DC Activation Research Articles

Multivariate analysis of morphological variation, biochemical content, antioxidant activity, and molecular characteristics of autochthonous Berberis crataegina DC. genotypes in Central Türkiye

BackgroundOne of the wild fruit species with a natural distribution in Türkiye, and historically used for medicinal purposes due to its rich composition, is Berberis crataegina DC. Various parts of the plant, including its roots, bark, leaves, flowers, and fruits, have been utilized in traditional medicine, while its fruits are also consumed in various forms as food. This study aimed to characterize the morphological, biochemical, and molecular traits of B. crataegina genotypes naturally growing in the Kayseri region, located in central Türkiye.ResultsThe fruit weight of the genotypes ranged from 0.047 to 0.137 g, fruit width from 3.06 to 4.64 mm, and fruit length from 5.80 to 9.05 mm. Similarly, the leaf traits of the genotypes exhibited wide variation. The total phenolic content ranged from 190.53 to 297.55 mg GAE/100 g, total flavonoid content from 82.03 to 203.89 mg QE/100 g, total anthocyanin content from 4.54 to 11.76 mg cyn-3 gluc/100 g, and total antioxidant capacity between 57.76 and 87.93%. A principal component analysis (PCA) of 11 traits identified four principal components with eigenvalues greater than 1. The first four components accounted for 71.89% of the total variation, with PCA1 explaining 23.48%, PCA2 18.68%, PCA3 16.39%, and PCA4 13.34%. ISSR molecular analysis using nine markers revealed a band count ranging from 4 to 13, polymorphic band count between 3 and 10, and polymorphism rates from 61.54 to 100%, with band lengths ranging from 200 to 1000 base pairs. According to the UPGMA dendrogram based on molecular analyses, the genetic similarity between the genotypes ranged from 0.64 to 1.00, with B2 and B13 being the most similar genotypes.ConclusionsIn conclusion, the Kayseri region is rich in B. crataegina genotypes with wide genetic variation. The genotypes identified in this region may serve as valuable genetic resources for future studies.

A review on ethnobotany, phytochemistry, and pharmacology of the genus Duhaldea DC.

The botanical drugs of genus Duhaldea DC. have been traditionally utilized in folk medicine for the treatment of a wide array of illnesses, encompassing fractures, bone wounds, carbuncles and poisoning, bronchitis, bruises, giddy with hypertension of qi, and lung deficiency cough. The genus Duhaldea DC. comprises 15 species widespread in Central, East, and Southeast Asia and 7 species (2 endemic) in China. The review aims to provide a systematic overview of ethnopharmacology, phytochemistry, and pharmacology of Duhaldea DC. and to explore the future therapeutic potential and scientific potential of this genus. The data were systematically collected from books and scientific databases such as PubMed, Web of Science, Google Scholar, CNKI, and doctoral and master's theses. To date, a total of 352 metabolites have been isolated from this genus, and terpenoids, flavonoids, phenylpropanoids, and inositol angelates are the primary contributors to the pharmacological activities of Duhaldea DC. The crude extracts and isolated phytochemical metabolites from this genus have been shown to exhibit various pharmacological activities, including anti-inflammatory, antimicrobial, anti-osteoporotic, anticancer, and antioxidant activities. Despite notable advancements in our understanding of the chemical constituents and pharmacological properties of Duhaldea DC., it is absolutely crucial to conduct additional research into the pharmacology and toxicology of these species to definitively ascertain their safety, efficacy, and quality.

P-type pilus PapG protein elicits toll-like receptor 2-mediated immune activation during cancer immunotherapy

The immune activation ability of FimH, an adhesion protein in pili of Escherichia coli (E. coli), has been recently reported. However, studies on the immune activity of PapG, another major pili terminal protein, have not been well explored. In this study, the immune stimulatory effect of purified recombinant PapG was evaluated. PapG treatment promoted dramatic changes in dendritic morphology of the bone marrow-derived dendritic cells (BMDCs) and induced upregulation of co-stimulatory molecule levels, major histocompatibility complex (MHC) I and II expression, and pro-inflammatory cytokine production in BMDCs. To identify the stimulatory receptor of PapG, an in silico study was performed. PapG exhibited strong binding affinity with murine toll-like receptor 2 (TLR2). In addition, PapG-induced activation of splenic DC and its subsets was unsuccessful in TLR2-knock out mice. Combination of PapG and ovalbumin (OVA) elicited OVA-specific T cell proliferation and cytokine production and cytotoxicity that consequently promoted anti-cancer immune responses against OVA-expressing B16 melanoma. Furthermore, PapG treatment induced activation of peripheral blood DCs and its subsets in humans in a TLR2 dependent manner. PapG-stimulated human conventional DC2 promoted syngeneic T cell proliferation and activation. The findings of this study demonstrated that PapG could be a useful immune stimulator for immunotherapy against cancer.

