Cytokine Release Research Articles

Protective effect of 6'-Sialyllactose on LPS-induced macrophage inflammation via regulating Nrf2-mediated oxidative stress and inflammatory signaling pathways.

Macrophages play a central role in cardiovascular diseases, like atherosclerosis, by accumulating in vessel walls and inducing sustained local inflammation marked by the release of chemokines, cytokines, and matrix-degrading enzymes. Recent studies indicate that 6'-sialyllactose (6'-SL) may mitigate inflammation by modulating the immune system. Here, we examined the impact of 6'-SL on lipopolysaccharide (LPS)-induced acute inflammation using RAW 264.7 cells and a mouse model. In vivo, ICR mice received pretreatment with 100 mg/kg 6'-SL for 2 h, followed by intraperitoneal LPS injection (10 mg/kg) for 6 h. In vitro, RAW 264.7 cells were preincubated with 6'-SL before LPS stimulation. Mechanistic insights were gained though Western blotting, qRT-PCR, and immunofluorescence analysis, while reactive oxygen species (ROS) production was assessed via DHE assay. 6'-SL effectively attenuated LPS-induced p38 MAPK and Akt phosphorylation, as well as p65 nuclear translocation. Additionally, 6'-SL inhibited LPS-induced expression of tissue damage marker MMP9, IL-1β, and MCP-1 by modulating NF-κB activation. It also reduced ROS levels, mediated by p38 MAPK and Akt pathways. Moreover, 6'-SL restored LPS-suppressed Nrf2 and HO-1 akin to specific inhibitors SB203580 and LY294002. Consistent with in vitro results, 6'-SL decreased oxidative stress, MMP9, and MCP-1 expression in mouse endothelium following LPS-induced macrophage activation. In summary, our findings suggest that 6'-SL holds promise in mitigating atherosclerosis by dampening LPS-induced acute macrophage inflammation.

Alcohol Activates Cannabinoid Receptor 1 and 2 in a Model of Pathogen Induced Pulmonary Inflammation

Alcohol use disorder (AUD) is defined as patterns of alcohol misuse and affects over 30 million people in the US. AUD is a systemic disease with the epidemiology of acute lung injury and excessive alcohol use established in the literature. However, the distinct mechanisms by which alcohol induces the risk of pulmonary inflammation are less clear. A compelling body of evidence shows that cannabinoid receptors (CB1R and CB2R) play a relevant role in AUD. For this study, we investigated the role of CBR signaling in pulmonary immune activation. Using a human macrophage cell line, we evaluated the expression of CBR1 and CBR2 after cells were exposed to EtOH, +/- cannabinoid agonists and antagonists by flow cytometry. We also evaluated the expression of cannabinoid receptors from the lungs of adolescent mice exposed to acute binge EtOH +/- cannabinoid agonists and antagonists at both resting state and after microbial challenge via western blot, rt-PCR, cytokine analysis, and histology. Our results suggest that EtOH exposure modulates the expression of CBR1 and CBR2. Second, EtOH may contribute to the release of DAMPs and other proinflammatory cytokines, Finally, microbial challenge induces pulmonary inflammation in acute binge EtOH-exposed mice, and this observed immune activation may be CBR-dependent. We have shown that adolescent binge drinking primes the lung to subsequent microbial infection in adulthood and this response can be mitigated with cannabinoid antagonists. These novel findings may provide a framework for developing potential novel therapeutics in AUD research.

Dasatinib interferes with HIV-1 proviral integration and the inflammatory potential of monocyte-derived macrophages from people with HIV

