Search

Tiejun Zhao,1 Hezhong Chen,1 Yuchao Dong,2 Jiajun Zhang,1 Haidong Huang,2 Ji Zhu,1 Wei Zhang21Institute of Cardiothoracic Surgery, 2Respiratory Department, Changhai Hospital, Shanghai, People's Republic of ChinaAbstract: In order to improve the therapeutic efficacy and minimize the side effects of lung cancer chemotherapy, the formulation of paclitaxel-loaded poly(glycolide-co-ε-caprolactone)-b-D-α-tocopheryl polyethylene glycol 2000 succinate nanoparticles (PTX-loaded [PGA-co-PCL]-b-TPGS2k NPs) was prepared. The novel amphiphilic copolymer (PGA-co-PCL)-b-TPGS2k was synthesized by ring-opening polymerization and characterized by proton nuclear magnetic resonance spectroscopy and gel permeation chromatography. The PTX-loaded (PGA-co-PCL)-b -TPGS2k NPs were characterized in terms of size, size distribution, zeta potential, drug encapsulation, surface morphology, and drug release. In vitro cellular uptakes of NPs were investigated with confocal laser scanning microscopy, indicating the coumarin 6-loaded (PGA-co-PCL)-b -TPGS2k NPs could be internalized by human lung cancer A-549 cells. The antitumor effect of PTX-loaded NPs was evaluated, both in vitro and in vivo, on an A-549 cell tumor-bearing mouse model via intratumoral injection. The commercial PTX formulation Taxol was chosen as the reference. Experimental results showed that the PTX-loaded NPs possessed higher cytotoxicity and could effectively inhibit the growth of tumor. All the results suggested that amphiphilic copolymer (PGA-co-PCL)-b -TPGS2k could act as a potential biological material for nanoformulation in the treatment of lung cancer.Keywords: (PGA-co-PCL)-b TPGS2k, paclitaxel, nanoparticles, drug delivery, lung cancer

The CRISPR-Cas13 system, an RNA-guided editing tool, has emerged as a highly efficient and stable RNA editing technique. Although the CRISPR-Cas13 system has been developed in several insect species, its application in lepidopterans has not yet been reported. In the present study, we evaluated the RNA cleavage activity of the CRISPR-Cas13 system in the silkworm ( Bombyx mori ), a model lepidopteran insect, both ex vivo and in vivo . We established two stable silkworm BmE cell lines expressing PspCas13b and CasRx, respectively. Further analysis demonstrated that both PspCas13b and CasRx effectively down-regulated the transcription of exogenously-introduced target and endogenous genes in these cell lines. In addition, we generated two transgenic silkworm strains, one expressing CasRx and the other expressing RNA-guided CRISPR RNA targeting Sex combs reduced ( Scr ). Further crossing experiments showed that CasRx induced a down-regulation of Scr transcription in silkworms, which impaired systemic growth of larvae. Overall, this study demonstrated that the CRISPR-Cas13 RNA editing system works efficiently in the silkworm, providing a potential alternative approach for RNA manipulation in lepidopteran insects.

Fatty acids (FAs) are essential nutrients that play multiple roles in cellular activities. To meet cell-specific needs, cells exhibit differential uptake of FAs in diverse physiological or pathological contexts, coordinating to maintain metabolic homeostasis. Cells tightly regulate the localization and transcription of CD36 and other key proteins that transport FAs across the plasma membrane in response to different stimuli. Dysregulation of FA uptake results in diseases such as obesity, steatotic liver, heart failure, and cancer progression. Targeting FA uptake might provide potential therapeutic strategies for metabolic diseases and cancer. Here, we review recent advances in context-specific regulation of FA uptake, focusing on the regulation of CD36 in metabolic organs and other cells., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Nonalcoholic steatohepatitis (NASH) is a prevalent chronic liver condition. However, the potential therapeutic benefits and underlying mechanism of nicotinate-curcumin (NC) in the treatment of NASH remain uncertain., Methods: A rat model of NASH induced by a high-fat and high-fructose diet was treated with nicotinate-curcumin (NC, 20, 40 mg·kg - 1 ), curcumin (Cur, 40 mg·kg - 1 ) and metformin (Met, 50 mg·kg - 1 ) for a duration of 4 weeks. The interaction between NASH, Cur and Aldo-Keto reductase family 1 member B10 (AKR1B10) was filter and analyzed using network pharmacology. The interaction of Cur, NC and AKR1B10 was analyzed using molecular docking techniques, and the binding energy of Cur and NC with AKR1B10 was compared. HepG2 cells were induced by Ox-LDL (25 µg·ml - 1 , 24 h) in high glucose medium. NC (20µM, 40µM), Cur (40µM) Met (150µM) and epalrestat (Epa, 75µM) were administered individually. The activities of ALT, AST, ALP and the levels of LDL, HDL, TG, TC and FFA in serum were quantified using a chemiluminescence assay. Based on the changes in the above indicators, score according to NAS standards. The activities of Acetyl-CoA and Malonyl-CoA were measured using an ELISA assay. And the expression and cellular localization of AKR1B10 and Acetyl-CoA carboxylase (ACCα) in HepG2 cells were detected by Western blotting and immunofluorescence., Results: The results of the animal experiments demonstrated that NASH rat model induced by a high-fat and high-fructose diet exhibited pronounced dysfunction in liver function and lipid metabolism. Additionally, there was a significant increase in serum levels of FFA and TG, as well as elevated expression of AKR1B10 and ACCα, and heightened activity of Acetyl-CoA and Malonyl-CoA in liver tissue. The administration of NC showed to enhance liver function in rats with NASH, leading to reductions in ALT, AST and ALP levels, and decrease in blood lipid and significant inhibition of FFA and TG synthesis in the liver. Network pharmacological analysis identified AKR1B10 and ACCα as potential targets for NASH treatment. Molecular docking studies revealed that both Cur and NC are capable of binding to AKR1B10, with NC exhibiting a stronger binding energy to AKR1B10. Western blot analysis demonstrated an upregulation in the expression of AKR1B10 and ACCα in the liver tissue of NASH rats, accompanied by elevated Acetyl-CoA and Malonyl-CoA activity, and increased levels of FFA and TG. The results of the HepG2 cell experiments induced by Ox-LDL suggest that NC significantly inhibited the expression and co-localization of AKR1B10 and ACCα, while also reduced levels of TC and LDL-C and increased level of HDL-C. These effects are accompanied by a decrease in the activities of ACCα and Malonyl-CoA, and levels of FFA and TG. Furthermore, the impact of NC appears to be more pronounced compared to Cur., Conclusion: NC could effectively treat NASH and improve liver function and lipid metabolism disorder. The mechanism of NC is related to the inhibition of AKR1B10/ACCα pathway and FFA/TG synthesis of liver., (© 2024. The Author(s).)

