Blockade of a novel MAP4K4-LATS2-SASH1-YAP1 cascade inhibits tumorigenesis and metastasis in luminal breast cancer.

Novel components in the noncanonical Hippo pathway that mediate the growth, metastasis, and drug resistance of breast cancer (BC) cells need to be identified. Here, we showed that expression of SAM and SH3 domain-containing protein 1 (SASH1) is negatively correlated with expression of mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) in a subpopulation of patients with luminal-subtype BC. Downregulated SASH1 and upregulated MAP4K4 synergistically regulated the proliferation, migration, and invasion of luminal-subtype BC cells. The expression of LATS2, SASH1, and YAP1 and the phosphorylation of YAP1 were negatively regulated by MAP4K4, and LATS2 then phosphorylated SASH1 to form a novel MAP4K4-LATS2-SASH1-YAP1 cascade. Dephosphorylation of Yes1 associated transcriptional regulator (YAP1), YAP1/TAZ nuclear translocation, and downstream transcriptional regulation of YAP1 were promoted by the combined effects of ectopic MAP4K4 expression and SASH1 silencing. Targeted inhibition of MAP4K4 blocked proliferation, cell migration, and ER signaling both in vitro and in vivo. Our findings reveal a novel MAP4K4-LATS2-SASH1-YAP1 phosphorylation cascade, a noncanonical Hippo pathway that mediates ER signaling, tumorigenesis, and metastasis in breast cancer. Targeted intervention with this noncanonical Hippo pathway may constitute a novel alternative therapeutic approach for endocrine-resistant BC.

CASK and FARP localize two classes of post-synaptic ACh receptors thereby promoting cholinergic transmission.

Changes in neurotransmitter receptor abundance at post-synaptic elements play a pivotal role in regulating synaptic strength. For this reason, there is significant interest in identifying and characterizing the scaffolds required for receptor localization at different synapses. Here we analyze the role of two C. elegans post-synaptic scaffolding proteins (LIN-2/CASK and FRM-3/FARP) at cholinergic neuromuscular junctions. Constitutive knockouts or muscle specific inactivation of lin-2 and frm-3 dramatically reduced spontaneous and evoked post-synaptic currents. These synaptic defects resulted from the decreased abundance of two classes of post-synaptic ionotropic acetylcholine receptors (ACR-16/CHRNA7 and levamisole-activated AChRs). LIN-2's AChR scaffolding function is mediated by its SH3 and PDZ domains, which interact with AChRs and FRM-3/FARP, respectively. Thus, our findings show that post-synaptic LIN-2/FRM-3 complexes promote cholinergic synaptic transmission by recruiting AChRs to post-synaptic elements.

Norcantharidin Enhances the Antitumor Effect of 5-Fluorouracil by Inducing Apoptosis of Cervical Cancer Cells: Network Pharmacology, Molecular Docking, and Experimental Validation.

The high recurrence rate of cervical cancer is a leading cause of cancer deaths in women. 5-Fluorouracil (5-FU) is an antitumor drug used to treat many types of cancer, but its diminishing effectiveness and side effects limit its use. Norcantharidin (NCTD), a demethylated derivative of cantharidin, exhibits various biological activities. Here, we investigated whether NCTD could potentiate 5-FU to induce cervical cancer cell death. To assess the cell viability and synergistic effects of the drugs, cell counting kit-8 and colony formation assays were performed using HR-HPV-positive cervical cancer cell lines. Annexin V-FITC/PI staining and TUNEL assays were performed to confirm the induction of apoptosis. The synergistic effect of NCTD on the antitumor activity of 5-FU was analyzed using network pharmacology, molecular docking, and molecular dynamics simulations. Apoptosis-related proteins were examined using immunoblotting. The combination of NCTD and 5-FU was synergistic in cervical cancer cell lines. Network pharmacological analysis identified 10 common targets of NCTD and 5-FU for cervical cancer treatment. Molecular docking showed the strong binding affinity of both compounds with CA12, CASP9, and PTGS1. Molecular dynamics simulations showed that the complex system of both drugs with caspase-9 could be in a stable state. NCTD enhanced 5-FU-mediated cytotoxicity by activating apoptosis-related proteins. NCTD acts synergistically with 5-FU to inhibit cervical cancer cell proliferation. NCTD enhances 5-FU-induced apoptosis in cervical cancer cell lines via the caspase-dependent pathway.

