Temporal shifts in the phytoplankton network in a large eutrophic shallow freshwater lake subjected to major environmental changes due to human interventions.

Phytoplankton communities are crucial components of aquatic ecosystems, and since they are highly interactive, they always form complex networks. Yet, our understanding of how interactive phytoplankton networks vary through time under changing environmental conditions is limited. Using a 29-year (339 months) long-term dataset on Lake Taihu, China, we constructed a temporal network comprising monthly sub-networks using "extended Local Similarity Analysis" and assessed how eutrophication, climate change, and restoration efforts influenced the temporal dynamics of network complexity and stability. The network architecture of phytoplankton showed strong dynamic changes with varying environments. Our results revealed cascading effects of eutrophication and climate change on phytoplankton network stability via changes in network complexity. The network stability of phytoplankton increased with average degree, modularity, and nestedness and decreased with connectance. Eutrophication (increasing nitrogen) stabilized the phytoplankton network, mainly by increasing its average degree, while climate change, i.e., warming and decreasing wind speed enhanced its stability by increasing the cohesion of phytoplankton communities directly and by decreasing the connectance of network indirectly. A remarkable shift and a major decrease in the temporal dynamics of phytoplankton network complexity (average degree, nestedness) and stability (robustness, persistence) were detected after 2007 when numerous eutrophication mitigation efforts (not all successful) were implemented, leading to simplified phytoplankton networks and reduced stability. Our findings provide new insights into the organization of phytoplankton networks under eutrophication (or re-oligotrophication) and climate change in subtropical shallow lakes.

StreamSAXS: a Python-based workflow platform for processing streaming SAXS/WAXS data.

StreamSAXS is a Python-based small- and wide-angle X-ray scattering (SAXS/WAXS) data analysis workflow platform with graphical user interface (GUI). It aims to provide an interactive and user-friendly tool for analysis of both batch data files and real-time data streams. Users can easily create customizable workflows through the GUI to meet their specific needs. One characteristic of StreamSAXS is its plug-in framework, which enables developers to extend the built-in workflow tasks. Another feature is the support for both already acquired and real-time data sources, allowing StreamSAXS to function as an offline analysis platform or be integrated into large-scale acquisition systems for end-to-end data management. This paper presents the core design of StreamSAXS and provides user cases demonstrating its utilization for SAXS/WAXS data analysis in offline and online scenarios.

The Relationship between physical activity, nutritional status, and sarcopenia in community- dwelling older adults with type 2 diabetes: a cross-sectional study.

AIM: This study was conducted in Urumqi, Xinjiang, to assess the prevalence of sarcopenia and to determine the relationship between physical activity, nutritional status, and sarcopenia among community-dwelling patients with type 2 diabetes mellitus. METHODS: Four hundred eight cases of older people patients with type 2 diabetes mellitus in the community in Urumqi, Xinjiang, from May to August 2022 were selected for a cross-sectional on-site survey, and general information questionnaires, clinical information surveys, physical function measurements, and criteria developed by the Asian sarcopenia working group in 2019 were selected for diagnosis of sarcopenia, and unifactorial and multifactorial binary Logistic regression were applied to analyze the influencing factors of T2DM combined with sarcopenia in patients with sarcopenia. RESULTS: Among the 408 patients, 84 (20.6%) had sarcopenia, with a prevalence of 12.6%, 32.1%, and 51.9% in those aged 60-70, 71- 80, and 81 or older respectively. The prevalence increased significantly with age. Adjusting for variables, the study found that FFM of the Left Leg (OR: 0.710, 95% CI: 0.612-0.804, P = 0.024), FFM of the Right Arm (OR: 0.710, 95% CI: 0.612-0.804, P < 0.001), Age (OR: 1.246, 95% CI: 1.031-1.505, P = 0.023), Fasting Blood Glucose (OR: 1.649, 95% CI: 1.066-2.550, P = 0.025), and Post-Prandial Blood Glucose (OR: 1.455, 95% CI: 0.999-2.118, P = 0.025) were independent associated factors. An increase in MNA score (OR: 0.398, 95% CI: 0.244-0.6500, P < 0.001), ASMI (OR: 0.000, 95% CI: 0.00-0.01, P < 0.001) walking energy expenditure (MET-min) (OR: 0.998, 95% CI: 0.996-0.999, P = 0.001) reduced the prevalence of sarcopenia. CONCLUSION: This study shows that increased age, increased skeletal muscle mass index, decreased right arm FFM, increased postprandial glucose, increased MNA scores, and increased walking energy expenditure (MET-min) were associated with type 2 diabetes with sarcopenia.

