Evidence of size-dependent toxicity of polystyrene nano- and microplastics in sea cucumber Apostichopus japonicus (Selenka, 1867) during the intestinal regeneration.

Microplastics are ubiquitous pollutants in the global marine environment. However, few studies have adequately explored the different toxic mechanisms of microplastics (MPs) and nanoplastics (NPs) in aquatic organisms. The sea cucumber, Apostichopus japonicus, is a key organism in the marine benthic ecosystem due to its crucial roles in biogeochemical cycles and food web. This study investigated the bioaccumulation and adverse effects of polystyrene micro- and nanoplastics (PS-M/NPs) of different sizes (20 µm, 1 µm and 80 nm) in the regenerated intestine of A. japonicus using multi-omics analysis. The results showed that after 30-day exposure at the concentration of 0.1 mg L-1, PS-MPs and PS-NPs accumulated to 155.41-175.04 µg g-1 and 337.95 µg g-1, respectively. This excessive accumulation led to increased levels of antioxidases (SOD, CAT, GPx and T-AOC) and reduced activities of immune enzymes (AKP, ACP and T-NOS), indicating oxidative damage and compromised immunity in the regenerated intestine. PS-NPs had more profound negative impacts on cell proliferation and differentiation compared to PS-MPs. Transcriptomic analysis revealed that PS-NPs primarily affected pathways related to cellular components, e.g., ribosome, and oxidative phosphorylation. In comparison, PS-MPs had greater influences on actin-related organization and organic compound metabolism. In the PS-M/NPs-treated groups, differentially expressed metabolites were mainly amino acids, fatty acids, glycerol phospholipid, and purine nucleosides. Additionally, microbial community reconstruction in the regenerated intestine was severely disrupted by the presence of PS-M/NPs. In the PS-NPs group, Burkholderiaceae abundance significantly increased while Rhodobacteraceae abundance decreased. Correlation analyses demonstrated that intestinal regeneration of A. japonicus was closely linked to its enteric microorganisms. These microbiota-host interactions were notably affected by different PS-M/NPs, with PS-NPs exposure causing the most remarkable disruption of mutual symbiosis. The multi-omic approaches used here provide novel insights into the size-dependent toxicity of PS-M/NPs and highlight their detrimental effects on invertebrates in M/NPs-polluted marine benthic ecosystems.

TIMP2 protects against sepsis-associated acute kidney injury by cAMP/NLRP3 axis-mediated pyroptosis.

The tissue inhibitor of metalloproteinases 2 (TIMP2) has emerged as a promising biomarker for predicting the risk of sepsis-associated acute kidney injury (SA-AKI). However, its exact role in SA-AKI and the underlying mechanism remains unclear. In this study, we investigated the impact of kidney tubule-specific Timp2 knockout mice on kidney injury and inflammation. Our findings demonstrated that Timp2-knockout mice exhibited more severe kidney injury than wild-type mice, along with elevated levels of pyroptosis markers NOD-like receptor protein 3 (NLRP3), Caspase1, and gasdermin D (GSDMD) in the early stage of SA-AKI. Conversely, the expression of exogenous TIMP2 in TIMP2-knockout mice still protected against kidney damage and inflammation. In in vitro experiments, using recombinant TIMP2 protein, TIMP2 knockdown demonstrated that exogenous TIMP2 inhibited pyroptosis of renal tubular cells stimulated by lipopolysaccharide (LPS). Mechanistically, TIMP2 promoted the ubiquitination and autophagy-dependent degradation of NLRP3 by increasing intracellular cyclic adenosine monophosphate (cAMP), which mediated NLRP3 degradation through recruiting the E3 ligase MARCH7, attenuating downstream pyroptosis, and thus alleviating primary tubular cell damage. These results revealed the renoprotective role of extracellular TIMP2 in SA-AKI by attenuating tubular pyroptosis, and suggested that exogenous administration of TIMP2 could be a promising therapeutic intervention for SA-AKI treatment.NEW & NOTEWORTHY Tissue inhibitor of metalloproteinase 2 (TIMP-2) has been found to be the best biomarker for predicting the risk of sepsis-associated acute kidney injury (SA-AKI). However, its role and the underlying mechanism in SA-AKI remain elusive. The authors demonstrated in this study using kidney tubule-specific knockout mice model of SA-AKI and primary renal tubule cells stimulated with lipopolysaccharide (LPS) that extracellular TIMP-2 promoted NOD-like receptor protein 3 (NLRP3) ubiquitination and autophagy-dependent degradation by increasing intracellular cyclic adenosine monophosphate (cAMP), thus attenuated pyroptosis and alleviated renal damage.

