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Background: Oxidative stress is widely acknowledged as a key pathogenic mechanism in diabetic nephropathy (DN). In recent years, the role of oxidative stress in DN has garnered increasing attention. However, no bibliometric analysis has yet been conducted on the relationship between oxidative stress and DN. This study aims to systematically analyze the relevant literature, identify trends in research, assess current hotspots, and predict future directions., Methods: We retrieved literature related to oxidative stress and DN from the Web of Science Core Collection database. We analyzed data on publication volume, countries/regions, institutions, journals, keywords, and other relevant metrics using VOSviewer, the Bibliometrix R package, and CiteSpace., Results: From 2014 to 2024, a total of 4076 publications related to oxidative stress and DN were published across 755 journals, showing a consistent upward trend each year. China and the United States are the leading contributors in this field and demonstrate close collaborative efforts. The top contributors by country, institution, journal, and author include: China (1919 publications), Jilin University and Central South University (69 publications each), BIOMEDICINE & PHARMACOTHERAPY (117 publications), and Prof. Sun Lin (33 publications). The most frequent keyword is "oxidative stress" (3683 occurrences). In the co-citation analysis, Alicic RZ's 2017 study was the most cited (144 citations). These findings highlight the critical importance of investigating the pathogenesis of DN from the oxidative stress perspective., Conclusion: This study demonstrates a steady increase in research on oxidative stress in DN since 2014, highlighting its central role in the pathogenesis of DN. Future research should focus on the molecular mechanisms of oxidative stress in DN and explore its therapeutic potential, to provide new strategies for the prevention and treatment of DN., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Wang, Wu, He, Chen, Jin, Zuo, Yang, Gao, Zhou and Gao.)

This study aims to explore the correlation between renal blood perfusion (RBP) and diabetic nephropathy (DN)., Methods: A total of 72 mice included db/db and db/m mice at the ages of 6, 14, and 22 weeks, forming six groups. RBP was assessed using Laser Speckle Contrast Imaging (LSCI). Kidney function markers and the extent of pathological damage were evaluated. Pearson correlation analysis was employed to predict the relationship between RBP and various indicators of kidney damage., Results: Compared to db/m mice of all ages, 6-week-old db/db mice showed no significant difference in kidney function markers and had no apparent pathological damage. However, db/db mice at other ages showed deteriorating kidney functions and evident pathological damage, which worsened with age. The RBP in db/m mice of all ages and 6-week-old db/db mice showed no significant difference; however, RBP in db/db mice demonstrated a significant declining trend with age. The correlation between RBP and kidney damage indicators was as follows: 24 h urinary microalbumin (r=-0.728), urinary transferrin (r=-0.834), urinary beta2-microglobulin (r=-0.755), urinary monocyte chemoattractant protein-1 (r=-0.786), Masson's trichrome staining (r=-0.872), and Periodic Acid-Schiff staining (r=-0.908)., Conclusion: RBP is strongly correlated with the extent of diabetic kidney damage.

Background: Loss-of-function mutations of ZBTB24 cause immunodeficiency, centromeric instability, and facial anomalies syndrome 2 (ICF2). ICF2 is a rare autosomal recessive disorder with immunological defects in serum antibodies and circulating memory B cells, resulting in recurrent and sometimes fatal respiratory and gastrointestinal infections. The genotype-phenotype correlation in patients with ICF2 indicates an essential role of ZBTB24 in the terminal differentiation of B cells., Methods: We used the clustered regularly interspaced short palindromic repeats (CRISPER)/Cas9 technology to generate B cell specific Zbtb24-deficient mice and verified the deletion specificity and efficiency by quantitative polymerase chain reaction (Q-PCR) and western blotting analyses in fluorescence-activated cell sorting (FACS)-sorted cells. The development, phenotype of B cells and in vivo responses to T cell dependent or independent antigens post immunization were analyzed by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Adoptive transfer experiment in combination with in vitro cultures of FACS-purified B cells and RNA-Seq analysis were utilized to specifically determine the impact of Zbtb24 on B cell biology as well as the underlying mechanisms., Results: Zbtb24 is dispensable for B cell development and maintenance in naive mice. Surprisingly, B cell specific deletion of Zbtb24 does not evidently compromise germinal center reactions and the resulting primary and secondary antibody responses induced by T cell dependent antigens (TD-Ags), but significantly inhibits T cell independent antigen-elicited antibody productions in vivo. At the cellular level, Zbtb24-deficiency specifically impedes the plasma cell differentiation of B1 cells without impairing their survival, activation and proliferation in vitro. Mechanistically, Zbtb24-ablation attenuates heme biosynthesis partially through mTORC1 in B1 cells, and addition of exogenous hemin abrogates the differentiation defects of Zbtb24-null B1 cells., Conclusions: Zbtb24 seems to regulate antibody responses against TD-Ags B cell extrinsically, but it specifically promotes the plasma cell differentiation of B1 cells via heme synthesis in mice. Our study also suggests that defected B1 functions contribute to recurrent infections in patients with ICF2., (© 2024. The Author(s).)

Background: Emerging evidence suggested that S-adenosylhomocysteine (SAH) may be a better serum biomarker for cardiovascular disease than homocysteine (Hcy). However, the role of SAH in hepatocellular carcinoma (HCC) prognosis remains unclear., Objectives: We aimed to prospectively explore the relationships between serum SAH and related metabolites [Hcy, S-adenosylmethionine (SAM)] with HCC survival, and to evaluate the effect modifications by gene polymorphisms in one-carbon metabolism key enzymes., Methods: We included 1080 newly diagnosed patients with HCC from the Guangdong Liver Cancer Cohort. Serum SAH, Hcy, and SAM were measured utilizing high-performance liquid chromatography-tandem mass spectrometry. Gene polymorphisms in one-carbon metabolism key enzymes were identified using kompetitive allele-specific polymerase chain reaction. Primary outcomes were liver cancer-specific survival (LCSS) and overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using multivariate Cox proportional hazards models., Results: After a median follow-up of 3.6 y, 601 deaths occurred, with 552 (92%) attributed to HCC. Multivariable analysis revealed that patients in the highest quartile of serum SAH concentrations were significantly associated with worse survival compared with those in the lowest quartile, with HRs of 1.58 (95% CI: 1.19, 2.10; P -trend = 0.002) for LCSS and 1.54 (95% CI: 1.18, 2.02; P -trend = 0.001) for OS. There were no significant interactions between serum SAH concentrations and genetic variants of one-carbon metabolism key enzymes. No significant associations were found between serum Hcy, SAM concentrations, and SAM/SAH ratio with LCSS or OS., Conclusions: Higher serum SAH concentrations, rather than Hcy, were independently associated with worse survival in patients with HCC, regardless of the genetic variants of one-carbon metabolism key enzymes. These findings suggest that SAH may be a novel metabolism-related prognostic biomarker for HCC., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Type 1 fimbria, the short hair-like appendage assembled on the bacterial surface, plays a pivotal role in adhesion and invasion in Edwardsiella piscicida . The type III secretion system (T3SS), another bacterial surface appendage, facilitates E. piscicida 's replication in vivo by delivering effectors into host cells. Our previous research demonstrated that E. piscicida T3SS protein EseJ inhibits adhesion and invasion of E. piscicida by suppressing type 1 fimbria. However, how EseJ suppresses type 1 fimbria remains elusive. In this study, a lacI -like operator (nt -245 to -1 of fimA ) upstream of type 1 fimbrial operon in E. piscicida was identified, and EseJ inhibits type 1 fimbria through the lacI -like operator. Moreover, through DNA pull-down and electrophoretic mobility shift assay, an AraC-type T3SS regulator, EsrC, was screened and verified to bind to nt -145 to -126 and nt -50 to -1 of fimA , suppressing type 1 fimbria. EseJ is almost abolished upon the depletion of EsrC. EsrC and EseJ impede type 1 fimbria expression. Intriguingly, nutrition and microbiota-derived indole activate type 1 fimbria through downregulating T3SS, alleviating EsrC or EseJ's inhibitory effect on lacI -like operator of type 1 fimbrial operon. By this study, it is revealed that upon entering the gastrointestinal tract, rich nutrients and indole downregulate T3SS and thereof upregulate type 1 fimbria, stimulating efficient adhesion and invasion; upon being internalized into epithelium, the limit in indole and nutrition switches on T3SS and thereof switches off type 1 fimbria, facilitating effector delivery to guarantee E. piscicida 's survival/replication in vivo .IMPORTANCEIn this work, we identified the lacI -like operator of type 1 fimbrial operon in E. piscicida , which was suppressed by the repressors-T3SS protein EseJ and EsrC. We unveiled that E. piscicida upregulates type 1 fimbria upon sensing rich nutrition and the microbiota-derived indole, thereof promoting the adhesion of E. piscicida . The increase of indole and nutrition promotes type 1 fimbria by downregulating T3SS. The decrease in EseJ and EsrC alleviates their suppression on type 1 fimbria, and vice versa ., Competing Interests: The authors declare no conflict of interest.

