Objective To observe influence of moxibustion at ＂Shenshu＂ （肾俞BL 23） and ＂Zusanli＂ （足三里 ST 36） on proteins expression of Ras, ERKI/2, and Raf in synovial tissues in rats with rheumatoid arthritis （RA） t...Objective To observe influence of moxibustion at ＂Shenshu＂ （肾俞BL 23） and ＂Zusanli＂ （足三里 ST 36） on proteins expression of Ras, ERKI/2, and Raf in synovial tissues in rats with rheumatoid arthritis （RA） to elucidate molecular mechanisms of moxibustion on treating RA. Methods Thirty Wistar rats were randomly divided into a normal control group （Group Cont）, a model group （Group Mod） and a moxibustion group （Group Mox） with 10 rats in each group. The model was established by using both environmental factors such as wind, cold and damp and a biological factor （Freund＇s complete adjuvant）. Suspended moxibustion was applied at bilateral BL 23 and ST 36 for 20 min, applied once daily for 15 days, starting from the 3rd day after modeling. Volumes of metaleg digiti pedis on the right side were measured before, after and 15 days after modeling. Protein expressions of Ras, ERK 1/2, p-ERKI/2 and Raf in synovium tissues were detected by western blot. Results After modeling, volumes of metaleg digiti pedis on the right side were significantly enlarged, compared with those of rats in Group Cont （P〈0.01）. After treatment by moxibustion for 15 days, the metatarsale girth of metaleg digiti pedis on the right side in Group Mox was significantly reduced, compared with that in Group Mod （P〈0.01）. Protein expressions of Ras, Raf, ERK1/2 and p-ERK1/2 in Group Mod were significantly increased, compared with those in Group Cont （P〈0.01） and Group Mox （P〈0.01）. Protein expressions of Ras, Raf, ERK1/2 and p-ERK1/2 in Group Mox were significantly lowered, compared with those in Group Mod （all P〈0.01）. Conclusions Moxibustion can suppress excessive protein expressions of Ras, Raf and ERK1/2 in synovium tissues of rats with experimental RA to inhibit abnormal activation of Ras-MAPK signal Pathway, which may be one of the molecular mechanisms of moxibustion in alleviating synovitis.展开更多
Objective To investigate effect of pinacidil, an ATP sensitive potassium channel （KATP） opener, on the neuronal apoptosis and its signaling transduction mechanism following focal cerebral ischemia-reperfusion in rat...Objective To investigate effect of pinacidil, an ATP sensitive potassium channel （KATP） opener, on the neuronal apoptosis and its signaling transduction mechanism following focal cerebral ischemia-reperfusion in rats. Methods One hundred male Wistar rats were randomly divided into four groups： A, sham-operated group; B, ischemia-reperfusion group; C, KATe opener treatment group; and D, KATe opener and blocker treatment group. The middle cerebral artery occlusion （MCAO） model was established by using the intraluminal suture occlusion method, neuronal apoptosis was determined by TUNEL staining, and expressions of caspase-8, caspase-9 and caspase-3 mRNA were detected by in situ hybridization. Results （1） The numbers of apoptotic neurons at 12 h, 24 h, 48 h, and 72 h were significantly less in group C than in groups B and D （P 〈 0.01 or P 〈 0.05）; and there was no difference between groups B and D at all time points （P 〉 0.05）. （2） The expressions of caspase-3 mRNA and caspase-8 mRNA at all times and the expressions of caspase-9 mRNA at 12 h, 24 h, 48 h, 72 h were significantly lower in group C than in groups B and D （P 〈 0.01 or P 〈 0.05）; and there were no differences between groups B and D at all time points （P 〉 0.05）. Conclusions KATP opener can significantly decrease the neuronal apoptosis and the expressions of caspase-3, caspase-8 and caspase-9 mRNAs following cerebral ischemiareperfusion. The neuronal apoptosis may be decreased by the inhibition of both mitochondrial and death-receptor signal pathways.展开更多
Background: Intramuscular fat(IMF) content is a vital parameter for assessing pork quality. Increasing evidence has shown that microRNAs(miRNAs) play an important role in regulating porcine IMF deposition. Here, a nov...Background: Intramuscular fat(IMF) content is a vital parameter for assessing pork quality. Increasing evidence has shown that microRNAs(miRNAs) play an important role in regulating porcine IMF deposition. Here, a novel miRNA implicated in porcine IMF adipogenesis was found, and its effect and regulatory mechanism were further explored with respect to intramuscular preadipocyte proliferation and differentiation.Results: By porcine adipose tissue miRNA sequencing analysis, we found that miR-146a-5p is a potential regulator of porcine IMF adipogenesis. Further studies showed that miR-146a-5p mimics inhibited porcine intramuscular preadipocyte proliferation and differentiation, while the miR-146a-5p inhibitor promoted cell proliferation and adipogenic differentiation. Mechanistically, miR-146a-5p suppressed cell proliferation by directly targeting SMAD family member 4(SMAD4) to attenuate TGF-β signaling. Moreover, miR-146a-5p inhibited the differentiation of intramuscular preadipocytes by targeting TNF receptor-associated factor 6(TRAF6) to weaken the AKT/mTORC1 signaling downstream of the TRAF6 pathway.Conclusions: MiR-146a-5p targets SMAD4 and TRAF6 to inhibit porcine intramuscular adipogenesis by attenuating TGF-β and AKT/mTORC1 signaling, respectively. These findings provide a novel miRNA biomarker for regulating intramuscular adipogenesis to promote pork quality.展开更多
Heart failure(HF)is a kind of continuous development syndrome of cardiac insufficiency caused by various heart diseases.Not only does the prevalence continue to rise,but the mortality rate and readmission rate remain ...Heart failure(HF)is a kind of continuous development syndrome of cardiac insufficiency caused by various heart diseases.Not only does the prevalence continue to rise,but the mortality rate and readmission rate remain high.Heart failure is also the end-stage of cardiovascular disease and the main cause of death of patients,which seriously affects the health and quality of life of people all over the world.Ventricular remodeling plays a key role in the occurrence and development of heart failure.Therefore,by improving ventricular remodeling,it is of important research value to explore the intervention of traditional Chinese medicine in the development of heart failure.Studies have shown that the mediation of multiple signaling pathways can lead to progressive aggravation of ventricular remodeling,and experimental studies often confirm the therapeutic effects of traditional Chinese medicine.Traditional Chinese medicine usually achieves the therapeutic effect of heart failure through multiple targets and multiple approaches.In recent years,there have been more and more researches on the role and mechanism of Chinese medicine intervention in heart failure.However,it is concluded that Chinese medicine intervention has less influence on heart failure signal pathways.This article summarizes the understanding of Chinese medicine on heart failure and the five signal pathways related to Chinese medicine intervention in heart failure.The 5 signaling pathways in the world,namely transforming growth factor-β1(TGF-β1)/signal transduction protein(Smads)signaling pathway,Toll-like receptor(TLR)/nuclear transcription factor-κB(NF-κB)inflammation signaling pathway,Renin-angiotensinaldosterone(RAAS)system,phosphoinositide 3-kinase(PI3K)-serine/threonine protein kinase(AKT)signaling pathway and mitogen-activated protein kinase(MAPK)dependent signaling pathway.展开更多
The melanoma differentiation-associated gene-7（mda-7）,IL-24,has the specific functions that induce cancer cell apoptosis without doing harm to normal cells. We systematically review the apoptotic signal pathways and...The melanoma differentiation-associated gene-7（mda-7）,IL-24,has the specific functions that induce cancer cell apoptosis without doing harm to normal cells. We systematically review the apoptotic signal pathways and their regulatory mechanisms induced by Ad.IL-24 and IL-24 in diverse cancer cells. IL-24 can participate in varied signal transduction pathways,including JAK,p38 MAPK,Wnt/β-catenin,JNK,ER stress and mitochondria-associated signal pathways. And we review five proteins interacting with IL-24,including Bip/GRP78,S1 R,PKR,Beclin1 and soluble clusterin,which are relative to the tumor-specific effect of IL-24. It is speculated that ER stress,G-protein pathways and MAPK signal pathways may be the primary upstream effectors which activate the sequential downstream mediators resulting in apoptosis induced by IL-24 in tumor cells. Experimental results also show that IL-24 sensitizes cancer cells and indirectly promotes apoptosis rather than functions as a direct apoptosis inducer itself.展开更多