Lactiplantibacillus plantarum DLPT4 Protects Against Cyclophosphamide-Induced Immunosuppression in Mice by Regulating Immune Response and Intestinal Flora.

In this study, the strain Lactiplantibacillus plantarum DLPT4 was investigated for the immunostimulatory activity in cyclophosphamide (CTX)-induced immunosuppressed BALB/c mice. L. plantarum DLPT4 was administered to BALB/c mice by oral gavage for 30 days, and CTX was injected intraperitoneally from the 25th to the 27th days. Intraperitoneal injection of CTX caused damage to the thymic cortex and intestines, and the immune dysfunction of the BALB/c mice. L. plantarum DLPT4 oral administration exerted immunoregulating effects evidenced by increasing serum immunoglobulin (IgA, IgG, and IgM) levels and reducing the genes expression of pro-inflammatory factors (IL-6, IL-1ß, and TNF-α) of the CTX-induced immunosuppressed mice. The results of the metagenome-sequencing analysis showed that oral administration of L. plantarum DLPT4 could regulate the intestinal microbial community of the immunosuppressed mice by changing the ratio of Lactiplantibacillus and Bifidobacterium. Meanwhile, the abundance of carbohydrate enzyme (CAZyme), immune diseases metabolic pathways, and AP-1/MAPK signaling pathways were enriched in the mice administrated with L. plantarum DLPT4. In conclusion, oral administration of L. plantarum DLPT4 ameliorated symptoms of CTX-induced immunosuppressed mice by regulating gut microbiota, influencing the abundance of carbohydrate esterase in the intestinal flora, and enhancing immune metabolic activity. L. plantarum DLPT4 could be a potential probiotic to regulate the immune response.

Bioaccumulation of functionalized polystyrene nanoplastics in sea cucumber Apostichopus japonicus (Selenka, 1867) and their toxic effects on oxidative stress, energy metabolism and mitochondrial pathway.

Micro/nano-plastics (M/NPs) are emerging contaminants in aquatic environment, however, little knowledge regarding the adverse effects of functionalized NPs has been documented so far. This study investigated the accumulation of different polystyrene nanoplastics (PS-NPs, i.e., plain PS, carboxyl-functional PS-COOH and amino-functional PS-NH2) at two particle sizes of 100 nm and 200 nm, and evaluated the impacts on oxidative stress, energy metabolism and mitochondrial pathway responses in intestine and respiratory tree of Apostichopus japonicus during the 20-d exposure experiment. The results showed that there were significant interactions of particle size and nanoplastic type on the accumulation of different PS-NPs. Exposure to NPs significantly increased the production of malondialdehyde, glutathione and reactive oxygen species, as well as the activities of antioxidant enzymes including glutathione reductase, superoxide dismutase and catalase, resulting in various degrees of oxidative damage in sea cucumber. The significant decrease in adenosine triphosphate content and increases in alkaline phosphatase and lactate dehydrogenase activities suggested that NPs impaired energy metabolism and modified their energy allocation. After 20-d exposure, the complex I, II and III activities in mitochondrial respiratory chain were significantly inhibited. Meanwhile, the Bax and Caspase-3 gene expression were significantly up-regulated, and Bacl-2 was down-regulated, indicating the toxicity on mitochondrial pathway of A. japonicus. The calculated IBR values elucidated the greater detriment to mitochondrial pathway than oxidative stress and energy metabolism. For 100 nm particle size, plain PS has stronger influence on all the biomarkers compared to PS-COOH/NH2, however, the opposite trends were observed in 200 nm PS-NPs. Furthermore, 100 nm PS-NPs were recognized to be more hazardous to sea cucumber than 200 nm microbeads. These findings provide new insights for understanding the differentiated toxic effects of functionalized NPs in marine invertebrates.

[Transcriptome changes upon Toll-like receptor 9 pathway activation in primary renal tubular epithelial cells].

