Lymph node-targeted STING agonist nanovaccine against chronic HBV infection.

Chronic hepatitis B virus (HBV) infection is a global health problem that substantially increases the risk of developing liver disease. The development of a novel strategy to induce anti-HB seroconversion and achieve a long-lasting immune response against chronic HBV infection remains challenging. Here, we found that chronic HBV infection affected the signaling pathway involved in STING-mediated induction of host immune responses in dendritic cells (DCs) and then generated a lymph node-targeted nanovaccine that co-delivered hepatitis B surface antigen (HBsAg) and cyclic diguanylate monophosphate (c-di-GMP) (named the PP-SG nanovaccine). The feasibility and efficiency of the PP-SG nanovaccine for CHB treatment were evaluated in HBV-carrier mice. Serum samples were analyzed for HBsAg, anti-HBs, HBV DNA, and alanine aminotransferase levels, and liver samples were evaluated for HBV DNA and RNA and HBcAg, accompanied by an analysis of HBV-specific cellular and humoral immune responses during PP-SG nanovaccine treatment. The PP-SG nanovaccine increased antigen phagocytosis and DC maturation, efficiently and safely eliminated HBV, achieved a long-lasting immune response against HBV reinjection, and disrupted chronic HBV infection-induced immune tolerance, as characterized by the generation and multifunctionality of HBV-specific CD8+ T and CD4+ T cells and the downregulation of immune checkpoint molecules. HBV-carrier mice immunized with the PP-SG nanovaccine achieved partial anti-HBs seroconversion. The PP-SG nanovaccine can induce sufficient and persistent viral suppression and achieve anti-HBs seroconversion, rendering it a promising vaccine candidate for clinical chronic hepatitis B therapy.

PD-1: A critical player and target for immune normalization.

Immune system imbalances contribute to the pathogenesis of several different diseases, and immunotherapy shows great therapeutic efficacy against tumours and infectious diseases with immune-mediated derivations. In recent years, molecules targeting the programmed cell death protein 1 (PD-1) immune checkpoint have attracted much attention, and related signalling pathways have been studied clearly. At present, several inhibitors and antibodies targeting PD-1 have been utilized as anti-tumour therapies. However, increasing evidence indicates that PD-1 blockade also has different degrees of adverse side effects, and these new explorations into the therapeutic safety of PD-1 inhibitors contribute to the emerging concept that immune normalization, rather than immune enhancement, is the ultimate goal of disease treatment. In this review, we summarize recent advancements in PD-1 research with regard to immune normalization and targeted therapy.

Temperature-Sensitive Sensors Modified with Poly(N-isopropylacrylamide): Enhancing Performance through Tailored Thermoresponsiveness.

The development of temperature-sensitive sensors upgraded by poly(N-isopropylacrylamide) (PNIPAM) represents a significant stride in enhancing performance and tailoring thermoresponsiveness. In this study, an array of temperature-responsive electrochemical sensors modified with different PNIPAM-based copolymer films were fabricated via a "coating and grafting" two-step film-forming technique on screen-printed platinum electrodes (SPPEs). Chemical composition, grafting density, equilibrium swelling, surface wettability, surface morphology, amperometric response, cyclic voltammograms, and other properties were evaluated for the modified SPPEs, successively. The modified SPPEs exhibited significant changes in their properties depending on the preparation concentrations, but all the resulting sensors showed excellent stability and repeatability. The modified sensors demonstrated favorable sensitivity to hydrogen peroxide and L-ascorbic acid. Furthermore, notable temperature-induced variations in electrical signals were observed as the electrodes were subjected to temperature fluctuations above and below the lower critical solution temperature (LCST). The ability to reversibly respond to temperature variations, coupled with the tunability of PNIPAM's thermoresponsive properties, opens up new possibilities for the design of sensors that can adapt to changing environments and optimize their performance accordingly.

Research Progress in Nanoparticle Inhibitors for Crude Oil Asphaltene Deposition.

