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Sepsis-associated encephalopathy (SAE) is a severe complication that affects the central nervous system and is a leading cause of increased morbidity and mortality in intensive care units. Psoralidin (PSO), a coumarin compound isolated from the traditional Chinese medicine Psoralea corylifolia L., can penetrate the blood-brain barrier and has various pharmacological activities, including anti-inflammation, anti-oxidation and anti-depression. This study aims to explore whether PSO alleviates SAE and delve into the underlying mechanisms. We found that PSO treatment significantly reduced sepsis scores, aspartate transaminase (AST) and aspartate transaminase (LDH), while increased anal temperature and neurological scores in CLP-injured mice. Moreover, PSO treatment ameliorated sepsis-associated cognitive impairment, mood, anxiety disorders, inhibited inflammatory responses, as well as attenuated endoplasmic reticulum stress (ERS). These results were also validated in vitro experiments, PSO treatment reduced ROS, inflammation response, and attenuated ERS in LPS-injured N2a cells. Importantly, tunicamycin (TUN), as ERS agonist, significantly reversed the protective effect of PSO on LPS-injured N2a cells, as evidenced by increased expression levels of IL-6, NLRP3, CHOP, and ATF6. Likewise, ATF6 overexpression also reversed the protective effect of PSO. In conclusion, these results confirmed that PSO has a protective effect on SAE, which was largely attributed to neuroinflammation and ERS. These findings provide new insights into the neuroprotective role of PSO and suggest that PSO is a new therapeutic intervention of SAE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The stability of aqueous zinc metal batteries is significantly affected by side reactions and dendrite growth on the anode interface, which primarily originate from water and anions. Herein, we introduce a multi H-bond site additive, 2, 2'-Sulfonyldiethanol (SDE), into an aqueous electrolyte to construct a sieving-type electric double layer (EDL) by hydrogen bond interlock in order to address these issues. On the one hand, SDE replaces H2O and SO42- anions that are adsorbed on the zinc anode surface, expelling H2O/SO42- from the EDL and thereby reducing the content of H2O/SO42- at the interface. On the other hand, when Zn2+ are de-solvated at the interface during the plating, the strong hydrogen bond interaction between SDE and H2O/SO42- can trap H2O/SO42- from the EDL, further decreasing their content at the interface. This effectively sieves them out of the zinc anode interface and inhibits the side reactions. Moreover, the unique characteristics of trapped SO42- anions can restrict their diffusion, thereby enhancing the transference number of Zn2+ and promoting dendrite-free deposition and growth of Zn. Consequently, utilizing an SDE/ZnSO4 electrolyte enables excellent cycling stability in Zn//Zn symmetrical cells and Zn//MnO2 full cells with lifespans exceeding 3500 h and 2500 cycles respectively., (© 2024 Wiley‐VCH GmbH.)

A novel Ir-Mn dual-atom electrocatalyst is synthesized by a facile ion-exchange method by incorporating Ir in SrMnO3, which yields an extremely high activity and stability for the oxygen evolution reaction (OER). The ion exchange process occurs in a self-limitation way, which favors the formation of Ir-Mn dual-atom in the IrMnO9 unit. The incorporation of Ir modulates the electronic structure of both Ir and Mn, thereby resulting in a shorter distance of the Ir-Mn dual-atom (2.41 Å) than the Mn-Mn dual-atom (2.49 Å). The modulated Ir-Mn dual-atom enables the same spin direction O (↑) of the adsorbed *O intermediates, thus facilitating the direct coupling of the two adsorbed *O intermediates to release O2 via the oxygen-oxygen radical coupling mechanism. Electrochemical tests reveal that the Ir-SrMnO3 exhibits a superior OER's activity with a low overpotential of 207 mV at 10 mA cm-2 and achieves a mass specific activity of 1100 A gIr-1 at 1.5 V. The proton-exchange-membrane water electrolyzer with the Ir-SrMnO3 catalyst exhibits a low electrolysis voltage of 1.63 V at 1.0 A cm-2 and a stable 2000-h operation with a decay of only 15 μV h-1 at 0.5 A cm-2., (© 2024 Wiley‐VCH GmbH.)

Fast-charging capability and calendar life are critical metrics in rechargeable batteries, especially in silicon-based batteries that are susceptible to sluggish Li+ desolvation kinetics and HF-induced corrosion. No existing electrolyte simultaneously tackles both these pivotal challenges. Here we report a microscopically heterogeneous covalent organic nanosheet (CON) colloid electrolyte for extremely fast-charging and long-calendar-life Si-based lithium-ion batteries. Theoretical calculations and operando Raman spectroscopy reveal the fundamental mechanism of the multiscale noncovalent interaction, which involves the mesoscopic CON attenuating the microscopic Li+-solvent coordination, thereby expediting the Li+ desolvation kinetics. This electrolyte design enables extremely fast-charging capabilities of the full cell, both at 8C (83.1% state of charge) and 10C (81.3% state of charge). Remarkably, the colloid electrolyte demonstrates record-breaking cycling performance at 10C (capacity retention of 92.39% after 400 cycles). Moreover, benefiting from the robust adsorption capability of mesoporous CON towards HF and water, a notable improvement is observed in the calendar life of the full cell. This study highlights the role of microscopically heterogeneous colloid electrolytes in enhancing the fast-charging capability and calendar life of Si-based Li-ion batteries. Our work offers fresh perspectives on electrolyte design with multiscale interactions, providing insightful guidance for the development of alkali-ion/metal batteries operating under harsh environments., (© 2024 Wiley‐VCH GmbH.)

Background: Transanal total mesorectal excision has emerged as a potential solution to certain limitations associated with laparoscopic total mesorectal excision in rectal cancer patients. Differences in surgical approaches have raised questions regarding their impact on the risk of postoperative urinary retention, with limited data available from large scale randomized clinical study., Objective: To report incidence of postoperative urinary retention and evaluate the associated risk factors for transanal total mesorectal excision., Design: In this randomized controlled trial (ClinicalTrials. gov NCT06147492), we retrieved 524 patients who received total mesorectal excision (TME) for stage I-III rectal cancer between June 2019 and April 2022, and the patients were randomly assigned in a 1:1 ratio to undergo either taTME or laTME., Patients: We enrolled 524 patients who underwent total mesorectal excision for stage I-III rectal cancer between June 2019 and April 2022., Main Outcome Measures: The incidence of postoperative urinary retention., Results: Among the 524 enrolled patients, 261 were randomized to the laTME group, while 263 were were randomized the taTME group. The median age was 58 years, and 340 participants (64.8 %) were male. Notably, 37 individuals (7.0 %) experienced postoperative urinary retention during the follow-up period, with no significant disparity was observed between the taTME and laTME groups (6.8 % and 7.2 %, respectively, P  = 0.98). Risk factors associated with PUR in patients following taTME encompassed early removal of the urinary catheter ( P  = 0.006), net infusion rate >4.09 ml kg -1 .h -1 ( P  = 0.006), and an age surpassing 65 years ( P  = 0.0321)., Limitations: The generalizability of the findings outside specialist rectal cancer centers may be limited ., Conclusions: Transanal total mesorectal excision was not found to heighten the risk of postoperative urinary retention. Nonetheless, it is advisable removing postoperative catheter beyond the initial day and exercising caution in the administration of intravenous fluids in clinical practice for taTME procedures., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

