Mechanism of immune activation mediated by genomic instability and its implication in radiotherapy combined with immune checkpoint inhibitors.

Various genetic and epigenetic changes associated with genomic instability (GI), including DNA damage repair defects, chromosomal instability, and mitochondrial GI, contribute to the development and progression of cancer. These alterations not only result in DNA leakage into the cytoplasm, either directly or through micronuclei, but also trigger downstream inflammatory signals, such as the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. Apart from directly inducing DNA damage to eliminate cancer cells, radiotherapy (RT) exerts its antitumor effects through intracellular DNA damage sensing mechanisms, leading to the activation of downstream inflammatory signaling pathways. This not only enables local tumor control but also reshapes the immune microenvironment, triggering systemic immune responses. The combination of RT and immunotherapy has emerged as a captivating avenue to increase the probability of abscopal effects, where distant tumors respond to treatment due to the systemic immunomodulatory effects. This review emphasizes the importance of GI in cancer biology and elucidates the mechanisms by which RT induces GI remodeling of the immune microenvironment. By elucidating the mechanisms of GI and RT-induced immune responses, we aim to emphasize the crucial importance of this approach in modern oncology. Understanding the impact of GI on tumor biological behavior and therapeutic response, as well as the possibility of activating systemic anti-tumor immunity through RT, will pave the way for the development of new treatment strategies and improve prognosis for patients.

Microbial Diversity Analyses of Fertilized Thitarodes Eggs and Soil Provide New Clues About the Occurrence of Chinese Cordyceps.

Chinese cordyceps is a well-known fungus-larva complex with medicinal and economic importance. At present the occurrence of Chinese cordyceps has not been fully illuminated. In this study, the microbial diversities of fertilized Thitarodes eggs from sites A (high occurrence rates of Chinese cordyceps), B (low occurrence rates), and C (no Chinese cordyceps) were analyzed using 16S rRNA and ITS gene-sequencing technique. The previous sequencing data of soil from the same sites were conjointly analyzed. The results showed that bacterial communities among the eggs were significantly different. The bacterial diversity and evenness were much higher on site A. Wolbachia was overwhelmingly predominant in the eggs of sites B and C, while Spiroplasma showed preference on site A. The fungal between-group differences in the eggs were not as significant as that of bacteria. Purpureocillium in Cordyceps-related families showed preference on site A. Wolbachia, Spiroplasma, and Purpureocillium were inferred to be closely related to Chinese cordyceps occurrence. Intra-kingdom and inter-kingdom network analyses suggest that closer correlations of microbial communities (especially closer fungal positive correlations) in fertilized eggs might promote Chinese cordyceps occurrence. Besides, metabolic pathway analysis showed that in fertilized eggs or soil the number of bacterial metabolic pathways with significant differences in every comparison between two sites was greater than that of fungi. Collectively, this study provides novel information about the occurrence of Chinese cordyceps, contributing to the large-scale artificial cultivation of Chinese cordyceps.

Harmine is an effective therapeutic small molecule for the treatment of cardiac hypertrophy.

Harmine is a ß-carboline alkaloid isolated from Banisteria caapi and Peganum harmala L with various pharmacological activities, including antioxidant, anti-inflammatory, antitumor, anti-depressant, and anti-leishmanial capabilities. Nevertheless, the pharmacological effect of harmine on cardiomyocytes and heart muscle has not been reported. Here we found a protective effect of harmine on cardiac hypertrophy in spontaneously hypertensive rats in vivo. Further, harmine could inhibit the phenotypes of norepinephrine-induced hypertrophy in human embryonic stem cell-derived cardiomyocytes in vitro. It reduced the enlarged cell surface area, reversed the increased calcium handling and contractility, and downregulated expression of hypertrophy-related genes in norepinephrine-induced hypertrophy of human cardiomyocytes derived from embryonic stem cells. We further showed that one of the potential underlying mechanism by which harmine alleviates cardiac hypertrophy relied on inhibition of NF-κB phosphorylation and the stimulated inflammatory cytokines in pathological ventricular remodeling. Our data suggest that harmine is a promising therapeutic agent for cardiac hypertrophy independent of blood pressure modulation and could be a promising addition of current medications for cardiac hypertrophy.