Repetitive traumatic brain injury-induced complement C1-related inflammation impairs long-term hippocampal neurogenesis.

JOURNAL/nrgr/04.03/01300535-202503000-00027/figure1/v/2024-06-17T092413Z/r/image-tiff Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus, leading to long-term cognitive impairment. However, the mechanism underlying this neurogenesis impairment remains unknown. In this study, we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury. Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development, delayed neuronal maturation, and reduced the complexity of neuronal dendrites and spines. Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval. Moreover, following repetitive traumatic brain injury, neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased, C1q binding protein levels were decreased, and canonical Wnt/ß-catenin signaling was downregulated. An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function. These findings suggest that repetitive traumatic brain injury-induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.

Histone methylation modification and diabetic kidney disease: Potential molecular mechanisms and therapeutic approaches (Review).

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end­stage renal disease, and is characterized by persistent proteinuria and decreased glomerular filtration rate. Despite extensive efforts, the increasing incidence highlights the urgent need for more effective treatments. Histone methylation is a crucial epigenetic modification, and its alteration can destabilize chromatin structure, thereby regulating the transcriptional activity of specific genes. Histone methylation serves a substantial role in the onset and progression of various diseases. In patients with DKD, changes in histone methylation are pivotal in mediating the interactions between genetic and environmental factors. Targeting these modifications shows promise in ameliorating renal histological manifestations, tissue fibrosis and proteinuria, and represents a novel therapeutic frontier with the potential to halt DKD progression. The present review focuses on the alterations in histone methylation during the development of DKD, systematically summarizes its impact on various renal parenchymal cells and underscores the potential of targeted histone methylation modifications in improving DKD outcomes.

Identification and characterization of Lacticaseibacillus rhamnosus HP-B1083-derived ß-glucuronidase and its application for baicalin biotransformation.

Baicalein, showing higher bioavailability and stronger pharmacological activity, can be obtained via a ß-glucuronidase (GUS)-catalyzed transformation of baicalein 7-O-ß-D-glucuronide (baicalin). Recently, we have found that the fermentation broth of Lacticaseibacillus rhamnosus HP-B1083 can efficiently convert baicalin to baicalein. In this study, the L. rhamnosus HP-B1083-derived enzyme involved in baicalin biotransformation was identified and characterized. First, the LruidA gene, encoding the responsible enzyme, was cloned and sequenced. Sequence analysis revealed that the deduced enzyme (designated as LrUidA) belonged to the glycosyl hydrolase family 2. The recombinant LrUidA was expressed and purified for characterization. LrUidA had a molecular weight of 70 kDa, with an optimal temperature of 50 °C and pH 4.5. Although LrUidA was susceptible to temperature, it possessed a relative pH stability. Its Michaelis-Menten constant, maximum reaction velocity and catalytic constant values were 9.710 mM, 13.08 mM/min/mg, and 14.95 s-1, respectively. Site-directed mutagenesis experiment results demonstrated that the enzyme reaction uses side chains of E509 and E415 to hydrolyze the glycosidic bond of baicalin and involves three negatively charged residues, E450, D451, and D452, respectively. Surprisingly, biotransformation was performed under optimized reaction conditions by incubating the purified enzyme with 0.1 % baicalin for 4 h, resulting in a considerable conversion ratio of 99 %. Altogether, our findings provide insights into the properties of L. rhamnosus HP-B1083-derived enzyme and expand our understanding regarding using GUS for the industrial production of baicalein.

The ZDHHC13/ZDHHC17 subfamily: From biological functions to therapeutic targets of diseases.

The ZDHHC13/ZDHHC17 subfamily belongs to the zinc finger DHHC-domain containing (ZDHHC) family, including ZDHHC13 and ZDHHC17. Recent studies have shown that the ZDHHC13/ZDHHC17 subfamily is involved in various pathological and physiological processes, including S-palmitoylation, Mg2+ transport, and CALCOCO1-mediated Golgiphagy. Moreover, the ZDHHC13/ZDHHC17 subfamily plays a crucial role in the occurrence and development of many diseases, including Huntington disease (HD), osteoporosis, atopic dermatitis, diabetes, and cancer. In the present review, we describe the distribution, structure, and post-translational modifications (PTMs) of the ZDHHC13/ZDHHC17 subfamily. Moreover, we effectively summarize the biological functions and associated diseases of this subfamily. Given the pleiotropy of the ZDHHC13/ZDHHC17 subfamily, it is imperative to conduct further research on its members to comprehend the pertinent pathophysiological mechanisms and to devise tactics for managing and controlling various diseases.

Intercellular Mitochondrial Transfer: The Novel Therapeutic Mechanism for Diseases.

