"Naringenin: A Promising Immunomodulator for Anti-Inflammatory, Neuroprotective, and Anti-Cancer Applications".

BACKGROUND: Inflammatory, immune, and neurodegenerative diseases constitute a category of persistent and debilitating conditions affecting millions worldwide, with inter-twined pathophysiological pathways. Recent research has spotlighted naturally occurring compounds like naringenin for potential therapeutic applications across multiple ailments. OBJECTIVE: This review offers an encompassing exploration of naringenin's anti-inflamma-tory, immune-protective, and neuroprotective mechanisms, elucidating its pharmacological targets, signal transduction pathways, safety profile, and insights from clinical investigations. METHODS: Data for this review were amassed through the scrutiny of various published studies via search engines such as PubMed and Google Scholar. Content from reputable publishers including Bentham Science, Taylor and Francis, Nature, PLOS ONE, among others, was referenced. RESULTS: Naringenin exhibits substantial anti-inflammatory effects by restraining the NF-κB signaling pathway. It activates Nrf2, renowned for its anti-inflammatory properties, inducing the release of hemeoxynase-1 by macrophages. Furthermore, naringenin treatment downregulates the expression of Th1 cytokines and inflammatory mediators. It also impedes xanthine oxidase, counteracts reactive oxygen species (ROS), scavenges superoxide radicals, mitigates the accessibility of oxygen-induced K+ erythrocytes, and reduces lipid peroxidation. Naringenin's antioxidant prowess holds promise for addressing neurological conditions. CONCLUSION: Extensive research has been undertaken to establish the anti-inflammatory, immunomodulatory, and neuroprotective attributes of naringenin across various medical domains, lending credence to its pharmacological utility. The principal obstacle to naringenin's adoption as a therapeutic agent remains the dearth of in vivo data. Efforts should focus on rendering naringenin delivery patient-friendly, economically viable, and technologically advanced.

Prognostic and Therapeutic Implications of Cell Division Cycle 20 Homolog in Breast Cancer.

Cell division cycle 20 homolog (CDC20) is a well-known regulator of cell cycle progression. Abnormal expression of CDC20 leads to mitotic defects, which play a significant role in cancer development. In breast cancer (BC), CDC20 has been identified as a biomarker that has been linked to poor patient outcomes. In this study, we investigated the association of CDC20 with BC prognosis and immune cell infiltration by using multiple online databases, including UALCAN, KM plotter, TIMER2.0, HPA, TNM-plot, bc-GenExMiner, LinkedOmics, STRING, and GEPIA. The results demonstrate that BC patients have an elevated CDC20 expression in tumor tissues compared with the adjacent normal tissue. In addition, BC patients with overexpressed CDC20 had a median survival of 63.6 months compared to 169.2 months in patients with low CDC20 expression. Prognostic analysis of the examined data indicated that elevated expression of CDC20 was associated with poor prognosis and a reduction of overall survival in BC patients. These findings were even more prevalent in chemoresistance triple-negative breast cancer (TNBC) patients. Furthermore, the Gene Set Enrichment Analysis tool indicated that CDC20 regulates BC cells' cell cycle and apoptosis. CDC20 also significantly correlates with increased infiltrating B cells, CD4+ T cells, neutrophils, and dendritic cells in BC. In conclusion, the findings of this study suggest that CDC20 may be involved in immunomodulating the tumor microenvironment and provide evidence that CDC20 inhibition may serve as a potential therapeutic approach for the treatment of BC patients. In addition, the data indicates that CDC20 can be a reliable prognostic biomarker for BC.

Peptide Blockers of PD-1-PD-L1 Interaction Reinvigorate PD-1-Suppressed T Cells and Curb Tumor Growth in Mice.

