Plant 22-nt siRNAs mediate translational repression and stress adaptation.

Small interfering RNAs (siRNAs) are essential for proper development and immunity in eukaryotes1. Plants produce siRNAs with lengths of 21, 22 or 24 nucleotides. The 21- and 24-nucleotide species mediate cleavage of messenger RNAs and DNA methylation2,3, respectively, but the biological functions of the 22-nucleotide siRNAs remain unknown. Here we report the identification and characterization of a group of endogenous 22-nucleotide siRNAs that are generated by the DICER-LIKE 2 (DCL2) protein in plants. When cytoplasmic RNA decay and DCL4 are deficient, the resulting massive accumulation of 22-nucleotide siRNAs causes pleiotropic growth disorders, including severe dwarfism, meristem defects and pigmentation. Notably, two genes that encode nitrate reductases-NIA1 and NIA2-produce nearly half of the 22-nucleotide siRNAs. Production of 22-nucleotide siRNAs triggers the amplification of gene silencing and induces translational repression both gene specifically and globally. Moreover, these 22-nucleotide siRNAs preferentially accumulate upon environmental stress, especially those siRNAs derived from NIA1/2, which act to restrain translation, inhibit plant growth and enhance stress responses. Thus, our research uncovers the unique properties of 22-nucleotide siRNAs, and reveals their importance in plant adaptation to environmental stresses.

IAA3-mediated repression of PIF proteins coordinates light and auxin signaling in Arabidopsis.

The exogenous light signal and endogenous auxin are two critical factors that antagonistically regulate hypocotyl growth. However, the regulatory mechanisms integrating light and auxin signaling pathways need further investigation. In this study, we identified a direct link between the light and auxin signaling pathways mediated by the auxin transcriptional repressor IAA3 and light-controlled PIF transcription factors in Arabidopsis. The gain-of-function mutation in IAA3 caused hyposensitivity to light, whereas disruption of IAA3 led to an elongated hypocotyl under different light intensity conditions, indicating that IAA3 is required in light regulated hypocotyl growth. Genetic studies showed that the function of IAA3 in hypocotyl elongation is dependent on PIFs. Our data further demonstrated that IAA3 interacts with PIFs in vitro and in vivo, and it attenuates the DNA binding activities of PIFs to the target genes. Moreover, IAA3 negatively regulates the expression of PIFs-dependent genes. Collectively, our study reveals an interplay mechanism of light and auxin on the regulation of hypocotyl growth, coordinated by the IAA3 and PIFs transcriptional regulatory module.

Resveratrol ameliorates liver fibrosis induced by nonpathogenic Staphylococcus in BALB/c mice through inhibiting its growth.

BACKGROUND: The altered gut microbiota is implicated in the pathogenesis of liver fibrosis. Resveratrol is a candidate for the treatment of liver fibrosis, which could ameliorate the dysregulation of gut microbiota in mice. This study aimed to clarify the role and mechanism of resveratrol in gut microbiota during liver fibrosis. METHODS: A mouse model of liver fibrosis induced by CCl4 was conducted to assess the effect of resveratrol on liver fibrosis. The changes of gut microbiota in liver fibrotic mice after resveratrol intervention were assessed using 16S ribosomal RNA sequencing. The mechanism of the gut microbiota dysregulation in liver fibrosis was investigated by Sirius red staining, immunohistochemical assay, bacterial translocation (BT), EUB338 fluorescence in situ hybridization, immunofluorescence, trans-epithelial electrical resistance analysis and paracellular permeability analysis. RESULTS: Resveratrol relieved CCl4-induced liver fibrosis. Besides, resveratrol restrained the gut microbiota Staphylococcus_lentus and Staphylococcus_xylosus in the liver fibrotic mice, and the Staphylococcus_xylosus and Staphylococcus_lentus facilitated the occurrence of BT and the cultures of them enhanced the permeability of intestine. The in vivo assay corroborated that the excessive Staphylococcus_xylosus and Staphylococcus_lentus canceled the protecting effect of resveratrol on liver fibrosis, and Staphylococcus_xylosus or Staphylococcus_lentus alone had a limited impact on the liver injury of normal mice. CONCLUSION: Resveratrol ameliorated liver fibrosis by restraining the growth of Staphylococcus_xylosus and Staphylococcus_lentus.