HIV-1 infection is efficiently controlled by the antiretroviral treatment (ART) but viral persistence in long-lived reservoirs formed by CD4 + T cells and macrophages impedes viral eradication and creates a chronic inflammatory environment. Dasatinib is a tyrosine kinase inhibitor clinically used against chronic myeloid leukemia (CML) that has also showed an anti-inflammatory potential. We previously reported that dasatinib is very efficient at interfering with HIV-1 infection of CD4 + T cells by preserving the antiviral activity of SAMHD1, an innate immune factor that blocks T-cell activation and proliferation and that is inactivated by phosphorylation at T592 (pSAMHD1). We observed that short-term treatment in vitro with dasatinib significantly reduced pSAMHD1 in monocyte-derived macrophages (MDMs) isolated from people with HIV (PWH) and healthy donors, interfering with HIV-1 infection. This inhibition was based on low levels of 2-LTR circles and proviral integration, while viral reverse transcription was not affected. MDMs isolated from people with CML on long-term treatment with dasatinib also showed low levels of pSAMHD1 and were resistant to HIV-1 infection. In addition, dasatinib decreased the inflammatory potential of MDMs by reducing the release of M1-related cytokines like TNFα, IL-1β, IL-6, CXCL8, and CXCL9, but preserving the antiviral activity through normal levels of IL-12 and IFNγ. Due to the production of M2-related anti-inflammatory cytokines like IL-1RA and IL-10 was also impaired, dasatinib appeared to interfere with MDMs differentiation. The use of dasatinib along with ART could be used against HIV-1 reservoir in CD4 and macrophages and to alleviate the chronic inflammation characteristic of PWH.

Polymer nanotherapeutics: A promising approach toward microglial inhibition in neurodegenerative diseases.

Nanoparticles (NPs) that target multiple transport mechanisms facilitate targeted delivery of active therapeutic agents to the central nervous system (CNS) and improve therapeutic transport and efficacy across the blood-brain barrier (BBB). CNS nanotherapeutics mostly target neurons and endothelial cells, however, microglial immune cells are the first line of defense against neuronal damage and brain infections. Through triggering release of inflammatory cytokines, chemokines and proteases, microglia can however precipitate neurological damage-a significant factor in neurodegenerative diseases. Thus, microglial inhibitory agents are attracting much attention among those researching and developing novel treatments for neurodegenerative disorders. The most established inhibitors of microglia investigated to date are resveratrol, curcumin, quercetin, and minocycline. Thus, there is great interest in developing novel agents that can bypass or easily cross the BBB. One such approach is the use of modified-nanocarriers as, or for, delivery of, therapeutic agents to the brain and wider CNS. For microglial inhibition, polymeric NPs are the preferred vehicles for choice. Here, we summarize the immunologic and neuroinflammatory role of microglia, established microglia inhibitor agents, challenges of CNS drug delivery, and the nanotherapeutics explored for microglia inhibition to date. We also discuss applications of the currently considered "most useful" polymeric NPs for microglial-inhibitor drug delivery in CNS-related diseases.

Exposure-biomarker analyses for cytokine release syndrome or infusion-related reaction, pain, and cytokine concentrations in serum during treatment with ubamatamab, a MUC16xCD3 bispecific antibody, among patients with recurrent ovarian cancer

Exposure-biomarker analyses for cytokine release syndrome or infusion-related reaction, pain, and cytokine concentrations in serum during treatment with ubamatamab, a MUC16xCD3 bispecific antibody, among patients with recurrent ovarian cancer

Harnessing Chimeric Antigen Receptor-engineered Invariant Natural Killer T Cells: Therapeutic Strategies for Cancer and the Tumor Microenvironment.

Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has emerged as a revolutionary approach for cancer treatment, especially for hematologic cancers. However, CAR-T therapy has some limitations, including cytokine release syndrome (CRS), immune cellassociated neurologic syndrome (ICANS), and difficulty in targeting solid tumors and delivering allogeneic cell therapy due to graft-versus-host disease (GvHD). Therefore, it is important to explore other cell sources for CAR engineering. Invariant natural killer T (iNKT) cells are a potential target, as they possess powerful antitumor ability and do not recognize mismatched major histocompatibility complexes (MHCs) and protein antigens, thus avoiding the risk of GvHD. CAR-engineered iNKT (CAR-iNKT) cell therapy offers a promising new approach to cancer immunotherapy by overcoming the drawbacks of CAR-T cell therapy while retaining potent antitumor capabilities. This review summarizes the current CAR-iNKT cell products, their functions and phenotypes, and their potential for off-the-shelf cancer immunotherapy.