Tryptanthrin (TRYP) is the main active ingredient in Indigo Naturalis. Studies have shown that TRYP had excellent anti-inflammatory activity, but its specific mechanism has been unclear. In this work, the differentially expressed proteins resulting from TRYP intervention in LPS-stimulated RAW264.7 cells were obtained based on tandem mass tag proteomics technology. The anti-inflammatory mechanism of TRYP was further validated by a combination of experiments using the LPS-induced RAW264.7 cell model in vitro and the DSS-induced UC mouse model (free drinking 2.5% DSS) in vivo. The results demonstrated that TRYP could inhibit levels of NO, IL-6, and TNF-α in LPS-induced RAW264.7 cells. Twelve differential proteins were screened out. And the results indicated that TRYP could inhibit upregulated levels of gp91phox, p22phox, FcεRIγ, IKKα/β, and p -IκBα and reduce ROS levels in vitro. Besides, after TRYP treatment, the health conditions of colitis mice were all improved. Furthermore, TRYP inhibited the activation of JAK/STAT3, nuclear translocation of NF-κB p65, and promoted the nuclear expression of Nrf2 in vitro and in vivo. This work preliminarily indicated that TRYP might suppress the TLR4/MyD88/ROS/NF-κB and JAK/STAT3 signaling pathways to exert anti-inflammatory effects. Additionally, TRYP could achieve antioxidant effects by regulating the Keap1/Nrf2 signaling pathway., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Triclocarban (TCC) and triclosan (TCS) have been detected ubiquitously in human body and evoked increasing concerns. This study aimed to reveal the induction risks of TCC and TCS on triple negative breast cancer through non-genomic GPER-mediated signaling pathways. Molecular simulation indicated that TCC exhibited higher GPER binding affinity than TCS theoretically. Calcium mobilization assay displayed that TCC/TCS activated GPER signaling pathway with the lowest observed effective concentrations (LOEC) of 10 nM/100 nM. TCC and TCS also upregulated MMP-2/9, EGFR, MAPK3 but downregulated MAPK8 via GPER-mediated signaling pathway. Proliferation assay showed that TCC/TCS induced 4 T1 breast cancer cells proliferation with the LOEC of 100 nM/1000 nM. Wound-healing and transwell assays showed that TCC/TCS promoted 4 T1 cells migration in a concentration-dependent manner with the LOEC of 10 nM. The effects of TCC on breast cancer cells proliferation and migration were stronger than TCS and both were regulated by GPER. TCC/TCS induced migratory effects were more significantly than proliferative effect. Mechanism study showed that TCC/TCS downregulated the expression of epithelial marker (E-cadherin) but upregulated mesenchymal markers (snail and N-cadherin), which was reversed by GPER inhibitor G15. These biomarkers results indicated that TCC/TCS-induced 4 T1 cells migration was a classic epithelial to mesenchymal transition mechanism regulated by GPER signaling pathway. Orthotopic tumor model verified that TCC promoted breast cancer in-situ tumor growth and distal tissue metastasis via GPER-mediated signaling pathway at human-exposure level of 10 mg/kg/d. TCC-induced tissue metastasis of breast cancer was more significantly than in-situ tumor growth. Overall, we demonstrated for the first time that TCC/TCS could activate the GPER signaling pathways to induce breast cancer progression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disease characterized by chronic visceral pain with a complex etiology and challenging treatment. Although accumulating evidence supports the involvement of central nervous system sensitization in the development of visceral pain, the precise molecular mechanisms remain incompletely understood. In this study, we highlight the critical regulatory role of lysine-specific demethylase 6B (KDM6B) in the anterior cingulate cortex (ACC) in chronic visceral pain. To simulate clinical IBS conditions, we utilized the neonatal maternal deprivation (NMD) mouse model. Our results demonstrated that NMD induced chronic visceral pain and anxiety-like behaviors in mice. Notably, the protein expression level of KDM6B significantly increased in the ACC of NMD mice, leading to a reduction in the expression level of H32K7me3. Immunofluorescence staining revealed that KDM6B primarily co-localizes with neurons in the ACC, with minimal presence in microglia and astrocytes. Injecting GSK-J4 (a KDM6B-specific inhibitor) into ACC of NMD mice, resulted in a significant alleviation in chronic visceral pain and anxiety-like behaviors, as well as a remarkable reduction in NR2B expression level. ChIP assay further indicated that KDM6B regulates NR2B expression by influencing the demethylation of H3K27me3. In summary, our findings underscore the critical role of KDM6B in regulating chronic visceral pain and anxiety-like behaviors in NMD mice. These insights provide a basis for further understanding the molecular pathways involved in IBS and may pave the way for targeted therapeutic interventions.

