Advancing vaccine development against Opisthorchis viverrini: A synergistic integration of omics technologies and advanced computational tools.

The liver fluke O. viverrini (Opisthorchis viverrini), a neglected tropical disease (NTD), endemic to the Great Mekong Subregion (GMS), mainly afflicts the northeastern region of Thailand. It is a leading cause of cholangiocarcinoma (CCA) in humans. Presently, the treatment modalities for opisthorchiasis incorporate the use of the antihelminthic drug praziquantel, the rapid occurrence of reinfection, and the looming threat of drug resistance highlight the urgent need for vaccine development. Recent advances in "omics" technologies have proven to be a powerful tool for such studies. Utilizing candidate proteins identified through proteomics and refined via immunoproteomics, reverse vaccinology (RV) offers promising prospects for designing vaccines targeting essential antibody responses to eliminate parasite. Machine learning-based computational tools can predict epitopes of candidate protein/antigens exhibiting high binding affinities for B cells, MHC classes I and II, indicating strong potential for triggering both humoral and cell-mediated immune responses. Subsequently, these vaccine designs can undergo population-specific testing and docking/dynamics studies to assess efficacy and synergistic immunogenicity. Hence, refining proteomics data through immunoinformatics and employing computational tools to generate antigen-specific targets for trials offers a targeted and efficient approach to vaccine development that applies to all domains of parasite infections. In this review, we delve into the strategic antigen selection process using omics modalities for the O. viverrini parasite and propose an innovative framework for vaccine design. We harness omics technologies to revolutionize vaccine development, promising accelerated discoveries and streamlined preclinical and clinical evaluations.

Exploration of the synergistic effect of chrysene-based core and benzothiophene acceptors on photovoltaic properties of organic solar cells.

To improve the efficacy of organic solar cells (OSCs), novel small acceptor molecules (CTD1-CTD7) were designed by modification at the terminal acceptors of reference compound CTR. The optoelectronic properties of the investigated compounds (CTD1-CTD7) were accomplished by employing density functional theory (DFT) in combination with time-dependent density functional theory (TD-DFT). The M06 functional along with a 6-311G(d,p) basis set was utilized for calculating various parameters such as: frontier molecular orbitals (FMO), absorption maxima (λmax), binding energy (Eb), transition density matrix (TDM), density of states (DOS), and open circuit voltage (Voc) of entitled chromophores. A red shift in the absorption spectra of all designed chromophores (CTD1-CTD7) was observed as compared to CTR, accompanied by low excitation energy. Particularly, CTD4 was characterized by the highest λmax value of 685.791 nm and the lowest transition energy value of 1.801 eV which might be ascribed to the robust electron-withdrawing end-capped acceptor group. The observed reduced binding energy (Eb) was linked to an elevated rate of exciton dissociation and substantial charge transfer from central core in HOMO towards terminal acceptors in LUMO. These results were further supported by the outcomes from TDM and DOS analyses. Among all entitled chromophores, CTD4 exhibited bathochromic shift (685.791 nm), minimum HOMO/LUMO band gap of 2.347 eV with greater CT. Thus, it can be concluded that by employing molecular engineering with efficient acceptor moieties, the efficiency of photovoltaic materials could be improved.

PART1 facilitates tumorigenesis and inhibits ferroptosis by regulating the miR-490-3p/SLC7A11 axis in hepatocellular carcinoma.

