Photoswitchable dynamics and RNAi synergist with tailored interface and controlled release reprogramming tumor immunosuppressive niche.

Immunosuppressive tumor microenvironment (ITM) severely limited the efficacy of immunotherapy against triple-negative breast cancer (TNBC). Herein, Apt-LPR, a light-activatable photodynamic therapy (PDT)/RNAi immune synergy-enhancer was constructed by co-loading miR-34a and photosensitizers in cationic liposomes (in phase III clinical trial). Interestingly, the introduction of tumor-specific aptamers creates a special "Liposome-Aptamer-Target" interface, where the aptamers are initially in a "lying down" state but transform to "standing up" after target binding. The interfacing mechanism was elaborately revealed by computational and practical experiments. This unique interface endowed Apt-LPR with neutralized surface potential of cationic liposomes to reduce non-specific cytotoxicity, enhanced DNase resistance to protect aptamers, and preserved target-binding ability for selective drug delivery. Upon near-infrared irradiation, the generated reactive oxygen species would oxidize unsaturated phospholipids to destabilize both liposomes and lysosomes, realizing stepwise lysosomal escape of miR-34a for tumor cell apoptosis and downregulation of PD-L1 to suppress immune escape. Together, tumor-associated antigens released from PDT-damaged mitochondria and endoplasmic reticulum could activate the suppressive immune cells to establish an "immune hot" milieu. The collaborative immune-enhancing strategy effectively aroused systemic antitumor immunity and inhibited primary and distal tumor progression as well as lung metastasis in 4T1 xenografted mouse models. The photo-controlled drug release and specific tumor-targeting capabilities of Apt-LPR were also visualized in MDA-MB-231 xenografted zebrafish models. Therefore, this photoswitchable PDT/RNAi immune stimulator offered a powerful approach to reprogramming ITM and reinforcing cancer immunotherapy efficacy.

Maternal immune activation upregulates the AU020206-IRFs-STAT1 axis in modulating cytokine production in the brain.

Maternal immune activation (MIA) is reported to increase the risk of psychiatric disorders in the offspring. However, the underlying mechanism remains unclear. Methods: We constructed a MIA mouse model by intraperitoneal injection of LPS into pregnant mice and evaluated the behaviors and gene expression profiles in the brains of the female and male offspring, respectively. Results: We found that the MIA female offspring exhibited increased anxiety and a large number of differentially expressed genes (DEGs) in the brain, which were enriched with candidate gene sets of psychiatric disorders and immune functions. In contrast, the MIA male offspring exhibited no significant abnormal behaviors and only a small number of DEGs that were not enriched with disease genes and immune functions. Therefore, we further pursued the downstream study on the molecular mechanism underlying the increased anxiety in the female offspring. We identified the lncRNA AU020206-IRFs-STAT1-cytokine axis by integrating lncRNA-protein interaction data and TF-promoter interaction data, and verified the axis in vitro and in vivo. Conclusion: This study illustrates that MIA upregulates the AU020206-IRFs-STAT1 axis in controlling the brain immunity linked to abnormal behaviors, providing a basis for understanding the role of MIA in psychiatric disorders.

Integrating Bulk and Single-Cell RNA-Seq Data to Identify Prognostic Features Related to Activated Dendritic Cells in Clear-Cell Renal-Cell Carcinoma.