Psoriasis is a complex skin disease and the pathogenesis of psoriasis is not clear.The purpose of this study is to identify the key driving genes and signal pathways involved in psoriasis and to predict the potential ...Psoriasis is a complex skin disease and the pathogenesis of psoriasis is not clear.The purpose of this study is to identify the key driving genes and signal pathways involved in psoriasis and to predict the potential miRNA,for further understanding the pathogenesis of psoriasis.Methods:Three gene expression profiling chips,including GSE67853,GSE78097,and GSE136757 with a total of 120 samples were collected and analyzed with R software.The protein-protein interaction network of differentially expressed genes was constructed with STRING database and Cytoscape.CIBERSORT was used to evaluate the infiltration of immune cells in psoriasis tissues,and the correlation between diagnostic markers and infiltrating immune cells was analyzed.Further,the key biomarkers were identified and the targeting miRNA of crucial genes was predicted.Results:A total of 201 differentially expressed genes(163 upregulated genes and 38 downregulated genes)were determined.CXCL1,CXCL2,and CXCL8,the critical biomarkers of psoriasis,were identified by different calculation methods.The potential critical signal pathway NOD-like receptor signaling pathway of psoriasis was explored by gene expression profiling chip gene enrichment analysis and differentially expressed gene enrichment analysis.Immune cell infiltration analysis found that CXCL1,CXCL2,CXCL8 was positively correlated with macrophages M1 and T cells CD4 memory activated and negatively correlated with macrophages M2 and mast cells resting.At the same time,through miRNA prediction,we found that hsa-miR-216a-3p and hsa-miR-6750-5p can be used as potential psoriasis targets.Conclusions:This research proposes a new comprehensive strategy to identify psoriasis’s potential biomarkers through cross-validation and significant scores of different calculation methods.In this research,we identified CXCL1,CXCL2,and CXCL8 as potential key biomarkers of psoriasis,and the NOD-like receptor signaling pathway is the critical signal pathway of psoriasis.Hsa-miR-216a-3p and hsa-miR-6750-5p can be used as potential psoriasis targets.展开更多
This narrative review examines recent advances in salivary biomarkers for oral squamous cell carcinoma(OSCC),a major subtype of oral cancer with persistently low five-year survival rates due to delayed diagnosis.Saliv...This narrative review examines recent advances in salivary biomarkers for oral squamous cell carcinoma(OSCC),a major subtype of oral cancer with persistently low five-year survival rates due to delayed diagnosis.Saliva has emerged as a noninvasive diagnostic medium capable of reflecting both local tumor activity and systemic physiological changes.Various salivary biomarkers,including microRNAs,cytokines,proteins,metabolites,and exosomes,have been linked to oncogenic signaling pathways involved in tumor progression,immune modulation,and therapeutic resistance.Advances in quantitative polymerase chain reaction,mass spectrometry,and next-generation sequencing have enabled comprehensive biomarker profiling,while point-of-care detection systems and saliva-based omics platforms are accelerating clinical translation.Remaining challenges include variability in salivary composition,lack of standardized collection protocols,and insufficient validation across large patient cohorts.This review highlights the mechanistic relevance,diagnostic potential,and translational challenges of salivary biomarkers in OSCC.展开更多
Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis,leading to a notably low five-year survival rate.This study offers a d...Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis,leading to a notably low five-year survival rate.This study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers,such as mutations in CDKN2A,KRAS,SMAD4,and TP53,along with the influence of cancer-associated fibroblasts(CAFs)on disease progression.In particular,we focused on the pivotal roles of signaling pathways such as the transforming growth factor-βand Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic strategies.This study provides new scientific perspectives on pancreatic cancer treatment,especially in the development of precision medicine and targeted therapeutic strategies,and demonstrates the importance of signaling pathway research in the development of effective therapeutic regimens.Future studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.展开更多
Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microgl...Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microglia play an important role in secondary injury and can be activated in response to traumatic brain injury.In this article,we review the origin and classification of microglia as well as the dynamic changes of microglia in traumatic brain injury.We also clarify the microglial polarization pathways and the therapeutic drugs targeting activated microglia.We found that regulating the signaling pathways involved in pro-inflammatory and anti-inflammatory microglia,such as the Toll-like receptor 4/nuclear factor-kappa B,mitogen-activated protein kinase,Janus kinase/signal transducer and activator of transcription,phosphoinositide 3-kinase/protein kinase B,Notch,and high mobility group box 1 pathways,can alleviate the inflammatory response triggered by microglia in traumatic brain injury,thereby exerting neuroprotective effects.We also reviewed the strategies developed on the basis of these pathways,such as drug and cell replacement therapies.Drugs that modulate inflammatory factors,such as rosuvastatin,have been shown to promote the polarization of antiinflammatory microglia and reduce the inflammatory response caused by traumatic brain injury.Mesenchymal stem cells possess anti-inflammatory properties,and clinical studies have confirmed their significant efficacy and safety in patients with traumatic brain injury.Additionally,advancements in mesenchymal stem cell-delivery methods—such as combinations of novel biomaterials,genetic engineering,and mesenchymal stem cell exosome therapy—have greatly enhanced the efficiency and therapeutic effects of mesenchymal stem cells in animal models.However,numerous challenges in the application of drug and mesenchymal stem cell treatment strategies remain to be addressed.In the future,new technologies,such as single-cell RNA sequencing and transcriptome analysis,can facilitate further experimental studies.Moreover,research involving non-human primates can help translate these treatment strategies to clinical practice.展开更多
Osteogenesis is the process of bone formation mediated by the osteoblasts,participating in various bone-related physiological processes including bone development,bone homeostasis and fracture healing.It exhibits temp...Osteogenesis is the process of bone formation mediated by the osteoblasts,participating in various bone-related physiological processes including bone development,bone homeostasis and fracture healing.It exhibits temporal and spatial interconnectivity with angiogenesis,constructed by multiple forms of cell communication occurring between bone and vascular endothelial cells.Molecular regulation among different cell types is crucial for coordinating osteogenesis and angiogenesis to facilitate bone remodeling,fracture healing,and other bone-related processes.The transmission of signaling molecules and the activation of their corresponding signal pathways are indispensable for various forms of cell communication.This communication acts as a“bridge”in coupling osteogenesis to angiogenesis.This article reviews the modes and processes of cell communication in osteogenesisangiogenesis coupling over the past decade,mainly focusing on interactions among bone-related cells and vascular endothelial cells to provide insights into the mechanism of cell communication of osteogenesis-angiogenesis coupling in different bone-related contexts.Moreover,clinical relevance and applications are also introduced in this review.展开更多