OBJECTIVE: To explore the effect of Toll-like receptor 9 (TLR9) signaling pathway activation on the transcriptome in the renal tubular cells. METHODS: Mouse primary renal tubular epithelial cells were extracted and cultured. When the degree of cell fusion reached 80%, they were divided into two groups, which were added with 10 µL phosphate buffered saline (PBS, PBS control group) and TLR9 activator cytosine phosphate guanidine oligodeoxynucleotide (CpG-ODN) with a final concentration of 5 µmol/L (CpG-ODN treatment group). The RNA sequencing was performed on the Illumina platform after extraction. DEGseq software was used to analyze the differential expression of genes between the two groups. Goatools and KOBAS online software were used to analyze the differential genes involved signal pathways. Homer software was used to predict transcription factors. RESULTS: Compared with the PBS control group, there were a total of 584 differentially expressed genes in the CpG-ODN treatment group, of which 102 were up-regulated and 482 were down-regulated. The most significantly enriched gene ontology (GO) terms of differentially expressed genes included response to interferon-ß, defense response to virus and other inflammatory pathway. The most significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways included 2'-5'-oligoadenylate synthase activity, regulation of ribonuclease activity, negative regulation of virus life cycle, cellular response to interferon-ßand defense response to protozoan. The results of transcription factor prediction showed that interferon regulatory factor 3 (IRF3) was the most significantly enriched transcription factor in the promoter sequence of differential genes; the most significant transcription factor downstream of TLR9 was IRF3, and other predicted transcription factors such as transcription factor 21 (TCF21), zinc finger protein 135 (ZNF135), and PR domain containing 4 (PRDM4) might be new candidates for TLR9 signaling pathway. CONCLUSIONS: CpG-ODN activates TLR9 signaling pathway, and primary renal tubular epithelial cells can directly respond to CpG-ODN stimulation and undergo transcriptome changes, which provides a basis for further research on the molecular mechanism of TLR9 pathway in sepsis induced acute kidney injury.

TIMP2 mediates endoplasmic reticulum stress contributing to sepsis-induced acute kidney injury.

Tissue inhibitor of metalloproteinase 2 (TIMP2) has been recognized as an important biomarker for predicting acute kidney injury (AKI) because of its involvement in the process of inflammation and apoptosis in septic AKI. Endoplasmic reticulum (ER) stress, a condition of disrupted ER homeostasis, is implicated in multiple pathophysiological processes, including kidney disease. Herein, we investigated the correlation between ER stress and septic AKI and further explored how TIMP2 regulated ER stress-mediated apoptosis. To assess the role of TIMP2 in sepsis-induced AKI, we used a cecal ligation and puncture (CLP) model in mice with tubule-specific deficiency of TIMP2 (Ksp-Cre/TIMP2flox/flox ) and their wild-type counterparts. Compared to the wild-type mice, TIMP2-deficient mice demonstrated lower serum creatinine levels and decreased ER stress-mediated apoptosis when subjected to CLP. Interestingly, in human kidney (HK-2) cells, overexpression of TIMP2 caused ER stress, whereas TIMP2 knockdown attenuated lipopolysaccharide-induced ER stress and apoptosis. TIMP2 interacted with the binding immunoglobulin protein, an ER chaperone, and facilitates its extracellular secretion, thereby triggering ER stress. This study identified that the deletion of TIMP2 in mouse tubules mitigated sepsis-induced AKI by inhibiting ER stress-mediated apoptosis, which might be a potential therapeutic strategy to alleviate renal injury.

ChIP-seq assay revealed histone modification H3K9ac involved in heat shock response of the sea cucumber Apostichopus japonicus.

