Kinome-wide siRNA screen identifies a DCLK2-TBK1 oncogenic signaling axis in clear cell renal cell carcinoma.

TANK-binding kinase 1 (TBK1) is a potential therapeutic target in multiple cancers, including clear cell renal cell carcinoma (ccRCC). However, targeting TBK1 in clinical practice is challenging. One approach to overcome this challenge would be to identify an upstream TBK1 regulator that could be targeted therapeutically in cancer specifically. In this study, we perform a kinome-wide small interfering RNA (siRNA) screen and identify doublecortin-like kinase 2 (DCLK2) as a TBK1 regulator in ccRCC. DCLK2 binds to and directly phosphorylates TBK1 on Ser172. Depletion of DCLK2 inhibits anchorage-independent colony growth and kidney tumorigenesis in orthotopic xenograft models. Conversely, overexpression of DCLK2203, a short isoform that predominates in ccRCC, promotes ccRCC cell growth and tumorigenesis in vivo. Mechanistically, DCLK2203 elicits its oncogenic signaling via TBK1 phosphorylation and activation. Taken together, these results suggest that DCLK2 is a TBK1 activator and potential therapeutic target for ccRCC.

Structures and Mechanisms in the cGAS-STING Innate Immunity Pathway.

Besides its role as the blueprint of life, DNA can also alert the cell to the presence of microbial pathogens as well as damaged or malignant cells. A major sensor of DNA that triggers the innate immune response is cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS), which produces the second messenger cGAMP. cGAMP activates stimulator of interferon genes (STING), which activates a signaling cascade leading to the production of type I interferons and other immune mediators. Recent research has demonstrated an expanding role of the cGAS-cGAMP-STING pathway in many physiological and pathological processes, including host defense against microbial infections, anti-tumor immunity, cellular senescence, autophagy, and autoimmune and inflammatory diseases. Biochemical and structural studies have elucidated the mechanism of signal transduction in the cGAS pathway at the atomic resolution. This review focuses on the structural and mechanistic insights into the roles of cGAS and STING in immunity and diseases revealed by these recent studies.

Activation of STING by targeting a pocket in the transmembrane domain.

Stimulator of interferon genes (STING) is an adaptor protein in innate immunity against DNA viruses or bacteria1-5. STING-mediated immunity could be exploited in the development of vaccines or cancer immunotherapies. STING is a transmembrane dimeric protein that is located in the endoplasmic reticulum or in the Golgi apparatus. STING is activated by the binding of its cytoplasmic ligand-binding domain to cyclic dinucleotides that are produced by the DNA sensor cyclic GMP-AMP (cGAMP) synthase or by invading bacteria1,6,7. Cyclic dinucleotides induce a conformational change in the STING ligand-binding domain, which leads to a high-order oligomerization of STING that is essential for triggering the downstream signalling pathways8,9. However, the cGAMP-induced STING oligomers tend to dissociate in solution and have not been resolved to high resolution, which limits our understanding of the activation mechanism. Here we show that a small-molecule agonist, compound 53 (C53)10, promotes the oligomerization and activation of human STING through a mechanism orthogonal to that of cGAMP. We determined a cryo-electron microscopy structure of STING bound to both C53 and cGAMP, revealing a stable oligomer that is formed by side-by-side packing and has a curled overall shape. Notably, C53 binds to a cryptic pocket in the STING transmembrane domain, between the two subunits of the STING dimer. This binding triggers outward shifts of transmembrane helices in the dimer, and induces inter-dimer interactions between these helices to mediate the formation of the high-order oligomer. Our functional analyses show that cGAMP and C53 together induce stronger activation of STING than either ligand alone.

Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization.

