N-terminal truncated trehalose-6-phosphate synthase 1 gene (△NIbTPS1) enhances the tolerance of sweet potato to abiotic stress.

Sweet potato [Ipomoea batatas (L.) Lam], the crop with the seventh highest annual production globally, is susceptible to various adverse environmental influences, and the study of stress-resistant genes is important for improving its tolerance to abiotic stress. The enzyme trehalose-6-phosphate synthase (TPS) is indispensable in the one pathway for synthesizing trehalose in plants. TPS is known to participate in stress response in plants, but information on TPS in sweet potato is limited. This study produced the N-terminal truncated IbTPS1 gene (△NIbTPS1) overexpression lines of Arabidopsis thaliana and sweet potato. Following salt and mannitol-induced drought treatment, the germination rate, root elongation, and fresh weight of the transgenic A. thaliana were significantly higher than that in the wild type. Overexpression of △NIbTPS1 elevated the photosynthetic efficiency (Fv/Fm) and the activity of superoxide dismutase, peroxidase, catalase, and ascorbate peroxidase in sweet potato during drought and salt treatments, while reducing malondialdehyde and O2∙- contents, although expression of the trehalose-6-phosphate phosphatase gene IbTPP and trehalose concentrations were not affected. Thus, overexpressing the △NIbTPS1 gene can improve the stress tolerance of sweet potato to drought and salt by enhancing the photosynthetic efficiency and antioxidative enzyme system. These results will contribute to understand the functions of the △NIbTPS1 gene and trehalose in the response mechanism of higher plants to abiotic stress.

Overexpression of sweetpotato glutamylcysteine synthetase (IbGCS) in Arabidopsis confers tolerance to drought and salt stresses.

Various environmental stresses induce the production of reactive oxygen species (ROS), which have deleterious effects on plant cells. Glutathione (GSH) is an antioxidant used to counteract reactive oxygen species. Glutathione is produced by glutamylcysteine synthetase (GCS) and glutathione synthetase (GS). However, evidence for the GCS gene in sweetpotato remains scarce. In this study, the full-length cDNA sequence of IbGCS isolated from sweetpotato cultivar Xu18 was 1566 bp in length, which encodes 521 amino acids. The qRT-PCR analysis revealed a significantly higher expression of the IbGCS in sweetpotato flowers, and the gene was induced by salinity, abscisic acid (ABA), drought, extreme temperature and heavy metal stresses. The seed germination rate, root elongation and fresh weight were promoted in T3 Arabidopsis IbGCS-overexpressing lines (OEs) in contrast to wild type (WT) plants under mannitol and salt stresses. In addition, the soil drought and salt stress experiment results indicated that IbGCS overexpression in Arabidopsis reduced the malondialdehyde (MDA) content, enhanced the levels of GCS activity, GSH and AsA content, and antioxidant enzyme activity. In summary, overexpressing IbGCS in Arabidopsis showed improved salt and drought tolerance.

Identification of patients with favorable prognosis after resection in intermediate-stage-hepatocellular carcinoma.

