Yan Zhong

Cancer immunotherapy harnesses the body's immune system to combat malignancies, building upon an understanding of tumor immunosurveillance and immune evasion mechanisms. This therapeutic approach reactivates anti-tumor immune responses and can be categorized into active, passive, and combined immunization strategies. Active immunotherapy engages the immune system to recognize and attack tumor cells by leveraging host immunity with cytokine supplementation or vaccination. Conversely, passive immunotherapy employs exogenous agents, such as monoclonal antibodies (anti-CTLA4, anti-PD1, anti-PD-L1) or adoptive cell transfers (ACT) with genetically engineered chimeric antigen receptor (CAR) T or NK cells, to exert anti-tumor effects. Over the past decades, CAR-T cell therapies have gained significant traction in oncological treatment, offering hope through their targeted approach. However, the potential adverse effects associated with CAR-T cells, including cytokine release syndrome (CRS), off-tumor toxicity, and neurotoxicity, warrant careful consideration. Recently, CAR-NK cell therapy has emerged as a promising alternative in the landscape of tumor immunotherapy, distinguished by its innate advantages over CAR-T cell modalities. In this review, we will synthesize the latest research and clinical advancements in CAR-NK cell therapies. We will elucidate the therapeutic benefits of employing CAR-NK cells in oncology and critically examine the developmental bottlenecks impeding their broader application. Our discussion aims to provide a comprehensive overview of the current status and future potential of CAR-NK cells in cancer immunotherapy.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammatory reactions and tissue damage in the joints. Long-term drug use in clinical practice is often accompanied by adverse reactions. Extracorporeal photopheresis (ECP) is an immunomodulatory therapy with few side effects, offering a potential and safe therapeutic alternative for RA through the induction of immune tolerance. This study aimed to investigate the therapeutic effects of ECP on RA using a collagen-induced arthritis (CIA) murine model, as well as to explore its immunomodulatory effects in vivo. Additionally, particular attention was given to the significant role of monocytes during the ECP process. METHODS: A murine model of rheumatoid arthritis was established by administering two injections of bovine type II collagen to DBA/1J mice. ECP, ECP-MD (mononuclear cells were depleted during the ECP), MTX, and PBS treatment were applied to the CIA mice. During the treatment process, clinical scores and body weight changes of CIA mice were closely monitored. After six treatment sessions, micro-CT images of the hind paws from live mice were captured. Ankle joints and paws of the mice were collected and processed for histological evaluation. Spleen samples were collected to measure the Th17/Treg cells ratio, and serum samples were collected to assess cytokine and anti-type II collagen IgG levels. Monocytes and dendritic cells populations before and after ECP in vitro were detected by flow cytometry. RESULT: ECP therapy significantly attenuated the progression of CIA, alleviated the severity of clinical symptoms in CIA mice and effectively suppressed synovial hyperplasia, inflammation, and cartilage damage. There was an expansion in the percentage of CD3 + CD4 + CD25 + FoxP3 + Tregs and a decrease in CD3 + CD4 + IL17A + Th17 cells in vivo. Furthermore, ECP reduced the serum levels of pro-inflammatory cytokines IL-6 (53.47 ± 7.074 pg/mL vs 5.142 ± 1.779 pg/mL, P < 0.05) and IL-17A (3.077 ± 0.401 pg/mL vs 0.238 ± 0.082 pg/mlL, P < 0.0001) compared with PBS. Interestingly, the depletion of monocytes during the ECP process did not lead to any improvement in clinical symptoms or histological scores in CIA mice. Moreover, the imbalance in the Th17/Treg cells ratio became even more pronounced, accompanied by an augmented secretion of pro-inflammatory cytokines IL-6 and IL-17A. In vitro, compared with cells without ECP treatment, the proportion of CD11b + cells were significantly reduced (P < 0.01), the proportion of CD11c + cells were significantly elevated (P < 0.001) 24 h after ECP treatment. Additionally, the expression of MHC II (P < 0.0001), CD80 (P < 0.01), and CD86 (P < 0.001) was downregulated in CD11c + cells 24 h after ECP treatment. CONCLUSION: Our study demonstrates that ECP exhibits a therapeutic effect comparable to conventional therapy in CIA mice, and the protective mechanisms of ECP against RA involve Th17/Treg cells ratio, which result in decreased IL-6 and IL-17A. Notably, monocytes derived from CIA mice are an indispensable part to the efficacy of ECP treatment, and the proportion of monocytes decreased and the proportion of tolerogenic dendritic cells increased after ECP treatment in vitro.

