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INTRODUCTION: Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) has been increasingly replaced by bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in the treatment of human immunodeficiency virus (HIV) owing to its more favorable pharmacokinetics and fewer drug-drug interactions. However, the effect of this switch on plasma lipids and lipidomic profiles remains poorly characterized. METHODS: HIV infected patients on an E/C/F/TAF regimen were recruited into the study and followed up every 12 weeks. Participants were divided into E/C/F/TAF and B/F/TAF groups depending on whether they were switched to B/F/TAF during follow-up. Clinical information and blood samples were collected at 0, 12, and 24 weeks, and lipidomic analysis was performed using liquid chromatography mass spectrometry. RESULTS: No significant differences were observed between the groups at baseline. At week 24, patients switched to B/F/TAF had lower triglyceride [mmol/L; 1.23 (0.62) versus 2.03 (0.75), P = 0.001] and very low-density lipoprotein cholesterol [mmol/L; 0.64 (0.26) versus 0.84 (0.32), P = 0.037) compared with patients who continued E/C/F/TAF therapy. Small decrease from baseline in Framingham general cardiovascular risk score (FRS) was observed in the B/F/TAF arm [week (W) 0: 2.59 (1.57) versus W24: 2.18 (1.01), P = 0.043]. Lipidomic analysis indicated that E/C/F/TAF treatment increased the levels of several diglycerides (DGs), triacylglycerols (TAGs), and lyso-phosphatidylcholines (LPCs), whereas switching to B/F/TAF led to increased sphingolipids and glycerophospholipids. After adjusting for demographic and clinical parameters, only DG (16:0/18:2), DG (18:2/22:6), DG (18:3/18:2), DG (20:5/18:2), TAG (18:3/18:2/21:5), TAG (20:5/18:2/22:6), and LPC (22:6) were found to be significantly associated with FRS (regression coefficient of 0.17-6.02, P < 0.05). Most of these FRS associate lipid species were significantly elevated in individuals treated with E/C/F/TAF instead of individuals treated with B/F/TAF. CONCLUSION: E/C/F/TAF promotes the accumulation of lipid species closely associated with cardiovascular disease (CVD) risk among people living with HIV, whereas B/F/TAF has a decreased impact on CVD-related lipid profile and is associated with lower CVD risk. A graphical abstract is available with this article. TRIAL REGISTRATION: ClinicalTrials.gov; identifier, NCT06019273.
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INTRODUCTION: Despite the high morbidity and mortality, the effective therapies for heart failure with preserved fraction (HFpEF) are limited as the poor understand of its pathophysiological basis. OBJECTIVE: This study was aimed to characterize the cellular heterogeneity and potential mechanisms of HFpEF at single-cell resolution. METHODS: An HFpEF mouse model was induced by a high-fat diet with N-nitro-L-arginine methyl ester. Cells from the hearts were subjected to single-cell sequencing. The key protein expression was measured with Immunohistochemistry and immunofluorescence staining. RESULTS: In HFpEF hearts, myocardial fibroblasts exhibited higher levels of fibrosis. Furthermore, an increased number of fibroblasts differentiated into high-metabolism and high-fibrosis phenotypes. The expression levels of genes encoding certain pro-angiogenic secreted proteins were decreased in the HFpEF group, as confirmed by bulk RNA sequencing. Additionally, the proportion of the endothelial cell (EC) lineages in the HFpEF group was significantly downregulated, with low angiogenesis and high apoptosis phenotypes observed in these EC lineages. Interestingly, the fibroblasts in the HFpEF heart might cross-link with the EC lineages via over-secretion of ANGPTL4, thus displaying an anti-angiogenic function. Immunohistochemistry and immunofluorescence staining then revealed the downregulation of vascular density and upregulation of ANGPTL4 expression in HFpEF hearts. Finally, we predicted ANGPTL4as a potential druggable target using DrugnomeAI. CONCLUSION: In conclusion, this study comprehensively characterized the angiogenesis impairment in HFpEF hearts at single-cell resolution and proposed that ANGPTL4 secretion by fibroblasts may be a potential mechanism underlying this angiogenic abnormality.
