Diagnosis and treatment of biliary mucinous cystic neoplasms: A single-center experience

Background: Biliary mucinous cystic neoplasms(BMCNs) are rare hepatobiliary cystic tumors, which can be divided into noninvasive and invasive types. This study aimed to investigate the diagnosis, treatment, and prognosis of BMCNs in a large single center. Methods: We analyzed 49 patients with BMCNs confirmed by postoperative pathology at the First Afflliated Hospital, Zhejiang University School of Medicine between January 2007 and December 2021. Results: Among the 49 patients, 37 were female(75.5%), and the average age was 57.04 years. Common symptoms included abdominal discomfort, jaundice and fever, while 22 patients(44.9%) had no symptoms. Serum carbohydrate antigen(CA) 19-9 and CA125 concentrations were elevated in 34.8% and 19.6% of patients, respectively. Forty-eight patients had tumors in the intrahepatic bile ducts and only one had a tumor in the extrahepatic bile duct. Forty-eight patients with noninvasive intrahepatic BMCNs were further analyzed in terms of pathological features: 34(70.8%) had low-grade intraepithelial neoplasms(LGINs), and 14(29.2%) had high-grade intraepithelial neoplasms(HGINs). The potential immunohistochemical markers of BMCNs were cytokeratin(CK) 19, CK7, estrogen receptor and progesterone receptor. Follow-up data for 37 patients with intrahepatic BMCNs were obtained. The median overall survival(OS) of BMCNs was not reached. The longest survival time was 137 months.The 5-and 10-year OS rates were 100% and 85.4%, respectively. The 5-and 10-year recurrence-free survival(RFS) rates were 93.9% and 80.2%, respectively. Conclusions: BMCNs are rare cystic neoplasms that commonly occur in middle-aged females. BMCNs can only be diagnosed and classified by postoperative pathology, as there are no specific clinical presentations, serological indicators or imaging modalities for preoperative diagnosis. Complete surgical resection is necessary for BMCNs, and the postoperative prognosis is favorable.

Current considerations on intraductal papillary neoplasms of the bile duct and pancreatic duct

Pancreatobiliary intraductal papillary neoplasms(IPNs)represent precursors of pancreatic cancer or bile duct cholangiocarcinoma that can be detected and treated.Despite advances in diagnostic methods,identifying these premalignant lesions is still challenging for treatment providers.Modern imaging,biomarkers and molecular tests for genomic alterations can be used for diagnosis and follow-up.Surgical intervention in combination with new chemotherapeutic agents is considered the optimal treatment for malignant cases.The balance between the risk of malignancy and any risk of resection guides management policy;therefore,treatment should be individualized based on a meticulous preoperative assessment of high-risk stigmata.IPN of the bile duct is more aggressive;thus,early diagnosis and surgery are crucial.The conservative management of low-risk pancreatic branch-duct lesions is safe and effective.

Experimental study on effect of recombinant human growth hormone combined with chemotherapy on stomach neoplasms implanted in nude mice

Objective: To investigate the effect of different doses of recombined growth hormone (rhGH) on stomach neo- plasms implanted in nude mice, and its efficacy in combining with chemotherapy (flurouracil, 5-FU). Methods: Human stom- ach neoplasms model was established in nude mice. The nude mice were divided into control group, moderate-dose of rhGH group, low-dose rhGH group, 5-FU group, moderate-dose rhGH/5-FU group, and low-dose rhGH/5-FU group. The results of each group were observed after ten days. Results: After therapy, the body mass of rhGH groups was significantly increased compared with control group (P<0.05), the body mass of rhGH/5-FU groups was significantly increased compared with 5-FU group (P<0.05), but it was no significant difference between rhGH/5-FU groups and control group (P>0.05). The average tumor mass and volume of rhGH groups were not significantly increased compared with control group (P>0.05), but they were significantly reduced in 5-FU group and rhGH/5-FU groups (P<0.05). They were no significant difference between rhGH/5- FU groups and 5-FU group (P>0.05). After treatment, the percentages of S, G0/G1 and G2/M phases and proliferation index (PI) were not significantly changed in rhGH groups compared with control group (P>0.05), and the same with rhGH/5-FU groups compared with 5-FU group (P>0.05). The difference caused by dose of rhGH was not significant. Conclusion: rhGH enhances body mass, does not stimulate tumor growth, and has no adverse effects on tumor bearing nude mice. Combined with flurouracil, rhGH does not influence the efficacy of chemotherapy, and has no effect on tumor cell cycle kinetics.

