ABSTRACT
BACKGROUND: Currently, the prevalence of obesity is on the rise annually. Bariatric surgery stands out as the most efficacious approach for addressing obesity. Obese patients are more prone to experience moderate to severe pain after surgery due to lower pain thresholds. Regional block, as an important component of multimodal analgesia in bariatric surgery, is crucial in reducing opioid consumption and alleviating postoperative pain in patients undergoing bariatric surgery. Transversus abdominis plane block (TAPB) has gained widespread utilization in bariatric surgery; however, its limitation of inadequate reduction of visceral pain in obese patients remains a significant concern. Therefore, it is imperative to explore new and more efficient strategies for analgesia. Quadratus lumborum block (QLB) has emerged as a popular nerve block in recent years, frequently utilized in conjunction with general anesthesia for abdominal surgery. In the cadaver study of QLB, it was confirmed that the dye level could reach up to T6 when using the subcostal anterior quadratus lumborum muscle approach, which could effectively reduce the incision pain and visceral pain of bariatric surgery patients during the perioperative period. However, there is currently a lack of research on the use of subcostal anterior QLB in patients undergoing bariatric surgery. Our study aims to investigate whether subcostal anterior QLB can provide superior perioperative analgesic efficacy for bariatric surgery under general anesthesia compared to TAPB, leading to reduced postoperative opioid consumption and a lower incidence of postoperative nausea and vomiting (PONV). METHODS AND DESIGN: This study is a prospective, randomized controlled trial aiming to recruit 66 patients undergoing bariatric surgery. The participants will be randomly allocated into two groups in a 1:1 ratio: subcostal anterior QLB group (n = 33) and TAPB group (n = 33). The study aims to investigate the efficacy of subcostal anterior QLB and TAPB in obese patients who are scheduled to undergo bariatric surgery. Our primary outcome is to observe the amount of opioids used in the two groups 24 h after operation. The secondary outcomes included VAS of pain during rest/activity after operation, the type and dose of additional analgesics, the occurrence and severity of PONV, the type and dose of additional antiemetic drugs, postoperative anesthesia care unit (PACU) time, time of first postoperative exhaust, time to first out of bed activity, time to first liquid diet and postoperative admission days. DISCUSSION: Opioid analgesics are prone to causing adverse reactions such as nausea, vomiting, and respiratory depression, especially in obese patients. Multimodal analgesia, including nerve block, can effectively reduce the dose of opioids and alleviate their adverse effects. Currently, TAPB is the most prevalent nerve block analgesia method for abdominal surgery. Recent studies have indicated that subcostal anterior QLB offers advantages over TAPB, including a wider block plane, faster onset, and longer maintenance time. It is not clear which of the two nerve block analgesia techniques is better for postoperative analgesia in patients undergoing bariatric surgery. Our objective in this investigation is to elucidate the superior method between TAPB and subcostal anterior QLB for postoperative pain management in bariatric surgery. TRIAL REGISTRATION: ChiCTR ChiCTR2300070556. Registered on 17 April 2023.
Subject(s)
Abdominal Muscles , Bariatric Surgery , Nerve Block , Pain, Postoperative , Humans , Pain, Postoperative/prevention & control , Pain, Postoperative/etiology , Pain, Postoperative/diagnosis , Nerve Block/methods , Nerve Block/adverse effects , Bariatric Surgery/adverse effects , Bariatric Surgery/methods , Prospective Studies , Abdominal Muscles/innervation , Pain Measurement , Randomized Controlled Trials as Topic , Treatment Outcome , Adult , Male , Female , Middle Aged , Obesity/surgery , Postoperative Nausea and Vomiting/prevention & control , Postoperative Nausea and Vomiting/etiologyABSTRACT
BACKGROUND: Intra-operative anaesthesia management should be optimised to reduce the occurrence of postoperative nausea and vomiting in high-risk patients; however, a single intervention may not effectively reduce postoperative nausea and vomiting in such patients. This study assessed the effect of an optimised anaesthetic protocol versus a conventional one on postoperative nausea and vomiting in patients who underwent laparoscopic sleeve gastrectomy. METHODS: A single-centre randomised trial was conducted at Peking University Shenzhen Hospital from June 2021 to December 2022. Among 168 patients who underwent laparoscopic sleeve gastrectomy, 116 qualified, and 103 completed the study with available data. Patients were categorized into the conventional group (received sevoflurane and standard fluids) and the optimised group (underwent propofol-based anaesthesia and was administered goal-directed fluids). The primary endpoints were postoperative