The ufmylation cascade controls COPII recruitment, anterograde transport, and sorting of nascent GPCRs at ER.

Ufmylation is implicated in multiple cellular processes, but little is known about its functions and regulation in protein trafficking. Here, we demonstrate that the genetic depletion of core components of the ufmylation cascade, including ubiquitin-fold modifier 1 (UFM1), UFM1 activation enzyme 5, UFM1-specific ligase 1 (UFL1), UFM1-specific protease 2, and UFM1-binding protein 1 (UFBP1) each markedly inhibits the endoplasmic reticulum (ER)-Golgi transport, surface delivery, and recruitment to COPII vesicles of a subset of G protein-coupled receptors (GPCRs) and UFBP1's function partially relies on UFM1 conjugation. We also show that UFBP1 and UFL1 interact with GPCRs and UFBP1 localizes at COPII vesicles coated with specific Sec24 isoforms. Furthermore, the UFBP1/UFL1-binding domain identified in the receptors effectively converts non-GPCR protein transport into the ufmylation-dependent pathway. Collectively, these data reveal important functions for the ufmylation system in GPCR recruitment to COPII vesicles, biosynthetic transport, and sorting at ER via UFBP1 ufmylation and interaction directly.

Enhanced degradation of emerging contaminants by Far-UVC photolysis of peracetic acid: Synergistic effect and mechanisms.

Krypton chloride (KrCl*) excimer lamps (222 nm) are used as a promising irradiation source to drive ultraviolet-based advanced oxidation processes (UV-AOPs) in water treatment. In this study, the UV222/peracetic acid (PAA) process is implemented as a novel UV-AOPs for the degradation of emerging contaminants (ECs) in water. The results demonstrate that UV222/PAA process exhibits excellent degradation performance for carbamazepine (CBZ), with a removal rate of 90.8 % within 45 min. Notably, the degradation of CBZ in the UV222/PAA process (90.8 %) was significantly higher than that in the UV254/PAA process (15.1 %) at the same UV dose. The UV222/PAA process exhibits superior electrical energy per order (EE/O) performance while reducing resource consumption associated with the high-energy UV254/PAA process. Quenching experiments and electron paramagnetic resonance (EPR) detection confirm that HO• play a dominant role in the reaction. The contributions of direct photolysis, HO•, and other active species (RO• and 1O2) are estimated to be 5 %, 88 %, and 7 %, respectively. In addition, the effects of Cl-, HCO3-, and humic acid (HA) on the degradation of CBZ are evaluated. The presence of relatively low concentrations of Cl-, HCO3-, and HA can inhibit CBZ degradation. The UV222/PAA oxidation process could also effectively degrade several other ECs (i.e., iohexol, sulfamethoxazole, acetochlor, ibuprofen), indicating the potential application of this process in pollutant removal. These findings will propel the development of the UV222/PAA process and provide valuable insights for its application in water treatment.

Enhancing dark fermentative hydrogen production from wheat straw through synergistic effects of active electric fields and enzymatic hydrolysis pretreatment.

