Discovering single cannabidiol or synergistic antitumor effects of cannabidiol and cytokine-induced killer cells on non-small cell lung cancer cells.

Introduction: A multitude of findings from cell cultures and animal studies are available to support the anti-cancer properties of cannabidiol (CBD). Since CBD acts on multiple molecular targets, its clinical adaptation, especially in combination with cancer immunotherapy regimen remains a serious concern. Methods: Considering this, we extensively studied the effect of CBD on the cytokine-induced killer (CIK) cell immunotherapy approach using multiple non-small cell lung cancer (NSCLC) cells harboring diverse genotypes. Results: Our analysis showed that, a) The Transient Receptor Potential Cation Channel Subfamily V Member 2 (TRPV2) channel was intracellularly expressed both in NSCLC cells and CIK cells. b) A synergistic effect of CIK combined with CBD, resulted in a significant increase in tumor lysis and Interferon gamma (IFN-g) production. c) CBD had a preference to elevate the CD25+CD69+ population and the CD62L_CD45RA+terminal effector memory (EMRA) population in NKT-CIK cells, suggesting early-stage activation and effector memory differentiation in CD3+CD56+ CIK cells. Of interest, we observed that CBD enhanced the calcium influx, which was mediated by the TRPV2 channel and elevated phosphor-Extracellular signal-Regulated Kinase (p-ERK) expression directly in CIK cells, whereas ERK selective inhibitor FR180204 inhibited the increasing cytotoxic CIK ability induced by CBD. Further examinations revealed that CBD induced DNA double-strand breaks via upregulation of histone H2AX phosphorylation in NSCLC cells and the migration and invasion ability of NSCLC cells suppressed by CBD were rescued using the TRPV2 antagonist (Tranilast) in the absence of CIK cells. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation. Conclusions: Taken together, CBD holds a great potential for treating NSCLC with CIK cell immunotherapy. In addition, we utilized NSCLC with different driver mutations to investigate the efficacy of CBD. Our findings might provide evidence for CBD-personized treatment with NSCLC patients.

Role of Dectin-1 in immune response of macrophages induced by Fonsecaea monophora wild strain and melanin-deficient mutant strain.

Chromoblastomycosis is a chronic granulomatous subcutaneous fungal disease caused mainly by Fonsecaea monophora in southern China. Melanin is an important virulence factor in wild strain (Mel+), and the strains lack of the polyketide synthase gene is a melanin-deficient mutant strain (Mel-). We investigated the effect of melanin in F. monophora on Dectin-1 receptor-mediated immune responses in macrophages. Conidia and tiny hyphae of Mel+ and Mel- were co-cultured with THP-1 macrophages expressing normal or low levels of Dectin-1. Compare the killing rate, phagocytosis rate, and expression levels of the inflammatory cytokines tumour necrosis factor-α, interleukin-1ß, interleukin-6, and nitric oxide in each group. The results showed that the killing rate, phagocytosis rate, and pro-inflammatory factor levels of Mel+ infected macrophages with normal expression of Dectin-1 were lower than those of Mel-. And the knockdown of Dectin-1 inhibited the phagocytic rate, killing rate, and proinflammatory factor expression in macrophages infected with Mel+ and Mel-. And there was no significant difference in the above indexes between Mel+ and Mel- groups in Dectin-1 knockdown macrophages. In summary, the study reveals that melanin of F. monophora inhibits the immune response effect of the host by hindering its binding to Dectin-1 on the surface of macrophage, which may lead to persistent fungal infections.

Inflammatory Biomarkers, Cognitive Functioning, and Brain Imaging Abnormalities in Bipolar Disorder: A Systematic Review.

