Effectiveness assessment of China's coastal wetland ecological restoration: A meta-analysis.

Due to the coastal wetland degradation caused by human activities and environmental changes, many coastal wetland restoration studies have been carried out in China to restore the degraded ecosystems, but it still lacks a comprehensive assessment of restoration effectiveness at national scale. In this study, a meta-analysis of 78 field studies was conducted to quantitatively assess the restoration effectiveness of biodiversity and ecosystem services in China's coastal wetlands. At the same time, we evaluated the impact factors such as ecosystem types, restoration methods and measures, and restoration time on restoration effectiveness. The results show that coastal wetland ecological restoration has improved the biodiversity and ecosystem services by 36.8 % and 38.2 % respectively within the time range reported in the research literature, but neither has returned to the level of natural ecosystems. Biodiversity recovery is significantly positively correlated with the recovery of ecosystem services, indicating the simultaneous recovery outcome. Compared with degraded wetlands, the effectiveness of passive restoration is better than that of active restoration. In the mangrove ecosystem, invasive species removal is the most effective among the restoration measures, and the restoration effectiveness of polyculture plantations is better than that of monoculture plantations. When time ranges from 0 to 20 years, the recovery level of coastal wetlands tends to increase with the extension of restoration time. However, when the restoration time is >20 years, the recovery level decreases, which may be related to the lack of maintenance and management measures in the later stage. Our study showcases the scientific evidence for future coastal wetland ecological restoration in China.

YME1L-mediated mitophagy protects renal tubular cells against cellular senescence under diabetic conditions.

BACKGROUND: The senescence of renal tubular epithelial cells (RTECs) is crucial in the progression of diabetic kidney disease (DKD). Accumulating evidence suggests a close association between insufficient mitophagy and RTEC senescence. Yeast mitochondrial escape 1-like 1 (YME1L), an inner mitochondrial membrane metalloprotease, maintains mitochondrial integrity. Its functions in DKD remain unclear. Here, we investigated whether YME1L can prevent the progression of DKD by regulating mitophagy and cellular senescence. METHODS: We analyzed YME1L expression in renal tubules of DKD patients and mice, explored transcriptomic changes associated with YME1L overexpression in RTECs, and assessed its impact on RTEC senescence and renal dysfunction using an HFD/STZ-induced DKD mouse model. Tubule-specific overexpression of YME1L was achieved through the use of recombinant adeno-associated virus 2/9 (rAAV 2/9). We conducted both in vivo and in vitro experiments to evaluate the effects of YME1L overexpression on mitophagy and mitochondrial function. Furthermore, we performed LC-MS/MS analysis to identify potential protein interactions involving YME1L and elucidate the underlying mechanisms. RESULTS: Our findings revealed a significant decrease in YME1L expression in the renal tubules of DKD patients and mice. However, tubule-specific overexpression of YME1L significantly alleviated RTEC senescence and renal dysfunction in the HFD/STZ-induced DKD mouse model. Moreover, YME1L overexpression exhibited positive effects on enhancing mitophagy and improving mitochondrial function both in vivo and in vitro. Mechanistically, our LC-MS/MS analysis uncovered a crucial mitophagy receptor, BCL2-like 13 (BCL2L13), as an interacting partner of YME1L. Furthermore, YME1L was found to promote the phosphorylation of BCL2L13, highlighting its role in regulating mitophagy. CONCLUSIONS: This study provides compelling evidence that YME1L plays a critical role in protecting RTECs from cellular senescence and impeding the progression of DKD. Overexpression of YME1L demonstrated significant therapeutic potential by ameliorating both RTEC senescence and renal dysfunction in the DKD mice. Moreover, our findings indicate that YME1L enhances mitophagy and improves mitochondrial function, potentially through its interaction with BCL2L13 and subsequent phosphorylation. These novel insights into the protective mechanisms of YME1L offer a promising strategy for developing therapies targeting DKD.

Identification and analysis of diverse cell death patterns in diabetic kidney disease using microarray-based transcriptome profiling and single-nucleus RNA sequencing.

