Animal experiments are essential tools in biomedical research, serving as a bridge between basic research and clinical trials. Systematic reviews and meta-analyses (SRs/MAs) of animal experiments are crucial methods for integrating evidence from animal experiment, which can facilitate the translation of findings into clinical research, reduce translational risks, and promote resource integration in basic research. With the continuous development of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, its application in SRs/MAs of animal experiments has gained increasing attention. This article first outlines the principles and specific applications of the GRADE methodology in SRs/MAs of animal experiments, including qualitative descriptive systematic reviews, meta-analyses, and network meta-analyses. It then deeply analyzes the misuse of the GRADE methodology in practice, including incorrect evidence grading, improper classification of evidence, misapplication in qualitative systematic reviews, inconsistencies between the documentation of the upgrading and downgrading process and results, and inappropriate use for making recommendations. Furthermore, this article comprehensively discusses the factors influencing the grading of evidence certainty in SRs/MAs of animal experiments, including the impact of bias risk, indirectness, inconsistency, imprecision, and publication bias on evidence downgrading, as well as the role of large effect sizes and cross-species consistency in evidence upgrading. Finally, in response to the issues discussed, improvement strategies are proposed, including further research and optimization of the GRADE methodology for SRs/MAs of animal experiments, the development of reporting guidelines tailored to the characteristics of SRs/MAs in animal experiment research, and enhanced professional training for researchers in the GRADE methodology. This article aims to improve the quality of evidence in SRs/MAs of animal experiments, strengthen their reliability in clinical decision-making, and promote the more efficient translation of findings from animal experiment research into clinical practice.

Receptor-interacting protein kinase 1 (RIPK1) plays an essential role in regulating the necroptosis and apoptosis in cerebral ischemia-reperfusion (I/R) injury. However, the regulation of RIPK1 kinase activity after cerebral I/R injury remains largely unknown. In this study, we found the downregulation of protein arginine methyltransferase 1 (PRMT1) was induced by cerebral I/R injury, which negatively correlated with the activation of RIPK1. Mechanistically, we proved that PRMT1 directly interacted with RIPK1 and catalyzed its asymmetric dimethylarginine, which then blocked RIPK1 homodimerization and suppressed its kinase activity. Moreover, pharmacological inhibition or genetic ablation of PRMT1 aggravated I/R injury by promoting RIPK1-mediated necroptosis and apoptosis, while PRMT1 overexpression protected against I/R injury by suppressing RIPK1 activation. Our findings revealed the molecular regulation of RIPK1 activation and demonstrated PRMT1 would be a potential therapeutic target for the treatment of ischemic stroke.

Allergic rhinitis (AR), a globally prevalent immune-mediated inflammatory condition, is still an incurable disease. In the present study, we have validated the impact of the Kelch-like ECH associated protein 1 (Keap1)-related oxidative stress and inflammatory response in clinical AR patient peripheral blood and nasal swab samples, emphasizing the biological relevance of Keap1 and AR. Targeting Keap1 -nuclear factor erythroid 2-related factor 2 (Nrf2) related anti-oxidative stress may be effective for AR intervention. Drawing inspiration from the Keap1 homodimerization and the E3 ligase characteristics, we herein present a design of novel bivalent molecules for chemical knockdown of Keap1. For the first time, we characterized ternary complexes of Keap1 dimer and one molecule of bivalent compounds. The best bivalent molecule 8 encompasses robust capacity to degrade Keap1 as a homoPROTAC^KEAP1. It efficaciously suppresses inflammatory cytokines in extensively different cells, including human nasal epithelial cells. Moreover, in an AR mouse model, we confirmed that the chemical degradation induced by homoPROTAC^KEAP1 led to therapeutic benefits in managing AR symptoms, oxidative stress and inflammation. In summary, our findings underscore the efficacy of targeting the Keap1 system through the homoPROTAC-ing technology as an innovative and promising treatment strategy for the incurable allergic disorders.

