Mechanobiological insight into brain diseases based on mechanosensitive channels: Common mechanisms and clinical potential.

BACKGROUND: As physical signals, mechanical cues regulate the neural cells in the brain. The mechanosensitive channels (MSCs) perceive the mechanical cues and transduce them by permeating specific ions or molecules across the plasma membrane, and finally trigger a series of intracellular bioelectrical and biochemical signals. Emerging evidence supports that wide-distributed, high-expressed MSCs like Piezo1 play important roles in several neurophysiological processes and neurological disorders. AIMS: To systematically conclude the functions of MSCs in the brain and provide a novel mechanobiological perspective for brain diseases. METHOD: We summarized the mechanical cues and MSCs detected in the brain and the research progress on the functional roles of MSCs in physiological conditions. We then concluded the pathological activation and downstream pathways triggered by MSCs in two categories of brain diseases, neurodegenerative diseases and place-occupying damages. Finally, we outlined the methods for manipulating MSCs and discussed their medical potential with some crucial outstanding issues. RESULTS: The MSCs present underlying common mechanisms in different brain diseases by acting as the "transportation hubs" to transduce the distinct signal patterns: the upstream mechanical cues and the downstream intracellular pathways. Manipulating the MSCs is feasible to alter the complicated downstream processes, providing them promising targets for clinical treatment. CONCLUSIONS: Recent research on MSCs provides a novel insight into brain diseases. The common mechanisms mediated by MSCs inspire a wide range of therapeutic potentials targeted on MSCs in different brain diseases.

Benthic foraminiferal community structure and its response to environmental factors revealed using high-throughput sequencing in the Zhoushan Fishing Ground, East China Sea.

Benthic foraminifera are excellent tools for monitoring marine environments and reconstructing paleoenvironments. This study investigated the structure and diversity of benthic foraminiferal communities in 20 superficial sediment samples obtained from the Zhoushan Fishing Ground (ZFG) using high-throughput sequencing based on small subunit ribosomal DNA and RNA amplification. The results revealed Rotaliida as the most dominant group, with spatial heterogeneity in foraminiferal distribution. Total benthic foraminiferal communities exhibited higher species richness and diversity compared to active communities. While heavy metal pollution in the ZFG was moderate, areas with elevated concentrations of heavy metals exhibited low diversity and richness in foraminiferal communities. Total foraminiferal community structure was primarily influenced by factors such as water depth and Hg, Pb, Cd, and Zn levels. Notably, Hg levels emerged as a critical factor impacting the structure and diversity of the active foraminiferal community. The dominant species, Operculina, exhibited tolerance toward heavy metal pollution.

Progress of Mitochondrial Function Regulation in Cardiac Regeneration.

Heart failure and myocardial infarction, global health concerns, stem from limited cardiac regeneration post-injury. Myocardial infarction, typically caused by coronary artery blockage, leads to cardiac muscle cell damage, progressing to heart failure. Addressing the adult heart's minimal self-repair capability is crucial, highlighting cardiac regeneration research's importance. Studies reveal a metabolic shift from anaerobic glycolysis to oxidative phosphorylation in neonates as a key factor in impaired cardiac regeneration, with mitochondria being central. The heart's high energy demands rely on a robust mitochondrial network, essential for cellular energy, cardiac health, and regenerative capacity. Mitochondria's influence extends to redox balance regulation, signaling molecule interactions, and apoptosis. Changes in mitochondrial morphology and quantity also impact cardiac cell regeneration. This article reviews mitochondria's multifaceted role in cardiac regeneration, particularly in myocardial infarction and heart failure models. Understanding mitochondrial function in cardiac regeneration aims to enhance myocardial infarction and heart failure treatment methods and insights.

An ACC-VTA-ACC positive-feedback loop mediates the persistence of neuropathic pain and emotional consequences.

