Associations of Gut and Circulating Microbiota with Circulating Vitamin D3, Type I Interferon, and Systemic Inflammation in Chronic Spontaneous Urticaria Patients.

Objective: To analyze the associations of the gut and circulating microbiota with circulating vitamin D3 (VD3), type I interferon (IFNI), systemic inflammation, and clinical profiles in chronic spontaneous urticaria (CSU) patients. Methods: A total of 36 CSU patients with VD3 insufficiency (VDI; serum 25(OH)VD3 <30 ng/mL) and 36 sex-, age-, and body mass index-matched CSU patients with non-VDI were enrolled. Fecal and serum bacteria were identified through 16S rRNA sequencing, and serum 25(OH)VD3 and inflammation biomarkers were assessed using ELISA kits. IFNI response was determined by measuring the stimulatory activity of serum on IFNI-stimulated response element in HEK293 cells in vitro with luciferase assays. Results: Higher urticarial activity score over 7 days (UAS7), higher frequency of levocetirizine resistance, and more severe proinflammation but weaker IFNI response were observed in VDI than non-VDI patients (all P<0.05). IFNI response was strongly positively associated with serum 25(OH)VD3 level in both groups (P<0.001). Compared to non-VDI patients, abundance of the fecal genera Prevotella 9, Escherichia-Shigella, and Klebsiella was significantly increased, while Bacteroides, Faecalibacterium, and Agathobacter were remarkably reduced in VDI patients (all P<0.05). Burkholderia-Caballeronia-Paraburkholderia (40.95%), Acinetobacter (3.05%), and Aquabacterium (2.37%) were the top three bacteria in sera from VDI patients. Both serum 25(OH)VD3 level and IFNI response were positively associated with fecal Bacteroides in the two groups (P<0.05). In non-VDI patients, there were moderately positive associations between IFNI response and fecal Lachnoclostridium, unclassified_f__Lachnospiraceae, and Phascolarctobacterium and between serum 25(OH)VD3 level and fecal Lachnoclostridium (all P<0.01). Circulating microbiota in VDI patients was closely related only to proinflammation and UAS7 (both P<0.05). Conclusion: Changes in gut but not circulating microbiota composition are associated with serum 25(OH)VD3 insufficiency and impaired IFNI homeostasis, which points to greater disease severity (UAS7) and systemic proinflammation in CSU patients.

ERK inhibition aids IFN-ß promoter activation during EV71 infection by blocking CRYAB degradation in SH-SY5Y cells.

Enterovirus 71 (EV71) can cause severe hand-foot-and-mouth disease with neurological complications. It has evolved multiple mechanisms to compromise the host type I interferon (IFN-I) response. In neuronal cells, EV71-mediated IFN-I antagonism may be associated with neural precursor cell-expressed developmentally downregulated 4-like (Nedd4L), the E3 ubiquitin ligase that can interact with alphaB-crystallin (CRYAB) in the regulation of Nav1.5 stability. Here, we investigated the effect of CRYAB stability on IFN-ß promoter activity in neuronal SH-SY5Y cells infected with EV71, and its relations to Nedd4 L and extracellular signal-regulated kinases (ERK). Results showed that EV71 infection significantly caused CRYAB degradation via the Nedd4L-proteasome pathway, which required ERK-mediated phosphorylation of Serine 45 in CRYAB. Subsequently, it was observed that siRNA- or EV71-mediated CRYAB reduction limited Poly(dAT)-activated IFN-ß promoter, and CRYAB stabilisation by U0126-mediated inhibition of ERK activation remarkably enhanced the activity of IFN-ß promoter upon EV71 challenge. Collectively, we elucidate a novel mechanism by which ERK activation contributes to EV71 immune escape via CRYAB/IFN-ß axis in SH-SY5Y cells, indicating that perturbing ERK activation is desirable for anti-EV71 therapy.

Bacterial DNA promoting inflammation via the Sgk1/Nedd4L/Syk pathway in mast cells contributes to antihistamine-nonresponsive CSU.

