IL3-Driven T Cell-Basophil Crosstalk Enhances Antitumor Immunity.

Cytotoxic T lymphocytes (CTL) are pivotal in combating cancer, yet their efficacy is often hindered by the immunosuppressive tumor microenvironment, resulting in CTL exhaustion. This study investigates the role of interleukin-3 (IL3) in orchestrating antitumor immunity through CTL modulation. We found that intratumoral CTLs exhibited a progressive decline in IL3 production, which was correlated with impaired cytotoxic function. Augmenting IL3 supplementation, through intraperitoneal administration of recombinant IL3, IL3-expressing tumor cells, or IL3-engineered CD8+ T cells, conferred protection against tumor progression, concomitant with increased CTL activity. CTLs were critical for this therapeutic efficacy as IL3 demonstrated no impact on tumor growth in Rag1 knockout mice or following CD8+ T-cell depletion. Rather than acting directly, CTL-derived IL3 exerted its influence on basophils, concomitantly amplifying antitumor immunity within CTLs. Introducing IL3-activated basophils retarded tumor progression, whereas basophil depletion diminished the effectiveness of IL3 supplementation. Furthermore, IL3 prompted basophils to produce IL4, which subsequently elevated CTL IFNγ production and viability. Further, the importance of basophil-derived IL4 was evident from the absence of benefits of IL3 supplementation in IL4 knockout tumor-bearing mice. Overall, this research has unveiled a role for IL3-mediated CTL-basophil cross-talk in regulating antitumor immunity and suggests harnessing IL3 sustenance as a promising approach for optimizing and enhancing cancer immunotherapy. See related Spotlight, p. 798.

Neuroprotective Effect of α-Lipoic Acid against Aß25-35-Induced Damage in BV2 Cells.

The prevalence of Alzheimer's disease (AD) is significantly increasing due to the aging world population, and the currently available drug treatments cannot cure or even slow its progression. α-lipoic acid (LA) is a biological factor widely found in spinach and meat and can dissolve in both lipid and aqueous phases. In medicine, LA has been shown to reduce the symptoms of diabetic polyneuropathy, acute kidney injury, cancers, and some metabolism-related diseases. This study to proves that α-lipoic acid (LA) can stabilize the cognitive function of patients with Alzheimer's disease (AD). BV2 cells were divided into control, LA, Aß25-35, and LA + Aß25-35 groups. Cell growth; IL-6, IL-1ß, TNF-α, IFN-γ, SOD, GPx, CAT, ROS, NO, and iNOS secretion; Wnt-related proteins; cell apoptosis; and cell activation were examined. Here, we found that LA could effectively repress apoptosis and changes in the morphology of microglia BV2 cells activated by Aß25-35, accompanied by the inhibition of the inflammatory response induced by Aß25-35. The Wnt/ß-catenin pathway is also involved in preventing Aß25-35-induced cytotoxicity in microglia by LA. We found an inhibitory effect of LA on microglia toxicity induced by Aß25-35, suggesting that a combination of anti-inflammatory and antioxidant substances may offer a promising approach to the treatment of AD.

Mitochondria-associated endoplasmic reticulum membranes: A promising toxicity regulation target.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic suborganelle membranes that physically couple endoplasmic reticulum (ER) and mitochondria to provide a platform for exchange of intracellular molecules and crosstalk between the two organelles. Dysfunctions of mitochondria and ER and imbalance of intracellular homeostasis have been discovered in the research of toxics. Cellular activities such as oxidative stress, ER stress, Ca2+ transport, autophagy, mitochondrial fusion and fission, and apoptosis mediated by MAMs are closely related to the toxicological effects of various toxicants. These cellular activities mediated by MAMs crosstalk with each other. Regulating the structure and function of MAMs can alleviate the damage caused by toxicants to some extent. In this review, we discuss the relationships between MAMs and the mechanisms of toxicological effects, and highlight MAMs as a potential target for protection against toxicants.

The neuroprotective effects of alpha-lipoic acid on an experimental model of Alzheimer's disease in PC12 cells.

With the growth of the aging population, the prevalence of Alzheimer's disease (AD) has increased and influenced the work and daily life of AD patients, imposing a heavy burden on society and the patients' families. AD is a progressive disease with a long duration, and the pathogenesis is very complicated. Here, we found that alpha-lipoic acid (LA), an endogenous, naturally synthesized compound, could attenuate amyloid beta fragment (Aß25-35 )-induced PC12 cell toxicity. Aß25-35 treatment largely decreased the viability of PC12 cells, increased reactive oxygen species (ROS) levels, and increased the percentage of apoptotic cells, which were accompanied by changes in the expression of the apoptosis-related genes. Further, the Wnt pathway was inactivated, and the expression of Wnt pathway-related proteins such as Frizzled2, GSK3ß, and phosphorylated GSK3ß were dysregulated after Aß25-35 treatment. LA efficiently attenuated Aß25-35 -induced PC12 cell apoptosis and downregulated the phosphorylation-mediated degradation of ß-catenin as well as GSK3ß. Our results demonstrate that LA rescues Aß25-35 -induced neurocytotoxicity through the Wnt-ß-catenin pathway.

Transient receptor potential ankyrin 1 and calcium: Interactions and association with disease (Review).

Calcium (Ca2+) is an essential signaling molecule in all cells. It is involved in numerous fundamental functions, including cell life and death. Abnormal regulation of Ca2+ homeostasis may cause human diseases. Usually known as a member of the transient receptor potential (TRP) family, TRP ankyrin 1 (TRPA1) is the only member of the ankyrin subfamily identified in mammals so far and widely expressed in cells and tissues. As it is involved in numerous sensory disorders such as pain and pruritus, TRPA1 is a potential target for the treatment of neuropathy. The functions of TRP family members are closely related to Ca2+. TRPA1 has a high permeability to Ca2+, sodium and potassium ions as a non-selective cation channel and the Ca2+ influx mediated by TRPA1 is involved in a variety of biological processes. In the present review, research on the relationship between the TRPA1 channel and Ca2+ ions and their interaction in disease-associated processes was summarised. The therapeutic potential of the TRPA1 channel is highlighted, which is expected to become a novel direction for the prevention and treatment of health conditions such as cancer and neurodegenerative diseases.