The TF/Nrf2/GSTP1 pathway is involved in stress-induced hepatocellular injury through ferroptosis.

Stress triggers a comprehensive pathophysiological cascade in organisms. However, there is a substantial gap in the research regarding the effects of stress on liver function. This study aimed to investigate the impact of restraint stress on hepatocellular damage and elucidate the underlying molecular mechanisms. An effective mouse restraint stress model was successfully developed, and liver function analysis was performed using laser speckle imaging, metabolomics and serum testing. Alterations in hepatocyte morphology were assessed using haematoxylin and eosin staining and transmission electron microscopy. Oxidative stress in hepatocytes was assessed using lipid reactive oxygen species and malondialdehyde. The methylation status and expression of GSTP1 were analysed using DNA sequencing and, real-time PCR, and the expression levels of GPX4, TF and Nrf2 were evaluated using real-time quantitative PCR, western blotting, and immunohistochemical staining. A stress-induced model was established in vitro by using dexamethasone-treated AML-12 cells. To investigate the underlying mechanisms, GSTP1 overexpression, small interfering RNA, ferroptosis and Nrf2 inhibitors were used. GSTP1 methylation contributes to stress-induced hepatocellular damage and dysfunction. GSTP1 is involved in ferroptosis-mediated hepatocellular injury induced by restraint stress via the TF/Nrf2 pathway. These findings suggest that stress-induced hepatocellular injury is associated with ferroptosis, which is regulated by TF/Nrf2/GSTP1.

Pathological changes in the spleen of mice subjected to different time courses of restraint stress.

The objective of this study was to investigate spleen pathology and immune cell subset alterations in mice exposed to acute and chronic restraint stress over various timeframes. A deeper understanding of stress-induced spleen injuries can provide new insights into the mechanisms underlying stress-induced disorders. C57BL/6N mice were restrained for different durations (1, 3, 7, 14 and 21 days) for 6-8 h daily. The control mice were observed at the same time points. Post restraint, behavioural experiments were conducted to assess spleen weight, gross morphology and microscopic histological changes. Immunohistochemical staining was used to detect changes in glucocorticoid receptor (GR) expression, immune cell subsets and cell proliferation in response to stress. Our analysis revealed significant behavioural abnormalities in the stressed mice. In particular, there was an increase in the nuclear expression of GR beginning on Day 3, and it peaked on Day 14. The spleens of stressed mice displayed a reduction in size, disordered internal tissue structure and reduced cell proliferation. NK cells and M2-type macrophages exhibited immune cell subset alterations under stress, whereas T or B cells remained unaltered. Restraint stress can lead to pathomorphological alterations in spleen morphology, cell proliferation and immune cell counts in mice. These findings suggest that stress-induced pathological changes can disrupt immune regulation during stress.

Circular RNA expression profiles and functional predication after restraint stress in the amygdala of rats.

Prolonged or repeated exposure to stress elevates the risk of various psychological diseases, many of which are characterized by central nervous system dysfunction. Recent studies have demonstrated that circular RNAs (circRNAs) are highly abundant in the mammalian brain. Although their precise expression and function remain unknown, they have been hypothesized to regulate transcriptional and post-transcriptional gene expression. In this investigation, we comprehensively analyzed whether restraint stress for 2 days altered the circRNA expression profile in the amygdala of male rats. The impact of restraint stress on behavior was evaluated using an elevated plus maze and open field test. Serum corticosterone levels were measured using an enzyme-linked immunosorbent assay. A total of 10,670 circRNAs were identified using RNA sequencing. Ten circRNAs were validated by reverse transcription and quantitative polymerase chain reaction analysis. Gene ontology and Kyoto encyclopedia of genes and genomes pathway analyzes supported the notion that genes associated with differentially expressed circRNAs are primarily implicated in neuronal activity and neurotransmitter transport. Moreover, the three differentially expressed circRNAs showed high specificity in the amygdala. Overall, these findings indicate that differentially expressed circRNAs are highly enriched in the amygdala and offer a potential direction for further research on restraint stress.

