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1.
Toxicology ; 503: 153767, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38437911

RESUMO

Ricin is a highly toxic plant toxin that can cause multi-organ failure, especially liver dysfunction, and is a potential bioterrorism agent. Despite the serious public health challenge posed by ricin, effective therapeutic for ricin-induced poisoning is currently unavailable. Therefore, it is important to explore the mechanism of ricin poisoning and develop appropriate treatment protocols accordingly. Previous studies have shown that lipid peroxidation and iron accumulation are associated with ricin poisoning. Ferroptosis is an iron-dependent form of cell death caused by excessive accumulation of lipid peroxide. The role and mechanism of ferroptosis in ricin poisoning are unclear and require further study. We investigated the effect of ferroptosis on ricin-induced liver injury and further elucidated the mechanism. The results showed that ferroptosis occurred in the liver of ricin-intoxicated rats, and Ferrostatin­1 could ameliorate hepatic ferroptosis and thus liver injury. Ricin induced liver injury by decreasing hepatic reduced glutathione and the protein level of glutathione peroxidase 4 and Solute Carrier Family 7 Member 11, increasing iron, malondialdehyde and reactive oxygen species, and mitochondrial damage, whereas Ferrostatin­1 pretreatment increased hepatic reduced glutathione and the protein level of glutathione peroxidase 4 and Solute Carrier Family 7 Member 11, decreased iron, malondialdehyde, and reactive oxygen species, and ameliorated mitochondrial damage, thereby alleviated liver injury. These results suggested that ferroptosis exacerbated liver injury after ricin poisoning and that inhibition of ferroptosis may be a novel strategy for the treatment of ricin poisoning.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Cicloexilaminas , Ferroptose , Doenças Transmitidas por Alimentos , Fenilenodiaminas , Ricina , Animais , Ratos , Ricina/toxicidade , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Espécies Reativas de Oxigênio , Ferro , Malondialdeído , Glutationa
2.
Appl Spectrosc ; 78(6): 605-615, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38404185

RESUMO

In this study, the application of low-level fusion (LLF) and high-level fusion (HLF) strategies using a combination of Fourier transform infrared spectroscopy (FT-IR) and Raman spectroscopy in the identification of antemortem and postmortem fracture at different postmortem intervals (PMIs) was investigated. On a technical level, the same hard tissue sample can be detected using a mix of FT-IR and Raman techniques. At the method level, two cutting-edge chemometrics approaches (LLF and HLF) combining FT-IR and Raman spectroscopic data are explored. The models were ranked in accordance with their parametric quality as follows: HLF and LLF + HLF models > LLF single model > Raman single model > FT-IR single model. The LLF model performed marginally better than the Raman model, however, when compared to other models, the HLF model performed considerably better. The HLF model achieved the best performance, with both cross-validation accuracy and test data set accuracy of 0.88. The importance of the feature wavelengths in the model construction process was subsequently evaluated by intersection fusion, and it was found that the absorbance bands of amide I, PO43- ν1 ν3, and CH2 in FT-IR and phenylalanine, CO32- ν1- PO43- ν3, and amide III in Raman have outstanding contributions to the construction of antemortem and postmortem fractures identification models. Overall, the combination of FT-IR and Raman with the HLF strategy is a novel and promising approach for developing antemortem and postmortem fracture identification models at different PMIs.


Assuntos
Fraturas Ósseas , Análise Espectral Raman , Análise Espectral Raman/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Humanos , Animais , Mudanças Depois da Morte
3.
Toxicol Appl Pharmacol ; 482: 116799, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38160893

RESUMO

Doxorubicin (DOX) is one of the most widely used antineoplastic drugs with known cardiotoxicity while other organ toxicity, such as hepatotoxicity is not well defined. This study was to explore the role of nicotinamide adenine dinucleotide (NAD+) in DOX-induced hepatotoxicity. DOX (20 mg/kg) induced acute liver injury and oxidative stress in C57BL/6 J mice at 48 h. Notably, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and NAD(P)H dehydrogenase quinone 1 (NQO1) were downregulated. NAD+ deficiency was confirmed due to DOX exposure. Mechanistically, the downregulation of nicotinamide mononucleotide adenylyl transferase 1 (NMNAT1), NMNAT2 and NMNAT3, while no alteration of nicotinamide phosphoribosyl transferase was proved. As a consequence of NAD+ deficiency, the expression of poly-ADP-ribose polymerase1 (PARP1), CD38 and Sirtuin1 (SIRT1) were reduced. Furthermore, supplementation of NAD+ (200 mg/kg/day) or its precursor nicotinamide mononucleotide (NMN) (500 mg/kg/day) alleviated liver injury, attenuated oxidative stress, and elevated the downregulation of Nrf2 and NQO1. More importantly, compromised expression of NMNAT1-3, PARP1, CD38 and SIRT1 were improved by NAD+ and NMN. In conclusion, NAD+ deficiency due to NMNATs expression inhibition may attribute to the pathogenesis of DOX-induced hepatotoxicity, thus providing new insights for mitigating DOX side effects.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , NAD , Camundongos , Animais , NAD/metabolismo , Mononucleotídeo de Nicotinamida/farmacologia , Sirtuína 1/metabolismo , Fator 2 Relacionado a NF-E2 , Camundongos Endogâmicos C57BL , Doxorrubicina/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia
4.
Proteome Sci ; 21(1): 13, 2023 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-37740197

