Targeting cullin neddylation for cancer and fibrotic diseases.

Protein neddylation is a post-translational modification, and its best recognized substrates are cullin family proteins, which are the core component of Cullin-RING ligases (CRLs). Given that most neddylation pathway proteins are overactivated in different cancers and fibrotic diseases, targeting neddylation becomes an emerging approach for the treatment of these diseases. To date, numerous neddylation inhibitors have been developed, of which MLN4924 has entered phase I/II/III clinical trials for cancer treatment, such as acute myeloid leukemia, melanoma, lymphoma and solid tumors. Here, we systematically describe the structures and biological functions of the critical enzymes in neddylation, highlight the medicinal chemistry advances in the development of neddylation inhibitors and propose the perspectives concerning targeting neddylation for cancer and fibrotic diseases.

The recent advance of Interleukin-1 receptor associated kinase 4 inhibitors for the treatment of inflammation and related diseases.

The interleukin-1 receptor associated kinase 4 (IRAK-4) is a member of serine-threonine kinase family, which plays an important role in the regulation of interleukin-1 receptors (IL-1R) and Toll-like receptors (TLRs) related signaling pathways. At present, the IRAK-4 mediated inflammation and related signaling pathways contribute to inflammation, which are also responsible for other autoimmune diseases and drug resistance in cancers. Therefore, targeting IRAK-4 to develop single-target, multi-target inhibitors and proteolysis-targeting chimera (PROTAC) degraders is an important direction for the treatment of inflammation and related diseases. Moreover, insight into the mechanism of action and structural optimization of the reported IRAK-4 inhibitors will provide the new direction to enrich the clinical therapies for inflammation and related diseases. In this comprehensive review, we introduced the recent advance of IRAK-4 inhibitors and degraders with regards to structural optimization, mechanism of action and clinical application that would be helpful for the development of more potent chemical entities against IRAK-4.

Exploration of Artemisinin Against IgA Nephropathy via AKT/Nrf2 Pathway by Bioinformatics and Experimental Validation.

Background: Artemisinin (ART) is a safe and effective antimalarial drug. In recent years, antimalarial drugs have demonstrated a good therapeutic efficacy in IgA nephropathy, suggesting that this may become a new treatment option. Purpose: We aimed to evaluate the effect and mechanism of artemisinin in IgA nephropathy. Methods: In this study, CMap database was used to predict the artemisinin therapeutic effect for IgA nephropathy. A network pharmacology approach was applied to explore the unknown mechanism of artemisinin in IgA nephropathy. We used molecular docking to predict the binding affinity of artemisinin with the targets. A mouse model of IgA nephropathy was established to investigate the therapeutic effect of artemisinin on IgA nephropathy. In vitro, the cell counting Kit-8 assay was used to evaluate the cytotoxicity of artemisinin. Flow cytometry and PCR assays were used to detect the effects of artemisinin on oxidative stress and fibrosis in lipopolysaccharide (LPS)-stimulated mesangial cells. Western blot and immunofluorescence were used to detect the expression of pathway proteins. Results: CMap analysis showed artemisinin may reverse the expression levels of differentially expressed genes in IgA nephropathy. Eighty-seven potential targets of artemisinin in the treatment of IgA nephropathy were screened. Among them, 15 hub targets were identified. Enrichment analysis and GSEA analysis indicated that response to reactive oxygen species is the core biological process. AKT1 and EGFR had the highest docking affinity with artemisinin. In vivo, artemisinin could improve renal injury and fibrosis in mice. In vitro, artemisinin attenuated LPS-induced oxidative stress and fibrosis promoted AKT phosphorylation and Nrf2 nuclear translocation. Conclusion: Artemisinin reduced the level of fibrosis and oxidative stress with IgA nephropathy through the AKT/Nrf2 pathway, which provided an alternative treatment for IgAN.

Adaptive and Adjustable MXene/Reduced Graphene Oxide Hybrid Aerogel Composites Integrated with Phase-Change Material and Thermochromic Coating for Synchronous Visible/Infrared Camouflages.

Although single-function camouflage under infrared/visible bands has made great advances, it is still difficult for camouflage materials to cope with the synergy detection spanning both visible and infrared spectra and adapt to complex and variable scenarios. Herein, a trilayer composite integrating thermal insulation, heat absorption, solar/electro-thermal conversions, and thermochromism is fabricated for visible and infrared dual camouflages by combining anisotropic MXene/reduced graphene oxide hybrid aerogel with the n-octadecane phase change material in its bottom and a thermochromic coating on its upper surface. Benefiting from the synergetic heat-transfer suppression derived from the thermal insulation of the porous aerogel layer and the heat absorption of the n-octadecane phase-change layer, the composite can serve as a cloak to hide the target signatures from the infrared images of its ambient surroundings during the day in the jungle and at night in all scenes and can assist the target in escaping visual surveillance by virtue of its green appearance. For desert scenarios, the composite can spontaneously increase its surface temperature via its solar-thermal energy conversion, merging infrared images of the targets into the high-temperature surroundings; meanwhile, it can vary the surface color from the original green to yellow, enabling the target to visually disappear from ambient sands and hills. This work provides a promising strategy for designing adaptive and adjustable integrated camouflage materials to counter multiband surveillance in complicated environments.