The effects of restraint stress on ceramide metabolism disorders in the rat liver: the role of CerS6 in hepatocyte injury.

BACKGROUND: Stress is implicated in various pathological conditions leading to liver injury. Existing evidence suggests that excessive stress can induce mitochondrial damage in hepatocytes, yet the underlying mechanism remains unclear. Ceramide synthase 6 (CerS6)-derived C16:0 ceramide is recognised as a lipotoxic substance capable of causing mitochondrial damage. However, the role of CerS6 in stress has received insufficient attention. This study aimed to explore the involvement of CerS6 in stress-induced hepatic damage and its associated mechanisms. METHODS: The rat restraint stress model and a corticosterone (CORT)-induced hepatocyte stress model were employed for in vivo and in vitro experimental analyses, respectively. Changes in mitochondrial damage and ceramide metabolism in hepatocytes induced by stress were evaluated. The impact of CORT on mitochondrial damage and ceramide metabolism in hepatocytes was assessed following CerS6 knockdown. Mitochondria were isolated using a commercial kit, and ceramides in liver tissue and hepatocytes were detected by LC-MS/MS. RESULTS: In comparison to the control group, rats subjected to one week of restraint exhibited elevated serum CORT levels. The liver displayed significant signs of mitochondrial damage, accompanied by increased CerS6 and mitochondrial C16:0 ceramide, along with activation of the AMPK/p38 MAPK pathway. In vitro studies demonstrated that CORT treatment of hepatocytes resulted in mitochondrial damage, concomitant with elevated CerS6 and mitochondrial C16:0 ceramide. Furthermore, CORT induced sequential phosphorylation of AMPK and p38 MAPK proteins, and inhibition of the p38 MAPK pathway using SB203580 mitigated the CORT-induced elevation in CerS6 protein. Knocking down CerS6 in hepatocytes inhibited both the increase in C16:0 ceramide and the release of mitochondrial cytochrome c induced by CORT. CONCLUSIONS: CerS6-associated C16:0 ceramide plays a mediating role in stress-induced mitochondrial damage in hepatocytes. The molecular mechanism is linked to CORT-induced activation of the AMPK/p38 MAPK pathway, leading to upregulated CerS6.

Phosphorylated CPI-17 and MLC2 as Biomarkers of Coronary Artery Spasm-Induced Sudden Cardiac Death.

Coronary artery spasm (CAS) plays an important role in the pathogeneses of various ischemic heart diseases and has gradually become a common cause of life-threatening arrhythmia. The specific molecular mechanism of CAS has not been fully elucidated, nor are there any specific diagnostic markers for the condition. Therefore, this study aimed to examine the specific molecular mechanism underlying CAS, and screen for potential diagnostic markers. To this end, we successfully constructed a rat CAS model and achieved in vitro culture of a human coronary-artery smooth-muscle cell (hCASMC) contraction model. Possible molecular mechanisms by which protein kinase C (PKC) regulated CAS through the C kinase-potentiated protein phosphatase 1 inhibitor of 17 kDa (CPI-17)/myosin II regulatory light chain (MLC2) pathway were studied in vivo and in vitro to screen for potential molecular markers of CAS. We performed hematoxylin and eosin staining, myocardial zymogram, and transmission electron microscopy to determine myocardial and coronary artery injury in CAS rats. Then, using immunohistochemical staining, immunofluorescence staining, and Western blotting, we further demonstrated a potential molecular mechanism by which PKC regulated CAS via the CPI-17/MLC2 pathway. The results showed that membrane translocation of PKCα occurred in the coronary arteries of CAS rats. CPI-17/MLC2 signaling was observably activated in coronary arteries undergoing CAS. In addition, in vitro treatment of hCASMCs with angiotensin II (Ang II) increased PKCα membrane translocation while consistently activating CPI-17/MLC2 signaling. Conversely, GF-109203X and calphostin C, specific inhibitors of PKC, inactivated CPI-17/MLC2 signaling. We also collected the coronary artery tissues from deceased subjects suspected to have died of CAS and measured their levels of phosphorylated CPI-17 (p-CPI-17) and MLC2 (p-MLC2). Immunohistochemical staining was positive for p-CPI-17 and p-MLC2 in the tissues of these subjects. These findings suggest that PKCα induced CAS through the CPI-17/MLC2 pathway; therefore, p-CPI-17 and p-MLC2 could be used as potential markers for CAS. Our data provide novel evidence that therapeutic strategies against PKC or CPI-17/MLC2 signaling might be promising in the treatment of CAS.