BACKGROUND: Diabetic kidney disease (DKD) is the most lethal complication of diabetes. Diverse programmed cell death (PCD) has emerged as a crucial disease phenotype that has the potential to serve as an indicator of renal function decline and can be used as a target for researching drugs for DKD. METHODS: Microarray-based transcriptome profiling and single-nucleus transcriptome sequencing (snRNA-seq) related to DKD were retrieved from the Gene Expression Omnibus (GEO) database. 13 PCD-related genes (including alkaliptosis, apoptosis, autophagy-dependent cell death, cuproptosis, disulfidptosis, entotic cell death, ferroptosis, lysosome-dependent cell death, necroptosis, netotic cell death, oxeiptosis, parthanatos, and pyroptosis) were obtained from various public databases and reviews. The gene set variation analysis (GSVA) analysis was used to explore the pathway activity of these 13 PCDs in DKD, and the pathway activity of these PCDs in different renal cells was studied based on DKD-related snRNA-seq data. To identify the core PCDs that play a significant role in DKD, we analyzed the relationships between different types of PCD and immune infiltration, fibrosis-related gene expression levels, glomerular filtration rate (GFR), and diagnostic efficiency in DKD. Using the Weighted Gene Co-expression Network Analysis (WGCNA) algorithm, we screened for core death genes among the core PCDs and constructed a cell death-related signature (CDS) risk score based on the Least Absolute Shrinkage and Selection Operator (LASSO). Finally, we validated the predictive performance of the CDS risk score in an independent validation set. RESULTS: We identified 4 core PCD pathways, namely entotic cell death, apoptosis, necroptosis, and pyroptosis in DKD, and further applied the WGCNA algorithm to screen 4 core death genes (CASP1, CYBB, PLA2G4A, and CTSS) and constructed a CDS risk score based on these genes. The CDS risk score demonstrated high diagnostic efficiency for DKD patients, and those with higher scores had higher levels of immune cell infiltration and poorer GFR. CONCLUSION: Our study sheds light on the fact that multiple PCDs contribute to the progression of DKD, highlighting potential therapeutic targets for treating this disease.

Ecliptasaponin A attenuates renal fibrosis by regulating the extracellular matrix of renal tubular cells.

Renal fibrosis is the most common manifestation of end-stage renal disease (ESRD), including diabetic kidney disease (DKD), but there is no effective treatment in renal fibrosis. Natural products are a rich source of clinical drug research and have been used in the clinical research of various diseases. In this study, we searched for traditional Chinese medicine monomers that attenuate fibrosis and assessed their effect on the fibrosis marker connective tissue growth factor (CTGF) in cells which we found ecliptasaponin A. Subsequently, we evaluated the effect of ecliptasaponin A on renal fibrosis in the classic renal fibrosis unilateral ureteral obstruction (UUO) mouse model and found that ecliptasaponin A could reduce the renal collagen fiber deposition and renal extracellular matrix (ECM) protein expression in UUO mice. In vitro, ecliptasaponin A can inhibit ECM protein expression in human kidney-2 (HK-2) cells induced by transforming growth factor-beta1 (TGFß1). To further clarify the mechanism of ecliptasaponin A in attenuating renal fibrosis, we performed transcriptome sequencing of HK-2 cells treated with TGFß1 and ecliptasaponin A. The functions and pathways were mainly enriched in the extracellular matrix and TGFß signalling pathway. Matrix metalloproteinase 10 (MMP10) and matrix metalloproteinase 13 (MMP13) are the main differentially expressed genes in extracellular matrix regulation. Then, we measured MMP10 and MMP13 in the cells and found that ecliptasaponin A had a significant inhibitory effect on MMP13 expression but not on MMP10 expression. Furthermore, we overexpressed MMP13 in HK-2 cells treated with TGFß1 and found that MMP13 promoted HK-2 cell injury. Our findings suggest that ecliptasaponin A can attenuate renal fibrosis, which may provide a new method for treating renal fibrosis clinically.

CERS6-derived ceramides aggravate kidney fibrosis by inhibiting PINK1-mediated mitophagy in diabetic kidney disease.