Background:Neurodegenerative diseases(NDs),including Alzheimer‘s disease,Parkinson‘s disease,and Huntington‘s disease,are complex and challenging due to their intricate pathophysiology and limited treatment options...Background:Neurodegenerative diseases(NDs),including Alzheimer‘s disease,Parkinson‘s disease,and Huntington‘s disease,are complex and challenging due to their intricate pathophysiology and limited treatment options.Methods:This review systematically sourced articles related to neurodegenerative diseases,neurodegeneration,quercetin,and clinical studies from primary medical databases,including Scopus,PubMed,and Web of Science.Results:Recent studies have included quercetin to impact the cellular and molecular pathways involved in neurodegeneration.Quercetin,a flavonoid abundant in vegetables and fruits,is gaining attention for its antioxidant,anti-inflammatory,and antiapoptotic properties.It regulates signaling pathways such as nuclear factor-κB(NF-κB),sirtuins,and phosphatidylinositol 3-kinase/protein kinase B(PI3K/Akt).These pathways are essential for cellular survival,inflammation regulation,and apoptosis.Preclinical and clinical studies have shown that quercetin improves symptoms and pathology in neurodegenerative models,indicating promising outcomes.Conclusions:The study explores the potential of incorporating laboratory research into practical medical treatment,focusing on quercetin‘s neuroprotective effects on NDs and its optimal dosage.展开更多
Steroidal alkaloids are the main active components in many medicinal plants and exhibit diverse biological activities.Axillaridine A(AA)is a newly discovered steroidal alkaloid.However,whether AA could suppress osteoc...Steroidal alkaloids are the main active components in many medicinal plants and exhibit diverse biological activities.Axillaridine A(AA)is a newly discovered steroidal alkaloid.However,whether AA could suppress osteoclastogenesis and alleviate ovariectomy-induced bone loss in mice remains unknown.In vitro,AA significantly suppressed the receptor activator of nuclear factor-κB(NF-κB)ligand(RANKL)-induced osteoclast differentiation via downregulating the expression of osteoclastogenesis-related marker genes,proteins,and transcriptional regulators,including tartrate-resistant acid phosphatase(TRAP),c-Src,matrix metallopeptidase-9(MMP-9),cathepsin K,nuclear factor of activated T cells,cytoplasmic 1(NFATc1),and c-Fos.This was achieved by blocking RANKL-RANK interaction and inhibiting RANKL-mediated RANK signaling pathways,including NF-κB,AKT,and mitogen-activated protein kinases(MAPKs)in osteoclast precursors.In vivo,AA significantly inhibited the ovariectomized(OVX)-induced body weight gain and blood glucose increase in mice.AA did not adversely affect the histomorphologies,weights,and indices of the kidney and liver in OVX mice.AA effectively ameliorated bone loss in OVX mice by inhibiting osteoclastogenesis.AA significantly inhibited the serum levels of tartrate-resistant acid phosphatase 5b(TRACP-5b)and C-telopeptide of type I collagen(CTX-I).AA significantly inhibited the OVX-induced expression of osteoclastogenesis-related marker genes and proteins in the femur.In summary,AA alleviates ovariectomy-induced bone loss in mice by suppressing osteoclastogenesis via inhibition of RANKL-mediated RANK signaling pathways and could be potentially used for the prevention and treatment of osteoclastrelated diseases such as osteoporosis.展开更多
Dear Editor,Sleep and memory are highly linked across species.Sleep gates and stabilizes memory,critical for memory processing.Insufficient sleep impairs cognition acutely/chronically,in vertebrates and invertebrates[...Dear Editor,Sleep and memory are highly linked across species.Sleep gates and stabilizes memory,critical for memory processing.Insufficient sleep impairs cognition acutely/chronically,in vertebrates and invertebrates[1,2].While key elements are characterized[3,4],how a single molecule integrates sleep and memory remains unknown.展开更多
In the article“MicroRNA-101 Targets CXCL12-Mediated Akt and Snail Signaling Pathways to Inhibit Cellular Proliferation and Invasion in Papillary Thyroid Carcinoma”(Oncology Research.2019 Jun 21;27(6):691-701,doi:10....In the article“MicroRNA-101 Targets CXCL12-Mediated Akt and Snail Signaling Pathways to Inhibit Cellular Proliferation and Invasion in Papillary Thyroid Carcinoma”(Oncology Research.2019 Jun 21;27(6):691-701,doi:10.3727/096504018X15426763753594),the IHC images for CXCL12 and Bcl-2 expressions in adjacent noncancer tissues(NCT)shown in Fig.5E were unintentionally duplicated.And Fig.5A,B was also unintentionally duplicated.These needed corrections to ensure the accuracy and integrity of the data presented.展开更多
Silicosis is an occupational lung disease caused by prolonged exposure to silica dust in the workplace.It has a complex pathogenesis and currently lacks effective treatments.Homoharringtonine(HHT)is a natural compound...Silicosis is an occupational lung disease caused by prolonged exposure to silica dust in the workplace.It has a complex pathogenesis and currently lacks effective treatments.Homoharringtonine(HHT)is a natural compound approved for the treatment of acute myeloid leukemia,but its effects on silicosis remain unclear.In the present study,we constructed a mouse model of silica(SiO_(2))-induced pulmonary fibrosis and evaluated the preventive and therapeutic effects of HHT.The results showed that HHT significantly attenuated the progression of SiO_(2)-induced pulmonary fibrosis in mice.We then used MRC-5,a human lung fibroblast cell line,to explore the mechanisms underlying HHT's inhibitory effects in vitro and found that HHT significantly inhibited the activation and migratory capacity of MRC-5 cells.Mechanistically,these effects were mediated by enhanced ubiquitination and degradation of the CCR1 protein.Furthermore,HHT exhibited favorable biocompatibility in vivo,and its preventive and therapeutic effects were validated in SiO_(2)-treated mice.Collectively,the current study demonstrates that HHT shows significant potential as a therapeutic agent for silicosis by targeting CCR1 and the PI3K/AKT/m TOR signaling pathway,highlighting it as a promising candidate for clinical translation for silicosis treatment.展开更多
Objective:To examine the effect of shikonin against streptozotocin(STZ)-induced diabetic retinopathy in rats and elucidate the underlying mechanisms.Methods:Intraperitoneal administration of STZ(65 mg/kg)was used for ...Objective:To examine the effect of shikonin against streptozotocin(STZ)-induced diabetic retinopathy in rats and elucidate the underlying mechanisms.Methods:Intraperitoneal administration of STZ(65 mg/kg)was used for the induction of diabetic retinopathy in rats.Rats received oral administration of shikonin(10,20,and 30 mg/kg).The blood glucose level,insulin,body weight,and organ weight were estimated.Advanced glycation end products(AGEs)levels in serum and lens as well as protein carbonyl content of the lens were determined.The parameters related to oxidative stress and inflammation,and the levels of nuclear factor erythroid 2-related factor 2(Nrf2),heme oxygenase-1(HO-1),intercellular adhesion molecule-1(ICAM-1),and vascular cell adhesion molecule 1(VCAM-1)were also measured.In addition,quantitative RT-PCR was performed to determine the mRNA expressions.Results:Shikonin treatment decreased glucose level and boosted insulin level,along with an increase in body weight and improved organ weight.It also lowered O2•−,ONOO−,serum and lens AGEs,and protein carbonyl content.Furthermore,shikonin treatment significantly alleviated oxidative stress and inflammation,as evidenced by reduced malonaldehyde,nitric oxide,tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),IL-6,cyclooxygenase-2,prostaglandin E2,protein carbonyl content,and nuclear factor kappa-B,and increased superoxide dismutase,glutathione,catalase,and glutathione peroxidase.Markedly decreased levels of ICAM-1 and VCAM-1,as well as heightened levels of Nrf2 and HO-1,were noticed after treatment with shikonin.Furthermore,the mRNA expressions of TNF-α,IL-1β,IL-6,ICAM-1,VCAM-1,RAGE,collagenⅣ,and fibronectin were significantly downregulated.Conclusions:Shikonin exhibits protective effects against STZ-induced diabetic retinopathy in rats via modulating the Nrf2/HO-1 and NF-κB signaling pathways.展开更多