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Background: Mycobacterium colombiense pneumonia in HIV-infected patients is relatively unusual but is associated with a high mortality rate, as well as high rates of misdiagnosis and delayed diagnosis. Clinical metagenome next-generation sequencing (mNGS) may have potential for its accurate and timely diagnosis. Case Presentation: We retrospectively reviewed the medical records of three HIV-infected patients who presented with M. colombiense pneumonia in Zhejiang Province between January 2019 and December 2020. No specific clinical presentations or radiological manifestations were found in any of the patients. The detection of M. colombiense is 28-55 days earlier using mNGS on bronchoalveolar lavage fluid (BALF) compared to traditional culture methods. A combined treatment of rifabutin, clarithromycin, or azithromycin, and ethambutol did not provide timely relief of symptoms in these three patients. In the early stage of treatment, moxifloxacin and linezolid were used for several weeks. The average course of treatment for all three patients was close to 17 months. Conclusion: We recommend early BALF mNGS for fast and accurate diagnosis of M. colombiense pneumonia in HIV-infected patients with low CD4 counts and long duration of symptoms. Further, moxifloxacin and linezolid may be beneficial in the early stage of treatment.
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The study aimed to examine the effects of virtual reality (VR) technology-based phase I cardiac rehabilitation (CR) program in elderly coronary heart disease (CHD) patients after percutaneous coronary intervention (PCI). Thirty-six cases of elderly CHD patients who underwent PCI in the First Affiliated Hospital of Chongqing Medical University from June 2022 to April 2023 were recruited by convenience sampling method. The patients were randomly assigned by means of random digital table method to two study groups: control group (n = 18), which received conventional nursing intervention after PCI, and experimental group (n = 18), which received a combined program of conventional nursing intervention together with CR program based on VR technology. The 6 min walk test (6MWT), Simple Physical Performance Battery (SPPB), SF-36 scale, Hospital Anxiety and Depression Scale (HADS) and Impact of Events Scale-Revised (IES-R) were tested before and after rehabilitation. Moreover, the incidence of major adverse cardiovascular events (MACE) was recorded at 3 months after PCI. After VR-based CR, the 6MWT distance and SPPB scores of patients in the experimental group were higher than those in control group (P < 0.05). The HADS scores and IES-R scores of the patients in the experimental group were lower than those in control group (P < 0.01), and the difference in SF-36 scale scores was not statistically significant between two groups (P > 0.05). The incidence of MACE was not significantly different at 3 months after PCI (P > 0.05). These results suggest that VR-based phase I CR program mitigates the degree of PCI postoperative stress, anxiety, and depression in elderly CHD patients, however, enhances the resistance to fatigue and does not increase the risk of adverse cardiac events, suggesting it is a safe intervention.
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Rehabilitación Cardiaca , Enfermedad Coronaria , Intervención Coronaria Percutánea , Realidad Virtual , Anciano , Humanos , Ansiedad , Rehabilitación Cardiaca/métodos , Enfermedad Coronaria/cirugía , Intervención Coronaria Percutánea/efectos adversosRESUMEN
BACKGROUND: We have reported a positive correlation between S100 calcium-binding protein (S100) A8/S100A9 and sepsis-induced lung damage before. However, limited knowledge exists concerning the biological role of S100A8/A9 in pulmonary vascular endothelial barrier dysfunction, as well as the diagnostic value of S100A8/A9 in sepsis. METHODS: Sepsis was induced in C57BL/6J mice and S100A9-knockout (KO) mice through the cecal ligation and puncture (CLP). Pulmonary vascular leakage was determined by measuring extravasated Evans blue (EB). Reverse transcription polymerase chain reaction and the histological score were used to evaluate inflammation and lung injury, respectively. Recombinant S100A8/A9 (rhS100A8/A9) was used to identify the effects of S100A8/A9 on endothelial barrier dysfunction in human umbilical vein endothelial cells (HUVECs). Additionally, the diagnostic value of S100A8/A9 in sepsis was assessed using receiver operating characteristic. RESULTS: S100A8/A9 expression was up-regulated in the lungs of CLP-operated mice. S100A9 KO significantly reversed CLP-induced hypothermia and hypotension, resulting in an improved survival rate. S100A9 KO also decreased the inflammatory response, EB leakage, and histological scores in the lungs of CLP-operated mice. Occludin and VE-cadherin expressions were decreased in the lungs of CLP-operated mice; However, S100A9 KO attenuated this decrease. Moreover, CLP-induced signal transducer and activator of transcription 3 (STAT3) and p38/extracellular signal-regulated kinase (ERK) signalling activation and apoptosis were mitigated by S100A9 KO in lungs. In addition, rhS100A8/A9 administration significantly decreased occludin and VE-cadherin expressions, increased the phosphorylated (p)-ERK/ERK, p-p38/p38, and B-cell leukaemia/lymphoma 2 protein (Bcl-2)-associated X protein/Bcl-2 ratios in HUVECs. CONCLUSION: The present study demonstrated S100A8/A9 aggravated sepsis-induced pulmonary inflammation, vascular permeability, and lung injury. This was achieved, at least partially, by activating the P38/STAT3/ERK signalling pathways. Moreover, S100A8/A9 showed the potential as a biomarker for sepsis diagnosis.