The central mechanisms underlying pain chronicity remain elusive. Here, we identify a reciprocal neuronal circuit in mice between the anterior cingulate cortex (ACC) and the ventral tegmental area (VTA) that mediates mutual exacerbation between hyperalgesia and allodynia and their emotional consequences and, thereby, the chronicity of neuropathic pain. ACC glutamatergic neurons (ACCGlu) projecting to the VTA indirectly inhibit dopaminergic neurons (VTADA) by activating local GABAergic interneurons (VTAGABA), and this effect is reinforced after nerve injury. VTADA neurons in turn project to the ACC and synapse to the initial ACCGlu neurons to convey feedback information from emotional changes. Thus, an ACCGlu-VTAGABA-VTADA-ACCGlu positive-feedback loop mediates the progression to and maintenance of persistent pain and comorbid anxiodepressive-like behavior. Disruption of this feedback loop relieves hyperalgesia and anxiodepressive-like behavior in a mouse model of neuropathic pain, both acutely and in the long term.

Boron Quantum Dots Pillared Ti3 C2 Tx Membrane Electrode with High Rate Performance for Supercapacitor.

A sonication-assisted liquid-phase preparation technique is developed to prepare boron quantum dots (BQDs) with a lateral size of 3 nm in a solution of NMP and NBA; it shows a direct bandgap semiconductor with a bandgap of 3 eV and a specific capacitance of 41 F g-1 . A BQDs(10)-Ti3 C2 Tx membrane electrode with excellent capacitance and high flexibility is prepared by using Ti3 C2 Tx nanosheets (NSs) as assembled units and BQDs as pillar; it gives a specific capacitance of 524 F g-1 at 1 A g-1 in 6 m H2 SO4 electrolyte, a high capacity retention of 75%, and a minimum relaxation time of 0.51 s. An all-solid-state BQDs(10)-Ti3 C2 Tx flexibility supercapacitor is assembled by using a BQDs(10)-Ti3 C2 Tx membrane as electrodes and PVA/H2 SO4 hydrogel as electrolyte; it not only shows an area specific capacitance of 552 mF cm-2 at 1.25 mA cm-2 , a retention rate of 75%, a capacity retention of 93% after 5000 cycles, and an energy density of 40.4 Wh cm-3 at a volume power density of 416 W cm-3 , but also provides superior flexibility and can be bent to different degrees, showing that the assembled BQDs(10)-Ti3 C2 Tx membrane electrode and BQDs(10)-Ti3 C2 Tx flexible supercapacitor display broad application prospects in field of portable/wearable electronic devices.

Stress can affect mitochondrial energy metabolism and AMPK/SIRT1 signaling pathway in rats.

OBJECTION: To investigate the potential link between aberrant mitochondrial energy metabolism mediated by the AMPK/SIRT1 pathway and the etiology of anxiety disorders. METHODS: The anxiety rat model was established by uncertain empty water bottle（UEWB）stress. Rats were submitted behavioral tests on the seventh, fourteenth, and twenty-first days and had the prefrontal cortex and amygdala removed for biochemical tests. The morphological alterations of the mitochondria in the medial prefrontal cortex and amygdala were examined by using a transmission electron microscope. Expression levels of AMPK, SIRT1, PGC-1, NRF-1 and NRF-2 were tested by western-blot analysis. ATP, respiratory chain complex and caspase enzyme expressions were tested by neurochemical and biochemical assays. RESULTS: Rats showed anxiety-like behavior after being exposed to the uncertain empty water bottle (UEWB) stress model. In model rats, mitochondrial structure is damaged, mitochondrial energy metabolism is decreased, and the expression of proteins associated with AMPK/SIRT1 pathway is significantly reduced in the brain. CONCLUSION: The level of mitochondrial energy metabolism correlates with anxiety-like behavior. The main mechanism of anxiety disorder is a disturbance of mitochondrial energy metabolism, which might be related to AMPK/SIRT1 pathway.

DSPose: Dual-Space-Driven Keypoint Topology Modeling for Human Pose Estimation.

