Multiple Modes Of Action Research Articles

Production and characterization of novel Anti-HIV Fc-fusion proteins in plant-based systems: Nicotiana benthamiana & tobacco BY-2 cell suspension

Multifunctional anti-HIV Fc-fusion proteins aim to tackle HIV efficiently through multiple modes of action. Although results have been promising, these recombinant proteins are hard to produce. This study explored the production and characterization of anti-HIV Fc-fusion proteins in plant-based systems, specifically Nicotiana benthamiana plants and tobacco BY-2 cell suspension. Fc-fusion protein expression in plants was optimized by incorporating codon optimization, ER retention signals, and hydrophobin fusion elements. Successful transient protein expression was achieved in N. benthamiana, with notable improvements in expression levels achieved through N-terminal hydrophobin fusion and ER retention signals. Stable expression in tobacco BY-2 resulted in varying accumulation levels being at highest 2.2.mg/g DW. The inclusion of hydrophobin significantly enhanced accumulation, providing potential benefits for downstream processing. Mass spectrometry analysis confirmed the presence of the ER retention signal and of N-glycans. Functional characterization revealed strong binding to CD64 and CD16a receptors, the latter being important for antibody-dependent cellular cytotoxicity (ADCC). Interaction with HIV antigens indicated potential neutralization capabilities. In conclusion, this research highlights the potential of plant-based systems for producing functional anti-HIV Fc-fusion proteins, offering a promising avenue for the development of these novel HIV therapies.

Screening the Potential f Fungal Derived Bioherbicide in Weed Management

Synthetic herbicides have long been a cornerstone of modern agriculture, providing effective weed control but often at significant environmental and health costs. These chemicals can persist in the environment, leach into groundwater, and harm non-target organisms, including humans. Additionally, the overuse of synthetic herbicides has led to the development of herbicide-resistant weeds, further complicating weed management strategies. In response to these challenges, researchers and farmers alike are increasingly turning to bioherbicides derived from fungi as a sustainable alternative. Fungal bioherbicides harness the natural antagonistic properties of fungi to target weeds. Unlike synthetic herbicides, which are chemically synthesized and often broad-spectrum in action, fungal bioherbicides utilize either the fungi themselves as pathogens or their metabolites to disrupt weed growth. This approach offers several distinct advantages:Target Specificity: Fungal bioherbicides can be highly specific to certain weed species or even to specific stages of weed growth. This specificity reduces collateral damage to non-target plants and organisms, making them particularly suitable for environmentally sensitive areas such as organic farms, riparian zones, and protected ecosystems. Environmental Friendliness: Unlike synthetic herbicides that can persist in the environment and accumulate in soil and water bodies, fungal bioherbicides generally have lower persistence. They degrade more rapidly and often have minimal impact on non-target organisms, thereby preserving biodiversity and ecosystem health. Reduced Risk of Resistance: Synthetic herbicides often face the challenge of herbicide-resistant weeds, which evolve due to continuous and widespread use. Fungal bioherbicides, by contrast, pose a lower risk of resistance development. This is because they typically act through multiple modes of action or biochemical pathways within the weed, making it harder for weeds to develop resistance mechanisms. Research into fungal-derived bioherbicides is actively exploring and harnessing these advantages. Scientists are screening diverse fungal species to identify potent pathogens or metabolites that effectively inhibit weed growth. Moreover, advances in biotechnology and genetic engineering allow for the enhancement of fungal strains to optimize their bioherbicidal properties while ensuring safety and efficacy. One promising example is the use of fungal pathogens like Phomamacrostoma and Colletotrichum truncatum, which have demonstrated efficacy against various weed species including common agricultural weeds like velvetleaf and pigweed. These fungi infect weeds through mechanisms such as spore attachment, penetration of plant tissues, and secretion of phytotoxic metabolites that inhibit weed growth. In addition to their direct impact on weed management, fungal bioherbicides contribute to sustainable agricultural practices by reducing reliance on synthetic chemicals. They align with principles of integrated pest management (IPM) by offering a biological control method that complements cultural and mechanical weed control strategies. Moving forward, continued research and development efforts are essential to refine fungal bioherbicides, optimize application techniques, and expand their practical use in diverse agricultural settings. Challenges such as formulation stability, cost-effectiveness, and regulatory approvals also need to be addressed to facilitate widespread adoption by farmers.

