YOD1 protects against MRSA sepsis-induced DIC through Lys33-linked deubiquitination of NLRP3.

Disseminated intravascular coagulation (DIC) is considered to be the most common and lethal complication of sepsis. NLR-family pyrin domain-containing-3 (NLRP3) inflammasome plays an important role in host defense against microbial pathogens, and its deregulation may cause coagulation cascade and should be strictly managed. Here, we identified the deubiquitinase YOD1, which played a vital role in regulating coagulation in a NLRP3 inflammasome-dependent manner in sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA). YOD1 interacted with NLRP3 to remove K33-linked ubiquitination of NLRP3 based on its deubiquitinating enzyme activity and specifically inhibited expression of NLRP3 as well as activation of NLRP3 inflammasome. Deficiency of YOD1 expression enhanced NLRP3 inflammasome activation and coagulation both in vitro and in vivo. In addition, pharmacological inhibition of the NLRP3 effectively improved coagulation and alleviated organ injury in Yod1-/- mice infected with MRSA. Thus, our study reported that YOD1 is a key regulator of coagulation during MRSA infection, and provided YOD1 as a potential therapeutic target for the treatment of NLRP3 inflammasome-related diseases, especially MRSA sepsis-induced DIC.

Melanin nanoparticles alleviate sepsis-induced myocardial injury by suppressing ferroptosis and inflammation.

Myocardial injury as one of the severe complications leads to the increasing morbidity and mortality in patients with sepsis. Recent studies reported that reactive oxygen species (ROS)-mediated ferroptosis plays a critical role in the development of heart diseases. Therefore, we hypothesized that anti-ferroptosis agent might be a novel potential therapeutic strategy for sepsis-induced cardiac injury. Herein, we demonstrated that a small biocompatible and MRI-visible melanin nanoparticles (MMPP) improves myocardial function by inhibiting ROS-related ferroptosis signaling pathway. In LPS-induced murine sepsis model, after a single dose intravenously injection of MMPP treatment, MMPP markedly alleviated the myocardial injury including cardiac function and heart structure disorder through suppressing iron-accumulation induced ferroptosis. In vitro, MMPP inhibited cardiomyocyte death by attenuating oxidative stress, inflammation and maintaining mitochondrial homeostasis. Collectively, our findings demonstrated that MMPP protected heart against sepsis-induced myocardial injury via inhibiting ferroptosis and inflammation, which might be a novel therapeutic approach in future.

Elevated mir-145-5p is associated with skeletal muscle dysfunction and triggers apoptotic cell death in C2C12 myotubes.

Skeletal muscle dysfunction is a common comorbidity of chronic obstructive pulmonary disease (COPD), and the molecular mechanisms regarding to the pathogenesis of this disease have not been elucidated. In this study, a novel miR-145-5p was significantly upregulated in the serum collected from patients with COPD-associated muscle atrophy, in contrast with the normal participants. Then, we evidenced that silencing of miR-145-5p suppressed cell death and elongated cell survival during cell culture process. Consistently, upregulation of miR-145-5p induced cell apoptosis and restrain cell viability in the C2C12 cells, suggesting that miR-145-5p contributes to cell death. Further experiments evidenced that miR-145-5p decreased the expression levels of phosphorylated PI3K (p-PI3K), Akt (p-Akt) and mTOR (p-mTOR) to inactivate the PI3K/Akt/mTOR pathway, and this pathway was also reactivated by miR-145-5p ablation. Finally, we proved that the protective effects of miR-145-5p ablation were abrogated by co-treating cells with PI3K inhibitor LY294002. Taken together, we concluded that miR-145-5p promoted cell death to facilitate muscle dysfunctions via inactivating the PI3K/Akt/mTOR pathway.

Promotion of Cervical Cancer Cell Proliferation by miR-130b Expression Level Changes and Inhibition of its Apoptosis by Targeting CDKN1A Gene.

BACKGROUND: Dysregulation of miR-130b expression is associated with the development of different cancers. However, the description of the biological roles of miR-130b in the growth and survival of cervical cancer cells is limited. METHODS: The miR-130b levels in cervical cancer cells during different stages of growth were determined using reverse transcription-quantitative PCR. The methylation level of DNA sequences upstream of the miR-130b gene was measured using an SYBR Green-based quantitative methylation- specific PCR. Reverse transcription-quantitative PCR, Western blotting, and fluorescence report assays were used to identify the miR-130b-targeted gene. Cell counting kit-8 and comet assays were used to determine cell viability and DNA damage levels in cells, respectively. EdU Apopllo488 in vitro Flow Cytometry kit, propidium iodide staining, anti-γ-H2AX antibody staining, and Annexin-V apoptosis kit were subsequently used to determine DNA synthesis rates, cell cycle distribution, count of DNA double-strand breaks, and levels of apoptotic cells. RESULTS: miR-130b levels increased at exponential phases of the growth of cervical cancer cells but reduced at stationary phases. The methylation of a prominent CpG island near the transcript start site suppressed the miR-130b gene expression. MiR-130b increased cell viability, promoted both DNA synthesis and G1 to S phase transition of the cells at exponential phases, but reduced cell viability accompanied by accumulations of DNA breaks and augmentations in apoptosis rates of the cells in stationary phases by targeting cyclin-dependent kinase inhibitor 1A mRNA. CONCLUSION: miR-130b promoted the growth of cervical cancer cells during the exponential phase, whereas it impaired the survival of cells during stationary phases.

[Study on Chemical Constituents of Fat-soluble Extraction from Lepidium meyenii].

OBJECTIVE: To study the chemical constituents of the fat-soluble extraction from Lepidium meyenii root. METHODS: Different extraction methods were studied, including supercritical carbon dioxide extraction, circumfluence extraction and steam distillation. Chemical constituents of the fat-soluble extraction from Lepidium meyenii were analyzed by GC/MS. RESULT: The number of compounds isolated by the above four methods were 38, 31, 14, 21 (specific gravity less than 1 in steam distillation) , and 25 (specific gravity greater than 1 in steam distillation), accounting for 85.79%, 81.18%, 62.08%, 98.36% (specific gravity less than 1 in steam distillation) and 81.54% (specific gravity greater than 1 in steam distillation) of each total peak area, respectively. CONCLUSION: This study lays a certain foundation for further study and development of functional factors in Lepidium meyenii root.