Human pose estimation is the basis of many downstream tasks, such as motor intervention, behavior understanding, and human-computer interaction. The existing human pose estimation methods rely too much on the similarity of keypoints at the image feature level, which is vulnerable to three problems: object occlusion, keypoints ghost, and neighbor pose interference. We propose a dual-space-driven topology model for the human pose estimation task. Firstly, the model extracts relatively accurate keypoints features through a Transformer-based feature extraction method. Then, the correlation of keypoints in the physical space is introduced to alleviate the error localization problem caused by excessive dependence on the feature-level representation of the model. Finally, through the graph convolutional neural network, the spatial correlation of keypoints and the feature correlation are effectively fused to obtain more accurate human pose estimation results. The experimental results on real datasets also further verify the effectiveness of our proposed model.

TRIM69: a marker of metastasis and potential sensitizer to 5-Fluorouracil and PD-1 blockers in colon adenocarcinoma.

BACKGROUND: Several proteins in the tripartite-motif (TRIM) family are associated with the development of colorectal cancer (CRC), but research on the role of TRIM69 was lacking. The present study examined the correlation between TRIM69 expression and colon adenocarcinoma (COAD). METHODS: mRNA sequencing data for COAD patients was extracted from The Cancer Genome Atlas to analyze correlations between TRIM69 expression and patients' clinical features as well as survival. Potential associations with immune cells and chemosensitivity also were predicted using various algorithms in the TIMER, Limma, clusterProfiler, GeneMANIA, and Gene Set Cancer Analysis platforms. Subsequently, polymerase chain reaction analysis and immunohistochemical staining were used to detect TRIM69 expression in COAD tissue samples from real-world patients. RESULTS: TRIM69 expression was lower in COAD tissues than in normal tissues and correlated with the pathologic stage and metastasis (M category). Additionally, TRIM69 was found to be involved in several immune-related pathways, notably the NOD-like signaling pathway. These results suggest that high TRIM69 expression has the potential to enhance tumor sensitivity to 5-fluorouracil and programmed cell death protein 1 (PD-1) blockers. CONCLUSIONS: From our findings that TRIM69 expression was significantly reduced in COAD compared with non-cancer tissues and associated with pathologic stage and metastasis, we conclude that increasing TRIM69 expression and/or activity may help to improve therapeutic outcomes. Accordingly, TRIM69 represents a potentially valuable marker of metastasis and target for adjuvant therapy in COAD.

Comparison and quantification of estrogen receptor-mediated responsiveness to endocrine disruptors in bivalves by using complementary model and a novel yeast assay approach.

Endocrine disrupting chemicals (EDCs) in estuaries and coastal habitats have been widely detected over the world and caused global concern. Bivalves have been shown to be vulnerable to endocrine disruption. However, estrogen receptors (ERs) sensitivity to steroids and EDCs has long been considered to be restricted to vertebrates. In the present study, a computational simulation docking model was applied to qualitatively predict the binding behavior of two bivalve ERs to estradiol and compared the docking activity with zebra fish ERa. A novel reconstituted yeast system was constructed by using transcriptional activator GAL-4 consists of ER-expressing plasmid and ERE (estrogen responsive element)-containing plasmid. The assays showed that bivalve ER specifically activate transcription in response to tested steroids and EDCs, but the activation ability is weaker compared to zebra fish ERa. The results corroborate the presence of an active ER in bivalve molluscs and provide a promising tool for screening of marine environmental pollutants active in disturbing ERs of bivalves, as well as understanding the underlying mechanism across taxonomic groups and phyla.

[Effect of Danzhi Xiaoyao Powder on behavior and mitochondrial morphology and function of anxiety model rats].

