Human Target Research Articles

Synthesis, spectral, Hirshfeld surface analysis, DFT, molecular docking and ADMET properties of (E)-4-fluoro-N'-(4‑hydroxy-3‑methoxy benzylidene)benzohydrazide (EFHMBH)

The synthesis, characterization, and theoretical studies of the E)-4-fluoro-N'-(4‑hydroxy-3-methoxybenzylidene)benzohydrazide (EFHMBH), have been reported in this study. The Single Crystal XRD, FT-IR, FT-Raman, and UV–Vis techniques were carried out to study the structural, and optical properties of the grown crystals. The molecular structure has been characterized by room-temperature single-crystal X-ray diffraction study which reveals that it has an angular shape with intramolecular and intermolecular hydrogen bonding. Crystal data for the title compound, C15H14FN2O4 (M = 305.28 g mol-1): monoclinic, space group P21/n, a = 8.0205 (6)Å, b = 17.0685 (13)Å, c = 10.9378 (9)Å, ß = 105.277 (3)°, V = 1452.9 (2) Å3, Z = 4, Dcalc = 1.396 Mg/m3, 21,326 reflections measured,4245 unique (Rint = 0.048) which were used in all calculations. The Hirshfeld surface analysis of the title compound shows that O…H/H…O(21.6 %), H…C/C…H(15.8 %), F…H/H…F(8.3 %), C…C(7.3 %) respectively, which exposed that the main intermolecular interactions. The geometrical optimization and the theoretical vibrational analysis are performed at B3LYP/6–31 ++ G(d,p) computational level under density functional theory (DFT) and correlated with experimental data. The HOMO-LUMO energy gap in the title compound is 4.0113 eV. The molecular electrostatic potential of the investigated compound has also been studied. The molecular docking analysis is performed against human HMG-CoA reductase-related target proteins, which shows better inhibitory activity of EFHMBH against the 1DQA receptor with the binding energy of -4.31 kcal/mol. Furthermore, to analysis, the physiochemical and pharmacokinetic features of EFHMBH are analyzed using the preADME online server.

Computational analysis of pathogen-host interactome for fast and low-risk in-silico drug repurposing in emerging viral threats like Mpox

Monkeypox (Mpox), a zoonotic illness triggered by the monkeypox virus (MPXV), poses a significant threat since it may be transmitted and has no cure. This work introduces a computational method to predict Protein–Protein Interactions (PPIs) during MPXV infection. The objective is to discover prospective drug targets and repurpose current potential Food and Drug Administration (FDA) drugs for therapeutic purposes. In this work, ensemble features, comprising 2–5 node graphlet attributes and protein composition-based features are utilized for Deep Learning (DL) models to predict PPIs. The technique that is used here demonstrated an excellent prediction performance for PPI on both the Human Integrated Protein–Protein Interaction Reference (HIPPIE) and MPXV-Human PPI datasets. In addition, the human protein targets for MPXV have been identified accurately along with the detection of possible therapeutic targets. Furthermore, the validation process included conducting docking research studies on potential FDA drugs like Nicotinamide Adenine Dinucleotide and Hydrogen (NADH), Fostamatinib, Glutamic acid, Cannabidiol, Copper, and Zinc in DrugBank identified via research on drug repurposing and the Drug Consensus Score (DCS) for MPXV. This has been achieved by employing the primary crystal structures of MPXV, which are now accessible. The docking study is also supported by Molecular Dynamics (MD) simulation. The results of our study emphasize the effectiveness of using ensemble feature-based PPI prediction to understand the molecular processes involved in viral infection and to aid in the development of repurposed drugs for emerging infectious diseases such as, but not limited to, Mpox. The source code and link to data used in this work is available at: https://github.com/CMATERJU-BIOINFO/In-Silico-Drug-Repurposing-Methodology-To-Suggest-Therapies-For-Emerging-Threats-like-Mpox.

Systemic identification of functionally conserved lncRNA metabolic regulators in human and mouse livers.

