A novel antidiuretic hormone governs tumour-induced renal dysfunction.

Maintenance of renal function and fluid transport are essential for vertebrates and invertebrates to adapt to physiological and pathological challenges. Human patients with malignant tumours frequently develop detrimental renal dysfunction and oliguria, and previous studies suggest the involvement of chemotherapeutic toxicity and tumour-associated inflammation1,2. However, how tumours might directly modulate renal functions remains largely unclear. Here, using conserved tumour models in Drosophila melanogaster3, we characterized isoform F of ion transport peptide (ITPF) as a fly antidiuretic hormone that is secreted by a subset of yki3SA gut tumour cells, impairs renal function and causes severe abdomen bloating and fluid accumulation. Mechanistically, tumour-derived ITPF targets the G-protein-coupled receptor TkR99D in stellate cells of Malpighian tubules-an excretory organ that is equivalent to renal tubules4-to activate nitric oxide synthase-cGMP signalling and inhibit fluid excretion. We further uncovered antidiuretic functions of mammalian neurokinin 3 receptor (NK3R), the homologue of fly TkR99D, as pharmaceutical blockade of NK3R efficiently alleviates renal tubular dysfunction in mice bearing different malignant tumours. Together, our results demonstrate a novel antidiuretic pathway mediating tumour-renal crosstalk across species and offer therapeutic opportunities for the treatment of cancer-associated renal dysfunction.

EIF5A2 specifically regulates the transcription of aging-related genes in human neuroblastoma cells.

BACKGROUND: Post-transcriptional regulation plays a critical role in controlling biological processes such as aging. Previous studies have shown that eukaryotic initiation factor 5A (EIF5A) might play a crucial role in aging. It is unknown whether EIF5A2, a second isoform of EIF5A, could impact aging through post-transcriptional regulation. METHODS: In the present study, EIF5A2 overexpression (EIF5A2-OE) was induced in SH-SY5Y cells. RNA-seq, bioinformatics analysis and RT-qPCR validation experiments were then performed to explore the molecular mechanism of EIF5A2-mediated transcriptional regulation. Cell viability, proportion of senescent cells and the cell cycle were respectively determined by Cell Counting Kit-8, SA-ß­galactosidase and flow cytometry to evaluate the cell senescence. RESULTS: A total of 190 downregulated and 126 upregulated genes related to EIF5A2-OE were identified. Genes closely related to cellular aging processes such as unfolded protein response (UPR), cell adhesion and calcium signaling pathway were under global transcriptional regulation. Moreover, EIF5A2-OE promoted the viability of SH-SY5Y cells and reduced cell senescence in vitro. Among 30 genes with the most significant expression differences in EIF5A2-OE cells, we identified eight genes, including ASNS, ATF3, ATF4, CEBPB, DDIT3, HERPUD1, HSPA5 and XBP1, enriched in the UPR. Through EIF5A2-tanscription factors (TFs)-targets regulation network in EIF5A2-OE cells, we found three TFs, BHLHE40, RHOXF1 and TBX20, that targeted at these eight UPR-related genes. Verification test via the published database of human glial cell tissue showed only BHLHE40 and RHOXF1 were significantly associated with EIF5A2. CONCLUSIONS: Our findings suggest that EIF5A2 may alleviate cell senescence in vitro and mediate UPR-related genes via specific TFs. Thus, EIF5A2 could function as a regulator of aging via the regulation of transcription, which greatly expands the current understanding of the mechanisms of EIF5A2-mediated gene regulation.

YAP1 protects against PM2.5-induced lung toxicity by suppressing pyroptosis and ferroptosis.

