Pannonibacter tanglangensis sp. nov., a New Species Isolated from Pond Sediment.

Two bacterial strains (XCT-34T and XCT-53) isolated from sediment samples of an artificial freshwater reservoir were analyzed using a polyphasic approach. The two isolates are aerobic, Gram-stain-negative, oxidase-negative, catalase-positive, motile with polar flagella, rod-shaped, and approximately 1.4-3.4 × 0.4-0.9 µm in size. Phylogenetic analyses based on 16S rRNA gene and whole-genome sequences showed that the two strains formed a distinct branch within the evolutionary radiation of the genus Pannonibacter, closest to Pannonibacter carbonis Q4.6T (KCTC 52466). Furthermore, lower than threshold average nucleotide identity values (ANI, 85.7-86.4%) and digital DNA-DNA hybridization values (dDDH, 22.3-30.5%) of the two strains compared to the nearest type strains also confirmed that they represented a novel species. Genomic analyses, including annotation of the KEGG pathways, prediction of the secondary metabolism biosynthetic gene clusters and PHI phenotypes, supported functional inference and differentiation of the strains from the closely related taxa. Results of chemotaxonomic and physiological studies revealed that their distinct phenotypic characteristics distinguished them from existing Pannonibacter species. Thus, the two strains are considered to represent a novel species of Pannonibacter, for which the name of Pannonibacter tanglangensis sp. nov. is proposed, with XCT-34T (= KCTC 82332T = GDMCC 1.1947T) as the respective type strain.

Targeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis.

Purinergic signaling plays a causal role in the pathogenesis of inflammatory bowel disease. Among purinoceptors, only P2Y14R is positively correlated with inflammatory score in mucosal biopsies of ulcerative colitis patients, nevertheless, the role of P2Y14R in ulcerative colitis remains unclear. Here, based on the over-expressions of P2Y14R in the intestinal epithelium of mice with experimental colitis, we find that male mice lacking P2Y14R in intestinal epithelial cells exhibit less intestinal injury induced by dextran sulfate sodium. Mechanistically, P2Y14R deletion limits the transcriptional activity of cAMP-response element binding protein through cAMP/PKA axis, which binds to the promoter of Ripk1, inhibiting necroptosis of intestinal epithelial cells. Furthermore, we design a hierarchical strategy combining virtual screening and chemical optimization to develop a P2Y14R antagonist HDL-16, which exhibits remarkable anti-colitis effects. Summarily, our study elucidates a previously unknown mechanism whereby P2Y14R participates in ulcerative colitis, providing a promising therapeutic target for inflammatory bowel disease.

TRIM14 suppressed the progression of NSCLC via hexosamine biosynthesis pathway.

Tripartite Motif 14 (TRIM14) is an oncoprotein that belongs to the E3 ligase TRIM family, which is involved in the progression of various tumors except for non-small cell lung carcinoma (NSCLC). However, little is currently known regarding the function and related mechanisms of TRIM14 in NSCLC. Here, we found that the TRIM14 protein was downregulated in lung adenocarcinoma tissues compared with the adjacent tissues, which can suppress tumor cell proliferation and migration both in vitro and in vivo. Moreover, TRIM14 can directly bind to glutamine fructose-6-phosphate amidotransferase 1 (GFAT1), which in turn results in the degradation of GFAT1 and reduced O-glycosylation levels. GFAT1 is a key enzyme in the rate-limiting step of the hexosamine biosynthetic pathway (HBP). Replenishment of N-acetyl-d-glucosamine can successfully reverse the inhibitory effect of TRIM14 on the NSCLC cell growth and migration as expected. Collectively, our data revealed that TRIM14 suppressed NSCLC cell proliferation and migration through ubiquitination and degradation of GFAT1, providing a new regulatory role for TRIM14 on HBP.

Macrophage P2Y6 receptor deletion attenuates atherosclerosis by limiting foam cell formation through phospholipase Cß/store-operated calcium entry/calreticulin/scavenger receptor A pathways.