Danzhi Xiaoyao Powder is a classical prescription for anxiety. This study aims to analyze the effect of this medicine on mitochondrial morphology and function of anxiety rats and explore the mechanism of it against anxiety. Specifically, uncertain empty bottle drinking water stimulation(21 days) was employed to induce anxiety in rats. The elevated plus-maze test and open field test were respectively performed on the 7 th, the 14 th, and the 21 st days of the stimulation, so as to detect the anxiety-related protein index brain-derived neurotrophic factor(BDNF) and evaluate the anxiety level of animals. On this basis, the effect of this prescription on anxiety rats was preliminarily evaluated. After the behavioral test on the 21 st day, rats were killed and the brain tissues were separated for the observation of the mitochondrial morphology and the determination of mitochondrial function-related indicators and the adenosine 5'-monophosphate-activated protein kinase(AMPK) level. The results showed that Danzhi Xiaoxiao Powder could alleviate the anxiety-like behavior of rats, significantly increase the percentage of time in open arm in elevated plus-maze test and the ration of activity time in the central area of the field, dose-dependently raise the activity levels of respiratory chain complex Ⅰ,Ⅱ,Ⅲ and Ⅳ and the adenosine triphosphate(ATP) content, and elevate the levels of BDNF and phosphorylated AMPK(p-AMPK). Clear structure and intact morphology of mitochondrial cristae in medial prefrontal cortex cells and amygdala were observed in the Danzhi Xiaoyao Powder group. In summary, Danzhi Xiaoyao Powder exerts therapeutic effect on anxiety, and the mechanism is the likelihood that p-AMPK protects the structure and maintains the function of mitochondria.

Total and active benthic foraminiferal community and their response to heavy metals revealed by high throughput DNA and RNA sequencing in the Zhejiang coastal waters, East China Sea.

Benthic foraminifera, large protists abundant in marine environments, have been widely used as bioindicators of environmental conditions. In this study, high-throughput sequencing based on small subunit rDNA and rRNA amplifications was used to investigate total and active benthic foraminifera community composition and diversity from nineteen and twelve superficial marine sediment samples in the Zhejiang coastal waters, respectively. The results showed that the dominant taxa of total foraminifera changed from Buliminellidae (hyaline) to Saccamminidae (agglutinated) from north to south along the coastal waters of Zhejiang Province. According to our survey, heavy metal contamination was moderate in Zhejiang coastal waters, and the potential ecological risks posed by Cd and Hg were higher. The contamination level of heavy metals at Yueqing Bay was the highest, followed by those at Sanmen Bay and Hangzhou Bay. Cd, Cu and grain size may be key factors affecting the distribution and composition of active foraminiferal communities.

Use of GAL4 factor-based yeast assay to quantify the effects of xenobiotics on RXR homodimer and RXR/PPAR heterodimer in scallop Chlamys farreri.

Retinoid X receptor (RXR) and peroxisome proliferators-activated receptors (PPAR) have been shown as important targets of endocrine disrupting effects caused by organotin compounds (OTCs). In vitro methods for non-model species are instrumental in revealing not only mechanism of toxicity but also basic biology. In the present study, we constructed the GAL4 factor-based recombinant yeast systems of RXRα/RXRα (RR), RXRα/PPARα (RPα) and RXRα/PPARγ (RPγ) of the scallop Chlamys farreri to investigate their transcriptional activity under the induction of OTCs (tributyltin chloride, triphenyltin chloride, tripropyltin chloride and bis(tributyltin)oxide), their spiked sediments and five other non­tin compounds (Wy14643, rosiglitazone, benzyl butyl phthalate, dicyclohexyl phthalate and bis(2-ethylhexyl) phthalate). The results showed that the natural ligand of RXR, 9-cis-retinoic acid (9cRA), induces transcriptional activity in all three systems, while four OTCs induced the transcriptional activity of the RR and RPα systems. None of the five potential non­tin endocrine disruptors induced effects on the RPα and RPγ systems. The spiked sediment experiment demonstrated the feasibility of the recombinant yeast systems constructed in this study for environmental sample detection. These results suggest that OTCs pose a threat to affect function of RXRα and PPARα of bivalve mollusks. The newly developed GAL4 factor-based yeast two-hybrid system can be used as a valuable tool for identification and quantification of compounds active in disturbing RXR and PPAR of bivalves.

Potencies of organotin compounds in scallop RXRa responsive activity with a GAL4-based reconstituted yeast assay in vitro.