Ultraviolet laser induced periodic surface structures positively influence osteogenic activity on titanium alloys

Background/ObjectiveEndoprostheses might fail due to complications such as implant loosening or periprosthetic infections. The surface topography of implant materials is known to influence osseointegration and attachment of pathogenic bacteria. Laser-Induced Periodic Surface Structures (LIPSS) can improve the surface topography of orthopedic implant materials. In this preclinical in vitro study, laser pulses with a wavelength in the ultraviolet (UV) spectrum were applied for the generation of LIPSS to positively influence formation of extracellular matrix by primary human Osteoblasts (hOBs) and to reduce microbial biofilm formation in vitro.MethodsLaser machining was employed for generating UV-LIPSS on sample disks made of Ti6Al4V and Ti6Al7Nb alloys. Sample disks with polished surfaces were used as controls. Scanning electron microscopy was used for visualization of surface topography and adherent cells. Metal ion release and cellular metal levels were investigated by inductively coupled plasma mass spectrometry. Cell culture of hOBs on sample disks with and without UV-LIPSS surface treatments was performed. Cells were investigated for their viability, proliferation, osteogenic function and cytokine release. Biofilm formation was facilitated by seeding Staphylococcus aureus on sample disks and quantified by wheat germ agglutinin (WGA) staining.ResultsUV-LIPSS modification results in topographies with a periodicity of 223 nm ≤ λ ≤ 278 nm. The release of metal ions was found increased for UV-LIPSS on Ti6Al4V and decreased for UV-LIPSS on Ti6Al7Nb, while cellular metal levels remain unaffected. Cellular adherence was decreased for hOBs on UV-LIPSS Ti6Al4V when compared to controls while proliferation rate was unaffected. Metabolic activity was lower on UV-LIPSS Ti6Al7Nb when compared to the control. Alkaline phosphatase activity was upregulated for hOBs grown on UV-LIPSS on both alloys. Less pro-inflammatory cytokines were released for cells grown on UV-LIPSS Ti6Al7Nb when compared to polished surfaces. WGA signals were significantly lower on UV-LIPSS Ti6Al7Nb indicating reduced formation of a S. aureus biofilm.ConclusionOur results suggest that UV-LIPSS texturing of Ti6Al7Nb positively influence bone forming function and cytokine secretion profile of hOBs in vitro. In addition, our results indicate diminished biofilm formation on UV-LIPSS treated Ti6Al7Nb surfaces. These effects might prove beneficial in the context of long-term arthroplasty outcomes.

Human epicardial adipose tissue-derived factors promote atrial endothelial dysfunction: role of pro-inflammatory cytokines and AT1R/NADPH oxidases/SGLT2 pro-oxidant pathway

Abstract Introduction Epicardial adipose tissue (EAT) has been suggested to contribute to left atrium dysfunction via paracrine mechanisms to induce endothelial dysfunction, pro-arrhythmogenic and pro-remodeling responses thereby favoring atrial fibrillation (AF) onset. Recently, sodium-glucose co-transporter2 inhibitors (SGLT2i) have been shown to reduce AF incidence, EAT volume, differentiation and inflammation, however, the underlying mechanisms are unknown. Purpose This study investigates the impact of human EAT-derived mediators on atrial endothelial cell function and, if so, to characterize the role of SGLT2 using the inhibitor empagliflozin (EMPA). Methods Epicardial and subcutaneous adipose tissues (SAT) were collected from 70 cardiac patients at a university hospital. Conditioned medium (CM, 24 h) from fats were applied to porcine atrial endothelial cells (AECs, first passage) for 24 h. Histology of tissues was assessed by haematoxylin and eosin staining, protein expression by Western blot analysis or immunofluorescence staining, mRNA levels by RT-qPCR, formation of reactive oxygen species (ROS) and nitric oxide (NO) by fluorescent probes, and pro-inflammatory cytokine levels by ELISA. Results Compared to SAT, EATs were more vascularized with increased infiltration of M1-like macrophages, expression of proinflammatory cytokines (IL-1ß, IL-6, TNF-α), markers of ECs VCAM-1 and eNOS, fibrosis TGF-β, NADPH oxidases NOX-1 and SGLT1/2. These effects were associated with a pro-oxidant response that was inhibited by neutralizing Abs directed against IL-1ß or IL-6, and by inhibition of either NOS, NADPH oxidases, ACE, AT1R or SGLT2. Levels of SGLT2 and ROS in EATs were higher in AF compared to non-AF patients and progressively increasing with age. CM of EATs showed higher concentrations of IL-1ß, IL-6, TNF-α and MCP-1 than that of SAT. Exposure of AECs to CM of EATs increased the level of oxidative stress that was positively correlated to the level of pro-inflammatory cytokines, and reduced basal and bradykinin-induced NO formation that was prevented by EMPA. It also resulted in upregulation of p53 and SGLT2 expression, and nuclear translocation of NF-kB by CM of the top quartile inflamed EATs but not by the lowest quartile of EATs or SATs, prevented by EMPA. Conclusion The findings indicate that compared to SATs, the EATs showed higher in situ expression and release of pro-inflammatory cytokines that contributed to oxidative stress involving the AT1R/NADPH oxidases/SGLT2 pro-oxidant pathway. CMs of inflamed EATs induced AECs dysfunction, oxidative stress and activation of NF-kB involving pro-inflammatory cytokines and SGLT2. Thus, SGLT2i appear as an interesting strategy to decrease EAT inflammation and improve endothelial function contributing to prevent cardiac remodeling and fibrotic responses.