Hydrogen, a clean and sustainable energy source, faces challenges from energy-intensive pre-processing technologies. This study explores the synergistic enhancement of active electric fields on enzymolysis of wheat straw and hydrogen production through dark fermentation. The active electric field enzymolysis system improved the adsorption capacity of wheat straw to cellulase, increasing cellulase activity by 18.0 %, causing a 39.1 % increase in reducing sugar content. In the active fermentation system, Clostridium_sensu_stricto_1 activity was enhanced in the first stage, increasing hydrogenase activity by 23.0 %, prolonging the first hydrogen production peak. Elevated reducing sugars were observed in the second stage, with Prevotella_9 and Bacteroides becoming the dominant hydrogen-producing bacteria in the third stage, leading to a second hydrogen production peak. Overall, cumulative hydrogen production was enhanced by 50.9 % compared to the control. The synergistic pretreatment with an active electric field and cellulase provides a novel approach for efficiently utilizing wheat straw.

WGCCRR: a web-based tool for genome-wide screening of convergent indels and substitutions of amino acids.

Summary: Genome-wide analyses of proteincoding gene sequences are being employed to examine the genetic basis of adaptive evolution in many organismal groups. Previous studies have revealed that convergent/parallel adaptive evolution may be caused by convergent/parallel amino acid changes. Similarly, detailed analysis of lineage-specific amino acid changes has shown correlations with certain lineage-specific traits. However, experimental validation remains the ultimate measure of causality. With the increasing availability of genomic data, a streamlined tool for such analyses would facilitate and expedite the screening of genetic loci that hold potential for adaptive evolution, while alleviating the bioinformatic burden for experimental biologists. In this study, we present a user-friendly web-based tool called WGCCRR (Whole Genome Comparative Coding Region Read) designed to screen both convergent/parallel and lineage-specific amino acid changes on a genome-wide scale. Our tool allows users to replicate previous analyses with just a few clicks, and the exported results are straightforward to interpret. In addition, we have also included amino acid indels that are usually neglected in previous work. Our website provides an efficient platform for screening candidate loci for downstream experimental tests. Availability and Implementation: The tool is available at: https://fishevo.xmu.edu.cn/.

Development of an atmospheric pressure plasma-based OES device for in-situ mapping of Cd and related elements in plants.

We have developed an innovative optical emission spectrometry imaging device integrating a diode laser for sample introduction and an atmospheric pressure plasma based on dielectric barrier discharge for atomization and excitation. By optimizing the device parameters and ensuring appropriate leaf moisture, we achieved effective imaging with a lateral resolution as low as 50 µm. This device allows for tracking the accumulation of Cd and related species such as K, Zn, and O2+∙, in plant leaves exposed to different Cd levels and culture times. The results obtained are comparable to established in-lab imaging and quantitative methods. With its features of compact construction, minimal sample preparation, ease of operation, and low limit of detection (0.04 µg/g for Cd), this novel methodology shows promise as an in-situ elemental imaging tool for interdisciplinary applications.

Advantages of robot-assisted resection of large mediastinal tumors: a single-center preliminary study.

Current study aims to assess the safety and efficacy of robot-assisted thoracoscopic surgery (RATS) for sizable mediastinal masses with a minimum diameter ≥6 cm, compared with video-assisted thoracoscopic surgery (VATS) and open surgery. This study enrolled 130 patients with mediastinal tumors with no less than 6 cm diameter in Zhongnan Hospital, Wuhan University, including 33 patients who underwent RATS, 52 patients who underwent VATS and 45 patients who underwent open surgery. After classifying based on mass size and whether it has invaded or not, we compared their clinical characteristics and perioperative outcomes. There was no significant difference in age, gender, mass size, myasthenia gravis, mass location, pathological types (p > 0.05) in three groups. Patients undergoing open surgery typically presenting at a more advanced stage (p < 0.05). No obvious difference was discovered in the average postoperative length of stay, operation duration, chest tube duration and average postoperative day 1 drainage output between RATS group and VATS group (p > 0.05), while intraoperative blood loss in RATS group was significantly lower than VATS group (p = 0.046). Moreover, the postoperative length of stay, operation duration, chest tube duration and intraoperative blood loss in RATS group were significantly lower than open surgery group (p < 0.001). RATS is a secure and efficient approach for removing large mediastinal masses at early postoperative period. In comparison with VATS, RATS is associated with lower intraoperative blood loss. Compared with open surgery, RATS is also associated with shorter postoperative length of stay, operation duration, chest tube duration and intraoperative blood loss.

