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1.
Clin Cosmet Investig Dermatol ; 17: 1111-1116, 2024.
Article in English | MEDLINE | ID: mdl-38770089

ABSTRACT

Pachyonychia congenita (PC) is a group of rare hereditary disorders, characterised by hypertrophic nails and palmoplantar keratoderma (PPK), particularly localised to the pressure areas of the feet. At a molecular level, it is caused by mutations in genes encoding KRT6A, KRT6B, KRT6C, KRT16, or KRT17. To identify the underlying gene mutation in a Chinese family with PC presenting with disabling palmoplantar keratoderma and subsequent associated acral melanoma. Genomic DNA was extracted from peripheral blood samples of three available individuals in the Chinese family, which included the patient and his two unaffected sisters. The index patient presented with severe palmoplantar keratoderma as well as a newly diagnosed acral malignant melanoma (MM). Whole-exome sequencing (WES) was carried out with amplification of exon 1 of KRT16 by polymerase chain reaction (PCR). PCR products were then sequenced to identify potential mutations. We identified the proline substitution mutation p.Arg127Pro (c.380G>C) in our patient's 1A domain of KRT16. The same mutation was not found in his sisters or unrelated healthy controls. The mutation (p.Arg127Pro (c.380G>C)) in KRT16 has been reported in Dutch patients with PC. However, it is the first such report of a patient with a PC of Chinese origin. In addition, the acral MM occurred under the background of genetic PPK caused by KRT16 mutation in this patient.

2.
Sci Rep ; 14(1): 8644, 2024 04 15.
Article in English | MEDLINE | ID: mdl-38622163

ABSTRACT

Gynostemma pentaphyllum (Thunb.) Makino (G. pentaphyllum) is a medicinal and edible plant with multiple functions of liver protection, anti-tumor, anti-inflammation, balancing blood sugar and blood lipids. The nutritional value of the G. pentaphyllum plant is mainly due to its rich variety of biologically active substances, such as flavonoids, terpenes and polysaccharides. In this study, we performed a comprehensive analysis combining metabolomics and root, stem and leaf transcriptomic data of G. pentaphyllum. We used transcriptomics and metabolomics data to construct a dynamic regulatory network diagram of G. pentaphyllum flavonoids and terpenoids, and screened the transcription factors involved in flavonoids and terpenoids, including basic helix-loop-helix (bHLH), myb-related, WRKY, AP2/ERF. Transcriptome analysis results showed that among the DEGs related to the synthesis of flavonoids and terpenoids, dihydroflavonol 4-reductase (DFR) and geranylgeranyl diphosphate synthases (GGPPS) were core genes. This study presents a dynamic image of gene expression in different tissues of G. pentaphyllum, elucidating the key genes and metabolites of flavonoids and terpenoids. This study is beneficial to a deeper understanding of the medicinal plants of G. pentaphyllum, and also provides a scientific basis for further regulatory mechanisms of plant natural product synthesis pathways and drug development.


Subject(s)
Flavonoids , Gynostemma , Flavonoids/metabolism , Gynostemma/genetics , Gynostemma/chemistry , Terpenes/metabolism , Plant Extracts/chemistry , Gene Expression Profiling
3.
Gene ; 893: 147944, 2024 Jan 30.
Article in English | MEDLINE | ID: mdl-38381510

ABSTRACT

Tannic acid (TA), a significant plant secondary metabolite, is contained in the daily food of Brandt's voles. Its adverse effect on gut function has been shown in earlier research, but the underlying molecular mechanisms remain uncertain. In this study, male Brandt's vole (13 weeks old) were divided into two groups and given 0 (control) or 1,200 (TA-treated) mg•kg-1 TA for 18 days. Then RNA sequencing was used to conduct a thorough transcriptome analysis on the duodenum, jejunum, and ileum of Brandt's voles. Results showed that TA significantly increased serum total cholesterol concentration (P < 0.05) and decreased the nutrient digestibility (P < 0.05) of Brandt's voles. Furthermore, there were 174 differentially expressed genes (DEGs) in the duodenum, 96 DEGs in the jejunum, and 88 DEGs in the ileum between the control and TA-treated groups. Enrichment analysis revealed that many genes associated with bile secretion, fat digestion and absorption, innate immune response, and tight junction such as ABCG2, ABCG8, PEAK1, and IFR2, etc. were altered after TA treatment, which were verified by quantitative real-time PCR. These findings suggested that TA can change the expression of intestinal genes, thereby, altering nutrition metabolism and immunological function, eventually hindering the growth of Brandt's voles. The results of this study provide a theoretical basis for explaining how TA affects the gut function of Brandt's voles at the molecular level.