The programmed cell death protein 1 (PD-1) plays a critical role in cancer immune evasion. Blocking the PD-1-PD-L1 interaction by monoclonal antibodies has shown remarkable clinical efficacy in treating certain types of cancer. However, antibodies are costly to produce, and antibody-based therapies can cause immune-related adverse events. To address the limitations associated with current PD-1/PD-L1 blockade immunotherapy, we aimed to develop peptide-based inhibitors of the PD-1/PD-L1 interaction as an alternative means to PD-1/PD-L1 blockade antibodies for anti-cancer immunotherapy. Through the functional screening of peptide arrays encompassing the ectodomains of PD-1 and PD-L1, followed by the optimization of the hit peptides for solubility and stability, we have identified a 16-mer peptide, named mL7N, with a remarkable efficacy in blocking the PD-1/PD-L1 interaction both in vitro and in vivo. The mL7N peptide effectively rejuvenated PD-1-suppressed T cells in multiple cellular systems designed to recapitulate the PD-1/PD-L1 interaction in the context of T-cell receptor signaling. Furthermore, PA-mL7N, a chimera of the mL7N peptide coupled to albumin-binding palmitic acid (PA), significantly promoted breast cancer cell killing by peripheral blood mononuclear cells ex vivo and significantly curbed tumor growth in a syngeneic mouse model of breast cancer. Our work raises the prospect that mL7N may serve as a prototype for the development of a new line of peptide-based immunomodulators targeting the PD-1/PD-L1 immune checkpoint with potential applications in cancer treatment.

A tumor targeted nano micelle carrying astragaloside IV for combination treatment of bladder cancer.

Immune checkpoint inhibitors (ICIs) are effective agents for tumor immunotherapy. However, their clinical effectiveness is unsatisfactory due to off-target effects and a suppressive immune microenvironment. This study developed a nanodrug delivery system for bladder cancer (BCa) using PCL-MPEG and PCL-PEG-CHO to synthesize internal hydrophobic and external hydrophilic micelles (PP) that encapsulated water-insoluble astragaloside IV (PPA). The aldehyde group on the surface of PPA reacted with the amino group of aPD-L1, allowing the decoration of this antibody on the surface of the micelles. The resultingPPA@aPD-L1effectively piggybacked astragaloside IV and aPD-L1 antibody. These findings suggest that PPA@aPD-L1 is relatively stable in circulation and efficiently binds to BCa cells with the aid of aPD-L1. Additionally, this strategy prolongs the drug's retention time in tumors. Compared to PBS, PP, and PPA with PPA + aPD-L1 groups, PPA@aPD-L1significantly prolonged the survival of mice with BCa and reduced tumor volume. Mechanistic studies showed that PPA inhibited the NF-κB and STAT3 signaling pathways in tumor cells. Additionally, PPA@aPD-L1increased IFN-γ and decreased IL-10 expression in bladder tumors, affecting the number and type of intratumorally infiltrating T cells. Our study presents a simple and effective drug delivery system that combines herbal monomers with ICIs. It has demonstrated a potent ability to suppress tumor growth and holds potential for future applications.

Immunomodulatory Effects of a Herbo-Mineral Ayurvedic Formulation in Experimental Models.

BACKGROUND: Ayurveda, an ancient Indian system of medicine, encapsulates comprehensive principles and formulations for disease prevention and treatment. A herbo-mineral Ayurvedic formulation, IMMBO, comprising Mandoor Bhasma and 18 herbs has shown promising results in treating allergic rhinitis in clinical studies. OBJECTIVE: This discussed series of experimental studies were conducted to explore the immuno-modulatory potential of IMMBO. METHODOLOGY: A series of experimental studies were carried out in immunosuppressed rats to explore the immune-modulatory effects of IMMBO. RESULTS: IMMBO was effective in reinstating neutrophil activation, stimulating cellular and humoral immunity, and counteracting immunosuppression at the molecular level. The modulation of key signalling molecules, including tumour necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukin-1 beta (IL-1ß), extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K), and nuclear factor-kappa B (NF-κb), showcased the formulation's multifaceted impact. Additionally, its ability to block histamine release suggests potential in controlling allergic states, positioning it as a promising therapeutic candidate for immune-related disorders. However, the precise mode of action remains elusive, warranting further in-depth pharmacological studies. CONCLUSION: This research substantiates the ancient Ayurvedic wisdom using modern scientific parameters, endorsing IMMBO's potential as an immune-modulatory agent.

Rice bran arabinoxylan compound as a natural product for cancer treatment - an evidence-based assessment of the effects and mechanisms.