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Lesión Pulmonar , Sepsis , Ratones , Animales , Humanos , Ocludina , Ratones Endogámicos C57BL , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Pulmón/metabolismo , Ratones Noqueados , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
Background: Sterile inflammation contributes to the pathogenesis of cardiac dysfunction caused by various conditions including pressure overload in hypertension. Mitochondrial DNA (mtDNA) released from damaged mitochondria has been implicated in cardiac inflammation. However, the upstream mechanisms governing mtDNA release and how mtDNA activates sterile inflammation in pressure-overloaded hearts remain largely unknown. Here, we investigated the role of inducible NO synthase (iNOS) on pressure overload-induced cytosolic accumulation of mtDNA and whether mtDNA activated inflammation through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Methods: To investigate whether the cGAS-STING cascade was involved in sterile inflammation and cardiac dysfunction upon pressure overload, cardiomyocyte-specific STING depletion mice and mice injected with adeno-associated virus-9 (AAV-9) to suppress the cGAS-STING cascade in the heart were subjected to transverse aortic constriction (TAC). iNOS null mice were used to determine the role of iNOS in cGAS-STING pathway activation in pressure-stressed hearts. Results: iNOS knockout abrogated mtDNA release and alleviated cardiac sterile inflammation resulting in improved cardiac function. Conversely, activating the cGAS-STING pathway blunted the protective effects of iNOS knockout. Moreover, iNOS activated the cGAS-STING pathway in isolated myocytes and this was prevented by depleting cytosolic mtDNA. In addition, disruption of the cGAS-STING pathway suppressed inflammatory cytokine transcription and modulated M1/M2 macrophage polarization, and thus mitigated cardiac remodeling and improved heart function. Finally, increased iNOS expression along with cytosolic mtDNA accumulation and cGAS-STING activation were also seen in human hypertensive hearts. Conclusion: Our findings demonstrate that mtDNA is released into the cytosol and triggers sterile inflammation through the cGAS-STING pathway leading to cardiac dysfunction after pressure overload. iNOS controls mtDNA release and subsequent cGAS activation in pressure-stressed hearts.
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ADN Mitocondrial , Cardiopatías , Óxido Nítrico Sintasa de Tipo II , Animales , Humanos , Ratones , Citosol/metabolismo , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Cardiopatías/metabolismo , Inflamación/metabolismo , Ratones Noqueados , Mitocondrias/metabolismo , Miocitos Cardíacos/metabolismo , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismoRESUMEN
BACKGROUND: S100 calcium-binding protein A9 (S100A9) is a danger-associated molecular pattern molecule that mediates the inflammatory response. Inflammation is essential in aging-related cardiovascular diseases. However, less is known regarding the role of S100A9 in vascular aging. METHODS: S100A9 null mice were used to investigate the role of S100A9 in aging-related pathologies. Artery rings were used to measure the functional characteristics of vascular with a pressurized myograph. Telomere length, Sirtuin activity, oxidative stress, and endothelial nitric oxide synthetase (eNOS) activity were used to elevate vascular senescence. Intraperitoneal glucose tolerance (IPGTT) and insulin sensitivity test (IST) were employed to investigate the effects of S100A9 on insulin resistance. Inflammation response was reflected by the concentration of inflammatory cytokines. The Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) inhibitors were used to identify the downstream molecular mechanisms of S100A9 in aging-induced senescence in endothelial cells. RESULTS: S100A9 expression in vascular increased with aging in mice and humans. Deficiency of S100A9 alleviated vascular senescence in aged mice, as evidenced by increased telomere length, Sirtuin activity, and eNOS activity. Meanwhile, S100A9 knockout improved endothelium-dependent vasodilatation and endothelial continuity in aged mice. Moreover, the increased insulin resistance, oxidative stress, and inflammation were mitigated by S100A9 deletion in aged mice. In vitro, S100A9 induced senescence in endothelial cells, and that effect was blunted by TLR4 but not RAGE inhibitors. CONCLUSION: The present study suggested that S100A9 may contribute to aging-related pathologies and endothelial dysfunction via the TLR4 pathway. Therefore, targeting S100A9/TLR4 signaling pathway may represent a crucial therapeutic strategy to prevent age-related cardiovascular diseases.