Inflammation centered on non-IgE-mediated mast cell activation characterizes chronic spontaneous urticaria resistant to nonsedating H1-antihistamines. We recently uncovered a strong positive association between inflammation and the fecal Escherichia. To further explore the actions of bacterial DNA derived from Escherichia on mast cells, intestinal permeability of patients with chronic spontaneous urticaria with or without nonsedating H1-antihistamine resistance and healthy controls were determined, and LAD2 cells with knockdown of Syk, Nedd4L, or Sgk1 or with incubation of inhibitors GS9973, GSK650394, and MG132 were posttreated with btDNA. We found that (i) serum intestinal permeability indices and bacterial DNA markedly increased in patients with chronic spontaneous urticaria with nonsedating H1-antihistamine resistance compared with those without (all P < 0.001), and bacterial DNA positively correlated with the degree of inflammation; (ii) IL-6 and TNF-α levels were time- and dose-dependently upregulated in bacterial DNA-stimulated LAD2 cells, which relied on unmethylated CpG in bacterial DNA and Toll-like receptor 9 protein in cells; (iii) Syk knockdown or inhibition of Syk Tyr525/526 phosphorylation blocked bacterial DNA-initiated cytokine production; (iv) Nedd4L interacted with Tyr525/526-phosphorylated Syk, and inhibition of Nedd4L Ser448 phosphorylation induced by bacterial DNA-activated Sgk1 was mandatory for bacterial DNA's proinflammatory property; and (v) Sgk1 suppression showed an inhibitory effect on bacterial DNA-induced inflammation by ensuring Nedd4L-mediated ubiquitination of Tyr525/526-phosphorylated Syk. Collectively, we identified previously unknown contributory roles of bacterial translocation and serum bacterial DNA on the inflammation phenotype in patients with chronic spontaneous urticaria with nonsedating H1-antihistamine resistance and further uncovered a vital negative regulatory role for the Sgk1/Nedd4L/Syk pathway in bacterial DNA-induced inflammation in LAD2 cells.

Phosphorylation of enteroviral 2Apro at Ser/Thr125 benefits its proteolytic activity and viral pathogenesis.

Enteroviral 2A proteinase (2Apro ), a well-established and important viral functional protein, plays a key role in shutting down cellular cap-dependent translation, mainly via its proteolytic activity, and creating optimal conditions for Enterovirus survival. Accumulated data show that viruses take advantage of various signaling cascades for their life cycle; studies performed by us and others have demonstrated that the extracellular signal-regulated kinase (ERK) pathway is essential for enterovirus A71 (EV-A71) and other viruses replication. We recently showed that ERK1/2 is required for the proteolytic activity of viral 2Apro ; however, the mechanism underlying the regulation of 2Apro remains unknown. Here, we demonstrated that the 125th residue Ser125 of EV-A71 2Apro or Thr125 of coxsackievirus B3 2Apro , which is highly conserved in the Enterovirus, was phosphorylated by ERK1/2. Importantly, 2Apro with phosphor-Ser/Thr125 had much stronger proteolytic activity toward eukaryotic initiation factor 4GI and rendered the virus more efficient for multiplication and pathogenesis in hSCARB2 knock-in mice than that in nonphospho-Ser/Thr125A (S/T125A) mutants. Notably, phosphorylation-mimic mutations caused deleterious changes in 2Apro catalytic function (S/T125D/E) and in viral propagation (S125D). Crystal structure simulation analysis showed that Ser125 phosphorylation in EV-A71 2Apro enabled catalytic Cys to adopt an optimal conformation in the catalytic triad His-Asp-Cys, which enhances 2Apro proteolysis. Therefore, we are the first to report Ser/Thr125 phosphorylation of 2Apro increases enteroviral adaptation to the host to ensure enteroviral multiplication, causing pathogenicity. Additionally, weakened viruses containing a S/T125A mutation could be a general strategy to develop attenuated Enterovirus vaccines.

Porokeratosis of the scrotum: a case report and literature review.

