MG53 protein rejuvenates hUC-MSCs and facilitates their therapeutic effects in AD mice by activating Nrf2 signaling pathway.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) transplantation is a promising therapy for Alzheimer's disease (AD). However, hUC-MSCs cultured in vitro easily exhibit replicative senescence, which restricts their application. Although MG53 protein demonstrates multiple roles for a variety of cells and tissues repair, it remains unknown whether MG53 could rejuvenate senescent hUC-MSCs and enhance their efficacy in AD model. Here, we firstly presented that MG53 reinstated senescent hUC-MSCs via the activation of the Nrf2 signaling pathway by increasing cell proliferation and migration, ameliorating senescence and oxidative stress, and decreasing the release of senescence-associated secretory phenotype. In vivo studies showed that MG53 treatment improved the therapeutic effect of senescent hUC-MSCs in AD mice. Furthermore, MG53 combined with young hUC-MSCs transplantation alleviated cognitive deficit and depression-like behavior in AD mice, reduced Aß deposition and Tau phosphorylation, promoted neurogenesis, and inhibited glia cells activation and oxidative stress by activating the Nrf2 signaling. Moreover, these neuroprotective effects mediated by MG53 and hUC-MSCs were partly reversed by Brusatol, a specific inhibitor of Nrf2 signaling. Taken together, our study revealed that MG53 could rejuvenate senescent hUC-MSCs and facilitate their efficacy in AD mice at least partly through activating Nrf2 signaling pathway, which suggest that the combined therapy of MG53 and hUC-MSCs may be a novel and effective strategy for AD.

Inverted U-shaped correlation between serum low-density lipoprotein cholesterol levels and cognitive functions of patients with type 2 diabetes mellitus.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) metabolic disorder is common in individuals with diabetes. The role of LDL-C in mild cognitive impairment (MCI) remains to be explored. We aim to investigate the associations between LDL-C at different levels and details of cognition decline in patients with type 2 diabetes mellitus (T2DM). METHODS: Patients with T2DM (n = 497) were recruited. Clinical parameters and neuropsychological tests were compared between patients with MCI and controls. Goodness of fit was assessed to determine the linear or U-shaped relationship between LDL-C and cognitive function. The cut-off point of LDL-C was calculated. Correlation and regression were carried out to explore the relationship between cognitive dysfunction and LDL-C levels above and below the cut-off point. RESULTS: Although no significant difference in LDL-C levels was detected in 235 patients with MCI, compared with 262 patients without MCI, inverted-U-shaped association was determined between LDL-C and Montreal Cognitive Assessment (MoCA). The cut-off point of LDL-C is 2.686 mmol/l. LDL-C (>2.686 mmol/l) is positively related to Trail Making Test B (TMTB) indicating executive function. LDL-C (<2.686 mmol/l) is positively associated with Clock Drawing Test (CDT) reflecting visual space function in patients with T2DM. CONCLUSION: Inverted U-shaped correlation was found between serum LDL-C and cognitive function in patients with T2DM. Despite that the mechanisms of different LDL-C levels involved in special cognitive dysfunctions remain incompletely clarified, excessive LDL-C damages executive function, while the deficient LDL-C impairs visual space function. TRIAL REGISTRATION: ChiCTR-OCC-15006060 .

Decreased Plasma Level of Lipoprotein Lipase Predicted Verbal Disfluency in Chinese Type 2 Diabetes Mellitus Patients with Early Cognitive Deficits.