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Enfermedades Cardiovasculares , Resistencia a la Insulina , Humanos , Ratones , Animales , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Células Endoteliales/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Calgranulina B/farmacología , Inflamación/genética , Inflamación/metabolismo , Receptor para Productos Finales de Glicación Avanzada/genética , Receptor para Productos Finales de Glicación Avanzada/metabolismoRESUMEN
BACKGROUND: Patients infected with HIV are at high risk of developing Epstein-Barr Virus (EBV)-related diseases. The genotype and viral biological behavior of EBV infection in patients with human immunodeficiency virus-1 (HIV) in China remain unclear. This study analyzed the characteristics of EBV in patients infected with HIV in southeastern China. METHODS: A total of 162 HIV-infected patients and 52 patients without HIV were enrolled in this study. EBV viral load in blood was determined by fluorescence quantitative PCR. EBV typing was performed using saliva according to polymorphisms in the EBNA3C region. EBV LMP-1 carboxy terminus (C-ter) was sequenced, and compared with the epidemic strains in the world. RESULTS: Among HIV infected patients, the EBV strain variant was mainly EBV-1, while EBV-2 had a higher viral load than EBV-1 (P = 0.001) and EBV-1/2 (P = 0.002). HIV infected patients had higher active virus replication. The EBV LMP-1 variants were mainly the China1 variant. HIV-infected patients had different nucleic acid positions of 30-bp deletion (del30) and had a higher incidence of high 33-bp tandem repeats (rep33) copies than non-HIV-infected patients. There was a difference in the mutations of EBV LMP-1 C-ter del30 and ins15 between HIV infected patients and the control group (P < 0.001). CONCLUSION: In southeastern China, EBV in HIV-infected patients had higher active virus replication; EBV infection was mainly EBV-1, and EBV-2 infection has higher EBV virus load; hotspot mutations of LMP-1 C-ter were different between HIV-infected patients and non-HIV-infected patients. TRIAL REGISTRATION: This study was approved by the ethics committee of the First Affiliated Hospital of Zhejiang University School of Medicine (Approval No. 2018764), and registered in Chinese Clinical Trial Registry on 3 June 2019 (ChiCTR, ChiCTR1900023600, http://www.chictr.org.cn/usercenter.aspx ).
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Infecciones por Virus de Epstein-Barr , Infecciones por VIH , VIH-1 , Humanos , Herpesvirus Humano 4/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/epidemiología , Infecciones por Virus de Epstein-Barr/genética , Secuencia de Bases , VIH-1/genética , China/epidemiología , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , ADN Viral/genéticaRESUMEN
BACKGROUND: Patients with human immunodeficiency virus-associated cryptococcal meningitis (HIV-CM) have persistent intracranial inflammation despite negative cerebrospinal fluid (CSF) fungal cultures after optimal treatment for CM, which could be devastating for the central nervous system. However, a definitive treatment strategy for persistent intracranial inflammation despite optimal antifungal therapies is undefined. METHODS: We identified 14 HIV-CM patients with persistent intracranial inflammation and conducted a 24-week, prospective, interventional study. All participants received lenalidomide (25 mg, p.o.) on days 1 to 21 of a 28-day cycle. Follow-up lasted for 24 weeks with visits at baseline and weeks 4, 8, 12, and 24. The primary endpoint was the change in clinical manifestations, routine CSF parameters, and MRI findings after lenalidomide treatment. An exploratory analysis was made on changes in cytokine levels in CSF. Safety and efficacy analyses were undertaken in patients who received at least one dose of lenalidomide. RESULTS: Of 14 participants, 11 patients completed the 24 weeks of follow-up. Rapid clinical remission following lenalidomide therapy was observed. Clinical manifestations (fever, headache, altered mentation) were reversed fully by week-4 and remained stable during follow-up. A significant reduction in white blood cell (WBC) count in CSF was noted occurred at week-4 (P = 0.009). The median protein concentration in CSF decreased from 1.4 (0.7-3.2) g/L at baseline to 0.9 (0.6-1.4) at week-4 (P = 0.004). The median albumin concentration in CSF decreased from 79.2 (48.4-149.8) mg/L at baseline to 55.3 (38.3-89.0) mg/L at week-4 (P = 0.011). The WBC count, protein level, and albumin level in CSF remained stable and approached a normal range through week-24. There was no significant change in immunoglobulin-G, intracranial pressure (ICP), or chloride-ion concentration at each visit. Brain MRI demonstrated multiple lesions to be absorbed post-therapy. Levels of tumor necrosis factor-α granulocyte colony stimulating factor, interleukin (IL)-6, and IL-17A decreased significantly during 24-week follow-up. Two (14.3%) patients had mild skin rash, which resolved spontaneously. Lenalidomide-related serious adverse events were not observed. CONCLUSION: Lenalidomide could improve persistent intracranial inflammation in HIV-CM patients significantly and was well tolerated without serious adverse events observed. And the additional randomized controlled study is required to further validate the finding.
