Clinical implication of naive and memory T cells in locally advanced cervical cancer:A proxy for tumor biology and short-term response prediction

Background:This study was designed to investigate the feasibility of tumor-infiltrating immune cells with different phenotypic characteristics for predicting short-term clinical responses in patients with locally advanced cervical cancer(LACC).Methods:Thirty-four patients who received concurrent chemoradiotherapy and twenty-one patients who merely underwent radiotherapy were enrolled in this study.We retrospectively analyzed the T cell markers(i.e.,CD3,CD4,CD8),memory markers(i.e.,CD45,CCR7),and differentiation markers(i.e.,CD27)in the peripheral blood and tumor tissues of patients with LACC before treatment based on flow cytometry.We also analyzed the relationship of T cell subsets between peripheral blood and tumor tissues,and their correlation with complete response or partial response.Results:The percentage of central memory CD8^(+)TCM(CD8^(+)CD45RA^(−)CD27^(+)CCR7^(+))cells in LACC patients was significantly lower than that of the control group.The percentage of CD8^(+)TN in the peripheral blood of LACC patients was significantly higher than that of tumor tissues.CD8^(+)TEM in the peripheral blood was significantly lower than that of tumor tissues.The percentage of CD8^(+)TN and CD8^(+)TCM in human papillomavirus(HPV)positive samples was significantly higher than that of HPV-negative samples.Similarly,the percentage of CD8^(+)TCM in tumor tissues was significantly higher in cancer tissue samples with lymph nodes compared with those without.Conclusion:A higher proportion of CD4^(+)TCM and a lower proportion of CD8^(+)TN in the tumor microenvironment of LACC may contribute to the therapy response prediction.

Cyclic biaxial tensile strain enhances osteogenic differentiation in rat bone marrow-derived mesenchymal stem cells via activating ERα-Wnt3a/β-catenin pathway

The present study was designed to investigate the role of estrogen receptorα(ERα)in biaxial tensile strain(BTS)regulated osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells(rBMSCs).rBMSCs were derived fromrats and overexpressed ERα.The rBMSCs were subjected to BTS at 1Hz with a strain of 2%for 4 h per day,3 days,with or without ERαinhibitor ICI 182,780(ICI).Then,bone mineralization was performed by Alizarin Red Staining.The markers of osteogenic differentiation and downstream Wnt3a/β-catenin signaling were detected by western blotting.Results showed that BTS enhanced the osteogenic differentiation of rBMSCs,increased protein expression levels of alkaline phosphatase(ALP),runt-related transcription factor 2(Runx2),collagen type I(Col I)and osteocalcin(OCN),and it increased the protein expression levels of estrogen receptor(ER)α(ERα),Wnt3a,andβ-catenin.BTS The activated Wnt3a/β-catenin signaling pathway induced by BTS was abolished by ICI 182,780(ICI).In addition,overexpressing ERαin rBMSCs promoted the osteogenic differentiation by BTS.Taken together,BTS induced osteogenic differentiation of rBMSCs via the ERαand downstream canonical Wnt3a/β-catenin pathway.

A nanostructured look of collagen apatite porosity into human mineralized collagen fibril

Bone tissue is a hierarchical material characterized at nanoscale by the mineralized collagen fibril,a recurring structure mainly composed of apatite minerals,collagen and water.Bone nanostructure has a fundamental role in determining the mechanical behavior of the tissue and its mass transport properties.Diffusion phenomenon allows to maintain an adequate supply of metabolites in the mechanisms of bone remodeling,adaptation and repair.Several analytical and computational models have been developed to analyze and predict bone tissue behavior.However,the fine replication of the natural tissue still represents a challenge.Insights on the structural organization at nanoscale and on the influence of apatite mineral crystals on the diffusion coefficient lead to outline the functional conditions for the development of biomimetic strategies for bone tissue engineering.Thorough understanding of bone nanostructure is essential to improve longevity of bioscaffolds and to decrease the risk of failure by controlling their mechanical and biological performance.