CONTEXT: Rice bran arabinoxylan compound (RBAC) is a natural immunomodulator with anticancer properties. OBJECTIVE: This study critically evaluates the available evidence on the biological pathways of RBAC and its effects on cancer treatment. METHODS: This secondary analysis of a scoping review includes studies evaluating the mechanisms of RBAC on healthy or malignant cells, animal models, or humans for cancer prevention or treatment. Data from randomized controlled trials on survival and quality of life outcomes were subjectd to meta analysis. RESULTS: The evidence synthesis was based on 38 articles. RBAC exhibited antitumor properties by promoting apoptosis and restoring immune function in cancer patients to enhance inflammatory and cytotoxic responses to block tumorigenesis. RBAC works synergistically with chemotherapeutic agents by upregulating drug transport. In a clinical trial, combining RBAC with chemoembolization in treating liver cancer showed improved response, reduced recurrence rates, and prolonged survival. RBAC also augments the endogenous antioxidant system to prevent oxidative stress and protect against radiation side effects. In addition, RBAC has chemoprotective effects. Animals and humans have exhibited reduced toxicity and side effects from chemotherapy. Meta analysis indicates that RBAC treatment increases the survival odds by 4.02-times (95% CI: 1.67, 9.69) in the first year and 2.89-times (95% CI: 1.56, 5.35) in the second year. CONCLUSION: RBAC is a natural product with immense potential in cancer treatment. Additional research is needed to characterize, quantify, and standardize the active ingredients in RBAC responsible for the anticancer effects. More well-designed, large-scale clinical trials are required to substantiate the treatment efficacies further.

Pembrolizumab-Induced Pancreatitis: Take It With a Grain of Salt.

Keytruda (pembrolizumab) is an immunomodulator that prevents the interaction between programmed cell death protein (PD-1) and programmed death ligand (PD-L1/2) on immune cells and tumour cells, thereby preventing T cell dysfunction. At times, mounting a strong immune response against tumour cells may not spare normal cells, leading to a variety of multisystemic adverse effects. With this, we present a case of a 64-year-old male who developed acute pancreatitis after completing eight cycles of Keytruda for castrate-resistant metastatic prostate cancer for six months, after all other causes of pancreatitis were excluded.

Exosomes: efficient macrophage-related immunomodulators in chronic lung diseases.

Macrophages, the predominant immune cells in the lungs, play a pivotal role in maintaining the delicate balance of the pulmonary immune microenvironment. However, in chronic inflammatory lung diseases and lung cancer, macrophage phenotypes undergo distinct transitions, with M1-predominant macrophages promoting inflammatory damage and M2-predominant macrophages fostering cancer progression. Exosomes, as critical mediators of intercellular signaling and substance exchange, participate in pathological reshaping of macrophages during development of pulmonary inflammatory diseases and lung cancer. Specifically, in inflammatory lung diseases, exosomes promote the pro-inflammatory phenotype of macrophages, suppress the anti-inflammatory phenotype, and subsequently, exosomes released by reshaped macrophages further exacerbate inflammatory damage. In cancer, exosomes promote pro-tumor tumor-associated macrophages (TAMs); inhibit anti-tumor TAMs; and exosomes released by TAMs further enhance tumor proliferation, metastasis, and resistance to chemotherapy. Simultaneously, exosomes exhibit a dual role, holding the potential to transmit immune-modulating molecules and load therapeutic agents and offering prospects for restoring immune dysregulation in macrophages during chronic inflammatory lung diseases and lung cancer. In chronic inflammatory lung diseases, this is manifested by exosomes reshaping anti-inflammatory macrophages, inhibiting pro-inflammatory macrophages, and alleviating inflammatory damage post-reshaping. In lung cancer, exosomes reshape anti-tumor macrophages, inhibit pro-tumor macrophages, and reshaped macrophages secrete exosomes that suppress lung cancer development. Looking ahead, efficient and targeted exosome-based therapies may emerge as a promising direction for treatment of pulmonary diseases.

Multi-functional nanomedicines for combinational cancer immunotherapy that transform cold tumors to hot tumors.

INTRODUCTION: Currently, cancer immunotherapy is widely used as a groundbreaking method that can completely cure advanced cancers. However, this new immunotherapy has the challenge of low patient response, which is often due to many patients' tumors having an immunosuppressive environment, known as cold tumors. AREAS COVERED: This review aims to introduce various nanomedicine-derived combinational cancer immunotherapy that can transform cold tumor into hot tumors. Initially, we discuss new technologies for combinational immunotherapy based on multifunctional nanomedicines that can deliver combinational immunogenic cell death (ICD) inducers, immune checkpoint blockades (ICBs) and immune modulators (IMs) to targeted tumor tissues at the same time. Ultimately, we highlight how multifunctional nanomedicines for combinational cancer immunotherapy can be used to transform cold tumor into hot tumors against advanced cancers. EXPERT OPINION: Nanomedicine-derived combinational cancer immunotherapy for delivering multiple ICD inducers, ICBs, and IMs at the same time is recognized as a new potential technology that can activate tumor immunity and simultaneously increase the therapeutic efficacy of immune cells that can transform effectively the cold tumors into hot tumors. Finally, nanomedicine-derived combinational cancer immunotherapy can solve the serious problems of low therapeutic efficacy that occurs when treating single drug or simple combinational drugs in cancer immunotherapy.

