Maternal dietary patterns during pregnancy derived by reduced-rank regression and birth weight in the Chinese population.

Few studies have investigated the association between maternal dietary patterns (DP) during pregnancy, derived from reduced-rank regression (RRR), and fetal growth. This study aims to identify DP during pregnancy associated with macro- and micronutrient intakes, using the RRR method, and to examine their relationship with birth weight (BW). We used data of 7194 women from a large-scale cross-sectional survey in Northwest China. Dietary protein, carbohydrate, haem Fe density and the ratio of PUFA and MUFA:SFA were used as the intermediate variables in the RRR model to extract DP. Generalised estimating equation models were applied to evaluate the associations between DP and BW and related outcomes (including BW z-score, low birth weight (LBW) and small for gestational age (SGA)). Four DP during pregnancy were identified. Socio-demographically disadvantaged pregnant women were more likely to have lower BW and lower adherence to DP1 (high legumes, soyabean products, vegetables and animal-source foods, with relative low wheat and oils). Women with medium and high adherence to DP1 had significantly increased BW (medium 28·6 (95 % CI 7·1, 50·1); high 25·2 (95 % CI 2·7, 47·6)) and BW z-score and had significantly reduced risks of LBW and SGA. The associations were stronger among women with babies <3100 g. There is no association between other DP and outcomes. Higher adherence to the DP that was high in legumes, soyabean products, vegetables and animal-source foods was associated with improved BW in the Chinese pregnant women, particularly among those with disadvantageous socio-demographic conditions.

l-Serine Lowers the Inflammatory Responses during Pasteurella multocida Infection.

Pasteurella multocida causes a variety of infectious diseases in various species of mammals and birds, resulting in enormous economic loss to the modern livestock and poultry industry. However, the mechanism of host-pathogen interaction is unclear. Here, we found that l-serine levels were significantly decreased in murine lungs infected with P. multocida Exogenous l-serine supplementation significantly increased the survival rate of mice and decreased the colonization of P. multocida in the lungs of mice. Notably, l-serine decreased the macrophage- and neutrophil-mediated inflammatory responses in mice during P. multocida infection.

Apolipoprotein O expression in mouse liver enhances hepatic lipid accumulation by impairing mitochondrial function.

Apolipoprotein O (ApoO) was recently observed in the cellular mitochondrial inner membrane, which plays a role in mitochondrial function and is associated with myocardiopathy. Empirical information on the physiological functions of apoO is therefore limited. In this study, we aimed to elucidate the effect of apoO on hepatic fatty acid metabolism. An adenoviral vector expressing hApoO was constructed and introduced into chow diet and high-fat diet induced mice and the L02 human hepatoma cell line. High levels of hApoO mRNA and protein were detected in the liver, and the expression of lipid metabolism genes was significantly altered compared with negative controls. The liver function indices (serum ALT and AST) were clearly elevated, and the ultrastructure of cellular mitochondria was distinctly altered in the liver after apoO overexpression. Further, mitochondrial membrane potential decreased with hApoO treatment in L02 cells. These results establish a link between apoO and lipid accumulation and could suggest a new pathway for regulating non-alcoholic fatty liver disease progression.

Microarray analysis provides new insights into the function of apolipoprotein O in HepG2 cell line.