Tenofovir Alafenamide for Pregnant Chinese Women With Active Chronic Hepatitis B: A Multicenter Prospective Study.

BACKGROUND & AIMS: Data on long-term tenofovir alafenamide (TAF) therapy for pregnant women with active chronic hepatitis B (CHB) (immune clearance and reactivation phases, currently and previously diagnosed) and their infants are lacking. METHODS: Pregnant women with active CHB treated with TAF and tenofovir disoproxil fumarate (TDF) were enrolled in this multicenter prospective study, and infants received immunoprophylaxis. The primary outcomes were rates of adverse (safety) events in pregnant women and defects in infants and fetuses. The secondary outcomes were virologic responses in pregnant women, infants' safety, hepatitis B surface antigen (HBsAg) status, and growth conditions. RESULTS: One hundred three and 104 pregnant women were enrolled and 102 and 104 infants were born in the TAF and TDF groups, respectively. In the TAF group, the mean age, gestational age, alanine aminotransferase level, and viral loads at treatment initiation were 29.3 years, 1.3 weeks, 122.2 U/L, and 5.1 log10 IU/mL, respectively. TAF was well-tolerated, and the most common adverse event was nausea (29.1%) during a mean of 2 years of treatment. Notably, 1 (1.0%) TAF-treated pregnant woman underwent induced abortion due to noncausal fetal cleft lip and palate. No infants in either group had birth defects. In the TAF group, the hepatitis B e antigen seroconversion rate was 20.7% at postpartum month 6, infants had normal growth parameters, and no infants were positive for HBsAg at 7 months. The TDF group had comparable safety and effectiveness profiles. CONCLUSIONS: TAF administered throughout or beginning in early pregnancy is generally safe and effective for pregnant women with active CHB and their infants.

Tenofovir Alafenamide to Prevent Perinatal Hepatitis B Transmission: A Multicenter, Prospective, Observational Study.

BACKGROUND: Few safety and effectiveness results have been published regarding the administration of tenofovir alafenamide fumarate (TAF) during pregnancy for the prevention of mother-to-child transmission (MTCT) of hepatitis B virus (HBV). METHODS: In this multicenter prospective observational study, pregnant women with HBV DNA levels higher than 200 000 IU/mL who received TAF or tenofovir disoproxil fumarate (TDF) from gestational weeks 24-35 to delivery were 1:1 enrolled and followed until postpartum month 6. Infants received immunoprophylaxis. The primary endpoint was the safety of mothers and infants. The secondary endpoint was the hepatitis B surface antigen (HBsAg)-positive rate at 7 months for infants. RESULTS: In total, 116 and 116 mothers were enrolled, and 117 and 116 infants were born, in the TAF and TDF groups, respectively. TAF was well tolerated during a mean treatment duration of 11.0 weeks. The most common maternal adverse event was nausea (19.0%). One (0.9%), 3 (2.6%), and 9 (7.8%) mothers had abnormal alanine aminotransferase levels at delivery and at postpartum months 3 and 6, respectively. The TDF group had safety profiles that were comparable to those of the TAF group. No infants had birth defects in either group. The infants' physical and neurological development at birth and at 7 months in the TAF group were comparable with those in the TDF group. The HBsAg positive rate was 0% at 7 months in all 233 infants. CONCLUSIONS: Antiviral prophylaxis with TAF was determined to be generally safe for both mothers and infants and reduced the MTCT rate to 0%.

PCSK9Qß-003 Vaccine Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice.