Endoscopic ultrasonography-related diagnostic accuracy and clinical significance on small rectal neuroendocrine neoplasms

This research aimed to examine the diagnostic accuracy and clinical significance of endoscopic ultrasonography(EUS)in the context of small rectal neuroendocrine neoplasms(NENs).A total of 108 patients with rectal subepithelial lesions(SELs)with a diameter of<20 mm were included in the analysis.The diagnosis and depth assessment of EUS was compared to the histology findings.The prevalence of NENs in rectal SELs was 78.7%(85/108).The sensitivity of EUS in detecting rectal NENs was 98.9%(84/85),while the specificity was 52.2%(12/23).Overall,the diagnostic accuracy of EUS in identifying rectal NENs was 88.9%(96/108).The overall accuracy rate for EUS in assessing the depth of invasion in rectal NENs was 92.9%(78/84).Therefore,EUS demonstrates reasonable diagnostic accuracy in detecting small rectal NENs,with good sensitivity but inferior specificity.EUS may also assist physicians in assessing the depth of invasion in small rectal NENs before endoscopic excision.

A Review of Type 1 and Type 2 Intraductal Papillary Neoplasms of the Bile Duct

Intraductal papillary neoplasm of the bile duct(IPNB)is a heterogeneous disease similar to intraductal papillary mucinous neoplasm of the pancreas.These lesions have been recognized as one of the three major precancerous lesions in the biliary tract since 2010.In 2018,Japanese and Korean pathologists reached a consensus,classifying IPNBs into type l and type 2 IPNBs.IPNBs are more prevalent in male patients in East Asia and are closely related to diseases such as cholelithiasis and schistosomiasis.From a molecular genetic perspective,IPNBs exhibit early genetic variations,and different molecular pathways may be involved in the tumorigenesis of type 1 and type 2 IPNBs.The histological subtypes of IPNBs include gastric,intestinal,pancreaticobiliary,or oncocytic subtypes,but type 1 IPNBs typically exhibit more regular and well-organized histological features than type 2 IPNBs and are more commonly found in the intrahepatic bile ducts with abundant mucin.Due to the rarity of these lesions and the absence of specific clinical and laboratory features,imaging is crucial for the preoperative diagnosis of IPNB,with local bile duct dilation and growth along the bile ducts being the main imaging features.Surgical resection remains the optimal treatment for IPNBs,but negative bile duct margins and the removal of lymph nodes in the hepatic hilum significantly improve the postoperative survival rates for patients with IPNBs.

Experimental investigation on the permeability of gap-graded soil due to horizontal suffusion considering boundary effect

The boundary condition is a crucial factor affecting the permeability variation due to suffusion.An experimental investigation on the permeability of gap-graded soil due to horizontal suffusion considering the boundary effect is conducted,where the hydraulic head difference(DH)varies,and the boundary includes non-loss and soil-loss conditions.Soil samples are filled into seven soil storerooms connected in turn.After evaluation,the variation in content of fine sand(ΔR_(f))and the hydraulic conductivity of soils in each storeroom(C_(i))are analyzed.In the non-loss test,the soil sample filling area is divided into runoff,transited,and accumulated areas according to the negative or positive ΔR_(f) values.ΔR_(f) increases from negative to positive along the seepage path,and Ci decreases from runoff area to transited area and then rebounds in accumulated area.In the soil-loss test,all soil sample filling areas belong to the runoff area,where the gentle-loss,strengthened-loss,and alleviated-loss parts are further divided.ΔR_(f) decreases from the gentle-loss part to the strengthened-loss part and then rebounds in the alleviated-loss part,and C_(i) increases and then decreases along the seepage path.The relationship between ΔR_(f) and Ci is different with the boundary condition.Ci exponentially decreases with ΔR_(f) in the non-loss test and increases with ΔR_(f) generally in the soil-loss test.

