Immunomodulatory Compounds Research Articles

Unlocking the Immunomodulatory Potential of Rosmarinic Acid Isolated from Punica granatum L. using Bioactivity-Guided Approach: In Silico, In Vitro, and In Vivo Approaches.

Punica granatum L. is well-known for its multifaceted therapeutic potential, including anti-inflammatory and immunomodulatory activities. This study aimed to characterize an immunomodulatory compound isolated from Punica granatum L. using a bioactivity-guided approach. Chromatographic techniques were adopted for isolation and purification of secondary metabolites. In silico, in vitro, and in vivo methods were performed to characterize the therapeutic potential of the isolated compound. Using preparative thin-layer chromatography, rosmarinic acid was isolated from F4 (column chromatography product obtained from a butanolic fraction of the extract). The impact of rosmarinic acid was assessed in rats using the neutrophil adhesion test, DTH response, and phagocytic index. In immunized rats, rosmarinic acid demonstrated significant immunomodulatory potential. Computational experiments, like molecular docking and molecular dynamics, were also conducted against two targeted receptors, Cereblon (PDB ID: 8AOQ) and human CD22 (PDB ID: 5VKM). Computational studies suggested that an increase in phagocytic index by rosmarinic acid could be attributed to inhibiting Cereblon and CD22. Pharmacokinetics and toxicity prediction also suggested the drug-likeness of rosmarinic acid. Rosmarinic acid is a potential candidate, but extensive research needs to be done to translate this molecule from bench to bedside.

Proteomic profiling of oleamide-mediated polarization in a primary human monocyte-derived tumor-associated macrophages (TAMs) model: a functional analysis.

Tumor-associated macrophages (TAMs) play a critical function in the development of tumors and are associated with protumor M2 phenotypes. Shifting TAMs towards antitumor M1 phenotypes holds promise for tumor immunotherapy. Oleamide, a primary fatty acid amide, has emerged as a potent anticancer and immunomodulatory compound. However, the regulatory effects of oleamide on TAM phenotypes remain unclear. We used real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) techniques to study the influence of oleamide on primary human monocyte-derived TAM phenotypes, and we investigated the protein expression profiles based on mass spectrometry to analyze the effect of oleamide on macrophage polarization. Moreover, the advantageous binding scores between oleamide and these target candidate proteins are examined using molecular docking. Our study revealed that oleamide effectively suppressed the M2-like TAM phenotype by reducing interleukin (IL)-10 production and downregulating M2-like markers, including vascular endothelial growth factor A (VEGFA), MYC proto-oncogene, bHLH transcription factor (c-Myc), and mannose receptor C-type 1 (CD206). Moreover, the conditioned medium derived from oleamide-treated TAMs induces apoptosis of MDA-MB-231 breast cancer cells. Proteomic analysis identified 20 candidate up- and down-regulation proteins targeted by oleamide, showing modulation activity associated with the promotion of the M1-like phenotype. Furthermore, molecular docking demonstrated favorable binding scores between oleamide and these candidate proteins. Collectively, our findings suggest that oleamide exerts a potent antitumor effect by promoting the antitumor M1-like TAM phenotype. These novel insights provide valuable resources for further investigations into oleamide and macrophage polarization which inhibit the progression of breast cancer, which may provide insight into immunotherapeutic approaches for cancer.

Modulation of M1/M2 Cytokines and Inflammatory Enzymes by Persicaria Species Leaf Extracts in Lipopolysaccharide-stimulated RAW 264.7 Cell Macrophages.