The effectiveness and safety of natural food and food-derived extract supplements for treating functional gastrointestinal disorders-current perspectives.

Functional gastrointestinal disorders (FGIDs) were highly prevalent and involve gastrointestinal discomfort characterized by non-organic abnormalities in the morphology and physiology of the gastrointestinal tract. According to the Rome IV criteria, irritable bowel syndrome and functional dyspepsia are the most common FGIDs. Complementary and alternative medicines are employed by increasing numbers of individuals around the world, and they include herbal and dietary supplements, acupuncture, and hypnosis. Of these, herbal and dietary supplements seem to have the greatest potential for relieving FGIDs, through multiple modes of action. However, despite the extensive application of natural extracts in alternative treatments for FGIDs, the safety and effectiveness of food and orally ingested food-derived extracts remain uncertain. Many randomized controlled trials have provided compelling evidence supporting their potential, as detailed in this review. The consumption of certain foods (eg, kiwifruit, mentha, ginger, etc) and food ingredients may contribute to the alleviation of symptoms associated with FGID,. However, it is crucial to emphasize that the short-term consumption of these components may not yield satisfactory efficacy. Physicians are advised to share both the benefits and potential risks of these alternative therapies with patients. Furthermore, larger randomized clinical trials with appropriate comparators are imperative.

The photoactivated antifungal activity and possible mode of action of sodium pheophorbide a on Diaporthe mahothocarpus causing leaf spot blight in Camellia oleifera

IntroductionSodium pheophorbide a (SPA) is a natural plant-derived photosensitizer, with high photoactivated antifungal activity against some phytopathogenic fungi. However, its fungicidal effect on Diaporthe mahothocarpus, a novel pathogen that causes Camellia oleifera leaf spot blight, is unclear.MethodsIn the present study, we explored its inhibitory effects on spore germination and mycelial growth of D. mahothocarpus. Then we determined its effects on the cell membrane, mycelial morphology, redox homeostasis, and cell death through bioassay. Finally, RNA-seq was used further to elucidate its mode of action at the transcriptional level.ResultsWe found that SPA effectively inhibited the growth of D. mahothocarpus, with half-maximal effective concentrations to inhibit mycelial growth and spore germination of 1.059 and 2.287 mg/mL, respectively. After 1.0 mg/mL SPA treatment, the conductivity and malondialdehyde content of D. mahothocarpus were significantly increased. Scanning electron microscopy and transmission electron microscopy indicated that SPA significantly affected the morphology and ultrastructure of D. mahothocarpus hyphae, revealing that SPA can destroy the mycelial morphology and cell structure, especially the cell membrane of D. mahothocarpus. Furthermore, transcriptome analysis revealed that SPA significantly suppressed the expression of genes involved in morphology, cell membrane permeability, and oxidative stress. Then, we also found that SPA significantly promoted the accumulation of reactive oxygen species (ROS) in of D. mahothocarpus, while it decreased the content of reduced glutathione, inhibited the enzyme activities of superoxide dismutase and catalase, and exacerbated DNA damage. Annexin V-FITC/PI staining also confirmed that 1.0 mg/mL SPA could significantly induce apoptosis and necrosis.DiscussionGenerally, SPA can induce ROS-mediated oxidative stress and cell death, thus destroying the cell membrane and hyphal morphology, and ultimately inhibiting mycelial growth, which indicates that SPA has multiple modes of action, providing a scientific basis for the use of SPA as an alternative plant-derived photoactivated fungicide against C. oleifera leaf spot blight.