BACKGROUND: Ferroptosis is associated with cancer progression and has a promising application for treating hepatocellular carcinoma (HCC). Long non-coding RNA (lncRNA) participates widely in the regulation of ferroptosis, but the key lncRNA regulators implicated in ferroptosis and their molecular mechanisms remain to be identified. METHODS: Bioinformatic analysis was performed in R based on The Cancer Genome Atlas Program (TCGA) public database. The relative expression of genes was detected by real-time quantitative PCR. Cell viability was assessed by the CCK8 assay. The cell cycle and apoptosis were detected by flow cytometry. Migration and invasion of HCC cells were detected by Transwell assay and wound healing assay. Expression of relevant proteins was detected by Western blotting. A dual-luciferase reporter assay was used to detect interactions between PART1 (or SLC7A11) and miR-490-3p. RESULTS: The PART1/miR-490-3p/SLC7A11 axis was identified as a potential regulatory pathway of ferroptosis in HCC. PART1 silencing reduced HCC cell proliferation, migration, and metastasis and promoted apoptosis and erastin-reduced ferroptosis. Further investigation revealed that PART1 acted as a competitive endogenous RNA (ceRNA) for miR-490-3p to enhance SLC7A11 expression. Overexpression of miR-490-3p downregulated the expression of SLC7A11, inhibiting the proliferation, invasion, and metastasis of HCC cells while promoting apoptosis and erastin-induced ferroptosis. Knockdown of PART1 in HCC cells significantly improved the sensitivity of HCC cells to sorafenib. CONCLUSION: Our results revealed that the PART1/miR-490-3p/SLC7A11 axis enhances HCC cell malignancy and suppresses ferroptosis, which provides a new perspective for understanding of the function of long chain non-coding RNAs in HCC. The PART1/miR-490-3p/SLC7A11 axis may be target for improving sorafenib sensitivity in HCC.

Synthesis, Characterizations, Hirshfeld Surface Analysis, DFT, and NLO Study of a Schiff Base Derived from Trifluoromethyl Amine.

We synthesized an imine-based (Schiff base) crystalline organic chromophore, i.e., (E)-2-ethoxy-6-(((3-(trifluoromethyl)phenyl)imino)methyl)phenol (ETPMP), and explored its nonlinear optical (NLO) properties. The crystalline structure of ETPMP was determined by the XRD technique and equated with the associated structures utilizing a Cambridge Structural Database search. The supramolecular assembly of ETPMP was investigated regarding intermolecular interactions and short contacts by Hirshfeld surface analysis. Void analysis was performed to check the mechanical response of the crystal. Supramolecular assembly was further inspected by interaction energy calculations that were performed with the B3LYP/6-31G(d,p) functional. Besides this, the NLO properties of ETPMP and other already reported crystal TFMOS were explored utilizing the M06/6-31G(d,p) functional of the DFT approach. An excellent agreement was observed between XRD and DFT results of geometric parameters of the above-mentioned crystals. Narrow band gap along with bathochromic shift (3.489 eV and 317.225 nm, respectively) were investigated in TFMOS than that of ETPMP. Owing to these unique properties, TFMOS possesses higher linear (⟨a⟩ = 3.835 × 10-23 esu) and nonlinear (γtot. = 1.346 × 10-34 esu) response as compared to ETPMP. The outcomes explicitly show the higher nonlinearity in TFMOS, highlighting its importance in potential NLO applications.

Identification of Novel Quinolone and Quinazoline Alkaloids as Phosphodiesterase 10A Inhibitors for Parkinson's Disease through a Computational Approach.

Phosphodiesterases (PDEs) are vital in signal transduction, specifically by hydrolyzing cAMP and cGMP. Within the PDE family, PDE10A is notable for its prominence in the striatum and its regulatory function over neurotransmitters in medium-spiny neurons. Given the dopamine deficiency in Parkinson's disease (PD) that affects striatal pathways, PDE10A inhibitors could offer therapeutic benefits by modulating D1 and D2 receptor signaling. This study was motivated by the successful history of quinazoline/quinazoline scaffolds in the inhibition of PDE10A. This study involved detailed in silico evaluations through docking followed by pharmacological, pharmacophoric, and pharmacokinetic analyses, prioritizing central nervous system (CNS)-active drug criteria. Seven cyclic peptides, those featuring the quinazoline/quinazoline moiety at both termini, exhibited notably enhanced docking scores compared to those of the remaining alkaloids within the screened library. We identified 7 quinolines and 1 quinazoline including Lepadin G, Aspernigerin, CJ-13536, Aurachin A, 2-Undecyl-4(1H)-quinolone, Huajiaosimuline 3-Prenyl-4-prenyloxyquinolin-2-one, and Isaindigotone that followed the standard CNS active drug criteria. The dominant quinoline ring in our study and its related quinazoline were central to our evaluations; therefore, the pharmacophoric features of these scaffolds were highlighted. The top alkaloids met all CNS-active drug properties; while nonmutagenic and without PAINS alerts, many indicated potential hepatotoxicity. Among the compounds, Huajiaosimuline was particularly significant due to its alignment with lead-likeness and CNS-active criteria. Aspernigerin demonstrated its affinity for numerous dopamine receptors, which signifies its potential to alter dopaminergic neurotransmission that is directly related to PD. Interestingly, the majority of these alkaloids had biological targets primarily associated with G protein-coupled receptors, critical in PD pathophysiology. They exhibit superior excretion parameters and toxicity end-points compared to the standard. Notably, selected alkaloids demonstrated stability in the binding pocket of PDE10A according to the molecular dynamic simulation results. Our findings emphasize the potential of these alkaloids as PDE10A inhibitors. Further experimental studies may be necessary to confirm their actual potency in inhibiting PDE10A before exploring their therapeutic potential in PD.