In view of a catalyst layer (CL) with low-Pt causing higher local transport resistance of O 2 (R local ), we propose a multi-study methodology that combines CO poisoning, the limiting current density method, and electrochemical impedance spectroscopy to reveal how real CL interfaces dominate R local . Experimental results indicate that the ionomer is not evenly distributed on the catalyst surface, and the uniformity of ionomer distribution does not show a positive correlation with the ionomer content. When the ionomer coverage on the supported catalyst surface is below 20 %, the ECSA is only 10 m 2 ·g -1 , and the ionomer coverage on the supported catalyst surface reaches 60 %, the ECSA is close to 40 m 2 ·g -1 . The ECSA has a positive correlation with ionomer coverage. Because the ECSA is measured by CO poisoning, it can be inferred that the platinum contacted with ionomer can generate effective active sites. Furthermore, a more uniform distribution of ionomer can create additional proton transport channels and reduce the distance for oxygen transport from the catalyst layer bulk to the active sites. A higher ECSA and a shorter distance for oxygen transport will reduce the R local , leading to better performance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The oncological safety of transanal total mesorectal excision (taTME) remains uncertain, and its special surgical approach may contribute to tumor cell dissemination. Thus, we conducted a study to investigate the impact of surgical approach on circulating tumor cell (CTC) counts and phenotypes in rectal cancer., Methods: This is a prospective randomized controlled study (ClinicalTrials: NCT05109130). The patients were randomized to either the taTME ( n  =   49) or laparoscopic TME (laTME) ( n  =   48) groups. Blood samples were collected from the central vein to measure CTC counts and phenotypes at three time points: preoperative (t1), immediately post-tumor removal (t2), and one week post-surgery (t3). The effect of surgical procedure on CTCs at each time point was analyzed, with the primary endpoint being the change in CTC counts from t1 to t3 for each surgical approach. This study adheres to Consolidated Standards of Reporting Trials Guidelines., Results: The baseline clinicopathologic characteristics of the laTME and taTME groups were balanced. The change in CTC count from t1 to t3 was 1.81 ± 5.66 in the laTME group and 2.18 ± 5.53 in the taTME group. The taTME surgery was non-inferior to laTME in terms of changing CTC counts (mean difference [MD]: -0.371; 95% confidence interval [CI]: -2.626 to 1.883, upper-sided 95% CI of 1.883 < 2, non-inferiority boundary value). Compared with that at t1, the CTC count at t2 did not change significantly. However, higher CTC counts were detected at t3 than at t2 in the taTME ( P  =   0.032) and laTME ( P  =   0.003) groups. From t1 to t3, CTC counts significantly increased in both the taTME ( P  =   0.008) and laTME ( P  =   0.031) groups. There were no significant differences in CTC phenotype changes between the two groups from t1 to t3., Conclusions: Compared with laTME, taTME did not affect CTC counts and phenotypes. Our findings indicate that taTME is not inferior to laTME in terms of CTC changes from an oncological perspective., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

Quasi-solid polymer electrolyte (QPE) lithium (Li)-metal battery holds significant promise in the application of high-energy-density batteries, yet it suffers from low ionic conductivity and poor oxidation stability. Herein, a novel self-built electric field (SBEF) strategy is proposed to enhance Li + transportation and accelerate the degradation dynamics of carbon-fluorine bond cleavage in LiTFSI by optimizing the termination of MXene. Among them, the SBEF induced by dielectric Nb 4 C 3 F 2 MXene effectively constructs highly conductive LiF-enriched SEI and CEI stable interfaces, moreover, enhances the electrochemical performance of the QPE. The related Li-ion transfer mechanism and dual-reinforced stable interface are thoroughly investigated using ab initio molecular dynamics, COMSOL, XPS depth profiling, and ToF-SIMS. This comprehensive approach results in a high conductivity of 1.34 mS cm -1 , leading to a small polarization of approximately 25 mV for Li//Li symmetric cell after 6000 h. Furthermore, it enables a prolonged cycle life at a high voltage of up to 4.6 V. Overall, this work not only broadens the application of MXene for QPE but also inspires the great potential of the self-built electric field in QPE-based high-voltage batteries., (© 2024 Wiley-VCH GmbH.)

The performance of thin lithium metal anodes is affected due to issues that weaken the electrode-electrolyte interphase. In this work, a coating layer serving as a Li + traffic controller based on hexadecyl trimethyl ammonium bis(trifluoromethanesulphonyl)imide ([CTA][TFSI]) and poly (vinylidene difluoride co-hexafluoropropylene) (P(VDF-HFP)) is used to stabilize the thin lithium metal interface. The CTA + ions in the coating layer can effectively regulate the distribution of Li + concentration to promote uniform deposition of lithium. The anion of [CTA][TFSI] can optimize solid electrolyte interphase (SEI) with inorganic-rich components, which improve the ionic conductivity and reaction kinetics. Furthermore, the flexible polymer skeleton can fortify the fragile SEI, facilitating the consistent operation of the battery. Due to these improvements, a thin Li metal anode (4 mAh cm -2 ) with a coating layer in a Li||Li symmetric cell demonstrates a lifespan of 600 h at 1 mA cm -2 and 1 mAh cm -2 . Notably, full cells with an ultra-low negative electrode/positive electrode = 1 (N/P = 1) demonstrate a stable performance over 200 cycles and 90 cycles at 0.5C and 1C (1C = 170 mA g -1 ), respectively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Aim: Neoadjuvant treatments (nCRT) are becoming the standard treatment for patients with stage II or III mid-low rectal cancer. Recently, some studies have shown that surgery alone may be sufficient for patients with T3 rectal cancer. This raises the question of whether nCRT is necessary for all patients with T3 rectal cancer. Therefore, this study compared the clinical outcomes of patients with MRI-defined T3, clear MRF mid-low rectal cancer treated with surgery alone (TME group) or nCRT followed by surgery (nCRT + TME group)., Methods: A total of 1509 patients were enrolled in this study. After a 1:1 propensity score matching analysis, 480 patients were included in each group. The primary endpoint was 3-year disease-free survival (DFS). The secondary endpoints included the perioperative outcomes, histopathologic outcomes, and other follow-up outcomes., Results: nCRT had advantages in rates of sphincter-preserving surgery and tumor downstaging, but it was accompanied by a higher rate of enterostomies. At 3 years after surgery, local recurrence occurred in 3.3% of patients in the TME group and in 3.5% of patients in the nCRT + TME group (P = 0.914), the DFS rates were 78.3% in the TME group and 75.3% in the nCRT + TME group (P = 0.188), and the overall survival rates were 90.3% in the TME group and 89.9% in the nCRT + TME group (P = 0.776)., Conclusions: Surgery alone versus nCRT followed by surgery may provide similar long-term oncological outcomes for patients with MRI-defined T3, clear MRF, and mid-low rectal cancer. nCRT may cause overtreatment in some patients., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Introduction: Myocardial ischemia-reperfusion (IR) injury is a common medical issue contributing to the onset and progression of ischemic heart diseases (IHD). Growth arrest-specific gene 6 (GAS6), a vitamin K-dependent secretory protein, promotes cell proliferation and inhibits inflammation and apoptosis through binding with Tyro3, Axl, and Mertk (TAM) receptors., Objectives: Our study aimed to examine the effect of GAS6 pathways activation as a potential new treatment in myocardial IR injury., Methods: Gain- and loss-of-function experiments were utilized to determine the roles of GAS6 in the pathological processes of myocardial IR injury., Results: Our results revealed down-regulated levels of GAS6, Axl, and SIRT1 in murine hearts subjected to IR injury, and cardiomyocytes challenged with hypoxia reoxygenation (HR) injury. GAS6 overexpression significantly improved cardiac dysfunction in mice subjected to myocardial IR injury, accompanied by reconciled mitochondrial dysfunction, oxidative stress, and apoptosis. In vitro experiments also observed a protective effect of GAS6 in cardiomyocytes. SIRT1 was found to function as a downstream regulator for GAS6/Axl signaling axis. Through screening a natural product library, a polyphenol natural compound catechin was identified to exhibit a protective effect by turning on GAS6/Axl-SIRT1 cascade., Conclusions: Together, our findings indicate that GAS6 emerges as a potential novel target in the management of myocardial IR injury and other related anomalies., (Copyright © 2023. Production and hosting by Elsevier B.V.)

