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Acute myocardial infarction (AMI) remains a dominant origin of morbidity, mortality and disability worldwide. Increases in reactive oxygen species (ROS) are key contributor to excessive cardiac injury after AMI. Here we developed an immobilized enzyme with Superoxide Dismutase (SOD) activity cross-link with Zr-based metal-organic framework (ZrMOF) (SOD-ZrMOF) for mitigate ROS-caused injury. In vitro and in vivo evidence indicates that SOD-ZrMOF exhibits excellent biocompatibility. By efficiently scavenging ROS and suppressing oxidative stress, SOD-ZrMOF can protect the function of mitochondria, reduce cell death and alleviate inflammation. More excitingly, long-term study using an animal model of AMI demonstrated that SOD-ZrMOF can reduce the infarct area, protect cardiac function, promote angiogenesis and inhibit pathological myocardial remodeling. Therefore, SOD-ZrMOF holds great potential as an efficacious and safe nanomaterial treatment for AMI., Graphical abstract Image 1, Highlights • We synthesized a superoxide dismutase immobilized nanocomposite with enhanced stability. • We tested the biocompatibility of SOD-ZrMOF and found it could promote the cell viability and proliferation of H9c2 cells. • SOD-ZrMOF shows excellent performance in protecting mitochondrial function of CMs by eliminating excessive ROS under hypoxia. • SOD-ZrMOF exhibited therapeutic effects on MI heart through inhibiting oxidative stress injury by NF-κB/HIF-1α pathway.

Background and Purpose— Cerebral ischemic stroke elicits profound responses of CD4 + T cells, which in turn significantly affect the ischemic brain injury. ACC1 (acetyl coenzyme A carboxylase 1) is a key enzyme that has been recently found to propagate CD4 + T cell–associated inflammation by mediating de novo fatty acid synthesis; however, its role in the context of ischemic stroke remains unknown. Methods— Focal cerebral ischemia was induced by transient middle cerebral artery occlusion for 60 minutes in mice. Seahorse XF glycolysis assay and targeted lipidomic profiling were used to detect metabolic changes in CD4 + T cell after stroke. CD4 cre mice were crossed with ACC1 fl/fl mice to generate the CD4 + T-cell–specific deletion of ACC1 (CD4 cre ACC1 fl/fl mice) mice. Pretreatment with calorie restriction (CR; with 30% reduction of food for 4 weeks before middle cerebral artery occlusion) or post-treatment with ACC1 inhibitor, soraphen A were both used to test the effect of ACC1 modulation on poststroke neuroinflammation. Results— Cerebral ischemic stroke increased glycolysis and fatty acid synthesis in peripheral CD4 + T cells, in which the expression of ACC1 was also upregulated. CR downregulated the expression of ACC1 in CD4 + T cells after stroke. Both CD4 cre ACC1 fl/fl mice and CR-pretreated mice exhibited significantly reduced ischemic brain injury and preserved the balance of peripheral regulatory T cells/T helper 17 (Th17) cells. Furthermore, conditional knockout of ACC1 in CD4 + T cells attenuated the protection exerted by CR both on ischemic brain injury and peripheral balance of regulatory T cells/Th17 cells. Pharmacological inhibition of ACC1 after middle cerebral artery occlusion attenuates neuroinflammation, preserves regulatory T cells/Th17 balance, and improves neurological outcomes after ischemic stroke. Conclusions— ACC1 is a novel immune metabolic modulation target to balance the regulatory T cells and Th17 cells and blunt neuroinflammation after stroke. Inhibition of ACC1 can be a previously unrecognized mechanism that underlies CR-afforded neuroprotection against cerebral ischemic stroke.

In this study, variations in the free radical concentration, degree of swelling (Q), and extraction yield of Buertai coal (C%, 80.4%) in 11 solvents with different characteristics were determined to investigate the interaction between the coal and solvent, as well as the bond cleavage during solvent extraction. Derivative thermogravimetry (DTG) results for the residues and raw coal were compared to confirm whether the covalent bond breaks during solvent extraction. The free radical concentration decreases in certain solvents but increases in a few others. The relative free radical concentration, Q, and extraction yield are positively correlated. The charge-transfer capability of the solvent, and in particular its electron-donating capability, plays an essential role in influencing the interaction between the coal and solvent. The increase in the free radical concentration during solvent extraction can be attributed to (1) the formation or decomposition of charge-transfer complexes, (2) dissociation of charge-transfer complexes into radical ions, and (3) breakage of weak covalent bonds. DTG results show the occurrence of weak covalent bonds breakage at temperatures of 133.9–320.1 °C during solvent extraction due to the reduction of the bond energy caused by the formation of radical ions.

