The ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson's disease (PD). Notably, the VA receives direct innervation from the hypothalamic histaminergic system. However, its role in PD remains unknown. Here, we assessed the contribution of histamine to VA neuronal activity and PD motor deficits. Functional magnetic resonance imaging showed reduced VA activity in PD patients. Optogenetic activation of VA neurons or histaminergic afferents significantly alleviated motor deficits in 6-OHDA-induced PD rats. Furthermore, histamine excited VA neurons via H1 and H2 receptors and their coupled hyperpolarization-activated cyclic nucleotide-gated channels, inward-rectifier K⁺ channels, or Ca²⁺-activated K⁺ channels. These results demonstrate that histaminergic afferents actively compensate for Parkinsonian motor deficits by biasing VA activity. These findings suggest that targeting VA histamine receptors and downstream ion channels may be a potential therapeutic strategy for PD motor dysfunction.
Animals ; Histamine/metabolism* ; Male ; Oxidopamine/toxicity* ; Rats ; Ventral Thalamic Nuclei/physiopathology* ; Rats, Sprague-Dawley ; Disease Models, Animal ; Parkinson Disease/metabolism* ; Neurons/physiology* ; Humans ; Optogenetics

Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis

Juvenile idiopathic arthritis (JIA) is the most common condition of chronic rheumatic disease in children. JIA is an autoimmune or autoinflammatory disease, with unclear mechanism and limited treatment efficacy. Recent studies have found a number of alterations in gut microbiota and its metabolites in children with JIA, which are related to the development and progression of JIA. This review focuses on the influence of the gut microbiota and its metabolites on immune function and the intestinal mucosal barrier and discuss the key role of the gut-joint axis in the pathogenesis of JIA and emerging treatment methods based on gut microbiota and its metabolites. This review could help elucidate the pathogenesis of JIA and identify the potential therapeutic targets for the prevention and treatment of JIA.
Humans ; Arthritis, Juvenile/physiopathology* ; Gastrointestinal Microbiome/physiology* ; Child ; Intestinal Mucosa

With Glycyrrhizae Radix et Rhizoma-Gypsum Fibrosum drug pair as the research object, supramolecular chemistry of traditional Chinese medicine(TCM) was used to study differences between the compatibility of herbal medicine Glycyrrhizae Radix et Rhizoma with mineral medicine Gypsum Fibrosum and its main component CaSO_4·2H_2O, so as to preliminarily discuss the scientific connotation of compatibility of Gypsum Fibrosum in clinical application. A Malvern particle sizer, a scanning electron microscope(SEM), and a conductivity meter were used to observe and determine the physical properties such as microscopic morphology, particle size, and conductivity of Gypsum Fibrosum, CaSO_4·2H_2O, and water decoctions of them with Glycyrrhizae Radix et Rhizoma. An inductively coupled plasma optical emission spectrometer(ICP-OES) was employed to detect the inorganic metal elements in Glycyrrhizae Radix et Rhizoma-Gypsum Fibrosum and Glycyrrhizae Radix et Rhizoma-CaSO_4·2H_2O. Isothermal titration calorimetry(ITC) was conducted to quantify the interactions of Gypsum Fibrosum and CaSO_4·2H_2O with Glycyrrhizae Radix et Rhizoma. A Fourier transform infrared spectrometer(FTIR) was used to analyze the characteristic absorption peak change of Glycyrrhizae Radix et Rhizoma-Gypsum Fibrosum and Glycyrrhizae Radix et Rhizoma-CaSO_4·2H_2O. X-ray diffraction(XRD) was performed to determine the crystal structure and phase composition of Glycyrrhizae Radix et Rhizoma-Gypsum Fibrosum and Glycyrrhizae Radix et Rhizoma-CaSO_4·2H_2O. Further, glycyrrhizic acid(GA) was substituted for Glycyrrhizae Radix et Rhizoma to co-decoct with Gypsum Fibrosum, CaSO_4·2H_2O, and freeze-dried powder of their respective water decoctions. The results of XRD were used for verification analysis. The results showed that although CaSO_4·2H_2O is the main component of Gypsum Fibrosum, there were significant differences between their decoctions and between the decoctions of them with Glycyrrhizae Radix et Rhizoma. Specifically,(1) Both CaSO_4·2H_2O and Gypsum Fibrosum were amorphous fibrous. However, the particle size and conductivity were significantly different between the decoctions of CaSO_4·2H_2O and Gypsum Fibrosum alone.