BACKGROUND: Apolipoprotein O (apoO) is a new member of the apolipoprotein family. However, data on its physiological functions are limited and inconsistent. Using a microarray expression analysis, this study explored the function of apoO in liver cells. METHODS: HepG2 cells were treated either with oleic acid or tumor necrosis factor-α for 24 h. mRNA and protein expression of apoO were assessed by quantitative real-time PCR (qRT-PCR) and Western blot respectively. An efficient lentiviral siRNA vector targeting the human apoO gene was designed and constructed. The gene expression profile of HepG2 human hepatocellular carcinoma cells transfected with the apoO silencing vector was investigated using a whole-genome oligonucleotide microarray. The expression levels of some altered genes were validated using qRT-PCR. RESULTS: ApoO expression in HepG2 cells was dramatically affected by lipid and inflammatory stimuli. A total of 282 differentially expressed genes in apoO-silenced HepG2 cells were identified by microarray analysis. These genes included those participating in fatty acid metabolism, such as ACSL4, RGS16, CROT and CYP4F11, and genes participating in the inflammatory response, such as NFKBIZ, TNFSF15, USP2, IL-17, CCL23, NOTCH2, APH-1B and N2N. The gene Uncoupling protein 2 (UCP2), which is involved in both these metabolic pathways, demonstrated significant changes in mRNA level after transfection. CONCLUSIONS: It is likely that apoO participates in fatty acid metabolism and the inflammatory response in HepG2 cells, and UCP2 may act as a mediator between lipid metabolism and inflammation in apoO-silenced HepG2 cells.

HSPA8 acts as an amyloidase to suppress necroptosis by inhibiting and reversing functional amyloid formation.

Ultra-stable fibrous structure is a hallmark of amyloids. In contrast to canonical disease-related amyloids, emerging research indicates that a significant number of cellular amyloids, termed 'functional amyloids', contribute to signal transduction as temporal signaling hubs in humans. However, it is unclear how these functional amyloids are effectively disassembled to terminate signal transduction. RHIM motif-containing amyloids, the largest functional amyloid family discovered thus far, play an important role in mediating necroptosis signal transduction in mammalian cells. Here, we identify heat shock protein family A member 8 (HSPA8) as a new type of enzyme - which we name as 'amyloidase' - that directly disassembles RHIM-amyloids to inhibit necroptosis signaling in cells and mice. Different from its role in chaperone-mediated autophagy where it selects substrates containing a KFERQ-like motif, HSPA8 specifically recognizes RHIM-containing proteins through a hydrophobic hexapeptide motif N(X1)φ(X3). The SBD domain of HSPA8 interacts with RHIM-containing proteins, preventing proximate RHIM monomers from stacking into functional fibrils; furthermore, with the NBD domain supplying energy via ATP hydrolysis, HSPA8 breaks down pre-formed RHIM-amyloids into non-functional monomers. Notably, HSPA8's amyloidase activity in disassembling functional RHIM-amyloids does not require its co-chaperone system. Using this amyloidase activity, HSPA8 reverses the initiator RHIM-amyloids (formed by RIP1, ZBP1, and TRIF) to prevent necroptosis initiation, and reverses RIP3-amyloid to prevent necroptosis execution, thus eliminating multi-level RHIM-amyloids to effectively prevent spontaneous necroptosis activation. The discovery that HSPA8 acts as an amyloidase dismantling functional amyloids provides a fundamental understanding of the reversibility nature of functional amyloids, a property distinguishing them from disease-related amyloids that are unbreakable in vivo.

Plasma apolipoprotein O level increased in the patients with acute coronary syndrome.

Apolipoprotein (apo) O is a novel apolipoprotein that is present predominantly in high density lipoprotein (HDL). However, overexpression of apoO does not impact on plasma HDL levels or functionality in human apoA-I transgenic mice. Thus, the physiological function of apoO is not yet known. In the present study, we investigated relationships between plasma apoO levels and high-sensitive C-reactive protein (hs-CRP) levels, as well as other lipid parameters in healthy subjects (n = 111) and patients with established acute coronary syndrome (ACS) (n = 50). ApoO was measured by the sandwich dot-blot technique with recombinant apoO as a protein standard. Mean apoO level in healthy subjects was 2.21 ± 0.83 µg/ml whereas it was 4.94 ± 1.59 µg/ml in ACS patients. There were significant differences in plasma level of apoO between two groups (P < 0.001). In univariate analysis, apoO correlated significantly with lg(hsCRP) (r = 0.48, P < 0.001) in ACS patients. Notably, no significant correlation between apoO and other lipid parameters was observed. Logistic regression analysis showed that plasma apoO level was an independent predictor of ACS (OR = 5.61, 95% CI 2.16-14.60, P < 0.001). In conclusion, apoO increased in ACS patients, and may be regarded as an independent inflammatory predictor of ACS patients.

