Acetyl-CoA synthetase 2 promotes diabetic renal tubular injury in mice by rewiring fatty acid metabolism through SIRT1/ChREBP pathway.

Diabetic nephropathy (DN) is characterized by chronic low-grade renal inflammatory responses, which greatly contribute to disease progression. Abnormal glucose metabolism disrupts renal lipid metabolism, leading to lipid accumulation, nephrotoxicity, and subsequent aseptic renal interstitial inflammation. In this study, we investigated the mechanisms underlying the renal inflammation in diabetes, driven by glucose-lipid metabolic rearrangement with a focus on the role of acetyl-CoA synthetase 2 (ACSS2) in lipid accumulation and renal tubular injury. Diabetic models were established in mice by the injection of streptozotocin and in human renal tubular epithelial HK-2 cells cultured under a high glucose (HG, 30 mmol/L) condition. We showed that the expression levels of ACSS2 were significantly increased in renal tubular epithelial cells (RTECs) from the diabetic mice and human diabetic kidney biopsy samples, and ACSS2 was co-localized with the pro-inflammatory cytokine IL-1ß in RTECs. Diabetic ACSS2-deficient mice exhibited reduced renal tubular injury and inflammatory responses. Similarly, ACSS2 knockdown or inhibition of ACSS2 by ACSS2i (10 µmol/L) in HK-2 cells significantly ameliorated HG-induced inflammation, mitochondrial stress, and fatty acid synthesis. Molecular docking revealed that ACSS2 interacted with Sirtuin 1 (SIRT1). In HG-treated HK-2 cells, we demonstrated that ACSS2 suppressed SIRT1 expression and activated fatty acid synthesis by modulating SIRT1-carbohydrate responsive element binding protein (ChREBP) activity, leading to mitochondrial oxidative stress and inflammation. We conclude that ACSS2 promotes mitochondrial oxidative stress and renal tubular inflammation in DN by regulating the SIRT1-ChREBP pathway. This highlights the potential therapeutic value of pharmacological inhibition of ACSS2 for alleviating renal inflammation and dysregulation of fatty acid metabolic homeostasis in DN. Metabolic inflammation in the renal region, driven by lipid metabolism disorder, is a key factor in renal injury in diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is abundantly expressed in renal tubular epithelial cells (RTECs) and highly upregulated in diabetic kidneys. Deleting ACSS2 reduces renal fatty acid accumulation and markers of renal tubular injury in diabetic mice. We demonstrate that ACSS2 deletion inhibits ChREBP-mediated fatty acid lipogenesis, mitochondrial oxidative stress, and inflammatory response in RTECs, which play a major role in the progression of diabetic renal tubular injury in the kidney. These findings support the potential use of ACSS2 inhibitors in treating patients with DN.

The ratio of neutrophils to lymphocytes effectively predicts clinical outcomes in idiopathic membranous nephropathy.

BACKGROUND: Systemic inflammatory indicators are important in the prognoses of various diseases. Such indicators, including the neutrophil-to-lymphocyte ratio (NLR), can be meaningful in predicting the clinical outcome in patients diagnosed with idiopathic membranous nephropathy (IMN). MATERIALS AND METHODS: 112 IMN patients diagnosed by renal biopsy were recruited retrospectively. The endpoint was defined as a combination of partial and complete remission. Statistical analysis determined the independent factors associated with clinical remission and the predictive utility of NLR. RESULTS: Within the 12-month follow-up period, 72 patients achieved clinical remission after treatment. Univariate analysis identified significant differences in serum albumin, estimated glomerular filtration rate (eGFR), proteinuria, neutrophil count, and NLR between the remission group and the non-remission group (all p < 0.05). Cox proportional hazards indicated that elevated eGFR (HR 1.022, 95% CI (1.009 - 1.035), p = 0.001), lower NLR (HR 0.345, 95% CI (0.237 - 0.501), p = 0.0001), and decreased proteinuria (HR 0.826, 95% CI (0.693 - 0.984), p = 0.032) were protective elements for remission. With an optimal cut-off value of 2.61, the pre-treatment NLR had an excellent ability to identify the remission (area under the curve (AUC), 0.785). Participants were separated into low- and high-NLR groups by using 2.61. Kaplan-Meier survival curves revealed significantly higher remission rates in the lower group (p < 0.0001). CONCLUSION: The NLR is an effective indicator for predicting clinical remission in patients with IMN.