Unlike protein-coding genes, the majority of human long non-coding RNAs (lncRNAs) lack conservation based on their sequences, posing a challenge for investigating their role in a pathophysiological context for clinical translation. This study explores the hypothesis that non-conserved lncRNAs in human and mouse livers may share similar metabolic functions, giving rise to functionally conserved lncRNA metabolic regulators (fcLMRs). We developed a sequence-independent strategy to select putative fcLMRs, and performed extensive analysis to determine the functional similarities of putative human and mouse LMR pairs (h/mLMRs). We found that several pairs of putative fcLMRs share similar functions in regulating gene expression. We further demonstrated that a pair of fcLMRs, h/mLMR1, robustly regulated triglyceride levels by modulating the expression of a similar set of lipogenic genes. Mechanistically, h/mLMR1 binds to PABPC1, a regulator of protein translation, via short motifs on either lncRNA with divergent sequences but similar structures. This interaction inhibits protein translation, activating an amino acid-mTOR-SREBP1 axis to regulate lipogenic gene expression. Intriguingly, PABPC1-binding motifs on each lncRNA fully rescued the functions of their corresponding LMRs in the opposite species. Given the elevated expression of h/mLMR1 in humans and mice with hepatic steatosis, the PABPC1-binding motif on hLMR1 emerges as a potential non-conserved human drug target whose functions can be fully validated in a physiologically relevant setting before clinical studies. Our study supports that fcLMRs represent a novel and prevalent biological phenomenon, and deep phenotyping of genetic mLMR mouse models constitutes a powerful approach to understand the pathophysiological role of lncRNAs in the human liver.

Microbiota transfer early after birth modulates genetic susceptibility to chronic arthritis in mice

Genetics is central to the susceptibility or resistance to autoimmunity, and mounting evidence indicates that the intestinal microbiota also plays an essential role. In murine arthritis models, short-chain fat acid supplementation reduces disease severity by modulating tryptophan-metabolizing bacteria. Common microbiota transfer methods modulate arthritis severity, however, they are not practical for chronic models such as pristane-induced arthritis (PIA). PIA-resistant (HIII) and PIA-susceptible (LIII) mice harbor diverse intestinal microbiomes, which might be implicated in their divergent susceptibility. To investigate this hypothesis, we used cross-fostering to stably transfer the microbiota. In this study, we show that extreme susceptibility to arthritis can be modulated by early microbiota transfer, with long-lasting effects. HIII and LIII pups were cross-fostered and injected with pristane after weaning. PIA severity in cross-fostered LIII mice was significantly reduced in the chronic phase. Metagenomic analyses showed that HIII and LIII microbiomes were partly shifted by cross-fostering. Microbial groups whose abundance was associated with either HIII or LIII mice presented similar composition in cross-fostered mice of the opposite strains, suggesting a role in PIA susceptibility. Identification of bacterial groups that modulate chronic arthritis will contribute novel insights on the pathogenesis of human rheumatoid arthritis and targets for replication and functional studies.

Infrared Image Human Target Detection Method Based on Deep Learning

Introduction: In this study, we investigate human target detection techniques for infrared target recognition in complicated backdrops using deep learning approaches. This study uses the human target detection of infrared images in various scenes as its research object. Method: A test was conducted using MatlabR2010a and the real-time C language development platform. The findings indicate that, in the unoptimized case, the computing speed of the method was only 0.34 seconds. However, following optimization, its performance significantly increased to meet the real-time performance requirements. Result: The research findings presented in this work will be crucial to the relief and rescue efforts following engineering mishaps. Conclusion: This study is innovative in that it develops a deep learning-based model for human target detection in infrared photos and thoroughly examines and improves its functionality.

Genomic Discovery and Structure-Activity Exploration of a Novel Family of Enzyme-Activated Covalent Cyclin-Dependent Kinase Inhibitors.

