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Abstract Early prediction of acute kidney injury (AKI) may provide a crucial opportunity for AKI prevention. To date, no prediction model targeting AKI among general hospitalized patients in developing countries has been published. Here we show a simple, real-time, interpretable AKI prediction model for general hospitalized patients developed from a large tertiary hospital in China, which has been validated across five independent, geographically distinct, different tiered hospitals. The model containing 20 readily available variables demonstrates consistent, high levels of predictive discrimination in validation cohort, with AUCs for serum creatinine-based AKI and severe AKI within 48 h ranging from 0.74–0.85 and 0.83–0.90 for transported models and from 0.81–0.90 and 0.88–0.95 for refitted models, respectively. With optimal probability cutoffs, the refitted model could predict AKI at a median of 72 (24–198) hours in advance in internal validation, and 54–90 h in advance in external validation. Broad application of the model in the future may provide an effective, convenient and cost-effective approach for AKI prevention.

Abstract Arteriovenous fistulas (AVFs) are the most common vascular access points for hemodialysis (HD), but they have a high incidence of postoperative dysfunction, mainly due to excessive neointimal hyperplasia (NIH). Our previous studies have revealed a highly conserved LncRNA-LncDACH1 as an important regulator of cardiomyocyte and fibroblast proliferation. Herein, we find that LncDACH1 regulates NIH in AVF in male mice with conditional knockout of smooth muscle cell-specific LncDACH1 and in male mice model of AVF with LncDACH1 overexpression by adeno-associated virus. Mechanistically, silence of LncDACH1 activates p-AKT through promoting the expression of heat shock protein 90 (HSP90) and serine/arginine-rich splicing factor protein kinase 1 (SRPK1). Moreover, LncDACH1 is transcriptionally activated by transcription factor KLF9 that binds directly to the promoter region of the LncDACH1 gene. In this work, during AVF NIH, LncDACH1 is downregulated by KLF9 and promotes NIH through the HSP90/ SRPK1/ AKT signaling axis.

Objectives: To explore the efficacy and safety of five traditional Chinese exercises (TCEs) in patients with fibromyalgia syndrome (FMS). Methods: The PubMed, Embase, Scopus, ProQuest, Web of Science, Cochrane, CNKI, WanFang, and VIP databases were comprehensively searched for randomized controlled trials (RCTs) related to TCEs published from inception until February 2023. Standardized mean differences (SMD) and 95% confidence intervals (CI) were used to determine the combined effects of the intervention, and the Cochrane risk-of-bias assessment tool and Review 5.2 software were used to assess methodological quality. The data were extracted and analyzed by the Stata15.0 random effects model. Results: Nineteen RCTs including 1315 participants were included in the analysis. The studies were found to be heterogeneous (I2 =86.2, P = 0.000), and thus a random effects model was used to combine the data. The results showed that traditional Chinese exercises had potentially beneficial effects on reducing pain (SMD =−0.66,95% CI [−1.08, −0.25], P = 0.002), improving sleep (SMD = −0.35,95% CI [−0.68,0. 01], P = 0.041) and relieving depression (SMD= −0.24,95% CI [−0.47, −0.02], P = 0.034) in FMS patients. However, no significant effects were found on improved quality of life (SMD =−0.20,95% CI [−0.48,0.09], P = 0.176). Conclusions: TCEs can improve pain, sleep quality and depression in patients with FMS and are safe. However, they do not improve the quality of life significantly. Further large-scale, high-quality, and multi-center RCTs are required to verify the efficacy of TCEs.

Introduction Renal osteodystrophy (ROD) is a type of bone metabolic disorder in patients with chronic kidney disease (CKD). Inflammation is associated with bone loss in ROD. However, its precise mechanism has not yet been elucidated. The present study was conducted to investigate whether exosomes (Exos) in bone marrow (BM) are involved in the pathogenesis of high-turnover ROD.Methods Bone mass, osteoclast number, and pro-inflammatory cytokines levels of BM supernatant were detected in adenine-induced ROD rats. The effect of Exos derived from BM (BM-Exos) of ROD (ROD-Exos) on inflammatory genes and osteoclast differentiation of BM-derived macrophages (BMMs) were further examined. Then, exosomal miRNA sequencing was performed and an miRNA-mRNA-pathway network was constructed.Results we found increased osteoclasts and decreased bone mass in ROD rats, as well as inflammatory activation in the BM niche. Furthermore, BMMs from ROD rats displayed overproduction of proinflammatory cytokines and increased osteoclast differentiation, accompanied by nuclear factor κB (NF-κB) signaling activation. Mechanistically, we found that ROD-Exos activates NF-κB signaling to promote the release of proinflammatory cytokines and increase osteoclast differentiation of BMMs. Meanwhile, a total of 24 differentially expressed miRNAs were identified between BM-Exos from ROD and normal control (NC). The miRNA-mRNA-pathway network suggests that rno-miR-9a-5p, rno-miR-133a-3p, rno-miR-30c-5p, rno-miR-206-3p, and rno-miR-17-5p might play pivotal roles in inflammation and osteoclast differentiation. Additionally, we validated that the expression of miR-9a-5p is upregulated in ROD-Exos.Conclusion The BM niche of ROD alters the miRNA cargo of BM-Exos to promote inflammation and osteoclast differentiation of BMMs, at least partially contributing to the pathogenesis of high-turnover ROD.

Mitochondrial abnormalities contribute to the development of diabetic nephropathy (DN). However, the precise mechanisms of mitochondrial dysfunction in DN remain unclear. Transient receptor potential canonical channel-6 (TRPC6), a non-selective cation channel permeable to Ca2+, has been shown to regulate mitochondrial dynamics. This study was therefore aimed to explore the regulatory role and mechanisms of TRPC6 in high glucose (HG)-induced mitochondrial dysfunction in podocytes. Here we found that TRPC6 expression and TRPC6-induced Ca2+ influx were increased in HG-treated podocytes. Furthermore, the TRPC6 inhibitor and TRPC6 siRNA ameliorated mitochondrial dysfunction and apoptosis in HG-treated podocytes. BAPTA-AM, an intracellular calcium chelating agent, attenuated mitochondrial fission under HG conditions as well. Then, we found the activity of calpain and cyclin-dependent kinase 5 (CDK5) was markedly enhanced in HG-treated podocytes, which can be blocked by pretreatment with the TRPC6 inhibitor. Calpain-1 inhibition by calpeptin or by calpain-1 siRNA transfection not only attenuated HG-induced mitochondrial fission but also reduced the activity of CDK5. Additionally, the CDK5 inhibitor and its siRNA decreased mitochondrial fragmentation in HG-treated podocytes. Collectively, we revealed the essential role of TRPC6 in regulating HG-induced mitochondrial fission and apoptosis through the calpain-1/CDK5 pathway in human podocytes, which may provide new insights into the pathogenesis of DN.

Abstract Background Membranous glomerulonephritis (MGN) is a common kidney disease. Despite many evidences support that many immune and inflammation-related genes could serve as effective biomarkers and treatment targets for MGN patients, the potential associations among MGN-, immune- and inflammation-related genes have not been sufficiently understood. Methods Here, a global immune-, inflammation- and MGN-associated triplets (IIMATs) network is constructed and analyzed. An integrated and computational approach is developed to identify dysregulated IIMATs for MGN patients based on expression and interaction data. Results 45 dysregulated IIMATs are identified in MGN by above method. Dysregulated patterns of these dysregulated IIMATs are complex and various. We identify four core clusters from dysregulated IIMATs network and some of these clusters could distinguish MGN and normal samples. Specially, some anti-cancer drugs including Tamoxifen, Bosutinib, Ponatinib and Nintedanib could become candidate drugs for MGN based on drug repurposing strategy follow IIMATs. Functional analysis shows these dysregulated IIMATs are associated with some key functions and chemokine signaling pathway. Conclusions The present study explored the associations among immune, inflammation and MGN. Some effective candidate drugs for MGN were identified based on immune and inflammation. Overall, these comprehensive results provide novel insights into the mechanisms and treatment of MGN.

