Prostate cancer remains a significant global health challenge, necessitating the development of novel therapeutic approaches. This study investigated the therapeutic potential of the Antrodia cinnamomea formula (XIANZHIFANG formula, XZF), comprising Antrodia cinnamomea, Sanghuangporus sanghuang, Ganoderma lucidum, Ganoderma sinense, and Inonotus obliquus, in prostate cancer treatment. HPLC analysis confirmed the presence of key triterpenoids, including Antcin A, B, C, K, and Zhankuic acid B, C, and 4,7-dimethoxy-5-methyl-1,3-benzodioxole. Cytotoxicity assays demonstrated that XZF (50-200 μg/mL) exhibited selective activity, maintaining viability in non-cancerous 293T-cells while enhancing the viability of activated CD8+ and CD4+ T-cells in a dose-dependent manner. XZF significantly reduced PD-1 expression in CD8+ T-cells but not in CD4+ T-cells and inhibited the PD-L1/PD-1 interaction, achieving 93% inhibition at 200 μg/mL. Furthermore, when combined with atezolizumab (1 μg/mL), XZF demonstrated complete blockade of PD-L1/PD-1 interaction. In prostate cancer cells, XZF exhibited differential antiproliferative effects. In PC-3 cells, XZF significantly reduced viability across a concentration range of 25-200 μg/mL, whereas DU145 cells showed only partial inhibition at higher concentrations (100-200 μg/mL). LNCaP cells exhibited a dose-dependent reduction in viability, mirroring the response pattern of PC-3 cells. Conditioned medium from XZF-treated macrophages, particularly human THP-1 cells, significantly suppressed the viability and migration of prostate cancer cells in a dose-dependent manner. Notably, the conditioned medium from XZF-treated THP-1 cells exhibited a stronger inhibitory effect on prostate cancer cell viability and migration compared to murine RAW 264.7 macrophages. These findings indicate that XZF exerts its therapeutic potential through multiple mechanisms, including direct antiproliferative effects on cancer cells, enhancement of T-cell responses, modulation of immune checkpoint pathways, and macrophage-mediated suppression of prostate cancer cell survival and migration. The pronounced effects observed in human macrophage models suggest a promising avenue for further investigation in clinical settings, particularly in combination with existing immunotherapies.

Macroautophagy (often-named autophagy), a catabolic process involving autophagy-related (Atg) genes, prevents the accumulation of harmful cytoplasmic components and mobilizes energy reserves in long-lived and self-renewing cells. Autophagy deficiency affects antigen presentation in conventional dendritic cells (DCs) without impacting their survival. However, previous studies did not address epidermal Langerhans cells (LCs). Here, we demonstrate that deletion of either Atg5 or Atg7 in LCs leads to their gradual depletion. ATG5-deficient LCs showed metabolic dysregulation and accumulated neutral lipids. Despite increased mitochondrial respiratory capacity, they were unable to process lipids, eventually leading them to ferroptosis. Finally, metabolically impaired LCs upregulated proinflammatory transcripts and showed decreased expression of neuronal interaction receptors. Altogether, autophagy represents a critical regulator of lipid storage and metabolism in LCs, allowing their maintenance in the epidermis.
© 2024 Arbogast et al.

