Mitochondrial dysfunction is a critical factor in the pathogenesis of Alzheimer's disease (AD). The mitochondrial contact site and cristae organizing system (MICOS) plays a pivotal role in shaping the inner mitochondrial membrane, forming cristae junctions and establishing interaction sites between the inner and outer mitochondrial membranes and thereby serving as a cornerstone of mitochondrial structure and function. In the past decade, MICOS abnormalities have been extensively linked to AD pathogenesis. In particular, dysregulated expression of MICOS subunits and mutations in MICOS-related genes have been identified in AD, often in association with hallmark pathological features such as amyloid-β plaque accumulation, neurofibrillary tangle formation, and neuronal apoptosis. Furthermore, MICOS subunits interact with several etiologically relevant proteins, significantly influencing AD progression. The intricate crosstalk between these proteins and MICOS subunits underscores the relevance of MICOS dysfunction in AD. Therapeutic strategies targeting MICOS subunits or their interacting proteins may offer novel approaches for AD treatment. In the present review, we introduce current understanding of MICOS structures and functions, highlight MICOS pathogenesis in AD, and summarize the available MICOS-targeting drugs potentially useful for AD.

Acute liver failure (ALF) is a life-threatening condition associated with macrophage-mediated inflammatory responses. Effective therapies and drugs are still lacking to date. Here, we reveal that a derivative of xanthohumol, CAM12203, alleviates lipopolysaccharide (LPS) + d-galactosamine (D-GalN)-induced ALF through limiting macrophage-mediated inflammation, with the most significant impact on interleukin-1β (IL-1β) transcription. Through biotin labeling-mediated pull-down and LC-MS/MS analysis, diacylglycerol kinase ζ (DGKζ), a lipid-metabolizing kinase, is identified as the direct target of CAM12203. Mechanistically, DGKζ is induced in macrophages upon inflammatory stimuli and is upregulated observed on clinical liver failure samples. Its product phosphatidic acid (PA) boosts phospholipase C (PLC)-inositol 1,4,5-trisphosphate (IP₃)-Ca²⁺ signaling and subsequent janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) cascade, ultimately promoting IL-1β production and liver failure. DGKζ knockdown/ablation or inhibition significantly impairs the DGKζ-STAT3-IL-1β pathway along with ALF progression. Finally, CAM12203 is confirmed to be a new DGKζ inhibitor and acts against inflammation in a DGKζ-reliant manner. Taken together, CAM12203 inhibits IL-1β transcription in macrophages by binding to DGKζ and blocking the DGKζ-STAT3 axis, thereby exerting an ameliorative effect on ALF. These results not only highlight CAM12203 as a promising lead compound for ALF treatment, but also define DGKζ as a novel therapeutic target.

Perineural invasion (PNI) by tumor cells is a key phenotype of highly-invasive oral squamous cell carcinoma (OSCC). Since Schwann cells (SCs) and fibroblasts maintain the physiological homeostasis of the peripheral nervous system, and we have focused on cancer-associated fibroblasts (CAFs) for decades, it's imperative to elucidate the impact of CAFs on SCs in PNI⁺ OSCCs. We describe a disease progression-driven shift of PNI^- towards PNI⁺ during the progression of early-stage OSCC (31%, n = 125) to late-stage OSCC (53%, n = 97), characterized by abundant CAFs and nerve demyelination. CAFs inhibited SC proliferation/migration and reduced neurotrophic factors and myelin in vitro, and this involved up-regulated ER stress and decreased MAPK signals. Moreover, CAFs also aggravated the paralysis of the hind limb and PNI in vivo. Unexpectedly, leukemia inhibitory factor (LIF) was exclusively expressed on CAFs and up-regulated in metastatic OSCC. The LIF inhibitor EC330 restored CAF-induced SC inactivation. Thus, OSCC-derived CAFs inactivate SCs to aggravate nerve injury and PNI development.
Schwann Cells/metabolism* ; Mouth Neoplasms/metabolism* ; Humans ; Cancer-Associated Fibroblasts/metabolism* ; Animals ; Carcinoma, Squamous Cell/metabolism* ; Neoplasm Invasiveness/pathology* ; Male ; Female ; Mice ; Cell Movement/physiology* ; Cell Proliferation/physiology* ; Cell Line, Tumor ; Leukemia Inhibitory Factor/metabolism* ; Middle Aged

