ObjectiveTo compare the differences in fungal community composition between lesional and non-lesional scalp areas in patients suffering from severe alopecia areata （AA）， and compare these with healthy scalp areas in control subjects. Additionally， to preliminarily explore the changes in scalp fungal communities in severe AA patients and their potential underlying immunological mechanisms. MethodsA total of 20 severe AA patients and 18 healthy controls were enrolled. Skin swab samples were collected from lesional and non-lesional scalp areas of severe AA patients， as well as from the normal scalp of healthy controls. The fungal internal transcribed spacer （ITS） region was amplified and analyzed using high-throughput sequencing. ResultsThe lesional scalp areas of severe AA patients exhibited higher α-diversity and species richness in fungal communities. Notably， the relative abundance of Ascomycota， along with genera such as Mycosphaerella， Aspergillus， Penicillium， and Wallemia， significantly increased in the bald regions. In contrast， Acremonium and Schizophyllum were more predominant in the non-lesional areas of severe AA patients. ConclusionDistinct region-specific differences in scalp fungal microbiota in severe AA patients suggests that fungal dysbiosis may play a potential role in the pathogenesis of alopecia areata. These findings provide new insights into the disease characteristics of severe AA from the perspective of scalp microecology.

Magnolol, a compound extracted from Magnolia officinalis, demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases. Its biological activities encompass anti-inflammatory, antioxidant, anticoagulant, and anti-diabetic effects. Growth/differentiation factor-15 (GDF-15), a member of the transforming growth factor β superfamily, is considered a potential therapeutic target for metabolic disorders. This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism. The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo, and determined the involvement of endoplasmic reticulum (ER) stress signaling in this process. Luciferase reporter assays, chromatin immunoprecipitation, and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4 (ATF4), CCAAT enhancer binding protein γ (CEBPG), and CCCTC-binding factor (CTCF). The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene, as well as the influence of single nucleotide polymorphisms (SNPs) on magnolol and ATF4-induced transcription activity. Results demonstrated that magnolol triggers GDF-15 production in endothelial cells (ECs), hepatoma cell line G2 (HepG2) and hepatoma cell line 3B (Hep3B) cell lines, and primary mouse hepatocytes. The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene. SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15. In high-fat diet ApoE^-/- mice, administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15. These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity, indicating its potential as a drug for the treatment of metabolic disorders.
Lignans/pharmacology* ; Growth Differentiation Factor 15/metabolism* ; Animals ; Biphenyl Compounds/pharmacology* ; Endoplasmic Reticulum Stress/drug effects* ; Activating Transcription Factor 4/genetics* ; Mice ; Humans ; Male ; Magnolia/chemistry* ; CCAAT-Enhancer-Binding Proteins/genetics* ; Mice, Inbred C57BL

Paramyxoviruses are important respiratory pathogens with substantial clinical relevance in pediatric infectious diseases. During infection, multiple forms of programmed cell death (PCD) may be induced, and this plays pivotal roles in viral replication, dissemination, and host immune responses, thereby profoundly influencing the viral life cycle and disease progression. On one hand, PCD facilitates the clearance of infected cells, restricts viral spread, and activates host immune defenses, thereby enhancing antiviral immunity. On the other hand, excessive or dysregulated cell death may lead to tissue damage and immune imbalance, creating a microenvironment conducive to viral replication and exacerbating disease severity. For instance, apoptosis-mediated by both extrinsic and intrinsic pathways-contributes to infection control but may also be hijacked by viruses to promote dissemination. Pyroptosis, driven by inflammasome activation, triggers lytic cell death and the release of pro-inflammatory cytokines. Necroptosis, mediated by the RIPK1-RIPK3-MLKL signaling axis, and pyroptosis both amplify innate immune responses but may concurrently induce inflammatory dysregulation. Immunogenic cell death (ICD), characterized by the release of damage-associated molecular patterns and neoantigens, activates antigen-specific immune responses and holds therapeutic potential for antiviral and antitumor interventions. Emerging evidence suggests that ferroptosis, through the modulation of iron metabolism and associated transporters, may also participate in viral replication and infected cell clearance. This review comprehensively summarizes the roles of apoptosis, pyroptosis, necroptosis, ICD, and ferroptosis in paramyxovirus infection, aiming to deepen the understanding of paramyxovirus pathogenesis and to provide insights for developing novel antiviral strategies.
Humans ; Paramyxoviridae Infections/pathology* ; Pyroptosis ; Apoptosis ; Virus Replication ; Necroptosis ; Inflammasomes ; Immunity, Innate ; Immunogenic Cell Death ; Paramyxoviridae/physiology* ; Signal Transduction