Currently, the alteration of external factors during crude oil extraction easily disrupts the thermodynamic equilibrium of asphaltene, resulting in the continuous flocculation and deposition of asphaltene molecules in crude oil. This accumulation within the pores of reservoir rocks obstructs the pore throat, hindering the efficient extraction of oil and gas, and consequently, affecting the recovery of oil and gas resources. Therefore, it is crucial to investigate the principles of asphaltene deposition inhibition and the synthesis of asphaltene inhibitors. In recent years, the development of nanotechnology has garnered significant attention due to its unique surface and volume effects. Nanoparticles possess a large specific surface area, high adsorption capacity, and excellent suspension and catalytic abilities, exhibiting unparalleled advantages compared with traditional organic asphaltene inhibitors, such as sodium dodecyl benzene sulfonate and salicylic acid. At present, there are three primary types of nanoparticle inhibitors: metal oxide nanoparticles, organic nanoparticles, and inorganic nonmetal nanoparticles. This paper reviews the recent advancements and application challenges of nanoparticle asphaltene deposition inhibition technology based on the mechanism of asphaltene deposition and nano-inhibitors. The aim was to provide insights for ongoing research in this field and to identify potential future research directions.

Structural Transformation and Photoluminescent Property of Manganese-Doped Bismuth-Based Perovskites.

Here, we synthesized pure Cs3Bi2Cl9 (CBC) and manganese (Mn)-doped crystals with different feeding ratios, leading to changes in structure and luminescence. The crystals Cs3Bi2Cl9-Mn (CBCM) formed by doping a minor amount of Mn2+ (Bi/Mn = 8:1) maintain the orthorhombic phase structure of the host, but when Bi/Mn = 2:1, the crystal structure is more inclined to form Cs4MnBi2Cl12 (CMBC) of a trigonal phase. Combined with density functional theory (DFT) calculation, the results demonstrate that a moderate amount of Mn2+ doping can create impurity energy levels in the forbidden band. However, as the structure transitions, the type of energy band structure changes from indirect to direct, with completely different electronic orbital features. Temperature-dependent time-resolved and steady-state photoluminescence spectroscopies are used to explore the structure-related thermal properties and transitional process. Differences energy transfer routes are revealed, with CBCM relying on intersystem energy transfer and CMBC mainly depending on direct excitation of Mn2+ to produce d-d transitions. Furthermore, since CMBC is temperature-sensitive, we perform the first photoluminescent (PL) lifetime temperature measurement using CBMC and obtain a maximum relative sensitivity of 1.7 %K-1 and an absolute sensitivity of 0.0099 K-1. Our work provides insight into the mechanism of Mn2+ doping-induced luminescence and offers a potentially effective doping strategy for improving the PL properties of lead-free metal halide perovskites.

Comparative Analysis of the Complete Mitochondrial Genomes of Apium graveolens and Apium leptophyllum Provide Insights into Evolution and Phylogeny Relationships.

The genus Apium, belonging to the family Apiaceae, comprises roughly 20 species. Only two species, Apium graveolens and Apium leptophyllum, are available in China and are both rich in nutrients and have favorable medicinal properties. However, the lack of genomic data has severely constrained the study of genetics and evolution in Apium plants. In this study, Illumina NovaSeq 6000 and Nanopore sequencing platforms were employed to identify the mitochondrial genomes of A. graveolens and A. leptophyllum. The complete lengths of the mitochondrial genomes of A. graveolens and A. leptophyllum were 263,017 bp and 260,164 bp, respectively, and contained 39 and 36 protein-coding genes, five and six rRNA genes, and 19 and 20 tRNA genes. Consistent with most angiosperms, both A. graveolens and A. leptophyllum showed a preference for codons encoding leucine (Leu). In the mitochondrial genome of A. graveolens, 335 SSRs were detected, which is higher than the 196 SSRs found in the mitochondrial genome of A. leptophyllum. Studies have shown that the most common RNA editing type is C-to-U, but, in our study, both A. graveolens and A. leptophyllum exhibited the U-C editing type. Furthermore, the transfer of the mitochondrial genomes of A. graveolens and A. leptophyllum into the chloroplast genomes revealed homologous sequences, accounting for 8.14% and 4.89% of the mitochondrial genome, respectively. Lastly, in comparing the mitochondrial genomes of 29 species, it was found that A. graveolens, A. leptophyllum, and Daucus carota form a sister group with a support rate of 100%. Overall, this investigation furnishes extensive insights into the mitochondrial genomes of A. graveolens and A. leptophyllum, thereby enhancing comprehension of the traits and evolutionary patterns within the Apium genus. Additionally, it offers supplementary data for evolutionary and comparative genomic analyses of other species within the Apiaceae family.