Background: Researchers have previously reported that mitochondrial DNA copy number (mtDNA-CN) can play different roles in microsatellite instable/mismatch repair-deficient (MSI/dMMR) and microsatellite stable/mismatch repair-proficient (MSS/pMMR) colorectal cancer (CRC). To support malignancy, dMMR CRC relies on glycolysis, while pMMR CRC favors oxidative phosphorylation. However, it is unclear whether mtDNA-CN changes are related to T cell infiltration in CRC., Methods: The mtDNA-CN was detected by qRT-PCR in 532 patients, and the expression of CD3 and CD8 in 485 patients was detected by immunohistochemistry. The correlation between mtDNA-CN and the prognosis of CRC patients was further analyzed, and the correlation between mtDNA-CN and T lymphocyte infiltration was also analyzed. Biopsy specimens from the immune checkpoint inhibitors (ICIs) treatment cohort were obtained to verify the correlation between mtDNA-CN and the efficacy of ICIs. The effects of mtDNA-CN and MMR status on gene expression were analyzed by RNA-seq., Results: Our results show that mtDNA-CN has inverse relationships to CRC prognosis in cases with different MMR statuses, potentially inducing the U-shaped association in CRC. The opposing correlations between mtDNA-CN and T lymphocyte infiltration in cases of dMMR CRC and pMMR CRC further suggest that mtDNA-CN might play an important role in CRC development. More importantly, cases of pMMR CRC with lower mtDNA-CN and of dMMR CRC with higher mtDNA-CN can benefit more dramatically from ICIs. Furthermore, RNA-seq revealed a link between the level of mtDNA-CN and T lymphocyte infiltration in CRC cases with different MMR statuses., Conclusion: Our study found a potential relationship between mtDNA-CN and CRC development that differs by MMR status, potentially providing a rationale for the use of mtDNA-CN as both a predictive biomarker and a therapeutic target for ICIs., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family (PGC-1s), consisting of three members encompassing PGC-1α, PGC-1β, and PGC-1-related coactivator (PRC), was discovered more than a quarter-century ago. PGC-1s are essential coordinators of many vital cellular events, including mitochondrial functions, oxidative stress, endoplasmic reticulum homeostasis, and inflammation. Accumulating evidence has shown that PGC-1s are implicated in many diseases, such as cancers, cardiac diseases and cardiovascular diseases, neurological disorders, kidney diseases, motor system diseases, and metabolic disorders. Examining the upstream modulators and co-activated partners of PGC-1s and identifying critical biological events modulated by downstream effectors of PGC-1s contribute to the presentation of the elaborate network of PGC-1s. Furthermore, discussing the correlation between PGC-1s and diseases as well as summarizing the therapy targeting PGC-1s helps make individualized and precise intervention methods. In this review, we summarize basic knowledge regarding the PGC-1s family as well as the molecular regulatory network, discuss the physio-pathological roles of PGC-1s in human diseases, review the application of PGC-1s, including the diagnostic and prognostic value of PGC-1s and several therapies in pre-clinical studies, and suggest several directions for future investigations. This review presents the immense potential of targeting PGC-1s in the treatment of diseases and hopefully facilitates the promotion of PGC-1s as new therapeutic targets., (© 2024. The Author(s).)

Objectives: Emerging evidence has demonstrated that tumour budding (TB) is negatively associated with T-lymphocyte infiltration in CRC. Despite extensive research, the molecular characteristics of immunologically 'hot' TB remain poorly understood., Methods: We quantified the number of TB by haematoxylin-eosin (H&E) sections and the densities of CD3 + and CD8 + T-lymphocytes by immunohistochemistry in a CRC cohort of 351 cases who underwent curative resection. We analysed the differential expression and T-lymphocyte infiltration score of 37 human epithelial keratins in CRC using RNA sequencing from the TCGA dataset. In 278 TB-positive cases, KRT17 expression was evaluated in tumour centre (TC) and TB with a staining score. Patient demographic, clinicopathological features and survival rates were analysed., Results: In a CRC cohort of 351 cases, low-grade TB was associated with high CD3 + and CD8 + T-cell densities in the invasive margin (IM) but not in the TC. Of 37 human epithelial keratins, only KRT17 expression in TB had an apparent association with TB-grade and T-lymphocyte infiltration. In 278 TB-positive cases, high KRT17 expression in TB (KRT17TB) was negatively associated with low-grade TB and positively associated with high CD3 + and CD8 + T-cell densities in IM. High KRT17TB predicted early tumour grade, absence of lymph node metastasis and absence of tumour deposits. Additionally, patients with high KRT17TB had good overall survival and disease-free survival. Notably, low KRT17TB can specifically identify those patients with a poor prognosis among colorectal cancer patients with low TB and high T-lymphocyte infiltration., Conclusions: KRT17 can be employed as a new indicator for distinguishing different immunological TBs., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Mutant KRAS (KRAS MUT ) is often exploited by cancers to shape tumor immunity, but the underlying mechanisms are not fully understood. Here we report that tumor-specific cytotoxic T lymphocytes (CTLs) from KRAS MUT cancers are sensitive to activation-induced cell death (AICD). circATXN7, an NF-κB-interacting circular RNA, governs T cell sensitivity to AICD by inactivating NF-κB. Mechanistically, histone lactylation derived from KRAS MUT tumor cell-produced lactic acid directly activates transcription of circATXN7, which binds to NF-κB p65 subunit and masks the p65 nuclear localization signal motif, thereby sequestering it in the cytoplasm. Clinically, circATXN7 upregulation in tumor-specific CTLs correlates with adverse clinical outcomes and immunotherapeutic resistance. Genetic ablation of circAtxn7 in CD8 + T cells leads to mutant-selective tumor inhibition, while also increases anti-PD1 efficacy in multiple tumor models in female mice. Furthermore, targeting circATXN7 in adoptively transferred tumor-reactive CTLs improves their antitumor activities. These findings provide insight into how lymphocyte-expressed circRNAs contribute to T-cell fate decisions and anticancer immunotherapies., (© 2024. The Author(s).)