Key Message: A major quantitative trait locus (QTL) for the hundred-seed weight (HSW) was identified and confirmed in the two distinct soybean populations, and the target gene GmCYP82C4 underlying this locus was identified that significantly associated with soybean seed weight, and it was selected during the soybean domestication and improvement process. Soybean is a major oil crop for human beings and the seed weight is a crucial goal of soybean breeding. However, only a limited number of target genes underlying the quantitative trait loci (QTLs) controlling seed weight in soybean are known so far. In the present study, six loci associated with hundred-seed weight (HSW) were detected in the first population of 573 soybean breeding lines by genome-wide association study (GWAS), and 64 gene models were predicted in these candidate QTL regions. The QTL qHSW_1 exhibits continuous association signals on chromosome four and was also validated by region association study (RAS) in the second soybean population (409 accessions) with wild, landrace, and cultivar soybean accessions. There were seven genes in qHSW_1 candidate region by linkage disequilibrium (LD) block analysis, and only Glyma.04G035500 (GmCYP82C4) showed specifically higher expression in flowers, pods, and seeds, indicating its crucial role in the soybean seed development. Significant differences in HSW trait were detected when the association panels are genotyped by single-nucleotide polymorphisms (SNPs) in putative GmCYP82C4 promoter region. Eight haplotypes were generated by six SNPs in GmCYP82C4 in the second soybean population, and two superior haplotypes (Hap2 and Hap4) of GmCYP82C4 were detected with average HSW of 18.27 g and 18.38 g, respectively. The genetic diversity of GmCYP82C4 was analyzed in the second soybean population, and GmCYP82C4 was most likely selected during the soybean domestication and improvement process, leading to the highest proportion of Hap2 of GmCYP82C4 both in landrace and cultivar subpopulations. The QTLs and GmCYP82C4 identified in this study provide novel genetic resources for soybean seed weight trait, and the GmCYP82C4 could be used for soybean molecular breeding to develop desirable seed weight in the future., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Different types of cells uptake fatty acids in response to different stimuli or physiological conditions; however, little is known about context-specific regulation of fatty acid uptake. Here, we show that muscle injury induces fatty acid uptake in muscle stem cells (MuSCs) to promote their proliferation and muscle regeneration. In humans and mice, fatty acids are mobilized after muscle injury. Through CD36, fatty acids function as both fuels and growth signals to promote MuSC proliferation. Mechanistically, injury triggers the translocation of CD36 in MuSCs, which relies on dynamic palmitoylation of STX11. Palmitoylation facilitates the formation of STX11/SNAP23/VAMP4 SANRE complex, which stimulates the fusion of CD36- and STX11-containing vesicles. Restricting fatty acid supply, blocking fatty acid uptake, or inhibiting STX11 palmitoylation attenuates muscle regeneration in mice. Our studies have identified a critical role of fatty acids in muscle regeneration and shed light on context-specific regulation of fatty acid sensing and uptake., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Many metabolic diseases are caused by disorders of lipid homeostasis. CIDEC, a lipid droplet (LD)-associated protein, plays a critical role in controlling LD fusion and lipid storage. However, regulators of CIDEC remain largely unknown. Here, we established a homogeneous time-resolved fluorescence (HTRF)-based high-throughput screening method and identified LPXN as a positive regulatory candidate for CIDEC. LPXN and Hic-5, the members of the Paxillin family, are focal adhesion adaptor proteins that contribute to the recruitment of specific kinases and phosphatases, cofactors, and structural proteins, participating in the transduction of extracellular signals into intracellular responses. Our data showed that Hic-5 and LPXN significantly increased the protein level of CIDEC and enhanced CIDEC stability not through triacylglycerol synthesis and FAK signaling pathways. Hic-5 and LPXN reduced the ubiquitination of CIDEC and inhibited its proteasome degradation pathway. Furthermore, Hic-5 and LPXN enlarged LDs and promoted lipid storage in adipocytes. Therefore, we identified Hic-5 and LPXN as novel regulators of CIDEC. Our current findings also suggest intervention with Hic-5 and LPXN might ameliorate ectopic fat storage by enhancing the lipid storage capacity of white adipose tissues., Competing Interests: Conflict of 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Adipocytes are the primary sites for fatty acid storage, but the synthesis rate of fatty acids is very low. The physiological significance of this phenomenon remains unclear. Here, we show that surplus fatty acid synthesis in adipocytes induces necroptosis and lipodystrophy. Transcriptional activation of FASN elevates fatty acid synthesis, but decreases NADPH level and increases ROS production, which ultimately leads to adipocyte necroptosis. We identify MED20, a subunit of the Mediator complex, as a negative regulator of FASN transcription. Adipocyte-specific male Med20 knockout mice progressively develop lipodystrophy, which is reversed by scavenging ROS. Further, in a murine model of HIV-associated lipodystrophy and a human patient with acquired lipodystrophy, ROS neutralization significantly improves metabolic disorders, indicating a causal role of ROS in disease onset. Our study well explains the low fatty acid synthesis rate in adipocytes, and sheds light on the management of acquired lipodystrophy., (© 2024. The Author(s).)

N 6 -methyladenosine (m 6 A) is the most prevalent post-transcriptional internal RNA modification, which is involved in the regulation of diverse physiological processes. Dynamic and reversible m 6 A modification has been shown to regulate glucose metabolism, and dysregulation of m 6 A modification contributes to glucose metabolic disorders in multiple organs and tissues including the pancreas, liver, adipose tissue, skeletal muscle, kidney, blood vessels, and so forth. In this review, the role and molecular mechanism of m 6 A modification in the regulation of glucose metabolism were summarized, the potential therapeutic strategies that improve glucose metabolism by targeting m 6 A modifiers were outlined, and feasible directions of future research in this field were discussed as well, providing clues for translational research on combating metabolic diseases based on m 6 A modification in the future.

The development of chronic liver disease can be promoted by excessive fat accumulation, dysbiosis, viral infections and persistent inflammatory responses, which can lead to liver inflammation, fibrosis and carcinogenesis. An in-depth understanding of the etiology leading to chronic liver disease and the underlying mechanisms influencing its development can help identify potential therapeutic targets for targeted treatment. Orphan nuclear receptors (ONRs) are receptors that have no corresponding endogenous ligands to bind to them. The study of these ONRs and their biological properties has facilitated the development of synthetic ligands, which are important for investigating the effective targets for the treatment of a wide range of diseases. In recent years, it has been found that ONRs are essential for maintaining normal liver function and their dysfunction can affect a variety of liver diseases. ONRs can influence pathophysiological activities such as liver lipid metabolism, inflammatory response and cancer cell proliferation by regulating hormones/transcription factors and affecting the biological clock, oxidative stress, etc. This review focuses on the regulation of ONRs, mainly including retinoid related orphan nuclear receptors (RORs), pregnane X receptor (PXR), leukocyte cell derived chemotaxin 2 (LECT2), Nur77, and hepatocyte nuclear factor 4α (HNF4α), on the development of different types of chronic liver diseases in different ways, in order to provide useful references for the therapeutic strategies of chronic liver diseases based on the regulation of ONRs.

Obesity has become a global pandemic. WDTC1 is a WD40-containing protein that functions as an anti-obesity factor. WDTC1 inhibits adipogenesis by working as an adaptor of the CUL4-DDB1 E3 ligase complex. It remains unclear about how WDTC1 is regulated. Here, we show that the TRiC/CCT functions as a chaperone to facilitate the protein folding of WDTC1 and proper function in adipogenesis. Through tandem purification, we identified the molecular chaperone TRiC/CCT as WDTC1-interacting proteins. WDTC1 bound the TRiC/CCT through its ADP domain, and the TRiC/CCT recognized WDTC1 through the CCT5 subunit. Disruption of the TRiC/CCT by knocking down CCT1 or CCT5 led to misfolding and lysosomal degradation of WDTC1. Furthermore, the knockdown of CCT1 or CCT5 eliminated the inhibitory effect of WDTC1 on adipogenesis. Our studies uncovered a critical role of the TRiC/CCT in the folding of WDTC1 and expanded our knowledge on the regulation of adipogenesis., 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 © 2023 Tang, Cen, Yao, Yin, Weng, Zhao and Wang.)