A WDR47 homolog facilitates ciliogenesis by modulating intraflagellar transport.

Cilia are conserved organelles found in many cell types in eukaryotes, and their dysfunction causes defects in environmental sensing and signaling transduction; such defects are termed ciliopathies. Distinct cilia have cell-specific morphologies and exert distinct functions. However, the underlying mechanisms of cell-specific ciliogenesis and regulation are unclear. Here, we identified a WD40-repeat (WDR) protein, NMTN-1 (the homolog of mammalian WDR47), and show that it is specifically required for ciliogenesis of AWB chemosensory neurons in C. elegans. NMTN-1 is expressed in the AWB chemosensory neuron pair, and is enriched at the basal body (BB) of the AWB cilia. Knockout of nmtn-1 causes abnormal AWB neuron cilia morphology, structural integrity, and induces aberrant AWB-mediated aversive behaviors. We further demonstrate that nmtn-1 deletion affects movement of intraflagellar transport (IFT) particles and their cargo delivery in AWB neurons. Our results indicate that NMTN-1 is essential for AWB neuron ciliary morphology and function, which reveal a novel mechanism for cell-specific ciliogenesis. Given that WDR47/NMTN-1 is conserved in mammals, our findings may help understanding of the process of cell-specific ciliogenesis and provide insights for treating ciliopathies.

Localized High-Concentration Sulfone Electrolytes with High-Voltage Stability and Flame Retardancy for Ni-Rich Lithium Metal Batteries.

The localized high-concentration electrolyte (LHCE) propels the advanced high-voltage battery system. Sulfone-based LHCE is a transformative direction compatible with high energy density and high safety. In this work, the application of lithium bis(trifluoromethanesulphonyl)imide and lithium bis(fluorosulfonyl)imide (LiFSI) in the LHCE system constructed from sulfolane and 1,1,2,2-tetrafluoroethyl-2,2,3,3-tetrafluoropropyl ether (TTE) is investigated. The addition of diluent causes an increase of contact ion pairs and ionic aggregates in the solvation cluster and an acceptable quantity of free solvent molecules. A small amount of LiFSI as an additive can synergistically decompose with TTE on the cathode and participate in the construction of both electrode interfaces. The designed electrolyte helps the Ni-rich system to cycle firmly at a high voltage of 4.5 V. Even with high mass load and lean electrolyte, it can keep a reversible specific capacity of 91.5% after 50 cycles. The constructed sulfone-based electrolyte system exhibits excellent thermal stability far beyond the commercial electrolytes. Further exploration of in-situ gelation has led to a quick conversion of the designed liquid electrolyte to the gel state, accompanied by preserved stability, which provides a direction for the synergistic development of LHCE with gel electrolytes.

Pyroptosis-related gene signature elicits immune response in rosacea.