Porokeratosis, a keratinizing disorder of unknown etiology, exhibits an autosomal dominant inheritance pattern or manifests as an isolated acquired dermatosis. This condition can occur at any site on the skin; however, scrotal lesions are extremely rare. Only 18 cases of scrotal lesions were identified through a comprehensive review of the relevant literature. Herein, we present a case of a 19-year-old patient with porokeratosis of the scrotum. Additionally, we provide a summary of the etiologies, clinical manifestations, and histopathology of scrotal porokeratosis, and present differential diagnoses by reviewing the related literature.

Endometrial microbiota from endometrial cancer and paired pericancer tissues in postmenopausal women: differences and clinical relevance.

OBJECTIVE: The incidence of postmenopausal endometrial cancer (EC) is rising, and the uterine microbiota has recently been suggested to be an etiology of EC. However, the differences in microbiota profiles in paired EC and the adjacent non-EC endometrium, and the functional microbiota of clinical relevance remain largely unknown. Therefore, we examined the differences in microbiota profiles between EC and non-EC endometrium and investigated their clinical relevance to EC. METHODS: Twenty-eight EC-affected postmenopausal women undergoing hysterectomy were enrolled. Endometrial microbiome from paired EC and adjacent non-EC tissue samples were detected using 16S rRNA sequencing, and the data were analyzed using R language software. RESULTS: The α diversity and evenness of the endometrial bacterial community significantly increased in EC tissues than those in pericancer tissues ( P < 0.05 for all variables). Lactobacillus and Gardnerella were the main bacterial genera present in both EC and adjacent non-EC-invading endometrium, whereas Prevotella , Atopobium , Anaerococcus , Dialister , Porphyromonas , and Peptoniphilus were more commonly enriched in the EC endometrium (corrected P < 0.05 for all variables). Finally, the abundance of some observed endometrial bacteria was associated with clinical aspects, particularly the vaginal pH, vaginal Lactobacillus abundance, and EC clinical stage. CONCLUSIONS: Paired EC and adjacent non-EC endometrium harbor different endometrial microbiota, and the functional bacteria residing in the endometrium are clinically relevant but require further investigation.

Altered gut microbiota and its metabolites correlate with plasma cytokines in schizophrenia inpatients with aggression.

BACKGROUND: The pathophysiological mechanisms of aggression are manifold and they may closely interconnect. Current study aimed to determine the gut microbiota and its metabolites, and clarify their correlations with inflammation, oxidation, leaky gut and clinical profiles underlying aggression in schizophrenia (ScZ). METHODS: Serum and stool specimens from ScZ inpatients with (ScZ-Ag, 25 cases) and without aggression (NScZ-Ag, 25 cases) were collected. Systemic inflammation, oxidation and leaky gut biomarkers were determined by ELISA, gut microbiota by 16S rRNA sequencing, short-chain fatty acids (SCFAs) by gas chromatography-mass spectrometry analysis and neurotransmitters by liquid chromatograph mass spectrometry analysis. RESULTS: Significantly higher systemic pro-inflammation, pro-oxidation and leaky gut biomarkers were observed in ScZ-Ag than NScZ-Ag group (all P<0.001). Compared to NScZ-Ag group, the alpha-diversity and evenness of fecal bacterial community were much lower, the abundance of fecal genera Prevotella was significantly increased, while that Bacteroides, Faecalibacterium, Blautia, Bifidobacterium,Collinsella and Eubacterium_coprostanoligenes were remarkably reduced in ScZ-Ag group (all corrected P<0.001). Meanwhile, 6 SCFAs and 6 neurotransmitters were much lower in ScZ-Ag group (all P<0.05). Finally, a few strongly positive or negative correlations among altered gut microbiota, SCFAs, systemic pro-inflammation, leaky gut, pro-oxidation and aggression severity were detected. CONCLUSIONS: These results demonstrate that pro-inflammation, pro-oxidation and leaky gut phenotypes relating to enteric dysbacteriosis and microbial SCFAs feature the aggression onset or severity in ScZ individuals.