Heat stress poses an increasing threat for the marine invertebrate Apostichopus japonicus. Histone lysine acetylation is a central chromatin modification for epigenetic regulation of gene expression during stress response. In this study, a genome-wide characterization for acetylated lysine 9 on histone H3 (H3K9ac) binding regions in normal temperature (18 °C) and heat-stress conditions (26 °C) via ChIP-seq were carried out. The results that revealed H3K9ac was an extensive epigenetic modulation in A. japonicus. The GO terms "regulation of transcription, DNA-templated" and "transcription coactivator activity" were significantly enriched in both groups. Particularly, various transcriptional factors (TFs) families showed notable modification of H3K9ac. Differentially acetylated regions (DARs) with H3K9ac modification under heat stress were identified with 24 hyperacetylated and 23 hypoacetylated peaks, respectively. We further examined the transcriptional expression for 13 genes with dysregulated H3K9ac level in the promoter regions by qRT-PCR. Combined H3K9ac ChIP-seq characteristics with the transcriptional expression, 5 up-up genes (ZCCHC3, RPA70, MTRR, ß-Gal and PHTF2) and 2 down-down genes (PRPF39 and BSL78_10147) were identified. Surprisingly, the increasing mRNA expression of NECAP1 under heat stress was negatively related to the decreasing H3K9ac level in its promoter region. Our research is the first genome-wide characterization for the epigenetic modification H3K9ac in A. japonicus, and will help to advance the understanding of the roles of H3K9ac in transcriptional regulation under heat-stress condition.

Adverse effects of dietary virgin (nano)microplastics on growth performance, immune response, and resistance to ammonia stress and pathogen challenge in juvenile sea cucumber Apostichopus japonicus (Selenka).

It has been well documented that micro- and nanoplastics are emerging pollutants in aquatic environments, and their potential toxic effects has attracted widespread concerns. Here, we evaluated the adverse effects of dietary polystyrene nanoplastics and microplastics (PS-N/MPs) on growth performance, oxidative stress induction, immune response, ammonia detoxification, and bacterial pathogen resistance of sea cucumber Apostichopus japonicus. After collection and acclimation, sea cucumbers were randomized into 3 groups (i.e., control, 100 nm PS-NPs and 20 µm PS-MPs at 100 mg kg-1 diet) for 60-day feeding experiment. Every group contained 360 sea cucumbers which were equally divided into 3 aquaria as biological triplicates. The results showed that the specific growth rate and final weight of the sea cucumbers fed with diets containing PS-N/MPs were significantly lower than those of control group. Dietary virgin PS-N/MPs significantly increased the reactive oxygen species production and malondialdehyde content in coelomic fluid, causing oxidative stress and damage to the growth and development of A. japonicus. During the experiment, 100 nm PS-NPs significantly induced the depletion in cellular and humoral immune parameters. The calculated IBR values based on multi-level biomarkers revealed the size-dependent toxic differences of PS-NPs > PS-MPs. The relative expression levels of GDH and GS mRNA showed first rise and then fall trends after exposure to ammonia, and 100 nm PS-NPs had a more profound impact on suppressing ammonia detoxification compared with 20 µm PS-MPs. Moreover, the expression of Hsp90, Hsp70, CL, TLR, and CASP2 genes were all down-regulated by ammonia exposure. Taken together of IBR results, ammonia stress test and pathogen challenge, we deduced that dietary 100 nm PS-NPs are more potentially hazardous than 20 µm PS-MPs. These findings provide valuable information for understanding the size-dependent toxic effects of PS-N/MPs and early risk warning on marine invertebrates.

Biosynthesis and Isotopic Routing of Dietary Protein by Sea Cucumber Apostichopus japonicus (Selenka): Evidence from Compound-Specific Carbon Stable Isotope Analysis.

Compound-specific stable isotope analysis of individual amino acids (AAs) has been widely used in studies on food webs, resource tracing, and biochemical cycling. In the present study, juvenile sea cucumbers Apostichopus japonicus were fed the microalga Cylindrotheca fusiformis (CF) or Sargassum thunbergii (ST) during a 130-day experiment. The δ13C values of individual AAs in the experimental diet and body wall of sea cucumbers were determined to calculate the variability in carbon isotopic fractionation (Δ13C) and elucidate the isotopic routing of essential AAs and biosynthesis of nonessential AAs. The results showed that the sea cucumbers fed with diet CF had higher specific growth and ingestion rates but relatively lower feed conversion efficiency compared to those fed with diet ST. The experimental diets were generally less abundant in nonessential AAs (i.e., glycine, serine, aspartic acid, and arginine) but more abundant in essential AAs (i.e., isoleucine, leucine, lysine, phenylalanine, and histidine) than body walls. The fluctuations in the δ13C values of total AAs analyzed were 19.8 ± 4.6‰ for diets and 21.3 ± 2.7‰ for body walls. Serine and threonine were 13C-enriched AAs, while leucine and phenylalanine were 13C-depleted AAs. The diet ST treatment exhibited more positive Δ13C values of nonessential AAs (e.g., glycine, alanine, aspartic acid, and proline) compared to diet CF. There were significant negative relationships between Δ13C values and differences in nonessential AA percent abundance between the experimental diets and body walls of sea cucumber (for diet CF: y = -0.79 - 0.56x, r2 = 0.47; diet ST: y = 0.75 - 0.29x, r2 = 0.51), which implied the flexibility in the routing of various dietary macronutrients (protein, lipids, and carbohydrates) by sea cucumber. This study can greatly provide a new understanding of nutrient utilization and metabolism routing during juvenile sea cucumber culturing.