The advancement of tissue clearing technology has significantly propelled neuroscience research. Nevertheless, the fluorescent proteins used in traditional transgenic mouse strains were not specifically optimized for tissue clearing procedures, resulting in a substantial decrease in fluorescent intensity after clearing. In this study, we developed the Ci1 reporter mouse strain (where Ci stands for the Chinese Institute for Brain Research, CIBR) based on the bright red fluorescent protein mScarlet. The Ci1 reporter exhibits no fluorescence leakage in various organs or tissue types and can be readily crossed with multiple tissue-specific Cre lines. Compared to the Ai14 mouse strain, the Ci1 reporter strain demonstrates lower non-specific leakage, stronger fluorescence intensity in different tissues, and better preservation of fluorescence following tissue clearing treatment. The creation of the Ci1 reporter provides a more effective tool for both neuroscience and other biomedical research applications.
Animals ; Luminescent Proteins/metabolism* ; Mice, Transgenic ; Mice ; Red Fluorescent Protein ; Brain/metabolism* ; Genes, Reporter ; Fluorescence

Regenerating periodontal bone defect surrounding periodontal tissue is crucial for orthodontic or dental implant treatment. The declined osteogenic ability of periodontal ligament stem cells (PDLSCs) induced by inflammation stimulus contributes to reduced capacity to regenerate periodontal bone, which brings about a huge challenge for treating periodontitis. Here, inspired by the adhesive property of mussels, we have created adhesive and mineralized hydrogel microspheres loaded with traditional compound cordycepin (MMS-CY). MMS-CY could adhere to the surface of alveolar bone, then promote the migration capacity of PDLSCs and thus recruit them to inflammatory periodontal tissues. Furthermore, MMS-CY rescued the impaired osteogenesis and ligament-forming capacity of PDLSCs, which were suppressed by the inflammation stimulus. Moreover, MMS-CY also displayed the excellent inhibitory effect on the osteoclastic activity. Mechanistically, MMS-CY inhibited the premature senescence induced by the inflammation stimulus through the nuclear factor erythroid 2-related factor (NRF2) pathway and reducing the DNA injury. Utilizing in vivo rat periodontitis model, MMS-CY was demonstrated to enhance the periodontal bone regeneration by improving osteogenesis and inhibiting the osteoclastic activity. Altogether, our study indicated that the multi-pronged approach is promising to promote the periodontal bone regeneration in periodontitis condition by reducing the inflammation-induced stem cell senescence and maintaining bone homeostasis.
Animals ; Bone Regeneration/drug effects* ; Rats ; Periodontal Ligament/cytology* ; Microspheres ; NF-E2-Related Factor 2 ; Hydrogels ; Periodontitis/therapy* ; Osteogenesis/drug effects* ; Disease Models, Animal ; Stem Cells ; Male ; Rats, Sprague-Dawley ; Humans

Background Work-related musculoskeletal disorders (WMSDs) are considered to be one of the biggest health problems in the workplace, seriously affecting the productivity and quality of life of the working population. Long working hours may associate with WMSDs, and leisure-time physical activity (LTPA) is beneficial for WMSDs. However, the independent and combined effects of these two factors on WMSDs remain poorly understood. Objective To explore the independent and joint relationships between long working hours, leisure time physical activity (LTPA), and WMSDs, and to provide a basis for prevention and intervention of WMSDs. Methods A cross-sectional survey was conducted among 1227 frontline workers from multiple secondary industry companies in Nanchong City in 2023 using cluster random sampling. Demographic characteristics information, weekly working hours, LTPA, personal health behaviors, and occupational factors were collected through questionnaires. The Chinese version of Musculoskeletal Disorders Questionnaire was used to assess WMSDs. χ² test and logistic regression were used to analyze the relationships between long working hours and/or LTPA and WMSDs. Results A total of 1227 workers were surveyed with a mean age of (41.3±9.3) years and 855 (69.7%) were male and 372 (30.3%) were female. Among then, 855 (69.7%) workers reported working >40 h per week, and 254 (20.7%) reported working ≥ 55 h per week; 561 (45.7%) reported no LTPA and 192 (15.6%) reported high LTPA. The overall positive rate of WMSDs was 57.4%. The positive rate of WMSDs was 71.3% in those working ≥55 h per week, which was significantly higher than those in the other groups (51.3%-58.2%, P<0.05). Comparison among the positive rate of WMSDs in the weekly working 41-48 h group (54.4%), the 49-54 h group (58.2%), and the ≤40 h group (51.3%) showed no statistically significant difference (P>0.05). The positive rate of WMSDs was higher in workers with no LTPA (59.0%)/low LTPA (58.9%) than in those with high LTPA (49.0%) (P<0.05). The logistic regression models showed that after adjusting gender, age, work experience, income per month, night shift, industry, prolonged fixed posture, prolonged repetition, smoking and alcohol drinking, compared with weekly working ≤40 h, the risk of WMSDs was higher in those with extra-long working hours (≥55 h·week⁻¹ ) (OR=2.155, 95%CI: 1.504, 3.088), whereas those with high LTPA had a lower risk of WMSDs (OR=0.614, 95% CI: 0.432, 0.874 ). The combination of no LTPA and extra-long working hours (≥55 h·week⁻¹) and low LTPA and extra-long working hours (≥55 h·week⁻¹) showed associations with WMSDs, with 2.360 and 2.049 times higher risk of WMSDs than that of the combination of no LTPA and standard working hours (≤40 h ·week⁻¹) respectively (P<0.05), whereas the combination of high LTPA and long working hours was not observed statistical significance (P>0.05). Conclusion Extra-long working hours and/or LTPA show different associations with the risk of WMSDs. Extra-long working hours are significantly positively associated with the risk of WMSDs, whereas high LTPA is significantly negatively associated with the risk of WMSDs. The combination of extra-long working hours with no or low LTPA is associated with elevated risk of reporting WMSDs, whereas no statistical significance is observed for the high LTPA-long work hours combination.