PURPOSE: Our group has developed a therapeutic vaccine targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), named PCSK9Qß-003. In this study, we investigated the potential effectiveness of the PCSK9Qß-003 vaccine on atherosclerosis. METHODS: Male ApoE-/- mice were randomly assigned to three groups: a phosphate-buffered saline (PBS) group, Qß virus-like particles (VLP) group, and PCSK9Qß-003 vaccine group. Mice in the PCSK9Qß-003 group were injected with the PCSK9Qß-003 vaccine four times (100 µg/time) over a period of 18 weeks. The effects of the vaccine on atherosclerotic plaque, cholesterol transport, inflammation and apoptosis were investigated. RESULTS: The PCSK9Qß-003 vaccine obviously decreased total cholesterol and low-density lipoprotein cholesterol in ApoE-/- mice. Compared with the other groups, the PCSK9Qß-003 vaccine significantly reduced the lesion area and promoted the stability of atherosclerotic plaque. The vaccine regulated cholesterol transport in the aorta of ApoE-/- mice by up-regulating the expression level of liver X receptor α and ATP binding cassette transporter A1. Additionally, macrophage infiltration and expression of monocyte chemoattractant protein-1 and tumor necrosis factor-α were significantly decreased in the mice administered the PCSK9Qß-003 vaccine. The vaccine also markedly reduced apoptosis in the lesion area of the aorta in ApoE-/- mice. CONCLUSIONS: The results demonstrated that the PCSK9Qß-003 vaccine attenuated the progression of atherosclerosis by modulating reverse cholesterol transport and inhibiting inflammation infiltration and apoptosis, which may provide a novel therapeutic approach for atherosclerosis and greatly improve treatment compliance among patients.

IL-17A-mediated ERK1/2/p65 signaling pathway is associated with cell apoptosis after non-alcoholic steatohepatitis.

Interleukin (IL)-17A is pro-inflammatory cytokine which has been identified as a noninvasive marker of the pathogenesis of non-alcoholic steatohepatitis (NASH). However, the underlying role of IL-17A in NASH progression remains unclear. This study was designed to investigate the biological function and molecular mechanism of IL-17A in the induction of NASH. The results showed that IL-17A was highly expressed in high-fat diet (HFD)-induced NASH mouse model. Intravenous injection of IL-17A exacerbated steatohepatitis process via promoting hepatocyte apoptosis. Furthermore, IL-17A-induced apoptosis was mediated by ERK1/2/p65 signaling pathway. In conclusion, we demonstrated that IL-17A-mediated ERK1/2/p65 signaling pathway was a promising target for the treatment of NASH. © 2018 IUBMB Life, 71(3):302-309, 2019.

Transcriptomics comparison reveals the diversity of ethylene and methyl-jasmonate in roles of TIA metabolism in Catharanthus roseus.

BACKGROUND: The medicinal plant, Catharanthus roseus (C. roseus), accumulates a wide range of terpenoid indole alkaloids (TIAs). Ethylene (ET) and methyl-jasmonate (MeJA) were previously reported as effective elicitors for the production of various valuable secondary metabolites of C. roseus, while a few ET or MeJA induced transcriptomic research is yet reported on this species. In this study, the de-novo transcriptome assembly of C. roseus is performed by using the next-generation sequencing technology. RESULTS: The result shows that phenolic biosynthesis genes respond specifically to ET in leaves, monoterpenoid biosynthesis genes respond specifically to MeJA in roots. By screening the database, 23 ATP-binding cassette (ABC) transporter partial sequences are identified in C. roseus. On this basis, more than 80 key genes that encode key enzymes (namely TIA pathway, transcriptional factor (TF) and candidate ABC transporter) of alkaloid synthesis in TIA biosynthetic pathways are chosen to explore the integrative responses to ET and MeJA at the transcriptional level. Our data indicated that TIA accumulation is strictly regulated by the TF ethylene responsive factor (ERF) and bHLH iridoid synthesis 1 (BIS1). The heatmap, combined with principal component analysis (PCA) of C. roseus, shows that ERF co-expression with ABC2 and ABC8 specific expression in roots affect the root-specific accumulation of vinblastine in C. roseus. On the contrast, BIS1 activities follow a similar pattern of ABC3 and CrTPT2 specific expression in leaves, which affects the leaf-specific accumulation of vindoline in C. roseus. CONCLUSIONS: Results presented above illustrate that ethylene has a stronger effect than MeJA on TIA induction at both transcriptional and metabolite level. Furthermore, meta-analysis reveals that ERF and BIS1 form a positive feedback loop connecting two ABC transporters respectively and are actively involved in TIAs responding to ET and MeJA in C. roseus.