Background/Aims: Intracellular Ca2+ signaling plays an important role in the regulation of autophagy. However, very little is known about the role of Ca2+ influx, which is induced by plasma membrane Ca2+ channels. Our previous study showed that transient receptor potential canonical channel-6 (TRPC6), a major Ca2+ influx pathway in podocytes, was activated by hypoxia. Here, we investigated whether TRPC6 is involved in hypoxia-induced autophagy in cultured human podocytes. Methods: In the present study, an immortalized human podocyte cell line was used. Fluo-3 fluorescence was utilized to determine intracellular Ca2+ concentration ([Ca2+]i), and western blotting was used to measure autophagy and protein expression. Results: We found that blockade TRPC6 by using either TRPC6 siRNA or a TRPC6 blocker attenuated hypoxia-induced autophagy, while enhancement of TRPC6 activity with a TRPC6 activator enhanced hypoxia-induced autophagy. Furthermore, TRPC6-dependent Ca2+ signaling is responsible for hypoxia-induced autophagy since both an intracellular and extracellular Ca2+ chelator abolished hypoxia-induced autophagy. Moreover, we found that blockade of TRPC6 by using either TRPC6 siRNA or a TRPC6 blocker decreased the expression of adenosine monophosphate-activated protein kinase (AMPK), an important signaling molecule in Ca2+-dependent autophagy activation, which is activated under hypoxic conditions. These data suggest that the involvement of TRPC6 in hypoxia-induced autophagy is associated with AMPK signaling. Conclusion: TRPC6 is essential for hypoxia-induced autophagy in podocytes.

Background/Aims: Risk factor studies for acute kidney injury (AKI) in China are lacking, especially those regarding non-traditional risk factors, such as laboratory indicators. Methods: All adult patients admitted to 38 tertiary and 22 secondary hospitals in China in any one month between July and December 2014 were surveyed. AKI patients were screened according to the Kidney Disease: Improving Global Outcomes’ definition of AKI. Logistic regression was used to analyze the risk factors for AKI, and Cox regression was used to analyze the risk of in-hospital mortality for AKI patients; additionally, a propensity score analysis was used to reconfirm the risk factors among laboratory indicators for mortality. Results: The morbidity of AKI was 0.97%. Independent risk factors for AKI were advancing age, male gender, hypertension, and chronic kidney disease. All-cause mortality was 16.5%. The predictors of mortality in AKI patients were advancing age, tumor, higher uric acid level and increases in Acute Physiologic Assessment and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores. The hazard ratio (HR) for mortality with uric acid levels > 9.1 mg/dl compared with ≤ 5.2 mg/dl was 1.78 (95% CI: 1.23 to 2.58) for the AKI patients as a group, and was 1.73 (95% CI: 1.24 to 2.42) for a propensity score-matched set. Conclusion: In addition to traditional risk factors, uric acid level is an independent predictor of all-cause mortality after AKI.

Background/Aims: Recent studies provided compelling evidence that stimulation of the calcium sensing receptor (CaSR) exerts direct renoprotective action at the glomerular podocyte level. This protective action may be attributed to the RhoA-dependent stabilization of the actin cytoskeleton. However, the underlying mechanisms remain unclear. Methods: In the present study, an immortalized human podocyte cell line was used. Fluo-3 fluorescence was utilized to determine intracellular Ca2+ concentration ([Ca2+]i), and western blotting was used to measure canonical transient receptor potential 6 (TRPC6) protein expression and RhoA activity. Stress fibers were detected by FITC-phalloidin. Results: Activating CaSR with a high extracellular Ca2+ concentration ([Ca2+]o) or R-568 (a type II CaSR agonist) induces an increase in the [Ca2+]i in a dose-dependent manner. This increase in [Ca2+]i is phospholipase C (PLC)-dependent and is smaller in the absence of extracellular Ca2+ than in the presence of 0.5 mM [Ca2+]o. The CaSR activation-induced [Ca2+]i increase is attenuated by the pharmacological blockage of TRPC6 channels or siRNA targeting TRPC6. These data suggest that TRPC6 is involved in CaSR activation-induced Ca2+ influx. Consistent with a previous study, CaSR stimulation results in an increase in RhoA activity. However, the knockdown of TRPC6 significantly abolished the RhoA activity increase induced by CaSR stimulation, suggesting that TRPC6-dependent Ca2+ entry is required for RhoA activation. The activated RhoA is involved in the formation of stress fibers and focal adhesions in response to CaSR stimulation because siRNA targeting RhoA attenuated the increase in the stress fiber mediated by CaSR stimulation. Moreover, this effect of CaSR activation on the formation of stress fibers is also abolished by the knockdown of TRPC6. Conclusion: TRPC6 is involved in the regulation of stress fiber formation and focal adhesions via the RhoA pathway in response to CaSR activation. This may explain the direct protective action of CaSR agonists.

Introduction Starting dialysis early or late both result in a low quality of life and a poor prognosis in patients undergoing haemodialysis. However, there remains no consensus on the optimal timing of dialysis initiation, mainly because of a lack of suitable methods to assess variations in dialysis initiation time. We have established a novel equation named DIFE (Dialysis Initiation based on Fuzzy-mathematics Equation) through a retrospective, multicentre clinical cohort study in China to determine the most suitable timing of dialysis initiation. The predictors of the DIFE include nine biochemical markers and clinical variables that together influence dialysis initiation. To externally validate the clinical accuracy of DIFE, we designed the assessment of DIFE (ADIFE) study as a prospective, open-label, multicentre, randomised controlled trial to assess the clinical outcomes among patients who initiate dialysis in an optimal start dialysis group and a late-start dialysis group, based on DIFE.Methods and analysis A total of 388 enrolled patients with end-stage renal disease will be randomised 1:1 to the optimal start dialysis group, with a DIFE value between 30 and 35, or the late-start dialysis group, with a DIFE value less than 30, using the Randomization and Trial Supply Management system. Participants will be assessed for changes in signs and symptoms, dialysis mode and parameters, biochemical and inflammatory markers, Subjective Global Assessment, Kidney Disease Quality of Life Short Form, Cognitive Assessment, medical costs, adverse events and concomitant medication at baseline, predialysis visiting stage and postdialysis visiting stage, every 12–24 weeks. The following data will be recorded on standardised online electronic case report forms. The primary endpoint is 3-year all-cause mortality. The secondary endpoints include non-fatal cerebrocardiovascular events, annual hospitalisation rate, quality of life, medical costs and haemodialysis related complications.Ethics and dissemination Ethical approval was obtained from the Ethics Committee of the First Affiliated Hospital of Dalian Medical University China (registration no: YJ-KY-2017–119) and the ethics committees of all participating centres. The final results of the ADIFE trial will be presented to the study sponsor, clinical researchers and the patient and public involvement reference group. Findings will be disseminated through peer-reviewed journals, Clinical Practice Guidelines and at scientific meetings.Trial registration number ClinicalTrial.gov. Registry (NCT03385902); pre-results.

