TBK1-Mediated DRP1 Targeting Confers Nucleic Acid Sensing to Reprogram Mitochondrial Dynamics and Physiology.

Mitochondrial morphology shifts rapidly to manage cellular metabolism, organelle integrity, and cell fate. It remains unknown whether innate nucleic acid sensing, the central and general mechanisms of monitoring both microbial invasion and cellular damage, can reprogram and govern mitochondrial dynamics and function. Here, we unexpectedly observed that upon activation of RIG-I-like receptor (RLR)-MAVS signaling, TBK1 directly phosphorylated DRP1/DNM1L, which disabled DRP1, preventing its high-order oligomerization and mitochondrial fragmentation function. The TBK1-DRP1 axis was essential for assembly of large MAVS aggregates and healthy antiviral immunity and underlay nutrient-triggered mitochondrial dynamics and cell fate determination. Knockin (KI) strategies mimicking TBK1-DRP1 signaling produced dominant-negative phenotypes reminiscent of human DRP1 inborn mutations, while interrupting the TBK1-DRP1 connection compromised antiviral responses. Thus, our findings establish an unrecognized function of innate immunity governing both morphology and physiology of a major organelle, identify a lacking loop during innate RNA sensing, and report an elegant mechanism of shaping mitochondrial dynamics.

Inhibition of mitochondrial citrate shuttle alleviates metabolic syndromes induced by high-fat diet.

The mitochondrial citrate shuttle, which relies on the solute carrier family 25 member 1 (SLC25A1), plays a pivotal role in transporting citrate from the mitochondria to the cytoplasm. This shuttle supports glycolysis, lipid biosynthesis, and protein acetylation. Previous research has primarily focused on SLC25A1 in pathological models, particularly high-fat diet (HFD)-induced obesity. However, the impact of SLC25A1 inhibition on nutrient metabolism under HFD remains unclear. To address this gap, we used zebrafish (Danio rerio) and Nile tilapia (Oreochromis niloticus) to evaluate the effects of inhibiting Slc25a1. In zebrafish, we administered Slc25a1-specific inhibitors (CTPI-2) for 4 wk, whereas Nile tilapia received intraperitoneal injections of dsRNA to knock down slc25a1b for 7 days. Inhibition of the mitochondrial citrate shuttle effectively protected zebrafish from HFD-induced obesity, hepatic steatosis, and insulin resistance. Of note, glucose tolerance was unaffected. Inhibition of Slc25a1 altered hepatic protein acetylation patterns, with decreased cytoplasmic acetylation and increased mitochondrial acetylation. Under HFD conditions, Slc25a1 inhibition promoted fatty acid oxidation and reduced hepatic triglyceride (TAG) accumulation by deacetylating carnitine palmitoyltransferase 1a (Cpt1a). In addition, Slc25a1 inhibition triggered acetylation-induced inactivation of Pdhe1α, leading to a reduction in glucose oxidative catabolism. This was accompanied by enhanced glucose uptake and storage in zebrafish livers. Furthermore, Slc25a1 inhibition under HFD conditions activated the SIRT1/PGC1α pathway, promoting mitochondrial proliferation and enhancing oxidative phosphorylation for energy production. Our findings provide new insights into the role of nonhistone protein acetylation via the mitochondrial citrate shuttle in the development of hepatic lipid deposition and hyperglycemia caused by HFD.NEW & NOTEWORTHY The mitochondrial citrate shuttle is a crucial physiological process for maintaining metabolic homeostasis. In the present study, we found that inhibition of mitochondrial citrate shuttle (Slc25a1) could alleviate metabolic syndromes induced by high-fat diet (HFD) through remodeling hepatic protein acetylation modification. Briefly, Slc25a1 inhibition reduces hepatic triglyceride deposition by deacetylating Cpt1a and reduces glucose oxidative catabolism by acetylating Pdhe1α. Our study provides new insights into the treatment of diet-induced metabolic syndromes.

Pparα activation stimulates autophagic flux through lipid catabolism-independent route.

