Human & Experimental Toxicology

Adibelli, Zelal; Sermenli, Hayrunisa Bas; Uc, Ziynet Alphan

doi: 10.1177/09603271241304368pmid: 39586578

IntroductionThe outbreak of acute kidney injury (AKI) due to mushroom poisoning is not a frequently encountered medical challenge. Herein, we present 13 mushroom poisoning cases associated with AKI related to Amanita Proxima (A. Proxima) causing poisoning reported in a short time period in Turkey.MethodsA total of 13 patients with AKI due to mushroom poisoning admitted to Usak Research and Training Hospital between November and December 2020 were included. Under morphological and microscopical investigations of mushroom specimens (from three patients), the species of the mushrooms were identified.ResultsThe median age of 13 patients presenting with AKI due to mushroom poisoning was 55 (ranging between 19 and 72 years), and 60.4% were males. Nausea and vomiting were the first symptoms in most patients and appeared at a mean time of 12.8 ± 7.6 h after ingesting mushrooms. Mean serum creatinine on admission was 7.2 ± 3.8 mg/dL. Kidney replacement therapy (KRT) was administered to all patients, and mortality occurred in two due to sepsis and heart failure (HF). Species of the mushroom specimens obtained from three patients were identified as A. Proxima, a rarely encountered type of mushroom. A. Proxima has a considerable similarity to a common and edible species specific to the Mediterranean Basin, known as A. Ovoidea.DiscussionBased on our findings, we emphasize the consideration of nephrotoxic mushrooms of the genus Amanita in the evaluation of mushroom poisoning cases, as well as the efforts needed to increase public awareness regarding the risk of fatal outcomes of consuming wild mushrooms.

Dong, MingXia; Xiao, Qing; Mei, YunTeng; Fan, Bao Liang; Liu, ChenWei

doi: 10.1177/09603271241303411pmid: 39592112

ObjectiveTo retrospectively analyze the etiology of non-diabetic retinopathy (DR) and non-traumatic vitreous haemorrhage (VH), and the effects of different anti-vascular endothelial growth factor (VEGF) drugs.MethodsA retrospective analysis was conducted on VH patients diagnosed as non-diabetic retinopathy or trauma. Among 101 patients treated with anti-VEGF drugs, there were 48 cases in the Conbercept group and 53 cases in the Ranibizumab group. The causes of bleeding and gender distribution of the included cases were analyzed.ResultsIn cases of retinal vein occlusion, the proportion of males was much higher than females (p < 0.05). After treatment, the best corrected visual acuity (BCVA), intraocular pressure, central macular thickness (CMT), aqueous humor VEGF, TNF-α, IL-10, and IL-6 of the two groups showed a decreasing trend (p < 0.05). The Conbercept group had markedly lower CMT than the Ranibizumab group (p < 0.05). In addition, there existed no significant statistical differences between the two groups in terms of BCVA, intraocular pressure, aqueous humor VEGF, TNF-α, IL-10, IL-6, incidence of adverse reactions, and recurrence rate (p > 0.05).ConclusionIn patients with non-DR and traumatic VH, retinal vein occlusion, perivenous retinitis, retinal tears/detachment, exudative AMD, and polypoidal choroidal vasculopathy were the main etiologies. Conbercept and Ranibizumab had comparable efficacy and could effectively improve visual acuity and aqueous humor inflammation, with high safety and low recurrence rate. Conbercept had a more pronounced effect on the reduction of CMT in patients.

Fan, Zhong; Lin, Wen-Hao; Liang, Cong; Li, Yu; Peng, Chun-Jin; Luo, Jie-Si; Tang, Wen-Yan; Zheng, Li-Min; Huang, Dan-Ping; Ke, Zhi-Yong; Wang, Li-Na; Zhang, Xiao-Li; Huang, Li-Bin