Background: Drug-induced liver injury (DILI) is one of the most common adverse events of medication use, and its incidence is increasing. However, early detection of DILI is a crucial challenge due to a lack of biomarkers and noninvasive tests., Aim: To identify salivary metabolic biomarkers of DILI for the future development of noninvasive diagnostic tools., Methods: Saliva samples from 31 DILI patients and 35 healthy controls (HCs) were subjected to untargeted metabolomics using ultrahigh-pressure liquid chromatography coupled with tandem mass spectrometry. Subsequent analyses, including partial least squares-discriminant analysis modeling, t tests and weighted metabolite coexpression network analysis (WMCNA), were conducted to identify key differentially expressed metabolites (DEMs) and metabolite sets. Furthermore, we utilized least absolute shrinkage and selection operato and random fores analyses for biomarker prediction. The use of each metabolite and metabolite set to detect DILI was evaluated with area under the receiver operating characteristic curves., Results: We found 247 differentially expressed salivary metabolites between the DILI group and the HC group. Using WMCNA, we identified a set of 8 DEMs closely related to liver injury for further prediction testing. Interestingly, the distinct separation of DILI patients and HCs was achieved with five metabolites, namely, 12-hydroxydodecanoic acid, 3-hydroxydecanoic acid, tetradecanedioic acid, hypoxanthine, and inosine (area under the curve: 0.733-1)., Conclusion: Salivary metabolomics revealed previously unreported metabolic alterations and diagnostic biomarkers in the saliva of DILI patients. Our study may provide a potentially feasible and noninvasive diagnostic method for DILI, but further validation is needed., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objectives: Oligo-/polysaccharides from Cyathula officinalis Kuan (COPs) and Achyranthes bidentata Blume (ABPs) have attracted researchers' attention in the fields of healthy food supplements and traditional Chinese medicine (Niúxī) due to their multiple bioactivities combined with their nontoxic and highly biocompatible nature. The purpose of this paper was to provide a systematic and comprehensive overview of the extraction, purification, and structural analysis methods, chemical characteristics, biological activities, and structure bioactivity relationship. Furthermore, the possible development trends and perspectives for future research, and traditional uses of Niúxī are also summarized., Methods: All the information was gathered from a library search and scientific databases., Key Findings: Although COPs and ABPs are derived from different plants, they have similar structural features in type, structure, and glycosidic linkage patterns and biological activities in vivo and in vitro. However, there are differences in monosaccharide compositions, which can be used as an identification mark., Conclusions: As traditional Chinese herbal medicine, C. officinalis and A. bidentata have similar pharmacological activities. The COPs and ABP possess wide pharmacological effects such as antitumor, antioxidant, anti-osteoporosis, and anti-inflammatory. Meanwhile, the biological activity and structure-activity relationship of purified COPs and ABPs are less studied, future research should focus on them., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Previous epidemiological and animal studies have showed the lipid metabolic disruption of antimicrobial triclocarban (TCC) and triclosan (TCS). However, the present in vivo researches were mainly devoted to the hepatic lipid metabolism, while the evidence about the impacts of TCC/TCS on the adipose tissue is very limited and the potential mechanism is unclear, especially the molecular initiation events. Moreover, little is known about the toxic difference between TCC and TCS. This study aimed to demonstrate the differential adipogenic activity of TCC/TCS as well as the potential molecular mechanism via peroxisome proliferator-activated receptors (PPARα/β/γ). The in vitro experiment based on 3T3-L1 cells showed that TCC/TCS promoted the differentiation of preadipocytes into mature adipocytes at nanomolar to micromolar concentrations, which was approach to their human exposure levels. We revealed for the first time by reporter gene assay that TCC could activate three PPARs signaling pathways in a concentration-dependent manner, while TCS only activate PPARβ. The molecular docking strategy was applied to simulate the interactions of TCC/TCS with PPARs, which explained well the different PPARs activities between TCC and TCS. TCC up-regulated the mRNA expression of three PPARs, but TCS only up-regulated PPARβ and PPARγ significantly. Meanwhile, TCC/TCS also promoted the expression of adipogenic genes targeted by PPARs to different extent. The cellular and simulating studies demonstrated that TCC exerted higher adipogenic effects and PPARs activities than TCS. Our mice in vivo experiment showed that TCC could lead to adipocyte size increase, adipocyte lipid accumulation growing, fat weight and body weight gain at human-related exposure levels, and high fat diet exacerbated these effects. Moreover, male mice tended to be more susceptible to TCC induced obesogenic effect than female mice. This work highlights the potential obesogenic risks of TCC/TCS via PPARs signaling pathways, and TCC deserves more concerns for its higher activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Dementia, with homocysteine (Hcy) as an important risk factor, is a severe public health problem in the aging society. Betaine serves as a methyl donor and plays an important role in reducing Hcy. However, the effects and mechanisms of betaine on Hcy-induced cognitive impairment remain unclear. Firstly, SD rats were injected with Hcy (400 μg/kg) through vena caudalis, and betaine (2.5 % w/v) was supplemented via drinking water for 14 days. Betaine supplementation could attenuate Hcy-induced cognitive impairment in the Y maze and novel object recognition tests by repairing brain injury. Meanwhile, microglial activation was observed to be inhibited by betaine supplementation using immunofluorescence and sholl analysis. Secondly, HMC3 cells were treated with betaine, which was found to decrease the ROS level, ameliorate cell membrane rupture, reduce the release of LDH, IL-18 and IL-1β, and attenuate the damage of microglia to neurons. Mechanistically, betaine alleviates cognitive impairment by inhibiting microglial pyroptosis via reducing the expressions of NLRP3, ASC, pro-caspase-1, cleaved-caspase-1, GSDMD, GSDMD-N, IL-18 and IL-1β. Betaine treatment can increase SAM/SAH ratio, confirming its enhancement on methylation capacity. Furthermore, betaine treatment was found to enhance N 6 -methyladenosine (m 6 A) modification of NLRP3 mRNA, and reduced the NLRP3 mRNA stability through increasing the expression of the m 6 A reader YTH N 6 -methyladenosine RNA binding protein 2 (YTHDF2). Finally, silencing YTHDF2 could reverse the inhibitory effect of betaine on pyroptosis. Our data demonstrated that betaine attenuated Hcy-induced cognitive impairment by suppressing microglia pyroptosis via inhibiting the NLRP3/caspase-1/GSDMD pathway in an m 6 A-YTHDF2-dependent manner., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Type III secretion system (T3SS) facilitates survival and replication of Edwardsiella piscicida in vivo . Identifying novel T3SS effectors and elucidating their functions are critical in understanding the pathogenesis of E. piscicida. E. piscicida T3SS effector EseG and EseJ was highly secreted when T3SS gatekeeper-containing protein complex EsaB-EsaL-EsaM was disrupted by EsaB deficiency. Based on this observation, concentrated secretomes of Δ esaB strain and Δ esaB Δ esaN strain were purified by loading them into SDS-PAGE gel for a short electrophoresis to remove impurities prior to the in-the gel digestion and mass spectrometry. Four reported T3SS effectors and two novel T3SS effector candidates EseQ (ETAE_2009) and Trx2 (ETAE_0559) were unraveled by quantitative comparison of the identified peptides. EseQ and Trx2 were revealed to be secreted and translocated in a T3SS-dependent manner through CyaA-based translocation assay and immunofluorescent staining, demonstrating that EseQ and Trx2 are the novel T3SS effectors of E. piscicida . Trx2 was found to suppress macrophage apoptosis as revealed by TUNEL staining and cleaved caspase-3 of infected J774A.1 monolayers. Moreover, Trx2 has been shown to inhibit the p65 phosphorylation and p65 translocation into the nucleus, thus blocking the NF-κB pathway. Furthermore, depletion of Trx2 slightly but significantly attenuates E. piscicida virulence in a fish infection model. Taken together, an efficient method was established in unraveling T3SS effectors in E. piscicida , and Trx2, one of the novel T3SS effectors identified in this study, was demonstrated to suppress apoptosis and block NF- κB pathway during E. piscicida infection. IMPORTANCE Edwardsiella piscicida is an intracellular bacterial pathogen that causes intestinal inflammation and hemorrhagic sepsis in fish and human. Virulence depends on the Edwardsiella type III secretion system (T3SS). Identifying the bacterial effector proteins secreted by T3SS and defining their role is key to understanding Edwardsiella pathogenesis. EsaB depletion disrupts the T3SS gatekeeper-containing protein complex, resulting in increased secretion of T3SS effectors EseG and EseJ. EseQ and Trx2 were shown to be the novel T3SS effectors of E. piscicida by a secretome comparison between ∆ esaB strain and ∆ esaB ∆ esaN strain (T3SS mutant), together with CyaA-based translocation assay. In addition, Trx2 has been shown to suppress macrophage apoptosis and block the NF-κB pathway. Together, this work expands the known repertoire of T3SS effectors and sheds light on the pathogenic mechanism of E. piscicida ., Competing Interests: The authors declare no conflict of interest.

Circular RNAs have been extensively studied in eukaryotes, but their presence and/or biological functionality in bacteria are unclear. Here, we show that a regulatory noncoding RNA (DucS) exists in both linear and circular conformation in Bacillus altitudinis. The linear forms promote B. altitudinis tolerance to H 2 O 2 stress, partly through increased translation of a stress-responsive gene, htrA. The 3' end sequences of the linear forms are crucial for RNA circularization, and formation of circular forms can decrease the levels of the regulatory linear cognates. Bioinformatic analysis of available RNA-seq datasets from 30 bacterial species revealed multiple circular RNA candidates, distinct from DucS, for all the examined species. Experiments testing for the presence of selected circular RNA candidates in four species successfully validated 7 out of 9 candidates from B. altitudinis and 4 out of 5 candidates from Bacillus paralicheniformis; However, none of the candidates tested for Bacillus subtilis and Escherichia coli were detected. Our work identifies a dual-conformation regulatory RNA in B. altitutidinis, and indicates that circular RNAs exist in diverse bacteria. However, circularization of specific RNAs does not seem to be conserved across species, and the circularization mechanisms and biological functionality of the circular forms remain unclear., (© 2023. Springer Nature Limited.)