Laser-induced crystal growth observed in CsPbBr3 perovskite nanoplatelets.

Benefiting from the easily adjustable optical properties of perovskite, CsPbBr3 nanocrystals (NCs) are considered to show their advantages in the field of display. Here, we report that a selective laser irradiation is used to induce CsPbBr3 nanostructural reshaping and then yielding a morphological change. Under 360 or 405 nm laser irradiation, a hierarchical crystal growth process occurs for the fabricated CsPbBr3 nanoplatelets (NPLs), which are first arranged in a side-by-side manner and reshaped into nanorods (NRs), and then NRs are arranged in the face-to-face manner to reshape into NCs. The entire process is monitored optically and microscopically, which showed that crystal growth relies on seeking a dynamic balance between heat dissipation and accumulation under laser irradiation. The heat on NPLs generated by laser irradiation dissipated with a low dissipation rate and thus led to temperature rising and lattice breaking, which turned out to be the driving force for the crystal growth in CsPbBr3 NPLs. This feasible laser irradiation-assisted method provides for crystal growth a reliable and scalable route toward the preparation of perovskite functional materials.

HBsAg Dampened STING Associated Activation of NK Cells in HBeAg-Negative CHB Patients.

NK cells play crucial roles in defending against persistent HBV. However, NK cells present dysfunction in chronic hepatitis B virus (CHB) infection, and the associated mechanism is still not fully understood. Except for the regulatory receptors, NK cells could also be regulated by the surface and intracellular pattern recognition receptors (PRRs). In the present study, we found that the level of the adaptor of DNA sensor STING in NK cells was significantly decreased in HBeAg-negative CHB patients, and it was positively associated with the degranulation ability of NK cells. Compared to NK cells from healthy donors, NK cells from HBeAg-negative CHB patients displayed a lower responsiveness to cGAMP stimulation. Further investigation showed that HBsAg could inhibit the STING expression in NK cells and suppress the response of NK cells to cGAMP. Significantly, STAT3 was identified to be a transcription factor that directly regulated STING transcription by binding to the promoter. In addition, STAT3 positively regulated the STING associated IFN-α response of NK cells. These findings suggested that STING is an important adaptor in NK cell recognition and activation, while HBsAg disturbs NK cell function by the STAT3-STING axis, providing a new mechanism of NK disability in HBeAg-negative CHB infection.

Synergetic Tumor Probes for Facilitating Therapeutic Delivery by Combined-Functionalized Peptide Ligands.

Both targeting and penetrating ability are the key characteristics for tissue probing and precise delivery. To construct an efficient nano probing and delivery system toward human epidermal growth factor receptor 2 (HER2) positive cancer, we established a nano liposomal system functionalized with a newly screened HER2 targeting peptide (HP2, YDLKEPEH) and the cell-penetrating peptide TAT simultaneously. Compared with the monofunctionalized liposomal probes, the dual-functional ones demonstrated a synergetic effect in cell uptake, drug delivery, and in vivo imaging. The improved efficacy of the synergetic system provides a prospective strategy for cancer diagnosis and therapy.

Drug Elimination Alteration in Acute Lymphoblastic Leukemia Mediated by Renal Transporters and Glomerular Filtration.