Altered Gut Microbiota in H1-Antihistamine-Resistant Chronic Spontaneous Urticaria Associates With Systemic Inflammation.

Background and Objective: Chronic spontaneous urticaria (CSU) is a histamine-mediated inflammatory skin disease, and second-generation non-sedating H1-antihistamines (nsAH) at licensed doses have long been the first-line therapy in CSU. However, about 50% of patients are resistant to nsAH, and the precise pathogenesis remains largely unknown but seems to be associated with low-level systemic or intestinal inflammation. We aim to determine the fecal microbial composition and clarify its correlation with the clinical profiles og CSU with nsAH resistance. Methods: A total of 25 CSU patients with or 19 CSU patients without nsAH resistance and 19 healthy controls (HC) were enrolled in this study. The intestinal microbiome was detected by 16S rRNA sequencing. The data were analyzed using R language software. Results: Significantly higher urticarial activity score for 7 days, stool calprotectin, erythrocyte sedimentation rate, serum C-reactive protein, and interleukin-6, but much lower alpha-diversity and evenness of fecal bacterial community were observed in CSU patients with nsAH resistance than in those without (P <0.05 for all variables). Compared to patients with nsAH-responsiveness, the abundance of fecal genera Prevotella, Megamonas, and Escherichia were significantly increased, while that of Blautia, Alistipes, Anaerostipes, and Lachnospira were remarkably reduced in nsAH-resistant patients (uncorrected P <0.05 for all variables). Finally, systemic not intestinal inflammation degree was positively correlated with genera Escherichia, while negatively with genera Blautia, Dorea, Lactobacillus, Eubacterium_hallii_group, and Roseburia. CSU without nsAH resistance and HC individuals showed almost unchanged genera bacterium. Conclusions: Among CSU patients, pro-inflammation phenotype relating to enteric dysbacteriosis features nsAH resistance in CSU patients. The results provide clues for future microbial-based or anti-inflammatory therapies on nsAH resistant CSU.

Skin Immunosenescence and Type 2 Inflammation: A Mini-Review With an Inflammaging Perspective.

Skin-resident stromal cells, including keratinocytes, fibroblasts, adipocytes, and immune cells including Langerhans cells, dendritic cells, T cells, and innate lymphoid cells, and their functional products work in concert to ensure the realization of skin barrier immunity. However, aging-induced immunosenescence predisposes the elderly to pruritic dermatoses, including type 2 inflammation-mediated. Inflammaging, characterized by chronic low level of pro-inflammatory cytokines released from senescent cells with the senescence-associated secretory phenotype (SASP), may drive immunosenescence and tangle with type 2 inflammatory dermatoses. The present mini-review summarizes current evidence on immunosenescence and type 2 inflammation in the skin and further focuses on future needs from an inflammaging perspective to clarify their complexity.

Curcumin assists anti-EV71 activity of IFN-α by inhibiting IFNAR1 reduction in SH-SY5Y cells.

BACKGROUND AND AIM: Enterovirus 71(EV71) can cause severe hand, foot, and mouth disease (HFMD) with brain tissue involvement. Few effective anti-EV71 drugs are presently available in clinical practice. Interferon-α (IFN-α) was ineffective while Curcumin was effective in restricting EV71 replication in non-neuronal cells. Ubiquitin-proteasome-mediated degradation of interferon-alpha receptor 1 (IFNAR1) protein contributes to IFN-α resistance. Current study aimed to determine synergistic inhibition of EV71 by Curcumin and IFN-α in human neuroblastoma SH-SY5Y cells. METHODS: SH-SY5Y cells were infected with mock-/Curcumin-pre-incubated EV71 or transfected with plasmid containing interferon-stimulated response element (ISRE) or mRNA containing viral internal ribosomal entry site (IRES) following by post-treatment with Curcumin with or without IFN-α. Supernatant IFN-α/ß was detected by ELISA. ISRE, IRSE, proteasome and deubiquitinating activity were measured by luciferase assay. EV71 RNA and viral protein or IFNAR1 were determined by qPCR and western blot, respectively. RESULTS: EV71 flailed to completely block IFN-α/ß production but inhibited IFN-α signal. Curcumin only slightly inhibited EV71 proliferation without modulating virus attachment and internalization. However, Curcumin addition restored IFN-α-mediated ISRE activity thus significantly inhibiting EV71 replication. Furthermore, EV71 also reduced IFNAR1 protein with proteasome-dependence in SH-SY5Y cells, which can be reversed by Curcumin addition with the evidence that it lowered proteasome activity. CONCLUSION: These data demonstrate that Curcumin assists anti-EV71 activity of IFN-α by inhibiting IFNAR1 reduction via ubiquitin-proteasome disruption in SH-SY5Y cells.

