Parkinson's disease is a neurodegenerative disease that mostly occurs in middle-aged and elderly people. It is characterized by progressive loss of dopaminergic neurons in the substantia nigra and aggregation of Lewy bodies, resulting in a series of motor symptoms and non-motor symptoms. Depression is the most important manifestation of non-motor symptoms, which seriously affects the quality of life of patients. Clinicians often use antidepressant drugs to improve the depressive symptoms of patients with Parkinson 's disease, but it is still urgent to solve the problems of drug side effects and drug resistance caused by such methods. Repetitive transcranial magnetic stimulation is a safe and non-invasive neuromodulation technique that can change the excitability of the corticospinal tract, induce the release of dopamine and other neurotransmitters, and further improve the depressive symptoms of patients with Parkinson 's disease. Based on this, this paper discusses and summarizes the research progress on the efficacy and potential mechanism of repetitive transcranial magnetic stimulation for improving depression in Parkinson 's disease at home and abroad, in order to provide reference for related clinical application research.
Humans ; Parkinson Disease/psychology* ; Transcranial Magnetic Stimulation/methods* ; Depression/etiology*

Obesity is a significant risk factor for cancer and is associated with breast cancer metastasis. Nevertheless, the mechanism by which alterations in systemic metabolism affect tumor microenvironment (TME) and consequently influence tumor metastasis remains inadequately understood. Herein, we found that perturbations in circulating metabolites induced by obesity promote metastasis-like phenotypes in breast cancer. Oleoylcarnitine (OLCarn) concentrations were elevated in the serum of obese mice and humans. Administration of exogenous OLCarn induces metastasis-like characteristics in breast cancer cells. Mechanistically, OLCarn directly interacts with the Arg176 site of adenylate cyclase 10 (ADCY10), leading to the activation of ADCY10 and enhancement of cAMP production. Mutations at Arg176 prevent OLCarn from binding to ADCY10, disrupting the ADCY10-mediated activation of cyclic adenosine monophosphate (cAMP) signaling pathway. This activation promotes transcription factor 4 (TCF4)-dependent kinesin family member C1 (KIFC1) transcription, thereby driving breast cancer metastasis. Conversely, the neutralization of both ADCY10 and KIFC1 through knockdown or pharmacological inhibition abrogates the oncogenic effects mediated by OLCarn. Hence, obesity-induced systemic environmental changes lead to the aberrant accumulation of OLCarn within the TME, making it a potential therapeutic target and biomarker for breast cancer.

Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death. However, the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear. Here, we identified that the expression of sterile alpha and TIR motif containing 1 (SARM1), was increased significantly in the ischemic cardiomyopathy patients, dilated cardiomyopathy patients (GSE116250) and fibrotic heart tissues of mice. Additionally, inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction (MI) mice. Moreover, SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function. Mechanically, elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1. Notably, by using the Click-iT reaction, we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1, thereby accelerating the fibrosis process. Based on the fibrosis-promoting effect of SARM1, we screened several drugs with anti-myocardial fibrosis activity. In conclusion, we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis. Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis. The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.

Cardiac fibrosis is characterized by an elevated amount of extracellular matrix (ECM) within the heart. However, the persistence of cardiac fibrosis ultimately diminishes contractility and precipitates cardiac dysfunction. Circular RNAs (circRNAs) are emerging as important regulators of cardiac fibrosis. Here, we elucidate the functional role of a specific circular RNA CELF1 in cardiac fibrosis and delineate a novel feedback loop mechanism. Functionally, circ-CELF1 was involved in enhancing fibrosis-related markers' expression and promoting the proliferation of cardiac fibroblasts (CFs), thereby exacerbating cardiac fibrosis. Mechanistically, circ-CELF1 reduced the ubiquitination-degradation rate of BRPF3, leading to an elevation of BRPF3 protein levels. Additionally, BRPF3 acted as a modular scaffold for the recruitment of histone acetyltransferase KAT7 to facilitate the induction of H3K14 acetylation within the promoters of the Celf1 gene. Thus, the transcription of Celf1 was dramatically activated, thereby inhibiting the subsequent response of their downstream target gene Smad7 expression to promote cardiac fibrosis. Moreover, Celf1 further promoted Celf1 pre-mRNA transcription and back-splicing, thereby establishing a feedback loop for circ-CELF1 production. Consequently, a novel feedback loop involving CELF1/circ-CELF1/BRPF3/KAT7 was established, suggesting that circ-CELF1 may serve as a potential novel therapeutic target for cardiac fibrosis.