Breast cancer(BC)is one of the most prevalent malignant tumors affecting women worldwide,with its incidence rate continuously increasing.As a result,treatment strategies for this disease have received considerable att...Breast cancer(BC)is one of the most prevalent malignant tumors affecting women worldwide,with its incidence rate continuously increasing.As a result,treatment strategies for this disease have received considerable attention.Research has highlighted the crucial role of the Hedgehog(Hh)signaling pathway in the initiation and progression of BC,particularly in promoting tumor growth and metastasis.Therefore,molecular targets within this pathway represent promising opportunities for the development of novel BC therapies.This study aims to elucidate the therapeutic mechanisms by which natural compounds modulate the Hh signaling pathway in BC.By conducting a comprehensive review of various natural compounds,including polyphenols,terpenes,and alkaloids,we reveal both common and unique regulatory mechanisms that influence this pathway.This investigation represents the first comprehensive analysis of five distinct mechanisms through which natural compounds modulate key molecules within the Hh pathway and their impact on the aggressive behaviors of BC.Furthermore,by exploring the structure-activity relationships between these compounds and their molecular targets,we shed light on the specific structural features that enable natural compounds to interact with various components of the Hh pathway.These novel insights contribute to advancing the development and clinical application of natural compound-based therapeutics.Our thorough review not only lays the groundwork for exploring innovative BC treatments but also opens new avenues for leveraging natural compounds in cancer therapy.展开更多
V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating ene...V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown.In this study,we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity(DIO)mice.Under normal chow diet feeding,overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight,fat mass,and impaired glucose tolerance.Conversely,Raf1 knockout in AgRP neurons protected against diet-induced obesity,reducing fat mass and improving glucose tolerance.Mechanistically,Raf1 activated the MAPK signaling pathway,culminating in the phosphorylation of cAMP response element-binding protein(CREB),which enhanced transcription of Agrp and Npy.Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis,highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance.Collectively,these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis,positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.展开更多
Objective:To investigate the anti-atherosclerosis effect of chikusetsusaponinⅣ(CSⅣ)against high-fat diet-induced atherosclerosis in rats.Methods:A high-fat diet was used for the induction of atherosclerosis in rats,...Objective:To investigate the anti-atherosclerosis effect of chikusetsusaponinⅣ(CSⅣ)against high-fat diet-induced atherosclerosis in rats.Methods:A high-fat diet was used for the induction of atherosclerosis in rats,and the rats received oral CSⅣor atorvastatin.The body weight,organ weights,food intake,calorie intake,lipid parameters,3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA)/mevalonate ratio,collagen,free fatty acid,cardiac parameters,apolipoprotein(A and B),antioxidant parameters,inflammatory cytokines,and inflammatory parameters were assessed.The mRNA expressions of interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),IL-6,IL-17,PI3K,AKT,and mTOR were estimated.Results:CSⅣsignificantly modulated food intake,body weight,organ weight(liver,kidney,and heart),and calories(P<0.05).Total cholesterol,triglycerides,very low-density lipoprotein cholesterol,low-density lipoprotein cholesterol,cardiovascular risk index-1,and cardiovascular risk index-2 were decreased,while high-density lipoprotein cholesterol and anti-atherogenic index were increased significantly in the CSⅣgroup(P<0.05).Besides,CSⅣsignificantly restored the level of HMG-CoA/mevalonate ratio,collagen,free fatty acid,cardiac parameters(creatinine kinase-MB,lactate dehydrogenase,cTnT,cTnI),apolipoprotein(apolipoprotein A and apolipoprotein B),antioxidant parameters(MDA,CAT,GPx,GSH,SOD),inflammatory cytokines(TNF-α,IL-1β,IL-6,IL-10),inflammatory parameters(COX-2,TGF-β,NF-κB),intercellular adhesion molecule-1,vascular cell adhesion molecule-1,and monocyte chemoattractant protein-1.CSⅣalso decreased the mRNA expression of IL-1β,TNF-α,IL-6,IL-17,PI3K,AKT,and mTOR.Conclusions:This study showed the anti-atherosclerosis effect of CSⅣagainst high-fat diet-induced atherosclerosis in rats via alteration of NF-κB/COX-2 and PI3K/AKT/mTOR signaling pathway.展开更多
Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in m...Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in mitigating intrahepatic cholestasis,the precise mechanisms underlying its therapeutic effects remain inadequately understood.This study aims to comprehensively investigate the pharmacological mechanisms underlying the therapeutic effects of ZZBPD in cholestatic liver injury(CLI).Methods:Firstly,we evaluated the hepatoprotective effects of ZZBPD on mice with CLI induced byα-naphthylisothiocyanate(ANIT),by measuring biochemical markers,inflammatory factors,and bile acid levels.Subsequently,we employed network pharmacology and single-cell RNA sequencing(scRNA-seq)to identify key targets and potential signaling pathways for the prevention and treatment of CLI.Finally,we further validated the mechanism of action of ZZBPD on these key targets through molecular docking,western blotting,and immunofluorescence techniques.Results:ZZBPD notably improved serum liver function,reduced hepatic inflammation,and restored bile acid balance.Through network pharmacology and scRNA-seq analysis,48 core targets were identified,including TNF,IL-6,and NFKB1,all of which are linked to the IL-17 and NF-κB signaling pathways,as shown by KEGG enrichment analysis.Molecular docking further confirmed stable interactions between ZZBPD’s key active components and molecules such as IL-6,IL-17,and NF-κB.Additionally,western blotting and immunofluorescence validated the downregulation of IL-17 and NF-κB protein expression in liver tissue.Conclusion:ZZBPD effectively treats CLI by activating pathways related to the bile acid receptor FXR,while also modulating the IL-17/NF-κB signaling pathway.This dual action enhances bile secretion and alleviates liver inflammation.These findings offer important insights into the pharmacological mechanisms of ZZBPD and underscore its potential as a promising therapeutic for CLI.展开更多
基金Supported by Naional Key Basic Research Program(973, No. 2009 CB 522905)
文摘Objective To observe influence of moxibustion at ＂Shenshu＂ （肾俞BL 23） and ＂Zusanli＂ （足三里 ST 36） on proteins expression of Ras, ERKI/2, and Raf in synovial tissues in rats with rheumatoid arthritis （RA） to elucidate molecular mechanisms of moxibustion on treating RA. Methods Thirty Wistar rats were randomly divided into a normal control group （Group Cont）, a model group （Group Mod） and a moxibustion group （Group Mox） with 10 rats in each group. The model was established by using both environmental factors such as wind, cold and damp and a biological factor （Freund＇s complete adjuvant）. Suspended moxibustion was applied at bilateral BL 23 and ST 36 for 20 min, applied once daily for 15 days, starting from the 3rd day after modeling. Volumes of metaleg digiti pedis on the right side were measured before, after and 15 days after modeling. Protein expressions of Ras, ERK 1/2, p-ERKI/2 and Raf in synovium tissues were detected by western blot. Results After modeling, volumes of metaleg digiti pedis on the right side were significantly enlarged, compared with those of rats in Group Cont （P〈0.01）. After treatment by moxibustion for 15 days, the metatarsale girth of metaleg digiti pedis on the right side in Group Mox was significantly reduced, compared with that in Group Mod （P〈0.01）. Protein expressions of Ras, Raf, ERK1/2 and p-ERK1/2 in Group Mod were significantly increased, compared with those in Group Cont （P〈0.01） and Group Mox （P〈0.01）. Protein expressions of Ras, Raf, ERK1/2 and p-ERK1/2 in Group Mox were significantly lowered, compared with those in Group Mod （all P〈0.01）. Conclusions Moxibustion can suppress excessive protein expressions of Ras, Raf and ERK1/2 in synovium tissues of rats with experimental RA to inhibit abnormal activation of Ras-MAPK signal Pathway, which may be one of the molecular mechanisms of moxibustion in alleviating synovitis.