CAG is a burdensome and progressive disease. Numerous studies have shown the effectiveness of RUT in digestive system diseases. The therapeutic effects of RUT on MNNG-induced CAG and the potential mechanisms were probed. MNNG administration was employed to establish a CAG model. The HE and ELISA methods were applied to detect the treatment effects. WB, qRT-PCR, immunohistochemistry, TUNEL, and GES-1 cell flow cytometry approaches were employed to probe the mechanisms. The CAG model was successfully established. The ELISA and HE staining data showed that the RUT treatment effects on CAG rats were reflected by the amelioration of histological damage. The qRT-PCR and WB analyses indicated that the protective effect of RUT is related to the upregulation of the SHH pathway and downregulation of the downstream of apoptosis to improve gastric cellular survival. Our data suggest that RUT induces a gastroprotective effect by upregulating the SHH signaling pathway and stimulating anti-apoptosis downstream.

Purpose: To test the hypothesis that daily supplementation with low-dose B vitamins plus betaine could significantly reduce plasma homocysteine concentrations in Chinese adults with hyperhomocysteinemia and free from background mandatory folic acid fortification., Methods: One hundred apparently healthy adults aged 18-65 years with hyperhomocysteinemia were recruited in South China from July 2019 to June 2021. They were randomly assigned to either the supplement group (daily supplementation: 400 μg folic acid, 8 mg vitamin B 6 , 6.4 μg vitamin B 12 and 1 g betaine) or the placebo group for 12 weeks. Fasting venous blood was collected at baseline, week 4 and week 12 to determine the concentrations of homocysteine, folate, vitamin B 12 and betaine. Generalized estimation equations were used for statistical analysis., Results: Statistically significant increments in blood concentrations of folate, vitamin B 12 and betaine after the intervention in the supplement group indicated good participant compliance. At baseline, there were no significant differences in plasma homocysteine concentration between the two groups (P = 0.265). After 12-week supplementation, compared with the placebo group, there was a significant reduction in plasma homocysteine concentrations in the supplement group (mean group difference - 3.87; covariate-adjusted P = 0.012; reduction rate 10.1%; covariate-adjusted P < 0.001). In the supplement group, the decreased concentration of plasma homocysteine was associated with increments of blood concentrations of both folate (β = -1.680, P = 0.004) and betaine (β = -1.421, P = 0.020) after 12 weeks of supplementation., Conclusions: Daily supplementation with low-dose B vitamins plus betaine for 12 weeks effectively decreased plasma homocysteine concentrations in Chinese adults with hyperhomocysteinemia., Trial Registration: This trial was registered at clinicaltrials.gov as NCT03720249 on October 25, 2018. Website: https://clinicaltrials.gov/ct2/show/NCT03720249 ., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

With the increase in the medical level, the improvement of adverse drug reaction(ADR) monitoring systems, and the enhancement of public awareness of safe medication, drug safety incidents have been frequently reported. Drug-induced liver injury(DILI), especially liver injury attributed to herbal and dietary supplements(HDS), has globally attracted high attention, bringing great threats and severe challenges to the people for drug safety management such as clinical medication and medical supervision. Consensus on drug-induced liver injury had been published by the Council for International Organizations of Medical Sciences(CIOMS) in 2020. In this consensus, liver injury attributed to HDS was included in a special chapter for the first time. The hot topics, including the definition of HDS-induced liver injury, epidemiological history, potential risk factors, collection of related risk signals, causality assessment, risk prevention, control and management were discussed from a global perspective. Based on the previous works, some experts from China were invited by CIOMS to undertake the compilation of this chapter. Meanwhile, a new causality assessment in DILI based on the integrated evidence chain(iEC) method was widely recognized by experts in China and abroad, and was recommended by this consensus. This paper briefly introduced the main contents, background, and characteristics of the Consensus on drug-induced liver injury. Significantly, a brief interpretation was illustrated to analyze the special highlights of Chapter 8, &quot;Liver injury attributed to HDS&quot;, so as to provide practical references for the medical staff and the researchers who worked on either Chinese or Western medicine in China.

Multiple single nucleotide polymorphisms may contribute to cognitive decline in Parkinson's disease. However, the mechanism by which these single nucleotide polymorphisms modify brain imaging phenotype remains unclear. The aim of this study was to investigate the potential effects of multiple single nucleotide polymorphisms on brain imaging phenotype in Parkinson's disease. Forty-eight Parkinson's disease patients and 39 matched healthy controls underwent genotyping and 7T magnetic resonance imaging. A cognitive-weighted polygenic risk score model was designed, in which the effect sizes were determined individually for 36 single nucleotide polymorphisms. The correlations between polygenic risk score, neuroimaging features, and clinical data were analyzed. Furthermore, individual single nucleotide polymorphism analysis was performed to explore the main effects of genotypes and their interactive effects with Parkinson's disease diagnosis. We found that, in Parkinson's disease, the polygenic risk score was correlated with the neural activity of the hippocampus, parahippocampus, and fusiform gyrus, and with hippocampal-prefrontal and fusiform-temporal connectivity, as well as with gray matter alterations in the orbitofrontal cortex. In addition, we found that single nucleotide polymorphisms in α-synuclein (SNCA) were associated with white matter microstructural changes in the superior corona radiata, corpus callosum, and external capsule. A single nucleotide polymorphism in catechol-O-methyltransferase was associated with the neural activities of the lingual, fusiform, and occipital gyri, which are involved in visual cognitive dysfunction. Furthermore, DRD3 was associated with frontal and temporal lobe function and structure. In conclusion, imaging genetics is useful for providing a better understanding of the genetic pathways involved in the pathophysiologic processes underlying Parkinson's disease. This study provides evidence of an association between genetic factors, cognitive functions, and multi-modality neuroimaging biomarkers in Parkinson's disease., Competing Interests: None

Flooding is the main natural factor in snail diffusion, and it has a negative impact on schistosomiasis transmission. There are few studies on the spread and migration of snails following a flood; therefore, we aimed to investigate the influence of flooding on snail diffusion and explore the characteristics and laws of snail diffusion in Jiangxi Province. By using a retrospective survey and cross-sectional survey, the data on snail spreading in Jiangxi Province from 2017 to 2021 were collected. The distribution, nature, and area of snail spread were systematically analyzed in combination with the hydrological situation, types of region, and types of flood. From 2017 to 2021, a total of 120 snail-spread environments were found, including in 92 hilly areas and in 28 lake areas. The areas caused by flood and by other means numbered 6 and 114, respectively. The proportions of recurrence, expansion, and first-time occurrences were 43.42%, 38.16%, and 18.42%, respectively, and the 14 new snail environments were only distributed in the hilly areas. With the exception of 2018, the ratio of snail-spread areas in the hilly region was higher than that in lake region in other years. The average density of live snails was 0.0184-1.6617 no./0.1 m 2 and 0.0028-0.2182 no./0.1 m 2 in the hilly region. Among the 114 environments affected by floods, 86 consisted of hilly environments, including 66 spreading environments affected by rainstorm floods, and 20 rainstorm debris flow environments. There were 28 lake areas, of which 10 were in the Jiangxi section of Yangtze River and were affected by rainstorm floods. Snail spread following flooding has a certain 'lag effect,' and = simple annual changes in hydrological characteristics have little effect on the diffusion of snails or on their density = in the affected environment, but it is more closely related to local floods. The hilly environments are more susceptible to floods than the lake region, and the risk of snail spread is much higher in the hilly than in the lake region.