Urine Output Calculated Using Actual Body Weight May Result in Overestimation of Acute Kidney Injury for Obese Patients.

GOAL: The derived hourly urine output (UO) indexed by body weight is one of the major criteria for the diagnosis of acute kidney injury (AKI). However, it is unclear whether actual body weight (ABW) or ideal body weight (IBW) should be used. This study aims to explore whether UO calculation based on ABW might lead to overestimation of AKI. METHOD: AKI patients identified in the Medical Information Mart for Intensive Care III database by different components of the Kidney Disease Improving Global Outcomes guidelines and different definitions of body weight were retrospectively studied. Hospital and 90-day mortality were compared to decide whether different patient groups had the same outcome. RESULTS: In the cohort of 14,725 patients, AKI was identified in 4,298 (29.19%) and 3,060 (20.78%) patients respectively when ABW or IBW was used (P < 0.01). Multivariate logistic regression revealed that AKI patients identified by UO calculated from ABW had similar hospital and 90-day mortality to that of patients with no evidence of AKI. Whereas AKI patients identified by serum creatinine changes, or those identified by both ABW and IBW, had twice higher the risks of hospital death and about 1.5 times higher the risks of 90-day death compared with thoese with no evidence of AKI. Results were confirmed in two separate sensitivity analyses where patients whose admission creatinine levels were within the normal reference ranges and patients identified as sepsis were studied. CONCLUSIONS: Calculating hourly body weight normalized UO using ABW may lead to underestimation of UO and overestimation of AKI.

Puerarin improves hepatic glucose and lipid homeostasis in vitro and in vivo by regulating the AMPK pathway.

Obesity is an increasingly concerning global health issue, which is accompanied by disruption of glucose and lipid metabolisms. The aim of this study was to uncover the potential and molecular actions of puerarin, a phytochemical, for alleviating metabolic dysfunctions of glucose and lipid metabolisms. A rat model fed a high fat and high fructose diet and a HepG2 cell model challenged with fructose combined with free fatty acid were utilized to identify the effects of puerarin on obesity-associated insulin resistance and hepatic steatosis. The molecular mechanisms underlying puerarin treatment effects were further investigated using qRT-PCR and western blotting. Results show that puerarin significantly ameliorated features of obesity in rats, including bodyweight, hyperlipidemia, hyperglycemia, glucose/insulin intolerance, insulin resistance, hepatic steatosis, and oxidative stress, which are related to the activation of AMPK and PI3K/Akt pathways in the liver. Puerarin reduced lipid accumulation and caused a reduction of the mRNA expression of lipogenic genes such as SREBP-1c, FAS, SCD-1, and HMGCR, and an increment in the phosphorylation of AMPK and ACC in HepG2 cells. Moreover, puerarin ameliorated insulin resistance by increasing GLUT4 mRNA expression and activating the PI3K/Akt pathway. Treatment with the AMPK inhibitor compound C partially abolished the beneficial effects of puerarin on lipid accumulation and insulin resistance in HepG2 cells, which indicated that the protective effects of puerarin partially depend on the AMPK pathway. The present study indicates that puerarin shows potential as a functional food therapeutic for the treatment of obesity.

Severe COVID-19: Immunosuppression or Hyperinflammation?