Objective: Recent studies have pointed to neuroinflammation and neurotrophic factors as crucial mediators in the pathophysiology origins of mood disorders. The aim of this review is to assess the potential association between cognitive impairment, brain imaging abnormalities, and inflammatory biomarkers in patients affected by bipolar disorder (BD). Method: Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, we systematically searched PubMed, Google Scholar, Scopus, and Web of Science databases, with no year restriction, up until August 2023, for human studies that examined the relationship between inflammatory markers and cognitive impairment in BD patients. Studies based on neuroimaging, such as MRI, DTI, and fMRI, were also included, along with those examining the moderating role of specific inflammatory markers in the alteration of the brain. Results: 59 human clinical studies satisfied the criteria for consideration. Most of the studies reviewed concur that inflammatory state, measured by peripheral blood levels of CRP and cytokines, constitutes an important contributor to cognitive impairment observed in patients with BD. Robust evidence indicates an association between cognitive impairment and CRP, IL-1RA, IL-6, and TNF-α with its receptors, whereas there is no convincing evidence for the involvement of other neuroinflammatory biomarkers. Neuroimaging studies suggest that brain structural/functional abnormalities seen in BD could also be linked to a neuroinflammatory condition. Conclusions: Current data provide evidence of a link between cognitive impairments observed in BD patients and mechanisms of neuroinflammation. Emerging evidence indicates that systemic inflammation might also play an important role in the deterioration of brain structures critical to cognitive functions in patients with BD. The convergence of findings across these studies strengthens our understanding of the complex neurobiological underpinnings of these disorders. Identification of BD specific inflammatory markers may be of assistance for future early therapeutic interventions.

Improving cell reinfusion to enhance the efficacy of chimeric antigen receptor T-cell therapy and alleviate complications.

Adoptive cell therapy (ACT) is a rapidly expanding area within the realm of transfusion medicine, focusing on the delivery of lymphocytes to trigger responses against tumors, viruses, or inflammation. This area has quickly evolved from its initial promise in immuno-oncology during preclinical trials to commercial approval of chimeric antigen receptor (CAR) T-cell therapies for leukemia and lymphoma (Jun and et al., 2018) [1]. CAR T-cell therapy has demonstrated success in treating hematological malignancies, particularly relapsed/refractory B-cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma (Qi and et al., 2022) [2]. However, its success in treating solid tumors faces challenges due to the short-lived presence of CAR-T cells in the body and diminished T cell functionality (Majzner and Mackall, 2019) [3]. CAR T-cell therapy functions by activating immune effector cells, yet significant side effects and short response durations remain considerable obstacles to its advancement. A prior study demonstrated that the therapeutic regimen can induce systemic inflammatory reactions, such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), tumor lysis syndrome (TLS), off-target effects, and other severe complications. This study aims to explore current research frontiers in this area.

Ustekinumab for pyoderma gangrenosum-like skin ulcerations in late-onset leukocyte adhesion deficiency.

Background: Leukocyte adhesion deficiency type 1 (LAD-1) is a congenital immunodeficiency leading to impaired trafficking of neutrophils to inflammation sites. Solitary or multiple pyoderma gangrenosum (PG)-like skin ulcers (PGLUs) have been reported previously in 13 children (aged 0.5-19 years) with LAD-1. Objective: Our aim was to report the case of a 10-year-old boy presenting with PGLUs as the first manifestation of LAD-1 treated with ustekinumab. Methods: We obtained in situ cytokine profiles. Results: PGLUs were triggered by cutaneous ringworm infection (Trichophyton tonsurans). Skin biopsy samples showed increased intralesional expression of IL-17A, Il-23, and IL-1ß as compared with their expression in healthy controls. After an unsuccessful attempt at treatment with oral methylprednisolone, ustekinumab induced regression of the ulcerations, associated with complete normalization of the cytokine profile. Conclusions: PGLUs, triggered by ringworm infection, can be a late harbinger of LAD-1. Ustekinumab is a safe and effective therapeutic option for patients with LAD-1 and PGLUs while bridging the time until stem cell transplantation.

Reliability, validity, and sensitivity of the Japanese version of the University of California Los Angeles scleroderma clinical trial consortium gastrointestinal tract instrument: Application to efficacy assessment of intravenous immunoglobulin administration.