Diabetic cardiomyopathy (DCM) is a medical condition characterized by cardiac remodeling and dysfunction in individuals with diabetes mellitus. Sarcoplasmic reticulum (SR) and mitochondrial Ca²⁺ overload in cardiomyocytes have been recognized as biological hallmarks in DCM; however, the specific factors underlying these abnormalities remain largely unknown. In this study, we aimed to investigate the role of a cardiac-specific long noncoding RNA, D830005E20Rik (Trdn-as), in DCM. Our results revealed the remarkably upregulation of Trdn-as in the hearts of the DCM mice and cardiomyocytes treated with high glucose (HG). Knocking down Trdn-as in cardiac tissues significantly improved cardiac dysfunction and remodeling in the DCM mice. Conversely, Trdn-as overexpression resulted in cardiac damage resembling that observed in the DCM mice. At the cellular level, Trdn-as induced Ca²⁺ overload in the SR and mitochondria, leading to mitochondrial dysfunction. RNA-seq and bioinformatics analyses identified calsequestrin 2 (Casq2), a primary calcium-binding protein in the junctional SR, as a potential target of Trdn-as. Further investigations revealed that Trdn-as facilitated the recruitment of METTL14 to the Casq2 mRNA, thereby enhancing the m⁶A modification of Casq2. This modification increased the stability of Casq2 mRNA and subsequently led to increased protein expression. When Casq2 was knocked down, the promoting effects of Trdn-as on Ca²⁺ overload and mitochondrial damage were mitigated. These findings provide valuable insights into the pathogenesis of DCM and suggest Trdn-as as a potential therapeutic target for this condition.
Animals ; Diabetic Cardiomyopathies/pathology* ; RNA, Long Noncoding/genetics* ; Myocytes, Cardiac/metabolism* ; Mice ; Calsequestrin/genetics* ; Calcium/metabolism* ; Male ; Sarcoplasmic Reticulum/metabolism* ; Methyltransferases/metabolism* ; Mice, Inbred C57BL ; Mitochondria, Heart/metabolism* ; Disease Models, Animal ; Mitochondria/metabolism*

Ovarian cancer poses a significant threat to women's health, necessitating effective therapeutic strategies. Emd-D, an emodin derivative, demonstrates enhanced pharmaceutical properties and bioavailability. In this study, Cell Counting Kit 8 (CCK8) assays and Ki-67 staining revealed dose-dependent inhibition of cell proliferation by Emd-D. Migration and invasion experiments confirmed its inhibitory effects on OVHM cells, while flow cytometry analysis demonstrated Emd-D-induced apoptosis. Mechanistic investigations elucidated that Emd-D functions as an inhibitor by directly binding to the glycolysis-related enzyme PFKFB4. This was corroborated by alterations in intracellular lactate and pyruvate levels, as well as glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) expression. PFKFB4 overexpression experiments further supported the dependence of Emd-D on PFKFB4-mediated glycolysis and SRC3/mTORC1 pathway-associated apoptosis. In vivo experiments exhibited reduced xenograft tumor sizes upon Emd-D treatment, accompanied by suppressed glycolysis and increased expression of Bax/Bcl-2 apoptotic proteins within the tumors. In conclusion, our findings demonstrate Emd-D's potential as an anti-ovarian cancer agent through inhibition of the PFKFB4-dependent glycolysis pathway and induction of apoptosis. These results provide a foundation for further exploration of Emd-D as a promising drug candidate for ovarian cancer treatment.
Female ; Humans ; Ovarian Neoplasms/physiopathology* ; Phosphofructokinase-2/genetics* ; Apoptosis/drug effects* ; Glycolysis/drug effects* ; Animals ; Cell Line, Tumor ; Mice ; Cell Proliferation/drug effects* ; Emodin/administration & dosage* ; Mice, Nude ; Mice, Inbred BALB C ; Hexokinase/metabolism* ; Xenograft Model Antitumor Assays

