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Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1 . Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis. Lipid metabolism has been linked to iNKT function largely as it impacts processing and presentation of lipids they recognize. Here the authors show that iNKT-intrinsic lipid biosynthesis is important for their function but is impaired in tumors, and its restoration with PPARγ agonist drugs promotes anti-tumor iNKT response.

Canker caused by ascomycetous Valsa species are among the most destructive diseases of woody plants worldwide. These pathogens are distinct from other pathogens because they only effectively attack tree bark in the field. To unravel the potential adaptation mechanism of bark colonization, we examined the genomes of Valsa mali and Valsa pyri that preferentially infect apple and pear, respectively. We reported the 44.7 and 35.7 Mb genomes of V. mali and V. pyri, respectively. We also identified the potential genomic determinants of wood colonization by comparing them with related cereal pathogens. Both genomes encode a plethora of pathogenicity‐related genes involved in plant cell wall degradation and secondary metabolite biosynthesis. In order to adapt to the nutrient limitation and low pH environment in bark, they seem to employ membrane transporters associated with nitrogen uptake and secrete proteases predominantly with acidic pH optima. Remarkably, both Valsa genomes are especially suited for pectin decomposition, but are limited in lignocellulose and cutin degradation. Besides many similarities, the two genomes show distinct variations in many secondary metabolism gene clusters. Our results show a potential adaptation of Valsa canker pathogens to colonize woody bark. Secondary metabolism gene clusters are probably responsible for this host specificity.

We previously reported that astrocyte-derived proinflammatory cytokine interleukin (IL)-17A could aggravate neuronal ischemic injuries and strength autophagy both in oxygen-glucose deprivation (OGD)/reoxygenation (R)-treated neurons and peri-infarct region of mice with middle cerebral artery occlusion (MCAO)/reperfusion (R)-simulated ischemic stroke. In this study, the role and molecular mechanism of IL-17A in autophagy were further explored under ischemic condition. We found that exogenous addition of rmIL-17A remarkably ( < 0.001) decreased cell viability, which companying with the increases of LC3 II accumulation ( < 0.05 or 0.01) and Beclin 1 levels ( < 0.05 or 0.001), and reduction of p62 levels ( < 0.01 or 0.001) in OGD/R-treated cortical neurons ( = 6). The levels of P-mTOR (Ser 2448) ( < 0.001) and P-S6 (Ser 240/244) ( < 0.01) significantly decreased without the involvement of Akt, ERK1/2 and AMPK in cortical neurons under rmIL-17A and OGD/R treatments ( = 6). Interestingly, the co-IP analysis exhibited that PP2B and mTOR could be reciprocally immunoprecipitated; and the addition of rmIL-17A increased their interactions, PP2B activities ( < 0.001), P-Src ( < 0.001), and P-PLCγ1 ( < 0.01) levels in OGD/R-treated neurons ( = 6 or 5). The PP2B inhibitor Cyclosporin A blocked the induction of excessive autophagy ( < 0.05 or <0.001) and increased cell viability ( < 0.001) after OGD/R and rmIL-17A treatments ( = 6). In addition, the ICV injection of IL-17A neutralizing mAb could attenuate autophagy levels ( < 0.01 or 0.001, = 6) and improve neurological functions ( < 0.01 or 0.001, = 10) of mice after 1 h MCAO/R 24 h or 7 d. These results suggested that IL-17A-mediated excessive autophagy aggravates neuronal ischemic injuries via Src-PP2B-mTOR pathway, and IL-17A neutralization may provide a potential therapeutic effect for ischemic stroke.

Idiopathic sudden sensorineural hearing loss (ISSNHL) is an emergency disease requiring immediate diagnosis and treatment. The incidence of ISSNHL in the Western countries’ population was estimated to 5–20 per 100,000 inhabitants. The etiology of ISSNHL remains unknown. Its pathogenesis is most often suggested to be due to a disturbed microcirculation and infection. Previous studies have reported that comorbidities, including hypertension, diabetes mellitus (DM), and hyperfibrinogenemia are risk factors of ISSNHL. This study aimed at investigating the clinical characteristics, laboratory parameters and comorbidities of patients with ISSNHL. Our study suggests that the annual incidence of ISSNHL in China mainland is 19 per 100 000. The clinical characteristics and prevalence of comorbidities of ISSNHL patients are different according to age distribution and hearing results. Moreover, the patients with vertigo, hypertension, DM and high TG suffered more often from severe hearing loss compared with the counterparts. This indicates that the cardiovascular and metabolic diseases (hypertension and hyperlipidemia) appeared to be closely associated with the occurrence and severity of ISSNHL.

Pulmonary fibrosis is a disease that severely affects the patients’ life quality, characterized by lung tissue remodeling and functional impairment. Recent research has found that the NLRP3 inflammasome plays an important role in the pathogenesis of pulmonary fibrosis. Although existing researches have revealed the potential role of NLRP3 in pulmonary fibrosis, many mysteries still remain regarding its specific mechanisms and clinical applications. This article aims to review the mechanisms of action of NLRP3 in pulmonary fibrosis, related signaling pathways, and the latest research progress on its potential as a therapeutic target, in hopes of providing new ideas and directions for future clinical treatment.

