Regulation of hepatocyte phospholipid peroxidation signaling by a Chinese patent medicine against psychological stress-induced liver injury.

BACKGROUND: Psychological stress is associated with various diseases including liver dysfunction, yet effective intervention strategies remain lacking due to the unrevealed pathogenesis mechanism. PURPOSE: This study aims to explore the relevance between BMAL1-controlled circadian rhythms and lipoxygenase 15 (ALOX15)-mediated phospholipids peroxidation in psychological stress-induced liver injury, and to investigate whether hepatocyte phospholipid peroxidation signaling is involved in the hepatoprotective effects of a Chinese patent medicine, Pien Tze Huang (PZH). METHODS: Restraint stress models were established to investigate the underlying molecular mechanisms of psychological stress-induced liver injury and the hepatoprotective effects of PZH. Redox lipidomics based on liquid chromatography-tandem mass spectrometry was applied for lipid profiling. RESULTS: The present study discovered that acute restraint stress could induce liver injury. Notably, lipidomic analysis confirmed that phospholipid peroxidation was accumulated in the livers of stressed mice. Additionally, the essential core circadian clock gene Brain and Muscle Arnt-like Protein-1 (Bmal1) was altered in stressed mice. Circadian disruption in mice, as well as BMAL1-overexpression in human HepaRG cells, also appeared to have a significant increase in phospholipid peroxidation, suggesting that stress-induced liver injury is closely related to circadian rhythm and phospholipid peroxidation. Subsequently, arachidonate 15-lipoxygenase (ALOX15), a critical enzyme that contributed to phospholipid peroxidation, was screened as a potential regulatory target of BMAL1. Mechanistically, BMAL1 promoted ALOX15 expression via direct binding to an E-box-like motif in the promoter. Finally, this study revealed that PZH treatment significantly relieved pathological symptoms of psychological stress-induced liver injury with a potential mechanism of alleviating ALOX15-mediated phospholipid peroxidation. CONCLUSION: Our findings illustrate the critical role of BMAL1-triggered phospholipid peroxidation in psychological stress-induced liver injury and provide new insight into treating psychological stress-associated liver diseases by TCM intervention.

[The Expression of METTL14 in Patients with Newly Diagnosed Acute Myeloid Leukemia and Its Clinical Significance].

OBJECTIVE: To detect the expression of RNA methyltransferase 14(METTL14) in bone marrow of patients with newly diagnosed acute myeloid leukemia (AML), and to investigate the clinical and prognostic significance of METTL14 expression in newly diagnosed AML. METHODS: Bone marrow samples were collected from 100 patients with newly diagnosed AML as observation group and 60 patients with iron deficiency anemia AML as control group. And collected the clinical data of the AML patients. Real-time quantitative PCR (qRT-PCR) was used to detect the expression level of METTL14 in AML and IDA patients. The relationship between the expression level of METTL14 and clinicopathological features, prognosis was analyzed. Kaplan-Meier curves were used to analyze the effect of METTL14 on overall survival (OS) in AML patients. Cox risk regression model was used to analyze the prognostic factors affecting in patients with AML. RESULTS: Compared with the control group, the expression of METTL14 was significantly increased in AML patients (P < 0.05). Compared with the METTL14 low-expression group, patients in the METTL14 high-expression group had advanced age, high bone marrow cell number, poor efficacyand poor prognosis(P < 0.05). The overall survival time of patients with the METTL14 high-expression group was significantly shorter than that of the low-expression group (P < 0.05). The high expression of METTL14 was an independent risk factor for poor prognosis in AML. CONCLUSION: METTL14 is significantly overexpressed in AML patients, and its correlated with poor clinicopathological features and poor prognosis. It can be used as a prognostic marker and potential therapeutie target for AML patients.

Mitigating phospholipid peroxidation of macrophages in stress-induced tumor microenvironment by natural ALOX15/PEBP1 complex inhibitors.

