Objective:To screen and identify the key active molecules,signaling pathways,and therapeutic targets of Shuxuening(SXN)injection for treating liver cirrhosis(LC)and to evaluate its therapeutic potential using a mouse ...Objective:To screen and identify the key active molecules,signaling pathways,and therapeutic targets of Shuxuening(SXN)injection for treating liver cirrhosis(LC)and to evaluate its therapeutic potential using a mouse model.Methods:Target genes of SXN and LC were retrieved from public databases,and enrichment analysis was performed.A proteineprotein interaction(PPI)network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins(STRING),and hub genes were identified using Molecular Complex Detection(MCODE).LC was induced in rats and mice via intraperitoneal injections of diethylnitrosamine and carbon tetrachloride(CCl4)for 12 weeks.Starting at week 7,SXN was administered intraperitoneally to the mice in the treatment group.Serum and liver tissues of the mice were collected for the detection of indicators,pathological staining,and expression analysis of hub targets using quantitative real-time polymerase chain reaction(qRT-PCR).Results:We identified 368 overlapping genes(OLGs)between SXN and LC targets.These OLGs were subsequently used to build a PPI network and to screen for hub genes.Enrichment analysis showed that these genes were associated with cancer-related pathways,including phosphoinositide-3-kinase/Akt and mitogen-activated protein kinase signaling and various cellular processes,such as responses to chemicals and metabolic regulation.In vivo experiments demonstrated that SXN treatment significantly improved liver function and pathology in CCl4-induced LC mice by reducing inflammation and collagen deposition.Furthermore,qRT-PCR demonstrated that SXN regulated the expression of MAPK8,AR and CASP3 in the livers of LC mice.Conclusion:This study highlighted the therapeutic effects of SXN in alleviating LC using both bioinformatics and experimental methods.The observed effect was associated with modulation of hub gene expression,particularly MAPK8,and CASP3.展开更多
Glassy polymers are widely used in biomedical applications in a solvent environment,yet their long-term performance is governed by the competing effects of physical aging and solvent-induced plasticization.Here,we dev...Glassy polymers are widely used in biomedical applications in a solvent environment,yet their long-term performance is governed by the competing effects of physical aging and solvent-induced plasticization.Here,we develop a constitutive model that explicitly couples the solvent concentration,structural relaxation,and mechanical response.This framework is built on a multiplicative decomposition of deformation and an Eyring-type flow rule,with structural evolution described by an effective temperature.A generalized shift factor is introduced to quantify how the solvent concentration and effective temperature jointly affect the relaxation time,thereby integrating physical aging and plasticization.The model is subsequently applied to methacrylate(MA)-based copolymer networks immersed in phosphate-buffered saline for up to nine months.Simulations accurately capture key experimental features,including the strong softening of highly swellable networks,the partial recovery due to aging,and the mitigating role of hydrophobic crosslinking in reducing solvent uptake.While the current single-mode description cannot reproduce the full relaxation spectrum,it establishes an efficient framework for predicting the long-term mechanical performance under coupled environmental and mechanical loading.This study provides a constitutive description of solvent-swollen glassy polymers,offering mechanistic insight into the interplay between plasticization and aging.Beyond biomedical MA networks,this framework establishes a foundation for predicting the long-term performance of polymer glasses under coupled aqueous environmental and mechanical loading.展开更多
Chronic pain after spine surgery(CPSS)is a complex disorder characterized by multifactorial pathogenesis that occurs in 8%–40%of patients undergoing lumbar spine surgery.We aimed to develop a rat model that mimics cl...Chronic pain after spine surgery(CPSS)is a complex disorder characterized by multifactorial pathogenesis that occurs in 8%–40%of patients undergoing lumbar spine surgery.We aimed to develop a rat model that mimics clinical CPSS conditions by taking two sequential surgical procedures.Step 1:A plastic rod was inserted into the left L5 intervertebral foramen to produce a steady compression on the dorsal root ganglion(DRG)and the spinal nerve,a common cause of low back pain(LBP).Step 2:The rod was removed after 7 days when rats exhibited mechanical and heat hypersensitivity in the ipsilateral hindpaw,followed by a full L5 laminectomy to mimic spine decompression surgery in LBP patients.The retention of the rod induced a prolonged LBP-like behavior but was quickly resolved after rod removal without laminectomy.However,rats that received laminectomy after rod removal developed heightened mechanical and heat sensitivity in the hindpaw,impaired gait,and reduced spontaneous exploration activity,indicating CPSS.Patch clamp recording revealed a significant augmentation in the intrinsic excitability of smalldiameter DRG neurons in CPSS rats.Administration of Dermorphin[D-Arg2,Lys4](1–4)amide(DALDA,5mg/kg,i.p.),a peripherally acting mu-opioid receptor(MOR)-preferred agonist,attenuated pain hypersensitivity,capsaicin-induced[Ca^(2+)]i rising and the increased intrinsic excitability of DRG neurons from CPSS rats.Our findings suggest that this new model,which mirrors the nature of CPSS developed in patients,may be useful for future studies of the underlying mechanisms.展开更多
Background:This investigation aimed to evaluate the therapeutic impact of the Yigan Xiaozheng formula on liver cirrhosis in rats,particularly induced by diethylnitrosamine(DEN).The study focused on analyzing liver str...Background:This investigation aimed to evaluate the therapeutic impact of the Yigan Xiaozheng formula on liver cirrhosis in rats,particularly induced by diethylnitrosamine(DEN).The study focused on analyzing liver structure,cell apoptosis,and the modulation of the Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway,employing a combination of network pharmacology and experimental approaches.Methods:A DEN-induced rat model of liver cirrhosis was established to assess the formula’s effectiveness.Parameters such as overall health,liver morphology,and survival were monitored.Network pharmacology was employed to decipher the active compounds and key targets of the formula in addressing liver cirrhosis.Predictions made via network pharmacology were substantiated through experimental validation in the animal model.Results:Administration of the Yigan Xiaozheng formula led to noticeable improvements in clinical symptoms of liver cirrhosis in rats,marked by enhanced body weight,lessened liver pathology,and higher survival rates.Network pharmacological analysis unveiled intricate interactions between active ingredients of the formula and cirrhosis-related targets.Protein-protein interaction(PPI)networks pinpointed crucial proteins and regulatory modules.Enrichment analysis underscored a significant involvement of the JAK2/STAT3 signaling pathway.On a molecular scale,the formula was observed to reduce the expression of BCL-2 associated X protein(Bax)and cytochrome C(Cyt-C),diminish the Bax/B-cell lymphoma 2(Bcl-2)ratio,and impede JAK2/STAT3 pathway activation,thereby curtailing liver fibrosis and cellular apoptosis.Conclusion:The study demonstrates the Yigan Xiaozheng formula’s capacity to ameliorate liver cirrhosis in a DEN-induced model,primarily through its active ingredients’interactions with cirrhosis targets and modulation of the JAK2/STAT3 pathway.These findings endorse the potential of this traditional Chinese medicinal formula as a viable treatment option for liver cirrhosis.