Levels of P3 and HBx mRNA and status of P3 methylation were analyzed in human hepatocellular carcinoma (HCC) samples, with and without hepatitis B virus (HBV) infection, using quantitative reverse transcription-PCR and bisulfite sequencing. In addition, the levels of P3 mRNA and P3 methylation were examined in HepG2 cells stably overexpressing HBx (HepG2-HBx). Finally, P3 promoter-luciferase constructs were cotransfected into HepG2 cells along with an HBx-expressing plasmid, and the effects of HBx on transcriptional activity and methylation of P3 were analyzed. Statistical analyses of the data were conducted by chi square test, Fisher's exact test, Student's t-test, Marn-Whitney U test, and Pearson's correlation coefficient test. RESULTS: The HBV-positive HCC specimens had significantly higher levels of P3 mRNA than the HBV-negative HCC specimens (-9.59 ± 3.22 vs. -12.97 ± 3.08 delta CT; P=0.006) but significantly lower levels of P3 methylation (mean values for the 17 CpG sites (36.9% ± 15.5% vs. 52.1% ± 19.1%; P=0.025). The P3 transcript abundance was positively correlated with the level of HBx expression and negatively correlated with the level of P3 methylation. The epigenetic results from experiments with the HepG2-HBx cells were similar. Transfection of HBx significantly decreased P3 methylation level and increased its activity. CONCLUSION: HBx expression may promote IGF-II expression by inducing hypomethylation of its P3 promoter in hepatocellular carcinoma.

[LncRNAs and cardiovascular diseases].

Cardiovascular disease has been a huge threat to human health. Studies of cardiovascular disease is always an important field of basic medicine. Noncoding RNAs, once thought to be useless, are gaining attention from researchers along with the development of genetics and medical informatics. Most of noncoding RNAs are long noncoding RNA. Evidences suggest that long noncoding RNAs are connected to cardiovascular doisease, yet we still dont know much about their functions and how they work. Here we review the functions and characteristics of long noncoding RNAs and the relationship between long noncoding RNAs and cardiovascular disease. These studies may contribute to better comprehension of the etiology and pathophysiology of cardiovascular disease.

[Role and mechanism of macrophage-mediated osteoimmune in osteonecrosis of the femoral head].

Objective: To summarize the research progress on the role of macrophage-mediated osteoimmune in osteonecrosis of the femoral head (ONFH) and its mechanisms. Methods: Recent studies on the role and mechanism of macrophage-mediated osteoimmune in ONFH at home and abroad were extensively reviewed. The classification and function of macrophages were summarized, the osteoimmune regulation of macrophages on chronic inflammation in ONFH was summarized, and the pathophysiological mechanism of osteonecrosis was expounded from the perspective of osteoimmune, which provided new ideas for the treatment of ONFH. Results: Macrophages are important immune cells involved in inflammatory response, which can differentiate into classically activated type (M1) and alternatively activated type (M2), and play specific functions to participate in and regulate the physiological and pathological processes of the body. Studies have shown that bone immune imbalance mediated by macrophages can cause local chronic inflammation and lead to the occurrence and development of ONFH. Therefore, regulating macrophage polarization is a potential ONFH treatment strategy. In chronic inflammatory microenvironment, inhibiting macrophage polarization to M1 can promote local inflammatory dissipation and effectively delay the progression of ONFH; regulating macrophage polarization to M2 can build a local osteoimmune microenvironment conducive to bone repair, which is helpful to necrotic tissue regeneration and repair to a certain extent. Conclusion: At present, it has been confirmed that macrophage-mediated chronic inflammatory immune microenvironment is an important mechanism for the occurrence and development of ONFH. It is necessary to study the subtypes of immune cells in ONFH, the interaction between immune cells and macrophages, and the interaction between various immune cells and macrophages, which is beneficial to the development of potential therapeutic methods for ONFH.