查看更多>>摘要：Glaucoma,an irreversible optic neuropathy,primarily affects retinal ganglion cells (RGC) and causes vision loss and blindness.The damage to RGCs in glaucoma oc-curs by various mechanisms,including elevated intraocular pressure,oxidative stress,inflammation,and other neurodegenerative processes.As the disease progresses,the loss of RGCs leads to vision loss.Therefore,protecting RGCs from damage and promoting their survival are important goals in managing glaucoma.In this regard,resveratrol (RES),a polyphenolic phytoalexin,exerts antioxidant effects and slows down the evolution and progression of glaucoma.The present review shows that RES plays a protective role in RGCs in cases of ischemic injury and hypoxia as well as in ErbB2 protein expression in the retina.Additionally,RES plays protective roles in RGCs by promoting cell growth,reducing apoptosis,and decreasing oxidative stress in H2O2 -exposed RGCs.RES was also found to inhibit oxidative stress damage in RGCs and suppress the activation of mitogen-activated protein kinase signaling pathways.RES could alleviate retinal function impairment by suppressing the hypoxia-inducible factor-1 alpha/vascular endothelial growth factor and p38/p53 axes while stimulating the PI3K/Akt pathway.Therefore,RES might exert potential therapeutic effects for managing glaucoma by protecting RGCs from damage and promoting their survival.
查看更多>>摘要：Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of vari-ous complications.The deep learning-based efficacy prediction system (DLEPS) is a forecasting tool that can effectively compete in drug screening and prediction based on gene expression changes.This study aimed to explore the protective effect and potential mechanisms of cinobufotalin (CB),a traditional Chinese medicine (TCM),on bone loss.Methods:DLEPS was employed for screening anti-osteoporotic agents according to gene profile changes in primary osteoporosis.Micro-CT,histological and morphologi-cal analysis were applied for the bone protective detection of CB,and the osteogenic differentiation/function in human bone marrow mesenchymal stem cells (hBMMSCs) were also investigated.The underlying mechanism was verified using qRT-PCR,Western blot (WB),immunofluorescence (IF),etc.Results:A safe concentration (0.25 mg/kg in vivo,0.05 μ M in vitro) of CB could ef-fectively preserve bone mass in estrogen deficiency-induced bone loss and promote osteogenic differentiation/function of hBMMSCs.Both BMPs/SMAD and Wnt/β-catenin signaling pathways participated in CB-induced osteogenic differentiation,further regulating the expression of osteogenesis-associated factors,and ultimately promoting osteogenesis.Conclusion:Our study demonstrated that CB could significantly reverse estro-gen deficiency-induced bone loss,further promoting osteogenic differentiation/function of hBMMSCs,with BMPs/SMAD and Wnt/β-catenin signaling pathways involved.
查看更多>>摘要：Background:Jiaohong pills (JHP) consist of Pericarpium Zanthoxyli (PZ) and Radix Rehmanniae ,two herbs that have been extensively investigated over many years due to their potential protective effects against cognitive decline and memory im-pairment.However,the precise mechanisms underlying the beneficial effects remain elusive.Here,research studies were conducted to investigate and validate the thera-peutic effects of JHP on Alzheimer's disease.Methods:BV-2 cell inflammation was induced by lipopolysaccharide.AD mice were administered amyloid-β (Aβ).Behavioral experiments were used to evaluate learn-ing and memory ability.The levels of nitric oxide (NO),tumor necrosis factor-alpha (TNF-α),interleukin-1β (IL-1β),and interleukin-10 (IL-10) were detected using enzyme-linked immunosorbent assay (ELISA).The protein expressions of inducible nitric oxide synthase (iNOS) and the phosphorylation level of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) were detected using Western blot.Nissl staining was used to detect neuronal degeneration.Results:The results demonstrated that an alcoholic extract of PZ significantly de-creased the levels of NO,IL-1β,TNF-α,and iNOS; increased the expression level of IL-10; and significantly decreased the phosphorylation levels of MAPK and NF-κB.These inhibitory effects were further confirmed in the AD mouse model.Meanwhile,JHP improved learning and memory function in AD mice,reduced neuronal damage,and enriched the Nissl bodies in the hippocampus.Moreover,IL-1β and TNF-α in the cortex were significantly downregulated after JHP administration,whereas IL-10 showed increased expression.Conclusions:It was found that JHP reduced neuroinflammatory response in AD mice by targeting the MAPK/NF-κB signaling pathway.