Rosacea is a complex chronic inflammatory skin disorder with high morbidity. Pyroptosis is known as a regulated inflammatory cell death. While its association with immune response to various inflammatory disorders is well established, little is known about its functional relevance of rosacea. So, we aimed to explore and enrich the pathogenesis involved in pyroptosis-related rosacea aggravations. In this study, we evaluated the pyroptosis-related patterns of rosacea by consensus clustering analysis of 45 ferroptosis-related genes (FRGs), with multiple immune cell infiltration analysis to identify the pyroptosis-mediated immune response in rosacea using GSE65914 dataset. The co-co-work between PRGs and WGCNA-revealed hub genes has established using PPI network. FRG signature was highlighted in rosacea using multi-transcriptomic and experiment analysis. Based on this, three distinct pyroptosis-related rosacea patterns (non/moderate/high) were identified, and the notably enriched pathways have revealed through GO, KEGG and GSEA analysis, especially immune-related pathways. Also, the XCell/MCPcount/ssGSEA/Cibersort underlined the immune-related signalling (NK cells, Monocyte, Neutrophil, Th2 cells, Macrophage), whose hub genes were identified through WGCNA (NOD2, MYD88, STAT1, HSPA4, CXCL8). Finally, we established a pyroptosis-immune co-work during the rosacea aggravations. FRGs may affect the progression of rosacea by regulating the immune cell infiltrations. In all, pyroptosis with its mediated immune cell infiltration is a critical factor during the development of rosacea.

Mitochondria-derived methylmalonic acid aggravates ischemia-reperfusion injury by activating reactive oxygen species-dependent ferroptosis.

Ferroptosis is a regulatory cell death process pivotal in myocardial ischemia-reperfusion (I/R) injury. However, the precise mechanism underlying myocardial ferroptosis remains less known. In this study, we investigated the pathophysiological mechanisms of methylmalonic acid (MMA) associated with ferroptosis activation in cardiomyocytes after I/R. We found an increase level of MMA in patients with acute myocardial injury after reperfusion and AC16 cells under hypoxia/reoxygenation (H/R) condition. MMA treatment was found to be associated with excessive oxidative stress in cardiomyocytes, leading to ferroptosis-related myocardial injury. In mice with I/R injury, MMA treatment aggravated myocardial oxidative stress and ferroptosis, which amplified the myocardial infarct size and cardiac dysfunction. Mechanistically, MMA promoted NOX2/4 expression to increase reactive oxygen species (ROS) production in cardiomyocytes, aggravating myocardial injury. Notably, the increased ROS further activated ferroptosis by inhibiting solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression. In addition, MMA decreased the ectopic nuclear distribution of nuclear factor E2-related factor 2 (NRF2) by increasing the interaction between NRF2 and kelch-like ECH-associated protein 1 (KEAP1). This impeded the activation of GPX4/SLC7A11, downstream of NRF2, activating ferroptosis and aggravating myocardial cell injury. Collectively, our study indicates that MMA activates oxidative stress and ROS generation, which induces ferroptosis to exacerbate cardiomyocyte injury in an I/R model. These findings may provide a new perspective for the clinical treatment of I/R injury and warrant further investigation.

Validation and update of a clinical score model to predict technical difficulty of colorectal endoscopic submucosal dissection: a multicenter prospective cohort study.

BACKGROUND AND AIMS: The Zhongshan colorectal endoscopic submucosal dissection (CR-ESD) score model was proposed to grade the technical difficulty of CR-ESD. The objective of this study was to prospectively validate and update the score model. METHODS: A multicenter prospective cohort analysis of CR-ESD was conducted. Individual data on patients, lesions, and outcomes of CR-ESD were used to validate the original model and further refine the difficulty of the prediction model. Data were randomly divided into discovery and internal validation cohorts. A multivariate Cox regression analysis was conducted on the discovery cohort to develop an updated risk-scoring system, which was then validated. RESULTS: Five hundred forty-eight patients with 565 colorectal lesions treated by ESD from 4 hospitals were included. In the prospective validation cohort, the area under the receiver-operating characteristic (ROC) curve for the original model was .707. Six risk factors were identified and assigned point values: tumor size (2 points for 30-50 mm, 3 points for ≥50 mm), at least two-thirds circumference of the lesion (3 points), tumor location in the cecum (2 points) or flexure (2 points), laterally spreading tumor-nongranular lesions (1 point), preceding biopsy sampling (1 point), and NBI International Colorectal Endoscopic type 3 (3 points). The updated model had an area under the ROC curve of .738 in the discovery cohort and of .782 in the validation cohort. Cases were categorized into easy (score = 0-1), intermediate (score = 2-3), difficult (score = 4-6), and very difficult (score ≥7) groups. Satisfactory discrimination and calibration were observed. CONCLUSIONS: The original model achieved an acceptable level of prediction in the prospective cohort. The updated model exhibited superior performance and can be used in place of the previous version. (Clinical trial registration number: ChiCTR2100047087.).