Norepinephrine-Activated p38 MAPK Pathway Mediates Stress-Induced Cytotoxic Edema of Basolateral Amygdala Astrocytes.

The amygdala is a core region in the limbic system that is highly sensitive to stress. Astrocytes are key players in stress disorders such as anxiety and depression. However, the effects of stress on the morphology and function of amygdala astrocytes and its potential mechanisms remain largely unknown. Hence, we performed in vivo and in vitro experiments using a restraint stress (RS) rat model and stress-induced astrocyte culture, respectively. Our data show that norepinephrine (NE) content increased, cytotoxic edema occurred, and aquaporin-4 (AQP4) expression was up-regulated in the basolateral amygdala (BLA) obtained from RS rats. Additionally, the p38 mitogen-activated protein kinase (MAPK) pathway was also observed to be significantly activated in the BLA of rats subjected to RS. The administration of NE to in vitro astrocytes increased the AQP4 level and induced cell edema. Furthermore, p38 MAPK signaling was activated. The NE inhibitor alpha-methyl-p-tyrosine (AMPT) alleviated cytotoxic edema in astrocytes, inhibited AQP4 expression, and inactivated the p38 MAPK pathway in RS rats. Meanwhile, in the in vitro experiment, the p38 MAPK signaling inhibitor SB203580 reversed NE-induced cytotoxic edema and down-regulated the expression of AQP4 in astrocytes. Briefly, NE-induced activation of the p38 MAPK pathway mediated cytotoxic edema in BLA astrocytes from RS rats. Thus, our data provide novel evidence that NE-induced p38 MAPK pathway activation may be one of the mechanisms leading to cytotoxic edema in BLA under stress conditions, which also could enable the development of an effective therapeutic strategy against cytotoxic edema in BLA under stress and provide new ideas for the treatment of neuropsychiatric diseases.

A statistical study of postmortem heart weight in Chinese adults.

INTRODUCTION: Objective assessment of cardiac hypertrophy in forensic pathology practice is of great significance for forensic pathologists, for whom reference values for normal heart weights are needed. Developed regions such as Europe, the United States, and Japan recalculate the weight of human organs at regular intervals, but in China, there has been no systematic calculation of the weights of human organs since 2006. AIMS: To statistically analyse the heart weight of Chinese adults postmortem and obtain a reference range. MATERIALS AND METHODS: 4170 adult autopsy reports were collected from 12 forensic departments in 10 provinces in China. The causes of death were classified by sex, and heart weight and the heart weight/body height ratio reference values were further calculated according to different body mass index and body heights. Finally, the cutoff value of cardiac hypertrophy in Chinese adults was calculated. RESULTS: In the group of non-cardiovascular disease causes of death, the cardiac weight of the electric death group was higher, while the heart weight of the prolonged bed-rest group was significantly reduced. After the electric death and prolonged bed-rest groups were excluded, heart weight, the heart weight/body height ratio, and cutoff values for cardiac hypertrophy were further classified and analysed according to body mass index. The mean reference values for heart weight in men and women with normal weight status were 325.82 ± 41.60 g and 286.39 ± 44.84 g, and the heart weight/body height ratios were 1.95 ± 0.23 in men and 1.82 ± 0.27, respectively. The cutoff values for cardiac hypertrophy were 387.35 g for men and 346.80 g for women. CONCLUSION: The heart weight reference values of both sexes in this study were significantly higher than those in 2006, which is considered related to the development of China's economy and the improvement of people's living standards. This study also suggests the need for a new round of statistical surveys and updated data on the weight of other organs.

Quantitative analysis of microglia morphological changes in the hypothalamus of chronically stressed rats.