Restoring colistin sensitivity in colistin-resistant Salmonella and Escherichia coli: combinatorial use of berberine and EDTA with colistin.

Colistin is last-resort antibiotic used to treat serious clinical infections caused by MDR bacterial pathogens. The recent emergence of transferable plasmid-mediated COL resistance gene mcr-1 has raised the specter of a rapid worldwide spread of COL resistance. Coupled with the fact of barren antibiotic development pipeline nowadays, a critical approach is to revitalize existing antibiotics using antibiotic adjuvants. Our research showed that berberine combined with EDTA effectively reversed COL resistance both in vivo and in vitro through multiple modes of action. The discovery of berberine in combination with EDTA as a new and safe COL adjuvant provides a therapeutic regimen for combating Gram-negative bacteria infections. Our findings provide a potential therapeutic option using existing antibiotics in combination with antibiotic adjuvants and address the prevalent infections caused by MDR Gram-negative pathogens worldwide.

English

Coccidiosis is one of the major parasitic diseases infecting almost all ruminants, including cows, buffalo, sheep, and goats. Coccidiosis is caused by the genus Eimeria, which are host-specific obligate intestinal parasites. These are found almost all over the world and cause infections leading to mortalities and morbidities. Coccidiosis is usually treated by ionophores and synthetic chemicals of various classes including ionophores and synthetic chemical drugs. These drugs have been effective against coccidiosis but emerging issues of anthelmintic resistance, public health concerns, and consumer demand for organic products are leading to minimizing the use of these drugs. Vaccination is also being used, but vaccine failure and high cost limit their use. Among alternatives, herbal medicines are promising replacements because of their complex formulations, multiple modes of action, easy availability, and cost-effectiveness. Various plants, their parts, various formulations like herbal preparations, and the active compounds found in them are being searched to control ruminant coccidiosis. Multiple groups of botanical formulations, i.e., Flavonoids, alkaloids, tannins, terpenes, sulfur compounds, etc. have been proven to be effective against the ruminant coccidiosis-causing agents. They can control various stages of Eimeria directly and indirectly by antioxidant and immunomodulatory actions. Further research is needed to determine the most suitable herbal preparations and their pharmacological interactions for the effective and sustainable control of coccidiosis in ruminants. This review highlights the significance of ruminant coccidiosis, botanical compounds used against ruminant coccidiosis their mechanisms of action, and reasons and benefits of herbal compounds.

Xylanase-Producing Microbes and Their Real-World Application

The present study is focused on the availability of microbial sources capable of producing xylanase, a hemicelluloses-degrading enzyme with multiple modes of action along with specificity, and their real-world applications. For the accumulation of suitable data, article surfing was carried out using multiple search engines viz. Hinari and PubMed; irrelevant and duplicate articles were discarded and articles were summarized in a narrative way herein. This review article was written aiming to bridge the recent research activities with the commercial activities of xylanase going on around the globe. The readers would be able to acknowledge themselves with the basic idea of the hydrolytic enzyme xylanase, their classification representing their different families, presenting the affinity of different families at the structural level, the sources, and the commercial implications that have been going on alone and in combination. The major hemicellulose, Xylan is digested with the help of combination other enzymes such as alpha-amylase, subtilisin, protease, and endo-1,3(4)-β-glucanase along with xylanase. Xylanase has a diverse applications such as pharmaceutical, food and feed, bakery, paper and pulp, textile, and bio-refinery industries. The objective of this review article is to compile microbial sources of this enzyme and its application for betterment of human kind.

Challenges and Recommendations in Assessing Potential Endocrine-Disrupting Properties of Metals in Aquatic Organisms.