Investigating the impacts of plant-based substances on the regulation of pro-inflammatory M1 and anti-inflammatory M2 cytokines could have significant implications for immune-related health conditions. Seven Persicaria plant species from sub-Saharan Africa were specifically selected for analysis, based on their traditional use in treating inflammation. To investigate the inhibitory effects of methanol leaf extracts from selected plants on enzymes involved in chronic inflammation. The inhibition of nitric oxide production, acetylcholinesterase activity, and 15-lipoxygenase activity was assessed using the Griess reagent method, Ellman's colorimetric method, and the ferrous oxidation-xylenol orange assay. The quantity of M1/M2 cytokines released was quantified using a flow cytometer. At a concentration of 50 µg/mL, the methanol extracts of P. limbata exhibited the highest NO inhibition (97.67%), followed by P. nepalensis (93.06%) and P. setosula (92.78%). The NO inhibition caused by the plant extracts was correlated directly with the decrease in NO release by the LPS-stimulated macrophages. Furthermore, the pro-inflammatory enzyme assays indicated that the methanol extracts of P. setosula exhibited the highest enzyme inhibitory activity (LOX 89.59%, AChE 72.12 %). This was followed by P. limbata (with 92.76% for LOX and 56.93% for AChE) and P. nepalensis (with 88.16% for LOX and 47.17% for AChE). Cytokine assays revealed that the extracts of P. limbata had significant dose-dependent suppressive effects on IFN-γ and TNF-α expression while promoting the secretion of IL-2, IL-4, IL-6, and IL-10. Extracts of P. limbata contain immunomodulatory compounds that could be further explored as potential remedies to target the molecular drivers of chronic inflammation.

Investigation of Advanced Nanoscale Biomaterials as Immune Modulators for Therapeutic Applications

Immunomodulatory agents play a crucial role in drug delivery by modulating the immune system's response to therapeutic agents, thereby enhancing treatment efficacy and safety. These agents can either stimulate the immune system to improve drug effectiveness, particularly in cancer and infectious diseases, or suppress it to prevent adverse reactions in conditions like organ transplantation and autoimmune diseases. The integration of immunomodulatory agents into drug delivery systems (DDS) enhances drug targeting, controls release, and optimizes pharmacokinetics. Advanced carriers such as nanoparticles and liposomes are employed to precisely deliver these agents, aligning with personalized medicine approaches to tailor treatments based on individual immune profiles. Despite their potential, challenges such as balancing immune modulation and addressing safety concerns remain. Ongoing research is focused on developing innovative DDS, improving targeting strategies, and identifying new immunomodulatory compounds to address these challenges. This abstract provides an overview of the role and impact of immunomodulatory agents in drug delivery systems and highlights the current trends and future directions in this evolving field.

Analysis of the immunomodulatory properties of mycobacterium cell wall fraction on the cytokine production of peripheral blood mononuclear cells of healthy dogs.

Mycobacterium cell wall fraction (MCWF) is derived from nonpathogenic Mycobacterium phlei and is used as an immunomodulatory compound in clinical practice, yet its mode-of-action requires further research. To evaluate the host response to MCWF in canine peripheral blood mononuclear cells (PBMCs) by using enzyme-linked immunosorbent assays (ELISA) and quantitative reverse transcription (qRT)-PCR for assessment of cytokines. Eight healthy Labrador retrievers. PBMCs were isolated from whole blood using density centrifugation. The cells were cultured with different concentrations of MCWF or a potent stimulator of cytokine production, phorbol 12-myristate 13-acetate/ionomycin, or left in cell culture medium for 24, 48 and 72 h. Cytokines were measured by ELISA for interleukin (IL)-4, IL-10 and interferon-gamma (IFN-γ), and by qRT-PCR for IL-4, IL-10, IL-13, IFN-γ, tumour necrosis factor alpha (TNF-α) and transforming growth factor-beta. A significant increase of IL-10 messenger ribonucleic acid (mRNA) was detected at all time points for all concentrations of MCWF (p < 0.05). Protein analysis reflected this finding, with a maximum IL-10 concentration of 300.6 ± 38.3 μg/mL. Compared to the negative control, post-stimulation elevation of IFN-γ mRNA was noted at 24 h with all concentrations of MCWF (p < 0.01), and TNF-α mRNA was increased for 0.5 μg/dL MCWF only at 72 h (p < 0.05). MCWF stimulation of PBMCs results in the elevation of both proinflammatory and regulatory cytokine mRNA. Further research into the role of MCWF as a systemically administered regulatory immunomodulator or adjuvant to allergen-specific immunotherapy should be considered.

