SAA1 deficiency alleviates cardiac remodeling by inhibiting NF-κB/p38/JNK and TGFß/Smad pathways.

Heart failure (HF) is the end stage of the progression of many cardiovascular diseases. Cardiac remodeling is the main pathophysiological process of cardiac function deterioration in HF patients. Inflammation is a key factor that stimulates cardiomyocyte hypertrophy, fibroblast proliferation, and transformation leading to myocardial remodeling, which severity is significantly related to the prognosis of patients. SAA1 (Serum amyloid A1) is a lipid-binding protein that was an important regulator involved in inflammation, whose biological functions in the heart remain rarely known. In this research, we intended to test the role of SAA1 in SAA1-deficient (SAA1-/- ), and wild-type mice were exposed to transverse aortic banding surgery to establish the model of cardiac remodeling. Besides, we assessed the functional effects of SAA1 on cardiac hypertrophy and fibrosis. The expression of SAA1 was increased in the mice transverse aortic banding model induced by pressure overload. After 8 weeks of transverse aortic banding, SAA1-/- mice displayed a lower level of cardiac fibrosis than wild-type mice, but did not significantly influence the cardiomyocyte hypertrophy. In addition, there was also no significant difference in cardiac fibrosis severity between wild-type-sham and knockout-sham mice. These findings are the first to reveal SAA1 absence hinders cardiac fibrosis after 8 weeks of transverse aortic banding. Furthermore, SAA1 deficiency had no significant effect on cardiac fibrosis and hypertrophy in the sham group in this study.

Remote Control and Noninvasive Detection Enabled by a High-performance NIR pc-LED.

In an increasing manner, near-infrared phosphor-converted light-emitting diodes (NIR pc-LEDs) are considered to be exemplary light sources owing to their notable attributes of elevated output power, economical nature, and exceptional portability. NIR phosphors are critical components of NIR pc-LEDs. Herein, we report a novel blue light excitable NIR phosphor CaLu2ZrScAl3O12:Cr3+ (CLZSA:Cr3+) as a crucial and efficient broadband NIR emitter. The CLZSA:Cr3+ phosphor displays an intense NIR broadband emission peaking at 776 nm and with a full width at half-maximum (fwhm) of 140 nm. The designed material also exhibits superior resistance to thermal quenching, as the intensity of emission at 423 K remains at 80% of that at room temperature. The constructed NIR pc-LED device based on CLZSA:Cr3+ demonstrates a high total output power of 68.4 mW at a drive current of 100 mA, along with a high photoelectric conversion efficiency of 23.0%. Impressively, the high-power NIR pc-LEDs are utilized as light sources for remote control and non-invasive detection, resulting in the excellent performance and remarkable achievement.

Development of a novel percutaneous digital flexible nephroscope: its use and application.

BACKGROUND: Renal calculi are one of the most frequent diseases in urology, and percutaneous nephrolithotomy (PCNL) being the gold standard for treating renal calculi larger than 2 cm. However, traditional rigid nephroscope cannot bend, presents significant limitations during PCNL. This study aims to develop a novel digital flexible nephroscope for PCNL and verify its safety and efficacy using 3D printed models and ex vivo porcine kidney models, providing new equipment for PCNL. METHODS: Based on the determined technical parameters, the novel digital flexible nephroscope was manufactured. First, 3D-printed model and ex vivo porcine kidney models were utilized to simulate the PCNL procedures. Then, the traditional rigid nephroscope and the novel digital flexible nephroscope were utilized to simulate the PCNL procedures on 10 ex vivo porcine kidneys for comparison. We observed and recorded the renal calyces visualized and accessed by both the traditional rigid nephroscope and the novel digital flexible nephroscope. RESULTS: In both the 3D printing and ex vivo porcine kidney models, the novel percutaneous digital flexible nephroscope smoothly entered the renal collecting system through the percutaneous renal tract. It freely changed angles to reach most target calyces, demonstrating significant advantages over the traditional rigid nephroscope. CONCLUSION: The successful development of the novel percutaneous digital flexible nephroscope allows it to be used either independently or as an adjunct in complex stone cases, providing more effective and safer surgical equipment for percutaneous nephrolithotomy.

PS-MPs promotes the progression of inflammation and fibrosis in diabetic nephropathy through NLRP3/Caspase-1 and TGF-ß1/Smad2/3 signaling pathways.