Fasudil-modified macrophages reduce inflammation and regulate the immune response in experimental autoimmune encephalomyelitis

Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system.Macrophage polarization plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis,a traditional experimental model of multiple sclerosis.This study investigated the effect of Fasudil on macrophages and examined the therapeutic potential of Fasudil-modified macrophages in experimental autoimmune encephalomyelitis.We found that Fasudil induced the conversion of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type,as shown by reduced expression of inducible nitric oxide synthase/nitric oxide,interleukin-12,and CD16/32 and increased expression of arginase-1,interleukin-10,CD14,and CD206,which was linked to inhibition of Rho kinase activity,decreased expression of toll-like receptors,nuclear factor-κB,and components of the mitogen-activated protein kinase signaling pathway,and generation of the pro-inflammatory cytokines tumor necrosis factor-α,interleukin-1β,and interleukin-6.Crucially,Fasudil-modified macrophages effectively decreased the impact of experimental autoimmune encephalomyelitis,resulting in later onset of disease,lower symptom scores,less weight loss,and reduced demyelination compared with unmodified macrophages.In addition,Fasudil-modified macrophages decreased interleukin-17 expression on CD4^(+)T cells and CD16/32,inducible nitric oxide synthase,and interleukin-12 expression on F4/80^(+)macrophages,as well as increasing interleukin-10 expression on CD4^(+)T cells and arginase-1,CD206,and interleukin-10 expression on F4/80^(+)macrophages,which improved immune regulation and reduced inflammation.These findings suggest that Fasudil-modified macrophages may help treat experimental autoimmune encephalomyelitis by inducing M2 macrophage polarization and inhibiting the inflammatory response,thereby providing new insight into cell immunotherapy for multiple sclerosis.

Aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders:progress of experimental models based on disease pathogenesis

Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism remains unknown.Therefore,experimental models of neuromyelitis optica spectrum disorders are essential for exploring its pathogenesis and in screening for therapeutic targets.Since most patients with neuromyelitis optica spectrum disorders are seropositive for IgG autoantibodies against aquaporin-4,which is highly expressed on the membrane of astrocyte endfeet,most current experimental models are based on aquaporin-4-IgG that initially targets astrocytes.These experimental models have successfully simulated many pathological features of neuromyelitis optica spectrum disorders,such as aquaporin-4 loss,astrocytopathy,granulocyte and macrophage infiltration,complement activation,demyelination,and neuronal loss;however,they do not fully capture the pathological process of human neuromyelitis optica spectrum disorders.In this review,we summarize the currently known pathogenic mechanisms and the development of associated experimental models in vitro,ex vivo,and in vivo for neuromyelitis optica spectrum disorders,suggest potential pathogenic mechanisms for further investigation,and provide guidance on experimental model choices.In addition,this review summarizes the latest information on pathologies and therapies for neuromyelitis optica spectrum disorders based on experimental models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders,offering further therapeutic targets and a theoretical basis for clinical trials.

Recent progresses in the development of tubular segmented-in-series solid oxide fuel cells:Experimental and numerical study

Solid oxide fuel cells(SOFCs)have attracted a great deal of interest because they have the highest efficiency without using any noble metal as catalysts among all the fuel cell technologies.However,traditional SOFCs suffer from having a higher volume,current leakage,complex connections,and difficulty in gas sealing.To solve these problems,Rolls-Royce has fabricated a simple design by stacking cells in series on an insulating porous support,resulting in the tubular segmented-in-series solid oxide fuel cells(SIS-SOFCs),which achieved higher output voltage.This work systematically reviews recent advances in the structures,preparation methods,perform-ances,and stability of tubular SIS-SOFCs in experimental and numerical studies.Finally,the challenges and future development of tubular SIS-SOFCs are also discussed.The findings of this work can help guide the direction and inspire innovation of future development in this field.