Glutamine and serum starvation alters the ATP production, oxidative stress, and abundance of mitochondrial RNAs in extracellular vesicles produced by cancer cells

Induction of autophagy represents an effective survival strategy for nutrient-deprived or stressed cancer cells. Autophagy contributes to the modulation of communication within the tumor microenvironment. Here, we conducted a study of the metabolic and signaling implications associated with autophagy induced by glutamine (Gln) and serum starvation and PI3K/mTOR inhibitor and autophagy inducer NVP-BEZ235 (BEZ) in the head and neck squamous cell carcinoma (HNSCC) cell line FaDu. We compared the effect of these different types of autophagy induction on ATP production, lipid peroxidation, mitophagy, RNA cargo of extracellular vesicles (EVs), and EVs-associated cytokine secretome of cancer cells. Both BEZ and starvation resulted in a decline in ATP production. Simultaneously, Gln starvation enhanced oxidative damage of cancer cells by lipid peroxidation. In starved cells, there was a discernible fragmentation of the mitochondrial network coupled with an increase in the presence of tumor susceptibility gene 101 (TSG101) on the mitochondrial membrane, indicative of the sorting of mitochondrial cargo into EVs. Consequently, the abundance of mitochondrial RNAs (mtRNAs) in EVs released by FaDu cells was enhanced. Notably, mtRNAs were also detectable in EVs isolated from the serum of both HNSCC patients and healthy controls. Starvation and BEZ reduced the production of EVs by cancer cells, yet the characteristic molecular profile of these EVs remained unchanged. We also found that alterations in the release of inflammatory cytokines constitute a principal response to autophagy induction. Importantly, the specific mechanism driving autophagy induction significantly influenced the composition of the EVs-associated cytokine secretome.

A matter of inflammation: CAR T-cell therapy and atrial fibrillation

Abstract Background Chimeric antigen receptor (CAR) T-cell therapy has been revolutionary in the treatment of blood cancers, but has been associated with arrhythmias such as atrial fibrillation (AF). Whether the incidence of AF has changed over time and if contributing risk factors are present remains to be defined. Methods Leveraging the Mayo Electronic Medical Record, we extracted a cohort of patients who underwent CAR T-cell therapy between 2016 and 2022. From this cohort, we identified those who had a diagnosis of AF at any point. We then defined the endpoint of interest as the first episode of new or recurrent AF during or after CAR T-cell infusion. Fine and Gray subdistribution hazard modeling was used to calculate the association of patient characteristics to the endpoint of interest. Variables with P<0.20 in univariate modeling were chosen for the multivariate model. Significance was defined as P<0.05. Results There were 328 patients who underwent CAR T-cell therapy between 2016 and 2022. Of this cohort, 27 (8.2%) patients had a pre-existing diagnosis of AF, of which 6 had recurrence of AF after CAR T (22.2%), while 21 (77.8%) did not. Of the 301 patients without a prior history of AF, 8 (2.7%) patients developed new-onset AF after CAR T. The majority of the 14 new or recurrent AF events (4.3% overall incidence) occurred within 30 days of receiving CAR T (N=10, 71.4%), the remainder after 180 days (Figure 1). No trend in declining incidence over time was noted. Prior AF, neurotoxicity, and inflammation (cytokine release syndrome and macrophage activating syndrome-like (MAS-L)) were strongly associated with the risk of developing new or recurrent AF (Table 1). Only presence of MAS-L remained an independent predictor in the multivariate model (HR 15.4, 95% CI 3.9-61.2, P<0.001). Conclusion AF is mainly seen early following CAR T-cell therapy, and mainly in association with severe inflammatory responses. Early and aggressive treatment of CRS and MAS-L may be recommendable for patients undergoing CAR-T therapy, especially for those with a prior history of AF.