Protein palmitoylation is a post-translational lipid modification of proteins. Accumulating evidence reveals that palmitoylation functions as a sorting signal to direct proteins to destinations; however, the sorting mechanism remains largely unknown. Here, we show that ARF6 plays a general role in targeting palmitoylated proteins from the Golgi to the plasma membrane (PM). Through shRNA screening, we identified ARF6 as the key small GTPase in targeting CD36, a palmitoylated protein, from the Golgi to the PM. We found that the N-terminal myristoylation of ARF6 is required for its binding with palmitoylated CD36, and the GTP-bound form of ARF6 facilitates the delivery of CD36 to the PM. Analysis of stable isotope labeling by amino acids in cell culture revealed that ARF6 might facilitate the sorting of 359 of the 531 palmitoylated PM proteins, indicating a general role of ARF6. Our study has thus identified a sorting mechanism for targeting palmitoylated proteins from the Golgi to the PM., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Objective: To investigate the effect of different postures on direct anterior approach(DAA) total hip arthroplasty., Methods: Total of 94 patients who underwent DAA total hip arthroplasty from July 2016 to June 2020 were retrospectively analyzed. They were divided into two groups according to different positions during the operation, including 45 cases in lateral position and 49 cases in supine position (with the aid of stent). The general data such as gender, affected limb, body mass index(BMI), incision length, operation time, intraoperative bleeding volume, drainage volume 24 hours after operation, hemoglobin difference before and after operation, first landing time after operation, postoperative hospitalization time, postoperative complications, visual analogue scale(VAS) at 1 day, 1, 2 weeks, 1, 3 and 6 months after operation, Harris score at 1, 2 weeks, 1, 3 and 6 months after operation were observed and compared between the two groups., Results: Patients in both groups were followed up for 6 to 12 months with an average of (8.31±2.22) months. There was no significant difference between two groups in gender, affected limb, age, height, weight, body mass index(BMI), preoperative VAS score and preoperative Harris score( P >0.05). The incision length, operation time, intraoperative bleeding volume, 24-hour drainage volume, hemoglobin difference before and after operation, first time to the ground and postoperative hospitalization time of patients in supine position (assisted by stent) group were all better than those in lateral position group( P <0.05);There was no significant difference in the number of blood transfusions during and after operation( P =0.550). There was no significant difference in anteversion angle and abduction angle in the supine position(with the aid of stent) group during and after operation ( P =0.825, P =0.066);There was significant difference in anteversion angle and abduction angle in the lateral position group during and after operation( P <0.05). VAS of patients in supine position (assisted by stent) group were lower than those in lateral position group at 1 day, 1, 2 weeks and 1 month after operation( P <0.05), and there was no statistical difference between two groups at 3 and 6 months after operation( P >0.05). Harris scores of patients in supine position(assisted by stent) group were higher than those in lateral position group at 1 week, 1 month and 3 months after operation( P <0.05), and there was no significant difference between two groups at 6 months after operation( P >0.05)., Conclusion: Compared with the lateral position, the supine position DAA total hip arthroplasty has the advantages of small incision, short operation time, less bleeding, early landing time, short hospitalization time, and small intraoperative acetabular cup position judgment error. It has the advantage of fast postoperative recovery, but the recovery of hip joint function is the same after 6 months.

Seed-flooding stress is one of major abiotic constraints that adversely affects soybean production worldwide. Identifying tolerant germplasms and revealing the genetic basis of seed-flooding tolerance are imperative goals for soybean breeding. In the present study, high-density linkage maps of two inter-specific recombinant inbred line (RIL) populations, named NJIRNP and NJIR4P, were utilized to identify major quantitative trait loci (QTLs) for seed-flooding tolerance using three parameters viz., germination rate (GR), normal seedling rate (NSR), and electrical conductivity (EC). A total of 25 and 18 QTLs were detected by composite interval mapping (CIM) and mixed-model-based composite interval mapping (MCIM), respectively, and 12 common QTLs were identified through both methods. All favorable alleles for the tolerance are notably from the wild soybean parent. Moreover, four digenic epistatic QTL pairs were identified, and three of them showed no main effects. In addition, the pigmented soybean genotypes exhibited high seed-flooding tolerance compared with yellow seed coat genotypes in both populations. Moreover, out of five identified QTLs, one major region containing multiple QTLs associated with all three traits was identified on Chromosome 8, and most of the QTLs within this hotspot were major loci ( R 2 > 10) and detectable in both populations and multiple environments. Based on the gene expression and functional annotation information, 10 candidate genes from QTL "hotspot 8-2" were screened for further analysis. Furthermore, the results of qRT-PCR and sequence analysis revealed that only one gene, GmDREB2 ( Glyma.08G137600 ), was significantly induced under flooding stress and displayed a TTC tribasic insertion mutation of the nucleotide sequence in the tolerant wild parent (PI342618B). GmDREB2 encodes an ERF transcription factor, and the subcellular localization analysis using green fluorescent protein (GFP) revealed that GmDREB2 protein was localized in the nucleus and plasma membrane. Furthermore, overexpression of GmDREB2 significantly promoted the growth of soybean hairy roots, which might indicate its critical role in seed-flooding stress. Thus, GmDREB2 was considered as the most possible candidate gene for seed-flooding tolerance.

Background: Whether statins can reduce major cardiovascular adverse events (MACE) in patients with coronary artery spasm (CAS) is controversial. And most of the relevant research to date has been conducted in Asia., Methods: We systematically searched electronic databases for studies on the effect of statins on MACE in patients with CAS in Asia and published up to September 2022. We included data on MACE in a statin therapy patient group and a no-statin therapy control group. We then evaluated the effect of statin therapy on MACE in patients with CAS in Asia by meta-analysis and trial sequential analysis (TSA). All statistical analyses were performed using Stata 16.0 software and TSA software., Results: A total of 10 studies ( n = 9333 patients) were included in the final analysis. Meta-analysis showed that the use of statins had a significant effect on MACE in CAS patients (with RR, 0.70; 95% CI, 0.49-0.99), and the sensitivity analysis further confirmed this finding. Subgroup analysis suggested that the correlation between statin therapy and reduced MACE endpoint was stronger in Japanese patients and patients followed up for more than 4 years. But our TSA results indicated that the available samples were insufficient and further research is needed., Conclusions: Our meta-analysis suggests that statin therapy can reduce MACE in patients with CAS in Asia, and the correlation between the two was stronger in Japanese patients and patients followed up for more than 4 years., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023 Tian-Jun Zhao et al.)