Abstract A070: Time-Dependent Oxidation and Aggregation of Vimentin upon Binding by β-lap Induced Immunogenic Cell Death

Abstract β-lapachone (β-lap) has been demonstrated as an NAD(P)H:quinone oxidoreductase1 (NQO1) bioactivatable compound. It initiated a futile redox cycle catalyzed by NQO1, resulting in reactive oxygen species (ROS) generation, with consumption of the reductive NAD(P)H. After a 4-h pulse of sufficiently lethal dose of β-lap, high levels of ROS diffused into nuclei to induce tumor-selective DNA damage and programmed necrosis in cancers overexpressing NQO1. Recently, our experiments showed that prolonged low dose β-lap administration exerted significant and NQO1 independent antitumor efficacy in mouse models with no overt signs of toxicity. Thus, we synthesized a photoactive β-lap probe to identify the molecular target of β-lap. Vimentin, a major constituent of the intermediate filament family of proteins, was identified as the direct binding target of β-lap. Vimentin was highly upregulated in multiple cancers including PDAC, and was a binding partner of β-lap with a dissociation constant at micromolar levels. Ligand binding assays in Panc1 cells employing β-lap as a specific competitor showed that vimentin was bound by β-lap-probe in a β-lap-competitive manner, and further confirmed that the in vivobinding target of β-lap was vimentin. Moreover, it was manifested that endogenous vimentin mRNA levels directly correlated with sensitivity to prolonged exposure of β-lap in a panel of pancreatic cancer cell lines, and knockout of vimentin in Panc1 cells markedly decreased lethality after prolonged exposure of β-lap. Mechanistically, we revealed that β-lap bound to vimentin and induced disulfide bonds that participated in disulfide cross-linking between a pair of vimentin dimers in a concentration and time dependent manner, forming vimentin oligomers of approximately 150 kDa. Prolonged exposure of β-lap promoted the disruption of filament architecture and vimentin degradation, ultimately resulting in cell death. In addition, the cell death by targeting vimentin exhibited a more inflammatory condition and enhanced DC activation. Together, our findings unveiled an unknown molecular target for β-lap and provided valuable insights into its mechanism of action. Targeting vimentin also presented a new strategy that inhibited the tumor growth and synergized with immunotherapy to disrupt immune evasion and reduce immune suppression against pancreatic cancers. Citation Format: Feng Qian, Lei Dou, Kaixin Wang, Yi Xia, Zhidong Chen, Yumeng Zu, Shuang Xi. Time-Dependent Oxidation and Aggregation of Vimentin upon Binding by β-lap Induced Immunogenic Cell Death [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A070.

A Multi-Functional Nanoadjuvant Coupling Manganese with Toll-Like 9 Agonist Stimulates Potent Innate and Adaptive Anti-Tumor Immunity.

The effectiveness of Toll-like 9 agonists (CpG) as an adjuvant for tumor immunotherapy is restricted due to their insufficient ability to activate anti-tumor immunity. To address that, the common nutrient metal ions are explored (Mn2+, Cu2+, Ca2+, Mg2+, Zn2+, Fe3+, and Al3+), identifying Mn2+ as a key enhancer of CpG to mediate immune activation by augmenting the STING-NF-κB pathway. Mn2+ and CpG are then self-assembled with epigallocatechin gallate (EGCG) into a nanoadjuvant MPN/CpG. Local delivery of MPN/CpG effectively inhibits tumor growth in a B16 melanoma-bearing mouse model, reshaping the tumor microenvironment (TME) by repolarizing M2-type tumor-associated macrophages (TAMs) to an M1-type and boosting intra-tumoral infiltration of CD8+/CD4+ T lymphocytes and DCs. Furthermore, compared to free CpG, MPN/CpG exhibits heightened accumulation in lymph nodes, enhancing CpG uptake and DC activation, consequently inducing significant antigen-specific cytotoxic CD8+ T cell immune response and humoral immunity. In a prophylactic tumor-bearing mouse model, MPN/CpG vaccination with OVA antigen significantly delays B16-OVA melanoma growth and extends mouse survival. These findings underscore the potential of MPN/CpG as a multifunctional adjuvant platform to drive powerful innate and adaptive immunity and regulate TME against tumors.