Background: Macrophage (Mφ) activation plays a critical role in the inflammatory response. Activated Mφ go through profound reprogramming of cellular metabolism. However, changes in their intracellular energy metabolism and its effect on inflammatory responses in Crohn's disease (CD) remain currently unclear. The aim of this study is to explore metabolic signatures of CD14+ Mφ and their potential role in CD pathogenesis as well as the underlying mechanisms., Methods: CD14+ Mφ were isolated from peripheral blood or intestinal tissues of CD patients and control subjects. Real-time flux measurements and enzyme-linked immunosorbent assay were used to determine the inflammatory states of Mφ and metabolic signatures. Multiple metabolic routes were suppressed to determine their relevance to cytokine production., Results: Intestinal CD14+ Mφ in CD patients exhibited activated glycolysis compared with those in control patients. Specifically, macrophagic glycolysis in CD largely induced inflammatory cytokine release. The intestinal inflammatory microenvironment in CD elicited abnormal glycolysis in Mφ. Mechanistically, CD14+ Mφ derived exosomes expressed membrane tumor necrosis factor (TNF), which engaged TNFR2 and triggered glycolytic activation via TNF/nuclear factor κB autocrine and paracrine signaling. Importantly, clinically applicable anti-TNF antibodies effectively prevented exosomal membrane TNF-induced glycolytic activation in CD14+ Mφ., Conclusions: CD14+ Mφ take part in CD pathogenesis by inducing glycolytic activation via membrane TNF-mediated exosomal autocrine and paracrine signaling. These results provide novel insights into pathogenesis of CD and enhance understanding of the mechanisms of anti-TNF agents., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: High tumour budding has been indicated as a risk factor of poor survival in colorectal cancer. This study aimed to investigate the impact of tumour budding grades and the use of adjuvant chemotherapy on prognosis in patients with colorectal cancer., Methods: This study included consecutive colorectal cancer patients who underwent radical surgery for primary colorectal adenocarcinoma at The Sixth Hospital of Sun Yat-sen University between 2009 and 2019. Tumour budding was assessed based on the recommendations of the International Tumor Budding Consensus Conference using haematoxylin and eosin (H&E)-stained slides with tumour samples. The primary outcome of interest was to correlate tumour budding with disease-free survival and overall survival; the secondary outcome was investigation of the impact of adjuvant therapy on different tumour budding grades. In addition, a subgroup analysis was performed for the effects of lymphocytic infiltration on adjuvant chemotherapy in patients with Bd3., Results: Of 709 eligible patients, 412 with colorectal cancer were included. According to the International Tumor Budding Consensus Conference, 210 (50.9 per cent), 127 (30.8 per cent) and 75 (18.2 per cent) were classified as low budding (Bd1), intermediate budding (Bd2) and high budding (Bd3) respectively. Patients with Bd1, Bd2 and Bd3 had 5-year disease-free survival rates of 82.9 per cent, 70.1 per cent and 49.3 per cent respectively, and 5-year overall survival rates of 90 per cent, 79.5 per cent and 62.7 per cent respectively (P <0.001). Adjuvant chemotherapy yielded a significant survival benefit in patients with Bd3 (5-year disease-free survival, 65 per cent versus 31.4 per cent, P <0.001; 5-year overall survival, 84.4 per cent versus 63.1 per cent, P <0.001), but not in those with Bd1 or Bd2. In patients with Bd3, the benefit of adjuvant chemotherapy was maintained in those with low, but not high lymphocytic infiltration., Conclusion: High grade of tumour budding was strongly correlated with poorer survival outcomes in colorectal cancer. Patients with Bd3 benefited from adjuvant chemotherapy, with the exclusion of patients with high lymphocytic infiltration., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: Myocardial injury is a severe complication of sepsis, resulting in substantial morbidity and mortality. Psoralidin (PSO), derived from the seeds of Psoralea corylifolia L., has garnered considerable attention due to its potent pharmacological effects, including anti-inflammatory and antibacterial effects., Purpose: Our previous work conducted affirmed that PSO has a protective effect on sepsis and septic myocardial injury, however the specific molecular mechanisms need further clarification., Study Design: This objective of this study was to use three analytic modalities and bioinformatics methods to identify potential targets, followed by experimental verification., Methods: A series of experiments methods (including echocardiography, HE, western blot, qPCR, RNA-seq, network pharmacology) were used to evaluate the effects of PSO against sepsis and septic myocardial injury in cecal ligation and puncture (CLP)-injured BALB/c mice and lipopolysaccharide (LPS)-injured HL-1 cardiomyocytes., Results: Firstly, a group of sepsis-related genes were identified by integrating database surveys, RNA-seq analysis, and weighted gene co-expression network analysis (WCGNA). Subsequently, the pharmacological targets of PSO were predicted. Furthermore, the identification of phosphoinositide 3- kinase regulatory subunit 5 (PIK3R5) as a crucial hub gene was accomplished via protein-protein interaction network and molecular docking approach. In vivo experiments showed that PSO treatment alleviated septic myocardial injury, as evidenced by improved cardiac function indicators and inflammation response. Similar results were obtained in vitro experiments. Importantly, the expression of PI3KR5 was decreased in the myocardium and cardiomyocytes, and the effect was reversed by PSO treatment., Conclusion: This study systematically revealed the key targets of PSO in the treatment of septic myocardial injury. These findings offer valuable insights into disease-drug targets, which have certain clinical significance to exploring disease biomarkers and potential therapeutic targets for septic patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background: Transanal total mesorectal excision (taTME) is a novel approach to radical surgery for low rectal cancer; however, it is not clear whether taTME causes a more severe inflammatory stress response than laparoscopic total mesorectal excision (laTME). Therefore, the authors conducted this study to address this question, with the secondary objective of analyzing the predictive effect of inflammatory indexes on postoperative infective complications between laTME and taTME., Methods: A total of 545 cases of laTME and 544 cases of taTME from the TaLaR randomized controlled trial were included. Inflammatory stress response was assessed via C-reactive protein (CRP), white blood cell count, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, lymphocyte-monocyte ratio, and prognostic nutritional index. Inflammatory indexes were measured and calculated preoperatively (t1) and on postoperative days one (t2) and seven (t3). The accuracy of inflammatory indexes as predictor of infective complications was evaluated by areas under the receiver operating characteristic curve., Results: Preoperative blood parameters were comparable between the two surgical methods. There were no significant differences in CRP, white blood cell count, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, lymphocyte-monocyte ratio, or prognostic nutritional index between the two surgical methods at any time point ( P >0.05). Among the inflammatory indexes at three time points, CRP on the first postoperative day was the most accurate predictor of infective complications, which is suitable for two surgical methods. The AUC was 0.7671 ( P <0.0001) with a cutoff of 39.84 mg/l, yielding 94% sensitivity and 47% specificity., Conclusions: Compared with laTME, taTME surgery has no obvious disadvantage with respect to the postoperative inflammatory stress response. In addition, inflammatory indexes were favorable in predicting infective complications, with the best results for CRP on the first postoperative day. Defining the specific predictors for laTME and taTME is unnecessary., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Sepsis is a major health threat and often results in heart failure. Growth arrest-specific gene 6 (GAS6), a 75-kDa vitamin K-dependent protein, participates in immune regulation and inflammation through binding to AXL (the TAM receptor family). This study was designed to examine the myocardial regulatory role of GAS6 in sepsis. Serum GAS6 levels were increased in septic patients and mice while myocardial GAS6 levels were decreased in septic mice. Single-cell RNA sequencing further revealed a decline in GAS6 levels of nearly all cell clusters including cardiomyocytes. GAS6 overexpression via adeno-associated virus 9 (AAV9) overtly improved cardiac dysfunction in cecum ligation and puncture (CLP)-challenged mice, along with alleviated mitochondrial injury, endoplasmic reticulum stress, oxidative stress, and apoptosis. However, GAS6-elicited beneficial effects were removed by GAS6 knockout. The in vitro study was similar to these findings. Our data also noted a downstream effector role for NLRP3 in GAS6-initiated myocardial response. GAS6 knockout led to elevated levels of NLRP3, the effect of which was reconciled by GAS6 overexpression. Taken together, these results revealed the therapeutical potential of targeting GAS6/AXL-NLRP3 signaling in the management of heart anomalies in sepsis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Circular RNAs (circRNAs) are crucial regulators of β-cell function and are involved in lipotoxicity-induced β-cell damage in type 2 diabetes mellitus (T2DM). We previously identified that circGlis3, a circRNA derived from exon 4 of the diabetes susceptibility gene Glis3 , was upregulated in lipotoxic β cells. However, the functional role and molecular mechanism of circGlis3 in β cells remain largely unknown. Here, we revealed that the splicing factor CUGBP Elav-Like Family Member 1 (CELF1) facilitated the biogenesis of circGlis3. Moreover, we established a transgenic mouse model and confirmed that the overexpression of circGlis3 impaired β-cell function. Mechanistically, circGlis3 bound to heterogeneous nuclear ribonucleoprotein F (hnRNPF) and blocked its nuclear translocation, thereby reducing Sirt1 levels. Additionally, circGlis3 encoded a 348aa protein that interacted with GLIS3 and inhibited its transcriptional activity. Our data uncover a critical role of circGlis3 in β-cell dysfunction, suggesting that circGlis3 may be a potential therapeutic target for T2DM., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Sepsis can cause various organ dysfunction, which heart failure may be associated with significant mortality. Recently, natural plant extracts have gradually attracted people's attention in the clinical treatment of cardiovascular diseases. Psoralidin (PSO) is one of the main bioactive compounds from the seeds of Psoralea corylifolia L and exhibits remarkable protective effects in diseases, including cancer, osteoporosis, and depression. Recently, NR1H3 is one of the emerging nuclear receptors targets for the various drugs. This study first reported the porotective role of PSO in septic myocardial injury, which was mainly attributed to the NR1H3-dependent manner. NR1H3 knockout mice subjected to cecal ligation and puncture (CLP) were used to investigate the involvement of NR1H3 in PSO protection. Our results showed that PSO prominently improved cardiac function, attenuated inflammation, inhibited oxidative stress, improved mitochondrial function, regulated ERS, suppressed apoptosis, and particularly increased NR1H3 and p-AMPK levels. However, NR1H3 knockout reversed the positive role of PSO in septic mice. Furthermore, activation of NR1H3 by T0901317 also increased the activity of AMPK and ACC in the HL-1 cardiomyocytes, indicating the regulatory relationship between NR1H3 and AMPK signaling. Together, this study demonstrated the beneficial effect of PSO in septic myocardial injury through activation of NR1H3/AMPK pathway., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Redox flow batteries have been discussed as scalable and simple stationary energy storage devices. However, currently developed systems encounter less competitive energy density and high costs, restricting their wider application. There is a lack of appropriate redox chemistry, preferably based on active materials that are abundant in nature and show high solubility in aqueous electrolytes. A nitrogen-centered redox cycle operating between the limiting species ammonia and nitrate via an eight-electron redox reaction stayed practically unnoticed, albeit its ubiquity in biological processes. Ammonia or nitrate are world-scale chemicals with high aqueous solubility, and are then comparably safe. We demonstrate here the successful implementation of such a nitrogen-based redox cycle between ammonia and nitrate with eight-electron transfer as a catholyte for Zn-based flow batteries, which continuously worked for 12.9 days with 930 charging-discharging cycles. A very competitive energy density of 577 Wh L -1 can be reached, which is well above most reported flow batteries (e.g. 8 times the standard Zn-bromide battery), demonstrating that the nitrogen cycle with eight-electron transfer can offer promising cathodic redox chemistry for safe, affordable, and scalable high-energy-density storage devices., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Poor infiltration of T lymphocytes has been regarded as a crucial mechanism of tumor immune escape. Here, we demonstrate a protective role of KRT17 in colorectal cancer, where KRT17 reversed the tumor immunosuppressive microenvironment by increasing T-lymphocyte infiltration. High-throughput RNA sequencing suggested that KRT17 was significantly upregulated in deficient mismatch repair (dMMR) tumors compared with proficient mismatch repair (pMMR) tumors. In a colorectal cancer cohort of 446 cases, KRT17 expression positively correlated with better clinical outcomes. Krt17 overexpression decreased xenograft tumor growth in immune-competent mice. T-cell depletion in a murine model showed that the presence of T lymphocytes was necessary for Krt17-mediated disruption of tumorigenesis. Mass spectrometry and coimmunoprecipitation assays suggested KRT17 caused YTHDF2 degradation through the ubiquitin-proteasome system. Through high-throughput RNA immunoprecipitation sequencing, we found that CXCL10 was the target gene of the N6-methyladenosine (m6A) "reader" YTHDF2. KRT17 synergized with anti-PD-1 for better tumor control in an immunotherapy-resistant murine model. In a cohort of patients with colorectal cancer receiving pembrolizumab, high KRT17 expression was found within the tumors of responders. Collectively, we elucidated a critical role of KRT17 in colorectal cancer to prevent immune escape. These findings present new insights into potential therapeutic strategies and effective markers of immunotherapy reactivity against pMMR tumors., (©2023 The Authors; Published by the American Association for Cancer Research.)