Mitochondria, the dynamic organelles responsible for energy production and cellular metabolism, have the metabolic function of extracting energy from nutrients and synthesizing crucial metabolites. Nevertheless, recent research unveils that intercellular mitochondrial transfer by tunneling nanotubes, tumor microtubes, gap junction intercellular communication, extracellular vesicles, endocytosis and cell fusion may regulate mitochondrial function within recipient cells, potentially contributing to disease treatment, such as nonalcoholic steatohepatitis, glioblastoma, ischemic stroke, bladder cancer and neurodegenerative diseases. This review introduces the principal approaches to intercellular mitochondrial transfer and examines its role in various diseases. Furthermore, we provide a comprehensive overview of the inhibitors and activators of intercellular mitochondrial transfer, offering a unique perspective to illustrate the relationship between intercellular mitochondrial transfer and diseases.

Autophagy receptor-inspired chimeras: a novel approach to facilitate the removal of protein aggregates and organelle by autophagy degradation. / 自噬受体激发嵌合体：一种通过自噬降解促进蛋白质聚集体和细胞器去除的新方法.

Neurodegenerative diseases (NDDs), mainly including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD), are sporadic and rare genetic disorders of the central nervous system. A key feature of these conditions is the slow accumulation of misfolded protein deposits in brain neurons, the excessive aggregation of which leads to neurotoxicity and further disorders of the nervous system.

Time to lymphoma treatment within 24 months in 'watch and wait' follicular lymphoma is associated with inferior outcomes: A multicentre analysis.

Some 'watch and wait' (W&W) FL patients suffer from rapid progression in a short term. Herein, we sought to identify these patients and also develop a risk score to screen them at diagnosis. Between 2008 and 2022, a total of 411 FL patients managed by the W&W strategy from 16 cancer centres were retrospectively enrolled in this study, and their time to lymphoma treatment (TLT) and progression-free survival (PFS) were evaluated. Thirty-five percent of W&W FL patients experienced TLT within 24 months (TLT24) after diagnosis. Their 5-year PFS rate was significantly lower than those without treatment at 24 months (62.3% vs. 89.5%). In multivariable analysis, five factors were identified as independent predictors of TLT24: stages III-IV, ß2 microglobulin ≥3 mg/L, lymphocyte-to-monocyte ratio <3.8, bone marrow involvement and spleen enlargement (above umbilical line). Their AUCs for TLT24 were 0.76 (95% CI, 0.70-0.82) in the training cohort and 0.76 (95% CI, 0.67-0.85) in the validation cohort respectively. Risk groups were also associated with PFS (p < 0.001). In FL patients initially managed by W&W, TLT24 was associated with poor outcomes. This multivariable model helps screening for predicting TLT24, which may be useful to identify candidates for early interventional treatment.

Streptococcus anginosus: A new pathogen of superficial gastritis, atrophic gastritis and gastric cancer.

A wealth of research indicates that superficial gastritis (SG) and atrophic gastritis (AG) are precursors to gastric cancer (GC). While Helicobacter pylori (H. pylori) has long been recognized as a key player in GC development, recent findings by Fu et al. have identified Streptococcus anginosus (S. anginosus) as an emerging pathogen that can trigger SG, AG and GC. S. anginosus, a gram-positive coccus, leverages its surface protein T. pallidum membrane protein C (TMPC) to engage with the annexin A2 (ANXA2) receptor of gastric epithelial cells, facilitating its colonization and invasion in the gastric mucosa. This leads to an upregulation of proinflammatory chemokines Ccl20 and Ccl8, causing prolonged effects on gastric barrier function and microbiota homeostasis, leading to SG. Moreover, these bacteria activate the mitogen-activated protein kinase (MAPK) signaling pathway, which is associated with the development of AG and GC. Importantly, inhibiting TMPC or knocking down ANXA2 can reduce S. anginosus colonization and invasion, lowering the chances of SG, AG, and GC. This paper highlights the molecular mechanisms of S. anginosus in SG, AG and GC, emphasizing the importance of a multi-pathogen strategy in gastric disease management and the need for further investigation into the role of S. anginosus in GC progression.

The S-Nitrosylation of Septin2 (SNO-Septin2) axis: A novel potential therapeutic target for treating aneurysms and dissection.

Aortic aneurysm and aortic dissection (AAD) are severe life-threatening cardiovascular disorders for which no approved pharmaceutical therapies are currently available. Protein S-nitrosylation (SNO) is a typical redox-dependent posttranslational modification whose role in AAD has yet to be described. Recently, Zhang et al. revealed for the first time that SNO modification of macrophage cytoskeletal protein septin2 promotes vascular inflammation and extracellular matrix degradation in aortic aneurysm. Mechanically, the TIAM1-RAC1(T lymphoma invasion and metastasis-inducing protein 1-Ras-related C3 botulinum toxin substrate 1) axis participates in the progression of AAD induced with S-nitrosylated septin2. More importantly, developing R-ketorolac and NSC23766 compounds that specifically target the TIAM1-RAC1 pathway may be new a potential strategy for alleviating AAD.