Zn(II)-based 2D coordination polymer bridged by isophthalate and Dipyridylsulphide : Structural characterisation, Schottky diode device and theoretical interpretation

The design of low cost, easy-to-prepare, soft-to-handle and sustainable material-based technology has been growing day-by-day. Coordination polymers (CPs) are such emerging materials those have been instructed as one of the premium resources to serve the electronic industry. In this aspect, we have designed a hetero-bridging Zn(II)-coordination polymer using two different bridging ligands - 4,4′-Dipyridylsulphide (4,4′-DPS) and 5-Nitroisophthalic acid (5-H2NIA), {[Zn(4,4′-DPS)2(5-HNIA)2(H2O)]n} (Zn-CP) and characterize the crystalline compound with Single Crystal X-ray diffraction (SCXRD) technique. The structure demonstrates that Zn-CP consists of two-dimensional (2D) network with distorted trigonal bipyramidal Zn(II) center (ZnN2O3). The self-assembly of 2D network by different non-covalent interactions forms three-dimensional (3D) supramolecular architecture. Hirshfeld surface analysis effectively evaluates the possibilities of non-covalent interactions present in Zn-CP. Density functional theory (DFT) based numerical calculation using crystallographic parameters has estimated the band gap 3.51 eV which implies the semiconducting nature of Zn-CP. This property has been endorsed by the determination of band gap from Tauc's plot (3.71 eV) using UV–Visible absorption data. The electrical conductivity of Zn-CP determined at room temperature is 8.54 x 10–7 S m-1. The DC activation energy of the device is 9.05 × 10–19 eV with the conductivity limit, 4.71 (Ω-m)-1 having Richardson constant, 7.07 × 10–10Am−2K−2and barrier height is 0.87 eV which suggests that the Zn-CP is n-type semiconductor. Thus, the present work may provide a facile pathway for laboratory-to-land application of such energy materials taking into consideration of technological aspect in the highly energy demanding era. Hence, the synthesized Zn-CP may have energy material application in the semiconducting industry.

Polyvinyl alcohol/carboxymethyl cellulose blended polymers doped with PPy/milled MWCNTs filler for Flexible optoelectronic and Energy Storage Applications

Using the solution casting procedure, poly (vinyl alcohol)/carboxymethyl cellulose/polypyrene/milled multiwall carbon nanotubes, PVA/CMC/PPy/x wt% milled MWCNTs blended polymers were formed. X-ray diffraction and scanning electron microscopy were employed to inspect the structure and morphology of the resulted blends. The lowest direct and indirect optical band gaps are (5, 4.3) eV and (4.37, 3.38) eV, respectively, achieved when the MWCNTs content in the doped blend was 0.25 wt %. By incorporating varying quantities of milled MWCNTs into the PVA/CMC/PPy blended polymer, consistent enhancements were observed in the optical dielectric constant and optical conductivity values. The blend with 0.25 wt% MWCNTs exhibited the maximum values of refractive index. The maximum electric dielectric constant and energy density values were attained as x = 0.15. The temperature impacted the dielectric constants and energy storage values. All blends fit with the CBH model. The impact of MWCNTs doping level and the temperature on the impedance spectroscopy and electric modulus of the host blend was explored. The sample with x = 0.15 has the smallest relaxation time. The impact of MWCNTs doping level on the dc conductivity, activation energy and conductivity mechanism of the host blend was explored. The doped blends with x = 0.15 is viable materials for energy storage purposes.

PDL1/HER2-Targeted Lipid-Encapsulated Oxygen Nanobubbles Combined with Photodynamic Therapy for HER2+ Breast Cancer Immunotherapy.