Triclosan (TCS) and triclocarban (TCC) have become ubiquitous pollutants detected in human body with concentrations up to hundreds of nanomolar levels. Previous studies about the hepatic lipid accumulation induced by TCS and TCC were focused on pollutant itself, which showed weak or no effects. High-fat diet (HFD), as a known environmental factor contributing to lipid metabolism-related disorders, its synergistic action with environmental pollutants deserves concern. The present study aimed to demonstrate the combined effects and potential molecular mechanisms of TCS and TCC with HFD at cellular and animal levels. The in vitro studies showed that TCC and TCS alone had negligible impact on lipid accumulation in HepG2 cells but induced lipid deposition at nanomolar levels when co-exposure with fatty acid. TCC exhibited much higher induction effects than TCS, which was related to their differential regulatory roles in adipogenic-related genes expression. The in vivo studies showed that TCC had little influence on hepatic lipid accumulation in mice fed with normal diet (ND) but could exacerbate the lipid accumulation in mice fed with HFD. Meanwhile, TCC-induced dyslipidemia in mice fed with HFD was more significant than that fed with ND. Therefore, we speculated that TCC might increase the risk of nonalcoholic fatty liver disease (NAFLD) and atherosclerosis in HFD humans. Molecular mechanism studies showed that TCC and TCS could bind to and activate estrogen-related receptor α (ERRα) and ERRγ as well as regulate their expression. TCC had higher activity on ERRα and ERRγ than TCS, which explained partly the differential regulatory roles of two receptors in the lipid accumulation induced by TCC and TCS. This work revealed synergistic effects and molecular mechanisms of TCC and TCS with excessive fatty acid on the hepatic lipid metabolism, which provided a novel insight into the toxic mechanism of pollutants from the perspective of dietary habits., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Neonicotinoid insecticides (NIs) have been widely detected in environmental media and human body with concentrations reaching hundreds of nanomolar to micromolar levels. However, the information about their human health toxicology and mechanism is deficient. Previous studies have implied that NIs might exert estrogenic disruption and promote breast cancer progression, but the molecular mechanism is unclear, especially the molecular initiating event. G protein-coupled estrogen receptor (GPER), as a candidate therapeutic target, plays vital roles in the development of breast cancer. This work aimed to reveal the potential mechanism through GPER pathway. Firstly, we screened the activities of seven most common NIs on GPER signal pathway by calcium mobilization assay. Clothianidin, acetamiprid (ACE), and dinotefuran activated GPER most potently and ACE displayed the highest agonistic activity with the lowest observed effective concentration (LOEC) of 1 μM. The molecular docking and dynamics simulation showed favored interaction trend between the NIs and GPER. The three NIs with GPER activity induced 4T1 breast cancer cells migration and ACE showed the highest potency with LOEC of 100 nM. ACE also induced 4T1 cells proliferation at high concentration of 50 μM and up-regulated GPER expression in a dose-dependent manner. We speculated that both the induction effects of ACE on 4T1 cells proliferation and migration might be owing to the activation and up-regulation of GPER. By using 4T1-Luc cells injected orthotopic tumor model, we found that ACE also promoted in-situ breast cancer growth and lung metastasis in normal mouse dependent on GPER. However, ACE only promoted in-situ breast cancer growth through GPER but not lung metastasis in ovariectomized mice, implying that the ACE-induced lung metastasis should be related to endogenous estrogen from ovary. Overall, we demonstrated that NIs promoted breast cancer progression via GPER pathway at human related exposure levels and their female health risks need urgent concerns., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

3-(2-Deoxy-β-d-erythropentofuranosyl)pyrimido[1,2- a ]purin-10(3 H )-one (M 1 dG) is an endogenous DNA adduct in bacterial and mammalian cells that could be explored as a biomarker for oxidative stress. Nonetheless, the lack of an efficient methodology for the preparation of M 1 dG hampers the deep investigation of its biosynthesis and biorelevant processes. In this project, we aimed to address this issue by developing a highly efficient method to synthesize M 1 dG and its analogues. This method has wide functional group tolerance, as various guanine-based nucleosides and nucleotides are suitable for the reaction. Furthermore, large-scale and derivatization reactions were carried out to showcase the possibility for biochemists to study DNA damage and repair processes in the future.

Excess acetaminophen(APAP) can be converted by the cytochrome P450 system to the toxic metabolite N-acetyl-p-benzoquinoneimine(NAPQI), which consumes glutathione(GSH). When GSH is depleted, NAPQI covalently binds with proteins, inducing mitochondrial dysfunction and oxidative stress and thereby leading to hepatotoxicity. Schisandrin C(SinC) is a dibenzocyclooctadiene derivative isolated from Schisandra chinensis. Although there is some evidence showing that SinC has hepatoprotective activity, its protective effect and mechanism on APAP-induced liver injury remain unclear. In this paper, an acute liver injury mouse model was established by intraperitoneal injection of APAP at a dose of 400 mg·kg~(-1) to evaluate the effect of SinC administration on the APAP-induced liver injury and its mechanism through an animal experiment. At the same time, a potential candidate drug was provi-ded for traditional Chinese medicine(TCM) prevention and treatment of overdose APAP-induced liver injury. In the APAP-induced liver injury mouse model, we found that SinC can relieve hepatic histopathological lesions and significantly reduce the activities of alanine aminotransferase(ALT), aspartate aminotransferase(AST) and alkaline phosphatase(ALP). It was also capable of increasing the content of GSH and superoxide dismutase(SOD) and decreasing the levels of total bilirubin(TBIL), direct bilirubin(DBIL), malondialdehyde(MDA), interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α). Further analysis showed that SinC decreased the content of CYP2 E1 in liver tissues at protein and mRNA levels and increased nuclear factor erythroid 2-related factor 2(Nrf2) and the expression of its downstream targets(including HO-1, NQO1 and GCLC). Taken together, the above results indicate that SinC can alleviate APAP-induced liver injury by reducing the expression of CYP2 E1, suppressing apoptosis, improving inflammatory response and activating the Nrf2 signaling pathway to inhibit oxidative stress.

Dietary intake of one-carbon metabolism-related nutrients has been linked to cancer-related outcomes, but their effects on hepatocellular carcinoma (HCC) mortality are still unknown. The objective was to assess whether pre-diagnostic dietary intakes of methionine, folate, Vitamin B6, Vitamin B12, riboflavin and niacin are associated with HCC survival in this prospective cohort study. In total, 905 newly diagnosed HCC patients were recruited in the Guangdong Liver Cancer Cohort study between September 2013 and April 2017. Dietary intake was assessed using a validated 79-item food frequency questionnaire. Cox proportional hazard regression models were utilized to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the overall and HCC-specific mortality. During a median of 791 days of follow-up, we documented 395 deaths, 353 (89%) of which resulted from HCC. The multivariate-adjusted HRs in the highest vs. the lowest quartile of methionine intake were 0.59 (95% CI: 0.42-0.80; P for trend = 0.001) for overall mortality and 0.68 (95% CI: 0.49-0.93; P for trend = 0.027) for HCC-specific mortality. However, no significant association of other micronutrients involved in one-carbon metabolism with HCC survival was observed. Our research suggests that a high level of methionine intake, but no other one-carbon metabolism-related nutrients, may improve survival in patients with newly diagnosed HCC.

Background: Aminoacyl-tRNA synthetases (ARSs) are enzymes responsible for attaching amino acids to tRNA, which enables protein synthesis. Mutations in isoleucyl-tRNA synthetase (IARS1) have recently been reported to be a genetic cause for growth retardation, intellectual disability, muscular hypotonia, and infantile hepatopathy (GRIDHH)., Case Presentation: In this study, we reported an additional case of compound heterozygous missense variations c.701 T > C (p.L234P) and c.1555C > T (p.R519C) in IARS1, which were identified using medical exome sequencing; c.701 T > C (p.L234P) was a novel variant, and c.1555C > T (p.R519C) was found in GnomAD. Unlike other reported patients, this individual presented prominently with recurrent liver failure, which led to her death at an early age of 19 months. She also had significant growth retardation, muscular hypotonia, chubby and flabby face, recurrent loose stools, and abnormal brain computed tomography (CT), while zinc deficiency and hearing loss were not present. Studies in zebrafish embryo modeling recapitulated some of the key phenotypic traits in embryo development, neurodevelopment, liver development, and myogenesis, demonstrating that these variations caused a loss of gene function in IARS1., Conclusions: We have found a novel mutation point c.701 T > C (p.L234P) in IARS1. Compound heterozygous mutations of c.701 T > C (p.L234P) and c.1555C > T (p.R519C) in IARS1 are pathogenic, which can cause GRIDHH in child., (© 2022. The Author(s).)