Fungi have historically been the source of numerous important medicinal compounds, but full exploitation of their genetic potential for drug development has been hampered in traditional discovery paradigms. Here we describe a radically different approach, top-down drug discovery (TD3), starting with a massive digital search through a database of over 100,000 fully genomicized fungi to identify loci encoding molecules with a predetermined human target. We exemplify TD3 by the selection of cyclin-dependent kinases (CDKs) as targets and the discovery of two molecules, 1 and 2, which inhibit therapeutically important human CDKs. 1 and 2 exhibit a remarkable mechanism, forming a site-selective covalent bond to the CDK active site Lys. We explored the structure-activity relationship via semi- and total synthesis, generating an analog, 43, with improved kinase selectivity, bioavailability, and efficacy. This work highlights the power of TD3 to identify mechanistically and structurally novel molecules for the development of new medicines.

Pornographic video detection based on semantic and image enhancement

Abstract Pornographic video detection is of significant importance in curbing the proliferation of pornographic information on online video platforms. However, existing works often employ generic frame extraction methods that ignore the low-latency requirements of detection scenarios and the characteristics of pornographic videos. Additionally, existing detection methods have difficulties in detail characterization and semantic understanding, resulting in low accuracy. Therefore, this paper proposes an efficient pornographic video detection framework based on semantic and image enhancement. Firstly, a keyframe extraction method tailored for pornographic video detection is proposed to select representative frames. Secondly, a light enhancement method is introduced to facilitate accurate capture of pornographic visual cues. Moreover, a compression-reconstruction network is employed to eliminate adversarial perturbations, enabling models to obtain reliable features. Subsequently, YOLOv5 is introduced to locate and crop human targets in keyframes, reducing background interference and enhancing the expression of human semantic information. Finally, MobileNetV3 is employed to determine if the human targets contain pornographic content. The proposed framework is validated on the publicly available NPDI dataset, achieving an accuracy of 95.9%, surpassing existing baseline methods.

Dissemination of pathogenic bacteria is reinforced by a MARTX toxin effector duet

Multiple bacterial genera take advantage of the multifunctional autoprocessing repeats-in-toxin (MARTX) toxin to invade host cells. Secretion of the MARTX toxin by Vibrio vulnificus, a deadly opportunistic pathogen that causes primary septicemia, the precursor of sepsis, is a major driver of infection; however, the molecular mechanism via which the toxin contributes to septicemia remains unclear. Here, we report the crystal and cryo-electron microscopy (EM) structures of a toxin effector duet comprising the domain of unknown function in the first position (DUF1)/Rho inactivation domain (RID) complexed with human targets. These structures reveal how the duet is used by bacteria as a potent weapon. The data show that DUF1 acts as a RID-dependent transforming NADase domain (RDTND) that disrupts NAD+ homeostasis by hijacking calmodulin. The cryo-EM structure of the RDTND-RID duet complexed with calmodulin and Rac1, together with immunological analyses in vitro and in mice, provide mechanistic insight into how V. vulnificus uses the duet to suppress ROS generation by depleting NAD(P)+ and modifying Rac1 in a mutually-reinforcing manner that ultimately paralyzes first line immune responses, promotes dissemination of invaders, and induces sepsis. These data may allow development of tools or strategies to combat MARTX toxin-related human diseases.

Cloud IoT-Oriented Secure College Physical Education Teaching Platform Vased on Deep Learning

In physical education (PE) teaching, the teaching platform is comprehensively applied to provide students with high-quality PE teaching resources to meet their learning needs in different forms. A human motion trajectory detection method is proposed based on deep learning and superpixels. The initial positioning of human body is performed through the attention mechanism and the YOLOv5 model, and the human target tracking is performed through superpixels. Aiming at the difficulty of cross-domain security management due to the lack of security infrastructure in multi-domain cloud IoT, a lightweight certificateless cross-domain authentication scheme is designed. Simulation results show that the proposed detection method has significantly improved accuracy and running time compared with traditional methods and can adapt to different detection scenarios. Furthermore, the proposed certificateless cross-domain authentication scheme can securely access sensor-generated data under the cloud IoT of the PE teaching platform in colleges.

Virtual screening, ADME prediction, drug-likeness, and molecular docking analysis of Fagonia indica chemical constituents against antidiabetic targets.

