Kuwanon H Inhibits Melanoma Growth through Cytotoxic Endoplasmic Reticulum Stress and Impaired Autophagy Flux.

Although great progress has been made recently in targeted and immune-based therapies, additional treatments are needed for most melanoma patients due to acquired chemoresistance, recurrence, or metastasis. Elevated autophagy is required for the pathogenesis of melanoma to attenuate metabolic stress, protecting cancer cells from chemotherapeutics or radiation. Thus, intervention with autophagy is a promising strategy for melanoma treatment. Here, we examined a novel antimelanoma natural compound named kuwanon H (KuH), which significantly inhibited melanoma cell growth in vitro/vivo. Mechanistically, KuH induced cytotoxic endoplasmic reticulum (ER) stress, which inhibited cell viability and induced apoptosis. Meanwhile, KuH-induced ER stress mediated autophagysome formation through the ATF4-DDIT3-TRIB3-AKT-MTOR axis. Importantly, KuH impaired autophagy flux, which contributed to the anticancer effects of KuH. Finally, our results showed that KuH enhanced the sensitivity of melanoma cells to cisplatin, both in vitro and in vivo, by impairing autophagy degradation of reactive oxygen species and damaged mitochondria. Our findings indicate that KuH is a promising candidate anticancer natural product for melanoma therapy.

Insight into crustacean cathepsins: Structure-evolutionary relationships and functional roles in physiological processes.

Cathepsins belong to a group of proteins that are present in both prokaryotic and eukaryotic organisms and have an extremely high degree of evolutionary conservation. These proteins are functionally active in extracellular environments as soluble enzymatic proteins or attached to plasma membrane receptors. In addition, they occur in cellular secretory vesicles, mitochondria, the cytosol, and within the nuclei of eukaryotic cells. Cathepsins are classified into various groups based on their sequence variations, leading to their structural and functional diversification. The molecular understanding of the physiology of crustaceans has shown that proteases, including cathepsins, are expressed ubiquitously. They also contain one of the central regulatory systems for crustacean reproduction, growth, and immune responses. This review focuses on various aspects of the crustaceans cathepsins and emphasizes their biological roles in different physiological processes such as reproduction, growth, development, and immune responses. We also describe the bioactivity of crustaceans cathepsins. Because of the vital biological roles that cathepsins play as cellular proteases in physiological processes, they have been proposed as potential novel targets for the development of management strategies for the aquaculture industries.

Association of Fluid Management With Mortality of Sepsis Patients With Congestive Heart Failure: A Retrospective Cohort Study.

Sepsis management includes intravenous fluid (IVF) resuscitation, but patients with pre-existing congestive heart failure (CHF) have a higher risk of fluid overload. Further, patients with sepsis with concomitant CHF present worse clinical outcomes. Nevertheless, there is limited evidence of the association between fluid management and the outcomes of patients with concomitant sepsis and CHF. This retrospective cohort study aimed to evaluate the association between fluid management and in-hospital mortality in patients with sepsis and concomitant heart failure (HF). The patients' data were extracted from the Multi-parameter Intelligent Monitoring in Intensive Care III Database. The primary outcome was in-hospital mortality. A restricted cubic spline model was used to explore the relationship between variables and in-hospital mortality. Logistic models were built using the linear spline function and design variables to investigate the association of fluid balance (FB), fluid intake (FI), and fluid accumulation index (FAI, calculated as the FB/FI ratio) with mortality. Overall, 1,801 patients were included. The overall mortality rate was 27.7%. After adjusting for confounding variables, FAI was found to be associated with in-hospital mortality, whereas FB and FI were not. With FAI values of 0-0.42 set as references, FAI values <0 were not associated with in-hospital mortality [odds ratio (OR): 1.078; 95% confidence interval (CI): 0.774-1.503], whereas FAI values > 0.42 were significantly associated with higher in-hospital mortality (OR: 1.461; 95% CI: 1.099-1.954). High FAI values (>0.42) were associated with high in-hospital mortality in patients with sepsis with HF, while FB and FI were not. Proper fluid management may improve the outcomes of patients with sepsis and concomitant HF.

Emodin Promotes Autophagy and Prevents Apoptosis in Sepsis-Associated Encephalopathy through Activating BDNF/TrkB Signaling.

OBJECTIVE: Sepsis-associated encephalopathy (SAE) is a severe and common complication of sepsis and can induce cognitive dysfunction and apoptosis of neurons and neuroinflammation. Emodin has been confirmed to have anti-inflammatory effects. Thus, we sought to investigate the role of Emodin in SAE. METHODS: The cecal ligation and puncture (CLP) method was used for the establishment of SAE in mice model. For treatment of Emodin, intraperitoneal injection of 20 mg/kg Emodin was performed before the surgery. The Morris water maze and open field tests were carried for measurement of cognitive dysfunction. Hematoxylin and eosin staining was for histological analysis of hippocampus. Cell apoptosis of hippocampus neurons was measured by TUNEL staining. Pro-inflammatory and anti-inflammatory cytokines in hippocampus tissue homogenate were evaluated by ELISA. BDNF/TrkB signaling-related proteins (TrkB, p-TrkB, and BDNF), autophagy-related proteins (LC3 II/I and Beclin-1), and apoptosis-related proteins (Bax, Bcl-2, and cleaved caspase-3) were detected by Western blotting. RESULTS: Emodin significantly inhibited apoptosis and induced autophagy in hippocampal neurons of CLP-treated mice. In addition, Emodin significantly ameliorated CLP-induced cognitive dysfunction and pathological injury in mice. Meanwhile, Emodin notably inhibited CLP-induced inflammatory responses in mice via upregulation of BDNF/TrkB signaling, while the effect of Emodin was partially reversed in the presence of K252a (BDNF/TrkB signaling inhibitor). CONCLUSION: Emodin significantly inhibited the progression of SAE via mediation of BDNF/TrkB signaling. Thus, Emodin might serve as a new agent for SAE treatment.

Prognostic value of the neutrophil-to-lymphocyte ratio in acute organophosphorus pesticide poisoning.

This study investigates the ability of blood neutrophil-to-lymphocyte ratio (NLR) to predict acute organophosphorus pesticide poisoning (AOPP). Clinical data of 385 patients with AOPP were obtained within 24 h of admission, and NLR values were calculated based on neutrophil and lymphocyte counts. The patients were divided into two groups - good and poor - based on prognosis. Poor prognosis included in-hospital death and severe poisoning. The factors affecting prognosis were analyzed by logistic regression analysis, and the prognostic value of NLR was evaluated using the area under the receiver operating characteristic curve (AUC). Univariate logistic regression analysis showed that NLR levels, serum cholinesterase, and creatinine levels were good predictors of AOPP. Multivariate logistic regression analysis showed that high NLR was an independent risk factor for severe poisoning (adjusted odds ratio [AOR], 1.13; 95% CI, 1.10-1.17; p < 0.05) and in-hospital mortality (AOR, 1.07; 95% CI, 1.03-1.11; p < 0.05). NLR values >13 and >17 had a moderate ability to predict severe poisoning and in-hospital mortality, respectively (AUC of 0.782 [95% CI, 0.74-0.824] and 0.714 [95% CI, 0.626-0.803], respectively). Our results show that high NLR at admission is an independent indicator of poor prognosis in AOPP and can be used to optimize treatment and manage patients.