Autophagy in sepsis: Degradation into exhaustion?

Ho, Jeffery; Yu, Jun; Wong, Sunny H.; Zhang, Lin; Liu, Xiao Dong; Wong, Wai Tat; Leung, C.C.H.; Choi, Gordon; Wang, Maggie Haitian; Gin, Tony; Chan, Matthew T. V.; Wu, William Ka Kei

doi:10.1080/15548627.2016.1179410

Cited by 126 publications

(93 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As sepsis progresses, the immune system is reprogrammed into a stage characterized by persistent inflammation and immunosuppression [69, 70]. These are mediated in part by miRNAs, which promote immune cell polarization, suppress proinflammatory cytokines, and control leukocyte apoptosis [71–74].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The involvement of regulatory non-coding RNAs in sepsis: a systematic review

Chan

Wong

et al. 2016

Crit Care

Self Cite

View full text Add to dashboard Cite

BackgroundSepsis coincides with altered gene expression in different tissues. Accumulating evidence has suggested that microRNAs, long non-coding RNAs, and circular RNAs are important molecules involved in the crosstalk with various pathways pertinent to innate immunity, mitochondrial functions, and apoptosis.MethodsWe searched articles indexed in PubMed (MEDLINE), EMBASE and Europe PubMed Central databases using the Medical Subject Heading (MeSH) or Title/Abstract words (“microRNA”, “long non-coding RNA”, “circular RNA”, “sepsis” and/or “septic shock”) from inception to Sep 2016. Studies investigating the role of host-derived microRNA, long non-coding RNA, and circular RNA in the pathogenesis of and as biomarkers or therapeutics in sepsis were included. Data were extracted in terms of the role of non-coding RNAs in pathogenesis, and their applicability for use as biomarkers or therapeutics in sepsis. Two independent researchers assessed the quality of studies using a modified guideline from the Systematic Review Center for Laboratory animal Experimentation (SYRCLE), a tool based on the Cochrane Collaboration Risk of Bias tool.ResultsObservational studies revealed dysregulation of non-coding RNAs in septic patients. Experimental studies confirmed their crosstalk with JNK/NF-κB and other cellular pathways pertinent to innate immunity, mitochondrial function, and apoptosis. Of the included studies, the SYRCLE scores ranged from 3 to 7 (average score of 4.55). This suggests a moderate risk of bias. Of the 10 articles investigating non-coding RNAs as biomarkers, none of them included a validation cohort. Selective reporting of sensitivity, specificity, and receiver operating curve was common.ConclusionsAlthough non-coding RNAs appear to be good candidates as biomarkers and therapeutics for sepsis, their differential expression across tissues complicated the process. Further investigation on organ-specific delivery of these regulatory molecules may be useful.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1555-3) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

“…For instance, miR-122 predicts the development of liver injury in septic patients [70, 126]. miR-574-5p and miR-155 may predict the development of septic shock, immunosuppression and respiratory failure [71, 127, 133, 134].…”

Section: Discussionmentioning

confidence: 99%

The involvement of regulatory non-coding RNAs in sepsis: a systematic review

Chan

Wong

et al. 2016

Crit Care

Self Cite

View full text Add to dashboard Cite

show abstract

“…Sepsis is estimated to affect at least 19 million patients worldwide, reminding scientists and clinicians that it remains a serious global health burden and a major clinical challenge (4)(5)(6). Sepsis-induced cardiomyopathy (SIc) is a common complication of sepsis involving a combination of dysregulated inflammatory response, oxidative stress, calcium regulation disorder, dysregulated autonomic nervous system, impaired autophagy, apoptotic damage, mitochondrial dysfunction and endothelial dysfunction (7)(8)(9). despite more aggressive approaches to prevent the progression of SIc, these strategies often turn out to be disappointing and the mechanisms of SIc are currently poorly elucidated.…”

Section: Introductionmentioning

confidence: 99%

Luteolin attenuates sepsis‑induced myocardial�injury by enhancing autophagy in mice

