ObjectiveTranscranial magneto-acoustic stimulation (TMAS) is an emerging non-invasive neuromodulation technique that may provide a novel non-pharmacological intervention strategy for Parkinson's disease (PD). PD is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), leading to motor impairments such as bradykinesia, tremor, and rigidity. Increasing evidence indicates that mitochondrial dysfunction and impaired mitochondrial quality control are central mechanisms underlying dopaminergic neuronal loss. In particular, abnormalities in mitophagy and mitochondrial fission-fusion balance contribute substantially to oxidative stress, energy metabolic failure, and neuronal injury. At present, most clinical treatments for PD mainly alleviate symptoms but do not effectively halt disease progression. Therefore, exploring new interventions targeting the core pathological mechanisms is of considerable significance. This study aims to investigate whether TMAS can improve neural damage and motor dysfunction in PD mice by regulating mitophagy and the fission/fusion dynamic balance, thereby providing theoretical and experimental support for its application in PD treatment. MethodsMale C57BL/6 mice were used in this study. A PD model was established by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 consecutive days. After model induction, mice in the intervention group received TMAS once daily for 14 consecutive days, whereas the corresponding control group received sham stimulation. The stimulation target was positioned over the primary motor cortex (M1). Motor performance was evaluated using the pole test and the open-field test. To verify the activation effect of TMAS on the target cortical region, c-Fos immunohistochemistry was performed in the M1. To assess nigral dopaminergic neuronal injury, tyrosine hydroxylase (TH) immunohistochemistry was used to quantify TH-positive neurons in the SNc. Mitochondrial function was evaluated by measuring reactive oxygen species (ROS) levels and adenosine triphosphate (ATP) content in the SNc. Western blot was further performed to determine the expression of mitophagy-related proteins, including PINK1, Parkin, LC3-II, and p62, as well as mitochondrial dynamics-related proteins, including Drp1 and Opa1. ResultsTMAS significantly increased the number of c-Fos-positive cells in M1 (P<0.000 1), indicating effective activation of neurons in the targeted cortical region. Compared with the control group, MPTP-treated mice exhibited marked motor dysfunction, including a significant reduction in total distance traveled in the open-field test (P<0.000 1) and mean speed (P=0.000 1), as well as significant prolongation of turn time and total climbing time in the pole test (P<0.000 1). These behavioral impairments were accompanied by a substantial loss of TH-positive dopaminergic neurons in the SNc, whereas TMAS significantly increased TH-positive neuron survival (P<0.000 1). In parallel, MPTP induced a pronounced increase in ROS levels and a significant reduction in ATP content, indicating severe mitochondrial dysfunction and energy metabolism impairment (P<0.01). TMAS treatment significantly improved motor performance, as reflected by the reversal of MPTP-induced impairment in the open-field and pole tests, and significantly reduced ROS accumulation (P<0.01) while restoring ATP production (P<0.001). At the molecular level, MPTP markedly downregulated PINK1 and Parkin, decreased p62 expression, increased LC3-II accumulation, elevated Drp1 expression, and reduced Opa1 expression, whereas TMAS significantly reversed these abnormalities, suggesting restoration of mitophagy-related mitochondrial quality control and re-establishment of mitochondrial fission-fusion balance. Collectively, these findings indicate that TMAS ameliorates MPTP-induced neurotoxicity and restores mitochondrial homeostasis and energy metabolism. ConclusionTMAS effectively attenuates neural damage and improves motor dysfunction in MPTP-induced PD mice. Its neuroprotective effects are closely associated with multidimensional regulation of the mitochondrial quality control system, including restoration of PINK1/Parkin-mediated mitophagy and rebalancing of Drp1/Opa1-related mitochondrial dynamics. Rather than acting only as a symptomatic neuromodulatory intervention, TMAS may influence a key pathological axis of PD by improving mitochondrial homeostasis in SNc and protecting nigral dopaminergic neurons. These findings provide experimental evidence supporting TMAS as a promising non-invasive physical intervention for PD.