BACKGROUND: The intricate interactions between chronic psychological stress and susceptibility to breast cancer have been recognized, yet the underlying mechanisms remain unexplored. Danzhi Xiaoyao Powder (DZXY), a traditional Chinese medicine (TCM) formula, has found clinical utility in the treatment of breast cancer. Macrophages, as the predominant immune cell population within the tumor microenvironment (TME), play a pivotal role in orchestrating tumor immunosurveillance. Emerging evidence suggests that lipid oxidation accumulation in TME macrophages, plays a critical role in breast cancer development and progression. However, a comprehensive understanding of the pharmacological mechanisms and active components of DZXY related to its clinical application in the treatment of stress-aggravated breast cancer remains elusive. PURPOSE: This study sought to explore the plausible regulatory mechanisms and identify the key active components of DZXY contributing to its therapeutic efficacy in the context of breast cancer. METHODS: Initially, we conducted an investigation into the relationship between the phagocytic capacity of macrophages damaged by psychological stress and phospholipid peroxidation using flow cytometry and LC-MS/MS-based phospholipomics. Subsequently, we evaluated the therapeutic efficacy of DZXY based on the results of the tumor size, tumor weight, the phospholipid peroxidation pathway and phagocytosis of macrophage. Additionally, the target-mediated characterization strategy based on binding of arachidonate 15-lipoxygenase (ALOX15) to phosphatidylethanolamine-binding protein-1 (PEBP1), including molecular docking analysis, microscale thermophoresis (MST) assay, co-immunoprecipitation analysis and activity verification, has been further implemented to reveal the key bio-active components in DZXY. Finally, we evaluated the therapeutic efficacy of isochlorogenic acid C (ICAC) based on the results of tumor size, tumor weight, the phospholipid peroxidation pathway, and macrophage phagocytosis in vivo. RESULTS: The present study demonstrated that phospholipid peroxides, as determined by LC-MS/MS-based phospholipidomics, triggered in macrophages, which in turn compromised their capacity to eliminate tumor cells through phagocytosis. Furthermore, we elucidate the mechanism behind stress-induced PEBP1 to form a complex with ALOX15, thereby mediating membrane phospholipid peroxidation in macrophages. DZXY, demonstrates potent anti-breast cancer therapeutic effects by disrupting the ALOX15/PEBP1 interaction and inhibiting phospholipid peroxidation, ultimately enhancing macrophages' phagocytic capability towards tumor cells. Notably, ICAC emerged as a promising active component in DZXY, which can inhibit the ALOX15/PEBP1 interaction, thereby mitigating phospholipid peroxidation in macrophages. CONCLUSION: Collectively, our findings elucidate stress increases the susceptibility of breast cancer by driving lipid peroxidation of macrophages and suggest the ALOX15/PEBP1 complex as a promising intervention target for DZXY.

[Expression of MCP-1 and CCR2 in Newly Diagnosed Diffuse Large B-Cell Lymphoma and Clinical Significance].

OBJECTIVE: To analyze the expression of MCP-1 and CCR2 in newly diagnosed diffuse large B-cell lymphoma (DLBCL), and to evaluate their correlation with clinicopathological features and prognosis. METHODS: A total of 141 patients with DLBCL diagnosed and treated in the Department of Hematology, the First Affiliated Hospital of Bengbu Medical College from January 2017 to May 2022 were retrospectively collected. The clinical characteristics, pathological data and prognostic factors of the patients were collected. Immunohistochemical staining was used to detect the expression of MCP-1 and CCR2 in the tissues of newly treated DLBCL patients, and to analyze the relationship between MCP-1 and clinical characteristics, prognosis and survival of patients. RESULTS: The expression of MCP-1 and CCR2 were correlated with Ann Arbor stage, IPI score, lactate dehydrogenase (LDH), Ki-67 index and therapeutic effect. There were no significant correlation between the expression of MCP-1 or CCR2 and other clinical histopathological parameters such as gender, age, ß2-microglobulin, BCL-2, BCL-6, Hans classification, initial location, B symptoms, bone marrow involvement. There was a statistical difference in OS and PFS between the MCP-1 or CCR2 positive group and the negative group, which was associated to poor prognosis.Univariate Cox regression analysis showed that ß2-microglobulin, Ki-67 index, IPI score, MCP-1, CCR2 expression levels and disease remission affected the PFS and OS of DLBCL patients (P < 0.05). Gender, age, LDH, BCL-2, BCL-6, Hans classification, primary tumor site, B symptoms, bone marrow involvement, Ann Arbor stage had no effect on PFS and OS (P >0.05). Multivariate analysis showed that ß2-microglobulin, Ki-67 index, IPI score, MCP-1, CCR2 expression levels and disease remission were independent influencing factors of patients (P < 0.05). CONCLUSION: The expression rate of MCP-1 or CCR2 in newly treated DLBCL is high, and it is correlated with the clinical features of poor prognosis such as stage and LDH of DLBCL patients, which is a poor prognostic factor affecting PFS and OS.