BACKGROUND: Diabetic nephropathy (DN) is a prevalent chronic microvascular complication of diabetes and the leading cause of end-stage renal disease (ESRD). Understanding the progressive etiology of DN is critical for the development of effective health policies and interventions. Recent research indicated that polystyrene microplastics (PS-MPs) contaminate our diets and accumulate in various organs, including the liver, kidneys, and muscles. METHODS: In this study, ten-week-old db/db mice and db/m mice were fed. Besides, db/db mice were divided into two groups: PS-MPs group (oral administration of 0.5 µm PS-MPs) and an H2O group, and they were fed for three months. A type II diabetes model was established using db/db mice to investigate the effects of PS-MPs on body weight, blood glucose level, renal function, and renal fibrosis. RESULTS: The results demonstrated that PS-MPs significantly exacerbated various biochemical indicators of renal tissue damage, including fasting blood glucose, serum creatinine, blood urea nitrogen, and blood uric acid. Additionally, PS-MPs worsened the pathological alterations and degree of fibrosis in renal tissue. An increased oxidative stress state and elevated levels of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and monocyte chemoattractant protein-1 (MCP-1) were identified. Furthermore, PS-MPs significantly enhanced renal fibrosis by inhibiting the transition from epithelial cells to mesenchymal cells, specifically through the inhibition of the TGF-ß/Smad signaling pathway. The expression levels of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), Caspase-1, and cleaved Caspase-1, which are inflammasome proteins, were significantly elevated in the PS-MPs group. CONCLUSION: The findings suggested that PS-MPs could aggravate kidney injury and renal fibrosis in db/db mice by promoting NLRP3/Caspase-1 and TGF-ß1/Smads signaling pathways. These findings had implications for elucidating the role of PS-MPs in DN progression, underscoring the necessity for additional research and public health interventions.

Toxicological effects of microplastics in renal ischemia-reperfusion injury.

The widespread presence of microplastics (MPs) in the environment poses a significant threat to biological survival and human health. However, our understanding of the toxic effects of MPs on the kidneys remains limited. This study aimed to investigate the underlying mechanism of the toxic effects of MPs on the kidneys using an ischemia-reperfusion (IR) mouse model. Four-week-old ICR mice were exposed to 0.5 µm MPs for 12 weeks prior to IR injury. The results showed that MPs exposure could aggravate the IR-induced damage to renal tubules and glomeruli. Although there were no significant changes in blood urea nitrogen and serum creatinine levels 7 days after IR, MPs treatment resulted in a slight increase in both parameters. In addition, the expression levels of inflammatory factors (MCP-1 and IL-6) at the mRNA level, as well as macrophage markers (CD68 and F4/80), were significantly higher in the MPs + IR group than in the Sham group after IR. Furthermore, MPs exposure exacerbated IR-induced renal fibrosis. Importantly, the expression of pyroptosis-related genes, including NLRP3, ASC, GSDMD, cleaved caspase-1, and IL-18, was significantly upregulated by MPs, indicating that MPs exacerbate pyroptosis in the context of renal IR. In conclusion, our findings suggest that MPs exposure can aggravate renal IR-induced pyroptosis by activating NLRP3-GSDMD signaling.

Microplastics cause hepatotoxicity in diabetic mice by disrupting glucolipid metabolism via PP2A/AMPK/HNF4A and promoting fibrosis via the Wnt/ß-catenin pathway.

In recent years, microplastics (MPs) have gained significant attention as a persistent environmental pollutant resulting from the decomposition of plastics, leading to their accumulation in the human body. The liver, particularly of individuals with type 2 diabetes mellitus (T2DM), is known to be more susceptible to the adverse effects of environmental pollutants. Therefore, to investigate the potential impact of MPs on the liver of diabetic mice and elucidate the underlying toxicological mechanisms, we exposed db/db mice to 0.5 µm MPs for 3 months. Our results revealed that MPs exposure resulted in several harmful effects, including decreased body weight, disruption of liver structure and function, elevated blood glucose levels, impaired glucose tolerance, and increased glycogen accumulation in the hepatic tissue of the mice. Furthermore, MPs exposure was found to promote hepatic gluconeogenesis by perturbing the PP2A/AMPK/HNF4A signaling pathway. In addition, MPs disrupt redox balance, leading to oxidative damage in the liver. This exposure also disrupted hepatic lipid metabolism, stimulating lipid synthesis while inhibiting catabolism, ultimately resulting in the development of fatty liver. Moreover, MPs were found to induce liver fibrosis by activating the Wnt/ß-catenin signaling pathway. Furthermore, MPs influenced adaptive thermogenesis in brown fat by modulating the expression of uncoupling protein 1 (UCP1) and genes associated with mitochondrial oxidative respiration thermogenesis in brown fat. In conclusion, our study demonstrates that MPs induce oxidative damage in the liver, disturb glucose and lipid metabolism, promote hepatic fibrosis, and influence adaptive thermogenesis in brown fat in diabetic mice. These findings underscore the potential adverse effects of MPs on liver health in individuals with T2DM and highlight the importance of further research in this area.