The mutation and overexpression of the epidermal growth factor receptor (EGFR) are associated with the development of a variety of cancers, making this prototypical dimerization-activated receptor tyrosine kinase a prominent target of cancer drugs. Using long-timescale molecular dynamics simulations, we find that the N lobe dimerization interface of the wild-type EGFR kinase domain is intrinsically disordered and that it becomes ordered only upon dimerization. Our simulations suggest, moreover, that some cancer-linked mutations distal to the dimerization interface, particularly the widespread L834R mutation (also referred to as L858R), facilitate EGFR dimerization by suppressing this local disorder. Corroborating these findings, our biophysical experiments and kinase enzymatic assays indicate that the L834R mutation causes abnormally high activity primarily by promoting EGFR dimerization rather than by allowing activation without dimerization. We also find that phosphorylation of EGFR kinase domain at Tyr845 may suppress the intrinsic disorder, suggesting a molecular mechanism for autonomous EGFR signaling.

Sorting nexin 5 mediates virus-induced autophagy and immunity.

Autophagy, a process of degradation that occurs via the lysosomal pathway, has an essential role in multiple aspects of immunity, including immune system development, regulation of innate and adaptive immune and inflammatory responses, selective degradation of intracellular microorganisms, and host protection against infectious diseases1,2. Autophagy is known to be induced by stimuli such as nutrient deprivation and suppression of mTOR, but little is known about how autophagosomal biogenesis is initiated in mammalian cells in response to viral infection. Here, using genome-wide short interfering RNA screens, we find that the endosomal protein sorting nexin 5 (SNX5)3,4 is essential for virus-induced, but not for basal, stress- or endosome-induced, autophagy. We show that SNX5 deletion increases cellular susceptibility to viral infection in vitro, and that Snx5 knockout in mice enhances lethality after infection with several human viruses. Mechanistically, SNX5 interacts with beclin 1 and ATG14-containing class III phosphatidylinositol-3-kinase (PI3KC3) complex 1 (PI3KC3-C1), increases the lipid kinase activity of purified PI3KC3-C1, and is required for endosomal generation of phosphatidylinositol-3-phosphate (PtdIns(3)P) and recruitment of the PtdIns(3)P-binding protein WIPI2 to virion-containing endosomes. These findings identify a context- and organelle-specific mechanism-SNX5-dependent PI3KC3-C1 activation at endosomes-for initiation of autophagy during viral infection.

Activation of human STING by a molecular glue-like compound.

Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING. Our cryo-EM structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models.

Structural basis of STING binding with and phosphorylation by TBK1.

The invasion of mammalian cytoplasm by microbial DNA from infectious pathogens or by self DNA from the nucleus or mitochondria represents a danger signal that alerts the host immune system1. Cyclic GMP-AMP synthase (cGAS) is a sensor of cytoplasmic DNA that activates the type-I interferon pathway2. On binding to DNA, cGAS is activated to catalyse the synthesis of cyclic GMP-AMP (cGAMP) from GTP and ATP3. cGAMP functions as a second messenger that binds to and activates stimulator of interferon genes (STING)3-9. STING then recruits and activates tank-binding kinase 1 (TBK1), which phosphorylates STING and the transcription factor IRF3 to induce type-I interferons and other cytokines10,11. However, how cGAMP-bound STING activates TBK1 and IRF3 is not understood. Here we present the cryo-electron microscopy structure of human TBK1 in complex with cGAMP-bound, full-length chicken STING. The structure reveals that the C-terminal tail of STING adopts a ß-strand-like conformation and inserts into a groove between the kinase domain of one TBK1 subunit and the scaffold and dimerization domain of the second subunit in the TBK1 dimer. In this binding mode, the phosphorylation site Ser366 in the STING tail cannot reach the kinase-domain active site of bound TBK1, which suggests that STING phosphorylation by TBK1 requires the oligomerization of both proteins. Mutational analyses validate the interaction mode between TBK1 and STING and support a model in which high-order oligomerization of STING and TBK1, induced by cGAMP, leads to STING phosphorylation by TBK1.

Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP.