MiR-19a Affects Hepatocyte Autophagy via Regulating lncRNA NBR2 and AMPK/PPARα in D-GalN/Lipopolysaccharide-Stimulated Hepatocytes.

This study aims to evaluate the potential involvement and regulatory mechanism of miR-19a in hepatocytes autophagy of acute liver failure (ALF). The in vitro hepatocytes injury model of primary hepatocyte and hepatocytes line HL-7702 was established by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) co-treatment. Relative expression level of miR-19a and NBR2 was determined by qRT-PCR. Protein expression of AMPK/PPARα and autophagy-related gene was determined by Western blot. In hepatic tissue of 20 ALF patients and D-GalN/LPS-stimulated hepatocytes, miR-19a was upregulated and NBR2 was downregulated. D-GalN/LPS stimulation caused the inactivation of AMPK/PPARα signaling and the decrease of autophagy-related LC3-II/LC3-I ratio and beclin-1 expression in hepatocytes. The expression of both AMPK/PPARα and NBR2 were negatively controlled by miR-19a overexpression or knockdown. Moreover, both NBR2 and PPARα were targeted regulated by miR-19a according to luciferase reporter assay. In D-GalN/LPS-stimulated hepatocytes, AMPK activation promoted PPARα expression. AMPK inactivation inhibited the pro-autophagy effect of miR-19a and caused the decrease of LC3-II/LC3-I ratio and beclin-1 expression. PPARα activation abrogated the anti-autophagy effect of miR-19a mimic and caused the increase of LC3-II/LC3-I ratio and beclin-1 expression. NBR2 knockdown reversed the anti-autophagy impact of miR-19a inhibitor and caused the decrease of LC3-II/LC3-I ratio and beclin-1 expression. In summary, our data suggested that miR-19a negatively controlled the autophagy of hepatocytes attenuated in D-GalN/LPS-stimulated hepatocytes via regulating NBR2 and AMPK/PPARα signaling. J. Cell. Biochem. 119: 358-365, 2018. © 2017 Wiley Periodicals, Inc.

Differential responses to Cd stress induced by exogenous application of Cu, Zn or Ca in the medicinal plant Catharanthus roseus.

Cd(II) is one of the most widespread and toxic heavy metals and seriously threatens plant growth, furthermore negatively affecting human health. For survival from this metal stress, plants always fight with Cd(II) toxicity by themselves or using other external factors. The effects of second metals copper (Cu(II)), zinc (Zn(II)) and calcium (Ca(II)) on the Cd(II)-affected root morphology, Cd(II) translocation and metabolic responses in Catharanthus roseus were investigated under hydroponic conditions. We found that the Cd-stressed plants displayed the browning and rot root symptom, excess H2O2 content, lipid peroxidation and Cd(II) accumulation in plants. However, the supplement with second metals largely alleviated Cd-induced toxicity, including browning and rot roots, oxidative stress and internal Cd(II) accumulation. The amended effects at metabolic and transcriptional levels involved in different second metals share either common or divergent strategies. They commonly repressed Cd uptake and promoted Cd(II) translocation from roots to shoots with divergent mechanisms. High Zn(II) could activate MTs expression in roots, while Cu(II) or Ca(II) did not under Cd(II) stress condition. The presence of Ca(II) under Cd stress condition largely initiated occurrence of lateral roots. We then grouped a metabolic diagram integrating terpenoid indole alkaloid (TIA) accumulation and TIA pathway gene expression to elucidate the metabolic response of C. roseus to Cd(II) alone or combined with second metals. The treatment with 100 Cd(II) alone largely promoted accumulation of vinblastine, vindoline, catharanthine and loganin, whereas depressed or little changed the expression levels of genes detected here, compared to 0 Cd(II) control. In the presence of Cd(II), the supplement with second metals displayed specific effect on different alkaloid. Among them, the metal Ca(II) is especially beneficial for serpentine accumulation, Zn(II) mainly promoted tabersonine production. However, the addition of Cu(II) commonly depressed accumulation of most alkaloids detected here. Generally, we presented different mechanisms by which the second metals used to alleviate Cd (II) toxicity. This plant has potential application in phytoremediation of Cd(II), due to relatively substantial accumulation of biomass, as well as secondary metabolites TIAs used as pharmaceutical materials when facing Cd stress.