Roxadustat Versus Erythropoietin: The Comparison of Efficacy in Reversing Ventricular Remodeling in Dialysis Patients with Anaemia.

Background: Renal anaemia and left ventricular hypertrophy are the main complications of chronic kidney disease and are shared among dialysis patients. This retrospective study aimed to compare the efficacies of the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat and recombinant human erythropoietin in reversing ventricular remodeling in dialysis patients with renal anaemia. Methods: A total of 204 participants underwent baseline examinations, including echocardiograms and laboratory tests, before being administered either treatment for at least 24 weeks from January 2018 to October 2021, after which follow-up examinations were conducted at 6 months. Propensity score matching based on key variables included age, gender, cardiovascular diseases, cardiovascular medications, dialysis course and the vascular access at baseline was performed to include populations with similar characteristics between groups. Results: In total, 136 patients were included with roxadustat or recombinant human erythropoietin. The left ventricular mass index after treatment with roxadustat and recombinant human erythropoietin both significantly decreased after 6 months, but there was no significant difference in the change in left ventricular mass index between the two groups. In addition, the left ventricular end-diastolic diameters and left ventricular wall thickness, systolic blood pressure, and diastolic blood pressure significantly decreased in the roxadustat group. Roxadustat and recombinant human erythropoietin also increased haemoglobin significantly, but there was no significant difference in the change in haemoglobin between the two groups. The results of multiple linear regression showed that the change in haemoglobin was independent factor affecting the improvement of left ventricular mass index. Conclusions: The increase of haemoglobin was associated with improving left ventricular hypertrophy in dialysis patients. However, the beneficial effects between roxadustat and recombinant human erythropoietin on left ventricular mass index did not show clear superiority or inferiority in six months.

Caspase 3/ROCK1 pathway mediates high glucose-induced platelet microparticles shedding.

BACKGROUND: Platelet microparticles (PMPs) are closely associated with diabetic macrovascular complications. This study aimed to explore the underlying mechanisms of high glucose-induced PMPs generation. METHODS: Washed platelets, obtained from the plasma of healthy male Sprague-Dawley rats, were incubated with high glucose. PMPs were isolated using gradient centrifugation and counted by flow cytometry. Expression and activity of ROCK1 and caspase3 were evaluated by real-time PCR, Western blotting, and activity assay kit. RESULTS: High glucose enhanced PMPs shedding in the presence of collagen. The mRNA and protein levels of ROCK1, but not ROCK2, were increased in platelets incubated with high glucose. Y-27632, an inhibitor of ROCK, blocked the increased PMPs shedding induced by high glucose. Expression and activity of caspase3 were elevated in platelets under the high glucose conditions. Z-DVED-FMK, a caspase3 inhibitor, inhibited ROCK1 activity and decreased the PMPs generation under high glucose. CONCLUSION: High glucose increased PMPs shedding via caspase3-ROCK1 signal pathway.

Platelet microparticles contribute to aortic vascular endothelial injury in diabetes via the mTORC1 pathway.

Platelet microparticles (PMPs) are closely associated with diabetic macrovascular complications. The present study aimed to investigate the effects of PMPs in diabetes on aortic vascular endothelial injury and to explore the underlying mechanisms. Peritoneal injection of streptozotocin was used to generate a diabetic rat model in vivo, and human umbilical vein endothelial cells (HUVECs) treated with PMPs were used in vitro. PMP levels in the circulation and aorta tissues were time-dependently increased in streptozotocin-induced diabetic rats at weeks 4, 8, and 12 (P < 0.05). Aspirin significantly inhibited the PMP levels at each time point (P < 0.05). In diabetic rats, the endothelial nitric oxide levels were decreased significantly combined with increased endothelial permeability. PMPs were internalized by HUVECs and primarily accumulated around the nuclei. PMPs inhibited endothelial nitric oxide levels to about 50% and caused approximately twofold increase in reactive oxygen species production. Furthermore, PMPs significantly decreased the endothelial glycocalyx area and expression levels of glypican-1 and occludin (P < 0.05). Interestingly, the PMP-induced endothelial injuries were prevented by raptor siRNA and rapamycin. In conclusion, increased PMPs levels contribute to aortic vascular endothelial injuries in diabetes through activating the mTORC1 pathway.