BACKGROUNDS: It is unclear which patients benefit from resection in intermediate-stage-hepatocellular carcinoma (HCC). The authors aimed to identify high-risk patients for early recurrence among patients with resectable intermediate-stage HCC. METHODS: This multicenter retrospective study included patients who underwent resection or trans-arterial chemoembolization (TACE) for intermediate-stage HCC (2008-2019). Multivariable Cox proportional analysis was performed to identify high-risk patients when treated with resection. A prediction score for 2-year recurrence-free survival (RFS) was developed using the training cohort and validated. The 2-year RFS in each risk group was compared with that in TACE group, after propensity score matching (PSM). RESULTS: A total of 1686 patients were included (480 and 1206 patients in the resection and TACE groups). During a median follow-up of 31.4 months, the 2-year RFS was significantly higher in the resection (47.7%) than in the TACE group (19.8%) [adjusted hazard ratio (aHR)=1.471, 95% CI: 1.199-1.803, P <0.001). On multivariate analysis, alpha-fetoprotein ≥5.0 ng/ml (aHR=0.202), ALBI grade ≥2 (aHR=0.709), tumor number ≥3 (aHR=0.404), and maximal tumor size ≥5 cm (aHR=0.323) were significantly associated with the lower risk of 2-year RFS in the resection group. The newly developed Surgery Risk score in BCLC-B (SR-B score) with four significant risk factors showed an area under the curve of 0.801 for the 2-year RFS and was validated. Based on the SR-B score, low-risk patients had a significantly higher 2-year RFS (training: aHR=5.834; validation: aHR=5.675) than high-risk patients (all P <0.001) did. In a PSM cohort, a low-risk resection group had a significantly higher (aHR=3.891); a high-risk resection group had a comparable 2-year RFS to those treated with TACE (aHR=0.816). CONCLUSIONS: Resection may be beneficial for resectable intermediate-stage HCC based on the SR-B score.

PAGE-B incorporating moderate HBV DNA levels predicts risk of HCC among patients entering into HBeAg-positive chronic hepatitis B.

BACKGROUND & AIMS: Recent studies reported that moderate HBV DNA levels are significantly associated with hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-positive, non-cirrhotic patients with chronic hepatitis B (CHB). We aimed to develop and validate a new risk score to predict HCC development using baseline moderate HBV DNA levels in patients entering into HBeAg-positive CHB from chronic infection. METHODS: This multicenter cohort study recruited 3,585 HBeAg-positive, non-cirrhotic patients who started antiviral treatment with entecavir or tenofovir disoproxil fumarate at phase change into CHB from chronic infection in 23 tertiary university-affiliated hospitals of South Korea (2012-2020). A new HCC risk score (PAGED-B) was developed (training cohort, n = 2,367) based on multivariable Cox models. Internal validation using bootstrap sampling and external validation (validation cohort, n = 1,218) were performed. RESULTS: Sixty (1.7%) patients developed HCC (median follow-up, 5.4 years). In the training cohort, age, gender, platelets, diabetes and moderate HBV DNA levels (5.00-7.99 log10 IU/ml) were independently associated with HCC development; the PAGED-B score (based on these five predictors) showed a time-dependent AUROC of 0.81 for the prediction of HCC development at 5 years. In the validation cohort, the AUROC of PAGED-B was 0.85, significantly higher than for other risk scores (PAGE-B, mPAGE-B, CAMD, and REAL-B). When stratified by the PAGED-B score, the HCC risk was significantly higher in high-risk patients than in low-risk patients (sub-distribution hazard ratio = 8.43 in the training and 11.59 in the validation cohorts, all p <0.001). CONCLUSIONS: The newly established PAGED-B score may enable risk stratification for HCC at the time of transition into HBeAg-positive CHB. IMPACT AND IMPLICATIONS: In this study, we developed and validated a new risk score to predict hepatocellular carcinoma (HCC) development in patients entering into hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) from chronic infection. The newly established PAGED-B score, which included baseline moderate HBV DNA levels (5-8 log10 IU/ml), improved on the predictive performance of prior risk scores. Based on a patient's age, gender, diabetic status, platelet count, and moderate DNA levels (5-8 log10 IU/ml) at the phase change into CHB from chronic infection, the PAGED-B score represents a reliable and easily available risk score to predict HCC development during the first 5 years of antiviral treatment in HBeAg-positive patients entering into CHB. With a scoring range from 0 to 12 points, the PAGED-B score significantly differentiated the 5-year HCC risk: low <7 points and high ≥7 points.

Mitochondrial E3 ligase MARCH5 is a safeguard against DNA-PKcs-mediated immune signaling in mitochondria-damaged cells.