展开更多
BACKGROUND UDP-glucose 6-dehydrogenase(UGDH)is a key enzyme in glucuronic acid metabolism and acts as a key mediator in several cancer developmental signaling pathways.AIM To offer a more systematic and comprehensive ...BACKGROUND UDP-glucose 6-dehydrogenase(UGDH)is a key enzyme in glucuronic acid metabolism and acts as a key mediator in several cancer developmental signaling pathways.AIM To offer a more systematic and comprehensive elucidation of the involvement of UGDH in the onset and progression of various malignancies.METHODS The role of UGDH in cancer was investigated via public databases.The data were analyzed via various R packages and websites,including TISIDB,cBioPortal,STRING,Cytoscape,GSCALite,and CancerSEA.A rat hepatocellular carcinoma(HCC)model was established via the intraperitoneal injection of diethylnitrosamine.Hematoxylin-eosin staining,Masson staining,Ki67 and UGDH immunohistochemical staining,and ARG1 immunofluorescence staining of liver tissues were performed.Real-time quantitative PCR and Western blotting were used to detect UGDH expression.The UGDH gene was knocked down in Huh7 cells,and CCK8 and nude mouse tumor xenograft assays were performed.RESULTS High UGDH expression is associated with poor clinical outcomes in HCC,lung adenocarcinoma,lung squamous cell carcinoma,and sarcoma patients and is differentially expressed across molecular and immune subtypes.UGDH is primarily involved in the pentose and glucuronate interconversion pathway.Its expression is positively correlated with T helper,Tcm,and Th2 cells in most cancers.Moreover,experimental results demonstrated that UGDH expression is elevated in HCC tissues and that its downregulation inhibits HCC cell proliferation.CONCLUSION Our study revealed that UGDH could be a valuable prognostic biomarker and potential therapeutic target in many cancers,especially liver and lung cancer.UGDH could promote HCC cell proliferation,potentially by modulating the pentose and glucuronate interconversion pathways.展开更多
Deep learning(DL)-based image reconstruction methods have garnered increasing interest in the last few years.Numerous studies demonstrate that DL-based reconstruction methods function admirably in optical tomographic ...Deep learning(DL)-based image reconstruction methods have garnered increasing interest in the last few years.Numerous studies demonstrate that DL-based reconstruction methods function admirably in optical tomographic imaging techniques,such as bioluminescence tomography(BLT).Nevertheless,nearly every existing DL-based method utilizes an explicit neural representation for the reconstruction problem,which either consumes much memory space or requires various complicated computations.In this paper,we present a neural field(NF)-based image reconstruction scheme for BLT that uses an implicit neural representation.The proposed NFbased method establishes a transformation between the coordinate of an arbitrary spatial point and the source value of the point with a relatively light-weight multilayer perceptron,which has remarkable computational efficiency.Another simple neural network composed of two fully connected layers and a 1D convolutional layer is used to generate the neural features.Results of simulations and experiments show that the proposed NF-based method has similar performance to the photon density complement network and the two-stage network,while consuming fewer floating point operations with fewer model parameters.展开更多
AIM:To investigate the prevalence of fatty liver discovered upon physical examination of Chinese patients and determine the associated clinical characteristics.METHODS:A total of 3433 consecutive patients who received...AIM:To investigate the prevalence of fatty liver discovered upon physical examination of Chinese patients and determine the associated clinical characteristics.METHODS:A total of 3433 consecutive patients who received physical examinations at the Huangpu Division of the First Affiliated Hospital at Sun Yat-sen University in Guangzhou,China from June 2010 to December2010 were retrospectively enrolled in the study.Results of biochemical tests,abdominal ultrasound,electrocardiography,and chest X-ray were collected.The diagnosis of fatty liver was made if a patient met any two of the three following ultrasonic criteria:(1)liver and kidney echo discrepancy and presence of an increased liver echogenicity(bright);(2)unclear intrahepatic duct structure;and(3)liver far field echo decay.RESULTS:The study population consisted of 2201males and 1232 females,with a mean age of 37.4±12.8 years.When all 3433 patients were considered,the overall prevalence of hyperlipidemia was 38.1%,of fatty liver was 26.0%,of increased alanine aminotransferase(ALT)and/or aspartate aminotransferase(AST)levels was 11.9%,of gallstone was 11.4%,of hyperglycemia was 7.3%,of hypertension was 7.1%,and of hyperuricemia was 6.2%.Of the 2605 patients who completed the abdominal ultrasonography exam,677(26.0%)were diagnosed with fatty liver and the prevalence was higher in males(32.5%vs females:15.3%,P<0.001).The overall prevalence of fatty liver increased with age,with the peak prevalence(39.5%)found in the 60 to 70-year-old age group.Among patients between the ages of 18 to 50-year-old,the prevalence of fatty liver was significantly higher in males(20.2%vs females:8.7%,P<0.001);the difference in prevalence between the two sexes in patients>50-year-old did not reach statistical significance.Only 430 of the patients diagnosed with fatty liver had complete information;among those,increased ALT and/or AST levels were detected in only 30%,with all disturbances being mild or moderate.In these 430 patients,the overall prevalence of hypertriglyceridemia was 31.4%,of mixed type hyperlipidemia was 20.9%,of hypercholesterolemia was 12.3%,of hyperglycemia was 17.6%,of hypertension was 16.0%,of hyperuricemia was 15.3%,and of gallstone was 14.4%.Again,the prevalences of hypertriglyceridemia and hyperuricemia were higher in males(hypertriglyceridemia,36.0%vs females:12.0%,P<0.05;hyperuricemia,17.3%vs females:7.2%,P<0.05);in contrast,however,the prevalences of mixed type hyperlipidemia and hypercholesterolemia was higher in females(mixed type hyperlipidemia,18.7% vs females:30.1%,P<0.05,hypercholesterolemia,9.5%vs females:24.1%,P<0.05).Finally,comparison of the fatty liver group to the non-fatty liver group showed that prevalences of hyperlipidemia,hyperglycemia,hypertension,and hyperuricemia were higher in the former(all P<0.01).CONCLUSION:A high prevalence of fatty liver is detected upon physical examination in Guangzhou,and the primary associated clinical findings are hyperlipidemia,hyperglycemia,hypertension,and hyperuricemia.展开更多
