Immunogenicity of COVID-19 vaccines in patients with cirrhosis: A meta-analysis.

The immunogenicity of COVID-19 vaccines in patients with liver cirrhosis remains largely unknown. The purpose of this meta-analysis was to investigate the immunogenicity of COVID-19 vaccines in patients with cirrhosis and compare the humoral and cellular immune responses following complete COVID-19 vaccination between cirrhosis patients and healthy controls. A systematic literature search was conducted in PubMed, EMBASE, and Web of Science from 1 January 2020 to 22 August 2023. Sixteen studies with 2127 cirrhosis patients were included. The pooled seroconversion rate in patients with cirrhosis following complete COVID-19 vaccination was 92.4% (95% CI, 86.2%-96%, I2 = 90%) with significant between-study heterogeneity. Moreover, COVID-19 vaccination elicited a higher humoral immune response in patients of compensated cirrhosis as compared with decompensated cirrhosis (RR = 1.069, 95% CI, 1.011-1.131, I2 = 17%, p = .019). Additionally, 10 studies were included for comparison analysis of seroconversion rate between cirrhosis patients and healthy controls. The results showed that the seroconversion rate in patients with cirrhosis was slightly lower compared with healthy controls (RR = 0.972, 95% CI, 0.955-0.989, I2 = 66%, p = .001). Meanwhile, the pooled RR of cellular immune response rate for cirrhosis patients vs. healthy controls was 0.678 (95% CI, 0.563-0.817, I2 = 0, p < .0001). Our meta-analysis demonstrated that COVID-19 vaccination elicited diminished humoral and cellular immune responses in patients of cirrhosis. Patients with cirrhosis particularly decompensated cirrhosis who have completed full-doses of COVID-19 vaccination should receive continuous attention and preemptive measures.

A network pharmacology approach to reveal the key ingredients in Scrophulariae Radix (SR) and their effects against Alzheimer's disease.

Background: Scrophulariae Radix (SR) is a commonly used medicinal plant. Alzheimer's disease (AD) is a neurodegenerative disease for which there is no effective treatment. This study aims to initially clarify the potential mechanism of SR in the treatment of AD based on network pharmacology and molecular docking techniques. Methods: The principal components and corresponding protein targets of SR were conducted by HPLC analysis and searched on TCMSP. AD targets were searched on DrugBank, Chemogenomics, TTD, OMIM and GeneCards databases. The compound-target network was constructed by Cytoscape3.8.2. The intersection of compound target and disease target was obtained and the coincidence target was imported into STRING database to construct a PPI network. We further performed GO and KEGG enrichment analysis on the targets. Meanwhile, molecular docking study and cell experiments were approved for the core target and the active compound. Results: Through multidatabase retrieval and integration, it was found that 17 components of SR could exert anti-AD effects against 40 targets. KEGG enrichment analysis indicated that Alzheimer's disease (hsa05010) was one of the most significant AD enrichment signalling pathways. Combined with the gene expression profile information in the AlzData database, 15 targets were found to be associated with tau or beta-amyloid protein (Aß). GO analysis indicated that the primary molecular functions of SR in the treatment of AD were neurotransmitter receptor activity (GO:0007268), postsynaptic neurotransmitter receptor activity (GO:0070997), and acetylcholine receptor activity (GO:0050435). Moreover, we explored the anti-AD effects of SR extract and ursolic acid (UA) using SH-SY5Y cells. Treatment of SH-SY5Y cells with 20 µM UA significantly reduced the oxidative damage to these neuronal cells. Conclusion: This study reveals the active ingredients and potential molecular mechanism of SR in the treatment of AD, and provides a theoretical basis for further basic research and clinical application.

Activation and Functional Alteration of Mucosal-Associated Invariant T Cells in Adult Patients With Community-Acquired Pneumonia.

Community-acquired pneumonia (CAP) remains the significant infectious cause of morbidity and mortality worldwide. Although mucosal-associated invariant T cells (MAIT) play roles in the pathogenesis of children CAP and ICU-associated pneumonia, their roles in adult CAP are largely unexplored. In this study, we investigated the frequency, phenotype, and function of MAIT cells in peripheral blood and bronchoalveolar lavage fluid (BALF) of adult CAP patients. Our data indicate that MAIT-cell frequency is profoundly lower in the peripheral blood of CAP patients compared to that in healthy individuals. Furthermore, the circulatory MAIT cells express higher levels of CD69 and PD-1 compared to those in healthy individuals. In BALF of CAP patients, MAIT-cell frequency is higher and MAIT cells express higher levels of CD69 and PD-1 compared to their matched blood counterparts. Levels of IL-17A and IFN-γ are increased in BALF of CAP patients compared to those in BALF of patients with pulmonary small nodules. The IL-17A/IFN-γ ratio is significantly positively correlated with MAIT frequency in BALF of CAP patients, suggesting a pathogenic role of MAIT-17 cells in CAP. Of note, blood MAIT-cell frequency in CAP patients is strongly negatively correlated with high-sensitivity C-reactive protein (hsCRP) and neutrophil count percentage in blood. The ability of circulating MAIT cells in CAP patients to produce IFN-γ is significantly impaired compared to those in healthy individuals. In summary, our findings suggest the possible involvement of MAIT cells in the immunopathogenesis of adult CAP.