Dendritic cells (DCs) serve as key regulators in tumor immunity, with activated DCs potentiating antitumor responses through the secretion of pro-inflammatory cytokines and the expression of co-stimulatory molecules. Most current studies focus on the relationship between DC subgroups and clear-cell renal-cell carcinoma (ccRCC), but there is limited research on the connection between DCs and ccRCC from the perspective of immune activation. In this study, activated DC genes were identified in both bulk and single-cell RNA-seq data. A prognostic model related to activated DCs was constructed using univariate, multivariate Cox regression and LASSO regression. The prognostic model was validated in three external validation sets: GSE167573, ICGC, and E-MTAB-1980. The prognostic model consists of five genes, PLCB2, XCR1, IFNG, HLA-DQB2, and SMIM24. The expression of these genes was validated in tissue samples using qRT-PCR. Stratified analysis revealed that the prognostic model was able to better predict outcomes in advanced ccRCC patients. The risk scores were associated with tumor progression, tumor mutation burden, immune cell infiltration, and adverse outcomes of immunotherapy. Notably, there was a strong correlation between the expression of the five genes and the sensitivity to JQ1, a BET inhibitor. Molecular docking indicated high-affinity binding of the proteins encoded by these genes with JQ1. In conclusion, our study reveals the crucial role of activated DCs in ccRCC, offering new insights into predicting immune response, targeted therapy effectiveness, and prognosis for ccRCC patients.

Maternal immune activation alters temporal precision of spike generation of CA1 pyramidal neurons by unbalancing GABAergic inhibition intheOffspring.

Infection during pregnancy represents a risk factor for neuropsychiatric disorders associated with neurodevelopmental alterations. A growing body of evidence from rodents and non-human primates shows that maternal inflammation induced by viral or bacterial infections results in several neurobiological alterations in the offspring. These changes may play an important role in the pathophysiology of psychiatric disorders like schizophrenia and autism spectrum disorders, whose clinical features include impairments in cognitive processing and social performance. Such alterations are causally associated with the maternal inflammatory response to infection rather than with the infection itself. Previously, we reported that CA1 pyramidal neurons of mice exposed to MIA exhibit increased excitability accompanied by a reduction in dendritic complexity. However, potential alterations in cellular and synaptic rules that shape the neuronal computational properties of the offspring remain to be determined. In this study, using mice as subjects, we identified a series of cellular and synaptic alterations endured by CA1 pyramidal neurons of the dorsal hippocampus in a lipopolysaccharide-induced maternal immune activation (MIA) model. Our data indicate that MIA reshapes the excitation-inhibition balance by decreasing the perisomatic GABAergic inhibition predominantly mediated by cholecystokinin-expressing Interneurons but not parvalbumin-expressing interneurons impinging on CA1 pyramidal neurons. These alterations yield a dysregulated amplification of the temporal and spatial synaptic integration. In addition, MIA-exposed offspring displayed social and anxiety-like abnormalities. These findings collectively contribute to understanding the cellular and synaptic alterations underlying the behavioral symptoms present in neurodevelopmental disorders associated with MIA.

Humoral and cellular immune response from first to fourth SARS-CoV-2 mRNA vaccination in anti-CD20-treated multiple sclerosis patients-a longitudinal cohort study.

Background: This study examines the humoral and cellular response in multiple sclerosis (MS) patients on anti-CD20 therapy before and after the 1st to 4th BNT162b2 mRNA SARS-CoV-2 vaccination and the relationship with breakthrough infection. Methods: Participants with McDonald 2017 MS that were treated with ocrelizumab were included. The study duration was throughout the COVID-19 pandemic until four months after fourth mRNA SARS-CoV-2 vaccination (BNT162b2). Longitudinal blood samples were analysed for: IgG antibodies of SARS-CoV-2 spike anti-receptor binding domain (anti-RBD), nucleocapsid IgG antibodies (anti-N) and activation induced marker expressing CD4+, CD8+ T-cells and concentration of ocrelizumab and anti-drug antibodies. Incidences of breakthrough infection were confirmed with SARS-CoV-2 PCR tests. Results: The rate of anti-RBD positive participants increased substantially between the third and fourth vaccination from 22.2% to 55.9% (median 54.7 BAU/mL; IQR: 14.5 - 221.2 BAU/mL and 607.7 BAU/mL; IQR: 29.4 - 784.6 BAU/mL, respectively). Within the same period 75% of participants experienced breakthrough infection. The fourth vaccination resulted in an additional increase in seropositive individuals (64.3%) (median 541.8 BAU/mL (IQR: 19.1-1007 BAU/mL). Breakthrough infection did not influence the cellular response without a significant change after the fourth vaccination. During the study period two participants had detectable anti-N, both after the fourth vaccination. No correlation was found between serum concentration of ocrelizumab and the humoral and cellular response. Discussion: Low levels or absence of specific anti-RBD following vaccination, with a significant increase after breakthrough infections and boosted by the fourth vaccination. T-cell reactivity remained sustained and unaffected by breakthrough infections.