Programmed death (PD) 1/PD ligand 1 (PDL1) inhibitors are immune checkpoint inhibitors (ICIs) that may facilitate HER2-positive breast cancer treatment; however, their clinical efficacy remains elusive. Oxygen-enhanced photodynamic therapy (PDT) increases immunogenic cell death (ICD), providing a promising strategy to render the tumor microenvironment more sensitive to the ICIs. Lipid-encapsulated oxygen nanobubbles (Lipo-NBs-O2) obtained using nanobubbles (NBs) water for oxygen delivery in vivo can facilitate enhanced PDT. Here, dual-receptor targeted Lipo-NBs-O2 (DRT@Lipo-NBs-O2) is prepared by modifying Lipo-NBs-O2 with anti-PDL1 scFv and the fusion protein anti-HER2 scFv-tandem-repeat cytochrome c (anti-HER2-nCytc). Copper phthalocyanine is the photosensitizer (PS). DRT@Lipo-PS-NBs-O2 plus near-infrared irradiation leads to robust ICD induction, increasing DC activation and CD8+ T-cell numbers. Modification with anti-PDL1 scFv improves tumor distribution of DRT@Lipo-PS-NBs-O2 and plays the ICI role, invigorating CD8+ T cells and boosting the effects of immunotherapy. Oxygen supplied through DRT@Lipo-PS-NBs-O2 reduces P-glycoprotein expression. Enhanced PDT and Cytc can cause tumor cell death, thereby reducing the immune burden. Under dual receptor targeting and laser local irradiation, tumor cells become subject to the combination effects of PDT, ICD, ICIs, and apoptosis; this effectively suppresses tumor growth and metastasis. Lipo-NBs-O2 affords a combination of oxygen delivery and multidrug therapy to alleviate HER2-positive breast cancer.

Effect of hydroxy-α-sanshool on lipid metabolism in liver and hepatocytes based on AMPK signaling pathway

BackgroundWith the increasing awareness of the safety of traditional Chinese medicine and food, as well as in-depth studies on the pharmacological activity and toxicity of Zanthoxylum armatum DC. (ZADC), it has been found that ZADC is hepatotoxic. However, the toxic substance basis and mechanism of action have not been fully elucidated. Hydroxy-α-sanshool (HAS) belongs to an amide compound in the fruits of ZADC, which may be hepatotoxic. However, the specific effects of HAS, including liver toxicity, are unclear. PurposeThe objectives of this research was to determine how HAS affects hepatic lipid metabolism, identify the mechanism underlying the accumulation of liver lipids by HAS, and offer assurances on the safe administration of HAS. MethodsAn in vivo experiment was performed by gavaging C57 BL/6 J mice with various dosages of HAS (5, 10, and 20 mg/kg). Biochemical indexes were measured, and histological analysis was performed to evaluate HAS hepatotoxicity. Hepatic lipid levels were determined using lipid indices and oil red O (ORO) staining. Intracellular lipid content were determined by biochemical analyses and ORO staining after treating HepG2 cells with different concentrations of HAS in vitro. Mitochondrial membrane potential, respiratory chain complex enzymes, and ATP levels were assessed by fluorescence labeling of mitochondria. The levels of proteins involved in lipogenesis and catabolism were determined using Western blotting. ResultsMice in the HAS group had elevated alanine and aspartate aminotransferase blood levels as well as increased liver index compared with the controls. The pathological findings showed hepatocellular necrosis. Serum and liver levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels were increased, whereas high-density lipoprotein cholesterol levels decreased. The ORO staining findings demonstrated elevated liver lipid levels. In vitro experiments demonstrated a notable elevation in triglyceride and total cholesterol levels in the HAS group. ATP, respiratory chain complex enzyme gene expression, mitochondrial membrane potential, and mitochondrial number were reduced in the HAS group. The levels of lipid synthesis-associated proteins (ACC, FASN, and SREBP-1c) were increased, and lipid catabolism-associated protein levels (PPARα and CPT1) and the p-AMPK/AMPK ratio were decreased in vivo and in vitro. ConclusionHAS has hepatotoxic effects, which can induce fatty acid synthesis and mitochondrial function damage by inhibiting the AMPK signaling pathway, resulting in aberrant lipid increases.

Co-delivery of STING and TLR7/8 agonists in antigen-based nanocapsules to dendritic cells enhances CD8+ T cell-mediated melanoma remission