Mitochondrial dysfunction is important in various chronic degenerative disorders, and aberrant immune responses elicited by cytoplasmic mitochondrial DNA (mtDNA) may be related. Here, we developed mtDNA-targeted MTERF1-FokI and TFAM-FokI endonuclease systems to induce mitochondrial DNA double-strand breaks (mtDSBs). In these cells, the mtDNA copy number was significantly reduced upon mtDSB induction. Interestingly, in cGAS knockout cells, synthesis of interferon ß1 and interferon-stimulated gene was increased upon mtDSB induction. We found that mtDSBs activated DNA-PKcs and HSPA8 in a VDAC1-dependent manner. Importantly, the mitochondrial E3 ligase MARCH5 bound active DNA-PKcs in cells with mtDSBs and reduced the type І interferon response through the degradation of DNA-PKcs. Likewise, mitochondrial damage caused by LPS treatment in RAW264.7 macrophage cells increased phospho-HSPA8 levels and the synthesis of mIFNB1 mRNA in a DNA-PKcs-dependent manner. Accordingly, in March5 knockout macrophages, phospho-HSPA8 levels and the synthesis of mIFNB1 mRNA were prolonged after LPS stimulation. Together, cytoplasmic mtDNA elicits a cellular immune response through DNA-PKcs, and mitochondrial MARCH5 may be a safeguard to prevent persistent inflammatory reactions.

Impact of Low Skeletal Muscle Mass on Long-Term Outcomes in Hepatocellular Carcinoma Treated with Trans-Arterial Radioembolization: A Retrospective Multi-Center Study.

Trans-arterial radioembolization (TARE) is a form of radiation therapy performed for hepatocellular carcinoma (HCC) via selective intra-arterial injection of Yttrium-90-loaded microspheres. This was a multi-center retrospective study of consecutive patients with HCC who underwent TARE between July 2009 and May 2019. Using pre-treatment computed tomography imaging, the total cross-sectional area (cm2) of the abdominal skeletal muscle at the third lumbar vertebra was measured. The skeletal muscle index (SMI) was calculated by normalizing the muscle area to patient height. In total, 347 patients (median age, 65 years; 284 male) were included in the study. A total of 108 (31.1%) patients had portal vein tumor thrombus (PVTT), and 126 (36.3%) were classified as LSMM. The median overall survival (OS) was 28.1 months (95% CI, 24.8-35.7), and median progression-free survival was 8.0 months (95% CI, 6.4-9.4). Multivariate Cox regression analysis revealed that LSMM (hazard ratio [HR], 1.36; 95% CI, 1.00-1.85, p = 0.05), PVTT (HR, 1.82; 95% CI, 1.33-2.49, p < 0.01), alpha-fetoprotein (AFP) (≥200 ng/mL) (HR 1.41; 95% CI, 1.04-1.92, p = 0.03), and albumin-bilirubin grade (2-3) (HR 1.74; 95% CI, 1.24-2.43, p < 0.01) were independently associated with poor OS. TARE provided favorable long-term outcomes for patients with advanced HCC. Pre-treatment LSMM independently associated with survival, suggesting its utility as a surrogate biomarker for identifying TARE candidates.

IbINV Positively Regulates Resistance to Black Rot Disease Caused by Ceratocystis fimbriata in Sweet Potato.

Black rot disease, caused by Ceratocystis fimbriata Ellis & Halsted, severely affects both plant growth and post-harvest storage of sweet potatoes. Invertase (INV) enzymes play essential roles in hydrolyzing sucrose into glucose and fructose and participate in the regulation of plant defense responses. However, little is known about the functions of INV in the growth and responses to black rot disease in sweet potato. In this study, we identified and characterized an INV-like gene, named IbINV, from sweet potato. IbINV contained a pectin methylesterase-conserved domain. IbINV transcripts were most abundant in the stem and were significantly induced in response to C. fimbriata, salicylic acid, and jasmonic acid treatments. Overexpressing IbINV in sweet potato (OEV plants) led to vigorous growth and high resistance to black rot disease, while the down-regulation of IbINV by RNA interference (RiV plants) resulted in reduced plant growth and high sensitivity to black rot disease. Furthermore, OEV plants contained a decreased sucrose content and increased hexoses content, which might be responsible for the increased INV activities; not surprisingly, RiV plants showed the opposite effects. Taken together, these results indicate that IbINV positively regulates plant growth and black rot disease resistance in sweet potato, mainly by modulating sugar metabolism.