Song

Fan

et al. 2020

Int J Mol Med

View full text Add to dashboard Cite

Sepsis-induced cardiomyopathy (SIc) is a complication of severe sepsis and septic shock characterized by an invertible myocardial depression. This study sought to explore the potential effects and mechanism of luteolin, a flavonoid polyphenolic compound, in lipopolysaccharide (LPS)-induced myocardial injury. Experimental mice were randomly allocated into 3 groups (25 mice in each group): The control group (Nc), the LPS group (LPS) and the LPS + luteolin group (LPS + Lut). Before the SIc model was induced, luteolin was dissolved in dMSO and injected intraperitoneally for 10 days into LPS + Lut group mice. Nc group and LPS group mice received an equal volume of dMSO for 10 days. On day 11, the animal model of sepsis-induced cardiac dysfunction was induced by intraperitoneal injection of LPS. A total of 12 h after LPS injection, measurements and comparisons were made among the groups. Luteolin administration improved cardiac function, attenuated the inflammatory response, alleviated mitochondrial injury, decreased oxidative stress, inhibited cardiac apoptosis and enhanced autophagy. In addition, luteolin significantly decreased the phosphorylation of AMP-activated protein kinase (AMPK) in septic heart tissue. The protective effect of luteolin was abolished by 3-methyladenine (an autophagy inhibitor) and dorsomorphin (compound c, an AMPK inhibitor), as evidenced by decreased autophagic activity, destabilized mitochondrial membrane potential and increased apoptosis in LPS-treated cardiomyocytes, but was mimicked by 5-aminoimidazole-4-carboxamide ribonucleotide (an AMPK activator), suggesting that luteolin attenuates LPS-induced myocardial injury by increasing autophagy through AMPK activation. Luteolin may be a promising therapeutic agent for treating SIc.

show abstract

“…We found that URMC-099 had no adverse effect on the body weight of the mice (Supplemental Figure 8B). As TFEB induces autophagy in tissue (26,43,44), we tested whether URMC-099 treatment leads to activation of autophagy in spleen and liver. Real-time quantitative PCR (qPCR) showed an upregulation of Tfeb, Map1lc3b, Necn1, and Sqstm1 levels in the livers of URMC-099-treated mice ( Figure 6A).…”

Section: Urmc-099 Retains Arv Nanoparticles In Autophagosomesmentioning

confidence: 99%

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Gnanadhas¹,

Dash²,

Sillman³

et al. 2017

Journal of Clinical Investigation

View full text Add to dashboard Cite

Long-acting anti-HIV products can substantively change the standard of care for patients with HIV/AIDS. To this end, hydrophobic antiretroviral drugs (ARVs) were recently developed for parenteral administration at monthly or longer intervals. While shorter-acting hydrophilic drugs can be made into nanocarrier-encased prodrugs, the nanocarrier encasement must be boosted to establish long-acting ARV depots. The mixed-lineage kinase 3 (MLK-3) inhibitor URMC-099 provides this function by affecting autophagy. Here, we have shown that URMC-099 facilitates ARV sequestration and its antiretroviral responses by promoting the nuclear translocation of the transcription factor EB (TFEB). In monocyte-derived macrophages, URMC-099 induction of autophagy led to retention of nanoparticles containing the antiretroviral protease inhibitor atazanavir. These nanoparticles were localized within macrophage autophagosomes, leading to a 4-fold enhancement of mitochondrial and cell vitality. In rodents, URMC-099 activation of autophagy led to 50-fold increases in the plasma drug concentration of the viral integrase inhibitor dolutegravir. These data paralleled URMC-099-mediated induction of autophagy and the previously reported antiretroviral responses in HIV-1-infected humanized mice. We conclude that pharmacologic induction of autophagy provides a means to extend the action of a long-acting, slow, effective release of antiretroviral therapy. Center for Neural Development and Disease, University of Rochester Medical Center (URMC), Rochester, New York, USA. Conflict of interest:H.A. Gelbard and H.E. Gendelman are members of the scientific advisory board for WavoDyne Therapeutics Inc., which is developing URMC-099 as a firstin-class MLK-3 inhibitor for clinical trials. URMC-099 is owned by URMC (patent nos. US 8,846,909 B2;8,877,772;and 9,181,247 and associated international patents). tion of TFEB mRNA by approximately 4-to 8-fold under different treatment conditions ( Figure 2F). With HIV-1 infection, TFEB mRNA levels were reduced by 2-to 3-fold compared with levels in uninfected controls, and URMC-099 could recover the phenotype. Increased TFEB translocation was delayed and did not reach significant levels until day 7 after URMC-099 treatment (Supplemental Figure 2B). These data confirm that URMC-099 regulates TFEB nuclear translocation in an mTORC1-dependent manner. URMC-099 stimulates autophagy in human MDMs. On the basis of the preceding data sets, we theorized that nuclear translocation of TFEB induces autophagy and lysosomal biogenesis. TFEB serves as the master regulator of both autophagy and lysosomal biogenesis (26), and such regulation could have a profound role in nanoART intracellular sequestration in MDMs. Thus, we examined the autophagosome markers microtubule-associated protein 1 light chain 3 β (LC3B, also known as MAP1LC3B) and beclin 1 (BECN1). Using Western blot assays, we found that each marker was significantly upregulated by URMC-099 ( Figure 3, A-C and Supplemental Figure 3A). URMC-099 increased the expression ...

show abstract

Autophagy in sepsis: Degradation into exhaustion?

Cited by 126 publications

References 81 publications

The involvement of regulatory non-coding RNAs in sepsis: a systematic review

The involvement of regulatory non-coding RNAs in sepsis: a systematic review

Luteolin attenuates sepsis‑induced myocardial�injury by enhancing autophagy in mice

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Contact Info

Product

Resources

About