Nutrition intake modifies the association between pulmonary function and cognitive performance among elderly Americans from NHANES 2011-2012.

PURPOSE: Nutrition intake is one of the modifiable risk factors for cognitive decline. Whether energy and protein intakes alter the association between pulmonary function (PF) and cognition has not been studied. METHODS: We made use of information from the U.S. National Health and Nutrition Examination Survey (NHANES) 2011-2012. PF measures, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF), were calculated, whereas cognitive function was assessed through four tests: the Immediate Recall test (IRT), the Delayed Recall test (DRT), the Animal Fluency test (AFT) and the Digit Symbol Substitution test (DSST). Energy and protein intakes were measured using the 24-h dietary recall method. Weighted generalized linear regression was performed upon adjustment for covariates. Further interaction analyses were conducted to investigate the effect of energy and protein intakes on the association between PF and cognition. RESULTS: We finally included 803 participants aged ≥ 60 years (54.4% female, weighted value). After adjusting for covariates, multiple measures (including FEV1, FVC, PEF, and composite PF) were all positively associated with better global cognition and the DSST score (P < 0.05). A stronger positive association between the DSST score and FEV1 (P for interaction = 0.001), FVC (P for interaction = 0.004), PEF (P for interaction = 0.003), and composite PF (P for interaction = 0.001) in lower energy intake. Similar results were observed in lower protein intake (all P for interaction < 0.05). CONCLUSION: Higher PF was independently associated with improved specific components of cognitive function (i.e., the DSST score). The positive association between PF and the DSST score was stronger in individuals with lower energy and protein intakes.

Prenatal hormone stress triggers embryonic cardiac hypertrophy outcome by ubiquitin-dependent degradation of mitochondrial mitofusin 2.

Prenatal stress has been extensively documented as a contributing factor to adverse cardiac development and function in fetuses and infants. The release of glucocorticoids (GCs), identified as a significant stressor, may be a potential factor inducing cardiac hypertrophy. However, the underlying mechanism remains largely unknown. Herein, we discovered that corticosterone (CORT) overload induced cardiac hypertrophy in embryonic chicks and fetal mice in vivo, as well as enlarged cardiomyocytes in vitro. The impaired mitochondria dynamics were observed in CORT-exposed cardiomyocytes, accompanied by dysfunction in oxidative phosphorylation and ATP production. This phenomenon was found to be linked to decreased mitochondrial fusion protein mitofusin 2 (MFN2). Subsequently, we found that CORT facilitated the ubiquitin-proteasome-system-dependent degradation of MFN2 with an enhanced binding of appoptosin to MFN2, serving as the underlying cause. Collectively, our findings provide a comprehensive understanding of the mechanisms by which exposure to stress hormones induces cardiac hypertrophy in fetuses.

Rapamycin Exacerbates Staphylococcus aureus Pneumonia by Inhibiting mTOR-RPS6 in Macrophages.

Purpose: This study aimed to explore the effect of Rapamycin (Rapa) in Staphylococcus aureus (S. aureus) pneumonia and clarify its possible mechanism. Methods: We investigated the effects of Rapa on S. aureus pneumonia in mouse models and in macrophages cultured in vitro. Two possible mechanisms were investigated: the mTOR-RPS6 pathway phosphorylation and phagocytosis. Furthermore, for the mechanism verification in vivo, mice with specific Mtor knockout in myeloid cells were constructed for pneumonia models. Results: Rapa exacerbated S. aureus pneumonia in mouse models, promoting chemokines secretion and inflammatory cells infiltration in lung. In vitro, Rapa upregulated the secretion of chemokines and cytokines in macrophages induced by S. aureus. Mechanistically, the mTOR-ribosomal protein S6 (RPS6) pathway in macrophages was phosphorylated in response to S. aureus infection, and the inhibition of RPS6 phosphorylation upregulated the inflammation level. However, Rapa did not increase the phagocytic activity. Accordingly, mice with specific Mtor knockout in myeloid cells experienced more severe S. aureus pneumonia. Conclusion: Rapa exacerbates S. aureus pneumonia by increasing the inflammatory levels of macrophages. Inhibition of mTOR-RPS6 pathway upregulates the expression of cytokines and chemokines in macrophages, thus increases inflammatory cells infiltration and exacerbates tissue damage.