BACKGROUND: Lipoprotein Lipase (LPL) is the rate-limiting enzyme catalyzing the hydrolysis of triglycerides and contributes to the amyloid-ß formation, which shows promise as a pathological factor of cognitive decline in Type 2 Diabetes Mellitus (T2DM). This study aimed to investigate the pathogenetic roles of LPL and rs328 polymorphism in Mild Cognitive Impairment (MCI) in patients with T2DM. METHODS: Chinese patients with T2DM were recruited and divided into two groups based on the Montreal Cognitive Assessment score. Demographic data were collected, LPL was measured and neuropsychological test results were examined. RESULTS: Seventy-nine patients with diabetes and MCI had significantly decreased plasma LPL levels (p = 0.007) when compared with health-cognition controls (n = 91). Correlation analysis revealed that LPL was positively correlated with clock drawing test (r = 0.158, p = 0.043) and logical memory test (r = 0.162, p = 0.037), while lipoprotein a (r = -0.214, p = 0.006) was inversely associated with LPL. Logistic regression analysis further demonstrated that LPL concentration was an independent factor for diabetic MCI (p = 0.036). No significant differences were observed in the distributions of rs328 variants between patients with MCI and the controls. Moreover, no remarkable association was found among plasma LPL levels, cognitive performances, and lipid levels between the genotypic subgroups. The trail making test A was increased in the GC group when compared with the CC genotype in the control group. CONCLUSION: Decreased plasma level of LPL could probably predict early cognitive deficits, especially verbal disfluency.

Single-Cell Transcriptomic Profiling of MAIT Cells in Patients With COVID-19.

Background: Mucosal-associated invariant T (MAIT) cells are considered to participate of the host immune response against acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, single-cell transcriptomic profiling of MAIT cells in patients with COVID-19 remains unexplored. Methods: We performed single-cell RNA sequencing analyses on peripheral MAIT cells from 13 patients with COVID-19 and 5 healthy donors. The transcriptional profiles of MAIT cells, together with assembled T-cell receptor sequences, were analyzed. Flow cytometry analysis was also performed to investigate the properties of MAIT cells. Results: We identified that differentially expressed genes (DEGs) of MAIT cells were involved in myeloid leukocyte activation and lymphocyte activation in patients with COVID-19. In addition, in MAIT cells from severe cases, more DEGs were enriched in adaptive cellular and humoral immune responses compared with those in moderate cases. Further analysis indicated that the increase of cell cytotoxicity (killing), chemotaxis, and apoptosis levels in MAIT cells were consistent with disease severity and displayed the highest levels in patients with severe disease. Interestingly, flow cytometry analysis showed that the frequencies of pyroptotic MAIT cells, but not the frequencies of apoptotic MAIT cells, were increased significantly in patients with COVID-19, suggesting pyroptosis is one of leading causes of MAIT cell deaths during SARS-CoV-2 infection. Importantly, there were more clonal expansions of MAIT cells in severe cases than in moderate cases. Conclusions: The results of the present study suggest that MAIT cells are likely to be involved in the host immune response against SARS-CoV-2 infection. Simultaneously, the transcriptomic data from MAIT cells provides a deeper understanding of the immune pathogenesis of the disease.

Glucagon-like peptide-1 attenuated carboxymethyl lysine induced neuronal apoptosis via peroxisome proliferation activated receptor-γ.

BACKGROUNDS AND AIMS: The role of peroxisome proliferator activated receptor-γ (PPAR-γ) in neuronal apoptosis remains unclear. We aim to investigate the role of PPAR-γ in glucagon-like peptide-1 (GLP-1) alleviated neuronal apoptosis induced by carboxymethyl-lysine (CML). MATERIALS AND METHODS: In vitro, PC12 cells were treated by CML/GLP-1. Moreover. the function of PPAR-γ was blocked by GW9662. In vivo, streptozotocin (STZ) was used to induce diabetic rats with neuronal apoptosis. The cognitive function of rats was observed by Morris water maze. Apoptosis was detected by TUNEL assay. Bcl2, Bax, PPAR-γ and receptor of GLP-1 (GLP-1R) were measured by western blotting or immunofluorescence. RESULTS: In vitro experiment, CML triggered apoptosis, down-regulated GLP-1R and PPAR-γ. Moreover, GLP-1 not only alleviated the apoptosis, but also increased levels of PPAR-γ. GW9662 abolished the neuroprotective effect of GLP-1 on PC12 cells from apoptosis. Furthermore, GLP-1R promoter sequences were detected in the PPAR-γ antibody pulled mixture. GPL-1 levels decreased, while CML levels increased in diabetic rats, compared with control rats. Additionally, we observed elevated bax, decreased bcl2, GLP-1R and PPAR-γ in diabetic rats. CONCLUSIONS: GLP-1 could attenuate neuronal apoptosis induced by CML. Additionally, PPAR-γ involves in this process.

