Schematic overview of pharmacokinetics-based identification of pseudoaldosterogenic compounds glycyrrhetic acid (8) and 24-hydroxyglycyrrhetic acid (M2D). The Gancao constituents glycyrrhizin (1) and licorice saponin G2 (2) are metabolically activated by glucuronidase of the colonic microbiota to the pseudoaldosterogenic metabolites 8 and M2D, respectively, which can access (via passive tubular reabsorption) and inhibit renal 11β-HSD2. The finding has implications for precisely defining conditions for safe use of the Gancao-containing herbal medicine.

NLRP3 inflammasome is implicated in inflammation-associated diseases such as multiple sclerosis. Liao et al. identified 1,2,4-TTB as a selective NLRP3 inflammasome inhibitor, which inhibited the aggregation of NLRP3 and ameliorated EAE progression and demyelination. This image illustrates the mechanism that 1,2,4-TTB inhibits NLRP3 inflammasome and the progression of EAE. See the article in pages 1769–1779.

Schematic diagram of the proposed mechanisms underlying the anti-fatigue activity of ganoderic acid (GA) in chemotherapy-treated mice bearing colon tumor. GA ameliorates 5-FU-induced peripheral muscle fatigue (left) and central fatigue (right) in mice bearing colon tumor by improving energy metabolism and inhibiting neuroinflammation, respectively. See the article in pages 1703–1713.

Beyond iron deposition, emerging evidence from key PD genes, differential regulatory proteins and cell-cell crosstalk further supports the involvement of ferroptosis in PD. The evidence was discussed in a fresh dimension and it could establish new subtypes of PD based on ferroptosis status to help precisely predict disease progression and formulate personalized treatments.

Schematic diagram of the role of FOXO3a in TMZ-induced BNIP3-mediated mitophagy. TMZ treatment induced the excessive generation of mitochondrial superoxide. The overproduction of mitochondrial superoxide not only resulted in mitochondrial depolarization and AIF translocation from mitochondria into nuclei but also led to intracellular accumulation of ROS and ROS-dependent DNA DSBs. Within nuclei, AIF could be recruited to γH2AX that are generated when DNA DSBs occur and could act as a nuclease to degrade DNA (chromatinolysis). Thus, mitochondrial superoxide contributes to TMZ-triggered glioma cell death. On the other hand, the expression of the transcription factor FOXO3a was upregulated by ROS and promoted the expression of BNIP3 and ATG5. BNIP3 was distributed to damaged mitochondria, and ATG5 initiated the formation of phagophores. Then, the mitochondria primed by BNIP3 were engulfed by phagophores to form mitophagosomes, and mitophagosomes fused with lysosomes to form mitolysosomes. Within mitolysosomes, mitochondria are eventually degraded by enzymes released from the lysosomes. Thus, autophagic removal of mitochondria with increased superoxide levels inhibited TMZ-induced glioma cell death via suppression of mitochondria-related oxidative stress. Taken together, these data show that FOXO3a protects glioma cells against temozolomide-induced DNA double-strand breaks via promotion of BNIP3-mediated mitophagy.

During the pathological process of pancreatic cancer, the composition of the gut microbiota changes (i.e., intestinal microbiota dysbiosis), and the gut barrier is impaired. As a result, certain gut microbes translocate to the pancreas and colonize the pancreas to induce a suppressive immune microenvironment that facilitates pancreatic cancer progression. See the article in pages 1027–1039.

Challenges and opportunities for network pharmacology-based research on traditional Chinese medicines against COVID-19. See the article in pages 845–847.

Drp1 can be SUMOylated by both SUMO-1 and SUMO-2/3. SUMO-1-ylation and deSUMO-2/3-ylation of Drp1 promotes its association with mitochondrial outer membrane (MOM), which facilitates mitochondrial fission and activates mitophagy. On the contrary, SUMO-2/3-ylation and deSUMO-1-ylation of Drp1 lead to accumulation of defective mitochondria and cardiomyocyte apoptosis.

NcRNAs involved in different mechanisms of DOX-induced cardiac cell apoptosis. MiR-499-5p and miR-532-3p regulate DOX-induced mitochondrial fission; miR-15b-5p, miR-23a, miR-29b, miR-146a and LincRNA-p21 regulate the DOX-induced decline in mitochondrial membrane potential and cytochrome c release; miR-15b-5p, miR-23a, miR-30 and LincRNA-p21 regulate DOX-induced ROS production; miR-140-5p, miR-451 and LincRNA-p21 regulate DOX-induced change of antioxidant levels; miR-378 regulates DOX-induced ER stress; miR-320a regulates the DOX-induced impact on microvessel density; miR-21, miR-34a-5p, miR-130a, miR-208a, miR-212/132, Linc00339, LncRNA CHRF, LncRNA Mhrt and CircRNA derived from the Ttn 105-111 gene regulate DOX-induced apoptosis with no clearly indicated mechanisms; and LncRNA FOXC2-AS1 regulates DOX-induced reduction in cell viability.

The progress of tumor metastasis is accompanied with significant mechanical changes of multifaceted factors, including cancerous cells and a wide range of microenvironmental cues. In this article, Li et al summarized the advances of atomic force microscopy (AFM) in revealing multiple types of micro/nanoscale mechanics associated with tumor development and metastasis.

The E3 ligases engage in the malignancy of UM. a MiR-17-3p inhibits MDM2-mediated degradation of TP53 through the UPS. However, LncRNA PVT1 in UM could disturb miR-17-3p-mediated inhibition of MDM2. b SKP2-mediated degradation of CDKN1B through the UPS induces UM growth. c Hypoxia induces transactivation of HIF1A that could be degraded through VHL-mediated UPS in normoxia. d RNF2-mediated ubiquitination of histone H2A executes completely different regulation of downstream genes in UM versus other tissues. e MYCBP2 elevates the sensitivity of UM cells to Trail-induced apoptosis by conjugating to C-MYC. However, miR-92a-3p overexpressed in UM reduces the protein level of MYCBP2. See the article in pages 179–188.

Immunotherapy has achieved great outcome in clinic, and PD-1/PD-L1 immunotherapy is the most promising one. Due to the limitations of monoclonal antibodies, the discovery of small molecule drugs blocking PD-1/PD-L1 signaling has attracted great interest. In this issue, Wu et al summarized the advances in small molecule inhibitors targeting the PD-1/PD-L1.