nausea and vomiting incidence and severity within 24 h. RESULTS: Postoperative nausea and vomiting assessment at 0-3 h post-surgery revealed no significant differences between groups. However, at 3-24 h, the optimised anaesthetic protocol group showed lower postoperative nausea and vomiting incidence and severity than those of the conventional group (P = 0.005). In the conventional group, 20 (37.04%) patients experienced moderate-to-severe postoperative nausea and vomiting, compared to six (12.25%) patients in the optimised group (odds ratio = 0.237; 95% CI = 0.086, 0.656; P = 0.006). No significant differences were noted in antiemetic treatment, moderate-to-severe pain incidence, anaesthesia recovery, post-anaesthetic care unit stay, or postoperative duration between the groups. While the total intra-operative infusion volumes were comparable, the optimised group had a significantly higher colloidal infusion volume (500 mL vs. 0 mL, P = 0.014) than that of the conventional group. CONCLUSIONS: The incidence and severity of postoperative nausea and vomiting 3-24 h postoperatively in patients who underwent laparoscopic sleeve gastrectomy were significantly lower with propofol-based total intravenous anaesthesia and goal-directed fluid therapy than with sevoflurane anaesthesia and traditional fluid management. Total intravenous anaesthesia is an effective multimodal antiemetic strategy for bariatric surgery. TRIAL REGISTRATION: This trial was registered with the Chinese Clinical Trial Registry (ChiCTR-TRC- 2,100,046,534, registration date: 21 May 2021).
Subject(s)
Gastrectomy , Laparoscopy , Postoperative Nausea and Vomiting , Propofol , Sevoflurane , Humans , Postoperative Nausea and Vomiting/prevention & control , Postoperative Nausea and Vomiting/epidemiology , Male , Female , Laparoscopy/methods , Gastrectomy/methods , Gastrectomy/adverse effects , Adult , Propofol/administration & dosage , Sevoflurane/administration & dosage , Middle Aged , Anesthetics, Intravenous/administration & dosage , Anesthetics, Inhalation/administration & dosage , Anesthesia/methodsABSTRACT
Vacuolar H+-ATPase (V-ATPase) is a multisubunit protein complex which, along with its accessory proteins, resides in almost every eukaryotic cell. It acts as a proton pump and as such is responsible for regulating pH in lysosomes, endosomes, and the extracellular space. Moreover, V-ATPase has been implicated in receptor-mediated signaling. Although numerous studies have explored the role of V-ATPase in cancer, osteoporosis, and neurodegenerative diseases, research on its involvement in vascular disease remains limited. Vascular diseases pose significant challenges to human health. This review aimed to shed light on the role of V-ATPase in hypertension and atherosclerosis. Furthermore, given that vascular complications are major complications of diabetes, this review also discusses the pathways through which V-ATPase may contribute to such complications. Beginning with an overview of the structure and function of V-ATPase in hypertension, atherosclerosis, and diabetes, this review ends by exploring the pharmacological potential of targeting V-ATPase.
Subject(s)
Atherosclerosis , Diabetes Mellitus , Hypertension , Vacuolar Proton-Translocating ATPases , Humans , Atherosclerosis/enzymology , Atherosclerosis/metabolism , Vacuolar Proton-Translocating ATPases/metabolism , Hypertension/enzymology , Animals , Diabetes Mellitus/enzymologyABSTRACT
Although the roles of E proteins and inhibitors of DNA-binding (Id) in T follicular helper (TFH) and T follicular regulatory (TFR) cells have been previously reported, direct models demonstrating the impact of multiple E protein members have been lacking. To suppress all E proteins including E2A, HEB and E2-2, we overexpressed Id1 in CD4 cells using a CD4-Id1 mouse model, to observe any changes in TFH and TFR cell differentiation. Our objective was to gain better understanding of the roles that E proteins and Id molecules play in the differentiation of TFH and TFR cells. The CD4-Id1 transgenic (TG) mice that we constructed overexpressed Id1 in CD4 cells, inhibiting E protein function. Our results showed an increase in the proportion and absolute numbers of Treg, TFH and TFR cells in the spleen of TG mice. Additionally, the expression of surface characterisation molecules PD-1 and ICOS was significantly upregulated in TFH and TFR cells. The study also revealed a downregulation of the marginal zone B cell precursor and an increase in the activation and secretion of IgG1 in spleen B cells. Furthermore, the peripheral TFH cells of TG mice enhanced the function of assisting B cells. RNA sequencing results indicated that a variety of TFH-related functional molecules were upregulated in TFH cells of Id1 TG mice. In conclusion, E proteins play a crucial role in regulating TFH/TFR cell differentiation and function and suppressing E protein activity promotes germinal centre humoral immunity, which has important implications for immune regulation and treating related diseases.