MARCH5-dependent NLRP3 ubiquitination is required for mitochondrial NLRP3-NEK7 complex formation and NLRP3 inflammasome activation.

The NLRP3 inflammasome plays a key role in responding to pathogens, and endogenous damage and mitochondria are intensively involved in inflammasome activation. The NLRP3 inflammasome forms multiprotein complexes and its sequential assembly is important for its activation. Here, we show that NLRP3 is ubiquitinated by the mitochondria-associated E3 ligase, MARCH5. Myeloid cell-specific March5 conditional knockout (March5 cKO) mice failed to secrete IL-1ß and IL-18 and exhibited an attenuated mortality rate upon LPS or Pseudomonas aeruginosa challenge. Macrophages derived from March5 cKO mice also did not produce IL-1ß and IL-18 after microbial infection. Mechanistically, MARCH5 interacts with the NACHT domain of NLRP3 and promotes K27-linked polyubiquitination on K324 and K430 residues of NLRP3. Ubiquitination-defective NLRP3 mutants on K324 and K430 residues are not able to bind to NEK7, nor form NLRP3 oligomers leading to abortive ASC speck formation and diminished IL-1ß production. Thus, MARCH5-dependent NLRP3 ubiquitination on the mitochondria is required for NLRP3-NEK7 complex formation and NLRP3 oligomerization. We propose that the E3 ligase MARCH5 is a regulator of NLRP3 inflammasome activation on the mitochondria.

Overexpression of potato ORANGE (StOR) and StOR mutant in Arabidopsis confers increased carotenoid accumulation and tolerance to abiotic stress.

ORANGE (OR) plays essential roles in regulating carotenoid homeostasis and enhancing the ability of plants to adapt to environmental stress. However, OR proteins have been functionally characterized in only a few plant species, and little is known about the role of potato OR (StOR). In this study, we characterized the StOR gene in potato (Solanum tuberosum L. cv. Atlantic). StOR is predominantly localized to the chloroplast, and its transcripts are tissue-specifically expressed and significantly induced in response to abiotic stress. Compared with wild type, overexpression of StOR increased ß-carotene levels up to 4.8-fold, whereas overexpression of StORHis with a conserved arginine to histidine substitution promoted ß-carotene accumulation up to 17.6-fold in Arabidopsis thaliana calli. Neither StOR nor StORHis overexpression dramatically affected the transcript levels of carotenoid biosynthetic genes. Furthermore, overexpression of either StOR or StORHis increased abiotic stress tolerance in Arabidopsis, which was associated with higher photosynthetic capacity and antioxidative activity. Taken together, these results indicate that StOR could be exploited as a potential new genetic tool for the improvement of crop nutritional quality and environmental stress tolerance.

Differential Responses of Antioxidant Enzymes and Lignin Metabolism in Susceptible and Resistant Sweetpotato Cultivars during Root-Knot Nematode Infection.

