The ultrafine powder of atractylodis macrocephalae rhizoma improves immune function in naturally aging rats by regulating the PI3K/Akt/NF-κB signaling pathway

BackgroundThe phenomenon of population aging presents a significant global challenge, with the aging population in China steadily increasing. As individuals progress in age, there is a gradual deterioration of human organs and systems, as well as a decline in the immune system, referred to as immunosenescence. Atractylodis macrocephalae rhizoma (BZ) has been historically used in China for its medicinal properties, including gastrointestinal improvement, immunomodulation, anti-aging, antioxidant effects, and anti-tumor effects. Nevertheless, there remains a gap in understanding the pharmacological and molecular mechanisms underlying its anti-immunosenescence effects.MethodsThis study employed UPLC-ESI-MS and network pharmacology to create a network map of BZ ultrafine powder (BZU) and its aging targets. Enrichment analysis was then used to identify the primary mechanistic pathways underlying BZU’s anti-immunosenescence effects. The primary components of BZU were quantitatively analyzed using high-performance liquid chromatography (HPLC). Naturally aging rats were used to examine the effects of different oral doses (0.25, 0.5, and 1 g/kg) of BZU over 5 weeks on aging performance, peripheral blood immunophenotyping and cell count, and splenic lymphocyte proliferation rate. To validate the findings of network pharmacology, quantitative RT-PCR, Western blotting, and immunofluorescence analyses were conducted.ResultsOur analyses demonstrated that BZU improved various indicators of aging in naturally aging rats, such as increasing the number of voluntary activities, enhance grip strength and fatigue resistance, increasing the microcirculatory blood flow and improving hematological levels. The BZU administration enhanced T and B lymphocyte proliferation and significantly improved the lymphocyte-to-T cell subpopulation ratio. It can elevate serum IL-2 and IL-4 levels while reducing IL-6, IFN-γ and TNF-α levels in naturally aging rats. Finally, it increased CD3 protein expression in the spleen while decreasing protein levels of PI3K, p-AKT, IKKα/β, and NF-κB. It also decreased the mRNA expression of Pik3cg, Akt1, Pdk1 and Nfκb1.ConclusionThese findings suggest that BZU may enhance lymphocyte proliferation by inhibiting the PI3K/Akt/NF-κB signaling pathway, correcting immune cell imbalances, reducing inflammatory responses, and ultimately enhancing immune function and potentially delaying aging

The off-target effects of AID in carcinogenesis

Activation-induced cytidine deaminase (AID) plays a crucial role in promoting B cell diversification through somatic hypermutation (SHM) and class switch recombination (CSR). While AID is primarily associated with the physiological function of humoral immune response, it has also been linked to the initiation and progression of lymphomas. Abnormalities in AID have been shown to disrupt gene networks and signaling pathways in both B-cell and T-cell lineage lymphoblastic leukemia, although the full extent of its role in carcinogenesis remains unclear. This review proposes an alternative role for AID and explores its off-target effects in regulating tumorigenesis. In this review, we first provide an overview of the physiological function of AID and its regulation. AID plays a crucial role in promoting B cell diversification through SHM and CSR. We then discuss the off-target effects of AID, which includes inducing mutations of non-Igs, epigenetic modification, and the alternative role as a cofactor. We also explore the networks that keep AID in line. Furthermore, we summarize the off-target effects of AID in autoimmune diseases and hematological neoplasms. Finally, we assess the off-target effects of AID in solid tumors. The primary focus of this review is to understand how and when AID targets specific gene loci and how this affects carcinogenesis. Overall, this review aims to provide a comprehensive understanding of the physiological and off-target effects of AID, which will contribute to the development of novel therapeutic strategies for autoimmune diseases, hematological neoplasms, and solid tumors

Lactylation as a cross-regulatory node in tumor metabolism and epigenetics: insights and therapeutic implications

Lactylation serves as a pivotal cross-regulatory mechanism linking tumor metabolic reprogramming and epigenetic regulation. This review comprehensively summarizes the mechanisms of lactylation writers, erasers, and readers, highlighting their tumor-specific functions, roles in immunosuppressive tumor microenvironment (TME) remodeling, and contributions to therapeutic resistance. Emerging targeting strategies, including metabolic inhibitors, epigenetic modulators, and combination immunotherapies, exhibit promising preclinical efficacy, highlighting their potential for clinical translation in overcoming therapy resistance and improving cancer immunotherapy