Long-term safety and efficacy of antibody ALXN2220 for depletion of cardiac amyloid transthyretin: results of treatment beyond 12 months in the open-label extension of study NI006-101

Abstract Introduction ALXN2220 (formerly NI006) is an investigational human monoclonal antibody in development for the treatment of transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). ALXN2220 is designed to deplete cardiac amyloid transthyretin (ATTR) deposits in patients with ATTR-CM on top of standard of care. Data from the first-in-human, ascending dose study NI006-101 show that ALXN2220 is safe and well tolerated. A reduction of surrogate markers of cardiac amyloid load and cardiac biomarkers was observed in participants receiving doses of ≥ 10mg/kg of ALXN2220 over a period of 12 months of treatment. Purpose Long-term safety, tolerability and efficacy of ALXN2220 treatment beyond 12 months was studied in a prolonged Open-Label Extension (OLE) of the NI006-101 study. Methods Participants completing 12 months in dose cohorts ≤ 30 mg/kg were allowed to receive additional 6 to 12 monthly open-label ALXN2220 infusions with up-titration of all participants to 30 mg/kg. Cardiac biomarkers were measured centrally, and serial cardiac imaging was performed with echocardiography and cardiac MRI or scintigraphy. Results Out of 27 participants completing 12 months, 23 (18 ATTRwt, all male, median age 70 years at screening (range 28-83)) continued treatment in the prolonged OLE. Median number of infusions of ALXN2220 received and median time followed across the full study were 20 infusions (range 11-24) and 125 weeks (range 83-153). Overall adherence to treatment was high in the prolonged OLE, 97% of planned infusions administered, 87% of participants received all planned doses. No severe or serious adverse events were considered related to ALXN2220 or resulted in the discontinuation during OLE, and no events of cytokine release syndrome or thrombocytopenia were observed. None of the participants had anti-drug antibodies throughout the trial. Cardiac biomarkers (NT-proBNP, troponin) and cardiac imaging indicated continued treatment effects beyond 12 months and supported the up-titration of participants who previously received lower doses of ALXN2220. Conclusions Up-titration and long-term treatment at a dose level of 30 mg/kg in the OLE was safe and well tolerated, with overall good adherence to treatment. Cardiac imaging and cardiac biomarker data indicated continued treatment effects beyond 12 months and supported the up-titration of patients to 30 mg/kg.

Shorter duration of Blinatumomab administration to 14 days has same efficacy and safety profile in treatment of relapsed/refractory B-cell precursor acute lymphoblastic leukemia: A retrospective single‐center study

Introduction: Treatment of patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (r/r BCP-ALL) remains a significant clinical challenge. Many new strategies are changing the treatment landscape of r/r BCP-ALL in recent years. Blinatumomab has improved outcomes in r/r BCP-ALL, though high treatment costs and extended hospital stays are significant concerns. We considered that shortening the duration of blinatumomab administration during induction therapy might solve these problems. Methods: We retrospectively analyzed 19 patients with r/r BCP-ALL treated with different duration of blinatumomab, where 10 patients received blinatumomab for 14 days (Bli 14 D group) and 9 received it for a longer duration (LT group, 21-28 days). Results: The overall response rate (ORR) was 63.2% (12/19) of patients in total, and the ORR rates in 14 D and LT groups were almost the same (60% and 66.6%, respectively). The median overall survival (OS) was not reached in either groups. The median event-free survival (EFS) time was 4.1 months in LT group and not reached in D14 group. The most common adverse events were consistent with previous reports, including cytokine release syndrome (CRS), neurologic toxicity, and hematological toxicity. Conclusion: A 14-day blinatumomab administration may be a promising and well-tolerated regimen in r/r BCP-ALL, offering the same ORR and survival rates.