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor outcome and lacks of approved targeted therapy. Overexpression of epidermal growth factor receptor (EGFR) is found in more than 50% TNBC and is suggested as a driving force in progression of TNBC; however, targeting EGFR using antibodies to prevent its dimerization and activation shows no significant benefits for TNBC patients. Here we report that EGFR monomer may activate signal transducer activator of transcription-3 (STAT3) in the absence of transmembrane protein TMEM25, whose expression is frequently decreased in human TNBC. Deficiency of TMEM25 allows EGFR monomer to phosphorylate STAT3 independent of ligand binding, and thus enhances basal STAT3 activation to promote TNBC progression in female mice. Moreover, supplying TMEM25 by adeno-associated virus strongly suppresses STAT3 activation and TNBC progression. Hence, our study reveals a role of monomeric-EGFR/STAT3 signaling pathway in TNBC progression and points out a potential targeted therapy for TNBC., (© 2023. The Author(s).)

In a recent article published in Nature , Patel et al . identified adipose triglyceride lipase (ATGL, also known as patatin-like phospholipase domain containing 2) as the first biosynthetic enzyme of fatty acid esters of hydroxy fatty acids (FAHFAs), further expanding the knowledge on bioactive lipid research and being a potential paradigm shift for ATGL studies., Competing Interests: Conflict of interest The authors declare that no conflict of interest exists.

Objective: To investigate the related factors of invasive transformation and prognosis for follicular lymphoma., Methods: A total of 168 patients with follicular lymphoma at First Affiliated Hospital of Zhengzhou University from August 2015 to January 2021 were collected, and the significance of each index in histological transformation (HT) and prognosis were analyzed., Results: Pathology grade3, Ki-67 index ≥40%, β 2 MG＞3 mg/L, LDH＞245 U/L, POD24 and non-invasion of bone marrow were associated with HT. Univariate analysis showed that the high risk of FLIPI-2, pathological grade 3, Ki-67≥40%, anemia, β 2 MG＞3 mg/L, LDH＞245 U/L and HT had significant adverse effects on PFS; β 2 MG＞3 mg/L, LDH＞245 U/L, POD24 and HT had significant adverse effects on OS. Cox multivariate analysis showed that the β 2 MG >3 mg/L and HT were independent risk factors of PFS, HT was independent risk factor of OS., Conclusion: The pathological grade, Ki-67, β 2 MG, LDH, POD24 and bone marrow invasion of FL can predict the risk of HT. Meanwhile, β 2 MG >3 mg/L and HT are significantly related to poor prognosis of FL.

Brown adipose tissue (BAT) plays an essential role in non-shivering thermogenesis. The phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) is identified as a lipid transporter that reciprocally transfers phospholipids between intracellular membrane structures. However, the physiological significance of PITPNC1 and its regulatory mechanism remain unclear. Here, we demonstrate that PITPNC1 is a key player in thermogenesis of BAT. While Pitpnc1 -/- mice do not differ with wildtype mice in body weight and insulin sensitivity on either chow or high-fat diet, they develop hypothermia when subjected to acute cold exposure at 4°C. The Pitpnc1 -/- brown adipocytes exhibit defective β-oxidation and abnormal thermogenesis-related metabolism pathways in mitochondria. The deficiency of lipid mobilization in Pitpnc1 -/- brown adipocytes might be the result of excessive accumulation of phosphatidylcholine and a reduction of phosphatidic acid. Our findings have uncovered significant roles of PITPNC1 in mitochondrial phospholipid homeostasis and BAT thermogenesis., (© 2022. The Author(s).)

Objective: To investigate the effect of curcumol on NOD-like receptor thermoprotein domain 3 (NLRP3) inflammasomes, and analyze the mechanism underlying curcumol against liver fibrosis., Methods: Thirty Kunming mice were divided into a control group, a model group and a curcumol group according to a random number table, 10 mice in each group. Mice were intraperitoneally injected with 40% carbon tetrachloride (CCl 4 :peanut oil, 2:3 preparation) at 5 mL/kg for 6 weeks, twice a week, for developing a liver fibrosis model. The mice in the control group were given the same amount of peanut oil twice a week for 6 weeks. The mice in the curcumol group were given curcumol (30 mL/kg) intragastrically, and the mice in the model and control groups were given the same amount of normal saline once a day for 6 weeks. Changes in liver structure were observed by hematoxylin and eosin (HE) and Masson staining. Liver function, liver fiber indices, and the expression of interleukin (IL)-10 and tumor necrosis factor-α (TNF-α) levels were determined by automatic biochemical analyzer and enzyme linked immunosorbent assay kit. Immunoblotting and reverse transcription-quantitative PCR (RT-qPCR) were performed to detect the expression of NLRP3 inflammasome-related molecules, TGF-β and collagen., Results: HE and Masson staining results showed that the hepatocytes of the model group were arranged irregularly with pseudo-lobular structure and a large amount of collagen deposition. The mice in the curcumol group had a significant decrease in liver function and liver fibers indices compared with the model group (P<0.05); RT-qPCR and Western blotting results reveal that, in the curcumol group, the mRNA and protein expression levels of NLRP3, IL-1 β, Caspase 1 and gasdermin D decreased significantly compared with the model group (P<0.05); immunohistochemical results showed that in the curcumol group, the protein expression levels of NLRP3 and IL-1 β decreased significantly compared with the model group (P<0.05)., Conclusion: A potential anti-liver fibrosis mechanism of curcumol may be associated with the inhibition of NLRP3 inflammasomes and decreasing the downstream inflammatory response., (© 2021. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Aberrant activation of EGFR due to overexpression or mutation is associated with poor prognosis in many types of tumors. Here we show that blocking the sorting system that directs EGFR to plasma membrane is a potent strategy to treat EGFR-dependent tumors. We find that EGFR palmitoylation by DHHC13 is critical for its plasma membrane localization and identify ARF6 as a key factor in this process. N-myristoylated ARF6 recognizes palmitoylated EGFR via lipid-lipid interaction, recruits the exocyst complex to promote EGFR budding from Golgi, and facilitates EGFR transporting to plasma membrane in a GTP-bound form. To evaluate the therapeutic potential of this sorting system, we design a cell-permeable peptide, N-myristoylated GKVL-TAT, and find it effectively disrupts plasma membrane localization of EGFR and significantly inhibits progression of EGFR-dependent tumors. Our findings shed lights on the underlying mechanism of how palmitoylation directs protein sorting and provide an potential strategy to manage EGFR-dependent tumors., (© 2022. The Author(s).)

Background: Disturbance of cholesterol homeostasis is considered as one of the manifestations of cancer. Cholesterol plays an essential role in the pleiotropic functions of cancer cells, including mediating membrane trafficking, intracellular signal transduction, and production of hormones and steroids. As a single transmembrane receptor, the low-density lipoprotein receptor (LDLR) can participate in intracellular cholesterol uptake and regulate cholesterol homeostasis. It has recently been found that LDLR is aberrantly expressed in a broad range of cancers, including colon cancer, prostate cancer, lung cancer, breast cancer and liver cancer. LDLR has also been found to be involved in various signaling pathways, such as the MAPK, NF-κB and PI3K/Akt signaling pathways, which affect cancer cells and their surrounding microenvironment. Moreover, LDLR may serve as an independent prognostic factor for lung cancer, breast cancer and pancreatic cancer, and is closely related to the survival of cancer patients. However, the role of LDLR in some cancers, such as prostate cancer, remains controversial. This may be due to the lack of normal feedback regulation of LDLR expression in cancer cells and the severe imbalance between LDLR-mediated cholesterol uptake and de novo biosynthesis of cholesterol., Conclusions: The imbalance of cholesterol homeostasis caused by abnormal LDLR expression provides new therapeutic opportunities for cancer. LDLR interferes with the occurrence and development of cancer by modulating cholesterol homeostasis and may become a novel target for the development of anti-cancer drugs. Herein, we systematically review the contribution of LDLR to cancer progression, especially its dysregulation and underlying mechanism in various malignancies. Besides, potential targeting and immunotherapeutic options are proposed., (© 2022. Springer Nature Switzerland AG.)