(2) Under SEM, Glycyrrhizae Radix et Rhizoma-CaSO_4·2H_2O was a hybrid system with various morphologies, while Glycyrrhizae Radix et Rhizoma-Gypsum Fibrosum presented uniform nanoparticles.(3) The particle sizes and conductivities of Glycyrrhizae Radix et Rhizoma-CaSO_4·2H_2O and Glycyrrhizae Radix et Rhizoma-Gypsum Fibrosum were significantly different and did not follow the same tendency as those of the decoctions of CaSO_4·2H_2O and Gypsum Fibrosum alone.(4) Compared with Glycyrrhizae Radix et Rhizoma-CaSO_4·2H_2O, Glycyrrhizae Radix et Rhizoma-Gypsum Fibrosum had stronger molecular binding ability and functional group structure change.(5) The crystal form was largely different between the freeze-dried powder of CaSO_4·2H_2O decoction and Gypsum Fibrosum decoction, and their crystal forms were also significantly different from those of the freeze-dried powder of Glycyrrhizae Radix et Rhizoma-CaSO_4·2H_2O and Glycyrrhizae Radix et Rhizoma-Gypsum Fibrosum decoctions. The reason for the series of differences is that Gypsum Fibrosum is richer in trace elements than CaSO_4·2H_2O. The XRD results of GA-Gypsum Fibrosum and GA-CaSO_4·2H_2O decoctions further prove the importance of trace elements in Gypsum Fibrosum for supramolecule formation. This research preliminarily reveals the influence of compatibility of Gypsum Fibrosum or CaSO_4·2H_2O on decoction phase state, material form, and crystal form, providing a basis for the rational clinical application of Gypsum Fibrosum.
Drugs, Chinese Herbal/chemistry* ; Calcium Sulfate/chemistry* ; Glycyrrhiza/chemistry* ; Crystallization ; Particle Size ; Medicine, Chinese Traditional ; Rhizome/chemistry*

Astragalus membranaceus(A. membranaceus), a traditional tonic, contains flavonoids as one of its main bioactive components and key indicators for quality standard detection. These compounds predominantly exist in glycosylated forms after glycosylation modification within the plant. The catalytic products of flavonoid glycosyltransferases in A. membranaceus have been reported to be mostly monoglycosides, and only AmUGT28 catalyzes luteolin to form diglycosides. In this study, we cloned a glycosyltransferase gene, AmGT90, from A. membranaceus, with an ORF length of 1 335 bp, encoding 444 amino acids, and the protein had a relative molecular mass of 50.5 kDa. Phylogenetic tree analysis indicated that AmGT90 belongs to the UGT74 family. In vitro enzymatic reaction showed that AmGT90 had broad substrate specificity and could catalyze the glycosylation of various flavonoids, including isoflavones, flavones, flavanones, and chalcones. AmGT90 not only catalyzed the formation of monoglycosides but also diglycosides. In addition, the mechanism of AmGT90 catalyzing the formation of diglycosides from luteolin was preliminarily explored. The experimental results showed that AmGT90 may preferentially recognize C4'-OH of luteolin and then recognize C7-OH to form diglycosides. This study reported a glycosyltransferase from A. membranaceus capable of converting flavonoids into monoglycosides and diglycosides. This finding not only enhances our understanding of the biosynthetic pathways of flavonoid glycosides in A. membranaceus but also introduces a new component for glycoside production through synthetic biology.