Ankylosing spondylitis(AS), a common type of spondyloarthropathy, is a chronic inflammatory autoimmune disease that mainly affects spine joints, causing severe, chronic pain;additionally, in more advanced cases, it ca...Ankylosing spondylitis(AS), a common type of spondyloarthropathy, is a chronic inflammatory autoimmune disease that mainly affects spine joints, causing severe, chronic pain;additionally, in more advanced cases, it can cause spine fusion. Significant progress in its pathophysiology and treatment has been achieved in the last decade. Immune cells and innate cytokines have been suggested to be crucial in the pathogenesis of AS, especially human leukocyte antigen(HLA)?B27 and the interleukin?23/17 axis.However, the pathogenesis of AS remains unclear. The current study reviewed the etiology and pathogenesis of AS, including genome-wide association studies and cytokine pathways. This study also summarized the current pharmaceutical and surgical treatment with a discussion of future potential therapies.展开更多
TGF-β 1–3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix(ECM). The biological functions of TGF-β in adu...TGF-β 1–3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix(ECM). The biological functions of TGF-β in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-β in maintaining stem cells and tissue homeostasis have not been well-documented until recent advances, which delineate their functions in a given context. Our recent findings, along with data reported by others, have clearly shown that temporal and spatial activation of TGF-β is involved in the recruitment of stem/progenitor cell participation in tissue regeneration/remodeling process, whereas sustained abnormalities in TGF-β ligand activation, regardless of genetic or environmental origin, will inevitably disrupt the normal physiology and lead to pathobiology of major diseases. Modulation of TGF-β signaling with different approaches has proven effective pre-clinically in the treatment of multiple pathologies such as sclerosis/fibrosis, tumor metastasis, osteoarthritis, and immune disorders. Thus, further elucidation of the mechanisms by which TGF-β is activated in different tissues/organs and how targeted cells respond in a context-dependent way can likely be translated with clinical benefits in the management of a broad range of diseases with the involvement of TGF-β.展开更多
Low back pain(LBP),as a leading cause of disability,is a common musculoskeletal disorder that results in major social and economic burdens.Recent research has identified inflammation and related signaling pathways as ...Low back pain(LBP),as a leading cause of disability,is a common musculoskeletal disorder that results in major social and economic burdens.Recent research has identified inflammation and related signaling pathways as important factors in the onset and progression of disc degeneration,a significant contributor to LBP.Inflammatory mediators also play an indispensable role in discogenic LBP.The suppression of LBP is a primary goal of clinical practice but has not received enough attention in disc research studies.Here,an overview of the advances in inflammation-related pain in disc degeneration is provided,with a discussion on the role of inflammation in IVD degeneration and pain induction.Puncture models,mechanical models,and spontaneous models as the main animal models to study painful disc degeneration are discussed,and the underlying signaling pathways are summarized.Furthermore,potential drug candidates,either under laboratory investigation or undergoing clinical trials,to suppress discogenic LBP by eliminating inflammation are explored.We hope to attract more research interest to address inflammation and pain in IDD and contribute to promoting more translational research.展开更多
The vast osteocytic network is believed to orchestrate bone metabolic activity in response to mechanical stimuli through production of sclerostin, RANKL, and osteoprotegerin(OPG). However, the mechanisms of osteocyte ...The vast osteocytic network is believed to orchestrate bone metabolic activity in response to mechanical stimuli through production of sclerostin, RANKL, and osteoprotegerin(OPG). However, the mechanisms of osteocyte mechanotransduction remain poorly understood. We've previously shown that osteocyte mechanosensitivity is encoded through unique intracellular calcium (Ca^(2+) ) dynamics. Here, by simultaneously monitoring Ca^(2+) and actin dynamics in single cells exposed to fluid shear flow, we detected actin network contractions immediately upon onset of flow-induced Ca^(2+) transients, which were facilitated by smooth muscle myosin and further confirmed in native osteocytes ex vivo. Actomyosin contractions have been linked to the secretion of extracellular vesicles(EVs), and our studies demonstrate that mechanical stimulation upregulates EV production in osteocytes through immunostaining for the secretory vesicle marker Lysosomal-associated membrane protein 1(LAMP1) and quantifying EV release in conditioned medium, both of which are blunted when Ca^(2+) signaling was inhibited by neomycin. Axial tibia compression was used to induce anabolic bone formation responses in mice, revealing upregulated LAMP1 and expected downregulation of sclerostin in vivo. This load-related increase in LAMP1 expression was inhibited in neomycin-injected mice compared to vehicle.Micro-computed tomography revealed significant load-related increases in both trabecular bone volume fraction and cortical thickness after two weeks of loading, which were blunted by neomycin treatment. In summary, we found mechanical stimulation of osteocytes activates Ca^(2+) -dependent contractions and enhances the production and release of EVs containing bone regulatory proteins. Further, blocking Ca^(2+) signaling significantly attenuates adaptation to mechanical loading in vivo, suggesting a critical role for Ca^(2+) -mediated signaling in bone adaptation.展开更多
