Comprehensive mapping of saliva by multiomics in children with idiopathic nephrotic syndrome.

AIM: Saliva can reflect an individual's physiological status or susceptibility to systemic disease. However, little attention has been given to salivary analysis in children with idiopathic nephrotic syndrome (INS). We aimed to perform a comprehensive analysis of saliva from INS children. METHODS: A total of 18 children (9 children with INS and 9 normal controls) were recruited. Saliva was collected from each INS patient in the acute and remission phases. 16S rRNA gene sequencing, widely targeted metabolomics, and 4D-DIA proteomics were performed. RESULTS: Actinobacteria and Firmicutes were significantly enriched in the pretreatment group compared with the normal control group, while Bacteroidota and Proteobacteria were significantly decreased. A total of 146 metabolites were identified as significantly different between INS children before treatment and normal controls, which covers 17 of 23 categories. KEGG enrichment analysis revealed three significantly enriched pathways, including ascorbate and aldarate metabolism, pentose and glucuronate interconversions, and terpenoid backbone biosynthesis (P < 0.05). A total of 389 differentially expressed proteins were selected between INS children before treatment and normal controls. According to the KEGG and GO enrichment analyses of the KOGs, abnormal ribosome structure and function and humoral immune disorders were the most prominent differences between INS patients and normal controls in the proteomic analysis. CONCLUSION: Oral microbiota dysbiosis may modulate the metabolic profile of saliva in children with INS. It is hypothesized that children with INS might have "abnormal ribosome structure and function" and "humoral immune disorders".

Loss of MTX2 causes mitochondrial dysfunction, podocyte injury, nephrotic proteinuria and glomerulopathy in mice and patients.

Proteinuria is a common and important clinical manifestation of chronic kidney disease (CKD) and an independent risk factor for the progression of kidney disease. As a component of the glomerular filtration barrier (GFB), podocyte plays a key role in the pathogenesis of glomerular diseases and proteinuria. However, the pathophysiology of glomerular diseases associated with mitochondrial function is incompletely understood. Here, we identified three novel mutations in MTX2, encoding a membrane protein in mitochondria, associated with multisystem manifestations including nephrotic proteinuria and kidney injury in two Chinese patients. Conditional podocyte-specific Mtx2 knockout (Pod-Mtx2-KO) mice present a series of podocyte and glomerular abnormalities from 8 weeks to old age, including microalbuminuria, glomerular mesangial hyperplasia, fusion and effacement of foot process. MTX2 deficiency impaired podocyte functions in vitro, manifested by reductions of adhesion, migration and endocytosis, which were further restored by overexpression of MTX2. Moreover, MTX2 defects led to abnormal mitochondrial structure and dysfunction, evidenced with defects of complex I and III, increased production of reactive oxygen species (ROS), and decreased protein levels of Sam50-CHCHD3-Mitofilin axis in the mitochondrial intermembrane space bridging (MIB) complex which is responsible for maintaining mitochondrial cristae morphology. Collectively, these findings reveal that the normal expression of MTX2 in glomerulus plays an important role in the adhesion, migration, endocytosis, proliferation and other physiological functions of podocytes, which may be realized by maintaining the morphological structure and function of mitochondria. Abnormal expression of MTX2 can lead to mitochondrial dysfunction and structural abnormalities by Sam50-CHCHD3-Mitofilin axis in podocyte, which further induces podocyte injury, glomerular lesions and proteinuria.

A spectrum of novel anti-vascular endothelial cells autoantibodies in idiopathic nephrotic syndrome patients.

Idiopathic nephrotic syndrome (INS) is a common renal disease characterized by disruption of the glomerular filtration barrier. In a previous study, we screened and identified podocyte autoantibodies in nephrotic syndrome patients and proposed the concept of autoimmune podocytopathy. However, circulating podocyte autoantibodies cannot reach podocytes unless glomerular endothelial cells have been damaged. Therefore, we speculate that INS patients may also have autoantibodies against vascular endothelial cells. Sera from INS patients were used as primary antibodies to screen and identify endothelial autoantibodies by hybridization with vascular endothelial cell proteins separated by two-dimensional electrophoresis. The clinical application value and pathogenicity of these autoantibodies were further verified by clinical study and in vivo and in vitro experiments. Nine kinds of autoantibodies against vascular endothelial cells were screened in patients with INS, which can cause endothelial cell damage. In addition, 89% of these patients were positive for at least one autoantibody.

Strategies and safety considerations of booster vaccination in COVID-19.