PDGF-BB/SA/Dex injectable hydrogels accelerate BMSC-mediated functional full thickness skin wound repair by promoting angiogenesis.

Wound healing is a well-orchestrated dynamic and interactive process, which needs a favorable microenvironment and suitable angiogenesis. Platelet derived growth factor-BB (PDGF-BB) plays a crucial role in wound healing. However, the short half-life of PDGF-BB limits its efficacy. In the present study, we successfully synthesized an injectable hydrogel with sodium alginate (SA) and dextran (Dex) as a delivery system to simultaneously deliver PDGF-BB and bone marrow-derived mesenchymal stem cells (BMSCs) in the wound. Our work demonstrates that the PDGF-BB protein enhanced the survival, migration and endothelial cell (EC) differentiation of BMSCs in vitro. The PDGF-BB/SA/Dex hydrogels could sustainably release PDGF-BB with excellent biocompatibility in vitro and in vivo. Besides, these composite hydrogels loaded with BMSCs could accelerate wound healing by improving epithelialization and collagen deposition. In addition, the PDGF-BB/SA/Dex hydrogels promoted the EC-differentiation of transplanted BMSCs and proliferation of hair follicle stem cells in the wound. Furthermore, the expressions of angiogenesis-specific markers, PDGFR-ß, p-PI3K, p-Akt, and p-eNOS, were obviously increased in the PDGF-BB/SA/Dex/BMSCs group. In conclusion, the PDGF-BB/SA/Dex injectable hydrogels could accelerate BMSC-mediated skin wound healing by promoting angiogenesis via the activation of the PDGF-BB/PDGFR-ß-mediated PI3K/Akt/eNOS pathway, which may provide a new therapeutic strategy for stem cell therapy in wound healing.

Elevated Plasma Free Fatty Acid Susceptible to Early Cognitive Impairment in Type 2 Diabetes Mellitus.

BACKGROUND: Elevated free fatty acid (FFA) induces lipotoxicity, attributed to diabetes and cognitive decline. Sterol regulatory element-binding protein-1c (SREBP-1c) regulates lipid metabolism. OBJECTIVE: We investigated the roles of FFA in mild cognitive impairment (MCI) of type 2 diabetes mellitus (T2DM) patients and determine its association with rs11868035 polymorphism. METHODS: We recruited 191 Chinese T2DM patients into two groups through Montreal Cognitive Assessment. Demographic and clinical data were collected, multiple domain cognitive functions were tested, plasma FFA levels were measured through ELISA, and SREBP-1c rs11868035 genotype was detected using the Seqnome method. RESULTS: In comparison with the healthy-cognition group (n = 128), the MCI group (n = 63) displayed lower glucose control (p = 0.012) and higher plasma FFA level (p = 0.021), which were independent risk factors of MCI in T2DM patients in multivariate regression analysis (OR = 1.270, p = 0.003; OR = 1.005, p = 0.036). Additionally, the plasma FFA levels of MCI patients were positively correlated with Stroop color word test-C time scores (r = 0.303, p = 0.021) and negatively related to apolipoprotein A1 levels (r = -0.311, p = 0.017), which are associated positively with verbal fluency test scores (r = 0.281, p = 0.033). Both scores reflected attention ability and executive function. Moreover, the G allele carriers of rs11868035 showed higher digit span test scores than non-carriers in T2DM patients (p = 0.019) but without correlation with plasma FFA levels. CONCLUSION: In T2DM, elevated plasma level of FFA, when combined with lower apolipoprotein A1 level portends abnormal cholesterol transport, were susceptible to early cognitive impairment, especially for attention and execution deficits. The G allele of SREBP-1c rs11868035 may be a protective factor for memory.