This study aimed to develop and assess the reliability, validity, and sensitivity of the Japanese version of the University of California Los Angeles Scleroderma Clinical Trial Consortium gastrointestinal tract (GIT) Instrument 2.0 (the GIT score), as an evaluation tool for GIT symptoms in systemic sclerosis (SSc). The Japanese version of the GIT score was constructed using the forward-backward method. The reliability and validity of this instrument were evaluated in a cohort of 38 SSc patients. Correlation analysis was conducted to assess the relationship between the GIT score and existing patient-reported outcome measures. Additionally, the sensitivity of the GIT score was examined by comparing GIT scores before and after intravenous immunoglobulin (IVIG) administration in 10 SSc-myositis overlap patients, as IVIG has recently demonstrated effectiveness in alleviating GIT symptoms of SSc. As a result, the Japanese version of the GIT score exhibited internal consistency and a significant association with the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease. Furthermore, the total GIT score, as well as the reflux and distention/bloating subscales, displayed moderate correlations with the EuroQol 5 dimensions (EQ-5D) pain/discomfort subscale and the Short Form-36 body pain subscale. Notably, following IVIG treatment, there was a statistically significant reduction in the total GIT score and multiple subscales. We first validated the Japanese version of the GIT score in Japanese SSc patients in real-world clinical settings. This instrument holds promise for application in future clinical trials involving this patient population.

Nobiletin alleviates methotrexate-induced hepatorenal toxicity in rats.

We investigated the possible ameliorative effects of nobiletin (NBL) against methotrexate (MTX)-induced hepatorenal toxicity in rats. Twenty-eight Wistar albino rats were randomly divided into four groups, namely: Control; MTX (administered 20 mg/kg MTX); MTX+NBL (administered 20 mg/kg MTX and 10 mg/kg NBL per day); and NBL (administered 10 mg/kg/day NBL). Histopathological, immunohistochemical and biochemical analyses were performed on the kidney and liver tissues of rats at the end of the study. MTX caused renal toxicity, as indicated by increases in malondialdehyde (MDA) and caspase-3, as well as decreases in reduced glutathione (GSH), glucose-6-phosphate dehydrogenase (G6PD), glutathione peroxidase (GPx), catalase (CAT) and B-cell lymphoma-2 (Bcl-2). MTX also caused hepatotoxicity, as indicated by increases in 8-hydroxy-2'-deoxyguanosine (8-OHdG), tumor necrosis factor alpha (TNF-α), MDA and caspase-3 and decrease in interleukin 10 (IL-10), GSH, total antioxidant capacity, GPx, G6PD, CAT and Bcl-2. MTX caused histopathological changes in kidney and liver tissues indicating tissue and cellular damage. Administration of NBL concurrently with methotrexate reduced oxidative stress, inflammatory and apoptotic signs, and prevented kidney and liver damage caused by methotrexate. We consider NBL has attenuating and ameliorating effects on methotrexate-induced hepatorenal toxicity.

Biomarkers in retinopathy of prematurity: a systematic review and meta-analysis.

Aim: Retinopathy of prematurity is a significant global cause of childhood blindness. This study aims to identify serum biomarkers that are associated with the development of ROP. Methods: A systematic review and meta-analysis was conducted using PRISMA guidelines. Three databases were searched (Pubmed, Scopus and Web of Science) from 2003 to March 2023. Only studies investigating serum biomarker levels in preterm infants (<37 weeks gestation) were included. Results: Meta-analysis suggests that low serum IGF-1 levels have a strong association with the development of ROP [SMD (95% CI) of -.46 [-.63, -.30], p < .001]. Meta-analysis suggests that higher serum glucose levels were associated with the development of ROP [SMD (95% CI) of 1.25 [.94, 1.55], p < .001]. Meta-analysis suggests that thrombocytopenia is associated with the development of ROP [SMD (95% CI) of -.62 [-.86, -.37], p < .001]. Conclusion: Low levels of serum IGF-1, high levels of serum glucose and thrombocytopenia all appear to have the strongest association with the development of ROP out of the 63 biomarkers investigated in this review. These associations highlight their potential use as diagnostic biomarkers in ROP, though further research is needed to establish the exact relationship between these biomarkers and disease pathogenesis.