Pollution from fine particulate matter (PM2.5) has become a major threat to public health and has been related to lung toxicity. One of the key regulators of the Hippo signaling system, Yes-associated protein 1 (YAP1), is speculated to play a role in ferroptosis development. Here, we focused on investigating the function of YAP1 in pyroptosis and ferroptosis, aiming to explore its therapeutic potential in PM2.5-induced lung toxicity. PM2.5-induced lung toxicity was induced in Wild-type WT and conditional YAP1-knockout mice, and lung epithelial cells were stimulatd by PM2.5 in vitro. We used western blot, transmission electron microscopy, and fluorescence microscopy to investigate pyroptosis- and ferroptosis-related characteristics. We found that PM2.5 leads to lung toxicity using mechanisms involving pyroptosis and ferroptosis. YAP1 knockdown impeded pyroptosis, ferroptosis, and PM2.5-induced lung damage, as shown by increased histopathology, higher levels of proinflammatory cytokines, GSDMD protein, lipid peroxidation, and iron accumulation, as well as increased NLRP3 inflammasome activation and decreased SLC7A11 expression. YAP1 silencing consistently promoted NLRP3 inflammasome activation and reduced SLC7A11 levels, aggravating PM2.5-induced cellular damage. In contrast, YAP1-overexpressing cells inhibited NLRP3 inflammasome activation and increased SLC7A11 levels, preventing pyroptosis and ferroptosis. Overall, our data suggest that YAP1 ameliorates PM2.5-induced lung injury by inhibiting NLRP3-mediated pyroptosis and SL7A11-dependent ferroptosis.

A New Small-Size Camera with Built-In Specific-Wavelength LED Lighting for Evaluating Chlorophyll Status of Fruit Trees.

To produce high-quality crops, not only excellent cultivation techniques but also accurate nutrient management techniques are important. In recent years, many nondestructive tools such as the chlorophyll meter "SPAD" and the leaf nitrogen meter "Agri Expert CCN" have been developed for measuring crop leaf chlorophyll and nitrogen contents. However, such devices are still relatively expensive for individual farmers. In this research, we developed a low-cost and small-size camera with built-in LEDs of several specific wavelengths for evaluating the nutrient status of fruit trees. A total of 2 camera prototypes were developed by integrating 3 independent LEDs of specific wavelengths (Camera 1: 950 nm, 660 nm and 560 nm; Camera 2: 950 nm, 660 nm and 727 nm) into the device. In addition, a simple software tool was developed to enable the camera to capture leaf images under different LED lighting conditions. Using the prototypes, we acquired images of apple leaves and investigated the possibility of using the images to estimate the leaf nutrient status indicator SPAD (chlorophyll) and CCN (nitrogen) values obtained using the above-mentioned standard tools. The results indicate that the Camera 1 prototype is superior to the Camera 2 prototype and can potentially be applied to the evaluation of nutrient status in apple leaves.

Annexin A2 (ANXA2) regulates the transcription and alternative splicing of inflammatory genes in renal tubular epithelial cells.

BACKGROUND: Renal inflammation plays a crucial role during the progression of Chronic kidney disease (CKD), but there is limited research on hub genes involved in renal inflammation. Here, we aimed to explore the effects of Annexin A2 (ANXA2), a potential inflammatory regulator, on gene expression in human proximal tubular epithelial (HK2) cells. RNA-sequencing and bioinformatics analysis were performed on ANXA2-knockdown versus control HK2 cells to reveal the differentially expressed genes (DEGs) and regulated alternative splicing events (RASEs). Then the DEGs and RASEs were validated by qRT-PCR. RESULTS: A total of 220 upregulated and 171 downregulated genes related to ANXA2 knockdown were identified. Genes enriched in inflammatory response pathways, such as interferon-mediated signaling, cytokine-mediated signaling, and nuclear factor κB signaling, were under global transcriptional and alternative splicing regulation by ANXA2 knockdown. qRT-PCR confirmed ANXA2-regulated transcription of chemokine gene CCL5, as well as interferon-regulating genes ISG15, IFI6, IFI44, IFITM1, and IRF7, in addition to alternative splicing of inflammatory genes UBA52, RBCK1, and LITAF. CONCLUSIONS: The present study indicated that ANXA2 plays a role in inflammatory response in HK2 cells that may be mediated via the regulation of transcription and alternative splicing of inflammation-related genes.