In recent years, liver fibrosis has become a hotspot in the field of liver diseases. MicroRNA(miRNA)-mediated Nod-like receptor pyrin domain containing 3(NLRP3) inflammasome activation is pivotal in the pathogenesis of liver fibrosis. The present study mainly discussed the role of miRNA-mediated NLRP3 inflammasome activation in the pathogenesis of liver fibrosis. Different miRNA molecules regulated liver fibrosis by mediating NLRP3 inflammasome activation, including miRNA-350-3 p(miR-350-3 p)/interleukin-6(IL-6)-mediated signal transducer and activator of transcription 3(STAT3)/c-myc signaling pathway, miR-148 a-induced autophagy and apoptosis of hepatic stellate cells via hedgehog signaling pathway, miR-155-mediated NLRP3 inflammasome by the negative feedback of the suppressor of cytokine signaling-1(SOCS-1), miR-181 a-mediated downstream NLRP3 inflammatory pathway activation through mitogen-activated protein kinase kinase(MEK)/extracellular signal-regulated kinase(ERK)/nuclear transcription factor κB(NF-κB) inflammatory pathway, miR-21-promoted expression of NF-κB and NLRP3 of RAW264.7 cells in mice by inhibiting tumor necrosis factor-α inducible protein 3(A20), and miR-20 b-promoted expression of IL-1β and IL-18 by activating NLRP3 signaling pathway. Additionally, the anti-liver fibrosis mechanism of different active components in Chinese medicines(such as Curcumae Rhizoma, Glycyrrhizae Radix et Rhizoma, Aurantii Fructus, Polygoni Cuspidati Rhizoma et Radix, Moutan Cortex, Paeoniae Radix Alba, Epimedii Folium, and Cinnamomi Cortex) was also explored based on the anti-liver fibrosis effect of miRNA-mediated NLRP3 inflammasome activation.

Lipid metabolism disorder is related to an increased risk of tumorigenesis and is involved in the rapid growth of cancer cells as well as the formation of metastatic lesions. Epidemiological studies have demonstrated that low-density lipoprotein (LDL) and oxidized low-density lipoprotein (ox-LDL) are closely associated with breast cancer, colorectal cancer, pancreatic cancer, and other malignancies, suggesting that LDL and ox-LDL play important roles during the occurrence and development of cancers. LDL can deliver cholesterol into cancer cells after binding to LDL receptor (LDLR). Activation of PI3K/Akt/mTOR signaling pathway induces transcription of the sterol regulatory element-binding proteins (SREBPs), which subsequently promotes cholesterol uptake and synthesis to meet the demand of cancer cells. Ox-LDL binds to the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and cluster of differentiation 36 (CD36) to induce mutations, resulting in inflammation, cell proliferation, and metastasis of cancer. Classic lipid-lowering drugs, statins, have been shown to reduce LDL levels in certain types of cancer. As LDL and ox-LDL play complicated roles in cancers, the potential therapeutic effect of targeting lipid metabolism in cancer therapy warrants more investigation., 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 © 2022 Deng, Zhu, Zhao, Li, Gu, Liao and Qin.)

Myelin sheath is an important structure to maintain functions of the nerves in central nervous system. Protein palmitoylation has been established as a sorting determinant for the transport of myelin-forming proteins to the myelin membrane, however, its function in the regulation of oligodendrocyte development remains unknown. Here, we show that an Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases, DHHC5, is involved in the control of oligodendrocyte development. Loss of Zdhhc5 in oligodendrocytes inhibits myelination and remyelination by reducing total myelinating oligodendrocyte population. STAT3 is the primary substrate for DHHC5 palmitoylation in oligodendrocytes. Zdhhc5 ablation reduces STAT3 palmitoylation and suppresses STAT3 phosphorylation and activation. As a result, the transcription of the myelin-related and anti-apoptosis genes is inhibited, leading to suppressed oligodendrocyte development and myelination. Our findings demonstrate a key role DHHC5 in controlling myelinogenesis., (© 2021 Wiley Periodicals LLC.)

The present study clarified the molecular mechanism of curcumol against liver fibrosis based on its effects on the autopha-gy and apoptosis of hepatic stellate cells. The hepatic stellate cells were divided into a blank control group, a transforming growth factor-β1(TGF-β1)(10 ng·mL~(-1)) group, and low-(12.5 mg·L~(-1)), medium-(25 mg·L~(-1)), and high-dose(50 mg·L~(-1)) curcumol groups. The effect of curcumol on the viability of hepatic stellate cells induced by TGF-β1 was detected by the MTT assay kit. The apo-ptosis in each group was determined by flow cytometry. Real-time fluorescence-based quantitative PCR(RT-PCR) was employed for the detection of mRNA expression of α-smooth muscle actin(α-SMA), type Ⅰ collagen(collagen Ⅰ), and type Ⅲ collagen(collagen Ⅲ). Western blot was used to detect the protein expression of p62, microtubule-associated protein 1 light chain 3(LC3), beclin1, B cell lymphoma 2(Bcl-2), and Bcl-2-associated X protein(Bax). Transmission electron microscopy(TEM) was used to observe cell morphology and autophagosome formation in each group. The autophagic flux was observed after cell infection with adenovirus under double fluorescence labeling. The cell viability assay revealed that compared with the TGF-β1 group, the curcumol groups showed significantly decreased cell viability. The apoptosis assay showed that the apoptosis rates of the curcumol groups were significantly higher than that of the TGF-β1 group. RT-PCR indicated that the mRNA expression of α-SMA, collagenⅠ, and collagen Ⅲ in the curcumol groups was significantly lower than that of the TGF-β1 group. Western blot showed that the expression of p62, LC3, beclin1, Bcl-2, and Bax in the curcumol groups was significantly different from that in the TGF-β1 group. As demonstrated by TEM, compared with the TGF-β1 group, the curcumol groups showed significantly increased autophagosomes. The detection of autophagic flow by the adenovirus under double fluorescence labeling showed that autolysosomes in the curcumol groups were significantly increased compared with those in the TGF-β1 group. Curcumol can induce the autophagy and apoptosis of hepatic stellate cells, which may be one of its anti-liver fibrosis mechanisms.