RESUMO

BACKGROUND: DCM is a common cardiomyopathy worldwide, which is characterized by ventricular dilatation and systolic dysfunction. DCM is one of the most widespread diseases contributing to sudden death and heart failure. However, our understanding of its molecular mechanisms is limited because of its etiology and underlying mechanisms. Hence, this study explored the underlying molecular mechanism of dilated cardiomyopathy through integrative analysis of data mining, iTRAQ-PRM proteomics and bioinformatics METHODS: DCM target genes were downloaded from the public databases. Next, DCM was induced in 20 rats by 8 weeks doxorubicin treatment (2.5 mg/kg/week). We applied isobaric tags for a relative and absolute quantification (iTRAQ) coupled with proteomics approach to identify differentially expressed proteins (DEPs) in myocardial tissue. After association analysis of the DEPs and the key target genes, subsequent analyses, including functional annotation, pathway enrichment, validation, were performed. RESULTS: Nine hundred thirty-five genes were identified as key target genes from public databases. Meanwhile, a total of 782 DEPs, including 348 up-regulated and 434 down-regulated proteins, were identified in our animal experiment. The functional annotation of these DEPs revealed complicated molecular mechanisms including TCA cycle, Oxidative phosphorylation, Cardiac muscle contraction. Moreover, the DEPs were analyzed for association with the key target genes screened in the public dataset. We further determined the importance of these three pathways. CONCLUSION: Our results demonstrate that TCA cycle, Oxidative phosphorylation, Cardiac muscle contraction played important roles in the detailed molecular mechanisms of DCM.

5.
Artigo em Inglês | MEDLINE | ID: mdl-37542619

RESUMO

Lung cancer is a high degree of malignancy. Although surgery, radiotherapy, and chemotherapy have made significant progress and become general methods of clinical treatment, the overall survival rate is still low. In recent years, targeted therapy and immunotherapy have a rapid development in the clinical treatment of tumors. Among them, natural killer (NK) cells have the advantages of rapid killing of diseased cells and low risk of graft-versus-host reaction. It is considered a great vector for chimeric antigen receptors (CARs), making them have good application prospects in tumor immunotherapy. However, its clinical application in lung cancer needs further research. Herein, we reported a case of a lung cancer patient undergoing CAR-NK cell immunotherapy after resection, which caused a cytokine storm and sudden death after the fourth treatment. This case report provides a reference for the forensic examination of cadavers that died after immunotherapy and challenges the clinical application of cell immunotherapy.

6.
Leg Med (Tokyo) ; 65: 102302, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37549592

RESUMO

Identification of mechanical asphyxia deaths without obvious injuries is a difficult problem for forensic medicine. This study aimed to identify molecular biological markers to predict death from mechanical asphyxia (smother). We established a smother model of mice by over the head with plastic bag tightly until the mice died and applied label-free proteomic technology to identify differentially expressed proteins (DEPs) in heart. A total of 3307 proteins were quantified, and a Fold Change (FC) > 1.2 (or <1/1.2) and Q value < 0.05 were considered as DEPs. Through comparative analysis, we identified 606 DEPs compared to the control group, comprising 219 upregulated and 387 downregulated proteins. Bioinformatics analysis (MCODE analysis) showed that the candidate proteins were mainly involved in regulation of ribosome function, myocardial contraction and calcium regulation, regulation of coagulation and regulation of mitochondrial oxidative respiration. Seven of these proteins were validated using parallel reaction monitoring (PRM), including fibrinogen alpha chain (FIBA), fibrinogen gamma chain (FIBG), Calsequestrin-2 (CASQ2), NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 (NDUAB), NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3 (NDUA3), NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 (NDUAD) and Rab7 (RAB7A). CASQ2 and FIBG were further validated by immunohistochemistry. In conclusion, our results may provide some auxiliary indices for identifying the death from mechanical asphyxia.


