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Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. Circular RNAs (circRNAs), a novel class of non-coding RNA, have been reported to be involved in the etiology of various malignancies. However, the underlying cellular mechanisms of circRNAs implicated in the pathogenesis of HCC remain unknown. In this study, we identified a functional RNA, hsa_circ_0000384 (circMRPS35), from public tumor databases using a set of computational analyses, and we further identified that circMRPS35 was highly expressed in 35 pairs of HCC from patients. Moreover, knockdown of the expression of circMRPS35 in Huh-7 and HCC-LM3 cells suppressed their proliferation, migration, invasion, clone formation, and cell cycle in vitro, and it suppressed tumor growth in vivo as well. Mechanically, circMRPS35 sponged microRNA-148a-3p (miR-148a), regulating the expression of Syntaxin 3 (STX3), which modulated the ubiquitination and degradation of phosphatase and tensin homolog (PTEN). Unexpectedly, we detected a peptide encoded by circMRPS35 (circMRPS35-168aa), which was significantly induced by chemotherapeutic drugs and promoted cisplatin resistance in HCC. These results demonstrated that circMRPS35 might be a novel mediator in HCC progress, and they raise the potential of a new biomarker for HCC diagnosis and prognosis, as well as a novel therapeutic target for HCC patients.

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.

Rationale: 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. Methods: 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. Results: 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. Conclusions: Taken together, these findings confirm an important role for CBD in PAH pathobiology.

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.

Intraventricular hemorrhage is a serious intracerebral hemorrhagic disease with high mortality and poor prognosis. This retrospective study designed to investigate the therapeutic effect of transcortical approach surgery versus extraventricular drainage (EVD) on patients with intraventricular hemorrhage. Patients with intraventricular hemorrhage in Zhongshan City People's Hospital from January 01, 2014 to June 01, 2019 were retrospectively examined. They were divided into transcortical approach surgery groups and EVD groups to analyze the clinical characteristics and prognosis. A total of 96 patients were enrolled in the study (24 in the transcortical approach surgery group and 72 in the EVD group). The efficiency of postoperative operation was 15/19 in the transcortical approach surgery group and 24/48 in the EVD group (P = .012). The Glasgow Outcome Scale was 3.63 ± 1.27 in the transcortical approach surgery group and 2.80 ± 1.87 in the EVD group (P = .049). The postoperative residual blood volume was 9.62 ± 3.64 mL in the transcortical approach surgery group and 33.60 ± 3.53 mL in the EVD group (P

SIRT1 is an NAD

Hepatocellular carcinoma (HCC), a common malignant tumor, is one of the main causes of cancer-related deaths worldwide. Circular RNAs (circRNAs), a novel class of non-coding RNA, have been reported to be involved in the etiology of various malignancy. However, the functions of circRNAs in HCC remain unclear. In this study, through mining the RNA sequencing databases from GEO datasets and subsequent experimental verification, we identified that hsa_circ_0000384 (circMRPS35) was highly expressed in HCC. Knockdown of circMRPS35 suppressed the proliferation, migration, invasion, clone formation and cell cycle of HCC cell lines both in vitro and in a xenograft mouse model. Mechanically, circMRPS35 sponged microRNA-148a-3p (miR-148a), which in turn regulated STX3-PTEN axis. Surprisingly, we detected a peptide encoded by circMRPS35 (circMRPS35-168aa), which was significantly induced by chemotherapeutic drugs and promoted cisplatin resistance in HCC cells. These results demonstrated that circMRPS35 might be a novel factor in HCC progress, and has a great potential as a new diagnosis and therapeutic target for treatment of HCC.

Human cervical cancer oncogene (HCCR-1), also named as LETMD1, is a LETM-domain containing outer mitochondrial membrane protein which plays an important role in the carcinogenesis of cancers. Surprisingly, we found that loss of Letmd1 in mice leads to multiply severe abnormities, such as the brown adipose tissue (BAT) whitening, disruption of thermogenesis, cold-induced death, diet-induced obesity, hyperglycinemia and insulin resistance. Mechanistically, deletion of Letmd1 in BAT causes the reduction of mitochondrial calcium ion, which in turn results in the suppressed fission of mitochondria, and ultimately leads to the depletion of Ucp1-mediated BAT heat production. This study indicates that LETMD1 plays a crucial role in controlling BAT thermogenesis and energy homeostasis by regulating mitochondrial structures and functions, and also provides a novel insight for the clinical biomarker and therapeutical target of oncogene for the metabolic disorders.HighlightsLetmd1 is an oncogene and also highly expressed in brown adipose tissue (BAT) of human and mice.Loss of Letmd1 leads to BAT whitening, diet-induced obesity, hyperglycemia and insulin resistant.Letmd1 knockout causes the disruption of thermogenesis and death at 4°C exposure.Deletion of Letmd1 results in mitochondrial calcium homeostasis disorders.Graphic 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.Graphical Abstracts