Molecular epidemiology and clone transmission of carbapenem-resistant <i>Acinetobacter baumannii</i> in ICU rooms

AbstractCarbapenem-resistant Acinetobacter baumannii (CRAB) is a major cause of nosocomial infections and hospital outbreaks worldwide, remaining a critical clinical concern. Here we characterized and investigated the phylogenetic relationships of 105 CRAB isolates on intensive care unit surfaces from one hospital in China collected over six years. All strains carried blaOXA-23, blaOXA-66 genes for carbapenem resistance, also had high resistance gene, virulence factor and insertion sequences burdens. Whole-genome sequencing revealed all strains belonged to ST2, the global clone CC2. The phylogenetic analysis based on the core genome showed all isolates was dominated by a single lineage of three clusters and eight different clones. Two clones were popular during the collection time. Using chi-square test to identify the epidemiologically meaningful groupings, we found the significant difference in community structure only present in strains from separation time. The haplotype and median-joining network analysis revealed genetic differences among clusters and changes occurred overtime in the dominating cluster. Our results highlighted substantial multidrug-resistant CRAB burden in hospital ICU environment, demonstrated potential clone outbreak in hospital.</jats:p

Synthesis and Biological Evaluation of PEGylated MWO4 Nanoparticles as Sonodynamic AID Inhibitors in Treating Diffuse Large B-Cell Lymphoma

Sonodynamic therapy (SDT) triggered by ultrasound (US) has attracted increasing attention owing to its ability to overcome critical limitations, including low tissue-penetration depth and phototoxicity in photodynamic therapy (PDT). Biogenic metal oxide nanoparticles (NPs) have been used as anti-cancer drugs due to their biocompatibility properties with most biological systems. Here, sonosensitizer MWO4-PEG NPs (M = Fe Mn Co Ni) were synthesized as inhibitors to activation-induced cytidine deaminase (AID), thus neutralizing the extensive carcinogenesis of AID in diffuse large B-cell lymphoma (DLBCL). The physiological properties of these nanomaterials were examined using transmission electron microscopy (TEM). The inhibition of NPs to AID was primarily identified by the affinity interaction prediction between reactive oxygen species (ROS) and AID through molecular dynamics and molecular docking technology. The cell apoptosis and ROS generation in US-triggered NPs treated DLBCL cells (with high levels of AID) were also detected to indicate the sonosensitivity and toxicity of MWO4-PEG NPs to DLBCL cells. The anti-lymphoma studies using DLBCL and AID-deficient DLBCL cell lines indicated a concentration-dependent profile. The synthesized MWO4-PEG NPs in this study manifested good sonodynamic inhibitory effects to AID and well treatment for AID-positive hematopoietic cancers

CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

In our previous studies, using a B cell vaccine (scFv-Her2), the targeting of tumor-associated antigen Her2 (human epidermal growth factor receptor-2) to B cells via the anti-CD19 single chain variable fragment (scFv) was shown to augment tumor-specific immunity, which enhanced tumor control in the prophylactic and therapeutic setting. However, the fusion protein displayed limited activity against established tumors, and local relapses often occurred following scFv-Her2 treatment, indicating that scFv-Her2-induced responses are inadequate to maintain anti-tumor immunity. In this study, targeting the IV region (D4) of the extracellular region of Her2 to B cells via CD19 molecules (scFv-Her2D4) was found to enhance IFN-γ-producing-CD8+ T cell infiltration in tumor tissues and reduced the number of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). However, negative co-stimulatory molecules such as programmed cell death protein-1 (PD-1), CD160, and LAG-3 on T cells and programmed death protein ligand-1 (PD-L1) on tumor cells were upregulated in the tumor microenvironment after scFv-Her2D4 treatment. Further, anti-PD1 administration enhanced the efficacy of scFv-Her2D4 and anti-tumor immunity, as evidenced by the reversal of tumor-infiltrating CD8+ T cell exhaustion and the reduction of MDSCs and Treg cells, which suppress T cells and alter the tumor immune microenvironment. Moreover, combining this with anti-PD1 antibodies promoted complete tumor rejection. Our data provide evidence of a close interaction among tumor vaccines, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and tumor vaccine therapy