Autophagy is a cellular process that involves the fusion of autophagosomes and lysosomes to degrade damaged proteins or organelles. Triglycerides are hydrolyzed by autophagy, releasing fatty acids for energy through mitochondrial fatty acid oxidation (FAO). Inhibited mitochondrial FAO induces autophagy, establishing a crosstalk between lipid catabolism and autophagy. Peroxisome proliferator-activated receptor α (PPARα), a transcription factor, stimulates lipid catabolism genes, including fatty acid transport and mitochondrial FAO, while also inducing autophagy through transcriptional regulation of transcription factor EB (TFEB). Therefore, the study explores whether PPARα regulates autophagy through TFEB transcriptional control or mitochondrial FAO. In aquaculture, addressing liver lipid accumulation in fish is crucial. Investigating the link between lipid catabolism and autophagy is significant for devising lipid-lowering strategies and maintaining fish health. The present study investigated the impact of dietary fenofibrate and L-carnitine on autophagy by activating Pparα and enhancing FAO in Nile tilapia (Oreochromis niloticus), respectively. The dietary fenofibrate and L-carnitine reduced liver lipid content and enhanced ATP production, particularly fenofibrate. FAO enhancement by L-carnitine showed no changes in autophagic protein levels and autophagic flux. Moreover, fenofibrate-activated Pparα promoted the expression and nuclear translocation of Tfeb, upregulating autophagic initiation and lysosomal biogenesis genes. Pparα activation exhibited an increasing trend of LC3II protein at the basal autophagy and cumulative p62 protein trends after autophagy inhibition in zebrafish liver cells. These data show that Pparα activation-induced autophagic flux should be independent of lipid catabolism.

Linking PAHs concentration, risk to PAHs source shift in soil and water in epikarst spring systems, Southwest China.

A systematic assessment of the variations in the ecological risk of PAHs and the key emission sources controlling the variations is of great importance to human health and aquatic organisms. PAH concentrations, composition, source, and ecological risk in soils and water in two different periods (2010-2011 and 2019) of three typical epikarst springs in Southwest China were investigated. Results showed that PAH concentrations in soil and water have an overall downward trend (a reduction of 57 % and 93 %, respectively) in the past 10 years, which is consistent with the downward trend in the relative contribution rate of raw coal production (a 66 % reduction). In terms of composition, the proportion of low-ring PAHs decreased, medium-ring and high-ring PAHs increased in the soil profile. The proportion of low-ring PAHs did not change obviously, the proportion of medium-ring PAHs increased, and the proportion of high-ring PAHs decreased in epikarst springs. The source of PAHs changed remarkably over time, the relative contribution of coal combustion to PAHs decreased from 38 % to 20 %, and the vehicle contribution of PAHs increased from 31 % to 44 % in soils. The relative contribution rate of unburned oil and coke oven and biomass combustion change is less. Furthermore, the ecological risk of PAHs in the soils was reduced from moderate risk 2 to moderate risk 1, the risk in epikarst spring was reduced from high risk to moderate risk 2 after 10 years. This study demonstrates that substituting petroleum and coal with green energies can reduce PAH concentrations and risk.

Prognostic Prediction Value and Biological Functions of Non-Apoptotic Regulated Cell Death Genes in Lung Adenocarcinoma.

Objective To explore the potential biological functions and prognostic prediction values of non-apoptotic regulated cell death genes (NARCDs) in lung adenocarcinoma.Methods Transcriptome data of lung adenocarcinoma were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. We identified differentially expressed NARCDs between lung adenocarcinoma tissues and normal tissues with R software. NARCDs signature was constructed with univariate Cox regression analysis and the least absolute shrinkage and selection operator Cox regression. The prognostic predictive capacity of NARCDs signature was assessed by Kaplan-Meier survival curve, receiver operating characteristic curve, and univariate and multivariate Cox regression analyses. Functional enrichment of NARCDs signature was analyzed with gene set variation analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes. In addition, differences in tumor mutational burden, tumor microenvironment, tumor immune dysfunction and exclusion score, and chemotherapeutic drug sensitivity were analyzed between the high and low NARCDs score groups. Finally, a protein-protein interaction network of NARCDs and immune-related genes was constructed by STRING and Cytoscape software. Results We identified 34 differentially expressed NARCDs associated with the prognosis, of which 16 genes (ATIC, AURKA, CA9, ITGB4, DDIT4, CDK5R1, CAV1, RRM2, GAPDH, SRXN1, NLRC4, GLS2, ADRB2, CX3CL1, GDF15, and ADRA1A) were selected to construct a NARCDs signature. NARCDs signature was identified as an independent prognostic factor (P < 0.001). Functional analysis showed that there were significant differences in mismatch repair, p53 signaling pathway, and cell cycle between the high NARCDs score group and low NARCDs score group (all P < 0.05). The NARCDs low score group had lower tumor mutational burden, higher immune score, higher tumor immune dysfunction and exclusion score, and lower drug sensitivity (all P < 0.05). In addition, the 10 hub genes (CXCL5, TLR4, JUN, IL6, CCL2, CXCL2, ILA, IFNG, IL33, and GAPDH) in protein-protein interaction network of NARCDs and immune-related genes were all immune-related genes. Conclusion The NARCDs prognostic signature based on the above 16 genes is an independent prognostic factor, which can effectively predict the clinical prognosis of patients of lung adenocarcinoma and provide help for clinical treatment.

