Immune Activation Research Articles

A humanized anti-b7h3×4-1BB bispecific antibody exerts potent antitumour effects through the activation of innate and adaptive immunity.

Agonistic monoclonal antibodies targeting 4-1BB have shown much preclinical promise, but their clinical development has been limited by obvious toxicity or unremarkable efficacy. Here, we generated two humanized anti-B7H3×4-1BB bsAbs (HK056-001/002) by fusing an anti-4-1BB scFv to the C-terminus of an anti-B7H3 with an intact Fc fragment from human IgG1 or IgG4. The two bsAbs were able to stimulate the 4-1BB signaling pathway, which was strictly dependent on B7H3 expression. In particular, HK056-001 retained Fc function and induced an ADCC effect in tumor cells, whereas HK056-002 did not. Strikingly, HK056-001 showed superior antitumour activity to HK056-002 both in vitro and in vivo. HK056-001 enhanced antitumour immunity and induced lasting antigen-specific immune memory to prevent tumor regrowth upon rechallenge, even at a dose as low as 2mg/kg. Furthermore, HK056-001 did not induce nonspecific production of proinflammatory cytokines and had no apparent ability to induce ADA production. In addition, HK056-001 has no significant liver toxicity in human 4-1BB-KI BALB/c mice bearing CT26-B7H3 tumors. The optimal anti-B7H3×4-1BB bsAb HK056-001 exhibited synergistic antitumour effects by inducing an ADCC effect (innate immunity) and activating the 4-1BB signaling pathway (adaptive immunity) upon cross-bridging with B7H3 with no obvious toxicity, which could potentially provide a better therapeutic window compared to what is seen with 4-1BB agonists.

Discovery of a non-nucleotide stimulator of interferon genes (STING) agonist with systemic antitumor effect.

Agonists of the stimulator of interferon genes (STING) pathway are increasingly being recognized as a promising new approach in the treatment of cancer. Although progress in clinical trials for STING agonists in antitumor applications has been slow, there is still an urgent need for developing new potent STING agonists with versatile potential applications. Herein, we developed and identified a non-nucleotide STING agonist called DW18343. DW18343 showed robust activation across different STING isoforms. Crystallography analysis revealed that DW18343 binds more deeply into the ligand binding domain (LBD) pocket of STING-H232 compared to other agonists such as MSA-2, SR-717, or cGAMP, which likely contributes to its high potency. DW18343 triggered downstream p-TBK1/p-IRF3 signaling, leading to the production of multiple cytokines. Additionally, DW18343 displayed broad and long-lasting antitumor effects in various syngeneic mouse tumor models, whether administered locally or systemically. Moreover, DW18343 induced immune memory to combat the growth of rechallenged tumors. Finally, DW18343 was shown to be an activator of both the innate and adaptive antitumor immunity in tumor tissue, potentially explaining its strong antitumor effects in vivo. In conclusion, DW18343 serves as a novel non-nucleotide STING agonist with systemic antitumor effect through the activation of antitumor immunity.

Key role of macrophages in the progression of hepatic fibrosis.

Liver fibrosis is a pathological change characterized by excessive deposition of extracellular matrix caused by chronic liver injury, and the mechanisms underlying its development are associated with endothelial cell injury, inflammatory immune cell activation, and HSC activation. Furthermore, hepatic macrophages exhibit remarkable heterogeneity and hold central functions in the evolution of liver fibrosis, with different subgroups exerting dual effects of promotion and regression. Currently, targeted macrophage therapy for reversing hepatic fibrosis has been extensively studied and has shown promising prospects. In this review, we will discuss the dual role of macrophages in liver fibrosis and provide new insights into reversing liver fibrosis based on macrophages.

Peptide fibrils as a vaccine: Proof of concept.