Upregulated IRF9 promotes cell apoptosis of hyperlipidemia acute pancreatitis with heart injury by regulating SIRT1

Hyperlipidemia acute pancreatitis(HLAP)is a significant cause of AP,characterized by recurrent attacks,more complications and high incidence and mortality.HLAP is often accompanied by single or multiple organ damage.Negative regulation of interferon-regulatory factor 9(IRF9)on sirtuin-1(SIRT1)contributes to a range of diseases.However,the function of IRF9 and SIRT1,and the relationship of the two in HLAP with heart injury remain to be illustrated so far.Animal models of HLAP were set up by feeding with high-fat chow and subsequently injecting 20%L-arginine intraperitoneally.The degree of pancreas and heart tissue injury was evaluated.Heart cell apoptosis was assayed by the TUNEL technique.IRF9,SIRT1,p53 and acetylated p53(Ac-p53)expression levels were measured by qRT-PCR and western blot.The correlation between SIRT1 and IRF9 expression levels was analyzed.Results showed that the damage degree in rat pancreas and heart tissues of AP and HLAP group was more distinctly and heart cell apoptosis was elevated.Pancreas,heart injury and cell apoptosis of the HLAP group were more remarkable than that of the AP group.Apparent increases of IRF9 and Ac-p53/p53 expression and a marked drop of SIRT1 expression were observed in the AP and HLAP group rather than NC and HLNC group.IRF9 and Ac-p53/p53 expression levels of the HLAP group were markedly raised compared with the AP group.SIRT1 expression of the HLAP group was obviously lower than that of the AP group.There was an inverse correlation between the decrease of SIRT1 and the increase of IRF9 in AP and HLAP groups.Based on the above findings,we drew a conclusion that in pancreatitis with heart injury,upregulated IRF9 inhibited SIRT1 expression,elevated the acetylation of p53,and increased myocardial cell apoptosis.Hyperlipidemia further exacerbated pancreas and heart injury and accelerated myocardial cell apoptosis.These results would furnish an experimental and theoretical basis to diagnose and therapy diseases.

Ultrastructure of multicellular dwarf males with external gametangium in Oedogonium macrandrium(Oedogoniales,Chlorophyta)

This is the first comprehensive ultrastructural study on dwarf males with external gametangia in the ge in the genus Oedogonium,from androspore germination to the liberation of mature male gametes.The ultrastructure of the process in O.macrandrium Wittrok is similar to that of Bulbochaete hiloensis(Nordstedt)Tiffany,butwith two remarkable differences.In O.macrandrium:(1)instead of a true transverse wall,only condensed mucilage appears between the gametes of each antheridial cell,and (2)the cell wall between the basal cell and the basal most antheridial cell has simple plasmodesmata similar to those present in the transverse walls of vegetative cells,which are absent in B.hiloensis.

Mesenchymal stem cell-derived exosomes as new remedy for the treatment of inflammatory eye diseases

Detrimental immune response has a crucially important role in the development and progression of inflammatory eye diseases.Inflammatory mediators and proteolytic enzymes released by activated immune cells induce serious injury of corneal epithelial cells and retinal ganglion cell which may result in the vision loss.Mesenchymal stem cells(MSCs)are regulatory cells which produce various immunosuppressive factors that modulate phenotype and function of inflammatory immune cells.However,several safety issues,including undesired differentiation and emboli formation,limit clinical use of MSCs.MSC-derived exosomes(MSC-Exos)are nano-sized extracellular vesicles which contain all MSC-derived immunoregulatory factors.Intraocular administration of MSCExos efficiently attenuated eye inflammation and significantly improved visual acuity in experimental animals without causing any severe side effects.As cell-free product,MSC-Exos addressed all safety issues related to the transplantation of MSCs.Therefore,MSC-Exos could be considered as potentially new remedy for the treatment of inflammatory eye diseases which efficacy should be explored in up-coming clinical trials.