Subject(s)
Arvicolinae , Gene Expression Profiling , Polyphenols , Animals , RNA-Seq , Sequence Analysis, RNA , Arvicolinae/genetics
4.
Article in English | MEDLINE | ID: mdl-38222858

ABSTRACT

Background: The traditional Matricaria chamomilla L. has been used to treat dermatitis for thousands of years. Due to emerging trends in alternative medicine, patients prefer natural remedies to relieve their symptoms. Therefore, finding safe and effective plant medicines for topical applications on the skin is an important treatment strategy for dermatologists. German chamomile (Matricaria chamomilla L.) from the Compositae family is a famous medicinal plant, often known as the "star of medicinal species."However, the function of Matricaria chamomilla essential oil on skin inflammation has not been thoroughly examined in earlier research. Methods: GC-MS analyzed the components of MCEO, and this study explored the anti-inflammation effects of MCEO on psoriasis with network pharmacological pathway prediction. Following this, we used clinical samples of psoriasis patients to confirm the secretory characteristic of relative inflammatory markers. The therapeutic effect of MCEO on skin inflammation was detected by examination of human keratinocytes HaCaT. At the same time, we prepared imiquimod-induced psoriatic-like skin inflammation in mice to investigate thoroughly the potential inhibition functions of MCEO on psoriatic skin injury and inflammation. Results: MCEO significantly reduced interleukin-22/tumor necrosis factor α/lipopolysaccharide-stimulated elevation of HaCaT cell inflammation, which was correlated with downregulating PI3K/Akt/mTOR and p38MAPK pathways activation mediated by MCEO in HaCaT cells treated with IL-22/TNF-α/LPS. Skin inflammation was evaluated based on the PASI score, HE staining, and relative inflammatory cytokine levels. The results showed that MCEO could significantly contribute to inflammatory skin disease treatment. Conclusion: MCEO inhibited inflammation in HaCaT keratinocytes induced by IL-22/TNF-α/LPS, the potential mechanisms associated with inhibiting excessive activation and crosstalk between PI3K/Akt/mTOR and p38MAPK pathways. MCEO ameliorated skin injury in IMQ-induced psoriatic-like skin inflammation of mice by downregulating the levels of inflammatory cytokines but not IL-17A. Thus, anti-inflammatory plant drugs with different targets with combined applications were a potential therapeutic strategy in psoriasis.

5.
Signal Transduct Target Ther ; 8(1): 194, 2023 05 09.
Article in English | MEDLINE | ID: mdl-37160897

ABSTRACT

Viral infection in respiratory tract usually leads to cell death, impairing respiratory function to cause severe disease. However, the diversity of clinical manifestations of SARS-CoV-2 infection increases the complexity and difficulty of viral infection prevention, and especially the high-frequency asymptomatic infection increases the risk of virus transmission. Studying how SARS-CoV-2 affects apoptotic pathway may help to understand the pathological process of its infection. Here, we uncovered SARS-CoV-2 imployed a distinct anti-apoptotic mechanism via its N protein. We found SARS-CoV-2 virus-like particles (trVLP) suppressed cell apoptosis, but the trVLP lacking N protein didn't. Further study verified that N protein repressed cell apoptosis in cultured cells, human lung organoids and mice. Mechanistically, N protein specifically interacted with anti-apoptotic protein MCL-1, and recruited a deubiquitinating enzyme USP15 to remove the K63-linked ubiquitination of MCL-1, which stabilized this protein and promoted it to hijack Bak in mitochondria. Importantly, N protein promoted the replications of IAV, DENV and ZIKV, and exacerbated death of IAV-infected mice, all of which could be blocked by a MCL-1 specific inhibitor, S63845. Altogether, we identifed a distinct anti-apoptotic function of the N protein, through which it promoted viral replication. These may explain how SARS-CoV-2 effectively replicates in asymptomatic individuals without cuasing respiratory dysfunction, and indicate a risk of enhanced coinfection with other viruses. We anticipate that abrogating the N/MCL-1-dominated apoptosis repression is conducive to the treatments of SARS-CoV-2 infection as well as coinfections with other viruses.