Based on the successful establishment of a rat model of chronic restraint stress, we used multiple algorithms to quantify the morphological changes of rat hypothalamic microglia from various perspectives, providing a pathomorphological basis for the subsequent study of molecular mechanisms of hypothalamic stress injury, such as neuroinflammation. To verify the successful establishment of the chronic stress model, an enzyme-linked immunosorbent assay was performed to detect serum glucocorticoid levels. Microglia labeled with Iba1 in frozen sections of rat hypothalamus were scanned and photographed at multiple levels using confocal microscopy. Subsequently, images were processed for external contouring and skeletonization, and morphological indices of microglia were calculated and analyzed using fractal, skeleton, and Sholl analysis. In addition, the co-expression of CD68 (a marker that can reflect phagocytic activity) and Iba1 was observed by immunofluorescence technique. Compared with the control group, microglia in the chronic stress group displayed reduced fractal dimension and lacunarity, increased density and circularity, enlarged soma areas, and shortened and reduced branches. Sholl analysis confirmed the reduced complexity of microglia following chronic stress. Meanwhile, microglia CD68 increased significantly, indicating that the microglia in the chronic stress group have greater phagocytosis activity. In summary, chronic restraint stress promoted the conversion of microglia in the rat hypothalamus to a less complex form, manifested as larger soma, shorter and fewer branches, more uniform and dense texture, and increased circularity; indeed, the shape of these microglia resembled that of amoeba and they displayed strong phagocytosis activity.

CCK2-receptor deficiency impairs immune balance by influencing CD4+ T cells development by inhibiting cortical-thymic-epithelial-cells.

Immune balance is crucial for an organism's survival and is inseparable from the regulation of the nervous system. Accumulating evidence indicates that cholecystokinin (CCK) plays an important role in mediating the immune response through the activation of cholecystokinin receptors (CCKRs). However, it remains unclear whether CCKRs deficiency may impair immune balance. Here, we showed that CCK2R-deficient adult mice were immunocompromised and had an increased risk of shock and even death in an endotoxemia (ETM)/endotoxin shock (ES) model. In addition, in both adult and juvenile mice, CCK2R deficiency not only influenced the development of CD4 single-positive (SP) thymocytes in thymic positive selection but also decreased the population of CD3+ CD4+ T cells in the spleen. More importantly, CCK2R deficiency inhibited the expression of major histocompatibility complex class II (MHC II) and CD83 on cortical thymic epithelial cells (cTECs) in juvenile and adult mice. Overall, our study suggests that CCK2R is essential for maintaining CD4+ T cell development in the thymus and reveals that CCK2R plays an important role in maintaining immune balance.

Effect of Ball Milling Time on the Microstructure and Properties of High-Silicon-Aluminum Composite.

The duration of ball milling greatly influences the characteristics of high-silicon-aluminum composite during the ball milling process. This study examines how the microstructure, thermal conductivity, and hardness of a high-silicon-aluminum composite are affected by different ball milling times. We exposed the powder to various durations of ball milling and employed different pellet ratios. Following this treatment, the powder underwent consolidation via discharge plasma sintering. Our findings show that with a pellet ratio of 10:1 and a milling duration of 8 h, the powder particles were refined, resulting in a more uniform and dense material composition. This refined material boasted a thermal conductivity of 111.6 W/m·K, a Brinell hardness of 136.8 HBW, and a density of 2.304 g/cm3. This method facilitates the creation of a uniform composite powder composition. It encourages the development of a fine-grain structure, which enables the production of particle-reinforced composites with superior properties.

Interleukin 6 (IL-6) Regulates GABAA Receptors in the Dorsomedial Hypothalamus Nucleus (DMH) through Activation of the JAK/STAT Pathway to Affect Heart Rate Variability in Stressed Rats.

