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Background hsa_circ_0001727 (circZKSCAN1) has been reported to be a tumor-associated circRNA by sponging microRNAs. Intriguingly, we found that circZKSCAN1 encoded a secretory peptide (circZKSaa) in the liver. The present study aims to elucidate the potential role and molecular mechanism of circZKSaa in the regulation of hepatocellular carcinoma (HCC) progression. Methods The circRNA profiling datasets (RNA-seq data GSE143233 and GSE140202) were reanalyzed and circZKSCAN1 was selected for further study. Mass spectrometry, polysome fractionation assay, dual-luciferase reporter, and a series of experiments showed that circZKSCAN1 encodes circZKSaa. Cell proliferation, apoptosis, and tumorigenesis in nude mice were examined to investigate the functions of circZKSaa. Mechanistically, the relationship between the circZKSaa and mTOR in HCC was verified by immunoprecipitation analyses, mass spectrometry, and immunofluorescence staining analyses. Results Receiver operating characteristic (ROC) analysis demonstrated that the secretory peptide circZKSaa encoded by circZKSCAN1 might be the potential biomarker for HCC tissues. Through a series of experiments, we found that circZKSaa inhibited HCC progression and sensitize HCC cells to sorafenib. Mechanistically, we found that the sponge function of circZKSCAN1 to microRNA is weak in HCC, while overexpression of circZKSaa promoted the interaction of FBXW7 with the mammalian target of rapamycin (mTOR) to promote the ubiquitination of mTOR, thereby inhibiting the PI3K/AKT/mTOR pathway. Furthermore, we found that the high expression of cicZKSCAN1 in sorafenib-treated HCC cells was regulated by QKI-5 . Conclusions These results reveal that a novel circZKSCAN1-encoded peptide acts as a tumor suppressor on PI3K/AKT/mTOR pathway, and sensitizes HCC cells to sorafenib via ubiquitination of mTOR. These findings demonstrated that circZKSaa has the potential to serve as a therapeutic target and biomarker for HCC treatment.

Promoting the coordinated development of digitalization and greening has become an important pathway for firms to achieve high-quality growth. Using panel data for A-share listed firms in China’s Yangtze River Basin from 2010 to 2022, this study examines the effect of supply chain innovation policy on firms’ digital–green development. We measure the synergy between digitalization and greening using a composite system synergy approach and identify the policy effect through a quasi-natural experiment based on the supply chain innovation policy, combined with a synthetic difference-in-differences model. The results show that the policy significantly improves the coordinated development of firm digitalization and greening, and the findings remain robust across a series of tests. Mechanism analysis indicates that this effect operates through three channels: easing financing constraints, increasing supply chain diversification, and promoting industrial chain modernization. Moderating effect tests further show that supply chain efficiency, supply chain resilience, and entrepreneurship strengthen the policy’s positive effect on digital–green development. Heterogeneity analysis suggests that the policy effect varies systematically with firm size, market competitiveness, and information asymmetry. This study provides micro-level evidence on how supply chain innovation policy can promote firms’ digital–green transformation and offers useful implications for policies aimed at improving firm competitiveness and supporting sustainable development.

In obesity, macrophages drive a low-grade systemic inflammation (LSI) and insulin resistance (IR). The ribosome biosynthesis protein NOC4 (NOC4) mediates 40 S ribosomal subunits synthesis in yeast. Hereby, we reported an unexpected location and function of NOC4L, which was preferentially expressed in human and mouse macrophages. NOC4L was decreased in both obese human and mice. The macrophage-specific deletion of Noc4l in mice displayed IR and LSI. Conversely, Noc4l overexpression by lentivirus treatment and transgenic mouse model improved glucose metabolism in mice. Importantly, we found that Noc4l can interact with TLR4 to inhibit its endocytosis and block the TRIF pathway, thereafter ameliorated LSI and IR in mice. Macrophage inflammation promotes insulin resistance during diet-induced obesity. Here the authors show that macrophage NOC4L is decreased in humans and mice with obesity, that macrophage NOC4L deficiency aggravated high-fat diet induced inflammation and insulin resistance, and that NOC4L interacts with toll-like receptor 4, to inhibit endocytosis, and thus blocks TLF4/TRIF inflammatory signaling.