Subject(s)
Cell Differentiation , Inhibitor of Differentiation Protein 1 , Mice, Transgenic , T Follicular Helper Cells , T-Lymphocytes, Regulatory , Animals , Inhibitor of Differentiation Protein 1/metabolism , Inhibitor of Differentiation Protein 1/genetics , Mice , T Follicular Helper Cells/immunology , T Follicular Helper Cells/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Programmed Cell Death 1 Receptor/metabolism , Programmed Cell Death 1 Receptor/genetics , Inducible T-Cell Co-Stimulator Protein/metabolism , Inducible T-Cell Co-Stimulator Protein/genetics , Up-Regulation , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Germinal Center/immunology , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , Lymphocyte Activation , Mice, Inbred C57BL , Immunoglobulin G/immunologyABSTRACT
E3 SUMO-protein ligase CBX4 (CBX4), a key component of polycomb-repressive complexes 1 (PRC1), has been reported to regulate a variety of genes implicated in tumor growth, metastasis, and angiogenesis. However, its role in T-cell-mediated antitumor immunity remains elusive. To shed light on this issue, we generated mice with T-cell-specific deletion of Cbx4. Tumor growth was increased in the knockout mice. Additionally, their tumor-infiltrating lymphocytes exhibited impaired tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) production, with an elevated programmed cell death protein 1 (PD-1) level. In fact, dysregulated Pdcd1 expression was observed in all major subsets of peripheral T cells from the knockout mice, which was accompanied by a functional defect in response to T-cell receptor (TCR) stimulation. In support of a direct link between CBX4 and PD-1, Cbx4 overexpression resulted in the downregulation of Pdcd1 expression. Epigenetic analyses indicated that Cbx4 deficiency leads to diminished accumulation of inhibitory histone modifications at conserved region (CR)-C and CR-B sites of the Pdcd1 promoter, namely mono-ubiquitinated histone H2A at lysine 119 (H2AK119ub1) and trimethylated histone H3 at lysine 27 (H3K27me3). Moreover, inhibition of either the E3 ligase activity of polycomb-repressive complexes 1 (PRC1) or the methyltransferase activity of polycomb-repressive complexes 2 (PRC2) restores Pdcd1 expression in Cbx4-transfected cells. Cumulatively, this study reveals a novel function of CBX4 in the regulation of T-cell function and expands our understanding of the epigenetic control of Pdcd1 expression.
Subject(s)
Neoplasms , Programmed Cell Death 1 Receptor , Animals , Mice , Programmed Cell Death 1 Receptor/genetics , Lysine , T-Lymphocytes/metabolism , Polycomb-Group Proteins/genetics , Polycomb-Group Proteins/metabolism , Ligases/genetics , Ligases/metabolism , Polycomb Repressive Complex 1/genetics , Polycomb Repressive Complex 1/metabolism , Neoplasms/genetics , Mice, KnockoutABSTRACT
In this paper, glutathione (GSH)-coated Zn-doped CdTe quantum dots (QDs) with different particle sizes were synthesized using the "reflow method", and the interaction mechanism between the two QDs and lactoferrin (LF) was investigated systemically with different spectroscopic methods. The steady-state fluorescence spectra showed that the LF formed a tight complex with the two QDs through static bursting and that the electrostatic force was the main driving force between the two LF-QDs systems. The complex generation process was found to be spontaneous (ΔG < 0) and accompanied by exothermic and increasing degrees of freedom (ΔH < 0, ΔS > 0) by using the temperature-dependent fluorescence spectroscopy. The critical transfer distance (R0) and donor-acceptor distance (r) of the two LF-QDs systems were obtained based on the fluorescence resonance energy transfer theory. In addition, it was observed that the QDs changed the secondary and tertiary structures of LF, leading to an increase in the hydrophobicity of LF. Further, the nano-effect of orange QDs on LF is much larger than that of green QDs. The above results provide a basis for metal-doped QDs with LF in safe nano-bio applications.