New tools and refined frameworks for identifying and regulating endocrine-disrupting chemicals (EDCs) are being developed as our scientific understanding of how they work advances. Although focus has largely been on organic chemicals, the potential for metals to act as EDCs in aquatic systems is receiving increasing attention. Metal interactions with the endocrine system are complicated because some metals are essential to physiological systems, including the endocrine system, and nonessential metals can have similar physiochemical attributes that allow substitution into or interference with these systems. Consequently, elevated metal exposure could potentially cause endocrine disruption (ED) but can also cause indirect effects on the endocrine system via multiple pathways or elicit physiologically appropriate compensatory endocrine-mediated responses (endocrine modulation). These latter two effects can be confused with, but are clearly not, ED. In the present study, we provide several case studies that exemplify the challenges encountered in evaluating the endocrine-disrupting (ED) potential of metals, followed by recommendations on how to meet them. Given that metals have multiple modes of action (MOAs), we recommend that assessments use metal-specific adverse outcome pathway networks to ensure that accurate causal links are made between MOAs and effects on the endocrine system. We recommend more focus on establishing molecular initiating events for chronic metal toxicity because these are poorly understood and would reduce uncertainty regarding the potential for metals to be EDCs. Finally, more generalized MOAs such as oxidative stress could be involved in metal interactions with the endocrine system, and we suggest it may be experimentally efficient to evaluate these MOAs when ED is inferred. These experiments, however, must provide explicit linkage to the ED endpoints of interest. Environ Toxicol Chem 2023;42:2564-2579. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Insect growth-regulating activity of 1-benzyl-2-methylbenzimidazole derivatives on silkworms.

Derivatives of 1-benzyl-2-methylbenzimidazoles (BMBIs) were synthesized to evaluate their biological activities against Bombyx mori, a lepidopteran model insect. Synthesized BMBIs exhibited two different biological activities: inhibition of development and acute lethality. From a structural perspective, the activity varied with the position of the substitutions on the 1-benzyl moiety; BMBIs with substitutions on the 2 and/or 4 positions had comparatively high activity in comparison with those with substitutions on the 3-position. There was more activity for the inhibition of development with low doses, and more for acute lethality with high doses. The activity was also affected by the applied stage, that is, application in the 4th instar mostly interfered the larval molting or pupation, whereas that in the 3rd instar caused more acute mortality. Taken together, these results suggest that BMBIs have multiple modes of action.

Engineered multi-walled carbon nanotubes for disinfecting wastewater

Discharging a considerable amount of untreated effluent directly into a water body significantly impacts water quality. Contaminated water can spread waterborne infections, resulting in exponentially high death rates worldwide. Although carbon nanotubes are frequently employed in industry, little is understood about how they may affect aquatic microbial ecosystems. Therefore, the present investigation aimed to exploit multi-walled carbon nanotubes (MWCNTs) as a potential disinfectant to eliminate waterborne bacteria during wastewater treatment. The current study utilized six different microbial strains, including Escherichia coli O157, Salmonella enterica, Staphylococcus aureus, Enterococcus faecalis, Risopus oryzae, and Rhizomucor miehei, to examine the antimicrobial properties of MWCNTs. The physical and morphological properties of MWCNTs were characterized using transmission electron microscope (TEM), scanning electron microscope (SEM), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), Dynamic light scattering (DLS), and zeta potential. The FTIR spectra of MWCNTs have appeared at 11,029 cm−1, and the zeta potential and particle size recorded at −28.89 mV and 425 nm, respectively. On the other hand, the results indicated that the width of the inhibition zone varied between 11 and 29 mm for E. coli O157, 11–31 mm for S. enterica, 16–37 mm for S. aureus, 14–34 mm for E.faecalis, 10–26 mm for R. oryzae, and 10–24 mm for Rh. miehei. The reduction rate of disinfection was estimated. The effective dose of MWCNTs (4xMIC) in a disinfection experiment could all selectedpathogens after 125 min exposure time. This study provided an overview of the antimicrobial properties of MWCNTs, their multiple modes of action against pathogens, and their usefulness in wastewater disinfection and microbial control. Thus, this current research work can also recommend MWCNTs as a good solution and beneficial disinfecting agent for inactivating waterborne pathogens within wastewater handling.