HIV-1-DNA/RNA and immunometabolism in monocytes: contribution to the chronic immune activation and inflammation in people with HIV-1.

BACKGROUND: Among people living with HIV-1 (PHIV), immunological non-responders (INR) experience incomplete immune recovery despite suppressive antiretroviral treatment (ART), facing more severe non-AIDS events than immunological responders (IR) due to higher chronic immune activation and inflammation (cIA/I). We analyzed the HIV-1 reservoir and immunometabolism in monocytes as a source of cIA/I. METHODS: Cross-sectional study in which 110 participants were enrolled: 25 treatment-naïve; 35 INR; 40 IR; and 10 healthy controls. Cell-associated HIV-1-DNA (HIV-DNA) and -RNA (HIV-RNA) were measured in FACS-isolated monocytes using digital droplet PCR. Intact, 5' deleted, and 3' deleted proviruses were quantified by the intact proviral DNA assay. Systemic inflammation, monocyte immunophenotype, and immunometabolism were characterized by immunoassays, flow cytometry, and real-time cellular bioenergetics measurements, respectively. FINDINGS: Monocytes from INR harbor higher HIV-RNA and HIV-DNA levels than IR. HIV-RNA was found in 14/21 treatment-naïve [2512 copies/106 TBP (331-4666)], 17/33 INR [240 (148-589)], and 15/28 IR [144 (15-309)], correlating directly with sCD163, IP-10, GLUT1high cells and glucose uptake, and inversely with the CD4+/CD8+ ratio. HIV-DNA was identified in all participants with detectable HIV-RNA, with intact provirus in 9/12 treatment-naïve [13 copies/106 monocytes (7-44)], 8/14 INR [46 (18-67)], and 9/13 IR [9 (7-24)]. INR presented glucose metabolism alterations and mitochondrial impairment; decreased coupling efficiency and BHI, and increased mitochondrial dysfunction inversely correlating with the CD4+/CD8+ ratio. INTERPRETATION: HIV-RNA, more than HIV-DNA, in monocytes and their altered metabolism are factors associated with the higher cIA/I that characterize INR. FUNDING: This work was supported by the European Regional Development Fund, ISCIII, grant PI20/01646. Other funding sources: Instituto de Salud Carlos III through the Subprogram Miguel Servet (CP19/00159) to AGV, PFIS contracts (FI19/00304) to EMM, (FI21/00165) to ASA, and (FI19/00083) to CGC, and a mobility grant (MV21/00103) to EMM, from the Ministerio de Ciencia e Innovación, Spain. AJM was granted by a CSL Centenary Award.

The rebalancing of the immune system at the maternal-fetal interface ameliorates autism-like behavior in adult offspring.

Maternal immune activation (MIA) is critical for imparting neuropathology and altered behaviors in offspring; however, maternal-fetal immune cell populations have not been thoroughly investigated in MIA-induced autism spectrum disorders (ASDs). Here, we report the single-cell transcriptional landscape of placental cells in both PBS- and poly(I:C)-induced MIA dams. We observed a decrease in regulatory T (Treg) cells but an increase in the M1 macrophage population at the maternal-fetal interface in MIA dams. Based on the Treg-targeting approach, we investigate an immunoregulatory protein, the helminth-derived heat shock protein 90α (Sjp90α), that induces maternal Treg cells and subsequently rescues the autism-like behaviors in adult offspring. Furthermore, in vivo depletion of maternal macrophages attenuates placental inflammatory reaction and reverses behavioral abnormalities in adult offspring. Notably, Sjp90α induces CD4+ T cell differentiation via scavenger receptor A (SR-A) on the macrophage in vitro. Our findings suggest a maternal Treg-targeted approach to alleviate MIA-induced autism-like behavior in adult offspring.