Bacterial outer membrane vesicles in the fight against cancer.

Bacterial outer membrane vesicles (OMVs) are diminutive vesicles naturally released by Gram-negative bacteria. These vesicles possess distinctive characteristics that attract attention for their potential use in drug administration and immunotherapy in cancer treatment. Therapeutic medicines may be delivered via OMVs directly to the tumor sites, thereby minimizing exposure to healthy cells and lowering the risk of systemic toxicity. Furthermore, the activation of the immune system by OMVs has been demonstrated to facilitate the recognition and elimination of cancer cells, which makes them a desirable tool for immunotherapy. They can also be genetically modified to carry specific antigens, immunomodulatory compounds, and small interfering RNAs, enhancing the immune response to cancerous cells and silencing genes associated with disease progression. Combining OMVs with other cancer treatments like chemotherapy and radiation has shown promising synergistic effects. This review highlights the crucial role of bacterial OMVs in cancer, emphasizing their potential as vectors for novel cancer targeted therapies. As researchers delve deeper into the complexities of these vesicles and their interactions with tumors, there is a growing sense of optimism that this avenue of study will bring positive outcomes and renewed hope to cancer patients in the foreseeable future.

Polymersomes with splenic avidity target red pulp myeloid cells for cancer immunotherapy.

Regulating innate immunity is an emerging approach to improve cancer immunotherapy. Such regulation requires engaging myeloid cells by delivering immunomodulatory compounds to hematopoietic organs, including the spleen. Here we present a polymersome-based nanocarrier with splenic avidity and propensity for red pulp myeloid cell uptake. We characterized the in vivo behaviour of four chemically identical yet topologically different polymersomes by in vivo positron emission tomography imaging and innovative flow and mass cytometry techniques. Upon intravenous administration, relatively large and spherical polymersomes accumulated rapidly in the spleen and efficiently targeted myeloid cells in the splenic red pulp. When loaded with β-glucan, intravenously administered polymersomes significantly reduced tumour growth in a mouse melanoma model. We initiated our nanotherapeutic's clinical translation with a biodistribution study in non-human primates, which revealed that the platform's splenic avidity is preserved across species.

Expression of Immunoglobulin M (IgM) and Immunoglobulin G (IgG) in Normal Wistar Rat Post-Cheral® Administration

Maintaining immunoglobulin levels in the body is important to protect the body from exposure to pathogens. One effort can be made by consuming herbs containing immunomodulatory compounds, such as Cheral®, which includes a combination of herbs Phyllanthus niruri and Curcuma longa. This research aims to determine the expression of immunoglobulin M (IgM) and immunoglobulin G (IgG) following the administration of Cheral® to Wistar rats. The study was conducted in vivo, utilizing 24 healthy male Wistar rats for a 90-day treatment period. The research was divided into four treatment groups, including a control group and three dosage groups: Dose 1 (156.25 mg/kg BW), Dose 2 (312.5 mg/kg BW), and Dose 3 (468.75 mg/kg BW). IgM and IgG were isolated from the spleen and analyzed using flow cytometry. Flow cytometry data were analyzed using SPSS with a one-way ANOVA and post hoc test (p-value &lt;0.05). The analysis showed that the relative number of IgM-producing cells in the control group was significantly higher than in the treatment groups, with a difference of 44.40%. In contrast, the relative number of IgG-producing cells in Dose 3 was significantly lower than all other treatment groups, showing a decrease of 29.21%. Overall, the expression of IgG and IgM did not differ substantially across all treatments. The lower IgG and IgM profiles compared to the control group indicate Cheral®'s ability to prevent infections and maintain the immune system of the rats throughout the treatment period.

Anti-Neuroinflammatory Effects of a Novel Bile Acid Derivative.