Rapid vaccine platforms development is crucial for responding to epidemics and pandemics of emerging infectious diseases, such as Ebola. This study explores the potential of peptide vaccines that self-organize into amyloid-like fibrils, aiming to enhance immunogenicity while considering safety and cross-reactivity. We synthesized two peptides, G33 and G31, corresponding to a segment of the Ebola virus GP2 protein, with G33 known to form amyloid-like fibrils. Their toxicity was assessed in vitro using an MTT assay on MDCK and A549 cell cultures. For in vivo studies, balb/c mice were immunized with these peptides. Immunogenicity was gauged by ELISA for specific antibodies against the recombinant eGP protein. Hematological parameters were determined, and histopathological changes in organs were documented post-euthanasia. Both peptides exhibited no cytotoxicity up to 500μg/mL. G33-immunized mice developed higher antibody titers than those receiving G31 or control, without significant alterations in hematological profiles. However, histological analysis showed periportal infiltration and lymphoid-macrophage clusters in the liver and kidneys, suggesting immune response activation. The homology between the G33 peptide and mammalian proteins poses risks of cross-reactivity. The amyloid-like fibrils formed by the G33 peptide elicited a stronger immune response without significant hematological changes, underlining the feasibility of fibril-based peptide vaccines. However, the potential for autoimmune responses due to molecular mimicry warrants further investigation before clinical applications can be considered.

KLRD1 (CD94): A Prognostic Biomarker and Therapeutic Candidate in Head and Neck Squamous Cell Carcinoma.

Background: Killer Cell Lectin Like Receptor D1 (KLRD1) plays a crucial role in antitumor immunity. However, its expression patterns across various cancers, its relationship with patient prognosis, and its potential as an immunotherapy target remain inadequately understood. Methods: We analyzed KLRD1 expression across various cancer types using multi-omics data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases, correlating it with patient prognosis. Single-cell RNA sequencing data were employed to further explore KLRD1 expression in natural killer (NK) cells and exhausted CD8+ T cells (CD8Tex). Functional enrichment analyses using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) identified the biological processes and pathways associated with KLRD1. Immune infiltration analysis, conducted via CIBERSORT, assessed the relationship between KLRD1 expression and immune cell infiltration within the tumor microenvironment. Furthermore, the Tracking Tumor Immunophenotype (TIP) meta-server and Easier tool were employed to assess the role of KLRD1 in the cancer immunity cycle and to predict immunotherapy responses. Drug sensitivity was predicted using tools like CellMiner and the Genomics of Drug Sensitivity in Cancer (GDSC) database to explore the link between KLRD1 expression and responsiveness to various anticancer drugs. Results: KLRD1 exhibits significant differential expression and strong prognostic value across cancers, particularly as an independent prognostic factor in head and neck squamous cell carcinoma (HNSC). Single-cell analysis revealed high expression of KLRD1 in NK and CD8Tex cells, indicating its critical role in antitumor immune responses. Functional enrichment analyses showed that KLRD1 is involved in several immune-related signaling pathways, including NK cell-mediated cytotoxicity and T cell receptor pathways. Immune infiltration analysis further confirmed a positive correlation between KLRD1 expression and the infiltration of various immune cells. Moreover, higher KLRD1 expression in HNSC is associated with enhanced immune pathway activity, increased sensitivity to cell division inhibitors, and the identification of arachidonyltrifluoromethane as a potential compound to counteract its oncogenic effects. Conclusion: In HNSC, KLRD1 is a key prognostic marker and potential target for personalized immunotherapy.

Harnessing miRNAs: A Novel Approach to Diagnosis and Treatment of Tuberculosis.

Mycobacterium tuberculosis (Mtb) complex, responsible for tuberculosis (TB) infection, continues to be a predominant global cause of mortality due to intricate host-pathogen interactions that affect disease progression. MicroRNAs (miRNAs), essential posttranscriptional regulators, have become pivotal modulators of these relationships. Recent findings indicate that miRNAs actively regulate immunological responses to Mtb complex by modulating autophagy, apoptosis, and immune cell activities. This has resulted in increased interest in miRNAs as prospective diagnostic indicators for TB, especially in differentiating active infection from latent or inactive stages. Variations in miRNA expression during Mtb infection indicate disease progression and offer insights into the immune response. Furthermore, miRNAs present potential as therapeutic targets in host-directed therapy (HDT) techniques for TB infection. This work examines the function of miRNAs in TB pathogenesis, with the objective of identifying particular miRNAs that regulate the immune response to the Mtb complex, evaluating their diagnostic value and exploring their therapeutic implications in host-directed therapy for TB infection. The objective is to enhance comprehension of how miRNAs can facilitate improved diagnosis and treatment of TB.