Varicocele-induced infertility （VCI） is a common andrological disease in clinical practice. Oxidative stress represents the primary mechanism through which varicocele causes male infertility. Traditional Chinese medicine （TCM） treatment， characterized by its multi-target， multi-component， multi-system， and multi-pathway actions， has achieved favorable outcomes in the field of VCI treatment. This paper summarizes the underlying oxidative stress mechanism of VCI and the relevant signaling pathways involved. By reviewing the current research status on how monomers， active fractions， compound formulas， and related preparations of TCM can intervene in oxidative stress through the regulation of these signaling pathways to improve VCI， it is found that the nuclear factor-erythroid 2-related factor 2 （Nrf2） signaling pathway， the mitogen-activated protein kinase （MAPK） signaling pathway， and the hypoxia-inducible factor-1α （HIF-1α） signaling pathway are closely related to the development of VCI. TCM monomers and active fractions （flavonoids from Cuscutae Semen， polysaccharides from Astragali Radix， curcumin， ginsenoside Rg1， hyperin and echinacoside）， as well as compound formulas and related preparations of TCM （modified Dahuang zhechong granules， Shengjing huoxue formula， modified Tianxiong san， Tongjingling， Bushen huoxue formula， Mailuoshutong pill， Zishen yutai pill， Danhong tongjing formula） can alleviate oxidative stress， reduce lipid peroxidation damage， improve mitochondrial dysfunction， decrease sperm DNA fragmentation， and inhibit apoptosis by activating the Nrf2 signaling pathways and inhibiting the MAPK and HIF-1α signaling pathways， thereby improving reproductive function.

Gliomas are the most common primary neuroepithelial tumors of the central nervous system in adults, of which glioblastoma is the deadliest subtype. Apart from the intrinsically indestructible characteristics of glioma (stem) cells, accumulating evidence suggests that the tumor microenvironment also plays a vital role in the refractoriness of glioblastoma. The primary functions of platelets are to stop bleeding and regulate thrombosis under physiological conditions. Furthermore, platelets are also active elements that participate in a variety of processes of tumor development, including tumor growth, invasion, and chemoresistance. Glioma cells recruit and activate resting platelets to become tumor-educated platelets (TEPs), which in turn can promote the proliferation, invasion, stemness, and chemoresistance of glioma cells. TEPs can be used to obtain genetic information about gliomas, which is helpful for early diagnosis and monitoring of therapeutic effects. Platelet membranes are intriguing biomimetic materials for developing efficacious drug carriers to enhance antiglioma activity. Herein, we review the recent research referring to the contribution of platelets to the malignant characteristics of gliomas and focusing on the molecular mechanisms mediating the interaction between TEPs and glioma (stem) cells, as well as present the challenges and opportunities in targeting platelets for glioma therapy.
Humans ; Glioma/metabolism* ; Blood Platelets/physiology* ; Brain Neoplasms/pathology* ; Tumor Microenvironment