查看更多>>摘要：Background:According to traditional Chinese medicine (TCM),drugs supplementing the vital energy,Qi,can eliminate tumors by restoring host immunity.The objective of this study is to investigate the underlying immune mechanisms of anti-tumor activity associated with Qi-supplementing herbs,specifically the paired use of Huangqi and Danggui.Methods:Analysis of compatibility regularity was conducted to screen the combina-tion of Qi-supplementing TCMs.Using the MTT assay and a transplanted tumor mice model,the anti-tumor effects of combination TCMs were investigated in vitro and in vivo.High content analysis and flow cytometry were then used to evaluate cel-lular immunity,followed by network pharmacology and molecular docking to dissect the significant active compounds and potential mechanisms.Finally,the anti-tumor activity and the mechanism of the active ingredients were verified by molecular experiments.Results:There is an optimal combination of Huangqi and Danggui that,administered as an aqueous extract,can activate immunity to suppress tumor and is more effec-tive than each drug on its own in vitro and in vivo.Based on network pharmacology analysis,PIK3R1 is the core target for the anti-tumor immunity activity of combined Huangqi and Danggui.Molecular docking analysis shows 6 components of the com-bined Danggui and Huangqi extract (quercetin,jaranol,isorhamnetin,kaempferol,calycosin,and suchilactone) that bind to PIK3R1.Jaranol is the most important com-ponent against breast cancer.The suchilactone/jaranol combination and,especially,the suchilactone/kaempferol combination are key for immunity enhancement and the anti-tumor effects of the extract.Conclusions:The combination of Huangqi and Danggui can activate immunity to sup-press breast cancer and is more effective than the individual drugs alone.
查看更多>>摘要：Background:YangshenDingzhi granules (YSDZ) are clinically effective in preventing and treating COVID-19.The present study elucidates the underlying mechanism of YSDZ intervention in viral pneumonia by employing serum pharmacochemistry and network pharmacology.Methods:The chemical constituents of YSDZ in the blood were examined using ultra-performance liquid chromatography-quadrupole/orbitrap high-resolution mass spec-trometry (UPLC-Q-Exactive Orbitrap MS).Potential protein targets were obtained from the SwissTargetPrediction database,and the target genes associated with viral pneumonia were identified using GeneCards,DisGeNET,and Online Mendelian Inheritance in Man (OMIM) databases.The intersection of blood component-related targets and disease-related targets was determined using Venny 2.1.Protein-protein interaction networks were constructed using the STRING database.The Metascape database was employed to perform enrichment analyses of Gene Ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling path-ways for the targets,while the Cytoscape 3.9.1 software was utilized to construct drug-component-disease-target-pathway networks.Further,in vitro and in vivo ex-periments were performed to establish the therapeutic effectiveness of YSDZ against viral pneumonia.Results:Fifteen compounds and 124 targets linked to viral pneumonia were detected in serum.Among these,MAPK1,MAPK3,AKT1,EGFR,and TNF play significant roles.In vitro tests revealed that the medicated serum suppressed the replication of H1N1,RSV,and SARS-CoV-2 replicon.Further,in vivo testing analysis shows that YSDZ de-creases the viral load in the lungs of mice infected with RSV and H1N1.Conclusion:The chemical constituents of YSDZ in the blood may elicit therapeutic effects against viral pneumonia by targeting multiple proteins and pathways.