The Relationship of Th1/Th2 Cytokine Polarization at Parturition in Cows and SOCS3 Level With Some Postpartum Diseases.

Th1/Th2 polarisation and suppressor of cytokine signalling-3 (SOCS3) are important indicators of the humoral and cellular immune system activity in cows. The aim of this study was to determine the correlation of postpartum diseases with the levels of Th1/Th2 polarisation and SOCS3 at the time of parturition. The study examined 180 cows (90 with normal parturition [NP] and 90 with dystocia [D]). Blood samples were taken from the cows once at the time of calving. Two subgroups were created among cows with NP: those without the postpartum disease (NP [-], n = 45) and those with postpartum disease (NP [+], n = 45). Likewise, two subgroups were created among D cows: those without postpartum disease (D [-], n = 45) and those with postpartum disease (D [+], n = 45). Cytokine analyses were performed using species-specific commercial ELISA kits. In the NP (-) group, it was found that Th1/Th2 cytokine polarisation was in the Th1 direction due to the increase in the concentration of IFN-γ, TNF-α and IL-2 in four subgroups grouping with different types of parturition and diseases. It was concluded that it would be appropriate to strengthen cellular immunity. In cases of postpartum diseases, Th1/Th2 polarisation shifted towards Th2 due to the increase in IL-4 and IL-5 concentrations in cows that performed NP and developed mastitis in the postpartum period. These results suggest that it would be beneficial to support the Th2 aspect (i.e. humoral immunity) in cows that have undergone NP and develop mastitis in the postpartum period.

Pharmacological inhibition of P300 with C646 ameliorates LPS-induced acute lung injury by modulating CXCL1 in M1 alveolar macrophages.

Acute lung injury (ALI) is an excessive inflammatory condition with the involvement of M1 alveolar macrophage (AM) polarization. Given the high mortality rate of ALI, elucidating its underlying mechanisms is crucial for identifying therapeutic targets. Inhibition of P300, a lysine acetyltransferase, has illustrated the potential to alleviate inflammatory diseases through the regulation of immune cell activation. However, little is known whether P300 inhibition could ameliorate ALI through regulating the polarization of M1 AMs. We established an LPS-induced ALI model and evaluated the effects of the P300 inhibitor C646 on pulmonary pathology, inflammation and M1 AM polarization via H&E staining, ELISA and flow cytometry. Additionally, the specific inflammatory mediators regulated by P300 in M1 AMs affecting ALI were analyzed by RNA sequencing and validated by intratracheal instillation experiment. Intratracheal instillation of LPS resulted in neutrophil accumulation within the pulmonary alveoli and interstitial areas, along with increased levels of total inflammatory cells and IL-1β in the lung. However, administration of C646 ameliorated these pulmonary pathology and inflammation, accompanied by a diminished proportion and quantity of M1 AMs in BALF. Furthermore, by taking the intersection of P300-targeted genes in macrophages from the Cistrome, genes upregulated after M1 polarization of AMs, and genes downregulated following C646 treatment in M1 AMs, we identified 'Cxcl1' among the intersecting genes. Also, intratracheal instillation of CXCL1 aggravated pulmonary pathology and inflammation in C646 treated-ALI models. Our study suggested that pharmacological inhibition of P300 with C646 ameliorated LPS-induced ALI by modulating CXCL1 in M1 AMs.

IRF1-RIG-I signaling defects in the aged alveolar epithelial cells may contribute to decreased pulmonary antiviral immune responses.