Retinoid X receptor (RXR) has been found to be a major target in various processes of endocrine disruption from the exposure to organotin compounds (OTCs), including imposex in gastropod mollusks. It was also reported in bivalves that OTCs caused intersex and skewed sex ratio. In order to evaluate the effect of these ligand-like OTCs, we constructed a reconstituted yeast system (CfRE system) based on GAL4 yeast two-hybrid principle using scallop Chlamys farreri retinoid X receptor (CfRXRa) and retinoid X response element (RXRE) to investigate the ligand-induced transactivation of CfRXRa. Responses of CfRXRa to 9-cis retinoic acid (9cRA) and tested four OTCs showed concentration-dependent response which is comparable with reported RXRa in vitro assay of human and gastropods. The detective limits of the CfRE system were found to be 100 nM for 9cRA and 10-1000 nM for the tested OTCs. While the tested non-Sn endocrine disrupting chemicals, including Benzo[a]pyrene, 2,4-Dichlorophenol, Nonylphenol, and Tetrabromobisphenol A, showed no effect on CfRXRa response. The present assay system may provide a valuable tool for screening assessments of unidentified environmental ligand chemicals on bivalve mollusks. It is also useful for comparison of sensitivity differences among species exposed to EDCs.

The interaction of S100A16 and GRP78 actives endoplasmic reticulum stress-mediated through the IRE1α/XBP1 pathway in renal tubulointerstitial fibrosis.

Recent studies have indicated that the development of acute and chronic kidney disease including renal fibrosis is associated with endoplasmic reticulum (ER) stress. S100 calcium-binding protein 16 (S100A16) as a novel member of the S100 family is involved in kidney disease; however, few studies have examined fibrotic kidneys for a relationship between S100A16 and ER stress. In our previous study, we identified GRP78 as a protein partner of S100A16 in HK-2 cells. Here, we confirmed a physical interaction between GRP78 and S100A16 in HK-2 cells and a markedly increased expression of GRP78 in the kidneys of unilateral ureteral occlusion mice. S100A16 overexpression in HK-2 cells by infection with Lenti-S100A16 also induced upregulation of ER stress markers, including GRP78, p-IRE1α, and XBP1s. Immunofluorescence staining demonstrated that the interaction between S100A16 and GRP78 predominantly occurred in the ER of control HK-2 cells. By contrast, HK-2 cells overexpressing S100A16 showed colocalization of S100A16 and GRP78 mainly in the cytoplasm. Pretreatment with BAPTA-AM, a calcium chelator, blunted the upregulation of renal fibrosis genes and ER stress markers induced by S100A16 overexpression in HK-2 cells and suppressed the cytoplasmic colocalization of GRP78 and S100A16. Co-immunoprecipitation studies suggested a competitive binding between S100A16 and IRE1α with GRP78 in HK-2 cells. Taken together, our findings demonstrate a significant increase in S100A16 expression in the cytoplasm following renal injury. GRP78 then moves into the cytoplasm and binds with S100A16 to promote the release of IRE1α. The subsequent phosphorylation of IRE1α then leads to XBP1 splicing that activates ER stress.

Effects of BαP and TBBPA on multixenobiotic resistance (MXR) related efflux transporter activity and gene expressions in gill cells of scallop Chlamys farreri.

The multixenobiotic resistance mechanism (MXR) provides aquatic organisms with the capacity to adapt to polluted environments, which can be inhibited by chemosensitizers. In the present study, the effect of two typical marine persistent organic pollutants, benzo(a)pyrene (BaP) and tetrabromobisphenol A (TBBPA), on the most relevant ABC transporters, ABCB1, ABCC1, and ABCG2 of scallop Chlamys farreri was tested. MXR transporter efflux activity of cultured gill cells of the scallops was evaluated by measuring the intracellular fluorescent intensity of Calcein-AM and rhodamine 123 with flow cytometry. The results showed that ABCB1 and ABCC1 transporters demonstrated increased activity compared with ABCG2 in mediating MXR efflux activity. BaP and TBBPA were able to suppress the efflux transporter activity of ABC transporters significantly, of which BaP revealed block effects by acting on the ABCB1 transporter. Additionally, exposure of BaP and TBBPA only significantly upregulated the expression level of ABCC1 gene. This study demonstrated the promising utility of efflux transporter activity in conjunction with biomarkers such as mRNA levels in identification of chemosensitizer.