Degenerative disc disease(DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus(NP) cells mediate mechanotransduction to maintain anabolic a...Degenerative disc disease(DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus(NP) cells mediate mechanotransduction to maintain anabolic activity in the discs. We found that mechanical stress promotes transport of parathyroid hormone 1 receptor(PTH1 R) to the cilia and enhances parathyroid hormone(PTH) signaling in NP cells. PTH induces transcription of integrin α_vβ_6 to activate the transforming growth factor(TGF)-β-connective tissue growth factor(CCN2)-matrix proteins signaling cascade. Intermittent injection of PTH(iPTH) effectively attenuates disc degeneration of aged mice by direct signaling through NP cells, specifically improving intervertebral disc height and volume by increasing levels of TGF-β activity, CCN2, and aggrecan. PTH1 R is expressed in both mouse and human NP cells. Importantly,knockout PTH1 R or cilia in the NP cells results in significant disc degeneration and blunts the effect of PTH on attenuation of aged discs. Thus, mechanical stress-induced transport of PTH1 R to the cilia enhances PTH signaling, which helps maintain intervertebral disc homeostasis, particularly during aging, indicating therapeutic potential of iPTH for DDD.展开更多
Prostaglandin E2(PGE2), a major cyclooxygenase-2(COX-2) product, is highly secreted by the osteoblast lineage in the subchondral bone tissue of osteoarthritis(OA) patients. However, NSAIDs, including COX-2 inhibitors,...Prostaglandin E2(PGE2), a major cyclooxygenase-2(COX-2) product, is highly secreted by the osteoblast lineage in the subchondral bone tissue of osteoarthritis(OA) patients. However, NSAIDs, including COX-2 inhibitors, have severe side effects during OA treatment. Therefore, the identification of novel drug targets of PGE2 signaling in OA progression is urgently needed. Osteoclasts play a critical role in subchondral bone homeostasis and OA-related pain. However, the mechanisms by which PGE2 regulates osteoclast function and subsequently subchondral bone homeostasis are largely unknown. Here, we show that PGE2 acts via EP4 receptors on osteoclasts during the progression of OA and OA-related pain. Our data show that while PGE2 mediates migration and osteoclastogenesis via its EP2 and EP4 receptors, tissue-specific knockout of only the EP4 receptor in osteoclasts(EP4 Lys M) reduced disease progression and osteophyte formation in a murine model of OA. Furthermore, OA-related pain was alleviated in the EP4 Lys M mice, with reduced Netrin-1 secretion and CGRP-positive sensory innervation of the subchondral bone. The expression of plateletderived growth factor-BB(PDGF-BB) was also lower in the EP4 Lys Mmice, which resulted in reduced type H blood vessel formation in subchondral bone. Importantly, we identified a novel potent EP4 antagonist, HL-43, which showed in vitro and in vivo effects consistent with those observed in the EP4 Lys Mmice. Finally, we showed that the Gαs/PI3 K/AKT/MAPK signaling pathway is downstream of EP4 activation via PGE2 in osteoclasts. Together, our data demonstrate that PGE2/EP4 signaling in osteoclasts mediates angiogenesis and sensory neuron innervation in subchondral bone, promoting OA progression and pain, and that inhibition of EP4 with HL-43 has therapeutic potential in OA.展开更多
In this study,Tremella fuciformis residues as raw material,dietary fibers from tremella were prepared by multiple enzymes.The structure of dietary fibers from tremella was studied by Fourier transform infrared(FTIR),X...In this study,Tremella fuciformis residues as raw material,dietary fibers from tremella were prepared by multiple enzymes.The structure of dietary fibers from tremella was studied by Fourier transform infrared(FTIR),X-ray diffraction analysis(XRD)and scanning electron microscopy(SEM).We analyzed their lipidlowering properties in vitro(water holding,oil holding swelling cholesterol and sodium cholate binding capacitises)and the hypolipidemic effects in mice.The results showed that tremella dietary fibers presented the infrared absorption spectrum characteristics of polysaccharides and the characteristic diffraction peaks of cellulose type I.SEM results indicated that the surface of insoluble dietary fiber(IDF)was porous,while the soluble dietary fiber(SDF)was relatively compact and spongy.IDF exhibited significantly higher water holding,oil holding,and swelling binding capacities than the corresponding SDF.However,SDF exhibited significantly higher viscosity than IDF.The results showed tremella dietary fibers were significant in swelling,water holding and oil holding,cholesterol and bile acids.In vivo experiment results in mice indicated that SDF has the best effect on hyperlipidemia mice than IDF and total dietary fiber(TDF).SDF showed that the total cholesterol(TC),triglyceride(TG)and low density lipoprotein cholesterol(LDL-C)contents dropped by 28.33%,18.65%,and 48.97%,respectively,while high density lipoprotein cholesterol(HDL-C)content increased by 43.80%.Compared with the high-fat control(HCM)group,the arteriosclerosis index(AI)and liver index(LI)of the SDF group mice showed significant differences,indicating that SDF has a good auxiliary effect of lowering blood lipids.The administration of tremella fibers improved the lipid metabolism disorderly situation of hyperlipidemia mice.These results provide a reference for further research and rational development of T.fuciformis.展开更多
There is currently no effective medical treatment for temporomandibular joint osteoarthritis(TMJ-OA) due to a limited understanding of its pathogenesis. This study was undertaken to investigate the key role of transfo...There is currently no effective medical treatment for temporomandibular joint osteoarthritis(TMJ-OA) due to a limited understanding of its pathogenesis. This study was undertaken to investigate the key role of transforming growth factor-β(TGF-β)signalling in the cartilage and subchondral bone of the TMJ using a temporomandibular joint disorder(TMD) rat model, an ageing mouse model and a Camurati–Engelmann disease(CED) mouse model. In the three animal models, the subchondral bone phenotypes in the mandibular condyles were evaluated by μCT, and changes in TMJ condyles were examined by TRAP staining and immunohistochemical analysis of Osterix and p-Smad2/3. Condyle degradation was confirmed by Safranin O staining, the Mankin and OARSI scoring systems and type X collagen(Col X), p-Smad2/3 a and Osterix immunohistochemical analyses. We found apparent histological phenotypes of TMJ-OA in the TMD, ageing and CED animal models, with abnormal activation of TGF-βsignalling in the condylar cartilage and subchondral bone. Moreover, inhibition of TGF-β receptor I attenuated TMJ-OA progression in the TMD models. Therefore, aberrant activation of TGF-β signalling could be a key player in TMJ-OA development.展开更多
基金Our study was funded by the Clinical Research Special Fund of Wu Jieping Medical Foundation(320.6750.2022-25-8)the Fundamental Research Funds for the Cornell University(2024-JYBXJSJJ042 and 2024-JYB-JBZD-058).