Translocating lipopolysaccharide correlates with the severity of enterovirus A71-induced HFMD by promoting pro-inflammation and viral IRES activity.

BACKGROUND: The increase of inflammation-inducing enterobacteria was recently observed in severe hand, foot, and mouth disease (HFMD) caused by Enterovirus A71 (EV-A71). This study aimed to verify the occurrence of bacterial translocation (BT) and further explore the contributory role of BT to severity of EV-A71-mediated HFMD cases. METHODS: Serum specimens from 65 mild and 65 severe EV-A71-associated HFMD cases and 65 healthy children were collected. EV-A71 VP1 in serum, inflammatory mediators including C-reactive protein, IL-1ß, IL-6, interferon-γ and tumor necrosis factor-α, BT related biomarkers including Claudin-3, intestinal fatty acid binding protein, lipopolysaccharide (LPS), soluble CD14 (sCD14) and endotoxin core antibody were measured by ELISA. Bacterial DNA (BactDNA) fragments were quantified by quantified PCR (qPCR). Rhabdomyosarcoma (RD) or SH-SY5Y cells, infected with LPS-pre-incubated EV-A71 or transfected with plasmid containing viral 2Apro or mRNA containing viral internal ribosomal entry site (IRES), were post-treated with or without LPS in vitro. EV-A71 RNA and viral or cellular proteins were determined by qPCR and western blot, respectively. RESULTS: Compared to mild HFMD patients, remarkably higher inflammatory mediators as well as BT-related biomarkers except BactDNA were observed in severe HFMD cases (all P < 0.05). In severe HFMD group, circulating concentrations of LPS and sCD14 showed statistical correlations with inflammation indices (all P < 0.05), serum levels of EV-A71 VP1 were found to be positively correlated with serum LPS (r = 0.341, P = 0.005) and serum sCD14 (r = 0.458, P < 0.001). In vitro, EV-A71 attachment and internalization were only slightly promoted by LPS pre-incubation; however, EV-A71 proliferation and viral 2Apro-mediated IRES activity were significantly accelerated by LPS post-treatment. CONCLUSIONS: Our results collectively indicate that gut-derived translocating LPS contributes to the severity of EV-A71-induced HFMD by driving inflammatory response and viral proliferation via viral 2Apro-mediated IRES.

Bacterial Translocation Associates With Aggression in Schizophrenia Inpatients.

Objective: Accumulating evidence indicates that inflammation abnormalities may contribute to aggression behaviors in psychotic patients, however, the possible sources of inflammation remain elusive. We aimed to evaluate the associations among aggression, inflammation, and bacterial translocation (BT) in aggression-affected schizophrenia (ScZ) inpatients with 2 weeks of antipsychotics discontinuation. Methods: Serum specimens collected from 112 aggression and 112 non-aggression individuals with ScZ and 56 healthy adults were used for quantifications of inflammation- or BT-related biomarkers. Aggression severity was assessed by Modified Overt Aggression Scale (MOAS). Results: Proinflammation phenotype dominated and leaky gut-induced BT occurred only in cases with ScZ with a history of aggression, and the MOAS score positively related to levels of C-reactive protein, interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α. Furthermore, serum levels of BT-derived lipopolysaccharide (LPS), as well as LPS-responded soluble CD14, were not only positively correlated with levels of above proinflammation mediators but also the total MOAS score and subscore for aggression against objects or others. Conclusion: Our results collectively demonstrate the presence of leaky gut and further correlate BT-derived LPS and soluble CD14 to onset or severity of aggression possibly by driving proinflammation response in inpatients with ScZ, which indicates that BT may be a novel anti-inflammation therapeutic target for aggression prophylaxis.