SHIP-1, a target of miR-155, regulates endothelial cell responses in lung fibrosis.

Src Homology 2-containing Inositol Phosphatase-1 (SHIP-1) is a target of miR-155, a pro-inflammatory factor. Deletion of the SHIP-1 gene in mice caused spontaneous lung inflammation and fibrosis. However, the role and function of endothelial miR-155 and SHIP-1 in lung fibrosis remain unknown. Using whole-body miR-155 knockout mice and endothelial cell-specific conditional miR-155 (VEC-Cre-miR-155 or VEC-miR-155) or SHIP-1 (VEC-SHIP-1) knockout mice, we assessed endothelial-mesenchymal transition (EndoMT) and fibrotic responses in bleomycin (BLM) induced lung fibrosis models. Primary mouse lung endothelial cells (MLEC) and human umbilical vein endothelial cells (HUVEC) with SHIP-1 knockdown were analyzed in TGF-ß1 or BLM, respectively, induced fibrotic responses. Fibrosis and EndoMT were significantly reduced in miR-155KO mice and changes in EndoMT markers in MLEC after TGF-ß1 stimulation confirmed the in vivo findings. Furthermore, lung fibrosis and EndoMT responses were reduced in VEC-miR-155 mice but significantly enhanced in VEC-SHIP-1 mice after BLM challenge. SHIP-1 knockdown in HUVEC cells resulted in enhanced EndoMT induced by BLM. Meanwhile, these changes involved the PI3K/AKT, JAK/STAT3, and SMAD/STAT signaling pathways. These studies demonstrate that endothelial miR-155 plays an important role in fibrotic responses in the lung through EndoMT. Endothelial SHIP-1 is essential in controlling fibrotic responses and SHIP-1 is a target of miR-155. Endothelial cells are an integral part in lung fibrosis.

Mast Cell-Specific Expression of Human Siglec-8 in Conditional Knock-in Mice.

Sialic acid-binding Ig-like lectin 8 (Siglec-8) is expressed on the surface of human eosinophils, mast cells, and basophils-cells that participate in allergic and other diseases. Ligation of Siglec-8 by specific glycan ligands or antibodies triggers eosinophil death and inhibits mast cell degranulation; consequences that could be leveraged as treatment. However, Siglec-8 is not expressed in murine and most other species, thus limiting preclinical studies in vivo. Based on a ROSA26 knock-in vector, a construct was generated that contains the CAG promoter, a LoxP-floxed-Neo-STOP fragment, and full-length Siglec-8 cDNA. Through homologous recombination, this Siglec-8 construct was targeted into the mouse genome of C57BL/6 embryonic stem (ES) cells, and chimeric mice carrying the ROSA26-Siglec-8 gene were generated. After cross-breeding to mast cell-selective Cre-recombinase transgenic lines (CPA3-Cre, and Mcpt5-Cre), the expression of Siglec-8 in different cell types was determined by RT-PCR and flow cytometry. Peritoneal mast cells (dual FcεRI⁺ and c-Kit⁺) showed the strongest levels of surface Siglec-8 expression by multicolor flow cytometry compared to expression levels on tissue-derived mast cells. Siglec-8 was seen on a small percentage of peritoneal basophils, but not other leukocytes from CPA3-Siglec-8 mice. Siglec-8 mRNA and surface protein were also detected on bone marrow-derived mast cells. Transgenic expression of Siglec-8 in mice did not affect endogenous numbers of mast cells when quantified from multiple tissues. Thus, we generated two novel mouse strains, in which human Siglec-8 is selectively expressed on mast cells. These mice may enable the study of Siglec-8 biology in mast cells and its therapeutic targeting in vivo.

[Hyperspectral Technique for Estimating the Shelf-Lives of Fresh Spinach Leaves Covered with Film].