Edwardsiella ictaluri, a Gram-negative intracellular pathogen, is the causative agent of enteric septicemia in channel catfish, and catfish aquaculture in China suffers heavy economic losses due to E. ictaluri infection. Vaccination is an effective control measure for this disease. In this study, an attenuated E. ictaluri strain was acquired through deletion mutation of the T3SS protein eseJ ei , and the ΔeseJ ei strain fails to replicate in the epithelioma papillosum of carp cells. The type 1 fimbria plays a pivotal role in the adhesion of E. ictaluri, and it was found in this study that deletion of -245 to -50 nt upstream of fimA increases its adhesion to around five times that of the WT strain. A hyper-adhesive and highly attenuated double mutant (ΔeseJ ei ΔfimA -245 - -50 strain) was constructed, and it was used as a vaccine candidate in yellow catfish via bath immersion at a dosage of 1 × 10 5  CFU/mL. It was found that this vaccine candidate can stimulate protection when challenged with E. ictaluri HSN-1 at 5 × 10 7  CFU/mL (∼20 × LD 50 ). The survival rate was 83.61% for the vaccinated group and 33.33% for the sham-vaccinated group. The RPS (relative percent of survival) of the vaccination trial reached 75.41%. In conclusion, the ΔeseJ ei ΔfimA -245 - -50 strain developed in this study can be used as a vaccine candidate. It excels in terms of ease of delivery (via bath immersion) and is highly efficient in stimulating protection against E. ictaluri infection., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Bactrocera dorsalis is a devastating pest on fruits and vegetables because the adult female is the key factor that determines the population density of offspring and the degree of host damage. Unfortunately, there is still a lack of effective female attractants for behavioral control. Males of B. dorsalis fed on methyl eugenol (ME) were shown to be more sexually attracted to females and, therefore, were more successful in mating over ME-deprived males., Results: In the current study, we demonstrated that (E)-coniferyl alcohol (E-CF), one of the ME metabolites in males, was highly attractive to sexually-mature females in laboratory bioassays. During the dusk courtship period, mature females showed the highest response to E-CF. However, there were no significant differences in olfactory responses to E-CF between virgin and mated mature females. Moreover, no obvious signs and symptoms of toxicity or death were observed in mice during a 14-day acute oral toxicity test. Toxicologically, no significant changes were observed in body weight, water intake, food consumption and absolute and relative organ weights between control and treated groups of healthy-looking mice, implying that E-CF could be regarded as non-toxic. Furthermore, cytotoxicity assessment revealed that E-CF was non-toxic against human fetal lung fibroblast 1 (HFL1), human breast cancer (MDA-MB-231), mouse embryonic hepatocytes (BNL-CL.2) and Spodoptera frugiperda ovary (SF-9) cell lines., Conclusions: E-CF proved to be an effective, promising and eco-friendly lure to B. dorsalis females. Therefore, this study may facilitate the development of novel control strategies against B. dorsalis in the field., (© 2021 Society of Chemical Industry.)

Background & Aims: Epidemiological evidence linking fibroblast growth factor 21 (FGF21) with hepatocellular carcinoma (HCC) prognosis lacked. We aimed to evaluate the associations between serum FGF21 levels and HCC survival in a large prospective cohort., Methods: 825 newly diagnosed, previously untreated HCC patients from the Guangdong Liver Cancer Cohort were enrolled between September 2013 and April 2017. Serum FGF21 levels were measured by ELISA. Liver cancer-specific survival (LCSS) and overall survival (OS) were calculated. Multivariable Cox proportional hazards models were performed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: Compared with patients in the lowest tertile of serum FGF21 levels, patients in the highest tertile had inferior survival outcomes. HRs in the fully adjusted models were 1.44 (95% CI: 1.07, 1.94; P -trend  = .014) and 1.48 (95% CI: 1.12, 1.97; P -trend  = .002) for LCSS and OS, respectively. The associations were not significantly modified by selected metabolic disorder diseases or state such as arterial hypertension, diabetes, dyslipidemia, fatty liver, cirrhosis, and body mass index ≥25.0 kg/m 2 , except for that stronger associations were observed in patients co-occurred more than three metabolic disorder diseases (P -interaction  = .046 for OS and .151 for LCSS), with an HR of 2.01 (95% CI: 1.04, 3.85; P -trend  = .009) for OS and 1.51 (95% CI: 0.73, 3.10; P -trend  = .195) for LCSS., Conclusions: Higher serum FGF21 levels were associated with worse survival in HCC patients, suggesting that serum FGF21 may be used as a novel metabolism-related prognostic biomarker for HCC., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Given the importance of B lymphocytes in inflammation and immune defense against pathogens, mice transgenic for Cre under the control of Cd19 promoter ( Cd19 Cre/+ mice) have been widely used to specifically investigate the role of loxP -flanked genes in B cell development/function. However, impacts of expression/insertion of the Cre transgene on the phenotype and function of B cells have not been carefully studied. Here, we show that the number of marginal zone B and B1a cells was selectively reduced in Cd19 Cre/+ mice, while B cell development in the bone marrow and total numbers of peripheral B cells were comparable between Cd19 Cre/+ and wild type C57BL/6 mice. Notably, humoral responses to both T cell-dependent and independent antigens were significantly increased in Cd19 Cre/+ mice. We speculate that these differences are mainly attributable to reduced surface CD19 levels caused by integration of the Cre-expressing cassette that inactivates one Cd19 allele. Moreover, our literature survey showed that expression of Cd19 Cre/+ alone may affect the development/progression of inflammatory and anti-infectious responses. Thus, our results have important implications for the design and interpretation of results on gene functions specifically targeted in B cells in the Cd19 Cre/+ mouse strain, for instance, in the context of (auto) inflammatory/infectious diseases.

Two new stilbenoids, stemobenoids A ( 1 ) and B ( 2 ), together with three known compounds were obtained from the roots of Stemona tuberosa . The structures of the new compounds were established by extensive spectroscopic analysis, including HRMS, 1D and 2D NMR data. Compounds 1 and 2 displayed potent quinone reductase inducing activity in Hepa 1c1c7 cells.

The present study evaluated the clinical efficacy and safety of Liuwei Wuling Tablets combined with conventional drugs for the treatment of liver fibrosis and cirrhosis in chronic hepatitis B. CNKI, Wanfang, VIP, CBM, PubMed, EMbase and Cochrane Library were searched for the relevant randomized controlled trials(RCTs) published from database inception to February 2021. All the retrieved papers were independently screened, extracted and evaluated by two researchers, followed by Meta-analysis by Review Manager 5.4. Finally, 18 RCTs were included, involving 2 168 patients(1 106 in the treatment group and 1 062 in the control group). The Meta-analysis results showed that compared with conventional drugs alone, Liuwei Wuling Tablets combined with conventional drugs could increase the effective rate of clinical treatment by reducing serum hyaluronic acid(HA), laminin(LN), procollagen type Ⅲ(PCⅢ), and type Ⅳ collagen(Ⅳ-C) to improve liver function, decreasing the levels of total bilirubin(TBiL), alanine amino-transferase(ALT), and aspartate aminotransferase(AST), and improving the negative conversion ratio of hepatitis B virus(HBV) DNA. In terms of safety, there were no serious adverse reactions in the treatment group and the control group. The results showed that Liuwei Wuling Tablets combined with antiviral or other conventional liver-protecting drugs could improve liver function, treat liver cirrhosis, and reduce liver fibrosis with high safety. However, due to the influence of literature quality and quantity, multi-center and high-quality RCTs with large sample size are needed for verification.