ObjectiveTo investigate the therapeutic effect of Baihe Wuyaotang （BWT） on non-alcoholic fatty liver disease （NAFLD） and elucidate its underlying mechanism. MethodC57BL/6J mice were randomly assigned to six groups： normal control， model， positive drug （pioglitazone hydrochloride 1.95×10^-3 g·kg^-1）， and low-， medium-， and high-dose BWT （1.3，2.5 and 5.1 g·kg^-1）. Following a 12-week high-fat diet （HFD） inducement， the mice underwent six weeks of therapeutic intervention with twice-daily drug administration. Body weight was monitored weekly throughout the treatment period. At the fifth week， glucose tolerance （GTT） and insulin tolerance （ITT） tests were conducted. Subsequently， the mice were euthanized for the collection of liver tissue and serum， and the subcutaneous adipose tissue （iWAT） and epididymal adipose tissue （eWAT） were weighed. Serum levels of total triglycerides （TG） and liver function indicators，such as alanine aminotransferase （ALT） and aspartate aminotransferase （AST）， were determined. Histological examinations， including oil red O staining， hematoxylin-eosin （HE） staining， Masson staining， and transmission electron microscopy， were performed to evaluate hepatic lipid deposition， pathological morphology， and ultrastructural changes， respectively. Meanwhile， Western blot and real-time quantitative polymerase chain reaction （Real-time PCR） were employed to analyze alterations， at both gene and protein levels， the insulin signaling pathway molecules， including insulin receptor substrate 1/2/protein kinase B/forkhead box gene O1 （IRS1/2/Akt/FoxO1）， glycogen synthesis enzymes phosphoenolpyruvate carboxy kinase （Pepck） and glucose-6-phosphatase （G6Pase）， lipid metabolism-related genes stearoyl-coA desaturase-1 （SCD-1） and carnitine palmitoyltransferase-1 （CPT-1）， fibrosis-associated molecules α-smooth muscle actin （α-SMA）， type Ⅰ collagen （CollagenⅠ）， and the fibrosis canonical signaling pathway transforming growth factor-β₁/drosophila mothers against decapentaplegic protein2/3（TGF-β₁/p-Smad/Smad2/3）， inflammatory factors such as interleukin（IL）-6， IL-8， IL-11， and IL-1β， autophagy markers LC3B Ⅱ/Ⅰ and p62/SQSTM1， and the expression of mammalian target of rapamycin （mTOR）. ResultCompared with the model group， BWT reduced the body weight and liver weight of NAFLD mice（P<0.05， P<0.01）， inhibited liver lipid accumulation， and reduced the weight of white fat： it reduced the weight of eWAT and iWAT（P<0.05， P<0.01） as well as the serum TG content（P<0.05， P<0.01）. BWT improved the liver function as reflected by the reduced ALT and AST content（P<0.05， P<0.01）. It improved liver insulin resistance by upregulating IRS2， p-Akt/Akt， p-FoxO1/FoxO1 expressions（P<0.05）. Besides， it improved glucose and lipid metabolism disorders： it reduced fasting blood glucose and postprandial blood glucose（P<0.05， P<0.01）， improved GTT and ITT（P<0.05， P<0.01）， reduced the expression of Pepck， G6Pase， and SCD-1（P<0.01）， and increased the expression of CPT-1（P<0.01）. The expressions of α-SMA， Collagen1， and TGF-β₁ proteins were down-regulated（P<0.05， P<0.01）， while the expression of p-Smad/Smad2/3 was downregulated（P<0.05）， suggesting BWT reduced liver fibrosis. BWT inhibited inflammation-related factors as it reduced the gene expression of IL-6， IL-8， IL-11 and IL-1β（P<0.01） and it enhanced autophagy by upregulating LC3B Ⅱ/Ⅰ expression（P<0.05）while downregulating the expression of p62/SQSTM1 and mTOR（P<0.05）. ConclusionBWT ameliorates NAFLD by multifaceted improvements， including improving IR and glucose and lipid metabolism， anti-inflammation， anti-fibrosis， and enhancing autophagy. In particular， BWT may enhance liver autophagy by inhibiting the mTOR-mediated signaling pathway.

