Protective mechanism of Paeoniae Radix Alba against chemical liver injury based on network pharmacology,molecular docking,and in vitro experiments

Objective:To explore and validate the potential targets of Paeoniae Radix Alba(P.Radix,Bai Shao)in protecting against chemical liver injury through network pharmacology,molecular docking technology,and in vitro cell experiments.Methods:Network pharmacology was used to identify the common potential targets of P.Radix and chemical liver injury.Molecular docking was used to fit the components,which were subsequently verified in vitro.A cell model of hepatic fibrosis was established by activating hepatic stellate cell(HSC)-LX2 cells with 10 ng/mL transforming growth factor-β1.The cells were exposed to different concentrations of total glucosides of paeony(TGP),the active substance of P.Radix,and then evaluated using the cell counting kit-8 assay,enzyme-linked immunosorbent assay,and western blot.Results:Analysis through network pharmacology revealed 13 key compounds of P.Radix,and the potential targets for preventing chemical liver injury were IL-6,AKT serine/threonine kinase 1,jun protooncogene,heat shock protein 90 alpha family class A member 1(HSP90AA1),peroxisome proliferator activated receptor gamma(PPARG),PTGS2,and CASP3.Gene Ontology(GO)enrichment analysis indicated the involvement of response to drugs,membrane rafts,and peptide binding.Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis revealed that the main pathways involved lipid and atherosclerosis and chemical carcinogenesis-receptor activation.Paeoniflorin and albiflorin exhibited strong affinity for HSP90AA1,PTGS2,PPARG,and CASP3.Different concentrations of TGP can inhibit the expression of COL-I,COL-III,IL-6,TNF-a,IL-1β,HSP-90a,and PTGS2 while increasing the expression of PPAR-γand CASP3 in activated HSC-LX2 cells.Conclusion:P.Radix primarily can regulate targets such as HSP90AA1,PTGS2,PPARG,CASP3.TGP,the main active compound of P.Radix,protects against chemical liver injury by reducing the inflammatory response,activating apoptotic proteins,and promoting the apoptosis of activated HSCs.

Epidemiology and etiology of chemical ocular injury:A brief review

Chemical ocular injury is one of the common ophthalmologic emergencies that can cause vision loss and serious complications.Despite all protective measures,it continues to be a serious public health problem,especially in young male patients.Although it is known that injuries occur most frequently in the workplace and in young male patients,there is a variable frequency and distribution in different regions around the world.In addition,with the coronavirus disease 2019 pandemic,there are changing trends in ocular chemical injuries.This review aims to specify an update on the epidemiological and etiological features of ocular chemical injuries.

Immune-mediated liver injury following COVID-19 vaccination

Liver injury secondary to vaccination is a rare adverse event that has recently come under attention thanks to the continuous pharmacovigilance following the widespread implementation of coronavirus disease 2019(COVID-19)vaccination protocols.All three most widely distributed severe acute respiratory syndrome coronavirus 2 vaccine formulations,e.g.,BNT162b2,mRNA-1273,and ChAdOx1-S,can induce liver injury that may involve immune-mediated pathways and result in autoimmune hepatitis-like presentation that may require therapeutic intervention in the form of corticosteroid administration.Various mechanisms have been proposed in an attempt to highlight immune checkpoint inhibition and thus establish causality with vaccination.The autoimmune features of such a reaction also prompt an in-depth investigation of the newly employed vaccine technologies.Novel vaccine delivery platforms,e.g.,mRNA-containing lipid nanoparticles and adenoviral vectors,contribute to the inflammatory background that leads to an exaggerated immune response,while patterns of molecular mimicry between the spike(S)protein and prominent liver antigens may account for the autoimmune presentation.Immune mediators triggered by vaccination or vaccine ingredients per se,including autoreactive antibodies,cytokines,and cytotoxic T-cell populations,may inflict hepatocellular damage through wellestablished pathways.We aim to review available data associated with immunemediated liver injury associated with COVID-19 vaccination and elucidate potential mechanisms underlying its pathogenesis.