Background: Loeys-Dietz syndrome (LDS) is an inherited disorder predisposing individuals to thoracic aortic aneurysm and dissection. Currently, there are no medical treatments except surgical resection. Although the genetic basis of LDS is well-understood, molecular mechanisms underlying the disease remain elusive, impeding the development of a therapeutic strategy. In addition, aortic smooth muscle cells (SMCs) have heterogenous embryonic origins, depending on their spatial location, and lineage-specific effects of pathogenic variants on SMC function, likely causing regionally constrained LDS manifestations, have been unexplored. Methods: We identified an LDS family with a dominant pathogenic variant in the TGFBR1 gene ( TGFBR1 A230T ) causing aortic root aneurysm and dissection. To accurately model the molecular defects caused by this mutation, we used human induced pluripotent stem cells from a subject with normal aorta to generate human induced pluripotent stem cells carrying TGFBR1 A230T , and corrected the mutation in patient-derived human induced pluripotent stem cells using CRISPR-Cas9 gene editing. After their lineage-specific SMC differentiation through cardiovascular progenitor cell (CPC) and neural crest stem cell lineages, we used conventional molecular techniques and single-cell RNA sequencing to characterize the molecular defects. The resulting data led to subsequent molecular and functional rescue experiments using activin A and rapamycin. Results: Our results indicate the TGFBR1 A230T mutation impairs contractile transcript and protein levels, and function in CPC-SMC, but not in neural crest stem cell–SMC. Single-cell RNA sequencing results implicate defective differentiation even in TGFBR1 A230T/+ CPC-SMC including disruption of SMC contraction and extracellular matrix formation. Comparison of patient-derived and mutation-corrected cells supported the contractile phenotype observed in the mutant CPC-SMC. TGFBR1 A230T selectively disrupted SMAD3 (SMAD family member 3) and AKT (AKT serine/threonine kinase) activation in CPC-SMC, and led to increased cell proliferation. Consistently, single-cell RNA sequencing revealed molecular similarities between a loss-of-function SMAD3 mutation ( SMAD3 c.652delA/+ ) and TGFBR1 A230T/+ . Last, combination treatment with activin A and rapamycin during or after SMC differentiation significantly improved the mutant CPC-SMC contractile gene expression and function, and rescued the mechanical properties of mutant CPC-SMC tissue constructs. Conclusions: This study reveals that a pathogenic TGFBR1 variant causes lineage-specific SMC defects informing the etiology of LDS-associated aortic root aneurysm. As a potential pharmacological strategy, our results highlight a combination treatment with activin A and rapamycin that can rescue the SMC defects caused by the variant.

Background Dietary factors, such as consumption of preserved foods, fresh vegetables, and fruits, have been linked to the risk of nasopharyngeal carcinoma (NPC). However, little is known about associations between dietary patterns and the risk of NPC in NPC-endemic areas. Objectives We aimed to evaluate whether dietary patterns are associated with NPC risk. Methods We studied 2554 newly diagnosed NPC patients aged 20–74 y living in 3 endemic regions of southern China, and 2648 population-based controls frequency-matched to case patients by age, sex, and region, between 2010 and 2014. Dietary components were derived from food frequency data in adulthood and adolescence using principal component analysis. Four dietary components were identified and highly similar in adulthood and adolescence. We used multivariable unconditional logistic regression to calculate ORs with 95% CIs for the association between dietary patterns and NPC risk. Results Compared with the lowest quartile, individuals in the highest quartile of the “plant-based factor” in adulthood had a 52% (OR: 0.48; 95% CI: 0.38, 0.59) decreased risk of NPC, and those in the highest quartile of the “animal-based factor” had a >2-fold (OR: 2.26; 95% CI: 1.85, 2.77) increased risk, with a monotonic dose-response trend (P-trend

Stroke mostly including ischemic stroke is the second leading mortality and disability worldwide. Oxidative stress injury occurred during ischemic stroke treatment generally. A high amount of reactive oxygen species (ROS) is involved in oxidative stress induction. Transient receptor potential vanilloid 1 (TRPV1) has been shown to regulate oxidative stress and apoptosis in microglia; however, the detailed mechanisms remain unclear. We aimed to explore whether autophagy-regulated oxidative stress and apoptosis are associated with TRPV1. The model of oxygen and glucose deprivation (OGD/R) in microglia was established. The siRNA of Atg5 and inhibitors and agonists of both autophagy and TRPV1 were involved in our study. Autophagy-related markers Atg5, LC3II/LC3I, and Beclin-1 were measured, and the autophagosome was observed under a transmission electron microscope (TEM). Caspase 3 was detected using ELISA. ROS and JC-1 were detected using flow cytometry. Apoptosis was observed by TUNEL. The results indicated that oxidative stress-induced injury and apoptosis may be impeded by the increasing autophagy, and TRPV1 inhibition could suppress the OGD/R-induced autophagy of microglia. However, the effect of TRPV1’s inhibitor on oxidative stress and apoptosis was not obvious when the autophagy was blocked. These findings suggested that TRPV1 may exhibit antioxidative and antiapoptosis effect on OGD/R-induced microglia. However, the experimental results do not fully demonstrate that the TRPV1-mediated antioxidative and antiapoptosis effect is through the affecting autophagy entirely.

Stroke is one of the world's leading causes of death and disability, posing enormous burden to the society. However, the pathogenesis and mechanisms that underlie brain injury and brain repair remain largely unknown. There's an unmet need of in-depth mechanistic research in this field. Zebrafish (Danio rerio) is a powerful tool in brain science research mainly due to its small size and transparent body, high genome synteny with human, and similar nervous system structures. It can be used to establish both hemorrhagic and ischemic stroke models easily and effectively through different ways. After the establishment of stroke model, research methods including behavioral test, in vivo imaging, and drug screening are available to explore mechanisms that underlie the brain injury and brain repair after stroke. This review focuses on the advantages and the feasibility of zebrafish stroke model, and will also introduce the key methods available for stroke studies in zebrafish, which may drive future mechanistic studies in the pursuit of discovering novel therapeutic targets for stroke patients.

