Corrigendum: Macrophage SREBP1 regulates skeletal muscle regeneration.

[This corrects the article DOI: 10.3389/fimmu.2023.1251784.].

Effect of electroacupuncture on neuronal programmed necrosis by regulating RIP1/RIP3/MLKL pathway in rats with cerebral ischemia reperfusion injury. / 电针调节RIP1/RIP3/MLKLé€šè·¯å¯¹è„‘ç¼ºè¡€å†çŒæ³¨æŸä¼¤å¤§é¼ ç¥žç»å ƒç¨‹åºæ€§åæ­»çš„å½±å“.

OBJECTIVES: To investigate the neuroprotective effect of electroacupuncture (EA) at "Quchi"(LI11) and "Zusanli"(ST36) in the rats with cerebral ischemia reperfusion injury and its influence on programmed necrosis of cerebral cortical neurons. METHODS: Sixty male SD rats were randomly divided into sham-operation group, model group, EA group and inhibitor group, with 15 rats in each group. Left middle cerebral artery occlusion model was established using the modified thread embolism method. In the sham-operation group, the carotid artery was exposed and dissociated in each rat. EA was applied to "Quchi"(LI11) and "Zusanli"(ST36) on the right side for 30 min each time, once daily for 7 days in the rats of the EA group. The rats in the inhibitor group were intraperitoneally injected with norstatin-1 (0.6 mg/kg) for consecutive 7 days. The neurological deficit score of rats in each group was observed. HE staining was adopted to detect the degree of pathological damage of the cerebral cortex in the infarction area. Using TUNEL staining, the apoptosis of cortical neurons in the infarction area was determined；the contents of tumor necrosis factor α (TNF-α), interleukin (IL)-1ß and IL-6 were detected by ELISA；the mRNA and protein expression of the receptor interacting protein-1 (RIP1), the receptor interacting protein-3 (RIP3) and the substrate mixed lineage kinase like protein (MLKL) were detected by fluorescence quantitative PCR and Western blot, respectively. RESULTS: In comparison with the sham-operation group, the neurological deficit score in the model group was higher(P<0.01)；HE staining showed that there was the pathological damage in the infarction area；the neuron apoptosis rate, the contents of TNF-α, IL-1ß and IL-6, and the mRNA and protein expressions of RIP1, RIP3 and MLKL increased(P<0.01) in the model group. In the EA group, the neurological deficit score was reduced(P<0.01)；HE staining showed that the pathological damage was ameliorated in the infarction area；the neuron apoptosis rate, the contents of TNF-α, IL-1ß and IL-6, and the mRNA and protein expressions of RIP1, RIP3, MLKL decreased(P<0.05, P<0.01) when compared with those in the model group. CONCLUSIONS: EA can attenuate cerebral ischemia reperfusion injury and display its neuroprotective effect probably through inhibiting programmed necrosis of cerebral cortical neurons in the rats.

Effect of LncRNA p21 regulating Hippo-YAP signaling pathway on formation of abdominal aortic aneurysm in mice and its mechanism / 中国药理学通报

Aim To investigate the effect of long non- coding RNA p21 (LncRNA p21) regulating Hippo- Yes-associated protein (Hippo-YAP) signaling pathway on the formation of abdominal aortic aneurysm (AAA) in mice. Methods C57BL/6 ApoE

Caspase-11 contributes to site-1 protease cleavage and SREBP1 activation in the inflammatory response of macrophages.

Sterol regulatory element-binding proteins (SREBPs) are key transcription factors that control fatty acid and cholesterol metabolism. As the major SREBP isoform in macrophages, SREBP1a is also required for inflammatory and phagocytotic functions. However, it is insufficiently understood how SREBP1a is activated by the innate immune response in macrophages. Here, we show that mouse caspase-11 is a novel inflammatory activator of SREBP1a in macrophages. Upon LPS treatment, caspase-11 was found to promote the processing of site-1 protease (S1P), an enzyme that mediates the cleavage and activation of SREBP1. We also determined that caspase-11 directly associates with S1P and cleaves it at a specific site. Furthermore, deletion of the Casp4 gene, which encodes caspase-11, impaired the activation of S1P and SREBP1 as well as altered the expression of genes regulated by SREBP1 in macrophages. These results demonstrate that the caspase-11/S1P pathway activates SREBP1 in response to LPS, thus regulating subsequent macrophage activation.