Experimental investigation on coal pore-fracture variation and fractal characteristics synergistically affected by solvents for improving clean gas extraction

Chemical solvents instead of pure water being as hydraulic fracturing fluid could effectively increase permeability and improve clean methane extraction efficiency.However,pore-fracture variation features of lean coal synergistically affected by solvents have not been fully understood.Ultrasonic testing,nuclear magnetic resonance analysis,liquid phase mass spectrometry was adopted to comprehensively analyze pore-fracture change characteristics of lean coal treated by combined solvent(NMP and CS_(2)).Meanwhile,quantitative characterization of above changing properties was conducted using geometric fractal theory.Relationship model between permeability,fractal dimension and porosity were established.Results indicate that the end face fractures of coal are well developed after CS2and combined solvent treatments,of which,end face box-counting fractal dimensions range from 1.1227 to 1.4767.Maximum decreases in ultrasonic longitudinal wave velocity of coal affected by NMP,CS_(2)and combined solvent are 2.700%,20.521%,22.454%,respectively.Solvent treatments could lead to increasing amount of both mesopores and macropores.Decrease ratio of fractal dimension Dsis 0.259%–2.159%,while permeability increases ratio of NMR ranges from 0.1904 to 6.4486.Meanwhile,combined solvent could dissolve coal polar and non-polar small molecules and expand flow space.Results could provide reference for solvent selection and parameter optimization of permeability-enhancement technology.

An internal ballistic model of electromagnetic railgun based on PFN coupled with multi-physical field and experimental validation

To accelerate the practicality of electromagnetic railguns,it is necessary to use a combination of threedimensional numerical simulation and experiments to study the mechanism of bore damage.In this paper,a three-dimensional numerical model of the augmented railgun with four parallel unconventional rails is introduced to simulate the internal ballistic process and realize the multi-physics field coupling calculation of the rail gun,and a test experiment of a medium-caliber electromagnetic launcher powered by pulse formation network(PFN)is carried out.Various test methods such as spectrometer,fiber grating and high-speed camera are used to test several parameters such as muzzle initial velocity,transient magnetic field strength and stress-strain of rail.Combining the simulation results and experimental data,the damage condition of the contact surface is analyzed.

Experimental Analysis of Radial Centrifugal Pump Shutdown

Centrifugal pumps are widely used in the metallurgy,coal,and building sectors.In order to study the hydraulic characteristics of a closed impeller centrifugal pump during its shutdown in the so-called power frequency and frequency conversion modes,experiments were carried to determine the characteristic evolution of parameters such as speed,inlet and outlet pressure,head,flow rate and shaft power.A quasi-steady-state method was also used to further investigate these transient behaviors.The results show that,compared to the power frequency input,the performance parameter curves for the frequency conversion input are less volatile and smoother.The characteristic time is longer and the response to shutdown is slower.The quasi-steady-state theoretical head-flow curves match the experimental head-flow curves more closely at low flow rates when the frequency conversion input is considered.Moreover,in this case,the similarity law predicts the hydraulic performance more accurately.

Trends and hotspots in gastrointestinal neoplasms risk assessment: A bibliometric analysis from 1984 to 2022

BACKGROUND Gastrointestinal neoplasm(GN)significantly impact the global cancer burden and mortality,necessitating early detection and treatment.Understanding the evolution and current state of research in this field is vital.AIM To conducts a comprehensive bibliometric analysis of publications from 1984 to 2022 to elucidate the trends and hotspots in the GN risk assessment research,focusing on key contributors,institutions,and thematic evolution.METHODS This study conducted a bibliometric analysis of data from the Web of Science Core Collection database using the"bibliometrix"R package,VOSviewer,and CiteSpace.The analysis focused on the distribution of publications,contributions by institutions and countries,and trends in keywords.The methods included data synthesis,network analysis,and visualization of international collaboration networks.RESULTS This analysis of 1371 articles on GN risk assessment revealed a notable evolution in terms of research focus and collaboration.It highlights the United States'critical role in advancing this field,with significant contributions from institutions such as Brigham and Women's Hospital and the National Cancer Institute.The last five years,substantial advancements have been made,representing nearly 45%of the examined literature.Publication rates have dramatically increased,from 20 articles in 2002 to 112 in 2022,reflecting intensified research efforts.This study underscores a growing trend toward interdisciplinary and international collaboration,with the Journal of Clinical Oncology standing out as a key publication outlet.This shift toward more comprehensive and collaborative research methods marks a significant step in addressing GN risks.CONCLUSION This study underscores advancements in GN risk assessment through genetic analyses and machine learning and reveals significant geographical disparities in research emphasis.This calls for enhanced global collaboration and integration of artificial intelligence to improve cancer prevention and treatment accuracy,ultimately enhancing worldwide patient care.