ABSTRACT: The ongoing coronavirus disease 2019 (COVID-19) pandemic has swept over the world and causes thousands of deaths. Although the clinical features of COVID-19 become much clearer than before, there are still further problems with the pathophysiological process and treatments of severe patients. One primary problem is with the paradoxical immune states in severe patients with COVID-19. Studies indicate that Severe Acute Respiratory Syndrome Coronavirus 2 can attack the immune system, manifested as a state of immunosuppression with a decrease in lymphocytes, whereas a state of hyperinflammation, presenting as elevated cytokine levels, is also detected in COVID-19. Therefore, discussing the specific status of immunity in COVID-19 will contribute to the understanding of its pathophysiology and the search for appropriate treatments. Here, we review all the available literature concerning the different immune states in COVID-19 and the underlying pathophysiological mechanisms. In addition, the association between immune states and the development and severity of disease as well as the impact on the selection of immunotherapy strategies are discussed in our review.

Lactobacillus plantarum Y44 alleviates oxidative stress by regulating gut microbiota and colonic barrier function in Balb/C mice with subcutaneous d-galactose injection.

Probiotics have been proved to ameliorate the symptoms of the host induced by oxidative stress. In this study, the protective effects of Lactobacillus plantarum Y44 on Balb/C mice injured by d-galactose (d-gal)-injection were examined. Six weeks of continuous subcutaneous d-gal injection caused liver and colon injury of the Balb/C mice. L. plantarum Y44 administration significantly reversed the injury by modulating hepatic protein expressions related to the Nrf-2/Keap-1 pathway, and enhancing expressions of colonic tight junction proteins. L. plantarum Y44 administration restored the d-gal injection-induced gut microbiota imbalance by manipulating the ratio of Firmicutes/Bacteroidetes (F/B) and Proteobacteria relative abundance at the phylum level, and manipulating relative abundances of Lactobacillaceae, Muribaculaceae, Ruminococcaceae, Desulfovibrionaceae, and Prevotellaceae at the family level. Moreover, the d-gal injection-induced glycerophospholipid metabolism disorder was ameliorated, evidenced by the decline of phosphatidyl ethanolamine (PE), phosphatidylcholine (PC), phosphatidyl serine (PS), and lysophosphatidyl choline (LysoPC) levels in the serum of the mice after the L. plantarum Y44 administration. Spearman correlation analysis revealed a significant correlation between changes in gut microbiota composition, glycerophospholipid levels, and oxidative stress-related indicators. In summary, L. plantarum Y44 administration ameliorated d-gal injection-induced oxidative stress in Balb/C mice by manipulating gut microbiota and intestinal barrier function, and further influenced the glycerophospholipid metabolism and hepatic Nrf-2/Keap-1 pathway-related protein expressions.

Galectins in turbot (Scophthalmus maximus L.): Characterization and expression profiling in mucosal tissues.

Galectins, a family of evolutionary conserved ß-galactoside-binding proteins, have been characterized in a wide range of species. Many reports have indicated vital roles of galectins in innate immunity, especially in the mucosal tissues against infection. However, the systematic identification of galectin gene family is still lacking in teleost. Here, we characterized the galectin gene family and investigated their expression profiles post bacterial challenge in turbot (Scophthalmus maximus L.). In this study, a total of 13 galectin genes were characterized in turbot, phylogenetic analyses revealed their strong relationships to half smooth tongue sole and puffer fish, and syntenic analyses confirmed the orthology suggested by the phylogenetic analysis. In addition, the copy number of galectin genes is similar across a broad spectrum of species from fish to amphibians, birds, and mammals, ranging from 8 to 16 genes. Furthermore, the galectin genes were widely expressed in all the examined turbot tissues, and most of the galectin genes were strongly expressed in mucosal tissues (skin, gill and intestine). Moreover, majority of the galectin genes were significantly regulated after Vibrio anguillarum infection in the intestine, gill and skin, suggesting that galectins were involved in the mucosal immune response to V. anguillarum infection in turbot. In addition, subcellular localization analysis showed lgals3a was distributed in the cytoplasm and nucleus. However, the knowledge of galectins are still limited in teleost species, further studies should be carried out to better characterize its detailed roles in teleost mucosal immunity.

Clinical Characteristics and Risk Factors for Mortality of COVID-19 Patients With Diabetes in Wuhan, China: A Two-Center, Retrospective Study.