Alveolar epithelial cells (AECs) are the primary targets of many pathogens and play an important role in sensing viruses and regulating immunity. Yet, little is known about the antiviral responses in the aged AECs. The responses of young or aged AECs after viral infection were analyzed using methods such as flow cytometry, quantitative real-time PCR, Western blot detection, and transwell chemotaxis assay. Deep sequencing and KEGG analysis were used to identify key pathways and genes associated with aged AECs, followed by functional analysis. The retinoic acid-inducible gene I (RIG-I) signaling is defective in aged AECs after influenza A virus (IAV) infection. The interferon regulatory factor 1 (IRF1) binds the promoter of RIG-I gene Ddx58 to activate its expression. The regulation of IRF1 is also defective in AECs from aged mice. Fewer NK cells, monocytes, and T cells are recruited by the cell supernatant from PR8-infected aged AECs. Importantly, IRF1-RIG-I signaling is also impaired in the AECs of elderly people after IAV infection. Ageing impairs IRF1-RIG-I signaling in AECs, and the defective responses in AECs may contribute to reduced immune cell recruitment and activation in aged individuals after pulmonary viral infection.

Exploring Antibacterial Activity of Fish Protein Hydrolysate In Vitro Against Vibrio Strains and Disease Resistance to V. harveyi in Turbot (Scophthalmus maximus)

This study was to investigate the in vitro antimicrobial activity of fish protein hydrolysate (FPH) against Vibrio harveyi, V. anguillarum, and V. scophthalmi, as well as the nonspecific immunity, intestinal microbiota, and disease resistance to V. harveyi in turbot. FPH was prepared from Pollock. The antibacterial activity of FPH was measured by the agar well diffusion, turbidometric assay, and plate count. The feeding trial was performed to study the effect of FPH on the resistance against V. harveyi in turbot after feeding three diets containing a high level of fish meal (FM), a high level of soybean meal (SM), and 100 g/kg FPH. Agar well diffusion showed the clearest inhibition zone of FPH was observed against V. harveyi, followed by V. scophthalmi. The bacterial growth curve and plate count showed a slight antibacterial effect of FPH against V. anguillarum. Results of the feeding trial showed that FPH enhanced antioxidant and immune responses before V. harveyi challenge as modulating immunoglobulin M (IgM), catalase (CAT), and myeloperoxidase (MPO) activities in serum, as well as the number of goblet cells in the intestine. Meanwhile, the expression of some pro‐inflammatory cytokines (interleukin‐1β [il-1β], il-6, and il-8) was downregulated in the FPH group after the V. harveyi challenge. Survival probability in the FPH group increased after challenging to V. harveyi based on the Kaplan–Meier analysis. Results of intestinal microbiota showed the relative abundance of Vibrio in the SM group was the highest, followed by the FPH and control groups. Similarly, the relative abundance of distal intestinal V. harveyi was significantly reduced in the FPH group by analyzing the vhhp2 gene. In conclusion, the present FPH against Vibrio strains was species‐specific, with stronger antibacterial activity to V. harveyi. Dietary FPH enhanced the nonspecific immunity and antibacterial activity of turbot, increasing the resistance to V. harveyi.

First-in-human phase I trial of the bispecific CD47 inhibitor and CD40 agonist Fc-fusion protein, SL-172154 in patients with platinum-resistant ovarian cancer

BackgroundSL-172154 is a hexameric fusion protein adjoining the extracellular domain of SIRPα to the extracellular domain of CD40L via an inert IgG4-derived Fc domain. In preclinical studies, a murine equivalent...

Innovating chitosan-based bioinks for dermal wound healing: Current progress and future prospects.