During diabetic kidney disease (DKD), ectopic ceramide (CER) accumulation in renal tubular epithelial cells (RTECs) is associated with interstitial fibrosis and albuminuria. As RTECs are primarily responsible for renal energy metabolism, their function is intimately linked to mitochondrial quality control. The role of CER synthesis in the progression of diabetic renal fibrosis has not been thoroughly investigated. In this study, we observed a significant upregulation of ceramide synthase 6 (Cers6) expression in the renal cortex of db/db mice, coinciding with increased production of CER (d18:1/14:0) and CER (d18:1/16:0) by Cer6. Concurrently, the number of damaged mitochondria in RTECs rose. Cers6 deficiency reduced the abnormal accumulation of CER (d18:1/14:0) and CER (d18:1/16:0) in the kidney cortex, restoring the PTEN-induced kinase 1 (PINK1)-mediated mitophagy in RTECs, and resulting in a decrease in damaged mitochondria and attenuation of interstitial fibrosis in DKD. Automated docking analysis suggested that both CER (d18:1/14:0) and CER (d18:1/16:0) could bind to the PINK1 protein. Furthermore, inhibiting PINK1 expression in CERS6 knockdown HK-2 cells diminished the therapeutic effect of CERS6 deficiency on DKD. In summary, CERS6-derived CER (d18:1/14:0) and CER (d18:1/16:0) inhibit PINK1-regulated mitophagy by possibly binding to the PINK1 protein, thereby exacerbating the progression of renal interstitial fibrosis in DKD.NEW & NOTEWORTHY This article addresses the roles of ceramide synthase 6 (CERS6) and CERS6-derived ceramides in renal tubular epithelial cells of diabetic kidney disease (DKD) associated interstitial fibrosis. Results from knockdown of CERS6 adjusted the ceramide pool in kidney cortex and markedly protected from diabetic-induced kidney fibrosis in vivo and in vitro. Mechanically, CERS6-derived ceramides might interact with PINK1 to inhibit PINK1/Parkin-mediated mitophagy and aggravate renal interstitial fibrosis in DKD.

Gut microbiota is associated with differential metabolic characteristics: A study on a defined cohort of Africans and Chinese.

Objective: This study intended to determine the associations between gut microbiota and glucose response in healthy individuals and analyze the connection between the gut microbiome and glucose-metabolism-related parameters. Methods: Fecal bacterial composition and anthropometric, body composition, body fat distribution, and biochemical measures were analyzed. A 75-g oral glucose tolerance test (OGTT) was given to each participant to investigate changes in glucagon-like peptide 1 (GLP-1), insulin, and glucose. The whole body fat and the regions of interest of local body composition were analyzed using dual-energy X-ray absorptiometry (DEXA), and gut microbiota composition was assessed through variable regions (V3-V4) of the bacterial 16s ribosomal RNA gene using high-throughput sequencing techniques. Spearman correlation analysis was used to evaluate the association between gut microbiota and clinical and metabolic changes. Results: The number of operational taxonomic units (OTUs) demonstrated a reduction in the diversity and composition of gut microbiota associated with enhanced adiposity, dyslipidemia, insulin resistance, and hyperglycemia. The alpha diversity revealed that microbiota diversity, richness, and composition were higher in the African group and lower in the Chinese group. Principal coordinates analysis (PCoA) plots of beta diversity showed significant variability in gut microbial community structure between the two groups (p = 0.0009). LEfSe analysis showed that phylum Bacteroidetes was significantly more abundant in the Chinese group, and this group also harbored members of the order Bacteroidales, family Bacteroidaceae, and genus Bacteroides. In contrast, the phylum Verrucomicrobia was significantly more prevalent in the African group (all p < 0.05). Concerning species, metastats analysis revealed 8 species in the Chinese group and 18 species in the African group that were significantly abundant. Spearman's correlation analysis demonstrated that gut microbiota correlated with the factors that related to glucose metabolism. Conclusion: Our data suggest that there is an interaction between gut microbiota, host physiology, and glucometabolic pathways, and this could contribute to adiposity and pathophysiology of hyperlipidemia, insulin resistance, and hyperglycemia. These findings provide an important basis for determining the relation between the gut microbiota and the pathogenesis of various metabolic disorders.

TRAP1 attenuates H9C2 myocardial cell injury induced by extracellular acidification via the inhibition of MPTP opening.