Rice Bran Arabinoxylan Compound and Quality of Life (RBAC-QoL) of Cancer Patients: An Interim Analysis of the RBAC-QoL Study.

Background The effect of rice bran arabinoxylan compound (RBAC), a plant-based immunomodulator, on the quality of life (QoL) in cancer patients and underlying physiological pathways remains unclear. Trial design The RBAC-QoL study, a double-blind, randomised, controlled pilot feasibility study, aimed to determine RBAC's effects on QoL and the associated action mechanisms. Primary outcomes were the EORTC QLQ-C30 functional, symptom, and global QoL scores with inflammatory, nutritional, and cytokine parameters as secondary and exploratory outcomes. Methods Participants were adults diagnosed with solid organ tumours (≥ stage II) undergoing active treatment in several outpatient centres in New South Wales, Australia. Interventions were RBAC or matched placebo at 3g/day for 24 weeks allocated through stratified randomisation with participants, oncologists, and data collectors blinded. Data was collected from five study visits six weeks apart. The trial remained ongoing as of December 2023. An interim intention-to-treat analysis was performed using repeated measure ANOVA with pairwise comparisons where statistical significance was observed and adjusted with covariates. Results Global QoL scores from currently available data (n = 16; RBAC = 7, placebo = 9) were statistically different between groups (F1,8 = 8.6, p = 0.019, eta2[g] = 0.267). Pairwise comparisons found significant differences at Week 6 (p = 0.032, Cohen's d = 1.454) and marginally at Week 12 (p = 0.069, d = 1.427). Age-adjusted analysis showed a continuous upward trend in QoL improvement over time with RBAC, while the placebo group did not deviate from baseline QoL. Significant elevations of serum white blood cell count (Week 18) and total protein (Weeks 12 and 18) were detected in the RBAC group compared to placebo. The total protein levels correlated highly with white blood cell count (Pearson's r = 0.539, p < 0.001) and moderately with the global QoL scores (r = 0.338, p = 0.01). No intervention-related adverse events were reported in both groups.  Conclusions RBAC improves QoL beyond placebo during active cancer treatment, possibly through the immuno-nutritional pathway - these findings, though preliminary, are valuable for future research. Funding and registration: Daiwa Pharmaceutical Co., Ltd, Japan; BioMedica Nutraceuticals Pty Ltd., Australia. ANZCTR Reg No: ACTRN12619000562178p.

Microencapsulation of Theobroma cacao L polyphenols: A high-value approach with in vitro anti-Trypanosoma cruzi, immunomodulatory and antioxidant activities.

Chagas disease (CHD) is the highest economic burden parasitosis worldwide and the most important cardiac infection, without therapeutic alternatives to halt or reverse its progression. In CHD-experimental models, antioxidant and anti-inflammatory compounds have demonstrated therapeutic potential in cardiac dysfunction. Theobroma cacao polyphenols are potent natural antioxidants with cardioprotective and anti-inflammatory action, which are susceptible to degradation, requiring technological approaches to guarantee their protection, stability, and controlled release. Here, 21 cocoa polyphenol-rich microencapsulates were produced by spray-drying and freeze-drying techniques using two wall materials (maltodextrin and gum arabic). Chemical (total and individual phenolic content and antioxidant activity), structural (morphology), and biological parameters (cytotoxicity, trypanocidal, antioxidant, and immunomodulatory activities) were assessed to determine the most efficient microencapsulation conditions on Trypanosoma cruzi-infected myocardioblast and macrophage cells. Significant antiproliferative properties against infected cells (superior to benznidazole) were found in two microencapsulates which also exhibited cardioprotective properties against oxidative stress, inflammation, and cell death.

Dual-responsive supramolecular photodynamic nanomedicine with activatable immunomodulation for enhanced antitumor therapy.

A major challenge facing photodynamic therapy (PDT) is that the activity of the immune-induced infiltrating CD8+ T cells is subject to the regulatory T lymphocytes (Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment (TME), a supramolecular photodynamic nanoparticle (DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated ß-cyclodextrin (DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration (Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile ß-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs. The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.