In the search for novel potent immunomodulatory nuclear factor-erythroid 2 related factor 2 (Nrf2) activators, a derivative of cholic bile acid, SB140, was synthesized. The synthesis of SB140 aimed to increase the electrophilic functionality of the compound, enhancing its ability to activate Nrf2. Effects of SB140 on microglial cells, myeloid-derived cells (MDC), and T cells were explored in the context of (central nervous system) CNS autoimmunity. SB140 potently activated Nrf2 signaling in MDC and microglia. It was efficient in reducing the ability of microglial cells to produce inflammatory nitric oxide, interleukin (IL)-6, and tumor necrosis factor (TNF). Also, SB140 reduced the proliferation of encephalitogenic T cells and the production of their effector cytokines: IL-17 and interferon (IFN)-γ. On the contrary, the effects of SB140 on anti-inflammatory IL-10 production in microglial and encephalitogenic T cells were limited or absent. These results show that SB140 is a potent Nrf2 activator, as well as an immunomodulatory compound. Thus, further research on the application of SB140 in the treatment of neuroinflammatory diseases is warranted. Animal models of multiple sclerosis and other inflammatory neurological disorders will be a suitable choice for such studies.

Immunomodulatory Compounds from the Sea: From the Origins to a Modern Marine Pharmacopoeia.

From sea shores to the abysses of the deep ocean, marine ecosystems have provided humanity with valuable medicinal resources. The use of marine organisms is discussed in ancient pharmacopoeias of different times and geographic regions and is still deeply rooted in traditional medicine. Thanks to present-day, large-scale bioprospecting and rigorous screening for bioactive metabolites, the ocean is coming back as an untapped resource of natural compounds with therapeutic potential. This renewed interest in marine drugs is propelled by a burgeoning research field investigating the molecular mechanisms by which newly identified compounds intervene in the pathophysiology of human diseases. Of great clinical relevance are molecules endowed with anti-inflammatory and immunomodulatory properties with emerging applications in the management of chronic inflammatory disorders, autoimmune diseases, and cancer. Here, we review the historical development of marine pharmacology in the Eastern and Western worlds and describe the status of marine drug discovery. Finally, we discuss the importance of conducting sustainable exploitation of marine resources through biotechnology.

Anti-HIV Activity and Immunomodulatory Properties of Fractionated Crude Extracts of Alternaria alternata.

Developing new anti-human immunodeficiency virus (HIV) drug candidates that target different sites in HIV-1 replication, with better resistance profiles and lower drug toxicity, is essential to eradicating HIV. This study investigated the potential of fractionated crude extracts of Alternaria alternata as immunomodulatory or anti-HIV drug candidates. Solid-phase extraction (SPE) was used to fractionate A. alternata PO4PR2 using three different columns: MAX (Mixed-mode, strong Anion-eXchange), MCX (Mixed-mode, strong Cation-eXchange), and HLB (Hydrophilic-Lipophilic Balance) with methanol gradient methods (5%, 45%, and 95%). An MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay was used to assess the cell viability and cytotoxicity of the fractionated crude extract A. alternata PO4PR2 in the TZM-bl cell lines. This was followed by a luciferase-based antiviral assay to assess the antiviral activity of A. alternata PO4PR2. A time of addition (TOA) assay was performed to ascertain the mechanism of inhibition employed by the fractionated crude extract of A. alternata PO4PR2 in the HIV life cycle. The p24 titer was determined using an ELISA, while a luciferase-based antiviral assay was used to evaluate the HIV percentage inhibition for different HIV-1 replication cycles. The TOA assay was established using antiviral drugs that target different sites in the HIV replication cycle. These included maraviroc, azidothymidine, raltegravir, and amprenavir. The immunomodulatory effect of the fractionated crude extracts on CD4+ T cells was measured by a flow cytometric analysis, for which fluorochrome-labelled monoclonal antibodies were used as markers for activation (CD38 and HLA-DR) and exhaustion (PD-1). The MCX fraction demonstrated a more significant anti-HIV inhibition than that of the fractions generated in other columns, with an IC50 of 0.3619 µg/mL, an HIV inhibition of 77%, 5% HLB (IC50: 0.7232 µg/mL; HIV inhibition of 64%), and 5% MAX (IC50: 5.240 µg/mL; HIV inhibition of 67%). It was evident from the time of addition data that the crude extract and the 5% MCX fraction inhibited viral binding (68%), reverse transcription (75%), integration (98%), and proteolysis (77%). It was shown that A. alternata (the MCX fraction) have a significant inhibitory effect on reverse transcription (75% HIV inhibition) and integration (100% HIV inhibition). The 5% MCX (p = 0.0062), 5% HLB (p = 0.0269), and 5% MAX (p = 0.0117) fractionated A. alternata crude extracts had low levels of CD4+ T cell (CD38 + HLA-DR+) activation compared to those of the AZT treatment, while CD4+ T cell activation was insignificant. The 5% MAX and HLB A. alternata fractions may possess immunomodulatory compounds with less anti-HIV-1 activity. A. alternata could be a key source of innovative anti-HIV drugs with immunomodulatory characteristics.