Subject(s)
COVID-19 , Coinfection , Zika Virus Infection , Zika Virus , Humans , Animals , Mice , Myeloid Cell Leukemia Sequence 1 Protein/genetics , SARS-CoV-2 , COVID-19/genetics , Virus Replication/genetics , Ubiquitin-Specific Proteases
6.
J Med Virol ; 95(2): e28475, 2023 02.
Article in English | MEDLINE | ID: mdl-36606607

ABSTRACT

Global coronavirus disease 2019 (COVID-19) pandemics highlight the need of developing vaccines with universal and durable protection against emerging SARS-CoV-2 variants. Here we developed an extended-release vaccine delivery system (GP-diABZI-RBD), consisting the original SARS-CoV-2 WA1 strain receptor-binding domain (RBD) as the antigen and diABZI stimulator of interferon genes (STING) agonist in conjunction with yeast ß-glucan particles (GP-diABZI) as the platform. GP-diABZI-RBD could activate STING pathway and inhibit SARS-CoV-2 replication. Compared to diABZI-RBD, intraperitoneal injection of GP-diABZI-RBD elicited robust cellular and humoral immune responses in mice. Using SARS-CoV-2 GFP/ΔN transcription and replication-competent virus-like particle system (trVLP), we demonstrated that GP-diABZI-RBD-prototype vaccine exhibited the strongest and durable humoral immune responses and antiviral protection; whereas GP-diABZI-RBD-Omicron displayed minimum neutralization responses against trVLP. By using pseudotype virus (PsVs) neutralization assay, we found that GP-diABZI-RBD-Prototype, GP-diABZI-RBD-Delta, and GP-diABZI-RBD-Gamma immunized mice sera could efficiently neutralize Delta and Gamma PsVs, but had weak protection against Omicron PsVs. In contrast, GP-diABZI-RBD-Omicron immunized mice sera displayed the strongest neutralization response to Omicron PsVs. Taken together, the results suggest that GP-diABZI can serve as a promising vaccine delivery system for enhancing durable humoral and cellular immunity against broad SARS-CoV-2 variants. Our study provides important scientific basis for developing SARS-CoV-2 VOC-specific vaccines.


Subject(s)
COVID-19 , Vaccines , Animals , Humans , Mice , SARS-CoV-2 , COVID-19 Vaccines , Immunity, Cellular , Antibodies, Neutralizing , Spike Glycoprotein, Coronavirus , Antibodies, Viral
7.
Cardiovasc Drugs Ther ; 37(3): 423-433, 2023 06.
Article in English | MEDLINE | ID: mdl-34973094

ABSTRACT

PURPOSE: To investigate the effects of the selective NLRP3 inflammasome inhibitor MCC950 on post-resuscitation myocardial function and survival in a rat model of cardiopulmonary resuscitation (CPR). METHODS: Thirty-six Sprague Dawley rats were randomized into three groups: (1) MCC950, (2) control, and (3) sham. Each group consisted of a 6 h non-survival subgroup (n = 6) and a 48 h survival subgroup (n = 6). Ventricular fibrillation (VF) was induced and untreated for 6 min. CPR was initiated and continued for 8 min. Resuscitation was attempted with a 4 J defibrillation. MCC950 (10 mg/kg) or vehicle was administered via intraperitoneal injection immediately after the return of spontaneous circulation (ROSC). Myocardial function and sublingual microcirculation were measured after ROSC in the non-survival subgroups. Plasma levels of interleukin Iß (IL-1ß) and cardiac troponin I (cTnI) were measured at baseline and 6 h in the non-survival subgroups. Heart tissue was harvested to measure the NLRP3 inflammasome constituents, including NLRP3, apoptosis-associated speck-like protein (ASC), Caspase-1, and IL-1ß. Survival duration and neurologic deficit score (NDS) were recorded and evaluated among survival groups. RESULTS: Post-resuscitation myocardial function and sublingual microcirculation were improved in MCC950 compared with control (p < 0.05). IL-1ß and cTnI were decreased in MCC950 compared to control (p < 0.01). The MCC950 treated groups showed significantly reduced ASC, caspase-1, and IL-1ß compared with the control group (p < 0.05). Survival at 48 h after ROSC was greater in MCC950 (p < 0.05) with improved NDS (p < 0.05). CONCLUSION: Administration of MCC950 following ROSC mitigates post-resuscitation myocardial dysfunction and improves survival.