Subject(s)
Cadmium Compounds , Quantum Dots , Lactoferrin , Quantum Dots/chemistry , Cadmium Compounds/chemistry , Tellurium/chemistry , Spectrometry, Fluorescence , Zinc/chemistryABSTRACT
The present study reports the case of a patient with diffuse large B-cell lymphoma (DLBCL) and monoclonal gammopathy (MG) secondary to immune thrombocytopenia purpura (ITP). The clinical diagnoses and investigations of this case are reported. To the best of our knowledge, this is the first study to report DLBCL and MG secondary to ITP. The patient presented with a rare constellation of diseases, which made the diagnosis and treatment difficult for the physicians. The patient was followed up for 10 years using the morphological examination of bone marrow cells after chemotherapy, and currently continues with follow-up examinations. Treatments and prognoses for ITP, DLBCL and MG are common. However, treatments and prognoses are unclear for patients with all three conditions. The different clinical manifestations and disease processes of DLBCL and MG secondary to ITP cause difficulties for physicians in terms of treatment and prognosis. The present case report describes the comprehensive evaluation, diagnosis and treatment of a patient with DLBCL and MG secondary to, and concurrent with, ITP.
ABSTRACT
BACKGROUND AND PURPOSE: Small interfering RNA (siRNA) targeting liver angiotensinogen lowers blood pressure, but its effects in hypertensive diabetes are unknown. EXPERIMENTAL APPROACH: To address this, TGR (mRen2)27 rats (angiotensin II-dependent hypertension model) were made diabetic with streptozotocin over 18 weeks and treated with either vehicle, angiotensinogen siRNA, the AT1 antagonist valsartan, the ACE inhibitor captopril, valsartan + siRNA or valsartan + captopril for the final 3 weeks. Mean arterial pressure (MAP) was measured via radiotelemetry. KEY RESULTS: MAP before treatment was 153 ± 2 mmHg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis and podocyte effacement, without a change in glomerular filtration rate. All treatments lowered MAP and cardiac hypertrophy, and the largest drop in MAP was observed with siRNA + valsartan. Treatment with siRNA lowered circulating angiotensinogen by >99%, and the lowest circulating angiotensin II and aldosterone levels occurred in the dual treatment groups. Angiotensinogen siRNA did not affect renal angiotensinogen mRNA expression, confirming its liver-specificity. Furthermore, only siRNA with or without valsartan lowered renal angiotensin I. All treatments lowered renal angiotensin II and the reduction was largest (>95%) in the siRNA + valsartan group. All treatments identically lowered albuminuria, whereas only siRNA with or without valsartan restored podocyte foot processes and reduced glomerulosclerosis. CONCLUSION AND IMPLICATIONS: Angiotensinogen siRNA exerts renoprotection in diabetic TGR (mRen2)27 rats and this relies, at least in part, on the suppression of renal angiotensin II formation from liver-derived angiotensinogen. Clinical trials should now address whether this is also beneficial in human diabetic kidney disease.
Subject(s)
Angiotensin II , Diabetes Mellitus, Experimental , Hypertension , Kidney Diseases , RNA, Small Interfering , Animals , Humans , Rats , Albuminuria , Angiotensin II/drug effects , Angiotensin II/genetics , Blood Pressure/drug effects , Blood Pressure/genetics , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Hypertension/drug therapy , Liver/metabolism , Renin/metabolism , Renin-Angiotensin System , Valsartan/pharmacology , Kidney Diseases/drug therapy , Kidney Diseases/metabolism , Kidney Diseases/prevention & control , RNA, Small Interfering/metabolism , RNA, Small Interfering/pharmacology , RNA, Small Interfering/therapeutic useABSTRACT
Background A single dose of small interfering RNA (siRNA) targeting liver angiotensinogen eliminates hepatic angiotensinogen and lowers blood pressure. Angiotensinogen elimination raises concerns for clinical application because an angiotensin rise is needed to maintain perfusion pressure during hypovolemia. Here, we investigated whether conventional vasopressors can raise arterial pressure after angiotensinogen depletion. Methods and Results Spontaneously hypertensive rats on a low-salt diet were treated with siRNA (10 mg/kg fortnightly) for 4 weeks, supplemented during the final 2 weeks with fludrocortisone (6 mg/kg per day), the α-adrenergic agonist midodrine (4 mg/kg per day), or a high-salt diet (all groups n=6-7). Pressor responsiveness to angiotensin II and norepinephrine was assessed before and after siRNA administration. Blood pressure was measured via radiotelemetry. Depletion of liver angiotensinogen by siRNA lowered plasma angiotensinogen concentrations by 99.2±0.1% and mean arterial pressure by 19 mm Hg. siRNA-mediated blood pressure lowering was rapidly reversed by intravenous angiotensin II or norepinephrine, or gradually reversed by fludrocortisone or high salt intake. Midodrine had no effect. Unexpectedly, fludrocortisone partially restored plasma angiotensinogen concentrations in siRNA-treated rats, and nearly abolished plasma renin concentrations. To investigate whether this angiotensinogen originated from nonhepatic sources, fludrocortisone was administered to mice lacking hepatic angiotensinogen. Fludrocortisone did not increase angiotensinogen in these mice, implying that the rise in angiotensinogen in the siRNA-treated rats must have depended on the liver, most likely reflecting diminished cleavage by renin. Conclusions Intact pressor responsiveness to conventional vasopressors provides pharmacological means to regulate the blood pressure-lowering effect of angiotensinogen siRNA and may support future therapeutic implementation of siRNA.