Root-knot nematodes (RKN) cause significant damage to sweetpotato plants and cause significant losses in yield and quality. Reactive oxygen species (ROS) play an important role in plant defenses, with levels of ROS-detoxifying antioxidant enzymes tightly regulated during pathogen infection. In this study, ROS metabolism was examined in three RKN-resistant and three RKN-susceptible sweetpotato cultivars. The antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) were assessed, as was lignin-related metabolism. In RKN-infected roots, both resistant and susceptible cultivars increased SOD activity to produce higher levels of hydrogen peroxide (H2O2). However, H2O2 removal by CAT activity differed between cultivars, with susceptible cultivars having higher CAT activity and lower overall H2O2 levels. In addition, the expression of phenylpropanoid-related phenylalanine ammonia-lyase and cinnamyl alcohol dehydrogenase genes, which encode enzymes involved in lignin metabolism, were higher in resistant cultivars, as were total phenolic and lignin contents. Enzyme activities and H2O2 levels were examined during the early (7 days) and late (28 days) phases of infection in representative susceptible and resistant cultivars, revealing contrasting changes in ROS levels and antioxidant responses in the different stages of infection. This study suggests that differences in antioxidant enzyme activities and ROS regulation in resistant and susceptible cultivars might explain reduced RKN infection in resistant cultivars, resulting in smaller RKN populations and overall higher resistance to infection and infestation by RKNs.

MAFLD might be better in identifying subjects with sarcopenia or cardiovascular risk than NAFLD: A nationwide study.

BACKGROUND AND AIM: Clinical features of non-alcoholic fatty liver disease (NAFLD), but not fulfilling the diagnostic criteria of metabolic dysfunction-associated fatty liver disease (MAFLD), remain unclear. We investigated the risk of sarcopenia and cardiovascular disease (CVD) in MAFLD and non-metabolic risk (MR) NAFLD. METHODS: Subjects were selected from the Korean National Health and Nutrition Examination Surveys 2008-2011. Liver steatosis was assessed using fatty liver index. Significant liver fibrosis was defined using fibrosis-4 index, categorized by age cut-offs. Sarcopenia was defined as the lowest quintile sarcopenia index. Atherosclerotic CVD (ASCVD) risk score > 10% was defined as high probability. RESULTS: A total of 7248 subjects had fatty liver (137 with non-MR NAFLD, 1752 with MAFLD/non-NAFLD, and 5359 with overlapping MAFLD and NAFLD). In non-MR NAFLD group 28 (20.4%) had significant fibrosis. The risk of sarcopenia (adjusted odds ratio [aOR] = 2.71, 95% confidence index [CI] = 1.27-5.78) and high probability of ASCVD (aOR = 2.79, 95% CI = 1.23-6.35) was significantly higher in MAFLD/non-NAFLD group than in non-MR NAFLD group (all P < 0.05). The risk of sarcopenia and high probability of ASCVD was similar between subjects with and without significant fibrosis in non-MR NAFLD group (all P > 0.05). However, the risk was significantly higher in MAFLD group than in non-MR NAFLD group (aOR = 3.38 for sarcopenia and 3.73 for ASCVD; all P < 0.05). CONCLUSIONS: The risks of sarcopenia and CVD were significantly higher in MAFLD group but did not differ according to fibrotic burden in non-MR NAFLD group. The MAFLD criteria might be better for identifying high-risk fatty liver disease than the NAFLD criteria.

Fibrotic Burden in the Liver Differs Across Metabolic Dysfunction-Associated Fatty Liver Disease Subtypes.