Advanced therapeutic strategies for HBV-related acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is increasingly recognized as a distinct clinical entity and is associated with a high short-term mortality. The most common cause of ACLF is chronic hepatitis B worldwide. Currently, there is no standardized approach for the management of ACLF and the efficacy and safety of therapeutic modalities are uncertain. DATA SOURCES: PubMed and Web of Science were searched for English-language articles. The search criteria focused on clinical trials and observational studies on the treatment of patients with HBV-related ACLF. RESULTS: Therapeutic approaches for ACLF in patients with chronic hepatitis B included nucleos(t)ide analogues, artificial liver support systems, immune regulatory therapy, stem cell therapy and liver transplantation. All of these therapeutic approaches have shown the potential to improve liver function and increase patients' survival rate, but most of the studies were not randomized or controlled. CONCLUSION: Substantial challenges for the treatment of HBV-related ACLF remain and further basic research and randomized controlled clinical trials are needed.

China-origin G1 group isolate FPV072 exhibits higher infectivity and pathogenicity than G2 group isolate FPV027.

Introduction: Feline parvovirus (FPV), a single-stranded DNA virus, is accountable for causing feline panleukopenia, a highly contagious and often lethal disease that primarily affects cats. The epidemiology prevalence and pathogenicity of FPV in certain regions of China, however, remains unclear. The aim of this research was to investigate the epidemiology of FPV in different regions of China in 2021 and compare its infectivity and pathogenicity. Methods: In this research, a total of 36 FPV strains were obtained from diverse regions across China. Phylogenetic analysis was performed based on the VP2 and NS1 sequences, and two representative strains, FPV027 and FPV072, which belonged to different branches, were selected for comparative assessment of infectivity and pathogenicity. Results and discussion: The results revealed that all strains were phylogenetically classified into two groups, G1 and G2, with a higher prevalence of G1 strains in China. Both in vitro and in vivo experiments demonstrated that FPV072 (G1 group) exhibited enhanced infectivity and pathogenicity compared to FPV027 (G2 Group). The structural alignment of the VP2 protein between the two viruses revealed mutations in residues 91, 232, and 300 that may contribute to differences in infectivity and pathogenicity. The findings from these observations will contribute significantly to the overall understanding of the molecular epidemiology of FPV in China and facilitate the development of an effective FPV vaccine.

Multiple factors and features dictate the selective production of ct-siRNA in Arabidopsis.

Coding transcript-derived siRNAs (ct-siRNAs) produced from specific endogenous loci can suppress the translation of their source genes to balance plant growth and stress response. In this study, we generated Arabidopsis mutants with deficiencies in RNA decay and/or post-transcriptional gene silencing (PTGS) pathways and performed comparative sRNA-seq analysis, revealing that multiple RNA decay and PTGS factors impede the ct-siRNA selective production. Genes that produce ct-siRNAs often show increased or unchanged expression and typically have higher GC content in sequence composition. The growth and development of plants can perturb the dynamic accumulation of ct-siRNAs from different gene loci. Two nitrate reductase genes, NIA1 and NIA2, produce massive amounts of 22-nt ct-siRNAs and are highly expressed in a subtype of mesophyll cells where DCL2 exhibits higher expression relative to DCL4, suggesting a potential role of cell-specific expression of ct-siRNAs. Overall, our findings unveil the multifaceted factors and features involved in the selective production and regulation of ct-siRNAs and enrich our understanding of gene silencing process in plants.