Self-Delivery Nanoplatform Based on Amphiphilic Apoptosis Peptide for Precise Mitochondria-Targeting Photothermal Therapy.

Mitochondria-targeting photothermal therapy could significantly enhance the tumor cell killing effect. However, since therapeutic reagents need to overcome a series of physiological obstacles to arrive at mitochondria accurately, precise mitochondria-targeting photothermal therapy still faces great challenges. In this study, we developed a self-delivery nanoplatform that specifically targeted the mitochondria of tumor cells for precise photothermal therapy. Photothermal agent IR780 was encapsulated by amphiphilic apoptotic peptide KLA with mitochondria-targeting ability to form nanomicelle KI by self-assembly through hydrophilic and hydrophobic interactions. Subsequently, negatively charged tumor-targeting polymer HA was coated on the surface of KI through electrostatic interactions, to obtain tumor mitochondria-targeting self-delivery nanoplatform HKI. Through CD44 receptor-mediated recognition, HKI was internalizated by tumor cells and then disassembled in an acidic environment with hyaluronidase in endosomes, resulting in the release of apoptotic peptide KLA and photothermal agent IR780 with mitochondria anchoring capacity, which achieved precise mitochondria guidance and destruction. This tumor mitochondria-targeting self-delivery nanoplatform was able to effectively deliver photothermal agents and apoptotic peptides to tumor cell mitochondria, resulting in precise destruction to mitochondria and enhancing tumor cell inhibition at the subcellular organelle level.

Attributing Atmospheric Phosphorus in the Himalayas: Biomass Burning vs Mineral Dust.

Atmospheric phosphorus is a vital nutrient for ecosystems whose sources and fate are still debated in the fragile Himalayan region, hindering our comprehension of its local ecological impact. This study provides novel insights into atmospheric phosphorus based on the study of total suspended particulate matter at the Qomolangma station. Contrary to the prevailing assumptions, we show that biomass burning (BB), not mineral dust, dominates total dissolved phosphorus (TDP, bioavailable) deposition in this arid region, especially during spring. While total phosphorus is mainly derived from dust (77% annually), TDP is largely affected by the transport of regional biomass-burning plumes from South Asia. During BB pollution episodes, TDP causing springtime TDP fluxes alone accounts for 43% of the annual budget. This suggests that BB outweighs dust in supplying bioavailable phosphorus, a critical nutrient, required to sustain Himalayas' ecological functions. Overall, this first-hand field evidence refines the regional and global phosphorus budget by demonstrating that BB emission, while still unrecognized, is a significant source of P, even in the remote mountains of the Himalayas. It also reveals the heterogeneity of atmospheric phosphorus deposition in that region, which will help predict changes in the impacted ecosystems as the deposition patterns vary.

Seizure control and adverse outcomes of lamotrigine use during pregnancy: A systematic review and meta-analysis.