Publisher Correction: Inflammation-activated CXCL16 pathway contributes to tubulointerstitial injury in mouse diabetic nephropathy.

The REFERENCES 1-35 are wrong because of the error in the process of typesetting.

Role of Podocyte Injury in Glomerulosclerosis.

Finding new therapeutic targets of glomerulosclerosis treatment is an ongoing quest. Due to a living environment of various stresses and pathological stimuli, podocytes are prone to injuries; moreover, as a cell without proliferative potential, loss of podocytes is vital in the pathogenesis of glomerulosclerosis. Thus, sufficient understanding of factors and underlying mechanisms of podocyte injury facilitates the advancement of treating and prevention of glomerulosclerosis. The clinical symptom of podocyte injury is proteinuria, sometimes with loss of kidney functions progressing to glomerulosclerosis. Injury-induced changes in podocyte physiology and function are actually not a simple passive process, but a complex interaction of proteins that comprise the anatomical structure of podocytes at molecular levels. This chapter lists several aspects of podocyte injuries along with potential mechanisms, including glucose and lipid metabolism disorder, hypertension, RAS activation, micro-inflammation, immune disorder, and other factors. These aspects are not technically separated items, but intertwined with each other in the pathogenesis of podocyte injuries.

Platelet Microparticles Mediate Glomerular Endothelial Injury in Early Diabetic Nephropathy.

BACKGROUND: Glomerular endothelium dysfunction, which plays a crucial role in the pathogenesis of early diabetic nephropathy, might be caused by circulating metabolic abnormalities. Platelet microparticles, extracellular vesicles released from activated platelets, have recently emerged as a novel regulator of vascular dysfunction. METHODS: We studied the effects of platelet microparticles on glomerular endothelial injury in early diabetic nephropathy in rats with streptozotocin-induced diabetes and primary rat glomerular endothelial cells. Isolated platelet microparticles were measured by flow cytometry. RESULTS: Plasma platelet microparticles were significantly increased in diabetic rats, an effect inhibited in aspirin-treated animals. In cultured glomerular endothelial cells, platelet microparticles induced production of reactive oxygen species, decreased nitric oxide levels, inhibited activities of endothelial nitric oxide synthase and SOD, increased permeability of the glomerular endothelium barrier, and reduced thickness of the endothelial surface layer. Conversely, inhibition of platelet microparticles in vivo by aspirin improved glomerular endothelial injury. Further analysis showed that platelet microparticles activated the mammalian target of rapamycin complex 1 (mTORC1) pathway in glomerular endothelial cells; inhibition of the mTORC1 pathway by rapamycin or raptor siRNA significantly protected against microparticle-induced glomerular endothelial injury in vivo and in vitro. Moreover, platelet microparticle-derived chemokine ligand 7 (CXCL7) contributed to glomerular endothelial injury, and antagonizing CXCL7 using CXCL7-neutralizing antibody or blocking CXCL7 receptors with a competitive inhibitor of CXCR1 and CXCR2 dramatically attenuated such injury. CONCLUSIONS: These findings demonstrate a pathogenic role of platelet microparticles in glomerular endothelium dysfunction, and suggest a potential therapeutic target, CXCL7, for treatment of early diabetic nephropathy.

Short hairpin RNA interference targeting interleukin 1 receptor type I in the paraventricular nucleus attenuates hypertension in rats.

