Tissue-Type Plasminogen Activator-Inhibitor Complex as an Early Predictor of Septic Shock: A Retrospective, Single-Center Study.

Background: Sepsis can progress to septic shock and death, and identifying biomarkers of this progression may permit timely intervention to prevent it. This study explored whether levels of tissue-type plasminogen activator-inhibitor complex (t-PAIC) in serum can predict septic shock early. Methods: We retrospectively analyzed 311 sepsis patients who had been admitted to the intensive care unit (ICU) at our tertiary care hospital between May 2018 and April 2021, and we divided them into those who progressed to septic shock (n = 203) or not (n = 108) based on sepsis-3 definition. After matching patients in the two groups based on propensity scoring, we screened for risk factors of septic shock using logistic regression. We assessed potential predictors of such shock based on the area under the receiver-operating characteristic curve (AUC), Kaplan-Meier survival curves, and correlation analysis. Results: After propensity score matching to generate two equal groups of 108 patients, we found that serum t-PAIC was significantly higher in septic shock patients. Uni- and multivariate logistic regression identified t-PAIC as an independent risk factor for septic shock (OR 1.14, 95% CI 1.09-1.19, P < 0.001) and a biomarker that predicted it with an AUC up to 0.875 (95% CI, 0.829-0.920). Based on the optimal cut-off of t-PAIC = 17.9 ng/mL, we found that patients at or above this threshold had significantly higher lactate levels and scores on the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA). Such patients also had significantly worse survival (HR 2.4, 95% CI 1.38-4.34, P = 0.004). Spearman's correlation coefficients were 0.66 between t-PAIC and lactate, and 0.52 between t-PAIC and SOFA. Conclusions: Serum levels of t-PAIC may be an independent risk factor for septic shock, and they may correlate with the severity of such shock.

New Is Old, and Old Is New: Recent Advances in Antibiotic-Based, Antibiotic-Free and Ethnomedical Treatments against Methicillin-Resistant Staphylococcus aureus Wound Infections.

Staphylococcus aureus is the most common pathogen of wound infections. Thus far, methicillin-resistant S. aureus (MRSA) has become the major causative agent in wound infections, especially for nosocomial infections. MRSA infections are seldom eradicated by routine antimicrobial therapies. More concerning, some strains have become resistant to the newest antibiotics of last resort. Furthermore, horizontal transfer of a polymyxin resistance gene, mcr-1, has been identified in Enterobacteriaceae, by which resistance to the last group of antibiotics will likely spread rapidly. The worst-case scenario, "a return to the pre-antibiotic era", is likely in sight. A perpetual goal for antibiotic research is the discovery of an antibiotic that lacks resistance potential, such as the recent discovery of teixobactin. However, when considering the issue from an ecological and evolutionary standpoint, it is evident that it is insufficient to solve the antibiotic dilemma through the use of antibiotics themselves. In this review, we summarized recent advances in antibiotic-based, antibiotic-free and ethnomedical treatments against MRSA wound infections to identify new clues to solve the antibiotic dilemma. One potential solution is to use ethnomedical drugs topically. Some ethnomedical drugs have been demonstrated to be effective antimicrobials against MRSA. A decline in antibiotic resistance can therefore be expected, as has been demonstrated when antibiotic-free treatments were used to limit the use of antibiotics. It is also anticipated that these drugs will have low resistance potential, although there is only minimal evidence to support this claim to date. More clinical trials and animal tests should be conducted on this topic.

[Resveratrol reduces inflammatory cytokines via inhibiting nuclear factor-κB and mitogen-activated protein kinase signal pathway in a rabbit atherosclerosis model].

OBJECTIVE: Inflammation serves as the initial pathologic step of cardiovascular diseases including atherosclerosis. Resveratrol possesses many pharmacological properties including antioxidant, cardioprotective and anti-cancer effects. In this study, we investigate the anti-inflammatory effect and mechanisms of resveratrol in an atherosclerotic rabbit model. METHODS: Rabbit were assigned to six groups (n = 10 each): control, high fat diet group, resveratrol low, medium and high dose groups, resveratrol pretreatment group. The serum tumor necrosis factor-α (TNF- α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) were analyzed by Enzyme-linked immuno sorbent assay(ELISA). Phosphorylation levels of mitogen-activated protein kinases (MAPKs) cascades and NF-κB were determined by Western blot. RESULTS: Compared with the control group, the expression of serum inflammatory factors IL-1ß, IL-6, TNF-α were increased in high-fat group (all P < 0.05). Compared with high-fat group, the expressions of IL-6, IL-1ß, TNF-α were significantly reduced in resveratrol low, medium, high dose groups and resveratrol pretreatment group (all P < 0.01), and this effect is dose-dependent. In addition, the NF-κB, p38MAPK, JNK, ERK1/2 protein phosphorylation in high-fat group were significantly upregulated compared with control group (P < 0.05), which (except ERK1/2 phosphorylation level) were significantly downregulated in resveratrol treatment group and resveratrol pretreatment group. CONCLUSION: This study indicates that resveratrol reduces serum inflammatory cytokines in this atherosclerotic rabbit model via down-regulation phosphorylation of NF-κB, and MAPKs signaling, which might serve as the anti-inflammatory molecular basis of resveratrol.

Surface display of domain III of Japanese encephalitis virus E protein on Salmonella typhimurium by using an ice nucleation protein.

A bacterial cell surface display technique based on an ice nucleation protein has been employed for the development of live vaccine against viral infection. Due to its ubiquitous ability to invade host cells, Salmonella typhimurium might be a good candidate for displaying viral antigens. We demonstrated the surface display of domain III of Japanese encephalitis virus E protein and the enhanced green fluorescent protein on S. typhimurium BRD509 using the ice nucleation protein. The effects of the motif in the ice nucleation protein on the effective display of integral protein were also investigated. The results showed that display motifs in the protein can target integral foreign protein on the surface of S. typhimurium BRD509. Moreover, recombinant strains with surface displayed viral proteins retained their invasiveness, suggesting that the recombinant S. typhimurium can be used as live vaccine vector for eliciting complete immunogenicity. The data may yield better understanding of the mechanism by which ice nucleation protein displays foreign proteins in the Salmonella strain.

Bacterial cell surface display: a method for studying Japanese encephalitis virus pathogenicity.

Infection with Japanese encephalitis virus (JEV), a mosquito-borne, neurotropic flavivirus, may cause acute encephalitis in humans. Recombinant Salmonella typhimurium BRD509 was constructed to display domain III of the envelope (E) protein of JEV (JEDIII) on its surface with the N-terminal domain of ice nucleation protein (INPN) as the display motif. Bacterial cell surface display was confirmed by Western blot analysis and immunohistochemical staining. Binding of recombinant INPN-JEDIII and JEDIII proteins to three mammalian cell lines was compared using a cell-binding ELISA; the human neuroblastoma cell line SK-N-SH, which had a low level of binding, was selected for further studies. The display of JEDIII on the surface of BRD509 did not significantly influence its invasiveness was confirmed by measuring released bacterial antigen using whole-cell ELISA. The relative expression of an apoptosis-related gene and total DNA damage were assessed to investigate the effects of infection on SK-N-SH cells. Compared to BRD509, infection with the recombinant bacterium reduced cell damage, suggesting that JEDIII may limit apoptosis during the early stages of JEV infection. Our studies demonstrated that it is feasible to study the pathogenesis of JEV using the approach described.