Acute Urticaria in Inpatients Undergoing Non-emergent Coronary Angiography With Corticosteroid Prophylaxis: A Retrospective Study.

Background and Aims: Acute urticaria (AU) is the most frequently reported immediate hypersensitivity reaction in skin by administration of iodinated contrast media (ICM). We aimed to establish the pattern and identify the risk factors of AU among inpatients undergoing non-emergent coronary angiography (CAG) with prophylactic corticosteroids in China. Methods: Medical records of 19,326 adult inpatients undergoing non-emergent CAG with prophylactic methylprednisolone in 2013-2019 were retrospectively investigated. AU was identified within 1 h post-ICM administration, and diffuse involvement was defined when wheals occur in two or more body parts, including the back, abdomen, chest, and extremities. Age- and sex-matched inpatients (1:4) without AU were randomly selected for assessment of risk factors. Results: Approximately 0.8% of CAG inpatients had AU, including 101 diffuse and 64 limited form. The diffuse AU was more common in settings of non-diagnostic CAG, iohexol used, average ICM injection≥3 ml/min, recurrent CAG, and past history of immediate hypersensitivity to ICM. Inpatients with preexisting allergies, decreased evaluated glomerular filtration rate, and increased high sensitivity C reactive protein or neutrophil-to-lymphocyte ratio prior to CAG had a higher probability of AU (odds ratio >1, P < 0.05 for all variables). All AU inpatients complained of pruritus, and mild itching predominated. AU dissipated in several days under treatment of ebastine or levocetirizine 10 mg/daily, but ebastine showed superiority. Conclusions: ICM-induced AU is not uncommon in non-emergent CAG inpatients with prophylactic methylprednisolone. Preexisting allergies, renal dysfunction, and mild inflammation are high-risk factors, and antihistamine monotherapy is a favorable candidate for ICM-related AU.

Contact sensitization to cosmetic series of allergens in female patients with rosacea: A prospective controlled study in China.

BACKGROUND: Allergic contact dermatitis to cosmetics (ACDC) complicates the diagnosis and treatment of rosacea, and is increasingly observed in daily practice. AIMS: The present study aimed to identify the contact allergens responsible for ACDC in Chinese female rosacea patients with or without suspected ACDC (SACDC). METHODS: From a total of 1267 women with rosacea, 122 with SACDC, 145 without SACDC, and 100 age-matched healthy controls without rosacea or SACDC were examined on a voluntary basis. Skin patch tests with C-1000 cosmetic series (Chemotechnique Diagnostics, Malmo, Sweden) were conducted, including 20 selected allergens. RESULTS: Positive allergic reaction was found in 85.2% and 33.8% of SACDC and non-SACDC (P < .001), respectively, and 27.0% of healthy volunteers. Most reactions occurred at day 3, and the majority of all the examinees including normal controls reacted to more than 1 allergen. In SACDC patients, leading allergens were methylchloroisothiazolinone/methylisothiazolinone (28.7%), linalool hydroperoxide (27.1%), fragrance mix I (21.3%), methylisothiazolinone (17.2%), limonene hydroperoxides (16.4%), formaldehyde (14.8%), myroxylon pereirae (13.9%), and propolis (10.7%); the overall allergic reaction rate positively correlated with new onset of facial pruritus (P < .001). The occurrence of irritant contact reactions correlated with positive allergic reactions in rosacea patients with or without SACDC (P = .032 or P < .001, respectively). CONCLUSIONS: Preservatives and fragrances are primary culprits for ACDC in Chinese female rosacea patients. Patch testing should be considered in the suspected patients.