[Expression and diagnostic value of lymphocyte subsets and activation status in non-Hodgkin's lymphoma-associated hemophagocytic lymphohistiocytosis].

Objective: To determine the expression and diagnostic value of peripheral blood lymphocytes and functional activation status in non-Hodgkin lymphoma with hemophagocytic lymphohistiocytosis (NHL-HLH) . Methods: We retrospectively analyzed clinical data from 30 newly diagnosed NHL-HLH patients admitted to Jiangsu Province Hospital from September 2022 to September 2023. We assessed peripheral blood lymphocytes and activation status by flow cytometry. Forty newly diagnosed patients with NHL who received treatment at our hospital during the same period and had lymphocyte and functional activation indexes were selected as the control group. The differences in relative and absolute lymphocyte counts and functional activation indexes between the two groups were compared. The optimal cutoff values for continuous variables were calculated from the receiver operating characteristic curve and logistic regression analysis was used to evaluate the risk factors in NHL patients with HLH. Results: A total of 30 NHL-HLH patients were evaluated, including 12 T-cell lymphoma and 18 B-cell lymphoma patients. Forty individuals were in the control group, which included 19 T-cell lymphoma and 21 B-cell lymphoma patients. The absolute counts of CD3(+) T, CD4(+) T, CD8(+) T, and NK cells, along with the relative count of NK cells, were significantly lower in the HLH group compared with that in the control group (all P values<0.01) . The expression of CD38 and HLA-DR on CD8(+) T-cell activated subgroups was significantly higher in the NHL-HLH group compared with that in the control group (CD8(+)CD38(+)/CD8(+) T expression median: 57.4% vs 21.5%, P<0.001; CD8(+)CD38(+)/CD8(+) T expression median: 49.7% vs 33.5%, P=0.028, respectively) . In addition, CD28 expression on CD4(+) and CD8(+) T cells was significantly higher in NHL-HLH patients (P<0.01) . ROC curve and multivariate logistic regression analyses revealed that absolute NK cell count ≤72.0 cells/µl, CD4(+)CD28(+)/CD4(+) T >94.2%, and CD8(+)CD28(+)/CD8(+) T >38.4% were risk factors for predicting the occurrence of NHL-HLH patients. The sensitivity and specificity of the regression model were 86.7% and 86.1%, respectively, with an area under the curve of 0.94 (P<0.001) . Conclusions: In NHL patients with HLH, there was a significant reduction in the absolute number of peripheral blood lymphocyte subpopulations, whereas T-cell function was notably activated. Specifically, absolute counts of NK cells ≤72.0 cells/µl, CD4(+)CD28(+)/CD4(+) T >94.2%, and CD8(+)CD28(+)/CD8(+) T >38.4% were identified as risk factors for predicting the development of NHL-HLH patients. This will assist in early clinical diagnosis and treatment.

Single-cell transcriptomics reveal distinctive patterns of fibroblast activation in heart failure with preserved ejection fraction.

Inflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease-specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF-specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 (Angptl4) next to basement membrane compounds, such as collagen IV (Col4a1). Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNFɑ with estimated fibroblast target genes including Col4a1 and Angptl4. Treatment with recombinant ANGPTL4 ameliorated the murine HFpEF phenotype and diastolic dysfunction by reducing collagen IV deposition from fibroblasts in vivo and in vitro. In line, ANGPTL4, was elevated in plasma samples of HFpEF patients and particularly high levels associated with a preserved global-longitudinal strain. Taken together, our study provides a comprehensive characterization of molecular fibroblast activation patterns in murine HFpEF, as well as the identification of Angiopoietin-like 4 as central mechanistic regulator with protective effects.