For patients with locally advanced rectal cancer (LARC) with pathological complete response (pCR), the clinical significance of the distribution extent of acellular mucin pools (AMP) distribution remains unclear, so this study was conducted to address key unanswered questions. We performed a retrospective analysis of 317 patients with LARC with pCR after preoperative chemoradiotherapy and total mesorectal resection from January 2011 to June 2020. Based on AMP existence and the deepest tissue layer of distribution, patients were assigned new stages. The patient information was recorded, and the main outcome measures included 5-year disease-free survival (DFS) and 5-year overall survival (OS). A total of 83/317 (26.2%) patients exhibited AMP, and disease recurrence occurred in 46/317 (14.5%) patients. Over the 5-year median follow-up period, the patients with AMP showed 5-year DFS rates (75.9% vs. 88.9%, P =0.004) and 5-year OS rates (85.5% vs. 95.7%, P =0.002) statistically lower than those of patients without AMP. Disease recurrence was seen in 15/54 (27.8%) patients with AMP within the subserosa and/or the serosa, or adipose tissue. Univariate and multivariate analysis showed that the existence of AMP within the subserosa and/or the serosa, or adipose tissue was an independent risk factor for DFS [hazard ratio (HR): 2.344; 95% confidence interval (CI): 1.256-4.376; P =0.007] and OS [HR: 3.374; 95% CI: 1.438-7.917; P =0.005]. The new stages based on the deepest extent of AMP were related to worse DFS ( P =0.004) and OS ( P =0.003) rates among patients with pCR. In conclusion, the presence of AMP might reduce the prognosis of LARC patients with pCR after chemoradiotherapy, especially in patients with AMP in deeper tissue layers. Therefore, the influence of the deepest AMP extent might be worth considering in staging. Moreover, the revised staging of patients with pCR according to the deepest extent of AMP, which is unrelated to the clinical T stage, might facilitate postoperative management., Competing Interests: Conflicts of Interest and Source of Funding: The authors declare there is no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Fibrosis is a universal aging-related pathological process in the different organ, but is actually a self-repair excessive response. To date, it still remains a large unmet therapeutic need to restore injured tissue architecture without detrimental side effects, due to the limited clinical success in the treatment of fibrotic disease. Although specific organ fibrosis and the associated triggers have distinct pathophysiological and clinical manifestations, they often share involved cascades and common traits, including inflammatory stimuli, endothelial cell injury, and macrophage recruitment. These pathological processes can be widely controlled by a kind of cytokines, namely chemokines. Chemokines act as a potent chemoattractant to regulate cell trafficking, angiogenesis, and extracellular matrix (ECM). Based on the position and number of N-terminal cysteine residues, chemokines are divided into four groups: the CXC group, the CX3C group, the (X)C group, and the CC group. The CC chemokine classes (28 members) is the most numerous and diverse subfamily of the four chemokine groups. In this Review, we summarized the latest advances in the understanding of the importance of CC chemokine in the pathogenesis of fibrosis and aging and discussed potential clinical therapeutic strategies and perspectives aimed at resolving excessive scarring formation., Competing Interests: Conflicts of interest The authors declare that they do not have any conflicts of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The Li dendrite growth and the liquid electrolyte volatilization under semi-open architecture are intrinsic issues for Li-O 2 battery. In this work, we propose a non-Newtonian fluid quasi-solid electrolyte (NNFQSE) SiO 2 -SO 3 Li/PVDF-HFP, which has both shear-thinning and shear-thickening properties. The component interactions among the sulfonated silica nanoparticles, liquid electrolyte, and polymer network are beneficial for decent Li + conductivity and high liquid electrolyte retention without volatilization. Furthermore, NNFQSE exhibits shear-thinning property to eliminate the stress of dendrite growth during repeated cycling. Meanwhile, when the force suddenly increases, such as a high current rate, the NNFQSE may dynamically turn shear-thickening to respond and mechanically stiffen to inhibit the lithium dendrite penetration. By coupling with the NNFQSE, the lithium symmetrical battery can run over 2000 h under 1 mA cm -2 at room temperature, and the quasi-solid Li-O 2 battery actualizes long life above 5000 h at 100 mA g -1 ., (© 2023. The Author(s).)

Imine-linked covalent organic frameworks (imine-COFs) represent the most sought-after class of COFs due to their broad monomer scope and ease of synthesis. Owing to the reversible nature of imine linkages, however, the chemical stability of most imine-COFs is still far from adequate. In this context, emerging strategies, ranging from linkage chemistry to interlayer interaction, have been employed to construct stable imine-COFs for their applications in electronics, sensing, and energy storage devices. This Concept article summarizes the latest advances aimed at tuning the structural stability of imine-COFs. Furthermore, this Concept provides a prospective for the precise design of stable imine-COFs based on the characteristics of structure, physical properties, and chemical functions, as well as the mechanism of structure locking and stabilization during crystal growth., (© 2022 Wiley-VCH GmbH.)

Most sepsis deaths are due to the development of multiple organ failure, in which heart failure is a recognized manifestation of sepsis. To date, the role of liver X receptors α (NR1H3) in sepsis is still uncertain. Here, we hypothesized that NR1H3 mediates multiple essential sepsis-related signalings to attenuate septic heart failure. Adult male C57BL/6 or Balbc mice and HL-1 myocardial cell line were performed for in vivo and in vitro experiments, respectively. NR1H3 knockout mice or NR1H3 agonist T0901317 was applied to evaluate the impact of NR1H3 on septic heart failure. We found decreased myocardial expression levels of NR1H3-related molecules while increased NLRP3 level in septic mice. NR1H3 knockout worsensed cardiac dysfunction and injury in mice subjected to cecal ligation and puncture (CLP), in association with exacerbated NLRP3-mediated inflammation, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis-related markers. The administration of T0901317 reduced systemic infection and improve cardiac dysfunction in septic mice. Moreover, Co-IP assays, luciferase reporter assays, and chromatin immunoprecipitation analysis, confirmed that NR1H3 directly repressed NLRP3 activity. Finally, RNA-seq detection further clarified an overview of the roles of NR1H3 in sepsis. In general, our findings indicate that NR1H3 had a significant protective effect against sepsis and sepsis-induced heart failure., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)