doi: 10.1177/09603271241303030pmid: 39586583

BackgroundAcute lymphoblastic leukemia (ALL) is one of the most common pediatric cancers, characterized by the malignant proliferation of leukemic cells. Despite advancements in treatment, the prognosis for refractory and relapsed ALL remains poor, underscoring the need for novel therapeutic targets and approaches.MethodsTo investigate the anti-leukemic properties of MG132, MTS assays were employed to assess cell viability, and flow cytometry was used to evaluate apoptosis. Mechanistic studies, including qRT-PCR, Western blotting, and lentivirus-mediated FOXO3a knockdown, were conducted to explore MG132’s effects on the Akt/FOXO3a/Bim signaling pathway. A xenograft mouse model was utilized to validate the in vivo efficacy of MG132 in suppressing tumor growth.ResultsMG132 inhibited cell proliferation and induced apoptosis in both ALL cell lines and primary cells in a concentration-dependent manner. Mechanistic studies revealed that MG132 promoted FOXO3a nuclear localization by suppressing Akt phosphorylation and preventing FOXO3a degradation, leading to increased Bim expression. Furthermore, FOXO3a knockdown significantly reduced MG132’s anti-proliferative effects. In vivo, MG132 markedly inhibited tumor growth in the xenograft model.ConclusionThese findings suggest that MG132 exerts potent anti-leukemic effects through modulation of the Akt/FOXO3a/Bim axis, offering a promising therapeutic avenue for treating ALL.

Shi, Min; Zhang, Lu; Bi, Fangfang; Ma, Xiaohong

doi: 10.1177/09603271241303320pmid: 39557042

IntroductionAbnormal activation of hypertrophic scar fibroblasts (HSF) plays an important role in the excessive fibrosis of hypertrophic scars (HS). However, the regulatory mechanism of HSF abnormal activation is not fully unclear. Early studies had shown that M2 macrophages were increased during scar formation. The aim of this study was to investigate the mechanism of M2 macrophage-derived exosomes (M2-EXOs) mediating HSF abnormal activation.MethodsThe blood samples of 20 normal people and 20 HS patients were collected from Xi’an Hospital of Traditional Chinese Medicine, and the level of M2 macrophages in the blood was measured by flow cytometry. Subsequently, HSFs were co-cultured with M2-THP-1 for 48 h to analyze the effect of M2 macrophages on the function of HSFs in vitro. HSFs were treated with exogenous chemokine (C-X-C motif) ligand 2 (CXCL2) or anti-CXCL2 to analyze the effect of CXCL2 on HSFs function and autophagy. HSFs were treated with exogenous CXCL2 and/or anti-CXCR7, and CXCL2 and/or 3MA to explore the molecular mechanism of CXCL2-mediated HS. Finally, a mouse HS model was constructed, and the effect of M2-Exos on the growth of HS was explored by subcutaneous injection of CXCL2 or M2-Exos in the scar site in vivo.ResultsWe found that the proportion of M2 macrophages in the blood of HS patients increased. CXCL2-rich M2-EXOs promoted the abnormal proliferation, migration, and collagen deposition of HSFs in vitro. CXCL2 increased the level of p-mTOR in HSF and promoted the expression of autophagy proteins LC3II/I and Atg5 in vitro. Further results showed that CXCL2 activated autophagy through CXCR7/PI3K/mTOR signal transduction, thereby promoting collagen deposition and fibrosis in vitro. Autophagy inhibitor 3-MA reversed the effect of CXCL2 on HSFs in vitro. In addition, in the HS mouse model, after treatment with M2-EXOs or CXCL2 in vivo, the scar recovery time was significantly prolonged and the scar damage was aggravated.DiscussionThese results suggest that the CXCL2/CXCR7/mTOR pathway may be a promising target for the treatment of HS. Abnormal activation of hypertrophic scar fibroblasts (HSFs) plays an important role in the excessive fibrosis of hypertrophic scars (HS). However, the regulatory mechanism of HSFs abnormal activation is not fully unclear. Early studies had shown that M2 macrophages were increased during scar formation. The aim of this study was to investigate the mechanism of M2 macrophage-derived exosomes (M2-EXOs) mediating HSFs abnormal activation. Here, we analyzed the proportion of M2 macrophages in total macrophages in the HS patient’s blood, and we found that the proportion of M2 macrophages were elevated in the blood of HS patients. We found that C-X-C motif chemokine 2 (CXCL2)-rich M2-EXOs promoted abnormal proliferation, migration, and collagen deposition in HSFs in vitro. CXCL2 increased the phosphorylation level of mTOR protein and promoted the expression levels of autophagy related proteins LC3II/I and Atg5 in HSF in vitro. CXCL2 activated autophagy through chemokine (C-X-C motif) receptor 7(CXCR7)/PI3K/mTOR signal transduction, and promoted collagen deposition and fibrosis in vitro. The autophagy inhibitor 3-Methyladenine (3-MA) reversed the effect of CXCL2 on HSFs in vitro. Meanwhile, in the HS mouse model, the scar recovery time was significantly prolonged and the scar injury was aggravated after treatment with M2-EXOs or CXCL2 in vivo. These results suggest that the CXCL2/CXCR7/mTOR pathway may be a promising target for the treatment of HS.