Background/Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is categorized into three subtypes: overweight/obese (OW), lean/normal weight with metabolic abnormalities, and diabetes mellitus (DM). We investigated whether fibrotic burden in liver differs across subtypes of MAFLD patients. Methods: This cross-sectional multicenter study was done in cohorts of subjects who underwent a comprehensive medical health checkup between January 2014 and December 2020. A total of 42,651 patients with ultrasound-diagnosed fatty liver were included. Patients were classified as no MAFLD, OW-MAFLD, lean-MAFLD, and DM-MAFLD. Advanced liver fibrosis was defined based on the nonalcoholic fatty liver disease fibrosis score (NFS) or fibrosis-4 (FIB-4) index. Results: The mean age of the patients was 50.0 years, and 74.1% were male. The proportion of patients with NFS-defined advanced liver fibrosis was the highest in DM-MAFLD (6.6%), followed by OW-MAFLD (2.0%), lean-MAFLD (1.3%), and no MAFLD (0.2%). The proportion of patients with FIB-4-defined advanced liver fibrosis was the highest in DM-MAFLD (8.6%), followed by lean-MAFLD (3.9%), OW-MAFLD (3.0%), and no MAFLD (2.0%). With the no MAFLD group as reference, the adjusted odds ratios (95% confidence intervals) for NFS-defined advanced liver fibrosis were 4.46 (2.09 to 9.51), 2.81 (1.12 to 6.39), and 9.52 (4.46 to 20.36) in OW-MAFLD, lean-MAFLD, and DM-MAFLD, respectively, and the adjusted odds ratios for FIB-4-defined advanced liver fibrosis were 1.03 (0.78 to 1.36), 1.14 (0.82 to 1.57), and 1.97 (1.48 to 2.62) in OW-MAFLD, lean-MAFLD, and DM-MAFLD. Conclusions: Fibrotic burden in the liver differs across MAFLD subtypes. Optimized surveillance strategies and therapeutic options might be needed for different MAFLD subtypes.

Association of Physical Activity With Risk of Liver Fibrosis, Sarcopenia, and Cardiovascular Disease in Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: International guidelines recommend physical activity for subjects with nonalcoholic fatty liver disease (NAFLD). This study investigated the association of physical activity with risk of liver fibrosis, sarcopenia, and cardiovascular disease (CVD) in NAFLD. METHODS: In this multicenter, retrospective study, 11,690 NAFLD subjects who underwent a health screening program and were assessed for physical activity (metabolic equivalent task [MET]-min/week) between 2014 and 2020 were recruited. Liver fibrosis was assessed by using the fibrosis-4 index, NAFLD fibrosis score, and FibroScan-AST score, sarcopenia by using multi-frequency bioelectric impedance analysis, and CVD risk by using atherosclerotic CVD (ASCVD) risk score, and coronary artery calcium (CAC) score were calculated. RESULTS: The prevalence of fibrosis, sarcopenia, high probability of ASCVD, and high CAC score significantly decreased with increasing quartiles of physical activity (all P for trend <.001). In a fully adjusted model, physical activity above 600 MET-min/week (≥third quartile) was independently associated with a reduced risk of fibrosis (adjusted odds ratio [aOR] = 0.59; 95% confidence interval [CI], 0.40-0.86), sarcopenia (aOR = 0.72; 95% CI, 0.58-0.88), high probability of ASCVD (aOR = 0.58; 95% CI, 0.46-0.73), and high CAC score (aOR = 0.32; 95% CI, 0.13-0.83; all P <.05). In addition, increasing amounts of physical activity were significantly associated with risk reduction between fibrosis, sarcopenia, and high probability of ASCVD (all P for trend <.001). In subjects with sarcopenic obesity or lean NAFLD, physical activity was also independently associated with reduced risk of fibrosis and high probability of ASCVD (all P <.05). CONCLUSIONS: Physical activity showed a protective effect against fibrosis, sarcopenia, and CVD in NAFLD.