Extracellular acidification leads to cardiac dysfunction in numerous diseases. Mitochondrial dysfunction plays an important role in this process. However, the mechanisms through which extracellular acidification induces mitochondrial dysfunction remain unclear. Tumor necrosis factor receptor­associated protein 1 (TRAP1) maintains mitochondrial function and cell viability in tumor and non­tumor cells. In the present study, extracellular acidification was found to induce H9C2 cell apoptosis, mitochondrial dysfunction and TRAP1 expression. The overexpression of TRAP1 attenuated H9C2 cell injury, while the silencing of TRAP1 exacerbated it. Moreover, mitochondrial permeability transition pore (MPTP) opening, which is associated with the mitochondrial apoptotic pathway and cell death, was also increased in acidic medium. The overexpression of TRAP1 inhibited MPTP opening, while the silencing of TRAP1 promoted it. The protective effect of TRAP1 on cardiomyocytes was abolished by the addition of a specific MPTP opening promoter. Similarly, a specific MPTP opening inhibitor reversed cell injury by silencing TRAP1. Taken together, the findings of the present study demonstrate that TRAP1 attenuates H9C2 cell injury induced by extracellular acidification by inhibiting MPTP opening.

Tumor Necrosis Factor Receptor-Associated Protein 1 Protects against Mitochondrial Injury by Preventing High Glucose-Induced mPTP Opening in Diabetes.

Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease worldwide. Renal tubular epithelial cell apoptosis and tubular atrophy have been recognized as indicators of the severity and progression of DKD, while the mechanism remains elusive. Tumor necrosis factor receptor-associated protein 1 (TRAP1) plays critical roles in apoptosis. The aim of this study was to investigate the protective role TRAP1 plays in DKD and to study the potential underlying mechanisms. TRAP1 expression was decreased, and mitochondria were injured in NRK-52e cells under high-glucose (HG) conditions. The overexpression of TRAP1 ameliorated HG-induced apoptosis, increased cell viability, maintained mitochondrial morphology, adenosine triphosphate (ATP) levels, and mitochondrial membrane potential (MMP), and buffered oxidative stress, whereas TRAP1 knockdown aggravated these effects. The protective effects of TRAP1 may be exerted via the inhibition of mitochondrial permeability transition pore (mPTP) opening, and the damage caused by TRAP1 knockdown can be partially reversed by treatment with the mPTP opening inhibitor cyclosporin A (CsA). In vivo, TRAP1 expression upregulation by AAV2/9 injection prevented renal dysfunction, ameliorated histopathological changes, maintained mitochondrial morphology and function, and reduced apoptosis and reactive oxygen species (ROS) in STZ-treated DKD rats. Thus, our results suggest that TRAP1 ameliorates diabetes-induced renal injury by preventing abnormal mPTP opening and maintaining mitochondrial structure and function, which may be treated as a potential target for DKD treatment.

Neuroprotective effects of an Nrf2 agonist on high glucose-induced damage in HT22 cells.

BACKGROUND: Oxidative stress is the hallmark of diabetic encephalopathy, which may be caused by hyperglycaemic toxicity. We aimed to discover pharmacologic targets to restore redox homeostasis. We identified the transcription factor Nrf2 as such a target. METHODS: HT22 cells were cultured in 25 or 50 mM D-glucose with various concentrations of sulforaphane (SFN) (from 1.25 to 5.0 µM). Cell viability was tested with the Cell Counting Kit-8 assay. Reactive oxygen species (ROS) production was detected with an inverted fluorescence microscope using the dichlorodihydrofluorescein-diacetate fluorescent probe. The expression of NF-E2-related factor 2 (Nrf2), haem oxygenase-1 (HO-1) and nuclear factor-κB (NF-κB) at the mRNA and protein levels was detected by reverse transcription quantitative polymerase chain reaction and western blotting. RESULT: We found that a high glucose concentration (50 mM) increased the generation of ROS, downregulated the expression of Nrf2/HO-1 and upregulated the expression of NF-κB. Moreover, HT22 cell viability significantly decreased after culture in high-glucose medium for 24, 48 and 72 h, whereas the activation of the Nrf2/HO-1 pathway using a pharmacological Nrf2 activator abrogated this high-glucose-induced toxicity. CONCLUSION: This study suggests that the activation of the Nrf2-ARE signalling pathway might be a therapeutic target for the treatment of diabetic encephalopathy.

Sodium ferulate attenuates high-glucose-induced oxidative injury in HT22 hippocampal cells.