The first-generation SARS-CoV-2 vaccines have played a significant role in controlling the COVID-19 pandemic, preventing severe diseases, and reducing mortality. However, the continuous emergence of SARS-CoV-2 variants, the persistence of breakthrough infections, and the seemingly rapid decline in the protective efficacy of SARS-CoV-2 vaccines have presented additional challenges for the next phase. There is an urgent need to confirm the necessity of further booster vaccination and combination vaccine approaches. This paper summarizes the latest literature on SARS-CoV-2 variants and vaccine effectiveness and concludes that it is essential to implement booster immunization strategies. Priority should be given to high-risk groups, the elderly, and immunocompromised people. In addition, heterologous vaccination has a longer duration of effect and a broader spectrum than homologous vaccination, making it more conducive to managing the immune escape of SARS-CoV-2 variants.

Performance and application evaluation of SARS-CoV-2 antigen assay.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid detection is the gold standard for the laboratory diagnosis of coronavirus disease 2019 (COVID-19). However, this method has high requirements for practitioners' skills and testing sites, so it is not easy to popularize and promote the application in places other than large hospitals. In addition, the detection flux of SARS-CoV-2 nucleic acid is small, and the whole detection process takes much time, which cannot meet the actual needs of rapid screening in large quantities. The WHO conditionally approved a batch of SARS-CoV-2 antigen reagents for clinical application to alleviate this contradiction. SARS-CoV-2 antigen detection offers a trade-off among clinical performance, speed and accessibility. With the gradual increase in clinical application, the accumulated clinical data show that the sensitivity and specificity of the SARS-CoV-2 antigen assay are over 80% and 97%, respectively, which can basically meet the requirements of the WHO. However, the sensitivity of the SARS-CoV-2 Antigen Assay among asymptomatic people in low prevalence areas of COVID-19 cannot meet the standard, leading to a large number of missed diagnoses. In addition, the detection ability of SARS-CoV-2 antigen reagent for different SARS-CoV-2 mutant strains differs greatly, especially for those escaping the COVID-19 vaccines. In terms of results interpretation, it is highly reliable to exclude SARS-CoV-2 infection based on the high negative predictive value of the SARS-CoV-2 antigen assay. However, in the low prevalence environment, the probability of false positives of the SARS-CoV-2 antigen assay is high, so the positive results need to be confirmed by the SARS-CoV-2 nucleic acid reagent. The SARS-CoV-2 antigen assay is only a supplement to SARS-CoV-2 nucleic acid detection and can never completely replace it. To date, SARS-CoV-2 nucleic acid detection continues to be the standard laboratory method for COVID-19 diagnosis.

Booster vaccination strategy: Necessity, immunization objectives, immunization strategy, and safety.

At present, the global COVID-19 epidemic has not been completely controlled, and epidemic prevention and control still face severe challenges. As there is no specific treatment for COVID-19, promoting roll-out vaccinations and building herd immunity are still the most effective and economic measures to control the COVID-19 pandemic. However, the neutralizing antibody level in the recipients decreases with time, and the vaccine's protective efficacy gradually weakens. It is still inconclusive whether it is necessary to carry out booster vaccination to strengthen the immune barrier to infection. In this paper, we combined the existing data on the effectiveness and persistence of COVID-19 vaccines. We found that it is necessary to carry out a booster vaccination strategy. However, not all subjects need to receive one more dose of vaccine 6 months after the initial immunization. Priority should be given to the high-risk groups, such as the elderly and people with immunodeficiency. A heterologous booster can induce higher immune responses and enhance immune protection than homologous vaccinations. However, more scientific data and clinical studies are needed to verify the safety of heterologous vaccination strategies.

Advances in laboratory detection methods and technology application of SARS-CoV-2.

At present, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is raging worldwide, and the coronavirus disease 2019 outbreak caused by SARS-CoV-2 seriously threatens the life and health of all humankind. There is no specific medicine for novel coronavirus yet. So, laboratory diagnoses of novel coronavirus as soon as possible and isolation of the source of infection play a vital role in preventing and controlling the epidemic. Therefore, selecting appropriate detection techniques and methods is particularly important to improve the efficiency of disease diagnosis and treatment and to curb the outbreak of infectious diseases. In this paper, virus nucleic acid, protein, and serum immunology were reviewed to provide a reference for further developing virus detection technology to provide better prevention and treatment strategies and research ideas for clinicians and researchers.

Grape seed proanthocyanidin inhibits monocrotaline-induced pulmonary arterial hypertension via attenuating inflammation: in vivo and in vitro studies.