Fagonia indica from Zygophyllaceae family is a medicinal specie with significant antidiabetic potential. The present study aimed to investigate the in vitro antidiabetic activity of Fagonia indica crude extract followed by an in silico screening of its phytoconstituents. For this purpose, crude extract of Fagonia indica was prepared and divided in three different parts, i.e., n-hexane, ethyl acetate, and methanolic fraction. Based on in vitro outcomes, the phytochemical substances of Fagonia indica were virtually screened through a literature survey and a screening library of compounds (1-13) was prepared. The clinical potential of these novel drug candidates was assessed by applying an ADME screening profile. Findings of SwissADME indicators (Absorption, Distribution, Metabolism, and Excretion) for the compounds (1-13) presented relatively optimal physicochemical characteristics, drug-likeness, and medicinal chemistry. The antidiabetic action of these leading drug candidates was optimized through molecular docking analysis against 3 different human pancreatic α-amylase macromolecular targets with (PDB ID 1B2Y), (PDB ID 3BAJ), and (PDB ID: 3OLI) by applying Virtual Docker (Molegro MVD). Metformin was taken as a reference standard for the sake of comparison. In vitro antidiabetic evaluation gave good results with promising α-amylase inhibitory action in the form of IC50 values, as for n-hexane extract = 206.3µM, ethyl acetate = 41.64µM, and methanolic extract = 9.61µM. According to in silico outcomes, all 13 phytoconstituents possess the best binding affinity with successful MolDock scores ranging from - 97.2003 to - 65.6877kcal/mol and show a great number of binding interactions than native drug metformin. Therefore, the current work concluded that the diabetic inhibition prospective of extract and the compounds of Fagonia indica may contribute to being investigated as a new class of antidiabetic drug or drug-like candidate for further studies.

Pharmacokinetics of isavuconazonium sulfate and its active metabolite isavuconazole in healthy dogs.

Invasive fungal infections (IFIs) are growing in importance in veterinary and human medicine. IFIs such as aspergillosis, blastomycosis, coccidioidomycosis and histoplasmosis remain challenging to treat in dogs. Isavuconazole is a novel antifungal medication that, when compared to currently used azoles, has an expanded spectrum of antifungal activity Rudramurthy (2011), Pfaller (2013), Spec (2018), has more predictable pharmacokinetics in humans Desai (2016), Cojutti (2021) and may cause fewer side effects such as liver and renal toxicity Maertens (2016), DiPippo (2018). The pharmacokinetic profile and safety of isavuconazole in dogs has not yet been characterized. The purpose of this study was to evaluate the pharmacokinetics of isavuconazole in healthy dogs that received a single dose of the prodrug isavuconazonium sulfate. Using full crossover design, six healthy beagle dogs received isavuconazonium sulfate at a mean (+/- SD) dose of 20.6 (+/- 2.8) mg/kg orally and 21.8 (+/- 4.2) mg/kg intravenously. Plasma was collected for batched pharmacokinetic analysis of prodrug and metabolite, isavuconazole, by ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). The median (Q1-Q3) maximum isavuconazole peak plasma concentration was estimated at 3,876.5 (2,811.0-4,800.0) ng/mL following oral administration, with a median (Q1-Q3) peak level at 1.3 (1.0-2.0) hours. Following intravenous administration, the median (Q1-Q3) isavuconazole peak plasma concentration was estimated at 3,221.5 (2,241.5-3,609.0) ng/mL, with a median (Q1-Q3) peak level at 0.4 (0.3-0.6) hours. The median (Q1-Q3) half-life of isavuconazole was 9.4 (7.0-12.2) hours and 14.0 (8.1-21.7) hours for oral and intravenous routes, respectively. One dog received inadvertent subcutaneous drug administration without any apparent adverse effects. Another dog experienced an anaphylactic reaction following accidental rapid drug infusion. No other drug-related adverse events were observed. At dosages used in this study, healthy dogs achieved isavuconazole plasma levels comparable to human therapeutic targets, and when properly administered the drug was well-tolerated.