PURPOSE: Drug elimination alteration has been well reported in acute lymphoblastic leukemia (ALL). Considering that transporters and glomerular filtration influence, to different extents, the drug disposition, and possible side effects, we evaluated the effects of ALL on major renal transporters and glomerular filtration mediated pharmacokinetic changes, as well as expression of renal drug transporters. METHODS: ALL xenograft models were established and intravenously injected with substrates of renal transporters and glomerular filtration separately in NOD/SCID mice. The plasma concentrations of substrates, after single doses, were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS: With the development of ALL, protein expression of MDR1, OAT3 and OCT2 were increased by 2.62-fold, 1.70-fold, and 1.45-fold, respectively, whereas expression of MRP2 and MRP4 were significantly decreased by 30.98% and 45.28% in the kidney of ALL groups compared with control groups. Clearance of MDR1-mediated digoxin, OAT3-mediated furosemide, and OCT2-mediated metformin increased by 3.04-fold, 1.47-fold, and 1.26-fold, respectively. However, clearance of MRPs-mediated methotrexate was reduced by 39.5%. These results are consistent with mRNA expression. Clearance of vancomycin and amikacin, as markers of glomerular filtration rate, had a 2.14 and 1.64-fold increase in ALL mice, respectively. CONCLUSIONS: The specific alteration of renal transporters and glomerular filtration in kidneys provide a rational explanation for changes in pharmacokinetics for ALL.

Poly I:C-based rHBVvac therapeutic vaccine eliminates HBV via generation of HBV-specific CD8+ effector memory T cells.

OBJECTIVE: Chronic hepatitis B (CHB) virus infection is a global health problem. Finding a cure for CHB remains a challenging task. DESIGN: In this study, poly I:C was employed as an adjuvant for HBV therapeutic vaccine (referred to as pHBV-vaccine) and the feasibility and efficiency of pHBV-vaccine in CHB treatment were evaluated in HBV-carrier mice. RESULTS: We found that pHBV-vaccine decreased HBsAg and HBV DNA efficiently and safely in HBV-carrier mice. Further investigation showed that pHBV-vaccine promoted maturation and antigen presentation ability of dendritic cells in vivo and in vitro. This vaccine successfully restored the exhaustion of antigen-specific CD8+ T cells and partly broke the immune tolerance established in HBV-carrier mice. pHBV-vaccine also enhanced the proliferation and polyfunctionality of HBV-specific CD11ahi CD8αlo cells. Importantly, we observed that T cell activation molecule KLRG1 was only expressed on HBV specific CD11ahi CD8αlo cells. Furthermore, pHBV-vaccine reduced the expression of Eomes and increased the serum IL-12 levels, which in turn promoted the generation of effector memory short-lived effector cells (SLECs) to exhibit a critical role in HBV clearance. SLECs induced by pHBV-vaccine might play a crucial role in protecting from HBV reinfection. CONCLUSIONS: Findings from this study provide a new basis for the development of therapeutic pHBV-vaccine, which might be a potential candidate for clinical CHB therapy.

IFN-γ protects from apoptotic neutrophil-mediated tissue injury during acute Listeria monocytogenes infection.

Listeria monocytogenes (LM) is a foodborne Gram-positive intracellular pathogen that can cause listeriosis in humans and animals. Although phagocytes are known to be involved in the response to this infection, the role of neutrophils is not entirely clear. Here, we have demonstrated that soon after LM infection, a large number of IFN-γ-producing neutrophils quickly accumulated in the spleen, blood, and peritoneal cavity. Both in vivo and in vitro experiments demonstrated that neutrophils were an important source of IFN-γ. IFN-γ played a critical protective role against acute LM infection, as demonstrated by the poor survival of Ifng-/- mice. Moreover, IFN-γ promoted bacterial clearance by the neutrophils, thereby inhibiting LM-induced neutrophil apoptosis and spleen damage. In addition to this, IFN-γ could effectively drive macrophage-mediated phagocytosis of apoptotic neutrophils, which was accompanied with TGF-ß secretion and was involved in protection against tissue injury. Importantly, by phagocytizing apoptotic neutrophils, macrophages obtained myeloperoxidase, an important bactericidal molecule only produced by neutrophils, which further promoted the antibacterial activity of macrophages. These findings demonstrate that neutrophils are an important source of IFN-γ at the early stage of LM infection, which is characterized by both LM elimination and tissue-protective effects.

TLR9 Regulates the NF-κB-NLRP3-IL-1ß Pathway Negatively in Salmonella-Induced NKG2D-Mediated Intestinal Inflammation.