Background and Aims: There is accumulating evidence that sympathetic nervous hyperactivity contributes to the pathogenesis of glomerular sclerosis independent of blood pressure effects. A previous study showed that α1-adrenoceptor (α1-AR) antagonists inhibit mesangial cell (MC) proliferation. However, the underlying mechanism remains unclear. Methods and Results: We found that α1-AR is expressed in a human mesangial cell line. The α1-AR agonist phenylephrine (PE) induced Ca2+ influx as well as release from intracellular Ca2+ stores. Blockade of TRPC6 with siRNA, anti-TRPC6 antibodies and a TRPC blocker attenuated the PE-induced [Ca2+]i increase. Additionally, the PE-induced [Ca2+]i increase was phospholipase C dependent. Furthermore, PE induced a [Ca2+]i increase even when the intracellular Ca2+ stores were already depleted. This effect was mimicked by an analog of diacylglycerol. These results suggested that, upon α1-AR stimulation, TRPC6 mediates Ca2+ influx via a receptor-operated Ca2+ entry mechanism. Finally, TRPC6 contributes to the PE-induced MC proliferation. The mechanisms are associated with the extracellular signal-regulated kinase (ERK) signaling pathway because blockade of TRPC6 and chelation of extracellular Ca2+ abrogated PE-induced ERK1/2 abrogated PE-induced ERK1/2 phosphorylation. Conclusion: TRPC6 channels are involved in α1-AR activation-induced Ca2+ entry, which mediates proliferation via ERK signaling in human MCs

Typically, most nephropathies can be categorized as complex human diseases in which the cumulative effect of multiple minor genes, combined with environmental and lifestyle factors, determines the disease phenotype. Thus, multi-target drugs would be more likely to facilitate comprehensive renoprotection than single-target agents. In this study, functional chemical-protein association analysis was performed to retrieve multi-target drugs of high pathway wideness from the STITCH 3.1 database. Pathway wideness of a drug evaluated the efficiency of regulation of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in quantity. We identified nine experimentally validated renoprotectants that exerted remarkable impact on KEGG pathways by targeting a limited number of proteins. We selected curcumin as an illustrative compound to display the advantage of multi-pathway drugs on renoprotection. We compared curcumin with hemin, an agonist of heme oxygenase-1 (HO-1), which significantly affects only one KEGG pathway, porphyrin and chlorophyll metabolism (adjusted p = 1.5×10-5). At the same concentration (10 µM), both curcumin and hemin equivalently mitigated oxidative stress in H2O2-treated glomerular mesangial cells. The benefit of using hemin was derived from its agonistic effect on HO-1, providing relief from oxidative stress. Selective inhibition of HO-1 completely blocked the action of hemin but not that of curcumin, suggesting simultaneous multi-pathway intervention by curcumin. Curcumin also increased cellular autophagy levels, enhancing its protective effect; however, hemin had no effects. Based on the fact that the dysregulation of multiple pathways is implicated in the etiology of complex diseases, we proposed a feasible method for identifying multi-pathway drugs from compounds with validated targets. Our efforts will help identify multi-pathway agents capable of providing comprehensive protection against renal injuries.

Calcium-sensing receptor (CaSR) has been demonstrated to be present in several tissues and cells unrelated to systemic calcium homeostasis, where it regulates a series of diverse cellular functions. A previous study indicated that CaSR is expressed in mouse glomerular mesangial cells (MCs), and stimulation of CaSR induces cell proliferation. However, the signaling cascades initiated by CaSR activation in MCs are currently unknown. In this study, our data demonstrate that CaSR mRNA and protein are expressed in a human mesangial cell line. Activating CaSR with high extracellular Ca2+ concentration ([Ca2+]o) or spermine induces a phospholipase C (PLC)-dependent increase in intracellular Ca2+ concentration ([Ca2+]i). Interestingly, the CaSR activation-induced increase in [Ca2+]i results not only from intracellular Ca2+ release from internal stores but also from canonical transient receptor potential (TRPC)-dependent Ca2+ influx. This increase in Ca2+ was attenuated by treatment with a nonselective TRPC channel blocker but not by treatment with a voltage-gated calcium blocker or Na+/Ca2+ exchanger inhibitor. Furthermore, stimulation of CaSR by high [Ca2+]o enhanced the expression of TRPC3 and TRPC6 but not TRPC1 and TRPC4, and siRNA targeting TRPC3 and TRPC6 attenuated the CaSR activation-induced [Ca2+]i increase. Further experiments indicate that 1-oleoyl-2-acetyl-sn-glycerol (OAG), a known activator of receptor-operated calcium channels, significantly enhances the CaSR activation-induced [Ca2+]i increase. Moreover, under conditions in which intracellular stores were already depleted with thapsigargin (TG), CaSR agonists also induced an increase in [Ca2+]i, suggesting that calcium influx stimulated by CaSR agonists does not require the release of calcium stores. Finally, our data indicate that pharmacological inhibition and knock down of TRPC3 and TRPC6 attenuates the CaSR activation-induced cell proliferation in human MCs. With these data, we conclude that CaSR activation mediates Ca2+ influx and cell proliferation via TRPC3 and TRPC6 in human MCs.

Male schizophrenia patients are known to have a heavier smoking pattern compared with the general population. However, the mechanism for this association is not known, though hypothesis that smoking could alleviate symptomatology of schizophrenia and reduce side effects of antipsychotics has been suggested. The aims of this study were to validate the heavier smoking pattern among male schizophrenia patients and to investigate the possible mechanisms for the association. To enhance the reliability of the study, we recruited two large independent samples with 604 and 535 male Chinese schizophrenia patients, and compared their smoking pattern with that of 535 healthy male controls recruited from general population. Validated multiple indicators and multiple causes structure equation model and regression models were used to investigate the association of smoking with factors of schizophrenia symptomatology and with the usage of antipsychotics and their extra-pyramidal side effects (EPS). Schizophrenia patients had significantly heavier smoking pattern compared with healthy controls in our sample (42.4% vs. 16.8%, p

Background: Despite the widespread use of voriconazole in antifungal treatment, its high pharmacokinetic and pharmacodynamic variability may lead to suboptimal efficacy, especially in intensive care unit (ICU) patients. Machine learning (ML), an artificial intelligence modeling approach, is increasingly being applied to personalized medicine. The effectiveness of ML models for predicting voriconazole blood concentrations in ICU patients, compared to traditional population pharmacokinetics (popPK) models, has been uncertain until now. This study aims to identify the most effective modeling strategy for voriconazole., Methods: We developed six ML models using 244 concentrations from 62 patients in our previous popPK dataset. Another additional dataset, consisting of 282 trough concentrations from 177 patients, was used to externally evaluate both ML models and five other published popPK models, utilizing prediction-based diagnostics, simulation-based diagnostics, and Bayesian forecasting., Results: The XGBoost model exhibited superior predictive performance among the six ML models, achieving an R 2 of 0.73. Its performance metrics (RMSE%: 127.21 %, median absolute prediction error: 29.65 %, median prediction error: 9.82 %, F20: 34.04 %, F30: 50.71 %) outperformed those of the best popPK model (RMSE%: 152.41 %, median absolute prediction error: 44.75 %, median prediction error: -0.99 %, F20: 23.40 %, F30: 36.88 %), suggesting greater accuracy and precision in predicting pharmacokinetics., Conclusions: Both ML and popPK models can be utilized for individualized voriconazole therapy. Our comparative study provides insights into the most effective methods for modeling and predicting voriconazole concentrations., Competing Interests: Declaration of competing interests None declared., (Copyright © 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Liver disease poses a significant threat to global public health, with arsenic (As) recognized as a major environmental toxin contributing to liver injury. However, the specific mechanisms and the protective effects of α-lipoic acid (LA) remain unclear. Therefore, this study employs network toxicology and network pharmacology to comprehensively analyze the hepatotoxic mechanism of As and the hepatoprotective mechanism of LA, and further verifies the mechanisms of peroxisomal β-oxidation and lipophagy in the process. The network analysis results show that As induces liver damage mainly through autophagy, apoptosis, lipid metabolism, and oxidative stress, whereas LA exerts its hepatoprotective properties mainly by regulating lipid metabolism. Further verifications find that As inhibits SIRT1 expression, activates the P53 and Notch pathways, damages mitochondria, inhibits peroxisomal β-oxidation, increases lipid accumulation, and enhances lipophagy in the liver, while LA intervention alleviates As-induced lipid accumulation and enhances lipophagy by targeting SIRT1, ameliorating mitochondrial damage, enhancing peroxisomal β-oxidation, thereby alleviating As-induced liver damage. This study further clarifies the mechanism of As hepatotoxicity and provides a theoretical basis for LA as a potential hepatoprotective agent., (© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Ethnopharmacological Relevance: Fructus Rubi (FR), a food material with medicinal value, is used in traditional Chinese medicine (TCM) for treatment of various kidney-related problems, such as impotence, spermatorrhea, and frequent urination. It is also frequently used to produce diverse functional foods in China., Aim of Study: The purpose of this research was to assess the therapeutic effects of FR diterpene glycosides on RWPE-1 epithelial cell (RWPE-1), a human normal prostatic epithelial cell, and benign prostate hyperplasia (BPH) rats, both of which had been exposed to dihydrotestosterone (DHT) and testosterone propionate (TP), respectively, and to investigate the mechanism of action., Methods: Target proteins that could stably bind to certain diterpene glycosides were screened through drug affinity responsive target stability combined with mass spectrometry (DARTS/MS). DHT-induced RWPE-1 cells were used to detect drug activity. TP was subcutaneously injected to induce BPH in rats. The extract of diterpene glycosides from FR (FDS) was orally administered for 28 days. The DHT levels in the serum and prostate tissue of the rats were measured through enzyme-linked immunosorbent assay (ELISA), and to analyze cell proliferation and epithelial-mesenchymal transition (EMT), the protein expression of prostate-specific antigen (PSA), androgen receptor (AR), steroid 5α-reductase type 2 (SRD5A2), proliferating cell nuclear antigen (PCNA), S100 calcium-binding protein A2 (S100A2), transforming growth factor-β1 (TGF-β1), E-cadherin, vimentin, and Smad4 was determined through western blotting (WB), immunohistochemistry (IHC), or immunofluorescence (IF)., Results: FDS reduced the proliferation of DHT-induced RWPE-1 cells. It also significantly inhibited rat prostate enlargement; decreased DHT levels in the serum and prostate tissue; inhibited the protein expression of AR, PSA, PCNA, S100A2, TGF-β1, E-cadherin, and Smad4; and increased the protein expression of E-cadherin., Conclusion: The present study is the first to report that diterpene glycosides isolated from FR inhibited BPH at the cellular level, regulated the proliferation of prostate cells through the androgen signaling pathway, and prevented EMT in the prostate through the S100A2-mediated TGF-β/Smad signaling pathway. These results indicate that FDS is a promising multitarget therapy for BPH., 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 B.V. All rights reserved.)