The dorsomedial hypothalamus nucleus (DMH) is an important component of the autonomic nervous system and plays a critical role in regulating the sympathetic outputs of the heart. Stress alters the neuronal activity of the DMH, affecting sympathetic outputs and triggering heart rate variability. However, the specific molecular mechanisms behind stress leading to abnormal DMH neuronal activity have still not been fully elucidated. Therefore, in the present study, we successfully constructed a stressed rat model and used it to investigate the potential molecular mechanisms by which IL-6 regulates GABAA receptors in the DMH through activation of the JAK/STAT pathway and thus affects heart rate variability in rats. By detecting the c-Fos expression of neurons in the DMH and electrocardiogram (ECG) changes in rats, we clarified the relationship between abnormal DMH neuronal activity and heart rate variability in stressed rats. Then, using ELISA, immunohistochemical staining, Western blotting, RT-qPCR, and RNAscope, we further explored the correlation between the IL-6/JAK/STAT signaling pathway and GABAA receptors. The data showed that an increase in IL-6 induced by stress inhibited GABAA receptors in DMH neurons by activating the JAK/STAT signaling pathway, while specific inhibition of the JAK/STAT signaling pathway using AG490 obviously reduced DMH neuronal activity and improved heart rate variability in rats. These findings suggest that IL-6 regulates the expression of GABAA receptors via the activation of the JAK/STAT pathway in the DMH, which may be an important cause of heart rate variability in stressed rats.

Endoplasmic reticulum stress induced by turbulence of mitochondrial fusion and fission was involved in stressed cardiomyocyte injury.

Mitochondria are sensitive organelles that sense intrinsic and extrinsic stressors and maintain cellular physiological functions through the dynamic homeostasis of mitochondrial fusion and fission. Numerous pathological processes are associated with mitochondrial fusion and fission disorders. However, the molecular mechanism by which stress induces cardiac pathophysiological changes through destabilising mitochondrial fusion and fission is unclear. Therefore, this study aimed to investigate whether the endoplasmic reticulum stress signalling pathway initiated by the turbulence of mitochondrial fusion and fission under stressful circumstances is involved in cardiomyocyte damage. Based on the successful establishment of the classical stress rat model of restraint plus ice water swimming, we measured the content of serum lactate dehydrogenase. We used haematoxylin-eosin staining, special histochemical staining, RT-qPCR and western blotting to clarify the cardiac pathology, ultrastructural changes and expression patterns of mitochondrial fusion and fission marker proteins and endoplasmic reticulum stress signalling pathway proteins. The results indicated that mitochondrial fusion and fission markers and proteins of the endoplasmic reticulum stress JNK signalling pathway showed significant abnormal dynamic changes with the prolongation of stress, and stabilisation of mitochondrial fusion and fission using Mdivi-1 could effectively improve these abnormal expressions and ameliorate cardiomyocyte injury. These findings suggest that stress could contribute to pathological cardiac injury, closely linked to the endoplasmic reticulum stress JNK signalling pathway induced by mitochondrial fusion and fission turbulence.

Antigen-Capturing Dendritic-Cell-Targeting Nanoparticles for Enhanced Tumor Immunotherapy Based on Photothermal-Therapy-Induced In Situ Vaccination.

In situ vaccines have revolutionized immunotherapy as they can stimulate tumor-specific immune responses, with the cancer being the antigen source. However, the heterogeneity of tumor antigens and insufficient dendritic cells (DCs) activation result in low cancer immunogenicity and hence poor vaccine response. Herein, a new in situ vaccine composed of acid-responsive liposome-coated polydopamine (PDA) nanoparticles modified with mannose and loaded with resiquimod (R848) is designed to promote the efficacy of immunotherapy. The in situ vaccine can actively target the tumor site based on the decomposition of the liposome, while the PDA nanoparticles promote photothermal therapy and capture the immunogenic cell-death-induced tumor-associated antigens based on the adsorption effect of dopamine-mimetic mussels. The PDA nanoparticles, which are modified with a mannose ligand, target the DCs and release R848 for activated antigen presentation. As a result, the in situ vaccine not only effectively activates the maturation of the DCs but also significantly enhances their effect on cytotoxic T lymphocyte cells. Furthermore, the vaccine effectively inhibits the distant recurrence and metastasis of tumors via long-term immune memory effects. Therefore, the in situ vaccine provides a potential strategy for improving the efficacy of cancer immunotherapy.