TLRs are key sensors for conserved bacterial molecules and play a critical role in host defense against invading pathogens. Although the roles of TLRs in defense against pathogen infection and in maintaining gut immune homeostasis have been studied, the precise functions of different TLRs in response to pathogen infection in the gut remain elusive. The present study investigated the role of TLR signaling in defense against the Gram-negative bacterial pathogen Salmonella typhimurium The results indicated that TLR9-deficient mice were more susceptible to S. typhimurium infection compared with wild-type and TLR2- or TLR4-deficient mice, as indicated by more severe intestinal damage and the highest bacterial load. TLR9 deficiency in intestinal epithelial cells (IECs) augmented the activation of NF-κB and NLRP3 inflammasomes significantly, resulting in increased secretion of IL-1ß. IL-1ß increased the expression of NKG2D on intestinal intraepithelial lymphocytes and NKG2D ligands on IECs, resulting in higher susceptibility of IECs to cytotoxicity of intestinal intraepithelial lymphocytes and damage to the epithelial barrier. We proposed that TLR9 regulates the NF-κB-NLRP3-IL-1ß pathway negatively in Salmonella-induced NKG2D-mediated intestinal inflammation and plays a critical role in defense against S. typhimurium infection and in the protection of intestinal integrity.

Intestinal Lamina Propria CD4+ T Cells Promote Bactericidal Activity of Macrophages via Galectin-9 and Tim-3 Interaction during Salmonella enterica Serovar Typhimurium Infection.

The intestinal immune system is crucial for protection from pathogenic infection and maintenance of mucosal homeostasis. We studied the intestinal immune microenvironment in a Salmonella enterica serovar Typhimurium intestinal infection mouse model. Intestinal lamina propria macrophages are the main effector cells in innate resistance to intracellular microbial pathogens. We found that S Typhimurium infection augmented Tim-3 expression on intestinal lamina propria CD4+ T cells and enhanced galectin-9 expression on F4/80+ CD11b+ macrophages. Moreover, CD4+ T cells promoted the activation and bactericidal activity of intestinal F4/80+ CD11b+ macrophages via the Tim-3/galectin-9 interaction during S Typhimurium infection. Blocking the Tim-3/galectin-9 interaction with α-lactose significantly attenuated the bactericidal activity of intracellular S Typhimurium by macrophages. Furthermore, the Tim-3/galectin-9 interaction promoted the formation and activation of inflammasomes, which led to caspase-1 cleavage and interleukin 1ß (IL-1ß) secretion. The secretion of active IL-1ß further improved bactericidal activity of macrophages and galectin-9 expression on macrophages. These results demonstrated the critical role of the cross talk between CD4+ T cells and macrophages, particularly the Tim-3/galectin-9 interaction, in antimicrobial immunity and the control of intestinal pathogenic infections.

Ultrafast spectroscopic studies of composition-dependent near-infrared-emitting alloyed CdSeTe quantum dots.

In this study, optical and structural characterizations of near-infrared-emitting alloyed CdSeTe quantum dots (QDs) are measured after the dissolution in toluene. Luminescence spectra are obtained from alloyed CdSeTe QDs under 800 nm femtosecond laser excitation. With increasing pump fluence, the line width or full width at half maximum (FWHM) of photoluminescence (PL) spectrum becomes larger than 10 nm due to increasing temperature. Ultrafast spectroscopic properties of CdSeTe QDs are investigated by means of time-resolved PL, transient absorption (TA) and Z scan techniques. Moreover, open-aperture (OA) Z scan measurement is used to clarify the composition and pump fluence dependence of optical nonlinearity under femtosecond laser excitation. With increasing pump fluence, evolution from saturable absorption to reverse saturable absorption in CdSeTe QDs is observed. The transition process is analyzed via a phenomenological model based on nonlinear absorption coefficient and saturation intensity, which indicates that CdSeTe QDs have potential for applications in all-optical switching devices.

HBV inhibits LPS-induced NLRP3 inflammasome activation and IL-1ß production via suppressing the NF-κB pathway and ROS production.