文摘Objective:To screen and identify the key active molecules,signaling pathways,and therapeutic targets of Shuxuening(SXN)injection for treating liver cirrhosis(LC)and to evaluate its therapeutic potential using a mouse model.Methods:Target genes of SXN and LC were retrieved from public databases,and enrichment analysis was performed.A proteineprotein interaction(PPI)network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins(STRING),and hub genes were identified using Molecular Complex Detection(MCODE).LC was induced in rats and mice via intraperitoneal injections of diethylnitrosamine and carbon tetrachloride(CCl4)for 12 weeks.Starting at week 7,SXN was administered intraperitoneally to the mice in the treatment group.Serum and liver tissues of the mice were collected for the detection of indicators,pathological staining,and expression analysis of hub targets using quantitative real-time polymerase chain reaction(qRT-PCR).Results:We identified 368 overlapping genes(OLGs)between SXN and LC targets.These OLGs were subsequently used to build a PPI network and to screen for hub genes.Enrichment analysis showed that these genes were associated with cancer-related pathways,including phosphoinositide-3-kinase/Akt and mitogen-activated protein kinase signaling and various cellular processes,such as responses to chemicals and metabolic regulation.In vivo experiments demonstrated that SXN treatment significantly improved liver function and pathology in CCl4-induced LC mice by reducing inflammation and collagen deposition.Furthermore,qRT-PCR demonstrated that SXN regulated the expression of MAPK8,AR and CASP3 in the livers of LC mice.Conclusion:This study highlighted the therapeutic effects of SXN in alleviating LC using both bioinformatics and experimental methods.The observed effect was associated with modulation of hub gene expression,particularly MAPK8,and CASP3.
基金the funding support from the Smart Medicine and Engineering Interdisciplinary Innovation Project of Ningbo University(No.ZHYG003)。
文摘Glassy polymers are widely used in biomedical applications in a solvent environment,yet their long-term performance is governed by the competing effects of physical aging and solvent-induced plasticization.Here,we develop a constitutive model that explicitly couples the solvent concentration,structural relaxation,and mechanical response.This framework is built on a multiplicative decomposition of deformation and an Eyring-type flow rule,with structural evolution described by an effective temperature.A generalized shift factor is introduced to quantify how the solvent concentration and effective temperature jointly affect the relaxation time,thereby integrating physical aging and plasticization.The model is subsequently applied to methacrylate(MA)-based copolymer networks immersed in phosphate-buffered saline for up to nine months.Simulations accurately capture key experimental features,including the strong softening of highly swellable networks,the partial recovery due to aging,and the mitigating role of hydrophobic crosslinking in reducing solvent uptake.While the current single-mode description cannot reproduce the full relaxation spectrum,it establishes an efficient framework for predicting the long-term mechanical performance under coupled environmental and mechanical loading.This study provides a constitutive description of solvent-swollen glassy polymers,offering mechanistic insight into the interplay between plasticization and aging.Beyond biomedical MA networks,this framework establishes a foundation for predicting the long-term performance of polymer glasses under coupled aqueous environmental and mechanical loading.
基金supported by the Neurosurgery Pain Research Institute at Johns Hopkins University and by the Lehner Family Foundation.
文摘Chronic pain after spine surgery(CPSS)is a complex disorder characterized by multifactorial pathogenesis that occurs in 8%–40%of patients undergoing lumbar spine surgery.We aimed to develop a rat model that mimics clinical CPSS conditions by taking two sequential surgical procedures.Step 1:A plastic rod was inserted into the left L5 intervertebral foramen to produce a steady compression on the dorsal root ganglion(DRG)and the spinal nerve,a common cause of low back pain(LBP).Step 2:The rod was removed after 7 days when rats exhibited mechanical and heat hypersensitivity in the ipsilateral hindpaw,followed by a full L5 laminectomy to mimic spine decompression surgery in LBP patients.The retention of the rod induced a prolonged LBP-like behavior but was quickly resolved after rod removal without laminectomy.However,rats that received laminectomy after rod removal developed heightened mechanical and heat sensitivity in the hindpaw,impaired gait,and reduced spontaneous exploration activity,indicating CPSS.Patch clamp recording revealed a significant augmentation in the intrinsic excitability of smalldiameter DRG neurons in CPSS rats.Administration of Dermorphin[D-Arg2,Lys4](1–4)amide(DALDA,5mg/kg,i.p.),a peripherally acting mu-opioid receptor(MOR)-preferred agonist,attenuated pain hypersensitivity,capsaicin-induced[Ca^(2+)]i rising and the increased intrinsic excitability of DRG neurons from CPSS rats.Our findings suggest that this new model,which mirrors the nature of CPSS developed in patients,may be useful for future studies of the underlying mechanisms.
基金supported by National Natural Science Foundation of China Grant Program(No.81603555).
文摘Background:This investigation aimed to evaluate the therapeutic impact of the Yigan Xiaozheng formula on liver cirrhosis in rats,particularly induced by diethylnitrosamine(DEN).The study focused on analyzing liver structure,cell apoptosis,and the modulation of the Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway,employing a combination of network pharmacology and experimental approaches.Methods:A DEN-induced rat model of liver cirrhosis was established to assess the formula’s effectiveness.Parameters such as overall health,liver morphology,and survival were monitored.Network pharmacology was employed to decipher the active compounds and key targets of the formula in addressing liver cirrhosis.Predictions made via network pharmacology were substantiated through experimental validation in the animal model.Results:Administration of the Yigan Xiaozheng formula led to noticeable improvements in clinical symptoms of liver cirrhosis in rats,marked by enhanced body weight,lessened liver pathology,and higher survival rates.Network pharmacological analysis unveiled intricate interactions between active ingredients of the formula and cirrhosis-related targets.Protein-protein interaction(PPI)networks pinpointed crucial proteins and regulatory modules.Enrichment analysis underscored a significant involvement of the JAK2/STAT3 signaling pathway.On a molecular scale,the formula was observed to reduce the expression of BCL-2 associated X protein(Bax)and cytochrome C(Cyt-C),diminish the Bax/B-cell lymphoma 2(Bcl-2)ratio,and impede JAK2/STAT3 pathway activation,thereby curtailing liver fibrosis and cellular apoptosis.Conclusion:The study demonstrates the Yigan Xiaozheng formula’s capacity to ameliorate liver cirrhosis in a DEN-induced model,primarily through its active ingredients’interactions with cirrhosis targets and modulation of the JAK2/STAT3 pathway.These findings endorse the potential of this traditional Chinese medicinal formula as a viable treatment option for liver cirrhosis.