Silk fibroin (SF), a pivotal biomaterial, holds immense promise for diverse applications within the realm of bone tissue engineering. SF is an ideal scaffold material with exceptional biocompatibility, mechanical robustness, biodegradability, and bioactivity. A plethora of investigations have corroborated SF's efficacy in supporting bone tissue repair and regeneration. This comprehensive review delves into the structural attributes, physicochemical characteristics, and extraction methodologies of SF. Moreover, it elucidates the strides taken in harnessing SF across a spectrum of forms, including films, hydrogels, scaffolds, electrospun fibers, and composites for bone tissue engineering applications. Moreover, the application bottleneck of SF as a bone repair material is highlighted, and its development prospects and potential biomedical applications are also presented in this review. We expect that this review can inspire the broad interest of a wide range of readers working in the fields of materials science, tissue engineering, biomaterials, bioengineering, and biomedicine.

The development of biomass material is an important approach to alleviating the excessive using of plastic packaging, by which the product could be more environmentally friendly and lower toxicity. In this study, we developed a biodegradable photodynamic antibacterial food packaging film using nitrogen-doped carbon quantum dots (N-CQDs) synthesized from crayfish shells, combined with konjac glucomannan (KGM) and sodium alginate (SA). Casting method was used to prepare the composite film and results indicated that incorporation of N-CQDs significantly enhanced the mechanical and barrier properties of the film by reducing the number of micropores. The N-CQDs endowed the film with strong antioxidant activity and UV resistance. The DPPH scavenging rate of the composite film reached 77.92 %, while the transmittance of ultraviolet (300 nm) was reduced to 16.97 %. Furthermore, under blue light irradiation, the film exhibited excellent photodynamic antibacterial effects against Shewanella putrefaciens and Staphylococcus aureus, achieving inhibition rates of 99.2 % and 98.99 %, respectively. The film solution demonstrated no cytotoxicity, and the composite film preserved crayfish meat for up to 8 days at 4 °C. Furthermore, the film almost completely degrading in soil within 14 days. These findings suggest that the KGM/SA/N-CQD film is a promising degradable antimicrobial material for food packaging applications., 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 © 2025. Published by Elsevier B.V.)

Objective: The current clinical data regarding the re-administration of PARPi maintenance therapy in platinum sensitive recurrent ovarian cancer (PSROC) is limited. This study aims to investigate the efficacy and associated factors of PARPi re-maintenance therapy in PSROC patients in China., Methods: In this study, there were 201 patients with PSROC who had received maintenance therapy previously and achieved complete or partial response after platinum-based chemotherapy upon recurrence. The re-maintenance therapy group (Re-PARPi) and chemotherapy alone group (Chem-A) were categorized based on whether PARPi was reused after recurrence chemotherapy. A propensity-score matching (PSM) analysis was conducted between re-maintenance therapy group (Re-PARPi-P) and chemotherapy alone group(Chem-A-P)to adjust for imbalanced risk factors. The efficacy was evaluated via progression-free survival (PFS) and prognostic factors were also analyzed., Results: In the PSM subgroup, the median PFS (mPFS) of Re-PARPi-P group (44 cases) and Chem-A-P (44 cases) group were 10.0 months and 6.5 months (HR 1.64, P=0.041) respectively, confirming that re-maintenance therapy was superior to relapse chemotherapy alone. The mPFS was 10.8 months in all patients in the Re-PARPi group (51 cases), with 11.0 months in BRCAm group and 10.2 months in BRCAwt group (P=0.806). Intervals of more than 6 months between two PARPi therapies might improve the efficacy of PARPi re-treatment (mPFS 11.2 months vs. 7.8 months, HR 3.94, P=0.005). Age, BRCA status, number of previous treatment lines, CA125 level prior to re-administration, and other factors were not significantly related to the efficacy of re-maintenance therapy. Patients with a frameshift mutation (p. Ile1824Aspfs3) in the C-terminal domain of BRCA1 germline gene had significantly better efficacy with PARPi re-treatment compared to other groups. Only nonsense mutation (p.Gln1037, p.Cys328, p.Leu1072) occur in BRCA germline gene with re-treatment with PARPi might be suboptimal. The incidence of PARRi re-treatment interruption was 3.9%., Conclusion: PARPi re-maintenance therapy in PSROC might improve prognosis compared to chemotherapy alone, regardless of their genetic mutation status. Patients with re-maintenance therapy might benefit if the interval between the use of PARP inhibitors exceeded 6 months. The structural domains of BRCA mutations with different sensitivity to PARPi might serve as a promising biomarker for optimizing treatment. Re-treatment with PARPi was well-tolerated., 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 © 2025 Wang, Yang, Guo, Li, Tuersun, Cao, Li, Liu, Li, Liu and Huang.)

Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) with clinical manifestations of respiratory distress and hypoxemia remains a significant cause of respiratory failure, boasting a persistently high incidence and mortality rate. Given the central role of M1 macrophages in the pathogenesis of acute lung injury (ALI), this study utilized the anti-inflammatory agent curcumin as a model drug. l-arginine (L-Arg) was employed as a targeting ligand, and chitosan was initially modified with l-arginine. Subsequently, it was utilized as a surface modifier to prepare inhalable nano-crystals loaded with curcumin (Arg-CS-Cur), aiming for specific targeting of pulmonary M1 macrophages. Compared with unmodified chitosan-curcumin nanocrystals (CS-Cur), Arg-CS-Cur exhibited higher uptake in vitro by M1 macrophages, as evidenced by flow cytometry showing the highest fluorescence intensity in the Arg-CS-Cur group (P < 0.01). In vivo accumulation was greater in inflamed lung tissues, as indicated by small animal imaging demonstrating higher lung fluorescence intensity in the DiR-Arg-CS-Cur group compared to the DiR-CS-Cur group in the rat ALI model (P < 0.05), peaking at 12 h. Moreover, Arg-CS-Cur demonstrated enhanced therapeutic effects in both LPS-induced RAW264.7 cells and ALI rat models. Specifically, treatment with Arg-CS-Cur significantly suppressed NO release and levels of TNF-α and IL-6 in RAW264.7 cells (p < 0.01), while in ALI rat models, expression levels of TNF-α and IL-6 in lung tissues were significantly lower than those in the model group (P < 0.01). Furthermore, lung tissue damage was significantly reduced, with histological scores significantly lower than those in the CS-Cur group (P < 0.01). In conclusion, these findings underscore the targeting potential of l-arginine-modified nanocrystals, which effectively enhance curcumin concentration in inflammatory environments by selectively targeting M1 macrophages. This study thus introduces novel perspectives and theoretical support for the development of targeted therapeutic interventions for acute inflammatory lung diseases, including ALI/ARDS., 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.)

Surfactant is generally regarded to enhance the hydrolysis rate and favor high efficiency which however has not been revealed in the lignocellulosic anaerobic co-digestion process. In particular, the responses and functions of fungal community exposing to surfactants remain largely unknown. In this study, the roles of dodecyl dimethyl benzyl ammonium chloride (DDBAC, cationic), linear alkylbenzene sulfonate (LAS, anionic) and Triton X-100 (TX, nonionic) surfactants on the lignocellulosic anaerobic co-digestion were investigated. 1 mg/L DDBAC, LAS and TX promoted the degradation of lignocellulose and increased biogas yields by 6.85%, 62.76% and 36.96% comparing with the control group (CK). LAS and TX stimulated the growth of Prevotella, Petrimonas and Romboutsia, produced higher activities of cellulase (averagely 4.22 and 3.73 times of CK), generated more volatile fatty acids (VFAs, averagely 2.94 and 2.44 times of CK) and NH 4 + -N (averagely 1.91 and 1.63 times of the control group), and finally realized efficient acetoclastic methanogenesis. The abundant fungi genera, Pseudallescheria, Pseudeurotium, Monascus and Aspergillus were significantly correlated to lignin, cellulose, VFAs, ammonia nitrogen (NH 4 + -N), cellulase and coenzyme F 420 activities (p < 0.05). Surfactants exposure damaged the connectivity of Proteobacteria with other microbes in the co-occurrence networks while increased the connectivity of Ascomycota to offset the disturbance of surfactants on the fungal community. The synergistic interaction between bacteria and fungi achieved efficient substrate degradation, contributed to the stability of microbial community and resulted in high biogas production. This research provided references for further management of surfactants exposed lignocellulosic anaerobic co-digestion process and systematically biowaste treatment in large-scale farms., 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 Ltd. All rights reserved.)

Purpose: The recurrence of esophageal squamous cell carcinoma (ESCC) in radiation therapy treatment presents a complex challenge due to its resistance to radiation. However, the mechanism underlying the development of radioresistance in ESCC remains unclear. In this study, we aim to uncover the mechanisms underlying radioresistance in ESCC cells and identify potential targets for radiosensitization., Methods: We established two radio-resistant cell lines, TE-1R and KYSE-150R, from the parental ESCC cell lines TE-1 and KYSE-150 through fractionated irradiation. A TMT-based quantitative proteomic profiling approach was applied to identify changes in protein expression patterns. Cell Counting Kit-8, colony formation, γH2AX foci immunofluorescence and comet assays were utilized to validate our findings. The downstream effectors of the DNA repair pathway were confirmed using an HR/NHEJ reporter assay and Western blot analysis. Furthermore, we evaluated the expression of potential targets in ESCC tissues through immunohistochemistry combined with mass spectrometry., Results: Over 2,000 proteins were quantitatively identified in the ESCC cell lysates. A comparison with radio-sensitive cells revealed 61 up-regulated and 14 down-regulated proteins in the radio-resistant cells. Additionally, radiation treatment induced 24 up-regulated and 12 down-regulated proteins in the radio-sensitive ESCC cells. Among the differentially expressed proteins, S100 calcium binding protein A6 (S100A6), glutamine gamma-glutamyltransferase 2 (TGM2), glycogen phosphorylase, brain form (PYGB), and Thymosin Beta 10 (TMSB10) were selected for further validation studies as they were found to be over-expressed in the accumulated radio-resistant ESCC cells and radio-resistant cells. Importantly, high S100A6 expression showed a positive correlation with cancer recurrence in ESCC patients. Our results suggest that several key proteins, including S100A6, TGM2, and PYGB, play a role in the development of radioresistance in ESCC., Conclusions: Our results revealed that several proteins including Protein S100-A6 (S100A6), Protein-glutamine gamma-glutamyltransferase 2 (TGM2), Glycogen phosphorylase, brain form (PYGB) were involved in radio-resistance development. These proteins could potentially serve as biomarkers for ESCC radio-resistance and as therapeutic targets to treat radio-resistant ESCC cells., (© 2024 The Author(s). PROTEOMICS ‐ Clinical Applications published by Wiley‐VCH GmbH.)