Millimeter-Wave Radar Detection and Localization of a Human in Indoor Complex Environments

Nowadays, it is still a great challenge to detect and locate indoor humans using a frequency-modulated continuous-wave radar accurately. Due to the interference of the indoor environment and complex objects such as green plants, the radar signal may penetrate, reflect, refract, and scatter, and the echo signals will contain noise, clutter, and multipath of different characteristics. Therefore, a method combined with comprehensive non-target signal removal and human localization is proposed to achieve position estimation of a human target. Time-variant clutter is innovatively mitigated through time accumulation using point clustering. Ghost targets are reduced according to propagation path matching. The experimental results show that the method can locate the real target human within an average error of 0.195 m in multiple complex environments with green plants, curtains, or furniture using a 77 GHz millimeter-wave radar. Meanwhile, the proposed method performs better than conventional methods. The detection probability is 81.250% when the human is behind a potted plant and is 90.286% when beside it.

Differential phagocytic expression of IC-21 macrophages and their scavenging receptors during inflammatory induction by oxysterol: A microscopic approach.

Phagocytosis by macrophages dates back to a long history in science, this present study deals with new approaches that have been analyzed and standardized towards the interesting aspects of primary and secondary macrophages. The distinct morphological differences in primary and secondary phagocytic cells were observed and the phagocytic response of secondary macrophages under the influence of 7-ketocholesterol and lipopolysaccharide was analyzed. The primary peritoneal and secondary IC-21 cells unveiled explicit differences in nuclear numbers shapes and sizes of the granules present within the cytoplasmic region. Further, potent inducers 7KCh and LPS influenced an effective activation of IC-21 macrophages and resulted in ROS generation, irregulated protein expressions of CD86, CD68, and CD206 with enhanced phagocytic responses towards goat, cow, and human RBC targets with significant phagocytic rate and index were observed. Moreover, a remarkable observation of target specificity and aggregations with IC-21 phagocytic macrophages revealed the notion that specific membrane receptors and secretory molecules (lysosomes) are primarily involved in their phagocytic mechanism. RESEARCH HIGHLIGHTS: IC-21 macrophages are peritoneal origin from mice but the primary peritoneal macrophages and cell line show distinct differences. IC-21 macrophages express target-specific phagocytosis. Phagocytosis in IC-21 macrophages is regulated by CD markers (68, 86, and 206).

DrugDomain: The evolutionary context of drugs and small molecules bound to domains.

Interactions between proteins and small organic compounds play a crucial role in regulating protein functions. These interactions can modulate various aspects of protein behavior, including enzymatic activity, signaling cascades, and structural stability. By binding to specific sites on proteins, small organic compounds can induce conformational changes, alter protein-protein interactions, or directly affect catalytic activity. Therefore, many drugs available on the market today are small molecules (72% of all approved drugs in the last 5 years). Proteins are composed of one or more domains: evolutionary units that convey function or fitness either singly or in concert with others. Understanding which domain(s) of the target protein binds to a drug can lead to additional opportunities for discovering novel targets. The evolutionary classification of protein domains (ECOD) classifies domains into an evolutionary hierarchy that focuses on distant homology. Previously, no structure-based protein domain classification existed that included information about both the interaction between small molecules or drugs and the structural domains of a target protein. This data is especially important for multidomain proteins and large complexes. Here, we present the DrugDomain database that reports the interaction between ECOD of human target proteins and DrugBank molecules and drugs. The pilot version of DrugDomain describes the interaction of 5160 DrugBank molecules associated with 2573 human proteins. It describes domains for all experimentally determined structures of these proteins and incorporates AlphaFold models when such structures are unavailable. The DrugDomain database is available online: http://prodata.swmed.edu/DrugDomain/.

Research on prevention and control tracking system based on 3D face recognition

In order to improve the tracking effect of prevention and control, this paper combines three-dimensional face recognition technology and posture recognition method to build a prevention and control tracking system, and designs a single-stage human target detection and posture estimation network based on thermal infrared images. By using infrared recognition methods, the face and human body shape can be directly recognized, overcoming the problem of traditional visual recognition methods being easily occluded. The network can simultaneously complete two tasks of human target detection and pose estimation in a multi-task manner. Moreover, this paper uses the knowledge distillation strategy to train a lightweight model to further reduce the amount of model parameters to improve the inference speed. In addition, this paper uses a single-stage human target detection and posture estimation network to judge the effect of prevention and control tracking. Through the prevention and control tracking effect test, it can be seen that the prevention and control tracking system based on 3D face recognition proposed in this paper can effectively improve the prevention and control tracking effect.