D-mannose alleviates intervertebral disc degeneration through glutamine metabolism.

BACKGROUND: Intervertebral disc degeneration (IVDD) is a multifaceted condition characterized by heterogeneity, wherein the balance between catabolism and anabolism in the extracellular matrix of nucleus pulposus (NP) cells plays a central role. Presently, the available treatments primarily focus on relieving symptoms associated with IVDD without offering an effective cure targeting its underlying pathophysiological processes. D-mannose (referred to as mannose) has demonstrated anti-catabolic properties in various diseases. Nevertheless, its therapeutic potential in IVDD has yet to be explored. METHODS: The study began with optimizing the mannose concentration for restoring NP cells. Transcriptomic analyses were employed to identify the mediators influenced by mannose, with the thioredoxin-interacting protein (Txnip) gene showing the most significant differences. Subsequently, small interfering RNA (siRNA) technology was used to demonstrate that Txnip is the key gene through which mannose exerts its effects. Techniques such as colocalization analysis, molecular docking, and overexpression assays further confirmed the direct regulatory relationship between mannose and TXNIP. To elucidate the mechanism of action of mannose, metabolomics techniques were employed to pinpoint glutamine as a core metabolite affected by mannose. Next, various methods, including integrated omics data and the Gene Expression Omnibus (GEO) database, were used to validate the one-way pathway through which TXNIP regulates glutamine. Finally, the therapeutic effect of mannose on IVDD was validated, elucidating the mechanistic role of TXNIP in glutamine metabolism in both intradiscal and orally treated rats. RESULTS: In both in vivo and in vitro experiments, it was discovered that mannose has potent efficacy in alleviating IVDD by inhibiting catabolism. From a mechanistic standpoint, it was shown that mannose exerts its anti-catabolic effects by directly targeting the transcription factor max-like protein X-interacting protein (MondoA), resulting in the upregulation of TXNIP. This upregulation, in turn, inhibits glutamine metabolism, ultimately accomplishing its anti-catabolic effects by suppressing the mitogen-activated protein kinase (MAPK) pathway. More importantly, in vivo experiments have further demonstrated that compared with intradiscal injections, oral administration of mannose at safe concentrations can achieve effective therapeutic outcomes. CONCLUSIONS: In summary, through integrated multiomics analysis, including both in vivo and in vitro experiments, this study demonstrated that mannose primarily exerts its anti-catabolic effects on IVDD through the TXNIP-glutamine axis. These findings provide strong evidence supporting the potential of the use of mannose in clinical applications for alleviating IVDD. Compared to existing clinically invasive or pain-relieving therapies for IVDD, the oral administration of mannose has characteristics that are more advantageous for clinical IVDD treatment.

Advancing two-stage hydrogen production from corn stover via dark fermentation: Contributions of thermally modified maifanite to microbial proliferation and pH self-regulation.

This study introduces a two-stage hydrogen production enhancement mechanism using natural particle additives, with a focus on the effects of thermally modified maifanite (TMM) and pH self-regulation on dark fermentation (DF). Initial single-factor experiments identified preliminary parameters for the addition of TMM, which were further optimized using a Box-Behnken design. The established optimal conditions which include mass of 5.5 g, particle size of 120 mesh, and temperature of 324 °C, resulted in a 28.7 % increase in cumulative hydrogen yield (CHY). During the primary hydrogen production stage, TMM significantly boosted the growth and activity of Clostridium_sensu_stricto_1, enhancing hydrogen output. Additionally, a pH self-regulating phenomenon was observed, capable of initiating secondary hydrogen production and further augmenting CHY. These findings presented a novel and efficient approach for optimizing biohydrogen production, offering significant implications for future research and application in sustainable energy technologies.