High-performance sulfonated polysulfone (SPSf) mixed-matrix membranes (MMMs) were fabricated via a nonsolvent-induced phase separation (NIPS) method using zeolitic imidazolate frameworks-67 (ZIF-67) as a crosslinker. Acid-base crosslinking occurred between the sulfonic acid groups of SPSf and the tertiary amine groups of the embedded ZIF-67, which improved the dispersion of ZIF-67 and simultaneously improved the membrane strzcture and permselectivity. The dispersion of ZIF-67 in the MMMs and the acid-base crosslinking reaction were verified by energy-dispersive X-ray spectroscopy (EDX), X-ray diffractometry (XRD), Fourier-transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). The pore structure analysis of MMMs indicated that filling ZIF-67 into SPSf enhanced the average surface pore sizes, surface porosities and more micropore in cross-sections. The crossflow filtrations showed the MMMs have higher pure water fluxes (57 to 111 L m−2 h−1) than the SPSf membrane (55 L m−2 h−1) but also higher bovine serum albumin (BSA) rejection rate of 93.9–95.8%, a model protein foulant. The MMMs showed a higher water contact angle than the SPSf membrane due to the addition of hydrophobic ZIF-67 and acid-base crosslinking, and also maintained high thermal stability evidenced by the thermogravimetric analysis (TGA) results. At the optimal ZIF-67 concentration of 0.3 wt%, the water flux of the SPSf-Z67-0.3 membrane was 82 L m−2 h−1 with a high BSA rejection rate of 95.3% at 0.1 MPa and better antifouling performance (FRR = 70%). Highlights An SPSf-matrix ultrafiltration (UF) membrane was developed by blending with hydrophobic ZIF-67.; ZIF-67 has good dispersibility and compatibility with SPSf of weak acid-base interaction.; Simultaneous enhancement in the permeability and selectivity of the MMMs.

Supplemental Digital Content is available in the text., Objective Alzheimer disease is characterized by progressive decline in cognitive function due to neurodegeneration induced by accumulation of Aβ and hyperphosphorylated tau protein. This study was conducted to explore the protective effect of vitamin K2 against Aβ42-induced neurotoxicity. Methods Alzheimer disease transgenic Drosophila model used in this study was amyloid beta with the arctic mutation expressed in neurons. Alzheimer disease flies were treated with vitamin K2 for 28 days after eclosion. Aβ42 level in brain was detected by ELISA. Autophagy-related genes and NDUFS3, the core subunit of mitochondrial complex I, were examined using real-Time PCR (RT-PCR) and western blot analysis. Results Vitamin K2 improved climbing ability (P = 0.0105), prolonged lifespan (P

AKR1C3 is an enzyme belonging to the aldo-ketoreductase family, the members of which catalyze redox transformations involved in biosynthesis, intermediary metabolism, and detoxification. AKR1C3 plays an important role in tumor progression and metastasis, however, little is known about the function and the molecular mechanism underlying the role of AKR1C3 in hepatocellular carcinoma (HCC). In this study, we report that AKR1C3 is significantly upregulated in HCC and that increased AKR1C3 is associated with poor survival. AKR1C3 positively regulated HCC cell proliferation and metastasis in vitro and in vivo. AKR1C3 promoted tumor proliferation and metastasis by activating NF-κB signaling. Furthermore, AKR1C3 regulated NF-κB activity by modulating TRAF6 and inducing its autoubiquitination in HCC cells. Activation of NF-κB released proinflammatory factors that facilitated the phosphorylation of STAT3 and increased tumor cell proliferation and invasion. Gain- and loss-of-function experiments showed that AKR1C3 promoted tumor proliferation and invasion via the IL6/STAT3 pathway. STAT3 also directly bound the AKR1C3 promoter and increased transcription of AKR1C3, thereby establishing a positive regulatory feedback loop. Treatment with the AKR1C3 inhibitors indocin and medroxyprogesterone acetate inhibited tumor growth and invasion and promoted apoptosis in HCC cells. Collectively, these results indicate that a AKR1C3/NF-κB/STAT3 signaling loop results in HCC cell proliferation and metastasis and could be a promising therapeutic target in HCC. Significance: These findings elucidate a novel AKR1C3-driven signaling loop that regulates proliferation and metastasis in HCC, providing potential prognostic and therapeutic targets in this disease.

Background: The potential effect of alcohol or tea intake on the risk of nasopharyngeal carcinoma (NPC) remains controversial. Methods: In a population-based case–control study in southern China, we assessed alcohol or tea intake from 2,441 histopathologically confirmed NPC cases and 2,546 controls. We calculated mean daily ethanol (g/day) and tea intake (mL/day). Fully adjusted ORs with 95% confidence intervals (CI) were estimated using logistic regression; potential dose–response trends were evaluated using restricted cubic spline analysis. Results: Compared with nondrinkers, no significantly increased NPC risk in men was observed among current alcohol drinkers overall (OR, 1.08; 95% CI, 0.93–1.25), nor among current heavy drinkers (OR for ≥90 g/day ethanol vs. none, 1.32; 95% CI, 0.95–1.84) or former alcohol drinkers. Current tea drinking was associated with a decreased NPC risk (OR, 0.73; 95% CI, 0.64–0.84). Compared with never drinkers, those with the low first three quintiles of mean daily current intake of tea were at significantly lower NPC risk (OR, 0.53, 0.68, and 0.65, respectively), but not significant for the next two quintiles. Current daily tea intake had a significant nonlinear dose–response relation with NPC risk. Conclusions: Our study suggests no significant association between alcohol and NPC risk. Tea drinking may moderately reduce NPC risk, but the lack of a monotonic dose–response association complicates causal inference. Impact: Tea drinking might be a healthy habit for preventing NPC. More studies on biological mechanisms that may link tea with NPC risk are needed.