Optimal duration of dual antiplatelet therapy followed by monotherapy in diabetic patients after percutaneous coronary intervention with drug­eluting stent implantation: a Bayesian network meta-analysis.

INTRODUCTION: The standard 12-month dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation that is recommended for the general population may not be suitable for patients with diabetes. OBJECTIVES: The study aimed to evaluate the efficacy and safety of short-term (≤3 months), medium-term (6 months), standard-term (12 months), and extended-term (>12 months) DAPT in diabetic patients with DES implantation and to compare the outcomes of DAPT discontinuation followed by monotherapy with aspirin versus a P2Y12 receptor inhibitor. PATIENTS AND METHODS: Randomized controlled trials published up to October 10, 2020 were searched in the PubMed, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov databases. A Bayesian network meta-analysis with a random-effects model was performed. A total of 18 randomized trials involving 20 536 patients with diabetes were included. RESULTS: The network analysis showed that short-term DAPT was the most optimal in terms of reducing the primary endpoint and was superior to extended-term DAPT (odds ratio [OR], 0.48; 95% CI, 0.25­0.85). Standard-term DAPT was also associated with a reduced primary endpoint in comparison with extended-term DAPT (OR, 0.56; 95% CI, 0.32­0.90). There was no noticeable difference with respect to the primary endpoint between short-term DAPT followed by monotherapy with aspirin and a P2Y12 inhibitor. No significant differences were observed in secondary endpoints, including all-cause mortality, cardiac mortality, myocardial infarction, stroke, target vessel revascularization, definite or probable stent thrombosis, and major bleeding event. CONCLUSIONS: Short-term DAPT, as compared with extended-term therapy, was associated with a reduced primary endpoint in patients with diabetes after PCI with DES implantation.

Increased Plasma Level of 24S-Hydroxycholesterol and Polymorphism of CYP46A1 SNP (rs754203) Are Associated With Mild Cognitive Impairment in Patients With Type 2 Diabetes.

BACKGROUND: Abnormal cholesterol metabolism is common in type 2 diabetes mellitus (T2DM) and causes dementia. Cholesterol 24S-hydroxylase (CYP46A1) converts cholesterol into 24S-hydroxycholesterol (24-OHC) and maintains cholesterol homeostasis in the brain. OBJECTIVE: This study aimed to investigate the roles of 24-OHC and the CYP46A1 (rs754203) polymorphism in patients with T2DM and mild cognitive impairment (MCI). METHODS: A total of 193 Chinese patients with T2DM were recruited into two groups according to the Montreal Cognitive Assessment (MoCA). Demographic and clinical data were collected, and neuropsychological tests were conducted. Enzyme-linked immunosorbent assay (ELISA) and Seqnome method were used to detect the concentration of plasma 24-OHC and the CYP46A1 rs754203 genotype, respectively. RESULTS: Compared with 118 healthy cognition participants, patients with MCI (n = 75) displayed a higher plasma level of 24-OHC and total cholesterol concentration (all p = 0.031), while no correlation was found between them. In the overall diabetes population, the plasma level of 24-OHC was negatively correlated with MoCA (r = -0.150, p = 0.039), and it was further proved to be an independent risk factor of diabetic MCI (OR = 1.848, p = 0.001). Additionally, patients with MCI and the CC genotype of CYP46A1 rs754203 showed the highest plasma level of 24-OHC even though the difference was not statistically significant, and they obtained low scores in both the verbal fluency test and Stroop color and word test A (p = 0.008 and p = 0.029, respectively). CONCLUSION: In patients with T2DM, high plasma level of 24-OHC and the CC genotype carrier of CYP46A1 rs754203 may portend a high risk of developing early cognitive impairment, including attention and executive deficits.

Pan-cancer analysis identifies ESM1 as a novel oncogene for esophageal cancer.

