Dioscin Attenuates Interleukin 1ß (IL-1ß)-Induced Catabolism and Apoptosis via Modulating the Toll-Like Receptor 4 (TLR4)/Nuclear Factor kappa B (NF-κB) Signaling in Human Nucleus Pulposus Cells.

BACKGROUND Nucleus pulposus (NP) cell dysfunction and apoptosis contribute to disc degeneration. Dioscin, a natural steroid saponin, has been demonstrated to have anti-inflammatory, antiapoptotic, and antioxidative effects in various diseases. However, little is known about the roles of dioscin in intervertebral disc degeneration. MATERIAL AND METHODS To evaluate the roles of dioscin in disc degeneration and its specific mechanism, human NP cells were incubated with IL-1ß and various concentrations of dioscin. Cell viability, extracellular matrix protein expression, catabolic factors, degree of apoptosis, inflammatory factors, and related signaling pathways were evaluated by western blotting, fluorescence immunostaining, TUNEL staining, and reverse transcription PCR. RESULTS Dioscin inhibited IL-1ß-activated apoptotic signaling and catabolic activity in NP cells. Dioscin suppressed TLR4/NF-0kappaB signaling, and attenuated the level of inflammatory mediators (IL-6, TNF-alpha) in IL-1ß-stimulated human NP cells. CONCLUSIONS Our work provides the first evidence that dioscin attenuates IL-1ß-activated inflammation and catabolic activity in human NP cells through inhibiting the TLR4/NF-kappaB pathway, indicating that dioscin is a new potential candidate for clinical therapy to attenuate disc degeneration.

Heparin-Binding Protein Promotes Acute Lung Injury in Sepsis Mice by Blocking the Aryl Hydrocarbon Receptor Signaling Pathway.

Purpose: This study aimed to explore the therapeutic effect and potential mechanism of heparin-binding protein (HBP) reduction on sepsis-related acute lung injury. Methods: We utilized a murine model of sepsis-induced by intraperitoneal injection of lipopolysaccharides (LPS) in C57BL/6J mice divided into four groups: Control, LPS, Anti-HBP, and ceftriaxone (CEF). Following sepsis induction, Anti-HBP or CEF treatments were administered, and survival rates were monitored for 48 h. We then used reverse-transcription quantitative PCR to analyze the expression levels of HBP in lung tissues, immunohistochemistry for protein localization, and Western blotting for protein quantification. Pulmonary inflammation was assessed using enzyme-linked immunosorbent assays of proinflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1ß, IL-6, and interferon-γ). The activation state of the aryl hydrocarbon receptor (AhR) signaling pathway was determined via Western blotting, evaluating both cytoplasmic and nuclear localization of AhR and the expression of cytochrome P450 1A1 protein by its target gene. Results: Anti-HBP specifically reduced HBP levels. The survival rate of mice in the Anti-HBP and CEF groups was much higher than that in the LPS group. The severity of lung injury and pulmonary inflammatory response in the Anti-HBP and CEF groups was significantly lower than that in the LPS group. AhR signaling pathway activation was observed in the Anti-HBP and CEF groups. Additionally, there was no significant difference in the above indices between the Anti-HBP and CEF groups. Conclusion: HBP downregulation in lung tissues significantly improved LPS-induced lung injury and the pulmonary inflammatory response, thereby prolonging the survival of sepsis mice, suggesting activation of the AhR signaling pathway. Moreover, the effect of lowering the HBP level was equivalent to that of the classical antibiotic CEF. Trial Registration: Not applicable.

Myocardial contractile and metabolic properties of familial hypertrophic cardiomyopathy caused by cardiac troponin I gene mutations: a simulation study.

Familial hypertrophic cardiomyopathy (FHC) is an inherited disease that is caused by sarcomeric protein gene mutations. The mechanism by which these mutant proteins cause disease is uncertain. Experimentally, cardiac troponin I (CTnI) gene mutations mainly alter myocardial performance via increases in the Ca(2+) sensitivity of cardiac contractility. In this study, we used an integrated simulation that links electrophysiology, contractile activity and energy metabolism of the myocardium to investigate alterations in myocardial contractile function and energy metabolism regulation as a result of increased Ca(2+) sensitivity in CTnI mutations. Simulation results reproduced the following typical features of FHC: (1) slower relaxation (diastolic dysfunction) caused by prolonged [Ca(2+)](i) and force transients; (2) higher energy consumption with the increase in Ca(2+) sensitivity; and (3) reduced fatty acid oxidation and enhanced glucose utilization in hypertrophied heart metabolism. Furthermore, the simulation indicated that in conditions of high energy consumption (that is, more than an 18.3% increase in total energy consumption), the myocardial energetic metabolic network switched from a net consumer to a net producer of lactate, resulting in a low coupling of glucose oxidation to glycolysis, which is a common feature of hypertrophied hearts. This study provides a novel systematic myocardial contractile and metabolic analysis to help elucidate the pathogenesis of FHC and suggests that the alterations in resting heart energy supply and demand could contribute to disease progression.

Cinnamic acid inhibits cell viability, invasion, and glycolysis in primary endometrial stromal cells by suppressing NF-κB-induced transcription of PKM2.