Enhancing salt tolerance and crop growth in agricultural systems: the impact of magnetized-ionized water irrigation on soil properties, microbial communities, and cotton growth.

BACKGROUND: The development of agricultural practices requires an understanding of the improvement of salt tolerance and crop growth in agricultural systems through magnetized-ionized water irrigation. METHOD: This study examined the impacts of fresh water (F), brackish water (B), magnetized-ionized fresh water (MIF), and magnetized-ionized brackish water (MIB) on soil properties and the growth of cotton seedlings through microbial analysis during the cotton seedling period. RESULTS: The results revealed that magnetized-ionized water irrigation improved soil water retention and promoted salt leaching. In comparison with F irrigation, plant height, leaf area index (LAI), dry matter accumulation (DM), and chlorophyll content (SPAD) levels increased by 3.61%, 4.07%, 5.76%, and 1.33%, respectively, under MIF irrigation. Similarly, when compared with B irrigation, LAI, DM, and SPAD increased by 5.13%, 6.12%, and 3.12% under MIB irrigation. Magnetized-ionized water irrigation also led to a notable rise in the relative abundance of beneficial soil bacterial communities, particularly Pseudomonas and Azoarcus, as well as fungal communities like Trichoderma, while reducing the prevalence of pathogenic fungi, such as Lasionectria, Gibberella, and Alternaria. Notably, this irrigation approach induced alterations in soil properties, and partial least squares path modeling revealed significant links between soil properties and both cotton growth and fungal community structure (with path coefficients of -0.884 and 0.693, respectively). CONCLUSION: This study elucidated the distinct effects of soil properties and growth indices on cotton yield during the seedling period, providing a crucial scientific foundation for enhancing future agricultural production through the use of magnetized-ionized water irrigation. © 2024 Society of Chemical Industry.

Crystal Field Engineering Yields New 3D Layered Solid Solution Phosphors (Ca/Sr)4MgAl2Si3O14:Eu2+ for White-Light-Emitting Diode Full-Spectrum Lighting.

The cation-equivalent substitution strategy has the ability to manipulate the luminescence color of phosphors and enhance their overall luminescence performance. A series of novel yellow feldspar-type 3D layered phosphors (Ca1-ySry)4MgAl2Si3O14:xEu2+ were synthesized using a high-temperature solid-state reaction. The solid solution phosphors belong to a tetragonal crystal system with a space group of P4̅21m and cell parameters of a = b = 7.75407-7.91794 Å, c = 5.04299-5.22543 Å, and V = 303.166-327.602 Å3. Under near-ultraviolet (n-UV) excitation, the luminescence color of the phosphor undergoes modulation from yellow-green (530 nm) to blue (467 nm) as the Sr2+ ion substitution ratio increases. This modulation is attributed to the gradual decrease in crystal field splitting energy. Additionally, both the Stokes shift and the full width of the luminescence spectra decrease. Furthermore, there is an increase in the quantum yield (QY) from 45.50 to 60.73%. Finally, the fabricated white-light-emitting diode devices emitted warm white light and achieved high Ra (Ra = 94, 96.6, 92.7) and low correlated color temperature (CCT = 3486, 3430, 3788 K), indicating that the prepared solid solution phosphors can be used as candidate materials for WLED lighting.

Efficiency and safety of high-power ablation guided by Lesion size index: An ex vivo porcine heart study.

