Angiogenin-mediated tsRNAs control inflammation and metabolic disorder by regulating NLRP3 inflammasome.

The cellular stress response system in immune cells plays a crucial role in regulating the development of inflammatory diseases. In response to cellular damage or microbial infection, the assembly of the NLRP3 inflammasome induces pyroptosis and the release of inflammatory cytokines. Meanwhile, Angiogenin (Ang)-mediated transfer RNA-derived small RNAs (tsRNAs) promote cell survival under stressful conditions. While both tsRNAs and inflammasomes are induced under stress conditions, the interplay between these two systems and their implications in regulating inflammatory diseases remains poorly understood. In this study, it was demonstrated that Ang deficiency exacerbated sodium arsenite-induced activation of NLRP3 inflammasome and pyroptosis. Moreover, Ang-induced 5'-tsRNAs inhibited NLRP3 inflammasome activation and pyroptosis. Mechanistically, 5'-tsRNAs recruit DDX3X protein into stress granules (SGs), consequently inhibiting the interaction between DDX3X and NLRP3, thus leading to the suppression of NLRP3 inflammasome activation. Furthermore, in vivo results showed that Ang deficiency led to the downregulation of tsRNAs, ultimately leading to an exacerbation of NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation and type-2 diabetes-related inflammation. Altogether, our study sheds a new light on the role of Ang-induced 5'-tsRNAs in regulating NLRP3 inflammasome activation via SGs, and highlights tsRNAs as a promising target for the treatment of NLRP3 inflammasome-related diseases.

Ribosome-targeting antibiotic control NLRP3-mediated inflammation by inhibiting mitochondrial DNA synthesis.

While antibiotics are designed to target bacteria specifically, most are known to affect host cell physiology. Certain classes of antibiotics have been reported to have immunosuppressive effects, but the underlying mechanisms remain elusive. Here, we show that doxycycline, a ribosomal-targeting antibiotic, effectively inhibited both mitochondrial translation and nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome-mediated caspase-1 activation and interleukin-1ß (IL-1ß) production in bone-marrow-derived macrophages (BMDMs). In addition, knockdown of mitochondrial methionyl-tRNA formyltransferase (Mtfmt), which is rate limiting for mitochondrial translation, also resulted in the inhibition of NLRP3 inflammasome-mediated caspase-1 activation and IL-1ß secretion. Furthermore, both doxycycline treatment and Mtfmt knockdown blocked the synthesis of mitochondrial DNA (mtDNA) and the generation of oxidized mtDNA (Ox-mtDNA), which serves as a ligand for NLRP3 inflammasome activation. In addition, in vivo results indicated that doxycycline mitigated NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation and endometritis. Taken together, the results unveil the antibiotics targeting the mitoribosome have the ability to mitigate NLRP3 inflammasome activation by inhibiting mitochondrial translation and mtDNA synthesis thus opening up new possibilities for the treatment of NLRP3-related diseases.

Sparse Low-Rank Multi-View Subspace Clustering With Consensus Anchors and Unified Bipartite Graph.

Anchor technology is popularly employed in multi-view subspace clustering (MVSC) to reduce the complexity cost. However, due to the sampling operation being performed on each individual view independently and not considering the distribution of samples in all views, the produced anchors are usually slightly distinguishable, failing to characterize the whole data. Moreover, it is necessary to fuse multiple separated graphs into one, which leads to the final clustering performance heavily subject to the fusion algorithm adopted. What is worse, existing MVSC methods generate dense bipartite graphs, where each sample is associated with all anchor candidates. We argue that this dense-connected mechanism will fail to capture the essential local structures and degrade the discrimination of samples belonging to the respective near anchor clusters. To alleviate these issues, we devise a clustering framework named SL-CAUBG. Specifically, we do not utilize sampling strategy but optimize to generate the consensus anchors within all views so as to explore the information between different views. Based on the consensus anchors, we skip the fusion stage and directly construct the unified bipartite graph across views. Most importantly, l1 norm and Laplacian-rank constraints employed on the unified bipartite graph make it capture both local and global structures simultaneously. l1 norm helps eliminate the scatters between anchors and samples by constructing sparse links and guarantees our graph to be with clear anchor-sample affinity relationship. Laplacian-rank helps extract the global characteristics by measuring the connectivity of unified bipartite graph. To deal with the nondifferentiable objective function caused by l1 norm, we adopt an iterative re-weighted method and the Newton's method. To handle the nonconvex Laplacian-rank, we equivalently transform it as a convex trace constraint. We also devise a four-step alternate method with linear complexity to solve the resultant problem. Substantial experiments show the superiority of our SL-CAUBG.