Cofilin participates in regulating alpha-epithelial sodium channel by interaction with 14-3-3 isoforms.

Renal epithelial sodium channel (ENaC) plays a crucial role in maintaining homeostasis and sodium absorption. While insulin participates in controlling sodium transport across the renal epithelium, the underlying molecular mechanism remain unclear. In this study, we found that insulin increased the expression and function of alpha-epithelial sodium channel (α-ENaC) as well as phosphorylation of cofilin, a family of actin-binding proteins which disassembles actin filaments, in mouse cortical collecting duct (mpkCCDc14) cells. The wild-type (WT) cofilin and its constitutively phosphorylated form (S3D), but not its constitutively non-phosphorylable form (S3A), contributed to the elevated expression on α-ENaC. Overexpression of 14-3-3ε, ß, or γ increased the expression of α-ENaC and cofilin phosphorylation, which was blunted by knockdown of 14-3-3ε, ß, or γ. Moreover, it was found that insulin increased the interaction between cofilin and 14-3-3 isoforms, which indicated relevance of 14-3-3 isoforms with cofilin. Furthermore, LIMK1/SSH1 pathway was involved in regulation of cofilin and α-ENaC expression by insulin. The results from this work indicate that cofilin participates in the regulation of α-ENaC by interaction with 14-3-3 isoforms.

Interaction of calcium binding protein S100A16 with myosin-9 promotes cytoskeleton reorganization in renal tubulointerstitial fibrosis.

Renal fibrosis arises by the generation of matrix-producing fibroblasts and myofibroblasts through the epithelial-mesenchymal transition (EMT), a process in which epithelial cells undergo a transition into a fibroblast phenotype. A key feature of the EMT is the reorganization of the cytoskeletons, which may involve the Ca2+-binding protein S100A16, a newly reported member of the S100 protein family. However, very few studies have examined the role of S100A16 in renal tubulointerstitial fibrosis. In this study, S100A16 expression was examined by immunohistochemical staining of kidney biopsy specimens from patients with various nephropathies and kidney tissues from a unilateral ureteral obstruction (UUO) mouse model. Renal histological changes were investigated in S100A16Tg, S100A16+/-, and WT mouse kidneys after UUO. The expression of epithelia marker E-cadherin, mesenchymal markers N-cadherin, and vimentin, extracellular matrix protein, and S100A16, as well as the organization of F-actin, were investigated in S100A16 overexpression or knockdown HK-2 cells. Mass spectrometry was employed to screen for S100A16 binding proteins in HK-2 cells. The results indicated that S100A16 is high expressed and associated with renal tubulointerstitial fibrosis in patient kidney biopsies and in those from UUO mice. S100A16 promotes renal interstitial fibrosis in UUO mice. S100A16 expression responded to increasing Ca2+ and interacted with myosin-9 during kidney injury or TGF-ß stimulation to promote cytoskeleton reorganization and EMT progression in renal tubulointerstitial fibrosis. Therefore, S100A16 is a critical regulator of renal tubulointerstitial fibroblast activation and is therefore a potential therapeutic target for the treatment of renal fibrosis.

Synthesis of novel caffeic acid derivatives and their protective effect against hydrogen peroxide induced oxidative stress via Nrf2 pathway.