In order to prolong the shelf-life of fruits and vegetables, plastic films have been covered on them to improve water retention and keep external bacteria away. It is of great significance to estimate the quality of packaged fruits and vegetables accurately by predicting the shelf-life of them. In this research, hyperspectral technology combined with chemometric methods were employed to estimate the shelf-life of fresh spinach leaves in the same environment. Hyperspectral data covering the range of Vis-NIR (380～1 030 nm) and NIR (874～1 734 nm) were acquired from 300 spinach leaves (75 dishs) which were stored in 4 ℃ among 5 periods (0 d, 2 d, 4 d, 6 d, 8 d). Meanwhile, the chlorophyll contents of all spinach leaves were determined. The mean spectra of 300 spinach leaves (200 leaves in training set and 100 leaves in prediction set) were extracted. And then, principal component analysis (PCA) on the training set of 200 spectra from 5 periods of shelf-life displayed apparent cluster. Partial least-squares discriminant analysis (PLS-DA) models were established according to spectral datas and the virtual levels that we ascribed to the different storage periods previously. The total discriminant accuracy rates of prediction set were 83% (VIS-NIR) and 81% (NIR), respectively. The result indicated that the classification and prediction on the shelf-life of fresh spinach can be realized with hyperspectral technology combined with chemometric methods, which offered a theoretical guidance to evaluate the quality of packaged spinach for consumers, and provided technical supports for the development of instruments used for testing the shelf-life of fruits and vegetables in further study.

The impact of expanded health system reform on governmental contributions and individual copayments in the new Chinese rural cooperative medical system.

In 2002, the Chinese central government created a new rural cooperative medical system (NCMS), ensuring that both central and local governments partner with rural residents to reduce their copayments, thus making healthcare more affordable. Yet, significant gaps in health status and healthcare utilization persisted between urban and rural communities. Therefore, in 2009, healthcare reform was expanded, with (i) increased government financing and (ii) sharply reduced individual copayments for outpatient and inpatient care. Analyzing data from China's Ministry of Health, the Rural Cooperative Information Network, and Statistical Yearbooks, our findings suggest that healthcare reform has reached its preliminary objectives-government financing has grown significantly in most rural provinces, especially those in poorer western and central China, and copayments in most rural provinces have been reduced. Significant intraprovincial inequality of support remains. The central government contributes more money for poor provinces than for rich ones; however, NCMS schemes operate at the county level, which vary significantly in their level of economic development and per capital gross domestic products (GDP) within a province. Data reveal that the compensation ratios for both outpatient and inpatient care are not adjusted to compensate for a rural county's level of economic development or per capita GDP. Consequently, a greater financial burden for healthcare persists among persons in the poorest rural regions. A recommendation for next step in healthcare reform is to pool resources at prefectural/municipal level and also adjust central government contributions according to the GDP level at prefectural/municipal level.

[Estimation and Visualization of Nitrogen Content in Citrus Canopy Based on Two Band Vegetation Index (TBVI)].

Nitrogen is a necessary and important element for the growth and development of fruit orchards. Timely, accurate and nondestructive monitoring of nitrogen status in fruit orchards would help maintain the fruit quality and efficient production of the orchard, and mitigate the pollution of water resources caused by excessive nitrogen fertilization. This study investigated the capability of hyperspectral imagery for estimating and visualizing the nitrogen content in citrus canopy. Hyperspectral images were obtained for leaf samples in laboratory as well as for the whole canopy in the field with ImSpector V10E (Spectral Imaging Ltd., Oulu, Finland). The spectral datas for each leaf sample were represented by the average spectral data extracted from the selected region of interest (ROI) in the hyperspectral images with the aid of ENVI software. The nitrogen content in each leaf sample was measured by the Dumas combustion method with the rapid N cube (Elementar Analytical, Germany). Simple correlation analysis and the two band vegetation index (TBVI) were then used to develop the spectra data-based nitrogen content prediction models. Results obtained through the formula calculation indicated that the model with the two band vegetation index (TBVI) based on the wavelengths 811 and 856 nm achieved the optimal estimation of nitrogen content in citrus leaves (R2 = 0.607 1). Furthermore, the canopy image for the identified TBVI was calculated, and the nitrogen content of the canopy was visualized by incorporating the model into the TBVI image. The tender leaves, middle-aged leaves and elder leaves showed distinct nitrogen status from highto low-levels in the canopy image. The results suggested the potential of hyperspectral imagery for the nondestructive detection and diagnosis of nitrogen status in citrus canopy in real time. Different from previous studies focused on nitrogen content prediction at leaf level, this study succeeded in predicting and visualizing the nutrient content of fruit trees at canopy level. This would provide valuable information for the implementation of individual tree-based fertilization schemes in precision orchard management practices.