OBJECTIVE: To analyze the clinical characteristics of a patient with Short rib-polydactyly syndrome type 6 (SRTD6) with long-term misdiagnosis, and improve its clinical recognition by reviewing the relevant literature. METHODS: A patient presented at the Children's Hospital Affiliated to Zhejiang University School of Medicine on August 19, 2024 for the discovery of liver dysfunction for 13 years and vision loss for 9 years was selected as the study subject. Her medical history, clinical data, laboratory findings and results of imaging examination were collected. High-throughput sequencing was carried out, and candidate variants were verified by Sanger sequencing. This study was approved by the Ethics Committee of the Hospital (Ethics No.: 2021-IRB-292). RESULTS: The patient had long-term unexplained liver dysfunction, vision loss, and growth delay. Blood acylcarnitine and urinary organic acid analysis have failed to found any abnormality. Previous genetic testing revealed a homozygous c.203A>C (p.Glu68Ala) missense variant in the ETFDH gene, leading to a misdiagnosis of various acyl-CoA dehydrogenase deficiencies. However, treatment with high-dose vitamin B₂ showed a poor effect. Physical examination revealed small hands, short and stubby fingers, and a narrow chest. Medical imaging showed shortened bilateral ribs, a narrowed chest, and short, thick metacarpals. High-throughput sequencing has detected a pathogenic homozygous c.1957C>T (p.R653*) nonsense variant in the NEK1 gene, confirming the diagnosis of SRTD6. CONCLUSION SRTD6 is characterized by rib and sternum dysplasia as the primary skeletal deformities, which is often accompanied by multi-organ impairment. Genetic testing can facilitate the precise diagnosis.
Humans ; Female ; Diagnostic Errors ; Short Rib-Polydactyly Syndrome/diagnosis* ; High-Throughput Nucleotide Sequencing

Objective:To analyze the clinical characteristics of a patient with Short rib-polydactyly syndrome type 6 (SRTD6) with long-term misdiagnosis, and improve its clinical recognition by reviewing the relevant literature.Methods:A patient presented at the Children′s Hospital Affiliated to Zhejiang University School of Medicine on August 19, 2024 for the discovery of liver dysfunction for 13 years and vision loss for 9 years was selected as the study subject. Her medical history, clinical data, laboratory findings and results of imaging examination were collected. High-throughput sequencing was carried out, and candidate variants were verified by Sanger sequencing. This study was approved by the Ethics Committee of the Hospital (Ethics No.: 2021-IRB-292).Results:The patient had long-term unexplained liver dysfunction, vision loss, and growth delay. Blood acylcarnitine and urinary organic acid analysis have failed to found any abnormality. Previous genetic testing revealed a homozygous c. 203A>C (p.Glu68Ala) missense variant in the ETFDH gene, leading to a misdiagnosis of various acyl-CoA dehydrogenase deficiencies. However, treatment with high-dose vitamin B2 showed a poor effect. Physical examination revealed small hands, short and stubby fingers, and a narrow chest. Medical imaging showed shortened bilateral ribs, a narrowed chest, and short, thick metacarpals. High-throughput sequencing has detected a pathogenic homozygous c. 1957C>T (p.R653*) nonsense variant in the NEK1 gene, confirming the diagnosis of SRTD6. Conclusion:SRTD6 is characterized by rib and sternum dysplasia as the primary skeletal deformities, which is often accompanied by multi-organ impairment. Genetic testing can facilitate the precise diagnosis.

OBJECTIVE: To explore the effectiveness of triple osteotomy in correcting severe hallux valgus with the first metatarsal pronation deformity. METHODS: A retrospective analysis was conducted on the clinical data of 29 patients (40 feet) with severe hallux valgus accompanied by the first metatarsal pronation deformity, who were admitted between January 2022 and December 2023 and met the selection criteria. There were 8 males (10 feet) and 21 females (30 feet), with an average age of 50.0 years (range, 44-62 years). The disease duration ranged from 5 to 9 years (mean, 6.5 years). All patients underwent triple osteotomy to correct the deformity. The American Orthopaedic Foot and Ankle Society (AOFAS) score and visual analogue scale (VAS) score were used to evaluate joint function and pain before and after operation. Based on pre- and post-operative X-ray films, hallux valgus angle (HVA), intermetatarsal angle (IMA), and distal metatarsal articular angle (DMAA) were measured to evaluate the correction of hallux valgus; the shape classification of the lateral edge of the first metatarsal and the pronation of first metatarsal angle (PFMA) were observed to assess the correction of the first metatarsal pronation deformity. RESULTS: A superficial infection occurred in 1 foot and the incison healed after dressing change; the remaining incisions healed by first intention. All patients were followed up 12-18 months (mean, 12.6 months). Three cases (4 feet) experienced limited movement of the metatarsophalangeal joint after operation, and the joint function recovered after strengthening functional exercises. During follow-up, no recurrence of deformity or secondary metatarsal pain occurred. Compared with preoperative scores, the AOFAS score increased and the VAS score decreased at last follow-up, and the differences were significant ( P<0.05). Radiographic examination showed that the osteotomy achieved bony healing, with the healing time of 2.5-6.2 months (mean, 4.1 months). The hallux valgus deformity was corrected, and the IMA, HVA, and DMAA were significantly smaller at last follow-up when compared with those before operation ( P<0.05). The first metatarsal pronation deformity was also corrected; there was no R-type (R-type for pronation deformity) on the lateral edge of the first metatarsal at last follow-up, and the PFMA decreased compared with preoperative levels ( P<0.05) and was corrected to the normal range. CONCLUSION Triple osteotomy can achieve good effectiveness for correcting severe hallux valgus with the first metatarsal pronation deformity. The functional training of the first metatarsophalangeal joint needs to be strengthened.
Humans ; Hallux Valgus/diagnostic imaging* ; Osteotomy/methods* ; Female ; Male ; Middle Aged ; Adult ; Retrospective Studies ; Metatarsal Bones/diagnostic imaging* ; Treatment Outcome ; Pronation ; Radiography