Bile acids ameliorates lipopolysaccharide-induced endometritis in mice by inhibiting NLRP3 inflammasome activation.

AIMS: Endometritis is a common inflammatory disorder affecting the reproductive health in both humans and livestock. The NLR family pyrin domain containing 3 (NLRP3) inflammasome has recently been identified as a possible therapeutic target for several inflammatory disorders. Bile acids (BAs) have been shown to possess anti-inflammatory properties by inhibiting the activation of the NLRP3 inflammasome. However, whether BAs ameliorate endometritis by targeting NLRP3 inflammasome remain poorly understood. MAIN METHODS: Female NLRP3+/+ and NLRP3-/- mice were subjected to uterine perfusion with lipopolysaccharide (LPS) to establish the endometritis model. For BAs pre-treatment, wild-type mice were administered oral gavage of BAs for seven days followed by uterine perfusion with LPS. All mice were euthanized and the uterine tissues were collected for analysis. KEY FINDINGS: The abundances of NLRP3 and interleukin-1 beta (IL-1ß) were significantly upregulated in the uterine tissues of endometritis mice. NLRP3 deficiency led to a reduction in the inflammatory response, neutrophil infiltration, and myeloperoxidase (MPO) activity in the uterus, as well as an inhibition of IL-1ß secretion. Moreover, BAs pre-treatment successfully decreased LPS-induced upregulation of NLRP3, ASC, and Caspase1, lessened histopathological alteration in the uterus, and notably reduced MPO activity and secretion of IL-1ß. SIGNIFICANCE: NLRP3 inflammasome is a promising target for endometritis treatment and BAs exhibit anti-inflammatory properties by repressing NLRP3 inflammasome activation, making them a possible novel therapeutic strategy for endometritis.

Regularized Simple Multiple Kernel k -Means With Kernel Average Alignment.

Multiple kernel clustering (MKC) aims to learn an optimal kernel to better serve for clustering from several precomputed basic kernels. Most MKC algorithms adhere to a common assumption that an optimal kernel is linearly combined by basic kernels. Based on a min-max framework, a newly proposed MKC method termed simple multiple kernel k -means (SimpleMKKM) can acquire a high-quality unified kernel. Although SimpleMKKM has achieved promising clustering performance, we observe that it cannot benefit from any prior knowledge. This would cause the learned partition matrix may seriously deviate from the expected one, especially in clustering tasks where the ground truth is absent during the learning course. To tackle this issue, we propose a novel algorithm termed regularized simple multiple kernel k -means with kernel average alignment (R-SMKKM-KAA). According to the experimental results of existing MKC algorithms, the average partition is a strong baseline to reflect true clustering. To gain knowledge from the average partition, we add the average alignment as a regularization term to prevent the learned unified partition from being far from the average partition. After that, we have designed an efficient solving algorithm to optimize the new resulting problem. In this way, both the incorporated prior knowledge and the combination of basic kernels are helpful to learn better unified partition. Consequently, the clustering performance can be significantly improved. Extensive experiments on nine common datasets have sufficiently demonstrated the effectiveness of incorporation of prior knowledge into SimpleMKKM.

Mitochondrial Methionyl-tRNA Formyltransferase Deficiency Alleviates Metaflammation by Modulating Mitochondrial Activity in Mice.

Various studies have revealed the association of metabolic diseases with inflammation. Mitochondria are key organelles involved in metabolic regulation and important drivers of inflammation. However, it is uncertain whether the inhibition of mitochondrial protein translation results in the development of metabolic diseases, such that the metabolic benefits related to the inhibition of mitochondrial activity remain unclear. Mitochondrial methionyl-tRNA formyltransferase (Mtfmt) functions in the early stages of mitochondrial translation. In this study, we reveal that feeding with a high-fat diet led to the upregulation of Mtfmt in the livers of mice and that a negative correlation existed between hepatic Mtfmt gene expression and fasting blood glucose levels. A knockout mouse model of Mtfmt was generated to explore its possible role in metabolic diseases and its underlying molecular mechanisms. Homozygous knockout mice experienced embryonic lethality, but heterozygous knockout mice showed a global reduction in Mtfmt expression and activity. Moreover, heterozygous mice showed increased glucose tolerance and reduced inflammation, which effects were induced by the high-fat diet. The cellular assays showed that Mtfmt deficiency reduced mitochondrial activity and the production of mitochondrial reactive oxygen species and blunted nuclear factor-κB activation, which, in turn, downregulated inflammation in macrophages. The results of this study indicate that targeting Mtfmt-mediated mitochondrial protein translation to regulate inflammation might provide a potential therapeutic strategy for metabolic diseases.