Responsive fluorescent microgels, that can selectively, reversibly, and rapidly convert the fluctuation in intracellular glucose level into fluorescence signal, have the potential use for intracellular glucometry to promote the understanding of physiology. Herein, we report one-pot synthesis of such a responsive fluorescent composite microgels, which is made of a representative apo-enzyme, apo-glucose oxidase (apo-GOx), interpenetrated in a composite gel network that is comprised of ZnO quantum dots covalently bonded onto crosslinked poly(ethylene glycol) dimethacrylate. The key of this one-pot synthesis is applying a high-temperature short-time heating (HTST) method, so that the naturally dynamic profile of apo-GOx can be maintained and harnessed on the composite microgels to allow the highly selective response to glucose over a glucose concentration range of 0–20 mM. While the composite microgels can undergo volume phase transitions and convert both an increase and a decrease in glucose concentration into fluorescence signal shortly (

Background Type 2 diabetes mellitus (T2DM) is the most common type of metabolic disorder involving multiple organ systems. Grape has been reported to improve the symptoms of T2DM, the precise mechanism of its action is unclear. Our study was aimed to determine the effect and mechanism of grape pomace extract in T2DM mice induced by high fat diet (HFD). Materials and methods Ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry were used to identify the main active compounds in grape pomace extract to improve T2DM. C57BLK/6J mice induced by HFD supplemented with or without quercetin were used to show the effects of quercetin improving T2DM. By online database research, bioinformatics analysis and molecular biology experiments, Estrogen receptor alpha (ERα)-lncSHGL (lncRNA suppressor of hepatic gluconeogenesis and lipogenesis) pathway was identify as the target for quercetin. Results Quercetin was identified as one of the most active compounds in grape pomace extract to improve T2DM. Quercetin could inhibit HFD-induced T2DM in mice by activing ERα. LncSHGL was identified as the downstream of ERα and inhibited HFD-induced T2DM. Conclusions Quercetin could be beneficial for T2DM by promoting lncSHGL transcription and activating the lncSHGL pathway, and may be used as a drug component to treat T2DM.

A series of novel praseodymium(Pr)-coordinated polymers with fluorene, phthalimide and bipyridine moieties in the main chain were synthesized via a coordination reaction and palladium-catalyzed Suzuki coupling polycondensation. Their structures, optical features and memory performance have been well studied. A resistive switching device with the configuration of ITO/polymer/Al was constructed using a spin-coating process. The device exhibits nonvolatile write-once-read-many-times (WORM) memory behavior. Based on the electrochemical properties and theoretical calculations of the polymers, the effects of the phthalimide moiety and neutral Pr complex on the polymer memory device performance were investigated. Our work offers valuable clues on the development of polymer memory devices.

Type III intraosseous meningioma is a very rare type of meningioma with extracranial extension. Herein, the author reported a case of type IIIC intraosseous meningioma with invasion of the superior sagittal sinus and skull periosteum. A 67-year-old woman was admitted to our hospital due to a mass on the left frontoparietal region for 4 years. Magnetic resonance imaging showed a skull tumor with invasion of the superior sagittal sinus. After partial resection of the tumor, pathological and immunohistochemical staining revealed that the epithelial meningioma derived from skull involved the skull periosteum. There was no enlargement of residual parasagittal tumor after 1 year of follow-up. The intraosseous meningioma in the present case was a rare benign tumor with good prognosis after surgery.

Background: Antiplatelet therapy is critical in the management of coronary artery diseases. For patients undergoing cardiac surgeries, including coronary artery bypass graft (CABG) and valve replacement, controversy remains in preoperative antiplatelet therapy concerning risk of bleeding. For safety concern, aspirin is recommended to be withdrawn 5 to 10 days before a cardiac surgery. Recent studies, however, indicate that preoperative aspirin may have a protective effect on cardiac surgery-associated acute kidney injury (CSA-AKI). Objective: To estimate the efficacy of preoperative aspirin in preventing CSA-AKI. Methods and results: Eligible studies included randomized controlled trials (RCTs) and observational studies (OSs) of patients, who had undergone CABG, valve replacement, or combined surgery. These studies compared preoperative aspirin with placebo/no aspirin and reported the least incidence of CSA-AKI. One RCT and five OSs met the inclusion criteria. Data retrieved suggested that aspirin prescribed within five days before cardiac surgery decreased post-operative renal failure [odds ratio (OR), 0.67; 95% confidence interval (CI), 0.50-0.89; P < 0.01] and 30-day mortality (OR, 0.64; 95% CI, 0.53-0.77; P < 0.01). One RCT and three OSs suggested aspirin protected from major adverse cardiocerebral events (MACE) (OR, 0.88; 95% CI, 0.76-1.01; P = 0.07). One RCT and two OSs suggested aspirin did not increase risk of re-exploration for bleeding (OR, 1.01; 95% CI, 0.76-1.34; P = 0.95). Conclusion: Preoperative low-dose aspirin decreases post-operative CSA-AKI, mortality, and MACE without increasing the risk of re-exploration. But most of the studies are observational. They lack a uniformed standard on prescription of aspirin and outcomes measurement. No stratification analysis is performed concerning different types of surgical procedures and comorbidities. More randomized controlled trials are necessary to confirm the efficacy and safety of preoperative aspirin prescription.

