Liver is the foremost organ of human being for drug metabolism,and it played a significant role in toxicity evaluation of drugs.Establishing a liver model in vitro can accelerate the process of the drug screening and ...Liver is the foremost organ of human being for drug metabolism,and it played a significant role in toxicity evaluation of drugs.Establishing a liver model in vitro can accelerate the process of the drug screening and new drug research and development.We provide a 3D printing based hepatic sinusoid-on-a-chip microdevice that reconstitutes organ-level liver functions to create a drug screening model of toxicity evaluation on chip.The microfluidic device,which recapitulates the hepatic sinusoid microenvironment,consists of PET polyporous membranes which mimic the perisinusoidal space,and experience fluid flow to mimic the hepatic arterial capillaries.The PET membrane was used to separate the hepatocyte and endotheliocyte.The endotheliocyte was cultured on the downside of the membrane and the hepatocyte were 3D seeded on the membrane via the 3D printer.This device was used to reproduce the in vitro liver model for drug toxicity assays.The expression of several biomarkers of liver was compared with the monoculture and 2D cultured conditions,and the results reveal that this organ-on-a-chip microdevice mimics the drug hepatoxicity that has not been possible by 2D cell-based and animal models,providing a useful platform for screening the drugs and developing an effective therapy in hepatopathy.展开更多
Pig and monkey are widely used models for exploration of human diseases and evaluation of drug efficiency and toxicity,but high cost limits their uses.Organoids have been shown to be promising models for drug test as ...Pig and monkey are widely used models for exploration of human diseases and evaluation of drug efficiency and toxicity,but high cost limits their uses.Organoids have been shown to be promising models for drug test as they reasonably preserve tissue structure and functions.However,colonic organoids of pig and monkey are not yet established.Here,we report a culture medium to support the growth of porcine and monkey colonic organoids.Wnt signaling and PGE2 are important for long-term expansion of the organoids,and their withdrawal results in lineage differentiation to mature cells.Furthermore,we observe that porcine colonic organoids are closer to human colonic organoids in terms of drug toxicity response.Successful establishment of porcine and monkey colonic organoids would facilitate the mechanistic investigation of the homeostatic regulation of the intestine of these animals and is useful for drug development and toxicity studies.展开更多
The liver is the organ by which the majority of sub-stances are metabolized, including psychotropic drugs. There are several pharmacokinetic changes in end-stage liver disease that can interfere with the metabolizatio...The liver is the organ by which the majority of sub-stances are metabolized, including psychotropic drugs. There are several pharmacokinetic changes in end-stage liver disease that can interfere with the metabolization of psychotropic drugs. This fact is particularly true in drugs with extensive first--pass metabolism, highly protein bound drugs and drugs depending on phase I hepatic metabolic reactions. Psychopharmacological agents are also associated with a risk of hepatotoxicity. The evidence is insufficient for definite conclusions regarding the prevalence and severity of psychiatric drug-induced liver injury. High-risk psychotropics are not advised when there is pre-existing liver disease, and after starting a psychotropic agent in a patient with hepatic impairment, frequent liver function/lesion monitoring is advised. The authors carefully review the pharmacokinetic disturbances induced by end-stage liver disease and the potential of psychopharmacological agents for liver toxicity.展开更多
Chemotherapy-induced toxicity,resulting from inter-individual variability in pharmacokinetics is emerging as a highly active area of investigation.Body composition analysis,primarily concerning the amount of fat mass(...Chemotherapy-induced toxicity,resulting from inter-individual variability in pharmacokinetics is emerging as a highly active area of investigation.Body composition analysis,primarily concerning the amount of fat mass(FM)and lean body mass(LBM),has provided a proof-concept that the inter-individual variability in pharmacokinetics and toxicity profiles may be partially explained by the discrepancies of FM and LBM in patients.Recent research suggests a close relationship among body composition,pharmacokinetics and toxicity of anticancer drugs.Because LBM and FM,significantly influence the exposure to drugs,they are considered as the promising predictors of chemotherapy-induced toxicity and a potential basis for optimizing the dosing of oncology drugs and the outcomes.Our review summarizes the recent studies rendering the aforementioned correlations to highlight that a critical evaluation of body composition has initiated a new era for dose standardization.展开更多
