Nonalcoholic fatty liver disease is becoming the most common chronic liver disease in Western countries, and limited therapeutic options are available. Here we uncovered a role for intestinal hypoxia-inducible factor (HIF) in hepatic steatosis. Human-intestine biopsies from individuals with or without obesity revealed that intestinal HIF-2α signaling was positively correlated with body-mass index and hepatic toxicity. The causality of this correlation was verified in mice with an intestine-specific disruption of Hif2a, in which high-fat-diet-induced hepatic steatosis and obesity were substantially lower as compared to control mice. PT2385, a HIF-2α-specific inhibitor, had preventive and therapeutic effects on metabolic disorders that were dependent on intestine HIF-2α. Intestine HIF-2α inhibition markedly reduced intestine and serum ceramide levels. Mechanistically, intestine HIF-2α regulates ceramide metabolism mainly from the salvage pathway, by positively regulating the expression of Neu3, the gene encoding neuraminidase 3. These results suggest that intestinal HIF-2α could be a viable target for hepatic steatosis therapy.

Background/Aims: Recent studies suggested the involvement of the Akt/mammalian target of rapamycin (mTOR) pathway in the pathogenesis of diabetic nephropathy. The effect of mTOR blockade by rapamycin in diabetic nephropathy was investigated, but in vivo study of rapamycin treatment in the course of early diabetes is still insufficient. This study was designed to determine the therapeutic effects of rapamycin on diabetic nephropathy at an early stage. Methods: Diabetes was induced in Sprague-Dawley rats with streptozotocin, and rapamycin (1 mg/kg) was administered by daily gavage for 4 weeks. Renal structural changes and some factors involved in the early pathogenesis of diabetic nephropathy were tested. The activation level of the Akt/mTOR pathway was also determined. Results: Rapamycin treatment reduced albuminuria, glomerular enlargement, glomerular basement membrane thickening, renal macrophage recruitment, and levels of renal mRNA expression of proliferating cell nuclear antigen, transforming growth factor-β₁, vascular endothelial growth factor, and monocyte chemoattractant protein-1 without change in blood glucose level and blood pressure in experimental diabetic rats. In addition, treatment with rapamycin also down-regulated the enhanced levels of renal p-Akt, phospho-p70S6 kinase, and phospho-ribosomal S6 protein in diabetic rats. Conclusions: Rapamycin treatment can prevent the early renal structural changes of diabetes in experimental rats, and thus halt the early steps of the development of diabetic nephropathy. mTOR blockade might be beneficial for the treatment of diabetic nephropathy.

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BackgroundInsulin resistance (IR) correlates closely with cardiovascular disease. C1q/TNF-related protein-3 (CTRP3) is a novel adipokine that modulates insulin activity in various diseases. This study investigated the relationship between CTRP3 and IR as well as systemic inflammation in newly diagnosed obese and hypertensive patients (NCT02226471).MethodsSerum CTRP3 levels, anthropometric, inflammatory and metabolic parameters were measured in 180 obesity and essential hypertensive patients and in 66 normal weight, normotensive subjects.ResultsThe serum CTRP3 levels in the obesity group were lower than those in the NW group; these levels were also lower in hypertensive subjects than in normotensive subjects. After adjusting for gender, systolic blood pressure (SBP) and diastolic blood pressure (DBP), a modestly linear relationship was observed between CTRP3 and waist circumference (WC) (r = -0.168, p = 0.009), waist-to-hip ratio (WHR) (r = -0.183, p = 0.004), homeostasis model assessment of IR (HOMA-IR) (r = -0.264, p = 0.000), triglycerides (TG) (r = -0.136, p = 0.034), fasting blood glucose (FBG) (r = -0.155, p = 0.016), fasting insulin (FINS) (r = -0.248, p = 0.000) and homeostasis model assessment of β-cell insulin secretion (HOMA-β) (r = -0.128, p = 0.047). Multiple stepwise regression analysis revealed that gender, DBP and HOMA-IR were independently associated with serum CTRP3 levels.ConclusionCTRP3 was an independent factor affecting blood pressure and IR, and may play an important role in the pathogenesis of obesity and hypertension.