Xia, Caiyun; Lai, Fuping; Wu, Jin; Zhan, Jiangshan; Zhang, Xiaojun; Yu, Xian; Liao, Ya; Zhang, Guiyi; Hu, Jie; Wang, Tinggang; Lu, Yuanlan

doi: 10.1177/09603271241302192pmid: 39624021

Mushroom poisoning has been identified as a primary cause of both foodborne disease outbreaks and related fatalities in China. Depending on the mushroom species ingested, target-organ damage can usually be attributed to the toxins presenting in the mushroom species ingested, which can ultimately lead to organ failure and death. Developing a joint risk prediction model for death caused by acute mushroom poisoning could accurately predict the risk of mortality in such cases, early initiation of bundled treatment could significantly reduce mortality.MethodsThis single-center, retrospective observational study was conducted on 455 patients with Undergoing Treatment for Mushroom Poisoning at Affiliated Hospital of Zunyi Medical University (AHZMU), the tertiary governmental hospital of China, between January 2013 and December 2020. We investigated the impact of prognostic factors, including the mortality rate of patients who completed treatment at AHZMU versus those transferred to AHZMU, average length of hospital stay, mortality rate for a latency period of > 6-h, major damaged organs, HOPE6-TALK scoring and established a predictive model to assess the severity of acute mushroom poisoning.ResultsIn 2013-2020, there are 455 patients of mushroom poisoning at AHZMU. Mushroom poisonings mainly concentrated in the summer and autumn months, resulted in 47 patients deaths. The first diagnosis cases at AHZMU resulting in a case fatality rate of 12.77% (6/47), Non-first diagnosis patients fatality accounting for 87.23% (41/47). The majority of deaths (89.36%) were attributed to liver injury. Death with incubation period >6-h accounting for 70.21% (33/47) of the total mortality rate. Logistic regression analysis revealed age and HOPE6 scores as independent risk factors, thereby establishing the logistic model equation, an examination via the ROC curve analysis indicates that a combination predictor values (Ycoalition) of 289.6 is the cut-off values for death resulting from acute mushroom poisoning.ConclusionThe attending physician should conduct an early HOPE6-TALK scoring and calculate the Ycoalition for patients with acute mushroom poisoning, as well as promptly identify the toxic mushrooms through morphological and molecular biological identification. Identify mushroom species and further infer the clinical type and clinical characteristics. For example, amanitoxion can cause acute liver injury with high mortality. Identify mushroom species that may cause organ damage so that timely implementation of the bundled therapy for poisonous mushrooms will increase the cure rate and reduce the mortality rate (Lu et al., 2019).

Qian, Hongyu; Zhou, Sufang; Qian, Rong; Li, Qingye; Zhang, Jian; Ding, Yanbing; Wang, Chuanxiang