BACKGROUND AND AIMS: Macrophage-derived foam cells play a causal role during the pathogenesis of atherosclerosis. P2Y6 receptor (P2Y6R) highly expressed has been considered as a disease-causing factor in atherogenesis, but the detailed mechanism remains unknown. This study aims to explore P2Y6R in regulation of macrophage foaming, atherogenesis, and its downstream pathways. Furthermore, the present study sought to find a potent P2Y6R antagonist and investigate the feasibility of P2Y6R-targeting therapy for atherosclerosis. METHODS: The P2Y6R expression was examined in human atherosclerotic plaques and mouse artery. Atherosclerosis animal models were established in whole-body P2Y6R or macrophage-specific P2Y6R knockout mice to evaluate the role of P2Y6R. RNA sequencing, DNA pull-down experiments, and proteomic approaches were performed to investigate the downstream mechanisms. High-throughput Glide docking pipeline from repurposing drug library was performed to find potent P2Y6R antagonists. RESULTS: The P2Y6R deficiency alleviated atherogenesis characterized by decreasing plaque formation and lipid deposition of the aorta. Mechanically, deletion of macrophage P2Y6R significantly inhibited uptake of oxidized low-density lipoprotein through decreasing scavenger receptor A expression mediated by phospholipase Cß/store-operated calcium entry pathways. More importantly, P2Y6R deficiency reduced the binding of scavenger receptor A to CALR, accompanied by dissociation of calreticulin and STIM1. Interestingly, thiamine pyrophosphate was found as a potent P2Y6R antagonist with excellent P2Y6R antagonistic activity and binding affinity, of which the pharmacodynamic effect and mechanism on atherosclerosis were verified. CONCLUSIONS: Macrophage P2Y6R regulates phospholipase Cß/store-operated calcium entry/calreticulin signalling pathway to increase scavenger receptor A protein level, thereby improving foam cell formation and atherosclerosis, indicating that the P2Y6R may be a potential therapeutic target for intervention of atherosclerotic diseases using P2Y6R antagonists including thiamine pyrophosphate.

Network pharmacology-based analysis of Jin-Si-Wei on the treatment of Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Jin-Si-Wei (JSW), a traditional Chinese medicine (TCM) formula, have cognitive enhancing effect and delay the memory decline in an animal model of AD， which has been reported. However, the therapeutic mechanism of JSW in the treatment of AD remains unclear. AIM OF THE STUDY: This study aimed to verify the pharmacodynamics of JSW in the treatment of AD, and to explore its potential mechanism based on network pharmacology, molecular docking and experimental validation both in vitro and in vivo. MATERIALS AND METHODS: In this study, the underlying mechanism of JSW against AD was investigated by the integration of network pharmacology. Then, the core pathways and biological process of JSW were verified by experiment, including behavioral test and pathological and biochemical assays with 6-month-old APPswe/PS1ΔE9 transgenic (APP/PS1) mice in vivo and verified with Aß1-42-stimulated SH-SY5Y cells in vitro. At last, molecular docking was used to show the binding activity of each active ingredient to the core genes of JSW treatment in AD. RESULTS: A Drug-Ingredient-Target network was established, which included 363 ingredients and 116 targets related to the JSW treatment of AD. The main metabolic pathway of JSW treatment for AD is neuroactive ligand-receptor interaction pathway, and biological processes are mainly involved in Aß metabolic process. In vivo experiments, compared with APP/PS1 mice, the cognitive and memory ability of mice was significantly improved after JSW administration. In brain tissue of APP/PS1 mice, JSW could increase the contents of low-density lipoprotein receptor-related protein 1 (LRP-1), enkephalinase (NEP) and Acetyl choline (ACh), and decrease the contents of Aß1-42, amyloid precursor protein (APP) and receptor for advanced glycation end products (RAGE), decrease the vitality of cholinesterase (AChE) and choline acetyltransferase (ChAT). Besides, JSW could increase α-secretase expression and decrease ß/γ-secretase expression, and improve the number and morphology of synapses in CA1 region of the hippocampus of APP/PS1 mice. In vitro experiments, Drug-Containing Serum (JSW-serum) has a neuroprotective effect by reducing the apoptosis on Aß1-42-stimulated SH-SY5Y cells. Molecular docking results showed that 2-Isopropyl-8-methylphenanthrene-3,4-dione had strong binding activity with PTGS2, which maybe a potential ingredient for the treatment of AD. CONCLUSIONS: JSW improves AD in APP/PS1 mice, and this therapeutic effect may be achieved in part by altering the neuroactive ligand-receptor interaction pathway.