Wnt3a-induced ST2 decellularized matrix ornamented PCL scaffold for bone tissue engineering

The limited bioactivity of scaffold materials is an important factor that restricts the development of bone tissue engineering.Wnt3a activates the classicWnt/β-catenin signaling pathway which effects bone growth and development by the accumulation ofβ-catenin in the nucleus.In this study,we fabricated 3D printed PCL scaffold with Wnt3a-induced murine bone marrow-derived stromal cell line ST2 decellularized matrix(Wnt3a-ST2-dCM-PCL)and ST2 decellularized matrix(ST2-dCM-PCL)by freeze-thaw cycle and DNase decellularization treatment which efficiently decellularized>90%DNA while preserved most protein.Compared to ST2-dCM-PCL,Wnt3a-ST2-dCM-PCL significantly enhanced newly-seeded ST2 proliferation,osteogenic differentiation and upregulated osteogenic marker genes alkaline phosphatase(Alp),Runx2,type I collagen(Col 1)and osteocalcin(Ocn)mRNA expression.After 14 days of osteogenic induction,Wnt3a-ST2-dCM-PCL promoted ST2 mineralization.These results demonstrated that Wnt3a-induced ST2 decellularized matrix improve scaffold materials’osteoinductivity and osteoconductivity.

Upregulation of microRNA-451a improves endothelial cell function in atherosclerosis by direct targeting of macrophage migration inhibitory factor

This study aims to detect the expression of selected circulating microRNAs(miRNA),including miRNA-451a,miRNA-486-5p and miR-10b-5p,and their prospective roles as biomarkers in patients with atherosclerosis.For this purpose,levels of miRNAs were detected by real-time quantitative polymerase chain reaction(RT-qPCR)in case(N=30)and healthy control(N=30)groups.Receiver operating characteristic(ROC)curve analysis was carried out to evaluate the diagnostic ability of miRNAs.The correlations of miR-451a with lipid parameters were evaluated using Pearson’s correlation coefficients.HUVEC tested by ox-LDL was used as a cellular model of atherosclerosis.Cell viability and apoptosis were detected by methyl thiazolyl tetrazolium(MTT)and flow cytometry(FC)assays.Luciferase assay was used to determine the miRNA binding site on target genes.The results showed that miRNA-451a expression level was significantly lower in patients than controls.ROC curve analysis showed that the areas under the curve(AUC)of plasma miRNA-451a was 0.90.The miRNA-451a expression level exhibited significant negative correlations with cholesterol(TC),triglyceride(TG),and low-density lipoprotein(LDL).Besides,miRNA-451a specifically binds to the 3’UTR of macrophage migration inhibitory factor(MIF)and mediated the cell proliferation and apoptosis of HUVECs exposed to ox-LDL.Furthermore,overexpression of miRNA-451a promoted the proliferation and alleviated apoptosis of HUVECs exposed to ox-LDL,while this result was attenuated by macrophage migration inhibitory factor(MIF)overexpression.Therefore,miRNA-451a could be considered as a potential biomarker for atherosclerosis and miRNA-451a might contribute to regulating atherosclerosis through targeting MIF.

Synergetic effects of shock waves with polydeoxyribonucleotides on rotator cuff tendon tear in a rabbit model

This work aimed to investigate the synergetic therapeutic effects of polydeoxyribonucleotides(PDRN)combined with extracorporeal shock waves therapy(ESWT)and the effects of the therapy according to ESWT sequences on a chronic traumatic full-thickness rotator cuff tear(RCT)in rabbit models.For this purpose,thirty-two rabbits were randomly allocated into 4 groups.An excision was made to create a 5-mm sized full-thickness RCT right proximal to the insertion site on the supraspinatus.After 6 weeks,4 different procedures(normal saline,Group 1;PDRN injection,Group 2;PDRN injection before ESWT,Group 3;PDRN injection after ESWT,Group 4)were performed.PDRN injection and radial type ESWT were each performed 4 times per week.Gross morphology,Immunohistochemistry,and motion analysis were performed at 4 weeks after treatments.All parameters including tear size,Masson’s trichrome(MT)staining,anti-collagen 1 monoclonal antibody immunostaining(COL-1),proliferating cell nuclear antigen(PCNA),vascular endothelial growth factor(VEGF),anti-platelet endothelial cell adhesion molecule-1 polyclonal antibody(PECAM-1),and motion analysis,were significantly greater in Group 2,Group 3,and Group 4 than in Group 1.In Group 4,all parameters were significantly greater than in Group 2,and parameters including MT staining,COL-1,PCNA,PECAM-1,and fast walking time were significantly greater than Group 3.There were no significant differences between Group 2 and Group 3.This study demonstrated that PDRN injection alone and combined with ESWT were more effective than control treatment and applying ESWT before PDRN injection was also shown to yield better outcomes in parameters including angiogenesis,cell proliferation,and fast walking time in a rabbit model with chronic traumatic full-thickness RCT.Therefore,the application of ESWT before PDRN injection could be recommended for optimal outcomes of the conservative treatments when the patients with full-thickness RCT are not suitable in surgical treatment.