BACKGROUND: Recent studies highlight the crucial role of endothelial cell-specific molecule 1 (ESM1) in the development of multiple cancer types. However, its aberrant expression and prognostic value in human pan-cancer have largely not been described. METHODS AND RESULTS: In this study, we used The Cancer Genome Atlas (TCGA) analysis databases to explore the expression level and prognostic significance of ESM1 in 33 types of human cancer. ESM1 was shown to be over-expressed in 12 cancer types, including BLCA, BRCA, COAD, CHOL, ESCA, HNSC, KIRC, KICH, LIHC, STAD, THCA, and UCEC. The expression of ESM1 was significantly correlated with the overall survival (OS) of patients in CESC, ESCA, KIRC, and KIRP. In addition, high ESM1 level indicated poor disease-free survival (DFS) of patients with ACC, ESCA, PRAD, LIHC, KIRP, and UCS. Through comparative analysis, we discovered that ESM1 was dramatically up-regulated in esophageal cancer (ESCA) and associated with worse patient OS and DFS. The elevation of ESM1 in ESCA was confirmed by the datasets from Cancer RNA-Seq Nexus (CRN) and Gene Expression Omnibus (GEO). Based on Gene Set Enrichment Analysis (GSEA), we analyzed the co-expressed genes of ESM1 in ESCA, and found that ESM1 was closely implicated in cell proliferation and migration and the regulation of Janus kinase (JAK) signaling pathway. Functionally, knockdown of ESM1 significantly suppressed cell proliferation and migration, and decreased the protein level of JAK1. CONCLUSIONS: Taken together, our results suggest for the first time that ESM1 functions as an oncogene and may be a clinical biomarker and/or therapeutic target in ESCA.

Sodium alginate/collagen hydrogel loaded with human umbilical cord mesenchymal stem cells promotes wound healing and skin remodeling.

Stem cell transplantation is a promising therapy for wound healing, but the low retention and survival of transplanted stem cells limit their application. Injectable hydrogels exert beneficial effects in skin tissue engineering. In this study, an injectable hydrogel composed of sodium alginate (SA) and collagen type I (Col) was synthesized as a tissue scaffold to improve the efficacy of stem cells in a full-thickness excision wound model. Our results showed that SA/Col hydrogel was injectable, biodegradable, and exhibited low immunogenicity, which could promote the retention and survival of hUC-MSCs in vivo. SA/Col loaded with hUC-MSCs showed reduced wound size (p < 0.05). Histological and immunofluorescence results confirmed that SA/Col loaded with hUC-MSCs significantly promoted the formation of granulation, enhanced collagen deposition and angiogenesis, increased VEGF and TGF-ß1 expression (p < 0.05), and mitigated inflammation evidenced by lower production of TNF-α and IL-1ß and higher release of IL-4 and IL-10 (p < 0.05). Furthermore, SA/Col loaded with hUC-MSCs significantly lowered the expression of NLRP3 inflammasome-related proteins (p < 0.05). Taken together, our results suggest that SA/Col loaded with hUC-MSCs promotes skin wound healing via partly inhibiting NLRP3 pathway, which has potential to the treatment of skin wounds.

Hepatitis C: milestones from discovery to clinical cure.

On October 5th, 2020, Drs. Harvey J. Alter, Michael Houghton and Charles M. Rice were rewarded with Nobel Prize in Physiology or Medicine for "the discovery of hepatitis C virus (HCV)". During the past 50 years, remarkable achievements have been made in treatment of HCV infection: it has changed from being a life-threatening chronic disease to being curable. In this commentary, we briefly summarized the milestone events in the "scientific journey" from the first report of non-A, non-B hepatitis and discovery of the pathogen (HCV) to final identification of efficacious direct-acting antivirals. Further, we address the challenges and unmet issues in this field.

Association of Low-Density Lipoprotein Receptor-Related Protein 1 and Its rs1799986 Polymorphism With Mild Cognitive Impairment in Chinese Patients With Type 2 Diabetes.

BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP1) is involved in cerebral glucose metabolism and amyloid-ß clearance. This study aimed to investigate the pathogenetic roles of LRP1 and its rs1799986 polymorphism in mild cognitive impairment (MCI) among patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 166 Chinese patients with T2DM were enrolled and divided into two groups according to Montreal Cognitive Assessment (MoCA) scores. Neuropsychological tests were performed. Soluble LRP1 (sLRP1) levels were assessed using enzyme-linked immunosorbent assay, and the genotype of LRP1 rs1799986 was detected using the Sequenom method. RESULTS: Diabetic patients with MCI (n = 60) exhibited significantly lower plasma sLRP1 levels (p = 0.033) and worse glucose control (p = 0.009) than the healthy cognition controls (n = 106). Multivariate regression analysis revealed plasma sLRP1 levels [odds ratio (OR) = 0.971, p = 0.005] and HbA1c (OR = 1.298, p = 0.003) as a risk factor for MCI in diabetic patients, in addition to insulin use and hypertension. However, there was no association between plasma sLRP1 levels and HbA1c. After adjusting for age, sex, and education level, plasma sLRP1 levels in the MCI group were negatively correlated with Stroop Color Word Test B number (r = -0.335, p = 0.011), which represents selective attention, cognitive flexibility, and processing speed. Additionally, patients with T2DM carrying the T allele of LRP1 rs1799986 showed higher Auditory Verbal Learning Test (AVLT) delayed recall scores (p = 0.025). CONCLUSION: Decreased plasma sLRP1 levels are associated with MCI, particularly with attention dysfunction, in patients with T2DM. Moreover, the T allele of LRP1 rs1799986 may decrease susceptibility to MCI. Further studies with large cohorts should be designed to elucidate the roles of LRP1 in hyperglycemia-induced cognitive decline.

MG53 Protects hUC-MSCs against Inflammatory Damage and Synergistically Enhances Their Efficacy in Neuroinflammation Injured Brain through Inhibiting NLRP3/Caspase-1/IL-1ß Axis.

The inflammatory microenvironment in a lesion is not conducive to the survival of stem cells. Improving the inflammatory microenvironment may be an alternative strategy to enhance the efficacy of stem cells. We evaluated the therapeutic effect and molecular mechanism of mitsugumin53 (MG53) on lipopolysaccharide (LPS)-induced damage in human umbilical cord mesenchymal stem cells (hUC-MSCs) and in C57/BL6 mice. MG53 significantly promoted the proliferation and migration of hUC-MSCs, protected hUC-MSCs against LPS-induced apoptosis and mitochondrial dysfunction, and reversed LPS-induced inflammatory cytokine release. Furthermore, MG53 combined with hUC-MSCs transplantation improved LPS-induced memory impairment and activated neurogenesis by promoting the migration of hUC-MSCs and enhancing ßIII-tubulin and doublecortin (DCX) expression. MG53 protein combined with hUC-MSCs improved the M1/M2 phenotype polarization of microglia accompanied by lower inducible nitric oxide synthase (iNOS) expression and higher arginase 1 (ARG1) expression. MG53 significantly suppressed the expression of tumor necrosis factor α (TNF-α), Toll-like receptor 4 (TLR4), nucleotide oligomerization domain-like receptor protein 3 (NLRP3), cleaved-caspase-1, and interleukin (IL)-1ß to alleviate LPS-induced neuroinflammation on hUC-MSCs and C57/BL6 mice. In conclusion, our results indicated that MG53 could protect hUC-MSCs against LPS-induced inflammatory damage and facilitate their efficacy in LPS-treated C57/BL6 mice partly by inhibiting the NLRP3/caspase-1/IL-1ß axis.

The CC Genotype of Insulin-Induced Gene 2 rs7566605 Is a Protective Factor of Hypercholesteremia Susceptible to Mild Cognitive Impairment, Especially to the Executive Function of Patients with Type 2 Diabetes Mellitus.