Rhodium(III)-Picolinamide Complexes Act as Anticancer and Antimetastasis Agents via Inducing Apoptosis and Autophagy.

As a continuation of our endeavors in discovering metal-based drugs with cytotoxic and antimetastatic activities, herein, we reported the syntheses of 11 new rhodium(III)-picolinamide complexes and the exploration of their potential anticancer activities. These Rh(III) complexes showed high antiproliferative activity against the tested cancer cell lines in vitro. The mechanism study indicated that Rh1 ([Rh(3a)(CH3CN)Cl2]) and Rh2 ([Rh(3b)(CH3CN)Cl2]) inhibited cell proliferation by multiple modes of action via cell cycle arrest, apoptosis, and autophagy and inhibited cell metastasis via FAK-regulated integrin β1-mediated suppression of EGFR expression. Furthermore, Rh1 and Rh2 significantly inhibited bladder cancer growth and breast cancer metastasis in a xenograft model. These rhodium(III) complexes could be developed as potential anticancer agents with antitumor growth and antimetastasis activity.

Exploiting fungi in bioremediation for cleaning-up emerging pollutants in aquatic ecosystems

Aquatic pollution negatively affects water bodies, marine ecosystems, public health, and economy. Restoration of contaminated habitats has attracted global interest since protecting the health of marine ecosystems is crucial. Bioremediation is a cost-effective and eco-friendly way of transforming hazardous, resistant contaminants into environmentally benign products using diverse biological treatments. Because of their robust morphology and broad metabolic capabilities, fungi play an important role in bioremediation. This review summarizes the features employed by aquatic fungi for detoxification and subsequent bioremediation of different toxic and recalcitrant compounds in aquatic ecosystems. It also details how mycoremediation may convert chemically-suspended matters, microbial, nutritional, and oxygen-depleting aquatic contaminants into ecologically less hazardous products using multiple modes of action. Mycoremediation can also be considered in future research studies on aquatic, including marine, ecosystems as a possible tool for sustainable management, providing a foundation for selecting and utilizing fungi either independently or in microbial consortia.

C-Alkylated flavonoids from the whole plants of Desmodium caudatum and their anti-TMV activity.

Natural products are important sources of biopesticides to control plant virus, and flavonoids are identified as promising anti-tobacco mosaic virus (TMV) agents. Since Desmodium caudatum is a rich source of flavonoids, this study focuses on the discovery of the new anti-TMV active flavonoids from D. caudatum and their possible mode of action. Three new (compounds 1-3) and nine known (compounds 4-12) C-alkylated flavonoids were isolated from D. caudatum. To the best of our knowledge, the framework of 1-3 was reported in natural products for the first time. In addition, 1-3, 5, and 6 showed notable anti-TMV activity with inhibition rates in the range of 35.8-64.3% at a concentration of 50 μg/mL, and these rates are higher than that of positive control (with inhibition rates of 34.6% ± 2.8). In addition, the structure-activity relationship study revealed that the (pyrrol-2-yl)methyl moiety on flavone can significantly increases the activity. This result is helpful to find new anti-TMV inhibitors. C-Alkylated flavonoids showed potent activities against TMV with multiple modes of actions. The increase of defense-related enzyme activities, up-regulate the expression of defense related genes, down-regulate the expression of Hsp70 protein by inhibiting the related Hsp genes that are involved in tobacco resistance to TMV. By the actions mentioned earlier, the infection of TMV was influenced, thereby achieving the effects of control of TMV. The successful isolation of the earlier-mentioned flavonoids provide the new source of biopesticides to TMV proliferation, and also contribute to the utilization of D. caudatum. © 2023 Society of Chemical Industry.