OBJECTIVE: This review aims to summarize existing evidence on the adverse pregnancy outcomes and seizure control effects of using lamotrigine (LTG) monotherapy in pregnancy women with epilepsy (WWE) during pregnancy. METHODS: A comprehensive search was conducted in various databases including Cochrane, Web of Science, CBM, PubMed, Embase, CNKI, and Pregnancy Registration Center databases to identify relevant studies. The search was concluded up to January 2024. Studies comparing LTG with other antiseizure medications (ASMs) for treating epilepsy in pregnant women were included, with no language or regional restrictions. RESULTS: A total of 19 studies were included for analysis, with 16 studies reporting adverse pregnancy outcomes and 6 studies reporting seizure control outcomes. Meta-analysis showed that compared to monotherapy with carbamazepine (CBZ), sodium valproate (VPA), and levetiracetam (LEV), LTG monotherapy had a slightly weaker ability to control seizures during pregnancy, with ORs and 95 %CIs of 0.65 (0.57-0.75; CBZ), 0.50 (0.32-0.79; VPA), and 0.55 (0.36-0.84; LEV). Regarding adverse pregnancy outcomes, the occurrence rate of LTG monotherapy was significantly lower than that of CBZ, VPA, phenytoin (PHT), and phenobarbital (PHB), with ORs and 95 %CIs ranging from 0.30 (0.25-0.35; VPA) to 0.68 (0.56-0.81; CBZ). CONCLUSION: Based on meta-analysis, LTG and LEV appear to be preferred medications for controlling seizures during pregnancy. This review provides further support for the use of LTG monotherapy in pregnant WWE, building upon existing evidence for clinical practitioners.

Optimization and biological evaluation of l-DOPA derivatives as potent influenza PAN endonuclease inhibitors with multi-site binding characteristics.

Emerging and potential influenza pandemics still are an enormous worldwide public health challenge. The PAN endonuclease has been proved to be a promising target for anti-influenza drug design. Here, we report the discovery and optimization of potent Y-shaped PAN inhibitors featuring multi-site binding characteristics with l-DOPA as a starting point. We systematically modified the hit 1 bearing two-binding characteristics based on structure-based rational design combined with multisite binding and conformational constraint strategies, generating four families of l-DOPA derivatives for SARs analysis. Among these substances, N, 3-di-substituted 1, 2, 3, 4-tetrahydroisoquinoline derivative T-31 displayed superior properties as a lead PAN endonuclease inhibitor and antiviral agent. The lead T-31 inhibited PAN endonuclease activity with an IC50 value of 0.15 µM and showed broad and submicromolar anti-influenza potency in cell-based assays. More importantly, T-31 could simultaneously target both influenza HA and the RdRp complex, thus interfering with virus entry into host cells and viral replication. This study offers a set of novel PAN endonuclease inhibitors with multi-site binding characteristics starting from the l-DOPA skeleton.

Identification of potential therapeutic targets for plaque vulnerability based on an integrated analysis.

BACKGROUND AND AIMS: This study aimed to explore potential hub genes and pathways of plaque vulnerability and to investigate possible therapeutic targets for acute coronary syndrome (ACS). METHODS AND RESULTS: Four microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs), weighted gene coexpression networks (WGCNA) and immune cell infiltration analysis (IIA) were used to identify the genes for plaque vulnerability. Then, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, Disease Ontology, Gene Ontology annotation and protein-protein interaction (PPI) network analyses were performed to explore the hub genes. Random forest and artificial neural networks were constructed for validation. Furthermore, the CMap and Herb databases were employed to explore possible therapeutic targets. A total of 168 DEGs with an adjusted P < 0.05 and approximately 1974 IIA genes were identified in GSE62646. Three modules were detected and associated with CAD-Class, including 891 genes that can be found in GSE90074. After removing duplicates, 114 hub genes were used for functional analysis. GO functions identified 157 items, and 6 pathways were enriched for the KEGG pathway at adjusted P < 0.05 (false discovery rate, FDR set at < 0.05). Random forest and artificial neural network models were built based on the GSE48060 and GSE34822 datasets, respectively, to validate the previous hub genes. Five genes (GZMA, GZMB, KLRB1, KLRD1 and TRPM6) were selected, and only two of them (GZMA and GZMB) were screened as therapeutic targets in the CMap and Herb databases. CONCLUSION: We performed a comprehensive analysis and validated GZMA and GZMB as a target for plaque vulnerability, which provides a therapeutic strategy for the prevention of ACS. However, whether it can be used as a predictor in blood samples requires further experimental verification.

Application of 18ß-glycyrrhetinic acid in the structural modification of natural products: a review.