BACKGROUND: Although Lesion size index (LSI) has been reported to highly predict radiofrequency lesion size in vitro, its accuracy in lesion size and steam pop estimation has not been well investigated for every possible scenario. METHODS: Initially, radiofrequency ablations were performed on porcine myocardial slabs at various power, CF, and time settings with blinded LSI. Subsequently, radiofrequency power at 20, 30, 40, 50, and 60 W was applied at CF values of 5, 10, 20, and 30 g to reach target LSIs of 4, 5, 6, and 7. Lesion size and steam pops were recorded for each ablation. RESULTS: Lesion size was positively correlated with LSI regardless of power settings (p < 0.001). The linear correlation coefficients of lesion size and LSI decreased at higher power settings. At high power combined with high CF settings (50 W/20 g), lesion depth and LSI showed an irrelevant correlation (p = 0.7855). High-power ablation shortened ablation time and increased the effect of resistive heating. LSI could predict the risk of steam pops at high-power settings with the optimal threshold of 5.65 (sensitivity, 94.1%; specificity, 46.1%). The ablation depth of the heavy heart was shallower than that of the light heart under similar ablation settings. CONCLUSIONS: LSI could predict radiofrequency lesion size and steam pops at high power settings in vitro, while synchronous high power and high CF should be avoided. Lighter hearts require relatively lower ablation settings to create appropriate ablation depth.

Identification of Hub Genes Correlated with the Initiation and Development in Chronic Kidney Disease via Bioinformatics Analysis.

INTRODUCTION: Chronic kidney disease (CKD) is a major public health issue worldwide, which is characterized by irreversible loss of nephron and renal function. However, the molecular mechanism of CKD remains underexplored. METHODS: This study integrated three transcriptional profile datasets to investigate the molecular mechanism of CKD. The differentially expressed genes (DEGs) between Sham control (Con) and unilateral ureteral obstruction (UUO)-operated mice were analyzed by utilizing the limma package in R. The shared DEGs were analyzed by Gene Ontology and functional enrichment. Protein-protein interactions (PPIs) were constructed by utilizing the STRING database. Hub genes were analyzed by MCODE and Cytohubba. We further validated the gene expression by using the other dataset and mouse UUO model. RESULTS: A total of 315 shared DEGs between Con and UUO samples were identified. Gene function and KEGG pathway enrichment revealed that DEGs were mainly enriched in inflammatory response, immune system process, and chemokine signaling pathway. Two modules were clustered based on PPI network analysis. Module 1 contained 13 genes related to macrophage activation, migration, and chemotaxis. Ten hub genes were identified by PPI network analysis. Subsequently, the expression levels of hub genes were validated with the other dataset. Finally, these four validated hub genes were further confirmed by our UUO mice. Three validated hub genes, Gng2, Pf4, and Ccl9, showed significant response to UUO. CONCLUSION: Our study reveals the coordination of genes during UUO and provides a promising gene panel for CKD treatment. GNG2 and PF4 were identified as potential targets for developing CKD drugs.

The microplastics exposure induce the kidney injury in mice revealed by RNA-seq.

Microplastics (MPs) may pollute drinking water, accumulate in the food chain, and release toxic chemicals that may cause a variety of diseases. The detrimental effects of MPs on kidney injury and fibrosis under long-term accumulation have not been fully documented. In this study, mice were exposed to MPs with three different diameters (80 nm, 0.5 µm, and 5 µm) to investigate the detrimental influences of MPs on the kidney. The results showed that MPs of different diameters caused varying degrees of injury to the murine kidney. MPs exposure can induce an inflammatory response, oxidative stress, and cell apoptosis in the kidney and induce kidney injury, which ultimately promotes kidney fibrosis. Furthermore, transcriptome data revealed that chronic exposure to MPs could alter the expressions of multiple genes related to immune response (80 nm) and circadian rhythm (0.5 µm, and 5 µm). Overall, our data provide new evidence and potential research for investigating the harm of MPs to kidney of mammals and even humans.

The male reproductive toxicity after nanoplastics and microplastics exposure: Sperm quality and changes of different cells in testis.