Glycosyltransferases/chemistry* ; Flavonoids/chemistry* ; Astragalus propinquus/classification* ; Phylogeny ; Glycosylation ; Plant Proteins/chemistry* ; Substrate Specificity ; Cloning, Molecular ; Amino Acid Sequence

OBJECTIVE: To compare the biomechanical properties of personalized Y-shaped plates with horizontal plates, vertical plates, and traditional Y-shaped plates in the treatment of distal humeral intra-articular fractures through finite element analysis, and to evaluate their potential for clinical application. METHODS: The study selected a 38-year-old male volunteer and obtained a three-dimensional model of the humerus by scanning his upper limbs using a 64-slice spiral CT. Four types of fracture-internal fixation models were constructed using Mimics 19.0, Geomagic Wrap 2017, Creo 6.0, and other software: horizontal plates, vertical plates, traditional Y-shaped plate, and personalized Y-shaped plate. The models were then meshed using Hypermesh 14.0 software, and material properties and boundary conditions were defined in Abaqus 6.14 software. AnyBody 7.3 software was used to simulate elbow flexion and extension movements, calculate muscle strength, joint forces, and load torques, and compare the peak stress and maximum displacement of the four fixation methods at different motion angles (10°, 30°, 50°, 70°, 90°, 110°, 130°, 150°) during elbow flexion and extension. RESULTS: Under dynamic loading during elbow flexion and extension, the personalized Y-shaped plate exhibits significant biomechanical advantages. During elbow flexion, the peak internal fixation stress of the personalized Y-shaped plate was (28.8±0.9) MPa, which was significantly lower than that of the horizontal plates, vertical plates, and traditional Y-shaped plate ( P<0.05). During elbow extension, the peak internal fixation stress of the personalized Y-shaped plate was (18.1±1.6) MPa, which was lower than those of the other three models, with significant differences when compared with horizontal plates and vertical plates ( P<0.05). Regarding the peak humeral stress, the personalized Y-shaped plate model showed mean values of (10.9±0.8) and (13.1±1.4) MPa during elbow flexion and extension, respectively, which were significantly lower than those of the other three models ( P<0.05). Displacement analysis showed that the maximum displacement of the humerus with the personalized Y-shaped plate during elbow flexion was (2.03±0.08) mm, slightly higher than that of the horizontal plates, but significantly lower than that of the vertical plates, showing significant differences ( P<0.05). During elbow extension, the maximum displacement of the humerus with the personalized Y-shaped plate was (1.93±0.13) mm, which was lower than that of the other three models, with significant differences when compared with vertical plates and traditional Y-shaped plates ( P<0.05). Stress contour analysis showed that the stress of the personalized Y-shaped plate was primarily concentrated at the bifurcation of the Y-shaped structure. Displacement contour analysis showed that the personalized Y-shaped plate effectively controlled the displacement of the distal humerus during both flexion and extension, demonstrating excellent stability. CONCLUSION The personalized Y-shaped plate demonstrates excellent biomechanical performance in the treatment of distal humeral intra-articular fractures, with lower stress and displacement, providing more stable fixation effects.