Apolipoprotein A5 internalized by human adipocytes modulates cellular triglyceride content.

Apolipoprotein A5 (apoA5), an important determinant of plasma triglyceride (TG) levels, has been recently reported to modulate TG metabolism in hepatocytes. In this study, we investigated whether apoA5 can be internalized by adipocytes and regulate cellular TG storage. Human preadipocytes, derived from subcutaneous adipose tissue of patients undergoing abdominal surgery, were differentiated into mature adipocytes. Pulse-chase experiments revealed that apoA5 was internalized into human adipocytes, and ∼70% of the apoA5 internalized during the pulse remained intracellular within a 24-h chase, while 30% was degraded. Preincubation with heparin and the receptor-associated protein, both of which prevented the apoA5 interaction with members of the low-density lipoprotein receptor gene family, markedly reduced the uptake of apoA5 by 61% and 52%, respectively, which were subsequently confirmed by Western blot analysis. Using confocal microscopy, we demonstrated that labeled apoA5 surrounded lipid droplets in human adipocytes and colocalized with the known lipid droplet protein perilipin. Importantly, treatment of adipocytes with apoA5 significantly decreased cellular TG storage. In conclusion, apoA5 can be internalized by human adipocytes and may act as a novel regulator to control TG storage in human adipocytes.

Co-expression of DDR2 and IFITM1 promotes breast cancer cell proliferation, migration and invasion and inhibits apoptosis.

PURPOSE: To investigate the roles of DDR2 and IFITM1 in breast cancer (BC). METHODS: The expression of DDR2 and IFITM1 in BC tissues and cell lines was measured. DDR2 and/or IFITM1 were knocked down in BT20 and MDA-MB-231 cells, after which the viability, mobility and apoptosis of the cells were tested. Xenograft mouse models were established through subcutaneous tumor transplantation. RESULTS: DDR2 and IFITM1 were highly expressed in invasive BC tissues and cell lines. Overexpression of DDR2 and/or IFITM1 was associated with poorer clinical outcomes and patient survival. Knockdown of DDR2 or IFITM1 suppressed the viability and invasiveness of BT20 and MDA-MB-231 cells and restrained the growth of xenograft tumors in nude mice. Simultaneous knockdown of IFITM1 and DDR2 surpassed knockdown of IFITM1 alone in suppressing BC development. CONCLUSIONS: DDR2 and IFITM1 are co-expressed to facilitate the malignant behaviors of BC cells and promote the development of tumors.

Al-MPS Obstructs EMT in Breast Cancer by Inhibiting Lipid Metabolism via miR-215-5p/SREBP1.

Alkali-extractable mycelial polysaccharide (Al-MPS) is a natural macromolecular polymer that has shown anti-hyperlipidemic and antitumor abilities. This study investigates the mechanism by which Al-MPS inhibits lipid metabolism and epithelial-mesenchymal transition (EMT) in breast cancer (BC). BC cells (MCF-7 and MDA-MB-231) were transfected and/or treated with Al-MPS. CCK-8, Transwell, and scratch assays were used to evaluate the tumorigenic behaviors of BC cells. The expression levels of SREBP1, E-cadherin, N-cadherin, Snail, vimentin, FASN, ACLY, and ACECS1 in BC cells were detected by Western blotting. Dual-luciferase reporter and RNA pull-down assays were performed to verify the binding between miR-215-5p and SREBP1 mRNA. Nude mice were injected with MDA-MB-231 cells and treated with Al-MPS. The changes in tumor volume and protein expression were monitored. miR-215-5p was downregulated and SREBP1 was upregulated in BC. Al-MPS increased miR-215-5p expression and inhibited SREBP1 expression, lipid metabolism, and EMT in BC. Inhibition of miR-215-5p or overexpression of SREBP1 promoted the tumorigenic behaviors of BC cells by stimulating lipid metabolism and counteracted the antitumor effect of Al-MPS. SREBP1 was a downstream target of miR-215-5p. In conclusion, Al-MPS inhibits lipid metabolism and EMT in BC via the miR-215-5p/SREBP1 axis. This study supports the application of polysaccharides in cancer treatment and the molecules regulated by Al-MPS may be used as biomarkers or therapeutic targets for BC.