Infections by pathogens that contain DNA trigger the production of type-I interferons and inflammatory cytokines through cyclic GMP-AMP synthase, which produces 2'3'-cyclic GMP-AMP (cGAMP) that binds to and activates stimulator of interferon genes (STING; also known as TMEM173, MITA, ERIS and MPYS)1-8. STING is an endoplasmic-reticulum membrane protein that contains four transmembrane helices followed by a cytoplasmic ligand-binding and signalling domain9-13. The cytoplasmic domain of STING forms a dimer, which undergoes a conformational change upon binding to cGAMP9,14. However, it remains unclear how this conformational change leads to STING activation. Here we present cryo-electron microscopy structures of full-length STING from human and chicken in the inactive dimeric state (about 80 kDa in size), as well as cGAMP-bound chicken STING in both the dimeric and tetrameric states. The structures show that the transmembrane and cytoplasmic regions interact to form an integrated, domain-swapped dimeric assembly. Closure of the ligand-binding domain, induced by cGAMP, leads to a 180° rotation of the ligand-binding domain relative to the transmembrane domain. This rotation is coupled to a conformational change in a loop on the side of the ligand-binding-domain dimer, which leads to the formation of the STING tetramer and higher-order oligomers through side-by-side packing. This model of STING oligomerization and activation is supported by our structure-based mutational analyses.

Cryo-electron Microscopic Analysis of Single-Pass Transmembrane Receptors.

Single-pass transmembrane receptors (SPTMRs) represent a diverse group of integral membrane proteins that are involved in many essential cellular processes, including signal transduction, cell adhesion, and transmembrane transport of materials. Dysregulation of the SPTMRs is linked with many human diseases. Despite extensive efforts in past decades, the mechanisms of action of the SPTMRs remain incompletely understood. One major hurdle is the lack of structures of the full-length SPTMRs in different functional states. Such structural information is difficult to obtain by traditional structural biology methods such as X-ray crystallography and nuclear magnetic resonance (NMR). The recent rapid development of single-particle cryo-electron microscopy (cryo-EM) has led to an exponential surge in the number of high-resolution structures of integral membrane proteins, including SPTMRs. Cryo-EM structures of SPTMRs solved in the past few years have tremendously improved our understanding of how SPTMRs function. In this review, we will highlight these progresses in the structural studies of SPTMRs by single-particle cryo-EM, analyze important structural details of each protein involved, and discuss their implications on the underlying mechanisms. Finally, we also briefly discuss remaining challenges and exciting opportunities in the field.

Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment.

Signaling by the epidermal growth factor receptor requires an allosteric interaction between the kinase domains of two receptors, whereby one activates the other. We show that the intracellular juxtamembrane segment of the receptor, known to potentiate kinase activity, is able to dimerize the kinase domains. The C-terminal half of the juxtamembrane segment latches the activated kinase domain to the activator, and the N-terminal half of this segment further potentiates dimerization, most likely by forming an antiparallel helical dimer that engages the transmembrane helices of the activated receptor. Our data are consistent with a mechanism in which the extracellular domains block the intrinsic ability of the transmembrane and cytoplasmic domains to dimerize and activate, with ligand binding releasing this block. The formation of the activating juxtamembrane latch is prevented by the C-terminal tails in a structure of an inactive kinase domain dimer, suggesting how alternative dimers can prevent ligand-independent activation.

The intracellular monoamine oxidase-A inhibitory activity and the protective effect of small hairtail-related peptides in nerve cells (SH-SY5Y).

This study was to investigate the inhibitory activity of small hairtail-related peptides (VFEVFW, LPNSLYQQ, LPNSLYQK, and FADAME) on intracellular monoamine oxidase-A (MAO-A) and their protective effects in a cell model. Specifically, the inhibition activity in SH-SY5Y cells indicated that VFEVFW and LPNSLYQK reduced ∼50% of MAO-A activity in cells, at 0.5 m m. The survival experiment demonstrated that the toxic effect of dexamethasone (DEX) on cells can be significantly alleviated in the presence of peptides, and these peptides can restore (>20%) the mitochondrial membrane potential of SH-SY5Y cells reduced by DEX. Circular dichroism displayed that peptides affected the secondary structure of MAO-A in a concentration-dependent manner. Finally, the real-time quantitative polymerase chain reaction assay revealed that the MAO-A inhibitory activity of the peptides was associated with the upregulation of brain derived neurotrophic factor/cAMP (Cyclic adenosine monophosphate) response element binding protein)/B-cell lymphoma-2 mRNA levels.