Subject(s)
Hypertension , Midodrine , Angiotensin II/pharmacology , Angiotensinogen/genetics , Angiotensinogen/metabolism , Animals , Blood Pressure/physiology , Fludrocortisone , Hypertension/drug therapy , Hypertension/therapy , Mice , Norepinephrine , RNA, Small Interfering/pharmacology , Rats , Renin/genetics , Renin-Angiotensin System , Vasoconstrictor Agents/pharmacology , Vasoconstrictor Agents/therapeutic useABSTRACT
The mechanism regulating the life span of short-lived plasma cells (SLPCs) remains poorly understood. Here we demonstrated that the EP4-mediated activation of AKT by PGE2 was required for the proper control of inositol-requiring transmembrane kinase endoribonuclease-1α (IRE1α) hyperactivation and hence the endoplasmic reticulum (ER) homeostasis in IgM-producing SLPCs. Disruption of the PGE2-EP4-AKT signaling pathway resulted in IRE1α-induced activation of JNK, leading to accelerated death of SLPCs. Consequently, Ptger4-deficient mice (C57BL/6) exhibited a markedly impaired IgM response to T-independent Ags and increased susceptibility to Streptococcus pneumoniae infection. This study reveals a highly selective impact of the PGE2-EP4 signal on the humoral immunity and provides a link between ER stress response and the life span of SLPCs.
Subject(s)
Cell Survival , Dinoprostone , Endoplasmic Reticulum Stress , Endoribonucleases , Plasma Cells , Protein Serine-Threonine Kinases , Animals , Cell Survival/immunology , Dinoprostone/immunology , Endoplasmic Reticulum Stress/immunology , Endoribonucleases/immunology , Immunoglobulin M/immunology , Mice , Mice, Inbred C57BL , Plasma Cells/immunology , Prostaglandins/immunology , Prostaglandins E/immunology , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/immunology , Proto-Oncogene Proteins c-akt/immunologyABSTRACT
AIM: Elevated Treg is relevant to persistent HBV infection, and the regulatory mechanism of Treg levels remains unclear. E proteins are important transcriptional regulators and could be antagonized by inhibitors of DNA-binding (Id) 1-4. We aim to clarify the role of Ids during HBV infection. MAIN METHODS: Changes of Ids and their relationship with Treg were investigated in both HBV transfection model and hepatitis B patients. Significance of Ids was studied by in vitro Treg differentiation induction with Id inhibited or over-expressed. The role of inflammatory cytokines for Id was studied by co-culture. RNA-Seq was conducted to explore the differentially expressed genes in Id-overexpressed CD4 T cells upon Treg differentiation induction conditions. KEY FINDINGS: Id-overexpressed mice attenuated virus clearance in HBV transfection model. In the HBV transfection mouse model, Tregs were up-regulated, with Id3 increased in Treg as well. Clinically, circulating Tregs in chronic hepatitis B (CHB) patients were elevated, and elevated Id3 transcriptional levels were positively correlated with Tregs. IL-1ß could up-regulate Id3 in Treg cells induced in vitro. RNA-Seq revealed that increased Id could cause a series of signaling pathway changes during Treg differentiation. SIGNIFICANCE: Id3 is elevated during HBV infection to ease Treg differentiation, and the antiviral immunity is influenced that make the infection to develop into chronic state.