Strychni Semen, characterized by its bitter taste and warm properties, has been confirmed to possess anti-tumor properties. However, the molecular mechanism of Strychni Semen in treating non-small cell lung cancer (NSCLC) needs further study. This study aimed to explore the molecular mechanism of Strychni Semen in treating NSCLC based on network pharmacology and molecular docking. The active components and targets of Strychni Semen were retrieved from the TCMSP, supplemented by the HERB database and the related literature. NSCLC-related targets were retrieved from the GeneCards, OMIM and DisGenet databases. The intersection targets of Strychni Semen in treating NSCLC were obtained via an online platform. The Protein-Protein Interaction (PPI) network was subsequently constructed to deeply analyse the interrelationship of the intersection targets via the String database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out via the Metascape database. The interactive networks between Strychni Semen and NSCLC were constructed via Cytoscape 3.9.1. Molecular docking detected interactions between the key components and the core targets. The core targets were validated via GEO datasets. 21 active components and 67 targets were identified, with 47 associated with NSCLC. The key active components were Stigmasterol, IcarideA, 2-Hydroxymethylanthraquinone, (+)-catechin, (2R)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one, (S)-Stylopine, Brucine and Isobrucine. The core targets were PTGS2, NR3C1, ESR1, CASP3 and PRKACA. Molecular docking revealed that these compounds undergo strong binding affinity with the core genes. GEO database indicated that PTGS2 was the most promising core target. In addition, Strychni Semen's effects on NSCLC involved mainly the Calcium pathway, the Estrogen pathway, and the cGMP-PKG and cAMP pathways. This study visually demonstrated the mechanism of the therapeutic effect of Strychni Semen in NSCLC through multiple components, targets and pathways which provides a basis for clinical treatment and further experimental research., Competing Interests: Declarations. Ethics Approval and Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background/aim: Solute carrier (SLC) family 15 member 2 (SLC15A2) is an integral member of the SLC family that plays a pivotal role in numerous biological processes, including the regulation of cellular signaling pathways. However, its role in prostate cancer (PCa) remains inadequately elucidated. This study aims to investigate the prognostic significance of SLC15A2 in PCa., Materials and Methods: We evaluated the expression levels and prognostic significance of SLC15A2 in multicenter cohorts of PCa through differential expression analysis, survival analysis, and Cox regression. These findings were validated through immunohistochemistry and in vitro experiments. Gene set enrichment analysis, mutation analysis, and methylation analysis were used to investigate the potential biological functions of SLC15A2. Finally, drug target prediction analysis was conducted to identify small molecule therapeutic agents specifically targeting SLC15A2 in PCa., Results: The expression level of SLC15A2 in PCa tissues was significantly lower compared to benign tissues, and reduced expression of SLC15A2 was often associated with early biochemical recurrence (BCR) and decreased overall survival in PCa patients. Moreover, results from in vitro experiments indicated that knockdown of SLC15A2 markedly enhanced the proliferation and migratory capacity of PCa cells. Enrichment analysis indicated that SLC15A2 predominantly activates pathways related to cell proliferation, adhesion, and lipid metabolism while inhibiting pathways associated with protein synthesis, degradation, RNA metabolism, and energy metabolism. Notably, the frequency of TP53 mutations and 8q24.21 copy number variations was significantly higher in the low SLC15A2 expression group. DNA hypermethylation of SLC15A2 at gene body linked to downregulation of SLC15A2 in PCa. Finally, analysis with the Connectivity Map database identified several promising small molecule drugs for PCa treatment, including rucaparib., Conclusion: Our findings suggest that SLC15A2 serves as a promising prognostic biomarker in PCa, enabling accurate risk stratification for BCR. This insight may contribute to the advancement of personalized treatment strategies for PCa., (Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Recent advances have uncovered an exotic sliding ferroelectric mechanism, which endows to design atomically thin ferroelectrics from non-ferroelectric parent monolayers. Although notable progress has been witnessed in understanding the fundamental properties, functional devices based on sliding ferroelectrics remain elusive. Here, we demonstrate the rewritable, non-volatile memories at room-temperature with a two-dimensional (2D) sliding ferroelectric semiconductor of rhombohedral-stacked bilayer MoS 2 . The 2D sliding ferroelectric memories (SFeMs) show superior performances with a large memory window of >8 V, a high conductance ratio of above 10 6 , a long retention time of >10 years, and a programming endurance greater than 10 4 cycles. Remarkably, flexible SFeMs are achieved with state-of-the-art performances competitive to their rigid counterparts and maintain their performances post bending over 10 3 cycles. Furthermore, synapse-specific Hebbian forms of plasticity and image recognition with a high accuracy of 97.81% are demonstrated based on flexible SFeMs., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Long non-coding RNA TMC3-AS1 is identified to be upregulated by lipopolysaccharide (LPS) in inflammatory disease, but its role in acute kidney injury (AKI) is almost unknown. The study investigated the involvement of TMC3-AS1 in LPS-induced AKI and its downstream molecular regulatory mechanism. Our data suggested that knocking down TMC3-AS1 significantly reduced renal dysfunction, tissue inflammation and tissue damage in LPS-induced mice, and promoted cell viability, inhibited inflammation, apoptosis and necrosis in LPS-stimulated human renal tubular epithelial cells HK2. Meanwhile, silencing TMC3-AS1 decreased the expression levels of Wnt5a, Atg5, NLRP3 and cleaved caspase1 and the ratio of LC3II/LC3I, but elevated p62 level in vivo and in vitro, suggesting the inhibitory effect of TMC3-AS1 silence on Wnt5a signaling, autophagy, and pyroptosis. Mechanically, TMC3-AS1 upregulated the expression of WNT5A mRNA and Wnt5a protein through competitively binding with miR-148a-3p, thus elevating the expression levels of autophagy and pyroptosis-associated markers in LPS-induced HK2 cells. MiR-148a-3p mimic also exerted protective effects on LPS-treated HK2 cells, which was counteracted by overexpressing WNT5A or TMC3-AS1. Altogether, these findings reveal that TMC3-AS1 inhibition restrains LPS-triggered AKI progression through inactivating Wnt5a -mediated autophagy and pyroptosis pathway., Competing Interests: Declaration of Competing Interest The authors declared no conflict of interest in this study., (Copyright © 2024. Published by Elsevier Ltd.)

Sulfur dioxide (SO 2 ) is a ubiquitous environmental pollutant that has been shown to be toxic to the male reproductive system, but the underlying mechanism remains unclear. Therefore, the SO 2 -treated mice and primary Leydig cell models were established to investigate the effects of SO 2 on the production of testosterone and its specific mechanism. The results demonstrated that SO 2 activated the ERK1/2 signaling pathway, leading to increased key proteins expression of testosterone biosynthesis and elevated testosterone levels. The addition of ERK1/2 inhibitor U0126 attenuated SO 2 -induced increases in key testosterone biosynthetic gene mRNA levels of Star, Cyp17a1, Hsd3b1, and testosterone. Low doses of SO 2 reduced the expression of BECLIN1 and LC3 proteins, increased P-4E-BP1 protein expression, and decreased autophagy in Leydig cells. Moreover, increasing doses of SO 2 correlate with enhanced Leydig cell autophagy and testosterone levels initially. However, increasing the dose of SO 2 resulted in a significant decrease in cell viability and ultimately decreased testosterone levels. These findings suggest that SO 2 promotes testosterone production by activating ERK1/2 and disrupting autophagy. This study enriched the dose-effect relationship of SO 2 on the male reproductive system and provided a theoretical reference for us to have a comprehensive and dynamic understanding of the SO 2 toxic mechanism., 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 B.V. All rights reserved.)

Background: A growing body of research supports the important role of the TH2 axis in alopecia areata (AA). Dupilumab is a humanized monoclonal antibody against IL-4Rα that downregulates TH2 response. Although efficacy has been shown in clinical trials, real-world data on the use of dupilumab in AA patients is limited., Objectives: To report on a case series of 10 patients with AA who were treated with dupilumab and provide real-world evidence regarding its efficacy in treating severe AA., Methods: In this retrospective single-center study, all AA patients treated with dupilumab treatment were included between May 2022 and October 2023. Clinical outcome measures (Severity of Alopecia Tool, SALT) and adverse events (AEs) were analyzed. In addition, a literature review was conducted to summarize the efficacy of AA with dupilumab and the characteristics of patients previously reported in the literature., Results: We identified 10 patients with AA who were or are being treated with dupilumab, with a median (range) treatment duration of 8 (3-15) months. Of these, four patients have high serum immunoglobulin E (IgE) levels (≥200IU/ml). The mean (IQR) pretreatment SALT score was 79% (52-100). Seven of 10 patients achieved at least 50% re-growth. Of those who improved, the mean (IQR) percentage change in SALT score at 3 months and the end of follow-up was 57% (29%-89%) and 95% (68-100), respectively. Notably, seven patients (70%) had white hair regrowth, with the white hair slowly decreasing over time and the proportion of pigmented black hair increasing. Dupilumab was well tolerated by all patients. No adverse events were reported., Conclusions: Overall, our research supports dupilumab as another candidate that possesses potential benefits for AA. High levels of IgE may be not prerequisites for dupilumab's successful treatment response.

Spinal Cord Injury (SCI) is a severe condition that often leads to substantial neurological impairments. This study aimed to explore the role of Aquaporin-4 (AQP4) in regulating astrocyte autophagy and neuroinflammation post-SCI, as well as to evaluate the therapeutic potential of AQP4 inhibition using the specific inhibitor TGN-020. Using Western blot, CCK8 assays, immunofluorescence staining, histopathological assessments, and behavioral analyses, we investigated the effects of TGN-020 on SCI-induced alterations in autophagy, neuroinflammation, astrocyte proliferation, neuronal damage, and motor function recovery in both rat and astrocyte models. Our findings indicate that TGN-020 significantly enhances astrocyte autophagy, reduces neuroinflammation, thereby leading to mitigated astrocyte activation by suppressing AQP4 expression. These beneficial effects are associated with the activation of the peroxisome proliferator-activated receptor-γ/mammalian target of rapamycin (PPAR-γ/mTOR) signaling pathway. Notably, the introduction of the PPAR-γ specific inhibitor GW9662 abrogated the positive regulatory effects of TGN-020 on SCI-induced autophagy and neuroinflammation. Collectively, our in vivo and in vitro experiments demonstrate that TGN-020, by down-regulating AQP4, activates the PPAR-γ/mTOR pathway, ameliorates astrocyte autophagy, diminishes neuroinflammation, and ultimately enhances motor function recovery., Competing Interests: Declaration of competing interest All authors declare that there are no conflicts of financial interests., (Copyright © 2024. Published by Elsevier Inc.)