Subject(s)
Cardiomyopathies , Cardiopulmonary Resuscitation , Heart Arrest , Rats , Animals , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Rats, Sprague-Dawley , Heart Arrest/therapy , Sulfonamides/pharmacology , Caspases , Disease Models, Animal
8.
Medicine (Baltimore) ; 101(43): e31252, 2022 Oct 28.
Article in English | MEDLINE | ID: mdl-36316918

ABSTRACT

To investigate the correlation of serum pentraxin 3 (PTX-3), soluble interleukin-2 receptor (SIL-2R), C-reactive protein (CRP), procalcitonin (PCT) levels, and acute physiology and chronic health evaluation II (APACHE II) scores in patients with severe acute pancreatitis (SAP). A total of 30 patients with SAP from October 2020 to October 2021 were selected as the SAP group, and 42 patients with mild acute pancreatitis (MAP) or moderate-severe acute pancreatitis (MSAP) was selected as the control group. The serum levels of PTX-3, SIL-2R, CRP, PCT, and APACHE II scores were evaluated. The serum levels of PTX-3, SIL-2R, CRP, PCT, and APACHE II scores at admission in the SAP group were significantly higher than those in the control group (all P < .05). Spearman analysis showed that serum PTX-3, SIL-2R, CRP, and PCT levels were positively correlated with APACHE II scores (all P < .05). The mortality rate within 28 days was 26.7% in the SAP group; moreover, the serum PTX-3, SIL-2R, CRP, and PCT levels and APACHE II scores at admission in the death group were significantly higher than those in the survival group (all P < .05). The receiver operating curve showed that the combined prediction value of all indicators (PTX-3 + SIL-2R + CRP + PCT + APACHE II) was superior to the single indicators, and the diagnostic sensitivity and specificity were 90.9% and 84.2%, respectively. Serum PTX-3, SIL-2R, CRP, and PCT levels and APACHE II scores have high guiding significance in early diagnosis and prognostic evaluation of SAP patients.


Subject(s)
C-Reactive Protein , Pancreatitis , Humans , APACHE , C-Reactive Protein/analysis , Calcitonin , Protein Precursors , Acute Disease , Pancreatitis/diagnosis , Calcitonin Gene-Related Peptide , Biomarkers , Prognosis , Receptors, Interleukin-2 , Procalcitonin
9.
Biomed Pharmacother ; 156: 113847, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36252353

ABSTRACT

Post-resuscitation cerebral ischemia-reperfusion injury (IRI) is a vital contributor to poor neurological prognosis. Exploring novel therapeutics that attenuate cerebral IRI is of great significance. Inflammation plays a role in the development of cerebral IRI after successful cardiopulmonary resuscitation (CPR). Monoacylglycerol lipase (MAGL) is an enzyme that is predominantly responsible for the metabolism of endocannabinoid 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) metabolites, which are associated with inflammation. Therefore, we investigated the efficacy of the MAGL inhibitor, JZL184, on cerebral IRI and further compared the effects to therapeutic hypothermia (TH). Thirty-six rats were randomized into three groups: 1) JZL184; 2) Control; 3) TH (N = 12 for each group). Animals underwent 6 min of ventricular fibrillation (VF) followed with 8 min of CPR. After return of spontaneous circulation (ROSC), rats received an intraperitoneal injection of JZL184 (16 mg/kg) or DMSO (20 mg/ml) or body cooling was initiated. Cerebral microcirculation, brain edema, blood brain barrier (BBB) permeability, serum neuron-specific enolase (NSE), S-100ß, interleukin-6 (IL-6) and interleukin-10 (IL-10) were quantified at 6 h post ROSC. Compared to control, treatment with JZL184 or TH was associated with significantly ameliorated cerebral microcirculation, mitigated brain edema, attenuated BBB permeability, decreased serum levels of NSE, S-100ß and IL-6, and increased serum IL-10 levels (p < 0.05). There was no significant difference in the above measurements between JZL184 and TH. JZL184 has comparable neuroprotective effects to therapeutic hypothermia on global cerebral IRI in a rat model of cardiac arrest (CA).


Subject(s)
Brain Edema , Cardiopulmonary Resuscitation , Heart Arrest , Hypothermia, Induced , Rats , Animals , Monoacylglycerol Lipases , Interleukin-10/metabolism , Monoglycerides , Brain Edema/drug therapy , Brain Edema/complications , Interleukin-6/metabolism , S100 Calcium Binding Protein beta Subunit , Heart Arrest/complications , Heart Arrest/drug therapy , Inflammation/complications
10.
Front Cardiovasc Med ; 9: 894004, 2022.
Article in English | MEDLINE | ID: mdl-35872886