Tubular cell transcriptional intermediary factor 1γ deficiency exacerbates kidney injury-induced tubular cell polyploidy and fibrosis.

Tubulointerstitial fibrosis is considered the final convergent pathway of progressive chronic kidney diseases (CKD) regardless of etiology. However, mechanisms underlying kidney injury-induced fibrosis largely remain unknown. Recent studies have indicated that transcriptional intermediary factor 1γ (TIF1γ) inhibits the progression of fibrosis in other organs. Here, we found that TIF1γ was highly expressed in the cytoplasm and nucleus of the kidney proximal tubule. Interestingly, we found tubular TIF1γ expression was decreased in patients with CKD, including those with diabetes, hypertension, and IgA nephropathy, and in mouse models with experimental kidney fibrosis (unilateral ureteral obstruction [UUO], folic acid nephropathy [FAN], and aristolochic acid-induced nephrotoxicity). Tubule-specific knock out of TIF1γ in mice exacerbated UUO- and FAN-induced tubular cell polyploidy and subsequent fibrosis, whereas overexpression of kidney TIF1γ protected mice against kidney fibrosis. Mechanistically, in tubular epithelial cells, TIF1γ exerted an antifibrotic role via transforming growth factor-ß (TGF-ß)-dependent and -independent signaling. TIF1γ hindered TGF-ß signaling directly by inhibiting the formation and activity of the transcription factor Smad complex in tubular cells, and we discovered that TIF1γ suppressed epidermal growth factor receptor (EGFR) signaling upstream of TGF-ß signaling in tubular cells by ubiquitylating EGFR at its lysine 851/905 sites thereby promoting EGFR internalization and lysosomal degradation. Pharmacological inhibition of EGFR signaling attenuated exacerbated polyploidization and the fibrotic phenotype in mice with tubule deletion of TIF1γ. Thus, tubular TIF1γ plays an important role in kidney fibrosis by suppressing profibrotic EGFR and TGF-ß signaling. Hence, our findings suggest that maintaining homeostasis of tubular TIF1γ may be a new therapeutic option for treating tubulointerstitial fibrosis and subsequent CKD.

Combined therapy of prednisone and mTOR inhibitor sirolimus for treating retroperitoneal fibrosis.

OBJECTIVES: Retroperitoneal fibrosis (RPF) is a rare autoimmune disease with fibrous tissue growth and inflammation in retroperitoneum. Its current treatments involve long-term uptake of glucocorticoids (e.g., prednisone) for controlling inflammation; however, side effects are common. We strived for an improved therapy for fibrosis remission while reducing side effects. METHODS: We surveyed gene-disease-drug databases and discovered that mammalian target of rapamycin (mTOR) was a key signalling protein in RPF and the mTOR inhibitor compound sirolimus affected many RPF pathways. We designed a therapy combining a gradual reduction of prednisone with a long-term, stable dosage of sirolimus. We then implemented a single-arm clinical trial and assessed the effects in eight RPF patients at 0, 12 and 48 weeks of treatment by measuring fibrous tissue mass by CT, markers of inflammation and kidney functions by lab tests, immune cell profiles by flow cytometry and plasma inflammatory proteins by Olink proteomics. RESULTS: With the combined therapy, fibrous tissue shrunk about by half, markers of acute inflammation reduced by 70% and most patients with abnormal kidney functions had them restored to normal range. Molecularly, fibrosis-related T cell subsets, including TH2, TH17 and circulating TFH cells, were reduced and tumour necrosis factor and related cytokines restored to healthy levels. No severe long-term side effects were observed. CONCLUSIONS: Our combined therapy resulted in significant fibrosis remission and an overall regression of the immune system towards healthy states, while achieving good tolerance. We concluded that this new therapy had the potential to replace the steroid monotherapy for treating RPF.