The aim of the present study was to investigate the protective effects of sodium ferulate (SF) on HT22 hippocampal cells under a high glucose concentration. Cells were cultured in normal glucose (25 mM D-glucose) or high glucose (50 mM D-glucose) with various concentrations of SF (50, 100, 250 or 500 µM) for 0, 48 and 72 h. Cell viability was tested using a Cell Counting Kit-8 assay. Reactive oxygen species (ROS) production was detected using flow cytometry. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and nuclear factor-κB (NF-κB) at the mRNA and protein levels were detected using a reverse transcription-quantitative polymerase chain reaction analysis and western blotting. HT22 hippocampal cell viability was revealed to be substantially decreased following culturing in high glucose medium (50 mM) for 48 and 72 h. The addition of 100 µM SF abrogated this high-glucose-induced toxicity, but higher concentrations of SF (250 and 500 µM) were harmful to the cells. Furthermore, a high glucose concentration increased the generation of ROS, downregulated the expression of Nrf2/HO-1 and upregulated the expression of NF-κB subsequent to culturing for 72 h, whereas the addition of the appropriate concentration of SF attenuated these effects. To the best of our knowledge, the present study is the first to report such results and provide evidence that SF protects HT22 cells from high glucose-induced toxicity by activating the Nrf2/HO-1 pathway and inhibiting the expression of NF-κB, which may be of therapeutic value in diabetic encephalopathy.

Neuroprotective effects of an Nrf2 agonist on high glucose-induced damage in HT22 cells

BACKGROUND: Oxidative stress is the hallmark of diabetic encephalopathy, which may be caused by hyperglycaemic toxicity. We aimed to discover pharmacologic targets to restore redox homeostasis. We identified the transcription factor Nrf2 as such a target. METHODS: HT22 cells were cultured in 25 or 50 mM D-glucose with various concentrations of sulforaphane (SFN) (from 1.25 to 5.0 µM). Cell viability was tested with the Cell Counting Kit-8 assay. Reactive oxygen species (ROS) production was detected with an inverted fluorescence microscope using the dichlorodihydrofluorescein-diacetate fluorescent probe. The expression of NF-E2-related factor 2 (Nrf2), haem oxygenase-1 (HO-1) and nuclear factor-κB (NF-κB) at the mRNA and protein levels was detected by reverse transcription quantitative polymerase chain reaction and western blotting. RESULT: We found that a high glucose concentration (50 mM) increased the generation of ROS, downregulated the expression of Nrf2/HO-1 and upregulated the expression of NF-κB. Moreover, HT22 cell viability significantly decreased after culture in high-glucose medium for 24, 48 and 72 h, whereas the activation of the Nrf2/HO-1 pathway using a pharmacological Nrf2 activator abrogated this high-glucose-induced toxicity. CONCLUSION: This study suggests that the activation of the Nrf2-ARE signalling pathway might be a therapeutic target for the treatment of diabetic encephalopathy.

Alpha-mangostin attenuates diabetic nephropathy in association with suppression of acid sphingomyelianse and endoplasmic reticulum stress.

AIMS: Diabetic nephropathy is a common complication of diabetes, but there are currently few treatment options. The aim of this study was to gain insight into the effect of alpha-mangostin on diabetic nephropathy and possible related mechanisms. METHODS: Goto-Kakizaki rats were used as a diabetic model and received alpha-mangostin or desipramine treatment with normal saline as a control. Ten age-matched Sprague Dawley rats were used as normal controls and treated with normal saline. At week 12, blood glucose, albuminuria, apoptosis and renal pathologic changes were assessed. Protein levels for acid sphingomyelinase, glucose-regulated protein 78, phosphorylated PKR-like ER-resident kinase, activated transcription factor 4, CCAAT/enhancer-binding protein, homologous protein), and cleaved-caspase12 were measured. RESULTS: The level of acid sphingomyelinase was significantly increased, and ER stress was activated in diabetic rat kidneys when compared to the control animals. When acid sphingomyelinase was inhibited by alpha-mangostin, the expression of ER stress-related proteins was down-regulated in association with decreased levels of diabetic kidney injury. CONCLUSIONS: Alpha-mangostin, an acid sphingomyelinase inhibitor plays a protective role in diabetic neuropathy by relieving ER stress induced-renal cell apoptosis.