Insufficient efficacy of tumor vaccines still represents a major challenge due to poor adjuvant potency. Combining antigen and adjuvants of different classes bears the potential to induce a broad spectrum of anti-tumor immune responses. Here we demonstrate a novel nanocarrier (NC)-based vaccine combining the type I interferon-triggering STING agonist diamidobenzimidazole (diABZI) compound 3 and the well-established TLR7/8 agonist resiquimod (R848). Encapsulation of both adjuvants into polymeric nanocapsules enables the simultaneous transport of immunostimulatory molecules with tumor antigens. Thereby achieved co-delivery further improved DC stimulation and subsequent anti-tumor immune responses.Combined encapsulation of R848 and diABZI enhanced DC activation and induced stronger antigen-specific T cell responses compared to the single adjuvant NC treatment or using soluble forms of antigens and adjuvants in vitro and in vivo. This was determined by the vigorous expression of CD80, CD83, and CD86. Furthermore, the dual adjuvant therapy initiated the highest secretion levels of different pro-inflammatory cytokines and chemokines.Moreover, a substantial antigen-specific T cell proliferation led to robust tumor remission in a murine B16 melanoma model. Subcutaneous administration of R848/diABZI-loaded NCs induced enhanced infiltration of CD4+ and CD8+ T cells as well as neutrophils in tumor-draining lymph nodes (LN) and tumor tissue. Encapsulating the melanoma-specific antigenic peptide of TRP2 into the adjuvant-loaded NCs reduced the growth of B16 melanoma and prolonged the overall survival. The herein presented novel anti-tumor vaccination strategy avoids the use of structural compounds, increases the antigen load of dendritic cells, uses a fixed combination of antigen and two potent adjuvants and bears the potential to induce vigorous antigen-specific anti-cancer immunity.

Correlations of structural, thermal and electrical properties of sodium doped complex borophosphosilicate glass

Borophosphosilicate glasses with varying sodium ion concentrations were investigated for their, structural, thermal, and electrical properties. All the obtained glasses were transparent except the glass with the highest sodium content, which exhibited translucency due to inhomogeneities. Increasing sodium content led to reduced boron and silicon content while maintaining a constant B/Si ratio, indicating progressive depolymerization of the glass network. Confocal microscopy, scanning electron microscopy, and atomic force microscopy showed homogeneous and granular structure for samples with lower sodium content, but higher sodium content resulted in visible agglomeration/nanocrystallization. X-ray diffractograms showed amorphous nature for most samples, with samples doped with the highest concentrations of Na2O showing several broad reflections suggesting nanoscale crystallinity. Fourier-transform infrared spectroscopy revealed shifts in dominant bands with increasing sodium content, indicating depolymerization of the borate network. An observed decrease in glass transition temperature and thermal stability with increasing sodium content was attributed to depolymerization and formation of non-bridging oxygens. Impedance spectroscopy revealed two relaxation processes associated with the transport of Na+ ions through two different regions. DC conductivity and activation energy predominantly increased with the sodium ion content at high temperatures.

Bioactive constituents from Tinospora cordifolia (willd.): Isolation, synthesis and their immunomodulatory activity

Traditional medicinal plants have been used for centuries for their immunomodulatory properties and therapeutic potentials. The present study aims to investigate the immunomodulatory constituents from traditional medicinal plant, Tinospora cordifolia (willd.). Our study resulted in the isolation of new compound, 27-hydroxy octacosyl ferulate (1) along with eleven known compounds (2−12). The structures of the isolated compounds were characterized by combination of NMR (1D and 2D) and Mass spectroscopic methods. The hemisynthesis of compound 12 (ferulic acid) yielded (12a-12d and 12e-12 m) derivatives. Further, the isolated compounds and synthesized derivatives were assessed for their immunomodulatory potentials by evaluating their cytotoxicity and pro-inflammatory effects against macrophage cells (IL-6) and DC activation markers (CD 11c and 86). The biological results indicated that crude extract displayed potent immunomodulatory activity while isolated compounds and synthetic analogues showed moderate activity. Among the tested compounds, new compound (1), quercetin (10) and derivatives 12b, 12c found to be non-cytotoxic and displayed immunomodulatory potentials. Therefore, these compounds can be studied for autoimmunity and other immune suppressing conditions.

The Immunomodulatory Effects and Mechanism of Wogonin for the Treatment of Multiple Sclerosis in a Murine Experimental Autoimmune Encephalomyelitis Model