ABSTRACT

Background: Previous studies have demonstrated that inflammation and impaired microcirculation are key factors in post-resuscitation syndromes. Here, we investigated whether methylprednisolone (MP) could improve myocardial function and microcirculation by suppressing the systemic inflammatory response following cardiopulmonary resuscitation (CPR) in a rat model of cardiac arrest (CA). Methods: Sprague-Dawley rats were randomly assigned to (1) sham, (2) control, and (3) drug groups. Ventricular fibrillation was induced and then followed by CPR. The rats were infused with either MP or vehicle at the start of CPR. Myocardial function and microcirculation were assessed at baseline and after the restoration of spontaneous circulation. Blood samples were drawn at baseline and 60-min post-resuscitation to assess serum cytokine (TNF-α, IL-1ß, and IL-6) levels. Results: Myocardial function [estimated by the ejection fraction (EF), myocardial performance index (MPI), and cardiac output (CO)] improved post-ROSC in the MP group compared with those in the control group (p < 0.05). MP decreased the levels of the aforementioned pro-inflammatory cytokines and alleviated cerebral, sublingual, and intestinal microcirculation compared with the control (p < 0.05). A negative correlation emerged between the cytokine profile and microcirculatory blood flow. Conclusion: MP treatment reduced post-resuscitation myocardial dysfunction, inhibited pro-inflammatory cytokines, and improved microcirculation in the initial recovery phase in a CA and resuscitation animal model. Therefore, MP could be a potential clinical target for CA patients in the early phase after CPR to alleviate myocardial dysfunction and improve prognosis.

11.
Eur J Pharmacol ; 926: 175037, 2022 Jul 05.
Article in English | MEDLINE | ID: mdl-35588872

ABSTRACT

The systemic inflammatory response following global myocardial ischemia/reperfusion (I/R) injury is a critical driver of poor outcomes. Both pyroptosis and necroptosis are involved in the systemic inflammatory response and contribute to regional myocardial I/R injury. This study aimed to explore the effect of necrosulfonamide (NSA) on post-resuscitation myocardial dysfunction in a rat model of cardiac arrest. Sprague-Dawley rats were randomly categorized to Sham, CPR and CPR-NSA groups. For rats in the latter two groups, ventricular fibrillation was induced without treatment for 6 min, with cardiopulmonary resuscitation (CPR) being sustained for 8 min. Rats were injected with NSA (10 mg/kg in DMSO) or vehicle at 5 min following return of spontaneous circulation. Myocardial function was measured by echocardiography, survival and neurological deficit score (NDS) were recorded at 24, 48, and 72 h after ROSC. Western blotting was used to assess pyroptosis- and necroptosis-related protein expression. ELISAs were used to measure levels of inflammatory cytokine. Rats in the CPR-NSA group were found to exhibit superior post-resuscitation myocardial function, and better NDS values in the group of CPR-NSA. Rats in the group of CPR-NSA exhibited median survival duration of 68 ± 8 h as compared to 34 ± 21 h in the CPR group. After treatment with NSA, NOD-like receptor 3 (NLRP3), GSDMD-N, phosphorylated-MLKL, and phosphorylated-RIP3 levels in cardiac tissue were reduced with corresponding reductions in inflammatory cytokine levels. Administration of NSA significantly improved myocardial dysfunction succeeding global myocardial I/R injury and enhanced survival outcomes through protective mechanisms potentially related to inhibition of pyroptosis and necroptosis pathways.


Subject(s)
Acrylamides , Cardiomyopathies , Cardiopulmonary Resuscitation , Heart Arrest , Necroptosis , Pyroptosis , Sulfonamides , Acrylamides/pharmacology , Animals , Cardiomyopathies/drug therapy , Cardiomyopathies/etiology , Cytokines , Disease Models, Animal , Heart Arrest/complications , Heart Arrest/drug therapy , Myocardial Reperfusion Injury/drug therapy , Necroptosis/drug effects , Pyroptosis/drug effects , Rats , Rats, Sprague-Dawley , Sulfonamides/pharmacology , Systemic Inflammatory Response Syndrome
12.
Mol Med Rep ; 25(4)2022 04.
Article in English | MEDLINE | ID: mdl-35211757