Fine-tuning of mononuclear phagocytes for improved inflammatory responses: role of soybean-derived immunomodulatory compounds

The concept of inflammation encompasses beneficial and detrimental aspects, which are referred to as infectious and sterile inflammations, respectively. Infectious inflammation plays a crucial role in host defense, whereas sterile inflammation encompasses allergic, autoimmune, and lifestyle-related diseases, leading to detrimental effects. Dendritic cells and macrophages, both of which are representative mononuclear phagocytes (MNPs), are essential for initiating immune responses, suggesting that the regulation of MNPs limits excessive inflammation. In this context, dietary components with immunomodulatory properties have been identified. Among them, soybean-derived compounds, including isoflavones, saponins, flavonoids, and bioactive peptides, act directly on MNPs to fine-tune immune responses. Notably, some soybean-derived compounds have demonstrated the ability to alleviate the symptom of allergy and autoimmunity in mouse models. In this review, we introduce and summarize the roles of soybean-derived compounds on MNP-mediated inflammatory responses. Understanding the mechanism by which soybean-derived molecules regulate MNPs could provide valuable insights for designing safe immunomodulators.

Action of Ergost-7-en-3- ol from (Acanthaster planci) stimulation of activity peritoneal macrophages

An is a compound capable of influencing the human immune system because it can maintain and restore the balance of the immune system by stimulating the immune system through phagocytosis, the complement system, IgA antibody secretion, the release of interferon α and γ, T and B lymphocytes, specific antibody systems, and cytokines. Immunomodulators can be obtained from natural sources, one of which is Acanthaster planci, which is one of the marine organisms that has important bioactive substances that can act as immunomodulators. The purpose of this research is to determine the immunomodulatory activity of chloroform fractions FrKl3.1.3.1 and FrKl3.1.3.2 and to identify the immunomodulatory compounds from the chloroform fraction FrKl3.1.3.1 of A. planci. The results of the study showed that the macrophage test of the FrKl3.1.3.1 fraction had higher activity compared to FrKl3.1.3.2, while the spectroscopic data analysis results showed that UV-VIS had a maximum absorption at a wavelength (λmax) of 240 nm, FTIR data (cm-1) showed the presence of hydroxyl (-OH) groups, alkene groups (double bonds (C=C)), and aliphatic C-H groups. The 1H-NMR data (CDCl3, 500 MHz) showed six methane groups, ten aliphatic methylene groups (-CH2-), nine geminal methylene groups, one methylene group with a double bond, and 13C-NMR and DEPT 135 data (CDCl3, 125 MHz) indicated that the A. planci FrKl3.1.3.1 fraction had 28 carbon atoms consisting of six methyl (-CH3) carbon atoms, ten methylene (-CH2) carbon atoms, and nine methine (-CH-) carbon atoms. From the spectroscopic analysis data, it is known that the chloroform fraction of A. planci FrKl3.1.3.1 is ergost-7-en-3-ol compound.

High S100A9 level predicts poor survival, and the S100A9 inhibitor paquinimod is a candidate for treating idiopathic pulmonary fibrosis

BackgroundS100A9 is a damage-associated molecular pattern protein that may play an important role in the inflammatory response and fibrotic processes. Paquinimod is an immunomodulatory compound that prevents S100A9 activity. Its...