ObjectiveTranscranial magneto-acoustic stimulation (TMAS) is an emerging non-invasive neuromodulation technique that may provide a novel non-pharmacological intervention strategy for Parkinson's disease (PD). PD is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), leading to motor impairments such as bradykinesia, tremor, and rigidity. Increasing evidence indicates that mitochondrial dysfunction and impaired mitochondrial quality control are central mechanisms underlying dopaminergic neuronal loss. In particular, abnormalities in mitophagy and mitochondrial fission-fusion balance contribute substantially to oxidative stress, energy metabolic failure, and neuronal injury. At present, most clinical treatments for PD mainly alleviate symptoms but do not effectively halt disease progression. Therefore, exploring new interventions targeting the core pathological mechanisms is of considerable significance. This study aims to investigate whether TMAS can improve neural damage and motor dysfunction in PD mice by regulating mitophagy and the fission/fusion dynamic balance, thereby providing theoretical and experimental support for its application in PD treatment. MethodsMale C57BL/6 mice were used in this study. A PD model was established by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 consecutive days. After model induction, mice in the intervention group received TMAS once daily for 14 consecutive days, whereas the corresponding control group received sham stimulation. The stimulation target was positioned over the primary motor cortex (M1). Motor performance was evaluated using the pole test and the open-field test. To verify the activation effect of TMAS on the target cortical region, c-Fos immunohistochemistry was performed in the M1. To assess nigral dopaminergic neuronal injury, tyrosine hydroxylase (TH) immunohistochemistry was used to quantify TH-positive neurons in the SNc. Mitochondrial function was evaluated by measuring reactive oxygen species (ROS) levels and adenosine triphosphate (ATP) content in the SNc. Western blot was further performed to determine the expression of mitophagy-related proteins, including PINK1, Parkin, LC3-II, and p62, as well as mitochondrial dynamics-related proteins, including Drp1 and Opa1. ResultsTMAS significantly increased the number of c-Fos-positive cells in M1 (P<0.000 1), indicating effective activation of neurons in the targeted cortical region. Compared with the control group, MPTP-treated mice exhibited marked motor dysfunction, including a significant reduction in total distance traveled in the open-field test (P<0.000 1) and mean speed (P=0.000 1), as well as significant prolongation of turn time and total climbing time in the pole test (P<0.000 1). These behavioral impairments were accompanied by a substantial loss of TH-positive dopaminergic neurons in the SNc, whereas TMAS significantly increased TH-positive neuron survival (P<0.000 1). In parallel, MPTP induced a pronounced increase in ROS levels and a significant reduction in ATP content, indicating severe mitochondrial dysfunction and energy metabolism impairment (P<0.01). TMAS treatment significantly improved motor performance, as reflected by the reversal of MPTP-induced impairment in the open-field and pole tests, and significantly reduced ROS accumulation (P<0.01) while restoring ATP production (P<0.001). At the molecular level, MPTP markedly downregulated PINK1 and Parkin, decreased p62 expression, increased LC3-II accumulation, elevated Drp1 expression, and reduced Opa1 expression, whereas TMAS significantly reversed these abnormalities, suggesting restoration of mitophagy-related mitochondrial quality control and re-establishment of mitochondrial fission-fusion balance. Collectively, these findings indicate that TMAS ameliorates MPTP-induced neurotoxicity and restores mitochondrial homeostasis and energy metabolism. ConclusionTMAS effectively attenuates neural damage and improves motor dysfunction in MPTP-induced PD mice. Its neuroprotective effects are closely associated with multidimensional regulation of the mitochondrial quality control system, including restoration of PINK1/Parkin-mediated mitophagy and rebalancing of Drp1/Opa1-related mitochondrial dynamics. Rather than acting only as a symptomatic neuromodulatory intervention, TMAS may influence a key pathological axis of PD by improving mitochondrial homeostasis in SNc and protecting nigral dopaminergic neurons. These findings provide experimental evidence supporting TMAS as a promising non-invasive physical intervention for PD.

