Cellular senescence is a cell state characterized by a generally permanent cell-cycle arrest, generating a broad secretome of inflammatory factors, contributing to pro-inflammatory milieu. Pyroptosis is a lytic and highly regulated cell death mechanism with pro-inflammatory characteristics, mediated by gasdermin (GSDM) family of proteins, which has six members in humans: GSDMA-E and PJVK (GSDMF). The interplay between senescence and pyroptotic cell death has been shown in some contexts; however, crosstalk between senescence and pyroptosis has not been studied in breast cancer. In the present study, it was found that breast tumors with high gasdermin expression have higher expression of senescence marker genes, namely CDKN1A (encoding p21), CDKN2A (encoding p16) and TP53 (encoding p53). This is especially true for high GSDMD- or GSDME-expressing breast tumors, which show higher mRNA levels of all three senescence marker genes. This high GSDM-dependent increases in the transcript levels of cellular senescence marker genes is more frequent in breast cancer than in non-malignant breast tissue, suggesting that the association between gasdermin family of genes and senesence marker genes in terms of expression levels is stronger in the case of tumor rather than normal tissue. This might point that, in breast cancer, pyroptosis and senescence might be associated; however, whether pyroptosis regulates senescence or vice versa, whether these two processes both reciprocally regulate and control each other, or even whether they share a common upstream regulatory pathway remain to be identified. These findings also support previous research demonstrating the promoting effect of pyroptosis on senesence, and that SASP (senescence-associated secretory phenotype) factors can induce GSDMD–dependent pyroptotic cell death in neighboring cells present in the same microenvironment, in certain contexts. Further mechanistic studies are required to better characterize the cellular and molecular connections between senescence and pyroptosis in breast cancer.
Plentiful studies have efficaciously communicated that plant originated dietary microRNAs (miRNAs) attenuate the expression regulation of human transcripts by cross-species post-transcriptional regulatory mechanism. The small non-coding plant microRNAs with regulatory potential exhibit cross-kingdom communication via oral consumption and transfer to non-plant host species wherein they regulate the cellular and biological processes of host species. Thus miRNA portray as the inter-species signalling molecules responsible for imparting pharmacological properties to conventionally used medicinal herbs. Herein, we aim to investigate and document the regulatory potential of miRNAs derived from Boerhaavia diffusa, one of the widely used herb by tribal communities to treat liver disorders.
In the present study small RNA profiling data have been generated with ~ 80 million sequences by adapting high-throughput sequencing from B. diffusa root sample and analysed using bioinformatics tools for identification of 27 novel and 3325 conserved miRNAs from 4,619,108 clean reads. Further potential targets, putative role, and functional implications of miRNAs were explored. Subsequently, target prediction resulted in identification 2782 targets and 326 targets against conserved and novel miRNAs respectively, which were further annotated for biological functions and associated pathways. Remarkably, the plausible novel miRNAs bdf-miR-8, bdf-miR-20, bdf-miR-10, bdf-miR-22 were targeting the most significant genes MAPK14, RB1, YAP1 and CDK6 involved in HCC oncogenesis. Kaposi's sarcoma-associated herpesvirus infection, Epstein-Barr virus infection, TNF signaling pathway, MAPK signaling pathway and p53 signaling pathway were inferred as the most significant pathways by pathway enrichment analysis.
Our findings, being the first-such attempt to testify and postulate the novel interpretations regarding the cross-species expression regulation of human transcripts by B. diffusa root derived miRNAs. Sustaining the human disease regulation by dietary miRNAs and elucidating their promising therapeutic application, experimental validations with molecular assessments are still needed.
Genetic constraint and population-specific variant landscapes are pivotal in evaluating drug target feasibility. Rac1, a GTPase implicated in treatment-resistant hypertension and Plasmodium falciparum invasion of red blood cells (RBCs), represents a high-priority therapeutic candidate. This study leverages genome aggregation database (gnomAD) data to analyze Rac1’s genetic profile, focusing on its dual role in host-pathogen interactions and cardiovascular pathology.
We interrogated Rac1’s genetic constraint metrics (LOEUF, missense Z-scores), minor allele frequencies (MAF), and functional annotations across five global populations: African/African American (AFR), Admixed American (AMR), East Asian (EAS), Non-Finnish European (NFE), and South Asian (SAS). Variant Effect Predictor (VEP) focused on 3’/5’ untranslated regions (UTRs), complemented by ANOVA to assess population-specific variant distributions.
Rac1 appears to demonstrate strong intolerance to loss-of-function mutations (LOEUF = 0.25), underscoring potential on-target toxicity risks. Population-specific MAF disparities emerged in UTRs: AFR exhibited the highest 3’ UTR mean MAF (0.0112) and maximum MAF (0.716), while 5’ UTR MAFs were uniformly low across populations (e.g., AFR = 0.0000605, NFE = 0.00000285). ANOVA revealed no significant population-dependent differences in UTR variant distributions (p-values: AFR = 0.676; AMR = 0.973; EAS = 0.967; NFE = 0.985; SAS = 0.976), supporting conserved regulatory architecture. Functional domains (e.g., GTPase-binding regions) lacked pathogenic variants, whereas non-conserved regions harbored missense polymorphisms. UTR variants clustered in transcriptionally active regions, potentially modulating Rac1’s roles in hypertension and RBC remodeling.
While Rac1’s high genetic constraint signals caution for direct inhibition, UTR variants and non-essential domains may present safer therapeutic windows for modulating its activity in treatment-resistant hypertension or disrupting Plasmodium invasion. AFR-specific enrichment of high-frequency 3’ UTR variants, despite globally conserved distributions, highlights the importance of inclusive trial designs to address genetic diversity in these conditions. This study illustrates how gnomAD-driven population genetics can refine target prioritization, balancing efficacy and safety in drug discovery pipelines for infectious and cardiovascular diseases.
The article titled “Histone H1 Deamidation Facilitates Chromatin Relaxation for DNA Repair” was published in Nature in April 2025 by Tian et al. It presents significant advancements in our understanding of the mechanisms underlying chromatin relaxation and DNA damage repair. The authors identified a post-translational modification—histone H1 deamidation—as a pivotal mechanism that promotes chromatin relaxation and facilitates the repair of DNA double-strand breaks (DSBs), in part by enabling subsequent acetylation modifications. This discovery not only deepens our understanding of the “deamidation–acetylation” cascade of linker histone modifications but also uncovers a promising new target for precisely modulating DNA repair capacity in cancer therapy.