Drug-induced liver injury and COVID-19:Use of artificial intelligence and the updated Roussel Uclaf Causality Assessment Method in clinical practice

BACKGROUND Liver injury is a relevant condition in coronavirus disease 2019(COVID-19)inpatients.Pathophysiology varies from direct infection by virus,systemic inflammation or drug-induced adverse reaction(DILI).DILI detection and monitoring is clinically relevant,as it may contribute to poor prognosis,prolonged hospitalization and increase indirect healthcare costs.Artificial Intelligence(AI)applied in data mining of electronic medical records combining abnormal liver tests,keyword searching tools,and risk factors analysis is a relevant opportunity for early DILI detection by automated algorithms.AIM To describe DILI cases in COVID-19 inpatients detected from data mining in electronic medical records(EMR)using AI and the updated Roussel Uclaf Causality Assessment Method(RUCAM).METHODS The study was conducted in March 2021 in a hospital in southern Brazil.The NoHarm©system uses AI to support decision making in clinical pharmacy.Hospital admissions were 100523 during this period,of which 478 met the inclusion criteria.From these,290 inpatients were excluded due to alternative causes of liver injury and/or due to not having COVID-19.We manually reviewed the EMR of 188 patients for DILI investigation.Absence of clinical information excluded most eligible patients.The DILI assessment causality was possible via the updated RUCAM in 17 patients.RESULTS Mean patient age was 53 years(SD±18.37;range 22-83),most were male(70%),and admitted to the non-intensive care unit sector(65%).Liver injury pattern was mainly mixed,mean time to normalization of liver markers was 10 d,and mean length of hospitalization was 20.5 d(SD±16;range 7-70).Almost all patients recovered from DILI and one patient died of multiple organ failure.There were 31 suspected drugs with the following RUCAM score:Possible(n=24),probable(n=5),and unlikely(n=2).DILI agents in our study were ivermectin,bicalutamide,linezolid,azithromycin,ceftriaxone,amoxicillin-clavulanate,tocilizumab,piperacillin-tazobactam,and albendazole.Lack of essential clinical information excluded most patients.Although rare,DILI is a relevant clinical condition in COVID-19 patients and may contribute to poor prognostics.CONCLUSION The incidence of DILI in COVID-19 inpatients is rare and the absence of relevant clinical information on EMR may underestimate DILI rates.Prospects involve creation and validation of alerts for risk factors in all DILI patients based on RUCAM assessment causality,alterations of liver biomarkers and AI and machine learning.

Effects of amniotic membrane transplantation on cytokines expression in chemically burned rat corneas

AIM: To investigate the effect of amniotic membrane transplantation (AMT) on the expressions of inflammatory-related, angiogenic-related and growth-related cytokines in rat corneas after chemical injury. METHODS: Alkali wounds were inflicted on the central corneas of rats by applying a round filter paper soaked in 1mol/L NaOH for 40 seconds. One week after alkali burn, 12 rats were randomly divided into 2 groups: the AMT group and the control group, and AMT was performed on the rats in the AMT group. Corneal opacity and neovascularization were observed by slit-lamp microscopy. The protein levels of interleukin (IL)-2, interferon (IFN)-gamma, IL-10 and transforming growth factor (TGF)-beta were determined by enzyme-linked immunosorbent assay 2 weeks after AMT. The mRNA levels of matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) were evaluated by real-time quantitative PCR. RESULTS: In the AMT group, the corneal opacity was improved (P =0.011) and the area of corneal neovascularization was significantly decreased (P=0.005) compared with the control group. The amount of IL-2 and IFN-gamma secreted by Th1 cells were decreased after AMT, whereas the amount of IL-10 and TGF-beta secreted by Th2 cells were increased ( P <0.05). The level of MMP-2 was significantly down-regulated (P=0.013) at the nnRNA level in the AMT group, while the expression of EGF was significantly higher (P= 0.022) compared with the control. CONCLUSION: AMT may suppress corneal neovascularization after chemical injury by modulating the expressions of soluble factors.