Purpose: This study aimed to evaluate the safety and efficacy of gemcitabine and cisplatin (GP) regimen in combination with immune checkpoint inhibitor sintilimab as neoadjuvant therapy for muscle-invasive bladder cancer (MIBC) patients and the feasibility of the following selective bladder sparing surgery. Materials and Methods: Patients with histopathologically confirmed urothelial carcinoma without distant metastases (T2-4a, N ≤ 1, M0, American Joint Committee of Cancer 8th) and with adequate organ function will be enrolled. The therapeutic regimen was sintilimab 200 mg once on day 8, gemcitabine 1,000 mg/m2 and cisplatin 35 mg/m2 once on days 1 and 8, every 21 days for four cycles. The primary endpoint was pathologic complete response (pCR, pT0N0) rate. The secondary end points were ypT < 2 rate, R0 resection rate, event-free survival, and safety. Results: From May 4, 2020, to May 20, 2023, 55 patients were enrolled. Forty-six patients were evaluated for efficacy. Among the 42 patients who underwent surgery, 16 patients (38.0%) achieved pCR. Thirty-three patients (78.6%) achieved pT < 2. With a median follow-up of 15.7 months, the 1-year event-free survival was 91.3%. Notwithstanding the poor pathological baseline characteristic of a high T3-T4a proportion (39.1%), a promising bladder preservation (including 22 patients transurethral resection of bladder tumor, 5 patients partial cystectomy, and 4 surveillances) rate was achieved (67.4%). The most common grade ≥ 3 treatment-related adverse events was neutropenia (n=15, 27.3%), which was related to chemotherapy. There were no grade 3 immune-related adverse events. Conclusion Neoadjuvant GP plus sintilimab is a promising regimen for MIBC patients, with relatively high pT < 2 rate and triggering the emerging roles for the multi-disciplinary team decision-making for bladder sparing surgery.

This study employed bioinformatics to screen the feature genes related to efferocytosis in diabetic kidney disease(DKD) and explores traditional Chinese medicine(TCM) regulating these feature genes. The GSE96804 and GSE30528 datasets were integrated as the training set, and the intersection of differentially expressed genes and efferocytosis-related genes(ERGs) was identified as DKD-ERGs. Subsequently, correlation analysis, protein-protein interaction(PPI) network construction, enrichment analysis, and immune infiltration analysis were performed. Consensus clustering was conducted on DKD patients based on the expression levels of DKD-ERGs, and the expression levels, immune infiltration characteristics, and gene set variations between different subtypes were explored. Eight machine learning models were constructed and their prediction performance was evaluated. The best-performing model was evaluated by nomograms, calibration curves, and external datasets, followed by the identification of efferocytosis-related feature genes associated with DKD. Finally, potential TCMs that can regulate these feature genes were predicted. The results showed that the training set contained 640 differentially expressed genes, and after intersecting with ERGs, 12 DKD-ERGs were obtained, which demonstrated mutual regulation and immune modulation effects. Consensus clustering divided DKD into two subtypes, C1 and C2. The support vector machine(SVM) model had the best performance, predicting that growth arrest-specific protein 6(GAS6), S100 calcium-binding protein A9(S100A9), C-X3-C motif chemokine ligand 1(CX3CL1), 5'-nucleotidase(NT5E), and interleukin 33(IL33) were the feature genes of DKD. Potential TCMs with therapeutic effects included Astragali Radix, Trionycis Carapax, Sargassum, Rhei Radix et Rhizoma, Curcumae Radix, and Alismatis Rhizoma, which mainly function to clear heat, replenish deficiency, activate blood, resolve stasis, and promote urination and drain dampness. Molecular docking revealed that the key components of these TCMs, including β-sitosterol, quercetin, and sitosterol, exhibited good binding activity with the five target genes. These results indicated that efferocytosis played a crucial role in the development and progression of DKD. The feature genes closely related to both DKD and efferocytosis, such as GAS6, S100A9, CX3CL1, NT5E, and IL33, were identified. TCMs such as Astragali Radix, Trionycis Carapa, Sargassum, Rhei Radix et Rhizoma, Curcumae Radix, and Alismatis Rhizoma may provide a new therapeutic strategy for DKD by regulating efferocytosis.