ATRT-10. SINGLE-CELL TRANSCRIPTOME ANALYSIS REVEALS CELLULAR HIERARCHIES AND THERAPEUTIC VULNERABILITIES OF ETMR

Abstract Embryonal tumors with multilayered rosettes (ETMR) are malignant brain tumors that occur predominantly in infants and young children. Most patients die within two years of diagnosis, and more effective, targeted therapies are urgently needed. To better characterize the oncogenic mechanisms of key driver alterations and to identify novel therapeutic targets, we set out to study the cellular heterogeneity of ETMR using single-cell RNA sequencing. Analyses conducted on >4,000 high-quality cells collected from eleven primary and relapse specimens revealed a common cellular hierarchy across all tumors: A highly proliferative neural stem cell-like population (SOX2+) that gives rise to intermediate progenitors (NEUROD1/NEUROG1+) and more differentiated neuron-like cells (STMN2/4+). These malignant cell populations closely overlap with histological patterns of ETMRs, as confirmed by multiplexed immunofluorescence microscopy on patients’ tumors. Comparison to single-cell datasets from human fetuses indicated high resemblance to normal cortical neurogenesis but also revealed key tumor-specific differences. These include expression of the chromosome 19 miRNA cluster (C19MC, the presumed driver in ~90% of ETMRs), which was restricted to the malignant stem cell-like population. Investigating oncogenic mechanisms of C19MC (comprising 46 miRNA genes) through transcriptome-wide RNA immunoprecipitation analysis, we identified extensive target gene regulation for most C19MC members, including distinct regulators of cell cycle, pluripotency, and neuronal differentiation. Silencing of C19MC families with antisense oligonucleotides resulted in pronounced reduction of ETMR cell line growth, indicating potential avenues for therapeutic targeting in the future. To identify more immediately actionable targets, we investigated inter-cellular signaling between malignant cell populations of ETMRs. Interestingly, we identified marked FGFR and NOTCH receptor-ligand interactions common to all tumors. An in vitro screen of experimental and approved small molecule inhibitors designed to target these interactions nominated several promising candidates for clinical evaluation. Our unpublished results provide much needed insight into targeting ETMR cellular states using multiple modes of action.

The impact of selenium on insects.

Selenium, a naturally occurring metalloid, is an essential trace element for many higher organisms, including humans. Humans primarily become exposed to selenium by ingesting food products containing trace amounts of selenium compounds. Although essential in these small amounts, selenium exhibits toxic effects at higher doses. Previous studies investigating the effects on insects of order Blattodea, Coleoptera, Diptera, Ephemeroptera, Hemiptera, Hymenoptera, Lepidoptera, Odonata, and Orthoptera revealed impacts on mortality, growth, development, and behavior. Nearly every study examining selenium toxicity has shown that insects are negatively affected by exposure to selenium in their food. However, there were no clear patterns of toxicity between insect orders or similarities between insect species within families. At this time, the potential for control will need to be determined on a species-by-species basis. We suspect that the multiple modes of action, including mutation-inducing modification of important amino acids as well as impacts on microbiome composition, influence this variability. There are relatively few studies that have examined the potential effects of selenium on beneficial insects, and the results have ranged from increased predation (a strong positive effect) to toxicity resulting in reduced population growth or even the effective elimination of the natural enemies (more common negative effects). As a result, in those pest systems where selenium use is contemplated, additional research may be necessary to ascertain if selenium use is compatible with key biological control agents. This review explores selenium as a potential insecticide and possible future directions for research.

Mesoporous silica shell in a core@shell nanocomposite design enables antibacterial action with multiple modes of action