Objectives:To explore the accuracy of pedicle screw placement assisted with improved 3D-print-ed drill guiding template in cervical spine.Methods:The clinical data of 60 patients undergone posterior cervical pedicle screw placement in our hospital between January 2016 and January 2023 were analyzed retro-spectively,including 30 males and 30 females with an average age of 17-84 years(58.7±13.8 years).The pa-tients were divided into guiding template group and free-hand group based on whether the guiding template was used to assist the placement of screws or not.The improved 3D-printed guiding template was used to assist cervical pedicle screw placement in the guiding template group(n=30),and the self-made angular-ruler was used in the free-hand group(n=30).There was no significant difference in age,gender ratio,and preoper-ative diagnosis between the two groups(P＞0.05).Cervical CT scan was performed at one week after surgery,and the accuracy of pedicle screw placement was evaluated according to the Kaneyama standard:Grade 0,the screw was completely in the pedicle;Grade 1,the size of screw penetrating the cortex＜50%of the screw diameter;Grade 2,the size of screw penetrating the cortex≥50%of the screw diameter but not com pletely out;Grade 3,the screw was completely on the outside of the pedicle.The accuracy of pedicle screw placement(ratio of grades 0 and 1)and complications such as vascular and nerve injury,incision infection,cerebrospinal fluid leakage,screw loosening and breakage caused by screw misplacement were recorded.Re-sults:A total of 152 pedicle screws were placed in the guiding template group,including 74 screws of grade 0,68 of grade 1,10 of grade 2 and 0 of grade 3,with an accuracy of screw placement of 93.4%.A total of 136 pedicle screws were placed in free-hand group,including 53 screws of grade 0,61 of grade 1,18 of grade 2 and 4 of grade 3,with an accuracy of screw placement of 83.8%.The accuracy of screw placement in the guiding template group was significantly higher than that in the free-hand group(P＜0.05).There were no related complications such as vascular and nerve injury,incision infection and cerebrospinal fluid leakage caused by misplacement of pedicle screws.The patients were followed up for 5-29 months(14.2±7.7months),and there were no complications such as screw loosening or breakage.Conclusions:Improved 3D-printed drill guiding template can improve the accuracy of pedicle screw placement in cervical spine.