METHODS: 233 T2DM patients with MCI or without MCI were recruited. Baseline data and genotype frequency were compared between MCI and non-MCI groups. Demographic parameters and neuropsychological tests results were analyzed among patients with different genotypes. Further correlation and regression analysis were conducted to find the association between cognition and cholesterol. RESULTS: Despite no significant statistical difference was detected, we observed higher levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) in patients with MCI than those without MCI. In addition, we observed higher TC and LDL levels in patients with GG or GC genotypes than those with CC genotype (P < 0.001, P = 0.004, or P < 0.001, P = 0.002). Interestingly, increased MoCA and decreased TMTB scores were found in patients with CC genotype, compared to those with GG or CG genotype (P = 0.009, P = 0.024, or P = 0.005, P = 0.109). Moreover, partial correlation (P = 0.030 and P = 0.004, respectively) and multiple linear regression (P = 0.030 and P = 0.005, respectively) showed that TC and LDL levels are associated with the TMTB score, indicating the executive function. CONCLUSIONS: CC genotype of INSIG-2 rs7566605 may be a protective factor of hypercholesteremia susceptible to MCI, especially to the executive function of T2DM. This trial is registered with ChiCTROCC15006060.

Hyperactive Follicular Helper T Cells Contribute to Dysregulated Humoral Immunity in Patients With Liver Cirrhosis.

Objectives: Liver cirrhosis (LC) is usually accompanied by cirrhosis associated immune dysfunction (CAID), including reduced naïve T cells and memory B cells. However, little is known regarding on follicular helper T (Tfh) cell compartments in cirrhotic patients, especially in the secondary lymphoid organs such as spleen. This study characterizes splenic Tfh cells and explores its association with humoral immunity and disease progression in cirrhotic patients. Methods: Using flow cytometry and histological staining, we analyzed the frequency and cytokine production of splenic Tfh cells from LC patients and healthy controls (HCs). Co-culture experiments of sorted Tfh and B cells were performed for functional analysis in vitro. The correlations between Tfh cells and disease progression markers as well as B cell subset perturbations were also examined. Results: PD-1highICOS+CXCR5+ Tfh cells were preferentially enriched in the spleen of cirrhotic patients, where they expressed higher levels of CXCR3 and produced more interleukin (IL)-21. Histologically, more splenic Tfh cells occupied the B cell follicular structure in LC patients where they shaped more active germinal centers (GCs) than those in HC spleens. In vitro, splenic Tfh cells in cirrhotic patients robustly induce plasma cell differentiation through IL-21 dependent manner. Finally, increased Tfh cell frequency is positively correlated with the plasma cells and disease severity in LC patients. Conclusions: We conclude that hyperactive Tfh cells contribute to dysregulated humoral immunity in patients with liver cirrhosis.

Higher Plasma Level of Nampt Presaging Memory Dysfunction in Chinese Type 2 Diabetes Patients with Mild Cognitive Impairment.

BACKGROUND: In addition to glucose metabolism, adipocytokine Nicotinamide phosphoribosyltransferase (Nampt) has been proposed as a multifunctional protein involved in insulin resistance. Insulin resistance always occurs before the onset of type 2 diabetes mellitus (T2DM) and damages the cognition of T2DM patients very early. OBJECTIVE: We aimed to investigate the role and potential clinical value of Nampt in early cognitive decline of T2DM. METHODS: A total of 195 Chinese T2DM patients were enrolled and divided into a mild cognition impairment (MCI) group and a healthy cognition group according to Montreal Cognitive Assessment (MoCA) score. Their cognitive function was extensively assessed. The plasma level of Nampt was measured via enzyme-linked immunosorbent assay. RESULTS: In the MCI group (n = 78, MoCA < 26), the plasma level of Nampt was significantly higher than the controls (p < 0.01). After adjusting for age, sex, and level of education, Nampt levels were negatively associated with most of the cognitive domains forecasting hypomnesia (all p < 0.007). Nevertheless, hierarchical regression analysis further revealed that Nampt was an independent risk factor of MCI in Chinese T2DM patients (all p < 0.05), including Logic Memory Test (ß= -0.31, p < 0.01), Auditory Verbal Learning Test delayed recall (ß= -0.26, p < 0.01), and so on, which represent memory function. Correlation analysis showed that Nampt related to insulin resistance (HOMA-IR), glycosylated hemoglobin (HbA1c), and lipid levels (all p < 0.05). CONCLUSIONS: We found that higher plasma level of Nampt presages memory dysfunction in MCI in Chinese T2DM patients. Further studies are necessary to confirm its scanning and prognosis prediction value of the disease clinically.