Drug-induced liver injury and COVID-19:A review for clinical practice

Coronavirus disease 2019(COVID-19)consists of a systemic disease that can present many complications.The infection presents broad clinical symptoms and a high rate of transmissibility.In addition to severe acute respiratory syndrome,the patients manifest complications beyond the respiratory system.The frequency of liver damage in COVID-19 patients ranges from 14.8% to 53% of patients.One should pay attention to drug-induced liver injury(DILI)in patients with COVID-19,especially considering the off-label use of drugs in prophylactic and therapeutic regimens applied on large scales.This review aims to present relevant information on the medication used so far in COVID-19 patients and its possible hepatotoxicity.We reviewed liver damage in patients with COVID-19 on PubMed and Virtual Health Library to investigate DILI cases.Four studies were selected,involving the medicines remdesivir,tocilizumab and a pharmacovigilance analysis study.The hepatotoxicity profile of drugs presented in the literature considers use in accordance to usual posology standards for treatment.However,drugs currently used in the management of COVID-19 follow different dosages and posology than those tested by the pharmaceutical industry.The deficiency of uniformity and standardization in the assessment of hepatotoxicity cases hinders the publication of information and the possibility of comparing information among healthcare professionals.It is suggested that severe liver injury in COVID-19 patients should be reported in pharmacovigilance institutions,and physicians should pay attention to any considerable abnormal liver test elevation as it can demonstrate unknown drug hepatotoxicity.Liver disorders in COVID-19 patients and the use of several concomitant off-label medications—with a potential risk of further damaging the liver-should at least be a warning sign for rapid identification and early intervention,thus preventing liver damage from contributing to severe impairment in patients.

Overview of drug induced liver injury in Brazil:What is the role of public health policy on the evidence?

BACKGROUND Adverse drug reactions are responsible for increased costs and morbidity in the health system.Hepatotoxicity can be induced both by non-prescription drugs and by those used for chronic diseases.It is the main cause of safety-related drug marketing withdrawals and could be responsible for irreversible and fatal injuries.AIM To identify and to summarize Brazilian studies reporting the drug-induced liver injury.METHODS A systematic review of Brazilian studies was carried out until June 2020.It was found 32 studies,being 10 retrospective cohorts,12 prospective cohorts,5 crosssectional,3 case-control,one case series and one randomized clinical trial.In most studies were investigated tuberculosis patients followed by other infectious conditions like human immunodeficiency virus(HIV)and hepatitis C virus.The hepatotoxicity ranged from one to 57%,led by isoniazid,rifampicin,and pyrazinamide.Few studies reported algorithm to assess causality.In most studies,there were moderate outcomes and it was necessary drug interruption.However,few severe outcomes,such as chronic liver damage and liver transplantation were reported.RESULTS Twenty-two different criteria for hepatotoxicity were found.The great heterogeneity did not allow a meta-analysis.Standardization of parameter of drug-induced liver injury and greater effort in pharmacovigilance could contribute to learn more about drug-induced liver injury(DILI)’s epidemiology in Brazil.CONCLUSION The development of strategic public health policies seems to have an influence on the DILI scientific evidence in Brazil due to main studies are in HIV and tuberculosis line care,two strategic health policies in Brazil.