Core@shell structured nanocomposites have received significant attention for their synergistic mode of antibacterial action. Identification of the accommodated unit’s function in the core@shell nanostructure is necessary in order to determine whether antibacterial synergism against bacterial cell growth that is provided within the same core@shell structure. Herein, a novel nanostructure(s) composed of a cerium oxide core and a porous silica shell (CeO2@pSiO2) accomodating curcumin and lectin was prepared, and the antibacterial synergism provided by the nanocomposite was identified. The resulting spherical-shaped CeO2@pSiO2 nanostructure allowed accommodation of curcumin loading (9 w/w%) and a lectin (concanavalin A) coating (15 w/w%). The antibacterial synergism was tested using a minimal inhibitory concentration assay against an Escherichia coli Gram-negative bacterial strain. Furthermore, the mechanisms of bacterial cell disruption induced by the curcumin-loaded and concanavalin A-coated CeO2@pSiO2 core@shell structure, namely the nanoantibiotic (nano-AB) and its design components, were identified. Our findings reveal that the mesoporous silica shell around the CeO2 core within the nano-AB design aids the accommodation of curcumin and concanavalin A and promotes destruction of bacterial cell motility and the permeability of the inner and outer bacterial cell membranes. Our findings strongly indicate the promising potential of a mesoporous silica shell around nanoparticles with a CeO2 core to provide synergistic antibacterial treatment and attack bacterial cells by different mechanisms of action.

Development of a kidney cancer ex vivo tumor model and image-based artificial intelligence tool for precision immunotherapy and combination therapy testing.

e16525 Background: Immuno-oncology (IO) initiated a major shift in the cancer treatment paradigm, as therapies no longer target cancer cells directly but rather restore and exploit a patient’s own antitumor immunity. However at present, there are no conclusive diagnostic tools capable of predicting combination immunotherapy response with high accuracy in renal cancer. We’ve developed an ex vivo IO model and multivariate analysis to predict clinical drug efficacy by combining patient tumor samples, functional assays, artificial intelligence and omics. This model recapitulates each patient’s tumor-immune microenvironment (TiME) and allows time-course bulk and single-cell resolution analyses of functional metrics in 3D. Methods: Human renal tumor resections and matched blood (N=20 REC approved) were processed for spatial transcriptomics and single cell isolation of tumor and PBMCs. Tumor-dissociated (tumor, stromal, immune, etc.) cells and PBMC subsets were characterized by flow cytometry (FCm). Target cells (tumor) and effector cells (PBMCs and subsets thereof, CD8+) were stained with different fluorescent dyes including viability probes (caspase 3/7, SYTOX) and encapsulated in hydrogels that recapitulate human TiME physiology. Cultures were treated with approved regimens including immune checkpoint (ipilimumab, pembrolizumab) and receptor-tyrosine kinase (TKI)(cabozantinib, lenvatinib) inhibitors. Cells were tracked over 7 days using 3D time-course confocal microscopy. Computer vision analysis detected and quantified behaviors such as immune infiltration, immune/tumor cell migration, T cell-mediated tumor killing and tumor viability in response to treatments. Results: Our preliminary data shows that treatment with pembrolizumab resulted in a 26% increase in the infiltration of CD8- PBMC fraction into the microtumor core and a 14% increase in infiltration of the CD8+ subset. Tumor cell death was 15% higher in pembro-treated samples compared to untreated and 30% higher compared to tumor cultures alone (no PBMCs). Migration speed of immune cells was found to be higher as cells invaded and slower through engagement/killing, peaking at day 1 (3 µm/min) and slowing to 2 and 1.5 µm/min for CD8+ and CD8- cells by day 3. FCm was used to characterize tumor cell subpopulations (cancer, endothelial, immune) and the expression of targets in each patient. Treatment with TKIs led to reduced phosphorylation of VEGFR, PDGFRβ and HGFR (N=3). Conclusions: Our platform allows time-course analysis of functional cell response metrics. The model tests treatment combinations across multiple modes of action and quantifies cell response including viability, death, migration, infiltration and immune-surveillance. Future work aims to further develop the platform to match/predict patient responses in breast (NCT05435352), kidney, and other tumors.

Treatments of COVID-19-Associated Taste and Saliva Secretory Disorders.