Glomerular deposition of fibrinogen predicts good prognosis of IgA nephropathy: a single-center cohort study.

PURPOSE: It has been proven that fibrinogen deposition exists in IgA nephropathy (IgAN), but its clinical significance has not been identified. We aim to investigate the clinical implication of fibrinogen deposition in evaluating the activity and prognosis of IgA nephropathy. METHODS: In this cohort, 935 adult IgAN patients were divided into 3 groups according to the intensity of glomerular fibrinogen deposition. Primary outcome refers to a composite event of either a ≥ 50% reduction in eGFR or ESRD (eGFR < 15 ml/min/1.73m2, dialysis, or renal transplantation). Factors associated with fibrinogen deposition and prognosis were identified. RESULTS: The results showed that the intensity of fibrinogen deposition was positively correlated with eGFR (P < 0.001), serum albumin (P = 0.041), and hemoglobin levels (P < 0.05), but negatively correlated with age (P = 0.04), serum fibrinogen levels (P < 0.001), serum C4 (P = 0.023), the proportion of patients with hypertension (P = 0.003), and the percentage of glomeruli sclerosis (P < 0.001). The prognostic analyses identified that fibrinogen deposition was an independent predictor for the progression of IgAN (P = 0.033). CONCLUSION: Our study indicated that the deposition of renal fibrinogen can predict the prognosis of IgAN with high reliability.

New drug approvals for 2021: Synthesis and clinical applications.

50 New drugs including 36 chemical entities and 14 biologics were approved by the U.S. Food and Drug Administration during 2021. Among the marketed drugs, 31 new small molecule agents (29 small molecule drugs and 2 diagnostic agents) with privileged structures and novel clinical applications represent as promising leads for the development of new drugs with the similar indications and improved therapeutic efficacy. This review is mainly focused on the clinical applications and synthetic methods of 29 small molecule drugs newly approved by the FDA in 2021. We believed that insight into the synthetic approaches of drug molecules would provide creative and practical inspirations for the development of more efficient and practical synthetic technologies to meet with new drug discovery.

Gut microbiota patterns associated with somatostatin in patients undergoing pancreaticoduodenectomy: a prospective study.

Postoperative pancreatic fistula (POPF) is a common and dreaded complication after pancreaticoduodenectomy (PD). The gut microbiota has been considered as an crucial mediator of postoperative complications, however, the precise roles of gut microbiota in POPF are unclear. A prospective study was developed to explore the effects of somatostatin on gut microbiota and we aim to identify the microbial alterations in the process of POPF. A total of 45 patients were randomly divided into PD group or additional somatostatin therapy group. The fecal sample of each patient was collected preoperatively and postoperatively and the gut microbiota was analyzed by 16S rRNA sequencing. Our study found that somatostatin therapy was independent risk factor for the occurrence of POPF, and it reduced the microbial diversity and richness in patients. At genus level, somatostatin therapy led to a decreased abundance in Bifidobacterium, Subdoligranulum and Dubosiella, whereas the abundance of Akkermansia, Enterococcus and Enterobacter were increased. The abundance levels of certain bacteria in the gut microbiota have significantly shifted in patients with POPF. The LEfSe analysis revealed that Ruminococcaceae could be used as microbial markers for distinguishing patients with high risk of POPF. Furthermore, Verrucomicrobia and Akkermansia could be used as preoperative biomarkers for identifying patients without POPF. Our prospective study highlights the specific communities related with somatostatin therapy and discovers POPF-associated microbial marker, which suggests that gut microbiota may become a diagnostic biomarker and potential therapeutic target for POPF.

Correction: Gut microbiota patterns associated with somatostatin in patients undergoing pancreaticoduodenectomy: a prospective study.

[This corrects the article DOI: 10.1038/s41420-020-00329-4.].

[Effect of a Mining and Smelting Plant on the Accumulation of Heavy Metals in Soils in Arid Areas in Xinjiang].

Arid and semi-arid regions in West China are ecologically fragile zones. Increasing attention has been focused on soil pollution triggered by mining and smelting in those areas. Nine heavy metals in the soil around a mining and smelting plant in Xinjiang were investigated using multivariate analysis, the geoaccumulation index, and GIS techniques. The heavy metals Cu and As were identified as the main pollutants in the study area. The accumulation of the heavy metals Cr, Zn, Ni, and Cd is small and weakly disturbed by human activity. Anthropogenic accumulation of Co and Pb was observed at a few sampling sites; its degree was also small. Anthropogenic accumulation of Mn in soil was not apparent. The factor analysis indicates two sources for the nine heavy metals in the soils. Source 1 includes As, Cu, Ni, Cr, Zn, Cd, and Co, while Source 2 includes Mn and Pb. The spatial distribution suggests that the sites with the highest As, Cu, Ni, Cr, Zn, Pb, Cd, and Co concentrations are in areas close to the tailing dump. The sealing tailing dump is the prior way to prevent the spread of heavy metals. The results also reveal that the PCA/APCS receptor model is not applicable for the quantification of the contribution of heavy metals in soils in this case.