文摘Objective To investigate effect of pinacidil, an ATP sensitive potassium channel （KATP） opener, on the neuronal apoptosis and its signaling transduction mechanism following focal cerebral ischemia-reperfusion in rats. Methods One hundred male Wistar rats were randomly divided into four groups： A, sham-operated group; B, ischemia-reperfusion group; C, KATe opener treatment group; and D, KATe opener and blocker treatment group. The middle cerebral artery occlusion （MCAO） model was established by using the intraluminal suture occlusion method, neuronal apoptosis was determined by TUNEL staining, and expressions of caspase-8, caspase-9 and caspase-3 mRNA were detected by in situ hybridization. Results （1） The numbers of apoptotic neurons at 12 h, 24 h, 48 h, and 72 h were significantly less in group C than in groups B and D （P 〈 0.01 or P 〈 0.05）; and there was no difference between groups B and D at all time points （P 〉 0.05）. （2） The expressions of caspase-3 mRNA and caspase-8 mRNA at all times and the expressions of caspase-9 mRNA at 12 h, 24 h, 48 h, 72 h were significantly lower in group C than in groups B and D （P 〈 0.01 or P 〈 0.05）; and there were no differences between groups B and D at all time points （P 〉 0.05）. Conclusions KATP opener can significantly decrease the neuronal apoptosis and the expressions of caspase-3, caspase-8 and caspase-9 mRNAs following cerebral ischemiareperfusion. The neuronal apoptosis may be decreased by the inhibition of both mitochondrial and death-receptor signal pathways.
基金supported by grants from the National Natural Science Foundation (31872979, 31572366)the National Key Research and Development Program of China (2017YFD0502002)the National Basic Research Programs of China (2015CB943102)。
文摘Background: Intramuscular fat(IMF) content is a vital parameter for assessing pork quality. Increasing evidence has shown that microRNAs(miRNAs) play an important role in regulating porcine IMF deposition. Here, a novel miRNA implicated in porcine IMF adipogenesis was found, and its effect and regulatory mechanism were further explored with respect to intramuscular preadipocyte proliferation and differentiation.Results: By porcine adipose tissue miRNA sequencing analysis, we found that miR-146a-5p is a potential regulator of porcine IMF adipogenesis. Further studies showed that miR-146a-5p mimics inhibited porcine intramuscular preadipocyte proliferation and differentiation, while the miR-146a-5p inhibitor promoted cell proliferation and adipogenic differentiation. Mechanistically, miR-146a-5p suppressed cell proliferation by directly targeting SMAD family member 4(SMAD4) to attenuate TGF-β signaling. Moreover, miR-146a-5p inhibited the differentiation of intramuscular preadipocytes by targeting TNF receptor-associated factor 6(TRAF6) to weaken the AKT/mTORC1 signaling downstream of the TRAF6 pathway.Conclusions: MiR-146a-5p targets SMAD4 and TRAF6 to inhibit porcine intramuscular adipogenesis by attenuating TGF-β and AKT/mTORC1 signaling, respectively. These findings provide a novel miRNA biomarker for regulating intramuscular adipogenesis to promote pork quality.
基金National Natural Science Foundation of China(No.81673891,No.81560760)Guangxi Medical and Health Appropriate Technology Research and Development Project(No.S201532)Guangxi Zhuang Yao Pharmaceutical Preparation Improvement Project of Traditional Chinese Medicine(No.GZZJ16-03)。
文摘Heart failure(HF)is a kind of continuous development syndrome of cardiac insufficiency caused by various heart diseases.Not only does the prevalence continue to rise,but the mortality rate and readmission rate remain high.Heart failure is also the end-stage of cardiovascular disease and the main cause of death of patients,which seriously affects the health and quality of life of people all over the world.Ventricular remodeling plays a key role in the occurrence and development of heart failure.Therefore,by improving ventricular remodeling,it is of important research value to explore the intervention of traditional Chinese medicine in the development of heart failure.Studies have shown that the mediation of multiple signaling pathways can lead to progressive aggravation of ventricular remodeling,and experimental studies often confirm the therapeutic effects of traditional Chinese medicine.Traditional Chinese medicine usually achieves the therapeutic effect of heart failure through multiple targets and multiple approaches.In recent years,there have been more and more researches on the role and mechanism of Chinese medicine intervention in heart failure.However,it is concluded that Chinese medicine intervention has less influence on heart failure signal pathways.This article summarizes the understanding of Chinese medicine on heart failure and the five signal pathways related to Chinese medicine intervention in heart failure.The 5 signaling pathways in the world,namely transforming growth factor-β1(TGF-β1)/signal transduction protein(Smads)signaling pathway,Toll-like receptor(TLR)/nuclear transcription factor-κB(NF-κB)inflammation signaling pathway,Renin-angiotensinaldosterone(RAAS)system,phosphoinositide 3-kinase(PI3K)-serine/threonine protein kinase(AKT)signaling pathway and mitogen-activated protein kinase(MAPK)dependent signaling pathway.
基金Supported by the National Program on Key Basic Research Project(973 Program)(2012CB518900)the National Natural Science Foundation of China(31160240,31260621)+2 种基金the 12th Five Years Key Programs for Science and Technology Development of China(2012ZX10002006)the Hangzhou Normal University Supporting Project(PE13002004042)the Natural Science Foundation of China of Jiangxi(20114BAB204016)
文摘The melanoma differentiation-associated gene-7（mda-7）,IL-24,has the specific functions that induce cancer cell apoptosis without doing harm to normal cells. We systematically review the apoptotic signal pathways and their regulatory mechanisms induced by Ad.IL-24 and IL-24 in diverse cancer cells. IL-24 can participate in varied signal transduction pathways,including JAK,p38 MAPK,Wnt/β-catenin,JNK,ER stress and mitochondria-associated signal pathways. And we review five proteins interacting with IL-24,including Bip/GRP78,S1 R,PKR,Beclin1 and soluble clusterin,which are relative to the tumor-specific effect of IL-24. It is speculated that ER stress,G-protein pathways and MAPK signal pathways may be the primary upstream effectors which activate the sequential downstream mediators resulting in apoptosis induced by IL-24 in tumor cells. Experimental results also show that IL-24 sensitizes cancer cells and indirectly promotes apoptosis rather than functions as a direct apoptosis inducer itself.