Nanoplastics (NPs) and Microplastics (MPs) pollution has become a severe threat to the planet and is a growing concern. However, their effects on male reproductive toxicity remain poorly understood. In this study, a series of morphological analyses were completed to explore the influence of NPs and MPs exposure on the testis in mice. After 12-weeks exposure, although both NPs and MPs exposure can lead to reproductive toxicity, compared with NPs exposure, exposure to MPs leads to a more significant increase in reproductive toxicity dependent on some particle size. Moreover, increased reproductive toxicities, including increased spermatogenesis disorders, and sperm physiological abnormality, oxidative stress, testis inflammation was more associated with MPs group than NPs group. Ultra-pathological structure observed by transmission electron microscopy indicated that both NPs and MPs have different effects on spermatogonia, spermatocytes and Sertoli cells. Exposure to MPs resulted in decreased Sertoli cell numbers and reduced Leydig cell area, and showed no effects on differentiation of Leydig cells by the expression level of the Insulin-Like factor 3 (INSL3) in Leydig cells. Transcriptomic sequencing analysis provided valuable insights into the differential effects of NPs and MPs on cellular processes. Specifically, our findings demonstrated that NPs were predominantly involved in the regulation of steroid biosynthesis, whereas MPs primarily influenced amino acid metabolism. This study demonstrates the effect of adult-stage reproductive toxicity in mice after exposure to NPs and MPs, which will deep the understanding of the NPs and MPs induced toxicity.

Seasonal heavy metal speciation in sediment and source tracking via Cu isotopic composition in Huangpu River, Shanghai, China.

The present study systematically analyzed and evaluated the variations in chemical speciation, pollution assessment, and source identification of heavy metals in sediments of Huangpu River. The methods employed included heavy metal concentration, chemical speciation and Cu isotopic compositions analysis. Results showed that the chemical speciation of sediment-bound heavy metals, characterized by significant seasonal variation, shifted from non-residual fractions dominating in spring and summer to residual fractions dominating in autumn and winter. Precipitation was identified as an important factor influencing the chemical speciation of sediment-bound heavy metals. Furthermore, ratio of the secondary phase to the primary phase, RSP (=Cnon-residual/Cresidual) values in Huangpu River sediments were higher than 1 in spring and summer, indicating that sediment-bound heavy metals in Huangpu River were mainly composed of non-residual fractions and could potentially be released into the river water. Principal component analysis (PCA) revealed that navigation, traffic, agricultural, and industrial activities could be the potential sources of heavy metal pollution. Notably, the δ65Cu values in Huangpu River sediments were observed to be isotopically lighter (from -0.37 to +0.18 ‰), suggesting that navigation might be the primary pollution source. These results will not only provide guidance in reducing heavy metal concentrations, but also serve as a crucial basis for policy making regarding heavy metal control.

Deficiency of mindin reduces renal injury after ischemia reperfusion.

BACKGROUND: Acute renal injury (AKI) secondary to ischemia reperfusion (IR) injury continues to be a significant perioperative problem and there is no effective treatment. Mindin belongs to the mindin/F-spondin family and involves in inflammation, proliferation, and cell apoptosis. Previous studies have explored the biological functions of mindin in liver and brain ischemic injury, but its role in AKI is unknown. METHOD: To investigate whether mindin has a pathogenic role, mindin knockout (KO) and wild-type (WT) mice were used to establish renal IR model. After 30 min of ischemia and 24 h of reperfusion, renal histology, serum creatinine, and inflammatory response were examined to assess kidney injury. In vitro, proinflammatory factors and inflammatory signaling pathways were measured in mindin overexpression or knockdown and vector cells after hypoxia/reoxygenation (HR). RESULTS: Following IR, the kidney mindin level was increased in WT mice and deletion of mindin provided significant protection for mice against IR-induced renal injury as manifested by attenuated the elevation of serum creatinine and blood urea nitrogen along with less severity for histological alterations. Mindin deficiency significantly suppressed inflammatory cell infiltration, TNF-α and MCP-1 production following renal IR injury. Mechanistic studies revealed that mindin deficiency inhibits TLR4/JNK/NF-κB signaling activation. In vitro, the expression levels of TNF-α and MCP-1 were increased in mindin overexpression cells compared with vector cells following HR. Moreover, TLR4/JNK/NF-κB signaling activation was elevated in the mindin overexpression cells in response to HR stimulation while mindin knockdown inhibited the activation of TLR4/JNK/ NF-κB signaling after HR in vitro. Further study showed that mindin protein interacted directly with TLR4 protein. And more, mindin protein was confirmed to be expressed massively in renal tubule tissues of human hydronephrosis patients. CONCLUSION: These data demonstrate that mindin is a critical modulator of renal IR injury through regulating inflammatory responses. TLR4/JNK/NF-κB signaling most likely mediates the biological function of mindin in this model of renal ischemia.

Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19.

RATIONALE: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. OBJECTIVE: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. METHODS AND RESULTS: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; P=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension. CONCLUSIONS: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.

Longitudinal Association Between Markers of Liver Injury and Mortality in COVID-19 in China.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) is a new infectious disease. To reveal the hepatic injury related to this disease and its clinical significance, we conducted a multicenter retrospective cohort study that included 5,771 adult patients with COVID-19 pneumonia in Hubei Province. APPROACH AND RESULTS: We reported the distributional and temporal patterns of liver injury indicators in these patients and determined their associated factors and death risk. Longitudinal liver function tests were retrospectively analyzed and correlated with the risk factors and death. Liver injury dynamic patterns differed in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBIL). AST elevated first, followed by ALT, in severe patients. ALP modestly increased during hospitalization and largely remained in the normal range. The fluctuation in TBIL levels was mild in the non-severe and the severe groups. AST abnormality was associated with the highest mortality risk compared with the other indicators of liver injury during hospitalization. Common factors associated with elevated liver injury indicators were lymphocyte count decrease, neutrophil count increase, and male gender. CONCLUSION: The dynamic patterns of liver injury indicators and their potential risk factors may provide an important explanation for the COVID-19-associated liver injury. Because elevated liver injury indicators, particularly AST, are strongly associated with the mortality risk, our study indicates that these parameters should be monitored during hospitalization.

Mindin deficiency alleviates renal fibrosis through inhibiting NF-κB and TGF-ß/Smad pathways.

Renal fibrosis acts as a clinical predictor in patients with chronic kidney disease and is characterized by excessive extracellular matrix (ECM) accumulation. Our previous study suggested that mindin can function as a mediator for liver steatosis pathogenesis. However, the role of mindin in renal fibrosis remains obscure. Here, tumour necrosis factor (TGF)-ß-treated HK-2 cells and global mindin knockout mouse were induced with renal ischaemia reperfusion injury (IRI) to test the relationship between mindin and renal fibrosis. In vitro, mindin overexpression promoted p65-the hub subunit of the NF-κB signalling pathway-translocation from the cytoplasm into the nucleus, resulting in NF-κB pathway activation in TGF-ß-treated HK-2 cells. Meanwhile, mindin activated the TGF-ß/Smad pathway, thereby causing fibrotic-related protein expression in vitro. Mindin-/- mice exhibited less kidney lesions than controls, with small renal tubular expansion, inflammatory cell infiltration, as well as collagen accumulation, following renal IRI. Mechanistically, mindin-/- mice suppressed p65 translocation and deactivated NF-κB pathway. Simultaneously, mindin disruption inhibited the TGF-ß/Smad pathway, alleviating the expression of ECM-related proteins. Hence, mindin may be a novel target of renal IRI in the treatment of renal fibrogenesis.

Inhibition of Interleukin-6/glycoprotein 130 signalling by Bazedoxifene ameliorates cardiac remodelling in pressure overload mice.

The role of IL-6 signalling in hypertensive heart disease and its sequelae is controversial. Our group demonstrated that Bazedoxifene suppressed IL-6/gp130 signalling in cancer cells but its effect on myocardial pathology induced by pressure overload is still unknown. We explored whether Bazedoxifene could confer benefits in wild-type C57BL/6J mice suffering from transverse aortic constriction (TAC) and the potential mechanisms in H9c2 myoblasts. Mice were randomized into three groups (Sham, TAC, TAC+Bazedoxifene, n = 10). Morphological and histological observations suggested TAC aggravated myocardial remodelling while long-term intake of Bazedoxifene (5 mg/kg, intragastric) attenuated pressure overload-induced pathology. Echocardiographic results indicated Bazedoxifene rescued cardiac function in part. We found Bazedoxifene decreased the mRNA expression of IL-6, MMP2, Col1A1, Col3A1 and periostin in murine hearts after 8-week surgery. By Western blot detection, we found Bazedoxifene exhibited an inhibition of STAT3 activation in mice three hours and 8 weeks after TAC. Acute TAC stress (3 hours) led to down-regulated ratio of LC3-Ⅱ/LC3-Ⅰ, while in mice after long-term (8 weeks) TAC this ratio becomes higher than that in Sham mice. Bazedoxifene inverted the autophagic alteration induced by TAC at both two time-points. In H9c2 myoblasts, Bazedoxifene suppressed the IL-6-induced STAT3 activation. Moreover, IL-6 reduced the ratio of LC3-Ⅱ/LC3-Ⅰ, promoted P62 expression but Bazedoxifene reversed both changes in H9c2 cells. Our data suggested Bazedoxifene inhibited IL-6/gp130 signalling and protected against cardiac remodelling together with function deterioration in TAC mice.