Metabolic pathway-based subtyping reveals distinct microenvironmental states associated with diffuse large B-cell lymphoma outcomes.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease that requires personalized clinical treatment. Assigning patients to different risk categories and cytogenetic abnormality and genetic mutation groups has been widely applied for prognostic stratification of DLBCL. Increasing evidence has demonstrated that dysregulated metabolic processes contribute to the initiation and progression of DLBCL. Metabolic competition within the tumor microenvironment is also known to influence immune cell metabolism. However, metabolism- and immune-related stratification has not been established. Here, 1660 genes involved in 84 metabolic pathways were selected and tested to establish metabolic clusters (MECs) of DLBCL. MECs established based on independent lymphoma datasets distinguished different survival outcomes. The CIBERSORT algorithm and EcoTyper were applied to quantify the relative abundance of immune cell types and identify variation in cell states for 13 lineages comprising the tumor micro environment among different MECs, respectively. Functional characterization showed that MECs were an indicator of the immune microenvironment and correlated with distinctive mutational characteristics and oncogenic signaling pathways. The novel immune-related MECs exhibited promising clinical prognostic value and potential for informing DLBCL treatment decisions.

CD58 Alterations Govern Antitumor Immune Responses by Inducing PDL1 and IDO in Diffuse Large B-Cell Lymphoma.

Recurrent abnormalities in immune surveillance-related genes affect the progression of diffuse large B-cell lymphoma (DLBCL) and modulate the response to therapeutic interventions. CD58 interacts with the CD2 receptor on T cells and NK cells and is recurrently mutated and deleted in DLBCL, suggesting that it may play a role in regulating antitumor immunity. In this study, we comprehensively analyzed the genomic characteristics of CD58 through targeted next-generation sequencing, RNA sequencing (RNA-seq), whole-exome sequencing, and single-cell RNA-seq in patients with newly diagnosed DLBCL. The CD58 mutation rate was 9.1%, and the copy number loss rate was 44.7% among all enrolled patients with DLBCL. Notably, CD58 genetic alterations, along with low CD58 expression, significantly correlated with reduced rates of response to R-CHOP therapy and inferior progression-free survival and overall survival. Single-cell RNA-seq revealed that CD58 expression in tumor cells was negatively correlated with CD8+ T-cell exhaustion/dysfunction status. Insufficient T-cell activation resulting from CD58 alterations could not be attributed solely to CD2 signaling. CD58 inhibited the activity of the JAK2/STAT1 pathway by activating the LYN/CD22/SH2 domain-containing phosphatase 1 (SHP1) axis, thereby limiting PDL1 and IDO expression. Elevated PDL1 and IDO expression in CD58-deficient DLBCL cells led to immune evasion and tumor-intrinsic resistance to chimeric antigen receptor T-cell therapy. Direct activation of CD58-CD2 costimulatory signaling in combination with anti-PDL1 blockade or IDO inhibitor sensitized CD58-deficient DLBCL to chimeric antigen receptor T-cell therapy. Collectively, this work identified the multiple roles of CD58 in regulating antitumor immune responses in DLBCL. Significance: Loss of CD58 mediates immune evasion and therapy resistance in diffuse large B-cell lymphoma by upregulating PDL1 and IDO through LYN/CD22/SHP1 signaling, providing potential targets and therapeutic strategies to improve patient treatment.

Molecular mechanisms of secretory autophagy and its potential role in diseases.

Autophagy is a cellular degradation system that recycles or degrades damaged organelles, viral particles, and aggregated proteins through the lysosomal pathway. Autophagy plays an indispensable role in cellular homeostasis and communication processes. An interesting aspect is that autophagy also mediates the secretion of cellular contents, a process known as secretory autophagy. Secretory autophagy differs from macroautophagy, which sequesters recruited proteins, organelles, or viral particles into autophagosomes and degrades these sequesters in lysosomes, while the secretory autophagy pathway participates in the extracellular export of cellular contents sequestered by autophagosomes through autophagy and endosomal modulators. Recent evidence reveals that secretory autophagy is pivotal in the occurrence and progression of diseases. In this review, we summarize the molecular mechanisms of secretory autophagy. Furthermore, we review the impact of secretory autophagy on diseases, including cancer, viral infectious diseases, neurodegenerative diseases, and cardiovascular diseases. Considering the pleiotropic actions of secretory autophagy on diseases, studying the mechanism of secretory autophagy may help to understand the relevant pathophysiological processes.

Cost-Effectiveness of First-Line Atezolizumab versus Chemotherapy in Non-Small-Cell Lung Cancer Patients Ineligible for Platinum-Containing Regimens.