Self-referenced refractive index sensor based on double-dips method with bimetal-dielectric and double-groove grating.

Self-referenced refractive index sensors allow more accurate measurements and reduce the influence of extraneous factors. This work proposed a high-sensitivity, self-referenced surface plasmon resonance sensor with Na grating and Au-ZnS composite grating. When Transverse Magnetic-polarized light is incident into the prism, three surface plasmon resonances are excited at the interface of Na-MgF2 grating and Au-ZnS grating. The first one is treated as the reference angle, the second and third are forward and backward surface plasmon resonance, respectively. Using the angular modulation, the single-dip sensitivities are 329.41 deg/RIU and 788.24 deg/RIU in the range of 1.330-1.347. To further improve the performance of the sensor, the double-dips method is adopted, and the average sensitivity in the range of 1.330-1.347 is 1117.65 deg/RIU, while the maximum reaches 4390 deg/RIU. Due to high sensitivity, a good figure of merit can be obtained even with a larger full width at half maximum of 3.30°. This proposed sensor provides potential application in the research of biomolecular detection and chemical testing.

The Adaptive Characteristics of Cholesterol and Bile Acid Metabolism in Nile Tilapia Fed a High-Fat Diet.

Since high-fat diet (HFD) intake elevates liver cholesterol and enhanced cholesterol-bile acid flux alleviates its lipid deposition, we assumed that the promoted cholesterol-bile acid flux is an adaptive metabolism in fish when fed an HFD. The present study investigated the characteristic of cholesterol and fatty acid metabolism in Nile tilapia (Oreochromis niloticus) after feeding an HFD (13% lipid level) for four and eight weeks. Visually healthy Nile tilapia fingerlings (average weight 3.50 ± 0.05 g) were randomly distributed into four treatments (4-week control diet or HFD and 8-week control diet or HFD). The liver lipid deposition and health statue, cholesterol/bile acid, and fatty acid metabolism were analyzed in fish after short-term and long-term HFD intake. The results showed that 4-week HFD feeding did not change serum alanine transaminase (ALT) and aspartate transferase (AST) enzyme activities, along with comparable liver malondialdehyde (MDA) content. But higher serum ALT and AST enzyme activities and liver MDA content were observed in fish fed 8-week HFD. Intriguingly, remarkably accumulated total cholesterol (mainly cholesterol ester, CE) was observed in the liver of fish fed 4-week HFD, along with slightly elevated free fatty acids (FFAs) and comparable TG contents. Further molecular analysis in the liver showed that obvious accumulation of CE and total bile acids (TBAs) in fish fed 4-week HFD was mainly attributed to the enhancement of cholesterol synthesis, esterification, and bile acid synthesis. Furthermore, the increased protein expressions of acyl-CoA oxidase 1/2 (Acox1 and Acox2), which serve as peroxisomal fatty acid ß-oxidation (FAO) rate-limiting enzymes and play key roles in the transformation of cholesterol into bile acids, were found in fish after 4-week HFD intake. Notably, 8-week HFD intake remarkably elevated FFA content (about 1.7-fold increase), and unaltered TBAs were found in fish liver, accompanied by suppressed Acox2 protein level and cholesterol/bile acid synthesis. Therefore, the robust cholesterol-bile acid flux serves as an adaptive metabolism in Nile tilapia when fed a short-term HFD and is possibly via stimulating peroxisomal FAO. This finding enlightens our understanding on the adaptive characteristics of cholesterol metabolism in fish fed an HFD and provides a new possible treatment strategy against metabolic disease induced by HFD in aquatic animals.

Mildronate triggers growth suppression and lipid accumulation in largemouth bass (Micropterus salmoides) through disturbing lipid metabolism.