Droplet Microfluidic-Based Low-Cost and High-Speed Microsphere Array Direct Writing Technology and Its Applications.

Microsphere arrays have significant applications and broad development prospects in various fields and disciplines. The simple, efficient, low-cost, automatic, and controllable preparation of microsphere arrays in multiple dimensions and morphologies is still a significant challenge. Here, a novel microsphere array direct writing technology was developed using a low-cost portable droplet microfluidic device and a high-precision XY movable platform. The proposed technology provided a powerful platform for the direct-writing preparation of microsphere arrays and was successfully applied to the precise and controllable fabrication of microsphere arrays with different sizes, shapes, structures, and arrangements. Additionally, gel microsphere arrays with metal ion patterns were fabricated using the microsphere arrays as templates and exhibited excellent performance in the visual analytical detection of heavy metal ions. Moreover, the simulated microsphere arrays offer a promising platform for rapidly generating high-viability and uniform 3D tumor spheroids. Therefore, given the superiority of this technology and the great potential of microsphere arrays, this simple high-speed microsphere array direct writing technology has a promising application in the multidisciplinary intersection of chemical, biological, and material sciences.

A comprehensive analysis of transcriptome and phenolic compound profiles suggests the role of flavonoids in cotyledon greening in Catharanthus roseus seedling.

During seedling photo-morphogenesis, cotyledon greening is a vital developmental process and a moment of responding to light stress. An increasing number of reports suggest the function of natural antioxidant protection of phenolic compounds in plant growth and development processes. Due to the antioxidant functions, flavonoids allow plants to respond to abiotic or biotic stresses. As one of the plants rich in secondary metabolites, Catharanthus roseus has drawn great academic interest due to its richness of diverse secondary metabolites with medicinal values. To assess the distribution and function of phenolic compounds during cotyledon greening, combined phenolic profiling and transcriptome were applied in C. roseus seedling through ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometer (UPLC-Q-TOF/MS) and high throughput RNA sequencing, respectively. Results herein showed that light-exposed greening cotyledon accumulated large amounts of C6C3C6-type flavonoids, suggesting the function in repressing reactive oxygen species (ROS) generation to improve light adaptation and seedling survival. Moreover, synergistic up-regulation of relevant genes involved in flavonoids pathway, including PAL, C4H, CHS, FLS, and F3'H, was monitored in response to light. Several crucial candidate transcription factors including bHLH, MYB, and B-box families were likely to function, and thereinto, CrHY5 (CRO_T122304) and CRO_T137938 revealed a prompt response to light, supposing to induce flavonoids accumulation by targeting CHS and FLS. Therefore, this study provided new insight into the potential regulation and underlying roles of flavonoids to improve light acclimation during cotyledon greening.

Inhibition of microRNA-30a alleviates vascular remodeling in pulmonary arterial hypertension.

The excessive and ectopic pulmonary artery smooth muscle cells (PASMCs) are crucial to the pathogenesis of pulmonary arteriole (PA) remodeling in pulmonary arterial hypertension (PAH). We previously found that microRNA (miR)-30a was significantly increased in acute myocardial infarction (AMI) patients and animals, as well as in cultured cardiomyocytes after hypoxia, suggesting that it might be strongly associated with hypoxia-related diseases. Here, we investigated the role of miR-30a in the PASMC remodeling of PAH. The expression of miR-30a was higher in the serum of PAH patients compared with healthy controls. miR-30a was mainly expressed in PAs and was increased in PASMCs after hypoxia, mediating the downregulation of p53 tumor suppressor protein (P53). Genetic knockout of miR-30a effectively decreased right ventricular (RV) systolic pressure (RVSP), PA, and RV remodeling in the Su5416/hypoxia-induced and monocrotaline (MCT)-induced PAH animals. Additionally, pharmacological inhibition of miR-30a via intratracheal liquid instillation (IT-L) delivery strategy showed high efficiency, which downregulated miR-30a to mitigate disease phenotype in the Su5416/hypoxia-induced PAH animals, and these beneficial effects could be partially reduced by simultaneous P53 inhibition. We demonstrate that inhibition of miR-30a could ameliorate experimental PAH through the miR-30a/P53 signaling pathway, and the IT-L delivery strategy shows good therapeutic outcomes, providing a novel and promising approach for the treatment of PAH.