BACKGROUND:   Endometriosis is a painful disorder characterized by the growth of endometrial tissue outside the uterine cavity. Here, we investigated the effects of the cinnamic acid isolated from the Chinese medicinal plant Cinnamomum cassia Presl on primary endometrial stromal cells. METHODS:   Immunohistochemistry was used to examine protein expression and cell purity. Quantitative RT-PCR was conducted to assess mRNA expression, and Western blot was performed to determine protein level. Cell viability was assessed using cell counting kit-8 (CCK-8) assay. Glycolysis and mitochondrial function were evaluated by measuring the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) of cells, respectively. Lastly, plasmid transfection and inhibitor treatment were used for overexpression and inhibition studies. RESULTS: Cinnamic acid inhibited cell viability and cell invasion, as well as decreased ECAR and OCR, in primary endometrial stromal cells. Cinnamic acid suppressed the effects of PKM2 overexpression, and inhibition of PKM2 using Compound 3k mimicked the effects of cinnamic acid. Treatment with Compound 3k and cinnamic acid did not lead to additive effects, but rather displayed effects similar to those of Compound 3k alone, suggesting that cinnamic acid elicits its effects on primary endometrial stromal cells by targeting PKM2. CONCLUSIONS:   Our study identified cinnamic acid as a novel compound from Cinnamomum cassia Presl that displays potent effects on primary endometrial stromal cell viability, invasion, and glycolysis, suggesting its potential use for endometriosis treatment.

Cryptotanshinone alleviates polycystic ovary syndrome in rats by regulating the HMGB1/TLR4/NF­κB signaling pathway.

Cryptotanshinone (CRY) has been demonstrated to reverse reproductive disorders. However, whether CRY is effective in the treatment of polycystic ovary syndrome (PCOS) remains unknown. The aim of the present study was to evaluate the therapeutic potential of CRY in PCOS. A rat model of PCOS was established by daily injection of human chorionic gonadotropin and insulin for 22 days. Total body weight and ovarian weight, as well as the levels of luteinizing hormone (LH) and the LH to follicle­stimulating hormone (FSH) ratio (LH/FSH) significantly increased in rats with PCOS, compared with controls. Moreover, the levels of testosterone (T), tumor necrosis factor (TNF)­α and high­mobility group box 1 protein (HMGB1) also increased. However, CRY treatment attenuated the increase in body weight, ovarian weight, LH, LH/FSH ratio, T, TNF­α and HMGB1 levels, compared with the PCOS group. Treatment with CRY also reduced NF­κB/p65, HMGB1 and toll­like receptor (TLR)4 mRNA and protein expression levels in the ovarian tissue and granulosa cells, both in vitro and in vivo. Thus, CRY significantly mitigated the changes in body weight, ovary weight, hormone levels and inflammatory factor levels observed in rats with PCOS. Thus, CRY protects against PCOS­induced damage of ovarian tissue, possibly through a regulatory pathway involving HMGB1, TLR4 and NF­κB.

A review: Driving factors and regulation strategies of microbial community structure and dynamics in wastewater treatment systems.

The performance and stabilization of biological wastewater treatment systems 1are closely related to the microbial community structure and dynamics. In this paper, the effects and mechanisms of influent composition, process configuration, operating parameters (dissolved oxygen [DO], pH, hydraulic retention time [HRT] and sludge retention time [SRT]) and environmental condition (temperature) to the change of microbial community structure and process performance (nitrification, denitrification, biological phosphorus removal, organics mineralization and utilization, etc.) are critically reviewed. Furthermore, some strategies for microbial community structure regulation, mainly bioaugmentation, process adjustment and operating parameters optimization, applied in the current wastewater treatment systems are also discussed. Although the recent studies have strengthened our understanding on the relationship between microbial community structure and wastewater treatment process performance, how to fully tap the microbial information, optimize the microbial community structure and maintain the process performance in wastewater treatment systems are still full of challenges.

Predicting protein secondary structure by a support vector machine based on a new coding scheme.

Protein structure prediction is one of the most important problems in modern computational biology. Protein secondary structure prediction is a key step in prediction of protein tertiary structure. There have emerged many methods based on machine learning techniques, such as neural networks (NN) and support vector machine (SVM) etc., to focus on the prediction of the secondary structures. In this paper, a new method was proposed based on SVM. Different from the existing methods, this method takes into account of the physical-chemical properties and structure properties of amino acids. When tested on the most popular dataset CB513, it achieved a Q(3) accuracy of 0.7844, which illustrates that it is one of the top range methods for protein of secondary structure prediction.

BETTY: prediction of beta-strand type from sequence.

Most secondary structure prediction programs do not distinguish between parallel and antiparallel beta-sheets. However, such knowledge would constrain the available topologies of a protein significantly, and therefore aid existing fold recognition algorithms. For this reason, we propose a technique which, in combination with existing secondary structure programs such as PSIPRED, allows one to distinguish between parallel and antiparallel beta-sheets. We propose the use of a support vector machine (SVM) procedure, BETTY, to predict parallel and antiparallel sheets from sequence. We found that there is a strong signal difference in the sequence profiles which SVMs can efficiently extract. With strand type assignment accuracies of 90.7% and 83.3% for antiparallel and parallel strands, respectively, our method adds considerably to existing information on current 3-class secondary structure predictions. BETTY has been implemented as an online service which academic researchers can access from our website http://www.fz-juelich.de/nic/cbb/service/service.php.