基金Supported by National Natural Science Foundation of China,No.82405314Horizontal Project of Dongzhimen Hospital,No.HX-DZM-202405+1 种基金Project of Beijing University of Chinese Medicine,No.DZMG-QNZX-24015Traditional Chinese Medicine Foundation of Xiamen,No.XWZY-2023-0616.
文摘BACKGROUND UDP-glucose 6-dehydrogenase(UGDH)is a key enzyme in glucuronic acid metabolism and acts as a key mediator in several cancer developmental signaling pathways.AIM To offer a more systematic and comprehensive elucidation of the involvement of UGDH in the onset and progression of various malignancies.METHODS The role of UGDH in cancer was investigated via public databases.The data were analyzed via various R packages and websites,including TISIDB,cBioPortal,STRING,Cytoscape,GSCALite,and CancerSEA.A rat hepatocellular carcinoma(HCC)model was established via the intraperitoneal injection of diethylnitrosamine.Hematoxylin-eosin staining,Masson staining,Ki67 and UGDH immunohistochemical staining,and ARG1 immunofluorescence staining of liver tissues were performed.Real-time quantitative PCR and Western blotting were used to detect UGDH expression.The UGDH gene was knocked down in Huh7 cells,and CCK8 and nude mouse tumor xenograft assays were performed.RESULTS High UGDH expression is associated with poor clinical outcomes in HCC,lung adenocarcinoma,lung squamous cell carcinoma,and sarcoma patients and is differentially expressed across molecular and immune subtypes.UGDH is primarily involved in the pentose and glucuronate interconversion pathway.Its expression is positively correlated with T helper,Tcm,and Th2 cells in most cancers.Moreover,experimental results demonstrated that UGDH expression is elevated in HCC tissues and that its downregulation inhibits HCC cell proliferation.CONCLUSION Our study revealed that UGDH could be a valuable prognostic biomarker and potential therapeutic target in many cancers,especially liver and lung cancer.UGDH could promote HCC cell proliferation,potentially by modulating the pentose and glucuronate interconversion pathways.
基金supported in part by the National Natural Science Foundation of China(62101278,62001379,62271023)Beijing Natural Science Foundation(7242269).
文摘Deep learning(DL)-based image reconstruction methods have garnered increasing interest in the last few years.Numerous studies demonstrate that DL-based reconstruction methods function admirably in optical tomographic imaging techniques,such as bioluminescence tomography(BLT).Nevertheless,nearly every existing DL-based method utilizes an explicit neural representation for the reconstruction problem,which either consumes much memory space or requires various complicated computations.In this paper,we present a neural field(NF)-based image reconstruction scheme for BLT that uses an implicit neural representation.The proposed NFbased method establishes a transformation between the coordinate of an arbitrary spatial point and the source value of the point with a relatively light-weight multilayer perceptron,which has remarkable computational efficiency.Another simple neural network composed of two fully connected layers and a 1D convolutional layer is used to generate the neural features.Results of simulations and experiments show that the proposed NF-based method has similar performance to the photon density complement network and the two-stage network,while consuming fewer floating point operations with fewer model parameters.
基金Supported by The Science and Technology Project of Guangdong ProvinceChina+3 种基金No.2010B031600047Shenzhen Jian An Pharmaceutical Company Limited for their support
文摘AIM:To investigate the prevalence of fatty liver discovered upon physical examination of Chinese patients and determine the associated clinical characteristics.METHODS:A total of 3433 consecutive patients who received physical examinations at the Huangpu Division of the First Affiliated Hospital at Sun Yat-sen University in Guangzhou,China from June 2010 to December2010 were retrospectively enrolled in the study.Results of biochemical tests,abdominal ultrasound,electrocardiography,and chest X-ray were collected.The diagnosis of fatty liver was made if a patient met any two of the three following ultrasonic criteria:(1)liver and kidney echo discrepancy and presence of an increased liver echogenicity(bright);(2)unclear intrahepatic duct structure;and(3)liver far field echo decay.RESULTS:The study population consisted of 2201males and 1232 females,with a mean age of 37.4±12.8 years.When all 3433 patients were considered,the overall prevalence of hyperlipidemia was 38.1%,of fatty liver was 26.0%,of increased alanine aminotransferase(ALT)and/or aspartate aminotransferase(AST)levels was 11.9%,of gallstone was 11.4%,of hyperglycemia was 7.3%,of hypertension was 7.1%,and of hyperuricemia was 6.2%.Of the 2605 patients who completed the abdominal ultrasonography exam,677(26.0%)were diagnosed with fatty liver and the prevalence was higher in males(32.5%vs females:15.3%,P<0.001).The overall prevalence of fatty liver increased with age,with the peak prevalence(39.5%)found in the 60 to 70-year-old age group.Among patients between the ages of 18 to 50-year-old,the prevalence of fatty liver was significantly higher in males(20.2%vs females:8.7%,P<0.001);the difference in prevalence between the two sexes in patients>50-year-old did not reach statistical significance.Only 430 of the patients diagnosed with fatty liver had complete information;among those,increased ALT and/or AST levels were detected in only 30%,with all disturbances being mild or moderate.In these 430 patients,the overall prevalence of hypertriglyceridemia was 31.4%,of mixed type hyperlipidemia was 20.9%,of hypercholesterolemia was 12.3%,of hyperglycemia was 17.6%,of hypertension was 16.0%,of hyperuricemia was 15.3%,and of gallstone was 14.4%.Again,the prevalences of hypertriglyceridemia and hyperuricemia were higher in males(hypertriglyceridemia,36.0%vs females:12.0%,P<0.05;hyperuricemia,17.3%vs females:7.2%,P<0.05);in contrast,however,the prevalences of mixed type hyperlipidemia and hypercholesterolemia was higher in females(mixed type hyperlipidemia,18.7% vs females:30.1%,P<0.05,hypercholesterolemia,9.5%vs females:24.1%,P<0.05).Finally,comparison of the fatty liver group to the non-fatty liver group showed that prevalences of hyperlipidemia,hyperglycemia,hypertension,and hyperuricemia were higher in the former(all P<0.01).CONCLUSION:A high prevalence of fatty liver is detected upon physical examination in Guangzhou,and the primary associated clinical findings are hyperlipidemia,hyperglycemia,hypertension,and hyperuricemia.