MiR-494-3p regulates cell proliferation and apoptosis via KLF7 in Schwann cells

Peripheral nerve injury is a common neurodegenerative disease,which causes disability and a huge economic burden for patients.MicroRNAs(miRNAs)have been acknowledged as major regulators and therapeutic targets of neurological disease.Thus,the functional studies of miRNAs in neurological disease will contribute to discover new therapeutic targets for peripheral nerve injury.Sprague Dawley rats treated sciatic nerve surgical injury were regarded as peripheral nerve injury model in vivo.The expression of miR-494-3p and Kruppel like factor7(KLF7)were measured by Real-time quantitative polymerase chain reaction(RT-qPCR)assay.In addition,western blot analysis was conducted to measure the protein levels of KLF7,Bax,Bcl-2,and C-caspase 3.Cell viability and apoptosis were detected in Schwann cells by EdU stain and flow cytometry,respectively.The interaction between miR-494-3p and KLF7 was investigated by dual-luciferase reporter assay.The expression of miR-494-3p was reduced at the beginning,but KLF7 was enhanced in Sprague Dawley rats with peripheral nerve injury.Knockdown of miR-494-3p promoted cell proliferation and suppressed apoptosis,while overexpression of miR-494-3p or silencing KLF7 led to opposite results.Moreover,the upregulation of KLF7 attenuated miR-494-3p overexpression-induced suppressive effects on viability and promotion of apoptosis in Schwann cells.MiR-494-3p negatively regulates KLF7 in Schwann cells to mediate proliferation and apoptosis.

Study on the clinical significance of TRPV2 and MMP2 expressions in ovarian cancer

Ovarian cancer was one of the most common malignant tumors in female reproductive organs.Moreover,epithelial ovarian cancer showed the highest mortality rate in gynecological tumors,posing serious threats to women’s life and health.Transient Receptor Potential Cation Channel Subfamily V Member 2(TRPV2)and matrix metalloproteinase-2 MMP-2 have been found to play important roles in regulating the pathogenesis of most tumors,but there were few studies exploring the relationships of TRPV2 and MMP-2 in OC.Therefore,we evaluated the expression of TRPV2 and MMP-2 proteins in cancer tissues and adjacent normal tissues of OC patients.Immunohistochemistry was used to analyze the expressions of TRPV2 and MMP-2 in cancer tissues(N=70)and adjacent normal tissues(N=70)of OC patients,and the correlation of TRPV2 and MMP-2 with the occurrence and development of OC was analyzed with the combination of clinicopathological parameters of OC patients.The results showed that the expressions of TRPV2 and MMP-2 in OC tissues were significantly higher than those in adjacent normal tissues,and there were significant differences in TRPV2 and MMP-2 expressions in terms of tumor stage,differentiation,and lymph node metastasis of OC.Taken together,our results showed that protein expressions of TRPV2 and MMP-2 were closely related associated with the occurrence and development of OC.