1H NMR-based urinary metabolic analysis of high-dose cyclophosphamide-induced toxicity in mice.

Cyclophosphamide (CP) is widely used in clinical fields. Beside its therapeutic effects, CP shows toxicity depending on dose and administration schedule. In this study, the urinary metabolic profiles were investigated in mice intraperitoneally injected with high-dose CP (150 mg/kg body weight) once a week over four weeks using nuclear magnetic resonance (NMR)-based metabolomics. Twenty-six metabolites were identified as potential biomarkers by multivariate statistical analysis. A decrease in isoleucine, alanine, N-acetylglutamic acid, proline, methionine, valine, phenylacetylglulamine, dimethylamine, hippurate, acetic acid, lactate, α-oxoglutarate, citrate, malonic acid, creatinine, niacin, ß-hydroxybutyrate, and betaine, whereas an increase in leucine, glutamate, glycine, taurine, phenylacetylglycine, glucose, creatine, and choline were observed in the urine of high-dose CP-treated mice. Metabolites related to amino acid metabolism, energy metabolism, and gut microbial metabolism were changed markedly in the urine. Further metabolic pathway analysis suggested that seven metabolic pathways, including alanine, aspartate, and glutamate metabolism, arginine biosynthesis, glyoxylate, and dicarboxylate metabolism, glycine, serine and threonine metabolism, d-glutamine and d-glutamate metabolism, arginine, and proline metabolism, citrate cycle, as well as the gut microbiota metabolism, were significantly involved in response to high-dose CP treatment. These findings help to predict the toxicity of CP and understand the biological mechanism of the toxicity of CP.

Trimethoprim-sulfamethoxazole prevents interstitial pneumonitis in B-cell lymphoma patients receiving chemotherapy: a propensity score matching analysis.

B-cell lymphoma is the most prevalent type of non-Hodgkin lymphoma, for which the standard treatment regimen includes rituximab combined with CHOP. However, some patients may develop interstitial pneumonitis (IP), which can be caused by various factors; one of the most important factors is Pneumocystis jirovecii. It is crucial to investigate the pathophysiology of IP and implement preventive measures since IP can be fatal for some people. The data were collected from the First Affiliated Hospital, Zhejiang University School of Medicine, where patients with B-cell lymphoma received the R-CHOP/R-CDOP regimen with or without prophylactic use of trimethoprim-sulfamethoxazole (TMP-SMX). Multivariable logistic regression and propensity score matching (PSM) were used to investigate any potential association. Eight hundred thirty-one patients with B-cell lymphoma were classified into two groups: the non-prophylaxis group without TMP-SMX (n=699) and the prophylaxis group with TMP-SMX (n = 132). IP occurred in 66 patients (9.4%, all in the non-prophylaxis group), with an onset median of three cycles of chemotherapy. Multiple logistic regression analysis demonstrated that IP incidence was associated with pegylated liposome doxorubicin (OR=3.29, 95% CI 1.84-5.90, P<0.001). After utilizing a 1:1 matching algorithm for PSM, 90 patients from each group were obtained. There was a statistical difference between the two cohorts in the IP incidence (non-prophylaxis 12.2% vs prophylaxis 0.0%, P <0.001). The prophylactic use of TMP-SMX could prevent the occurrence of IP whose risk factor was pegylated liposome doxorubicin after chemotherapy for B-cell lymphoma.

Viral pseudo-enzymes activate RIG-I via deamidation to evade cytokine production.