基金supported by the Beijing Natural Science Foundation youth project (7184325)the China Postdoctoral Foundation NO.62 general program
文摘Ankylosing spondylitis(AS), a common type of spondyloarthropathy, is a chronic inflammatory autoimmune disease that mainly affects spine joints, causing severe, chronic pain;additionally, in more advanced cases, it can cause spine fusion. Significant progress in its pathophysiology and treatment has been achieved in the last decade. Immune cells and innate cytokines have been suggested to be crucial in the pathogenesis of AS, especially human leukocyte antigen(HLA)?B27 and the interleukin?23/17 axis.However, the pathogenesis of AS remains unclear. The current study reviewed the etiology and pathogenesis of AS, including genome-wide association studies and cytokine pathways. This study also summarized the current pharmaceutical and surgical treatment with a discussion of future potential therapies.
基金supported by U.S. National Institutes of Health grants (AR063943 and DK057501 to X.C. AR064833 to J.L.C.)+3 种基金the National Natural Science Foundation of China (81771099 to X.X.)the Key Project for Frontier Research of Science and Technology Department of Sichuan Province (2016JY0006 to X.Z.)Sichuan Province Science and Technology Innovation Team Program (2017TD0016 to Q.Y.).X.X.supported by the visiting scholar fellowship from West China Hospital of Stomatology, Sichuan University
文摘TGF-β 1–3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix(ECM). The biological functions of TGF-β in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-β in maintaining stem cells and tissue homeostasis have not been well-documented until recent advances, which delineate their functions in a given context. Our recent findings, along with data reported by others, have clearly shown that temporal and spatial activation of TGF-β is involved in the recruitment of stem/progenitor cell participation in tissue regeneration/remodeling process, whereas sustained abnormalities in TGF-β ligand activation, regardless of genetic or environmental origin, will inevitably disrupt the normal physiology and lead to pathobiology of major diseases. Modulation of TGF-β signaling with different approaches has proven effective pre-clinically in the treatment of multiple pathologies such as sclerosis/fibrosis, tumor metastasis, osteoarthritis, and immune disorders. Thus, further elucidation of the mechanisms by which TGF-β is activated in different tissues/organs and how targeted cells respond in a context-dependent way can likely be translated with clinical benefits in the management of a broad range of diseases with the involvement of TGF-β.
基金the National Natural Science Foundation of China(81772386,81702191,81572175,81371984,and 81071511)the Guangdong-Hong Kong Joint Innovation Project of Guangdong Province(2017A050506019)the Natural Science Foundation of Guangdong Province,China(2020A1515011031).
文摘Low back pain(LBP),as a leading cause of disability,is a common musculoskeletal disorder that results in major social and economic burdens.Recent research has identified inflammation and related signaling pathways as important factors in the onset and progression of disc degeneration,a significant contributor to LBP.Inflammatory mediators also play an indispensable role in discogenic LBP.The suppression of LBP is a primary goal of clinical practice but has not received enough attention in disc research studies.Here,an overview of the advances in inflammation-related pain in disc degeneration is provided,with a discussion on the role of inflammation in IVD degeneration and pain induction.Puncture models,mechanical models,and spontaneous models as the main animal models to study painful disc degeneration are discussed,and the underlying signaling pathways are summarized.Furthermore,potential drug candidates,either under laboratory investigation or undergoing clinical trials,to suppress discogenic LBP by eliminating inflammation are explored.We hope to attract more research interest to address inflammation and pain in IDD and contribute to promoting more translational research.
基金supported by NIH R01 AR052461 and NIH R01 AR069148supported by a NSF Graduate Research Fellowship. A. E. M.supported by training grant T32 AR059038
文摘The vast osteocytic network is believed to orchestrate bone metabolic activity in response to mechanical stimuli through production of sclerostin, RANKL, and osteoprotegerin(OPG). However, the mechanisms of osteocyte mechanotransduction remain poorly understood. We've previously shown that osteocyte mechanosensitivity is encoded through unique intracellular calcium (Ca^(2+) ) dynamics. Here, by simultaneously monitoring Ca^(2+) and actin dynamics in single cells exposed to fluid shear flow, we detected actin network contractions immediately upon onset of flow-induced Ca^(2+) transients, which were facilitated by smooth muscle myosin and further confirmed in native osteocytes ex vivo. Actomyosin contractions have been linked to the secretion of extracellular vesicles(EVs), and our studies demonstrate that mechanical stimulation upregulates EV production in osteocytes through immunostaining for the secretory vesicle marker Lysosomal-associated membrane protein 1(LAMP1) and quantifying EV release in conditioned medium, both of which are blunted when Ca^(2+) signaling was inhibited by neomycin. Axial tibia compression was used to induce anabolic bone formation responses in mice, revealing upregulated LAMP1 and expected downregulation of sclerostin in vivo. This load-related increase in LAMP1 expression was inhibited in neomycin-injected mice compared to vehicle.Micro-computed tomography revealed significant load-related increases in both trabecular bone volume fraction and cortical thickness after two weeks of loading, which were blunted by neomycin treatment. In summary, we found mechanical stimulation of osteocytes activates Ca^(2+) -dependent contractions and enhances the production and release of EVs containing bone regulatory proteins. Further, blocking Ca^(2+) signaling significantly attenuates adaptation to mechanical loading in vivo, suggesting a critical role for Ca^(2+) -mediated signaling in bone adaptation.