Deep venous thrombosis (DVT) has insidious clinical symptoms, and only a few patients suffer from lower limb swelling, tenderness and dorsal flexion pain. We aimed to explore the ultrasonographic features and risk factors of postoperative lower limb DVT in patients with lower limb fractures. Ninety patients with lower limb fractures admitted from January 1st, 2021 to June 30th, 2023 were selected. Color Doppler ultrasonography was performed one month after operation, and the ultrasonographic features were recorded. DVT was diagnosed according to the results of venography, based on which the patients were divided into a DVT group and a non-DVT group. Their basic and treatment-related data were compared. The risk factors for postoperative DVT were screened by multivariate logistic regression analysis. A total of 63 cases were diagnosed with DVT by venography, with a detection rate of 70.00%. A total of 69 cases were diagnosed with DVT by ultrasonography, with a detection rate of 76.67% (P>0.05). The concurrent internal medicine diseases, associated injuries, no preventive measures for thrombosis, operation time ≥2 h, no active or passive exercise after operation, pelvic and proximal femoral fractures, knee fractures and tibiofibular fractures were risk factors for postoperative DVT in patients with lower limb fractures (P<0.05). Ultrasonography is effective for diagnosing postoperative lower limb DVT in patients with lower limb fractures. Related preventive measures should be taken promptly to control the risk factors.

Objective: Pancreatic cancer is characterized by low survival rate and rapid deterioration. Methyltransferase-like 14 (METTL14), as N6-methyladenosine (m6A) methyltransferase, is closely related to tumor progression. The purpose of this study is to look into how METTL14 affects pancreatic cancer tumorigenesis, cell division, and apoptosis., Material and Methods: We examined and contrasted the levels of METTL14 protein and messenger RNA expression in human pancreatic ductal cells and human pancreatic cancer cells. After silencing or upregulating METTL14, the proliferative ability, migration ability, and cell apoptosis of pancreatic tumor cells was detected by colony-forming assay, wound scratch healing assay, cell counting kit 8 assay, and terminal deoxynucleotidyl transferasemediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling assay. Following the use of c-Myc inhibitor (10058-F4), western blot analysis was carried out to investigate the key factor expression and c-Myc signaling pathway activation status., Results: METTL14 was preferentially expressed in human pancreatic cancer cells PANC-1 and SW1990 than in human normal pancreatic duct cells human pancreatic nestin-expressing cells (HPNE) ( P < 0.001). Overexpression of METTL14 increased the tumorigenic and proliferative ability of pancreatic cancer cells. Overexpression of METTL14 decreased apoptosis rate. Western blot assay showed that nucleus b-catenin increased when METTL14 was overexpressed, and nucleus b-catenin decreased when METTL14 was silenced in PANC-1 cell ( P < 0.01). The protein expression of other key factors, such as c-Myc, matrix metalloproteinase (MMP)-9, and MMP-2, were also affected. The use of c-Myc inhibitor (10058-F4) on the basis of OE-METTL14 reversed the effect of the overexpression of METTL14 on promoting the tumorigenesis and cell proliferation of pancreatic cancer cell lines PANC-1 and SW1990., Conclusion: METTL14 promoted the tumorigenesis and proliferation of pancreatic cancer cells by the c-Myc signaling pathway., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by Scientific Scholar.)

Objective: To investigate the potential protective mechanisms of aconite polysaccharide (FZPS-1) during cryopreservation, with a particular emphasis on morphological changes in autophagy in rat abdominal aorta., Methods: Thirty-six male SD rats were divided into the control group, the cryopreserved model group, and the FZPS-1 intervention group treated with different concentrations of FZPS-1. The structural changes of the abdominal aortic wall were assessed via Masson staining, while cytolysosomes were identified using transmission electron microscopy (TEM). The expression of Beclin-1, LC3-II, and P62 was detected by immunohistochemistry (IHC) and western blot separately. Bcl-2 and Bax mRNA expression was measured by RT-qPCR., Results: Compared with the control group, the abdominal aortic wall in the model group was severely damaged. Contrarily, FZPS-1 10 mg/mL and 20 mg/mL groups had relatively normal structure of the blood vessel wall, higher cytolysosome counts, and increased Beclin-1 and LC3-II expression compared with the model group (all P<0.05); P62 expression also increased in the FZPS-1 20 mg/mL group (P<0.05). Compared with the control group, the mRNA expression of Bcl-2 in the cryopreservation model group was reduced (P<0.05), while Bax was increased (P<0.05). Compared with the cryopreservation model group, the mRNA expression of Bcl-2 was upregulated, while Bax was downregulated in the FPS 10 mg/L group (P<0.05)., Conclusion: During liquid nitrogen cryopreservation, autophagy is inhibited in the rat abdominal aorta, and the blood vessel wall structure is damaged. FZPS-1, as a cryoprotectant, can enhance autophagy and mitigate blood vessel wall damage in the rat abdominal aorta., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The objective of this investigation was to identify the risk factors linked to major adverse outcomes (MAO) subsequent to total arch replacement with frozen elephant trunk procedure (TAR+FET) surgery among patients diagnosed with acute type A aortic dissection (ATAAD). Additionally, the study aimed to elucidate the influence of these adverse outcomes on the long-term prognosis of the patients., Method: 670 ATAAD patients received the TAR+FET procedure. Multivariable logistic regression was used to investigate the risk factors associated with in-hospital MAO. Additionally, long-term survival outcomes were assessed through follow-up observations of all patients., Results: The overall in-hospital mortality was 4.33%. Among 670 patients, 169 patients (25.22%) developed postoperative MAO. Multivariate analysis showed that in-hospital MAO was positively associated with age (OR = 1.025, 95%CI: 1.005-1.045, P = 0.014), lower limb symptoms (OR = 2.562, 95%CI: 1.407-4.666, P = 0.002), involvement of coronary artery (OR = 2.027, 95%CI: 1.312-3.130, P = 0.001), involvement of left renal artery (OR = 1.998, 95%CI: 1.359-2.938, P < 0.001), CPB time (OR = 1.011, 95%CI: 1.007-1.015, P < 0.001) and WBC counts (OR = 1.045, 95%CI: 1.007-1.083, P = 0.019). MAO group showed a worse long-term prognosis than those non-MAO group (P = 0.002)., Conclusions: While TAR+FET can be an effective treatment option for ATAAD patients, careful patient selection and management are essential in minimizing the risk of MAO and ensuring long-term success., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

As an environmental pollutant, fluoride-induced liver damage is directly linked to mitochondrial alteration and oxidative stress. Selenium's antioxidant capacity has been shown to alleviate liver damage. Emerging research proves that E3 ubiquitin ligase Park2 (Parkin)-mediated mitophagy may be a therapeutic target for fluorosis. The current study explored the effect of diverse selenium sources on fluoride-caused liver injury and the role of Parkin-mediated mitophagy in this intervention process. Therefore, this study established a fluoride-different selenium sources co-intervention wild-type (WT) mouse model and a fluoride-optimum selenium sources co-intervention Parkin gene knockout (Parkin-/-) mouse model. Our results show that selenomethionine (SeMet) is the optimum selenium supplementation form for mice suffering from fluorosis when compared to sodium selenite and chitosan nano‑selenium because mice from the F-SeMet group showed more closely normal growth and development levels of liver function, antioxidant capacity, and anti-inflammatory ability. Explicitly, SeMet ameliorated liver inflammation and cell apoptosis in fluoride-toxic mice, accomplished through downregulating the mRNA and protein expression levels associated with mitochondrial fusion and fission, mitophagy, apoptosis, inflammatory signalling pathway of nuclear factor-kappa B (NF-κB), reducing the protein expression levels of PARKIN, PTEN-induced putative kinase1 (PINK1), SQSTM1/p62 (P62), microtubule-associated protein light chain 3 (LC3), cysteinyl aspartate specific proteinase 3 (CASPAS3), as well as restraining the content of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and interferon-γ (IFN-γ). The Parkin-/- showed comparable positive effects to the SeMet in the liver of fluorosis mice. The structure of the mitochondria, mRNA, protein expression levels, and the content of proinflammatory factors in mice from the F Parkin-/- and F + SeMet Parkin-/- groups closely resembled those in the F + SeMet WT group. Overall, the above results indicated that SeMet could alleviate fluoride-triggered inflammation and apoptosis in mice liver via blocking Parkin-mediated mitophagy., 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 B.V. All rights reserved.)