Acute ischemic stroke(AIS)is associated with high mortality and disability rates,presenting a substantial challenge to global public health challenge.Intravenous thrombolysis(IVT)is recognized as a cornerstone of early AIS treatment and is recommended as the standard therapeutic approach by both national and international guidelines.However,the clinical efficacy of IVT remains suboptimal due to several limitations,including a narrow therapeutic time window and the inevitable activation of the coagulation system and platelet aggregagation during thrombolysis.These factors may contribute to adverse outcomes such as early neurological deterioration(END)and vascular re-occlusion.Antiplatelet therapy(APT),which inhibits platelet aggregations,reduces microthrombus formation,and stabilizes the vascular endothelium with multifaceted mechanisms,has emerged as a promising adjunctive strategy to IVT,offering potential synergistic effects.This review summarized the latest evidence from both domestic and international studies,focusing on the mechanisms of APT,recent clinical advancements in IVT combined with APT,and the safety and efficacy of APT administration at different time windows relative to IVT.Emphasis is placed on the influence of various antiplatelet agents,dosing regimens,and initiation timing on therapeutic outcomes,alongside a comprehensive evaluation in the context of current guideline recommendations and clinical practice.Current guidelines recommend initiating APT 24 h after IVT,following imaging confirmation to exclude the risk of intracranial hemorrhage.However,the efficacy and safety of earlier APT initiation remain inconclusive.Individualized treatment strategies,such as early administration of low-dose,short-acting APT or combination therapy in specific patient subgroups,may effectively balance therapeutic benefits and risks.The adjunctive use of APT in IVT holds promise for enhancing efficacy and improving clinical outcomes,but precise stratification of safety and efficacy is essential.Future research should focus on optimizing combination IVT and APT strategies through individualized patient profiling,appropriate drug selection,and dynamic imaging monitoring to achieve precision management in AIS treatment.

Objective To investigate the effects of Jiuwei Jianbu Drink on oxidative stress and inflammatory injury in rats with knee osteoarthritis via the high mobility group box-1 protein(HMGB1)/receptor for advanced glycation endproducts(RAGE)/phosphatidyli-nositol 3-kinase(PI3K)/protein kinase B(Akt)signaling pathway.Methods A total of 60 rats were randomly divided into six groups according to the random number table method:blank control group,model group,positive drug group,and Jiuwei Jianbu Drink low-,medium-,and high-dose groups,with 10 rats in each group.Except for the blank control group,knee osteoarthritis models were estab-lished in the other groups,which were then subjected to corresponding treatments.Knee joint diameter and mechanical pain and thermal pain threshold changes were observed.Hematoxylin-eosin staining and safranin O/fast green staining were used to assess pathological changes in cartilage tissue.Oxidative stress markers and inflammatory factor levels in knee joint cartilage tissue of each group were meas-ured.Western blot was used to detect the expression of proteins related to the HMGB1/RAGE/PI3 K/Akt signaling pathway in knee joint tissues.Results Compared with the blank control group,the model group exhibited increased knee joint diameter and decreased mechan-ical pain and thermal pain threshold.Jiuwei Jianbu Drink at all doses groups and the positive control group significantly improved these in-dicators in a dose-dependent manner(P＜0.05).Additionally,the Mankin score and Osteoarthritis Research Society International(OARSI)score in the model group were significantly higher than those in the blank control group,while Jiuwei Jianbu Drink intervention significantly reduced the OARSI score,with the best effect observed in the high-dose group(P＜0.05).Compared with the blank con-trol group,the model group showed increased levels of nitric oxide(NO)and malondialdehyde(MDA),decreased levels of superoxide dismutase(SOD)and glutathione peroxidase(GSH-Px),and significantly elevated levels of tumor necrosis factor-alpha(TNF-α)and interleukin-1β(IL-1β).Compared with the model group,Jiuwei Jianbu Drink significantly inhibited oxidative stress and inflam-matory responses,especially at high doses(P＜0.05).Moreover,the expression of HMGB1,RAGE,p-PI3K/PI3K,and p-Akt/Akt in the model group was higher than that in the blank control group,while Jiuwei Jianbu Drink intervention dose-dependently downregulat-ed the expression of these proteins(P＜0.05).Conclusion Jiuwei Jianbu Drink alleviates oxidative stress and inflammatory injury in rats with knee osteoarthritis by inhibiting the HMGB1/RAGE/PI3K/Akt signaling pathway,thereby improving cartilage pathological chan-ges and demonstrating potential therapeutic value.