Epidemiological studies have shown that plasma HDL-C levels are closely related to the risk of prostate cancer, breast cancer, and other malignancies. As one of the key carriers of cholesterol regulation, high-density lipoprotein (HDL) plays an important role in tumorigenesis and cancer development through anti-inflammation, antioxidation, immune-modulation, and mediating cholesterol transportation in cancer cells and noncancer cells. In addition, the occurrence and progression of cancer are closely related to the alteration of the tumor microenvironment (TME). Cancer cells synthesize and secrete a variety of cytokines and other factors to promote the reprogramming of surrounding cells and shape the microenvironment suitable for cancer survival. By analyzing the effect of HDL on the infiltrating immune cells in the TME, as well as the relationship between HDL and tumor-associated angiogenesis, it is suggested that a moderate increase in the level of HDL in vivo with consequent improvement of the function of HDL in the TME and induction of intracellular cholesterol efflux may be a promising strategy for cancer therapy., (© 2021 Wiley Periodicals LLC.)

Objective: The aim of this study was to evaluate the prognostic value of a novel scoring system, based on D‑dimer, total cholesterol, high-sensitivity cardiac troponin T (hs-cTnT), and serum albumin levels, in patients with heart failure., Methods: A total of 221 patients diagnosed with heart failure between May 2016 to January 2020 were enrolled in this retrospective study. The prognostic significance of the biomarkers D‑dimer, total cholesterol, hs-cTnT, and serum albumin was determined with univariate and multivariate Cox proportional hazard models. A novel prognostic score based on these predictors was established. The Kaplan-Meier method and log-rank test were used to compare the adverse outcomes of patients in different risk groups., Result: Results from univariate and multivariate analyses showed that high D‑dimer, low serum albumin, high hs-cTnT, and low total cholesterol levels were independent prognostic factors for adverse outcomes (D-dimer >0.63 mg/l, HR = 1.84, 95% CI = 1.16-2.94, p = 0.010; serum albumin >34 g/l, HR = 0.67, 95% CI = 0.45-0.99, p = 0.046; hs-cTnT >24.06 pg/ml, HR = 1.65, 95% CI = 1.08-2.53, p = 0.020; total cholesterol >3.68 mmol/l, HR = 0.63, 95% CI = 0.43-0.92, p = 0.017). Moreover, all the patients were stratified into low-risk or high-risk group according to a scoring system based on these four markers. Kaplan-Meier analyses demonstrated that patients in the high-risk group were more prone to having adverse outcomes compared with patients in the low-risk group., Conclusion: D‑dimer, total cholesterol, hs-cTnT, and serum albumin levels were independent prognostic factors in the setting of heart failure. A novel and comprehensive scoring system based on these biomarkers is an easily available and effective tool for predicting the adverse outcomes of patients with heart failure., (© 2020. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Ethnic groups are physiologically and genetically adapted to their diets. Inuit bear a frequent AS160 R684X mutation that causes type 2 diabetes. Whether this mutation evolutionarily confers adaptation in Inuit and how it causes metabolic disorders upon dietary changes are unknown due to limitations in human studies. Here, we develop a genetically modified rat model bearing an orthologous AS160 R693X mutation, which mimics human patients exhibiting postprandial hyperglycemia and hyperinsulinemia. Importantly, a sugar-rich diet aggravates metabolic abnormalities in AS160 R693X rats. The AS160 R693X mutation diminishes a dominant long-variant AS160 without affecting a minor short-variant AS160 in skeletal muscle, which suppresses muscle glucose utilization but induces fatty acid oxidation. This fuel switch suggests a possible adaptation in Inuit who traditionally had lipid-rich hypoglycemic diets. Finally, induction of the short-variant AS160 restores glucose utilization in rat myocytes and a mouse model. Our findings have implications for development of precision treatments for patients bearing the AS160 R684X mutation., (© 2021 by the American Diabetes Association.)

MED20 is a non-essential subunit of the transcriptional coactivator Mediator complex, but its physiological function remains largely unknown. Here, we identify MED20 as a substrate of the anti-obesity CRL4-WDTC1 E3 ubiquitin ligase complex through affinity purification and candidate screening. Overexpression of WDTC1 leads to degradation of MED20, whereas depletion of WDTC1 or CUL4A/B causes accumulation of MED20. Depleting MED20 inhibits adipogenesis, and a non-degradable MED20 mutant restores adipogenesis in WDTC1-overexpressing cells. Furthermore, knockout of Med20 in preadipocytes abolishes development of brown adipose tissues. Removing one allele of Med20 in preadipocytes protects mice from diet-induced obesity and reverses weight gain in Cul4a- or Cul4b-depleted mice. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis reveals that MED20 organizes the early adipogenic complex by bridging C/EBPβ and RNA polymerase II to promote transcription of the central adipogenic factor, PPARγ. Our findings have thus uncovered a critical role of MED20 in promoting adipogenesis, development of adipose tissue and diet-induced obesity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Obesity has become a global pandemic. Identification of key factors in adipogenesis helps to tackle obesity and related metabolic diseases. Here, we show that DDB1 binds the histone reader BRWD3 to promote adipogenesis and diet-induced obesity. Although typically recognized as a component of the CUL4-RING E3 ubiquitin ligase complex, DDB1 stimulates adipogenesis independently of CUL4. A DDB1 mutant that does not bind CUL4A or CUL4B fully restores adipogenesis in DDB1-deficient cells. Ddb1 +/- mice show delayed postnatal development of white adipose tissues and are protected from diet-induced obesity. Mechanistically, by interacting with BRWD3, DDB1 is recruited to acetylated histones in the proximal promoters of ELK1 downstream immediate early response genes and facilitates the release of paused RNA polymerase II, thereby activating the transcriptional cascade in adipogenesis. Our findings have uncovered a CUL4-independent function of DDB1 in promoting the transcriptional cascade of adipogenesis, development of adipose tissues, and onset of obesity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neointimal hyperplasia caused by the excessive proliferation of vascular smooth muscle cells (VSMCs) is the pathological basis of restenosis. However, there are few effective strategies to prevent restenosis. Celastrol, a pentacyclic triterpene, has been recently documented to be beneficial to certain cardiovascular diseases. Based on its significant effect on autophagy, we proposed that celastrol could attenuate restenosis through enhancing autophagy of VSMCs. In the present study, we found that celastrol effectively inhibited the intimal hyperplasia and hyperproliferation of VSMCs by inducing autophagy. It was revealed that autophagy promoted by celastrol could induce the lysosomal degradation of c-MYC, which might be a possible mechanism contributing to the reduction of VSMCs proliferation. The Wnt5a/PKC/mTOR signaling pathway was found to be an underlying mechanism for celastrol to induce autophagy and inhibit the VSMCs proliferation. These observations indicate that celastrol may be a novel drug with a great potential to prevent restenosis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Glioma is the most common primary tumor in the central nervous system. However, the development of glioma and effective therapeutic strategies remain elusive. Here, we identify GPR17 as a potential target to treat glioma. Data mining with human LGG and GBM samples reveals that GPR17 is negatively correlated with glioma development. Overexpressing GPR17 inhibits glioma cell proliferation and induces apoptosis by raising ROS levels. GPR17-overexpressing glioma cells are less tumorigenic in the brain than in control cells. Mechanistically, GPR17 inhibits the transcription of RNF2, a key component in the PRC1 complex, through cAMP/PKA/NF-κB signaling, leading to reduced histone H2A monoubiquitination. ChIP-Seq and RNA-Seq analyses reveal KLF9 as a direct target of RNF2. KLF9 mediates the functions of GPR17 and RNF2 in glioma cells. Furthermore, activation of GPR17 by its agonist inhibits glioma formation. Our findings have thus identified GPR17 as a key regulator of glioma development and a potential therapeutic target for gliomas.