RIG-I is a pattern recognition receptor that senses viral RNA and is crucial for host innate immune defense. Here, we describe a mechanism of RIG-I activation through amidotransferase-mediated deamidation. We show that viral homologs of phosphoribosylformylglycinamidine synthetase (PFAS), although lacking intrinsic enzyme activity, recruit cellular PFAS to deamidate and activate RIG-I. Accordingly, depletion and biochemical inhibition of PFAS impair RIG-I deamidation and concomitant activation. Purified PFAS and viral homolog thereof deamidate RIG-I in vitro. Ultimately, herpesvirus hijacks activated RIG-I to avoid antiviral cytokine production; loss of RIG-I or inhibition of RIG-I deamidation results in elevated cytokine production. Together, these findings demonstrate a surprising mechanism of RIG-I activation that is mediated by an enzyme.

Isolation and Identification of Lipid-Lowering Peptides from Sacha Inchi Meal.

Sacha inchi meal (SIM) is a by-product of sacha inchi (considered as a "super-food") processing. In previous studies, we found that SIM protein hydrolysates exhibited pancreatic lipase inhibition activity. In this study, 10 bioactive peptides from those hydrolysates were identified. The top five peptides (NLYYKVV (NV-7), WWYVK (WK-5), WLLMWPYK (WK-8), EGLLMWPY (EY-8), and FPFFGYVWK (FK-9)) with strong pancreatic lipase inhibition activity had IC50 values of 34.01-246.50 µM, and displayed various inhibition types (mixed, non-competitive, and competitive type) by enzyme inhibition kinetics analysis. Fluorescence quenching analysis demonstrated that the interaction between the peptides and pancreatic lipase was mainly hydrogen bond and van der Waals force. The key residues involved in the peptide-enzyme interaction were determined by molecular docking. Moreover, the top two peptides were found to significantly inhibit fat accumulation and regulate lipid metabolism by alleviating the level of reactive oxygen species in HepG2 cells. Collectively, sacha inchi meal-derived peptides displayed potent lipid-lowering activity and could be used as materials of functional food.

Isolation and identification of dipeptidyl peptidase-IV inhibitory peptides from Sacha inchi meal.

BACKGROUND: Sacha inchi meal (SIM) is a by-product of oil processing. Our previous studies showed that SIM hydrolysates exhibited dipeptidyl peptidase-IV (DPP-IV) inhibition activity. The objective of the present work was to identify and characterize the bioactive peptides from protein hydrolysates of SIM; enzyme kinetics and peptide-enzyme interaction were also investigated. RESULTS: From SIM hydrolysates, ten peptides responsible for the activity were identified: GPSRGF (GF-6), FPILSPDPA (FA-9), APYRRGGKI (AI-9), WPYH (WH-4), DPATWLALPT (DT-10), NPEDEFRQQ (NQ-9), APESKPVGV (AV-9), LEWRDR (LR-6), APVYWVQ (AQ-7) and LLMWPY (LY-6). The IC50 values of five peptides (GF-6, WH-4, AQ-7, AV-9 and LY-6) with better inhibitory activity on DPP-IV were within the range of 23.43-128.40 µmol L-1 . AQ-7 had the best activity, with an IC50 value of 23.43 µmol L-1 . Enzyme kinetics indicated the presence of various inhibition types (mixed, non-competitive and competitive). Isothermal titration microcalorimetry showed that the main forces of the binding sites between peptide (GF-6 or AQ-7) and DPP-IV were hydrogen bond, hydrophobic interaction and van der Waals force. The key residues involved in peptide-enzyme interaction were determined by molecular docking. Furthermore, at a concentration of 800 µmol L-1 , GF-6 was found to significantly increase the glucose consumption in insulin-resistant HepG2 cells (P < 0.05) compared with the model group. CONCLUSION: Sacha inchi meal-derived peptides displayed potent DPP-IV inhibition activity and could be used in the health food industry and as lead compounds for diabetes therapy. © 2023 Society of Chemical Industry.