Bioinformatic Analysis of the Subproteomic Profile of Cardiomyopathic Tissue.

Following large-scale protein separation by two-dimensional gel electrophoresis or liquid chromatography, mass spectrometry-based proteomics can be used for the swift identification and characterization of cardiac proteins and their various proteoforms. Comparative cardiac proteomics has been widely applied for the systematic analysis of heart disease and the establishment of novel diagnostic protein biomarkers. The X-linked neuromuscular disorder Duchenne muscular dystrophy is a multisystemic disease that is characterized by late-onset cardiomyopathy. This chapter outlines the bioinformatic analysis of the subproteomic profile of cardiac tissue from wild-type versus the dystrophic mdx-4cv mouse model of dystrophinopathy.

Macrophage SREBP1 regulates skeletal muscle regeneration.

Macrophages are essential for the proper inflammatory and reparative processes that lead to regeneration of skeletal muscle after injury. Recent studies have demonstrated close links between the function of activated macrophages and their cellular metabolism. Sterol regulatory element-binding protein 1 (SREBP1) is a key regulator of lipid metabolism and has been shown to affect the activated states of macrophages. However, its role in tissue repair and regeneration is poorly understood. Here we show that systemic deletion of Srebf1, encoding SREBP1, or macrophage-specific deletion of Srebf1a, encoding SREBP1a, delays resolution of inflammation and impairs skeletal muscle regeneration after injury. Srebf1 deficiency impairs mitochondrial function in macrophages and suppresses the accumulation of macrophages at sites of muscle injury. Lipidomic analyses showed the reduction of major phospholipid species in Srebf1 -/- muscle myeloid cells. Moreover, diet supplementation with eicosapentaenoic acid restored the accumulation of macrophages and their mitochondrial gene expression and improved muscle regeneration. Collectively, our results demonstrate that SREBP1 in macrophages is essential for repair and regeneration of skeletal muscle after injury and suggest that SREBP1-mediated fatty acid metabolism and phospholipid remodeling are critical for proper macrophage function in tissue repair.

Anabolism and signaling pathways of phytomelatonin.

Phytomelatonin is a small multifunctional molecule found ubiquitously in plants, which plays an important role in plant growth, development, and biotic and abiotic stress responses. The classical biosynthetic and metabolic pathways of phytomelatonin have been elucidated, and uncovering alternative pathways has deepened our understanding of phytomelatonin synthesis. Phytomelatonin functions mainly via two pathways. In the direct pathway, phytomelatonin mediates the stress-induced reactive oxygen species burst through its strong antioxidant capacity. In the indirect pathway, phytomelatonin acts as a signal to activate signaling cascades and crosstalk with other plant hormones. The phytomelatonin receptor PMTR1/CAND2 was discovered in 2018, which enhanced our understanding of phytomelatonin function. This review summarizes the classical and potential pathways involved in phytomelatonin synthesis and metabolism. To elucidate the functions of phytomelatonin, we focus on the crosstalk between phytomelatonin and other phytohormones. We propose two models to explain how PMTR1 transmits the phytomelatonin signal through the G protein and MAPK cascade. This review will facilitate the identification of additional signaling molecules that function downstream of the phytomelatonin signaling pathway, thus improving our understanding of phytomelatonin signal transmission.

Effects of velvet antler polypeptide on Rho/ROCK pathway in APP/ PSl double transgenic mice / 解剖学报

Objective To study the effect of velvet antler polypeptides (VAP) on Rho/ROCK pathway in APP/ PSl double transgenic mice. Methods APP/PSl double transgenic mice were randomly divided into model group and velvet antler polypeptide group, 20 mice in each group, and control group consisting of 20 mice of the same litter and the same gender negative. The mice in VAP group were given velvet antler polypeptide 100 mg/kg by intragastric administration once a day for 28 days. After treatment, the water maze experiment was detected and recorded the escape latency and the number of crossing platforms of the mice; the ultrastructures of the synapse were observed by transmission electron microscopy; the expression of Rhs homolog gene family member A(RhoA) and Rho associated coiled-coil forming protein kinase II(ROCKII) in the hippocampal CAI area were observed by immunofluorescence. The expression levels of RhoA and ROCKII protein in the hippocampus were detected by Western blotting. The contents of hippocampus amyloid (3-protein(A(3),

Alterations of Signaling Pathways in Essential Thrombocythemia with Calreticulin Mutation.