Risk Stratification for Sarcopenic Obesity in Subjects With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: The impact of the severity of sarcopenic obesity (SO) in nonalcoholic fatty liver disease (NAFLD) on the risk of significant liver fibrosis or cardiovascular disease (CVD) remains unclear. We aimed to identify high-risk subjects with SO for significant liver fibrosis or CVD among subjects with SO and NAFLD. METHODS: This multicenter, retrospective study involved 23,889 subjects with NAFLD who underwent a health screening program (2014-2020). Sarcopenia was defined based on gender-specific sarcopenia index cutoff using multi-frequency bioelectric impedance analysis. High-risk subjects with SO were defined as those with significant liver fibrosis by fibrosis-4 index >2.67 or atherosclerotic CVD risk score >20%. Multivariable logistic regression analysis for identifying high-risk subjects with SO was performed in a cross-sectional cohort with SO, and further validation was performed in a longitudinal cohort. RESULTS: SO prevalence was 5.4% (n = 1297 of 23,889). Older age (unstandardized beta [ß] = 3.23; P < .001), male (ß = 1.66; P = .027), sarcopenia index (ß = -6.25; P = .019), and metabolic syndrome (ß = 1.75; P < .001) were significant risk factors for high-risk SO. Based on a high-risk SO screening model, high-risk subjects with SO had significantly higher odds of significant liver fibrosis (training: adjusted odds ratio [aOR], 3.72; validation: aOR, 2.38) or CVD (training: aOR, 5.20; validation: aOR, 3.71) than subjects without SO (all P < .001). In subgroup analyses, the cumulative incidence of significant liver fibrosis or CVD development was significantly higher in high-risk subjects with SO than in low-risk subjects with SO in a longitudinal cohort considering all-cause mortality and liver transplantation as competing risks (sub-distribution hazard ratio, 5.37; P < .001). CONCLUSION: The high-risk screening model may enable the identification of high-risk subjects with SO with NAFLD.

Metabolic dysfunction associated fatty liver disease identifies subjects with cardiovascular risk better than non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is the main cause of mortality in subjects with non-alcoholic fatty liver disease (NAFLD). We investigated the association between CVD risk and metabolic dysfunction-associated fatty liver disease (MAFLD) or NAFLD and the influence of significant liver fibrosis on the CVD risk. METHODS: Subjects who underwent a comprehensive medical check-up were recruited (2014-2019). Significant liver fibrosis was defined using NAFLD fibrosis score, fibrosis-4 index, aspartate aminotransferase to platelet ratio index, or FibroScan-aspartate aminotransferase score. High probability of atherosclerotic CVD (ASCVD) was defined as ASCVD risk score > 10%. RESULTS: Of the study population (n = 78 762), 27 047 (34.3%) and 24 036 (30.5%) subjects had MAFLD and NAFLD respectively. A total of 1084 (4.0%) or 921 (3.8%) subjects had previous CVD history in MAFLD or NAFLD subgroup respectively. The previous CVD history and high probability of ASCVD were significantly higher in MAFLD or NAFLD subgroup with significant liver fibrosis than in the other groups (all p < .001). In multivariable analysis, MAFLD was independently associated with previous CVD history after adjusting for confounders (adjusted odds ratio [aOR] = 1.10, p = .038), whereas NAFLD was not (all p > .05). MAFLD (aOR = 1.40) or NAFLD (aOR = 1.22) was independently associated with high probability of ASCVD after full adjustment respectively (all p < .001). Significant liver fibrosis was independently associated with previous CVD history and high probability of ASCVD after adjustment in MAFLD or NAFLD subgroup respectively (all p < .05). CONCLUSION: MAFLD might better identify subjects with CVD risk than NAFLD. Fibrosis assessment might be helpful for detailed prognostication in subjects with MAFLD.

Regulation of nuclear DNA damage response by mitochondrial morphofunctional pathway.

Cells are constantly challenged by genotoxic stresses that can lead to genome instability. The integrity of the nuclear genome is preserved by the DNA damage response (DDR) and repair. Additionally, these stresses can induce mitochondria to transiently hyperfuse; however, it remains unclear whether canonical DDR is linked to these mitochondrial morphological changes. Here, we report that the abolition of mitochondrial fusion causes a substantial defect in the ATM-mediated DDR signaling. This deficiency is overcome by the restoration of mitochondria fusion. In cells with fragmented mitochondria, genotoxic stress-induced activation of JNK and its translocation to DNA lesion are lost. Importantly, the mitochondrial fusion machinery of MFN1/MFN2 associates with Sab (SH3BP5) and JNK, and these interactions are indispensable for the Sab-mediated activation of JNK and the ATM-mediated DDR signaling. Accordingly, the formation of BRCA1 and 53BP1 foci, as well as homology and end-joining repair are impaired in cells with fragmented mitochondria. Together, these data show that mitochondrial fusion-dependent JNK signaling is essential for the DDR, providing vital insight into the integration of nuclear and cytoplasmic stress signals.