Dietary protein has been linked with all-cause and cancer mortality. However, the relationship between dietary protein and the prognosis of hepatocellular carcinoma (HCC) is still unknown. The purpose of this study was to investigate whether dietary protein intake was related to HCC mortality using data from the Guangdong Liver Cancer Cohort (GLCC), a prospective cohort study of HCC survivors established at the Sun Yat-sen University Cancer Center. Dietary information one year before the diagnosis of HCC was obtained through a 79-item semi-quantitative food frequency questionnaire (FFQ). A total of 883 patients with newly diagnosed HCC who were recruited between September 2013 and April 2017 were included in this study. The hazard ratio (HR) and 95% confidence intervals (95% CIs) were estimated by Cox proportional hazard models. The multivariate-adjusted HRs in the highest vs. the lowest tertile of total protein intake were 0.68 (95% CI: 0.52-0.91, P -trend = 0.007) for all-cause mortality and 0.74 (95% CI: 0.55-0.99, P -trend = 0.040) for HCC-specific mortality. However, the associations of animal protein intake, plant protein intake, and animal-to-plant protein ratio with all-cause and HCC-specific mortality were not significant (all P -trend >0.05). Our research suggests that higher prediagnostic dietary intake of total protein was associated with reduced all-cause and HCC-specific mortality.

Scope: The muscle loss during aging results from the blunt of protein synthesis and poses threat to the elderly health. This study aims to investigate whether betaine affects muscle loss by improving protein synthesis., Methods and Results: Male C57BL/6J mice are raised from age 12 or 15 months. Mice are fed with AIN-93M diet without or with 2% w/v betaine in distilled water as control group or betaine intervention group (Bet), respectively. Betaine supplementation to mice demonstrates better body composition, grip strength, and motor function. Muscle morphology upregulates expression of myogenic regulate factors, and elevates myosin heavy chain and also improves in Bet group. Betaine promotes muscle protein synthesis via tethering mammalian target of rapamycin complex1 protein kinase (mTORC1) on the lysosomal membrane thereby activating mTORC1 signaling. All these effects aforementioned are time-dependent (p < 0.05). Ultrahigh-performance liquid chromatography results show that betaine increases S-adenosyl-l-methionine (SAM) via methionine cycle. SAM sensor-Samtor-overexpression in C2C12 cells could displace mTORC1 from lysosome thereby inhibiting the mTORC1 signaling. Addition of betaine attenuates this inhibition by increasing SAM level and then disrupting interaction of Samtor complex., Conclusions: These observations indicate that betaine could promisingly promote protein synthesis to delay age-related muscle loss., (© 2021 Wiley-VCH GmbH.)

Bacterial resistance to drugs is a global problem requiring the urgent development of new antibiotics. Antimicrobial peptides (AMPs) are excellent candidates for the design of novel antibiotics to combat microbial resistance. In this research, we identified four new peptides (U-VVTX-Vp1a, U-VVTX-Vp1b, U-VVTX-Vp2a, and U-VVTX-Vp2b, respectively) from the venom of Vespa velutina, and tested their antimicrobial, antioxidant, and hemolytic effects. All four peptides showed scavenging ability against DPPH, ABTS + , and •OH free radicals. Of note, Vp1b strongly inhibited the growth of Staphylococcus aureus and Escherichia coli bacteria at concentrations of 60 and 120 μM. Due to their low hemolytic activity, all four peptides could be utilized in the development of new antioxidants and as candidates for the design of novel antimicrobial agents., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The development and differentiation of T cells represents a long and highly coordinated, yet flexible at some points, pathway, along which the sequential and dynamic expressions of different transcriptional factors play prominent roles at multiple steps. The large ZBTB family comprises a diverse group of transcriptional factors, and many of them have emerged as critical factors that regulate the lineage commitment, differentiation and effector function of hematopoietic-derived cells as well as a variety of other developmental events. Within the T-cell lineage, several ZBTB proteins, including ZBTB1, ZBTB17, ZBTB7B (THPOK) and BCL6 (ZBTB27), mainly regulate the development and/or differentiation of conventional CD4/CD8 αβ + T cells, whereas ZBTB16 (PLZF) is essential for the development and function of innate-like unconventional γ δ + T & invariant NKT cells. Given the critical role of T cells in host defenses against infections/tumors and in the pathogenesis of many inflammatory disorders, we herein summarize the roles of fourteen ZBTB family members in the development, differentiation and effector function of both conventional and unconventional T cells as well as the underlying molecular mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cheng, He, Gao, Zhao and Wang.)

In this study, a hypothetical protein (ORF02740) secreted by Edwardsiella piscicida was identified. We renamed the ORF02740 protein as EvpQ, which is encoded by a mobile genetic element (MGE) in E. piscicida genome. The evpQ gene is spaced by 513 genes from type VI secretion system (T6SS) gene cluster. Low GC content, three tRNA, and three transposase genes nearby evpQ define this MGE that evpQ localizes as a genomic island. Sequence analysis reveals that EvpQ shares a conserved domain of C70 family cysteine protease and shares 23.91% identity with T3SS effector AvrRpt2 of phytopathogenic Erwinia amylovora. Instead, EvpQ of E. piscicida is proved to be secreted at a T6SS-dependent manner, and it can be translocated into host cells. EvpQ is thereof a novel T6SS effector. Significantly decreased competitive index of Δ evpQ strain in blue gourami fish (0.53 ± 0.27 in head kidney and 0.44 ± 0.19 in spleen) indicates that EvpQ contributes to the pathogenesis of E. piscicida . At 8-, 18-, and 24-h post-subculture into DMEM, the transcription of evpQ was found to be negatively regulated by Fur and positively regulated by EsrC, and the steady-state protein levels of EvpQ are negatively controlled by RpoS. Our study lays a foundation for further understanding the pathogenic role of T6SS in edwardsiellosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Liu, Liao, He, Sun, Nie and Xie.)

Objective: To investigate the effect of virtual reality (VR) video-based pre-discharge psychological intervention on the post-discharge emotions of patients with deep facial burn. Methods: From October 2017 to September 2019, 84 patients with deep facial burn who were hospitalized in the First Hospital of Jilin University and met the inclusion criteria were enrolled in the prospective randomized controlled study were. According to the random number table, the patients were divided into two groups, with 40 cases (21 males and 19 females) left in VR video group, aged 18-53 years and 41 cases (22 males and 19 females) in general video group, aged 19-55 years after several patients dropped out in follow-up. Seven patients who had been treated in the First Hospital of Jilin University from January 2014 to December 2016 and returned to work and life after recovering from the deep facial burn were selected, and then the pictures and corresponding commentaries before and after burn injuries, the problems and solutions after discharge, and the image data of living status of each patient were edited and recorded into a video. From seven days before discharge, the patients in VR video group began to watch videos by wearing VR glasses, while the patients in general video group began to watch videos on a tablet computer, for 7 days . On the 7th day before discharge (before watching the videos) and one month after discharge, the Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS), and Social Avoidance and Distress (SAD) Scale were used to evaluate the level of anxiety, depression, and social avoidance and distress of patients in both groups. Data were statistically analyzed with paired or independent sample t test, chi-square test, or Fisher's exact probability test. Results: On the 7th day before discharge, the scores of anxiety, depression, and social avoidance and distress of patients in general video group were (34±7), (34±6), and (11.5±3.9) points, respectively, close to (35±7), (35±5), and (10.5±3.9) points in VR video group ( t =-0.803, -1.050, 1.122, P >0.05), and the scores of both groups were higher than the national norms. One month after discharge, the scores of anxiety, depression, and social avoidance and distress of patients in VR video group were (31±5), (31±5), and (7.2±2.5) points, respectively, significantly lower than the scores on the 7th day before discharge ( t =6.609, 7.492, 7.622, P <0.01); the scores of anxiety, depression, and social avoidance and distress of patients in general video group were (37±7), (38±8), and (13.9±7.4) points, respectively, significantly higher than the scores on the 7th day before discharge ( t =2.802, 3.599, 2.739, P <0.01). One month after discharge, the scores of anxiety, depression, and social avoidance and distress of patients in VR video group were significantly lower than those in general video group ( t =4.722, 5.043, 5.490, P <0.01). Conclusions: Pre-discharge psychological intervention of patients with deep facial burn using VR videos can alleviate their bad emotions after discharge, such as anxiety, depression, and social avoidance and distress.