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Infecciones por VIH , Meningitis Criptocócica , Humanos , Meningitis Criptocócica/complicaciones , Meningitis Criptocócica/tratamiento farmacológico , Meningitis Criptocócica/líquido cefalorraquídeo , Lenalidomida/uso terapéutico , Estudios Prospectivos , VIH , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Inflamación/complicaciones , Albúminas/uso terapéuticoRESUMEN
Savolitinib, a small-molecule inhibitor of the receptor tyrosine kinase mesenchymal-epithelial transition (MET) factor, was approved for the treatment of non-small cell lung cancer (NSCLC) by the China National Medical Products Administration in June 2021. Its safety for NSCLC treatment has been confirmed in several prospective cohort studies. Herein, we report a rare case of shock, a serious adverse event, after treatment with savolitinib in an HIV-1-positive patient with advanced NSCLC. A 38-year-old man with an 8-year history of HIV-1 positivity was diagnosed with NSCLC 5 years ago; the lung cancer recurred after surgical resection. Despite chemotherapy, immunotherapy, and targeted therapy, tumor progression continued. He received savolitinib because of MET amplification. In the first 2 weeks of savolitinib use, he developed a mild rash on his trunk. In the following month, he was hospitalized for fever and circulatory shock thrice after taking savolitinib 400 mg. He had no urticaria or eosinophilia. During the three hospitalizations, he was negative for pathogens. His condition gradually improved after treatment with antibiotics, steroids, and vasopressors. Attention should be paid to the occurrence of septic shock-like presentations when using savolitinib in HIV-1 patients with NSCLC.
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INTRODUCTION: Despite the high morbidity and mortality of heart failure with preserved fraction (HFpEF), there are currently no effective therapies for this condition. Moreover, the pathophysiological basis of HFpEF remains poorly understood. OBJECTIVE: The aim of the present study was to investigate the role of inducible nitric oxide synthase (iNOS) and its underlying mechanism in a high-fat diet and Nω-nitro-L-arginine methyl ester-induced HFpEF mouse model. METHODS: The selective iNOS inhibitor L-NIL was used to examine the effects of short-term iNOS inhibition, whereas the long-term effects of iNOS deficiency were evaluated using iNOS-null mice. Cardiac and mitochondrial function, oxidative stress and Akt S-nitrosylation were then measured. RESULTS: The results demonstrated that both pharmacological inhibition and iNOS knockout mitigated mitochondrial dysfunction, oxidative stress and Akt S-nitrosylation, leading to an ameliorated HFpEF phenotype in mice. In vitro, iNOS directly induced Akt S-nitrosylation at cysteine 224 residues , leading to oxidative stress, while inhibiting insulin-mediated glucose uptake in myocytes. CONCLUSION: Altogether, the present findings suggested an important role for iNOS in the pathophysiological development of HFpEF, indicating that iNOS inhibition may represent a potential therapeutic strategy for HFpEF.
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Insuficiencia Cardíaca , Mitocondrias , Óxido Nítrico Sintasa de Tipo II , Proteínas Proto-Oncogénicas c-akt , Animales , Ratones , Insuficiencia Cardíaca/metabolismo , Mitocondrias/metabolismo , Mitocondrias/patología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Volumen Sistólico/fisiologíaRESUMEN
BACKGROUND: Diabetes exacerbates vascular injury by triggering endothelial dysfunction. Endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) both play major roles in endothelial dysfunction. However, effects of hypoglycaemia, the main complication of the insulin therapy to the glycemic control in diabetes, on eNOS activity and iNOS expression, and underlying mechanisms in diabetes remain unknown. Hence, we aimed to determine the effects of hypoglycaemia on eNOS activity and iNOS expression in different arterial beds of diabetic rats. METHODS: Sprague-Dawley rats were subjected to Streptozotocin (STZ) combined with high fat diet (HFD) to induce diabetes and then received insulin injection to attain acute and recurrent hypoglycaemia. Immunoblotting was used to analyse the phosphorylation and O-glycosylation status of eNOS and iNOS level from thoracic aorta and mesenteric artery tissue. Indicators of oxidative stress from plasm were determined, and endothelial-dependent vasodilation was detected via wire myograph system. RESULTS: Hypoglycaemia was associated with a marked increase in eNOS O-GlcNAcylation and decrease in Serine (Ser)-1177 phosphorylation from thoracic aortas and mesenteric arteries. Moreover, hypoglycaemia resulted in elevated phosphorylation of eNOS at Threonine (Thr)-495 site in mesenteric arteries. Besides, changes in these post-translational modifications were associated with increased O-GlcNAc transferase (OGT), decreased phosphorylation of Akt at Ser-473, and increased protein kinase C α subunit (PKCα). iNOS expression was induced in hypoglycaemia. Furthermore, endothelial-dependent vasodilation was impaired under insulin-induced hypoglycaemia, and further in recurrent hypoglycaemia. CONCLUSIONS: Conclusively, these findings strongly indicate that hypoglycaemia-dependent vascular dysfunction in diabetes is mediated through altered eNOS activity and iNOS expression. Therefore, this implies that therapeutic modulation of eNOS activity and iNOS expression in diabetics under intensive glucose control may prevent and treat adverse cardiovascular events.