[Development of prediction models for determining N content in citrus leaves based on hyperspectral imaging technology].

The present study presents prediction models for determining the N content in citrus leaves by using hyperspectral imaging technology combined with several chemometrics methods. The steps followed in this study are: hyperspectral image scanning, extracting average spectra curves, pretreatment of raw spectra data, extracting characteristic wavelengths with successive projection algorithm and developing prediction models for determining N content in citrus leaves. The authors obtained three optimal pretreatment methods through comparing eleven different pretreatment methods including Savitzky-Golay (SG) smoothing, standard normal variate (SNV), multiplicative scatter correction (MSC), first derivative (1-Der) and so on. These selected pretreatment methods are SG smoothing, detrending and SG smoothing-detrending. Based on these three pretreatment methods, the authros first extracted the characteristic wavelengths respectively with successive projection algorithm, and then used the spectral reflectance of the extracted characteristic wavelengths as input variables of partial least squares regression (PLS), multiple linear regression (MLR) and back propagation neural network (BPNN) modeling. Hence, the authors developed three prediction models with each pretreatment method, and obtained nine models in total. Among all the nine prediction models, the two models based on the methods of SG smoothing-detrending-SPA-BPNN (R(p): 0.8513, RMSEP: 0.1881) and detrending-SPABPNN (R(p): 0.8609, RMSEP: 0.1595) were found to have achieved the best prediction results. The final results show that using hyperspectra data to determine N content in citrus leaves is feasible. This would provide a theoretical basis for real-time and accurate monitoring of N content in citrus leaves as well as rational N fertilizer application during the plant's growth.

Ergothioneine and its congeners: anti-ageing mechanisms and pharmacophore biosynthesis.

Ergothioneine, Ovothiol, and Selenoneine are sulfur/selenium-containing histidine-derived natural products widely distributed across different organisms. They exhibit significant antioxidant properties, making them as potential lead compounds for promoting health. Increasing evidence suggests that Ergothioneine is positively correlated with healthy ageing and longevity. The mechanisms underlying Ergothioneine's regulation of the ageing process at cellular and molecular levels are beginning to be understood. In this review, we provide an in-depth and extensive coverage of the anti-ageing studies on Ergothioneine and discuss its possible intracellular targeting pathways. In addition, we highlight the recent efforts in elucidating the biosynthetic details for Ergothioneine, Ovothiol, and Selenoneine, with a particular focus on the study of their pharmacophore-forming enzymology.

The effect of multimorbidity patterns on physical and cognitive function in diabetes patients: a longitudinal cohort of middle-aged and older adults in China.