Amphotericin B(AmB)is an amphiphilic drug commonly formulated in liposomes and administered intravenously to treat systemic fungal infections.Recent studies on the liposomal drug product have shed light on the AmB agg...Amphotericin B(AmB)is an amphiphilic drug commonly formulated in liposomes and administered intravenously to treat systemic fungal infections.Recent studies on the liposomal drug product have shed light on the AmB aggregation status in the bilayer,which heat treatment(curing)modifies.Although toxicity was found related to aggregation status-loose aggregates significantly more toxic than tight aggregates-the precise mechanism linking aggregation and toxicitywas notwell understood.This study directlymeasured drug release rate fromvarious AmB liposomal preparations made with modified curing protocols to evaluate correlations among drug aggregation state,drug release,and in vitro toxicity.UV–Vis spectroscopy of these products detected unique curing-induced changes in the UV spectral features:a∼25nm blue-shift of the main absorption peak(λ_(max))in aqueous buffer and a decrease in the OD_(346)/OD_(322) ratio upon thermal curing,reflecting tighter aggregation.In vitro release testing(IVRT)data showed,by applying and fitting first-order release kinetic models for one or two pools,that curing impacts two significant changes:a 3–5-fold drop in the overall drug release rate and a ten-fold decrease in the ratio between the loosely aggregated and the tightly aggregated,more thermodynamically stable drug pool.The kinetic data thus corroborated the trend independently deduced from the UV–Vis spectral data.The in vitro toxicity assay indicated a decreased toxicity with curing,as shown by the significantly increased concentration,causing half-maximal potassium release(TC50).The data suggest that the release of AmB requires dissociation of the tight complexes within the bilayer and that the reduced toxicity relates to this slower rate of dissociation.This study demonstrates the relationship between AmB aggregation status within the lipid bilayer and drug release(directly measured rate constants),providing a mechanistic link between aggregation status and in vitro toxicity in the liposomal formulations.展开更多
Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical d...Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local 02 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca^2＋-dependent ATPase, reduced capability to sequester Ca^2＋ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.展开更多
To investigate the neurotoxicity of intrathecal injections of dexmedetomidine,Sprague-Dawley rats were intrathecally injected with dexmedetomidine at doses of 0.75,1.50 and 3.00μg/kg into the spinal dorsal horn.We fo...To investigate the neurotoxicity of intrathecal injections of dexmedetomidine,Sprague-Dawley rats were intrathecally injected with dexmedetomidine at doses of 0.75,1.50 and 3.00μg/kg into the spinal dorsal horn.We found that c-Fos expression in the rat spinal dorsal horn peaked at 7 hours following the 3.00μg/kg dexmedetomidine injection,while the levels of c-Fos expression following 0.75 and 1.50μg/kg dexmedetomidine were similar to those in the spinal dorsal horn of normal rats. At 48 hours following administration,the level of c-Fos expression was similar to normal levels.In addition,the intrathecal injections of dexmedetomidine increased paw withdrawal mechanical thresholds and prolonged thermal tail flick latencies.These results indicate that dexmedetomidine has pronounced antinociceptive effects.However,dexmedetomidine appears to have neurotoxic effects in the spinal cord because it increased c-Fos expression in the spinal dorsal horn within 7 hours following administration.展开更多
AIM: To analyze the prevalence of thiopurine-methyltransferase (TPMT) genotypes and their association with drug toxicity in inflammatory bowel disease (IBD) patients from southeastern Brazil.