Investigating the Biological Efficacy of Albumin-Enriched Platelet-Rich Fibrin (Alb-PRF): A Study on Cytokine Dynamics and Osteoblast Behavior

The development of effective biomaterials for tissue regeneration has led to the exploration of blood derivatives such as leucocyte- and platelet-rich fibrin (L-PRF). A novel variant, Albumin-Enriched Platelet-Rich Fibrin (Alb-PRF), has been introduced to improve structural stability and bioactivity, making it a promising candidate for bone regeneration. This study aimed to evaluate Alb-PRF’s capacity for cytokine and growth factor release, along with its effects on the proliferation, differentiation, and mineralization of human osteoblasts in vitro. Alb-PRF membranes were analyzed using histological, scanning electron microscopy, and fluorescence microscopy techniques. Cytokine and growth factor release was quantified over seven days, and osteoinductive potential was evaluated with MG-63 osteoblast-like cells. Structural analysis showed Alb-PRF as a biphasic, highly cellularized material that releases lower levels of inflammatory cytokines and higher concentrations of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) compared to L-PRF. Alb-PRF exhibited higher early alkaline phosphatase activity and in vitro mineralization (p < 0.05) and significantly increased the OPG/RANKL mRNA ratio (p < 0.05). These results indicate that Alb-PRF has promising potential as a scaffold for bone repair, warranting further in vivo and clinical assessments to confirm its suitability for clinical applications.

Fenebrutinib, a Bruton’s tyrosine kinase inhibitor, blocks distinct human microglial signaling pathways

BackgroundBruton’s tyrosine kinase (BTK) is an intracellular signaling enzyme that regulates B-lymphocyte and myeloid cell functions. Due to its involvement in both innate and adaptive immune compartments, BTK inhibitors have emerged as a therapeutic option in autoimmune disorders such as multiple sclerosis (MS). Brain-penetrant, small-molecule BTK inhibitors may also address compartmentalized neuroinflammation, which is proposed to underlie MS disease progression. BTK is expressed by microglia, which are the resident innate immune cells of the brain; however, the precise roles of microglial BTK and impact of BTK inhibitors on microglial functions are still being elucidated. Research on the effects of BTK inhibitors has been limited to rodent disease models. This is the first study reporting effects in human microglia.MethodsHere we characterize the pharmacological and functional properties of fenebrutinib, a potent, highly selective, noncovalent, reversible, brain-penetrant BTK inhibitor, in human microglia and complex human brain cell systems, including brain organoids.ResultsWe find that fenebrutinib blocks the deleterious effects of microglial Fc gamma receptor (FcγR) activation, including cytokine and chemokine release, microglial clustering and neurite damage in diverse human brain cell systems. Gene expression analyses identified pathways linked to inflammation, matrix metalloproteinase production and cholesterol metabolism that were modulated by fenebrutinib treatment. In contrast, fenebrutinib had no significant impact on human microglial pathways linked to Toll-like receptor 4 (TLR4) and NACHT, LRR and PYD domains-containing protein 3 (NLRP3) signaling or myelin phagocytosis.ConclusionsOur study enhances the understanding of BTK functions in human microglial signaling that are relevant to MS pathogenesis and suggests that fenebrutinib could attenuate detrimental microglial activity associated with FcγR activation in people with MS.

Comparative Analysis of Bispecific Antibodies and CAR T-Cell Therapy in Follicular Lymphoma.

The treatment landscape for relapsed/refractory follicular lymphoma (RR-FL) is marked by a pivotal debate between chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAbs). While both CAR-T therapy and BsAbs target similar immunobiology and molecular markers, their efficacy comparisons are hindered by the lack of direct clinical trial comparisons. Key trials, such as the ZUMA-5 study, underscore axicabtagene ciloleucel (axi-cel)'s efficacy in treating RR-FL, achieving a 79% complete response rate with a median duration of response exceeding 3 years. Similarly, lisocabtagene maraleucel (liso-cel) in the TRANSCEND FL study reports a 94% complete response rate, emphasizing robust outcomes in heavily pretreated patients. Among BsAbs, mosunetuzumab showed promise in the GO29781 trial, with a 62% overall response rate in heavily pretreated RR-FL patients. Thus, CAR-T therapy offers potential curative benefits with a single infusion. However, its efficacy is tempered by significant adverse events such as cytokine release syndrome (CRS), neurotoxicity, and cytopenias, requiring specialized management and patient monitoring. In contrast, BsAbs provide a more tolerable treatment option counterbalancing by lower response rates and frequent dosing requirements. Personalized treatment strategies are crucial because of these distinct efficacy and safety profiles. When considering cost-effectiveness, both therapies need to be evaluated in the context of their clinical outcomes and quality of life improvements. Cost-effectiveness considerations are essential; while CAR-T therapies incur higher initial costs, their potential for long-term remission may mitigate expenses associated with repeated treatments or hospitalizations. Future research into resistance mechanisms and optimal therapeutic sequencing will further refine RR-FL management strategies.