Abstract Multiple sclerosis (MS) stands out as the most prevalent inflammatory autoimmune disease affecting the central nervous system (CNS). The primary driver of MS involves myelin-specific autoreactive T cells that infiltrate the CNS, initiating attacks on myelinated axons and triggering neuroinflammatory responses. Wogonin, a flavonoid, exhibits pharmacologic properties, including neuroprotective, anticancer, antiviral, anti-inflammatory, and anti-oxyradical effects. Our study demonstrates that wogonin significantly suppresses TLR-dependent DC activation, migration, and the expression of adhesion molecules in LPS-stimulated bone marrow-derived dendritic cells (BMDCs). In the experimental autoimmune encephalomyelitis (EAE) model, preventive treatment with wogonin led to reduced lymphocyte infiltration, prevented demyelination in the CNS, and consequently mitigated disease symptoms. Moreover, wogonin suppressed the release of neuroinflammatory cytokines by activated microglial cells, Th1 cells, Th2 cells, and Th17 cells in vitro and exerted therapeutic effects on attenuating the disease severity in the early disease onset stage and late disease progression stage. Our study suggests that wogonin treatment may not only prevent the onset of MS by inhibiting DC activation and migration but also potentially ameliorate the progression of MS by reducing neuroinflammation. This opens avenues for the development of new approaches in the therapy of autoimmune diseases.

The role of CMKLR1 in lymphocyte activation and localization within the CNS during West Nile Virus Encephalitis

Abstract Continued West Nile virus (WNV) outbreaks causing neuroinvasive disease in the US highlight the urgent need to decipher CNS viral control mechanisms. DCs are pivotal in recruiting and reactivating CNS-infiltrating lymphocytes for viral clearance. However, the molecular mechanisms that regulate DC recruitment and activation remain unknown. In CNS-related autoimmune disorders, CMKLR1, a chemokine receptor expressed by a DC subset, aids their recruitment and activation via its ligand, chemerin. To investigate the role of CMKLR1 during WNND, we infected WT and CMKLR1-/- mice with WNV. CMKLR1-/- mice exhibited a slight increase in mortality but elevated clinical scores accompanied by increased CNS viral loads compared to WT. We hypothesize that CMKLR1 restricts WNV neuropathogenesis by regulating the activation and localization of antiviral T cells within the CNS during WNV encephalitis. Determining the role of CMKLR1 in effector T cell activation and migration may provide insights into local molecular mechanisms controlling lymphocyte function and fate within the CNS during WNV.

Elucidation of Spatial Cooperativity in Chemo-Immunotherapy by a Sequential Dual-pH-Responsive Drug Delivery System.

Combining immune checkpoint blockade with chemotherapy through nanotechnology is promising in terms of safety and efficacy. However, the distinct subcellular distribution of each ingredient's action site makes it challenging to acquire an optimal synergism. Herein, a dual-pH responsive hybrid polymeric micelle system, HNP(αPDL16.9, Dox5.3), is constructed as a proof-of-concept for the spatial cooperativity in chemo-immunotherapy. HNP retains the inherent pH-transition of each polymer, with stepwise disassembly under discrete pH thresholds. Within weakly acidic extracellular tumor environment, αPDL1 is first released to block the checkpoint on cell membranes. The remaining intact Doxorubicin-loaded micelle NP(Dox)5.3 displays significant tropism toward tumor cells and releases Dox upon lysosomal pH for efficient tumor immunogenic cell death without immune toxicity. This sequential-released pattern boosts DC activation and primes CD8+ T cells, leading to enhanced therapeutic performance than single agent or an inverse-ordered combination in multiple murine tumor models. Using HNP, the indispensable role of conventional type 1 DC (cDC1) is identified in chemo-immunotherapy. A co-signature of cDC1 and CD8 correlates with cancer patient survival after neoadjuvant Pembrolizumab plus chemotherapy in clinic. This study highlights spatial cooperativity of chemo- and immuno-agents in immunoregulation and provides insights into the rational design of drug combination for future nanotherapeutics development.

Investigation of the relationship between morphology-electrical transport phenomena in iron-doped quaternary glass nanocomposite

The Fe doped nano nanocomposite glassy system xFe·(1-x)·(0.3 V2O5·0.2MoO3·0.4CdO·0.1ZnO) (x = 0.2, 0.3, and 0.4) has been studied by different techniques. Lattice strain (ɛ) increases with increasing iron (x) content in the glass system, which facilitates the enhancement of electrical phenomena such as transport using the polaron hopping mechanism. The AC conductivity spectra at different temperatures have been computed using Almond–West formalism and a modified correlated barrier hopping model. AC, as well as DC conductivity, have increased with increasing Fe content in compositions. The DC activation energies are found to be 0.53, 0.48, and 0.44 eV for the values of x = 0.2, 0.3, and 0.4 respectively. Both DC activation energy (Eσ) and activation energy (EH) for hopping frequency have decreased with Fe content. AC conductivity scaling data has explored that the common electrical relaxation mechanism is temperature-independent as well as composition-dependent.