Therapeutic experiments are commonly performed on laboratory animals to inves-tigate the possible mechanism(s)of action of toxic agents as well as drugs or sub-stances under consideration.The use of toxins in laborato...Therapeutic experiments are commonly performed on laboratory animals to inves-tigate the possible mechanism(s)of action of toxic agents as well as drugs or sub-stances under consideration.The use of toxins in laboratory animal models,including rats,is intended to cause toxicity.This study aimed to investigate different models of hepatotoxicity and nephrotoxicity in laboratory animals to help researchers advance their research goals.The current narrative review used databases such as Medline,Web of Science,Scopus,and Embase and appropriate keywords until June 2021.Nephrotoxicity and hepatotoxicity models derived from some toxic agents such as cisplatin,acetaminophen,doxorubicin,some anticancer drugs,and other materials through various signaling pathways are investigated.To understand the models of renal or hepatotoxicity in laboratory animals,we have provided a list of toxic agents and their toxicity procedures in this review.展开更多
BACKGROUND Drug toxicity is a common and even serious problem in the gastrointestinal tract that is thought to be caused by a broad spectrum of agents.Although withdrawal of the causative agent would cure the disease ...BACKGROUND Drug toxicity is a common and even serious problem in the gastrointestinal tract that is thought to be caused by a broad spectrum of agents.Although withdrawal of the causative agent would cure the disease knowledge is scarce and mostly derives from case reports and series.AIM To investigate potential triggers of drug-induced colitis(DiC).METHODS We conducted a retrospective,observational case control study.Patients were assigned to DiC or one of two age-and gender-matched control groups(noninflammatory controls and inflammatory colitis of another cause)based on histopathological findings.Histopathology was reassessed in a subset of patients(28 DiC with atherosclerosis,DiC without atherosclerosis and ischaemic colitis each)for validation purposes.Medical history was collected from the electronic database and patient records.Statistical analysis included chi-squared test,t-test,logistic and multivariate regression models.RESULTS Drug-induced colitis was detected in 211 endoscopically sampled biopsy specimens of the colon mucosa(7%of all screened colonoscopic biopsy samples);a total of 633 patients were included equally matched throughout the three groups(291 males,mean age:62.1±16.1 years).In the univariate analysis,DiC was associated with diuretics,dihydropyridines,glycosides,ASS,platelet aggregation inhibitors,nonsteroidal anti-inflammatory drugs(NSAIDs),statins and fibrates,and with atherosclerosis,particularly coronary heart disease,and hyperlipoproteinaemia.Echocardiographic parameters did not show substantial differences.In the multivariate analysis only fibrates[odds ratio(OR)=9.1],NSAIDs(OR=6.7)and atherosclerosis(OR=2.1)proved to be associated with DiC.Both DiC reassessment groups presented milder inflammation than ischaemic colitis.The DiC patients with atherosclerosis exhibited histological features from both DiC without atherosclerosis and ischaemic colitis.CONCLUSION Several drugs indicated for the treatment of cardiovascular and related diseases are associated with DiC.Atherosclerosis and microcirculatory disturbances seem to play an important pathogenetic role.展开更多
Liver injury is a common cause of drug approval withdrawal during drug development,pre-clinical research,and clinical treatment.If not properly treated,patients with severe liver injury can suffer from acute liver fai...Liver injury is a common cause of drug approval withdrawal during drug development,pre-clinical research,and clinical treatment.If not properly treated,patients with severe liver injury can suffer from acute liver failure or even death.Thus,utilization of the convenient in vitro hepatotoxicity assessment model for early detection of drug-induced hepatotoxicity is vital for drug development and safe personalized medication.Biomaterials(e.g.,hydrogels,nanofibers,decellularized liver matrix)and bioengineering technologies(e.g.,microarrays,micropatterns,3D printing,and microfluidics)have been applied for in vitro hepatotoxicity assessment models.This review summarizes the structure and functions of the liver as well as the components of in vitro hepatotoxicity assessment models.In addition,it highlights the latest advances in developing hepatotoxicity models with the ultimate goal of further clinical translation.展开更多