Association of acute kidney injury with the severity and mortality of SARS-CoV-2 infection: A meta-analysis.

BACKGROUND: we aimed to explore the relationship of acute kidney injury (AKI) with the severity and mortality of coronavirus disease 2019 (COVID-19). METHODS: A systematic literature search was conducted in PubMed, EMBASE, Scopus, Web of Science, MedRxiv Database. We compared the laboratory indicators of renal impairment and incidences of AKI in the severe versus non-severe cases, and survival versus non-survival cases, respectively. RESULTS: In 41 studies with 10,335 COVID-19 patients, the serum creatinine (sCr) in severe cases was much higher than that in non-severe cases (SMD = 0.34, 95% CI: 0.29-0.39), with a similar trend for blood urea nitrogen (BUN) (SMD = 0.66, 95%CI: 0.51-0.81), hematuria (OR = 1.59, 95% CI: 1.15-2.19), and proteinuria (OR = 2.92, 95% CI: 1.58-5.38). The estimated glomerular filtration rate decreased significantly in severe cases compared with non-severe cases (SMD = -0.45, 95% CI: -0.67- -0.23). Moreover, the pooled OR of continuous renal replacement therapy (CRRT) and AKI prevalence for severe vs. non-severe cases was 12.99 (95%CI: 4.03-41.89) and 13.16 (95%CI: 10.16-17.05), respectively. Additionally, 11 studies with 3759 COVID-19 patients were included for analysis of disease mortality. The results showed the levels of sCr and BUN in non-survival cases remarkably elevated compared with survival patients, respectively (SMD = 0.97, SMD = 1.49). The pooled OR of CRRT and AKI prevalence for non-survival vs. survival cases was 31.51 (95%CI: 6.55-151.59) and 77.48 (95%CI: 24.52-244.85), respectively. CONCLUSIONS: AKI is closely related with severity and mortality of COVID-19, which gives awareness for doctors to pay more attention for risk screening, early identification and timely treatment of AKI.

Acute stress enhances learning and memory by activating acid-sensing ion channels in rats.

Acute stress has been shown to enhance learning and memory ability, predominantly through the action of corticosteroid stress hormones. However, the valuable targets for promoting learning and memory induced by acute stress and the underlying molecular mechanisms remain unclear. Acid-sensing ion channels (ASICs) play an important role in central neuronal systems and involves in depression, synaptic plasticity and learning and memory. In the current study, we used a combination of electrophysiological and behavioral approaches in an effort to explore the effects of acute stress on ASICs. We found that corticosterone (CORT) induced by acute stress caused a potentiation of ASICs current via glucocorticoid receptors (GRs) not mineralocorticoid receptors (MRs). Meanwhile, CORT did not produce an increase of ASICs current by pretreated with GF109203X, an antagonist of protein kinase C (PKC), whereas CORT did result in a markedly enhancement of ASICs current by bryostatin 1, an agonist of PKC, suggesting that potentiation of ASICs function may be depended on PKC activating. More importantly, an antagonist of ASICs, amiloride (10 µM) reduced the performance of learning and memory induced by acute stress, which is further suggesting that ASICs as the key components involves in cognitive processes induced by acute stress. These results indicate that acute stress causes the enhancement of ASICs function by activating PKC signaling pathway, which leads to potentiated learning and memory.

Parathyroid hormone-related peptide (1-34) reduces alveolar bone loss in type 1 diabetic rats.