Subject(s)
Hepatitis B virus/immunology , Hepatitis B, Chronic/immunology , Inhibitor of Differentiation Proteins/metabolism , Neoplasm Proteins/metabolism , T-Lymphocytes, Regulatory/immunology , Adult , Animals , Cell Differentiation , Female , Gene Expression Regulation , Humans , Inhibitor of Differentiation Proteins/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Middle Aged , Neoplasm Proteins/genetics , RNA-Seq , Up-RegulationABSTRACT
PURPOSE: A growing number of publications have paid close attention to the chest computed tomography (CT) detection of COVID-19 with inconsistent diagnostic accuracy, the present meta-analysis assessed the available evidence regarding the overall performance of chest CT for COVID-19. METHODS: 2 × 2 diagnostic table was extracted from each of the included studies. Data on specificity (SPE), sensitivity (SEN), negative likelihood ratio (LR-), positive likelihood ratio (LR+), and diagnostic odds ratio (DOR) were calculated purposefully. RESULTS: Fifteen COVID-19 related publications met our inclusion criteria and were judged qualified for the meta-analysis. The following were summary estimates for diagnostic parameters of chest CT for COVID-19: SPE, 0.49 (95% CI 46-52%); SEN, 0.94 (95% CI 93-95%); LR-, 0.15 (95% CI 11-20%); LR+, 1.93 (95% CI 145-256%); DOR, 17.14 (95% CI 918-3199%); and the area under the receiver operating characteristic curve (AUC), 0.93. CONCLUSION: Chest CT has high SEN, but the SPE is not ideal. It is highly recommended to use a combination of different diagnostic tools to achieve sufficient SEN and SPE. It should be taken into account as a diagnostic tool for current COVID-19 detection, especially for patients with symptoms. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40336-021-00434-z.
ABSTRACT
[Figure: see text].
Subject(s)
Angiotensinogen/genetics , Kidney/metabolism , Liver/metabolism , Renal Insufficiency, Chronic/genetics , Angiotensin II/blood , Angiotensinogen/metabolism , Animals , Antihypertensive Agents/pharmacology , Arterial Pressure/drug effects , Arterial Pressure/physiology , Captopril/pharmacology , Disease Models, Animal , Kidney/drug effects , Kidney/pathology , Liver/pathology , Losartan/pharmacology , RNA, Small Interfering , Rats , Renal Insufficiency, Chronic/metabolism , Renin-Angiotensin System/drug effectsABSTRACT
Brain renin-angiotensin system (RAS) activation is thought to mediate deoxycorticosterone acetate (DOCA)-salt hypertension, an animal model for human primary hyperaldosteronism. Here, we determined whether brainstem angiotensin II is generated from locally synthesized angiotensinogen and mediates DOCA-salt hypertension. To this end, chronic DOCA-salt-hypertensive rats were treated with liver-directed siRNA targeted to angiotensinogen, the angiotensin II type 1 receptor antagonist valsartan, or the mineralocorticoid receptor antagonist spironolactone (n = 6-8/group). We quantified circulating angiotensinogen and renin by enzyme-kinetic assay, tissue angiotensinogen by Western blotting, and angiotensin metabolites by LC-MS/MS. In rats without DOCA-salt, circulating angiotensin II was detected in all rats, whereas brainstem angiotensin II was detected in 5 out of 7 rats. DOCA-salt increased mean arterial pressure by 19 ± 1 mmHg and suppressed circulating renin and angiotensin II by >90%, while brainstem angiotensin II became undetectable in 5 out of 7 rats (<6 fmol/g). Gene silencing of liver angiotensinogen using siRNA lowered circulating angiotensinogen by 97 ± 0.3%, and made brainstem angiotensin II undetectable in all rats (P<0.05 vs. non-DOCA-salt), although brainstem angiotensinogen remained intact. As expected for this model, neither siRNA nor valsartan attenuated the hypertensive response to DOCA-salt, whereas spironolactone normalized blood pressure and restored brain angiotensin II together with circulating renin and angiotensin II. In conclusion, despite local synthesis of angiotensinogen in the brain, brain angiotensin II depended on circulating angiotensinogen. That DOCA-salt suppressed circulating and brain angiotensin II in parallel, while spironolactone simultaneously increased brain angiotensin II and lowered blood pressure, indicates that DOCA-salt hypertension is not mediated by brain RAS activation.