18ß-Glycyrrhetinic acid (GA) is an oleane-type pentacyclic triterpene saponin obtained from glycyrrhizic acid by removing 2 glucuronic acid groups. GA and its analogues are active substances of glycyrrhiza aicd, with similar structure and important pharmacological effects such as anti-inflammatory, anti-diabetes, anti-tumor and anti-fibrosis. Although GA combined compounds are in the clinical trial stages, its application potential is severely restricted by its low bioavailability, water solubility and membrane permeability. In this article, synthetic methods and structure-activity relationships (SARs) of GA derivatives from 2018 to present are reviewed based on pharmacological activity. It is hoped that this review can provide reference for the future development of potential GA preclinical candidate compounds, and furnish ideas for the development of pentacyclic triterpenoid lead compounds.

Prevalence, predictors, and outcomes of acute respiratory distress syndrome in severe stroke.

OBJECTIVES: Patients with severe stroke are at high risk of developing acute respiratory distress syndrome (ARDS), but this severe complication was often under-diagnosed and rarely explored in stroke patients. We aimed to investigate the prevalence, early predictors, and outcomes of ARDS in severe stroke. METHODS: This prospective study included consecutive patients admitted to neurological intensive care unit (neuro-ICU) with severe stroke, including acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The incidence of ARDS was examined, and baseline characteristics and severity scores on admission were investigated as potential early predictors for ARDS. The in-hospital mortality, length of neuro-ICU stay, the total cost in neuro-ICU, and neurological functions at 90 days were explored. RESULTS: Of 140 patients included, 35 (25.0%) developed ARDS. Over 90% of ARDS cases occurred within 1 week of admission. Procalcitonin (OR 1.310 95% CI 1.005-1.707, P = 0.046) and PaO2/FiO2 on admission (OR 0.986, 95% CI 0.979-0.993, P < 0.001) were independently associated with ARDS, and high brain natriuretic peptide (OR 0.994, 95% CI 0.989-0.998, P = 0.003) was a red flag biomarker warning that the respiratory symptoms may be caused by cardiac failure rather than ARDS. ARDS patients had longer stays and higher expenses in neuro-ICU. Among patients with ARDS, 25 (62.5%) were moderate or severe ARDS. All the patients with moderate to severe ARDS had an unfavorable outcome at 90 days. CONCLUSIONS: ARDS is common in patients with severe stroke, with most cases occurring in the first week of admission. Procalcitonin and PaO2/FiO2 on admission are early predictors of ARDS. ARDS worsens both short-term and long-term outcomes. The conflict in respiratory support strategies between ARDS and severe stroke needs to be further studied.

Progress of studies on natural products for glioblastoma therapy.

Glioblastoma (GBM) is the most common, malignant, and lethal primary brain tumor in adults. Up to now, the chemotherapy approaches for GBM are limited. Therefore, more studies on identifying and exploring new chemotherapy drugs or strategies overcome the GBM are essential. Natural products are an important source of drugs against various human diseases including cancers. With the better understanding of the molecular etiology of GBM, the development of new anti-GBM drugs has been increasing. Here, we summarized recent researches of natural products for the GBM therapy and their potential mechanisms in details, which will provide new ideas for the research on natural products and promote developing drugs from nature products for GBM therapy.

[Critical influencing factors on quality of traditional Chinese medicine preparations from perspective of process and equipment].

The quality of traditional Chinese medicine preparations is directly related to the safety of patients. Among the various factors, the process and corresponding critical equipment are critical factors influencing the quality of the preparations. To improve the quality of traditional Chinese medicine preparations, this article summarizes and analyzes the problems in the process links and corresponding critical equipment in the manufacturing process of traditional Chinese medicine preparations. Furthermore, a critical quality attribute evaluation system is established based on safety and effectiveness combined with the drug properties, preparation process, and preparation characteristics, providing a basis for the process and equipment improvements aimed at quality enhancement.