Adaptive Robust Servo Control for Vertical Electric Stabilization System of Tank and Experimental Validation

A tracking stability control problem for the vertical electric stabilization system of moving tank based on adaptive robust servo control is addressed.This paper mainly focuses on two types of possibly fast timevarying but bounded uncertainty within the vertical electric stabilization system:model parameter uncertainty and uncertain nonlinearity.First,the vertical electric stabilization system is constructed as an uncertain nonlinear dynamic system that can reflect the practical mechanics transfer process of the system.Second,the dynamical equation in the form of state space is established by designing the angular tracking error.Third,the comprehensive parameter of system uncertainty is designed to estimate the most conservative effects of uncertainty.Finally,an adaptive robust servo control which can effectively handle the combined effects of complex nonlinearity and uncertainty is proposed.The feasibility of the proposed control strategy under the practical physical condition is validated through the tests on the experimental platform.This paper pioneers the introduction of the internal nonlinearity and uncertainty of the vertical electric stabilization system into the settlement of the tracking stability control problem,and validates the advanced servo control strategy through experiment for the first time.

Optimization of Center of Gravity Position and Anti-Wave Plate Angle of Amphibious Unmanned Vehicle Based on Orthogonal Experimental Method

When the amphibious vehicle navigates in water,the angle of the anti-wave plate and the position of the center of gravity greatly influence the navigation characteristics.In the relevant research on reducing the navigation resistance of amphibious vehicles by adjusting the angle of the anti-wave plate,there is a lack of scientific selection of parameters and reasonable research of simulation results by using mathematical methods,and the influence of the center of gravity position on navigation characteristics is not considered at the same time.To study the influence of the combinations of the angle of the anti-wave plate and the position of the center of gravity on the resistance reduction characteristics,a numerical calculation model of the amphibious unmanned vehicle was established by using the theory of computational fluid dynamics,and the experimental data verified the correctness of the numerical model.Based on this numerical model,the navigation characteristics of the amphibious unmanned vehicle were studied when the center of gravity was located at different positions,and the orthogonal experimental design method was used to optimize the parameters of the angle of the anti-wave plate and the position of the center of gravity.The results show that through the parameter optimization analysis based on the orthogonal experimental method,the combination of the optimal angle of the anti-wave plate and the position of the center of gravity is obtained.And the numerical simulation result of resistance is consistent with the predicted optimal solution.Compared with the maximum navigational resistance,the parameter optimization reduces the navigational resistance of the amphibious unmanned vehicle by 24%.

Mixed neuroendocrine non-neuroendocrine neoplasms in gastroenteropancreatic tract

Mixed neuroendocrine non-neuroendocrine neoplasms(MiNENs)are a hetero-geneous group of malignant neoplasms that can settle in the gastroenteropan-creatic tract.They are composed of a neuroendocrine(NE)and a non-NE compo-nent in at least 30%of each tumour.The non-NE component can include different histological combinations of glandular,squamous,mucinous and sarcomatoid phenotypes,and one or both of the components can be low-or high grade malignant.Recent changes in the nomenclature of these neoplasms might lead to great deal of confusion,and the lack of specific clinical trials is the main reason why their management is difficult.The review aims to clarify the definition of MiNEN and analyze available evidence about their diagnosis and treatment options according to their location and extension through careful analysis of the available data.It would be important to reach a general consensus on their diagnosis in order to construct a classification that remains stable over time and facilitates the design of clinical trials that,due to their low incidence,will require long recruitment periods.