Vascular remodelling refers to abnormal changes in the structure and function of blood vessel walls caused by injury, and is the main pathological basis of cardiovascular diseases such as atherosclerosis, hypertension, and pulmonary hypertension. Among them, the neointimal hyperplasia caused by abnormal proliferation of vascular smooth muscle cells (VSMCs) plays a key role in the pathogenesis of vascular remodelling. Perivascular adipose tissue (PVAT) can release vasoactive substances to target VSMCs and regulate the pathological process of vascular remodelling. Specifically, PVAT can promote the conversion of VSMCs phenotype from contraction to synthesis by secreting visfatin, leptin, and resistin, and participate in the development of vascular remodelling-related diseases. Conversely, it can also inhibit the growth of VSMCs by secreting adiponectin and omentin to prevent neointimal hyperplasia and alleviate vascular remodelling. Therefore, exploring and developing new drugs or other treatments that facilitate the beneficial effects of PVAT on VSMCs is a potential strategy for prevention or treatment of vascular remodelling-related cardiovascular diseases.

Clear cell renal cell carcinoma (ccRCC) is characterized by abnormal lipid accumulation. Celastrol is a pentacyclic triterpene extracted from Tripterygium wilfordii Hook F with anti-cancer activity. In the present study, the anticancer effects of celastrol on ccRCC and the underlying mechanisms were studied. Patients with reduced high density lipoprotein (HDL) and elevated levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL) was found to have higher risk of ccRCC. In ccRCC clinical samples and cell lines, caveolin-1 (CAV-1) was highly expressed. CAV-1 was identified as a potential prognostic biomarker for ccRCC. Celastrol inhibited tumor growth and decreased lipid deposition promoted by high-fat diet in vivo . Celastrol reduced lipid accumulation and caveolae abundance, inhibited the binding of CAV-1 and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in ccRCC cells. Furthermore, celastrol attenuated stemness through blocking Wnt/β-catenin pathway after knockdown of CAV-1 and LOX-1. Therefore, the findings suggest that celastrol may be a promising active ingredient from traditional Chinese medicine for anti-cancer therapy., 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 Zhang, Zhu, Wang, Liu, Zhao, Wu, Liao and Qin.)

Objective: To analyze the virus genome mutation of mothers with C genotype HBV and explore its relationship with HBV intrauterine transmission. Methods: A total of 399 mothers carrying HBV and their newborns hospitalized in the obstetrics department of the Third People's Hospital of Taiyuan from 2011 to 2013 were selected. Necessary information about mothers and children was obtained through a questionnaire survey and medical records. HBV DNA and HBV serological markers were detected by quantitative fluorescence PCR and electrochemiluminescence. Within 24 hours after birth and before active/passive immunization, those with positive HBsAg and/or HBV DNA in femoral venous blood were determined as HBV intrauterine transmission. According to the requirements of cloning and sequencing, mothers' HBV DNA load should be ≥10 6 IU/ml. Among 54 cases of HBV intrauterine transmission, 22 pairs of mothers and their newborns meeting the requirements of cloning and sequencing were used as the intrauterine transmission group. The same number of mothers and their newborns without intrauterine transmission was selected as the random seed method's control group. After PCR amplification of HBV DNA, gene cloning, and sequencing, the gene mutation analysis of mothers with C genotype HBV was performed. Results: Among the 44 samples, 39 (88.63%, 39/44) were genotype C, 2 were genotype B, and 3 were mixed genotype B, and C. A total of 406 clone beads from 42 mothers with C genotype HBV were analyzed for gene mutation, including 204 in the intrauterine transmission group and 202 in the control group. The base substitution mutation rate of PreS1, S, C, and P regions in the HBV intrauterine transmission group were significantly lower than those in the control group ( χ 2 ranged from 8.67 to 40.73, P <0.05). The mutation rate of base deletion in PreC and X regions in the HBV intrauterine transmission group was lower than that in the control group ( χ 2 values were 17.82 and 34.78, P <0.001). Two clones in the X region had 31 bp insertion mutations between nt1644 and nt1645, and two clones had 27 bp insertion mutations between nt1649 and nt1650, all of which took place in the control group. Conclusions: The base substitution mutations in the PreS1, S, C, and P segments of the HBV genome in mothers with C genotype HBV were associated with the occurrence of intrauterine transmission of HBV. Deletion mutations in the PreC region, insertion and deletion mutations in the X region may reduce intrauterine transmission risk.

The sympathetic nervous system-catecholamine-uncoupling protein 1 (UCP1) axis plays an essential role in non-shivering adaptive thermogenesis. However, whether there exists a direct effector that physically connects catecholamine signalling to UCP1 in response to acute cold is unknown. Here we report that outer mitochondrial membrane-located AIDA is phosphorylated at S161 by the catecholamine-activated protein kinase A (PKA). Phosphorylated AIDA translocates to the intermembrane space, where it binds to and activates the uncoupling activity of UCP1 by promoting cysteine oxidation of UCP1. Adipocyte-specific depletion of AIDA abrogates UCP1-dependent thermogenesis, resulting in hypothermia during acute cold exposure. Re-expression of S161A-AIDA, unlike wild-type AIDA, fails to restore the acute cold response in Aida-knockout mice. The PKA-AIDA-UCP1 axis is highly conserved in mammals, including hibernators. Denervation of the sympathetic postganglionic fibres abolishes cold-induced AIDA-dependent thermogenesis. These findings uncover a direct mechanistic link between sympathetic input and UCP1-mediated adaptive thermogenesis.

Aim: To evaluate the clinical value of plasma D-dimer/fibrinogen ratio (DFR) in patients hospitalized for heart failure (HF). Methods: Clinical data of 235 patients were retrospectively analyzed. Kaplan-Meier method and Cox regression analysis were used to identify significant prognosticators. Results: The Kaplan-Meier analysis showed that a higher DFR level was significantly associated with an increase in the end point outcomes, including HF readmission, thrombotic events and death (log-rank test: p < 0.001). The multivariate Cox regression analysis showed that the high tertile of DFR was significantly associated with the study end points (HR: 2.18; 95% CI: 1.31-3.62; p = 0.003), compared with the low tertile. Conclusion:  DFR is a reliable prognostic indicator for patients hospitalized for HF.

Nuclear receptor Nur77 participates in multiple metabolic regulations and plays paradoxical roles in tumorigeneses. Herein, we demonstrated that the knockout of Nur77 stimulated mammary tumor development in two mouse models, which would be reversed by a specific reexpression of Nur77 in mammary tissues. Mechanistically, Nur77 interacted and recruited corepressors, the SWI/SNF complex, to the promoters of CD36 and FABP4 to suppress their transcriptions, which hampered the fatty acid uptake, leading to the inhibition of cell proliferation. Peroxisome proliferator-activated receptor-γ (PPARγ) played an antagonistic role in this process through binding to Nur77 to facilitate ubiquitin ligase Trim13-mediated ubiquitination and degradation of Nur77. Cocrystallographic and functional analysis revealed that Csn-B, a Nur77-targeting compound, promoted the formation of Nur77 homodimer to prevent PPARγ binding by steric hindrance, thereby strengthening the Nur77's inhibitory role in breast cancer. Therefore, our study reveals a regulatory function of Nur77 in breast cancer via impeding fatty acid uptake., Competing Interests: The authors declare no competing interest.