Blood pressure is controlled by tonic sympathetic activities, excessive activation of which contributes to the pathogenesis and progression of hypertension. Interleukin (IL)-1ß in the paraventricular nucleus (PVN) is involved in sympathetic overdrive and hypertension. Here, we investigated the therapeutic effects of IL-1 receptor type I (IL-1R1) gene silencing in the PVN on hypertension. Recombinant lentivirus vectors expressing a short hairpin RNA (shRNA) targeting IL-1R1 (Lv-shR-IL-1R1) or a control shRNA were microinjected into PVN of spontaneously hypertensive rats (SHRs) and normotensive WKY rats. The fluorescence of green fluorescent protein-labelled vectors appeared at 2 weeks after injection and persisted for at least 8 weeks. IL-1R1 protein expression in the PVN was reduced 4 weeks after Lv-shR-IL-1R1 injection in SHRs. IL-1R1 interference also reduced basal sympathetic activity, cardiac sympathetic afferent reflex in SHRs. Depressor effects were observed from week 2 to 10 after Lv-shR-IL-1R1 treatment in SHRs, with the most prominent effects seen at the end of week 4. Furthermore, Lv-shR-IL-1R1 treatment decreased the ratio of left ventricular weight to body weight and cross-sectional areas of myocardial cells in SHRs. Additionally, Lv-shR-IL-1R1 treatment prevented an increase in superoxide anion and pro-inflammatory cytokines (PICs, TNF-α and IL-1ß) in the PVN of SHR, and upregulated anti-inflammatory cytokine (AIC, IL-10) expression. These results indicate that shRNA interference targeting IL-1R1 in the PVN decreases arterial blood pressure, attenuates excessive sympathetic activity and cardiac sympathetic afferent reflex, and improves myocardial remodelling in SHRs by restoring the balance between PICs and AICs to attenuate oxidative stress.

Inflammation-activated CXCL16 pathway contributes to tubulointerstitial injury in mouse diabetic nephropathy.

Inflammation and lipid disorders play crucial roles in synergistically accelerating the progression of diabetic nephropathy (DN). In this study we investigated how inflammation and lipid disorders caused tubulointerstitial injury in DN in vivo and in vitro. Diabetic db/db mice were injected with 10% casein (0.5 mL, sc) every other day for 8 weeks to cause chronic inflammation. Compared with db/db mice, casein-injected db/db mice showed exacerbated tubulointerstitial injury, evidenced by increased secretion of extracellular matrix (ECM) and cholesterol accumulation in tubulointerstitium, which was accompanied by activation of the CXC chemokine ligand 16 (CXCL16) pathway. In the in vitro study, we treated HK-2 cells with IL-1ß (5 ng/mL) and high glucose (30 mmol/L). IL-1ß treatment increased cholesterol accumulation in HK-2 cells, leading to greatly increased ROS production, ECM protein expression levels, which was accompanied by the upregulated expression levels of proteins in the CXCL16 pathway. In contrast, after CXCL16 in HK-2 cells was knocked down by siRNA, the IL-1ß-deteriorated changes were attenuated. In conclusion, inflammation accelerates renal tubulointerstitial lesions in mouse DN via increasing the activity of CXCL16 pathway.

Lipoprotein(a) accelerated the progression of atherosclerosis in patients with end-stage renal disease.

BACKGROUND: Increased plasma level of lipoprotein(a) (Lpa) is a risk factor of cardiovascular diseases. This study aimed to explore the role of Lpa in the progression of atherosclerosis in patients with end-stage renal disease (ESRD) and to investigate whether its potential mechanism is mediated by CXC chemokine ligand 16 (CXCL16) and low-density lipoprotein receptor (LDLr). METHODS: This is a retrospective clinical study. From January 2015 to April 2016, forty-six ESRD patients from Danyang First People's Hospital were investigated. The patients were grouped according to their plasma Lpa levels: control group (Lpa < 300 mg/l, n = 23) and high Lpa group (Lpa ≥ 300 mg/l, n = 23). ESRD Patients with acute infective diseases, cancer, and/or chronic active hepatitis were excluded. Biochemical indexes and lipid profiles of the patients were measured. Surgically removed tissues from the radial arteries of ESRD patients receiving arteriovenostomy were used for the preliminary evaluation of atherosclerosis. Haematoxylin-eosin (HE) and filipin staining were used to observe foam cell formation. Protein expression levels of Lpa, CXCL16, and LDLr were detected by immunohistochemistry staining and immunofluorescent staining. RESULTS: There was more foam cell formation and cholesterol accumulation in the radial arteries of the high Lpa group than in those of the control group. Furthermore, the expression levels of Lpa, CXCL16, and LDLr were significantly increased in the radial arteries of the high Lpa group. Correlation analyses showed that the protein expression levels of Lpa (r = 0.72, P < 0.01), LDLr (r = 0.54, P < 0.01), and CXCL16 (r = 0.6, P < 0.01) in the radial arteries of ESRD patients were positively correlated with the plasma Lpa levels. Further analyses showed that the co-expression of Lpa with LDLr or CXCL16 was increased in the high Lpa group. CONCLUSIONS: High plasma Lpa levels accelerated the progression of atherosclerosis in ESRD through inducing Lpa accumulation in the arteries, which was associated with LDLr and CXCL16. These two lipoproteins could both be major lipoprotein components that regulate the entry of Lpa into arterial cells.