ABSTRACT

Advanced glycation end products (AGEs) have been widely reported to play an important role in osteoporosis (OP), particularly in diabetes­related OP. The aim of the present study was to investigate the effect of AGEs on osteoblast function and the underlying mechanisms. The level of bone mineral density (BMD), serum AGEs and fasting blood glucose (FBG) was measured in patients with OP and healthy individuals, and the correlation between AGE levels and BMD or FBG was then analyzed. For the in vitro experiments, the hFOB1.19 osteoblast cell line was cultured in medium containing AGEs and serum from healthy individuals or patients with OP, and with or without type­2 diabetes mellitus (T2DM). Cell proliferation, differentiation, mineralization, apoptosis and ferroptosis were evaluated using Cell Counting Kit­8 and alkaline phosphatase (ALP) assays, Alizarin red and TUNEL staining, iron indicator, lipid peroxidation tests and western blot analysis, respectively. In a separate set of experiments, the ferroptosis inhibitor, deferoxamine (DFO), was also added to the culture medium of cells treated with AGEs and serum from patients with OP and T2DM. The results demonstrated that patients with OP had a higher level of serum AGEs and FBG compared with that in healthy individuals. The level of serum AGEs in patients with OP was negatively correlated with BMD, but was positively correlated with FBG. In addition, AGEs and serum from patients with OP markedly inhibited hFOB1.19 cell proliferation, ALP production and mineralized nodule formation. Apoptosis and ferroptosis were significantly promoted by AGEs and serum from patients with OP. Moreover, serum from OP patients with T2DM caused stronger effect than that from OP patients with normal FBG. However, DFO reversed the effects induced by AGEs and serum from patients with OP and T2DM on hFOB1.19 cells. Collectively, AGEs could disrupt the functions of osteoblasts by inducing cell ferroptosis, thus contributing to OP.


Subject(s)
Ferroptosis , Osteoporosis , Cell Differentiation , Glycation End Products, Advanced/metabolism , Humans , Osteoblasts/metabolism , Osteoporosis/metabolism
13.
Chinese Journal of School Health ; (12): 610-613, 2022.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-924116

ABSTRACT

Objective@#To explore the epidemiological characteristics of elevated serum uric acid in college students and its association with glycolipid metabolism, providing reference for health care intervention and education of college students.@*Methods@#From September 2020 to November 2021, a retrospective study was conducted among 989 college students in Taizhou area by stratified cluster random sampling method, and a questionnaire was issued to all college students. Serum uric acid (SUA), high density lipoprotein (HDL), low density lipoprotein (LDL), fasting plasma glucose(FPG), 2 h postprandial blood glucose (2 hPG), total cholesterol (TC), triglyceride (TG) levels were detected by urease immunoassay and enzyme linked immunosorbent assay.@*Results@#Waist circumference, body mass index, systolic blood pressure and diastolic blood pressure in higher serum uric acid group were higher than those in normal group ( t =21.72,5.74,5.45,12.23, P <0.05). The SUA, FPG, TG, 2 hPG, LDL and TC in serum uric acid increased group were higher than those in normal group, while HDL was lower than those in normal group ( t =13.85, 23.97, 10.24, 7.62, 34.91, 8.27, -8.15, P <0.05). Pearson correlation analysis showed that the levels of FPG, TG, 2 hPG, LDL and TC were positively correlated with SUA levels ( r =0.63, 0.72, 0.69, 0.16, 0.81, P <0.01). HDL was negatively correlated with SUA level ( r = -0.52, P <0.01). The glucolipid metabolism indexes were included into the binary Logistic regression model analysis, and the results showed that FPG, TG, LDL and TC were positively correlated with higher serum uric acid. HDL was negatively correlated with the incidence of higher serum uric acid ( P <0.05).@*Conclusion@#Male sex, alcohol consumption, smoking, and elevated blood pressure can contribute to higher serum uric acid, which has been found to be associated with glycolipid metabolism.