Comparative transcriptomic analysis reveals the molecular changes of acute pancreatitis in experimental models

BACKGROUND Acute pancreatitis(AP)encompasses a spectrum of pancreatic inflammatory conditions,ranging from mild inflammation to severe pancreatic necrosis and multisystem organ failure.Given the challenges associated with obtaining human pancreatic samples,research on AP predominantly relies on animal models.In this study,we aimed to elucidate the fundamental molecular mechanisms underlying AP using various AP models.AIM To investigate the shared molecular changes underlying the development of AP across varying severity levels.METHODS AP was induced in animal models through treatment with caerulein alone or in combination with lipopolysaccharide(LPS).Additionally,using Ptf1αto drive the specific expression of the hM3 promoter in pancreatic acinar cells transgenic C57BL/6J-hM3/Ptf1α(cre)mice were administered Clozapine N-oxide to induce AP.Subsequently,we conducted RNA sequencing of pancreatic tissues and validated the expression of significantly different genes using the Gene Expression Omnibus(GEO)database.RESULTS Caerulein-induced AP showed severe inflammation and edema,which were exacerbated when combined with LPS and accompanied by partial pancreatic tissue necrosis.Compared with the control group,RNA sequencing analysis revealed 880 significantly differentially expressed genes in the caerulein model and 885 in the caerulein combined with the LPS model.Kyoto Encyclopedia of Genes and Genomes enrichment analysis and Gene Set Enrichment Analysis indicated substantial enrichment of the TLR and NOD-like receptor signaling pathway,TLR signaling pathway,and NF-κB signaling pathway,alongside elevated levels of apoptosis-related pathways,such as apoptosis,P53 pathway,and phagosome pathway.The significantly elevated genes in the TLR and NOD-like receptor signaling pathways,as well as in the apoptosis pathway,were validated through quantitative real-time PCR experiments in animal models.Validation from the GEO database revealed that only MYD88 concurred in both mouse pancreatic tissue and human AP peripheral blood,while TLR1,TLR7,RIPK3,and OAS2 genes exhibited marked elevation in human AP.The genes TUBA1A and GADD45A played significant roles in apoptosis within human AP.The transgenic mouse model hM3/Ptf1α(cre)successfully validated significant differential genes in the TLR and NOD-like receptor signaling pathways as well as the apoptosis pathway,indicating that these pathways represent shared pathological processes in AP across different models.CONCLUSION The TLR and NOD receptor signaling pathways play crucial roles in the inflammatory progression of AP,notably the MYD88 gene.Apoptosis holds a central position in the necrotic processes of AP,with TUBA1A and GADD45A genes exhibiting prominence in human AP.

Auto-parametric resonance of a continuous-beam-bridge model under two-point periodic excitation:an experimental investigation and stability analysis

The auto-parametric resonance of a continuous-beam bridge model subjected to a two-point periodic excitation is experimentally and numerically investigated in this study.An auto-parametric resonance experiment of the test model is conducted to observe and measure the auto-parametric resonance of a continuous beam under a two-point excitation on columns.The parametric vibration equation is established for the test model using the finite-element method.The auto-parametric resonance stability of the structure is analyzed by using Newmark's method and the energy-growth exponent method.The effects of the phase difference of the two-point excitation on the stability boundaries of auto-parametric resonance are studied for the test model.Compared with the experiment,the numerical instability predictions of auto-parametric resonance are consistent with the test phenomena,and the numerical stability boundaries of auto-parametric resonance agree with the experimental ones.For a continuous beam bridge,when the ratio of multipoint excitation frequency(applied to the columns)to natural frequency of the continuous girder is approximately equal to 2,the continuous beam may undergo a strong auto-parametric resonance.Combined with the present experiment and analysis,a hypothesis of Volgograd Bridge's serpentine vibration is discussed.