Bioinformatics Analysis of Molecular Interactions between Endoplasmic Reticulum Stress and Ferroptosis under Stress Exposure.

Stress has become a universal biological phenomenon in the body, which leads to pathophysiological changes. However, the molecular network interactions between endoplasmic reticulum (ER) stress and ferroptosis under stressful conditions are not clear. For this purpose, we screened the gene expression profile of GSE173795 for intersection with ferroptosis genes and screened 68 differentially expressed genes (DEGs) (63 up-regulated, 5 down-regulated), mainly related to lipid and atherosclerosis, autophagy-animal, mitophagy-animal, focal adhesion, DNA replication, proteasome, oocyte meiosis, toll-like receptor signaling pathway, cell cycle, etc. Immune infiltration analysis revealed that stress resulted in decreased B cells memory, T cells CD8 and T cells CD4 memory resting, monocytes, macrophages M2, and increased B cells naive, T cells follicular helper, and macrophages M1. 19 core-DEGs (ASNS, TRIB3, ATF4, EIF2S1, CEBPG, RELA, HSPA5, DDIT3, STAT3, MAP3K5, HIF1A, HNF4A, MAPK14, HMOX1, CDKN1A, KRAS, SP1, SIRT1, EGFR) were screened, all of which were up-regulated DEGs. These biological processes and pathways were mainly involved in responding to ER stress, lipid and atherosclerosis, cellular response to stress, cellular response to chemical stress, and regulation of DNA-templated transcription in response to stress, etc. Spearman analysis did not find MAPK14 to be significantly associated with immune cells. Other core-DEGs were associated with immune cells, including B cells naive, T cells follicular helper, and monocytes. Based on core-DEGs, 283 miRNAs were predicted. Among the 22 miRNAs with highly cross-linked DEGs, 11 had upstream lncRNA, mainly targeting STAT3, SP1, CDKN1A, and SIRT1, and a total of 39 lncRNA were obtained. 85 potential drugs targeting 11 core-DEGs were identified and were expected to be potential immunotherapeutic agents for stress injury. Our experiments also confirmed that Liproxstatin-1 alleviates common cross-linked proteins between ER stress and ferroptosis. In conclusion, our study explored the molecular mechanisms and network interactions among stress-ER stress-ferroptosis from a novel perspective, which provides new research ideas for studying stressful injury.

Synthesis of aryloxyacetamides from arylboronic acids and 2-bromoacetonitrile promoted by alkaline solutions of hydrogen peroxide.

A novel and metal catalyst-free synthesis of aryloxyacetamides from the corresponding arylboronic acids and 2-bromoacetonitrile promoted by alkaline solutions of hydrogen peroxide has been developed involving an oxidation-reduction of eco-friendly H2O2 with simultaneous reaction ipso-hydroxylation of arylboronic acid and hydration of the nitrile. This protocol is compatible with sensitive substituents attached to the arylboronic acid and provides desired products in moderate to good yields in pure water.

IL-4 induces reparative phenotype of RPE cells and protects against retinal neurodegeneration via Nrf2 activation.

Retinal degeneration is a kind of neurodegeneration characterized by progressive neuronal death and dysfunction of retinal pigment epithelium (RPE) cells, leading to permanent visual impairment. It still lacks effective therapeutic options and new drugs are highly warranted. In this study, we found the expression of IL-4, a critical regulator of immunity, was reduced in both patients and mouse models. Importantly, exogenous intravitreal IL-4 application could exert a novel neuroprotective effect, characterized by well-preserved RPE layer and neuroretinal structure, as well as amplified wave-amplitudes in ERG. The RNA-seq analysis revealed that IL-4 treatment suppressed the essential oxidative and pro-inflammatory pathways in the degenerative retina. Particularly, IL-4 upregulated the IL-4Rα on RPE cells and induced a reparative phenotype via the activation of Nrf2 both in vitro and in vivo. Furthermore, the Nrf2-/- mice displayed no recovery in response to IL-4 application, highlighting a significant role of Nrf2 in IL-4-mediated protection. Our data provides evidence that IL-4 protects against retinal neurodegeneration by its antioxidant and anti-inflammatory property through IL-4Rα upregulation and Nrf2 activation in RPE cells. The IL-4/IL-4Rα-Nrf2 axis maybe the potential targets for the development of novel therapies for neurodegenerative diseases.