14.
Biomed Pharmacother ; 143: 112093, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34474352

ABSTRACT

Cardiac arrest (CA) remains a major public health issue. Inflammatory responses with overproduction of interleukin-1ß regulated by NLRP3 inflammasome activation play a crucial role in cerebral ischemia/reperfusion injury. We investigated the effects of the selective NLRP3-inflammasome inhibitor MCC950 on post-resuscitation cerebral function and neurologic outcome in a rat model of cardiac arrest. Thirty-six male rats were randomized into the MCC950 group, the control group, or the sham group (N = 12 of each group). Each group was divided into a 6 h non-survival subgroup (N = 6) and a 24 h survival subgroup (N = 6). Ventricular fibrillation (VF) was electrically induced and untreated for 6 min, followed by 8 min of precordial compressions and mechanical ventilation. Resuscitation was attempted with a 4J defibrillation. Either MCC950 (10 mg/kg) or vehicle was injected intraperitoneally immediately after the return of spontaneous circulation (ROSC). Rats in the sham group underwent the same surgical procedures without VF and CPR. Brain edema, cerebral microcirculation, plasma interleukin Iß (IL-1ß), and neuron-specific enolase (NSE) concentration were measured at 6 h post-ROSC of non-survival subgroups, while 24 h survival rate, neurological deficits were measured at 24 h post-ROSC of survival subgroups. Post-resuscitation brain edema was significantly reduced in animals treated with MCC950 (p < 0.05). Cerebral perfused vessel density (PVD) and microcirculatory flow index (MFI) values were significantly higher in the MCC950 group compared with the control group (p < 0.05). The plasma concentrations of IL-1ß and NSE were significantly decreased in animals treated with MCC950 compared with the control group (p < 0.05). 24 h-survival rate and neurological deficits score (NDS) was also significantly improved in the MCC950 group compared with the control group (p < 0.05). NLRP3 inflammasome blockade with MCC950 at ROSC reduces the circulatory level of IL-1ß, preserves cerebral microcirculation, mitigates cerebral edema, improves the 24 h-survival rate, and neurological deficits.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Brain Edema/prevention & control , Brain/drug effects , Cardiopulmonary Resuscitation/adverse effects , Furans/pharmacology , Indenes/pharmacology , Inflammasomes/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Sulfonamides/pharmacology , Animals , Brain/metabolism , Brain/pathology , Brain/physiopathology , Brain Edema/metabolism , Brain Edema/pathology , Brain Edema/physiopathology , Cerebrovascular Circulation/drug effects , Disease Models, Animal , Inflammasomes/metabolism , Interleukin-1beta/metabolism , Male , Microcirculation/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Rats, Sprague-Dawley , Signal Transduction
16.
Nat Commun ; 12(1): 4664, 2021 08 02.
Article in English | MEDLINE | ID: mdl-34341353

ABSTRACT

Excessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are also associated with COVID-19 severity. Here, we show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice. Mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1ß and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by MCC950 (a specific inhibitor of NLRP3) and Ac-YVAD-cmk (an inhibitor of caspase-1). Therefore, this study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.


Subject(s)
COVID-19/metabolism , Coronavirus Nucleocapsid Proteins/metabolism , Inflammasomes/metabolism , Inflammation/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/metabolism , Animals , COVID-19/virology , Cells, Cultured , Cytokines/metabolism , HEK293 Cells , Humans , Inflammasomes/genetics , Lung Injury/genetics , Lung Injury/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Phosphoproteins/metabolism , Protein Binding , SARS-CoV-2/physiology , THP-1 Cells
17.
PLoS Pathog ; 17(7): e1008603, 2021 07.
Article in English | MEDLINE | ID: mdl-34310658

ABSTRACT

Dengue virus (DENV) is a mosquito-borne pathogen that causes a spectrum of diseases including life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular leakage is a common clinical crisis in DHF/DSS patients and highly associated with increased endothelial permeability. The presence of vascular leakage causes hypotension, circulatory failure, and disseminated intravascular coagulation as the disease progresses of DHF/DSS patients, which can lead to the death of patients. However, the mechanisms by which DENV infection caused the vascular leakage are not fully understood. This study reveals a distinct mechanism by which DENV induces endothelial permeability and vascular leakage in human endothelial cells and mice tissues. We initially show that DENV2 promotes the matrix metalloproteinase-9 (MMP-9) expression and secretion in DHF patients' sera, peripheral blood mononuclear cells (PBMCs), and macrophages. This study further reveals that DENV non-structural protein 1 (NS1) induces MMP-9 expression through activating the nuclear factor κB (NF-κB) signaling pathway. Additionally, NS1 facilitates the MMP-9 enzymatic activity, which alters the adhesion and tight junction and vascular leakage in human endothelial cells and mouse tissues. Moreover, NS1 recruits MMP-9 to interact with ß-catenin and Zona occludens protein-1/2 (ZO-1 and ZO-2) and to degrade the important adhesion and tight junction proteins, thereby inducing endothelial hyperpermeability and vascular leakage in human endothelial cells and mouse tissues. Thus, we reveal that DENV NS1 and MMP-9 cooperatively induce vascular leakage by impairing endothelial cell adhesion and tight junction, and suggest that MMP-9 may serve as a potential target for the treatment of hypovolemia in DSS/DHF patients.