High level of immunoglobulin G targeting mycoplasma or cytomegalovirus in the newborn increases risk of ADHD.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder typically detected in childhood. Although ADHD has been demonstrated to have a strong genetic component, environmental risk factors, such as maternal infections during pregnancy, may also play a role. We therefore measured the immunological response to 5 abundant microorganisms (Toxoplasmosis Gondii, cytomegalovirus (CMV), Herpes Simplex Virus 1, Epstein Barr Virus and mycoplasma pneumoniae) in newborn heel prick samples of 1679 ADHD cases and 2948 matching controls as part of the iPSYCH Danish case-cohort study. We found an association between high anti-CMV (OR 1.30, 95 % CI [1.09,1.55], p = 0.015) and anti-mycoplasma (OR 1.30, 95 % CI [1.07,1.59], p = 0.037) signal and those newborns later being diagnosed with ADHD. The risk estimate remained increased when controlling for ADHD polygenic risk score as well as penicillin prescriptions. We saw a dose-response association with the amount of positive anti-microorganism titers increasing the risk of being diagnosed with ADHD later in life (p = 0.01 for the trend), suggesting that the more activated the immune system is prior to or at birth, the higher the risk is for a later diagnosis with ADHD. If the associations are causal, they emphasize the importance of a healthy life style during pregnancy to reduce the risk of infections when pregnant and the associated risks for the child.

Does the kynurenine pathway play a pathogenic role in autism spectrum disorder?

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in communication, sociability, and repetitive/stereotyped behavior. The etiology of autism is diverse, with genetic susceptibility playing an important role alongside environmental insults and conditions. Human and preclinical studies have shown that ASD is commonly accompanied by inflammation, and inhibition of the inflammatory response can ameliorate, or prevent the phenotype in preclinical studies. The kynurenine pathway, responsible for tryptophan metabolism, is upregulated by inflammation. Hence, this metabolic route has drawn the attention of investigators across different disciplines such as cancer, immunology, and neuroscience. Over the past decade, studies have identified evidence that the kynurenine pathway is also altered in autism spectrum disorders. In this mini review, we will explore the current status quo of the link between the kynurenine pathway and ASD, shedding light on the compelling but still preliminary evidence of this relationship.

Single-cell transcriptomics reveals tumor microenvironment remodeling in hepatocellular carcinoma with varying tumor subclonal complexity.

Introduction: The complexity of tumor cell subclonal structure has been extensively investigated in hepatocellular carcinoma. However, the role of subclonal complexity in reshaping the tumor microenvironment (TME) remains poorly understood. Methods: We integrated single-cell transcriptome sequencing data from four independent HCC cohorts, involving 30 samples, to decode the associations between tumor subclonal complexity and the TME. We proposed a robust metric to accurately quantify the degree of subclonal complexity for each sample based on discrete copy number variations (CNVs) profiles. Results: We found that tumor cells in the high-complexity group originated from the cell lineage with FGB overexpression and exhibited high levels of transcription factors associated with poor survival. In contrast, tumor cells in low-complexity patients showed activation of more hallmark signaling pathways, more active cell-cell communications within the TME and a higher immune activation status. Additionally, cytokines signaling activity analysis suggested a link between HMGB1 expressed by a specific endothelial subtype and T cell proliferation. Discussion: Our study sheds light on the intricate relationship between the complexity of subclonal structure and the TME, offering novel insights into potential therapeutic targets for HCC.

Profiling metabolome of mouse embryonic cerebrospinal fluid following maternal immune activation.