Serum cytokines profile changes in amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder, characterized by progressive limb weakness, dysphagia, dysphonia, and respiratory failure due to degeneration of upper and lower motor neurons. The pathogenesis of ALS is still unclear. Neuroinflammation has been found to be involved in its development and progression. Cytokines play a significant role in the inflammatory process. This study aims to identify novel biomarkers that may assist in the diagnosis of ALS. Methods: In Fujian Medical University Union Hospital and Huashan Hospital Fudan University, two independent centers, we prospectively recruited 50 ALS patients, and 41 healthy controls (25 ALS and 26 controls in the first stage and 25 ALS and 15 controls in the validation stage). An 18-plex Luminex kit was used to screen the serum cytokines levels in the first stage. Commercial ELISA kits were used to measure the levels of target cytokines in the validation stage. A single-molecule array HD-X platform was applied to assess the levels of serum neurofilament light chain (NFL). Results: The levels of serum IL-18 were markedly increased in patients with ALS in the first stage (p = 0.016). The ROC curve showed an area under the curve at 0.695 (95% CI 0.50-0.84) in distinguishing ALS patients from healthy controls. The IL-21 was decreased in elderly patients when grouped by 55 years old (the medium age). Furthermore, the IL-5, IL-13, IL-18, and NFL had a positive relationship with the disease progression of ALS. We also found that serum IL-18 was markedly increased in ALS patients in the validation stage (167.67 [148.25-175.59] vs 116.44 [102.43-122.19]pg/ml, p < 0.0015). Conclusion: In this study, we identified systemic cytokine profile changes in the serum of ALS patients, especially the elevated IL-18, as well as the decreased IL-21 in elder patients. These changes in serum cytokine profiles may shed new light on an in-depth understanding of the immunopathogenic characteristics of ALS.

Modelling of macrophage responses to biomaterials in vitro: state-of-the-art and the need for the improvement.

The increasing use of medical implants in various areas of medicine, particularly in orthopedic surgery, oncology, cardiology and dentistry, displayed the limitations in long-term integration of available biomaterials. The effective functioning and successful integration of implants requires not only technical excellence of materials but also consideration of the dynamics of biomaterial interaction with the immune system throughout the entire duration of implant use. The acute as well as long-term decisions about the efficiency of implant integration are done by local resident tissue macrophages and monocyte-derived macrophages that start to be recruited during tissue damage, when implant is installed, and are continuously recruited during the healing phase. Our review summarized the knowledge about the currently used macrophages-based in vitro cells system that include murine and human cells lines and primary ex vivo differentiated macrophages. We provided the information about most frequently examined biomarkers for acute inflammation, chronic inflammation, foreign body response and fibrosis, indicating the benefits and limitations of the model systems. Particular attention is given to the scavenging function of macrophages that controls dynamic composition of peri-implant microenvironment and ensures timely clearance of microorganisms, cytokines, metabolites, extracellular matrix components, dying cells as well as implant debris. We outline the perspective for the application of 3D systems for modelling implant interaction with the immune system in human tissue-specific microenvironment avoiding animal experimentation.

Histological and biochemical changes in a rat rotator cuff tear model with or without the subacromial bursa.

The subacromial bursa (SAB) plays an important role in the tendon healing process. Based on previous reports, co-culture of the rotator cuff (RC) and SAB have been shown to increase the tendon-related gene expressions, inflammatory cytokines, and tensile strength. However, the nature of the specific biochemical alterations during the inflammatory and repair phases of tendon healing with or without the SAB remain unknown. Using a full-thickness RC tear rat model, we determined how the presence or absence of the SAB alters the histological characteristics and gene expressions. After 3 and 6 weeks, tissues were collected for histological and real-time quantitative polymerase chain reaction (RT-qPCR) evaluations. Results showed greater cell density at 3 weeks, neovascularization and tendon thickening at 6 weeks with SAB preservation. Immunostaining revealed significant increases in type 3 collagen (COL3) expression at 6 weeks with SAB preservation. The RT-qPCR results showed that SAB preservation induced significant increases in the expression of scleraxis, matrix metalloproteinase-13 (MMP-13), interleukin-1ß (IL-1ß), and inducible nitric oxide synthase (iNOS) at 3 weeks and significant increases in COL3, IL-10, and arginase-1 (Arg-1) at 6 weeks. An RC tear undergoes more appropriate inflammatory and repair phases during the tendon healing process when the SAB is retained.

S1PR3 agonism and S1P lyase inhibition rescue mice in the severe state of experimental sepsis.