Nanozyme-based sensing of dopamine using cobalt-doped hydroxyapatite nanocomposite from waste bones.

Dopamine is one of the most important neurotransmitters and plays a crucial role in various neurological, renal, and cardiovascular systems. However, the abnormal levels of dopamine mainly point to Parkinson's, Alzheimer's, cardiovascular diseases, etc. Hydroxyapatite (HAp), owing to its catalytic nature, nanoporous structure, easy synthesis, and biocompatibility, is a promising matrix material. These characteristics make HAp a material of choice for doping metals such as cobalt. The synthesized cobalt-doped hydroxyapatite (Co-HAp) was used as a colorimetric sensing platform for dopamine. The successful synthesis of the platform was confirmed by characterization with FTIR, SEM, EDX, XRD, TGA, etc. The platform demonstrated intrinsic peroxidase-like activity in the presence of H2O2, resulting in the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB). The proposed sensor detected dopamine in a linear range of 0.9-35 µM, a limit of detection of 0.51 µM, limit of quantification of 1.7 µM, and an R2 of 0.993. The optimization of the proposed sensor was done with different parameters, such as the amount of mimic enzyme, H2O2, pH, TMB concentration, and time. The proposed sensor showed the best response at 5 mg of the mimic enzyme, pH 5, 12 mM TMB, and 8 mM H2O2, with a short response time of only 2 min. The fabricated platform was successfully applied to detect dopamine in physiological solutions.

Development of a subunit vaccine against the cholangiocarcinoma causing Opisthorchis viverrini: a computational approach.

Opisthorchis viverrini is the etiological agent of the disease opisthorchiasis and related cholangiocarcinoma (CCA). It infects fish-eating mammals and more than 10 million people in Southeast Asia suffered from opisthorchiasis with a high fatality rate. The only effective drug against this parasite is Praziquantel, which has significant side effects. Due to the lack of appropriate treatment options and the high death rate, there is a dire need to develop novel therapies against this pathogen. In this study, we designed a multi-epitope chimeric vaccine design against O. viverrini by using immunoinformatics approaches. Non-allergenic and immunogenic MHC-1, MHC-2, and B cell epitopes of three candidate proteins thioredoxin peroxidase (Ov-TPx-1), cathepsin F1 (Ov-CF-1) and calreticulin (Ov-CALR) of O. viverrini, were predicted to construct a potent multiepitope vaccine. The coverage of the HLA-alleles of these selected epitopes was determined globally. Four vaccine constructs made by different adjuvants and linkers were evaluated in the context of their physicochemical properties, antigenicity, and allergenicity. Protein-protein docking and MD simulation found that vaccines 3 was more stable and had a higher binding affinity for TLR2 and TLR4 immune receptors. In-silico restriction cloning of vaccine model led to the formation of plasmid constructs for expression in a suitable host. Finally, the immune simulation showed strong immunological reactions to the engineered vaccine. These findings suggest that the final vaccine construct has the potential to be validated by in vivo and in vitro experiments to confirm its efficacy against the CCA causing O. viverrini.

Corrigendum: Structural informatics approach for designing an epitope-based vaccine against the brain-eating Naegleria fowleri.

[This corrects the article DOI: 10.3389/fimmu.2023.1284621.].