OBJECTIVE: Diabetes is common in COVID-19 patients and associated with unfavorable outcomes. We aimed to describe the characteristics and outcomes and to analyze the risk factors for in-hospital mortality of COVID-19 patients with diabetes. RESEARCH DESIGN AND METHODS: This two-center retrospective study was performed at two tertiary hospitals in Wuhan, China. Confirmed COVID-19 patients with diabetes (N = 153) who were discharged or died from 1 January 2020 to 8 March 2020 were identified. One sex- and age-matched COVID-19 patient without diabetes was randomly selected for each patient with diabetes. Demographic, clinical, and laboratory data were abstracted. Cox proportional hazards regression analyses were performed to identify the risk factors associated with the mortality in these patients. RESULTS: Of 1,561 COVID-19 patients, 153 (9.8%) had diabetes, with a median age of 64.0 (interquartile range 56.0-72.0) years. A higher proportion of intensive care unit admission (17.6% vs. 7.8%, P = 0.01) and more fatal cases (20.3% vs. 10.5%, P = 0.017) were identified in COVID-19 patients with diabetes than in the matched patients. Multivariable Cox regression analyses of these 306 patients showed that hypertension (hazard ratio [HR] 2.50, 95% CI 1.30-4.78), cardiovascular disease (HR 2.24, 95% CI 1.19-4.23), and chronic pulmonary disease (HR 2.51, 95% CI 1.07-5.90) were independently associated with in-hospital death. Diabetes (HR 1.58, 95% CI 0.84-2.99) was not statistically significantly associated with in-hospital death after adjustment. Among patients with diabetes, nonsurvivors were older (76.0 vs. 63.0 years), most were male (71.0% vs. 29.0%), and they were more likely to have underlying hypertension (83.9% vs. 50.0%) and cardiovascular disease (45.2% vs. 14.8%) (all P values <0.05). Age ≥70 years (HR 2.39, 95% CI 1.03-5.56) and hypertension (HR 3.10, 95% CI 1.14-8.44) were independent risk factors for in-hospital death of patients with diabetes. CONCLUSIONS: COVID-19 patients with diabetes had worse outcomes compared with the sex- and age-matched patients without diabetes. Older age and comorbid hypertension independently contributed to in-hospital death of patients with diabetes.

Reactive Oxygen Species-Induced Lipid Peroxidation in Apoptosis, Autophagy, and Ferroptosis.

Reactive oxygen species- (ROS-) induced lipid peroxidation plays a critical role in cell death including apoptosis, autophagy, and ferroptosis. This fundamental and conserved mechanism is based on an excess of ROS which attacks biomembranes, propagates lipid peroxidation chain reactions, and subsequently induces different types of cell death. A highly evolved sophisticated antioxidant system exists that acts to protect the cells from oxidative damage. In this review, we discussed how ROS propagate lipid peroxidation chain reactions and how the products of lipid peroxidation initiate apoptosis and autophagy in current models. We also discussed the mechanism of lipid peroxidation during ferroptosis, and we summarized lipid peroxidation in pathological conditions of critical illness. We aim to bring a more global and integrative sight to know how different ROS-induced lipid peroxidation occurs among apoptosis, autophagy, and ferroptosis.

Lysine Acetylation is an Important Post-Translational Modification that Modulates Heat Shock Response in the Sea Cucumber Apostichopus japonicus.

Heat stress (HS) is an important factor for the survival of the marine organism Apostichopus japonicus. Lysine acetylation is a pivotal post-translational modification that modulates diverse physiological processes including heat shock response (HSR). In this study, 4028 lysine acetylation sites in 1439 proteins were identified in A. japonicus by acetylproteome sequencing. A total of 13 motifs were characterized around the acetylated lysine sites. Gene Ontology analysis showed that major acetylated protein groups were involved in "oxidation-reduction process", "ribosome", and "protein binding" terms. Compared to the control group, the acetylation quantitation of 25 and 41 lysine sites changed after 6 and 48 h HS. Notably, lysine acetyltransferase CREB-binding protein (CBP) was identified to have differential acetylation quantitation at multiple lysine sites under HS. Various chaperones, such as caseinolytic peptidase B protein homolog (CLBP), T-complex protein 1 (TCP1), and cyclophilin A (CYP1), showed differential acetylation quantitation after 48 h HS. Additionally, many translation-associated proteins, such as ribosomal proteins, translation initiation factor (IF), and elongation factors (EFs), had differential acetylation quantitation under HS. These proteins represented specific interaction networks. Collectively, our results offer novel insight into the complex HSR in A. japonicus and provide a resource for further mechanistic studies examining the regulation of protein function by lysine acetylation.