Inflammation in pulmonary arterioles initiates and maintains pathological processes in pulmonary arterial hypertension (PAH), and inhibition of it attenuates PAH development. Grape seed proanthocyanidin (GSP) is believed to be effective in protecting vascular system via inhibiting inflammation, while its effect on pulmonary circulation remains inconclusive. In this study, we made observations in monocrotaline (MCT)-induced PAH rats and found decreases in mean pulmonary arterial pressure, pulmonary vessel resistance, right ventricular hypertrophy index, percentage of medial wall thickness, percentage of medial wall area, and lung weight of wet and dry tissue ratio after GSP administration in vivo. At the cellular and molecular levels, we also found several effects of GSP on MCT-induced PAH: (a) endothelial nitric oxide synthase expression in lung tissue and plasma NO level were increased; (b) Ca2+ level in pulmonary arterial smooth muscle cell (PASMC) was decreased; (c) transcription of inflammatory factors such as myeloperoxidase, interleukin (IL)-1ß, IL-6 and tumor necrosis factor alpha (TNF-α) was down-regulated in lung tissue; (d) nuclear factor-κB pathway was inhibited as IκBα was less phosphorylated; (e) TNFα-induced PASMC overproliferation could be inhibited. These results indicated a possible mechanism of GSP reversing pulmonary vascular remodeling and vascular contraction by inhibiting inflammation, and it may be useful for preventing PAH development.

Apple polyphenol relieves hypoxia-induced pulmonary arterial hypertension via pulmonary endothelium protection and smooth muscle relaxation: In vivo and in vitro studies.

AIM: This study aims to test the effect of apple polyphenol (APP) on hypoxia-induced pulmonary arterial hypertension (PAH) and explore its possible underlying mechanisms. METHODS AND RESULTS: Rats were treated with control, APP, hypoxia (8 h/d), hypoxia + APP. Mean pulmonary arterial pressure (mPAP) and pulmonary vessel resistance (PVR) were examined. Phenylephrine (PE)-pretreated pulmonary vessel rings were prepared for observation of APP administration. eNOS, sGC inhibitors (L-NAME, MB), Ca2+ channel blockers (NiCl2, Calhex231), K+ channel blockers (4-AP, 5-HD, TEA, BaCl2) were applied to pulmonary vessel rings and pulmonary arterial smooth muscle cell (PASMC). Flow cytometry analysis and CCK-8 assay were applied to detect apoptosis of pulmonary artery endothelium cell (PAEC). Caspase-3, NO, eNOS, iNOS were detected in PAEC. APP reversed mPAP and PVR elevation in vivo. Contraction of pulmonary vessel rings with/without endothelium induced by hypoxia were inhibited by APP. APP effect was hindered by L-NAME or MB, and could be reduced by K+channel blockers. Further, APP was found to decrease cytosolic Ca2+ in PASMC and protect PAEC from apoptosis. In PAEC, Caspase-3, iNOS were decreased and NO, eNOS were increased after APP administration. CONCLUSIONS: APP reverses pulmonary vasoconstriction through enzyme expression and cation channel activities, thus has effects of PASMC relaxation and PAEC protection.

Astragalus Polysaccharides Attenuate Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats.

Astragalus polysaccharides (APS) have been shown to possess a variety of biological activities including anti-oxidant and anti-inflammation functions in a number of diseases. However, their function in pulmonary arterial hypertension (PAH) is still unknown. Rats received APS (200[Formula: see text]mg/kg once two days) for 2 weeks after being injected with monocrotaline (MCT; 60[Formula: see text]mg/kg). The pulmonary hemodynamic index, right ventricular hypertrophy, and lung morphological features of the rat models were examined, as well as the NO/eNOS ratio of wet lung and dry lung weight and MPO. A qRT-PCR and p-I[Formula: see text]B was used to assess IL-1[Formula: see text], IL-6 and TNF-[Formula: see text] and WB was used to detect the total I[Formula: see text]B. Based on these measurements, it was found that APS reversed the MCT-induced increase in mean pulmonary arterial pressure (mPAP) (from 32.731[Formula: see text]mmHg to 26.707[Formula: see text]mmHg), decreased pulmonary vascular resistance (PVR) (from 289.021[Formula: see text]mmHg[Formula: see text][Formula: see text] min/L to 246.351[Formula: see text]mmHg[Formula: see text][Formula: see text][Formula: see text]min/L), and reduced right ventricular hypertrophy (from 289.021[Formula: see text]mmHg[Formula: see text][Formula: see text][Formula: see text]min/L to 246.351 mmHg[Formula: see text][Formula: see text][Formula: see text]min/L) ([Formula: see text]0.05). In terms of pulmonary artery remodeling, the WT% and WA% decreased with the addition of APS. In addition, it was found that APS promoted the synthesis of eNOS and the secretion of NO, promoting vasodilation and APS decreased the MCT-induced elevation of MPO, IL-1[Formula: see text], IL-6 and TNF-[Formula: see text], reducing inflammation. Furthermore, APS was able to inhibit the activation of pho-I[Formula: see text]B[Formula: see text]. In couclusion, APS ameliorates MCT-induced pulmonary artery hypertension by inhibiting pulmonary arterial remodeling partially via eNOS/NO and NF-[Formula: see text]B signaling pathways.