The field of three-dimensional (3D) bio/printing, known as additive manufacturing (AM), heavily relies on bioinks possessing suitable mechanical properties and compatibility with living cells. Among the array of potential hydrogel precursor materials, chitosan (CS) has garnered significant attention due to its remarkable physicochemical and biological attributes. These attributes include biodegradability, nontoxicity, antimicrobial properties, wound healing promotion, and immune system activation, making CS a highly appealing hydrogel-based bioink candidate. This review explores the transformative potential of CS-based bioink for enhancing dermal wound healing therapies. We highlight CS's unique qualities that make it an optimal choice for bioink development. Advancements in 3D bio/printing technology for tissue engineering (TE) are discussed, followed by an examination of strategies for CS-based bioink formulation and their impacts on wound healing. To address the progress in translating advanced wound healing from lab to clinic, we highlight the current and ongoing research in CS-based bioink for 3D bio/printing in skin wound healing applications. Finally, we explore current evidence, commercialization prospects, emerging innovations like 4D printing, and the challenges and future directions in this promising field.

Vitamin D and Tinospora cordifolia modulate TLR3 and TLR4 pathways, reduce inflammation, and maintain antimicrobial peptide levels in infected mice

The activation of Toll-Like Receptor-3 (TLR3) and Toll-Like Receptor-4 (TLR4) signalling pathways is a regular pathway for immune system activation during infection. This study aimed to investigate the effects of vitamin D (VD) and Tinospora cordifolia ethanol extract (TC) on TLR3 and TLR4 receptor protein expression, proinflammatory cytokine (IL1 and IL-6) production, and antimicrobial peptide cathelicidin (CAP) production in CD11b+ cells of mice infected with Escherichia coli. The treatments consisted of administration of VD (0.325 µg/kg bw), TC (100 mg/kg bw), and a combination of both in the same dose for 28 days, followed by induction of E. coli infection on day 29. The flow cytometry method was analyzed of TLR3, TLR4, IL-1, IL-6, and CAP expression in CD11b+ cells of experimental animals. The following measurement results were compared with healthy controls and infected animals with the significance of differences between treatments analyzed by One-way ANOVA with p < 0.05. The results showed that administering VD, TC, and a combination of both reduced the expression of TLR3, TLR4, and IL-1 compared to treating infected animals. The combination treatment of VD + TC increased CAP production more than all other treatments. This significant finding suggests that the combination of VD + TC has the potential to control inflammation without disrupting the body’s defence mechanisms against infection, providing valuable insights for the field of immunology.

Lung-targeted delivery of PTEN mRNA combined with anti-PD-1-mediated immunotherapy for In Situ lung cancer treatment.

mRNA-based protein replacement therapy has become one of the most widely applied forms of mRNA therapy, with lipid nanoparticles (LNPs) being extensively studied as efficient delivery platforms for mRNA. However, existing LNPs tend to accumulate in the liver or kidneys after intravenous injection, highlighting the need to develop vectors capable of targeting specific organs. In this study, we synthesized a small library of ionizable lipids and identified PPz-2R1 as a promising candidate, exhibiting lung-targeting capabilities, high mRNA transfection efficiency, and good stability through structure-activity relationship studies. In an in situ lung cancer model with PTEN deletion, precise delivery of PTEN mRNA to the lungs restored the cancer-suppressing function of the PTEN protein and successfully alleviated the immunosuppressive tumor microenvironment in the lungs by modulating immune cell activity and cytokine levels. Additionally, the upregulation of PD-L1 expression at the tumor site was triggered. Building on this, in vivo treatment with PTEN mRNA combined with anti-PD-1 therapy was tested in tumor-bearing mice. The results demonstrated that the combined treatment strategy effectively overcame immune escape, promoted T cell infiltration, improved survival rates over 60 days, and significantly inhibited tumor growth. Furthermore, the combination treatment was more effective than either therapy alone. This study presents an effective and practical strategy for the targeted treatment of lung diseases and relevant combination therapies. STATEMENT OF SIGNIFICANCE: Lipid nanoparticles (LNPs) have been extensively studied as efficient delivery vectors for mRNA. However, it remains essential to develop vectors that can specifically target distinct organs. In this study, we designed and synthesized a series of piperazine-containing ionizable lipids and their analogues, which were initially explored as lung-targeting vectors for PTEN mRNA delivery. Through screening in both in vitro and in vivo experiments, we found that the leading LNPs-assisted PTEN mRNA-mediated protein supplementation therapy effectively downregulated Treg expression and activated immune cells, thereby reversing the immunosuppressive tumor microenvironment in a mouse model of lung cancer. Furthermore, when combined with anti-PD-1-mediated immunotherapy, the combination therapy exhibited the strongest tumor growth inhibition. This approach offers a novel strategy for the targeted treatment of lung diseases and associated combination therapies.