Subcutaneous daratumumab in Chinese patients with relapsed or refractory multiple myeloma: an open-label, multicenter, phase 1 study (MMY1010).

Despite recent progress in multiple myeloma (MM) treatments, most patients will relapse and require additional treatment. Intravenous daratumumab, a human IgGκ monoclonal antibody targeting CD38, has shown good efficacy in the treatment of MM. A subcutaneous version of daratumumab was formulated to reduce the burden of intravenous infusions. We aimed to investigate the efficacy and safety of subcutaneous daratumumab in Chinese patients with relapsed/refractory MM based on the demonstrated noninferiority of subcutaneous daratumumab to intravenous daratumumab, with a shorter administration time and reduced infusion-related reaction rate in global studies. This phase 1, multicenter study (MMY1010; ClinicalTrials.gov Identifier: NCT04121260) evaluated subcutaneous daratumumab in Chinese patients with relapsed/refractory MM after 1 prior line (n = 1) or ≥2 prior lines (n = 20) of therapy, including a proteasome inhibitor and an immunomodulatory drug. Primary endpoints were pharmacokinetics and safety. Mean (standard deviation) maximum trough concentration of daratumumab was 826 (335) μg/mL, which was consistent with prior studies of subcutaneous daratumumab and intravenous daratumumab. Safety was consistent with safety profiles observed in other daratumumab studies, with no new safety concerns identified. Incidences of infusion-related reactions and injection-site reactions were low and consistent with other subcutaneous daratumumab studies. At a median follow-up of 7.5 months, the overall response rate was 57.1%, with a very good partial response or better rate of 38.1% and complete response or better rate of 19.0%. Our results demonstrate a favorable benefit/risk profile of subcutaneous daratumumab in Chinese patients with relapsed/refractory MM, potentially impacting clinical administration of daratumumab in this population.

Dynamic response of armor-piercing bullets to blunt and penetration with protective gelatin

To investigate the coupled damage mechanism of blunt impact and bullets penetration after penetrating ballistic plates against human body targets, experiments were conducted using 6.8 mm caliber armor-piercing bullets against gelatin targets with protective coatings. A numerical analysis model was developed to simulate bullet penetration into gelatin with protective coatings, obtaining endpoint characteristic quantities such as bullet velocity changes, changes in energy distribution, pressure, stress, and stress wave variations within the gelatin target after protection. The results indicate that at a velocity of 640 m·s-1, the 6.8 mm caliber armor-piercing round failed to penetrate the ballistic plate yet still caused a blunt impact depression of 37 mm in depth. Under conditions where the bullet did not penetrate the ballistic plate, approximately 80% of the bullet's kinetic energy was absorbed by the ballistic plate. At a velocity of 740 m·s-1, the bullet penetrated the ballistic plate, resulting in a blunt impact depression depth of 56 mm and an instantaneous cavity with a maximum diameter of 60 mm. During the process of penetrating the ballistic plate, approximately 50% of the bullet's kinetic energy was absorbed by the ballistic plate, and about 40% of the remaining kinetic energy transferred into the gelatin during the penetration of the target.

Identification of a mimotope of a complex gp41 Human Immunodeficiency VIrus epitope related to a non-structural protein of Hepacivirus previously implicated in Kawasaki disease.