Circular RNA circMRPS35 regulates progression and autophagy in osteosarcoma cells by recruiting KAT6B to govern FOXO3.

Osteosarcoma serves as frequently occurred bone malignancy that displays low survival rate and high incidence of metastasis. Circular RNAs (circRNAs) have been reported as the crucial molecules in osteosarcoma development. However, the effect of circRNA circMRPS35 on osteosarcoma remains unclear. Here, we aimed to explore the function of circMRPS35 in the regulation of autophagy and progression of osteosarcoma. The colony formation numbers and Edu-positive osteosarcoma cells were repressed by the overexpression of circMRPS35. Meanwhile, the overexpression of circMRPS35 increased the apoptosis rate of osteosarcoma cells. The expression levels of autophagy markers, including LC3 and Beclin1, were enhanced by the overexpression of circMRPS35 in osteosarcoma cells. Mechanically, the depletion of circMRPS35 reduced the enrichment of histone H3 lysine 23 acetylation (H3K23ac) on forkhead box O3 (FOXO3) promoter in osteosarcoma cells. The interaction of circMRPS35 and KAT6B was identified. The knockdown of KAT6B reduced the enrichment of H3K23ac on FOXO3 promoter in osteosarcoma cells. The depletion of circMRPS35 repressed the expression of FOXO3 in the MG63 and MNNG/HOS cells, whereas the overexpression of KAT6B reversed the effect. Significantly, KAT6B promotes apoptosis and autophagy of osteosarcoma cells. The overexpression of circMRPS35 induced the apoptosis and autophagy of osteosarcoma cells, in which the depletion of KAT6B or FOXO3 reversed the effect. The overexpression of circMRPS35 inhibited the tumor growth in vivo , whereas the depletion of KAT6B could reverse the effect in the mice. Therefore, we concluded that circRNA circMRPS35 repressed progression and induced autophagy of osteosarcoma cells.

Differentiated Effects and Determinants of Home Blood Pressure Telemonitoring: Three-Year Cohort Study in Jieshou, Anhui, China.

BACKGROUND: Home blood pressure telemonitoring (HBPT) is witnessing rapid diffusion worldwide. Contemporary studies documented mainly short-term (6-12 months) effects of HBPT, and there are limited data about its uptake. OBJECTIVE: The aim of this study was to explore the 3-year use and determinants of HBPT, and the interactions with systolic and diastolic blood pressure (SBP/DBP) and overall blood pressure (BP) control rate. METHODS: HBPT records were obtained from a 3-year cohort of 5658 patients with hypertension in Jieshou, Anhui, China, and data from a structured household survey of a random sample (n=3005) of the cohort. The data analysis comprised (1) timeline trajectories of the rates of monthly active HBPT and mean SBP/DBP for overall and subgroups of patients with varied start-month SBP/DBP; and (2) multivariable linear, logistic, and percentile regression analyses using SBP/DBP, BP control rate, and yearly times of HBPT as the dependent variable, respectively. RESULTS: HBPT was followed by mixed changes in mean monthly SBP/DBP for varied patient groups. The magnitude of changes ranged from -43 to +39 mmHg for SBP and from -27 to +15 mmHg for DBP. The monthly rates of active HBPT all exhibited a rapid and then gradually slower decline. When controlled for commonly reported confounders, times of HBPT in the last year were found to have decreasing correlation coefficients for SBP/DBP (from 0.16 to -0.35 and from 0.11 to -0.35, respectively) and for BP control rate (from 0.53 to -0.62). CONCLUSIONS: HBPT had major and "target-converging" effects on SBP/DBP. The magnitude of changes was much greater than commonly reported. BP, variation in BP, and time were the most important determinants of HBPT uptake. Age, education, duration of hypertension, family history, and diagnosis of hypertension complications were also linked to the uptake but at weaker strength. There is a clear need for differentiated thinking over the application and assessment of HBPT, and for identifying and correcting/leveraging potential outdated/new opportunities or beliefs.