Melittin inhibited glycolysis and induced cell apoptosis in cisplatinresistant lung adenocarcinoma cells via TRIM8

Chemotherapy is widely used for non-small cell lung cancer(NSCLC)patients at a late stage;however,NSCLC patients often acquire resistance to chemotherapeutic drugs,thus limiting the therapy efficacy.Melittin,a major component of bee venom,possesses anti-tumor activity in various cancer cells.Here,we examined the effects of melittin on A549/DDP cisplatin-resistant lung adenocarcinoma cells and xenografts formed from this cell line and investigated the possible target of melittin.Treatment with melittin resulted in the induction of cell apoptosis,glycolysis inhibition,and reduction of phosphorylated AKT(p-AKT)in A549/DDP cells.We also identified that tripartite motif-containing 8(TRIM8)was a potential target of melittin.Moreover,we found that TRIM8 mRNA expression was elevated in NSCLC specimens as compared to adjacent normal tissues(N=25)and that patients with high expression of TRIM8 had a poor prognosis for lung adenocarcinoma.The knockdown of TRIM8 had a similar effect of melittin,while overexpression of TRIM8 reversed the effects of melittin in A549/DDP cells.More importantly,we revealed that melittin enhanced cisplatin sensitivity in A549/DDP cells and tumor growth in vivo using a xenograft model of A549/DDP cells.In conclusion,melittin appears to be a potential chemotherapy sensitization agent in NSCLC.

Association of hypoxia-inducible factor-1α (HIF1α) 1772C/T genepolymorphism with susceptibility to renal cell carcinoma/prostatecancer

In this study,we used a meta-analysis method to evaluate the relationship between hypoxia-inducible factor-1α(HIF1α)1772C/T gene polymorphism(rs 11549465)and renal cell carcinoma(RCC)/prostate cancer risk.We searched for relevant studies(before March 1,2019)on Cochrane Library,Embase,and PubMed.Studies meeting the inclusion criteria were recruited into this meta-analysis.The outcome of dichotomous data was showed in the way of odds ratios(OR),and 95%confidence intervals(CI)were also counted.In this investigation,there was no association between HIF1α1772C/T gene polymorphism and susceptibility to RCC in Caucasians,Asians as well as overall populations.In addition,HIF1α1772C/T gene polymorphism was not found to be relevant to the survival in RCC.Interestingly,the T allele was relevant to prostate cancer risk in all populations,but not in Caucasians and Asians.However,the TT genotype and the CC genotype were not related to prostate cancer susceptibility in Asian,Caucasian,and all populations.In conclusion,the T allele of the HIF1α1772C/T gene polymorphism was related to prostate cancer risk in the overall populations.

DIRECTIVE BOARD

LECTURE A1 ATHEROSCLEROSIS:FROM CAVEMAN TO COMPUTER ERA Filippini,F Cátedra de Clínica Médica y Terapéutica,Universidad Nacional de Rosario;Cátedra de Fisiopatología de Adultos,Universidad Abierta Interamericana;Sociedad Argentina de Lípidos;Sociedad Argentina de Hipertensión.E-mail fernando.r.filippini@gmail.com Atherosclerosis is the leading cause of death in the Western World.Since the Framingham Heart Study,hypertension,smoking and hypercholesterolemia are identified as major risk factors.Years later,diabetes was added to the pathogenesis of atherosclerosis.In addition,a widespread progressive weight gain in recent decades has led to the development of the so-called metabolic syndrome.This disease combines hypertension,dysglycemia and dyslipidemia in a process in which insulin resistance is the common pathophysiological mechanism.Homo sapiens is believed to have developed the bases of such process 50,000 years ago by generating a central fat reserve which would enable the species to survive times of food scarcity.Human fossils show that obesity was not prevalent in our ancestors due to the high energy expenditure they were subjected to.However,Western World humans,while endowed with Paleolithic genes,are required low energy expenditures and the available food is constantly abundant,and is frequently of inadequate quality.This has triggered the current obesity epidemics and the resulting atherosclerotic complications.The thrifty gene hypothesis attempted but failed to explain the syndrome.The thrifty phenotype hypothesis,the inflammatory hypothesis mediated by adipocytokines and other hypotheses have been proposed to account for the origin of the epidemics.However,it must be resolved if insulin resistance has cheated the evolutionary mechanisms,or if scientists have not selected the causal hypotheses properly.