Immunomodulatory options for neurodevelopmental spectrum conditions: are we there yet?

About 3-7% of the worldwide population is diagnosed with a neurodevelopmental condition, including autism and attention-deficit hyperactivity disorder. Nonetheless, the aetiology of these conditions is unclear and support options are limited or not effective for all those diagnosed. Cumulating evidence, however, supports a role of the immune system in neurodevelopment, and immune dysregulations have been implicated in neurodevelopmental atypicalities. This knowledge offers tremendous opportunities, especially the possibility to adopt immunomodulatory compounds, which are already available and safe to use, for the management of neurodevelopmental difficulties. This perspective discusses the potential of immune-based interventions in neurodevelopmental care. Here, the application of existing immunomodulatory compounds to symptom management is justified by findings of immune dysregulations across neurodevelopmental conditions and preliminary, encouraging immune-based clinical trials. Still, key considerations are presented, specifically the necessity of immune biomarkers to ensure the right support option for the right (subgroup of) individuals within the neurodevelopmental spectrum.

Melatonin as an immunomodulator in CD19-targeting CAR-T cell therapy: managing cytokine release syndrome

BackgroundChimeric antigen receptor CAR-T cell therapies have ushered in a new era of treatment for specific blood cancers, offering unparalleled efficacy in cases of treatment resistance or relapse. However, the emergence of cytokine release syndrome (CRS) as a side effect poses a challenge to the widespread application of CAR-T cell therapies. Melatonin, a natural hormone produced by the pineal gland known for its antioxidant and anti-inflammatory properties, has been explored for its potential immunomodulatory effects. Despite this, its specific role in mitigating CAR-T cell-induced CRS remains poorly understood.MethodsIn this study, our aim was to investigate the potential of melatonin as an immunomodulatory agent in the context of CD19-targeting CAR-T cell therapy and its impact on associated side effects. Using a mouse model, we evaluated the effects of melatonin on CAR-T cell-induced CRS and overall survival. Additionally, we assessed whether melatonin administration had any detrimental effects on the antitumor efficacy and persistence of CD19 CAR-T cells.ResultsOur findings demonstrate that melatonin effectively mitigated the severity of CAR-T cell-induced CRS in the mouse model, leading to improved overall survival outcomes. Remarkably, melatonin administration did not compromise the antitumor effectiveness or persistence of CD19 CAR-T cells, indicating its compatibility with therapeutic goals. These results suggest melatonin's potential as an immunomodulatory compound to alleviate CRS without compromising the therapeutic benefits of CAR-T cell therapy.ConclusionThe study's outcomes shed light on melatonin's promise as a valuable addition to the existing treatment protocols for CAR-T cell therapies. By attenuating CAR-T cell-induced CRS while preserving the therapeutic impact of CAR-T cells, melatonin offers a potential strategy for optimizing and refining the safety and efficacy profile of CAR-T cell therapy. This research contributes to the evolving understanding of how to harness immunomodulatory agents to enhance the clinical application of innovative cancer treatments.

Macroalgae: Marine players in vaccinology

Although seaweeds have been used for decades as food, medicinal plants, and nutritional supplements, their use as a vaccine production and delivery platform has been barely explored, despite the availability of several genetic tools for seaweed transformation. The present review introduces seaweeds and their valuable immunomodulatory compounds in perspective as vaccine production and mucosal delivery platform. Genetic engineering tools are reviewed for macroalgal transformation, and the recombinant proteins produced in this platform are summarized. Finally, the hurdles and opportunities on seaweed potential as a vaccine production platform and delivery vehicle are proposed. As expected, seaweeds can soon be exploited to produce vaccine candidates due to their biological characteristics, including accelerated growth, photosynthetic capacity, and bioactive compound production, as well as the genetic engineering tools available. With all these properties -plus the commercial seaweed industry- this new envisioned technology can be adopted to improve human and animal health.