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RNA has important and diverse biological roles, but the molecular methods to manipulate it spatiotemporally are limited. Here, an engineered photoactivatable RNA N6‐methyladenosine (m6A) editing system with CRISPR‐Cas13 is designed to direct specific m6A editing. Light‐inducible heterodimerizing proteins CIBN and CRY2PHR are fused to catalytically inactive PguCas13 (dCas13) and m6A effectors, respectively. This system, referred to as PAMEC, enables the spatiotemporal control of m6A editing in response to blue light. Further optimization of this system to create a highly efficient version, known as PAMECR, allows the manipulation of multiple genes robustly and simultaneously. When coupled with an upconversion nanoparticle film, the optogenetic operation window is extended from the visible range to tissue‐penetrable near‐infrared wavelengths, which offers an appealing avenue to remotely control RNA editing. These results show that PAMEC is a promising optogenetic platform for flexible and efficient targeting of RNA, with broad applicability for epitranscriptome engineering, imaging, and future therapeutic development.

ObjectiveThis study aimed to assess the efficacy and safety of camrelizumab plus apatinib in patients with resectable hepatocellular carcinoma (HCC) as neoadjuvant therapy.MethodsInitially, 20 patients with HCC were screened and 18 patients with resectable HCC were enrolled in this open-label, single-arm, phase II clinical trial. Patients received three cycles of neoadjuvant therapy including three doses of camrelizumab concurrent with apatinib for 21 days followed by surgery. Four to 8 weeks after surgery, patients received eight cycles of adjuvant therapy with camrelizumab in combination with apatinib. Major pathological reactions (MPR), complete pathological reactions (pCR), objective response rate (ORR), relapse-free survival (RFS), and adverse events (AE) were assessed. In addition, cancer tissue and plasma samples were collected before and after treatment, and genetic differences between responding and non-responding lesions were compared by tumor immune microenvironment (TIME) analysis, circulating tumor DNA (ctDNA) analysis and proteomics analysis.ResultsIn 18 patients with HCC who completed neoadjuvant therapy, 3 (16.7%) and 6 (33.3%) patients with HCC reached ORR based on Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and modified RECIST criteria, respectively. Of the 17 patients with HCC who received surgical resection, 3 (17.6%) patients with HCC reported MPR and 1 (5.9%) patient with HCC achieved pCR. The 1-year RFS rate of the enrolled patients was 53.85% (95% CI: 24.77% to 75.99%). Grade 3/4 AEs were reported in 3 (16.7%) of the 18 patients, with the most common AEs being rash (11.1%), hypertension (5.6%), drug-induced liver damage (5.6%), and neutropenia (5.6%) in the preoperative phase. The 289 NanoString panel RNA sequencing showed that TIME cell infiltration especially dendritic cells (DCs) infiltration was better in responding tumors than in non-responding tumors. Our results of ctDNA revealed a higher positive rate (100%) among patients with HCC with stage IIb–IIIa disease. When comparing patients with pCR/MPR and non-MPR, we observed more mutations in patients who achieved pCR/MPR at baseline (6 mutations vs 2.5 mutations, p=0.025). Patients who were ctDNA positive after adjuvant therapy presented a trend of shorter RFS than those who were ctDNA negative. Proteomic analysis suggested that abnormal glucose metabolism in patients with multifocal HCC might be related to different sensitivity of treatment in different lesions.ConclusionPerioperative camrelizumab plus apatinib displays a promising efficacy and manageable toxicity in patients with resectable HCC. DCs infiltration might be a predictive marker of response to camrelizumab and apatinib as well as patients’ recurrence. ctDNA as a compose biomarker can predict pathological response and relapse. Abnormal glucose metabolism in patients with multifocal HCC may be related to different sensitivity of treatment in different lesions.Trial registration numberNCT04297202.

Our findings demonstrated that low expression of H19, induced by mechanical unloading, leads to development of DOP through inhibition of Wnt signaling by promoting Dkk4 expression.