Upregulation of long noncoding RNA zinc finger antisense 1 enhances epithelial-mesenchymal transition in vitro and predicts poor prognosis in glioma.

Increasing evidence indicates that long noncoding RNAs play important roles in development and progression of various cancers. Zinc finger antisense 1 is a novel long noncoding RNA whose clinical significance, biological function, and underlying mechanism are still undetermined in glioma. In this study, we reported that zinc finger antisense 1 expression was markedly upregulated in glioma and tightly correlated with clinical stage. Moreover, patients with high zinc finger antisense 1 expression had shorter survival. Multivariate Cox regression analysis provided a clue that, probably, zinc finger antisense 1 level could serve as an independent prognostic factor for glioma. Functionally, zinc finger antisense 1 acted as an oncogene in glioma because its knockdown could promote apoptosis and significantly inhibit cell proliferation, migration, and invasion. Furthermore, zinc finger antisense 1 silencing could result in cell cycle arrest at the G0/G1 phase and correspondingly decrease the percentage of S phase cells in both U87 and U251 cell lines. Moreover, it was found that silenced zinc finger antisense 1 could impair migration and invasion by inhibiting the epithelial-mesenchymal transition through reducing the expression of MMP2, MMP9, N-cadherin, Integrin ß1, ZEB1, Twist, and Snail as well as increasing E-cadherin level in glioma. Taken together, our data identified that zinc finger antisense 1 might act as a valuable prognostic biomarker and potential therapeutic target for glioma.

Effects of prenatal caffeine exposure on glucose homeostasis of adult offspring rats.

Epidemiological evidences show that prenatal caffeine exposure (PCE) could induce intrauterine growth retardation (IUGR). The IUGR offspring also present glucose intolerance and type 2 diabetes mellitus after maturity. We have previously demonstrated that PCE induced IUGR and increased susceptibility to adult metabolic syndrome in rats. This study aimed to further investigate the effects of PCE on glucose homeostasis in adult offspring rats. Pregnant rats were administered caffeine (120 mg/kg/day, intragastrically) from gestational days 11 to 20. PCE offspring presented partial catch-up growth pattern after birth, characterizing by the increased body weight gain rates. Meanwhile, PCE had no significant influences on the basal blood glucose and insulin phenotypes of adult offspring but increased the glucose tolerance, glucose-stimulated insulin section and ß cell sensitivity to glucose in female progeny. The insulin sensitivity of both male and female PCE offspring were enhanced accompanied with reduced ß cell fraction and mass. Western blotting results revealed that significant augmentation in protein expression of hepatic insulin signaling elements of PCE females, including insulin receptor (INSR), insulin receptor substrate 1 (IRS-1) and the phosphorylation of serine-threonine protein kinase (Akt), was also potentiated. In conclusion, we demonstrated that PCE reduced the pancreatic ß mass but increased the glucose tolerance in adult offspring rats, especially for females. The adaptive compensatory enhancement of ß cell responsiveness to glucose and elevated insulin sensitivity mainly mediated by upregulated hepatic insulin signaling might coordinately contribute to the increased glucose tolerance.