Exercise reduces the risk of chronic kidney disease in individuals with nonalcoholic fatty liver disease: A nationwide cohort study.

AIMS: Recent studies of individuals with nonalcoholic fatty liver disease (NAFLD) have indicated benefits of exercise in improving outcomes. We investigated whether exercise reduces the risk of chronic kidney disease (CKD) in individuals with NAFLD. METHODS: A total of 7275 participants from the Korea National Health and Nutrition Examination Survey (KNHANES) cohort, and 40,418 participants with NAFLD from the National Health Insurance Service (NHIS) cohort were included for the cross-sectional and longitudinal analyses, respectively. For the cross-sectional analysis, the primary outcome was prevalent CKD, defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2. For the longitudinal analysis, the primary outcome was incident CKD, defined as the occurrence of eGFR <60 mL/min/1.73m2 or proteinuria (≥ trace) on two consecutive measurements during follow-up. RESULTS: In the KNHANES cohort, prevalent CKD was observed in 229 (6.1%), 48 (2.6%), and 36 (2.1%) participants in the 0, 1-2, and ≥ 3 exercise sessions/week groups, respectively. The likelihood of prevalent CKD was lowest in participants allocated to the ≥ 3 sessions/week group (adjusted OR 0.49; 95% CI, 0.33-0.71; P < 0.001). During a median follow-up of 5.0 years in the NHIS cohort, incident CKD occurred in 1,047 (9.7/1,000 person-years), 188 (7.3/1,000 person-years), and 478 (7.4/1,000 person-years) participants in the 0, 1-2, and ≥ 3 sessions/week groups, respectively. The risk of incident CKD was lowest in participants allocated to the ≥ 3 sessions/week group (adjusted HR 0.85; 95% CI, 0.76-0.95; P = 0.004). CONCLUSIONS: Exercise was significantly associated with a reduced risk of both prevalent and incident CKD in individuals with NAFLD.

Flooding Tolerance in Sweet Potato (Ipomoea batatas (L.) Lam) Is Mediated by Reactive Oxygen Species and Nitric Oxide.

Flooding is harmful to almost all higher plants, including crop species. Most cultivars of the root crop sweet potato are able to tolerate environmental stresses such as drought, high temperature, and high salinity. They are, however, relatively sensitive to flooding stress, which greatly reduces yield and commercial value. Previous transcriptomic analysis of flood-sensitive and flood-resistant sweet potato cultivars identified genes that were likely to contribute to protection against flooding stress, including genes related to ethylene (ET), reactive oxygen species (ROS), and nitric oxide (NO) metabolism. Although each sweet potato cultivar can be classified as either tolerant or sensitive to flooding stress, the molecular mechanisms of flooding resistance in ET, ROS, and NO regulation-mediated responses have not yet been reported. Therefore, this study characterized the regulation of ET, ROS, and NO metabolism in two sweet potato cultivars-one flood-tolerant cultivar and one flood-sensitive cultivar-under early flooding treatment conditions. The expression of ERFVII genes, which are involved in low oxygen signaling, was upregulated in leaves during flooding stress treatments. In addition, levels of respiratory burst oxidase homologs and metallothionein-mediated ROS scavenging were greatly increased in the early stage of flooding in the flood-tolerant sweet potato cultivar compared with the flood-sensitive cultivar. The expression of genes involved in NO biosynthesis and scavenging was also upregulated in the tolerant cultivar. Finally, NO scavenging-related MDHAR expressions and enzymatic activity were higher in the flood-tolerant cultivar than in the flood-sensitive cultivar. These results indicate that, in sweet potato, genes involved in ET, ROS, and NO regulation play an important part in response mechanisms against flooding stress.