Humans ; Male ; Adult ; Healthy Volunteers ; Finite Element Analysis ; Tomography, Spiral Computed ; Models, Anatomic ; Biomechanical Phenomena ; Humeral Fractures, Distal/surgery* ; Fracture Fixation, Internal/instrumentation* ; Bone Plates ; Computer Simulation ; Precision Medicine/methods* ; Elbow Joint/surgery* ; Elbow/surgery* ; Humerus/surgery* ; Torque ; Stress, Mechanical ; Intra-Articular Fractures/surgery* ; Prosthesis Design/methods* ; Imaging, Three-Dimensional ; Range of Motion, Articular

OBJECTIVE: To evaluate the clinical efficacy and safety of clavicular anatomical plate in the treatment of clavicular Allmanic fracture. METHODS: Between January 2016 and December 2022, 27 patients with Allman ⅡC distal clavicle fractures were treated with clavicular anatomical plate. There were 19 males and 8 females, aged from 16 to 69 years old, with an average of (39.74±12.71) years old. There were 15 patients on the left side and 12 patients on the right side. There were 15 patients with single clavicle fracture and 12 patients complicated with other parts of the body or organ injury. The broken ends of the fractures were fixed with clavicular anatomical plate, including common compression clavicular anatomical plate in 19 patients and locking clavicular anatomical plate in 8 patients. The operation time and hospitalization days were recorded. Visual analogue scales (VAS) were utilized to assess subjective pain levels both preoperatively and 3 days postoperatively. Postoperatively, patients were monitored at intervals of 1 to 3 months until X-ray films confirmed fracture healing. In accordance with the University of California, Los Angeles (UCLA) shoulder rating system, evaluations were conducted on postoperative pain alleviation, functional recovery, range of motion in forward flexion, strength in forward flexion, and patient satisfaction. RESULTS: All patients were followed up for a period ranging from 12 to 18 months with an average of (14.70±1.61) months, and all clavicular fractures achieved successful union. The wounds of 24 patients healed in one stage, and 3 patients developed bleeding and exudation, they were cured after dressing change. There were no complications such as infection, plate and screw fracture, vascular and nerve injury. The operation time was(67.56±11.01) min. Significant differences were observed in pain relief, functional improvement, range of motion for forward flexion, strength of forward flexion, patient satisfaction, and overall scores at preoperative, 3 months postoperatively, 6 months postoperatively, and at the final follow-up(P<0.001). CONCLUSION The utilization of clavicular anatomical plates for the management of Allman typeⅡC fractures can provide early and stable fixation without compromising the acromioclavicular joint, thereby enabling patients to commence early mobilization and ensuring optimal fracture healing.
Humans ; Male ; Female ; Clavicle/surgery* ; Adult ; Bone Plates ; Middle Aged ; Fractures, Bone/physiopathology* ; Adolescent ; Aged ; Fracture Fixation, Internal/instrumentation* ; Young Adult

OBJECTIVE: To establish a two-segment vertebrectomy model using the finite element method, and to measure and compare the biomechanical properties of the lower cervical anterior transpedicular root screw (ATPRS) plate system, lower cervical anterior pedicle screw (ATPS) plate system, and lower cervical anterior cervical locked-plate (ACLP) system on this model. METHODS: CT data of the cervical spine (C₀-T₁) from a 34-year-old healthy adult male volunteer were collected. A nonlinear complete model of the lower cervical spine (C₃-C₇) was established using Mimics 10.01 software, based on which the ATPRS fixation model, ATPS fixation model, and ACLP fixation model were constructed respectively. An axial pressure of 75 N and a pure couple moment of 1.5 N·m were applied to C3 to make the model perform flexion-extension, left-right lateral bending, and left-right rotation movements. The range of motion (ROM) and stress distribution of each model under different working conditions were compared. RESULTS: The ROM of the C₄-C₇ segments in the ACLP group, ATPS group, and ATPRS group was reduced to 0.65° (-95.2%), 0.58° (-95.7%), and 0.62° (-95.4%) respectively compared with the intact model during flexion-extension movement;during lateral bending movement, it was reduced to 0.58° (-95.2%), 0.51°(-95.8%), and 0.60° (-95.1%) respectively;during rotation movement, it was reduced to 1.17° (-89.6%), 1.26° (-88.8%), and 1.27°(-88.7%) respectively. In terms of the stress on the titanium mesh graft, the ATPS group and ATPRS group had the maximum load during extension and the minimum load during flexion. Compared with the ACLP group, the stress on the titanium mesh graft in ATPS and ATPRS decreased by (-33.7%) and (-15.8%) in flexion, (-29.4%) and (-13.2%) in extension, (-26.2%) and (-23.4%) in lateral bending, and (-18.8%) and (-5.4%) in rotation, respectively. In terms of bone-screw interface stress, the peak bone stress near the C₇ screw in the ACLP group, ATPS group, and ATPRS group increased by 49.2%, 45.0%, and 47.6% respectively compared with the peak bone stress near the C₄ screw during extension. However, during flexion and lateral bending, there was no significant difference in the peak bone stress near the C₄ and C₇ screws. During rotation, the difference between the peak bone stress near the C₄ screw and that near the C₇ screw showed that in the ACLP group, left rotation (37.6%) was similar to right rotation (36.7%), while in the ATPS group and ATPRS group, left rotation was lower than right rotation. CONCLUSION Compared with the ACLP group, the ATPS group and ATPRS group have greater fixation stiffness and more stable fixation. However, in rotational movement, due to the uneven distribution of fixation stiffness, the stress distribution during torsion is uneven, but it is still better than the ACLP group. This indicates that ATPRS, like ATPS, has good primary stability, providing favorable conditions for bone graft fusion.