Sepsis is characterized as life-threatening organ dysfunction caused by a dysregulated host response to an infection. Despite numerous clinical trials that addressed this syndrome, there is still no causative treatment available to dampen its severity. Curtailing the infection at an early stage with anti-infectives is the only effective treatment regime besides intensive care. In search for additional treatment options, we recently discovered the inhibition of the sphingosine 1-phosphate (S1P) lyase and subsequent activation of the S1P receptor type 3 (S1PR3) in pre-conditioning experiments as promising targets for sepsis prevention. Here, we demonstrate that treatment of septic mice with the direct S1P lyase inhibitor C31 or the S1PR3 agonist CYM5541 in the advanced phase of sepsis resulted in a significantly increased survival rate. A single dose of each compound led to a rapid decline of sepsis severity in treated mice and coincided with decreased cytokine release and increased lung barrier function with unaltered bacterial load. The survival benefit of both compounds was completely lost in S1PR3 deficient mice. Treatment of the murine macrophage cell line J774.1 with either C31 or CYM5541 resulted in decreased protein kinase B (Akt) and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) phosphorylation without alteration of the mitogen-activated protein kinase (MAPK) p38 and p44/42 phosphorylation. Thus, activation of S1PR3 in the acute phase of sepsis by direct agonism or S1P lyase inhibition dampened Akt and JNK phosphorylation, resulting in decreased cytokine release, improved lung barrier stability, rapid decline of sepsis severity and better survival in mice.

Nursing Considerations for Cytokine Release Syndrome in Relapsed/Refractory Multiple Myeloma: Experience with Teclistamab from the MajesTEC-1 Study.

OBJECTIVES: Cytokine release syndrome (CRS) is a systemic inflammatory response that is commonly observed as a class effect of T-cell-redirecting therapies. This article provides important practical guidance for nurses relating to the diagnosis, monitoring, and management of CRS in patients receiving teclistamab, based on experience from the MajesTEC-1 clinical trial and real-life nursing practice. METHODS: MajesTEC-1 is a phase 1/2 study of teclistamab in heavily pretreated patients with relapsed/refractory multiple myeloma. To mitigate the risk of high-grade CRS, patients were carefully monitored for early signs and symptoms of CRS (including fever, which must have fully resolved before teclistamab administration). RESULTS: A survey of nurses from several of the study sites provided additional real-life insights into nursing best practices for managing CRS from four academic institutions in three countries. CONCLUSIONS: In MajesTEC-1, 72% of patients treated with teclistamab experienced CRS, the majority of which was low grade. All cases resolved and none led to treatment discontinuation. Real-life supportive measures for CRS are generally aligned with those outlined in the study. IMPLICATIONS FOR NURSING PRACTICE: Because nurses are on the frontline of patient care, they play a crucial role in promptly recognizing the signs and symptoms of CRS and responding with timely and appropriate supportive treatment. This review provides important practical guidance for nurses on diagnosis, monitoring, and management of CRS in patients receiving teclistamab, based on experience from the MajesTEC-1 trial and real-life nursing practice.

Consolidating data on the association of IL-6 and IL-10 polymorphisms with the development of glaucoma: a meta-analysis.

BACKGROUND: The study aimed to investigate the association of IL-6 and IL-10 polymorphisms with susceptibility to glaucoma by analyzing all relevant individual studies. MATERIALS AND METHODS: Relevant articles were gathered from PubMed, Web of Science, Embase, WanFang, and CNKI databases up to 15 October 2023. Odds ratios (ORs) were used to evaluate the association strengths, along with 95% confidence intervals (CIs). RESULTS: Seven case-control studies involving 1408 cases and 1789 controls on the IL-6 -174 G>C polymorphism, and three studies with 675 cases and 1100 controls on the IL-6 -572 G>C were included. Moreover, three separate studies, each comprising 442 cases and 672 controls, investigated the IL-10 -592C>A, -819T>C, and -1082A>G polymorphisms. The combined data indicated a significant association between -592C>A, -819T>C, and -1082A>G at IL-10 gene and IL-6 -572 G>C with glaucoma susceptibility, with no correlation found for IL-6 -174 G>C. CONCLUSIONS: The study found that IL-10 -592C>A, -819T>C, -1082A>G, and IL-6 -572 G>C polymorphisms were linked to glaucoma risk. However, no significant association was observed for IL-6 -174 G>C. These findings imply a possible connection between genetic variations in these genes and glaucoma risk. Further research is crucial to fully understand the underlying mechanisms and their significance in managing and preventing glaucoma.