doi: 10.1177/09603271241304372pmid: 39710598

IntroductionThe incidence of cerebral ischemia-reperfusion injury (I/R) is complex which seriously threatens the life safety of patients. Neither its prevention nor its treatment has been successful so far. Proteins that bind to DNA and belong to the C2/H2 zinc finger family are known as Krüppel-like factors (KLFs). Among them, KLF6 plays a vital role in proliferation, metabolism, inflammation, and damage responses, although its function in I/R remains largely unexplored.MethodsIn this study, we induced cerebral ischemia in rats using the middle cerebral artery occlusion (MCAO) model. Neural function, cerebral infarction volume, cognitive function, cortical pathological lesions, ferroptosis, and oxidative stress were measured.ResultsOur findings indicated that the MCAO model exhibited signs of ferroptosis and a concurrent increase in KLF6 levels. Inhibition of KLF6 resulted in a significant decrease in the escape latency during swimming tests (p < .05), an increase in the frequency of platform crossings, and prolonged duration in the target quadrant compared to the control group. Additionally, silencing KLF6 mitigated MCAO-induced brain injury and reduced oxidative stress and ferroptosis, as evidenced by altered levels of Nrf2/HO-1 signaling proteins.DiscussionIn conclusion, our results suggest that silencing KLF6 may protect against MCAO-induced pyroptosis, oxidative stress, and neurological dysfunction by inactivating the Nrf2/HO-1 signaling pathway. This study offers new perspectives on the molecular mechanisms related to MCAO and emphasizes the significance of targeting KLF6 for future therapeutic approaches.

Yuan, Ru; Wu, Chunxia

doi: 10.1177/09603271231218707pmid: 38487884

BackgroundBupivacaine (BUP), a long-acting local anesthetic, has been widely used in analgesia and anesthesia. However, evidence strongly suggests that excessive application of BUP may lead to neurotoxicity in neurons. Sphingosine kinase 2 (SPHK2) has been reported to exert neuroprotective effects. In this study, we intended to investigate the potential role and mechanism of SPHK2 in BUP-induced neurotoxicity in dorsal root ganglion (DRG) neurons. MethodsDRG neurons were cultured with BUP to simulate BUP-induced neurotoxicity in vitro. CCK-8, LDH, and flow cytometry assays were performed to detect the viability, LDH activity, and apoptosis of DRG neurons. RT-qPCR and western blotting was applied to measure gene and protein expression. Levels. MeRIP-qPCR was applied for quantification of m6A modification. RIP-qPCR was used to analyze the interaction between SPHK2 and YTHDF1.ResultsSPHK2 expression significantly declined in DRG neurons upon exposure to BUP. BUP challenge substantially reduced the cell viability and increased the apoptosis rate in DRG neurons, which was partly abolished by SPHK2 upregulation. YTHDF1, an N6-methyladenosine (m6A) reader, promoted SPHK2 expression in BUP-treated DRG neurons in an m6A-dependent manner. YTHDF1 knockdown partly eliminated the increase in SPHK2 protein level and the protection against BUP-triggered neurotoxicity in DRG neurons mediated by SPHK2 overexpression. Moreover, SPHK2 activated the PI3K/AKT signaling to protect against BUP-induced cytotoxic effects on DRG neurons.ConclusionsIn sum, YTHDF1-mediated SPHK2 upregulation ameliorated BUP-induced neurotoxicity in DRG neurons via promoting activation of the PI3K/AKT signaling pathway.

El-Sarnagawy, Ghada N; Abdelnoor, Amira A; Ghonem, Mona M

doi: 10.1177/09603271241302208pmid: 39561050

BackgroundUntil now, no definite standardized method has been used to promptly assess the severity and outcome of acute aluminum phosphide (ALP) poisoning. The current study aimed to evaluate the performance of the new Poisoning Mortality Score (PMS) and PGI score for predicting mortality in acute ALP-poisoned patients, highlighting the accuracy of new PMS components.Patients and MethodsA 2-year cross-sectional study was conducted on ALP-poisoned patients admitted to Tanta University Poison Control Centre from April 2021 to March 2023. Socio-demographics, poisoning data, and initial vital signs were recorded. Additionally, new PMS and PGI scores were calculated on admission. Patients were categorized according to the mortality outcome into survivors and nonsurvivors.ResultsOut of 160 included ALP poisoned patients, mortality was recorded in 112 (70%) patients. The nonsurvivors had significantly higher median PGI and new PMS values than survivors. New PMS, vital signs component of new PMS, and PGI conveyed good discriminatory power for predicting mortality (AUC = 0.883, 0.873, and 0.817, respectively). Although the new PMS outperformed PGI in all predictive metrics, no significant difference in AUCs was observed between the new PMS and its vital signs component.ConclusionThe new PMS vital signs component is closely aligned with the new PMS. Thus, it can be used as a valid, comprehensive, and practical tool to substitute the whole score calculation for rapid ALP-poisoned patient assessment to enhance emergency clinical decision-making.