AIM: This study was aimed to synthesize novel caffeic acid derivatives and evaluate their potential applications for the treatment of oxidative stress associated disease. MAIN METHODS: Caffeic acid sulfonamide derivatives were synthesized by coupling sulfonamides to the backbone of caffeic acid and fully characterized by melting point test, FT-IR, MS, NMR, UV-vis and n-octanol-water distribution assay. Their free radical scavenging ability was evaluated using DPPH assay and cytotoxicity against A549 cells were determined by MTT assay. The protective effect of these derivatives against hydrogen peroxide (H2O2) induced oxidative injury was assessed in A549 cells from cell viability, production of reactive oxygen species (ROS) and malondialdehyde (MDA), alternation of antioxidase activities, and expressions of Nrf2 and its target genes. KEY FINDINGS: Six novel caffeic acid sulfonamide derivatives were obtained. The derivatives showed better liphophilicity than the parent caffeic acid. CASMZ, CAST and CASQ exhibited similar DPPH scavenging capability as caffeic acid, while the protection of hydroxyl groups on the benzene ring with acetyl groups caused decrease in radical scavenging activity. No inhibitory effect on the proliferation of A549 cells were observed up to a concentration of 50 µM. Pre-treatment of cells with these derivatives strongly inhibited H2O2 induced decrease of cell viability, reduced the production of ROS and MDA, promoted antioxidase activities, and further upregulated the expression of Nrf2 and its target genes. SIGNIFICANCE: Caffeic acid sulfonamide derivatives were synthesized with simple reactions under mild conditions. They might protect cells from H2O2-induced oxidative injury via Nrf2 pathway.

HUWE1 promotes EGFR ubiquitination and degradation to protect against renal tubulointerstitial fibrosis.

Injury of renal tubular epithelial cells is a key feature of the pathogenicity associated with tubulointerstitial fibrosis and other kidney diseases. HUWE1, an E3 ubiquitin ligase, acts by participating in ubiquitination and degradation of its target proteins. However, the detailed mechanisms by which HUWE1 might regulate fibrosis in renal tubular epithelial cells have not been established. Here, the possible regulation of renal tubulointerstitial fibrosis by HUWE1 was investigated by examining the expression of HUWE1 and EGFR in unilateral ureteral obstruction (UUO) mice. Markedly consistent reciprocal changes in HUWE1 and EGFR expression were observed at the protein and mRNA levels in the kidney after UUO injury. Expression of HUWE1 inhibited TGF-ß-induced injury to HK-2 cells, while HUWE1 overexpression decreased the expression of EGFR. Further analysis indicated that HUWE1 physically interacted with EGFR and promoted its ubiquitination and degradation. HUWE1 expression also showed clinical relevance in renal disease, as it notably decreased in multiple types of clinical nephropathy, while EGFR expression significantly increased when compared to the normal kidney. Therefore, this study demonstrated that HUWE1, which serves as an E3 ubiquitin ligase specific for EGFR, promotes EGFR ubiquitination and degradation, thereby regulating EGFR expression and providing protection against kidney injury.

Synthesis of caffeic acid sulfonamide derivatives and their protective effect against H2O2 induced oxidative damage in A549 cells.

Exogenous antioxidants are considered as important therapeutic tools for oxidative stress associated disorders as they can regulate the redox state, which is associated with cell and organ function. Inspired by natural polyphenols, six new caffeic acid sulfonamide derivatives were synthesized by coupling sulfonamides to the backbone of caffeic acid with good yields. Their structure and lipophilicity were characterized by 1H nuclear magnetic resonance (NMR), 13C{1H} NMR, infrared spectroscopy (IR) and oil-water partition coefficient assay. Their free radical scavenging activity and antioxidant activity were assessed by DPPH assay and hydrogen peroxide (H2O2) induced oxidative stress in human lung carcinoma A549 cells. The oil-water partition coefficient results indicate that the conjugation of sulfonamides increases the lipophilicity of caffeic acid. The CASMD, CASDZ and CASN results show higher free radical scavenging effects compared with vitamin C. The derivatives do not show any inhibitory effect on the proliferation of A549 cells up to a concentration of 200 µM, except CASDZ which significantly inhibits the growth of A549 cells at a concentration of 200 µM. In addition, the obtained derivatives markedly attenuate H2O2 induced decrease of cell viability, inhibit the production of ROS and MDA, and promote the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). Besides, treatment of H2O2 stimulated A549 cells with caffeic acid sulfonamide derivatives further increases mRNA expression of NF-E2-related factor 2 (Nrf2) and its target genes, including heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1) and thioredoxin reductase 1 (TXNRD1). These results suggest that these new caffeic acid sulfonamide derivatives have higher lipophilicity and better antioxidant activities than the parent caffeic acid, and they might be able to control the antioxidant response in cells via the Nrf2 pathway.