Efficacy of Juanbi capsule on ameliorating knee osteoarthritis:a network pharmacology and experimental verification-based study

Background:The purpose of the study was to investigate the active ingredients and potential biochemical mechanisms of Juanbi capsule in knee osteoarthritis based on network pharmacology,molecular docking and animal experiments.Methods:Chemical components for each drug in the Juanbi capsule were obtained from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,while the target proteins for knee osteoarthritis were retrieved from the Drugbank,GeneCards,and OMIM databases.The study compared information on knee osteoarthritis and the targets of drugs to identify common elements.The data was imported into the STRING platform to generate a protein-protein interaction network diagram.Subsequently,a“component-target”network diagram was created using the screened drug components and target information with Cytoscape software.Common targets were imported into Metascape for GO function and KEGG pathway enrichment analysis.AutoDockTools was utilized to predict the molecular docking of the primary chemical components and core targets.Ultimately,the key targets were validated through animal experiments.Results:Juanbi capsule ameliorated Knee osteoarthritis mainly by affecting tumor necrosis factor,interleukin1β,MMP9,PTGS2,VEGFA,TP53,and other cytokines through quercetin,kaempferol,andβ-sitosterol.The drug also influenced the AGE-RAGE,interleukin-17,tumor necrosis factor,Relaxin,and NF-κB signaling pathways.The network pharmacology analysis results were further validated in animal experiments.The results indicated that Juanbi capsule could decrease the levels of tumor necrosis factor-αand interleukin-1βin the serum and synovial fluid of knee osteoarthritis rats and also down-regulate the expression levels of MMP9 and PTGS2 proteins in the articular cartilage.Conclusion:Juanbi capsule may improve the knee bone microstructure and reduce the expression of inflammatory factors of knee osteoarthritis via multiple targets and multiple signaling pathways.

Potential application of Nardostachyos Radix et Rhizoma-Rhubarb for the treatment of diabetic kidney disease based on network pharmacology and cell culture experimental verification

BACKGROUND Diabetic kidney disease(DKD)is one of the serious complications of diabetes mellitus,and the existing treatments cannot meet the needs of today's patients.Traditional Chinese medicine has been validated for its efficacy in DKD after many years of clinical application.However,the specific mechanism by which it works is still unclear.Elucidating the molecular mechanism of the Nardostachyos Radix et Rhizoma-rhubarb drug pair(NRDP)for the treatment of DKD will provide a new way of thinking for the research and development of new drugs.AIM To investigate the mechanism of the NRDP in DKD by network pharmacology combined with molecular docking,and then verify the initial findings by in vitro experiments.METHODS The Traditional Chinese Medicine Systems Pharmacology(TCMSP)database was used to screen active ingredient targets of NRDP.Targets for DKD were obtained based on the Genecards,OMIM,and TTD databases.The VENNY 2.1 database was used to obtain DKD and NRDP intersection targets and their Venn diagram,and Cytoscape 3.9.0 was used to build a"drug-component-target-disease"network.The String database was used to construct protein interaction networks.Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis and Gene Ontology analysis were performed based on the DAVID database.After selecting the targets and the active ingredients,Autodock software was used to perform molecular docking.In experimental validation using renal tubular epithelial cells(TCMK-1),we used the Cell Counting Kit-8 assay to detect the effect of NRDP on cell viability,with glucose solution used to mimic a hyperglycemic environment.Flow cytometry was used to detect the cell cycle progression and apoptosis.Western blot was used to detect the protein expression of STAT3,p-STAT3,BAX,BCL-2,Caspase9,and Caspase3.RESULTS A total of 10 active ingredients and 85 targets with 111 disease-related signaling pathways were obtained for NRDP.Enrichment analysis of KEGG pathways was performed to determine advanced glycation end products(AGEs)-receptor for AGEs(RAGE)signaling as the core pathway.Molecular docking showed good binding between each active ingredient and its core targets.In vitro experiments showed that NRDP inhibited the viability of TCMK-1 cells,blocked cell cycle progression in the G0/G1 phase,and reduced apoptosis in a concentrationdependent manner.Based on the results of Western blot analysis,NRDP differentially downregulated p-STAT3,BAX,Caspase3,and Caspase9 protein levels(P<0.01 or P<0.05).In addition,BAX/BCL-2 and p-STAT3/STAT3 ratios were reduced,while BCL-2 and STAT3 protein expression was upregulated(P<0.01).CONCLUSION NRDP may upregulate BCL-2 and STAT3 protein expression,and downregulate BAX,Caspase3,and Caspase9 protein expression,thus activating the AGE-RAGE signaling pathway,inhibiting the vitality of TCMK-1 cells,reducing their apoptosis.and arresting them in the G0/G1 phase to protect them from damage by high glucose.