Anabolic androgenic steroid-induced liver injury:An update

Anabolic androgenic steroids(AASs)are a group of molecules including endogenous testosterone and synthetic derivatives that have both androgenic and anabolic effects.These properties make them therapeutically beneficial in medical conditions such as hypogonadism.However,they are commonly bought illegally and misused for their anabolic,skeletal muscle building,and performanceenhancing effects.Supraphysiologic and long-term use of AASs affects all organs,leading to cardiovascular,neurological,endocrine,gastrointestinal,renal,and hematologic disorders.Hepatotoxicity is one of the major concerns regarding AASs treatment and abuse.Testosterone and its derivatives have been most often shown to induce a specific form of cholestasis,peliosis hepatis,and hepatic benign and malignant tumors.It is currently believed that mechanisms of pathogenesis of these disorders include disturbance of antioxidative factors,upregulation of bile acid synthesis,and induction of hepatocyte hyperplasia.Most toxicity cases are treated with supportive measures and liver function normalizes with discontinuation of AAS.However,some long-term consequences are irreversible.AAS-induced liver injury should be taken in consideration in patients with liver disorders,especially with the increasing unintentional ingestion of supplements containing AAS.In this paper,we review the most current knowledge about AAS-associated adverse effects on the liver,and their clinical presentations,prevalence,and pathophysiological mechanisms.

Common eye drops and their implications for p H measurements in the management of chemical eye injuries

Dear Sir,Eye drops(single use)commonly used in clinics do have varying pH values.The use of such drops in the initial management of chemical eye injury may influence the accuracy of pH measurement of the eye,and subsequently influence its management.Chemical eye injury is an ophthalmic emergency,which may be caused by exposure to an acidic(pH【4)or an alkali(pH】10)solution to the eye.Rinsing the eye decreases the concentration of these solutions on ocular surface.The initial management would be copious irrigation with clean or sterile water or Ringer’s solution(pH 7.3-7.4)or its equivalent,of a

A narrative review of limbal stem cell deficiency&severe ocular surface disease

Background and Objective:Limbal stem cell deficiency(LSCD)describes the clinical condition when there is dysfunction of the corneal epithelial stem/progenitor cells and the inability to sustain the normal homeostasis of the corneal epithelium.The limbal stem cells are located in a specialized area of the eye called the palisades of Vogt(POV).There have been significant advances in the diagnosis and management of LSCD over the past decade and this review focuses on the pathophysiology of LSCD,its clinical manifestations,diagnosis,and causes.Methods:Papers regarding LSCD were searched using PubMed to identify the current state of diagnosis and causes of LSCD published through to June 2022.Key Content and Findings:LSCD is clinically demonstrated by a whorl-epitheliopathy,loss of the POV,and conjunctivalization of the cornea.The diagnosis of this condition is based on clinical examination and aided by the use of impression cytology,in vivo confocal microscopy,and anterior segment optical coherence tomography(asOCT).There are many causes of LSCD,but those which are most common include chemical injuries,aniridia,contact lens wear,and Stevens-Johnson syndrome(SJS).Conclusions:While this condition is most commonly encountered by corneal specialists,it is important that other ophthalmologists recognize the possibility of LSCD as it may arise in other co-morbid eye conditions.

Applied Technology of Botanical Pesticides against Empoasca pirisuga Matumura

[Objectives] The paper was to explore the control effects of different botanical pesticides against Empoasca pirisuga Matumura. [Methods] 5% Eucalyptol SL, 0.5% matrine SL and 50% thiacloprid WDG were used to control E. pirisuga , and the decline rate of insect population was investigated. [Results] Eucalyptol had good control effect on E. pirisuga , with slow effect but long duration. It was harmless to natural enemies in tea gardens, with high safety and no chemical injury. [Conclusions] The study provides a theoretical basis for the application of botanical pesticides in tea production.