Neuroprotective effects of human umbilical cord-derived mesenchymal stromal cells combined with nimodipine against radiation-induced brain injury through inhibition of apoptosis.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) possess the ability to repair brain injuries. Additionally, nimodipine is a neuroprotective agent that increases cerebral blood flow and may help with the homing of MSCs to the injury site. Here we investigate the effectiveness of a combined human umbilical cord-derived MSCs and nimodipine therapy in radiation-induced brain injury (RIBI). METHODS: Female mice received whole brain irradiation (WBI) and were treated with saline, nimodipine, hUC-MSCs, or hUC-MSCs combined with nimodipine. Body weight was measured weekly. An open field test for locomotor activity and a step-down avoidance test for learning and memory function were conducted at week 4 and week 12 post-WBI. The histological damage was evaluated by hematoxylin and eosin staining and glial fibrillary acidic protein immunohistochemistry. Quantitative polymerase chain reaction and Western blotting were used to detect apoptosis-related mediators (p53, Bax and Bcl-2). RESULTS: In mice receiving the hUC-MSCs or the combined treatment, their body weight recovered, their locomotor and cognitive ability improved, and the percentage of necrotic neurons and astrocytes was reduced. The combined therapy was significantly (P < 0.05) more effective than hUC-MSCs alone; these mice showed decreased expression of pro-apoptotic indicators (p53, Bax) and increased expression of an anti-apoptotic indicator (Bcl-2), which may protect brain cells. CONCLUSIONS: We demonstrated that hUC-MSCs therapy helps recover body weight loss and behavior dysfunction in a mice model of RIBI. Moreover, the effectiveness of the combined hUC-MSCs and nimodipine therapy is due to apoptosis inhibition and enhancing homing of MSCs to the injured brain.

Establishment of a nanoparticle-assisted RT-PCR assay to distinguish field strains and attenuated strains of porcine epidemic diarrhea virus.

Porcine epidemic diarrhea virus (PEDV) can cause serious disease and even death in neonatal piglets, resulting in serious damage to the swine industry worldwide. Open reading frame 3 (ORF3) is the only accessory gene in the PEDV genome. Previous studies have indicated that PEDV vaccine strains have a partial deletion in ORF3. In this study, a nanoparticle-assisted polymerase chain reaction (nanoparticle-assisted RT-PCR) assay targeting the ORF3 of PEDV was developed to distinguish PEDV field strains from attenuated strains by using a specific pair of primers. The PCR products of field strains and attenuated strains were 264 bp and 215 bp in length, respectively. The sensitivity and specificity of this assay were also assessed. The nanoparticle-assisted RT-PCR assay was 10-100 times more sensitive than the conventional RT-PCR assay, with no cross-reactions when amplifying porcine pseudorabies virus (PRV), porcine circovirus type 2 (PCV2), classical swine fever virus (CSFV), porcine parvovirus (PPV), porcine reproductive and respiratory syndrome virus (PRRSV), porcine rotavirus (RV), and porcine transmissible gastroenteritis virus (TGEV). The nanoparticle-assisted RT-PCR assay we describe here can be used to distinguish field strains from vaccine strains of PEDV, and it shows promise for reducing economic loss due to PEDV infection.

Characterization of HJ-PI01 as a novel Pim-2 inhibitor that induces apoptosis and autophagic cell death in triple-negative human breast cancer.