Since the worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, treating taste and saliva secretory disorders associated with coronavirus disease 2019 (COVID-19) has become a critical issue. The aim of the present study was to update information on treatments applicable to such oral symptoms and discuss their pathogenic mechanisms. The literature search indicated that different treatments using tetracycline, corticosteroids, zinc, stellate ganglion block, phytochemical curcumin, traditional herbal medicine, nutraceutical vitamin D, photobiomodulation, antiviral drugs, malic acid sialagogue, chewing gum, acupuncture, and/or moxibustion have potential effects on COVID-19-associated ageusia/dysgeusia/hypogeusia and xerostomia/dry mouth/hyposalivation. These treatments have multiple modes of action on viral cellular entry and replication, cell proliferation and differentiation, immunity, and/or SARS-CoV-2 infection-induced pathological conditions such as inflammation, cytokine storm, pyroptosis, neuropathy, zinc dyshomeostasis, and dysautonomia. An understanding of currently available treatment options is required for dental professionals because they may treat patients who were infected with SARS-CoV-2 or who recovered from COVID-19, and become aware of their abnormal taste and salivary secretion. By doing so, dentists and dental hygienists could play a crucial role in managing COVID-19 oral symptoms and contribute to improving the oral health-related quality of life of the relevant patients.

Phytochemistry, Pharmacology and Mode of Action of the Anti-Bacterial Artemisia Plants.

Over 70,000 people die of bacterial infections worldwide annually. Antibiotics have been liberally used to treat these diseases and, consequently, antibiotic resistance and drug ineffectiveness has been generated. In this environment, new anti-bacterial compounds are being urgently sought. Around 500 Artemisia species have been identified worldwide. Most species of this genus are aromatic and have multiple functions. Research into the Artemisia plants has expanded rapidly in recent years. Herein, we aim to update and summarize recent information about the phytochemistry, pharmacology and toxicology of the Artemisia plants. A literature search of articles published between 2003 to 2022 in PubMed, Google Scholar, Web of Science databases, and KNApSAcK metabolomics databases revealed that 20 Artemisia species and 75 compounds have been documented to possess anti-bacterial functions and multiple modes of action. We focus and discuss the progress in understanding the chemistry (structure and plant species source), anti-bacterial activities, and possible mechanisms of these phytochemicals. Mechanistic studies show that terpenoids, flavonoids, coumarins and others (miscellaneous group) were able to destroy cell walls and membranes in bacteria and interfere with DNA, proteins, enzymes and so on in bacteria. An overview of new anti-bacterial strategies using plant compounds and extracts is also provided.

Preclinical characterization of ISB 1342, a CD38 × CD3 T-cell engager for relapsed/refractory multiple myeloma

AbstractAlthough treatment of multiple myeloma (MM) with daratumumab significantly extends the patient’s lifespan, resistance to therapy is inevitable. ISB 1342 was designed to target MM cells from patients with relapsed/refractory MM (r/r MM) displaying lower sensitivity to daratumumab. ISB 1342 is a bispecific antibody with a high-affinity Fab binding to CD38 on tumor cells on a different epitope than daratumumab and a detuned scFv domain affinity binding to CD3ε on T cells, to mitigate the risk of life-threatening cytokine release syndrome, using the Bispecific Engagement by Antibodies based on the TCR (BEAT) platform. In vitro, ISB 1342 efficiently killed cell lines with different levels of CD38, including those with a lower sensitivity to daratumumab. In a killing assay where multiple modes of action were enabled, ISB 1342 showed higher cytotoxicity toward MM cells compared with daratumumab. This activity was retained when used in sequential or concomitant combinations with daratumumab. The efficacy of ISB 1342 was maintained in daratumumab-treated bone marrow patient samples showing lower sensitivity to daratumumab. ISB 1342 induced complete tumor control in 2 therapeutic mouse models, unlike daratumumab. Finally, in cynomolgus monkeys, ISB 1342 displayed an acceptable toxicology profile. These data suggest that ISB 1342 may be an option in patients with r/r MM refractory to prior anti-CD38 bivalent monoclonal antibody therapies. It is currently being developed in a phase 1 clinical study.