lncRNA NORAD alleviates dysfunction of renal proximal tubular epithelial cells during the sepsis-associated acute kidney injury by modulating the miR-155-5p-PDK1 axis.

The sepsis-associated acute kidney injury (Sa-AKI) is closely related to high mortality rates worldwide. Injury to the renal proximal tubular epithelial cells (RPTECs), caused by pathological conditions, is a major cause of acute kidney injury (AKI). The lncRNA NORAD has been reported to be positively associated with kidney cancers. However, the biological roles and underlying mechanisms of NORAD in RPTECs during AKI are still unclear. In this study, we found that NORAD was significantly downregulated in RPTECs from AKI tissues. Overexpression of NORAD alleviated RPTECs injury induced by lipopolysaccharide (LPS). Additionally, glucose metabolism was significantly impaired during AKI, and LPS treatment inhibited glucose metabolism in RPTECs. We demonstrated that NORAD rescued the LPS-induced inhibition of glucose metabolism in RPTECs. Furthermore, miRNA-155-5p was significantly upregulated in RPTECs from AKI. Through bioinformatics analysis, RNA pull-down, RNA IP, and luciferase assays, we showed that NORAD directly associated with miR-155-5p to downregulate its expression. Moreover, overexpression of miR-155-5p inhibited glucose metabolism by directly targeting the 3'UTR of the glucose metabolism enzyme, pyruvate dehydrogenase kinase 1 (PDK1). Finally, rescue experiments validated that NORAD's protective effect on RPTECs injury was mediated through modulation of the miR-155-5p-PDK1-glucose metabolism pathway. In summary, these results reveal that lncRNA NORAD can alleviate RPTECs dysfunction by targeting the miR-155-5p-PDK1 axis, suggesting that NORAD has the potential to contribute to the development of therapeutic approaches against Sa-AKI.

Post-ingestive stability of a mulberry Kunitz-type protease inhibitor MnKTI-1 in the digestive lumen of silkworm: dual inhibition towards α-amylase and serine protease.

BACKGROUND: Adaptation of specialist insects to their host plants and defense responses of plants to phytophagous insects have been extensively recognized while the dynamic interaction between these two events has been largely underestimated. Here, we provide evidence for characterization of an unrevealed dynamic interaction mode of digestive enzymes of specialist insect silkworm and inhibitor of its host plant mulberry tree. RESULTS: MnKTI-1, a mulberry Kunitz-type protease inhibitor, whose messenger RNA (mRNA) transcription and protein expression in mulberry leaf were severely triggered and up-regulated by tens of times in a matter of hours in response to silkworm, Bombyx mori, and other mulberry pest insects, suggesting a quick response and broad spectrum to insect herbivory. MnKTI-1 proteins were detected in gut content and frass of specialist B. mori, and exhibited significant post-ingestive stability. Recombinant refolded MnKTI-1 (rMnKTI-1) displayed binding affinity to digestive enzymes and a dual inhibitory activity to α-amylase BmAmy and serine protease BmSP2956 in digestive juice of silkworm. Moreover, data from in vitro assays proved that the inhibition of recombinant rMnKTI-1 to BmAmy can be reverted by pre-incubation with BmSP15920, an inactivated silkworm digestive protease that lack of complete catalytic triad. CONCLUSION: These findings demonstrate that mulberry MnKTI-1 has the potential to inhibit the digestive enzyme activities of its specialist insect herbivore silkworm, whereas this insect may employ inactivated proteases to block protease inhibitors to accomplish food digestion. The current work provides an insight to better understand the interacting mode between host plant Kunitz protease inhibitors and herbivorous insect digestive enzymes. © 2024 Society of Chemical Industry.

Mulberry-derived miR168a downregulates BmMthl1 to promote physical development and fecundity in silkworms.

Plant-derived miRNAs and their interactions with host organisms are considered important factors in regulating host physiological processes. In this study, we investigated the interaction between the silkworm, an oligophagous insect, and its primary food source, mulberry, to determine whether mulberry-derived miRNAs can penetrate silkworm cells and regulate their functions. Our results demonstrated that miR168a from mulberry leaves enters the silkworm hemolymph and binds to the silkworm Argonaute1 BmAGO1, which is transported via vesicles secreted by silkworm cells to exert its regulatory functions. In vivo and in vitro functional studies revealed that miR168a targets the mRNA of silkworm G protein-coupled receptor, BmMthl1, thereby inhibiting its expression and activating the JNK-FoxO pathway. This activation reduces oxidative stress responses, prolongs the lifespan of silkworms, and improves their reproductive capacity. These findings highlight the challenges of replacing mulberry leaves with alternative protein sources and provide a foundation for developing silkworm germplasms suitable for factory rearing.

Impact of acute kidney injury on the risk of mortality in patients with cirrhosis: a systematic review and meta-analysis.

OBJECTIVE: To compare the risk of mortality in patients with cirrhosis with and without the associated acute kidney injury (AKI). METHODS: We performed a systematic search in the PubMed, Embase, and Scopus databases for observational studies that were done on patients with cirrhosis. Eligible studies reported AKI in patients with cirrhosis and compared mortality among patients with and without AKI. We used a random-effects model, using STATA version 16.0, for deriving pooled effect sizes that were reported as odds ratio (OR) with 95% confidence intervals (CIs). RESULTS: Thirty-two studies were included. In patients with cirrhosis, AKI was significantly associated with higher in-hospital mortality (OR 5.92), and mortality at 30 days (OR 4.78), 90 days (OR 4.34), and at 1 year follow-up (OR 4.82) compared to patients without AKI. CONCLUSIONS: AKI is associated with an increased risk of mortality in patients with cirrhosis. Careful monitoring to identify the development of AKI and early prompt management is necessary.

Circular RNA HIPK3 aggravates sepsis-induced acute kidney injury via modulating the microRNA-338/forkhead box A1 axis.

Circular RNAs (circRNAs) have been extensively studied in various diseases, including sepsis-induced acute kidney injury (AKI). This research intended to elucidate the mechanism of circular RNA HIPK3 (circHIPK3) in sepsis-engendered AKI. Human tubule epithelial cells (HK2) were stimulated with lipopolysaccharide (LPS) to establish a septic AKI cell model. The gene expression levels were evaluated by RT-qPCR. Cell viability, apoptosis, and cell cycle distribution were assessed through CCK-8 and flow cytometry assays. The potential interactions between genes were verified by luciferase reporter and RIP assays. The results displayed that circHIPK3 expression was enhanced in septic AKI patients and LPS-triggered HK2 cells. Moreover, circHIPK3 interference expedited HK2 cell viability and attenuated apoptosis, inflammatory and oxidative damages following LPS stimulation. Furthermore, circHIPK3 functioned as a molecular sponge for miR-338, and forkhead box A1 (FOXA1) was negatively regulated by miR-338. CircHIPK3 aggravated cell injury in LPS-treated HK2 via targeting miR-338, and FOXA1 addition overturned the suppressing impacts of miR-338-3p augmentation on LPS-activated HK2 cell damage. Finally, we demonstrated that circHIPK3 modulated LPS-induced cell damage via the miR-338/FOXA1 axis. In sum, our results elaborated that circHIPK3 knockdown attenuated LPS-triggered HK2 cell injury by regulating FOXA1 expression via interacting with miR-338, suggesting that circHIPK3 might be a potential biomarker and therapeutic target for sepsis-induced AKI patients.