We have previously isolated a highly mutated VH1-02 antibody termed group C 76-Q13-6F5 (6F5) that targets a conformational epitope on gp41. 6F5 has the capacity to mediate Ab dependent cell cytotoxicity (ADCC). When the VH1-02 group C 76 antibodies variable chain sequence was reverted to germline (76Canc), this still retained ADCC activity. Due to this ability for the 76Canc germline antibody to functionally target this epitope, we sought to identify a protein target for vaccine development. Initially, we interrogated peptide targeting by screening a microarray containing 29,127 linear peptides. Western blot and ELISAs were used to confirm binding and explore human serum targeting. Autoimmune targeting was further interrogated on a yeast-displayed human protein microarray. 76Canc specifically recognized a number of acidic peptides. Meme analysis identified a peptide sequence similar to a non-structural protein of Hepacivirus previously implicated in Kawasaki disease (KD). Binding was confirmed to top peptides, including the Hepacivirus-related and KD-related peptide. On serum competitions studies using samples from children with KD compared to controls, targeting of this epitope showed no specific correlation to having KD. Human protein autoantigen screening was also reassuring. This study identifies a peptide that can mimic the gp41 epitope targeted by 76C group antibodies (i.e. a mimotope). We show little risk of autoimmune targeting including any inflammation similar to KD, implying non-specific targeting of this peptide during KD. Development of such peptides as the basis for vaccination should proceed cautiously.

ADME, Molecular Targets, Docking, and Dynamic Simulation Studies of Phytoconstituents of Cymbopogon citratus (DC.)

Cymbopogon citratus (DC) Stapf. is utilized in both culinary and medicinal contexts, wherein its extracts demonstrate a range of therapeutic properties, including antidiabetic, antioxidant, and anti-inflammatory activities. This investigation aimed to computationally analyze phytochemicals of C. citratus, evaluating their pharmacokinetics and binding dynamics. The findings revealed a combination of high and low gastrointestinal absorption (GIA) for C. citratus (DC.) phytochemicals, with some exhibiting permeability across the blood-brain barrier (BBB). Xanthine dehydrogenase/oxidase (XDH) emerged as the primary human molecular target of C. citratus phytocompounds, while XDH and matrix metalloproteinase-9 (MMP9) have central connectivity in the protein interaction network. Orientin has best binding affinity with XDH (−9.083 kcal.mol−1) and MMP9 (−9.051 kcal.mol−1). Molecular dynamic simulations indicated the favorable stability and interactions of XDH with orientin and quercetin, respectively. In summary, this investigation underscores the potential of twenty-six (26) phytochemicals in C. citratus extract to combat cancer and neurodegenerative diseases through mechanisms targeting XDH and MMP9.

The JMU-SalVac-System: A Novel, Versatile Approach to Oral Live Vaccine Development.

Salmonella enterica Serovar Typhi Ty21a (Ty21a) is the only licensed oral vaccine against typhoid fever. Due to its excellent safety profile, it has been used as a promising vector strain for the expression of heterologous antigens for mucosal immunization. As the efficacy of any bacterial live vector vaccine correlates with its ability to express and present sufficient antigen, the genes for antigen expression are traditionally located on plasmids with antibiotic resistance genes for stabilization. However, for use in humans, antibiotic selection of plasmids is not applicable, leading to segregational loss of the antigen-producing plasmid. Therefore, we developed an oral Ty21a-based vaccine platform technology, the JMU-SalVac-system (Julius-Maximilians-Universität Würzburg) in which the antigen delivery plasmids (pSalVac-plasmid-series) are stabilized by a ΔtyrS/tyrS+-based balanced-lethal system (BLS). The system is made up of the chromosomal knockout of the essential tyrosyl-tRNA-synthetase gene (tyrS) and the in trans complementation of tyrS on the pSalVac-plasmid. Further novel functional features of the pSalVac-plasmids are the presence of two different expression cassettes for the expression of protein antigens. In this study, we present the construction of vaccine strains with BLS plasmids for antigen expression. The expression of cytosolic and secreted mRFP and cholera toxin subunit B (CTB) proteins as model antigens is used to demonstrate the versatility of the approach. As proof of concept, we show the induction of previously described in vivo inducible promoters cloned into pSalVac-plasmids during infection of primary macrophages and demonstrate the expression of model vaccine antigens in these relevant human target cells. Therefore, antigen delivery strains developed with the JMU-SalVac technology are promising, safe and stable vaccine strains to be used against mucosal infections in humans.