文摘Psoriasis is a complex skin disease and the pathogenesis of psoriasis is not clear.The purpose of this study is to identify the key driving genes and signal pathways involved in psoriasis and to predict the potential miRNA,for further understanding the pathogenesis of psoriasis.Methods:Three gene expression profiling chips,including GSE67853,GSE78097,and GSE136757 with a total of 120 samples were collected and analyzed with R software.The protein-protein interaction network of differentially expressed genes was constructed with STRING database and Cytoscape.CIBERSORT was used to evaluate the infiltration of immune cells in psoriasis tissues,and the correlation between diagnostic markers and infiltrating immune cells was analyzed.Further,the key biomarkers were identified and the targeting miRNA of crucial genes was predicted.Results:A total of 201 differentially expressed genes(163 upregulated genes and 38 downregulated genes)were determined.CXCL1,CXCL2,and CXCL8,the critical biomarkers of psoriasis,were identified by different calculation methods.The potential critical signal pathway NOD-like receptor signaling pathway of psoriasis was explored by gene expression profiling chip gene enrichment analysis and differentially expressed gene enrichment analysis.Immune cell infiltration analysis found that CXCL1,CXCL2,CXCL8 was positively correlated with macrophages M1 and T cells CD4 memory activated and negatively correlated with macrophages M2 and mast cells resting.At the same time,through miRNA prediction,we found that hsa-miR-216a-3p and hsa-miR-6750-5p can be used as potential psoriasis targets.Conclusions:This research proposes a new comprehensive strategy to identify psoriasis’s potential biomarkers through cross-validation and significant scores of different calculation methods.In this research,we identified CXCL1,CXCL2,and CXCL8 as potential key biomarkers of psoriasis,and the NOD-like receptor signaling pathway is the critical signal pathway of psoriasis.Hsa-miR-216a-3p and hsa-miR-6750-5p can be used as potential psoriasis targets.
基金supported by the College of Oral Medicine,Taipei Medical University,Taipei,Taiwan(Grant No.TMUCOM202502)supported by Taipei Medical University Hospital,Taipei,Taiwan(Grant No.114TMUH-NE-05).
文摘This narrative review examines recent advances in salivary biomarkers for oral squamous cell carcinoma(OSCC),a major subtype of oral cancer with persistently low five-year survival rates due to delayed diagnosis.Saliva has emerged as a noninvasive diagnostic medium capable of reflecting both local tumor activity and systemic physiological changes.Various salivary biomarkers,including microRNAs,cytokines,proteins,metabolites,and exosomes,have been linked to oncogenic signaling pathways involved in tumor progression,immune modulation,and therapeutic resistance.Advances in quantitative polymerase chain reaction,mass spectrometry,and next-generation sequencing have enabled comprehensive biomarker profiling,while point-of-care detection systems and saliva-based omics platforms are accelerating clinical translation.Remaining challenges include variability in salivary composition,lack of standardized collection protocols,and insufficient validation across large patient cohorts.This review highlights the mechanistic relevance,diagnostic potential,and translational challenges of salivary biomarkers in OSCC.
基金Supported by National Key Research and Development Program Project,No.2017YFC1700601Shaanxi Provincial Key Research and Development Program Project,No.2018SF-350Leading Talents in Scientific and Technological Innovation of the Shaanxi Province Special Support Plan,No.00518。
文摘Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis,leading to a notably low five-year survival rate.This study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers,such as mutations in CDKN2A,KRAS,SMAD4,and TP53,along with the influence of cancer-associated fibroblasts(CAFs)on disease progression.In particular,we focused on the pivotal roles of signaling pathways such as the transforming growth factor-βand Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic strategies.This study provides new scientific perspectives on pancreatic cancer treatment,especially in the development of precision medicine and targeted therapeutic strategies,and demonstrates the importance of signaling pathway research in the development of effective therapeutic regimens.Future studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.
基金supported by the Natural Science Foundation of Yunnan Province,No.202401AS070086(to ZW)the National Key Research and Development Program of China,No.2018YFA0801403(to ZW)+1 种基金Yunnan Science and Technology Talent and Platform Plan,No.202105AC160041(to ZW)the Natural Science Foundation of China,No.31960120(to ZW)。
文摘Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microglia play an important role in secondary injury and can be activated in response to traumatic brain injury.In this article,we review the origin and classification of microglia as well as the dynamic changes of microglia in traumatic brain injury.We also clarify the microglial polarization pathways and the therapeutic drugs targeting activated microglia.We found that regulating the signaling pathways involved in pro-inflammatory and anti-inflammatory microglia,such as the Toll-like receptor 4/nuclear factor-kappa B,mitogen-activated protein kinase,Janus kinase/signal transducer and activator of transcription,phosphoinositide 3-kinase/protein kinase B,Notch,and high mobility group box 1 pathways,can alleviate the inflammatory response triggered by microglia in traumatic brain injury,thereby exerting neuroprotective effects.We also reviewed the strategies developed on the basis of these pathways,such as drug and cell replacement therapies.Drugs that modulate inflammatory factors,such as rosuvastatin,have been shown to promote the polarization of antiinflammatory microglia and reduce the inflammatory response caused by traumatic brain injury.Mesenchymal stem cells possess anti-inflammatory properties,and clinical studies have confirmed their significant efficacy and safety in patients with traumatic brain injury.Additionally,advancements in mesenchymal stem cell-delivery methods—such as combinations of novel biomaterials,genetic engineering,and mesenchymal stem cell exosome therapy—have greatly enhanced the efficiency and therapeutic effects of mesenchymal stem cells in animal models.However,numerous challenges in the application of drug and mesenchymal stem cell treatment strategies remain to be addressed.In the future,new technologies,such as single-cell RNA sequencing and transcriptome analysis,can facilitate further experimental studies.Moreover,research involving non-human primates can help translate these treatment strategies to clinical practice.
基金supported by central government-guided major science and technology project of Hebei province 236Z7709G(M.C.Q.)Tangshan science and technology project 23130216E(M.C.Q.)+8 种基金key research projects of North China University of Science and Technology ZD-YG-202309(M.C.Q.)National Natural Science Foundations of China 82230030 and 81871492(Y.L.)Beijing International Science and Technology Cooperation Project Z221100002722003(Y.L.)Beijing Natural Science Foundation L234017(Y.L.)Peking University Medicine plus X Pilot Program-Key Technologies R&D Project 2024YXXLHGG004(Y.L.)Key R&D Plan of Ningxia Hui Autonomous Region 2020BCG01001(Y.L.)First-Class Discipline Team of Kunming Medical University 2024XKTDTS08(Y.L.)Innovative Research Team of High-level Local Universities in Shanghai SHSMU-ZLCX20212402(Y.L.)Postdoctoral Fellowship Program of CPSF under Grant Number GZB20240038(X.J.C.).