A step towards 6D WAXD tensor tomography.

X-ray scattering/diffraction tensor tomography techniques are promising methods to acquire the 3D texture information of heterogeneous biological tissues at micrometre resolution. However, the methods suffer from a long overall acquisition time due to multi-dimensional scanning across real and reciprocal space. Here, a new approach is introduced to obtain 3D reciprocal information of each illuminated scanning volume using mathematic modeling, which is equivalent to a physical scanning procedure for collecting the full reciprocal information required for voxel reconstruction. The virtual reciprocal scanning scheme was validated by a simulated 6D wide-angle X-ray diffraction tomography experiment. The theoretical validation of the method represents an important technological advancement for 6D diffraction tensor tomography and a crucial step towards pervasive applications in the characterization of heterogeneous materials.

Estimating the prevalence of depression in people with acute coronary syndromes: A systematic review and meta-analysis.

BACKGROUND: The epidemic of acute coronary syndromes (ACS) poses a great challenge to depression. However, the prevalence of depression among ACS patients has not been fully determined. This meta-analysis aimed to provide an estimation of the global prevalence of depression among ACS patients (ACS depression). METHODS: Online databases including PubMed, Cochrane Library, Web of Science, and Scopus were searched for all relevant studies that reported the prevalence of ACS depression through March 2023. Pooled prevalence of ACS depression with 95% confidence interval (CI) was estimated by the random-effect model. All statistical analyses were performed using comprehensive meta-analysis software. This review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (identifier CRD42023409338). RESULTS: A total of 28 studies (17 cohort studies, 9 cross-sectional studies, and 2 case-control studies) were included. The overall pooled prevalence of depression in ACS, derived from 28 studies, was 28.5% (95% CI: 0.28-0.29, P = .000, I2 = 99%). 21 included studies showed a prevalence of 20.3% (95% CI: 0.20-0.21, P = .000, I2 = 96%) in men, and the prevalence in women was 13.6% (95% CI: 0.13-0.14, P = .000, I2 = 95%). Subgroup analysis showed the lowest prevalence in Europe (20.7%, 95% CI: 0.20-0.22, P = .000, I2 = 98%); On different diagnostic criteria, the diagnostic and statistical manual of mental disorders (DSM-IV) (36.8%, 95% CI: 0.35-0.38, P = .000, I2 = 96%) has the highest prevalence. In terms of end year of data collection, the prevalence of ACS depression was lower for studies that ended data collection after 2012 (25.7%, 95% CI: 0.25-0.27, P = .000, I2 = 99%) than in studies before 2012 (30%, 95% CI: 0.29-0.31, P = .000, I2 = 98%). CONCLUSION SUBSECTIONS: This systematic review and meta-analysis suggest high global prevalence of depression among ACS patients, underlining the necessity of more preventive interventions among ACS patients especially in Asian and North American regions.

Identification of Differentially Expressed Genes in Cold Storage-associated Kidney Transplantation.

BACKGROUND: Although it is acknowledged that ischemia-reperfusion injury is the primary pathology of cold storage-associated kidney transplantation, its underlying mechanism is not well elucidated. METHODS: To extend the understanding of molecular events and mine hub genes posttransplantation, we performed bulk RNA sequencing at different time points (24 h, day 7, and day 14) on a murine kidney transplantation model with prolonged cold storage (10 h). RESULTS: In the present study, we showed that genes related to the regulation of apoptotic process, DNA damage response, cell cycle/proliferation, and inflammatory response were steadily elevated at 24 h and day 7. The upregulated gene profiling delicately transformed to extracellular matrix organization and fibrosis at day 14. It is prominent that metabolism-associated genes persistently took the first place among downregulated genes. The gene ontology terms of particular note to enrich are fatty acid oxidation and mitochondria energy metabolism. Correspondingly, the key enzymes of the above processes were the products of hub genes as recognized. Moreover, we highlighted the proximal tubular cell-specific increased genes at 24 h by combining the data with public RNA-Seq performed on proximal tubules. We also focused on ferroptosis-related genes and fatty acid oxidation genes to show profound gene dysregulation in kidney transplantation. CONCLUSIONS: The comprehensive characterization of transcriptomic analysis may help provide diagnostic biomarkers and therapeutic targets in kidney transplantation.