Vaccine Against PCSK9 Improved Renal Fibrosis by Regulating Fatty Acid ß-Oxidation.

Background Defects in the renal fatty acid ß-oxidation pathway have been implicated in the development of renal fibrosis. Our group has developed a therapeutic vaccine targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), named PCSK9Qß-003. In this study, we investigated the potential effectiveness of the PCSK9Qß-003 vaccine on hypercholesterolemia with renal fibrosis. Methods and Results The low-density lipoprotein receptor+/- male mice fed with a high-cholesterol (1%) Western diet were randomly assigned into 4 groups: the sham group (or the control group), the phosphate-buffered saline group, the Qß virus-like particles group and the PCSK9Qß-003 vaccine group. Mice of the PCSK9Qß-003 group were injected with the PCSK9Qß-003 vaccine (100 µg/time) every 2 or 4 weeks. The mice were administered with either unilateral ureteral obstruction for 2 weeks or N-nitro-l-arginine methyl ester (50 mg/kg per day) for 6 weeks to establish a renal fibrosis model. Compared with the other 3 groups, the PCSK9Qß-003 vaccine obviously decreased total cholesterol and low-density lipoprotein cholesterol in low-density lipoprotein receptor+/- mice with hypercholesterolemia. Compared with the phosphate-buffered saline and Qß virus-like particles groups, the PCSK9Qß-003 vaccine improved hepatic steatosis and renal function. Histology analysis showed that the PCSK9Qß-003 vaccine significantly ameliorated renal lipid accumulation and renal fibrosis. Moreover, the PCSK9Qß-003 vaccine obviously upregulated the expression of low-density lipoprotein receptor, very-low-density lipoprotein receptor, sterol-regulatory element binding protein 2, and fatty acid ß-oxidation-related factors, and ameliorated renal fibrosis-related molecules both in the unilateral ureteral obstruction and N-nitro-l-arginine methyl ester models. Conclusions This study suggested that the PCSK9Qß-003 vaccine improved renal lipid accumulation and renal fibrosis by regulating fatty acid ß-oxidation, which may provide a promising method for treating hypercholesterolemia with renal fibrosis.

Short-term Peginterferon-Induced High Functional Cure Rate in Inactive Chronic Hepatitis B Virus Carriers With Low Surface Antigen Levels.

BACKGROUND: None of the current guidelines recommend antiviral therapy for inactive hepatitis B virus (HBV) carriers (IHCs). METHODS: In this real-world, multicenter, nonrandomized study, 32 participants meeting the inclusion criteria were enrolled 1:1 for treatment with peginterferon α-2b or monitoring without treatment based on participant preference. The expected treatment duration was 48 weeks. The primary end point was hepatitis B surface antigen (HBsAg) loss. The HBV vaccine could be injected after HBsAg loss. RESULTS: All patients had HBsAg levels of <20 IU/mL. The mean baseline HBsAg levels were 6.6 IU/mL and 5.8 IU/mL in the treated and untreated groups, respectively. Fifteen (93.8%) participants achieved HBsAg loss, 5 obtained HBsAg seroconversion after undergoing a mean of 19.7 weeks of therapy in the treated group, and no one in the follow-up group achieved HBsAg loss during a mean follow-up time of 12.6 months (P < .0001). Generally, the therapy was well tolerated. Nine of 11 individuals who exhibited HBsAg loss benefited from receiving the HBV vaccine. CONCLUSIONS: This study provides justification for further studies of short-course peginterferon α-2b for the functional cure of IHCs with low HBsAg levels. Additionally, HBV vaccine injection is beneficial after interferon-induced HBsAg loss.