OBJECTIVE: To investigate the role of parathyroid hormone related protein (PTHrP) in diabetic periodontitis. METHODS: After injected with 55mg/kg streptozotocin, diabetic rats were treated subcutaneously with low-dose (40µg/kg, once daily for 5days per week), middle-dose (80µg/kg) or high-dose (160µg/kg) PTHrP(1-34) peptide. Treatment continued for 12 weeks. Changes in periodontal tissues were confirmed by micro-computerized tomography assay and H&E analysis. We used tartrate resistant acid phosphatase (TRAP) staining to identify osteoclast cells. The expression of TNF-α, IL-1ß and IL-6 was assessed by immunohistochemistry and Western blot. RESULTS: Tooth-supporting structure loss was observed in periodontal tissues of diabetic rats. PTHrP (1-34) attenuated alveolar bone loss, especially in the middle-dose and high-dose group. Whereas TNF-α, IL-1ß and IL-6 protein levels were increased in the diabetic gingival tissues, PTHrP (1-34) treatment inhibited the increase of IL-1ß and IL-6, but had no effect on TNF-α. CONCLUSION: Type 1 diabetes increased the susceptibility to periodontal disease. Intermittent administration of PTHrP (1-34) exhibited an inhibitory effect on alveolar bone resorption and the gingival inflammation in periodontal tissues of diabetic rats.

Hyperoside protects against chronic mild stress-induced learning and memory deficits.

Hyperoside (quercetin-3-O-b-d-galactosidepyranose) is a plant-derived flavonoid mainly found in fruits, fruit juices (most notably flavanols, flavanones, and anthocyanins) and Chinese traditional medicines. It has been applied to relieve pain and improve cardiovascular functions in clinic. However, the effects of hyperoside on cognitive impairment induced by chronic stress and the underlying molecular mechanisms remain unclear. In the current study, we used chronic mild stress (CMS) rats to investigate the effects of hyperoside on learning and memory and further explore the possible mechanisms. Our results demonstrated that hyperoside reduced the escape latency and the swimming distance of CMS rats in Morris water maze test and reversed depressive symptoms in forced swim test (FST) and sucrose preference test. In addition, hyperoside increased the expression of brain-derived neurotrophic factor (BDNF) in hippocampus of CMS rats without influencing the corticosterone (CORT) level in blood plasma. Furthermore, K252a, an inhibitor of the BDNF receptor TrkB, prevented the protective effects of hyperoside on learning and memory in CMS rats. Taken together, these results indicate that hyperoside reverses the cognitive impairment induced by CMS, which is associated with the regulation of BDNF signaling pathway.

CD8(low)CD28(-) T Cells: A Human CD8 T-Suppressor Subpopulation With Alloantigen Specificity Induced by Soluble HLA-A2 Dimer In Vitro.

CD8(+) suppressor T cells have been demonstrated to provide protection of allografts from rejection. We previously reported that soluble peptide/HLA-A2 dimer shows peptide-specific inhibitory effects on alloresponse in a coculture of peptide-pulsed T2 cells with HLA-A2 negative lymphocytes in vitro. Here we found a subset of CD8(low)CD28(-) T cells that was induced in the dimer-treated coculture. Importantly, this population showed hyporesponsiveness to the alloantigen restimulation as well as alloantigen-specific suppression on alloreactive T cells in a cell-cell contact-dependent fashion. The suppressive mechanisms of CD8(low)CD28(-) T cells involved an elevated expression of membrane-bound TGF-ß1, but not Foxp3, CTLA-4, or IL-10. Furthermore, an overrepresention of CD8(low)CD28(-) T cells was observed in the patients after allogeneic platelet transfusion and positively correlated with the elevated concentrations of plasma HLA class I antigens. Our findings demonstrated that soluble HLA-A2 dimer could efficiently induce the tolerant CD8(low)CD28(-) T cells with alloantigen-specific suppression on alloreactive T cells. This study might provide a new strategy for preparation of donor-specific suppressor T cells and represent an attractive alternative for induction of allograft tolerance.

Resolvin E1 reduces hepatic fibrosis in mice with Schistosoma japonicum infection.