PURPOSE: Though mutations of the calreticulin (CALR) gene have been identified in essential thrombocythemia patients, the detailed mechanisms for CALR mutations have not been completely clarified. Our study is aimed at characterizing alteration of protein expression in ET patients with mutated CALRdel52 and further recognizing possible involvement of signaling pathways associated with CALR mutations. PATIENTS AND METHODS: Protein pathway array was performed to analyze the expression levels of proteins involved in various signaling pathways in peripheral blood neutrophils from 18 ET patients with mutated CALRdel52 , 20 ET patients with JAK2V617F mutation and 20 controls. RESULTS: We found 20 proteins differentially expressed in ET patients with mutated CALRdel52 compared with healthy controls. These proteins were associated with molecular mechanisms of cancer in ingenuity pathways analysis (IPA) network. We identified top ten canonical pathways which including apoptotic pathways and cellular cytokine pathways might participate in pathogenesis of ET with mutated CALRdel52 . Additionally, there were 8 proteins found to be dysregulated differently between ET patients with mutated CALRdel52 and those with JAK2V617F mutation. These proteins might be related to the unique signaling pathways activated by CALRdel52 mutation which were different to JAK/STATs pathway by JAK2V617F mutation. CONCLUSION: Our study demonstrated that numerous alterations of signaling proteins and pathways in ET patients with mutated CALRdel52 . These findings could help to gain insights into the pathological mechanisms of ET.

Characteristics of the Urinary Proteome in Women with Overactive Bladder Syndrome: A Case-Control Study.

Despite an estimated prevalence of 13% in women, the exact etiology of non-neurogenic overactive bladder syndrome is unclear. The aim of our study was to gain a better understanding of the pathophysiology of female overactive bladder syndrome by mapping the urinary proteomic profile. We collected urine samples of 20 patients with overactive bladder syndrome and of 20 controls. We used mass spectrometric analysis for label-free quantitation, Swissprot human database for data search, Scaffold for data allocation and the Reactome Knowledgebase for final pathway enrichment analysis. We identified 1897 proteins at a false discovery rate of 1% and significance level p < 0.001. Thirty-seven significant proteins of the case group and 53 of the control group met the criteria for further pathway analysis (p < 0.0003 and Log2 (fold change) >2). Significant proteins of the overactive bladder group were, according to the 25 most relevant pathways, mainly involved in cellular response to stress and apoptosis. In the control group, significant pathways mainly concerned immunological, microbial-protective processes and tissue- elasticity processes. These findings may suggest a loss of protective factors as well as increased cellular response to stress and apoptosis in overactive bladder syndrome.

The protective effect of nnano-selenium against cadmium-induced cerebellar injury via the heat shock protein pathway in chicken.

Cadmium (Cd) is one of the toxic environmental heavy metals that poses health hazard to animals due to its toxicity. Nano-Selenium (Nano-Se) is a Nano-composite form of Se, which has emerged as a promising therapeutic agent for its protective roles against heavy metals-induced toxicity. Heat shock proteins (HSPs) play a critical role in cellular homeostasis. However, the potential protective effects of Nano-Se against Cd-induced cerebellar toxicity remain to be illustrated. To investigate the toxic effects of Cd on chicken's cerebellum, and the protective effects of Nano-Se against Cd-induced cerebellar toxicity, a total of 80 male chicks were divided into four groups and treated as follows: (A) 0 mg/kg Cd, (B) 1 mg/kg Nano-Se (C) 140 mg/kg Cd + 1 mg/kg Nano-Se (D) 140 mg/kg Cd for 90 days. We tested heat shock protein pathway-related factors including heat shock factors (HSFs) HSF1, HSF2, HSF3 and heat shock proteins (HSPs) HSP10, HSP25, HSP27, HSP40, HSP60, HSP70 and HSP90 expressions. Histopathological results showed that Cd treatment caused degradation of Purkinje cells. In addition, HSFs and HSPs expression decreased significantly in the Cd group. Nano-Se co-treatment with Cd enhanced the expression of HSFs and HSPs. In summary, our findings explicated a potential protective effect of Nano-Se against Cd-induced cerebellar injury in chicken, suggesting that Nano-Se is a promising therapeutic agent for the treatment of Cd toxicity.

