Genetic variants altering cis-regulation of normal gene expression (cis-eQTLs) have been extensively mapped in human cells and tissues, but the extent by which controlled, environmental perturbation influences cis-eQTLs is unclear. We carried out large-scale induction experiments using primary human bone cells derived from unrelated donors of Swedish origin treated with 18 different stimuli (7 treatments and 2 controls, each assessed at 2 time points). The treatments with the largest impact on the transcriptome, verified on two independent expression arrays, included BMP-2 (t = 2h), dexamethasone (DEX) (t = 24h), and PGE₂ (t = 24h). Using these treatments and control, we performed expression profiling for 18,144 RefSeq transcripts on biological replicates of the complete study cohort of 113 individuals (n_total = 782) and combined it with genome-wide SNP-genotyping data in order to map treatment-specific cis-eQTLs (defined as SNPs located within the gene ±250 kb). We found that 93% of cis-eQTLs at 1% FDR were observed in at least one additional treatment, and in fact, on average, only 1.4% of the cis-eQTLs were considered as treatment-specific at high confidence. The relative invariability of cis-regulation following perturbation was reiterated independently by genome-wide allelic expression tests where only a small proportion of variance could be attributed to treatment. Treatment-specific cis-regulatory effects were, however, 2- to 6-fold more abundant among differently expressed genes upon treatment. We further followed-up and validated the DEX–specific cis-regulation of the MYO6 and TNC loci and found top cis-regulatory variants located 180 kb and 250 kb upstream of the transcription start sites, respectively. Our results suggest that, as opposed to tissue-specificity of cis-eQTLs, the interactions between cellular environment and cis-variants are relatively rare (∼1.5%), but that detection of such specific interactions can be achieved by a combination of functional genomic approaches as described here. Population variation in normal gene expression has been convincingly shown to be under strong genetic control where the main genetic variants are located within close proximity to the gene itself (so called cis-acting). However, the extent to which controlled, environmental stimuli influences cis-regulation of gene expression is unclear. Here, we combine different functional genomic approaches and examine the role of common genetic variants on induced gene expression in a population panel of primary human cells derived from ∼100 unrelated donors treated under multiple conditions. Using these approaches, we find that the interaction between cellular environment and cis-variants are relatively rare, with only a small proportion of the identified genetic variants being specific to treatment. However, although treatment-specific genetic regulation of gene expression seems to be infrequent, we prove its existence by thorough validation of treatment-specific effects of the glucocorticoid-specific regulation of TNC expression. Taken together, these findings indicate that the regulatory landscape within a cell is very stable but, by combining functional genomic tools gene-environmental interactions of clinical importance, can be detected and possibly used as biomarkers in future pharmacogenomic studies.

Prostate cancer is the second most common malignancy among men worldwide. However, conventional chemotherapy, such as taxane therapy, fails to exhibit efficient treatment for almost half of the patients. In this study, a nano-drug delivery system based on black phosphorus nanosheets (BP NSs) was developed, which was then employed as a multifunctional nanoplatform for targeted combinational chemo-photothermal therapy against prostate cancer. Zinc ion (Zn²⁺), which has been proven to be able to inhibit prostate cancer cell proliferation, was also introduced into this system. Zn²⁺ coordination could not only enhance the therapeutic effect of combined chemo-photothermal therapy, but also improve the intrinsic instability of BP NSs through the stabilization of its lone pair electrons. The in vivo study showed the outstanding performance of this system in targeted photothermal/chemotherapy of prostate cancer without side effect to normal organs.

Since 2019, coronavirus disease 2019 (COVID-19) has swept the world and become a new virus threatening the health of all mankind. The survey found that prostate cancer accounts for one in three male cancer patients infected with COVID-19. This undoubtedly makes prostate cancer patients face a more difficult situation. Prostate cancer is the second most harmful malignant tumor in men because of its insidious onset, easy metastasis, and easy development into castration-resistant prostate cancer even after treatment. Due to its high immunogenicity and a small number of specific infiltrating T cells with tumor-associated antigens in the tissue, it is difficult to obtain a good therapeutic effect with immune checkpoint blocking therapy alone. Therefore, in the current study, we developed a platform carrying Doxorubicin (DOX)-loaded black phosphate nanometer combined with photothermal therapy (PTT) and found this drug combination stimulated the immungentic cell death (ICD) process in PC-3 cells and DC maturation. More importantly, zinc ions have a good immunomodulatory function against infectious diseases, and can improve the killing ability of the nanosystem against prostate cancer cells. The introduction of Aptamer (Apt) enhances the targeting of the entire nanomedicine. We hope that this excellent combination will lead to effective treatment strategies for prostate cancer patients infected with COVID-19.