文摘Osteogenesis is the process of bone formation mediated by the osteoblasts,participating in various bone-related physiological processes including bone development,bone homeostasis and fracture healing.It exhibits temporal and spatial interconnectivity with angiogenesis,constructed by multiple forms of cell communication occurring between bone and vascular endothelial cells.Molecular regulation among different cell types is crucial for coordinating osteogenesis and angiogenesis to facilitate bone remodeling,fracture healing,and other bone-related processes.The transmission of signaling molecules and the activation of their corresponding signal pathways are indispensable for various forms of cell communication.This communication acts as a“bridge”in coupling osteogenesis to angiogenesis.This article reviews the modes and processes of cell communication in osteogenesisangiogenesis coupling over the past decade,mainly focusing on interactions among bone-related cells and vascular endothelial cells to provide insights into the mechanism of cell communication of osteogenesis-angiogenesis coupling in different bone-related contexts.Moreover,clinical relevance and applications are also introduced in this review.
基金financially supporting this work through the Large Research Group Project under grant number R.G.P.2/510/45。
文摘Background:Neurodegenerative diseases(NDs),including Alzheimer‘s disease,Parkinson‘s disease,and Huntington‘s disease,are complex and challenging due to their intricate pathophysiology and limited treatment options.Methods:This review systematically sourced articles related to neurodegenerative diseases,neurodegeneration,quercetin,and clinical studies from primary medical databases,including Scopus,PubMed,and Web of Science.Results:Recent studies have included quercetin to impact the cellular and molecular pathways involved in neurodegeneration.Quercetin,a flavonoid abundant in vegetables and fruits,is gaining attention for its antioxidant,anti-inflammatory,and antiapoptotic properties.It regulates signaling pathways such as nuclear factor-κB(NF-κB),sirtuins,and phosphatidylinositol 3-kinase/protein kinase B(PI3K/Akt).These pathways are essential for cellular survival,inflammation regulation,and apoptosis.Preclinical and clinical studies have shown that quercetin improves symptoms and pathology in neurodegenerative models,indicating promising outcomes.Conclusions:The study explores the potential of incorporating laboratory research into practical medical treatment,focusing on quercetin‘s neuroprotective effects on NDs and its optimal dosage.
基金supported by the grants from the National Natural Science Foundation of China(82404638)the Xingdian Talent Plan of Yunnan Province(XDYC-QNRC-2023-0427 and XDYC-YLXZ2022-0025)the Natural Science Foundation of Yunnan Province(202101BD070001-034,202101BD070001-049,202201AT070267,and 202201AU070183)。
文摘Steroidal alkaloids are the main active components in many medicinal plants and exhibit diverse biological activities.Axillaridine A(AA)is a newly discovered steroidal alkaloid.However,whether AA could suppress osteoclastogenesis and alleviate ovariectomy-induced bone loss in mice remains unknown.In vitro,AA significantly suppressed the receptor activator of nuclear factor-κB(NF-κB)ligand(RANKL)-induced osteoclast differentiation via downregulating the expression of osteoclastogenesis-related marker genes,proteins,and transcriptional regulators,including tartrate-resistant acid phosphatase(TRAP),c-Src,matrix metallopeptidase-9(MMP-9),cathepsin K,nuclear factor of activated T cells,cytoplasmic 1(NFATc1),and c-Fos.This was achieved by blocking RANKL-RANK interaction and inhibiting RANKL-mediated RANK signaling pathways,including NF-κB,AKT,and mitogen-activated protein kinases(MAPKs)in osteoclast precursors.In vivo,AA significantly inhibited the ovariectomized(OVX)-induced body weight gain and blood glucose increase in mice.AA did not adversely affect the histomorphologies,weights,and indices of the kidney and liver in OVX mice.AA effectively ameliorated bone loss in OVX mice by inhibiting osteoclastogenesis.AA significantly inhibited the serum levels of tartrate-resistant acid phosphatase 5b(TRACP-5b)and C-telopeptide of type I collagen(CTX-I).AA significantly inhibited the OVX-induced expression of osteoclastogenesis-related marker genes and proteins in the femur.In summary,AA alleviates ovariectomy-induced bone loss in mice by suppressing osteoclastogenesis via inhibition of RANKL-mediated RANK signaling pathways and could be potentially used for the prevention and treatment of osteoclastrelated diseases such as osteoporosis.
基金supported by the National Natural Science Foundation of China(32371063,82341248,and 32071009)Guangdong Basic and Applied Basic Research Foundation(2024A1515011500)the Shenzhen Science and Technology Program(ZDSYS20200811142401005).
文摘Dear Editor,Sleep and memory are highly linked across species.Sleep gates and stabilizes memory,critical for memory processing.Insufficient sleep impairs cognition acutely/chronically,in vertebrates and invertebrates[1,2].While key elements are characterized[3,4],how a single molecule integrates sleep and memory remains unknown.
文摘In the article“MicroRNA-101 Targets CXCL12-Mediated Akt and Snail Signaling Pathways to Inhibit Cellular Proliferation and Invasion in Papillary Thyroid Carcinoma”(Oncology Research.2019 Jun 21;27(6):691-701,doi:10.3727/096504018X15426763753594),the IHC images for CXCL12 and Bcl-2 expressions in adjacent noncancer tissues(NCT)shown in Fig.5E were unintentionally duplicated.And Fig.5A,B was also unintentionally duplicated.These needed corrections to ensure the accuracy and integrity of the data presented.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82473601 to Y.L.,82404234 to W.S.,and 82073518 to C.N.)the Foundation of Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning(Grant No.2022-2023ZYBKF04 to C.N.)。
文摘Silicosis is an occupational lung disease caused by prolonged exposure to silica dust in the workplace.It has a complex pathogenesis and currently lacks effective treatments.Homoharringtonine(HHT)is a natural compound approved for the treatment of acute myeloid leukemia,but its effects on silicosis remain unclear.In the present study,we constructed a mouse model of silica(SiO_(2))-induced pulmonary fibrosis and evaluated the preventive and therapeutic effects of HHT.The results showed that HHT significantly attenuated the progression of SiO_(2)-induced pulmonary fibrosis in mice.We then used MRC-5,a human lung fibroblast cell line,to explore the mechanisms underlying HHT's inhibitory effects in vitro and found that HHT significantly inhibited the activation and migratory capacity of MRC-5 cells.Mechanistically,these effects were mediated by enhanced ubiquitination and degradation of the CCR1 protein.Furthermore,HHT exhibited favorable biocompatibility in vivo,and its preventive and therapeutic effects were validated in SiO_(2)-treated mice.Collectively,the current study demonstrates that HHT shows significant potential as a therapeutic agent for silicosis by targeting CCR1 and the PI3K/AKT/m TOR signaling pathway,highlighting it as a promising candidate for clinical translation for silicosis treatment.
文摘Objective:To examine the effect of shikonin against streptozotocin(STZ)-induced diabetic retinopathy in rats and elucidate the underlying mechanisms.Methods:Intraperitoneal administration of STZ(65 mg/kg)was used for the induction of diabetic retinopathy in rats.Rats received oral administration of shikonin(10,20,and 30 mg/kg).The blood glucose level,insulin,body weight,and organ weight were estimated.Advanced glycation end products(AGEs)levels in serum and lens as well as protein carbonyl content of the lens were determined.The parameters related to oxidative stress and inflammation,and the levels of nuclear factor erythroid 2-related factor 2(Nrf2),heme oxygenase-1(HO-1),intercellular adhesion molecule-1(ICAM-1),and vascular cell adhesion molecule 1(VCAM-1)were also measured.In addition,quantitative RT-PCR was performed to determine the mRNA expressions.Results:Shikonin treatment decreased glucose level and boosted insulin level,along with an increase in body weight and improved organ weight.It also lowered O2•−,ONOO−,serum and lens AGEs,and protein carbonyl content.Furthermore,shikonin treatment significantly alleviated oxidative stress and inflammation,as evidenced by reduced malonaldehyde,nitric oxide,tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),IL-6,cyclooxygenase-2,prostaglandin E2,protein carbonyl content,and nuclear factor kappa-B,and increased superoxide dismutase,glutathione,catalase,and glutathione peroxidase.Markedly decreased levels of ICAM-1 and VCAM-1,as well as heightened levels of Nrf2 and HO-1,were noticed after treatment with shikonin.Furthermore,the mRNA expressions of TNF-α,IL-1β,IL-6,ICAM-1,VCAM-1,RAGE,collagenⅣ,and fibronectin were significantly downregulated.Conclusions:Shikonin exhibits protective effects against STZ-induced diabetic retinopathy in rats via modulating the Nrf2/HO-1 and NF-κB signaling pathways.