Humans ; Computational Biology ; Diabetic Nephropathies/physiopathology* ; Protein Interaction Maps ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal ; Phagocytosis/genetics* ; Efferocytosis

Moringa oleifera, widely utilized in Ayurvedic medicine, is recognized for its leaves, seeds, and velamen possessing traditional effects such as vātahara(wind alleviation), sirovirecaka(brain clearing), and hridya(mental nourishment). This study aims to identify the medicinal part of ■ in the Sārasvata ghee formulation as described in the Bower Manuscript, while investigating the ameliorative effects of different medicinal parts of M. oleifera on learning and memory deficits in mice and elucidating the underlying molecular mechanisms. A total of 144 male ICR mice were randomly assigned to the following groups: control, model(scopolamine hydrobromide, Sco, 2 mg·kg~(-1)), donepezil(donepezil hydrochloride, Don, 3 mg·kg~(-1)), M. oleifera leaf low-, medium-, and high-dose groups(0.5, 1, 2 g·kg~(-1)), M. oleifera seeds low-, medium-, and high-dose groups(0.25, 0.5, 1 g·kg~(-1)), and M. oleifera velamen low-, medium-, and high-dose groups(0.31, 0.62, 1.24 g·kg~(-1)). Learning and memory abilities were assessed using the passive avoidance test and Morris water maze. Nissl and HE staining were employed to examine histopathological changes in the hippocampus. Transcriptomics and targeted metabolomics were used to screen differential genes and metabolites, with MetaboAnalyst 6.0 and O2PLS methods applied to identify key disease-related targets and pathways. RESULTS:: demonstrated that M. oleifera leaf(1 g·kg~(-1)) significantly ameliorated Sco-induced learning and memory deficits, outperforming M. oleifera seeds(0.25 g·kg~(-1)) and M. oleifera velamen(1.24 g·kg~(-1)). This was evidenced by improved behavioral performance, reversal of neuronal damage, and reduced acetylcholinesterase(AChE) activity. Multi-omics analysis revealed that M. oleifera leaf upregulated Tuba1c gene expression through the synaptic vesicle cycle, enhancing glutamate(Glu), dopamine(DA), and acetylcholine(ACh) release via Tuba1c-Glu associations for neuroprotection. M. oleifera seeds targeted the dopaminergic synapse pathway, promoting memory consolidation through Drd2-ACh associations. M. oleifera velamen was associated with the cocaine addiction pathway, modulating dopamine metabolism via Adora2a-DOPAC, with limited relevance to learning and memory. In conclusion, M. oleifera leaf exhibits superior efficacy and mechanistic advantages over M. oleifera seeds and velamen, suggesting that the ■ in the Sārasvata ghee formulation is likely M. oleifera leaf, providing scientific evidence for its identification in ancient texts.
Animals ; Moringa oleifera/chemistry* ; Male ; Mice ; Seeds/chemistry* ; Plant Leaves/chemistry* ; Mice, Inbred ICR ; Memory Disorders/psychology* ; Transcriptome/drug effects* ; Memory/drug effects* ; Learning/drug effects* ; Metabolomics ; Humans ; Drugs, Chinese Herbal/administration & dosage* ; Maze Learning/drug effects*

OBJECTIVE: To evaluate the effects of posterior cruciate ligament(PCL) resection on soft tissue elasticity and knee stability in total knee arthroplasty(TKA). METHODS: Six adult cadaveric knee specimens (involving 10 knees) were included in the study. With the assistance of the robotic system(TiRobot Recon, TINAVI, Beijing), total knee arthroplasty (TKA) was performed sequentially using cruciate retaining (CR) prostheses and posterior stabilizing (PS) prostheses. Between the two surgical procedures, the femoral and tibial osteotomy surfaces were not altered;only the posterior cruciate ligament (PCL) was resected and the intercondylar fossa was treated. After installing the femoral trial component, a soft tissue balance solver was used to apply tension ranging from 30 N to 90 N in 5 N increments at 0°, 10°, and 90° of knee flexion. Meanwhile, the medial and lateral joint gaps were measured synchronously. Based on the tension-gap coupling data, the equivalent elastic coefficients of the medial and lateral soft tissue sleeves at different knee flexion angles, as well as the range of the joint line convergence angle (JLCA) under fixed varus-valgus stress, were calculated. Additionally, the gap balance status under 80 N of tension was analyzed. Self-control comparisons of each indicator were conducted before and after PCL resection to analyze the change patterns. RESULTS: After PCL resection, in the fully extended position (knee flexion 0°). The medial equivalent elastic coefficient was 32.2 (25.7, 63.3) N·mm^-1 for the CR prosthesis and 27.7 (22.0, 51.9) N·mm^-1 for the PS prosthesis, and the statistically significant difference (P=0.013). The range of JLCA was 0.41°(0.26, 0.55)° for the CR prosthesis, which was smaller than 0.75° (0.40, 0.98)° for the PS prosthesis, and the difference was statistically significant(P=0.041). At 90° of knee flexion, the medial joint gap was 10.7(10.1, 11.7) mm for the CR prosthesis, which was smaller than 12.1(10.9, 15.1) mm for the PS prosthesis, with a statistically significant difference(P=0.011). No statistically significant differences were observed in other joint gaps. CONCLUSION PCL resection reduces the rigidity of the medial soft tissues in the fully extended knee and increases the medial joint gap in the flexed position, thereby affecting knee stability and balance. This finding suggests that PS and CR prostheses may require different morphological designs, and there should be differences in indications and osteotomy strategies between CR-TKA and PS-TKA. CR-TKA is more suitable for patients with preoperative medial soft tissue laxity.