Case report: Myocarditis following COVID-19 protein subunit vaccination.

We report findings in a 34-year-old female patient who presented with fulminant myocarditis 8 days after receiving the first dose of the ZF2001 RBD-subunit vaccine against coronavirus disease 2019 (COVID-19). Autopsy showed severe interstitial myocarditis, including multiple patchy infiltrations of lymphocytes and monocytes in the myocardium of the left and right ventricular walls associated with myocyte degeneration and necrosis. This report highlights the details of clinical presentations and autopsy findings of myocarditis after ZF2001 (RBD-subunit vaccine) vaccination. The correlation between vaccination and death due to myocarditis is discussed.

A Nanounit Strategy Disrupts Energy Metabolism and Alleviates Immunosuppression for Cancer Therapy.

Aberrant energy metabolism not only endows tumor cells with unlimited proliferative capacity but also contributes to the establishment of the glucose-deficient/lactate-rich immunosuppressive tumor microenvironment (ITM) impairing antitumor immunity. Herein, a novel metabolic nanoregulator (D/B/CQ@ZIF-8@CS) was developed by enveloping 2-deoxy-d-glucose (2-DG), BAY-876, and chloroquine (CQ) into zeolitic imidazolate framework-8 (ZIF-8) to simultaneously deprive the energy/nutrition supply of tumor cells and relieve the ITM for synergetic tumor starvation-immunotherapy. Aerobic glycolysis, glucose uptake, and autophagy flux could be concurrently blocked by D/B/CQ@ZIF-8@CS, cutting off the nutrition/energy supply and the source of lactate. Furthermore, inhibition of glucose uptake and aerobic glycolysis could effectively reverse the glucose-deficient/lactate-rich ITM, thus functionally inactivating regulatory T cells and augmenting anti-CTLA-4 immunotherapy. Such a two-pronged strategy would provide new insights for the design of metabolic intervention-based synergistic cancer therapy.

Unexpected death from hepatic abscess 16 months after toothbrush ingestion.

The development of a hepatic abscess secondary to foreign body (FB) ingestion remains rare in forensic practice. Herein, we present a case of a prisoner who died in the hospital and a forensic autopsy was performed to confirm the cause of death. A 14.5-cm-long toothbrush handle was found in the duodenum and had penetrated the right lobe of the liver, consistent with the repeated abdominal pain in his clinical history. The clinical history and investigation confirmed that he had ingested the toothbrush handle 16 months prior. This case highlights a rare complication of intentional ingestion of foreign bodies, and pathologists should be aware of this rare entity which links hepatic abscess and FB ingestion.

A fatal case of accidental oral formaldehyde poisoning and its pathomorphological characteristics.

Formaldehyde is a colourless irritating gas at room temperature, which, therefore, is usually stored in liquid form. This compound is often used as an antiseptic, disinfectant and fumigant in biology and medicine. Formaldehyde, as a potential carcinogen confirmed by the World Health Organization (WHO), is seriously harmful to human systems, such as the respiratory system, immune system and reproductive system. This article reports a case of a 50-year-old woman who died after accidentally drinking 25% formaldehyde solution in a transparent plastic bottle. Anatomical examination revealed fixed tissue morphology of the stomach and adjacent organs. The toxicity test results showed that the concentrations of formaldehyde in the blood and gastric tissue were 36.56 mg/kg and 274.48 mg/kg, respectively, which was consistent with death from formaldehyde poisoning. Due to the particular smell of formaldehyde, poisoning by accidentally drinking formaldehyde solution is rare. Of late, the mechanism of death from formaldehyde poisoning is that it rapidly causes coagulation of tissue cell protein, which may lose its normal function. Based on the pathological characteristics of the case, we put forward a new viewpoint on the mechanism of death from formaldehyde poisoning in which formaldehyde causes rapid fixation of blood in the tissue, thus leading to acute circulatory disturbance.