查看更多>>摘要：Background:Around the world,there is a high incidence of gastric ulcers.YS,an extract from the Chinese herb Albizzia chinensis (Osbeck) Merr,has potential thera-peutic applications for gastrointestinal diseases.Here we elucidated the protective effect and underlying mechanism of action of YS on gastric ulcer in rats injured by ethanol.Methods:The ethanol-induced gastric ulcer rat model was used to assess the pro-tective effect of YS.A pathological examination of gastric tissue was performed by H&E staining.GES-1 cells damaged by hydrogen peroxide were used to simu-late oxidative damage in gastric mucosal epithelial cells.Endogenous NRF2 was knocked down using small interfering RNA.Immunoprecipitation was used to detect ubiquitination of NRF2.Co-immunoprecipitation was used to detect the NRF2-Keap1 interaction.Results:YS (10 and 30 mg/kg,i.g.) significantly reduced the ulcer index,decreased MDA level,and increased SOD and GSH levels in gastric tissues damaged by ethanol.YS promoted NRF2 translocation from cytoplasm to nucleus and enhanced the NQO1 and HO-1 expression levels in injured rat gastric tissue.In addition,YS regulated NQO1 and HO-1 via NRF2 in H2O2 -induced oxidative injured GES-1 cells.Further studies on the underlying mechanism indicated that YS reduced the interaction between NRF2 and Keap1 and decreased ubiquitylation of NRF2,thereby increasing its stability and expression of downstream factors.NRF2 knockdown abolished the effect of YS on MDA and SOD in GES-1 cells treated with H2O2.Conclusion:YS reduced the NRF2-Keap1 interaction,promoting NRF2 transloca-tion into the nucleus,which increasing the transcription and translation of NQO1 and HO-1 and improved the antioxidant capacity of rat stomach.
查看更多>>摘要：Use of animal models in preclinical transplant research is essential to the optimization of human allografts for clinical transplantation.Animal models of organ donation and preservation help to advance and improve technical elements of solid organ recovery and facilitate research of ischemia-reperfusion injury,organ preservation strategies,and future donor-based interventions.Important considerations include cost,public opinion regarding the conduct of animal research,translational value,and relevance of the animal model for clinical practice.We present an overview of two porcine mod-els of organ donation: donation following brain death (DBD) and donation following circulatory death (DCD).The cardiovascular anatomy and physiology of pigs closely resembles those of humans,making this species the most appropriate for pre-clinical research.Pigs are also considered a potential source of organs for human heart and kidney xenotransplantation.It is imperative to minimize animal loss during procedures that are surgically complex.We present our experience with these models and de-scribe in detail the use cases,procedural approach,challenges,alternatives,and limi-tations of each model.
查看更多>>摘要：Diabetes mellitus is one of the world's most prevalent and complex metabolic disorders,and it is a rapidly growing global public health issue.It is characterized by hyperglyce-mia,a condition involving a high blood glucose level brought on by deficiencies in insulin secretion,decreased activity of insulin,or both.Prolonged effects of diabetes include cardiovascular problems,retinopathy,neuropathy,nephropathy,and vascular altera-tions in both macro-and micro-blood vessels.In vivo and in vitro models have always been important for investigating and characterizing disease pathogenesis,identifying targets,and reviewing novel treatment options and medications.Fully understanding these models is crucial for the researchers so this review summarizes the different ex-perimental in vivo and in vitro model options used to study diabetes and its conse-quences.The most popular in vivo studies involves the small animal models,such as rodent models,chemically induced diabetogens like streptozotocin and alloxan,and the possibility of deleting or overexpressing a specific gene by knockout and transgenic technologies on these animals.Other models include virally induced models,diet/nutri-tion induced diabetic animals,surgically induced models or pancreatectomy models,and non-obese models.Large animals or non-rodent models like porcine (pig),canine (dog),nonhuman primate,and Zebrafish models are also outlined.The in vitro models discussed are murine and human beta-cell lines and pancreatic islets,human stem cells,and organoid cultures.The other enzymatic in vitro tests to assess diabetes include assay of amylase inhibition and inhibition of α-glucosidase activity.