BACKGROUND & AIMS: Hepatitis B virus (HBV) has developed strategies to evade immune responses. However, the mechanisms involved remain unclear. The NLRP3 inflammasome plays crucial roles in antiviral host defense and its downstream factor IL-1ß has been shown to inhibit HBV infection in vivo. This study aims to assess whether HBV can affect the NLRP3 inflammasome signaling pathways and shed light on the underlying mechanisms HBV utilizes to evade host innate immune responses. METHODS: HBV inhibition of the lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation was evaluated by Western blot, quantitative RT-PCR, flow cytometry and immunofluorescence. RESULTS: Kupffer cells expressed significantly more NLRP3 and IL-1ß after LPS stimulation; whereas, chronic HBV infection suppressed LPS-induced NLRP3 and pro-IL-1ß expression as well as IL-1ß maturation. This inhibitory activity is mediated by HBeAg, and is involved in the inhibition of NF-κB signal pathway and reactive oxygen species (ROS) production. The inhibitory effect of HBeAg was confirmed in patients with chronic hepatitis B (CHB) and hepatocellular carcinoma by comparing the levels of IL-1ß and NLRP3-related proteins in para-carcinoma tissues from HBeAg-positive or negative patients. Moreover, chronic HBV infection increases the susceptibility of mice to S. typhimurium infection, possibly via inhibiting the NLRP3 inflammasome activation and IL-1ß production. CONCLUSIONS: HBeAg inhibits LPS-induced NLRP3 inflammasome activation and IL-1ß production via suppressing NF-κB pathway and ROS production. This finding provides a novel mechanism for HBV-mediated suppression of innate immune responses, and identifies new therapeutic targets for chronic HBV infection and related diseases. LAY SUMMARY: HBeAg suppresses LPS-induced NLRP3 inflammasome activation and IL-1ß production in two ways, one is to repress NLRP3 and pro-IL-1ß expression via inhibiting NF-κB phosphorylation, and the other is to repress caspase-1 activation and IL-1ß maturation via inhibiting ROS production. This effect contributes to the HBV persistence and immune tolerance.

NK cells are the crucial antitumor mediators when STAT3-mediated immunosuppression is blocked in hepatocellular carcinoma.

STAT3 is highly activated in a wide variety of cancers and functions to promote tumor survival. We previously reported that blocking STAT3 activation inhibited human hepatocellular carcinoma (HCC) growth in vitro, but whether this treatment also triggered antitumor immune responses in vivo remained unknown. In this study, we found that blocking the STAT3 pathway in HCC cells dramatically inhibited murine HCC growth in vivo and prolonged survival of tumor-bearing mice. Importantly, the presence of STAT3-blocked HCC augmented NK cell cytotoxicity against HCC and increased expression of molecules associated with NK cell activation and cytotoxicity. In T cell-deficient nude mice, a unique NK cell-mediated antitumor function against STAT3-blocked HCC was suggested. NK cells were shown to be necessary and sufficient in NK or T cell depletion experiments, or by adoptively transferring NK cells. Furthermore, regulatory T cells and immunosuppressive IL-10 and TGF-ß cytokines were reduced in mice bearing STAT3-blocked HCC cells, suggesting that these factors may be involved in HCC-induced NK cell suppression. These findings indicate that blocking STAT3 in HCC cells can initiate innate immunity in vivo.

Toll-Like receptor 2 (TLR2) and TLR9 play opposing roles in host innate immunity against Salmonella enterica serovar Typhimurium infection.

Toll-like receptors (TLRs) are evolutionarily conserved host proteins that are essential for effective host defense against pathogens. However, recent studies suggest that some TLRs can negatively regulate immune responses. We observed here that TLR2 and TLR9 played opposite roles in regulating innate immunity against oral infection of Salmonella enterica serovar Typhimurium in mice. While TLR9-/- mice exhibited shortened survival, an increased cytokine storm, and more severe Salmonella hepatitis than wild-type (WT) mice, TLR2-/- mice exhibited the opposite phenomenon. Further studies demonstrated that TLR2 deficiency and TLR9 deficiency in macrophages both disrupted NK cell cytotoxicity against S. Typhimurium-infected macrophages by downregulating NK cell degranulation and gamma interferon (IFN-γ) production through decreased macrophage expression of the RAE-1 NKG2D ligand. But more importantly, we found that S. Typhimurium-infected TLR2-/- macrophages upregulated inducible nitric oxide synthase (iNOS) expression, resulting in a lower bacterial load than that in WT macrophages in vitro and livers in vivo as well as low proinflammatory cytokine levels. In contrast, TLR9-/- macrophages showed decreased reactive oxygen species (ROS) expression concomitant with a high bacterial load in the macrophages and in livers of TLR9-/- mice. TLR9-/- macrophages were also more susceptible than WT macrophages to S. Typhimurium-induced necroptosis in vitro, likely contributing to bacterial spread and transmission in vivo. Collectively, these findings indicate that TLR2 negatively regulates anti-S. Typhimurium immunity, whereas TLR9 is vital to host defense and survival against S. Typhimurium invasion. TLR2 antagonists or TLR9 agonists may thus serve as potential anti-S. Typhimurium therapeutic agents.