Regulatory effect of microRNA-223-3p on breast cancer cell processes via the Hippo/Yap signaling pathway.

According to the 2018 global cancer statistics, the incidence and mortality rates of breast cancer are increasing gradually, which seriously threatens the health of women. MicroRNA-223-3p (miR-223-3p) can promote the proliferation and invasion of breast cancer cells. Hippo/Yes-related protein (Yap) signaling pathway activation has been found in a variety of tumors. The present study aimed to investigate the potential mechanism of miR-223-3p in breast cancer. The Cell Counting Kit-8 assay was used to detect cell viability and flow cytometry was used to detect apoptosis. The abilities of cell migration and invasion were detected using scratch and Transwell assays, as well as reverse transcription-quantitative PCR and western blotting to detect gene and protein expression, respectively. The current results demonstrated that miR-223-3p transcription levels were increased in breast cancer cells, and inhibition of miR-223-3p gene expression decreased cell proliferation, migration and invasion. Additionally, inhibition of miR-223-3p expression inhibited epithelial-mesenchymal transition (EMT) in breast cancer cells. miR-223-3p promoted cell proliferation, migration, invasion and EMT, and the western blotting results demonstrated that miR-223-3p inhibition increased the phosphorylation of Yap1 and the protein expression levels of large tumor suppressor kinase 1. In conclusion, results from the present results suggested that miR-223-3p may promote cell proliferation, migration, invasion and EMT through the Hippo/Yap signaling pathway. Therefore, miR-223-3p may be a potential biomarker for breast cancer.

Mechanism of Xiaoying Daotan decoction in treating Hashimoto's thyroiditis based on the Notch/Treg/Th17 pathway.

BACKGROUND: The study created mice model of Hashimoto's thyroiditis (HT) and induced thyroid inflammatory cell lines, exploring the mechanism of Xiaoying Daotan decoction on HT. METHODS: Divided HT mice models into model group (0.2 mL saline), Western medicine group (0.2 mL levothyroxine sodium tablets), traditional Chinese medicine group (0.2 mL Xiaoyin Daotan prescription), and Notch protein inhibition group (0.2 mL Xiaoyin Daotan prescription). After treatment, serum Notch protein expression and T cell (Treg)/T helper cell 17 (Th17) cytokines levels were detected through Enzyme linked immunosorbent assay (ELISA). Use real-time qualitative polymerase chain reaction detected Notch protein expression. Thyroid inflammatory cell lines were induced and divided into 5 groups: blank group, iNotch group (knocking down the Notch protein gene of thyroid inflammatory cells), NC group (Notch protein carrier negative control group), iNotch + DS group and DS group (knocking down the Notch protein gene of thyroid inflammatory cells). The cells were treated with serum containing Xiaoying Daotan decoction. After culture, detected Notch protein expression level and Treg/Th17 cytokine level in each group. RESULTS: For the animal experiment, the serum Notch protein expression, the serum levels of key activating proteins Signal Transducer and Activator of Transcription 3 (STAT3), RAR-related orphan receptor gamma T (RORγt), and interleukin (IL)-22 of Th17 cells of mice in the model group was significantly higher than that of the other groups. Compared with the model group and Western medicine group, the serum transforming growth factor-ß (TGF-ß) level of the mice in the traditional Chinese medicine group and the Notch protein inhibition group was significantly higher. All the differences were statistically significant (P<0.05). For the cell experiment, the ß-actin value of Notch protein in thyroid inflammatory cell genes was significantly downregulated and the key activation protein of Treg was significantly upregulated in iNotch + DS group and DS group compared with the other 3 groups. Levels of Th17 key activating proteins STAT3, IL-17, and IL-22 in the iNotch group, iNotch + DS group, and DS group were lower than those of the blank group and NC group, both with statistically significant difference (P<0.001). CONCLUSIONS: The mechanism of Xiaoying Daotan decoction on HT could be related to the immune inflammatory response of the Treg/Th17 cell axis mediated by the Notch protein pathway.