Effect of seasonal high temperature on the immune response in Apostichopus japonicus by transcriptome analysis.

The sea cucumber Apostichopus japonicus is a flourishing aquaculture species in China. However, there are challenges for sea cucumber aquaculture, one of which is the high temperature in summer. In this study, we explored the transcriptome expression profiles with seasons (APR, JUN and JUL) in the muscle tissue of A. japonicus. The temperature of the natural coast was 13 °C, 21 °C and 25 °C respectively when sampling. Compared with APR group, changes of expression profiles were more significant in JUL group than that in JUN group. A total of 46 differential expressed genes (DEGs) involved in both innate and adaptive immunity were highlighted, including 27 up-regulated and 19 down-regulated genes. They were further grouped into 10 sub-classes: heat shock, coagulation cascades, antigen processing and presentation, inflammatory response, transporter activity, immunoglobulin, lectin C, cell adhesion, reactive oxygen species (ROS) scavenging, apoptosis and autophagy. The study will offer deep insights of the molecular mechanisms underlying the physiological responses to seasonal high temperature in A. japonicus. Particularly, knowledge about the immunological effects of seasonal temperature on the species is critical for the optimal management practices for both wild and aquaculture populations.

Incidence, Risk factors, and Biomarkers Predicting Ischemic or Hemorrhagic Stroke Associated Acute Kidney Injury and Outcome: A Retrospective Study in a General Intensive Care Unit.

OBJECTIVE: We investigated the epidemiology, risk factors, and predictive parameters for ischemic or hemorrhagic stroke-associated acute kidney injury (AKI) and mortality in a general intensive care unit (ICU) in China. METHODS: During 5 years, 479 stroke patients were screened, and 381 were enrolled. AKI was diagnosed within 7 days after ICU admission, based on the Kidney Disease Improving Global Outcomes criteria. Risk factors of AKI were assessed by Logistic regression analyses, and the predictive biomarkers for AKI were determined using receiver operating characteristic (ROC) curves. Also examined were factors influencing 28-day mortality, using Cox regression analyses and Kaplan-Meier curves. -Results: Among all, 115 (30.18%) patients developed AKI. Multivariate regression analyses revealed that the following features at ICU admission significantly increased the risk of developing AKI: an increased National Institutes of Health Stroke Scale score (OR 1.136, p < 0.001) and Acute Physiology and Chronic Health Evaluation II score (OR 1.107, p = 0.042); hypertension (OR 2.346, p = 0.008); use of loop diuretics (OR 1.961, p = 0.032); and higher serum cystatin C (sCysC; OR 8.156, p = 0.001). The area under the ROC curves for predicting AKI using sCysC was 0.772, slightly better than that of other biomarkers. The sCysC ≥0.93 mg/L (hazard ratio 1.844, p = 0.004) significantly predicted 28-day mortality. CONCLUSIONS: Among stroke patients in ICU, we identified significant risk factors of stroke-associated AKI. Serum CysC level at ICU admission was an important biomarker for predicting AKI and 28-day mortality.

Understanding microRNAs regulation in heat shock response in the sea cucumber Apostichopus japonicus.

The sea cucumber Apostichopus japonicus is a valuable species in China. The extreme high temperature in the summer often results in high mortality. MicroRNAs (miRNAs) play important post-transcriptional regulatory roles in gene expression and can influence heat shock response (HSR) greatly. In this study, we determined the expression profiles of miRNAs under heat stress (HS) in A. japonicus by using high-throughput sequencing technique. Among the differential expression miRNAs, we highlighted 41 differentially expressed miRNAs, many of which were involved in immunity process and disease regulation. Gene ontology and pathway analyses of putative target genes were also carried out. Cell-substrate adherens junction and cell-substrate junction were significantly enriched in GO analysis. Moreover, we made a correlation analysis between remarkable miRNAs and the differentially expressed genes (DEGs) in sea cucumbers under HS. We identified 17 key miRNA-target pairs potentially regulated HSR of sea cucumbers. These results will provide new insights about miRNAs regulation and molecular adaptive mechanisms in sea cucumbers under HS.