Small Noncoding RNAs Contribute to Sperm Oxidative Stress-Induced Programming of Behavioral and Metabolic Phenotypes in Offspring.

There is growing evidence that paternal environmental information alters small noncoding RNAs (sncRNAs) in sperm and in turn can induce alterations of metabolic and behavioral phenotypes of the next generation. However, the potential mediators of the effects remain to be elucidated. A great diversity of environmental insults and stresses can convergently induce the elevation of reactive oxygen species (ROS) in sperm; nonetheless, it remains unclear whether ROS mediates the biogenesis of sncRNAs in sperm and participates in the reprogramming of offspring phenotypes. Here, we show that ROS could induce the alteration of sncRNA profiles in sperm, especially for transfer RNA-derived small RNAs (tsRNAs) and ribosomal RNA-derived small RNAs (rsRNAs). Zygotic injection of 29-34 nt RNA fractions (predominantly tsRNAs and rsRNAs) from oxidative stress (OS) sperm could induce depressive-like and anxiety-like behaviors in male offspring. Moreover, zygotic injection with synthetic RNAs partially resembled OS sperm-induced depressive-like and anxiety-like behaviors in offspring. Male offspring maintained on a chow diet was found to develop impaired glucose tolerance and hyperactive hepatic gluconeogenesis, accompanied by the upregulation of hepatic gluconeogenic and lipolytic genes. Together, our results have shown that ROS-induced alteration of sncRNA profiles in sperm contributes to the alterations of behavioral and metabolic phenotypes of the offspring.

Parameter-Free and Scalable Incomplete Multiview Clustering With Prototype Graph.

Multiview clustering (MVC) seamlessly combines homogeneous information and allocates data samples into different communities, which has shown significant effectiveness for unsupervised tasks in recent years. However, some views of samples may be incomplete due to unfinished data collection or storage failure in reality, which refers to the so-called incomplete multiview clustering (IMVC). Despite many IMVC pioneer frameworks have been introduced, the majority of their approaches are limited by the cubic time complexity and quadratic space complexity which heavily prevent them from being employed in large-scale IMVC tasks. Moreover, the massively introduced hyper-parameters in existing methods are not practical in real applications. Inspired by recent unsupervised multiview prototype progress, we propose a novel parameter-free and scalable incomplete multiview clustering framework with the prototype graph termed PSIMVC-PG to solve the aforementioned issues. Different from existing full pair-wise graph studying, we construct an incomplete prototype graph to flexibly capture the relations between existing instances and discriminate prototypes. Moreover, PSIMVC-PG can directly obtain the prototype graph without pre-process of searching hyper-parameters. We conduct massive experiments on various incomplete multiview tasks, and the performances show clear advantages over existing methods. The code of PSIMVC-PG can be publicly downloaded at https://github.com/wangsiwei2010/PSIMVC-PG.

Fast Incomplete Multi-View Clustering With View-Independent Anchors.

Multi-view clustering (MVC) methods aim to exploit consistent and complementary information among each view and achieve encouraging performance improvement than single-view counterparts. In practical applications, it is common to obtain instances with partially available information, raising researches of incomplete multi-view clustering (IMC) issues. Recently, several fast IMC methods have been proposed to process the large-scale partial data. Though with considerable acceleration, these methods seek view-shared anchors and ignore specific information among single views. To tackle the above issue, we propose a fast IMC with view-independent anchors (FIMVC-VIA) method in this article. Specifically, we learn individual anchors based on the diversity of distribution among each incomplete view and construct a unified anchor graph following the principle of consistent clustering structure. By constructing an anchor graph instead of pairwise full graph, the time and space complexities of our proposed FIMVC-VIA are proven to be linearly related to the number of samples, which can efficiently solve the large-scale task. The experiment performed on benchmarks with different missing rate illustrates the improvement in complexity and effectiveness of our method compared with other IMC methods. Our code is publicly available at https://github.com/Tracesource/ FIMVC-VIA.