AIM: Pim-2 is a short-lived serine/threonine kinase, which plays a key role in metastasis of breast cancer through persistent activation of STAT3. Although the crystal structure of Pim-2 has been reported, but thus far no specific Pim-2-targeted compounds have been reported. In this study, we identified a novel Pim-2 inhibitor, HJ-PI01, by in silico analysis and experimental validation. METHODS: The protein-protein interaction (PPI) network, chemical synthesis, molecular docking, and molecular dynamics (MD) simulations were used to design and discover the new Pim-2 inhibitor HJ-PI01. The anti-tumor effects of HJ-PI01 were evaluated in human breast MDA-MB-231, MDA-MB-468, MDA-MB-436, MCF-7 cells in vitro and in MDA-MB-231 xenograft mice, which were treated with HJ-PI01 (40 mg·kg(-1)·d(-1), ig) with or without lienal polypeptide (50 mg·kg(-1)·d(-1), ip) for 10 d. The apoptosis/autophage-inducing mechanisms of HJ-PI01 were elucidated using Western blots, immunoblots, flow cytometry, transmission electron microscopy and fluorescence microscopy. RESULTS: Based on the PrePPI network, the potential partners interacting with Pim-2 in regulating apoptosis (160 protein pairs) and autophagy (47 protein pairs) were identified. Based on the structural characteristics of Pim-2, a total of 15 compounds (HJ-PI01 to HJ-P015) were synthesized, which showed moderate or remarkable anti-proliferative potency in the human breast cancer cell lines tested. The most effective compound HJ-PI01 exerted a robust inhibition on MDA-MB-231 cells compared with chlorpromazine and the pan-Pim inhibitor PI003. Molecular dynamics (MD) simulation revealed that HJ-PI01 had a good binding score with Pim-2. Moreover, HJ-PI01 (300 nmol/L) induced death receptor-dependent and mitochondrial apoptosis as well as autophagic death in MDA-MB-231 cells. In MDA-MB-231 xenograft mice, administration of HJ-PI01 remarkably inhibited the tumor growth and induced tumor cell apoptosis in vivo. Co-administration of HJ-PI01 with lienal polypeptide could improve the anti-tumor activity of HJ-PI01 and reduce its toxicity. CONCLUSION: The newly synthesized compound, HJ-PI01, can induce death receptor/mitochondrial apoptosis and autophagic cell death by targeting Pim-2 in human breast cancer cells in vitro and in vivo.

Activation of the CXCL16/CXCR6 Pathway by Inflammation Contributes to Atherosclerosis in Patients with End-stage Renal Disease.

Background: Chronic inflammation plays a critical role in the progression of atherosclerosis (AS). This study aimed to determine the effects of the CXC chemokine ligand 16 (CXCL16)/CXC chemokine receptor 6 (CXCR6) pathway on cholesterol accumulation in the radial arteries of end-stage renal disease (ESRD) patients with concomitant microinflammation and to further investigate the potential effects of the purinergic receptor P2X ligand-gated ion channel 7 (P2X7R). Methods: Forty-three ESRD patients were divided into the control group (n=17) and the inflamed group (n=26) based on plasma C-reactive protein (CRP) levels. Biochemical indexes and lipid profiles of the patients were determined. Surgically removed tissues from the radial arteries of patients receiving arteriovenostomy were used for preliminary evaluation of AS. Haematoxylin-eosin (HE) and Filipin staining were performed to assess foam cell formation. CXCL16/CXCR6 pathway-related protein expression, P2X7R protein expression and the expression of monocyte chemotactic protein-1 (MCP-1), tumour necrosis factor-α (TNF-α), and CD68 were detected by immunohistochemical and immunofluorescence staining. Results: Inflammation increased both MCP-1 and TNF-α expression and macrophage infiltration in radial arteries. Additionally, foam cell formation significantly increased in the radial arteries of the inflamed group compared to that of the controls. Further analysis showed that protein expression of CXCL16, CXCR6, disintegrin and metalloproteinase-10 (ADAM10) in the radial arteries of the inflamed group was significantly increased. Furthermore, CXCL16 expression was positively correlated with P2X7R expression in the radial arteries of ESRD patients. Conclusions: Inflammation contributed to foam cell formation in the radial arteries of ESRD patients via activation of the CXCL16/CXCR6 pathway, which may be regulated by P2X7R.

Paraventricular nucleus is involved in the central pathway of adipose afferent reflex in rats.

Increasing evidence indicates a link between sympathetic nervous system activation and obesity, but the underlying mechanisms remain elusive. The adipose afferent reflex (AAR) is a sympathoexcitatory reflex that is activated by afferent neurotransmission from the white adipose tissue (WAT). This study aimed to investigate whether the hypothalamic paraventricular nucleus (PVH) is an important component of the central neurocircuitry of the AAR. In anesthetized rats, the discharge activity of individual PVH neurons was recorded in vivo. Activation of WAT afferents was initiated by capsaicin injection, and the AAR was evaluated by monitoring renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses. The responses of PVH neurons to activation of WAT afferents were evaluated by c-fos immunoreactivity and the discharge activity of individual PVH neurons, which was recorded using extracellular single-unit recording. After activation of WAT afferents, both individual PVH neuron discharge activity and c-fos immunoreactivity increased. Bilateral selective lesions of the neurons in the PVH with kainic acid abolished the AAR. These results indicate that PVH is an important component of the central neurocircuitry of the AAR.