Comprehensive analysis of pain genes in prognosis of kidney renal clear cell carcinoma and tumor immunotherapy: A comprehensive bioinformatic study.

Background: The effect of pain genes (NAV1, EHMT2, SP1, SLC6A4, COMT, OPRM1, OPRD1, CYP2D6, and CYP3A4) have not been reported previously in kidney renal clear cell carcinoma (KIRC) patients and thus we made a comprehensive analysis of pain genes in the prognosis of KIRC and tumor immunotherapy. Methods: In this study, TCGA, Kaplan-Meier plotter, Metascape, STRING, Human Protein Atlas, Single Cell Expression Atlas database, LinkedOmics, cBioPortal, MethSurv, CancerSEA, COSMIC database and R package (ggplot2, version 3.3.3) were used for comprehensive analysis of pain genes in KIRC. Pearson and Spearman correlation coefficients were for co-expression analysis. Immunotherapy and TISIDB database were used for tumor Immunotherapy. Results: Representative pain genes (SP1, SLC6A4, COMT, OPRD1, CYP2D6, and CYP3A4) were statistically significant (p < 0.0001) in the prognosis of KIRC. Immunotherapy (anti-PD-1 therapy, anti-PD-L1 therapy, and anti-CTLA4 therapy) and immunomodulator (immunoinhibitor, immunostimulator, and MHC molecule) in KIRC were significant associated with pain genes (SP1, SLC6A4, COMT, OPRD1, CYP2D6, and CYP3A4), which were the important addition to clinical decision making for patients. Conclusions: Our study uncovered a mechanism for the effect of pain genes on KIRC outcome via the modulation of associated co-expression gene networks, gene variation, and tumor Immunotherapy.

Molecular Targets of Valeric Acid: A Bioactive Natural Product for Endocrine, Metabolic, and Immunological Disorders.

BACKGROUNDS: Postbiotics produced by gut microbiota have exhibited diverse pharmacological activities. Valeric acid, a postbiotic material produced by gut microbiota and some plant species like valerian, has been explored to have diverse pharmacological activities. METHODS: This narrative review aims to summarise the beneficial role of valeric acid for different health conditions along with its underlying mechanism. In order to get ample scientific evidence, various databases like Science Direct, PubMed, Scopus, Google Scholar and Google were exhaustively explored to collect relevant information. Collected data were arranged and analyzed to reach meaningful a conclusion regarding the bioactivity profiling of valeric acid, its mechanism, and future prospects. RESULTS: Valeric acid belongs to short-chain fatty acids (SCFAs) compounds like acetate, propionate, butyrate, pentanoic (valeric) acid, and hexanoic (caproic) acid. Valeric acid has been identified as one of the potent histone deacetylase (HDAC) inhibitors. In different preclinical in -vitro and in-vivo studies, valeric acid has been found to have anti-cancer, anti-diabetic, antihypertensive, anti-inflammatory, and immunomodulatory activity and affects molecular pathways of different diseases like Alzheimer's, Parkinson's, and epilepsy. CONCLUSION: These findings highlight the role of valeric acid as a potential novel therapeutic agent for endocrine, metabolic and immunity-related health conditions, and it must be tested under clinical conditions to develop as a promising drug.

The ß-Carboline Harmine Has a Protective Immunomodulatory Role in Nonhealing Cutaneous Leishmaniasis.

Cutaneous leishmaniasis affects 1 million people worldwide annually. Although conventional treatments primarily target the parasite, there is growing interest in host immune modulation. In this study, we investigated the impact of synthetic ß-carboline harmine (ACB1801), previously shown to be immunoregulatory in cancer, on the pathology caused by a drug-resistant Leishmania major strain causing persistent cutaneous lesions. Exposure to ACB1801 in vitro had a modest impact on parasite burden within host macrophages. Moreover, it significantly increased major histocompatibility complex II and costimulatory molecule expression on infected dendritic cells, suggesting an enhanced immune response. In vivo, ACB1801 monotherapy led to a substantial reduction in lesion development and parasite burden in infected C57BL/6 mice, comparable with efficacy of amphotericin B. Transcriptomics analysis further supported ACB1801 immunomodulatory effects, revealing an enrichment of TNF-α, IFN-γ, and major histocompatibility complex II antigen presentation signatures in the draining lymph nodes of treated mice. Flow cytometry analysis confirmed an increased frequency (1.5×) of protective CD4+IFN-γ+TNF-α+ T cells and a decreased frequency (2×) in suppressive IL-10+FoxP3- T cells at the site of infection and in draining lymph nodes. In addition, ACB1801 downregulated the aryl hydrocarbon receptor signaling, known to enhance immunosuppressive cytokines. Thus, these results suggest a potential use for ACB1801 alone or in combination therapy for cutaneous leishmaniasis.