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Diabetes Mellitus Experimental , Hipoglucemia , Insulinas , Enfermedades Vasculares , Ratas , Animales , Óxido Nítrico Sintasa de Tipo III/metabolismo , Vasodilatación , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas Sprague-Dawley , Endotelio Vascular/metabolismo , Fosforilación , Insulinas/metabolismo , Insulinas/farmacología , Insulinas/uso terapéutico , Óxido Nítrico/metabolismoRESUMEN
Vascular smooth muscle cells (VSMCs) play a central role in atherosclerosis progression, but the functional changes in VSMCs and the associated cellular crosstalk during atherosclerosis progression remain unknown. Here we show that scRNA-seq analysis of proximal adjacent (PA) and atherosclerotic core (AC) regions of human carotid artery plaques identifies functional alterations in macrophage-like VSMCs, elucidating the main state differences between PA and AC VSMCs. And, IL-1ß mediates macrophage-macrophage-like VSMC crosstalk through regulating key transcription factors involved in macrophage-like VSMCs functional alterations during atherosclerosis progression. In vitro assays reveal VSMCs trans-differentiated into a macrophage-like phenotype and then functional alterations in response to macrophage-derived stimuli. IL-1ß promots the adhesion, inflammation, and apoptosis of macrophage-like VSMCs in a STAT3 dependent manner. The current findings provide interesting insight into the macrophages-macrophage-like VSMC crosstalk, which would drive functional alterations in the latter cell type through IL-1ß/STAT3 axis during atherosclerosis progression.
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Aterosclerosis , Músculo Liso Vascular , Humanos , Miocitos del Músculo Liso , Macrófagos , Recuento de Leucocitos , Factor de Transcripción STAT3RESUMEN
Optical-microcavity-enhanced light-matter interaction offers a powerful tool to develop fast and precise sensing techniques, spurring applications in the detection of biochemical targets ranging from cells, nanoparticles, and large molecules. However, the intrinsic inertness of such pristine microresonators limits their spread in new fields such as gas detection. Here, a functionalized microlaser sensor is realized by depositing graphene in an erbium-doped over-modal microsphere. By using a 980 nm pump, multiple laser lines excited in different mode families of the microresonator are co-generated in a single device. The interference between these splitting mode lasers produce beat notes in the electrical domain (0.2-1.1 MHz) with sub-kHz accuracy, thanks to the graphene-induced intracavity backward scattering. This allows for lab-free multispecies gas identification from a mixture, and ultrasensitive gas detection down to individual molecule.
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Proton pump inhibitors (PPIs) are often prescribed in association with clopidogrel and aspirin to patients with myocardial infraction (MI), but their effects on heart is controversial. The purpose of this study was to investigate the effects and potential mechanism of omeprazole (OME) and esomeprazole (ESO) in myocardial ischemia reperfusion (I/R) injury. In the present study, mice were treated with OME, ESO or vehicle for 3 weeks and then subjected to myocardial I/R or sham surgery. At 1 day after surgery, echocardiography was performed to access cardiac injury. Hematoxylin and eosin (H&E) staining was performed to evaluate cardiomyocyte morphology. The IL1ß was evaluated by Immunohistochemistry (IHC). Elisa was used to detect cTnt content in serum. The expression of CD86, CD206, CHOP, ATF6, eIF2α and p eIF2α were determined by Western blot (WB). The result showed that ESO markedly improved the left ventricular ejection fraction (LVEF), shortening fraction (FS), suppressed inflammatory infiltration, endoplasmic reticulum stress (ERS) and decreased proinflammatory macrophages in I/R hearts, while OME had no significant effects on cardiac function, inflammation and ERS in the I/R heart. In conclusion, ESO but not OME pretreatment reduces the proportion of proinflammatory macrophages, inhibits endoplasmic reticulum stress, and alleviates I/R injury in mice, indicating that ESO maybe a more proper PPI than OME for application in I/R injury.