The Application of Traditional Chinese Medicine-Derived Formulations in Cancer Immunotherapy: A Review.

Cancer immunotherapy is an advanced therapeutic approach that harnesses the body's immune system to target and eliminate tumor cells. Traditional Chinese medicine (TCM), with a history rooted in centuries of clinical practice, plays a crucial role in enhancing immune responses, alleviating cancer-related symptoms, and reducing the risks of infections and complications in cancer patients. This review systematically examines the current literature on TCM-based formulations in cancer immunotherapy. It explores the mechanisms by which TCM augments immune responses, particularly focusing on how these formulations influence both innate and adaptive immunity. Various TCM herbs and compounds, their active ingredients, and their application in cancer prevention and treatment were analyzed through an integrated review of preclinical studies, clinical trials, and molecular mechanistic investigations. TCM formulations contribute to cancer therapy by modulating the body's internal environment to improve immune defense. They enhance the immune system's ability to detect and destroy cancer cells, promote apoptosis in tumor cells, inhibit tumor growth and metastasis, and augment the effectiveness of conventional cancer treatments. The review highlights specific TCM herbs and formulations that have demonstrated significant anti-cancer properties, including their ability to strengthen immune responses and provide synergistic effects with existing cancer therapies. TCM-derived formulations represent a promising addition to cancer immunotherapy. The mechanisms through which these formulations enhance anti-tumor immunity are multifaceted, involving modulation of immune cell activity, apoptosis induction, and suppression of tumor progression. As cancer immunotherapy evolves, the integration of TCM into conventional treatment regimens may offer enhanced therapeutic efficacy, reduced side effects, and improved overall outcomes for cancer patients. Further clinical research is needed to fully elucidate the therapeutic potential and safety of TCM-based immunotherapeutic strategies in cancer care.

From Pioneering Discoveries to Innovative Therapies: A Journey Through the History and Advancements of Nanoparticles in Breast Cancer Treatment.

Nanoparticle technology has revolutionized breast cancer treatment by offering innovative solutions addressing the gaps in traditional treatment methods. This paper aimed to comprehensively explore the historical journey and advancements of nanoparticles in breast cancer treatment, highlighting their transformative impact on modern medicine. The discussion traces the evolution of nanoparticle-based therapies from their early conceptualization to their current applications and future potential. We initially explored the historical context of breast cancer treatment, highlighting the limitations of conventional therapies, such as surgery, radiation, and chemotherapy. The advent of nanotechnology has introduced a new era characterized by the development of various nanoparticles, including liposomes, dendrimers, and gold nanoparticles, designed to target cancer cells with remarkable precision. We further described the mechanisms of action for nanoparticles, including passive and active targeting, and reviewed significant breakthroughs and clinical trials that have validated their efficacy. Current applications of nanoparticles in breast cancer treatment have been examined, showcasing clinically approved therapies and comparing their effectiveness with traditional methods. This article also discusses the latest advancements in nanoparticle research, including drug delivery systems and combination therapy innovations, while addressing the current technical, biological, and regulatory challenges. The technical challenges include efficient and targeted delivery to tumor sites without affecting healthy tissue; biological, such as potential toxicity, immune system activation, or resistance mechanisms; economic, involving high production and scaling costs; and regulatory, requiring rigorous testing for safety, efficacy, and long-term effects to meet stringent approval standards. Finally, we have explored emerging trends, the potential for personalized medicine, and the ethical and social implications of this transformative technology. In conclusion, through comprehensive analysis and case studies, this paper underscores the profound impact of nanoparticles on breast cancer treatment and their future potential.