Histamine stimulates human microglia to alter cellular prion protein expression via the HRH2 histamine receptor

Although the cellular prion protein (PrPC) has been evolutionarily conserved, the role of this protein remains elusive. Recent evidence indicates that PrPC may be involved in neuroinflammation and the immune response in the brain, and its expression may be modified via various mechanisms. Histamine is a proinflammatory mediator and neurotransmitter that stimulates numerous cells via interactions with histamine receptors 1-4 (HRH1-4). Since microglia are the innate immune cells of the central nervous system, we hypothesized that histamine-induced stimulation regulates the expression of PrPC in human-derived microglia. The human microglial clone 3 (HMC3) cell line was treated with histamine, and intracellular calcium levels were measured via a calcium flux assay. Cytokine production was monitored by enzyme-linked immunosorbent assay (ELISA). Western blotting and quantitative reverse transcription-polymerase chain reaction were used to determine protein and gene expression of HRH1-4. Flow cytometry and western blotting were used to measure PrPC expression levels. Fluorescence microscopy was used to examine Iba-1 and PrPC localization. HMC3 cells stimulated by histamine exhibited increased intracellular calcium levels and increased release of IL-6 and IL-8, while also modifying PrPC localization. HMC3 stimulated with histamine for 6 and 24 hours exhibited increased surface PrPC expression. Specifically, we found that stimulation of the HRH2 receptor was responsible for changes in surface PrPC. Histamine-induced increases in surface PrPC were attenuated following inhibition of the HRH2 receptor via the HRH2 antagonist ranitidine. These changes were unique to HRH2 activation, as stimulation of HRH1, HRH3, or HRH4 did not alter surface PrPC. Prolonged stimulation of HMC3 decreased PrPC expression following 48 and 72 hours of histamine stimulation. HMC3 cells can be stimulated by histamine to undergo intracellular calcium influx. Surface expression levels of PrPC on HMC3 cells are altered by histamine exposure, primarily mediated by HRH2. While histamine exposure also increases release of IL-6 and IL-8 in these cells, this cytokine release is not fully dependent on PrPC levels, as IL-6 release is only partially reduced and IL-8 release is unchanged under the conditions of HRH2 blockade that prevent PrPC changes. Overall, this suggests that PrPC may play a role in modulating microglial responses.

Association Between the Gut Microbiota and Alzheimer's Disease: An Update on Signaling Pathways and Translational Therapeutics.

Alzheimer's disease (AD) is a cognitive disease with high morbidity and mortality. In AD patients, the diversity of the gut microbiota is altered, which influences pathology through the gut-brain axis. Probiotic therapy alleviates pathological and psychological consequences by restoring the diversity of the gut microbial flora. This study addresses the role of altered gut microbiota in the progression of neuroinflammation, which is a major hallmark of AD. This process begins with the activation of glial cells, leading to the release of proinflammatory cytokines and the modulation of cholinergic anti-inflammatory pathways. Short-chain fatty acids, which are bacterial metabolites, provide neuroprotective effects and maintain blood‒brain barrier integrity. Furthermore, the gut microbiota stimulates oxidative stress and mitochondrial dysfunction, which promote AD progression. The signaling pathways involved in gut dysbiosis-mediated neuroinflammation-mediated promotion of AD include cGAS-STING, C/EBPβ/AEP, RAGE, TLR4 Myd88, and the NLRP3 inflammasome. Preclinical studies have shown that natural extracts such as Ganmaidazao extract, isoorentin, camelia oil, Sparassis crispa-1, and xanthocerasides improve gut health and can delay the worsening of AD. Clinical studies using probiotics such as Bifidobacterium spp., yeast beta-glucan, and drugs such as sodium oligomannate and rifaximine have shown improvements in gut health, resulting in the amelioration of AD symptoms. This study incorporates the most current research on the pathophysiology of AD involving the gut microbiota and highlights the knowledge gaps that need to be filled to develop potent therapeutics against AD.