Butein imparts free radical scavenging, anti-oxidative and proapoptotic properties in the flower extracts of Butea monosperma

The flower of Butea monosperma(Lam.)(Fabaceae)has been used in traditional Indian medicine in the treatment of many ailments including liver disorders.To understand the pharmacological basis of its beneficial effects,the extracts of dried flowers in water,methanol,butanol,ethyl acetate and acetone were evaluated for free radical scavenging and pro-apoptotic activities in cell cultures(human hepatoma Huh-7 cell line and immortalized AML-12 mouse hepatocytes).Butrin and butein-the active constituents of flower extracts-were used as reference molecules.The levels of cell injury markers like lactate dehydrogenase,glutathione and lipid peroxidation and primary antioxidant enzymes glutathione S-transferase and catalase were also measured.The aqueous and butanolic extracts exhibited better 2,2-diphenyl-1-picrylhydrazyl scavenging and cytotoxic activities in hepatoma cells than in immortalized hepatocytes.Interestingly,butein inhibited 2,2-diphenyl-1-picrylhydrazyl radical better than butrin.The aqueous and butanolic extracts were further investigated for hepatoprotection against carbon tertrachloride-induced biochemical changes and cell death.Both extracts,just as butrin and butein,significantly reversed the cellular glutathione levels and lipid peroxidation,and glutathione–S-transferase activity.Lactate dehydrogenase leakage and cell death were also prevented.However,only butein revived the catalase activity.Thus,the butein content of Butea monosperma flower extracts is important for free radical scavenging activity,apoptotic cell death and protection against oxidative injury in hepatic cells.

A novel mutation in ROR2 led to the loss of function of ROR2 and inhibited the osteogenic differentiation capability of bone marrow mesenchymal stem cells(BMSCs)

Receptor tyrosine kinase-like orphan receptor 2(ROR2)has a vital role in osteogenesis.However,the mechanism underlying the regulation of ROR2 in osteogenic differentiation is still poorly comprehended.A previous study by our research group showed that a novel compound heterozygous ROR2 variation accounted for the autosomal recessive Robinow syndrome(ARRS).This study attempted to explore the impact of the ROR2:c.904C>T variant specifically on the osteogenic differentiation of BMSCs.Methods:Coimmunoprecipitation(CoIP)-western blotting was carried out to identify the interaction between ROR2 and Wnt5a.Double-immunofluorescence staining was used for determining the expressions and co-localization of ROR2 and Wnt5a in bone marrow mesenchymal stem cells(BMSCs).Western blot(WB)analysis and quantitative reverse transcription polymerase chain reaction(RT-qPCR)were conducted to identify the expression levels of ROR2 in the BMSCs transfected with LV-shROR2 or LV-ROR2-c.904C>T.The alkaline phosphatase(ALP)activity was detected,and Alizarin Red S staining was done for evaluating the osteogenic differentiation of BMSCs.RT-qPCR was employed to identify the expression of the sphingomyelin synthase 1(SMS1)mRNA in the BMSCs transfected with LV-shROR2 or LV-ROR2-c.904C>T and the mRNA expression levels of Runt-related transcription factor 2(RUNX2),osteocalcin(OCN),and osteopontin(OPN).WB was performed to confirm the protein expressions of extracellular regulated protein kinases1(ERK),P-ERK,Smad family member1/5/8(Smad1/5/8),P-Smad1/5/8,P-P38,P38,RUNX2,OCN,and OPN in the BMSCs transfected with LV-shROR2/LV-ROR2-c.904C>T and sphingomyelin(SM).Results:The ROR2:c.904C>T mutant altered the subcellular localization of the ROR2 protein,which caused an impaired interaction between ROR2 and Wnt5a.The depletion of ROR2 restricted the osteogenic differentiation capability of BMSCs and downregulated the expression of SMS1.SM treatment could reverse the inhibition of osteoblastic differentiation in ROR2-depleted BMSCs.Conclusion:The findings of this work revealed that the ROR2:c.904C>T variant led to the loss of function of ROR2,which impaired the interaction between ROR2 and Wnt5a and also controlled the osteogenic differentiation capability of BMSCs.Furthermore,SM was revealed to be engaged in the osteoblastic differentiation of BMSCs regulated by ROR2,which renders SM a potential target in the therapy for ARRS.