This study was aimed at preliminarily investigating the molecular biological functions of the PPE65 protein from Myco-bacterium tuberculosis,and providing foundational data for tuberculosis prevention and control.The basic biological properties of the PPE65 gene-encoded protein were predicted with bioinformatics tools.Sequence information for the Mycobacterium tuberculosis Rv3621c gene and PPE65 protein was retrieved from the NCBI database.The Rv3621c gene was amplified through PCR with the H37Rv genome as a template,then cloned into the pET22b(+)expression vector.The recombinant pET22b(+)-PPE65 plasmid was transformed into Escherichia coli BL21(DE3)competent cells for IPTG-induced expression.Solubility analysis,purification,and identification of the recombinant PPE65 protein were performed.BEAS-2B cells were treated with various concentrations of PPE65 protein for 24 h,and cell proliferation was assessed with CCK-8 assays.PPE65 was found to be composed of 413 amino acids and to have a molecular formula of C????H????N???O???S??,a relative molecular mass of 40 679.88,a theoretical isoelectric point of 4.60,an ali-phatic index of 81.94,and an average hydrophilicity value of 0.319,thus indicating a stable hydrophobic protein lacking signal pep-tides or transmembrane domains.Secondary structure analysis revealed 53.03%α-helix(Hh),2.66%β-sheet(Ee),and 44.31%ran-dom coil(Cc).Bioinformatics predictions identified 38 B-cell epitopes and 22 CTL/Th-cell epitopes.The full-length PPE65 gene(1 308 bp)was confirmed through double restriction enzyme digestion and sequencing,thereby validating the correct construction of the pET22b(+)-PPE65 recombinant plasmid.SDS-PAGE analysis demonstrated that the recombinant protein was found in inclusion bodies,and a single band at 43.7 kDa was observed after purification.Western blotting revealed specific binding to mouse-derived His monoclonal antibodies,thereby confirming successful expression of the PPE65 protein.BEAS-2B cells treated with a PPE65 protein concentration gradient(2.5-20 μg/mL)exhibited a dose-dependent increase in cell number.Compared with those in the PBS control group,TGF-β relative expression levels were significantly higher in all treatment groups(t2.5=4.893,P<0.001,t5.0=4.640,P<0.05,t10=7.535,P<0.05,t20=16.44,P<0.000 1).This study elucidated the structural characteristics of the PPE65 protein,successfully obtained the recombinant protein through prokaryotic expression and purification,and demonstrated its ability to promote BEAS-2B cell proliferation.The underlying mechanism might involve suppression of TGF-β/S mad signaling pathway activation.These findings provide a theoretical basis for understanding the role and regulatory mechanisms of PPE65 during M.tuberculosis infection.