Optimization method for human-robot command combinations of hexapod robot based on multi-objective constraints.

Due to the heavy burden on human drivers when remotely controlling hexapod robots in complex terrain environments, there is a critical need for robot intelligence to assist in generating control commands. Therefore, this study proposes a mapping process framework that generates a combination of human-robot commands based on decision target values, focusing on the task of robot intelligence assisting drivers in generating human-robot command combinations. Furthermore, human-robot state constraints are quantified as geometric constraints on robot motion and driver fatigue constraints. By optimizing and filtering the feasible set of human-robot commands based on human-robot state constraints, instruction combinations are formed and recommended to the driver in real-time, thereby enhancing the efficiency and safety of human-machine coordination. To validate the effectiveness of the proposed method, a remote human-robot collaborative driving control system based on wearable devices is designed and implemented. Experimental results demonstrate that drivers utilizing the human-robot command recommendation system exhibit significantly improved robot walking stability and reduced collision rates compared to individual driving.

JMJD3 activation contributes to renal protection and regeneration following acute kidney injury in mice.

We have recently demonstrated that Jumonji domain-containing protein D3 (JMJD3), a histone demethylase of histone H3 on lysine 27 (H3K27me3), is protective against renal fibrosis, but its role in acute kidney injury (AKI) remains unexplored. Here, we report that JMJD3 activity is required for renal protection and regeneration in murine models of AKI induced by ischemia/reperfusion (I/R) and folic acid (FA). Injury to the kidney upregulated JMJD3 expression and induced expression of H3K27me3, which was coincident with renal dysfunction, renal tubular cell injury/apoptosis, and proliferation. Blocking JMJD3 activity by GSKJ4 led to worsening renal dysfunction and pathological changes by aggravating tubular epithelial cell injury and apoptosis in both murine models of AKI. JMJD3 inhibition by GSKJ4 also reduced renal tubular cell proliferation and suppressed expression of cyclin E and phosphorylation of CDK2, but increased p21 expression in the injured kidney. Furthermore, inactivation of JMJD3 enhanced I/R- or FA-induced expression of TGF-ß1, vimentin, and Snail, phosphorylation of Smad3, STAT3, and NF-κB, and increased renal infiltration by F4/80 (+) macrophages. Finally, GSKJ4 treatment caused further downregulation of Klotho, BMP-7, Smad7, and E-cadherin, all of which are associated with renal protection and have anti-fibrotic effects. Therefore, these data provide strong evidence that JMJD3 activation contributes to renal tubular epithelial cell survival and regeneration after AKI.

Corrigendum: Persistent activation of autophagy after cisplatin nephrotoxicity promotes renal fibrosis and chronic kidney disease.

[This corrects the article DOI: 10.3389/fphar.2022.918732.].

Hypermethylation leads to the loss of HOXA5, resulting in JAG1 expression and NOTCH signaling contributing to kidney fibrosis.