The individual N- and C-lobes of calmodulin tether to the Cav1.2 channel and rescue the channel activity from run-down in ventricular myocytes of guinea-pig heart.

The present study examined the binding of the individual N- and C-lobes of calmodulin (CaM) to Cav1.2 at different Ca(2+) concentration ([Ca(2+)]) from ≈ free to 2mM, and found that they may bind to Cav1.2 Ca(2+)-dependently. In particular, using the patch-clamp technique, we confirmed that the N- or C-lobes can rescue the basal activity of Cav1.2 from run-down, demonstrating the functional relevance of the individual lobes. The data imply that at resting [Ca(2+)], CaM may tether to the channel with its single lobe, leading to multiple CaM molecule binding to increase the grade of Ca(2+)-dependent regulation of Cav1.2.

Lentiviral delivery of biglycan promotes proliferation and increases osteogenic potential of bone marrow-derived mesenchymal stem cells in vitro.

Mesenchymal stem cells (MSCs) are multipotent progenitor nonhematopoietic cells that have emerged as an attractive cell source for tissue engineering. Biglycan (BGN), an extracellular matrix component, has been reported to play a crucial role in bone formation. However, the role of BGN in MSCs remains unknown. Using lentiviral gene delivery, we sought to investigate the cellular effects of BGN on proliferation and osteogenic potential of bone marrow-derived MSCs in vitro. We found that MSCs with lentiviral transduction of BGN exhibited an increase in growth ability and the percentage of the S phase, together with significantly reduced mRNA levels of p21 and p27. Furthermore, lentiviral transduction of BGN in MSCs also increased alkaline phosphatase activity, stimulated the mineralization capacity, and enhanced expression of Runx2, Osteocalcin, collagen I, transforming growth factor (TGF)-ß1, p-Smad2 and p-Smad3. Taken together, our data suggest that BGN overexpression positively regulates proliferation and osteogenic potential of MSCs, and TGF-ß signaling pathway may be involved in BGN-induced osteogenic potential of MSCs.

The effects of chronic aluminum exposure on learning and memory of rats by observing the changes of Ras/Raf/ERK signal transduction pathway.

OBJECTIVE: To investigate the effects of chronic aluminum (Al) exposure on learning and memory function of rats by observing the changes of Ras/Raf/ERK (Ras/ERK) signaling pathway. METHODS: Eighty weaned Wistar rats were divided into four groups ad libitum, 20 rats in each group. The four groups were fed with drinking water containing 0% (control), 0.2%, 0.4% and 0.6% (Al exposure) AlCl(3) for 3months individually to set up aluminum exposure models. The laboratory was maintained at 18-23°C and 45-55% relative humidity. Graphite furnace atomic absorption spectrometry was used to detect the content of Al in brain and blood. Western blot and real-time PCR (RT-PCR) were used to determine the protein and mRNA expression levels for Ras, Raf1, ERK2 and CREB. RESULTS: Chronic Al exposure increased the content of Al in rats' blood and brain. It increased expression of Ras in the hippocampi compared with the control but the expression decreased along the Al exposure groups (p<0.05). Similarly, Raf1, ERK2 and CREB expressions decreased compared to the control in a dose-dependent manner (p<0.05). CONCLUSION: Chronic Al exposure may affect learning and memory through impact on Ras/ERK signal pathway.

Supplementation of konjac glucomannan into a low-fiber Chinese diet promoted bowel movement and improved colonic ecology in constipated adults: a placebo-controlled, diet-controlled trial.

OBJECTIVES: This diet-controlled study was designed to examine effects of konjac glucomannan (KGM) supplement on the bowel habits and colonic ecology in 7 constipated subjects. In addition, the mechanisms by which KGM modulated the bowel habit were explored. METHODS: Seven constipated subjects who passed bowel movement less than once a day participated in this diet-controlled linear study that consisted of a 21-d placebo period, a 7-d adaptation period, and a 21-d KGM-supplemented (1.5 g, tid) period. The large bowel response and fecal characteristics were recorded daily. Stools were collected individually on days 15-21 of placebo and KGM periods for analyses of colonic ecology indices such as fecal microflora, pH and short chain fatty acid content. Fecal component was determined to illustrate the fermentation of KGM. RESULTS: KGM supplement slightly but significantly increased the weekly defecation frequency from 4.1 +/- 0.6 to 5.3 +/- 0.6 and slightly eased the bowel movement. The fecal wet weight (g/d) and percent moisture were not significantly altered with the fiber supplement. However, the dry fecal weight (g/d) was increased mainly in the soluble mass. KGM supplement increased the fecal concentration (log counts/g wet feces) of lactobacilli, and the daily output (log counts/d) of bifidobacteria, lactobacilli and total bacteria in this diet-controlled study. In addition, fermentation of KGM resulted in greater fecal acetate, propionate and i-butyrate concentrations and lower fecal pH. CONCLUSION: The modest dose of KGM supplement promoted bowel movement by 30% and improved colonic ecology in constipated adults.