The clinical features and prognosis of 100 AIDS-related lymphoma cases.

To improve outcomes and risk assessment, we systematically analyzed the clinical features of patients with acquired immunodeficiency syndrome (AIDS)-related lymphoma (ARL) and identified survival-associated factors. Data were collected from 100 patients diagnosed with ARL at the Henan Provincial Infectious Disease Hospital in China. The progression-free survival (PFS) duration and 2-year overall survival (OS) rate were determined. A multivariate analysis was used to evaluate the associations between survival and the following variables: sex, age, histological subtype, Ann Arbor stage, lactate dehydrogenase (LDH) level, primary site, baseline CD4+ count, use of chemotherapy, and age-adjusted international prognostic index IPI (aaIPI). The timing of combined antiretroviral therapy (cART) relative to chemotherapy was also assessed. The PFS duration and 2-year OS rate were significantly higher in the chemotherapy vs. the non-chemotherapy group (P < 0.001), but did not differ significantly between patients who received chemotherapy before vs. simultaneously as cART (P > 0.05). Age, aaIPI, chemotherapy, LDH level, and the Burkitt/Burkitt-like lymphoma subtype were significant prognostic factors for 2-year OS; the other factors were not associated with prognosis. Our results show that cART plus chemotherapy significantly improves the survival of patients with ARL and identifies several prognostic factors.

Polarization of granulocytic myeloid-derived suppressor cells by hepatitis C core protein is mediated via IL-10/STAT3 signalling.

Myeloid-derived suppressor cells (MDSCs) have been described as suppressors of T-cell function in many malignancies. Impaired T-cell responses have been observed in patients with chronic hepatitis C virus infection (CHC), which is reportedly associated with the establishment of persistent HCV infection. Therefore, we hypothesized that MDSCs also play a role in chronic HCV infection. MDSCs in the peripheral blood of 206 patients with CHC and 20 healthy donors were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMCs) of healthy donors cultured with hepatitis C virus core protein (HCVc) were stimulated with or without interleukin 10 (IL-10). Compared to healthy donors and certain CHC patients with sustained viral response (SVR), CHC patients without SVR presented with a dramatic elevation of G-MDSCs with the HLA-DR-/low CD33+ CD14- CD11b+ phenotype in peripheral blood. The frequency of G-MDSCs in CHC patients was positively correlated with serum HCVc, and G-MDSCs were induced from healthy PBMCs by adding exogenous HCVc. Furthermore, we revealed a potential mechanism by which HCVc mediates G-MDSC polarization; activation of ERK1/2 resulting in IL-10 production and IL-10-activated STAT3 signalling. Finally, we confirmed that HCVc-induced G-MDSCs suppress the proliferation and production of IFN-γ in autologous T-cells. We also found that the frequency of G-MDSCs in serum was associated with CHC prognosis. HCVc maintains immunosuppression by promoting IL-10/STAT3-dependent differentiation of G-MDSCs from PBMCs, resulting in the impaired functioning of T-cells. G-MDSCs may thus be a promising biomarker for predicting prognosis of CHC patients.

Current progress in host innate and adaptive immunity against hepatitis C virus infection.

Hepatitis C virus (HCV) infects more than 170 million people worldwide and is the main cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Although the newly developed direct-acting antivirals (DAAs) have transformed the treatment of HCV infection, controlling HCV infection on a global scale remains a challenge because of the high cost, low resistance barrier of DAAs and lack of HCV vaccine. The host immune responses associated with HCV infection, especially HCV-specific T cellular immunity, determine the outcome of HCV infection: either acute or chronic infection. It is important to fully interpret the immunopathogenesis of HCV infection and consequently to exploit effective strategies to eliminate HCV. Here, we review the current progress in HCV immunology, which will deepen our understanding of the spectrum of HCV infection and immunity in humans.