Background: The prevalence of diabetes has increased rapidly, and comorbid chronic conditions are common among diabetes patients. However, little is known about the pattern of multimorbidity in diabetes patients and the effect on physical and cognitive function. This study aimed to assess the disease clusters and patterns of multimorbidity in diabetes patients using a novel latent class analysis (LCA) approach in middle-aged and older adults and explore the association between different clusters of multimorbidity in diabetes and the effect on physical and cognitive function. Methods: This national observational study included 1,985 diabetes patients from the four waves of the China Health and Retirement Longitudinal Study (CHARLS) in 2011 to 2018. Thirteen chronic diseases were used in latent class analysis to identify the patterns of multimorbidity in diabetes, which span the cardiovascular, physical, psychological, and metabolic systems. Cognitive function is assessed via a structured questionnaire in three domains: memory, executive function, and orientation. We combined activities of daily living (ADL) with instrumental activities of daily living (IADL) to measure physical function. Linear mixed models and negative binomial regression models were used to analyze the association between patterns of multimorbidity in diabetes and the effect on cognitive function and disability, respectively. Results: A sample of 1,985 diabetic patients was identified, of which 1,889 (95.2%) had multimorbidity; their average age was 60.6 years (standard deviation (SD) = 9.5), and 53.1% were women. Three clusters were identified: "cardio-metabolic" (n = 972, 51.5%), "mental-dyslipidemia-arthritis" (n = 584, 30.9%), and "multisystem morbidity" (n = 333, 17.6%). Compared with diabetes alone, the "multisystem morbidity" class had an increased association with global cognitive decline. All patterns of multimorbidity were associated with an increased risk of memory decline and disability; however, the "multisystem morbidity" group also had the strongest association and presented a higher ADL-IADL disability (ratio = 4.22, 95% CI = 2.52, 7.08) and decline in memory Z scores (ß = -0.322, 95% CI = -0.550, -0.095, p = 0.0058). Conclusion: Significant longitudinal associations between different patterns of multimorbidity in diabetes patients and memory decline and disability were observed in this study. Future studies are needed to understand the underlying mechanisms and common risk factors for multimorbidity in diabetes patients and to propose treatments that are more effective.

Limited and time-delayed internal resource allocation generates oscillations and chaos in the dynamics of citrus crops.

Alternate bearing or masting is a yield variability phenomenon in perennial crops. The complex dynamics in this phenomenon have stimulated much ecological research. Motivated by data from an eight-year experiment with forty-eight individual trees, we explored the mechanism inherent to these dynamics in Satsuma mandarin (Citrus unshiu Marc.). By integrating high-resolution imaging technology, we found that the canopy structure and reproduction output of individual citrus crops are mutually dependent on each other. Furthermore, it was revealed that the mature leaves in early season contribute their energy to the fruiting of the current growing season, whereas the younger leaves show a delayed contribution to the next growing season. We thus hypothesized that the annual yield variability might be caused by the limited and time-delayed resource allocation in individual plants. A novel lattice model based on this hypothesis demonstrates that this pattern of resource allocation will generate oscillations and chaos in citrus yield.

A nomogram to predict the risk of sarcopenia in older people.

The burden of sarcopenia is increasing worldwide. However, most cases of sarcopenia are undiagnosed due to the lack of simple screening tools. This study aimed to develop and validate an individualized and simple nomogram for predicting sarcopenia in older adults. A total of 180 medical examination populations aged ≥60 years were enrolled in this study. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia 2019 consensus. The primary data were randomly divided into training and validation sets. Univariate logistic regression analysis was performed to select the risk factors of sarcopenia, which were subjected to the least absolute shrinkage and selection operator for feature selection. A nomogram was established using multivariate logistic regression analysis by incorporating the features selected in the least absolute shrinkage and selection operator regression model. The discrimination and calibration of the predictive model were verified by the concordance index, receiver operating characteristic curve, and calibration curve. In this study, 55 cases of sarcopenia were available. Risk predictors included age, albumin, blood urea nitrogen, grip strength, and calf circumference. The model had good discrimination and calibration capabilities. concordance index was 0.92 (95% confidence interval: 0.84-1.00), and the area under the receiver operating characteristic curve was 0.92 (95% confidence interval: 0.83-1.00) in the validation set. The Hosmer-Lemeshow test had a P value of .94. The predictive model in this study will be a clinically useful tool for predicting the risk of sarcopenia, and it will facilitate earlier detection and therapeutic intervention for sarcopenia.