Feruloylated Oligosaccharides Prevented Influenza-Induced Lung Inflammation via the RIG-I/MAVS/TRAF3 Pathway.

Uncontrolled inflammation contributes significantly to the mortality in acute respiratory infections. Our previous research has demonstrated that maize bran feruloylated oligosaccharides (FOs) possess notable anti-inflammatory properties linked to the NF-kB pathway regulation. In this study, we clarified that the oral administration of FOs moderately inhibited H1N1 virus infection and reduced lung inflammation in influenza-infected mice by decreasing a wide spectrum of cytokines (IFN-α, IFN-ß, IL-6, IL-10, and IL-23) in the lungs. The mechanism involves FOs suppressing the transduction of the RIG-I/MAVS/TRAF3 signaling pathway, subsequently lowering the expression of NF-κB. In silico analysis suggests that FOs have a greater binding affinity for the RIG-I/MAVS signaling complex. This indicates that FOs have potential as promising targets for immune modulation. Moreover, in MAVS knockout mice, we confirmed that the anti-inflammatory function of FOs against influenza depends on MAVS. Comprehensive analysis using 16S rRNA gene sequencing and metabolite profiling techniques showed that FOs have the potential to restore immunity by modulating the gut microbiota. In conclusion, our study demonstrates that FOs are effective anti-inflammatory phytochemicals in inhibiting lung inflammation caused by influenza. This suggests that FOs could serve as a potential nutritional strategy for preventing the H1N1 virus infection and associated lung inflammation.

New insights of acylation stimulating protein in modulating the pathological progression of metabolic syndromes.

Obesity is associated with insulin resistance, hypertension, and coronary artery diseases which are grouped as metabolic syndrome. Rather than being a storage for energy, the adipocytes could synthesis and secret diverse hormones and molecules, named as adipokines. Under obese status, the adipocytes are dysfunctional with excessively producing the inflammatory related cytokines, such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor α (TNF-α). Concerning on the vital role of adipokines, it is proposed that one of the critical pathological factors of obesity is the dysfunctional adipocytic pathways. Among these adipokines, acylation stimulating protein, as an adipokine synthesized by adipocytes during the process of cell differentiation, is shown to activate the metabolism of triglyceride (TG) by regulating the catabolism of glucose and free fatty acid (FFA). Recent attention has paid to explore the underlying mechanism whereby acylation stimulating protein influences the biological function of adipocyte and the pathological development of obesity. In the present review, we summarized the progression of acylation stimulating protein in modulating the physiological and hormonal catabolism which affects fat distribution. Furthermore, the potential mechanisms which acylation stimulating protein regulates the metabolism of adipose tissue and the process of metabolic syndrome were also summarized.

STING agonist, SMA-2, inhibits clear cell renal cell carcinoma through improving tumor microenvironment.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent and lethal subtype of kidney cancer, patients with ccRCC usually have very poor prognosis and short survival. Therefore, it is urgent to develop more effective therapeutics or medications to suppress ccRCC progression. Here, we demonstrated that STING agonist, MSA-2 significantly inhibits tumor progress and prolongs the survival of ccRCC mice by promoting cytokines secretion. Moreover, MSA-2 triggered the trafficking and infiltration of CD8+ T cells, supported by the generation of a chemokine milieu that promoted recruitment and modulation of the immunosuppressive TME in ccRCC. These findings suggest that MSA-2 potentially serves an effective and preferable adjuvant immunotherapy of ccRCC.

Exploring secretory proteome and cytokine kinetic of human peripheral blood mononuclear cells exposed to methicillin-resistant Staphylococcus aureus biofilms and planktonic bacteria.

