Aristolochic acid nephropathy (AAN) is characterized by acute proximal tubule necrosis and immune cell infiltration, contributing to the global burden of chronic kidney disease and urothelial cancer. Although the proximal tubule has been defined as the primary target of aristolochic acids I (AAI), the mechanistic underpinning of gross renal deterioration caused by AAI has not been explicitly explained, prohibiting effective therapeutic intervention. To this point, we employed integrated single-cell RNA-Seq, bulk RNA-Seq, and mass spectrometry–based proteomics to analyze the mouse kidney after acute AAI exposure. Our results reveal a dramatic reduction of proximal tubule epithelial cells, associated with apoptotic and inflammatory pathways, indicating permanent damage beyond repair. We found the enriched development pathways in other nephron segments, suggesting activation of reparative programs triggered by AAI. The divergent response may be attributed to the segment-specific distribution of organic anion channels along the nephron, including OAT1 and OAT3. Moreover, we observed dramatic activation and recruitment of cytotoxic T and macrophage M1 cells, highlighting inflammation as a principal contributor to permanent renal injury. Ligand-receptor pairing revealed that critical intercellular crosstalk underpins damage-induced activation of immune cells. These results provide potentially novel insight into the AAI-induced kidney injury and point out possible pathways for future therapeutic intervention.

Objectives: To reveal epidemic trend and possible origins of SARS-CoV-2 by exploring its evolution and molecular characteristics based on a large number of genomes since it has infected millions of people and spread quickly all over the world. Methods: Various evolution analysis methods were employed. Results: The estimated Ka/Ks ratio of SARS-CoV-2 is 1.008 or 1.094 based on 622 or 3624 SARS-CoV-2 genomes, and the time to the most recent common ancestor (tMRCA) was inferred in late September 2019. Further 9 key specific sites of highly linkage and four major haplotypes H1, H2, H3 and H4 were found. The Ka/Ks, detected population size and development trends of each major haplotype showed H3 and H4 subgroups were going through a purify evolution and almost disappeared after detection, indicating H3 and H4 might have existed for a long time, while H1 and H2 subgroups were going through a near neutral or neutral evolution and globally increased with time. Notably the frequency of H1 was generally high in Europe and correlated to death rate (r>0.37). Conclusions: In this study, the evolution and molecular characteristics of more than 16000 genomic sequences provided a new perspective for revealing epidemiology of SARS-CoV-2.

The discovery of epitopes is helpful to the development of SARS-CoV-2 vaccine. The sequences of the surface protein of SARS-CoV-2 and its proximal sequences were obtained by BLAST, the sequences of the whole genome of SARS-CoV-2 were obtained from the GenBank. Based on the NCBI Reference Sequence: NC_045512.2, the conformational and linear B cell epitopes of the surface protein were predicted separately by various prediction methods. Furthermore, the conservation of the epitopes, the adaptability and other evolutionary characteristics were also analyzed. 7 epitopes were predicted, including 5 linear epitopes and 2 conformational epitopes, one of the linear and one of the conformational were coincide. The epitope D mutated easily, but the other epitopes were very conservative and the epitope C was the most conservative. It is worth mentioning that all of the 6 dominated epitopes were absolutely conservative in nearly 1000 SARS-CoV-2 genomes, and they deserved further study. The findings would facilitate the vaccine development, had the potential to be directly applied on the treatment in this disease, but also have the potential to prevent the possible threats caused by other types of coronavirus.

Background: Sepsis is a complex and heterogeneous syndrome characterized by dysregulated immune responses and multiple forms of programmed cell death (PCD). Comprehensive understanding of the PCD landscape may provide insights into prognosis and therapeutic targets, whereas its role in sepsis is not well-explored. Methods: Using the microarray dataset for sepsis (GSE65682), we systematically profiled 14 PCD patterns in sepsis and stratified patients into molecular subtypes with distinct immune landscapes and clinical outcomes. PCD-related prognostic signature was developed and validated across multiple cohorts. Single-cell and multi-organ transcriptomic analyses were conducted to elucidate cellular heterogeneity and temporal dynamics. Molecular docking was used to explore interactions between active compounds of Simiao Yongan Decoction (SMYAD) and key PCD-related proteins. Results: Two clusters with differential transcriptional programs and immune infiltration patterns were identified, in which Cluster 1 showed poorer prognosis. We then developed a seven-gene signature (ELANE, CTSG, MPO, CAMP, TFRC, IL1B, CASP5) that effectively stratified patients by survival outcomes, with robust predictive performance across independent datasets. Neutrophils, monocytes, plasma, and dendritic cells were major mediators of PCD-associated immune dysregulation, in which neutrophils showing the strongest response. Temporal transcriptomics revealed peak expression of prognostic genes in bone marrow and peripheral blood within three days post-onset, suggesting an early therapeutic window. Finally, molecular docking indicated that SMYAD compounds may target PCD proteins (MPO, ELANE, IL1B) and modulate immune responses. Conclusion: This study delineates the multi-dimensional role of PCD in sepsis, establishes a reliable prognostic model with strong predictive value, and highlights SMYAD as a potential multi-target therapy. These findings provide new avenues for risk stratification and suggest the promise of integrating PCD biology with adjunctive immunomodulatory strategies.

Potent STING agonists are among the most promising strategies for reversing immunosuppression in “cold” tumors, but in vivo antitumor efficacy is frequently limited by dose-limiting systemic toxicity and inadequate tumor selectivity. To achieve localized STING activation and robust systemic immunity, we combined STING agonism with photodynamic therapy (PDT), creating a carrier-free nanoplatform (Ce6&SR717 NPs) through self-assembly of SR717 (STING agonist) and Ce6 (chlorin e6, photosensitizer). This excipient-free design achieves maximum drug loading, alleviates carrier-related safety issues, and realizes the spatiotemporally synchronized activation of PDT-induced immunogenic cell death and STING signaling through irradiation, which establishes an auto-amplifying cycle of on-site antigen release and systemic immune priming. In the murine breast cancer model, Ce6&SR717 NPs plus laser irradiation dramatically increased CD8 ⁺ T-cell infiltration within the tumor, triggered strong systemic antitumor immunity, and suppressed both primary and distant tumors. Collectively, these results identify Ce6&SR717 NPs as a safe and efficient modality for synergistic photo-immunotherapy of immunologically cold tumors.

Colorectal cancer (CRC) occurs as the third most common cancer with high mortality across the world. Understanding the intratumoral immune cell heterogeneity and their responses to various therapies is crucial for enhancing patient outcomes. This study aimed to characterise and evaluate the immune microenvironment landscapes of CRC shaped by different therapies including CD73 inhibitor, PD‐1 blockade and photothermal therapy (PTT). Our investigation revealed that three therapies could commonly modulate the down‐regulation of Treg, M2 macrophage and Ptprj + G4 granulocyte, up‐regulation of effector/memory T cell, M1 macorphage and Hilpda + G1 granulocyte. Moreover, we identified the uniquely dis‐regulated cell types and pathway activities response to each therapy, such as CD73 inhibitor enriched more Cd8+ memory and central memory (CM) cell, PD‐1 blockade with more Cd8+ CTL and Cxcl3 + G2 granulocyte, and PTT with more Cd8+ effector memory and Rethlg + G3 granulocyte cell. These responses disordered the glycolysis, angiogenesis, phagocytosis functions and cellular communication to reshape the CRC tumour immune microenvironment. We provide the detail insights into the intratumoral immunomodulation preferences of CRC mice treated with CD73 inhibitor, PD‐1 blockade and PTT therapies, which might contribute to the ongoing development of more effective anticancer strategies.