Many metabolic diseases in fish are often associated with lowered mitochondrial fatty acid ß-oxidation (FAO). However, the physiological role of mitochondrial FAO in lipid metabolism has not been verified in many carnivorous fish species, for example in largemouth bass (Micropterus salmonids). In the present study, a specific mitochondrial FAO inhibitor, mildronate (MD), was used to investigate the effects of impaired mitochondrial FAO on growth performance, health status, and lipid metabolism of largemouth bass. The results showed that the dietary MD treatment significantly suppressed growth performance and caused heavy lipid accumulation, especially neutral lipid, in the liver. The MD-treated fish exhibited lower monounsaturated fatty acid and higher long-chain polyunsaturated fatty acids in the muscle. The MD treatment downregulated the gene expressions in lipolysis and lipogenesis, as well as the expressions of the genes and some key proteins in FAO without enhancing peroxisomal FAO. Additionally, the MD-treated fish had lower serum aspartate aminotransferase activity and lower pro-inflammation- and apoptosis-related genes in the liver. Taken together, MD treatment markedly induced lipid accumulation via depressing lipid catabolism. Our findings reveal the pivotal roles of mitochondrial FAO in maintaining health and lipid homeostasis in largemouth bass and could be hopeful in understanding metabolic diseases in farmed carnivorous fish.

The effect of partial replacement of fish meal by soy protein concentrate on growth performance, immune responses, gut morphology and intestinal inflammation for juvenile hybrid grouper (Epinephelus fuscoguttatus ♀ × Epinephelus lanceolatus ♂).

An 8-week feeding trial was conducted to investigate the effects of partial replacement of fish meal by soy protein concentrate (SPC) on the growth performance, immune responses, intestine morphology and relation gene expression of intestinal inflammation for juvenile hybrid grouper (Epinephelus fuscoguttatus ♀ × Epinephelus lanceolatus ♂) (initial weight 12.5 ±â€¯0.00 g). Eight isonitrogenous and isolipidic diets (48.61% protein and 11.17% lipid) were formulated by replacing 0% (the control), 11%, 22%, 33%, 44%, 55%, 66%, and 77% of fish meal (FM) with SPC, respectively (the eight dietary be named FM, S11, S22, S33, S44, S55, S66, and S77, respectively). With the replacement level increased, the final body weight, weight gain ratio (WGR), specific growth rate (SGR), and survival rate of fish were significantly decreased (P < 0.05) compared with the group FM. By contrast, the feed conversion ratio (FCR) of fish was significantly increased (P < 0.05) when the replacement level up to 44%. Partial FM replacement by SPC (ranging from 11% to 77%) substantially reduced (P < 0.05) the serum total protein, albumin, and total cholesterol contents compared with the group FM. Liver total superoxide dismutase, glutathione peroxidase, catalase activities, and total antioxidant capacity showed the same trend of gradual increase first and then decrease. Their highest values were found in the replacement levels of 55%, 33%, 22%, and 55% and were significantly higher (P < 0.05) than the control group. The lowest malondialdehyde content was observed in group S77 and was significantly lower (P < 0.05) than that of the control group. The complements C3 and C4 contents of fish fed with experimental diets (replacement level ranged from 11% to 66%) were significantly higher (P < 0.05) than the group FM. The liver lysozyme activity of the control group was the lowest and was significantly lower than that of other dietary treatments (P < 0.05). Villus length and muscle thickness in the intestine of fish were significantly lower (P < 0.05) than other groups when the replacement level exceeded 44%. With dietary replacement levels increased, the TLR22, MyD88, p65, pro-inflammatory cytokines (IL-1ß, TNF-α, IL-12P40 and INF-γ) and anti-inflammatory cytokines (TGF-ß, IL-10, epinecidin, MHCIIß and hepcidin) mRNA levels in the proximal intestine were significantly up-regulated (P < 0.05). The TLR22, MyD88, p65, pro-inflammatory cytokines (IL-1ß, TNF-α, IL-12P40 and INF-γ) and anti-inflammatory cytokines (TGF-ß, IL-10, MHCIIß and hepcidin) mRNA levels in the mid intestine were significantly up-regulated (P < 0.05). The mRNA levels of TLR22, anti-inflammatory cytokines (IL-1ß, TNF-α, IL-12P40, INF-γ) and anti-inflammatory cytokines (TGF-ß, IL-10, epinecidin, MHCIIß and hepcidin) in the distal intestine were significantly down-regulated (P < 0.05). The mRNA expression of MyD88 and p65 mRNA were showed a tend increased first and then decreased, and the highest values were observed in group S33 and S55 (P < 0.05), respectively. Based on the present work, the correlation between WGR and FM replacement level with SPC was described using the broken-line model, which estimated the optimum FM replacement to 37.23% for juvenile hybrid grouper dietary.