Previous studies have highlighted associations between certain inflammatory cytokines and Ménière's Disease (MD), such as interleukin (IL) -13 and IL-1β. This Mendelian randomization aims to comprehensively evaluate the causal relationships between 91 inflammatory cytokines and MD. A comprehensive two-sample Mendelian randomization (MR) analysis was conducted to determine the causal association between inflammatory cytokines and MD. Utilizing publicly accessible genetic datasets, we explored causal links between 91 inflammatory cytokines and MD risk. Comprehensive sensitivity analyses were employed to assess the robustness, heterogeneity, and presence of horizontal pleiotropy in our findings. Our findings indicate that MD causally influences the levels of two cytokine types: IL-10 (P=0.048, OR=0.945, 95%CI =0.894~1.000) and Neurotrophin-3 (P=0.045, OR=0954, 95%CI =0.910~0.999). Furthermore, three cytokines exhibited significant causal effects on MD: CD40L receptor (P=0.008, OR=0.865, 95%CI =0.777-0.963), Delta and Notch-like epidermal growth factor-related receptor (DNER) (P=0.010, OR=1.216, 95%CI =1.048-1.412), and STAM binding protein (P=0.044, OR=0.776, 95%CI =0.606-0.993). This study suggests that the CD40L receptor, DNER, and STAM binding protein could potentially serve as upstream determinants of MD. Furthermore, our results imply that when MD is regarded as the exposure variable in MR analysis, it may causally correlate with elevated levels of IL-10 and Neurotrophin-3. Using these cytokines for MD diagnosis or as potential therapeutic targets holds great clinical significance.

Background IQ motif-containing GTPase-activating proteins (IQGAPs) are a group of scaffold proteins which have been identified to be involved in tumor initiation and progression in diverse types of cancer. Clinical studies and experimental evidence suggest that IQGAPs play an essential role in hepatocellular carcinoma (HCC) progression and alterations in their expression are closely related to patient prognosis. However, the different expression patterns and prognostic values of all three IQGAP isoforms in HCC have not yet been analyzed simultaneously. Methods We analyzed the transcriptional and survival data of IQGAPs in HCC patients using Oncomine, UALCAN, Kaplan–Meier Plotter, cBioPortal, and GeneMANIA. We further examined tumor and adjacent normal tissues from 250 HCC patients using immunohistochemistry to assess the relationship between IQGAPs expression and clinicopathological features and validate the prognostic value of IQGAPs. In addition, we analyzed transcriptional changes of IQGAPs with regards to survival data in HCC patients from the TCGA-LIHC (liver hepatocellular carcinoma) cohort to validate our results. Results We found that the expression levels of IQGAP1 and 3 were significantly elevated in HCC tissues than in normal liver tissues, whereas the expression level of IQGAP2 was decreased in the former than in the latter. The clinical data showed that positive IQGAP1 expression was associated with larger tumor size, advanced tumor-node-metastasis (TNM) stage, poor relapse-free survival (RFS), and overall survival (OS), and positive IQGAP3 expression was associated with poorer tumor differentiation, RFS, and OS. Conversely, positive IQGAP2 expression predicted less tumor numbers and microvascular invasion, as well as higher RFS and OS in these patients. Conclusions IQGAPs may serve as new prognostic biomarkers and potential targets for precision therapy in HCC.

Liver transplantation is currently the only effective treatment for patients with end-stage liver disease; however, donor liver scarcity is a notable concern. As a result, extensive endeavors have been made to diversify the source of donor livers. For example, the use of a decellularized scaffold in liver engineering has gained considerable attention in recent years. The decellularized scaffold preserves the original orchestral structure and bioactive chemicals of the liver, and has the potential to create a de novo liver that is fit for transplantation after recellularization. The structure of the liver and hepatic extracellular matrix, decellularization, recellularization, and recent developments are discussed in this review. Additionally, the criteria for assessment and major obstacles in using a decellularized scaffold are covered in detail.

We aimed to investigate the prevalence of stroke and related vascular risk factors in adult population aged 40 years and older in China. We conducted a prospective cross-sectional survey in nationally representative sample of 207323 individuals from all 31 Chinese provinces in 2013. Data were used to analyze the prevalence of stroke by age, sex, geographical regions and educational level. The age-standardized prevalence of stroke was significantly higher in men than in women in all age groups (P < 0.001). The age-standardized prevalence of stroke was significantly higher in rural than in urban residents among both men and women (P < 0.001). The prevalence of stroke was inversely associated with educational level. There were striking geographical variations in stroke prevalence in China with a higher prevalence of stroke in northern provinces as compared with southern provinces of the country. The age-standardized prevalence of hypertension, diabetes, dyslipidemia, atrial fibrillation and obesity in the Chinese population aged 40 years and older were 35.24%, 9.55%, 58.72%, 1.57% and 4.09%, respectively. Stroke and related vascular risk factors remains a major public threat in China and effective primary preventive strategies that aimed at reducing the burden of stroke and its risk factors are urgently needed.

The scaffold protein family of IQ motif-containing GTPase-activating proteins (IQGAP1, 2, and 3) share a high degree of homology and comprise six functional domains. IQGAPs bind and regulate the cytoskeleton, interact with MAP kinases and calmodulin, and have GTPase-related activity, as well as a RasGAP domain. Thus, IQGAPs regulate multiple cellular processes and pathways, affecting cell division, growth, cell–cell interactions, migration, and invasion. In the past decade, significant evidence on the function of IQGAPs in signal transduction during carcinogenesis has emerged. Compared with IQGAP1, IQGAP2 and IQGAP3 were less analyzed. In this review, we summarize the different signaling pathways affected by IQGAP2 and IQGAP3, and the antithetic roles of IQGAP2 and IQGAP3 in different types of cancer. IQGAP2 expression is reduced and plays a tumor suppressor role in most solid cancer types, while IQGAP3 is overexpressed and acts as an oncogene. In lymphoma, for example, IQGAPs have partially opposite functions. There is considerable evidence that IQGAPs regulate a multitude of pathways to modulate cancer processes and chemoresistance, but some questions, such as how they trigger this signaling, through which domains, and why they play opposite roles on the same pathways, are still unanswered.