Human-derived tumor models are essential for preclinical development of new anti-cancer drug entities.Generating animal models bearing tumors of human origin,such as patient-derived or cell line-derived xenograft tumo...Human-derived tumor models are essential for preclinical development of new anti-cancer drug entities.Generating animal models bearing tumors of human origin,such as patient-derived or cell line-derived xenograft tumors,is dependent on immuno-deficient strains.Tumor-bearing immunodeficient mice are susceptible to develop-ing unwanted disorders primarily irrelevant to the tumor nature;and if get involved with such disorders,reliability of the study results will be undermined,inevitably con-founding the research in general.Therefore,a rigorous health surveillance and clinical monitoring system,along with the establishment of a strictly controlled barrier facility to maintain a pathogen-free state,are mandatory.Even if all pathogen control and biosafety measures are followed,there are various noninfectious disorders capable of causing tissue and multiorgan damage in immunodeficient animals.Therefore,the re-searchers should be aware of sentinel signs to carefully monitor and impartially report them.This review discusses clinical signs of common unwanted disorders in experi-mental immunodeficient mice,and how to examine and report them.展开更多
基金The National Key R&D Program of China(No.2018YFA0108202)National Science Foundation,China(Nos.61971410,61801464,62001458 and 61801465)+3 种基金Shanghai Sailing Program(No.20YF1457100)China Postdoctoal Science Foundation(No.2020000246)Shanghai Engineer&Technology Research Center of Internet of Things for Respiratory Medicine(No.20DZ2254400)the Science and Technology Commission of Shanghai Municipality(No.19511104200)。
文摘Liver is the foremost organ of human being for drug metabolism,and it played a significant role in toxicity evaluation of drugs.Establishing a liver model in vitro can accelerate the process of the drug screening and new drug research and development.We provide a 3D printing based hepatic sinusoid-on-a-chip microdevice that reconstitutes organ-level liver functions to create a drug screening model of toxicity evaluation on chip.The microfluidic device,which recapitulates the hepatic sinusoid microenvironment,consists of PET polyporous membranes which mimic the perisinusoidal space,and experience fluid flow to mimic the hepatic arterial capillaries.The PET membrane was used to separate the hepatocyte and endotheliocyte.The endotheliocyte was cultured on the downside of the membrane and the hepatocyte were 3D seeded on the membrane via the 3D printer.This device was used to reproduce the in vitro liver model for drug toxicity assays.The expression of several biomarkers of liver was compared with the monoculture and 2D cultured conditions,and the results reveal that this organ-on-a-chip microdevice mimics the drug hepatoxicity that has not been possible by 2D cell-based and animal models,providing a useful platform for screening the drugs and developing an effective therapy in hepatopathy.
基金This work was supported by grants from the National Key Research and Development Program of China(2017YFA0103601)the National Natural Science Foundation of China(31730056 and 31988101)to YGC.
文摘Pig and monkey are widely used models for exploration of human diseases and evaluation of drug efficiency and toxicity,but high cost limits their uses.Organoids have been shown to be promising models for drug test as they reasonably preserve tissue structure and functions.However,colonic organoids of pig and monkey are not yet established.Here,we report a culture medium to support the growth of porcine and monkey colonic organoids.Wnt signaling and PGE2 are important for long-term expansion of the organoids,and their withdrawal results in lineage differentiation to mature cells.Furthermore,we observe that porcine colonic organoids are closer to human colonic organoids in terms of drug toxicity response.Successful establishment of porcine and monkey colonic organoids would facilitate the mechanistic investigation of the homeostatic regulation of the intestine of these animals and is useful for drug development and toxicity studies.
文摘The liver is the organ by which the majority of sub-stances are metabolized, including psychotropic drugs. There are several pharmacokinetic changes in end-stage liver disease that can interfere with the metabolization of psychotropic drugs. This fact is particularly true in drugs with extensive first--pass metabolism, highly protein bound drugs and drugs depending on phase I hepatic metabolic reactions. Psychopharmacological agents are also associated with a risk of hepatotoxicity. The evidence is insufficient for definite conclusions regarding the prevalence and severity of psychiatric drug-induced liver injury. High-risk psychotropics are not advised when there is pre-existing liver disease, and after starting a psychotropic agent in a patient with hepatic impairment, frequent liver function/lesion monitoring is advised. The authors carefully review the pharmacokinetic disturbances induced by end-stage liver disease and the potential of psychopharmacological agents for liver toxicity.