How single-cell techniques help us look into lung cancer heterogeneity and immunotherapy.

Lung cancer patients tend to have strong intratumoral and intertumoral heterogeneity and complex tumor microenvironment, which are major contributors to the efficacy of and drug resistance to immunotherapy. From a new perspective, single-cell techniques offer an innovative way to look at the intricate cellular interactions between tumors and the immune system and help us gain insights into lung cancer and its response to immunotherapy. This article reviews the application of single-cell techniques in lung cancer, with focuses directed on the heterogeneity of lung cancer and the efficacy of immunotherapy. This review provides both theoretical and experimental information for the future development of immunotherapy and personalized treatment for the management of lung cancer.

Pharmacological inhibition of MDM4 alleviates pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology with no cure. A better understanding of the disease processes and identification of druggable targets will benefit the development of effective therapies for IPF. We previously reported that MDM4 promoted lung fibrosis through the MDM4-p53-dependent pathway. However, it remained unclear whether targeting this pathway would have any therapeutic potential. In this study, we evaluated the efficacy of XI-011, a small molecular inhibitor of MDM4, for treating lung fibrosis. We found that XI-011 significantly reduced MDM4 expression and increased the expression of total and acetylated p53 in primary human myofibroblasts and a murine fibrotic model. XI-011 treatment resulted in the resolution of lung fibrosis in mice with no notable impact on normal fibroblast death or the morphology of healthy lungs. Based on these findings, we propose that XI-011 might be a promising therapeutic drug candidate for treating pulmonary fibrosis.

Polysaccharide from Strongylocentrotus nudus eggs regulates intestinal epithelial autophagy through CD36/PI3K-Akt pathway to ameliorate inflammatory bowel disease.

Sea urchin is a popular food all over the world, of which eggs are main edible part. Previous studies suggested that polysaccharides from eggs of Strongylocentrotus nudus (SEP) exhibited immunomodulatory activities during anti-tumor therapy, nevertheless, effects of SEP on inflammatory bowel disease and its underlying mechanisms have never been reported. In the present study, we showed that the SEP inhibited dextran sodium sulfate-induced ulcerative colitis characterized by decreased disease activity index, restored colon length and body weight, improved histopathological changes, down-regulation of inflammatory cytokines levels and Th17/Treg ratios in C57BL/6 J mice. Moreover, immunofluorescence analysis suggested that SEP repaired gut barrier in UC mice, while 16S rDNA sequencing exhibited improved intestinal flora. Mechanistically, we found SEP significantly modulated autophagy-related factors in intestinal epithelial cells (IECs), while might contributed to pathogenesis of UC. Furthermore, we demonstrated PI3K/Akt pathway was involved in regulatory effect of SEP on lipopolysaccharide-induced autophagy of HT-29 cells. Besides, among possible polysaccharide binding receptors, change of the CD36 expression was most significant, which was associated with PI3K/Akt signals. Collectively, our study showed for the first time that the SEP might be used a prebiotic agent to improve IBD through regulating CD36-PI3K/Akt mediated autophagy of IECs.

Metabolite Analysis of Alternaria Mycotoxins by LC-MS/MS and Multiple Tools.