Infection-related hospitalization after intensive immunosuppressive therapy among lupus nephritis and ANCA glomerulonephritis patients.

Introduction: This study aimed to investigate the clinical characteristics, risk factors, and outcomes of infection-related hospitalization (IRH) in patients with lupus nephritis (LN) and ANCA glomerulonephritis after intensive immunosuppressive therapy.Methods: Patients diagnosed with LN or ANCA glomerulonephritis who received intensive immunosuppressive therapy at the First Affiliated Hospital of Sun Yat-sen University from 2005 to 2014 were enrolled. Demographics, laboratory parameters, immunosuppressive agents, and IRH details were collected. Multivariable Cox regression was used, and hazard ratios (HRs) and 95% confidence intervals (CIs) were reported.Results: Totally, 872 patients with 806 LN and 66 ANCA glomerulonephritis were enrolled, and 304 (34.9%) patients with 433 episodes of IRH were recorded. ANCA glomerulonephritis patients were more vulnerable to IRH than LN patients (53.0% vs. 33.4%, p = .001). Multivariable Cox regression analysis showed that ANCA glomerulonephritis (HR = 1.62, 95% CI: 1.06-2.49, p = .027), diabetes (HR = 1.82, 95% CI: 1.03-3.22, p = .039) and a higher initial dose of prednisone (HR = 1.01, 95% CI: 1.00-1.02, p = .013) were associated with a higher likelihood of IRH. Higher albumin (HR = 0.96, 95% CI: 0.94-0.98, p < .001), globulin (HR = 0.98, 95% CI: 0.96-0.99, p = .008), and eGFR (HR = 0.99, 95% CI: 0.99-1.00, p < .001), were associated with a lower likelihood of IRH. The rates of transfer to ICU and mortality for ANCA glomerulonephritis patients were higher than those for LN patients (22.9% vs. 1.9%, p < .001, and 20.0% vs. 0.7%, p < .001, respectively).Conclusions: ANCA glomerulonephritis patients had a higher risk of IRH and poorer outcome once infected after intensive immunosuppressive therapy than LN patients. More strict control for infection risks is required for ANCA glomerulonephritis patients who undergo intensive immunosuppressive therapy.

Outcomes of primary membranous nephropathy based on serum anti-phospholipase A2 receptor antibodies and glomerular phospholipase A2 receptor antigen status: a retrospective cohort study.

INTRODUCTION: Primary membranous nephropathy (PMN) is associated with the anti-phospholipase A2 receptor (anti-PLA2R) antibody in 70% of cases. Some anti-PLA2R-negative patients have the PLA2R antigen in renal tissue. This study examined the prognosis of patients with PMN according to their serum anti-PLA2R antibody (SAb) and glomerular PLA2R antigen (GAg) status. METHODS: Patients diagnosed with PMN were included retrospectively. Patients were grouped according to their PLA2R status into the SAb-/GAg-, SAb-/GAg+, and SAb+/GAg + groups. Baseline data, renal biopsy results, treatment, and clinical data were compared among the groups. Cox univariable and multivariable analyses examined the factors related to complete remission (CR). RESULTS: A total of 114 patients were enrolled; 10 (9%) in the SAb-/GAg-, 23 (20%) in the SAb-/GAg+, and 81 (71%) in the SAb+/GAg+ groups. Cumulative CR rate showed a significant difference between the SAb-/GAg - and SAb+/GAg+ groups (log-rank p = 0.003). The multivariable Cox proportional hazard analysis showed that age (HR = 0.968; 95%CI = 0.946-0.990; p = 0.005), SAb+/GAg+ versus SAb-/GAg- (HR = 0.387; 95%CI = 0.190-0.788; p = 0.009), SAb-/GAg+ versus SAb-/GAg- (HR = 0.398; 95%CI = 0.169, 0.939; p = 0.035), total renal chronicity score ≥2 (HR = 0.461, 95%CI: 0.277-0.766, p = 0.003), and IgA deposition (HR = 2.596; 95%CI = 1.227-5.492; p = 0.013) were all independently related (p < 0.05) to CR. CONCLUSIONS: The SAb and GAg status was an indicator of PMN prognosis. The patients with SAb-/GAg - had an increased likelihood of achieving CR than those with SAb-/GAg+ and SAb+/GAg+.