Cellular Caspase-3 Contributes to EV-A71 2Apro-Mediated Down-Regulation of IFNAR1 at the Translation Level.

Enterovirus A71 (EV-A71) is the major pathogen responsible for the severe hand, foot and mouth disease worldwide, for which few effective antiviral drugs are presently available. Interferon-α (IFN-α) has been used in antiviral therapy for decades; it has been reported that EV-A71 antagonizes the antiviral activity of IFN-α based on viral 2Apro-mediated reduction of the interferon-alpha receptor 1 (IFNAR1); however, the mechanism remains unknown. Here, we showed a significant increase in IFNAR1 protein induced by IFN-α in RD cells, whereas EV-A71 infection caused obvious down-regulation of the IFNAR1 protein and blockage of IFN-α signaling. Subsequently, we observed that EV-A71 2Apro inhibited IFNAR1 translation by cleavage of the eukaryotic initiation factor 4GI (eIF4GI), without affecting IFNAR1 mRNA levels induced by IFN-α. The inhibition of IFNAR1 translation also occurred in puromycin-induced apoptotic cells when caspase-3 cleaved eIF4GI. Importantly, we verified that 2Apro could activate cellular caspase-3, which was subsequently involved in eIF4GI cleavage mediated by 2Apro. Furthermore, inhibition of caspase-3 activation resulted in the partial restoration of IFNAR1 in cells transfected with 2A or infected with EV-A71, suggesting the pivotal role of both viral 2Apro and caspase-3 activation in the disturbance of IFN-α signaling. Collectively, we elucidate a novel mechanism by which cellular caspase-3 contributes to viral 2Apro-mediated down-regulation of IFNAR1 at the translation level during EV-A71 infection, indicating that caspase-3 inhibition could be a potential complementary strategy to improve clinical anti-EV-A71 therapy with IFN-α.

Heme oxygenase-1 exerts pro-apoptotic effects on hepatic stellate cells in vitro through regulation of nuclear factor-κB.

Heme oxygenase-1 (HO-1) is an antioxidant and cytoprotective protein, which has been proven to alleviate the proliferation of hepatic stellate cells (HSCs) and the development of liver fibrosis. However, the role of HO-1 in HSC apoptosis remains unclear. The aim of the present study was to investigate the effect of HO-1 on HSC apoptosis and its possible underlying mechanisms. HSCs-T6 were incubated with different concentrations of hemin (HO-1 chemical inducer) and Znpp-IX (HO-1 chemical inhibitor) for 12, 24 and 48 h. Cell viability was determined using an MTT assay. HSCs were classified into 4 groups as follows: Control, hemin, Znpp-IX and hemin+Znpp-IX co-treatment groups. Apoptosis was quantitatively measured by Annexin V/propidium iodide double staining and a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. The mRNA and protein expression of HO-1, α-smooth muscle actin, B-cell lymphoma (Bcl)-2, caspase-3 and nuclear factor (NF)-κB p65 were measured using quantitative polymerase chain reaction and western blotting. The levels of tumor growth factor (TGF)-ß and interleukin (IL)-6 in HSC supernatants were examined by ELISA. The results demonstrated that HO-1 exerted antiproliferative effects on HSCs in a time- and concentration-dependent manner. Increasing HO-1 expression induced HSC apoptosis in vitro as demonstrated by a significant decrease in Bcl-2 and an increase in caspase-3 expression. Additionally, the expression of NF-κB p65 and its downstream inflammatory factors TGF-ß and IL-6 in the HO-1 overexpression group was significantly decreased compared with the control group. Therefore, the present study provided evidence that HO-1 serves an anti-fibrosis role in the liver by enhancing HSC apoptosis, which was partially associated with the regulation of NF-κB and its downstream effectors.

HBsAg seroclearance or seroconversion induced by peg-interferon alpha and lamivudine or adefovir combination therapy in chronic hepatitis B treatment: a meta-analysis and systematic review.