The formation of well-defined finite-sized aggregates represents an attractive goal in supramolecular chemistry. In particular, construction of discrete π-stacked dye assemblies remains a challenge. Reported here is the design and synthesis of a novel type of discrete π-stacked aggregate from two comparable perylenediimide (PDI) dyads (PEP and PBP). The criss-cross PEP-PBP dimers in solution and (PBP-PEP)-(PEP-PBP) tetramers in the solid state are well elucidated using single-crystal X-ray diffraction, dynamic light scattering, and diffusion-ordered NMR spectroscopy. Extensive π–π stacking between the PDI units of PEP and PBP as well as repulsive interactions of swallow-tailed alkyl substituents are responsible for the selective formation of discrete dimer and tetramer stacks. Our results reveal a new approach to preparing discrete π stacks that are appealing for making assemblies with well-defined optoelectronic properties.

Glioblastoma (GBM) is the most common primary malignant brain tumor that nearly always results in a bad prognosis. Temozolomide plus radiotherapy (TEM+RAD) is the most common treatment for newly diagnosed GBM. With the development of molecularly targeted drugs, several clinical trials were reported; however, the efficacy of the treatment remains controversial. So we attempted to measure the dose of the molecularly targeted drug that could improve the prognosis of those patients. The appropriate electronic databases (PubMed, MEDLINE, EMBASE, and the Cochrane Library) were searched for relevant studies. A meta-analysis was performed after determining which studies met the inclusion criteria. Six randomized, controlled trials (RCTs) were identified for this meta-analysis, comprising 2,637 GBM patients. The benefit of overall survival (OS) was hazard ratio (HZ), 0.936 [95% confidence interval (CI), 0.852‐1.028]. The benefit with respect to progression-free survival (PFS) rate was HZ of 0.796 (95% CI, 0.701‐0.903). OS benefit of cilengitide was HZ of 0.792 (95% CI, 0.642‐0.977). The adverse effects higher than grade 3 were 57.7% in the experimental group and 44.1% in the placebo group (odds ratio, 1.679; 95% CI, 1.434‐1.967). The addition of molecularly targeted drugs to TEM + RAD did not improve the OS of patients with GBM; however, it did improve PFS in patients treated by cilengitide who could not get improvement in OS. The rate of adverse effects was higher in the experimental group than in the placebo group.

Osteopetrosis is a group of heterogeneous disorders caused by the dysfunction of osteoclasts. The CLCN7 and TCIRG1 genes are the major obligate genes responsible for infantile malignant osteopetrosis (IMO). IMO patients usually die in infancy or before three years of age. In this study, we report a patient who was diagnosed with IMO at seven months of age. The patient presented with classical radiological features of IMO. She also exhibited erythropenia, thrombocytopenia, hepatosplenomegaly and neurodegeneration. The parents discontinued any medical treatment for the patient. Surprisingly, the patient's condition did not deteriorate when she was admitted a second time at the age of four years and nine months, despite not receiving any medical support during the untreated period. We sequenced the CLCN7 and TCIRG1 genes of the patient and her parents and identified a novel c.285+1G>A (IVS3+1G>A) mutation and the known c.896C>T (p.Ala299Val) mutation. The novel c.285+1G>A mutation occurred on the splice donor of the third intron of CLCN7. This mutation was predicted to interfere with normal splicing between exons 3 and 4, thereby truncating 711 amino acids from the C terminus and resulting in the loss of all of the functional domains of the encoded protein. The c.896C>T (p.Ala299Val) mutation was a previously known pathogenic mutation. We did not find any pathogenic mutations in the TCIRG1 gene. CLCN7-related osteopetrosis is known to have a high phenotype heterogeneity. Our study demonstrates a wide heterogeneity in the progression of the phenotypes and expanded the mutational spectrum for the CLCN7 gene.

Rationale:H7N9 infection causes acute respiratory distress syndrome with high mortality. The use of glucocorticoids in the acute phase lessened inflammatory responses. Some case reports suggested that secondary organizing pneumonia (SOP) could occur at the recovery stage of the influenza vir

BACKGROUND: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. METHODS: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. RESULTS: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). CONCLUSIONS: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.