A feasibility study on improving the non-invasive detection accuracy of bottled Shuanghuanglian oral liquid using near infrared spectroscopy.

The ultimate goal of the study is to present a strategy to improve the accuracy of near-infrared spectroscopy detection of Shuanghuanglian oral liquid in glass bottles without damaging the primary packaging. we adopted the multi-position spectral modeling (MPSM) method to correct the spectral variation caused by the difference of bottle and measuring position, so as to improve the measurement accuracy and find the best site combination for measuring Shuanghuanglian oral liquid. Baicalin, total flavonoids and soluble solid contents were considered as the quality indicators of the oral liquid, and partial least squares (PLS) models were employed for the single-position and multi-position spectra, respectively. The root mean square error of the validation set (RMSEP) of the optimum multi-position models are 0.7412 mg/mL for baicalin, 1.1259 mg/mL for total flavonoids and 0.9491% for soluble solids contents. Compared with the traditional single-position spectral modeling method (SPSM method), MPSM method improved the prediction accuracy of baicalin, total flavonoids and soluble solid contents by 26.84%, 31.97% and 58.14% respectively. The results showed that the MPSM method can improve the measurement accuracy of bottled oral liquid and is an effective method to eliminate the uncertainty of measurement conditions.

Slc6a13 Deficiency Attenuates Pasteurella multocida Infection-Induced Inflammation via Glycine-Inflammasome Signaling.

We have previously demonstrated that Slc6a13-deficient (Slc6a13-/-; KO) mice are resistant to P. multocida infection, which might be in connection with macrophage-mediated inflammation; however, the specific metabolic mechanism is still enigmatic. Here we reproduce the less sensitive to P. multocida infection in overall survival assays as well as reduced bacterial loads, tissue lesions, and inflammation of lungs in KO mice. The transcriptome sequencing analysis of wild-type (WT) and KO mice shows a large number of differentially expressed genes that are enriched in amino acid metabolism by functional analysis. Of note, glycine levels are substantially increased in the lungs of KO mice with or without P. multocida infection in comparison to the WT controls. Interestingly, exogenous glycine supplementation alleviates P. multocida infection-induced inflammation. Mechanistically, glycine reduces the production of inflammatory cytokines in macrophages by blocking the activation of inflammasome (NALP1, NLRP3, NLRC4, AIM2, and Caspase-1). Together, Slc6a13 deficiency attenuates P. multocida infection through lessening the excessive inflammatory responses of macrophages involving glycine-inflammasome signaling.

Association between Long-Term Changes in Dietary Percentage of Energy from Fat and Obesity: Evidence from over 20 Years of Longitudinal Data.