[DuzhongButiansu Capsules improve adenine-induced reproductive dysfunction in male rats].

OBJECTIVE: To study the effect of DuzhongButiansu Capsules (DBC) on adenine-induced reproductive dysfunction (RD) in male rats. METHODS: Eighty male SD rats were randomly divided into six groups, blank control (n = 8), solvent control (n = 8), RD model control (n = 16), Shengjing Capsules (SJC) (n = 16), low-dose DBC (n = 16) and high-dose DBC (n = 16). The RD model was made by intragastric administration of adenine at 200 mg/kg/d for 5 successive weeks in the latter four groups of animals, and in the meantime the rats in the latter three groups were treated intragastrically with SJC at 0.560 mg/kg/d and DBC at 0.242 and 0.968 mg/kg/d, respectively. At the end of the fourth week, all the rats were mated with female ones in a 1:1 ratio for 7 days. Then the male rats were killed and the right epididymides collected for detection of sperm concentration and motility, and the female ones sacrificed after fed for another 2 weeks and the numbers of pregnancies and fetal rats were recorded. The heart, liver, spleen, lung, kidney, thymus, testis, epididymis and seminal vesicle were harvested for obtainment of the visceral coefficients and semen parameters, observation of the histopathological changes in the testis, epididymis and kidneys by HE staining, measurement of the levels of serum T, E2, FSH and LH by ELISA, detection of the contents of serum glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), malondialdehyde (MDA) and creatinine (Scr), blood urea nitrogen (BUN), and determination of the expressions of Bax, Bcl-2, Caspase-3 and Caspase-9 proteins in the renal tissue by immunohistochemistry. RESULTS: No statistically significant difference was observed between the blank control and solvent control groups in any of the indexes obtained (P > 0.05).Compared with the blank controls, the rats in the RD model control group showed significantly decreased sperm concentration (ï¼»40.67 ± 7.37ï¼½vs ï¼»27.10 ± 2.72ï¼½ ×106/ml, P < 0.01), sperm motility (ï¼»54.75 ± 3.92ï¼½%vs ï¼»25.60 ± 4.83ï¼½%, P < 0.01) and pregnancy rate (85.7% vs 43.8%, P < 0.01). The rats in thelow- and high-dose DBCgroups exhibited remarkable increases in sperm concentration (ï¼»53.00 ± 4.55ï¼½% and ï¼»65.63 ± 12.47ï¼½% ×106/ml, P < 0.01) and sperm motility (ï¼»53.50 ± 8.83ï¼½% and ï¼»54.33 ± 7.92ï¼½ %, P < 0.01), and so did those in the high-dose DBC group in pregnancy rate (54.5%, P < 0.01).After medication, the animals showed markedly increased body weight and visceral coefficients of the testis, epididymis and seminal vesicle (P < 0.05 or P < 0.01), recovered morphology of the testis, epididymis and kidneys, reduced levels of Scr, BUN, FSH, LH and MDA in the serum (P < 0.05 or P < 0.01), increased contents of T, SOD and GSH-PX (P < 0.05 or P < 0.01), down-regulated expressions of Bax, Caspase-3 and Caspase-9 and up-regulated expression of Bcl-2 in the renal tissue (P < 0.05 or P < 0.01). CONCLUSIONS: DBC can improve adenine-induced reproductive dysfunction in male rats, which may be attributed to its effects of inhibiting the apoptosis of proteins, improving oxidative stress and elevating the levels of reproductive hormones.

The G-protein Coupled Receptor GPR8 Regulates Secondary Metabolism in Trichoderma reesei.