Evaluation of Olive Leaf Phenolic Compounds' Gastrointestinal Stability Based on Co-Administration and Microencapsulation with Non-Digestible Carbohydrates.

The large generation of olive by-products has motivated their revalorization into high-added-value products. In this regard, olive leaves pose as an interesting source of bioactive compounds, due to their phenolic content with commonly known antioxidant, anti-inflammatory, and immunomodulatory properties, with potential application in non-communicable diseases. However, their effectiveness and applicability into functional foods is limited by their instability under gastrointestinal conditions. Thus, the development of protective formulations is essential. In this study, the spray-drying encapsulation of a phenolic-rich olive leaf extract with inulin as the encapsulating agent was optimized. Then, the behavior of the free extract under gastrointestinal conditions, its co-administration with the encapsulating agent, and the optimized microencapsulated formulation were studied through an in vitro gastrointestinal digestion process following the INFOGEST protocol. Digestion of the free extract resulted in the degradation of most compounds, whereas this was minimized in the co-administration of the non-encapsulated extract with the encapsulating agent. This protective effect, related to its interaction with inulin, was similar to the microencapsulated formulation. Thus, both approaches, co-administration and microencapsulation with inulin, could be promising strategies for the improvement of the stability of these anti-inflammatory and immunomodulatory compounds under gastrointestinal conditions, enhancing their beneficial effect.

Assessing the effect of β-glucan diets on innate immune response of tilapia macrophages against trichlorfon exposure: an in vitro study

The widespread use of pesticides in some areas where fish species such as tilapia are farmed may cause damage to the environment and affect commercial fish and therefore, human health. Water leaching with the pesticide trichlorfon, during the fumigation season in the field, can affect water quality in fish farms and consequently affect fish health. At the same time, the use of immunomodulatory compounds such as β-glucan supplied in the diet has become widespread in fish farms as it has been shown that improves the overall immune response. The present research examines the immunomodulatory impacts observed in macrophages of Nile tilapia (Oreochromis niloticus) after being fed a diet supplemented with β-glucan for 15 days, followed by their in vitro exposure to trichlorfon, an organophosphate pesticide, at concentrations of 100 and 500 µg mL−1 for 24 h. The results showed that β-glucan diet improved the viability of cells exposed to trichlorfon and their antioxidant capacity. However, β-glucan did not counteract the effects of the pesticide as for the ability to protect against bacterial infection. From the present results, it can be concluded that β-glucan feeding exerted a protective role against oxidative damage in cells, but it was not enough to reduce the deleterious effects of trichlorfon on the microbicidal capacity of macrophages exposed to this pesticide.

CAR-modified Cellular Therapies in Chronic Lymphocytic Leukemia: Is the Uphill Road Getting Less Steep?

The clinical development of chimeric antigen receptor (CAR) T-cell therapy has been more challenging for chronic lymphocytic leukemia (CLL) compared to other settings. One of the main reasons is the CLL-associated state of immune dysfunction that specifically involves patient-derived T cells. Here, we provide an overview of the clinical results obtained with CAR T-cell therapy in CLL, describing the identified immunologic reasons for the inferior efficacy. Novel CAR T-cell formulations, such as lisocabtagene maraleucel, administered alone or in combination with the Bruton tyrosine kinase inhibitor ibrutinib, are currently under investigation. These approaches are based on the rationale that improving the quality of the T-cell source and of the CAR T-cell product may deliver a more functional therapeutic weapon. Further strategies to boost the efficacy of CAR T cells should rely not only on the production of CAR T cells with an improved cellular composition but also on additional changes. Such alterations could include (1) the coadministration of immunomodulatory agents capable of counteracting CLL-related immunological alterations, (2) the design of improved CAR constructs (such as third- and fourth-generation CARs), (3) the incorporation into the manufacturing process of immunomodulatory compounds overcoming the T-cell defects, and (4) the use of allogeneic CAR T cells or alternative CAR-modified cellular vectors. These strategies may allow to develop more effective CAR-modified cellular therapies capable of counteracting the more aggressive and still incurable forms of CLL.