Objectives: This study assessed the associations between long-term trajectories of percentage of energy from fat (PEF) and obesity among Chinese adults. Methods: Longitudinal data collected by the China Health and Nutrition Survey from 1991 to 2015 were analyzed. A body mass index ≥28.0 was defined as general obesity. Participants' baseline PEF levels were categorized as lower than the recommendation of the Chinese Dietary Guideline (<20%), meeting the recommendation (20−30%), and higher than the recommendation (>30%). Patterns of PEF trajectories were identified by latent class trajectory analysis for overall participants and participants in different baseline PEF groups, respectively. Cox proportional hazards regression models with shared frailty were used to estimate associations between PEF and obesity. Results: Data on 13,025 participants with 72,191 visits were analyzed. Four patterns of PEF trajectory were identified for overall participants and participants in three different baseline PEF groups, respectively. Among overall participants, compared with "Baseline Low then Increase Pattern" (from 12% to 20%), participants with "Baseline Normal-Low then Increase-to-High Pattern" (from 20% to 32%) had a higher hazard of obesity (hazard ratio (HR) and 95% confident interval (CI) at 1.18 (1.01−1.37)). Compared with the "Stable Pattern" group (stable at around 18% and 22%, respectively), participants with "Sudden-Increase Pattern" (from 18% to 30%) in the baseline group whose PEF levels were lower than the recommendation and those with "Sudden-Increase then Decrease Pattern" (rapidly increased from 25% to 40%, and then decreased) in the baseline group who met the recommendation had higher hazards of obesity (HRs and 95% CIs being 1.65 (1.13−2.41) and 1.59 (1.03−2.46), respectively). Conclusions: Adults with a trajectory that involved a sudden increase to a high-level PEF had a higher risk of general obesity. People should avoid increasing PEF suddenly.

Construction and expression of recombinant fusion protein of thioredoxin-ApoO.

OBJECTIVE: To construct human apolipoprotein O (apolipoprotein O, ApoO) expression vector and obtain recombinant fusion protein thioredoxin (Trx)-ApoO by pET prokaryotic expression system. METHODS: The ApoO gene fragment from the human liver cDNA library was amplified by PCR. The resulting product was cloned into pET-32a(+) vector and sequenced. The confirmed cDNA was cloned into plasmid E.coli DH10B and then transformed into E.coli BL 21 (DE3) where it was induced to express protein by isopropyl ß-D-1-thiogalactopyranoside (IPTG). The fusion protein was purified by Ni-NTA resin. RESULTS: The ApoO gene was cloned by PCR and a 519 bp DNA fragment was shown on the agarose electrophoresis. The cloned gene was sequenced and demonstrated to have the same sequence as that of human ApoO gene in GenBank which justified a successful construction of recombinant plasmid. ApoO cDNA gene fragment was induced by IPTG, and a 34 kD recombinant fusion protein Trx-ApoO was tested on sodium dodecyl sulfate polyacrylamide (SDS-PAGE). CONCLUSION: Human ApoO gene is successfully cloned and its recombinant fusion protein Trx-ApoO is expressed.

Long-term BMI change trajectories in Chinese adults and its association with the hazard of type 2 diabetes: evidence from a 20-year China Health and Nutrition Survey.

INTRODUCTION: To investigate the relationship between long-term change trajectory in body mass index (BMI) and the hazard of type 2 diabetes among Chinese adults. RESEARCH DESIGN AND METHODS: Data were obtained from the China Health and Nutrition Survey (CHNS). Type 2 diabetes was reported by participants themselves in each survey wave. The duration of follow-up was defined as the period from the first visit to the first time self-reported type 2 diabetes, death, or other loss to follow-up from CHNS. The patterns of change trajectories in BMI were derived by latent class trajectory analysis method. The Fine and Gray regression model was used to estimate HRs with corresponding 95% CIs for type 2 diabetes. RESULTS: Four patterns of the trajectories of change in BMI were identified among Chinese adults, 42.7% of participants had stable BMI change, 40.8% for moderate BMI gain, 8.9% for substantial BMI gain and 7.7% for weight loss. During the follow-up with mean 11.2 years (158 637 person-years contributed by 14 185 participants), 498 people with type 2 diabetes (3.7%) occurred. Risk of type 2 diabetes was increased by 47% among people who gained BMI more substantially and rapidly (HR: 1.47, 95% CI 1.08 to 2.02, p=0.016) and increased by 20% among those in people with the moderate BMI gain (HR: 1.20, 95% CI 0.98 to 1.48, p=0.078), compared with those with stable BMI change. CONCLUSIONS: Long-term substantial gain of BMI was significantly associated with an increased risk of type 2 diabetes in the Chinese adults.