BACKGROUND AND AIMS: Seroclearance or seroconversion of hepatitis B surface antigen (HBsAg) is generally considered as the clinical endpoint. The purpose of the present meta-analysis was to evaluate pegylated interferon alpha (PEG-IFNα) with or without lamivudine (LAM) or adefovir (ADV) combination treatment in HBsAg seroclearance or seroconversion with CHB. METHODS: Randomized controlled trials of adults with CHB prior to May 30th 2015, with 48-52 weeks of PEG-IFNα and LAM or ADV combination therapy or monotherapy, were included. Review Manager Software 5.2.0 was used for meta-analysis. RESULTS: No statistical difference was noticed in HBsAg seroclearance (9.9% vs 7.1%, OR = 1.47, 95% CI 0.75, 2.90; p = 0.26) or observed in HBsAg seroconversion (4.2% vs 3.7%, OR = 1.17, 95% CI 0.57, 2.37; p = 0.67) between PEG-IFNα + LAM and PEG-IFNα + placebo for 24-26 weeks follow-up after treatment on hepatitis B e antigen (HBeAg)-positive CHB. Statistical difference was not showed in HBsAg disappearance (10.5% vs 6.4%, OR = 1.68, 95% CI 0.75, 3.76; p = 0.21) but was demonstrated in HBsAg seroconversion (6.3% vs 0%, OR = 7.22, 95% CI 1.23, 42.40; p = 0.03) between PEG-IFNα + ADV and PEG-IFNα for 48-52 weeks treatment on HBeAg-positive CHB By systematical evaluation, there were no differences in HBsAg disappearance and seroconversion between PEG-IFNα + placebo and PEG-IFNα + LAM for 48-52 weeks treatment on HBeAg-positive CHB. There were no differences in HBsAg disappearance and seroconversion between PEG-IFNα + placebo and PEG-IFNα + LAM during 24 weeks to 3 years follow-up after treatment on HBeAg-negative CHB by systematical evaluation. CONCLUSION: The combination between PEG-IFNα and LAM or ADV was not superior to monotherapy of PEG-IFNα in terms of HBsAg seroclearance or seroconversion.

Outcomes of catheter ablation of atrial fibrillation in patients with hypertrophic cardiomyopathy: a systematic review and meta-analysis.

AIMS: Over the past decade, catheter ablation (CA) has become an established therapy for symptomatic atrial fibrillation (AF). Atrial fibrillation is common in hypertrophic cardiomyopathy (HCM) patients, and restoring sinus rhythm is of great clinical benefit to them. Therefore, we conducted a systematic review and meta-analysis of the available data to evaluate the effectiveness and safety of CA for AF in patients with HCM. METHODS AND RESULTS: Six databases were searched to identify studies describing outcomes of CA of AF in HCM patients with a mean follow-up of ≥12 months after the index procedure. The following data were extracted: (i) single-procedure success, (ii) multiple-procedure success, and (iii) drug-free success. Fifteen studies involving 531 patients were included. Single-procedure freedom from atrial arrhythmia at the latest follow-up was 45.5% [95% confidence interval (CI): 34.8-56.2%]. With multiple procedures, the final success rate was 66.1% (95% CI: 55.3-76.9%) overall, 71.8% (95% CI: 61.6-82.0%) in paroxysmal AF, and 47.5% (95% CI: 36.0-59.0%) in non-paroxysmal AF. Without anti-arrhythmic drugs (AADs), single-procedure success rate at latest follow-up was 32.9% (95% CI: 21.7-41.1%); after multiple procedures, this raised to 50.4% (95% CI: 39.2-61.6%). The incidence of serious periprocedural complications was acceptable [5.1% (95% CI: 2.8-9.6%)]. Substantial heterogeneity (I(2)> 50%) was noted in the above groups. CONCLUSIONS: Catheter ablation of AF in patients with HCM is feasible, although more repeat procedures and AAD are needed to prevent AF recurrence.