The aim of this study was to investigate whether resolvin E1 (RvE1) protects against hepatic fibrosis in a murine model of liver fibrosis induced by Schistosoma japonicum infection. A total of 30 pathogen-free Kunming mice were randomly and equally divided into three groups: Control (uninfected, untreated), model (infected, untreated) and RvE1 intervention (infected, RvE1-treated; 100 ng daily). The mice were infected with Schistosoma japonicum by inoculating the abdominal skin with 20±2 cercariae to induce models of liver fibrosis. The area and numbers of the granulomas in the livers were assessed through histopathology after 70 days of treatment. The levels of tumor necrosis factor (TNF)-α and interferon (IFN)-γ were evaluated in the serum by enzyme-linked immunosorbent assay (ELISA). The expression levels of TNF-α were detected in the hepatic tissue by reverse transcription-polymerase chain reaction and western blot analysis. The activity levels of alanine aminotransferase and aspartate aminotransferase were determined in the serum by ELISA. The expression levels of laminin (LN), hyaluronic acid (HA), procollagen type III (PC-III) and type IV collagen (IV-C) were detected in the serum by radioimmunoassays. The results revealed that the mean area of the granulomas was smaller in the RvE1 intervention group compared with that in the model group. Following RvE1 treatment, the serum levels of TNF-α were lower than those in the model group, while the serum levels of IFN-γ were higher compared with those in the model group. The expression levels of TNF-α were lower in the hepatic tissue following RvE1 treatment compared with those in the model group. The indicators of liver fibrosis, the levels of LN, HA, PC-III and IV-C in the serum, were lower following RvE1 treatment than those in the model group. In conclusion, RvE1 treatment may reduce the growth of granulomas, thereby slowing the process of hepatic fibrosis, and this effect may be the result of anti-inflammatory and immune system adjustment.

A similarity in peptide cross-reactivity between alloantigen- and nominal antigen-induced CD8+ T cell responses in vitro.

Raising tumor-specific allorestricted T cells in vitro for adoptive transfusion is expected to circumvent host tumor tolerance. However, it has been assumed that alloreactive T cell clones activated in vitro ranges from peptide-specific with high avidity to peptide-degenerate with low avidity. In this study, we examined the peptide specificity and cross-reactivity of T cell responses in vitro to an allogeneic epitope and a nominal epitope with a modified co-culture of lymphocytes and autologous monocytes. After binding to the monocyte via the interaction of its Fc part and the cell surface IgG Fc receptor type I (FcγRI), a fusion protein consisting of the extracellular domains of HLA-A2 molecule and the Fc region of IgG1 (the dimer) introduced a single epitope into the co-culture. The dimer-coated monocytes stimulated the proliferation of autologous CD8(+) T cells after co-culturing. The CD8(+) T cell responses were self-HLA-restricted for HLA-A2-positive (HLA-A2+ve) samples and allo-HLA-restricted for HLA-A2-negative (HLA-A2-ve) samples, since the co-cultural bulks stained with HLA-A2 tetramers, human interferon-gamma (IFN-γ) production in response to T cell receptor (TCR) ligands, and cytotoxicity against a panel of target cells exhibited peptide-specific properties. Two HLA-A2-restricted peptides with sequence homology were included, allowing the comparison of cross-reactivity between allo-antigen- and nominal antigen-induced CD8(+) T cell responses. Interestingly, the allo- and self-HLA-restricted CD8(+) T cell responses were similar in the peptide cross-reactivity, although the allorestricted T cell response seemed, overall, more intensive and had higher binding affinity to specific tetramer. Our findings indicated the alloreactive T cells raised by the co-culture in vitro were as peptide specific and cross-reactive as the self-HLA-restricted ones.

Soluble MOG35-55/I-A(b) dimers ameliorate experimental autoimmune encephalomyelitis by reducing encephalitogenic T cells.

The MOG35-55 peptide-induced experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice is a useful animal model to explore therapeutic approaches to T cell-mediated autoimmune diseases because the dominant T-cell epitope(s) have been defined. It is rational that antigen-specific immunosuppression can be induced by using MHC-peptide complexes as specific TCR ligand(s) that interact with autoreactive T cells in the absence of co-stimulation. In this study, a soluble divalent MOG35-55/I-A(b) fusion protein (MOG35-55/I-A(b) dimer) was constructed to specifically target the autoreactive CD4+ T cells in the EAE mouse. Intraperitoneal administration of the MOG35-55/I-A(b) dimer significantly delayed and ameliorated EAE symptoms by reducing EAE-related inflammation in the mouse CNS and reducing encephalitogenic Th1 and Th17 cells in the peripheral lymphoid organs. We observed that dimer intervention at a concentration of 1.2 nM suppressed MOG35-55 peptide-specific 2D2 transgenic T cells (2D2 T cells) proliferation by over 90% after in vitro activation with MOG35-55 peptide. The mechanisms involved in this antigen-specific dimer-mediated suppression were found to be downregulated TCR-CD3 expression as well as upregulated expression of membrane-bound TGF-ß (mTGF-ß) and IL-10 suppressive cytokines by the autoreactive CD4+ T cells. Collectively, our data demonstrates that soluble divalent MHC class II molecules can abrogate pathogenic T cells in EAE. Furthermore, our data suggests that this strategy may provide an efficient and clinically useful option to treat autoimmune diseases.