Therapeutic recovery of hepatitis B virus (HBV)-induced hepatocyte-intrinsic immune defect reverses systemic adaptive immune tolerance.

UNLABELLED: Hepatitis B virus (HBV) persistence aggravates hepatic immunotolerance, leading to the failure of cell-intrinsic type I interferon and antiviral response, but whether and how HBV-induced hepatocyte-intrinsic tolerance influences systemic adaptive immunity has never been reported, which is becoming the major obstacle for chronic HBV therapy. In this study, an HBV-persistent mouse, established by hydrodynamic injection of an HBV-genome-containing plasmid, exhibited not only hepatocyte-intrinsic but also systemic immunotolerance to HBV rechallenge. HBV-specific CD8(+) T-cell and anti-HBs antibody generation were systemically impaired by HBV persistence in hepatocytes. Interestingly, HBV-induced hepatocyte-intrinsic immune tolerance was reversed when a dually functional vector containing both an immunostimulating single-stranded RNA (ssRNA) and an HBx-silencing short hairpin RNA (shRNA) was administered, and the systemic anti-HBV adaptive immune responses, including CD8(+) T-cell and anti-HBs antibody responses, were efficiently recovered. During this process, CD8(+) T cells and interferon-gamma (IFN-γ) secreted play a critical role in clearance of HBV. However, when IFN-α/ß receptor was blocked or the Toll-like receptor (TLR)7 signaling pathway was inhibited, the activation of CD8(+) T cells and clearance of HBV was significantly impaired. CONCLUSION: These results suggest that recovery of HBV-impaired hepatocyte-intrinsic innate immunity by the dually functional vector might overcome systemic adaptive immunotolerance in an IFN-α- and TLR7-dependent manner. The strategy holds promise for therapeutic intervention of chronic persistent virus infection and associated cancers.

Nimodipine ameliorates liver fibrosis via reshaping liver immune microenvironment in TAA-induced in mice.

Nimodipine, a calcium antagonist, exert beneficial neurovascular protective effects in clinic. Recently, Calcium channel blockers (CCBs) was reported to protect against liver fibrosis in mice, while the exact effects of Nimodipine on liver injury and hepatic fibrosis remain unclear. In this study, we assessed the effect of nimodipine in Thioacetamide (TAA)-induced liver fibrosis mouse model. Then, the collagen deposition and liver inflammation were assessed by HE straining. Also, the frequency and phenotype of NK cells, CD4+T and CD8+T cells and MDSC in liver and spleen were analyzed using flow cytometry. Furthermore, activation and apoptosis of primary Hepatic stellate cells (HSCs) and HSC line LX2 were detected using α-SMA staining and TUNEL assay, respectively. We found that nimodipine administration significantly attenuated liver inflammation and fibrosis. And the increase of the numbers of hepatic NK and NKT cells, a reversed CD4+/CD8+T ratio, and reduced the numbers of MDSC were observed after nimodipine treatment. Furthermore, nimodipine administration significantly decreased α-SMA expression in liver tissues, and increased TUNEL staining adjacent to hepatic stellate cells. Nimodipine also reduced the proliferation of LX2, and significantly promoted high level of apoptosis in vitro. Moreover, nimodipine downregulated Bcl-2 and Bcl-xl, simultaneously increased expression of JNK, p-JNK, and Caspase-3. Together, nimodipine mediated suppression of growth and fibrogenesis of HSCs may warrant its potential use in the treatment of liver fibrosis.