Humans ; Posterior Cruciate Ligament/physiopathology* ; Knee Joint/physiopathology* ; Arthroplasty, Replacement, Knee ; Elasticity ; Male ; Female ; Middle Aged ; Aged ; Biomechanical Phenomena ; Adult

OBJECTIVE: To investigate the predictive role of the modified Endothelial Activation and Stress Index (mEASIX) in the efficacy of chimeric antigen receptor T-cell (CAR-T) therapy and cytokine release syndrome (CRS). METHODS: The clinical data of 70 relapsed and refractory (R/R) B-cell tumor patients who were treated with CAR-T therapy from September 1, 2018 to February 28, 2023 in the Department of Hematology, Affiliated Hospital of Xuzhou Medical University, were retrospectively analyzed. The value of log-2 mEASIX before conditioning (-7 d) was calculated, and the patients were divided into a low-mEASIX group (42 patients) and a high-mEASIX group (28 patients) based on the cut-off value of 5.443 determined by the receiver operating characteristic (ROC) curve. Eventually, the predictive role of mEASIX before conditioning on the efficacy of CAR-T cell therapy and CRS was analyzed. RESULTS: The high-mEASIX group exhibited significantly worse median overall survival (OS) and median progression-free survival (PFS) in comparison to the low mEASIX group (OS: 3.2 months vs not reached, P < 0.01; PFS: 1.3 months vs 6.0 months, P =0.009). The incidence of grade ≥2 CRS in the high-mEASIX group was substantially higher than that in the low-mEASIX group (57.1% vs 19.0%, P =0.007). The degree of remission after CAR-T therapy (P =0.001), whether CRS occurs or not (P =0.041), the lactate dehydrogenase (LDH) level before conditioning (P =0.046), and the mEASIX score before conditioning (P =0.047) were independent influencing factors for the OS of patients receiving CAR-T cell therapy. CONCLUSION The mEASIX score before conditioning can predict OS and the incidence of grade ≥2 CRS in patients with relapsed and refractory B-cell tumors who receive CAR-T cell therapy.