Oxidative stress plays a key part in cardiovascular event. Growth arrest-specific gene 6 (GAS6) is a vitamin K-dependent ligand which has been shown to exert important effects in heart. The effects of GAS6 were evaluated against hydrogen peroxide (H 2 O 2 ) ‑induced oxidative stress injury in HL-1 cardiomyocytes. A series of experimental methods were used to analyze the effects of GAS6 on cell viability, apoptosis, oxidative stress, mitochondrial function and AMPK/ACC signaling in H 2 O 2 ‑injured HL-1 cells. In this study, we found that H 2 O 2 reduced cell viability, increased apoptotic rate and intracellular reactive oxygen species (ROS). Meanwhile, H 2 O 2 decreased the protein levels of GAS6, and increased the protein level of p-AMPK/AMPK, p-ACC/ACC. Then, we observed that overexpression of GAS6 significantly reduced cell death, manifested as increased cell viability, improved oxidative stress, apoptosis and upregulated the levels of GAS6, p-Axl/Axl, Nrf2, NQO1, HO-1, Bcl-2/Bax, PGC-1α, NRF1, TFAM, p-AMPK/AMPK, and p-ACC/ACC-related protein expression in HL-1 cells and H 2 O 2 ‑injured cardiomyocytes. To further verify the results, we successfully constructed GAS6 lentiviral vectors, and found GAS6 shRNA partially reversed the above results. These data suggest that AMPK/ACC may be a downstream effector molecule in the antioxidant action of GAS6. In summary, our findings indicate that activation GAS6/Axl-AMPK signaling protects H 2 O 2 ‑induced oxidative stress which is accompanied by the amelioration of oxidative stress, apoptosis, and mitochondrial function., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The aqueous electrocatalytic reduction of NO 3 - into NH 3 (NitrRR) presents a sustainable route applicable to NH 3 production and potentially energy storage. However, the NitrRR involves a directly eight-electron transfer process generally required a large overpotential (<-0.2 V versus reversible hydrogen electrode (vs. RHE)) to reach optimal efficiency. Here, inspired by biological nitrate respiration, the NitrRR was separated into two stages along a [2+6]-electron pathway to alleviate the kinetic barrier. The system employed a Cu nanowire catalyst produces NO 2 - and NH 3 with current efficiencies of 91.5 % and 100 %, respectively at lower overpotentials (>+0.1 vs. RHE). The high efficiency for such a reduction process was further explored in a zinc-nitrate battery. This battery could be specified by a high output voltage of 0.70 V, an average energy density of 566.7 Wh L -1 at 10 mA cm -2 and a power density of 14.1 mW cm -2 , which is well beyond all previously reported similar concepts., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Despite being regulated globally for almost three decades, halocarbon continues to play a vital role in climate change and ozone layer because of its long lifetime in the ambient air. In recent years, unexpected halocarbon emissions have been found in Asia, raising concerns about ozone recovery. As a number of studies focused on halocarbon variations and source profiles, there is an increasing need to identify halocarbon source origins. In this study, an eight-month regular air sampling was conducted at a coastal site in Hong Kong from November 2020 to June 2021, and seventeen halocarbon species were selected for extensive investigation after advanced sample analysis in our laboratory. The temporal variations of halocarbon mixing ratio enhancements were analyzed, and the spatial variations of source origins were investigated by wind sectors and backward trajectory statistics. Our results indicate lower enhancements beyond the background values for major regulated CFCs and CCl 4 than later controlled HCFCs and HFCs, suggesting the greater progress of Montreal Protocol implementation for the former species. The notable high enhancement values of non-regulated halocarbons from the north direction indicate their widespread usage in China. The source apportionment analysis estimates the contributions from six emission sectors on measured halocarbons, including solvent usage (43.57 ± 4.08 %), refrigerant residues (17.05 ± 5.71 %), cleaning agent/chemical production (13.18 ± 4.76 %), refrigerant replacements (13.06 ± 2.13 %), solvent residues (8.65 ± 3.28 %), and foaming agent (4.49 ± 1.08 %). Trajectories statistical analysis suggests that industrial solvent was mainly contributed by eastern China (i.e., Shandong and YRD), cleaning agent/chemical production was spread over southeast China (i.e., YRD and Fujian), and refrigeration replacements were dominant in Hong Kong surrounding regions. This work provides insight into the progress made in implementing the Montreal Protocol in Hong Kong and the surrounding region and the importance of continuous emission control., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The roles of oncogenic KRAS in tumor immune evasion remain poorly understood. Here, mutant KRAS is identified as a key driver of tumor immune evasion in colorectal cancer (CRC). In human CRC specimens, a significant reduction in cytotoxic CD8 + T-cell tumor infiltration is found in patients with mutant versus wild type KRAS. This phenomenon is confirmed by preclinical models of CRC, and further study showed KRAS mutant tumors exhibited poor response to anti-PD-1 and adoptive T-cell therapies. Mechanistic analysis revealed lactic acid derived from mutant KRAS-expressing tumor cells sensitized tumor-specific cytotoxic CD8 + T-cells to activation-induced cell death via NF-κB inactivation; this may underlie the inverse association between intratumoral cytotoxic CD8 + T-cells and KRAS mutation. Importantly, KRAS mutated tumor resistance to immunotherapies can be overcome by inhibiting KRAS or blocking lactic acid production. Together, this work suggests the KRAS-mediated immune program is an exploitable therapeutic approach for the treatment of patients with KRAS mutant CRC., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Molecule aggregation in solution is acknowledged to be universal and can regulate the molecule's physiochemical properties, which however has been rarely investigated in electrochemistry. Herein, an electrochemical method is developed to quantitatively study the aggregation behavior of the target molecule methyl viologen dichloride. It is found that the oxidation state dicationic ions stay discrete, while the singly-reduced state monoradicals yield a concentration-dependent aggregation behavior. As a result, the molecule's energy level and its redox potential can be effectively regulated. This work does not only provide a method to investigate the molecular aggregation, but also demonstrates the feasibility to tune redox flow battery's performance by regulating the aggregation behavior., (© 2022 Wiley-VCH GmbH.)

Background: Acute myocardial infarction (MI) is considered to be the main cause of congestive heart failure. The aim of this study was to provide an in-depth analysis of athophysiological processes and provide key targets for intervention in the occurrence of acute MI., Methods: A rat model of MI was established by ligation of left anterior descending branch. Heart tissue, epicardial adipose tissue (EAT) and subcutaneous adipose tissue (SAT) were collected. H9c2 cells were used to explore the mechanism of complement factor D (CFD) regulating cardiomyocyte apoptosis., Results: Myocardial apoptosis were observed in MI rat, and more EAT was found in the MI group in vivo. The conditioned medium prepared by EAT (EAT-CM) significantly reduced the activity of H9c2 cells. The content of CFD in EAT was significantly increased, and CFD promoted cardiomyocyte apoptosis in vitro and CFD-IN1 (a selective inhibitor of CFD) could revised this effect. CFD induced poly ADP-ribosepolymerase-1 (PARP-1) overactivation. Furthermore, the addition of pan-caspase inhibitor Z-VAD in the SAT-CM + CFD group couldn't affect H9c2 cell apoptosis. CFD induced cell apoptosis via PARP-1 activation and PARP-1 inhibitor 3-Aminobenzamide could revise this effect. The injection of CFD-IN1 in MI rat model confirmed that inhibition of CFD activity alleviated cardiomyocytes apoptosis., Conclusion: Our findings indicate that EAT mediating cardiomyocyte apoptosis after MI through secretion of CFD and activation of PARP-1 activity., Competing Interests: Conflict of interest All authors declare that there is no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Background: Recurrence represents a well-known poor prognostic factor for colorectal cancer (CRC) patients. This study aimed to establish an effective prognostic prediction model based on noninvasive circulating tumor DNA methylation markers for CRC patients receiving radical surgery., Results: Two methylation markers (cg11186405 and cg17296166) were identified by Cox regression and receiver operating characteristics, which could classify CRC patients into high recurrence risk and low recurrence risk group. The 3-year disease-free survival was significantly different between CRC patients with low and high recurrence risk [Training set: hazard ratio (HR) 28.776, 95% confidence interval (CI) 3.594-230.400; P = 0.002; Validation set: HR 7.796, 95% CI 1.425-42.660, P = 0.018]. The nomogram based on the above two methylation markers and TNM stage was established which demonstrated robust prognostic prediction potential, as evidenced by the decision curve analysis result., Conclusions: A cell-free DNA methylation model consisting of two DNA methylation markers is a promising method for prognostic prediction in CRC patients., (© 2022. The Author(s).)