文摘Chemotherapy-induced toxicity,resulting from inter-individual variability in pharmacokinetics is emerging as a highly active area of investigation.Body composition analysis,primarily concerning the amount of fat mass(FM)and lean body mass(LBM),has provided a proof-concept that the inter-individual variability in pharmacokinetics and toxicity profiles may be partially explained by the discrepancies of FM and LBM in patients.Recent research suggests a close relationship among body composition,pharmacokinetics and toxicity of anticancer drugs.Because LBM and FM,significantly influence the exposure to drugs,they are considered as the promising predictors of chemotherapy-induced toxicity and a potential basis for optimizing the dosing of oncology drugs and the outcomes.Our review summarizes the recent studies rendering the aforementioned correlations to highlight that a critical evaluation of body composition has initiated a new era for dose standardization.
基金financially supported by the Offi ce of Research and Standards, Office of Generic Drugs, CDER at the FDA (75F40120C00055)
文摘Amphotericin B(AmB)is an amphiphilic drug commonly formulated in liposomes and administered intravenously to treat systemic fungal infections.Recent studies on the liposomal drug product have shed light on the AmB aggregation status in the bilayer,which heat treatment(curing)modifies.Although toxicity was found related to aggregation status-loose aggregates significantly more toxic than tight aggregates-the precise mechanism linking aggregation and toxicitywas notwell understood.This study directlymeasured drug release rate fromvarious AmB liposomal preparations made with modified curing protocols to evaluate correlations among drug aggregation state,drug release,and in vitro toxicity.UV–Vis spectroscopy of these products detected unique curing-induced changes in the UV spectral features:a∼25nm blue-shift of the main absorption peak(λ_(max))in aqueous buffer and a decrease in the OD_(346)/OD_(322) ratio upon thermal curing,reflecting tighter aggregation.In vitro release testing(IVRT)data showed,by applying and fitting first-order release kinetic models for one or two pools,that curing impacts two significant changes:a 3–5-fold drop in the overall drug release rate and a ten-fold decrease in the ratio between the loosely aggregated and the tightly aggregated,more thermodynamically stable drug pool.The kinetic data thus corroborated the trend independently deduced from the UV–Vis spectral data.The in vitro toxicity assay indicated a decreased toxicity with curing,as shown by the significantly increased concentration,causing half-maximal potassium release(TC50).The data suggest that the release of AmB requires dissociation of the tight complexes within the bilayer and that the reduced toxicity relates to this slower rate of dissociation.This study demonstrates the relationship between AmB aggregation status within the lipid bilayer and drug release(directly measured rate constants),providing a mechanistic link between aggregation status and in vitro toxicity in the liposomal formulations.
文摘Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local 02 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca^2＋-dependent ATPase, reduced capability to sequester Ca^2＋ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.
文摘To investigate the neurotoxicity of intrathecal injections of dexmedetomidine,Sprague-Dawley rats were intrathecally injected with dexmedetomidine at doses of 0.75,1.50 and 3.00μg/kg into the spinal dorsal horn.We found that c-Fos expression in the rat spinal dorsal horn peaked at 7 hours following the 3.00μg/kg dexmedetomidine injection,while the levels of c-Fos expression following 0.75 and 1.50μg/kg dexmedetomidine were similar to those in the spinal dorsal horn of normal rats. At 48 hours following administration,the level of c-Fos expression was similar to normal levels.In addition,the intrathecal injections of dexmedetomidine increased paw withdrawal mechanical thresholds and prolonged thermal tail flick latencies.These results indicate that dexmedetomidine has pronounced antinociceptive effects.However,dexmedetomidine appears to have neurotoxic effects in the spinal cord because it increased c-Fos expression in the spinal dorsal horn within 7 hours following administration.
基金Supported by Brazilian research agencies CNPq and FAPERJ for financial support
文摘AIM: To analyze the prevalence of thiopurine-methyltransferase (TPMT) genotypes and their association with drug toxicity in inflammatory bowel disease (IBD) patients from southeastern Brazil.
文摘Therapeutic experiments are commonly performed on laboratory animals to inves-tigate the possible mechanism(s)of action of toxic agents as well as drugs or sub-stances under consideration.The use of toxins in laboratory animal models,including rats,is intended to cause toxicity.This study aimed to investigate different models of hepatotoxicity and nephrotoxicity in laboratory animals to help researchers advance their research goals.The current narrative review used databases such as Medline,Web of Science,Scopus,and Embase and appropriate keywords until June 2021.Nephrotoxicity and hepatotoxicity models derived from some toxic agents such as cisplatin,acetaminophen,doxorubicin,some anticancer drugs,and other materials through various signaling pathways are investigated.To understand the models of renal or hepatotoxicity in laboratory animals,we have provided a list of toxic agents and their toxicity procedures in this review.