Cytokine Release Syndrome/therapy* ; Immunotherapy, Adoptive/methods* ; Humans ; Lymphoma, B-Cell/therapy* ; Retrospective Studies ; Hematology ; China ; Receptors, Chimeric Antigen/blood* ; Predictive Value of Tests

OBJECTIVE: To explore the therapeutic effects and underlying mechanisms of Dendrobium officinale (Tiepi Shihu) extract (DOE) on insomnia. METHODS: Forty-two male Sprague-Dawley rats were randomly divided into 6 groups (n=7 per group): normal control, model control, melatonin (MT, 40 mg/kg), and 3-dose DOE (0.25, 0.50, and 1.00 g/kg) groups. Rats were raised in a strong-light (10,000 LUX) and -noise (>80 db) environment (12 h/d) for 16 weeks to induce insomnia, and from week 10 to week 16, MT and DOE were correspondingly administered to rats. The behavior tests including sodium pentobarbital-induced sleep experiment, sucrose preference test, and autonomous activity test were used to evaluate changes in sleep and emotions of rats. The metabolic-related indicators such as blood pressure, blood viscosity, blood glucose, and uric acid in rats were measured. The pathological changes in the cornu ammonis 1 (CA1) region of rat brain were evaluated using hematoxylin and eosin staining and Nissl staining. Additionally, the sleep-related factors gamma-aminobutyric acid (GABA), glutamate (GA), 5-hydroxytryptamine (5-HT), and interleukin-6 (IL-6) were measured using enzyme linked immunosorbent assay. Finally, we screened potential sleep-improving receptors of DOE using polymerase chain reaction (PCR) array and validated the results with quantitative PCR and immunohistochemistry. RESULTS: DOE significantly improved rats' sleep and mood, increased the sodium pentobarbital-induced sleep time and sucrose preference index, and reduced autonomic activity times (P<0.05 or P<0.01). DOE also had a good effect on metabolic abnormalities, significantly reducing triglyceride, blood glucose, blood pressure, and blood viscosity indicators (P<0.05 or P<0.01). DOE significantly increased the GABA content in hippocampus and reduced the GA/GABA ratio and IL-6 level (P<0.05 or P<0.01). In addition, DOE improved the pathological changes such as the disorder of cell arrangement in the hippocampus and the decrease of Nissel bodies. Seven differential genes were screened by PCR array, and the GABA_A receptors (Gabra5, Gabra6, Gabrq) were selected for verification. The results showed that DOE could up-regulate their expressions (P<0.05 or P<0.01). CONCLUSION DOE demonstrated remarkable potential for improving insomnia, which may be through regulating GABA_A receptors expressions and GA/GABA ratio.
Animals ; Dendrobium/chemistry* ; Rats, Sprague-Dawley ; Male ; Sleep Initiation and Maintenance Disorders/blood* ; Plant Extracts/therapeutic use* ; Receptors, GABA-A/metabolism* ; Noise/adverse effects* ; Light/adverse effects* ; gamma-Aminobutyric Acid/metabolism* ; Sleep/drug effects* ; Rats ; Receptors, GABA/metabolism*

Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by aberrant wound healing, excessive scarring and the formation of myofibroblastic foci. Although the role of alternative splicing (AS) in the pathogenesis of organ fibrosis has garnered increasing attention, its specific contribution to pulmonary fibrosis remains incompletely understood. In this study, we identified an up-regulation of serine/arginine-rich splicing factor 7 (SRSF7) in lung fibroblasts derived from IPF patients and a bleomycin (BLM)-induced mouse model, and further characterized its functional role in both human fetal lung fibroblasts and mice. We demonstrated that enhanced expression of Srsf7 in mice spontaneously induced alveolar collagen accumulation. Mechanistically, we investigated alternative splicing events and revealed that SRSF7 modulates the alternative splicing of pyruvate kinase (PKM), leading to metabolic dysregulation and fibroblast activation. In vivo studies showed that fibroblast-specific knockout of Srsf7 in conditional knockout mice conferred resistance to bleomycin-induced pulmonary fibrosis. Importantly, through drug screening, we identified lomitapide as a novel modulator of SRSF7, which effectively mitigated experimental pulmonary fibrosis. Collectively, our findings elucidate a molecular pathway by which SRSF7 drives fibroblast metabolic dysregulation and propose a potential therapeutic strategy for pulmonary fibrosis.

Apical microsurgery is accurate and minimally invasive, produces few complications, and has a success rate of more than 90%. However, due to the lack of awareness and understanding of apical microsurgery by dental general practitioners and even endodontists, many clinical problems remain to be overcome. The consensus has gathered well-known domestic experts to hold a series of special discussions and reached the consensus. This document specifies the indications, contraindications, preoperative preparations, operational procedures, complication prevention measures, and efficacy evaluation of apical microsurgery and is applicable to dentists who perform apical microsurgery after systematic training.
Microsurgery/standards* ; Humans ; Apicoectomy ; Contraindications, Procedure ; Tooth Apex/diagnostic imaging* ; Postoperative Complications/prevention & control* ; Consensus ; Treatment Outcome