Ginsenoside Rb1 Reduces D-GalN/LPS-induced Acute Liver Injury by Regulating TLR4/NF-κB Signaling and NLRP3 Inflammasome

Background and Aims:The effect of ginsenoside Rb1 on D-galactosamine(D-GalN)/lipopolysaccharide(LPS)-induced acute liver injury(ALI)is unknown.The aim of this study was to evaluate the effect of ginsenoside Rb1 on ALI and its underlying mechanisms.Methods:Mice were pretreated with ginsenoside Rb1 by intraperitoneal injection for 3 days before D-GalN/LPS treatment,to induce ALI.The survival rate was monitored every hour for 24 h,and serum biochemical parameters,hepatic index and histopathological analysis were evaluated to measure the degree of liver injury.ELISA was used to detect oxidative stress and inflammatory cytokines in hepatic tissue and serum.Immunohistochemistry staining,RT-PCR and western blotting were performed to evaluate the expression of toll-like receptor 4(TLR4),nuclear factorkappa B(NF-κB),and NLR family,pyrin domain-containing 3 protein(NLRP3)in liver tissue and Kupffer cells(KCs).Results:Ginsenoside Rb1 improved survival with D-GalN/LPS-induced ALI by up to 80%,significantly ameliorated the increased alanine and aspartate transaminase,restored the hepatic pathological changes and reduced the levels of oxidative stress and inflammatory cytokines altered by D-GalN/LPS.Compared to the control group,the KCs were increased in the D-GalN/LPS groups but did not increase significantly with Rb1 pretreatment.D-GalN/LPS could upregulate while Rb1 pretreatment could downregulate the expression of interleukin(IL)-1β,IL-18,NLRP3,apoptosis associated specklike protein containing CARD(ASC)and caspase-1 in isolated KCs.Furthermore,ginsenoside Rb1 inhibited activation of the TLR4/NF-κB signaling pathway and NLRP3 inflammasome induced by D-GalN/LPS administration.Conclusions:Ginsenoside Rb1 protects mice against D-GalN/LPS-induced ALI by attenuating oxidative stress and the inflammatory response through the TLR4/NF-κB signaling pathway and NLRP3 inflammasome activation.

Protective effect of Chushizi(Fructus Broussonetiae)on acetaminophen-induced rat hepatitis by inhibiting the Toll-like receptor 3/c-Jun N-terminal kinase/c-jun/c-fos/janus protein tyrosine kinase/activators of transcription 3 pathway

OBJECTIVE:To observe the intervention of Chushizi(Fructus Broussonetiae)(CSZ)on drug-induced liver injury(DILI)in rats,as well as indicators of liver function,serum levels of inflammatory cytokines,and expression of proteins and m RNA associated with toll-like receptor 3(TLR3)and the signal transducer and activator of transcription 3(STAT3)pathway in the liver[TLR3,janus protein tyrosine kinase 2(JAK2),c-jun,c-fos,c-Jun N-terminal kinase 2(JNK2),and STAT3].METHODS:Forty specified pathogen free grade Sprague-Dawley rats were randomly divided into the control group,the model group,the silybin group and the CSZ group.Rats were given acetaminophen(APAP)to trigger DILI.Histopathology of the liver was observed by hematoxylin-eosin staining.The levels of alanine aminotransferase(ALT),aspartate transaminase(AST),direct bilirubin(DBIL),and total bilirubin(TBIL)in serum were detected by a semi-automatic biochemical instrument.Content of tumor necrosis factor alpha(TNF-α),interleukin(IL)-6,IL-13,and IL-22 in serum were detected by the enzyme-linked immunosorbent assay,the expression of TLR3,phosphorylation of JAK2(p-JAK2),while c-jun and c-fos proteins in the liver were determined by immunohistochemistry;expression of JNK2,and STAT3 in the liver were assayed by Western blot and real-time quantitative polymerase chain reaction.P-JNK2 and p-STAT3 in the liver were assayed by Western blot.RESULTS:After treatment,the activity of ALT,AST,and concentrations of TBIL,DBIL,TNF-α,IL-6,as well as IL-13 in serum,were lower than those in the model group,and expression of p-JAK2,TLR3,c-jun,c-fos,p-STAT3,and p-JNK2 could be downregulated.CONCLUSION:Our findings suggest that CSZ is a valid medicine to alleviate APAP-induced DILI,while its partial mechanism may regulate the TLR3/JNK/c-jun/c-fos/JAK/STAT3 pathway.