Rhein: A potent immunomodulator empowering largemouth bass against MSRV infection.

Micropterus salmoides rhabdovirus (MSRV) is a significant viral pathogen in largemouth bass aquaculture, causing substantial annual economic losses. However, effective prevention methods remain elusive for various reasons. Medicinal plant extracts have emerged as valuable tools in preventing and managing aquatic animal diseases. Thus, the search for immunomodulators with straightforward, safe structures in plant extracts is imperative to ensure the continued health and growth of the largemouth bass industry. In our research, we employed epithelioma papulosum cyprinid (EPC) cells and largemouth bass as models to assess the anti-MSRV properties and immunomodulatory effects of ten plant-derived bioactive compounds. Among them, rhein demonstrated noteworthy potential, exhibiting a 75 % reduction in viral replication in vitro at a concentration of 50 mg/L. Furthermore, rhein pre-treatment significantly inhibited MSRV genome replication in EPC cells, with the highest inhibition rate reaching 64.8 % after 24 h, underscoring rhein's preventive impact against MSRV. Likewise, rhein displayed remarkable therapeutic effects on EPC cells during the early stages of MSRV infection, achieving a maximum inhibition rate of 85.6 % in viral replication. Subsequent investigations unveiled that rhein, with its consistent activity, effectively mitigated cytopathic effects (CPE) and nuclear damage induced by MSRV infection. Moreover, it restrained mitochondrial membrane depolarization and reduced the apoptosis rate by 38.8 %. In vivo experiments reinforced these findings, demonstrating that intraperitoneal injection of rhein enhanced the expression levels of immune related genes in multiple organs, hindered virus replication, and curtailed the mortality rate of MSRV-infected largemouth bass by 29 %. Collectively, our study endorses the utility of rhein as an immunomodulator to combat MSRV infections in largemouth bass. This not only underscores the potential of rhein as a broad-spectrum antiviral and means to bolster the immune response but also highlights the role of apoptosis as an immunological marker, making it an invaluable addition to the armamentarium against aquatic viral pathogens.

A Cocktail of Natural Compounds Holds Promise for New Immunotherapeutic Potential in Head and Neck Cancer.

OBJECTIVE: To obtain detailed understanding on the gene regulation of natural compounds in altering prognosis of head and neck squamous cell carcinomas (HNSC). METHODS: Gene expression data of HNSC samples and peripheral blood mononuclear cells (PBMCs) of HNSC patients were collected from Gene Expression Omnibus (GEO). Differential gene expression analysis of GEO datasets were achieved by the GEO2R tool. Common differentially expressed gerres (DEGs) were screened by comparing DEGs of HNSC with those of PBMCs. The combination was further analyzed for regulating pathways and biological processes that were affected. RESULTS: Totally 110 DEGs were retrieved and identified to be involved in biological processes related to tumor regulation. Then 102 natural compounds were screened for a combination such that the expression of all 110 commonly DEGs was altered. A combination of salidroside, ginsenoside Rd, oridonin, britanin, and scutellarein was chosen. A multifaceted, multi-dimensional tumor regression was showed by altering autophagy, apoptosis, inhibiting cell proliferation, angiogenesis, metastasis and inflammatory cytokines production. CONCLUSIONS: This study has helped develop a unique combination of natural compounds that will markedly reduce the propensity of development of drug resistance in tumors and immune evasion by tumors. The result is crucial to developing a combinatorial natural therapeutic cocktail with accentuated immunotherapeutic potential.

Pre-treatment inflamed tumor immune microenvironment is associated with FOLFIRINOX response in pancreatic cancer.