Background: Septic heart failure accounts for high mortality rates globally. With a strong reducing capacity, zero-valent iron nanoparticles (nanoFe) have been applied in many fields. However, the precise roles and mechanisms of nanoFe in septic cardiomyopathy remain unknown., Results: NanoFe was prepared via the liquid-phase reduction method and functionalized with the biocompatible polymer sodium carboxymethylcellulose (CMC). We then successfully constructed a mouse model of septic myocardial injury by challenging with cecal ligation and puncture (CLP). Our findings demonstrated that nanoFe has a significant protective effect on CLP-induced septic myocardial injury. This may be achieved by attenuating inflammation and oxidative stress, improving mitochondrial function, regulating endoplasmic reticulum stress, and activating the AMPK pathway. The RNA-seq results supported the role of nanoFe treatment in regulating a transcriptional profile consistent with its role in response to sepsis., Conclusions: The results provide a theoretical basis for the application strategy and combination of nanoFe in sepsis and septic myocardial injury., (© 2022. The Author(s).)

Introduction: Adriamycin (ADR) is an efficient and common broad-spectrum anticancer drug. However, the cumulative and dose-dependent toxicity induced by ADR severely limits its application in the clinic. Previous studies found that psoralidin (PSO) exhibits remarkable therapeutic effects against multiple cancers., Objectives: The aim of this study was to determine if PSO has beneficial effects on ADR-induced cardiotoxicity and to investigate the underlying mechanisms., Methods: ADR-induced cardiotoxicity models were established in BALB/c mice and HL-1 cardiomyocytes. A series of experimental methods were used to evaluate the effects of PSO on cardiac function indicators, blood biochemical parameters, histopathology, oxidative stress, apoptosis, mitochondrial function, fibrosis, and SIRT1/PPARγ signaling., Results: PSO significantly improved cardiac function indicators, blood biochemical parameters, and mitochondrial function and reduced the degree of myocardial fibrosis, oxidative stress, and apoptosis in ADR-injured mice. PSO significantly increased cell viability, inhibited the release of LDH, reduced oxidative stress and apoptosis, and improved mitochondrial function in ADR-injured HL-1 cells. Moreover, we also demonstrated there was cross-talk between SIRT1 and PPARγ, as shown by SIRT1 siRNA significantly decreasing the expression of PPARγ and GW9662 (a PPARγ antagonist), which remarkably reduced the expression of SIRT1., Conclusion: In summary, this study proved for the first time the beneficial effect of PSO on ADR-induced cardiotoxicity through activation of the SIRT1/PPARγ signaling pathway. Therefore, these findings may favor PSO as a potential cardioprotective drug candidate to alleviate ADR-induced cardiotoxicity in the clinic and improve the application of ADR in oncotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Production and hosting by Elsevier B.V.)

The development of effective, stable anhydrous proton-conductive materials is vital but challenging. Covalent organic frameworks (COFs) are promising platforms for ion and molecule conduction owing to their pre-designable structures and tailor-made functionalities. However, their poor chemical stability is due to weak interlayer interactions and intrinsic reversibility of linkages. Herein, we present a strategy for enhancing the interlayer interactions of two-dimensional COFs via importing planar, rigid triazine units into the center of C 3 -symmetric monomers. The developed triazine-core-based COF (denoted as TPT-COF) possesses a well-defined crystalline structure, ordered nanochannels, and prominent porosity. The proton conductivity was ≈10 times those of non-triazinyl COFs, even reaching up to 1.27×10 -2  S cm -1 at 160 °C. Furthermore, the TPT-COF exhibited structural ultrastability, making it an effective proton transport platform with remarkable conductivity and long-term durability., (© 2022 Wiley-VCH GmbH.)

Electrochemical reduction of CO 2 (CO 2 RR) to value-added chemicals is an effective way to harvest renewable energy and utilize carbon dioxide. However, the electrocatalysts for CO 2 RR suffer from insufficient activity and selectivity due to the limitation of CO 2 activation. In this work, a Ni-doped Bi nanosheet (Ni@Bi-NS) electrocatalyst is synthesized for the electrochemical reduction of CO 2 to HCOOH. Physicochemical characterization methods are extensively used to investigate the composition and structure of the materials. Electrochemical results reveal that for the production of HCOOH, the obtained Ni@Bi-NS exhibits an equivalent current density of 51.12 mA cm -2 at -1.10 V, which is much higher than the pure Bi-NS (18.00 mA cm -2 at -1.10 V). A high Faradaic efficiency over 92.0 % for HCOOH is achieved in a wide potential range from -0.80 to -1.10 V, and particularly, the highest efficiency of 98.4 % is achieved at -0.90 V. Both experimental and theoretical results reveal that the superior activity and selectivity are attributed to the doping effect of Ni on the Bi nanosheet. The density functional theory calculation reveals that upon doping, the charge is transferred from Ni to the adjacent Bi atoms, which shifts the p-orbital electronic density states towards the Fermi level. The resultant strong orbital hybridization between Bi and the π* orbitals of CO 2 facilitates the formation of *OCHO intermediates and favors its activation. This work provides an effective strategy to develop active and selective electrocatalysts for CO 2 RR by modulating the electronic density state., (© 2022 Wiley-VCH GmbH.)

Introduction: Since transanal total mesorectal excision (taTME) was introduced, it has become an important topic in rectal cancer treatment. Many previous studies reported positive relevant short-term results, histopathological results, and associated complications. Recently, concerns regarding the oncological safety of taTME have been raised due to reports showing high local recurrences (LR) rates. Therefore, this study aimed to compare the 3-year outcomes between taTME and laparoscopic total mesorectal excision (laTME) for mid-low rectal cancer., Methods: A total of 104 patients who underwent taTME were matched with 208 patients treated by laTME. The primary endpoint was 3-year LR rate; secondary endpoints in this matched-cohort study included the perioperative outcomes and histopathological outcomes., Results: taTME was associated with lower permanent ostomy rate (1% vs 13.5%) and lower conversion rate (0% vs 3.4%) compared to laTME. A similar quality of resected specimens was detected for each group. In both groups, the local recurrence rate was 3.8%. Within 3 years after surgery, the disease-free survival (DFS) rates were 78.8% in the taTME group and 76.9% in the laTME group (P = 0.640), while the overall survival (OS) rates were 93.3% in the taTME group and 89.9% in the laTME group (P = 0.327)., Conclusion: No significant differences regarding 3-year local recurrence rate (3.8%) were observed in the taTME group compared to laTME group., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The development of the electrocatalyst-integrated electrodes with HER/OER bifunctional activity is desirable to reduce the cost and simplify the system of the practical water electrolyzers. Herein, we construct a new type of Ni 3 Fe 1- x Cr x (0 ≤ x < 0.3) intermetallic integrated electrodes for overall water splitting via an ultrafast carbothermal shock method. The obtained Ni 3 Fe 0.9 Cr 0.1 /CACC electrode exhibits the optimum performance among all developed electrocatalyst electrodes in this work, and the overpotential is merely 239 mV for OER and 128 mV for HER at 10 mA cm -2 . In addition, the Ni 3 Fe 0.9 Cr 0.1 /CACC electrode shows excellent durability during both OER and HER stability tests at a high current density of 100 mA cm -2 . An electrolyzer, which was assembled with Ni 3 Fe 0.9 Cr 0.1 /CACC electrodes as both the anode and cathode, operates with a low cell voltage of 1.59 V at 10 mA cm -2 . It has been found that the impressive OER activity of Ni 3 Fe 0.9 Cr 0.1 nanoparticles (NPs) can be ascribed to the stimulative formation of the OER-active Ni 3+ /Fe 3+ species by the substituted Cr, while the enhanced HER activity is caused by the Cr substitution, which decreases the water dissociation energy barrier. This work provides an ultrafast and facile strategy to develop electrocatalyst-integrated electrodes with low cost and impressive HER/OER bifunctional performance for overall water splitting.