In order to investigate the response of soil respiration, soil microbial biomass carbon and nitrogen, and hydrothermal factors to the addition of biochar and straw, we used an LI-8100 soil carbon flux meter (LI-COR, Lincoln, USA) to study changes in soil respiration and microbial biomass under four treatments:conventional fertilization (CK), conventional fertilization +2.25t·hm -2 biochar-C (T1), conventional fertilizer +2.25t·hm -2 straw-C (T2), and conventional fertilizer +2.25t·hm -2 (biochar-C+straw-C), biochar-C:straw-C=1:1 (T3). The results showed that:① the addition of biochar and straw significantly increased the soil respiration rate and total CO 2 emissions, with the largest increase in T3 and the smallest increase in T1. The effect of T1 on soil respiration was promoted in the early stage and later inhibited. ② The microbial biomass carbon and nitrogen and the number of functional bacterial colonies increased significantly with biochar and straw amendments. T1 had a significant promotion effect on nitrogen-fixing bacteria, while T2 had no significant effect on the number of fungi, and T3 showed a positive interaction effect. Soil respiration rates were significantly and positively related to soil microbial biomass carbon and nitrogen as well as to the number of bacteria and actinomycetes. ③ The 5 cm soil temperature of T3 significantly increased by 4.53%. The soil respiration rate and soil temperature showed a significant exponential correlation. To sum up, adding straw and biochar with equal carbon content can significantly increase the soil respiration rate and microbial biomass, and the interaction effect between biochar and straw is positive. Compared with that of the straw treatments, the application of biochar can reduce carbon mineralization to a certain extent, and the effect of carbon sequestration is better.

Ferulic acid (FA) has potential therapeutic effects in multiple diseases including cardiovascular diseases. However, the effect and molecular basis of FA in heart failure (HF) has not been thoroughly elucidated. Herein, we investigated the roles and mechanisms of FA in HF in isoproterenol (ISO)-induced HF rat model. Results found that FA ameliorated cardiac dysfunction, alleviated oxidative stress, reduced cell/myocardium injury-related enzyme plasma level, inhibited cardiocyte apoptosis in ISO-induced HF rat models. Moreover, FA reduced the co-localization of Keap1 and nuclear factor-E2-related factor 2 (Nrf2) in heart tissues of ISO-induced HF rats, and FA alleviated the inhibitory effects of ISO on expressions of p-Nrf2, heme oxygenase-1 (HO-1) and reduced nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 (NQO1). Additionally, Nrf2 signaling pathway inhibitor ML385 showed adverse effects. FA weakened the effects of ML385 in ISO-induced HF rat models. Collectively, FA ameliorated HF by decreasing oxidative stress and inhibiting cardiocyte apoptosis via activating Nrf2 pathway in ISO-induced HF rats. Our data elucidated the underling molecular mechanism and provided a novel insight into the cardioprotective function of FA, thus suggested the therapeutic potential of FA in HF treatment.

Aeromonas salmonicida is a gram-negative bacterium that is the causative agent of furunculosis. An A. salmonicida strain was isolated from diseased turbot (Scophthalmus maximus) with the sign of furunculosis from North China. Based on vapA gene, the strain was further classified as A. salmonicida subsp. masoucida RZ6S-1. Culturing RZ6S-1 strain at high temperature (28°C) obtained the virulence attenuated strain RZ6S. Genome sequence comparison between the two strains revealed the loss of the type IV secretion system (T4SS) and type III secretion system (T3SS) from the native plasmid pAsmB-1 and pAsmC-1 of wild-type strain RZ6S-1, respectively. Further study demonstrated that the wild-type strain RZ6S-1, but not its derivative mutant RZ6S, can stimulate apoptosis. Elevated protein level of cleaved caspase-3 was detected from epithelioma papulosum cyprinid (EPC) cells infected with wild-type strain RZ6S-1 as compared with that infected with RZ6S strain. Meanwhile, the invasion of the mutant strain RZ6S was about 17-fold higher than the wild-type strain RZ6S-1, suggesting that some protein(s) from A. salmonicida subsp. masoucida RZ6S-1 suppress its invasion. The RZ6S mutant strain was attenuated, since its LD 50 is over 10,000 times higher compared to the wild-type strain as revealed in the turbot infection model., (© 2020 John Wiley & Sons Ltd.)

Aim: Adherence to dietary recommendations has been linked to a reduced risk of developing hepatocellular carcinoma (HCC) and dying of chronic liver disease. However, its role in the prognosis of HCC is still unclear. We prospectively investigated the association of two dietary quality indices, the Chinese Healthy Eating Index (CHEI) and the Healthy Eating Index-2015 (HEI-2015), with all-cause and HCC-specific mortality in a large prospective cohort of HCC survivors., Methods: We included 887 patients with newly diagnosed, previously untreated HCC enrolled in the Guangdong Liver Cancer Cohort (GLCC) between September 2013 and April 2017 in the analysis. CHEI and HEI-2015 scores were calculated based on the dietary intake in the year before diagnosis of HCC. Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for each index., Results: During a median follow-up of 797 days, 389 deaths were identified, including 347 from HCC. Higher CHEI scores, reflecting favorable adherence to the 2016 Dietary Guidelines for Chinese, were associated with a lower risk of all-cause mortality (T 3 vs. T 1 : HR = 0.75, 95% CI: 0.58-0.98) and HCC-specific mortality (T 3 vs. T 1 : HR = 0.74, 95% CI: 0.56-0.98). Non-significant, inverse associations of HEI-2015 score with all-cause mortality (T 3 vs. T 1 : HR = 0.86, 95% CI: 0.67-1.11) and HCC-specific mortality (T 3 vs. T 1 : HR = 0.93, 95% CI: 0.71-1.21) were suggested., Conclusions: Our findings suggest that better adherence to the 2016 Dietary Guidelines for Chinese may reduce the risk of all-cause and HCC-specific mortality in patients with HCC., (© 2020 The Japan Society of Hepatology.)

Background: Patients with hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) present a complex and poor prognosis. Systemic inflammation plays an important role in its pathogenesis, and interleukin-6 (IL-6) as a pro-inflammatory cytokine is related with severe liver impairment and also plays a role in promoting liver regeneration. Whether serum IL-6 influences HBV-ACLF prognosis has not been studied., Aim: To determine the impact of serum IL-6 on outcome of patients with HBV-ACLF., Methods: We performed a retrospective study of 412 HBV-ACLF patients. The findings were analyzed with regard to mortality and the serum IL-6 level at baseline, as well as dynamic changes of serum IL-6 within 4 wk., Results: The serum IL-6 level was associated with mortality. Within 4 wk, deceased patients had significantly higher levels of IL-6 at baseline than surviving patients [17.9 (7.3-57.6) vs 10.4 (4.7-22.3), P = 0.011]. Patients with high IL-6 levels (> 11.8 pg/mL) had a higher mortality within 4 wk than those with low IL-6 levels (≤ 11.8 pg/mL) (24.2% vs 13.2%, P = 0.004). The odds ratios calculated using univariate and multivariate logistic regression were 2.10 (95% confidence interval [CI]: 1.26-3.51, P = 0.005) and 2.11 (95%CI: 1.15-3.90, P = 0.017), respectively. The mortality between weeks 5 and 8 in patients with high IL-6 levels at 4 wk was 15.0%, which was significantly higher than the 6.6% mortality rate in patients with low IL-6 levels at 4 wk (hazard ratio = 2.39, 95%CI: 1.05-5.41, P = 0.037). The mortality was 5.0% in patients with high IL-6 levels at baseline and low IL-6 levels at 4 wk, 7.5% in patients with low IL-6 levels both at baseline and at 4 wk, 11.5% in patients with low IL-6 levels at baseline and high IL-6 levels at 4 wk, and 16.7% in patients with high IL-6 levels both at baseline and at 4 wk. The increasing trend of the mortality rate with the dynamic changes of IL-6 was significant ( P for trend = 0.023)., Conclusion: A high level of serum IL-6 is an independent risk factor for mortality in patients with HBV-ACLF. Furthermore, a sustained high level or dynamic elevated level of serum IL-6 indicates a higher mortality., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)