Crocin-I alleviates the depression-like behaviors probably via modulating "microbiota-gut-brain" axis in mice exposed to chronic restraint stress.

BACKGROUND: Depressive disorder is rapidly advancing in the worldwide, and therapeutic strategy through "gut-brain" axis has been proved to be effective. Crocin, has been found to have antidepressant activity. However, there is no thorough research for the effects of crocin-I (a major active component of crocin) on depression and its underlying mechanism. METHODS: We investigated the antidepressant effect of six-week oral administration of crocin-I in a mice model of depression induced by four-week CRS. Based on the "microbiota-gut-brain" axis, we determined the effects of crocin-I administration on gut microbiota, intestinal barrier function, short chain fatty acids and neurochemical indicators. RESULTS: Administration of crocin-I at a dose of 40 mg/kg for six weeks mitigated depression-like behaviors of depressed mice as evidenced by behaviors tests. In addition, crocin-I reduced the levels of lipopolysaccharide (LPS), Interleukin-6and tumor necrosis factor-α (TNF-α) in serum and TNF-α expression in the hippocampus, and increased the hippocampal brain-derived neurotrophic factor. Besides, 16 s rRNA sequencing revealed that crocin-I mitigated the gut microbiota dysbiosis in depressed mice as represented by the decreased abundance of Proteobacteria and Bacteroidetes, Sutterella spp. and Ruminococcus spp. and increased abundances of Firmicutes, Lactobacillus spp. and Bacteroides spp. Moreover, gas chromatography-mass spectrometry revealed that crocin-I reversed the decreased levels of short-chain fatty acids (SCFAs) in feces of depressed mice. Furthermore, crocin-I improved the impaired intestinal barrier by increasing expression of Occludin and Claudin-1, which contributed to the decreased LPS leakage. LIMITATIONS: Only the male mice were used; the dose-effect relationship should be observed. CONCLUSION: These results suggested that crocin-I effectively alleviated depression-like behavior, likely depended on the gut microbiota and its modulation of intestinal barrier and SCFAs.

Bisphenol A and the Risk of Obesity a Systematic Review With Meta-Analysis of the Epidemiological Evidence.

Bisphenol A (BPA) is suspected to be associated with several chronic metabolic diseases. The aim of the present study was to review previous epidemiological studies that examined the relationship between BPA exposure and the risk of obesity. PubMed, Web of Science, and Embase databases were systematically searched by 2 independent investigators for articles published from the start of database coverage until January 1, 2020. Subsequently, the reference list of each relevant article was scanned for any other potentially eligible publications. We included observational studies published in English that measured urinary BPA. Odds ratios with corresponding 95% confidence intervals for the highest versus lowest level of BPA were calculated. Ten studies with a sample size from 888 to 4793 participants met our inclusion criteria. We found a positive correlation between the level of BPA and obesity risk. A dose-response analysis revealed that 1-ng/mL increase in BPA increased the risk of obesity by 11%. The similar results were for different type of obesity, gender, and age.

Transcriptomic Analysis of Chicken Lungs Infected With Avian and Bovine Pasteurella multocida Serotype A.

Pasteurella multocida (P. multocida) is a common animal pathogen responsible for many animal diseases. Strains from different hosts exhibit disparate degrees of effect in other species. Here, we characterize an avian P. multocida serogroup A strain (PmQ) showing high lethality to chickens and a bovine P. multocida serogroup A strain (PmCQ2) with no lethality to chickens. We used RNA-seq to profile the transcriptomes of chicken lungs infected with PmQ and PmCQ2. A total of 1,649 differentially expressed genes (DEGs) due to PmQ infection (831 upregulated genes and 818 downregulated genes) and 1427 DEGs (633 upregulated genes and 794 downregulated genes) due to PmCQ2 infection were identified. Functional analysis of these DEGs demonstrated that the TNF signaling pathway, the toll-like receptor signaling pathway, complement and coagulation cascades, and cytokine-cytokine receptor interaction were both enriched in PmQ and PmCQ2 infection. STAT and apoptosis signaling pathways were uniquely enriched by PmQ infection, and the NOD-like receptor signaling pathway was enriched only by PmCQ2 infection. Cell-type enrichment analysis of the transcriptomes showed that immune cells, including macrophages and granulocytes, were enriched in both infection groups. Collectively, our study profiled the transcriptomic response of chicken lungs infected with P. multocida and provided valuable information to understand the chicken responses to P. multocida infection.