Myocardial dysfunction is well-recognized manifestations of organ dysfunction in sepsis, which is the leading cause of death in critically ill patients. The underlying mechanisms associated with sepsis-induced myocardial injury (SIMI) include cardiac contractility, inflammatory response, oxidative stress, and apoptosis. Kudzu celery decoction (KCD) is composed of a variety of traditional Chinese medicine (TCM) such as kudzu and celery. The previous study found that the main ingredients in kudzu and celery have also been proved to have anti-inflammatory, antioxidative, and other biological activities. In this study, the therapeutic effects of KCD were evaluated in the cecal ligation and puncture (CLP) model of BALB/c mice. The effects of KCD on cardiac function, myocardium damage, inflammation, and fibrosis in CLP-injured mice were analyzed with echocardiography, histological staining, and quantitative real-time PCR. The results showed that KCD treatment improved the anal temperature, sepsis score, blood routine parameters, and blood biochemical parameters in CLP-injured mice. Then, we observed that KCD could remarkably alleviate cardiac dysfunction, myocardial fibrosis, oxidative stress, and inflammation in CLP-injured mice. In this study, we confirmed that KCD has a significant protective effect on SIMI, which may favor KCD a potential cardioprotective drug candidate to alleviate SIMI and further amplify the application of TCM prescription in clinic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lin Zhao et al.)

Adipose-derived stem cells (ADSCs) play a vital role in colorectal cancer (CRC) progression, but the mechanism remains largely unknown. Herein, we found that ADSCs isolated from CRC patients produced more cysteine-rich 61 (Cyr61) than those from healthy donors, and the elevated serum Cyr61 levels were associated with advanced TNM stages. Moreover, serum Cyr61 displayed a better diagnostic value for CRC compared to carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9). Mechanistically, integrin α V β 5 was identified as the functional receptor by which Cyr61 promotes CRC cell metastasis in vitro and in vivo by activating the α V β 5 /FAK/NF-κB signaling pathway. In addition, Cyr61 promotes vasculogenic mimicry (VM) formation, thereby promoting tumor growth and metastasis through a α V β 5 /FAK/HIF-1α/STAT3/MMP2 signaling cascade. Histologically, xenografts and clinical samples of CRC both exhibited VM, which was correlated with HIF-1α and MMP2 activation. Notably, we demonstrated the synergistic effect of combined anti-VM therapy (integrin α V β 5 inhibitor) and anti-VEGF therapy (bevacizumab) in patient-derived xenograft models. Further investigation showed that CRC cell-derived exosomal STAT3 promoted Cyr61 transcription in ADSCs. These findings indicate that Cyr61 derived from ADSCs plays a critical role in promoting CRC progression via integrin α V β 5 and provides a novel antitumor strategy by targeting Cyr61/α V β 5 ., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

A novel organic molecule, 2,4,6-tris[1-(trimethylamonium)propyl-4-pyridiniumyl]-1,3,5-triazine hexachloride, was developed as a reversible six-electron storage electrolyte for use in an aqueous redox flow battery (ARFB). Physicochemical characterization reveals that the molecule evolves from a radical to a biradical and finally to a quinoid structure upon accepting four electrons. Both the diffusion coefficient and the rate constant were sufficiently high to run a flow battery with low concentration and kinetics polarization losses. In a demonstration unit, the assembled flow battery affords a high specific capacity of 33.0 Ah L -1 and a peak power density of 273 mW cm -2 . This work highlights the rational design of electroactive organics that can manipulate multi-electron transfer in a reversible way, which will pave the way to development of energy-dense, manageable and low-cost ARFBs., (© 2021 Wiley-VCH GmbH.)

Adverse myocardial remodeling, manifesting pathologically as myocardial hypertrophy and fibrosis, often follows myocardial infarction (MI) and results in cardiac dysfunction. In this study, an obvious epicardial adipose tissue (EAT) was observed in the rat model of MI and the EAT weights were positively correlated with cardiomyocyte size and myocardial fibrosis areas in the MI 2- and 4-week groups. Then, rat cardiomyocyte cell line H9C2 and primary rat cardiac fibroblasts were cultured in conditioned media generated from EAT of rats in the MI 4-week group (EAT-CM). Functionally, EAT-CM enlarged the cell surface area of H9C2 cells and reinforced cardiac fibroblast activation into myofibroblasts by elevating intracellular reactive oxygen species (ROS) levels. Mechanistically, miR-134-5p was upregulated by EAT-CM in both H9C2 cells and primary rat cardiac fibroblasts. miR-134-5p knockdown promoted histone H3K14 acetylation of manganese superoxide dismutase and catalase by upregulating lysine acetyltransferase 7 expression, thereby decreasing ROS level. An in vivo study showed that miR-134-5p knockdown limited adverse myocardial remodeling in the rat model of MI, manifesting as alleviation of cardiomyocyte hypertrophy and fibrosis. In general, our study clarified a new pathological mechanism involving an EAT/miRNA axis that explains the adverse myocardial remodeling occurring after MI., (© 2021. The Author(s).)

Ischemia-reperfusion injury (IRI) is a process whereby an initial ischemia injury and subsequent recovery of blood flow, which leads to the propagation of an innate immune response and the changes of structural and functional of multiple organs. Therefore, IRI is considered to be a great challenge in clinical treatment such as organ transplantation or coronary angioplasty. In recent years, ethyl pyruvate (EP), a derivative of pyruvate, has received great attention because of its stability and low toxicity. Previous studies have proved that EP has various pharmacological activities, including anti-inflammation, anti-oxidative stress, anti-apoptosis, and anti-fibrosis. Compelling evidence has indicated EP plays a beneficial role in a variety of acute injury models, such as brain IRI, myocardial IRI, renal IRI, and hepatic IRI. Moreover, EP can not only effectively inhibit multiple IRI-induced pathological processes, but also improve the structural and functional lesion of tissues and organs. In this study, we review the recent progress in the research on EP and discuss their implications for a better understanding of multiple organ IRI, and the prospects of targeting the EP for therapeutic intervention., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Collisional electrochemistry between single particles and a biomimetic polarized micro-liquid/liquid interface has emerged as a novel and powerful analytical method for measurements of single particles. Using this platform, rapid detection of liposomes at the single particle level is reported herein. Individual potassium, sodium, or protonated dopamine-encapsulated (pristine or protein-decorated) liposomes collide and fuse with the polarized micro-liquid/liquid interface accompanying the release of ions, which are recorded as spike-like current transients of stochastic nature. The sizing and concentration of the liposomes can be readily estimated by quantifying the amount of encapsulated ions in individual liposomes via integrating each current spike versus time and the spike frequency, respectively. We call this type of nanosensing technology "Faradaic counter". The estimated liposome size distribution by this method is in line with the dynamic light scattering (DLS) measurements, implying that the quantized current spikes are indeed caused by the collisions of individual liposomes. The reported electrochemical sensing technology may become a viable alternative to DLS and other commercial nanoparticle analysis systems, for example, nanoparticle tracking analysis.

Oncogenic KRAS has been previously identified to act in a cell-intrinsic manner to modulate multiple biological functions of colorectal cancer (CRC). Here, we demonstrate a cell-extrinsic role of KRAS, where KRAS engages with the tumor microenvironment by functional reprogramming of tumor-associated macrophages (TAMs). In human CRC specimens, mutant KRAS positively correlates with the presence of TAMs. Mutationally activated KRAS in tumor cells reprograms macrophages to a TAM-like phenotype via a combination effect of tumor-derived CSF2 and lactate. In turn, KRAS-reprogrammed macrophages were shown to not only promote tumor progression but also induce the resistance of tumor cells to cetuximab therapy. Mechanistically, KRAS drives the production of CSF2 and lactate in tumor cells by stabilizing hypoxia-inducible factor-1α (HIF-1α), a transcription factor that controls the expression of CSF2 and glycolytic genes. Mutant KRAS increased the production of reactive oxygen species, an inhibitor of prolyl hydroxylase activity which decreases HIF-1α hydroxylation, leading to enhanced HIF-1α stabilization. This cell-extrinsic mechanism awards KRAS a critical role in engineering a permissive microenvironment to promote tumor malignancy, and may present new insights on potential therapeutic defense strategies against mutant KRAS tumors.