A Long Noncoding RNA ZEB1-AS1 Promotes Tumorigenesis and Predicts Poor Prognosis in Glioma.

Emerging studies show that long noncoding RNAs (lncRNAs) have important roles in carcinogenesis. lncRNA ZEB1 antisense 1 (ZEB1-AS1) is a novel lncRNA, whose clinical significance, biological function, and underlying mechanism remains unclear in glioma. Here, we found that ZEB1-AS1 was highly expressed in glioma tissues, being closely related to clinical stage of glioma. Moreover, patients with high ZEB1-AS1 levels had poor prognoses, with the evidence provided by multivariate Cox regression analysis indicating that ZEB1-AS1 expression could serve as an independent prognostic factor in glioma patients. Functionally, silencing of ZEB1-AS1 could significantly inhibit cell proliferation, migration, and invasion, as well as promote apoptosis. Knockdown of ZEB1-AS1 significantly induced the G0/G1 phase arrest and correspondingly decreased the percentage of S phase cells. Further analysis indicated that ZEB1-AS1 could regulate the cell cycle by inhibiting the expression of G1/S transition key regulators, such as Cyclin D1 and CDK2. Furthermore, ZEB1-AS1 functioned as an important regulator of migration and invasion via activating epithelial to mesenchymal transition (EMT) through up-regulating the expression of ZEB1, MMP2, MMP9, N-cadherin, and Integrin-ß1 as well as decreasing E-cadherin levels in the metastatic progression of glioma. Additionally, forced down-regulation of ZEB1-AS1 could dramatically promote apoptosis by increasing the expression level of Bax and reducing Bcl-2 expression in glioma. Taken together, our data suggest that ZEB1-AS1 may serve as a new prognostic biomarker and therapeutic target of glioma.

Influence of PTGS1, PTGFR, and MRP4 genetic variants on intraocular pressure response to latanoprost in Chinese primary open-angle glaucoma patients.

PURPOSE: The purpose of this study is to evaluate the association between variants in prostaglandin-endoperoxide synthase 1 (PTGS1), prostaglandin F (2α) receptor (PTGFR), and multidrug resistance protein 4 (MRP4) genes and intraocular pressure (IOP) response to latanoprost in Chinese patients with primary open-angle glaucoma (POAG). METHODS: The IOP response to latanoprost was evaluated by percent IOP reduction (%ΔIOP) in the treated eye with the formula %ΔIOP = (Baseline IOP values - IOP values posttreatment) / Baseline IOP values × 100 %. Polymorphisms in PTGS1 (rs3842787 and rs10306114), PTGFR (rs3753380 and rs3766355), and MRP4 (rs11568658 and rs11568668) genes were detected by direct DNA sequencing. The differences among %ΔIOP of genotypes or haplotypes were obtained by use of the Mann-Whitney U test. Association analyses were performed by multiple linear regression analysis. RESULTS: Latanoprost were prescribed to 63 subjects, 60 of which met the inclusion/exclusion criteria for the current study. Notably, the %ΔIOP in the rs11568658 GT heterozygous genotype was 10.4 %ΔIOP lower than that of GG homozygous wild-type on day 7 (15.7 ± 2.52 vs. 26.1 ± 2.88, P=0.003), and the corresponding results in the rs10306114 AG heterozygous genotype and AT haplotype constructed by rs3753380 and rs3766355 on day 7 were 7.2 and 10.3 %ΔIOP (P<0.05). Interestingly, similar results were also observed on day 30 (P=0.008, P=0.006, and P=0.002, respectively). Multiple regression analysis showed that heterozygous genotypes of rs10306114, rs11568658, and carrier of AT haplotype were significantly correlated with the lower %ΔIOP. On day 30, the above variations explained 9.9, 10.7, and 17.7 % of the total variability of %ΔIOP in the Chinese POAG patients, respectively. CONCLUSION: rs10306114, rs3753380, rs3766355, and rs11568658 single-nucleotide polymorphisms (SNPs) correlate with a response to latanoprost treatment in patients with POAG. These SNPs may be important determinants of variability in response to latanoprost.