We combined the outcomes of all randomised controlled trials to investigate the safety and efficacy of steroid avoidance or withdrawal (SAW) regimens in paediatric kidney transplantation compared with steroid-based (SB) regimens. A systematic literature search of PubMed, Embase, Cochrane Library, the trials registry and BIOSIS previews was performed. A change in the height standardised Z-score from baseline (ΔHSDS) and acute rejection were the primary endpoints. Eight reports from 5 randomised controlled trials were included, with a total of 528 patients. Sufficient evidence of a significant increase in the ΔHSDS was observed in the SAW group (mean difference (MD) = 0.38, 95% confidence interval (CI) 0.07-0.68, P = 0.01), particularly within the first year post-withdrawal (MD = 0.22, 95% CI 0.10-0.35, P = 0.0003) and in the prepubertal recipients (MD = 0.60, 95% CI 0.21-0.98, P = 0.002). There was no significant difference in the risk of acute rejection between the groups (relative risk = 1.04, 95% CI 0.80-1.36, P = 0.77). The SAW regimen is justified in select paediatric renal allograft recipients because it provides significant benefits in post-transplant growth within the first year post-withdrawal with minimal effects on the risk of acute rejection, graft function, and graft and patient survival within 3 years post-withdrawal. These select paediatric recipients should have the following characteristics: prepubertal; Caucasian; with primary disease not related to immunological factors; de novo kidney transplant recipient; with low panel reactive antibody.

SIRT1 is an NAD + -dependent deacetylase and plays an important role in the deacetylation of both histone and non-histone proteins. Many studies revealed that SIRT1 is upregulated in a variety of tumors and tightly associated with tumorigenesis and cancer progression, but the detailed underlying mechanism of the biological processes remains unclarified. In the present study, we found a nucleolar protein NOC4L, human ortholog of yeast Noc4p, which is essential for the nuclear export of the ribosomal 40S subunit and could bind to SIRT1 to inhibit SIRT1 mediated deacetylation of p53. NOC4L interacts with SIRT1 in variety of cells under nucleolar stress and directly interacts with SIRT1 in vitro. Furthermore, we determined the C-terminal of NOC4L and the catalytic domain of SIRT1 were required for their interaction. Overexpression of NOC4L did not change the protein levels of SIRT1 or p53, but increased the acetylation of p53 and promoted cell apoptosis. Additionally, NOC4L inhibited tumor cell proliferation in a p53-dependent manner and restrained tumor growth in a nude mice xenograft model. Clinically, colorectal cancer patients with the high expression of NOC4L had a better prognosis as TP53 was normally expressed, but no significant difference was observed in survival with mutant TP53 . Taken together, our results identified a novel SIRT1 regulatory protein and broaden our understanding of the molecular mechanism of how nucleolar protein NOC4L regulates p53 under nucleolar stress. This research provides an insight into tumorigenesis and cell self-protection in the early stage of DNA damage.

Brown and beige adipose tissues dissipate chemical energy in the form of heat to maintain your body temperature in cold conditions. The impaired function of these tissues results in various metabolic diseases in humans and mice. By bioinformatical analyses, we identified a functional thermogenic regulator of adipose tissue, Androgen-dependent tissue factor pathway inhibitor [TFPI]-regulating protein ( Adtrp ), which was significantly overexpressed in and functionally activated the mature brown/beige adipocytes. Hereby, we knocked out Adtrp in mice which led to multiple abnormalities in thermogenesis, metabolism, and maturation of brown/beige adipocytes causing excess lipid accumulation in brown adipose tissue (BAT) and cold intolerance. The capability of thermogenesis in brown/beige adipose tissues could be recovered in Adtrp KO mice upon direct β3-adrenergic receptor (β3-AR) stimulation by CL316,243 treatment. Our mechanistic studies revealed that Adtrp by binding to S100 calcium-binding protein b (S100b) indirectly mediated the secretion of S100b, which in turn promoted the β3-AR mediated thermogenesis via sympathetic innervation. These results may provide a novel insight into Adtrp in metabolism via regulating the differentiation and thermogenesis of adipose tissues in mice.