Staphylococcus aureus is a highly successful pathogen infecting various body parts and forming biofilms on natural and artificial surfaces resulting in difficult-to-treat and chronic infections. We investigated the secreted cytokines and proteomes of isolated peripheral blood mononuclear cells (PBMCs) from healthy volunteers exposed to methicillin-resistant S. aureus (MRSA) biofilms or planktonic bacteria. Additionally, the cytokine profiles in sera from patients with community-acquired pneumonia (CAP) caused by S. aureus were investigated. The aim was to gain insights into the immune response involved and differentiate between the planktonic and sessile MRSA forms. We identified 321 and 298 targets that were significantly differently expressed in PBMCs when exposed to planktonic or biofilm-embedded bacteria, respectively. PBMCs exposed to planktonic MRSA cells secreted increased levels of TNF-α, while IL-18 was elevated when exposed to the biofilm. The machine-learning analyses of the cytokine profiles obtained for the in vitro PBMCs and CAP sera distinguished between the two types of bacteria forms based on cytokines IL-18, IL12, and IL-17, and with a lower importance IL-6. Particularly, IL-18 which has not been correlated with S. aureus biofilms so far might represent a suitable marker for monitoring chronification during MRSA infection to individualize the therapy, but this hypothesis must be proved in clinical trials.

TNF-α is a predictive marker in distinguishing myeloproliferative neoplasm and idiopathic erythrocytosis/thrombocytosis: development and validation of a non-invasive diagnostic model.

Purpose: Philadelphia-chromosome negative myeloproliferative neoplasms (MPN) exhibit phenotypic similarities with JAK/STAT-unmutated idiopathic erythrocytosis and thrombocytosis (IE/IT). We aimed to develop a clinical diagnostic model to discern MPN and IE/IT. Methods: A retrospective study was performed on 77 MPN patients and 32 IE/IT patients in our center from January 2018 to December 2023. We investigated the role of hemogram, cytokine and spleen size in differentiating MPN and IE/IT among newly onset erythrocytosis and thrombocytosis patients. Independent influencing factors were integrated into a nomogram for individualized risk prediction. The calibration and discrimination ability of the model were evaluated by concordance index (C-index), calibration curve. Results: MPN had significantly higher TNF-α level than IE/IT, and the TNF-α level is correlated with MF-grade. Multivariable analyses revealed that TNF-α, PLT count, age, size of spleen were independent diagnostic factors in differentiating MPN and IE/IT. Nomograms integrated the above 4 factors for differentiating MPN and IE/IT was internally validated and had good performance, the C-index of the model is 0.979. Conclusion: The elevation of serum TNF-α in MPN patients is of diagnostic significance and is correlated with the severity of myelofibrosis. The nomogram incorporating TNF-α with age, PLT count and spleen size presents a noteworthy tool in the preliminary discrimination of MPN patients and those with idiopathic erythrocytosis or thrombocytosis. This highlights the potential of cytokines as biomarkers in hematologic disorders.

Immunomodulating Phytochemicals: An Insight Into Their Potential Use in Cytokine Storm Situations.

Phytochemicals are compounds found in plants that possess a variety of bioactive properties, including antioxidant and immunomodulatory properties. Recent studies have highlighted the potential of phytochemicals in targeting specific signalling pathways involved in cytokine storm, a life-threatening clinical condition resulting from excessive immune cell activation and oversupply of proinflammatory cytokines. Several studies have documented the immunomodulatory effects of phytochemicals on immune function, including their ability to regulate essential cellular and molecular interactions of immune system cells. This makes them a promising alternative for cytokine storm management, especially when combined with existing chemotherapies. Furthermore, phytochemicals have been found to target multiple signalling pathways, including the TNF-α/NF-κB, IL-1/NF-κB, IFN-γ/JAK/STAT, and IL-6/JAK-STAT. These pathways play critical roles in the development and progression of cytokine storm, and targeting them with phytochemicals represents a promising strategy for controlling cytokine release and the subsequent inflammation. Studies have also investigated certain families of plant-related constituents and their potential immunomodulatory actions. In vivo and in vitro studies have reported the immunomodulatory effects of phytochemicals, which provide viable alternatives in the management of cytokine storm syndrome. The collective data from previous studies suggest that phytochemicals represent a potentially functional source of cytokine storm treatment and promote further exploration of these compounds as immunomodulatory agents for suppressing specific signalling cascade responses. Overall, the previous research findings support the use of phytochemicals as a complementary approach in managing cytokine storm and improving patient outcomes.