基金supported by the National Natural Science Foundation of China(Grant No.:82174222)Shandong Province Natural Science Foundation,China(Grant No.:ZR2021LZY015).
文摘Breast cancer(BC)is one of the most prevalent malignant tumors affecting women worldwide,with its incidence rate continuously increasing.As a result,treatment strategies for this disease have received considerable attention.Research has highlighted the crucial role of the Hedgehog(Hh)signaling pathway in the initiation and progression of BC,particularly in promoting tumor growth and metastasis.Therefore,molecular targets within this pathway represent promising opportunities for the development of novel BC therapies.This study aims to elucidate the therapeutic mechanisms by which natural compounds modulate the Hh signaling pathway in BC.By conducting a comprehensive review of various natural compounds,including polyphenols,terpenes,and alkaloids,we reveal both common and unique regulatory mechanisms that influence this pathway.This investigation represents the first comprehensive analysis of five distinct mechanisms through which natural compounds modulate key molecules within the Hh pathway and their impact on the aggressive behaviors of BC.Furthermore,by exploring the structure-activity relationships between these compounds and their molecular targets,we shed light on the specific structural features that enable natural compounds to interact with various components of the Hh pathway.These novel insights contribute to advancing the development and clinical application of natural compound-based therapeutics.Our thorough review not only lays the groundwork for exploring innovative BC treatments but also opens new avenues for leveraging natural compounds in cancer therapy.
基金support from various sources,including the National Natural Science Foundation of China(Grant Nos.81570774,82070872,92049118,and 82370854)the Junior Thousand Talents Program of China,and the Nanjing Medical University Startup Fund(All awarded to J.L.)support provided by Jiangsu Province's Innovation Personal as well as Innovative and Entrepreneurial Team of Jiangsu Province(Grant No.JSSCTD2021)(All awarded to J.L.).
文摘V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown.In this study,we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity(DIO)mice.Under normal chow diet feeding,overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight,fat mass,and impaired glucose tolerance.Conversely,Raf1 knockout in AgRP neurons protected against diet-induced obesity,reducing fat mass and improving glucose tolerance.Mechanistically,Raf1 activated the MAPK signaling pathway,culminating in the phosphorylation of cAMP response element-binding protein(CREB),which enhanced transcription of Agrp and Npy.Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis,highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance.Collectively,these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis,positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.
基金funded by the Yancheng Municipal Health Commission 2024 Medical Research Project(YK2024166).
文摘Objective:To investigate the anti-atherosclerosis effect of chikusetsusaponinⅣ(CSⅣ)against high-fat diet-induced atherosclerosis in rats.Methods:A high-fat diet was used for the induction of atherosclerosis in rats,and the rats received oral CSⅣor atorvastatin.The body weight,organ weights,food intake,calorie intake,lipid parameters,3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA)/mevalonate ratio,collagen,free fatty acid,cardiac parameters,apolipoprotein(A and B),antioxidant parameters,inflammatory cytokines,and inflammatory parameters were assessed.The mRNA expressions of interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),IL-6,IL-17,PI3K,AKT,and mTOR were estimated.Results:CSⅣsignificantly modulated food intake,body weight,organ weight(liver,kidney,and heart),and calories(P<0.05).Total cholesterol,triglycerides,very low-density lipoprotein cholesterol,low-density lipoprotein cholesterol,cardiovascular risk index-1,and cardiovascular risk index-2 were decreased,while high-density lipoprotein cholesterol and anti-atherogenic index were increased significantly in the CSⅣgroup(P<0.05).Besides,CSⅣsignificantly restored the level of HMG-CoA/mevalonate ratio,collagen,free fatty acid,cardiac parameters(creatinine kinase-MB,lactate dehydrogenase,cTnT,cTnI),apolipoprotein(apolipoprotein A and apolipoprotein B),antioxidant parameters(MDA,CAT,GPx,GSH,SOD),inflammatory cytokines(TNF-α,IL-1β,IL-6,IL-10),inflammatory parameters(COX-2,TGF-β,NF-κB),intercellular adhesion molecule-1,vascular cell adhesion molecule-1,and monocyte chemoattractant protein-1.CSⅣalso decreased the mRNA expression of IL-1β,TNF-α,IL-6,IL-17,PI3K,AKT,and mTOR.Conclusions:This study showed the anti-atherosclerosis effect of CSⅣagainst high-fat diet-induced atherosclerosis in rats via alteration of NF-κB/COX-2 and PI3K/AKT/mTOR signaling pathway.
基金supported by the National Science Foundation of China(No.82405004,82474253)the Natural Science Foundation postdoctoral project of Chongqing(CSTB2022NSCQ-BHX0709)+2 种基金Chongqing Wanzhou District doctoral“through train”scientific research project(wzstc-20220124)Natural Science Foundation of Chongqing,China(No.Cstc2021jcyj-msxmX0996)Chongqing Wanzhou District Science and Health Joint Medical Research Project(wzstc-kw2023032)。
文摘Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in mitigating intrahepatic cholestasis,the precise mechanisms underlying its therapeutic effects remain inadequately understood.This study aims to comprehensively investigate the pharmacological mechanisms underlying the therapeutic effects of ZZBPD in cholestatic liver injury(CLI).Methods:Firstly,we evaluated the hepatoprotective effects of ZZBPD on mice with CLI induced byα-naphthylisothiocyanate(ANIT),by measuring biochemical markers,inflammatory factors,and bile acid levels.Subsequently,we employed network pharmacology and single-cell RNA sequencing(scRNA-seq)to identify key targets and potential signaling pathways for the prevention and treatment of CLI.Finally,we further validated the mechanism of action of ZZBPD on these key targets through molecular docking,western blotting,and immunofluorescence techniques.Results:ZZBPD notably improved serum liver function,reduced hepatic inflammation,and restored bile acid balance.Through network pharmacology and scRNA-seq analysis,48 core targets were identified,including TNF,IL-6,and NFKB1,all of which are linked to the IL-17 and NF-κB signaling pathways,as shown by KEGG enrichment analysis.Molecular docking further confirmed stable interactions between ZZBPD’s key active components and molecules such as IL-6,IL-17,and NF-κB.Additionally,western blotting and immunofluorescence validated the downregulation of IL-17 and NF-κB protein expression in liver tissue.Conclusion:ZZBPD effectively treats CLI by activating pathways related to the bile acid receptor FXR,while also modulating the IL-17/NF-κB signaling pathway.This dual action enhances bile secretion and alleviates liver inflammation.These findings offer important insights into the pharmacological mechanisms of ZZBPD and underscore its potential as a promising therapeutic for CLI.