Subject(s)
Dengue/pathology , Endothelial Cells/metabolism , Matrix Metalloproteinase 9/metabolism , Viral Nonstructural Proteins/metabolism , Animals , Capillary Permeability/physiology , Cell Adhesion/physiology , Dengue/metabolism , Dengue/virology , Dengue Virus/metabolism , Humans , Mice , Tight Junctions/metabolism
18.
Biomed Pharmacother ; 140: 111743, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34020243

ABSTRACT

Brain mitochondria are more sensitive to global ischemia compared to heart mitochondria. Complex I in the electron transport chain (ETC) is sensitive to ischemic injury and is a major control point of the rate of ADP stimulated oxygen consumption. The purpose of this study was to explore whether changes in cerebral and myocardial mitochondria differ after cardiac arrest. Animals were randomized into 4 groups (n = 6): 1) Sham 2) VF 3) VF+CPR 4) ROSC 1hr. Ventricular Fibrillation (VF) was induced through a guide wire advanced from the right jugular vein into the ventricle and untreated for 8 min. Resuscitation was attempted with a 4J defibrillation after 8 min of cardiopulmonary resuscitation (CPR). Brain mitochondria and cardiac mitochondrial subpopulations were isolated. Calcium retention capacity was measured to assess susceptibility to mitochondrial permeability transition pore opening. ADP stimulated oxygen consumption and ETC activity assays were performed. Brain mitochondria are far more sensitive to injury during cardiac arrest and resuscitation compared to cardiac mitochondria. Complex I is highly sensitive to injury in brain mitochondria. With markedly decreased calcium retention capacity, mitochondria contribute to cerebral reperfusion injury. Therapeutic preservation of cerebral mitochondrial activity and mitochondrial function during cardiac arrest may improve post-resuscitation neurologic function.


Subject(s)
Brain/metabolism , Cardiopulmonary Resuscitation , Heart Arrest/metabolism , Mitochondria/metabolism , Myocardium/metabolism , Adenosine Diphosphate/metabolism , Animals , Calcium/metabolism , Disease Models, Animal , Electron Transport Chain Complex Proteins/metabolism , Heart Arrest/therapy , Male , Mitochondrial Permeability Transition Pore/metabolism , Oxygen Consumption , Rats, Sprague-Dawley
19.
Andrologia ; 53(6): e14060, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33782980

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD), the liver component of metabolic syndrome, is considered to be associated with high risk of prostatic diseases but a systematic review has not been conducted. Under a comprehensive review of the eligible clinical studies, a potential positive association between NAFLD and benign prostatic hyperplasia/prostate cancer (BPH/PCa) has been postulated. Insulin resistance and metabolic aberrations are considered to be the potential mechanism for such association. However, the relationship between NAFLD and other prostatic diseases, that is, prostatic inflammation and lower urinary tract symptoms, seems vague due to limited relevant studies in the literatures. The present review highlights that clinicians should be conscious of the detrimental effect of NAFLD on the development of BPH and PCa.


Subject(s)
Insulin Resistance , Lower Urinary Tract Symptoms , Non-alcoholic Fatty Liver Disease , Prostatic Hyperplasia , Prostatitis , Humans , Lower Urinary Tract Symptoms/epidemiology , Lower Urinary Tract Symptoms/etiology , Male , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/epidemiology , Prostatic Hyperplasia/complications , Prostatic Hyperplasia/epidemiology
20.
Dermatol Ther (Heidelb) ; 11(1): 25-38, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33206326

ABSTRACT

INTRODUCTION: Psoriasis is a common skin disease, with chronic inflammation and a complex etiology. It has long been recognized that chronic skin conditions and mental health disorders are often co-morbid. Thus, the concept of the gut-brain-skin axis emphasized in mental health disorders may also regulate the health of skin. RESULTS: The gut microbiota has been found to be the bridge between the immune system and nervous system. By leveraging clinical cases and animal models of psoriasis, an important communication pathway has been identified along the gut-brain-skin axis that is associated with the modulation of neurotransmitters from the microbiota. Furthermore, mammalian neurotransmitters, including dopamine, serotonin, or γ-aminobutyric acid (GABA), can be produced and/or consumed by several types of bacteria. Other studies suggest that manipulating these neurotransmitters by bacteria may have an effect on host physiology, and the levels of neurotransmitter can be altered by microbiota-based interventions. CONCLUSIONS: Nonetheless, it is unknown whether or not the manipulation of neurotransmitter levels by bacteria can affect the occurrence and development of psoriasis. Notably, preliminary experiments found that oral consumption of probiotics improves the clinical symptoms in patients with psoriasis, perhaps correlated with the gut microbiome-mediated crosstalk between the immune system and the nervous system by secreting neurotransmitters in psoriasis. In this review, the communication along the gut-brain-skin axis is discussed.

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