Subject(s)
Angiotensin II/metabolism , Hypertension/physiopathology , Renin-Angiotensin System/drug effects , Angiotensinogen/blood , Animals , Brain/metabolism , Brain Stem/metabolism , Desoxycorticosterone Acetate/administration & dosage , Hypertension/chemically induced , Male , Rats, Sprague-Dawley , Renin/blood , Sodium Chloride, Dietary/administration & dosage , Valsartan/pharmacologyABSTRACT
Objective: Elevated plasma cholesterol concentrations contributes to ischemic cardiovascular diseases. Recently, we showed that inhibiting hepatic (pro)renin receptor [(P)RR] attenuated diet-induced hypercholesterolemia and hypertriglyceridemia in low-density lipoprotein receptor (LDLR) deficient mice. The purpose of this study was to determine whether inhibiting hepatic (P)RR could attenuate atherosclerosis. Approach and Results: Eight-week-old male LDLR-/- mice were injected with either saline or N-acetylgalactosamine-modified antisense oligonucleotides (G-ASOs) primarily targeting hepatic (P)RR and were fed a western-type diet (WTD) for 16 weeks. (P)RR G-ASOs markedly reduced plasma cholesterol concentrations from 2,211 ± 146 to 1,128 ± 121 mg/dL. Fast protein liquid chromatography (FPLC) analyses revealed that cholesterol in very low-density lipoprotein (VLDL) and intermediate density lipoprotein (IDL)/LDL fraction were potently reduced by (P)RR G-ASOs. Moreover, (P)RR G-ASOs reduced plasma triglyceride concentrations by more than 80%. Strikingly, despite marked reduction in plasma lipid concentrations, atherosclerosis was not reduced but rather increased in these mice. Further testing in ApoE-/- mice confirmed that (P)RR G-ASOs reduced plasma lipid concentrations but not atherosclerosis. Transcriptomic analysis of the aortas revealed that (P)RR G-ASOs induced the expression of the genes involved in immune responses and inflammation. Further investigation revealed that (P)RR G-ASOs also inhibited (P)RR in macrophages and in enhanced inflammatory responses to exogenous stimuli. Moreover, deleting the (P)RR in macrophages resulted in accelerated atherosclerosis in WTD fed ApoE-/- mice. Conclusion: (P)RR G-ASOs reduced the plasma lipids in atherosclerotic mice due to hepatic (P)RR deficiency. However, augmented pro-inflammatory responses in macrophages due to (P)RR downregulation counteracted the beneficial effects of lowered plasma lipid concentrations on atherosclerosis. Our study demonstrated that hepatic (P)RR and macrophage (P)RR played a counteracting role in atherosclerosis.
ABSTRACT
The rational design and realization of multiscale porous structures has been a long-standing challenge in membrane science. Block copolymers (BCPs) with their self-assembly-enabled nanodomains have the potential to make structural breakthroughs. An amphipathic Janus membrane, with a hierarchical multiscale hyperporous structure constituted by polystyrene-b-poly(4-vinylpyridine) (PS4VP) and polyvinylidene fluoride (PVDF) blocks, was designed and synthesized in this work. Hydrophobic PVDF dominated one side of the membrane, and hydrophilic PS4VP, with nanopores that formed inside the macroporous channels of PVDF via a self-assembly approach, dominated the other side. Candida Rugosa Lipase (CRL), as a model biocatalyst, was immobilized in the PS4VP nanopores via injection. The immobilized lipase was exactly suspended at the interface of the organic and aqueous phases, owing to the amphipathic property of the Janus membrane. The designed structures and catalysis performances were further characterized. The immobilized lipase exhibited a three times higher specific activity than free lipase, and the relative activity still remained above 90% after 10 cycles of reusing, indicating the observable promotion and the guaranteed stability of the Janus membrane in interfacial catalysis. This work provided a general, facile and unique example for the design and synthesis of a hierarchical multiscale hyperporous membrane for interfacial catalysis.
ABSTRACT
PURPOSE OF REVIEW: To summarize all available data on targeting angiotensinogen with RNA-based therapeutics as a new tool to combat cardiovascular diseases. RECENT FINDINGS: Liver-targeted, stable antisense oligonucleotides and small interfering RNA targeting angiotensinogen are now available, and may allow treatment with at most a few injections per year, thereby improving adherence. Promising results have been obtained in hypertensive animal models, as well as in rodent models of atherosclerosis, polycystic kidney disease and pulmonary fibrosis. The next step will be to evaluate the optimal degree of suppression, synergy with existing renin-angiotensin-aldosterone system blockers, and to determine harmful effects of suppressing angiotensinogen in the context of common comorbidities, such as heart failure and chronic kidney disease. SUMMARY: Targeting angiotensinogen with RNA-based therapeutics is a promising new tool to treat hypertension and diseases beyond. Their long-lasting effects are particularly exciting, and if translated to a clinical application of at most a few administrations per year, may help to eliminate nonadherence.