Preparation, Mechanical Properties, and Biocompatibility of Graphene Oxide-Reinforced Chitin Monofilament Absorbable Surgical Sutures.

Chitin (CT) is a good material to prepare surgical sutures due to its conspicuous biological characteristics. However, the poor mechanical strength of pure CT sutures limits its application. In order to improve its strength, a composite monofilament absorbable suture was prepared in this study using graphene oxide and chitin (GO-CT) using a green method. FT-IR spectra showed that GO-CT contained the characteristic functional groups of GO and CT, indicating that a GO-CT suture was successfully obtained. With the addition of a small amount of GO (1.6wt% solution) in chitin, the breaking tensile strength, knot strength, and knot-pull strength of the GO-CT suture were significantly improved compared to the CT suture. The biocompatibility of the GO-CT suture in vitro was checked by tetrazolium-based colorimetric assays and no cytotoxicity to L929 cells was found. In vivo, the subcutaneous implantation of GO-CT sutures in the dorsal skin of rats found no abnormalities by hematoxylin-eosin staining. Furthermore, there were no significant changes in the gene expression of the inflammatory mediators, interleukin 1ß (IL-1ß), tumor necrosis factor-α, IL-6, IL-17A, interferon-γ, or IL-10; however, the expression of transforming growth factor ß was significantly increased in the first week. In summary, GO-CT sutures may have potential as a suture material in the clinic.

Astilbin Inhibits the Activity of Sortase A from Streptococcus mutans.

Streptococcus mutans (S. mutans) is the primary etiological agent of dental caries. The S. mutans enzyme sortase A (SrtA) is responsible for anchoring bacterial cell wall surface proteins involved in host cell attachment and biofilm formation. Thus, SrtA is an attractive target for inhibiting dental caries caused by S. mutans-associated acid fermentation. In this study, we observed that astilbin, a flavanone compound extracted from Rhizoma Smilacis Glabrae, has potent inhibitory activity against the S. mutans SrtA, with an IC50 of 7.5 µg/mL. In addition, astilbin was proven to reduce the formation of biofilm while without affecting the growth of S. mutans. The results of a molecular dynamics simulation and a mutation analysis revealed that the Arg213, Leu111, and Leu116 of SrtA are important for the interaction between SrtA and astilbin. The results of this study demonstrate the potential of using astilbin as a nonbactericidal agent to modulate pathogenicity of S. mutans by inhibiting the activity of SrtA.

Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation.

The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl4)-induced acute liver injury. Mice were intraperitoneally injected with CCl4 (0.15ml/kg). In CCl4+OCA group, mice were orally with OCA (5mg/kg) 48, 24 and 1h before CCl4. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl4-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl4-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl4-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl4-induced hepatic pro-inflammatory gene Tnf-α and Il-1ß. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl4-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl4-induced acute liver injury. These results suggest that OCA protects against CCl4-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury.

[Chemical Constituents from Infructescence of Platycarya strobilacea].

Objective: To study the chemical constituents of the chloroform and acetic ether fractions from infructescence of Platycarya strobilacea. Methods: The compounds were isolated and purified by various chromatographic methods. Spectral analysis were taken to identify the structures. Results: Eleven compounds were isolated and identified as dotriacontane( 1), ursolic acid( 2),hexacosene( 3),ß-sitosterol( 4),daucosterol( 5),2,5,8-trihydroxy-3-methoxy-1,4-naphthalenedione( 6),3,3'-dimethoxyellagic acid( 7),ellagic acid( 8),4'-hydroxyisoflavone-7-O-ß-D-galactoside( 9),3,3'-dimethoxyellagic acid-4'-O-ß-D-xylopyroside( 10), gallic acid( 11). Conclusion: Compounds 1,3 ~ 6,9,10 are isolated from this genus for the first time, compounds 1 ~ 6,9,10 are isolated from this plant for the first time.

MicroRNA-30b functions as a tumour suppressor in human colorectal cancer by targeting KRAS, PIK3CD and BCL2.