Changing environmental conditions are of utmost importance for regulation of secondary metabolism in fungi. Different environmental cues including the carbon source, light and the presence of a mating partner can lead to altered production of compounds. Thereby, the heterotrimeric G-protein pathway is of major importance for sensing and adjustment of gene regulation. Regulation of secondary metabolism is crucial in the biotechnological workhorse Trichoderma reesei for knowledge-based adjustment in industrial fermentations, but also with respect to the potential use as a host for heterologous compound production. We investigated the function of the class VII G-protein coupled receptor (GPCR) gene gpr8 that is localized in the vicinity of the SOR cluster, which is responsible for biosynthesis of sorbicillinoids. GPR8 positively impacts regulation of the genes in this cluster in darkness. Accordingly, abundance of trichodimerol and dihydrotrichotetronine as well as other secondary metabolites is decreased in the deletion mutant. Transcriptome analysis moreover showed the major role of GPR8 being exerted in darkness with a considerable influence on regulation of secondary metabolism. Genes regulated in Δgpr8 overlap with those regulated directly or indirectly by the transcription factor YPR2, especially concerning genes related to secondary metabolism. The predicted FAD/FMN containing dehydrogenase gene sor7, one of the positive targets of the cascade triggered by GPR8, has a positive effect on secondary metabolite production, but also cellulase gene expression. Hence SOR7 has some overlapping, but also additional functions compared to GPR8. The G-protein coupled receptor GPR8 exerts a light dependent impact on secondary metabolism, which is in part mediated by the transcription factor YPR2 and the function of SOR7. Hence, T. reesei may apply GPR8 to adjust production of secondary metabolites and hence chemical communication to signals from the environment.

Hijacking of Lipid Droplets by Hepatitis C, Dengue and Zika Viruses-From Viral Protein Moonlighting to Extracellular Release.

Hijacking and manipulation of host cell biosynthetic pathways by human enveloped viruses are essential for the viral lifecycle. Flaviviridae members, including hepatitis C, dengue and Zika viruses, extensively manipulate host lipid metabolism, underlining the importance of lipid droplets (LDs) in viral infection. LDs are dynamic cytoplasmic organelles that can act as sequestration platforms for a unique subset of host and viral proteins. Transient recruitment and mobilization of proteins to LDs during viral infection impacts host-cell biological properties, LD functionality and canonical protein functions. Notably, recent studies identified LDs in the nucleus and also identified that LDs are transported extracellularly via an autophagy-mediated mechanism, indicating a novel role for autophagy in Flaviviridae infections. These developments underline an unsuspected diversity and localization of LDs and potential moonlighting functions of LD-associated proteins during infection. This review summarizes recent breakthroughs concerning the LD hijacking activities of hepatitis C, dengue and Zika viruses and potential roles of cytoplasmic, nuclear and extracellular LD-associated viral proteins during infection.

Adipocyte Reprogramming by the Transcriptional Coregulator GPS2 Impacts Beta Cell Insulin Secretion.

Glucose homeostasis is maintained through organ crosstalk that regulates secretion of insulin to keep blood glucose levels within a physiological range. In type 2 diabetes, this coordinated response is altered, leading to a deregulation of beta cell function and inadequate insulin secretion. Reprogramming of white adipose tissue has a central role in this deregulation, but the critical regulatory components remain unclear. Here, we demonstrate that expression of the transcriptional coregulator GPS2 in white adipose tissue is correlated with insulin secretion rate in humans. The causality of this relationship is confirmed using adipocyte-specific GPS2 knockout mice, in which inappropriate secretion of insulin promotes glucose intolerance. This phenotype is driven by adipose-tissue-secreted factors, which cause increased pancreatic islet inflammation and impaired beta cell function. Thus, our study suggests that, in mice and in humans, GPS2 controls the reprogramming of white adipocytes to influence pancreatic islet function and insulin secretion.

MicroRNA­93 promotes angiogenesis and attenuates remodeling via inactivation of the Hippo/Yap pathway by targeting Lats2 after myocardial infarctionω.