Two types of peptides derived from the neurotoxin GsMTx4 inhibit a mechanosensitive potassium channel by modifying the mechanogate.

Atrial fibrillation is the most common sustained cardiac arrhythmia in humans. Current atrial fibrillation antiarrhythmic drugs have limited efficacy and carry the risk of ventricular proarrhythmia. GsMTx4, a mechanosensitive channel-selective inhibitor, has been shown to suppress arrhythmias through the inhibition of stretch-activated channels (SACs) in the heart. The cost of synthesizing this peptide is a major obstacle to clinical use. Here, we studied two types of short peptides derived from GsMTx4 for their effects on a stretch-activated big potassium channel (SAKcaC) from the heart. Type I, a 17-residue peptide (referred to as Pept 01), showed comparable efficacy, whereas type II (i.e., Pept 02), a 10-residue peptide, exerted even more potent inhibitory efficacy on SAKcaC compared with GsMTx4. We identified through mutagenesis important sequences required for peptide functions. In addition, molecular dynamics simulations revealed common structural features with a hydrophobic head followed by a positively charged protrusion that may be involved in peptide channel-lipid interactions. Furthermore, we suggest that these short peptides may inhibit SAKcaC through a specific modification to the mechanogate, as the inhibitory effects for both types of peptides were mostly abolished when tested with a mechano-insensitive channel variant (STREX-del) and a nonmechanosensitive big potassium (mouse Slo1) channel. These findings may offer an opportunity for the development of a new class of drugs in the treatment of cardiac arrhythmia generated by excitatory SACs in the heart.

IKKα aggravates renal fibrogenesis by positively regulating the Wnt/ß-catenin pathway.

AKI (acute kidney injury) with maladaptive repair plays exacerbated role in renal fibrosis characterized by tubulointerstitial fibrosis. Previously, we reported that IKKα contributed to kidney regeneration and inhibited inflammation. Here, we first identified the role and mechanism of IKKα on TGF-ß1-induced fibrosis in human tubular epithelial cells and fibrotic kidneys. IKKα was up-regulated in kidney tubular epithelium in unilateral ureteral obstruction (UUO) and unilateral ischemic reperfusion injury (UIRI) mice. Immunohistochemical staining showed that IKKα was positively correlated with the extent of kidney fibrosis in tissue biopsies from chronic kidney disease (CKD) patients. Compared with wild-type controls, Ksp-IKKα-/- mice exhibited inactivated Wnt/ß-catenin pathway, decreased serum creatinine and interstitial fibrosis in the kidney after IRI. In TGF-ß1-stimulated human tubular epithelial cells, IKKα overexpression enhanced ß-catenin nuclear translocation. Blocking IKKα by siRNA specifically suppressed ß-catenin activation and downstream profibrotic genes such as fibronectin and α-smooth muscle actin (α-SMA). Taken together, our study demonstrated that IKKα aggravated renal fibrogenesis by activating Wnt/ß-catenin signalling pathway, providing a new target for the treatment of kidney fibrosis.

Inductive Effect on Single-Atom Sites.

Single-atom catalysts exhibit promising electrocatalytic activity, a trait that can be further enhanced through the introduction of heteroatom doping within the carbon skeleton. Nonetheless, the intricate relationship between the doping positions and activity remains incompletely elucidated. This contribution sheds light on an inductive effect of single-atom sites, showcasing that the activity of the oxygen reduction reaction (ORR) can be augmented by reducing the spatial gap between the doped heteroatom and the single-atom sites. Drawing inspiration from this inductive effect, we propose a synthesis strategy involving ligand modification aimed at precisely adjusting the distance between dopants and single-atom sites. This precise synthesis leads to optimized electrocatalytic activity for the ORR. The resultant electrocatalyst, characterized by Fe-N3P1 single-atom sites, demonstrates remarkable ORR activity, thus exhibiting great potential in zinc-air batteries and fuel cells.