The embryonic cerebrospinal fluid (eCSF) plays an essential role in the development of the central nervous system (CNS), influencing processes from neurogenesis to lifelong cognitive functions. An important process affecting eCSF composition is inflammation. Inflammation during development can be studied using the maternal immune activation (MIA) mouse model, which displays altered cytokine eCSF composition and mimics neurodevelopmental disorders including autism spectrum disorder (ASD). The limited nature of eCSF as a biosample restricts its research and has hindered our understanding of the eCSF's role in brain pathologies. Specifically, investigation of the small molecule composition of the eCSF is lacking, leaving this aspect of the eCSF composition under-studied. We report here the eCSF metabolome as a resource for investigating developmental neuropathologies from a metabolic perspective. Our reference metabolome includes comprehensive MS1 and MS2 datasets and evaluates two mouse strains (CD-1 and C57Bl/6) and two developmental time points (E12.5 and E14.5). We illustrate the reference metabolome's utility by using untargeted metabolomics to identify eCSF-specific compositional changes following MIA. We uncover MIA-relevant metabolic pathways as differentially abundant in eCSF and validate changes in glucocorticoid and kynurenine pathways through targeted metabolomics approaches. Our resource will guide future studies into the causes of MIA neuropathology and the impact of eCSF composition on brain development.

Synaptic proteome perturbations after maternal immune activation: Identification of embryonic and adult hippocampal changes.

BACKGROUND: Maternal immune activation (MIA) triggers neurobiological changes in offspring, potentially reshaping the molecular synaptic landscape, with the hippocampus being particularly vulnerable. However, critical details regarding developmental timing of these changes and whether they differ between males and females remain unclear. METHODS: We induced MIA in C57BL/6J mice on gestational day nine using the viral mimetic poly(I:C) and performed mass spectrometry-based proteomic analyses on hippocampal synaptoneurosomes of embryonic (E18) and adult (20 ± 1 weeks) MIA offspring. RESULTS: In the embryonic synaptoneurosomes, MIA led to lipid, polysaccharide, and glycoprotein metabolism pathway disruptions. In the adult synaptic proteome, we observed a dynamic shift toward transmembrane trafficking, intracellular signalling cascades, including cell death and growth, and cytoskeletal organisation. In adults, many associated pathways overlapped between males and females. However, we found distinct sex-specific enrichment of dopaminergic and glutamatergic pathways. We identified 50 proteins altered by MIA in both embryonic and adult samples (28 with the same directionality), mainly involved in presynaptic structure and synaptic vesicle function. We probed human phenome-wide association study data in the cognitive and psychiatric domains, and 49 of the 50 genes encoding these proteins were significantly associated with the investigated phenotypes. CONCLUSIONS: Our data emphasise the dynamic effects of viral-like MIA on developing and mature hippocampi and provide novel targets for study following prenatal immune challenges. The 22 proteins that changed directionality from the embryonic to adult hippocampus, suggestive of compensatory over-adaptions, are particularly attractive for future investigations.

Maternal prenatal immune activation associated with brain tissue microstructure and metabolite concentrations in newborn infants.

Few human studies have assessed the association of prenatal maternal immune activation (MIA) with measures of brain development and psychiatric risk in newborn offspring. Our goal was to identify the effects of MIA during the 2nd and 3rd trimesters of pregnancy on newborn measures of brain metabolite concentrations, tissue microstructure, and motor development. This was a prospective longitudinal cohort study conducted with nulliparous pregnant women who were aged 14 to 19 years and recruited in their 2nd trimester, as well as their children who were followed through 14 months of age. MIA was indexed by maternal interleukin-6 (IL-6) and C-reactive protein (CRP) in both trimesters of pregnancy. Primary outcomes included: (1) newborn brain metabolite concentrations as ratios to creatine (N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr) measured using Magnetic Resonance Spectroscopy; (2) newborn fractional anisotropy and mean diffusivity, measured using Diffusion Tensor Imaging; and (3) indices of motor development, assessed prenatally and postnatally at ages 4- and 14-months. Maternal IL-6 and CRP levels associated significantly with both metabolites in the putamen, thalamus, insula, and the internal capsule. Maternal IL-6 associated significantly with fractional anisotropy in the putamen, caudate, thalamus, insula, and precuneus, and with mean diffusivity in the inferior parietal and middle temporal gyrus. CRP associated significantly with fractional anisotropy in the thalamus, insula, and putamen. Significant associations were found in common regions across imaging modalities, though the direction of associations differed by immune marker. In addition, both maternal IL-6 and CRP (in both trimesters) prenatally associated significantly with offspring motor development at 4- and 14-months of age. The left thalamus mediated effects of IL-6 on postnatal motor development. These findings demonstrate that levels of MIA in mid- to late pregnancy in a generally healthy sample associate with tissue characteristics in newborn brain regions that primarily support motor integration and coordination, as well as behavioral regulation. Those brain effects may contribute to differences in motor development.