Introduction: Pancreatic adenocarcinoma (PDAC) is an aggressive tumor with limited response to both chemotherapy and immunotherapy. Pre-treatment tumor features within the tumor immune microenvironment (TiME) may influence treatment response. We hypothesized that the pre-treatment TiME composition differs between metastatic and primary lesions and would be associated with response to modified FOLFIRINOX (mFFX) or gemcitabine-based (Gem-based) therapy. Methods: Using RNAseq data from a cohort of treatment-naïve, advanced PDAC patients in the COMPASS trial, differential gene expression analysis of key immunomodulatory genes in were analyzed based on multiple parameters including tumor site, response to mFFX, and response to Gem-based treatment. The relative proportions of immune cell infiltration were defined using CIBERSORTx and Dirichlet regression. Results: 145 samples were included in the analysis; 83 received mFFX, 62 received Gem-based therapy. Metastatic liver samples had both increased macrophage (1.2 times more, p < 0.05) and increased eosinophil infiltration (1.4 times more, p < 0.05) compared to primary lesion samples. Further analysis of the specific macrophage phenotypes revealed an increased M2 macrophage fraction in the liver samples. The pre-treatment CD8 T-cell, dendritic cell, and neutrophil infiltration of metastatic samples were associated with therapy response to mFFX (p < 0.05), while mast cell infiltration was associated with response to Gem-based therapy (p < 0.05). Multiple immunoinhibitory genes such as ADORA2A, CSF1R, KDR/VEGFR2, LAG3, PDCD1LG2, and TGFB1 and immunostimulatory genes including C10orf54, CXCL12, and TNFSF14/LIGHT were significantly associated with worse survival in patients who received mFFX (p = 0.01). There were no immunomodulatory genes associated with survival in the Gem-based cohort. Discussion: Our evidence implies that essential differences in the PDAC TiME exist between primary and metastatic tumors and an inflamed pretreatment TiME is associated with mFFX response. Defining components of the PDAC TiME that influence therapy response will provide opportunities for targeted therapeutic strategies that may need to be accounted for in designing personalized therapy to improve outcomes.

Bioavailability of bioactive compounds in Hibiscus sabdariffa beverage as a potential anti-inflammatory.

The absorption and metabolism of bioactive compounds (BCs) in a Hibiscus sabdariffa drink (HbD) were evaluated by the in vivo bioavailability of organic acids (OA) and phenolic compounds (PC's). An acute single-blind clinical study in humans was conducted. Twelve volunteers consumed a HbD and a control drink (CD). Urine and plasma samples were taken after consuming both beverages. OA and PC's of the beverages (HbD and CD) and the biological samples (urine and plasma) were characterized by HPLC-DAD-MS. Thirthy-eight compounds in HbD and four CD were detected and quantified, equivalent to 937.37 mg and 1.22 mg per 60 mL, respectively. Hibiscus acid was the most abundant OA in both drinks. Additionally, hydroxycinnamic acids, flavonoids, anthocyanins, and anthocyanidins were also detected in HbD, although their amount represented 10% of the total BCs. 25 different metabolites were identified, 15 in urine and 23 in plasma. The microbiota extensively biotransformed PCs and their amount was lower than organic acids, particularly hibiscus acid and hydroxycitric acid. The colonic metabolites derived from PCs and organic acids would be behind the anti-inflammatory bioactivity described for Hibiscus sabdariffa L. (Malvaceae family). However, further studies are necessary to evaluate the metabolites responsible for their anti-inflammatory activity.

Immunomodulatory effects of inactivated Ligilactobacillus salivarius CECT 9609 on respiratory epithelial cells.

The microbiota in humans and animals play crucial roles in defense against pathogens and offer a promising natural source for immunomodulatory products. However, the development of physiologically relevant model systems and protocols for testing such products remains challenging. In this study, we present an experimental condition where various natural products derived from the registered lactic acid bacteria Ligilactobacillus salivarius CECT 9609, known for their immunomodulatory activity, were tested. These products included live and inactivated bacteria, as well as fermentation products at different concentrations and culture times. Using our established model system, we observed no morphological changes in the airway epithelium upon exposure to Pasteurella multocida, a common respiratory pathogen. However, early molecular changes associated with the innate immune response were detected through transcript analysis. By employing diverse methodologies ranging from microscopy to next-generation sequencing (NGS), we characterized the interaction of these natural products with the airway epithelium and their potential beneficial effects in the presence of P. multocida infection. In particular, our discovery highlights that among all Ligilactobacillus salivarius CECT 9609 products tested, only inactivated cells preserve the conformation and morphology of respiratory epithelial cells, while also reversing or altering the natural immune responses triggered by Pasteurella multocida. These findings lay the groundwork for further exploration into the protective role of these bacteria and their derivatives.