Objective Parkinson's disease is a common neurodegenerative disease. Here, we investigated the protective effect and potential mechanisms of propionate on the intestinal epithelial barrier in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease. Methods Gas chromatography was used to determine short-chain fatty acids (SCFA) concentrations in the fecal samples of Parkinson's disease patients and healthy controls. The stepping test was used to analyze forelimb akinesia, whisker test was used to analyze sensorimotor injury, cylinder test was used to analyze sensorimotor function, and Western blotting was used to analyze protein expression. Results The concentrations of SCFAs, including acetate, butyrate and propionate, were significantly downregulated in the fecal samples of Parkinson's disease patients, and among the SCFAs, propionate decreased the most. Propionate administration improved the stepping test score, whisker test score and cylinder test score of MPTP-induced Parkinson's disease mice. Additionally, propionate administration increased the protein expression of zonula occludens-1 and occludin. Moreover, the effects of propionate on motor behavior and the intestinal epithelial barrier were dependent on the proteirrserinc-threonine kinases (AKT) signaling pathway. More importantly, treatment with SC79, a specific AKT agonist, abolished the effects of propionate on the intestinal epithelial barrier and motor behavior. Conclusion Our results demonstrated that propionate, which was decreased in the fecal samples of Parkinson's disease patients, exerted beneficial effects on intestinal epithelial barrier function and improved motor behavior in MPTP-induced Parkinson's disease mice through the AKT signaling pathway.

Abdominal aortic aneurysm (AAA) is an aging-related degenerative disease. miR-188-5p was reported to induce cell senescence and play a key role in aging-related disease. Therefore, in this study, we investigated miR-188-5p expression during progression in experimental AAAs. Furthermore, we investigated whether inhibition of miR-188-5p could suppress AAA progression. Experimental AAAs were created in 9-12-week-old male C57BL/6J mice by transient intra-aortic infusion of porcine pancreatic elastase. Expression of miR-188-5p levels were assessed in aneurysmal and control aortae during the progression of aneurysm. For inhibition experiment, miR-188 inhibiting group mice were injected with AAV2-miR188-5p sponge through tail vein and control group mice were injected with AAV2-CMV-GFP. Influences on experimental AAA progression were assessed by measurements of aortic diameter and histopathologic analysis at sacrifice. Meanwhile, immunohistochemistry and fluorescence in situ hybridization were used to determine the inflammatory cells infiltration and colocalization of miR-188-5p in aortic sections. Expression of miR-188-5p is upregulated during progression of AAA. Importantly, miR-188-5p inhibition treatment prevented enlargement of experimental aneurysms. Meanwhile, miR-188-5p inhibition regimens attenuated medial elastin degradation, smooth muscle cell depletion, and mural angiogenesis and the accumulation of macrophages, T cells, and angiogenesis. Furthermore, colocalization of miR188-5p with CD68 and CD3 was observed, which suggest miR-188-5p was expressed mainly in infiltrated macrophages and T cells. Expression of miR-188-5p is increased in experimental AAAs. Treatment with miR-188-5p inhibition limits experimental AAA progression, with histologic evidence of reduced neovessels and attenuated mural leukocyte infiltration. These findings underscore the potential significance of miR-188-5p in aneurysm pathogenesis and as a target for suppression of AAA disease.

With the modification of DSM-5 mixed features specifier, a brief scale to screen mixed features in patients with mood disorders is needed in clinical practice. This study aimed to explore the psychometric properties of the Chinese version of the Clinically Useful Depression Outcome Scale supplemented with DSM-5 Mixed subtype (CUDOS-M-C) for the Chinese patients with mood disorders.Overall, 300 patients with major depressive episode were recruited. All participants were assessed using CUDOS-M-C, Young Mania Rating Scale, Hamilton Anxiety Scale and Montgomery-Asberg Depression Rating Scale. The receiver operating characteristic (ROC) curve analysis was used to calculate the optimal cut-off values of CUDOS-M-C score. The reliability and validity of CUDOS-M-C were examined using Cronbach's alpha, intraclass correlation coefficient (ICC) and principal component analysis (PCA).The results of PCA indicated two-factor structure as the best solution for CUDOS-M-C, which explained 54.82% of cumulative variance. The Cronbach's alpha was 0.892 and the ICC was 0.853. The area under the ROC curve of the CUDOS-M-C for participants with mixed depression was 0.927 (p0.001) and the suitable cut-off value was 8, with a sensitivity of 91.6% and specificity of 79.9%.Most of the patients were recruited from eastern China and further research with larger sample is warranted. And this study did not perform confirmatory factor analysis to identify the generalization of factor structure of CUDOS-M-C. Besides, the study performed the test-retest reliability of CUDOS-M-C and further analysis is needed to ascertain the patient's post-treatment changes.The CUDOS-M-C demonstrated to have satisfactory psychometric properties as a self-report scale, and could be applied to screen patients with mixed depression in clinical practice.