Colorectal cancer (CRC) is the third most common cancer in the USA. MicroRNAs play important roles in the pathogenesis of CRC. In this study, we investigated the role of miR-30b in CRC and found that its expression was significantly lower in CRC tissues than that in normal tissues. We showed that a low expression level of miR-30b was closely related to poor differentiation, advanced TNM stage and poor prognosis of CRC. Further experiments showed that over-expression of miR-30b suppressed CRC cell proliferation in vitro and tumour growth in vivo. Specifically, miR-30b promoted G1 arrest and induced apoptosis. Moreover, KRAS, PIK3CD and BCL2 were identified as direct and functional targets of miR-30b. MiR-30b directly targeted the 3'-untranslated regions of their mRNAs and repressed their expression. This study revealed functional and mechanistic links between miRNA-30b and oncogene KRAS, PIK3CD and BCL2 in the pathogenesis of CRC. MiR-30b not only plays important roles in the regulation of cell proliferation and tumour growth in CRC, but is also a potential prognostic marker or therapeutic target for CRC. Restoration of miR-30b expression may represent a promising therapeutic approach for targeting malignant CRC.

Metastasis-Associated in Colon Cancer-1 Associates With Poor Prognosis and Promotes Cell Invasion and Angiogenesis in Human Cervical Cancer.

OBJECTIVE: The aim of this study is to investigate the clinicopathologic significance and potential role of metastasis-associated in colon cancer-1 (MACC1) in the progression of cervical cancer. METHODS: MACC1 expression was examined in cervical cancer cell lines, 6 matched cervical cancer tissues, and adjacent noncancerous tissues using Western blotting and real-time reverse transcriptase polymerase chain reaction. MACC1 protein expression and localization were determined in 181 paraffin-embedded archived cervical cancer samples using immunohistochemistry. Statistical analyses were applied to evaluate the clinicopathologic significance. The effects of MACC1 on cell migration, invasion, and angiogenesis were examined using migration assay, wound healing assay, 3-dimensional morphogenesis assay, and chicken chorioallantoic membrane assay. Western blotting was performed to examine the impact of MACC1 on the Akt and nuclear factor κB signaling pathways. RESULTS: Both protein and messenger RNA levels of MACC1 was up-regulated in cervical cancer cell lines and cervical cancer tissues, as compared with normal tissues. High MACC1 expression was detected in 96 (53%) of 181 of the cervical cancer tissues. In addition, high MACC1 expression correlated significantly with aggressiveness of cervical cancer, including International Federation of Gynecology and Obstetric stage (P = 0.001), pelvic lymph node metastasis (P = 0.004), recurrence (P = 0.037), and poor survival (P = 0.001). Moreover, enforced expression of MACC1 in cervical cancer cell lines significantly enhanced cell migration, invasion, and angiogenesis. Conversely, knockdown of MACC1 caused an inhibition of cell migration, invasion, and angiogenesis. Up-regulation of MACC1 increased, but knockdown of MACC1 decreased the expression of matrix metalloproteinase-2 and matrix metalloproteinase-9. Furthermore, enforced expression of MACC1 could enhance, but knockdown of MACC1 could reduce AKT and nuclear factor κB pathway activity. CONCLUSIONS: Our findings suggest that MACC1 protein, as a valuable marker of cervical cancer prognosis, plays an important role in the progression of human cervical cancer cells.

[Hepatocyte growth factor intervention on rats with pulmonary hypertension and effect of endothelial cell membrane microparticles].

OBJECTIVE: To explore the effect of transfection of adenovirus carrying hepatocyte growth factor (HGF) on pulmonary arterial hypertension (PAH) and endothelial cell membrane microparticles (EMP) in a rat model, and the underlying mechanism. METHODS: Forty healthy male SD rats were randomly divided into four groups, the normal control group (NOR group), monocrotaline (MCT)-induced pulmonary hypertension group (PAH group), HGF treatment of PAH group (HGF group and THGF group) each with 10 rats. NOR group and the PAH Group: intratracheal instillation of 0.2 ml PBS solution; HGF group: intratracheal instillation of 0.2 ml HGF one times; THGF Group: intratracheal instillation of 0.2 ml HGF one times, and then 1 week repeat again. Different interventions after 2 weeks, the rats was measured mean pulmonary arterial pressure, right ventricular hypertrophy index calculation, HE staining index of pulmonary arterial wall thickness, area index, plasma levels of endothelial cell microparticles. RESULTS: HGF intratracheal instillation after 2 weeks, HGF and THGF groups of SD rats mPAP, RVHI, TI, AI decreased significantly compared with PAH group (P < 0.05). PAH group was increased in particulate levels at different time points significantly higher levels of horizontal (P < 0.05). The EMP levels in HGF group which at 7 and 14 days after dosing were significantly decreased compared with PAH.It still higher than the NOR group (P < 0.05). And after administration of 7 days, 14 days, the EMP level of HGF group was significantly lower than before administration (P < 0.05). CONCLUSIONS: Thought airway instillation transfected HGF, pulmonary artery pressure can reduce greater degree, but can't achieve complete reversal. It can inhibit the pulmonary artery wall thickening and maintain effective lumen area, delaying the right ventricular hypertrophy by reducing the membrane particles within the lung, thereby promoting endothelial cell repair to achieve the goal of intervention in pulmonary hypertension.