[Nondestructive measurement of cellular ATP contents in vegetables using UV-Vis-NIR spectroscopy].

The cellular ATP content level in agricultural products directly reflects cell viability, therefore it can be potentially used as an indicator of freshness and quality of agricultural products during storage. Spectral data of sample spinach leaves were obtained using a UV-Vis-NIR spectrophotometer UV-3600. Protoplast suspensions were prepared by following the conventional physical-chemical methods, and the ATP contents in protoplasts were determined by the firefly luciferase bioluminescence technology. Person's correlation analysis was performed to identify the key wavelengths. Models were developed for estimating the ATP contents in spinach protoplasts based on the two identified key wavelengths, i. e. the ultraviolet 298 nm and the near-infrared 730 nm wavelengths. Results showed that both of the two key wavelengths (298 and 730 nm) have a considerable promise in estimating the ATP content in spinach protoplasts (R2 = 0.802 9 and 0.901 respectively). The spectroscopy based estimation of cellular ATP content in vegetables proposed in this study provides a new approach to the accurate, rapid, and non-destructive evaluation of the freshness of vegetables.

Bidirectional Association between Hypertension and NAFLD: A Systematic Review and Meta-Analysis of Observational Studies.

An increasing body of evidence connects non-alcoholic fatty liver disease (NAFLD) to hypertension. The objective of this systematic review and meta-analysis was to estimate the nature and magnitude of the association between NAFLD and hypertension. We systematically searched PubMed, Embase, Cochrane Library, and Web of Science for observational studies published up to May 1, 2021. Cohort studies that reported data on the association between NAFLD and incident hypertension or between hypertension and incident NAFLD were included. We used random-effects models to conduct meta-analysis on the measures of association from individual studies. A total of 11 studies were eligible for inclusion, among which 4 studies including 25,260 participants reported the association between hypertension and new-onset NAFLD. The presence of hypertension was significantly associated with an increased risk of incident NAFLD (HR 1.63, 95% CI: 1.41-1.88; I 2 = 37.6%). On the other hand, 9 studies with data on 46,487 participants analyzed the effects of NAFLD on incident hypertension. Pooled analysis showed that the presence of NAFLD was significantly associated with an increased incidence of hypertension (HR 1.55, 95% CI: 1.29-1.87; I 2 = 80.5%). There was significant heterogeneity among the studies in this analysis (p < 0.01). Sensitivity analyses showed that the magnitude of the association was significantly different in subgroups stratified by a mean age of participants and geographical location, which explains part of the heterogeneity. In conclusion, this meta-analysis indicates the existence of a bidirectional relationship between NAFLD and hypertension independent of traditional cardiometabolic risk factors.

Nrf2 Deficiency Exacerbated CLP-Induced Pulmonary Injury and Inflammation through Autophagy- and NF-κB/PPARγ-Mediated Macrophage Polarization.

The balance between M1 and M2 macrophage polarization is involved in the regulation of pulmonary inflammation. Nuclear factor erythroid-derived 2-like 2 (Nfe2l2, also known as Nrf2), a nuclear transcription factor, is reported to play protective roles in acute lung injury (ALI) and inflammation, and increasing evidence indicates that the protective effects of Nrf2 are closely related to autophagy. This study aimed to explore whether Nrf2 is involved in sepsis-induced acute pulmonary injury and inflammation and in the role of macrophage polarization in the process. In the present study, sepsis patients, an Nrf2 knockout mouse that underwent cecal ligation and puncture (CLP), and lipopolysaccharide (LPS)-treated macrophage cell lines were employed to investigate the potential functions of Nrf2 in sepsis-induced lung injury and the underlying mechanisms. Clinical studies showed that the NRF2 mRNA level was inversely correlated with pulmonary inflammation and disease severity in patients with sepsis. Analyses in a CLP-treated Nrf2 knockout mouse model indicated that an Nrf2 deficiency promoted a CLP-induced increase in M1 macrophage polarization and apoptosis and inhibited CLP-induced upregulation of the autophagy level in lung tissues. Experiments in RAW264.7 cells revealed that Nrf2 overexpression inhibited M1 macrophage polarization but promoted M2 macrophage polarization by improving the autophagy, and Nrf2 overexpression promoted PPARγ but inhibited NF-κB nuclear translocation. In conclusion, these results indicate that Nrf2 plays a protective role in sepsis-induced pulmonary injury and inflammation through the regulation of autophagy- and NF-κB/PPARγ-mediated macrophage polarization.