Trocar opening: silicone oil removal with phacoemulsification and intraocular lens implantation.

AIM: To evaluate the efficacy and safety of a modified technique [trocar opening (TO)] for silicone oil removal (SOR) in combination with phacoemulsification and intraocular lens (IOL) implantation. METHODS: A total of 60 eyes of 60 patients with cataract and silicone oil-filled eyes were enrolled in this study. The patients were divided into two groups: the patients in the control group underwent 23-gauge pars plana active SOR surgery with phacoemulsification and IOL implantation, while the patients in the TO group underwent TO methods during surgery. Best corrected visual acuity (BCVA), surgery time, intraocular pressure, and operative complications were observed 6mo after surgery. RESULTS: There was no significant difference between the two groups in terms of age, gender, preoperative, intraocular pressure, or time of silicone oil stay. Prior to surgery, the mean BCVA for the control and TO groups was 1.34±0.44 and 1.36±0.42. At 6mo following surgery, the mean BCVA improved to 0.74±0.36 and 0.77±0.32, respectively (P<0.001). There was no significant difference between the two groups. The mean SOR time was 6.9±2.3min and 4.8±1.2min in the control and TO groups (P=0.008). The total operation time was 28.2±8.5min and 24.6±6.4min, respectively (P=0.035). Posterior capsule rupture occurred in four eyes of control and none of TO group (P<0.01). Late recurrent retinal detachment occurred in one eye in the control group (2mo after surgery) and in one eye in the TO group (4mo after surgery). CONCLUSION: TO is a simple, effective, time-saving, and safe method for SOR combined with phacoemulsification and IOL implantation.

The ATRQß-001 vaccine improves cardiac function and prevents postinfarction cardiac remodeling in mice.

We invented the ATRQß-001 hypertension vaccine, which targeted angiotensin II type 1 receptor (AT1R) and showed a desirable blocking effect for AT1R. The purpose of this study was to investigate whether the ATRQß-001 vaccine could improve cardiac function and prevent cardiac remodeling after acute myocardial infarction (AMI). C57BL/6 male mice were randomly assigned into four groups: sham + VLP, MI + VLP, MI + ATRQß-001, and MI + valsartan. Mice were administered Qß virus-like particle (Qß-VLP, 100 µg/time), ATRQß-001 vaccine (100 µg/time), and valsartan (6 mg/kg/day) before AMI, which was induced by permanently ligating the left anterior descending coronary artery. The effect of the ATRQß-001 vaccine on cardiac function and cardiac remodeling was observed by following up for 1 week, 4 weeks, and 12 weeks post MI. The ATRQß-001 vaccine significantly reduced sudden cardiac death and increased survival rates (compared with MI + VLP, 80% versus 55% and mean estimate (days) 68.4 ± 7.0 versus 47.8 ± 8.9, respectively; p = 0.046) post MI. Echocardiography showed that the ATRQß-001 vaccine remarkably improved cardiac function (left ventricular ejection fraction, 24.8 ± 7.0% versus 13.2 ± 3.8%, p = 0.005) post MI. Histological analysis revealed that the ATRQß-001 vaccine obviously mitigated myocardial inflammation, apoptosis, and fibrosis after AMI. Further, the ATRQß-001 vaccine significantly inhibited the TGF-ß1/Smad2/3 signaling pathway. Assessment of the renin-angiotensin system (RAS) demonstrated that the ATRQß-001 vaccine did not cause obvious feedback of circulating RAS, but prominently attenuated the expression of AT1R, compared with the other groups at 4 and 12 weeks after AMI. In conclusion, the ATRQß-001 vaccine decreased mortality and improved cardiac function and remodeling after AMI.