Fatty acids (FAs) are essential nutrients, but how they are transported into cells remains unclear. Here, we show that FAs trigger caveolae-dependent CD36 internalization, which in turn delivers FAs into adipocytes. During the process, binding of FAs to CD36 activates its downstream kinase LYN, which phosphorylates DHHC5, the palmitoyl acyltransferase of CD36, at Tyr91 and inactivates it. CD36 then gets depalmitoylated by APT1 and recruits another tyrosine kinase SYK to phosphorylate JNK and VAVs to initiate endocytic uptake of FAs. Blocking CD36 internalization by inhibiting APT1, LYN or SYK abolishes CD36-dependent FA uptake. Restricting CD36 at either palmitoylated or depalmitoylated state eliminates its FA uptake activity, indicating an essential role of dynamic palmitoylation of CD36. Furthermore, blocking endocytosis by targeting LYN or SYK inhibits CD36-dependent lipid droplet growth in adipocytes and high-fat-diet induced weight gain in mice. Our study has uncovered a dynamic palmitoylation-regulated endocytic pathway to take up FAs.

Microbes are often subjected to oxidative stress in nature that badly affects their growth rate and viability. Although the response of microbes against oxidative stress has been characterized at the chemical, physiological, and molecular levels, the mechanism of gene-regulation network adaptations of bacteria in response to oxidative stress remains largely unknown. In this study, transcriptomic profiling of glyphosate-tolerant Enterobacter strain NRS-1 was analyzed under 9 mM H 2 O 2 stress using RNA-seq and qRT-PCR. The lag period in the growth of NRS-1 was very short compared with wild-type strain under H 2 O 2 treatment. A total of 113 genes are identified as differentially expressed genes (DEGs) under H 2 O 2 that include 38 upregulated and 75 downregulated transcripts. But not any genes regulated by major oxidative regulons, viz., oxyR, soxR, rpoS, perR, ohrR, and σ в , have been reported in DEGs, hence potentially reflecting that specific changes have occurred in NRS-1 for adaptation to oxidative stress. Based on the functions of the DEGs, six elements namely formate dehydrogenase, processes associated with iron ions, repair programs, multidrug resistance, antioxidant defense, and energy generation (mqo, sdhC) might have contributed for stress tolerance in NRS-1. These elements are proposed to form a molecular network explaining gene response of NRS-1 to stress, and ensure global cell protection and growth recovery of NRS-1. These findings enrich the view of gene regulation in bacteria in response to H 2 O 2 oxidative stress.

Objective: To analyze the relationship between maternal mutations in basal core promoter region of hepatitis B virus (HBV) genotype C and intrauterine transmission. Methods: We collected information on general demographic characteristics and process of delivery among 399 pairs of consecutive HBsAg-positive mothers and their neonates, from the Third People's Hospital of Taiyuan in Shanxi province, China. Fluorescence quantitative polymerase chain reaction (FQ-PCR) and Electro-chemiluminescence immuno-assay (ECLIA) kits were used to detect both maternal and neonatal HBV DNA and serological markers in the peripheral blood. From 113 mothers with HBV DNA load ≥10(6) IU/ml, we selected 22 mothers whose neonates were with intrauterine transmission and randomly selected the same number of mothers whose neonates were without intrauterine transmission, as controls. The whole-length HBV DNA were extracted, amplified, cloned, sequenced and genotyped. Finally, a total of 39 mothers with genotype C of HBV were selected for mutation analysis. Results: Thirty-nine cases of genotype C (88.63 % ) were finally included in the study, with 19 cases in the intrauterine transmission group and 20 cases as controls. Rates of A1762T/G1764A double mutations were significantly different between the intrauterine transmission group and the control group (7.53 % vs. 27.72 % , P <0.001). Results from the multivariate analysis showed that the A1762T/G1764A double mutations had reduced the risk of intrauterine transmission (a OR =0.065, 95 %CI : 0.006-0.746, P =0.028). Maternal A1762T/G1764A double mutations appeared to be possibly associated with neonatal HBeAg ( P =0.050). Conclusion: A1762T/G1764A double mutations of HBV DNA from the genotype C of those HBsAg-positive mothers could reduced the risk of HBV intrauterine transmission during pregnancy.

The direct hydrogenation of CO 2 using H 2 gas is a one-stone-two-birds route to produce highly value-added hydrocarbon compounds and to lower the CO 2 level in the atmosphere. However, the transformation of CO 2 and H 2 into hydrocarbons has always been a great challenge while ensuring both the activity and selectivity over abundant-element-based nanocatalysts. In this work, we designed a Schottky heterojunction composed of electron-rich MoC nanoparticles embedded inside an optimized nitrogen-doped carbon support (MoC@NC) as the first example of noble-metal-free heterogeneous catalysts to boost the activity of and specific selectivity for CO 2 hydrogenation to formic acid (FA) in liquid phase under mild conditions (2 MPa pressure and 70 °C). The MoC@NC catalyst with a high turnover frequency (TOF) of 8.20 mol FA mol MoC -1 h -1 at 140 °C and an excellent reusability are more favorable for real applications., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2020 Science China Press. Published by Elsevier B.V. All rights reserved.)

Bulbus Lilii , as a medicinal and edible plant, has anti-inflammatory, anti-oxidative and immunopotentiating pharmacological activities, which seems to be therapeutic on cancer prevention. The purpose of this study was to investigate the effects of total saponins from Lilium lancifolium (TSLL) on proliferation, apoptosis and migration of human gastric carcinoma cells lines SGC-7901 and HGC-27 and its underlying mechanism. The results showed that TSLL inhibited the proliferation of gastric carcinoma cells by suppressing the level of proliferating cell nuclear antigen (PCNA) and increased p21 level. TSLL induced cells apoptosis by up-regulating expression of pro-apoptotic protein Bax and down-regulating anti-apoptotic protein Bcl-2 expression. Meanwhile, TSLL remarkably inhibited cell migration and invasion, decreased matrix metalloproteinase-2 (MMP-2) expression and increased tissue inhibitor of metalloproteinases-1 (TIMP-1) expression. Notably, TSLL had stronger anti-cancer effect on undifferentiated HGC-27 cells than differentiated SGC-7901 cells. Accordingly, TSLL might be a promising candidate to prevent and suppress the growth of gastric carcinoma cells., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Enzyme catalysts always show an excellent catalytic selectivity, which is important in biochemistry, especially in catalytic synthesis and biopharming. This selectivity is achieved by combining the binding effect induced by the electrostatic effect of the enzyme to attract a specific substrate and then the prearrangement of the substrates inside the enzyme pocket. Herein, we report a proof-of-concept application of an interfacial electrostatic field induced by constructing Schottky heterojunctions to mimic the electrostatic catalysis of an enzyme. In combination with the 3 D structure, a transition metal/carbon dyad was designed by nanoconfinement methods to promote the differential binding effect and the space-induced organization of the reaction intermediate (vanillyl alcohol) to develop a new one-step hydrogenolysis of vanillin for the production of 2-methoxy-4-methylphenol with a remarkably high selectivity (>99 %)., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)