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Daño por Reperfusión Miocárdica , Daño por Reperfusión , Animales , Apoptosis , Estrés del Retículo Endoplásmico , Esomeprazol/farmacología , Esomeprazol/uso terapéutico , Ratones , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
Background: The HIV-1 reservoir is a major barrier to curative strategies. Inflammation is an important factor for HIV-1 reservoir persistence. Lenalidomide regulates inflammatory cytokines efficiently. We examined whether lenalidomide could inhibit HIV-1 transcription and reduce systemic inflammation in people living with HIV. Methods: Lenalidomide was administered orally for 48 weeks to patients with HIV-associated cryptococcal meningitis (HIV-CM). A HIV-1 latency model was treated with or without lenalidomide ex vivo for 5 days. The primary endpoints were change in HIV reservoir markers and inflammatory cytokines in both the cohort and cell model. Results: Thirteen participants were enrolled from May 2019 to September 2020. The median change in cell-associated (CA) HIV RNA between baseline and 48 weeks was 0.81 log10 copies/million peripheral blood mononuclear cells (PBMCs). The CA HIV RNA decreased significantly in the cohort (P = 0.021). Serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) gradually diminished with lenalidomide treatment until 48 weeks (P = 0.007, P = 0.014, respectively). C-reactive protein/IL-6/TNF-α and CA HIV RNA were significantly correlated (P = 0.0027, 0.0496, and 0.0346, respectively). Lenalidomide also significantly decreased HIV core P24 (P = 0.0038) and CA HIV RNA in CD8-depleted PBMCs (P = 0.0178) ex vivo. TNF-α and IL-6 were significantly reduced in the CD8-depleted PBMC supernatant (P = 0.004, P < 0.0001, respectively) while IL-10 levels increased significantly on lenalidomide compared to no-lenalidomide treatment (P < 0.0001). Conclusions: Lenalidomide was preliminarily confirmed to reduce the level of cell- associated HIV RNA and improve persistent inflammation in patients with HIV-Associated cryptococcal meningitis, which was a potential intervention for clinical use to inhibit viral transcription of the HIV-1 reservoir and reduced HIV-related inflammation in HIV-1 patients during ART.
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Infecciones por VIH , VIH-1 , Meningitis Criptocócica , Citocinas , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Inflamación/tratamiento farmacológico , Interleucina-6 , Lenalidomida/uso terapéutico , Leucocitos Mononucleares , Meningitis Criptocócica/tratamiento farmacológico , Proyectos Piloto , ARN Viral , Factor de Necrosis Tumoral alfaRESUMEN
Excessive oxidative stress is a major causative factor of endothelial dysfunction in hypertension. As an endogenous pro-oxidant, thioredoxin-interacting protein (TXNIP) contributes to oxidative damage in various tissues. The present study aimed to investigate the role of TXNIP in mediating endothelial dysfunction in hypertension. In vivo, an experimental model of acquired hypertension was established with two-kidney, one-clip (2K1C) surgery. The expression of TXNIP in the vascular endothelial cells of multiple vessels was significantly increased in hypertensive rats compared with sham-operated rats. Resveratrol, a TXNIP inhibitor, suppressed vascular oxidative damage and increased the expression and activity of eNOS in the aorta of hypertensive rats. Notably, impaired endothelium-dependent vasodilation was effectively improved by TXNIP inhibition in hypertensive rats. In vitro, we observed that Ang II increased the expression of TXNIP in primary human aortic endothelial cells (HAECs) and that TXNIP knockdown by RNA interference alleviated cellular oxidative stress damage and mitigated the impaired eNOS activation and intracellular nitric oxide (NO) production observed in Ang II-treated HAECs. However, inhibiting thioredoxin (TRX) with PX-12 completely blunted the protective effect of silencing TXNIP. In addition, TXNIP knockdown facilitated TRX expression and promoted TRX nuclear translocation to further activate AP1 and REF1. TRX overexpression exhibited favorable effects on eNOS/NO homeostasis in Ang II-treated HAECs. Thus, TXNIP contributes to oxidative stress and endothelial dysfunction in hypertension, and these effects are dependent on the antioxidant capacity of TRX, suggesting that targeting TXNIP may be a novel strategy for antihypertensive therapy.