查看更多>>摘要：Background:Circular RNAs (circRNAs) have been recognized as significant regulators of pulmonary hypertension (PH); however,the differential expression and function of circRNAs in different vascular cells under hypoxia remain unknown.Here,we identi-fied co-differentially expressed circRNAs and determined their putative roles in the proliferation of pulmonary artery smooth muscle cells (PASMCs),pulmonary micro-vascular endothelial cells (PMECs),and pericytes (PCs) under hypoxia.Methods:Whole transcriptome sequencing was performed to analyze the differential expression of circRNAs in three different vascular cell types.Bioinformatic analysis was used to predict their putative biological function.Quantitative real-time polymer-ase chain reaction,Cell Counting Kit-8,and EdU Cell Proliferation assays were carried out to determine the role of circular postmeiotic segregation 1 (circPMS1) as well as its potential sponge mechanism in PASMCs,PMECs,and PCs.Results:PASMCs,PMECs,and PCs exhibited 16,99,and 31 differentially expressed circRNAs under hypoxia,respectively.CircPMS1 was upregulated in PASMCs,PMECs,and PCs under hypoxia and enhanced the proliferation of vascular cells.CircPMS1 may upregulate DEP domain containing 1 (DEPDC1) and RNA polymerase Ⅱ subunit D expression by targeting microRNA-432-5p (miR-432-5p) in PASMCs,upregulate MAX interactor 1 (MXI1) expression by targeting miR-433-3p in PMECs,and upregulate zinc finger AN1-type containing 5 (ZFAND5) expression by targeting miR-3613-5p in PCs.Conclusions:Our results suggest that circPMS1 promotes cell proliferation through the miR-432-5p/DEPDC1 or miR-432-5p/POL2D axis in PASMCs,through the miR-433-3p/MXI1 axis in PMECs,and through the miR-3613-5p/ZFAND5 axis in PCs,which provides putative targets for the early diagnosis and treatment of PH.
查看更多>>摘要：Background:Bitter taste receptors (Tas2rs) are generally considered to sense various bitter compounds to escape the intake of toxic substances.Bitter taste receptors have been found to widely express in extraoral tissues and have important physiological functions outside the gustatory system in vivo.Methods:To investigate the physiological functions of the bitter taste receptor cluster Tas2r106/Tas2r104/Tas2r105/Tas2r114 in lingual and extraoral tissues,mul-tiple Tas2rs mutant mice and Gnat3 were produced using CRISPR/Cas9 gene-editing technique.A mixture containing Cas9 and sgRNA mRNAs for Tas2rs and Gnat3 gene was microinjected into the cytoplasm of the zygotes.Then,T7EN1 assays and se-quencing were used to screen genetic mutation at the target sites in founder mice.Quantitative real-time polymerase chain reaction (qRT-PCR) and immunostaining were used to study the expression level of taste signaling cascade and bitter taste receptor in taste buds.Perception to taste substance was also studied using two-bottle preference tests.Results:We successfully produced several Tas2rs and Gnat3 mutant mice using the CRISPR/Cas9 technique.Immunostaining results showed that the expression of GNAT3 and PLCB2 was not altered in Tas2rs mutant mice.But qRT-PCR results re-vealed the changed expression profile of mTas2rs gene in taste buds of these mutant mice.With two-bottle preference tests,these mutant mice eliminate responses to cycloheximide due to genetic mutation of Tas2r105 .In addition,these mutant mice showed a loss of taste perception to quinine dihydrochloride,denatonium benzoate,and cucurbitacin B (CuB).Gnat3 -mediated taste receptor and its signal pathway con-tribute to CuB perception.Conclusions:These findings implied that these mutant mice would be a valuable means to understand the biological functions of TAS2Rs in extraoral tissues and investigate bitter compound-induced responses mediated by these TAS2Rs in many extraoral tissues.
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