Assuntos
Asfixia , Proteômica , Camundongos , Animais , Proteômica/métodos , NADH Desidrogenase , Ubiquinona , Biomarcadores , Fibrinogênio
7.
J Integr Neurosci ; 22(1): 21, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36722232

RESUMO

BACKGROUND: Epilepsy is a disease caused by paroxysmal abnormal supersynchronous electrical activity of brain neurons, and it is also one of the most common illnesses in neurology. Among the causes, hippocampal sclerosis may be one of the main causes of temporal lobe epilepsy. However, the pathogenesis of hippocampal sclerosis in epilepsy remains unclear. METHODS: We established an epilepsy model by intraperitoneal injection of pentetrazol (PTZ) into Sprague-Dawley rats, and applied isobaric tags for relative and absolute quantitation (iTRAQ) technology to identify differentially expressed proteins (DEPs) in the hippocampus. We quantified a total of 3782 proteins. DEPs were defined as proteins with a fold change >1.2 (or <0.83) and a Q value (p-adjusted) <0.05. RESULTS: Comparing the epilepsy group and the control group, we identified 170 DEPs, comprising 109 upregulated and 61 downregulated proteins. According to bioinformatics analysis, the DEPs were primarily involved in long-term potentiation, the calcium signalling pathway, aldosterone synthesis and secretion, carbon metabolism, and dopaminergic synapses. Four of these proteins were validated using parallel reaction monitoring (PRM), including Glud1, Atp1a2, Prkcg and Arpc3. CONCLUSIONS: Our research results may provide further insight into the molecular pathology of hippocampal injury in epilepsy.


Assuntos
Epilepsia do Lobo Temporal , Epilepsia , Esclerose Hipocampal , Ratos , Animais , Ratos Sprague-Dawley , Proteômica , Epilepsia/induzido quimicamente , Epilepsia do Lobo Temporal/induzido quimicamente , Hipocampo
8.
Toxics ; 12(1)2023 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-38250973

RESUMO

Due to nonspecific pathological changes and the rapid degradation of insulin in postmortem blood samples, the identification of the cause of death during insulin overdose has always been a difficulty in forensic medicine. At present, there is a lack of studies on the toxicological changes and related mechanisms of an insulin overdose, and the specific molecular markers of insulin overdose are still unclear. In this study, an animal model of insulin overdose was established, and 24 SD rats were randomly divided into a control group, insulin overdose group, and a recovery group (n = 8). We detected the biochemical changes and analyzed the toxicological mechanism of an insulin overdose. The results showed that after insulin overdose, the rats developed irregular convulsions, Eclampsia, Opisthotonos, and other symptoms. The levels of glucose, glycogen, and C-peptide in the body decreased significantly, while the levels of lactate, insulin, and glucagon increased significantly. The decrease in plasma K+ was accompanied by the increase in skeletal muscle K+. The PI3K-AKT signaling pathway was significantly activated in skeletal muscle, and the translocation of GLUT4/Na+-K+-ATPase to sarcolemma was significantly increased. Rare glycogenic hepatopathy occurred in the recovery group after insulin overdose. Our study showed that insulin overdose also plays a role in skeletal muscle cells, mainly through the PI3K-Akt signaling pathway. Therefore, the detection of signaling pathway proteins of the skeletal muscle cell membrane GLUT4 and Na+-K+-ATPase has a certain auxiliary diagnostic value for forensic insulin overdose identification. Glycogen detection in the liver and skeletal muscle is important for the diagnosis of insulin overdose, but it still needs to be differentiated from other causes of death. Skeletal muscle has great potential for insulin detection, and the ratio of insulin to the C-peptide (I:C) can determine whether an exogenous insulin overdose is present.