Pulmonary arterial hypertension (PAH) is a chronic disease associated with enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) and dysfunctional mitochondria, and the clinical therapeutic option for PAH is very limited. Recent studies showed that cannabidiol (CBD), a non-psychoactive constituent of cannabinoids, possessed antioxidant effect towards several cardiovascular diseases, whereas the mechanistic effect of CBD in PAH is unknown. In this study, the effects of CBD in PAH were determined by analyzing its preventive and therapeutic actions in PAH rodent models in vivo and PASMCs' proliferation test in vitro. Additionally, CBD's roles in mitochondrial function and oxidant stress were also assessed in PASMCs. We found that CBD reversed the pathological changes observed in both Sugen-hypoxia and monocrotaline-induced PAH rodent models in a cannabinoid receptors-independent manner. Our results also demonstrated that CBD significantly inhibited the PASMCs' proliferation in PAH mice with less inflammation and reactive oxygen species levels. Moreover, CBD alleviated rodent PAH by recovering mitochondrial energy metabolism, normalizing the hypoxia-induced oxidant stress, reducing the lactate overaccumulation and abnormal glycolysis. Taken together, these findings confirm an important role for CBD in PAH pathobiology.

Given the increasing prevalence of global warming and the frequent occurrence of extreme weather events and other challenges, countries are increasingly recognizing the importance of green and sustainable development. This paper uses the multi-period double difference and PSM-DID method to test the impact of green finance policies on the ESG performance of Chinese listed companies. Research has shown that implementing pilot zone policies can improve corporate ESG performance, especially for enterprises with low business reputations, fierce industry competition, severe information asymmetry, and state-owned attributes. The GFPZ policy drives companies to improve their ESG performance through two paths: promoting environmental innovation and strengthening restrictions on corporate financing. In addition, the increase in economic policy uncertainty hinders the positive impact of GFPZ policies on improving corporate ESG performance. This study enriches the existing micro-research on green finance policies from the perspective of enterprises. It provides empirical evidence and research insights to support the further improvement of pilot zone policies, the promotion of green sustainable development, and the improvement of corporate ESG performance.

Abstract Pulmonary artery hypertension (PAH) is a chronic disease associated with enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) and dysfunctional mitochondria, which was with limited therapeutic options. It has been proved that cannabidiol (CBD) had antioxidant effects in many cardiovascular diseases, whereas the efficacy of CBD in PAH is unknown. To defined the effect of CBD in PAH, we explored the functions of CBD in both PASMCs proliferation test in vitro, and preventive and therapeutic PAH rodent models in vivo. The roles of CBD in mitochondria function and the oxidant stress were assessed in human PASMCs and PAH mice. We found that CBD significantly inhibited hyperproliferation of hypoxia-induced PASMCs, and intragastrically administered CBD could reverse the pathological changes in both Sugen-hypoxia and MCT-induced PAH mice models. Mechanical analysis demonstrated that CBD alleviated PAH by recovering mitochondrial energy metabolism, normalizing the hypoxia-induced oxidant stress, inhibiting abnormal glycolysis and lactate accumulation in cannabinoids receptors-independent manner. Thus, CBD could be a potential drug for PAH. Figure1 Figure1 * Download figure * Open in new tab Competing Interest Statement The authors have declared no competing interest. * Abbreviation PAH pulmonary artery hypertension PASMCs pulmonary artery smooth muscle cells CBD cannabidiol ROS reactive oxygen species Nfe2l2 nuclear factor E2 related factor 2 Hmox-1 heme oxygenase 1 Sod superoxide dismutase Nqo1 quinone oxidoreductase 1 Cnr cannabinoids receptor TRPA1 transient receptor potential A1 PPARγ peroxisome proliferator-activated receptor GPR G Protein-Coupled Receptor Sugen vascular endothelial growth factor receptor blocker SU-5416 MCT monocrotaline RVSP right ventricular systolic pressure RVH right ventricular hypertrophy IHC immunohistochemical PFKFB3 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 OCR O2 consumption rate ECAR extracellular acidification rate DRP1 dynamin-1-like protein FIS1 mitochondrial fission 1 protein OPA1 optic atrophy type 1 (OPA1) MFN1/2 mitofusin 1/2 MIEF1 mitochondrial elongation factor 1 GR glutathione reductase GSH glutathione peroxidase MDA Malondialdehyde Keap1 Kelch-like ECH-associated protein 1 Glut1 Glucose transporter 1 PDK1 pyruvate dehydrogenase lipoamide kinase isozyme 1