Targeting protein modification: a new direction for immunotherapy of pancreatic cancer.

Post-translational modifications (PTMs) alter protein conformation by covalently attaching functional groups to substrates, influencing their biological activity, mechanisms of action, and functional performance. PTMs and their interactions are essential to many critical signal transduction processes, including tumor transformation, cancer progression, and metastasis in pancreatic cancer. Additionally, advancements in tumor immunotherapy indicate that PTMs are essential in immune cell activation, transport, and energy metabolism. This study aimed to investigate the effects of different PTMs on immunotherapy for pancreatic cancer, providing new perspectives and suggesting directions for future research.

Discovery and exploration of adaptive immune response-related drug targets in diabetic retinopathy by Mendelian randomization

Discovery and exploration of adaptive immune response-related drug targets in diabetic retinopathy by Mendelian randomization

Unraveling the ROS-Inflammation-Immune Balance: A New Perspective on Aging and Disease.

Increased entropy is a common cause of disease and aging. Lifespan entropy is the overall increase in disorder caused by a person over their lifetime. Aging leads to the excessive production of reactive oxygen species (ROS), which damage the antioxidant system and disrupt redox balance. Organ aging causes chronic inflammation, disrupting the balance of proinflammatory and anti-inflammatory factors. Inflammaging, which is a chronic low-grade inflammatory state, is activated by oxidative stress and can lead to immune system senescence. During this process, entropy increases significantly as the body transitions from a state of low order to high disorder. However, the connection among inflammation, aging, and immune system activity is still not fully understood. This review introduces the idea of the ROS-inflammation-immune balance for the first time and suggests that this balance may be connected to aging and the development of age-related diseases. We also explored how the balance of these three factors controls and affects age-related diseases. Moreover, imbalance in the relationship described above disrupts the regular structures of cells and alters their functions, leading to cellular damage and the emergence of a disorganized state marked by increased entropy. Maintaining a low entropy state is crucial for preventing and reversing aging processes. Consequently, we examined the current preclinical evidence for antiaging medications that target this balance. Ultimately, comprehending the intricate relationships between these three factors and the risk of age-related diseases in organisms will aid in the development of clinical interventions that promote long-term health.

Single-cell transcriptomics identifies the common perturbations of monocyte/macrophage lineage cells in inflammaging of bone marrow.

Bone marrow inflammaging is a low-grade chronic inflammation that induces bone marrow aging. Multiple age-related and inflammatory diseases involve bone marrow inflammaging. Whether common pathological pathways exist in bone marrow inflammaging remains unclear. We collected bone marrow from telomerase-deficient mice (telomerase RNA component, TERCko/ko), 5×FAD mice and Dmp1 Cre -DTA ki/wt mice and High-fat diet-fed mice (HFD), and lumbar 5 nerve compression mice. We performed scRNA-Seq analysis on bone marrow obtained from these mouse models to investigate the potential shared pathway of bone marrow inflammation. We identified the monocyte/macrophage lineage was activated via the App-Cd74 axis in multiple aging and inflammatory mouse models. Increased expression of CD38 and Ly6a, and decreased expression of Col1a and Lif in macrophages serve as shared changes in different mouse models. The activated macrophages, interacting with other cells, control the expansion of B cells via the CD52-Siglec-G axis. The Ccl6-Ccr2 and Ccl9-Ccr1 ligand-receptor pairs, along with Fn1 and C3-related pathways in macrophages, were associated with immune cell activation and the recruitment of lymphocytes. Interactions with mesenchymal cells were enriched for integrins (Itga4), Fn1, and adhesion molecules (Vcam1). Our study demonstrates that monocyte/macrophage lineage stimulation is a key event in bone marrow inflammaging. We identified common differentially expressed genes and activated pathways in this lineage, suggesting potential targets for future interventions. Our study revealed shared genes and ligand-receptor pairs in the activated monocyte/macrophage lineage within inflammaging bone marrow. These findings offer potential therapeutic targets for cell-specific anti-inflammatory treatments.