Alternaria fungi are widely distributed plant pathogens that invade crop products, causing significant economic damage. In addition, toxic secondary metabolites produced by the fungi can also endanger consumers. Many of these secondary metabolites are chemically characterized as mycotoxins. In this study, Q Exactive Orbitrap mass spectrometry was used for the non-targeted analysis of the metabolome of seven Alternaria isolates cultured on Potato Carrot Agar (PCA), Potato Dextrose Agar (PDA) and Potato Sucrose Agar (PSA) medium. Due to the difficulty of detecting modified toxins, an analytical strategy with multiple visual analysis tools was also used to determine the presence of sulfate conjugated toxins, as well as to visualize the molecular network of Alternaria toxins. The results show that PSA medium exhibits more advantageous properties for the culture of Alternaria, with more toxigenic species and quantities and more obvious metabolic pathways. Based on high-resolution tandem mass spectrometry (MS/MS) data, the mycotoxins and their metabolites were mainly clustered into four groups: alternariol (AOH)/alternariol monomethyl ether (AME)/altenusin (ALU)/altenuene (ALT)/dehydroaltenusin (DHA)/Desmethyldehydroaltenusin (DMDA) families, Altertoxin-I (ATX-I) family, tentoxin (TEN) family and tenuazonic acid (TeA) family. Moreover, the PSA medium is more suitable for the accumulation of AOH, AME, ALU, ALT, DHA and DMDA, while the PDA medium is more suitable for the accumulation of ATX-I, TEN and TeA. This research may provide theoretical support for the metabolomics study of Alternaria.

HQL6 serves as a novel P2Y14 receptor antagonist to ameliorate acute gouty arthritis through inhibiting macrophage pyroptosis.

Acute gouty arthritis (AGA) has been classified as an autoinflammatory disease caused by deposition of monosodium urate crystals (MSU), accompanied by swellingofjoint and severe pain. Limited clinical therapy and highincidence indicate that the development of effective drugs for AGA is an urgent need. Our previous study found that P2Y14 receptor (P2Y14R) was a potential target in anti-gout treatment through regulating pyroptosis of macrophages under exposure of MSU. Based on previous work, we carried out further structure modifications and led to a more effective antagonist HQL6 with IC50 of 3.007 nM. Extensive profiling of HQL6 has demonstrated that its high selectivity, good pharmacokinetic properties, and reliable in vivo anti-gout efficacy. Moreover, P2Y14R has been demonstrated to be the key target of HQL6 since the diminished effects on adenylate cyclase inhibitor-induced acute gouty arthritis in P2Y14R knockout rats. More importantly, results of single point mutant experiments exhibited that HQL6 might interact with Lys277 as favorable residue in the binding pocket of P2Y14R. Therefore, we confirmed that P2Y14R was a promising drug target for AGA, and HQL6 would be an available candidate for further drug development.

MiR-1249 on Endothelial Extracellular Vesicles Mediates Cigarette Smoke-Induced Pulmonary Hypertension by Inhibiting HDAC10 (Histone Deacetylase 10)-NFκB (Nuclear Factor κB)-CaSR (Calcium-Sensing Receptor) Cascade.