The impact and underlying mechanisms of astragalus polysaccharide (APS) on prostate cancer, particularly its role in immunomodulation, remain inadequately elucidated.
This study employed the XTT assay for assessing proliferation in prostate cancer cells and macrophages. T cell proliferation was determined using the Carboxyfluorescein diacetate succinimidyl ester labeling assay. APS's effect on T cells and macrophages was scrutinized via flow cytometry, Western blot analysis, ELISA, quantitative PCR and cytokine membrane arrays. The effect of APS on interaction between PD-L1 and PD-1 was investigated by the PD-L1/PD-1 homogeneous assay. Additionally, the impact of conditioned medium from T cells and macrophages on PC-3 cell migration was explored through migration assays.
It was observed that APS at concentrations of 1 and 5 mg/mL enhanced the proliferation of CD8+ T cells. At a concentration of 5 mg/mL, APS activated both CD4+ and CD8+ T cells, attenuated PD-L1 expression in prostate cancer cells stimulated with interferon gamma (IFN-γ) or oxaliplatin, and moderately decreased the population of PD-1+ CD4+ and PD-1+ CD8+ T cells. Furthermore, APS at this concentration impeded the interaction between PD-L1 and PD-1, inhibited the promotion of prostate cancer migration mediated by RAW 264.7 cells, THP-1 cells, CD4+ T cells, and CD8+ T cells, and initiated apoptosis in prostate cancer cells treated with conditioned medium from APS (5 mg/mL)-treated CD8+ T cells, RAW 264.7 cells, or THP-1 cells.
The findings indicate a potential role of 5 mg/mL APS in modulating the PD-1/PD-L1 pathway and influencing the immune response, encompassing T cells and macrophages. Consequently, further in vivo research is recommended to assess the efficacy of APS.
© 2024 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Recent studies have revealed a structural role for DNA ligase 4 (Lig4) in the maintenance of a repair complex during non-homologous end joining (NHEJ) of DNA double-strand breaks. In cultured cell lines, catalytically inactive Lig4 can partially alleviate the severe DNA repair phenotypes observed in cells lacking Lig4. To study the structural role of Lig4 in vivo, a mouse strain harboring a point mutation to Lig4's catalytic site was generated. In contrast to the ablation of Lig4, catalytically inactive Lig4 mice are born alive. These mice display marked growth retardation and have clear deficits in lymphocyte development. We considered that the milder phenotype results from inactive Lig4 help to recruit another ligase to the repair complex. We next generated a mouse strain deficient for nuclear Lig3. Nuclear Lig3-deficient mice are moderately smaller and have elevated incidences of cerebral ventricle dilation but otherwise appear normal. Strikingly, in experiments crossing these two strains, mice lacking nuclear Lig3 and expressing inactive Lig4 were not obtained. Timed mating revealed that fetuses harboring both mutations underwent resorption, establishing an embryonic lethal genetic interaction. These data suggest that Lig3 is recruited to NHEJ complexes to facilitate end joining in the presence (but not activity) of Lig4.
© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.

Background: Alzheimer's Disease (AD) is a neuropathological condition marked by cognitive deterioration and chronic neuroinflammation. Previous investigations have unveiled a strong correlation between the gut microbiota and the progression of AD. In this study, our objective is to probe the effects of Parabacteroides distasonis ( P.distasonis ), previously found to be conspicuously diminished in AD patients, on the APP/PS1 mice model. Methods: : To assess the impact of orally administered P.distasonis on gut microbiota and metabolites, we utilized 16s rDNA sequencing and GC-MS to analyze gut composition and short-chain fatty acids in APP/PS1 mice after one month of P.distasonis gavage. To investigate the effects of P.distasonis administration over a six-month period on APP/PS1 mice, we evaluated cognitive function using novel object recognition and Y-maze tests, assessed intestinal barrier integrity and AD-related pathological features with immunofluorescence, and analyzed immune cell subpopulations in intestine, blood, spleen, and brain tissues via flow cytometry. The Luminex assay was employed to detect inflammatory cytokine secretion in the same regions. Results: : One-month oral administration of P.distasonis modulated the gut microbiota, elevated butyrate levels. Six-month oral administration of P.distasonis improved cognitive function in APP/PS1 mice, reducing Aβ deposition and inhibiting glial cell proliferation. It also amplified Treg cells within the gut, concomitant with the decreased Th1 proliferation and intestinal inflammation. Additionally, we observed the migration of peripheral CD4 + T cells to the brain through chemotaxis, accompanied by an increase in Treg cells and higher levels of anti-inflammatory factors such as IL-10 and TGF-β in the brain. Collectively, these multifaceted effects contributed to the alleviation of neuroinflammation. Conclusion: These findings underscore the potential of transplanting P.distasonis in alleviating AD-related pathology, suggesting a role for gut microbiota in neuroinflammation attenuation.