Objective Hyperuricaemia and gout are common metabolic disorders. However, the causal relationships between blood metabolites and serum urate levels, as well as gout, remain unclear. A systematic evaluation of the causal connections between blood metabolites, hyperuricemia, and gout could enhance early screening and prevention of hyperuricemia and gout in clinical settings, providing novel insights and approaches for clinical treatment. Methods In this study, we employed a bidirectional two-sample Mendelian randomization analysis utilizing data from a genome-wide association study involving 7,286 participants, encompassing 486 blood metabolites. Serum urate and gout data were sourced from the Chronic Kidney Disease Genetics consortium, including 288,649 participants for serum urate and 9,819 African American and 753,994 European individuals for gout. Initially, LDSC methodology was applied to identify blood metabolites with a genetic relationship to serum urate and gout. Subsequently, inverse-variance weighting was employed as the primary analysis method, with a series of sensitivity and pleiotropy analyses conducted to assess the robustness of the results. Results Following LDSC, 133 blood metabolites exhibited a potential genetic relationship with serum urate and gout. In the primary Mendelian randomization analysis using inverse-variance weighting, 19 blood metabolites were recognized as potentially influencing serum urate levels and gout. Subsequently, the IVW p-values of potential metabolites were corrected using the false discovery rate method. We find leucine (IVW P FDR = 0.00004), N-acetylornithine (IVW P FDR = 0.0295), N1-methyl-3-pyridone-4-carboxamide (IVW P FDR = 0.0295), and succinyl carnitine (IVW P FDR = 0.00004) were identified as significant risk factors for elevated serum urate levels. Additionally, 1-oleoylglycerol (IVW P FDR = 0.0007) may lead to a substantial increase in the risk of gout. Succinyl carnitine exhibited acceptable weak heterogeneity, and the results for other blood metabolites remained robust after sensitivity, heterogeneity, and pleiotropy testing. We conducted an enrichment analysis on potential blood metabolites, followed by a metabolic pathway analysis revealing four pathways associated with serum urate levels. Conclusion The identified causal relationships between these metabolites and serum urate and gout offer a novel perspective, providing new mechanistic insights into serum urate levels and gout.

Objective Observational studies have suggested an increased risk of cardiovascular disease in individuals with ankylosing spondylitis. However, these studies are prone to confounding factors and reverse causality. To address these limitations, we conducted a Mendelian randomization study to assess the causal relationship between AS and CVD. Methods The study population comprises 9,069 individuals with ankylosing spondylitis and 509,093 individuals with either of six common cardiovascular diseases and a related indicator. Causal analysis using summary effect estimates and inverse variance weighting were employed as the main methods. Results The CAUSE analysis showed no evidence of a causal relationship between AS and CVD. The odds ratios for total CVD, heart failure, myocardial infarction, valvular heart disease, ischemic heart disease, and venous thromboembolism, Arterial stiffness index, were as follows: OR, 1.01; 95% confidence interval, 0.96–1.05; P = 0.91; OR, 1.03; 95% CI, 0.99–1.08; P = 0.50; OR, 0.94; 95% CI, 0.86–1.03; P = 0.53; OR, 0.99; 95% CI, 0.94–1.04; P = 0.99; OR, 0.98; 95% CI, 0.91–1.04; P = 0.94; OR, 0.98; 95% CI, 0.91–1.04; P = 0.99; β, −0.0019; 95% CI, 0.97–1.01; P = 0.99. The IVW and weighted median methods also yielded consistent results, and no heterogeneity or pleiotropy was found. Likewise, a reverse Mendelian randomization analysis did not uncover a heritable causal relationship between AS and CVD. Conclusion This Mendelian randomization study does not support a causal relationship between AS and CVD. Further research is needed to confirm this association.

Antioxidant peptides derived from woody oil resource by-products exhibit strong free radical scavenging abilities and offer potential applications in functional foods, nutraceuticals, and cosmetics. This review summarizes the latest advances in preparation technologies, including enzymatic hydrolysis, microbial fermentation, chemical synthesis, recombinant expression, and molecular imprinting, each with distinct advantages in yield, selectivity, and scalability. The structure-activity relationships of antioxidant peptides are explored with respect to amino acid composition, molecular weight, and 3D conformation, which collectively determine their bioactivity and stability. Additionally, emerging delivery systems-such as nanoliposomes, microencapsulation, and cell-penetrating peptides-are discussed for their role in enhancing peptide stability, absorption, and targeted release. Mechanistic studies reveal that antioxidant peptides from woody oil resources act through network pharmacology, engaging core signaling pathways, including Nrf2/ARE, PI3K/Akt, AMPK, and JAK/STAT, to regulate oxidative stress, mitochondrial health, and inflammation. Preliminary safety data from in vitro, animal, and early clinical studies suggest low toxicity and favorable tolerability. The integration of omics technologies, molecular docking, and bioinformatics is accelerating the mechanism-driven design and functional validation of peptides. In conclusion, antioxidant peptides derived from woody oil resources represent a sustainable, multifunctional, and scalable solution for improving human health and promoting a circular bioeconomy. Future research should focus on structural optimization, delivery enhancement, and clinical validation to facilitate their industrial translation.