Legumain is a predictor of all-cause mortality and potential therapeutic target in acute myocardial infarction.

The prognostic impact of extracellular matrix (ECM) modulation and its regulatory mechanism post-acute myocardial infarction (AMI), require further clarification. Herein, we explore the predictive role of legumain-which showed the ability in ECM degradation-in an AMI patient cohort and investigate the underlying mechanisms. A total of 212 AMI patients and 323 healthy controls were enrolled in the study. Moreover, AMI was induced in mice by permanent ligation of the left anterior descending artery and fibroblasts were adopted for mechanism analysis. Based on the cut-off value for the receiver-operating characteristics curve, AMI patients were stratified into low (n = 168) and high (n = 44) plasma legumain concentration (PLG) groups. However, PLG was significantly higher in AMI patients than that in the healthy controls (median 5.9 µg/L [interquartile range: 4.2-9.3 µg/L] vs. median 4.4 µg/L [interquartile range: 3.2-6.1 µg/L], P < 0.001). All-cause mortality was significantly higher in the high PLG group compared to that in the low PLG group (median follow-up period, 39.2 months; 31.8% vs. 12.5%; P = 0.002). Multivariate Cox regression analysis showed that high PLG was associated with increased all-cause mortality after adjusting for clinical confounders (HR = 3.1, 95% confidence interval (CI) = 1.4-7.0, P = 0.005). In accordance with the clinical observations, legumain concentration was also increased in peripheral blood, and infarcted cardiac tissue from experimental AMI mice. Pharmacological blockade of legumain with RR-11a, improved cardiac function, decreased cardiac rupture rate, and attenuated left chamber dilation and wall thinning post-AMI. Hence, plasma legumain concentration is of prognostic value in AMI patients. Moreover, legumain aggravates cardiac remodelling through promoting ECM degradation which occurs, at least partially, via activation of the MMP-2 pathway.

Membrane-bound TNF mediates microtubule-targeting chemotherapeutics-induced cancer cytolysis via juxtacrine inter-cancer-cell death signaling.

Microtubule-targeting agents (MTAs) are a class of most widely used chemotherapeutics and their mechanism of action has long been assumed to be mitotic arrest of rapidly dividing tumor cells. In contrast to such notion, here we show-in many cancer cell types-MTAs function by triggering membrane TNF (memTNF)-mediated cancer-cell-to-cancer-cell killing, which differs greatly from other non-MTA cell-cycle-arresting agents. The killing is through programmed cell death (PCD), either in way of necroptosis when RIP3 kinase is expressed, or of apoptosis in its absence. Mechanistically, MTAs induce memTNF transcription via the JNK-cJun signaling pathway. With respect to chemotherapy regimens, our results establish that memTNF-mediated killing is significantly augmented by IAP antagonists (Smac mimetics) in a broad spectrum of cancer types, and with their effects most prominently manifested in patient-derived xenograft (PDX) models in which cell-cell contacts are highly reminiscent of human tumors. Therefore, our finding indicates that memTNF can serve as a marker for patient responsiveness, and Smac mimetics will be effective adjuvants for MTA chemotherapeutics. The present study reframes our fundamental biochemical understanding of how MTAs take advantage of the natural tight contact of tumor cells and utilize memTNF-mediated death signaling to induce the entire tumor regression.