文摘BACKGROUND Drug toxicity is a common and even serious problem in the gastrointestinal tract that is thought to be caused by a broad spectrum of agents.Although withdrawal of the causative agent would cure the disease knowledge is scarce and mostly derives from case reports and series.AIM To investigate potential triggers of drug-induced colitis(DiC).METHODS We conducted a retrospective,observational case control study.Patients were assigned to DiC or one of two age-and gender-matched control groups(noninflammatory controls and inflammatory colitis of another cause)based on histopathological findings.Histopathology was reassessed in a subset of patients(28 DiC with atherosclerosis,DiC without atherosclerosis and ischaemic colitis each)for validation purposes.Medical history was collected from the electronic database and patient records.Statistical analysis included chi-squared test,t-test,logistic and multivariate regression models.RESULTS Drug-induced colitis was detected in 211 endoscopically sampled biopsy specimens of the colon mucosa(7%of all screened colonoscopic biopsy samples);a total of 633 patients were included equally matched throughout the three groups(291 males,mean age:62.1±16.1 years).In the univariate analysis,DiC was associated with diuretics,dihydropyridines,glycosides,ASS,platelet aggregation inhibitors,nonsteroidal anti-inflammatory drugs(NSAIDs),statins and fibrates,and with atherosclerosis,particularly coronary heart disease,and hyperlipoproteinaemia.Echocardiographic parameters did not show substantial differences.In the multivariate analysis only fibrates[odds ratio(OR)=9.1],NSAIDs(OR=6.7)and atherosclerosis(OR=2.1)proved to be associated with DiC.Both DiC reassessment groups presented milder inflammation than ischaemic colitis.The DiC patients with atherosclerosis exhibited histological features from both DiC without atherosclerosis and ischaemic colitis.CONCLUSION Several drugs indicated for the treatment of cardiovascular and related diseases are associated with DiC.Atherosclerosis and microcirculatory disturbances seem to play an important pathogenetic role.
基金supports from General Program from the National Natural Science Foundation of China(No.31871016)the National Key Research and Development Program(2016YFC1101302)from the Ministry of Science and Technology of China.
文摘Liver injury is a common cause of drug approval withdrawal during drug development,pre-clinical research,and clinical treatment.If not properly treated,patients with severe liver injury can suffer from acute liver failure or even death.Thus,utilization of the convenient in vitro hepatotoxicity assessment model for early detection of drug-induced hepatotoxicity is vital for drug development and safe personalized medication.Biomaterials(e.g.,hydrogels,nanofibers,decellularized liver matrix)and bioengineering technologies(e.g.,microarrays,micropatterns,3D printing,and microfluidics)have been applied for in vitro hepatotoxicity assessment models.This review summarizes the structure and functions of the liver as well as the components of in vitro hepatotoxicity assessment models.In addition,it highlights the latest advances in developing hepatotoxicity models with the ultimate goal of further clinical translation.
文摘Human-derived tumor models are essential for preclinical development of new anti-cancer drug entities.Generating animal models bearing tumors of human origin,such as patient-derived or cell line-derived xenograft tumors,is dependent on immuno-deficient strains.Tumor-bearing immunodeficient mice are susceptible to develop-ing unwanted disorders primarily irrelevant to the tumor nature;and if get involved with such disorders,reliability of the study results will be undermined,inevitably con-founding the research in general.Therefore,a rigorous health surveillance and clinical monitoring system,along with the establishment of a strictly controlled barrier facility to maintain a pathogen-free state,are mandatory.Even if all pathogen control and biosafety measures are followed,there are various noninfectious disorders capable of causing tissue and multiorgan damage in immunodeficient animals.Therefore,the re-searchers should be aware of sentinel signs to carefully monitor and impartially report them.This review discusses clinical signs of common unwanted disorders in experi-mental immunodeficient mice,and how to examine and report them.