Background: Cystitis glandularis is a metaplastic lesion of the bladder mucosa. The underlying pathogenesis of cystitis glandularis and the potential association between the therapeutic effects of pachymic acid and ferroptosis remain unclear. Methods: Human bladder epithelial cells (SV40-immortalized human urothelial cells-1 (SV-HUC-1)) and Sprague–Dawley rat bladders were treated with lipopolysaccharide, with pachymic acid and ferrostatin-1 used as interventions. Cell viability was determined using the Cell Counting Kit-8 (CCK-8) assay. Levels of reactive oxygen species, glutathione, and malondialdehyde were quantified in both cells and tissues. Levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in rat bladder tissues were quantified using enzyme-linked immunosorbent assay kits. The expression levels of nuclear factor erythroid 2-related factor 2, glutathione peroxidase 4, and solute carrier family 7 member 11 were analyzed, and bladder inflammation was evaluated using hematoxylin and eosin staining. The mitochondrial ultrastructure of bladder tissue was examined using transmission electron microscopy. Results: Lipopolysaccharide treatment reduced cell viability, increased malondialdehyde and reactive oxygen species levels, and decreased glutathione levels in both cells and tissues. The levels of nuclear factor erythroid 2 related factor 2, glutathione peroxidase 4, and solute carrier family 7 member 11 were reduced, while those of inflammation markers were elevated. Lipopolysaccharide stimulation induced mitochondrial structural damage in rat bladder tissues. Treatment with pachymic acid and ferrostatin-1 partially reversed these effects. Conclusions: Ferroptosis plays a critical role in lipopolysaccharide-induced cystitis glandularis. Pachymic acid may alleviate cystitis glandularis by inhibiting ferroptosis, offering a novel therapeutic strategy for the clinical management of this disease.

Background: Peroxisome proliferator‐activated receptor‐gamma coactivator‐1α (PGC‐1α), a regulator of mitochondrial function, plays a critical role in inflammation and may be involved in cystitis glandularis (CG) development.Methods: LPS was administered to establish a CG model in female Sprague–Dawley (SD) rats and to induce cellular injury in the human urothelial cell line SV‐HUC‐1. Subsequently, to elucidate the role of PGC‐1α signaling in CG, both the animal and cellular models were treated with ZLN005, a specific activator of PGC‐1α. Cell viability was assessed using the cell‐counting kit‐8 (CCK8) assay. Mitochondrial damage was quantified by measuring reactive oxygen species (ROS), assessing mitochondrial membrane potential, and examining mitochondrial ultrastructure via transmission electron microscopy (TEM). Enzyme‐linked immunosorbent assays (ELISA) were utilized to determine the levels of inflammatory cytokines, namely, IL‐1β, IL‐6, and TNF‐α. Furthermore, the protein expression of silent information regulation 1 (SIRT1), PGC‐1α, mitochondrial transcription factor A (TFAM), nuclear respiratory factor 1 (NRF1), and nuclear respiratory factor 2 (NRF2) was evaluated using immunohistochemistry and/or Western blot analysis.Results: LPS‐treated rat bladder exhibited histological characteristics of CG, including increased urothelial proliferation and inflammation. PGC‐1α protein levels were downregulated in human CG tissues, LPS‐treated rat bladders, and SV‐HUC‐1 cells. Mitochondrial damage was observed in both rat CG and LPS‐irritated cells with elevated ROS and diminished mitochondrial membrane potential. TEM documented mitochondrial morphological injury of the urothelium in rat CG. ZLN005 attenuated LPS‐induced epithelial hyperplasia and inflammatory cytokine secretion in the rat CG model. Furthermore, ZLN005 partially reversed LPS‐induced mitochondrial damage, as indicated by reduced ROS levels, restored mitochondrial membrane potential, and mitigated mitochondrial morphological injury in both rat CG and LPS‐stimulated cells. In addition, ZLN005 restored the expression of PGC‐1α and its associated signaling proteins SIRT1, TFAM, NRF1, and NRF2.Conclusions: The downregulation of PGC‐1α suggests its potential as a molecular marker for the progression of CG. Targeting the PGC‐1α signaling pathway may offer an effective therapeutic intervention for the clinical management of CG.