Objective To investigate the effects of Jiuwei Jianbu Drink on oxidative stress and inflammatory injury in rats with knee osteoarthritis via the high mobility group box-1 protein(HMGB1)/receptor for advanced glycation endproducts(RAGE)/phosphatidyli-nositol 3-kinase(PI3K)/protein kinase B(Akt)signaling pathway.Methods A total of 60 rats were randomly divided into six groups according to the random number table method:blank control group,model group,positive drug group,and Jiuwei Jianbu Drink low-,medium-,and high-dose groups,with 10 rats in each group.Except for the blank control group,knee osteoarthritis models were estab-lished in the other groups,which were then subjected to corresponding treatments.Knee joint diameter and mechanical pain and thermal pain threshold changes were observed.Hematoxylin-eosin staining and safranin O/fast green staining were used to assess pathological changes in cartilage tissue.Oxidative stress markers and inflammatory factor levels in knee joint cartilage tissue of each group were meas-ured.Western blot was used to detect the expression of proteins related to the HMGB1/RAGE/PI3 K/Akt signaling pathway in knee joint tissues.Results Compared with the blank control group,the model group exhibited increased knee joint diameter and decreased mechan-ical pain and thermal pain threshold.Jiuwei Jianbu Drink at all doses groups and the positive control group significantly improved these in-dicators in a dose-dependent manner(P＜0.05).Additionally,the Mankin score and Osteoarthritis Research Society International(OARSI)score in the model group were significantly higher than those in the blank control group,while Jiuwei Jianbu Drink intervention significantly reduced the OARSI score,with the best effect observed in the high-dose group(P＜0.05).Compared with the blank con-trol group,the model group showed increased levels of nitric oxide(NO)and malondialdehyde(MDA),decreased levels of superoxide dismutase(SOD)and glutathione peroxidase(GSH-Px),and significantly elevated levels of tumor necrosis factor-alpha(TNF-α)and interleukin-1β(IL-1β).Compared with the model group,Jiuwei Jianbu Drink significantly inhibited oxidative stress and inflam-matory responses,especially at high doses(P＜0.05).Moreover,the expression of HMGB1,RAGE,p-PI3K/PI3K,and p-Akt/Akt in the model group was higher than that in the blank control group,while Jiuwei Jianbu Drink intervention dose-dependently downregulat-ed the expression of these proteins(P＜0.05).Conclusion Jiuwei Jianbu Drink alleviates oxidative stress and inflammatory injury in rats with knee osteoarthritis by inhibiting the HMGB1/RAGE/PI3K/Akt signaling pathway,thereby improving cartilage pathological chan-ges and demonstrating potential therapeutic value.

Cerebral small vessel disease represents a group of common vascular disorders involving pathological changes in arterioles,capillaries and venules,with microvascular investigation remaining a key challenge in stroke.With high signal-to-noise ratio and high contrast enabled by enhanced field strength,7T MRI can surpass the resolution limits of 3T MRI,revealing structural and functional abnormalities in cerebral small vessels below 400 μm,as well as detecting subtle lesions in brain tissue.This paper reviews the research progress of multimodal high-resolution imaging techniques based on 7T MRI,such as time-of-flight angiography,phase contrast imaging and susceptibility imaging,in the study of cerebral small vessel disease.Utilizing these technologies,7T MRI can clearly display the structure of cerebral small vessels,such as the lenticulostriate arteries and deep medullary veins,and measure functional parameters like flow velocity and susceptibility.Additionally,it can sensitively detect cerebral microbleeds and cortical cerebral microinfarct.These imaging data provide valuable information for detecting early features of cerebral small vessel disease and assessing its progression,offering new insights into its pathogenesis.Combined with artificial intelligence-based image analysis methods,7T MRI holds great promise for early diagnosis and progression evaluation in cerebral small vessel disease.