The hyperglycemic environment and the presence of bacterial infections delay the healing of diabetic wounds. Herein, glucose oxidase (GOx) and Fe3O4/TiO2/Ag3PO4 were embedded in a polyacrylic acid-calcium phosphate (PAA-CaPs@Nps@GOx) hydrogel through an in situ biomimetic mineralization approach. The GOx encapsulation efficiency was 96.75% and exhibited exceptional enzyme activity stability. Moreover, the co-immobilization of GOx and Fe3O4/TiO2/Ag3PO4 nanoparticles generated a simple and multifunctional antibacterial platform with the advantages of decreasing blood glucose concentration and efficiently producing reactive oxygen species (ROS). In addition, the degradation rate of the hydrogel was controlled by regulating the concentration of phosphate thus controlling the release of Fe3O4/TiO2/Ag3PO4 and GOx. As a result, both the potential toxicity and oxidative stress associated with the antimicrobial biomaterial can be controlled within the body therefore potentially preventing detriment. In vivo results indicated that the PAA-CaPs@Nps@GOx hydrogel effectively promoted diabetic wound healing and showed great potential for clinical applications of chronic wound management.

Background: Covid-19 has started to spread within China since the end of December 2019. Despite government’s immediate actions and strict control, more and more people were infected every day. As such a contagious virus can spread easily and rapidly between people, the whole country was put into lockdown and people were forced into isolation. In order to understand the impact of Covid-19 on mental health well-being, Chinese researchers have conducted several studies. However, no consistent results were obtained. Therefore, a meta-analysis was conducted. Methods: We searched Embase, PubMed, and Web of Science databases to find literature from December 2019 to April 2020 related to Covid-19 and mental health, among which results such as comments, letters, reviews and case reports were excluded. The incidence of anxiety and depression in the population was synthesized and discussed. Results: A total of 27,475 subjects were included in 12 studies. Random effect model is used to account for the data. The results showed that the incidence of anxiety was 25% (95% CI: 0.19–0.32), and the incidence of depression was 28% (95% CI: 0.17–0.38). Significant heterogeneity was detected across studies regarding these incidence estimates. Subgroup analysis included the study population and assessment tools, and sensitivity analysis was done to explore the sources of heterogeneity. Conclusions: Owing to the significant heterogeneity detected in studies regarding this pooled prevalence of anxiety and depression, we must interpret the results with caution. As the epidemic is ongoing, it is vital to set up a comprehensive crisis prevention system, which integrating epidemiological monitoring, screening and psychological crisis prevention and interventions.

Provirus integration site Moloney murine leukemia virus (Pim-1) is a proto-oncogene reported to be associated with cell proliferation, differentiation and survival. This study was to explore the neuroprotective role of Pim-1 in a rat model subjected to optic nerve crush (ONC), and discuss its related molecules in improving the intrinsic regeneration ability of retinal ganglion cells (RGCs). Immunofluorescence staining showed that AAV2- Pim-1 infected 71% RGCs and some amacrine cells in the retina. Real-time PCR and Western blotting showed that retina infection with AAV2- Pim-1 up-regulated the Pim-1 mRNA and protein expressions compared with AAV2-GFP group. Hematoxylin-Eosin (HE) staining, γ-synuclein immunohistochemistry, Cholera toxin B (CTB) tracing and TUNEL showed that RGCs transduction with AAV2-Pim-1 prior to ONC promoted the survival of damaged RGCs and decreased cell apoptosis. RITC anterograde labeling showed that Pim-1 overexpression increased axon regeneration and promoted the recovery of visual function by pupillary light reflex and flash visual evoked potential. Western blotting showed that Pim- 1 overexpression up-regulated the expression of Stat3, p-Stat3, Akt1, p-Akt1, Akt2 and p-Akt2, as well as βIII-tubulin, GAP-43 and 4E-BP1, and downregulated the expression of SOCS1 and SOCS3, Cleaved caspase 3, Bad and Bax. These results demonstrate that Pim-1 exerted a neuroprotective effect by promoting nerve regeneration and functional recovery of RGCs. In addition, it enhanced the intrinsic regeneration capacity of RGCs after ONC by activating Stat3, Akt1 and Akt2 pathways, and inhibiting the mitochondrial apoptosis pathways. These findings suggest that Pim-1 may prove to be a potential therapeutic target for the clinical treatment of optic nerve injury.

Hippo signaling functions to limit cellular growth, but the aberrant nuclear accumulation of its downstream YAP1 leads to carcinogenesis. YAP1/TEAD complex activates the oncogenic downstream transcription, such as CTGF and c-Myc. How YAP1 is protected in the cytoplasm from ubiquitin-mediated degradation remains elusive. In this study, a member of Angiomotin (Motin) family, AMOTL1 (Angiomotin Like 1), was screened out as the only one to promote YAP1 nuclear accumulation by several clinical cohorts, which was further confirmed by the cellular functional assays. The interaction between YAP1 and AMOTL1 was suggested by co-immunoprecipitation and immunofluorescent staining. The clinical significance of the AMOTL1–YAP1–CTGF axis in gastric cancer (GC) was analyzed by multiple clinical cohorts. Moreover, the therapeutic effect of targeting the oncogenic axis was appraised by drug-sensitivity tests and xenograft-formation assays. The upregulation of AMOTL1 is associated with unfavorable clinical outcomes of GC, and knocking down AMOTL1 impairs its oncogenic properties. The cytoplasmic interaction between AMOTL1 and YAP1 protects each other from ubiquitin-mediated degradation. AMOTL1 promotes YAP1 translocation into the nuclei to activate the downstream expression, such as CTGF. Knocking down AMOTL1, YAP1, and CTGF enhances the therapeutic efficacies of the first-line anticancer drugs. Taken together, AMOTL1 plays an oncogenic role in gastric carcinogenesis through interacting with YAP1 and promoting its nuclear accumulation. A combination of AMOTL1, YAP1, and CTGF expression might serve as a surrogate of Hippo activation status. The co-activation of the AMOTL1/YAP1–CTGF axis is associated with poor clinical outcomes of GC patients, and targeting this oncogenic axis may enhance the chemotherapeutic effects.