Subject(s)
Angiotensinogen/antagonists & inhibitors , Hypertension/drug therapy , Angiotensinogen/genetics , Animals , Humans , Oligonucleotides, Antisense/therapeutic use , RNA, Small Interfering/therapeutic use , Renin-Angiotensin System/drug effectsABSTRACT
Glucagon-like peptide-1 (GLP-1), an incretin hormone plays an important role in regulating glucose homeostasis. The therapeutic use of native GLP-1 is inadequate due to its short in vivo half-life. We recently developed a novel GLP-1 mimetics supaglutide, and demonstrated that this formulation retained native GLP-1 biological activities and possessed long-lasting GLP-1 actions. In this study, we further examined its abilities in regulating blood glucose in diabetic mice. We found that supaglutide stimulated insulin secretion in both mouse and human islets in a dose-dependent fashion. Oral glucose tolerance test conducted in normal ICR mice showed that supaglutide significantly decreased postprandial glucose excursions in a dose-dependent fashion. In type 2 diabetic db/db mice, a single-dose injection of supaglutide significantly decreased blood glucose levels, and this efficacy was lasted for at least 72 h in a dose-dependent fashion. During a 4-weeks intervention course supaglutide (twice injections per week) dose-dependently and significantly decreased fasting and random blood glucose levels in hyperglycemic db/db mice. Supaglutide, at a dose of 1.2 mg/kg, significantly reduced serum fructosamine levels. This was associated with significant enlargement of beta-cell mass, increased pancreatic insulin content, and increased plasma insulin level. Notably, during the intervention course supaglutide significantly reduced body-weight gain in these obese diabetic mice, associated with reduced fat mass (but not the lean mass), improved lipid profile, i.e., declined serum triglyceride, and free fatty acid levels compared to the placebo control. These finding reveals that supaglutide exerts beneficial effects in regulating blood glucose and lipid homeostasis in diabetic db/db mice.
ABSTRACT
The development of a sensitive, quick-responding, and robust glucose sensor is consistently pursued for use in numerous applications. Here, we propose a new method for preparing a Cu2O electrode for the electrochemical detection of glucose concentration. The Cu2O glucose electrode was prepared by in situ electrical oxidation in an alkaline solution, in which Cu2O nanoparticles were deposited on the electrode surface to form a thin film, followed by the growth of Cu(OH)2 nanorods or nanotubes. The morphology and electrocatalytic activity of a Cu2O glucose electrode can be tuned by the current density, reaction time, and NaOH concentration. The results from XRD, SEM, and a Raman spectrum show that the electrode surface was coated with cubic Cu2O nanoparticles with diameters ranging from 50 to 150 nm. The electrode exhibited a detection limit of 0.0275 mM, a peak sensitivity of 2524.9 µA·cm-2·mM-1, and a linear response range from 0.1 to 1 mM. The presence of high concentrations of ascorbic acid, uric acid, dopamine and lactose appeared to have no effects on the detection of glucose, indicating a high specificity and robustness of this electrode.
ABSTRACT
Both oxidative stress and inflammation contribute to the development of insulin resistance (IR). Curcumin (Cur) not only has an anti-inflammatory effect but also has an antioxidative stress effect via the activation of NF-E2-related factor 2 (Nrf2). Since there is close cross-communication between inflammation and oxidative stress, we examined whether Cur could modulate Nrf2 function via its anti-inflammatory ability and investigated its underlying mechanism. In this study, we show that Cur inhibits inflammatory signaling and Kelch-like ECH-associated protein 1 (Keap1) expression, which is accompanied by the activation of the Nrf2 system. We further identified that the proinflammatory cytokine tumor necrosis factor alpha (TNFα) could stimulate Keap1 synthesis and increase Nrf2 polyubiquitination, but these effects could be significantly inhibited by Cur treatment. This study demonstrates that Cur-induced Nrf2 activation occurs through the inhibition of inflammatory signaling-mediated upregulation of Keap1, contributing to its beneficial effects on redox homeostasis and insulin sensitivity.