Association between blood arsenic concentration and dyslipidemia: Mediating effect of lipid peroxidation in the elderly.

BACKGROUND: The earlier investigations have revealed heavy metals exposure is implicated in the pathogenesis of dyslipidemia. The goal was to evaluated the relationship of blood arsenic (As) concentration with dyslipidemia in the elderly through a cross-sectional study. METHODS: The entire 360 elderly population were selected. Fasting blood specimens, demographic information, and clinical characteristics were obtained. The concentration of blood As was detected using ICP-MS. Serum 8-iso-PGF2α, a biomarker of lipid peroxidation, was measured by ELISA. RESULTS: Pearson correlative analysis hinted there were strong relationships of blood As with liver function indices in the elderly. Besides, blood As was positively associated with total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C), and apolipoprotein A-I (ApoA I). Further multivariate linear and logistic regression suggested that the incidences of TC and LDL-C elevation were upregulated with the rising tertiles of blood As. Blood As was positively related with the prevalence of dyslipidemia (OR=3.609; 95%CI: 1.353, 6.961). Additionally, serum 8-iso-PGF2α was dramatically and positively linked to the levels of blood As and lipid profiles. Mediation analyses verified that 8-iso-PGF2α partially mediated the correlations between blood As with TC (36.63%) and LDL-C (34.03%). CONCLUSION: Blood As concentration is positively related to lipid profiles in the elderly. Higher blood As concentration elevates the prevalence of dyslipidemia. Lipid peroxidation partially mediates the correlation of As exposure with dyslipidemia.

Outcomes of single-procedure radiofrequency catheter ablation for idiopathic ventricular arrhythmias: a single-centre retrospective cohort study.

OBJECTIVES: Radiofrequency catheter ablation is the first-line treatment for idiopathic premature ventricular complexes (PVCs) and ventricular tachycardias (VTs). However, the outcomes were less compared among the categories. The study aims to assess the effectiveness and safety of catheter ablation for idiopathic PVC/VTs in a single high-volume centre, using the right ventricular outflow tract (RVOT) as a reference. DESIGN: Retrospective cohort study. SETTING: Patient data were collected from a tertiary hospital in Guizhou, China. PARTICIPANTS: Between September 2013 and September 2022, 1028 patients (male: 41.3%; age: 46.5±15.6 years) who underwent the first catheter ablation for idiopathic monomorphic PVC/VTs were enrolled. OUTCOME MEASURES: Acute success, procedure-related complications, and long-term recurrence were assessed. Antiarrhythmic drugs (AADs) were not administrated after procedures unless recurrence was identified. RESULTS: The overall acute success rate was 90.3%, with 368 patients (35.8%) experiencing left ventricular PVC/VTs. No cases of third-degree atrioventricular block or death were reported. Complications were more common in patients with left ventricular PVC/VTs than those with right-sided ones (4.6% vs 0.1%, p<0.001). A total of 926 patients (90.1%) were followed up for an average of 9.7±3.7 months, and only the PVC/VTs category was found to be associated with long-term success rates. The RVOT, endocardial left ventricular outflow tract (endoLVOT), tricuspid annulus (TA) free wall, posterior septum and fascicular VT had long-term success rates exceeding 85%. Other types of PVC/VTs showed significantly higher risks of recurrence. CONCLUSIONS: Besides RVOT and fascicular VT, single-procedure catheter ablation without AADs is highly effective for endoLVOT, TA-free wall and posterior septum. Patients with left ventricular PVC/VTs have higher complication risks compared with right ones.