Purpose: The IPSOS study provided evidence supporting the efficacy and tolerability of first-line atezolizumab compared to single-agent chemotherapy for non-small-cell lung cancer (NSCLC) patients ineligible for treatment with a platinum-containing regimen. This study aimed to assess the cost-effectiveness of atezolizumab specifically in this population, considering the perspective of the Chinese healthcare system. Patients and Methods: In this analysis, a three-state Markov model was utilized. The survival data were derived from the IPSOS clinical trial. Direct medical costs and utility values were collected from national authoritative database and published literature. The primary outcomes were costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). To ensure the robustness of our model, both one-way and probabilistic sensitivity analyses were conducted. Results: Atezolizumab monotherapy led to an increase in costs of $4139.23 compared to single-agent chemotherapy. Additionally, it resulted in a gain of 0.14 QALYs, leading to an ICER of $29,365.79 per QALY, which was below the willingness-to-pay threshold of $36,066 per QALY used in the model. One-way sensitivity analyses revealed cost of atezolizumab and utility of progressive disease (PD) as major influencing factors for ICER. Furthermore, probabilistic sensitivity analyses confirmed our base-case results. Conclusion: From the perspective of the Chinese healthcare system, atezolizumab emerges as a cost-effective choice for the first-line treatment of NSCLC patients ineligible for platinum-based chemotherapy.

Epidemiological features and prognosis for primary gastrointestinal follicular lymphoma.

Primary gastrointestinal follicular lymphoma (PGI-FL) is a rare extra-nodal lymphoma. Its epidemiology and prognosis remain unclear. We performed a retrospective analysis of eligible patients with 1648 PGI-FL and 34 892 nodal FL (N-FL) in the Surveillance, Epidemiology and End Results (SEER) database. The age-adjusted average annual incidence of PGI-FL was 0.111/100000. The median overall survival (OS) for PGI-FL and N-FL patients was 207 and 165 months respectively. The 5-year diffuse large B-cell lymphoma (DLBCL) transformation rates were 2.1% and 2.6% respectively. Age, sex, grade, Ann Arbor stage, primary site and radiation were independent prognostic factors (p < 0.05). Nomograms were constructed to predict 1-, 5- and 10-year OS and disease-specific survival (DSS). The receiver operating characteristic curves and calibration plots showed the established nomograms had robust and accurate performance. Patients were classified into three risk groups according to nomogram score. In conclusion, the incidence of PGI-FL has increased over the past 40 years, and PGI-FL has a better prognosis and a lower DLBCL transformation rate than N-FL. The nomograms were developed and validated as an individualized tool to predict survival. Patients were divided into three risk groups to assist clinicians in identifying high-risk patients and choosing the optimal individualized treatments.

ZIP transporters-regulated Zn2+ homeostasis: A novel determinant of human diseases.

As an essential trace element for organisms, zinc participates in various physiological processes, such as RNA transcription, DNA replication, cell proliferation, and cell differentiation. The destruction of zinc homeostasis is associated with various diseases. Zinc homeostasis is controlled by the cooperative action of zinc transporter proteins that are responsible for the influx and efflux of zinc. Zinc transporter proteins are mainly categorized into two families: Zrt/Irt-like protein (SLC39A/ZIP) family and zinc transporter (SLC30A/ZNT) family. ZIP transporters contain 14 members, namely ZIP1-14, which can be further divided into four subfamilies. Currently, ZIP transporters-regulated zinc homeostasis is one of the research hotspots. Cumulative evidence suggests that ZIP transporters-regulated zinc homeostasis may cause physiological dysfunction and contribute to the onset and progression of diverse diseases, such as cancers, neurological diseases, and cardiovascular diseases. In this review, we initially discuss the structure and distribution of ZIP transporters. Furthermore, we comprehensively review the latest research progress of ZIP transporters-regulated zinc homeostasis in diseases, providing a new perspective into new therapeutic targets for treating related diseases.

MST1/2: Important regulators of Hippo pathway in immune system associated diseases.

The Hippo signaling pathway is first found in Drosophila and is highly conserved in evolution. Previous studies on this pathway in mammals have revealed its key role in cell proliferation and differentiation, organ size control, and carcinogenesis. Apart from these, recent findings indicate that mammalian Ste20-like kinases 1 and 2 (MST1/2) have significant effects on immune regulation. In this review, we summarize the updated understanding of how MST1/2 affect the regulation of the immune system and the specific mechanism. The effect of MST1/2 on immune cells and its role in the tumor immune microenvironment can alter the body's response to tumor cells. The relationship between MST1/2 and the immune system suggests new directions in the manipulation of immune responses for clinical immunotherapy, especially for tumor treatment.