OBJECTIVE: To evaluate the effectiveness of functional perforator flaps utilizing the superficial circumflex iliac artery as a vascular pedicle, as well as chimeric iliac bone flaps, in the reconstruction of composite tissue defects in the hand and foot. METHODS: A retrospective review of the clinical data from 13 patients suffering from severe hand or foot injuries, treated between May 2019 and January 2025, was conducted. The cohort comprised 8 males and 5 females, with ages ranging from 31 to 67 years (mean, 48.5 years). The injuries caused by mechanical crush incidents (n=9) and traffic accidents (n=4). The distribution of injury sites included 8 cases involving the hand and 5 cases involving the foot. Preoperatively, all patients exhibited bone defects ranging from 2.0 to 6.5 cm and soft tissue defects ranging from 10 to 210 cm². Reconstruction was performed using functional perforator flaps based on the superficial circumflex iliac artery and chimeric iliac bone flaps. The size of iliac bone flaps ranged from 2.5 cm×1.0 cm×1.0 cm to 7.0 cm×2.0 cm×1.5 cm, while the size of the soft tissue flaps ranged from 4 cm×3 cm to 15 cm×8 cm. In 1 case with a significant hand defect, a posterior interosseous artery perforator flap measuring 10.0 cm×4.5 cm was utilized as an adjunct. Likewise, an anterolateral thigh perforator flap measuring 25 cm×7 cm was combined in 1 case involving a foot defect. All donor sites were primarily closed. Postoperative flap survival was monitored, and bone healing was evaluated through imaging examination. Functional outcomes were assessed based on the location of the defects: for hand injuries, grip strength, pinch strength, and flap two-point discrimination were measured; for foot injuries, the American Orthopaedic Foot & Ankle Society (AOFAS) score, visual analogue scale (VAS) score, Maryland Foot Score, plantar pressure distribution and gait symmetry index (GSI) were evaluated. RESULTS: All flaps survived completely, with primary healing observed at both donor and recipient sites. All patients were followed up 6-18 months (mean, 12.2 months). No significant flap swelling or deformity was observed. Imaging examination showed a bone callus crossing rate of 92.3% (12/13) at 3 months after operation, and bone density recovered to more than 80% of the healthy side at 6 months. The time required for bone flap integration ranged from 2 to 6 months (mean, 3.2 months). One patient with a foot injury exhibited hypertrophic scarring at the donor site; however, no major complication, such as infection or bone nonunion, was noted. At 6 months after operation, grip strength in 8 patients involving the hand recovered to 75%-90% of the healthy side (mean, 83.2%), while pinch strength recovered to 70%-85% (mean, 80%). Flap two-point discrimination ranged from 8 to 12 mm, approaching the sensory capacity of the healthy side (5-8 mm). Among the 5 patients involving the foot, the AOFAS score at 8 months was 80.5±7.3, VAS score was 5.2±1.6. According to the Maryland Foot Score, 2 cases were rated as excellent and 3 as good. Gait analysis at 6 months after operation showed GSI above 90%, with plantar pressure distribution closely resembling that of the contralateral foot. CONCLUSION The use of functional perforator flaps based on the superficial circumflex iliac artery, combined with chimeric iliac bone flaps, provides a reliable vascular supply and effective functional restoration for the simultaneous repair of composite bone and soft tissue defects in the hand or foot. This technique represents a viable and effective reconstructive option for composite tissue defects in these anatomical regions.
Humans ; Male ; Middle Aged ; Female ; Perforator Flap/transplantation* ; Adult ; Plastic Surgery Procedures/methods* ; Hand Injuries/surgery* ; Aged ; Retrospective Studies ; Foot Injuries/surgery* ; Ilium/transplantation* ; Iliac Artery/surgery* ; Soft Tissue Injuries/surgery* ; Bone Transplantation/methods* ; Treatment Outcome

Natural products (NPs) have historically been a fundamental source for drug discovery. Yet the complex nature of NPs presents substantial challenges in pinpointing bioactive constituents, and corresponding targets. In the present study, an innovative natural product virtual screening-interaction-phenotype (NP-VIP) strategy that integrates virtual screening, chemical proteomics, and metabolomics to identify and validate the bioactive targets of NPs. This approach reduces false positive results and enhances the efficiency of target identification. Salvia miltiorrhiza (SM), a herb with recognized therapeutic potential against ischemic stroke (IS), was used to illustrate the workflow. Utilizing virtual screening, chemical proteomics, and metabolomics, potential therapeutic targets for SM in the IS treatment were identified, totaling 29, 100, and 78, respectively. Further analysis via the NP-VIP strategy highlighted five high-confidence targets, including poly [ADP-ribose] polymerase 1 (PARP1), signal transducer and activator of transcription 3 (STAT3), amyloid precursor protein (APP), glutamate-ammonia ligase (GLUL), and glutamate decarboxylase 67 (GAD67). These targets were subsequently validated and found to play critical roles in the neuroprotective effects of SM. The study not only underscores the importance of SM in treating IS but also sets a precedent for NP research, proposing a comprehensive approach that could be adapted for broader pharmacological explorations.