BACKGROUND: Overproduction of endothelial extracellular vesicles (eEVs) is correlated with pulmonary hypertension progression, but the precise mechanism remains largely unclear. METHODS: MicroRNA-chip and real-time polymerase chain reaction were conducted to screen and validate microRNA profiles in blood plasma eEVs of rats and human with or without cigarette smoking. Pulmonary artery smooth muscle cells were cultured to study signaling pathways. Pulmonary hypertension phenotypes were evaluated in wild-type and calcium-sensing receptor knockout rats to identify the pathophysiological significance of the microRNA pathway. RESULTS: MicroR-1249 was predominant highly expressed in eEVs from plasma of rats exposed to cigarette smoking, and confirmed in eEVs from plasma of human smokers as well as in eEVs from cigarette smoke extract-treated pulmonary artery endothelial cells, but not in cigarette smoke extract-treated pulmonary artery smooth muscle cells. In cultured pulmonary artery smooth muscle cells, microR-1249 downregulated the expression of histone deacetylase 10, which in turn enhanced the acetylated form of NFκB (nuclear factor κB) level and its nuclear translocation leading to increased expression of calcium-sensing receptor. In rats, the repression of microR-1249 in eEVs by microR-1249 inhibitor, histone deacetylase 10 overexpression, or calcium-sensing receptor knockout profoundly inhibited the proliferative capacities and diminished apoptosis-resistance of pulmonary artery smooth muscle cells and pulmonary hypertension development in rats intravenously administrated with eEVs preparation from cigarette smoke extract-treated pulmonary artery endothelial cells. CONCLUSIONS: Cigarette smoke-enriched microR-1249 in endothelial extracellular vesicles facilitates the hyperproliferative and antiapoptotic status of pulmonary artery smooth muscle cells promoting pulmonary hypertension evolution through the inhibition of histone deacetylase 10-NFκB-calcium-sensing receptor cascade.

Post-operative uric acid: a predictor for 30-days mortality of acute type A aortic dissection repair.

BACKGROUND: Hyperuricemia is associated with aortic dissection and cardiovascular diseases. The implication of high serum uric acid (UA) level after acute aortic dissection repair remains unknown. The aim of this study is to explore the role of peri-operative serum UA level in predicting 30-days mortality with acute type A aortic dissection (AAAD) patients, who underwent surgery. METHODS: This study retrospectively enrolled 209 consecutive patients with AAAD, who underwent surgery in Xiangya Hospital from 2017 to 2020. Post-operative laboratory examinations were measured within 24 h after surgery. Univariate analysis and logistic regression analysis were used for predictor finding. RESULTS: 209 consecutive AAAD patients were included, 14.3% (n = 30) were dead within 30 days after surgery. By univariate analysis, we found AAAD repair patients with 30-days mortality had a higher prevalence of cerebral malperfusion, lower pre-operative fibrinogen, longer cardiopulmonary bypass and aortic crossclamp time, and higher post-operative day 1 (POD1) creatinine and urea levels. Both pre-operative (433.80 ± 152.59 vs. 373.46 ± 108.31 mmol/L, p = 0.038) and POD1 (559.78 ± 162.23 vs. 391.29 ± 145.19 mmol/L, p < 0.001) UA level were higher in mortality group than in survival group. In regression model, only cerebral malperfusion (OR, 7.938, 95% CI 1.252-50.323; p = 0.028) and POD1 UA level (OR, 2.562; 95% CI 1.635-4.014; p < 0.001) were independent predictors of 30-days mortality in AAAD repair patients. According to the ROC curve, the POD1 UA level provided positive value for 30-days mortality in AAAD repair patients with 0.799 areas under the curve. The optimum cutoff value selected by ROC curve was 500.15 mmol/L, with a sensitivity of 65% and a specificity of 86%. CONCLUSION: Pre- and post-operative hyperuricemia are potentially associated with worsened outcomes in AAAD surgery patients. The POD1 UA level has a predictive role in 30-days mortality in AAAD repair patients.

Application of retrograde cerebral perfusion in aortic root replacement combined with right half aortic arch replacement. / é€†è¡Œè„‘çŒæ³¨åœ¨ä¸»åŠ¨è„‰æ ¹éƒ¨å’Œå³åŠå¼“ç½®æ¢æ‰‹æœ¯ä¸­çš„åº”ç”¨.