Monocytes perturbation implicated in the association of stress hyperglycemia with postoperative poor prognosis in non-diabetic patients with Stanford type-A acute aortic dissection

ObjectivesThe study aimed to investigate the interaction of intraoperative stress hyperglycemia with monocyte functions and their impact on major adverse events (MAEs) in acute aortic dissection (AAD) patients who underwent open repair surgery.MethodsA total of 321 adults who underwent open surgery for AAD at two tertiary medical centers in China were enrolled in the study. The primary endpoint was defined as the incidence and characteristics of perioperative stress hyperglycemia. The secondary endpoints included the incidence of postoperative MAEs, postoperative monocyte counts and inflammatory cytokine expression. Multi-logistic, linear regression and receiver operating characteristic (ROC) curve analyses were used to establish relationships between intraoperative time-weighted average glucose (TWAG), day-one postoperative monocyte counts, serum inflammatory cytokines and postoperative outcomes. In addition, in vitro experiments were conducted to evaluate changes in the inflammatory features of monocytes under high glucose conditions.ResultsIntraoperative hyperglycemia, as indicated by a TWAG level over 142 mg/dL, was associated with elevated postoperative monocyte counts and inflammatory cytokines, which correlated with extended intensive care unit (ICU) stays and worsened outcomes. In vitro, high glucose treatment induced mitochondrial impairment in monocytes, increased the release of inflammatory cytokines and the proportion of classical monocytes from AAD patients.ConclusionsIntraoperative stress hyperglycemia, in combination with day-one postoperative monocyte counts, were clinically significant for predicting adverse outcomes in AAD patients undergoing open repair surgery. Elevated glucose concentrations shaped the inflammatory features of monocytes in AAD by impairing mitochondrial functions.Graphical abstractHigh glucose-driven mitochondrial functional impairment mediates a more pronounced monocytic inflammatory state in Stanford type-A AAD.

First reported case of thymoma-associated multiorgan autoimmunity induced by COVID-19.

Thymoma-associated multiorgan autoimmunity (TAMA) presents with skin symptoms similar to those of graft-versus-host disease (GVHD), liver dysfunction, and enteritis, in the absence of a history of hematopoietic stem cell or bone marrow transplantation. TAMA is a type of paraneoplastic syndrome associated with thymoma. Its etiology is unclear but is thought to be a result of breakdown of immune tolerance. Histopathologically, TAMA is characterized by epidermal acanthosis with parakeratosis, individual cell keratinization, liquefaction degeneration, and intraepidermal infiltration of CD8-positive lymphocytes. A 64-year-old female patient with a history of myasthenia gravis and thymoma treated with prednisolone (10 mg/day) and cyclosporine (150 mg/day) experienced erythema on her trunk after coronavirus disease 2019 (COVID-19) onset. A psoriatic drug eruption was suspected and the possible causative drug was discontinued, but the skin rash failed to improve. A skin biopsy demonstrated GVHD-like histopathological findings. Diarrhea, abdominal pain, and duodenal perforation occurred concurrently, leading to the diagnosis of TAMA. Thereafter, the patient continued prednisolone and cyclosporine in the same doses as the TAMA treatment and added topical steroids. During the disease course, candida fungemia and cytomegalovirus infection developed, resulting in the patient's death. The TAMA was considered to have been caused by the release of inflammatory cytokines, autoreactive T cell activation, and regulatory T cell dysfunction induced by COVID-19.

Monitoring the Cascade of Monocyte-Derived Macrophages to Influenza Virus Infection in Human Alveolus Chips.

Respiratory viruses ravage the world and seriously threaten people's health. Despite intense research efforts, the immune mechanism underlying respiratory virus-induced acute lung injury (ALI) and pulmonary fibrosis (PF) has not been fully elucidated. Here, the cascade of monocyte-derived macrophages to influenza A virus infection is monitored on an optimized human alveolus chip to reveal the role of macrophages in the development of ALI and PF. We find that viral infection causes damage to the alveolar air-liquid barrier and the release of inflammatory cytokines, which induce the M0 macrophages to gather and polarize to the M1 phenotype at the damaged site through recruitment, adhesion, migration, and activation, leading to ALI. Afterward, M1 macrophages polarize into the M2 phenotype, and then transform into myofibroblasts, followed by enhanced secretion of various anti-inflammatory cytokines and profibrotic cytokines, to promote PF. Our study provides an insight into the pathogenesis of virus-induced ALI and PF, which will assist in the development of therapeutic strategies and drugs for treating influenza and other respiratory virus infections.