Humans ; Finite Element Analysis ; Male ; Cervical Vertebrae/physiopathology* ; Adult ; Biomechanical Phenomena ; Bone Plates ; Bone Screws ; Range of Motion, Articular ; Fracture Fixation, Internal

PURPOSE: To investigate the protective effect of sub-hypothermic mechanical perfusion combined with membrane lung oxygenation on ischemic hypoxic injury of yorkshire brain tissue caused by traumatic blood loss. METHODS: This article performed a random controlled trial. Brain tissue of 7 yorkshire was selected and divided into the sub-low temperature anterograde machine perfusion group (n = 4) and the blank control group (n = 3) using the random number table method. A yorkshire model of brain tissue injury induced by traumatic blood loss was established. Firstly, the perfusion temperature and blood oxygen saturation were monitored in real-time during the perfusion process. The number of red blood cells, hemoglobin content, NA⁺, K⁺, and Ca²⁺ ions concentrations and pH of the perfusate were detected. Following perfusion, we specifically examined the parietal lobe to assess its water content. The prefrontal cortex and hippocampus were then dissected for histological evaluation, allowing us to investigate potential regional differences in tissue injury. The blank control group was sampled directly before perfusion. All statistical analyses and graphs were performed using GraphPad Prism 8.0 Student t-test. All tests were two-sided, and p value of less than 0.05 was considered to indicate statistical significance. RESULTS: The contents of red blood cells and hemoglobin during perfusion were maintained at normal levels but more red blood cells were destroyed 3 h after the perfusion. The blood oxygen saturation of the perfusion group was maintained at 95% - 98%. NA⁺ and K⁺ concentrations were normal most of the time during perfusion but increased significantly at about 4 h. The Ca²⁺ concentration remained within the normal range at each period. Glucose levels were slightly higher than the baseline level. The pH of the perfusion solution was slightly lower at the beginning of perfusion, and then gradually increased to the normal level. The water content of brain tissue in the sub-low and docile perfusion group was 78.95% ± 0.39%, which was significantly higher than that in the control group (75.27% ± 0.55%, t = 10.49, p < 0.001), and the difference was statistically significant. Compared with the blank control group, the structure and morphology of pyramidal neurons in the prefrontal cortex and CA1 region of the hippocampal gyrus were similar, and their integrity was better. The structural integrity of granulosa neurons was destroyed and cell edema increased in the perfusion group compared with the blank control group. Immunofluorescence staining for glail fibrillary acidic protein and Iba1, markers of glial cells, revealed well-preserved cell structures in the perfusion group. While there were indications of abnormal cellular activity, the analysis showed no significant difference in axon thickness or integrity compared to the 1-h blank control group. CONCLUSIONS Mild hypothermic machine perfusion can improve ischemia and hypoxia injury of yorkshire brain tissue caused by traumatic blood loss and delay the necrosis and apoptosis of yorkshire brain tissue by continuous oxygen supply, maintaining ion homeostasis and reducing tissue metabolism level.
Animals ; Perfusion/methods* ; Disease Models, Animal ; Brain Injuries/etiology* ; Swine ; Male ; Hypothermia, Induced/methods*