OBJECTIVES: After cardiac surgery involving the aortic arch, the incidence of neurological complications remains high, therefore it is very important to take measures to protect brain. This study is to investigate the safety and effectiveness of deep hypothermic circulatory arrest and retrograde cerebral perfusion for aortic root combined with right half aortic arch replacement. METHODS: Clinical data of 31 patients, who underwent aortic root and right half aortic arch replacement with deep hypothermic circulatory arrest and retrograde cerebral perfusion in Xiangya Hospital, Central South University, were retrospectively analyzed. This cohort included 23 aortic aneurysms and 8 aortic dissections. Aortic root replacement was conducted in 26 patients by Bentall procedures, and 5 patients by David procedures. Time of deep hypothermic circulatory arrest and retrograde cerebral perfusion in surgery was (21.9±5.2) min. The in-hospital mortality, postoperative neurological dysfunction and other major adverse complications were observed and recorded. RESULTS: No in-hospital death and permanent neurological dysfunction occurred. Two patients had transient neurological dysfunction and 2 patients with aortic dissection requiring long-time ventilation due to hypoxemia, 1 patient underwent resternotomy. During 6-36 months of follow-up, all patients recovered satisfactorily. CONCLUSIONS: Deep hypothermic circulatory arrest and retrograde cerebral perfusion can be safely and effectively applied in aortic root and right half aortic arch replacement, and which can simplify the surgical procedures and be worth of clinical promotion.

Platelet-Derived TGF (Transforming Growth Factor)-ß1 Enhances the Aerobic Glycolysis of Pulmonary Arterial Smooth Muscle Cells by PKM2 (Pyruvate Kinase Muscle Isoform 2) Upregulation.

BACKGROUND: Metabolic reprogramming is a hallmark of pulmonary arterial hypertension. Platelet activation has been implicated in pulmonary arterial hypertension (PAH), whereas the role of platelet in the pathogenesis of PAH remains unclear. METHODS: First, we explored the platelet function of semaxanib' a inhibitor of VEGF receptor (SU5416)/hypoxia mice and monocrotaline-injected rats PAH model. Then we investigated pulmonary arterial smooth muscle cell aerobic glycolysis after being treated with platelet supernatant. TGF (transforming growth factor)-ßRI, pyruvate kinase muscle 2, and other antagonists were applied to identify the underlying mechanism. In addition, platelet-specific deletion TGF-ß1 mice were exposed to chronic hypoxia and SU5416. Cardiopulmonary hemodynamics, vascular remodeling, and aerobic glycolysis of pulmonary arterial smooth muscle cell were determined. RESULTS: Here, we demonstrate that platelet-released TGF-ß1 enhances the aerobic glycolysis of pulmonary arterial smooth muscle cells after platelet activation via increasing pyruvate kinase muscle 2 expression. Mechanistically, platelet-derived TGF-ß1 regulate spyruvate kinase muscle 2 expression through mTOR (mammalian target of rapamycin)/c-Myc/PTBP-1(polypyrimidine tract binding protein 1)/hnRNPA-1(heterogeneous nuclear ribonucleoprotein A1) pathway. Platelet TGF-ß1 deficiency mice are significantly protected from SU5416 plus chronic hypoxia-induced PAH, including attenuated increases in right ventricular systolic pressure and less pulmonary vascular remodeling. Also, in Pf4cre+ Tgfb1fl/fl mice, pulmonary arterial smooth muscle cells showed lower glycolysis capacity and their pyruvate kinase muscle 2 expression decreased. CONCLUSIONS: Our data demonstrate that TGF-ß1 released by platelet contributes to the pathogenesis of PAH and further highlights the role of platelet in PAH.

Peptide Blocking Self-Polymerization of Extracellular Calcium-Sensing Receptor Attenuates Hypoxia-Induced Pulmonary Hypertension.

[Figure: see text].

Treatment of thoracoabdominal aortic aneurysm by prosthetic vessel replacement under left heart bypass. / å·¦å¿ƒè½¬æµä¸‹äººå·¥è¡€ç®¡ç½®æ¢æœ¯æ²»ç–—èƒ¸è ¹ä¸»åŠ¨è„‰ç˜¤.