9.
Bioinorg Chem Appl ; 2022: 1729131, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36065391

RESUMO

Age-related changes in bone tissue have always been an important part of bone research, and age estimation is also of great significance in forensic work. In our study, FTIR and Raman microspectroscopy were combined to explore the structural and chronological age-related changes in the occipital bones of 40 male donors. The FTIR micro-ATR mode not only achieves the comparison of FTIR and Raman efficiency but also provides a new pattern for the joint detection of FTIR and Raman in hard tissue. Statistical analysis and PCA results revealed that the structure had little effect on the FTIR and Raman results. The FTIR and Raman mineral/matrix ratio, carbonate/phosphate ratio, crystallinity, and collagen maturity of the whole showed an increasing trend during maturation, and a significant correlation was found between FTIR and Raman by comparing four outcomes. Furthermore, the results indicated that the cutoff point of the change in the relative proportion of organic matrix and inorganic minerals in males was between 19 and 35 years old, and the changes in the relative proportion of organic matrix and inorganic minerals may play a key role in age estimation. Ultimately, we established age estimation regression models. The FTIR GA-PLS regression model has the best performance and is more suitable for our experiment (RMSECV = 10.405, RMSEP = 9.2654, R 2CV = 0.814, and R 2Pred = 0.828). Overall, FTIR and Raman combined with chemometrics are an ideal method to estimate chronological age based on age-dependent component changes in male occipital bones. Our experiment provides a proof of concept and potential experimental method for chronological age estimation.

10.
Leg Med (Tokyo) ; 53: 101930, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34130173

RESUMO

The aim of this study was to detect the postmortem serum total IgE levels in frozen corpses and identify whether the death incident caused by an anaphylaxis in forensic medicine. Autopsy cases with pathological death (total, n = 106; 4-214 h postmortem) include cardiac disease (n = 15), pulmonary infection (n = 12), central nervous system disorder (n = 6), pulmonary emboliszn (n = 7), hapetic disease (n = 5), kidney disease (n = 6), enteric disease (n = 10), necrotizing pancreatitis (n = 7), diffuse peritonitis (n = 6), MODS (n = 6), toxicosis (n = 5:), anaphylactic shock (n = 7), bronchial asthma (n = 8) and other disease (n = 6) were examined. Results showed that there was no significant difference between serum IgE levels and ages, postmortem intervals (PMIs), gender as well as survival time. Serum IgE levels of deaths due to anaphylactic shock and bronchial asthma were higher than that of other groups. Forensic pathology examination results showed the main pathology changes of bronchial asthma were mucous congestion in bronchial lumen and eosinophils infiltration in bronchial mucosa. The main pathological features of anaphylactic shock were laryngeal edema and eosinophils infiltration in multiple organs (lung and spleen). This research proved that there was a great significance for IgE to infer whether the individual died due to an anaphylaxis even for a long PMI in frozen corpses. Furthermore, we can also preliminarily determine the type of allergic death combined with the examination of forensic pathology. These findings further verify the feasibility of postmortem serum IgE in the diagnosis of forensic causes of death and broaden the application scope of this marker.


Assuntos
Anafilaxia , Anafilaxia/diagnóstico , Autopsia , Cadáver , Medicina Legal , Patologia Legal , Humanos , Imunoglobulina E
11.
J Forensic Leg Med ; 81: 102204, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34192655

RESUMO

Systemic vasculitis (SV) is a condition characterized by vascular inflammatory disease that often involves the medium and small arteries of various organs throughout the body. SV is difficult to diagnose due to the diversity of clinical symptoms and manifestations, and only tissue biopsy is of great significance. Even so, complications or secondary lesions of SV can also lead to death. In forensic medicine, we can often observe multiple vasculitis in histological observations, which is easily overlooked as a primary cause of death in the final diagnosis. Twenty SV cases were registered in our institution from a total of 1088 completed autopsies, which represents 1.83% of the total autopsies. The ages of these 20 SV patients ranged from 16 to 73 years, and the mean age was 41.1 ± 15.9 years. SV usually involves multiple organs, such as the heart, lung, liver, kidney, gastrointestinal system and brain, simultaneously. The intensity of the lesions in the heart and kidney seemed to be more severe than the lesion intensity in other organs in most cases. The causes of death were identified as acute myocarditis (8 cases), acute heart failure (3 cases), cerebral artery rupture (3 cases), cardiovascular artery rupture (2 cases), acute interstitial pneumonia (2 cases), aortic aneurysm rupture (1 case) and acute renal failure (1 case). The typical histopathological changes (smooth muscle degeneration, fibrinoid necrosis, inflammatory cell infiltration and microthrombosis) of arteries observed in this study were of great significance for diagnosing SV. In this article, we try to analyse and summarize the lesion characteristics in cases of death caused by SV in order to provide some help for forensic workers in identifying such cases.


Assuntos
Patologia Legal , Vasculite Sistêmica/diagnóstico , Vasculite Sistêmica/patologia , Adolescente , Adulto , Idoso , Autopsia , Causas de Morte , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mudanças Depois da Morte , Estudos Retrospectivos , Adulto Jovem
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