Objective:To analyze the effectiveness of multicomponent exercise (ME) in old adults, and provide reference for the promotion of healthy aging.Methods:Literature on ME intervention for old adults published until February 29, 2024 were retrieved from Web of Science, PubMed, Scopus, Embase, EBSCO, Cochrane Library, CNKI, Wanfang Data, and VIP Database. After screening and evaluation, an umbrella review was conducted.Results:In total, 15 systematic reviews and Meta-analyzes (193 randomized controlled trials and 19 203 participants) were included. The umbrella review suggested that the average standardized mean difference ( SMD) affecting physical function/health of ME was between 0.40 and 1.00, the average SMD affecting brain health was between -0.30 and 1.60, the average SMD affecting mood/mental health was between 0.01 and 0.20, and the average SMD affecting quality of life was between -0.20 and 0.40. Effects of ME on lower limb strength [mean difference ( MD)=1.1] and aerobic capacity ( MD=0.8) were better compared with general strength exercise and aerobic exercise respectively. Effects of ME on cognitive function ( MD=0.99) were better compared with strength exercise ( MD=0.84), aerobic exercise ( MD=0.77), and mind-body exercise ( MD=0.63). Effects of ME on executive function ( MD=0.72) were better compared with aerobic exercise ( MD=0.62), strength exercise ( MD=0.44), and mind-body exercise ( MD=0.36). Effects of ME on activity of daily living ( SMD=0.32) were better compared with strength exercise ( SMD=0.12). Conclusions:ME can clearly improve the physical function/health and brain health in old adults. The impact varies with different participants, exercise program designs, and assessment methods. However, its effect on mood/mental health and the quality of life still need further verification. ME might show better effects compared with general single component exercise (such as strength exercise, aerobic exercise) and mind-body exercise in improving lower limb strength, aerobic capacity, cognitive function, executive function, and activity of daily living in specific elderly populations. Given the impact of the quantity, quality and heterogeneity of the reviews included, the conclusions mentioned above still need validation in practice.

Objective:To investigate the role and mechanism of negative pressure wound therapy (NPWT) in a rabbit full-thickness wound model using non-targeted metabolomics.Methods:Eighteen male New Zealand rabbits (11-12 weeks old) were used. Two symmetrical circular full-thickness skin defects were created on the back of each rabbit. The animals were randomly divided into three groups: Control group (no treatment), Saline group (debridement with saline irrigation), and NPWT+ Saline group (saline debridement followed by 2 h of NPWT at -125 mm Hg once daily for two weeks). Wound healing was documented on days 0, 3, 7, 10, and 14. The wound healing rate was calculated as (original area-unhealed area)/original area × 100%. Histopathological changes were evaluated via hematoxylin and eosin (HE) staining. Metabolomic profiling of wound tissues was performed using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Differential metabolites were identified, and pathway enrichment analysis was conducted. Oxidative stress markers, including superoxide dismutase (SOD) and catalase (CAT) activities and malondialdehyde (MDA) content, were measured using commercial kits. Data were analyzed using SPSS 20.0. One-way ANOVA with Tukey’s HSD test or Welch’s ANOVA with Games-Howell test was applied as appropriate.Results:On days 3, 10, and 14, the wound healing rate in the NPWT+ Saline group was significantly higher than that in the Control and Saline groups ( P<0.05). On day 7, the NPWT+ Saline group showed a significantly higher healing rate than the Saline group ( P<0.01), but no significant difference compared with the Control group ( P>0.05). HE staining on day 7 revealed enhanced epithelialization, thicker granulation tissue, higher microvessel density, and more abundant, well-organized collagen in the NPWT+ Saline group. By day 14, all groups had formed relatively continuous epithelial structures. Non-targeted metabolomics identified riboflavin and spermidine as differential metabolites. Pathway analysis highlighted riboflavin metabolism and glutathione metabolism as the most significantly enriched pathways. Compared with the Control and Saline groups, the NPWT+ Saline group exhibited significantly increased CAT and SOD activities ( P<0.05) and decreased MDA content ( P<0.01), indicating reduced oxidative stress. Conclusion:NPWT may promote wound healing by elevating riboflavin and spermidine levels, thereby modulating riboflavin and glutathione metabolism and regulating local redox reactions.

Objective It analyzes the current research status of the"one hospital with multiple campuses"construc-tion in public hospitals in China,focuses on research hotspots and evolution trends,and provides references for the research on"one hospital with multiple campuses"in public hospitals.Methods Using CiteSpace 6.3.R1 software,a visual analysis was conducted on 323 academic journal articles related to"one hospital with multiple campuses"in public hospitals from CNKI from 2014 to 2024.Results Over the past decade,the number of publications in this field has shown an overall upward trend;a core author group has initially formed but the density of the collaboration net-work is low;the institutions with the highest number of publications are mainly healthcare institutions and universi-ties;High-frequency keywords include public hospitals,homogenization,financial management,etc;research hot-spots generally show a trend from foundational construction to system integration,from extensive expansion to re-fined internal management,and from single-factor optimization to technology empowerment and multidimensional integration.Conclusion The research on the"one hospital with multiple campuses"construction of public hospitals in our country is clearly driven by policy,with research efforts distributed in a dual-core structure of"medical institu-tions-universities".However,interdisciplinary collaboration needs to be strengthened.Future research can focus on areas such as healthcare professionals,medical quality,the integration of business and finance systems,and inno-vation in emergency management mechanisms,providing support for the high-quality development of public hospi-tals with"one hospital with multiple campuses".