A systematic review of spirostanol saponins and anticancer natural products isolated from Tacca plantaginea (Hance) Drenth.

The plant genus Tacca comprises twenty species including Tacca plantaginea, essentially distributed in the Indo-China region. Medicinal preparations from the rhizomes are used traditionally to treat gastrointestinal ailments, stomach aches and inflammatory disorders. A variety of bioactive molecules have been isolated from T. plantaginea, including potent anticancer steroids such as the taccanolides which interfere with microtubules dynamic. Other efficient anticancer natural products have been isolated from the plant, in particular a series of diosgenin/yamogenin-type sapogenins including taccaoside (monodesmosidic) and taccaoside A (bidesmosidic). Taccaoside A displays marked anticancer properties through two complementary mechanisms: a direct action on cancer stem cells via HRas and Pi3K/Akt signaling and an indirect immunomodulatory action via activation of cytotoxic T cells. A similar mechanism of action has been invoked with a total saponin extract from Schizocapsa plantaginea Hance (synonym to T. plantaginea) and the saponin SSPH 1. This saponin reduced tumor growth in mice through stimulation of cytotoxic T lymphocytes. Other bioactive products have been isolated from T. plantaginea, including withanolide-type steroids (plantagiolides, chantriolides), diarylheptanoids (plantagineosides) and different saponins (diosbulbisides, lieguonins). The discussion centers around the mechanism of action of spirostanol saponins, with the objective to promote their study as immuno-active anticancer agents.

Immune activation and immune-associated neurotoxicity in Long-COVID: A systematic review and meta-analysis of 103 studies comprising 58 cytokines/chemokines/growth factors.

BACKGROUND: Multiple studies have shown that Long COVID (LC) disease is associated with heightened immune activation, as evidenced by elevated levels of inflammatory mediators. However, there is no comprehensive meta-analysis focusing on activation of the immune inflammatory response system (IRS) and the compensatory immunoregulatory system (CIRS) along with other immune phenotypes in LC patients. OBJECTIVES: This meta-analysis is designed to explore the IRS and CIRS profiles in LC patients, the individual cytokines, chemokines, growth factors, along with C-reactive protein (CRP) and immune-associated neurotoxicity. METHODS: To gather relevant studies for our research, we conducted a thorough search using databases such as PubMed, Google Scholar, and SciFinder, covering all available literature up to July 5th, 2024. RESULTS: The current meta-analysis encompassed 103 studies that examined multiple immune profiles, C-reactive protein, and 58 cytokines/chemokines/growth factors in 5502 LC patients versus 5962 normal controls (NC). LC patients showed significant increases in IRS/CIRS ratio (standardized mean difference (SMD: 0.156, confidence interval (CI): 0.062;0.250), IRS (SMD: 0.338, CI: 0.236;0.440), M1 macrophage (SMD: 0.371, CI: 0.263;0.480), T helper (Th)1 (SMD: 0.316, CI: 0.185;0.446), Th17 (SMD: 0.439, CI: 0.302;0.577) and immune-associated neurotoxicity (SMD: 0.384, CI: 0.271;0.497). In addition, CRP and 21 different cytokines displayed significantly elevated levels in LC patients compared to NC. CONCLUSION: LC disease is characterized by IRS activation and increased immune-associated neurotoxicity.