<i>In Vivo</i> Hepatoprotective Activity of Hydroalcohol Extract of <i>Gyrocarpus asiaticus</i> Willd and <i>Lactuca runcinata</i> DC

Objective: Investigation of hepatoprotective activity of Gyrocarpus asiaticus Willd (GA) and Lactuca runcinata DC (LR) prepared by hydroalcohol extraction. Methodology: Albino rats were used for the in vivo experiments for the determination of oral acute toxicity study. For these experiments, 6 groups were created of which 5 groups were for each plant extract and 1 group for control. A total of 11 groups were made for the toxicity study. Each group required 2 albino mice. Different doses of 0.025, 0.2, 0.5, 2, and 5 gm/kg body weight were administered orally for each plant extract. For the control group, these were administered with distilled water. For hepatoprotective activity, albino rats were randomly divided into 5 (control, toxic, standard, 2 samples) groups, and 4 animals were randomly divided into each group. For 2 plants, a total of 7 groups were made. 5% gum acacia was used as the vehicle. For induced hepatotoxicity CCl4 and as a standard drug silymarin was used. Result and Discussion: Plant extracts did not show any toxicity, and no histopathological changes were seen in the liver, kidney, or lungs due to toxicity. In the study of GA Willd and LR DC extract prepared by hydroalcohol solution, there was evidence of protection against CCl4-induced hepatotoxicity in the Histopathological study of the liver of albino rats. Conclusion: Hydroalcohol extract of LR DC and GA Willd shows no oral acute toxicity and LR DC shows no significant hepatoprotective activity but GA Willd shows significant hepatoprotective activity

Fine tuning of CpG spatial distribution with DNA origami for improved cancer vaccination.

Multivalent presentation of ligands often enhances receptor activation and downstream signalling. DNA origami offers a precise nanoscale spacing of ligands, a potentially useful feature for therapeutic nanoparticles. Here we use a square-block DNA origami platform to explore the importance of the spacing of CpG oligonucleotides. CpG engages Toll-like receptors and therefore acts to activate dendritic cells. Through in vitro cell culture studies and in vivo tumour treatment models, we demonstrate that square blocks induce Th1 immune polarization when CpG is spaced at 3.5 nm. We observe that this DNA origami vaccine enhances DC activation, antigen cross-presentation, CD8 T-cell activation, Th1-polarized CD4 activation and natural-killer-cell activation. The vaccine also effectively synergizes with anti-PD-L1 for improved cancer immunotherapy in melanoma and lymphoma models and induces long-term T-cell memory. Our results suggest that DNA origami may serve as a platform for controlling adjuvant spacing and co-delivering antigens in vaccines.

Network-based screening identifies sitagliptin as an antitumor drug targeting dendritic cells

BackgroundDendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. The identification of drugs...

Utilizing murine dendritic cell line DC2.4 to evaluate the immunogenicity of subunit vaccines in vitro.

Subunit vaccines hold substantial promise in controlling infectious diseases, due to their superior safety profile, specific immunogenicity, simplified manufacturing processes, and well-defined chemical compositions. One of the most important end-targets of vaccines is a subset of lymphocytes originating from the thymus, known as T cells, which possess the ability to mount an antigen-specific immune response. Furthermore, vaccines confer long-term immunity through the generation of memory T cell pools. Dendritic cells are essential for the activation of T cells and the induction of adaptive immunity, making them key for the in vitro evaluation of vaccine efficacy. Upon internalization by dendritic cells, vaccine-bearing antigens are processed, and suitable fragments are presented to T cells by major histocompatibility complex (MHC) molecules. In addition, DCs can secrete various cytokines to crosstalk with T cells to coordinate subsequent immune responses. Here, we generated an in vitro model using the immortalized murine dendritic cell line, DC2.4, to recapitulate the process of antigen uptake and DC maturation, measured as the elevation of CD40, MHC-II, CD80 and CD86 on the cell surface. The levels of key DC cytokines, tumor necrosis alpha (TNF-α) and interleukin-10 (IL-10) were measured to better define DC activation. This information served as a cost-effective and rapid proxy for assessing the antigen presentation efficacy of various vaccine formulations, demonstrating a strong correlation with previously published in vivo study outcomes. Hence, our assay enables the selection of the lead vaccine candidates based on DC activation capacity prior to in vivo animal studies.