Pyridomycin, a cyclodepsipeptide with potent antimycobacterial activity, specifically inhibits the InhA enoyl reductase of Mycobacterium tuberculosis. Structure-activity relationship studies indicated that the enolic acid moiety in the pyridomycin core system is an important pharmacophoric group, and the natural configuration of the C-10 hydroxyl contributes to the bioactivity of pyridomycin. The ring structure of pyridomycin was generated by the nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) hybrid system (PyrE-PyrF-PyrG). Bioinformatics analysis reveals that short-chain dehydrogenase/reductase (SDR) family protein Pyr2 functions as a 3-oxoacyl acyl carrier protein (ACP) reductase in the pyridomycin pathway. Inactivation of pyr2 resulted in accumulation of pyridomycin B, a new pyridomycin analogue featured with enol moiety in pyridyl alanine moiety and a saturated 3-methylvaleric acid group. The elucidated structure of pyridomycin B suggests that rather than functioning as a post-tailoring enzyme, Pyr2 catalyzes ketoreduction to form the C-10 hydroxyl group in pyridyl alanine moiety and the double bond formation of the enolic acid moiety derived from isoleucine when the intermediate assembled by PKS-NRPS machinery is still tethered to the last NRPS module in a special energy-saving manner. Ser-His-Lys residues constitute the active site of Pyr2, which is different from the typically conserved Tyr-based catalytic triad in the majority of SDRs. Site-directed mutation identified that His154 in the active site is a critical residue for pyridomycin B production. These findings will improve our understanding of pyridomycin biosynthetic logic, identify the missing link for the double bound formation of enol ester in pyridomycin, and enable the creation of chemical diversity of pyridomycin derivatives. IMPORTANCE Tuberculosis (TB) is one of the world’s leading causes of death by infection. Recently, pyridomycin, the antituberculous natural product from Streptomyces has garnered considerable attention for being determined as a target inhibitor of InhA enoyl reductase of Mycobacterium tuberculosis. In this study, we report a new pyridomycin analogue from mutant HTT12, demonstrate the essential role of a previously ignored gene pyr2 in pyridomycin biosynthetic pathway, and imply that Pyr2 functions as a trans ketoreductase (KR) contributing to the formation of functional groups of pyridomycin utilizing a distinct catalytic mechanism. As enol moiety are important for pharmaceutical activities of pyridomycin, our work would expand our understanding of the mechanism of SDR family proteins and set the stage for future bioengineering of new pyridomycin derivatives.

Cervical cancer is one of the most severe and prevalent female malignancies and a global health issue. The molecular mechanisms underlying cervical cancer development are poorly investigated. As a type of extracellular membrane vesicles, EVs from cancer cells are involved in cancer progression by delivering regulatory factors, such as proteins, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). In this study, we identified an innovative function of extracellular vesicle (EV) lncRNA AGAP2-AS1 in regulating cervical cancer cell proliferation. The EVs were isolated from the cervical cancer cells and were observed by transmission electron microscopy (TEM) and were confirmed by analyzing exosome markers. The depletion of AGAP2-AS1 by siRNA significantly reduced its expression in the exosomes from cervical cancer and in the cervical cancer treated with AGAP2-AS1-knockdown exosomes. The expression of AGAP2-AS1 was elevated in the clinical cervical cancer tissues compared with the adjacent normal tissues. The depletion of EV AGAP2-AS1 reduced cell viabilities and Edu-positive cervical cancer cells, while it enhanced cervical cancer cell apoptosis. Tumorigenicity analysis in nude mice showed that the silencing of EV AGAP2-AS1 attenuated cervical cancer cell growth in vivo. Regarding the mechanism, we identified that AGAP2-AS1 increased SIRT1 expression by sponging miR-3064-5p in cervical cancer cells. The overexpression of SIRT1 or the inhibition of miR-3064-5p reversed EV AGAP2-AS1 depletion-inhibited cancer cell proliferation in vitro. Consequently, we concluded that EV lncRNA AGAP2-AS1 contributed to cervical cancer cell proliferation through regulating the miR-3064-5p/SIRT1 axis. The clinical values of EV lncRNA AGAP2-AS1 and miR-3064-5p deserve to be explored in cervical cancer diagnosis and treatments.