Bazedoxifene exhibits growth suppressive activity by targeting interleukin-6/glycoprotein 130/signal transducer and activator of transcription 3 signaling in hepatocellular carcinoma.

The interleukin (IL)-6/glycoprotein (GP)130/signal transducer and activator of transcription (STAT)3 pathway is emerging as a target for the treatment of hepatocellular carcinoma. IL-6 binds to IL-6R, forming a binary complex, which further combines with GP130 to transduce extracellular signaling by activating STAT3. Therefore, blocking the interaction between IL-6 and GP130 may inhibit the IL-6/GP130/STAT3 signaling pathway and its biological effects. It has been reported that bazedoxifene acetate (BAZ), a selective estrogen receptor modulator approved by the US Food and Drug Administration, could inhibit IL-6/GP130 protein-protein interactions. Western blot, immunofluorescence staining, wound healing and colony formation assays were used to detect the effect of BAZ on liver cancer cells. Cell viability was evaluated by MTT assay. Apoptosis of cells was determined using the Annexin V-FITC detection kit. Mouse xenograft tumor models were utilized to evaluate the effect of BAZ in vivo. Our data showed that BAZ inhibited STAT3 phosphorylation (P-STAT3) and expression of STAT3 downstream genes, inducing apoptosis in liver cancer cells. BAZ inhibited P-STAT3 induced by IL-6, but not by leukemia inhibitory factor. BAZ inhibited P-STAT1 and P-STAT6 less significantly as elicited by interferon-α, interferon-γ and IL-4. In addition, pretreatment of BAZ impeded the translocation of STAT3 to nuclei induced by IL-6. BAZ inhibited cell viability, wound healing and colony formation in vitro. Furthermore, tumor growth in HEPG2 mouse xenografts were significantly inhibited by daily intragastric gavage of BAZ. Our results suggest that BAZ inhibited the growth of hepatocellular carcinoma in vitro and in vivo, indicating another potential strategy for HCC prevention and therapy.

Ubiquitin-Specific Peptidase 10 (USP10) Inhibits Hepatic Steatosis, Insulin Resistance, and Inflammation Through Sirt6.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance and inflammation, and the pathogenic mechanism of NAFLD is poorly understood. Ubiquitin-specific peptidase 10 (USP10), a member of the ubiquitin-specific protease family, is involved in environmental stress responses, tumor growth, inflammation, and cellular metabolism. However, the role of USP10 in hepatic steatosis, insulin resistance, and inflammation remains largely unexplored. USP10 expression was detected in livers of patients with NAFLD, mice with high-fat diet (HFD)-induced obesity, and genetically obese (ob/ob) mice, as well as in palmitate-induced hepatocytes. The function of USP10 in hepatic steatosis, insulin resistance, and inflammation was investigated using hepatocyte-specific USP10 deficiency or overexpression in mice induced by HFD treatment or genetic defect. The molecular mechanisms underlying USP10-regulated hepatic steatosis were further investigated in HFD-treated mice. USP10 expression was significantly decreased in the fatty livers of NAFLD patients and obese mice and in palmitate-treated hepatocytes. USP10 deficiency exacerbated the metabolic dysfunction induced by HFD treatment for 12 weeks. Conversely, USP10 overexpression significantly suppressed metabolic dysfunction in mice after HFD treatment and inhibited the development of NAFLD in ob/ob mice. Further investigation indicated that USP10 regulates hepatic steatosis by interacting with Sirt6 and inhibiting its ubiquitination and degradation. Sirt6 overexpression markedly ameliorated the effects of USP10 deficiency in hepatic steatosis, insulin resistance, and inflammation. Conversely, Sirt6 deficiency decreased the ameliorative effects of USP10 overexpression in response to HFD treatment. Conclusion: USP10 inhibits hepatic steatosis, insulin resistance, and inflammation through Sirt6.