The fetal programming effect of maternal immune activation (MIA) on the offspring's immune system.

The first 1000 days of life is a critical period of development in which adverse circumstances can have long-term consequences for the child's health. Maternal immune activation is associated with increased risk of neurodevelopmental disorders in the child. Aberrant immune responses have been reported in individuals with neurodevelopmental disorders. Moreover, lasting effects of maternal immune activation on the offspring's immune system have been reported. Taken together, this indicates that the effect of maternal immune activation is not limited to the central nervous system. Here, we explore the impact of maternal immune activation on the immune system of the offspring. We first describe the development of the immune system and provide an overview of reported alterations in the cytokine profiles, immune cell profiles, immune cell function, and immune induction in pre-clinical models. Additionally, we highlight recent research on the impact of maternal COVID-19 exposure on the neonatal immune system and the potential health consequences for the child. Our review shows that maternal immune activation alters the offspring's immune system under certain conditions, but the reported effects are conflicting and inconsistent. In general, epigenetic modifications are considered the mechanism for fetal programming. The available data was insufficient to identify specific pathways that may contribute to immune programming. As a consequence of the COVID-19 pandemic, more research now focuses on the possible health effects of maternal immune activation on the offspring. Future research addressing the offspring's immune response to maternal immune activation can elucidate specific pathways that contribute to fetal immune programming and the long-term health effects for the offspring.

Advances from targeted therapy for non-metastatic HER2-positive inflammatory breast cancer.

Among inflammatory breast cancer (IBC) patients, over one-third have HER2-overexpressing (HER2+) tumors. Pathologic complete response (pCR) rates to neoadjuvant targeted and chemotherapy for patients with HER2+ non-metastatic IBC now apporach 60% and favorable long-term survival rates are being reported for those with a pCR. Immune mechanisms contributing to this phenomenon include antibody-mediated immune activation and induction of memory T-cell reponses which may explain the sustained antitumor response seen after discontinuation of targeted therapies.

Efficacy of steroid therapy for improving native liver survival after pediatric acute liver failure with immune activation.

AIM: Recent evidence suggests that acute liver failure (ALF) in some patients may reflect a dysregulated immune response, and that corticosteroids improve survival of the native liver in ALF patients with high serum alanine aminotransferase levels, which are an indication of liver inflammation. However, it is unclear whether steroids are effective for pediatric acute liver failure (PALF). The aim of this retrospective case-control study is to examine whether steroid therapy for PALF accompanied by immune activation improves the survival of native liver and to identify factors that predict responses to steroid treatment. METHODS: Of 38 patients with PALF treated at Kyoto University Hospital from February 2006 to August 2022, 19 receiving steroids who met the specific criteria for identifying the pathophysiology of immune activity in the liver (the "Steroid group"), and seven steroid-free patients who also met the criteria ("Nonsteroid group") were enrolled. Patients in the "Steroid group" were categorized as "responders" or "nonresponders" according to treatment outcome. Clinical and histological data were analyzed. RESULTS: Survival of the native liver in the Steroid group was significantly higher than that in the Nonsteroid group (68% vs. 0%, respectively; p = 0.0052). Nonresponders were significantly younger, with higher Model for End-stage Liver Disease and pediatric end-stage liver disease scores, higher prothrombin time - international normalized ratio, and higher serum ferritin levels than responders. Massive hepatic necrosis was more common in nonresponders. CONCLUSION: Steroid therapy is effective for PALF patients with liver inflammation; however, liver transplantation should be prioritized for young children with ALF accompanied by severe coagulopathy or massive hepatic necrosis.