Background Diet, environment, and genomic context have a significant impact on humans’ intestinal microbiota. Moreover, migration may be accompanied by changes in human eating habits and living environment, which could, in turn, affect the intestinal microbiota. Located in southwestern China, Tibet has an average altitude of 4,000 meters and is known as the world’s roof. Xianyang is situated in the plains of central China, with an average altitude of about 400 meters. Methods To understand the association between intestinal microbiota and population migration, we collected the fecal samples from 30 Tibetan women on the first day (as TI1st), six months (as TI2nd), and ten months (as TI3rd) following migration from Tibet to Xianyang. Fecal samples were collected from 29 individuals (belonging to the Han women) as a control. The dietary information of the Tibetan women and the Han women was gathered. We performed a 16S rRNA gene survey of the collected fecal samples using Illumina MiSeq sequencing. Results Following the migration, the alpha and beta diversity of Tibetan women’s intestinal microbiota appeared unaffected. Linear discriminant analysis effect size (LEfSe) analysis showed that Klebsiella, Blautia, and Veillonella are potential biomarkers at TI1st, while Proteobacteria and Enterobacteriaceae were common in TI3rd. Finally, functional prediction by phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) found no significant up-regulation or down-regulation gene pathway in the intestinal microbiota of Tibetan women after migration. The present study reveals that the higher stability in Tibetan women’s intestinal microbiota was less affected by the environment and diet, indicating that Tibetan women’s intestinal microbiota is relatively stable. The main limitations of the study were the small sample size and all volunteers were women.

Nasopharyngeal carcinoma (NPC) is a malignancy with unique biological and clinical characteristics. It has highly associated with Epstein–Barr virus (EBV) infection and is sensitive to radiotherapy. Due to the extreme relevance between EBV infection and incidence of NPC, testing antibodies against EBV has been applied to screening “high-risk” populations of NPC. The pathological diagnosis of nasopharyngeal biopsy is the gold standard for the diagnosis of NPC. Radiotherapy has been recognized as the first choice for NPC treatment. With the improvement of intensity-modulated radiation therapy (IMRT), the 5-year disease-specific survival rate in NPC patients at an early stage has reached 95%. However, the efficacy brought by radiotherapy has reached the bottleneck in advanced patients. Recently, the 5-year overall survival rate was increased around 60-80% in locoregionally advanced NPC patients by introducing concurrent chemoradiotherapy. In addition, molecular targeted therapy and immunotherapy have been introduced to many clinical trials. In this chapter, we mainly focus on the current early screening and diagnosis of NPC patients, and the development of therapeutic approaches.

Objective. To explore the influencing factors of daytime sleepiness in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and the correlation between daytime sleepiness and pulse oxygen decline rate in patients with severe OSAHS. Methods. From January 2018 to April 2021, 246 consecutive patients with OSAHS diagnosed by polysomnography (PSG) in our hospital were selected. All patients were grouped according to the minimum nocturnal oxygen saturation and apnea hypopnea index (AHI). There were 33 cases in the no sleep hypoxia group, 34 cases in the mild hypoxia group, 119 cases in the moderate hypoxia group, and 60 cases in the severe hypoxia group. There were 30 cases in the simple snoring group, 55 cases in the mild OSAHS group, 48 cases in the moderate OSAHS group, and 113 cases in the severe OSAHS group. The Epworth Sleepiness Scale (ESS) scores of each group were compared. All patients were grouped according to ESS score. Those with score ≥9 were included in the lethargy group (n = 118), and those with score ≤10 were included in the no lethargy group (n = 128). Univariate and multivariate logistic regression analyses were used to explore the influencing factors of daytime sleepiness in OSAHS patients. Pearson correlation analysis showed the correlation between ESS score and pulse oxygen decline rate in patients with severe OSAHS. Results. The ESS score of the severe hypoxia group > the moderate hypoxia group > the mild hypoxia group > the no sleep hypoxia group. There was significant difference among the groups (F = 19.700, P < 0.0001 ). There were significant differences between the severe hypoxia group and other groups and between the moderate hypoxia group and the no sleep hypoxia group and the mild hypoxia group ( P < 0.05 ). The ESS score of the severe OSAHS group > the moderate OSAHS group > the mild OSAHS group > the simple snoring group. There was significant difference among the groups (F = 19.000, P < 0.0001 ). There were significant differences between the severe OSAHS group and other groups and between the moderate OSAHS group and the simple snoring group ( P < 0.05 ). Univariate analysis showed that BMI, neck circumference, snoring degree, total apnea hypopnea time, AHI, micro arousal index (MAI), oxygen saturation (CT90%), lowest oxygen saturation (LSaO2), and mean oxygen saturation (MSaO2) were the influencing factors of daytime sleepiness in OSAHS patients ( P < 0.05 ). Multiple logistic regression analysis showed that AHI and CT90% were independent risk factors for daytime sleepiness in OSAHS patients ( P < 0.05 ). Pearson correlation analysis showed that there was a positive correlation between ESS score and pulse oxygen decline rate in patients with severe OSAHS (r = 0.765, P < 0.0001 ). Conclusion. OSAHS patients may be accompanied by daytime sleepiness in varying degrees, which may be independently related to AHI and CT90%. The degree of daytime sleepiness in patients with severe OSAHS may be closely related to the decline rate of pulse oxygen, which should be paid great attention in clinic.

Background: Dexamethasone (DEX) is widely adopted to reduce tumor-associated edema in glioblastoma (GBM) patients despite its side effects. However, the benefits of using DEX in GBM patients remains elusive.Methods: In this study, we performed a comprehensive meta-analysis to address this concern. We searched the relevant studies from PubMed, Web of Science, and EMBASE databases, and then applied random or fixed-effects models to generate estimated summary hazard radios (HRs) and the 95% confidence intervals (CIs). Moreover, subgroup and sensitivity analysis were conducted and publication bias were further evaluated.Results: Ten articles with a total of 2,230 GBM patients were eligible according to the inclusion criteria. In the assessment of overall survival (OS), meta-analysis data revealed that DEX was significantly associated with the poor prognosis of GBM patients (HR=1.44, 95% CI=1.32−1.57). In the progression-free survival (PFS), the pooled results indicated that the use of DEX can increase 48% death risk for GBM patients (HR=1.48, 95% CI=1.11−1.98). Subgroup analyses revealed that DEX was associated with poorer outcome of GBM in subgroup of newly diagnosed patients and GBM patients treated with ≥ 2mg/day. Sensitivity analyses showed that no study changed the pooled results materially for both OS and PFS analyses. The funnel plot had no obvious asymmetry.Conclusion: Our findings partly confirmed that use of DEX was associated with poor treatment outcome in GBM patients. To reach a definitive conclusion, large samples from multi-centers are urgent to address this concern.