CO 2 electroreduction is a potential pathway to achieve net-zero emissions in the chemical industry. Yet, CO 2 loss, resulting from (bi)carbonate formation, renders the process energy-intensive. Acidic environments can address the issue but at the expense of compromised product Faradaic efficiencies (FEs), particularly for multi-carbon (C 2+ ) products, as rapid diffusion and migration of protons (H + ) favors competing H 2 and CO production. Here, we present a strategy of tuning the 2-position substituent length on benzimidazole (BIM)-based copper (Cu) coordination polymer (CuCP) precatalyst - to enhance CO 2 reduction to C 2+ products in acidic environments. Lengthening the substituent from H to nonyl enhances H + diffusion retardation and decreases Cu-Cu coordination numbers (CNs), favoring further reduction of CO. This leads to a nearly 24× enhancement of selectivity towards CO hydrogenation and C-C coupling at 60 mA cm -2 . We report the highest C 2+ product FE of more than 70% at 260 mA cm -2 on pentyl-CuCP and demonstrate a CO 2 -to-C 2+ single-pass conversion (SPC) of ~54% at 180 mA cm -2 using pentyl-CuCP in zero-gap electrolyzers., (© 2024. The Author(s).)

Obstructive sleep apnea (OSA), a condition often linked with hypertension, has an undefined relationship with renalase, a protein known for regulating blood pressure. This study aimed to investigate the relationship between serum renalase levels as well as renalase functional single nucleotide polymorphism (SNP) rs2296545 variant and hypertension in a Han Chinese OSA population. 126 subjects underwent serum renalase detection, with linear regression being performed to evaluate the relationship between serum renalase levels and OSA-related traits. Additional 4275 subjects were obtained rs2296545 genotype information by SNP microarray. And binary logistic regression was used to assess the effect of rs2296545 on hypertension risk. Molecular dynamics simulation and molecular docking were utilized to access the protein structures and the interplay between protein and catecholamines of wild-type and rs2296545 mutant renalase. The results showed that serum renalase levels were significantly higher in the severe OSA group. Further analysis showed renalase levels were positively correlated with blood pressure in the non-OSA group and negatively correlated in the severe OSA group. For rs2296545 polymorphism analysis, the hypertension risk significantly increased for the recessive model CC/GG + CG (OR = 1.211, 95% CI: 1.025-1.431) and the additive model CC/CG (OR = 1.223, 95% CI: 1.025-1.458) in the severe OSA. The rs2296545 polymorphism affected protein structure, and led to increase binding free energy, weakening interactions between renalase and catecholamines. In conclusion, serum renalase levels had independent association with blood pressure. And rs2296545 polymorphism may influence on susceptibility to hypertension by altering protein ability to bind to catecholamines, which might contribute to the intervention of hypertension in the OSA population., (© 2024. The Author(s).)

Background and Study Aim: Gastric cancer (GC) is one of the most common gastrointestinal tumors characterized by aggressive development and poor prognosis. Circular RNAs (circRNAs) have been used as prognostic biomarkers and therapeutic targets in many cancers, including GC. Hsa&#95;circ&#95;0008667 is differentially expressed in GC; however, its function and clinical significance remained unelucidated. Therefore, this study aimed to investigate the role and significance of hsa&#95;circ&#95;0008667 in GC and its potential as a biomarker and therapeutic target of GC., Patients and Methods: Through quantitative reverse-transcription real-time PCR, hsa&#95;circ&#95;0008667 expression in GC tissues and cells were analyzed, followed by statistical analyses to assess the clinical significance. Cell Counting Kit-8 and Transwell assays were performed to examine the effects of hsa&#95;circ&#95;0008667 silencing on GC cell growth and metastasis. Additionally, correlation analysis was performed to assess the relationship between hsa&#95;circ&#95;0008667 and miR-9-5p, which was further validated through luciferase reporter assay., Results: Hsa&#95;circ&#95;0008667 was considerably upregulated and tightly correlated with lymph node metastasis and the tumor-node-metastasis stage, which was predictive of poor prognosis in patients with GC. Hsa&#95;circ&#95;0008667 silencing suppressed GC cell proliferation, migration, and invasion. Furthermore, hsa&#95;circ&#95;0008667 negatively regulated miR-9-5p expression. MiR-9-5p downregulation enhanced GC malignancy and reversed hsa&#95;circ&#95;0008667 knockdown-mediated GC suppression., Conclusion: The findings of this study suggest hsa&#95;circ&#95;0008667 to be a prognostic biomarker and tumor promoter of GC via miR-9-5p modulation., Competing Interests: Declaration of 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., (Copyright © 2024 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Generalizing out-of-distribution (OoD) is critical but challenging in real applications such as unmanned aerial vehicle (UAV) flight control. Previous machine learning-based control has shown promise in dealing with complex real-world environments but suffers huge performance degradation facing OoD scenarios, posing risks to the stability and safety of UAVs. In this paper, we found that the introduced random noises during training surprisingly yield theoretically guaranteed performances via a proposed functional optimization framework. More encouragingly, this framework does not involve common Lyapunov assumptions used in this field, making it more widely applicable. With this framework, the upperbound for control error is induced. We also proved that the induced random noises can lead to lower OoD control errors. Based on our theoretical analysis, we further propose OoD-Control to generalize control in unseen environments. Numerical experiments demonstrate the superiority of the proposed algorithm, surpassing previous state-of-the-art by 65% under challenging unseen environments. We further extend to outdoor real-world experiments and found that the control error is reduced by 50% approximately.

Metastasis suppressor 1 (MTSS1) has been reported to play important roles in suppressing cancer progression. In this study, we investigated the underlying mechanism that regulates MTSS1 expression. We showed that in breast cancer cells, lncRNA-SNHG15-induced cell invasion and proliferation was accompanied with the decreased expression of MTSS1 mRNA. Further study revealed that SNHG15 mediated MTSS1 repression through blocking its promoter activity. Mechanistically, SNHG15 complexes with DDX5 and RTF1 and interacts with the core promoter of the MTSS1 gene to interfere with RNA-Pol-II-directed transcriptional initiation. Association with DDX5 stabilizes SNHG15 while binding to RTF1 allows SNHG15 to carry RTF1 to the core promoter, where RTF1 forms a complex with PNA pl II to enhance transcriptional pausing. Our findings revealed a molecular mechanism by which SNHG15 serves as a regulator to suppresses MTSS1 transcription via interaction with the gene core promoter.

Traditional models for Imbalanced Fault Diagnosis (IFD) face challenges in practical applications due to domain shifts caused by varying working conditions and machinery. Domain Generalization (DG) models provide an advantage over traditional approaches by learning class-discriminative and domain-invariant feature representations, allowing them to generalize to unseen target data. However, the scarcity of fault samples relative to healthy ones limits their application in real-world industrial scenarios. In this paper, we propose a Domain Mixed-Enhanced Domain Generalization Network (DEMDGN) that enhances IFD performance by utilizing mixup-based data augmentation and domain-based discrepancy metrics to align feature distributions across multiple heterogeneous source domains. By creating domain-invariant features, DEMDGN allows robust fault diagnosis under varying conditions. Extensive experiments on one marine machinery dataset and two bearing datasets demonstrate that the proposed method effectively addresses class imbalance and domain shift problems, achieving superior diagnostic performance., (© 2024. The Author(s).)