OBJECTIVES: Thoracoabdominal aortic aneurysm (TAAA) prosthetic vessel replacement is one of the most complex operations in the field of cardiovascular surgery. The key to success of this operation is to prevent and avoid ischemia of important organs while repairing TAAA. This study aims to summarize and analyze the effect of prosthetic vessel replacement under left heart bypass in the treatment of TAAA. METHODS: Data of 15 patients with TAAA who underwent prosthetic vessel replacement under left heart bypass in Xiangya Hospital of Central South University were retrospectively analyzed. According to Crawford classification, there were 2 cases of type I, 8 cases of type II, 3 cases of type III, and 2 cases of type V. There were 14 cases of selective operation and 1 case of emergency operation. All operations were performed under left heart bypass, and cerebrospinal fluid drainage was performed before operation. Left heart bypass was established by intubation of left inferior pulmonary vein and distal abdominal aorta or left femoral artery. The thoracoabdominal aorta was replaced segment by segment. After aortic dissection, the kidneys were perfused with cold crystalloid renal protective solution, and the celiac trunk and superior mesenteric artery were perfused with warm blood. RESULTS: One patient with TAAA after aortic dissection of type A died. During the operation, straight blood vessels were used to repair TAAA, and the celiac artery branches were trimmed into island shape and anastomosed with prosthetic vessels. After the operation, massive bleeding occurred at the anastomotic stoma, then anaphylactic reaction occurred during massive blood transfusion, resulting in death. One patient suffered from paraplegia due to ischemic injury of spinal cord. The other patients recovered well and were discharged. The postoperative ventilation time was (16.5±13.8) h and the postoperative hospital stay was (10±4) d. The amount of red blood cell transfusion was (13±9) U. The patients were followed up for 2 months to 2 years, and the recovery was satisfactory. CONCLUSIONS: The effect of prosthetic vessel replacement under left heart bypass in the treatment of TAAA is good, which is worthy of clinical promotion.

Protein S-Palmitoylation and Lung Diseases.

S-palmitoylation of protein is a posttranslational, reversible lipid modification; it was catalyzed by a family of 23 mammalian palmitoyl acyltransferases in humans. S-palmitoylation can impact protein function by regulating protein sorting, secretion, trafficking, stability, and protein interaction. Thus, S-palmitoylation plays a crucial role in many human diseases including mental illness and cancers. In this chapter, we systematically reviewed the influence of S-palmitoylation on protein performance, the characteristics of S-palmitoylation regulating protein function, and the role of S-palmitoylation in pulmonary inflammation and pulmonary hypertension and summed up the treatment strategies of S-palmitoylation-related diseases and the research status of targeted S-palmitoylation agonists/inhibitors. In conclusion, we highlighted the potential role of S-palmitoylation and depalmitoylation in the treatment of human diseases.

The piperine derivative HJ105 inhibits Aß1-42-induced neuroinflammation and oxidative damage via the Keap1-Nrf2-TXNIP axis.

BACKGROUND: Piperine is a great lead compound, as a phytopharmaceutical with reported neuroprotective effects in neurodegenerative diseases. HJ105, a piperine derivative with high affinity to Keap1 receptor, attracts increasing attention in Alzheimer's disease (AD) treatment. PURPOSE: This work mainly aimed to study HJ105's therapeutic effects on Aß1-42-associated AD and the underpinning mechanisms. METHODS: In the in vivo part, a rat model of AD was established by bilateral intra-hippocampal administration of aggregated Aß1-42, followed by a month of intragastric HJ105 or donepezil administration. Spatial and learning memories were detected by the Morris water maze assay, passive avoidance learning as well as Y-maze test. The morphology of hippocampal neurons was assessed by hematoxylin-eosin (H&E) staining. In addition, the amounts of the IL-1ß and TNF-α were obtained with specific ELISA kits. More importantly, apoptosis-related proteins and factors involved in Nrf2/TXNIP/NLPR3 pathways were detected by Western blot, while the interaction between Keap1 and Nrf2 was assessed by co-immunoprecipitation. In the in vitro part, human neuroblastoma (SH-SY5Y) cells were applied to evaluate the role of HJ105 on Aß1-42-induced neuronal damage. RESULTS: Treatment of HJ105 not only reversed memory impairment, but also protected neurons in the hippocampus by inhibiting Bax/Bcl2 ratio increase. HJ105 decreased TXNIP expression, suppressing NLRP3 inflammasome activation in the hippocampus, which in turn counteracted the upregulation of IL-1ß and TNF-α. Notably, HJ105 exerted an inhibitory effect on Keap1-Nrf2 interaction and upregulated nuclear Nrf2, which conversely increased the expression levels of superoxide dismutase, catalase and glutathione peroxidase and downregulated malondialdehyde. Additionally, neurotoxicity induced by Aß1-42 in SH-SY5Y cells was alleviated by HJ105. CONCLUSION: Overall, HJ105 exerts neuroprotective effects in SH-SY5Y cells induced by Aß1-42 as well as in experimental rats with AD by decreasing apoptosis, oxidative stress and neuroinflammation, partly via suppression of Keap1-Nrf2 complex generation. HJ105 might represent a promising compound for AD treatment.