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Elevated levels of plasma free fatty acids (FFAs) lead to endothelial dysfunction, a process that is involved in the pathogenesis of atherosclerosis. Endothelial-to-mesenchymal transformation (EndMT) has been reported to accelerate endothelial dysfunction during the process of atherosclerosis. However, the underlying mechanisms of EndMT remain poorly understood. The present study aimed to investigate the role of the cytosolic DNA-sensing cyclic GMP-AMP synthase-stimulator interferon gene (cGAS-STING) pathway in palmitic acid (PA)-induced EndMT. Human aortic endothelial cells (HAECs) were exposed to different concentrations of PA, and subsequently its effects on EndMT and the cGAS-STING pathway were assessed. To investigate the role of cGAS-STING pathway on PA-induced EndMT, RNA interference was used to knockdown the expression of cGAS in HAECs prior to their exposure to PA. First, it was observed that PA reduced cell viability and intracellular nitric oxide production, and increased migratory capacity of the HAECs as well as the cellular oxidative stress response, leading to EndMT. Moreover, it was observed that the cGAS-STING pathway was activated in PA-exposed primary HAECs. Activating cGAS-STING pathway via mtDNA directing lead to EndMT in HAECs. Interestingly, cGAS knockdown by RNA interference attenuated PA-induced inflammation, oxidative stress and EndMT in HAECs. Taken together, the results of the present study suggested that the cytosolic DNA-sensing cGAS-STING pathway may have important roles in PA-induced EndMT in endothelial cells.
Asunto(s)
Aterosclerosis , Ácido Palmítico , ADN Mitocondrial/metabolismo , Células Endoteliales/metabolismo , Humanos , Interferones/farmacología , Proteínas de la Membrana/metabolismo , Nucleotidiltransferasas/metabolismo , Ácido Palmítico/farmacología , Transducción de SeñalRESUMEN
BACKGROUND: The impact of ventriculoperitoneal shunt on cerebrospinal fluid (CSF) biochemical profiles in HIV-associated cryptococcal meningitis (HCM) patients remains unclear. METHODS: Twenty-nine HCM patients who underwent ventriculoperitoneal shunt (the VPS group) and 57 HCM patients who did not undergo ventriculoperitoneal shunt (the non-VPS group) were enrolled in this propensity score matching analysis. Demographic characteristics, symptoms, CSF biochemical profiles, and adverse events were compared between the two groups. The Kaplan-Meier method was used to analyze the survival rate. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for increased CSF protein levels. RESULTS: After 24 weeks of treatment, the intracranial pressure was significantly lower in the VPS group than in the non-VPS group (mmH2O; 155.0 [120.0-190.0] vs. 200.0 [142.5-290.0]; P = 0.025), and the rate of neuroimaging improvement was significantly higher in the VPS group (16/17 [94.1%] vs. 2/10 [20%]; P < 0.001). Furthermore, the 24-week cumulative survival rates were also significantly higher in the VPS group (96.6% vs. 83.5%, P = 0.025). Notably, the CSF protein levels were higher in the VPS group than in the non-VPS group at each examination time, and the CSF glucose was lower in the VPS group than in the non-VPS group even at the 12-week follow-up. In the multivariate analysis, we found that VPS placement was an independent risk factor for increased CSF protein (odds ratio [OR]: 27.8, 95% confidence interval [95% CI] 2.2-348.7; P = 0.010). CONCLUSIONS: VPS decreased the intracranial pressure, improved neuroimaging radiology and reduced the 24-week mortality in HCM patients. However, VPS significantly altered the CSF profiles, which could lead to misdiagnosis of tuberculous meningitis and some of them were diagnosed with immune reconstitution inflammatory syndrome. Physicians should be aware of these changes in the CSF profiles of patients with HCM undergoing VPS.
Asunto(s)
Infecciones por VIH , Meningitis Criptocócica , Tuberculosis Meníngea , Infecciones por VIH/complicaciones , Humanos , Meningitis Criptocócica/complicaciones , Estudios Retrospectivos , Tuberculosis Meníngea/complicaciones , Derivación VentriculoperitonealRESUMEN
Myocardial ischemia-reperfusion injury (MIRI) is a phenomenon that reperfusion leads to irreversible damage to the myocardium and increases mortality in acute myocardial infarction (AMI) patients. There is no effective drug to treat MIRI. Tubeimoside I (TBM) is a triterpenoid saponin purified from Chinese traditional medicine tubeimu. In this study, 4 mg/kg TBM was given to mice intraperitoneally at 15 min after ischemia. And TBM treatment improved postischemic cardiac function, decreased infarct size, diminished lactate dehydrogenase release, ameliorated oxidative stress, and reduced apoptotic index. Notably, ischemia-reperfusion induced a significant decrease in cardiac SIRT3 expression and activity, while TBM treatment upregulated SIRT3's expression and activity. However, the cardioprotective effects of TBM were largely abolished by a SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP). This suggests that SIRT3 plays an essential role in TBM's cardioprotective effects. In vitro, TBM also protected H9c2 cells against simulated ischemia/reperfusion (SIR) injury by attenuating oxidative stress and apoptosis, and siSIRT3 diminished its protective effects. Taken together, our results demonstrate for the first time that TBM protects against MIRI through SIRT3-dependent regulation of oxidative stress and apoptosis. TBM might be a potential drug candidate for MIRI treatment.