基金supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Numbers AR071432 and AR063943
文摘Degenerative disc disease(DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus(NP) cells mediate mechanotransduction to maintain anabolic activity in the discs. We found that mechanical stress promotes transport of parathyroid hormone 1 receptor(PTH1 R) to the cilia and enhances parathyroid hormone(PTH) signaling in NP cells. PTH induces transcription of integrin α_vβ_6 to activate the transforming growth factor(TGF)-β-connective tissue growth factor(CCN2)-matrix proteins signaling cascade. Intermittent injection of PTH(iPTH) effectively attenuates disc degeneration of aged mice by direct signaling through NP cells, specifically improving intervertebral disc height and volume by increasing levels of TGF-β activity, CCN2, and aggrecan. PTH1 R is expressed in both mouse and human NP cells. Importantly,knockout PTH1 R or cilia in the NP cells results in significant disc degeneration and blunts the effect of PTH on attenuation of aged discs. Thus, mechanical stress-induced transport of PTH1 R to the cilia enhances PTH signaling, which helps maintain intervertebral disc homeostasis, particularly during aging, indicating therapeutic potential of iPTH for DDD.
基金supported by grants from the National Key Research and Development Program of China (2020YFC2002800 to J.L. and 2018YFC1105102 to J.L.)the National Natural Science Foundation of China (91949127, 92168204 to J.L.)the Fundamental Research Funds for the Central Universities (22120210586)
文摘Prostaglandin E2(PGE2), a major cyclooxygenase-2(COX-2) product, is highly secreted by the osteoblast lineage in the subchondral bone tissue of osteoarthritis(OA) patients. However, NSAIDs, including COX-2 inhibitors, have severe side effects during OA treatment. Therefore, the identification of novel drug targets of PGE2 signaling in OA progression is urgently needed. Osteoclasts play a critical role in subchondral bone homeostasis and OA-related pain. However, the mechanisms by which PGE2 regulates osteoclast function and subsequently subchondral bone homeostasis are largely unknown. Here, we show that PGE2 acts via EP4 receptors on osteoclasts during the progression of OA and OA-related pain. Our data show that while PGE2 mediates migration and osteoclastogenesis via its EP2 and EP4 receptors, tissue-specific knockout of only the EP4 receptor in osteoclasts(EP4 Lys M) reduced disease progression and osteophyte formation in a murine model of OA. Furthermore, OA-related pain was alleviated in the EP4 Lys M mice, with reduced Netrin-1 secretion and CGRP-positive sensory innervation of the subchondral bone. The expression of plateletderived growth factor-BB(PDGF-BB) was also lower in the EP4 Lys Mmice, which resulted in reduced type H blood vessel formation in subchondral bone. Importantly, we identified a novel potent EP4 antagonist, HL-43, which showed in vitro and in vivo effects consistent with those observed in the EP4 Lys Mmice. Finally, we showed that the Gαs/PI3 K/AKT/MAPK signaling pathway is downstream of EP4 activation via PGE2 in osteoclasts. Together, our data demonstrate that PGE2/EP4 signaling in osteoclasts mediates angiogenesis and sensory neuron innervation in subchondral bone, promoting OA progression and pain, and that inhibition of EP4 with HL-43 has therapeutic potential in OA.
基金financially supported by the Key Projects of the National Research and Development Program of China(2018YFD0400204)。
文摘In this study,Tremella fuciformis residues as raw material,dietary fibers from tremella were prepared by multiple enzymes.The structure of dietary fibers from tremella was studied by Fourier transform infrared(FTIR),X-ray diffraction analysis(XRD)and scanning electron microscopy(SEM).We analyzed their lipidlowering properties in vitro(water holding,oil holding swelling cholesterol and sodium cholate binding capacitises)and the hypolipidemic effects in mice.The results showed that tremella dietary fibers presented the infrared absorption spectrum characteristics of polysaccharides and the characteristic diffraction peaks of cellulose type I.SEM results indicated that the surface of insoluble dietary fiber(IDF)was porous,while the soluble dietary fiber(SDF)was relatively compact and spongy.IDF exhibited significantly higher water holding,oil holding,and swelling binding capacities than the corresponding SDF.However,SDF exhibited significantly higher viscosity than IDF.The results showed tremella dietary fibers were significant in swelling,water holding and oil holding,cholesterol and bile acids.In vivo experiment results in mice indicated that SDF has the best effect on hyperlipidemia mice than IDF and total dietary fiber(TDF).SDF showed that the total cholesterol(TC),triglyceride(TG)and low density lipoprotein cholesterol(LDL-C)contents dropped by 28.33%,18.65%,and 48.97%,respectively,while high density lipoprotein cholesterol(HDL-C)content increased by 43.80%.Compared with the high-fat control(HCM)group,the arteriosclerosis index(AI)and liver index(LI)of the SDF group mice showed significant differences,indicating that SDF has a good auxiliary effect of lowering blood lipids.The administration of tremella fibers improved the lipid metabolism disorderly situation of hyperlipidemia mice.These results provide a reference for further research and rational development of T.fuciformis.
基金supported by 2016JQ0054 and NSFC grants 81470711 to L.Z.National Key Research and Development Program of China 2016YFC1102700 to X.Z.
文摘There is currently no effective medical treatment for temporomandibular joint osteoarthritis(TMJ-OA) due to a limited understanding of its pathogenesis. This study was undertaken to investigate the key role of transforming growth factor-β(TGF-β)signalling in the cartilage and subchondral bone of the TMJ using a temporomandibular joint disorder(TMD) rat model, an ageing mouse model and a Camurati–Engelmann disease(CED) mouse model. In the three animal models, the subchondral bone phenotypes in the mandibular condyles were evaluated by μCT, and changes in TMJ condyles were examined by TRAP staining and immunohistochemical analysis of Osterix and p-Smad2/3. Condyle degradation was confirmed by Safranin O staining, the Mankin and OARSI scoring systems and type X collagen(Col X), p-Smad2/3 a and Osterix immunohistochemical analyses. We found apparent histological phenotypes of TMJ-OA in the TMD, ageing and CED animal models, with abnormal activation of TGF-βsignalling in the condylar cartilage and subchondral bone. Moreover, inhibition of TGF-β receptor I attenuated TMJ-OA progression in the TMD models. Therefore, aberrant activation of TGF-β signalling could be a key player in TMJ-OA development.