Inactivation of the Hippo pathway protects the myocardium from cardiac ischemic injury. MicroRNAs (miRs) have been reported to play pivotal roles in the progression of myocardial infarction (MI). The present study examined whether miR­93 could promote angiogenesis and attenuate remodeling after MI via inactivation of the Hippo/Yes­associated protein (Yap) pathway, by targeting large tumor suppressor kinase 2 (Lats2). It was identified that transfection of human umbilical vein endothelial cells with miR­93 mimic significantly decreased Lats2 expression and Yap phosphorylation, increased cell viability and migration, and attenuated cell apoptosis following hypoxia/reoxygenation injury. Moreover, increased expression of miR­93 resulted in an improvement of cardiac function, promotion of angiogenesis and attenuation of remodeling after MI. Additionally, miR­93 overexpression significantly decreased intracellular adhesion molecule 1 and vascular cell adhesion protein 1 expression levels, as well as attenuated the infiltration of neutrophils and macrophages into the myocardium after MI. Furthermore, it was found that miR­93 overexpression significantly suppressed Lats2 expression and decreased the levels of phosphorylated Yap in the myocardium after MI. Collectively, the present results suggested that miR­93 may exert a protective effect against MI via inactivation of the Hippo/Yap pathway by targeting Lats2.

Fluorofenidone Alleviates Renal Fibrosis by Inhibiting Necroptosis Through RIPK3/MLKL Pathway.

Cell death and sterile inflammation are major mechanisms of renal fibrosis, which eventually develop into end-stage renal disease. "Necroptosis" is a type of caspase-independent regulated cell death, and sterile inflammatory response caused by tissue injury is strongly related to necrosis. Fluorofenidone (AKF-PD) is a novel compound shown to ameliorate renal fibrosis and associated inflammation. We investigated whether AKF-PD could alleviate renal fibrosis by inhibiting necroptosis. Unilateral ureteral obstruction (UUO) was used to induce renal tubulointerstitial fibrosis in C57BL/6J mice. AKF-PD (500 mg/kg) or necrostatin-1 (Nec-1; 1.65 mg/kg) was administered simultaneously for 3 and 7 days. Obstructed kidneys and serum were harvested after euthanasia. AKF-PD and Nec-1 ameliorated renal tubular damage, inflammatory-cell infiltration, and collagen deposition, and the expression of proinflammatory factors (interlukin-1ß, tumor necrosis factor [TNF]-α) and chemokines (monocyte chemoattractant protein-1) decreased. AKF-PD or Nec-1 treatment protected renal tubular epithelial cells from necrosis and reduced the release of lactate dehydrogenase in serum. Simultaneously, production of receptor-interacting protein kinase (RIPK)3 and mixed lineage kinase domain-like protein (MLKL) was also reduced 3 and 7 days after UUO. AKF-PD and Nec-1 significantly decreased the percentage of cell necrosis, inhibiting the phosphorylation of MLKL and RIPK3 in TNF-α- and Z-VAD-stimulated human proximal tubular epithelial (HK-2) cells. In conclusion, AKF-PD and Nec-1 have effective anti-inflammatory and antifibrotic activity in UUO-induced renal tubulointerstitial fibrosis, potentially mediated by the RIPK3/MLKL pathway.

Novel genetic variants in HDAC2 and PPARGC1A of the CREB-binding protein pathway predict survival of non-small-cell lung cancer.

The CREB-binding protein (CBP) pathway plays an important role in transcription and activity of acetyltransferase that acetylates lysine residues of histones and nonhistone proteins. In the present study, we hypothesized that genetic variants in the CBP pathway genes played a role in survival of non-small-cell lung cancer (NSCLC). We tested this hypothesis using the genotyping data from the genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In the single-locus analysis, we evaluated associations between 13 176 (1107 genotyped and 12 069 imputed) single-nucleotide polymorphisms (SNPs) in 72 genes and survival of 1185 patients with NSCLC. The identified 106 significant SNPs in the discovery were further validated in additional genotyping data from another GWAS dataset of 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study. The combined results of two datasets showed that two independent, potentially functional SNPs (i.e., HDAC2 rs13213007G>A and PPARGC1A rs60571065T>A) were significantly associated with NSCLC overall survival, with a combined hazards ratio (HR) of 1.26 (95% confidence interval (CI), 1.09-1.45; P = .002) and 1.23 (1.04-1.47; P = .017), respectively. Furthermore, we performed an expression quantitative trait loci analysis and found that the survival-associated HDAC2 rs13213007A allele (GA+AA), but not PPARGC1A rs60571065A allele (TA+AA), was significantly associated with increased messenger RNA expression levels of HDAC2 in 373 lymphoblastoid cell lines. These results indicate that the HDAC2 rs13213007A allele is a potential predictor of NSCLC survival, likely by altering the HDAC2 expression.