Epigenetic regulations, including DNA methylation, are critical to the development and progression of kidney fibrosis, but the underlying mechanisms remain elusive. Here, we show that fibrosis of the mouse kidney was associated with the induction of DNA methyltransferases and increases in global DNA methylation and was alleviated by the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-Aza). Genome-wide analysis demonstrated the hypermethylation of 94 genes in mouse unilateral ureteral obstruction kidneys, which was markedly reduced by 5-Aza. Among these genes, Hoxa5 was hypermethylated at its gene promoter, and this hypermethylation was associated with reduced HOXA5 expression in fibrotic mouse kidneys after ureteral obstruction or unilateral ischemia-reperfusion injury. 5-Aza prevented Hoxa5 hypermethylation, restored HOXA5 expression, and suppressed kidney fibrosis. Downregulation of HOXA5 was verified in human kidney biopsies from patients with chronic kidney disease and correlated with the increased kidney fibrosis and DNA methylation. Kidney fibrosis was aggravated by conditional knockout of Hoxa5 and alleviated by conditional knockin of Hoxa5 in kidney proximal tubules of mice. Mechanistically, we found that HOXA5 repressed Jag1 transcription by directly binding to its gene promoter, resulting in the suppression of JAG1-NOTCH signaling during kidney fibrosis. Thus, our results indicate that loss of HOXA5 via DNA methylation contributes to fibrogenesis in kidney diseases by inducing JAG1 and consequent activation of the NOTCH signaling pathway.

Identification of TACSTD2 as novel therapeutic targets for cisplatin-induced acute kidney injury by multi-omics data integration.

Cisplatin-induced acute kidney injury (CP-AKI) is a common complication in cancer patients. Although ferroptosis is believed to contribute to the progression of CP-AKI, its mechanisms remain incompletely understood. In this study, after initially processed individual omics datasets, we integrated multi-omics data to construct a ferroptosis network in the kidney, resulting in the identification of the key driver TACSTD2. In vitro and in vivo results showed that TACSTD2 was notably upregulated in cisplatin-treated kidneys and BUMPT cells. Overexpression of TACSTD2 accelerated ferroptosis, while its gene disruption decelerated ferroptosis, likely mediated by its potential downstream targets HMGB1, IRF6, and LCN2. Drug prediction and molecular docking were further used to propose that drugs targeting TACSTD2 may have therapeutic potential in CP-AKI, such as parthenolide, progesterone, premarin, estradiol and rosiglitazone. Our findings suggest a significant association between ferroptosis and the development of CP-AKI, with TACSTD2 playing a crucial role in modulating ferroptosis, which provides novel perspectives on the pathogenesis and treatment of CP-AKI.

Enhanced STAT3/PIK3R1/mTOR signaling triggers tubular cell inflammation and apoptosis in septic-induced acute kidney injury: implications for therapeutic intervention.

Septic acute kidney injury (AKI) is a severe form of renal dysfunction associated with high morbidity and mortality rates. However, the pathophysiological mechanisms underlying septic AKI remain incompletely understood. Herein, we investigated the signaling pathways involved in septic AKI using the mouse models of lipopolysaccharide (LPS) treatment and cecal ligation and puncture (CLP). In these models, renal inflammation and tubular cell apoptosis were accompanied by the aberrant activation of the mechanistic target of rapamycin (mTOR) and the signal transducer and activator of transcription 3 (STAT3) signaling pathways. Pharmacological inhibition of either mTOR or STAT3 significantly improved renal function and reduced apoptosis and inflammation. Interestingly, inhibition of STAT3 with pharmacological inhibitors or small interfering RNA blocked LPS-induced mTOR activation in renal tubular cells, indicating a role of STAT3 in mTOR activation. Moreover, knockdown of STAT3 reduced the expression of the phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1/p85α), a key subunit of the phosphatidylinositol 3-kinase for AKT and mTOR activation. Chromatin immunoprecipitation assay also proved the binding of STAT3 to PIK3R1 gene promoter in LPS-treated kidney tubular cells. In addition, knockdown of PIK3R1 suppressed mTOR activation during LPS treatment. These findings highlight the dysregulation of mTOR and STAT3 pathways as critical mechanisms underlying the inflammatory and apoptotic phenotypes observed in renal tubular cells during septic AKI, suggesting the STAT3/ PIK3R1/mTOR pathway as a therapeutic target of septic AKI.