Konjac acts as a natural laxative by increasing stool bulk and improving colonic ecology in healthy adults.

OBJECTIVE: Konjac glucomannan (KGM) has been shown to relieve constipation, which could be associated with increased stool bulk and improved colonic ecology. METHODS: This placebo-controlled study consisted of a 21-d placebo period, a 7-d adaptation period when volunteers consumed KGM progressively, and a 21-d KGM-supplemented period (1.5 g/meal, 4.5 g/d). Eight healthy adults consumed 7-d cycle menus of typical low-fiber Chinese food throughout the study. The gastrointestinal response was monitored daily. Stools were fully collected on days 15 to 21 of placebo and KGM periods to determine the fecal mass, components, microflora, and short-chain fatty acid contents. RESULTS: The KGM supplement significantly increased the mean defecation frequency (number/day), wet stool weight, and dry stool weight (g/d) by approximately 27.0% (P < 0.05), 30.2% (P < 0.05), and 21.7% (P < 0.05), respectively. The dry fecal mass increased mainly in the plant and soluble material, whereas bacterial mass tended to increase from 12.9 +/- 1.6 to 13.6 +/- 2.7 g/d (P > 0.05). However, KGM significantly promoted the fecal concentrations (log counts/g wet feces) of lactobacilli (P < 0.05) and total bacteria (P < 0.05), and promoted the daily output (log counts per day) of bifidobacteria (P < 0.05), lactobacilli (P < 0.05), and total bacteria (P < 0.05) as evaluated by the fluorescence in situ hybridization method. KGM supplement also promoted colonic fermentation as shown in the decreased fecal pH (P < 0.05) and increased fecal short-chain fatty acid concentrations (P < 0.05). CONCLUSION: Supplementation of KGM into a low-fiber diet promoted the defecation frequency in healthy adults, possibly by increasing the stool bulk, thus promoting the growth of lactic acid bacteria and colonic fermentation.

[Effect of lead on learn and memory and release of intracellular free Ca2+ from calcium pool in dissociated mouse hippocampal neurons].

OBJECTIVE: To study effect of lead on learn and memory and the release of intracellular free Ca2+ from calcium pool in dissociated mouse hippocampal neurons. METHODS: Using a water maze we measured the ability of spatial learning of mouses. Digesting with low concentration of trypsin and gently triturating mode were used to dissociate hippocampal neurons. Using inositol 1,4,5-triphosphate (IP3) sensitive calcium store antagonist-heparine and non-IP3 sensitive calcium store (ryanodine) antagonist-procaine to stimulate hippocampal neurons, and observed the effect of Pb2+ on [Ca2+]i of hippocampal neurons by Fura-2 double wavelength fluoremetry. RESULTS: In the Morris water maze task, results indicated that mouses having drink lead water displayed significant impairment in their performance, and this extent of impairment showed in lead concentration dependent manner. Compared with control group, in condition of none of extracellular free calcium, 25 micromol x L(-1) of Pb2+ induced markedly increase of intracellular free calcium of hippocampal neurons in mouse. Heparin (IP3 sensitive calcium store antagonist) of 30 microg x ml(-1) and procaine (non-IP3 sensitive calcium store atagonist) of 0.1 mg x ml(-1) blocked the increases of [Ca2+]i in mouse hippocampal neurons elicited by 25 micromol x L(-1) of Pb2+. CONCLUSION: Chronic exposure to lead (Pb2+) reduces the ability of spatial learing and memory of mice. High level of Pb2+ facilitated release of intracellular free calcium from IP3 sensitive and non-IP3 sensitive calcium store and induced the increases of intracellular free calcium in mouse hippocampal neurons.