Objectives:To explore the safety and accuracy of subaxial cervical pedicle screw(CPS)insertion assisted with optimized 3D-printed drill guiding template(DGT).Methods:A retrospective study was conducted to analyze the clinical data of 42 patients aged 32-74 years(50.1±9.8 years)who underwent posterior cervi-cal pedicle screw intemal fixation between August 2016 and October 2022.The patients were followed up for 13-25 months(19.6±3.2 months).They were divided into two groups of guiding template group(n=22)and free-hand group(n=20)according to the method of pedicle screw insertion.In the guiding template group,the sub-axial CPSs insertions were assisted with 3D-printed DGT,designed individually for each patient based on the design scheme of an optimized pedicle drill guiding template,and the patients consisted of 12 males and 10 females,among which 6 patients were with cervical spine injury or spinal cord injury,9 were with ossifica-tion of posterior longitudinal ligament(OPLL),5 were with intraspinal tumor,and 2 were with cervical spondy-lotic myelopathy.In the free-hand group,the subaxial CPSs were inserted with free hand according to the cervical parameters such as pedicle angle and diameter on the CT images measured before operation,and the patients consisted of 10 males and 10 females,among which 4 patients were with cervical spine injury or spinal cord injury,10 with OPLL,5 with intraspinal tumor,and 1 with cervical spondylotic myelopathy.There were no significant differences in sex,age,disease,and preoperative visual analogue scale(VAS)score and Japanese Orthopaedic Association(JO A)score between the two groups(P＞0.05).The operative time,intraopera-tive blood loss,and postoperative 12 months of VAS and JOA scores were recorded and compared.CT scan was performed at 1 week after operation on cervical spine,and the accuracy of pedicle screw placement was evaluated in accordance with Kaneyama's evaluation method:Grade 0,screw was contained in the pedicle;Grade 1,screw penetrated pedicle＜50％of the screw diameter;Grade 2,screw penetrated pedicle＞50％of the screw diameter;Grade 3,screw completely penetrated the pedicle.Grades 0 and 1 were considered accurate placement,and grades 2 and 3 were considered misplacement.The perioperative complications were recorded for each patient in the two groups.Results:The operative time,intra-operative blood loss in guiding template group(102.2±16.1min,89.3±17.7mL)were statistically less than those in free-hand group(142.8±20.9min,133.3±34.0mL)(P＜0.01).A total of 216 CPSs were placed:118 in the guiding template group,including 90 screws of grade 0,22 screws of grade 1,5 screws of grade 2,1 screw of grade 3,with an accuracy rate of 94.9％(112/118);And 98 in the free-hand group,including 48 screws of grade 0,36 screws of grade 1,10 screws of grade 2,and 4 screws of grade 3,with an accuracy rate of 85.7％(84/98).The accuracy rate of pedicle screw insertion was significant higher in the guiding template group than that in the free-hand group(P＜0.05).No major neurovascular complications nor internal fixation loosening or breakages were observed in two groups of patients.At 12 months after operation,the VAS score in both groups was statistically less than that before operation(P＜0.01),and the JOA score in both groups was statistically more than that before opera-tion(P＜0.01),and there were no significant differences in VAS score and JOA score between groups,respec-tively(P＞0.05).Conclusions:The optimized design scheme of 3D-printed DGT is helpful in improving the ac-curacy and safety of subaxial CPS insertion.

Purpose To study the clinical and pathological features of angiomatoid fibrous histocytoma(AFH)and to ex-plore its diagnosis,differential diagnosis and prognosis.Meth-ods The clinicopathological and follow-up data were analyzed in 14 cases of AFH,and the literatures were reviewed.Results There were 11 males and 3 females.The age ranged from 11 months to 12 years and 11 months,with average 5.9 years.3 cases were located in limbs,and 5 cases in trunk,5 cases in head and neck region,and 1 of intracranial tumor.Histological-ly,14 cases were composed of fibrous capsules and lymphocyte sheaths,and cell nucleus were vacuolar,forming fascicles with focal whirling and synteny.Intralesional pseudoangiomatous spaces were noted in 9 cases.Calcification was found in 2 ca-ses.2 cases showed high mitotic acticity(11/10 HPF).Scle-rosing and/or myxoid stroma was seen in 3 cases.Tumors were immunopositive for desmin(10/14),EMA(12/14),CD99(12/14),SMA(9/12),ALK(7/8),and the average of Ki67 index was 16％.7 cases harbored EWSR1 rearrangenent(part-ner gene not identified),2 cases had EWSR1-ATF1 fusion and 2 EWSR1-CREB1 fusion.Clinical follow-up information was a-vailable for 14 cases(average 46 months).All the 14 cases were alive without recurrence and metastasis.Conclusion AFH is a borderline or low-grade malignant tumor,often demon-strates indolent behavior in children,but rarely recurs and me-tastasizes.The diagnosis and differential diagnosis require a comprehensive analysis of clinical features,histopathologic changes,immunohistochemical finding and EWSR1 or FUS gene detection results.