Biochanin A,as the Lrg1/TGF-β/Smad2 pathway blockade,attenuates blood-brain barrier damage after cerebral ischemiareperfusion by modulating leukocyte migration patterns

Background:Biochanin A is an excellent dietary isoflavone that has the concomitant function of both medicine and foodstuff.The attenuation function of biochanin A on blood-brain barrier(BBB)damage induced by cerebral ischemia-reperfusion remains unclear.Methods:C57BL/6 mice were subjected to 1 h middle cerebral artery occlusion(MCAO)followed by 24 h reperfusion.The infarct volume of the brain was stained by TTC,while leakage of the brain was quantitatively stained by Evans blue,and the neurologic deficit score was measured.Microglial-induced morphologic changes were observed via immunofluorescence staining,and rolling and adhering leukocytes in venules were observed via two-photon imaging,while the inner fluorescein isothiocyanate-albumin of venules were compared with those of surrounding interstitial area through venular albumin leakage.Results:The attenuation effect of biochanin A on tight junction injury was compared in ischemia-reperfusion mice or conventional knockdown of leucine-richα2-glycoprotein 1(Lrg1)mice.Biochanin A could ameliorate BBB injury in mice with cerebral ischemiareperfusion in a dose-dependent manner by strengthening the immunostaining volume of occludin,claudin-5,and zonula occludens-1.The amoeba morphologic changes of microglial combined with the elevated expression of Lrg1 could be relieved under the treatment of biochanin A.Biochanin A played a countervailing role on the rolling leukocytes in the vessel,while the leakage of blood vessels was reduced.Biochanin A diminished its functions to further improved attenuation for tight junction injury on conventional Lrg1-knockout mice,as well as the inhibition effects on TGF-β1,and the phosphorylation of suppressor of mothers against decapentaplegic 2(Smad2)/Smad2 via western blot assay.Conclusion:Biochanin A could alleviate tight junction injury induced by cerebral ischemiareperfusion and blocked the Lrg1/TGF-β/Smad2 pathway to modulate leukocyte migration patterns.

SARS-CoV-2 induced myocarditis:Current knowledge about its molecular and pathophysiological mechanisms

The existence of an inflammatory process in the heart muscle,related to a progressive worsening of myocardial function,different etiopathogenetic mechanisms concur and often overlap,thus making the diagnosis and the therapeutic approach complex.As the COVID-19 pandemic progresses,the effects of the disease on the organ systems and in particular on the cardiovascular system are becoming more and more profound.Cardiac involvement is a well-known event with a high percentage of findings in the heart’s magnetic field,even in asymptomatic areas.There are numerous uncertainties regarding their evolution,in the long and short term,due not only to a difficult to determine the varied clinical expression and the rarely performed intramyocardial biopsy which additionally presents diagnostic problems but also in part to different clinical prognosis.Today,the new SARS-CoV-2 virus that uses the angiotensin converting enzyme 2(ACE2)which is present at high levels in myocardial cells as its entrance it can create even severe heart injury.The pathophysiology in all of these cases can involve multiple immune and non-immune mechanisms within organs and vessels and can be occur in the clinical phases.Possible mechanisms of direct and indirect myocardial infarction in patients with COVID-19 include additional lesion and oxygen-rich and generalized inflammation response with myocardial immune hyperactivity(myocarditis).Therefore,these can occur through the excessive release of cytokines,the presence of thrombocytopenia,endocrine damage,heart failure,arrhythmias and more.Patients can show average signs of myocardial damage,and some develop spontaneous cardiac complications,such as heart failure,arrhythmias and,rarely,rare cardiogenic disorders.Pathophysiology in all of these may involve multiple mechanisms within the cytokine cephalic membrane,endocrine damage and thrombogenicity.The diagnosis of this myocardial injuri is mainly based on the myocardial enzyme troponin.This viewpoint paper explains today’s knowledge on viral myocarditis,in particular that from SARS-CoV-2 infection,if there is a connection with other possible biomolecular pathogenetic factors that can influence its natural course.In fact,it is for this reason that the pathogenetic mechanisms are analyzed and described.At the same time,its possible interaction with other parameters that are documented risk factors for cardiovascular disease was examined.Although these biomolecular findings were mainly related to necrotic parts of the myocardium,it is important to recognize that myocardial damage early for a better approach and prognosis.