Objective:To identify the development trajectories of self-neglect behavior in older adults and explore the associated influencing factors.Methods:A fixed cohort was constructed based on the data from three surveys of Chinese longitudinal healthy longevity survey (CLHLS) from 2011 to 2018. A total of eight variables from 4 dimensions including living environment, lifestyle, social interaction, and health care were selected to evaluate self-neglect. Group-based trajectory model was used to identify the development trajectory of self-neglect behavior in the older adults, and polynomial Logistic regression model was used to explore its influencing factors by Stata 16.1.Results:Finally, 2 754 older adults aged 60 and above were included.The development trajectory of self-neglect behavior in older adults, based on the group-based trajectory model, can be classified into stable-low group ( n=268, 9.7%), descending-moderate group ( n=2 224, 80.8%), and decreasing-high group ( n=262, 9.5%). Polynomial Logistic regression showed that, compared with stable-low group, living in rural areas ( B=1.116, OR=3.053, 95% CI= 2.278-4.091) and higher activities of daily living scores( B=0.137, OR=1.147, 95% CI=1.046-1.258) were the risk factors of descending-moderate group. Education levels with 1-6 years( B=-0.398, OR=0.672, 95% CI=0.469-0.963), >6 years( B=-1.072, OR=0.342, 95% CI=0.229-0.513), being married( B=-0.476, OR=0.621, 95% CI=0.444-0.870), self-reported good health( B=-0.808, OR=0.446, 95% CI= 0.213-0.932), improved health status( B=-0.704, OR=0.495, 95% CI=0.320-0.766), self-reported average economic status( B=-1.065, OR=0.345, 95% CI=0.148-0.802), self-reported good economic status( B=-1.634, OR=0.195, 95% CI=0.082-0.467), and a higher cognition score( B=-0.142, OR=0.867, 95% CI=0.798-0.942) served as protective factors of descending-moderate group. In addition to the above factors, being in the age group of 75-89 years( B=0.481, OR=1.617, 95% CI=1.057-2.473) was a risk factor for decreasing-high group compared to stable-low group. Conclusions:Three types of self-neglect behavior trajectories among older adults were identified in this study, suggesting that physical health and economy are the influencing factors of the development trajectory of self-neglect of the elderly.

Methods:From February 2018 to January 2022, the clinical data of 1 123 patients who underwent Starclose vascular closure device, Angio-Seal and Exoseal vascular occlusion devices and Perclose ProGlide vascular suture device at femoral artery puncture hemostasis after neuro-intervention, in the Department of Interventional Radiology (Eastern District), The First Affiliated Hospital of Zhengzhou University, were retrospectively analyzed. The patients were divided into three groups based on the intervention method: the closure group (Starclose, n=271), the occlusion group (Angio-Seal, n=327 and Exoseal, n=352) and the suture group (ProGlide, n=173). Next, the hemostatic efficacy and complications associated with the three devices were analyzed and compared. Additionally, regression analysis was conducted to identify any relevant factors that may contribute to complications. Results:Three vascular hemostatic devices demonstrated effective hemostasis and the success rate were 92.6% in the closure group (Starclose), 93.4% in the occlusion group (Angio-Seal 93.0% and Exoseal 93.8%) and 89.6% in the suture group (ProGlide). There was no statistically significant difference( χ2=3.026, P=0.388). Single or multiple complications were observed in 102 patients (9.1%), including local oozing (16 cases in the closure group, 39 cases in the occlusion group, 13 cases in the suture group), local hematoma (14 cases in the closure group, 31 cases in the occlusion group, 11 cases in the suture group), pseudoaneurysm (13 cases in the closure group, 35 cases in the occlusion group, 10 cases in the suture group), local infection (2 cases in the closure group, 3 cases in the occlusion group, 1 case in the suture group). There were no statistically significant differences ( P>0.05). Moreover, serious complications such as femoral artery occlusion, embolus shedding and permanent nerve injury weren′t observed in the three groups. Multivariate logistic regression analysis revealed that overweight ( OR=1.562,95% CI 1.023—2.385, P=0.039), femoral artery with calcified plaque ( OR=1.934,95% CI 1.172-3.189, P=0.010), combined use of multiple antiplatelet drugs ( OR=1.769,95% CI 1.103—2.839, P=0.018), use of an 8F sheath( OR=2.824,95% CI 1.406—5.671, P=0.004) and the operator′s proficiency ( OR=0.508,95% CI 0.328—0.788, P=0.002) were the independent factors influencing complications, of which the first four were identified as risk-promoting factors for complications while the operator′s rich experience and high proficiency were the protective factors. Conclusions:Three hemostatic devices demonstrate effective hemostasis and comparable rates of complications at femoral artery puncture hemostasis after neuro-intervention. Overweight, femoral artery with calcified plaque, combined use of multiple antiplatelet drugs, use of an 8 F sheath and the operator′s proficiency were independent factors influencing complications.Ojective:To investigate the efficacy and complications associated with vascular suture, closure and occlusion devices at femoral artery puncture hemostasis after neuro-intervention.