Acute paraquat (PQ) poisoning results in severe acute lung injury and pulmonary fibrosis, and there is no specific antidote; thus, the mortality rate of PQ poisoning is extremely high. The mechanism of poisoning may be associated with endoplasmic reticulum stress, oxidative stress damage and organ/tissue inflammation. Recent studies have reported that human amnion-derived mesenchymal stem cells (hAMSCs) secrete a variety of cytokines, and that hAMSC-conditioned medium (CM) has anti-inflammatory and immunomodulatory effects. The aim of the present study was to investigate whether hAMSC-CM exerts protective effects against PQ toxicity in A549 cells. The data demonstrated that the activity of A549 cells was decreased after 24 h of PQ exposure and that the cell viability of the hAMSC-CM intervention group was higher compared with the PQ-only group. hAMSC-CM intervention decreased cell damage, apoptosis rates, oxidative stress indexes, Bax/Bcl-2 ratios and CHOP expression levels in poisoned cells by CCK-8 experiment, apoptosis detection, ROS content detection, and Western blot analysis respectively. In conclusion, hAMSC-CM may attenuate the cell damage caused by PQ by reducing endoplasmic reticulum stress and oxidative stress.

Stroke remains the leading cause of long-term disability worldwide with significant long-term sequelae. However, there is no highly effective treatment to enhance post-stroke recovery despite extensive efforts in exploring rehabilitative therapies. Neurorehabilitation is recognized as the cornerstone of functional restoration therapy in stroke, where treatments are focused on neuroplastic regulation to reverse neural structural disruption and improve neurofunctional networks. Post-stroke neuroplasticity changes begin within hours of symptom onset and reaches a plateau by 3 to 4 weeks within the global brain in animal studies. It plays a determining role in spontaneous stroke recovery. Microglia are immediately activated following cerebral ischemia, which has been found both proximal to the primary ischemic injury and at the remote brain regions which have functional connections to the primary injury area. Microglia exhibit different activation profiles based on the microenvironment and adaptively switch their phenotypes in a spatiotemporal manner in response to brain injuries. Microglial activation coincides with neuroplasticity after stroke, which provides the fundamental base for the microglia-mediated inflammatory responses involved in the entire neural network rewiring and brain repair. Microglial activation exerts important effects on spontaneous recovery after stroke, including structural and functional reestablishment of neurovascular networks, neurogenesis, axonal remodeling, and blood vessel regeneration. In this review, we focus on the crosstalk between microglial activation and endogenous neuroplasticity, with a special focus on the plastic alterations in the whole brain network and their implications for structural and functional restoration after stroke. We then summarize recent advances in the impacts of microglial phenotype polarization on brain plasticity, trying to discuss the potential efficacy of microglia-based extrinsic restorative interventions in promoting post-stroke recovery.

Xiuyuan Zhang, Tingting Huang, Yiming Li, Hong Qiu Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of ChinaCorrespondence: Hong QiuDepartment of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, 430030, Hubei, People’s Republic of ChinaEmail tjqiuhong@163.comPurpose: Thrombospondin 1 (THBS1) is an endogenous inhibitor of angiogenesis, but it also promotes tumor invasion, metastasis, and immune response in the tumor environment. Previous research has found that THBS1 is highly expressed in many tumors and has a negative correlation with tumor prognosis. However, research on the relationship between THBS1 and immune infiltration in GC is less well documented, and the objective of our study was to investigate the role of THBS1 expression in GC.Patients and Methods: The expression of THBS1 in GC was analyzed by Oncomine, TIMER, TGCA, GEO and IHC staining. Analysis of the signaling pathways associated with THBS1 expression in GC uses GSEA. The relationship between THBS1 expression and immune infiltration was analyzed by the ESTIMATE algorithm, single-cell transcriptome analysis, TIMER2 database and CIBERSORT algorithm. Finally, the relationship between THBS1 expression and drug sensitivity was analyzed by the CellMiner database.Results: THBS1 was overexpressed in GC and was associated with poor prognosis, and high THBS1 expression was an independent risk factor. GSEA results showed that high THBS1 expression in GC was associated with tumorigenesis, adhesion, and significant immune enrichment. THBS1 expression was most strongly correlated with tumor-associated macrophages (TAMs), M2 macrophages and cancer-associated fibroblast (CAFs) in GC. THBS1 expression positively correlates with most immune checkpoint members, suggesting that THBS1 may play an important role in the tumor microenvironment. THBS1 overexpression was negatively correlated with some drug sensitivities, such as Oxaliplatin.Conclusion: Upregulation of THBS1 was positively correlated with poor prognosis and immunosuppression in GC and negatively correlated with anticancer drug sensitivity, suggesting that THBS1 may serve as a potential target for the treatment of GC.Keywords: THBS1, gastric cancer, drug sensitivity, prognosis, tumor microenvironment