Design, synthesis and biological evaluation of 1H-indazole derivatives as novel ASK1 inhibitors.

Apoptosis signal-regulating kinase 1 (ASK1, MAP3K5), a member of the mitogen-activated protein kinase (MAPK) signaling pathway, is involved in cell survival, differentiation, stress response, and apoptosis. ASK1 kinase inhibition has emerged as a promising therapeutic strategy for inflammatory disease. A series of novel ASK1 inhibitors with 1H-indazole scaffold were designed, synthesized and evaluated for their ASK1 kinase activity and AP1-HEK293 cell inhibitory effect. Systematic structure-activity relationship (SAR) efforts led to the discovery of promising compound 15, which showed excellent in vitro ASK1 kinase activity and potent inhibitory effects on ASK1 in AP1-HEK293 cells. In a tumor necrosis factor-α (TNF-α)-induced HT-29 intestinal epithelial cell model, compound 15 exhibited a significantly protective effect on cell viability comparable to that of GS-4997; moreover, compound 15 exhibited no obvious cytotoxicity against HT-29 cells at concentrations up to 25 µM. Mechanistic research demonstrated that compound 15 suppresses phosphorylation in the ASK1-p38/JNK signaling pathway in HT-29 cells, and regulates the expression levels of apoptosis-related proteins. Altogether, these results show that compound 15 may serve as a potential candidate compound for the treatment of inflammatory bowel disease (IBD).

AIMP3 inhibits cell growth and metastasis of lung adenocarcinoma through activating a miR-96-5p-AIMP3-p53 axis.

Aminoacyl-tRNA synthetase-interacting multifunctional protein-3 (AIMP3) is a tumour suppressor, however, the roles of AIMP3 in non-small cell lung cancer (NSCLC) are not explored yet. Here, we reported that AIMP3 significantly inhibited the cell growth and metastasis of NSCLC (lung adenocarcinoma) in vitro and in vivo. We have firstly identified that AIMP3 was down-regulated in human NSCLC tissues compared with adjacent normal lung tissues using immunohistochemistry and western blot assays. Overexpression of AIMP3 markedly suppressed the proliferation and migration of cancer cells in a p53-dependent manner. Furthermore, we observed that AIMP3 significantly suppressed tumour growth and metastasis of A549 cells in xenograft nude mice. Mechanically, we identified that AIMP3 was a direct target of miR-96-5p, and we also observed that there was a negative correlation between AIMP3 and miR-96-5p expression in paired NSCLC clinic samples. Ectopic miR-96-5p expression promoted the proliferation and migration of cancer cells in vitro and tumour growth and metastasis in vivo which partially depended on AIMP3. Taken together, our results demonstrated that the axis of miR-96-5p-AIMP3-p53 played an important role in lung adenocarcinoma, which may provide a new strategy for the diagnosis and treatment of NSCLC.