YAP1 protects against septic liver injury via ferroptosis resistance.

BACKGROUND: The liver plays crucial roles in sepsis and is one of the major targets for sepsis-related injuries. Ferroptosis, a newly emerged form of lytic cell death, has been implicated in sepsis related organ failure. Yes-associated protein1 (YAP1), a key regulator of the Hippo signaling pathway, may be involved in ferroptosis development. This study aimed to elucidate the role of YAP1 in septic liver injury through regulating ferroptosis, especially ferritinophagy-mediated ferroptosis. RESULTS: Cecal ligation and puncture (CLP) models were constructed in control (Yap1flfl) and liver-conditional knockout mice (Yap1fl/fl Alb-Cre) to induce septic liver injury, while LO2 cells with or without YAP1 overexpression/deletion were stimulated by lipopolysaccharide (LPS) in vitro. Our study showed YAP1 knockdown aggravated CLP-induced liver injury and inflammation, as well as accelerated hepatocyte ferroptosis, revealed by down-regulated expression of GPX4, FTH1 and SLC7A11, along with up-regulated expression of SFXN1 and NCOA4. Consistently, YAP1 deficiency aggravated LO2 cells ferroptosis, but YAP1 overexpression alleviated LPS-induced LO2 ferritinophagy, as evidenced by reduced mitochondrial ROS and Fe2+, along with down-regulated expression of SFXN1 and NCOA4. Further co-IP assay verified that YAP1 disrupted the interaction between NCOA4 and FTH1, thus prevent the degradation of ferritin to Fe2+, further reduced the ROS production and suppressed ferroptosis. CONCLUSION: YAP1 inhibits ferritinophagy-mediated ferroptosis in hepatocytes, and YAP1 deficiency aggravates sepsis-induced liver injury.

Hemophagocytic Lymphohistiocytosis Associated with Synergistic Defects of AP3B1 and ATM Genes: A Case Report and Literature Review.

Hemophagocytic lymphohistiocytosis (HLH) is an overwhelming immune system activation that manifests as hyperinflammation and life-threatening multiple organ failure. However, the clinical manifestations of the systemic inflammatory response in sepsis and fulminant cytokine storm caused by HLH macrophage activation are very similar and difficult to distinguish. HLH triggered by two novel gene defects manifesting with multiorgan dysfunction syndrome (MODS) and distributive shock has not been reported. A 14-year-old male patient was hospitalized with a high fever, his condition deteriorated rapidly, accompanied by cytopenia, shock, and MODS, and he was subsequently transferred to our intensive care unit (ICU) for symptomatic and organ-supportive treatments. Laboratory indicators of cytopenia, hypofibrinogenemia, hypertriglyceridemia, hyperferritinemia, high soluble CD25, low natural killer (NK) cell cytotoxicity, and hemophagocytosis in the bone marrow confirmed the diagnosis of HLH. Molecular genetic analysis revealed that two novel heterozygous gene mutations in AP3B1 (c.3197 C > T) and ATM (c.8077 G > T) might have accounted for the onset. After treatment, the patient's condition successfully improved. This case report demonstrates the timely determination of underlying triggers and critical care supports (supportive and etiological treatment) of HLH related to the improved outcome.