Reducing lipid peroxidation attenuates stress-induced susceptibility to herpes simplex virus type 1.

Psychological stress increases the susceptibility to herpes simplex virus type 1 (HSV-1) infection. There is no effective intervention due to the unknown pathogenesis mechanisms. In this study we explored the molecular mechanisms underlying stress-induced HSV-1 susceptibility and the antiviral effect of a natural compound rosmarinic acid (RA) in vivo and in vitro. Mice were administered RA (11.7, 23.4 mg·kg-1·d-1, i.g.) or acyclovir (ACV, 206 mg·kg-1·d-1, i.g.) for 23 days. The mice were subjected to restraint stress for 7 days followed by intranasal infection with HSV-1 on D7. At the end of RA or ACV treatment, mouse plasma samples and brain tissues were collected for analysis. We showed that both RA and ACV treatment significantly decreased stress-augmented mortality and alleviated eye swelling and neurological symptoms in HSV-1-infected mice. In SH-SY5Y cells and PC12 cells exposed to the stress hormone corticosterone (CORT) plus HSV-1, RA (100 µM) significantly increased the cell viability, and inhibited CORT-induced elevation in the expression of viral proteins and genes. We demonstrated that CORT (50 µM) triggered lipoxygenase 15 (ALOX15)-mediated redox imbalance in the neuronal cells, increasing the level of 4-HNE-conjugated STING, which impaired STING translocation from the endoplasmic reticulum to Golgi; the abnormality of STING-mediated innate immunity led to HSV-1 susceptibility. We revealed that RA was an inhibitor of lipid peroxidation by directly targeting ALOX15, thus RA could rescue stress-weakened neuronal innate immune response, thereby reducing HSV-1 susceptibility in vivo and in vitro. This study illustrates the critical role of lipid peroxidation in stress-induced HSV-1 susceptibility and reveals the potential for developing RA as an effective intervention in anti-HSV-1 therapy.

Phospholipid peroxidation-driven modification of chondrogenic transcription factor mediates alkoxyl radicals-induced impairment of embryonic bone development.

Maternal stress has been associated with poor birth outcomes, including preterm birth, infant mortality, and low birth weight. Bone development disorders in the embryo as a result of maternal stress are believed to be mediated through oxidative stress damage. Various species of free radicals, such as alkoxyl radicals, can be formed through endogenous redox response or exogenous stimuli in the womb and transmitted to embryos. Yet, whether these free radicals lead to abnormal fetal bone development is unclear. Here, we demonstrate prenatal bone growth retardation and ferroptosis-related signals of chondrocytes were induced by classic alkoxyl radical generators. We also show that alkoxyl radicals lead to significant accumulation of oxidized phospholipids in chondrocytes, through the iron-mediated Fenton reaction in embryos. We further demonstrate a role for the lipid peroxidation end product, 4-HNE, which forms adducts with the pivotal chondrogenesis transcription factor SOX9, leading to its degradation, therefore dampening chondrogenesis. Our data define a critical role for phospholipid peroxidation in alkoxyl radicals-evoked abnormal chondrogenesis, and pinpoint it being a precise target for treating oxidative stress-related bone development disorders.

Factors associated with adherence to colonoscopy among individuals who were positive in the preliminary screening for colorectal neoplasms.

OBJECTIVES: This study aimed to investigate the potential factors associated with adherence to colonoscopy among participants who were preliminarily screened positive in a community-based colorectal cancer screening program in China. METHODS: This study analyzed data from 1219 out of 6971 community residents who were identified as positive cases by the well-validated high-risk factor questionnaire (HRFQ) or fecal immunochemical test (FIT) in the preliminary screening stage for colorectal neoplasms. Patients showing adherence to colonoscopy were defined as those who received positive results in a preliminary screening for colorectal neoplasms and later received a colonoscopy examination as required. The associations of social-demographic factors, lifestyle behaviors, history of diabetes, body mass index (BMI), and risk factors in the HRFQ with adherence to colonoscopy were evaluated using logistic regression models. RESULTS: Among 1219 participants who preliminarily screened positive, the top five risk factors reported by the participants were chronic constipation (25.9%), hematochezia (23.5%), family history of CRC in first-degree relatives (22.1%), chronic diarrhea (21.8%), and history of polyps (16.6%). Around 14.2% of participants who preliminarily screened positive reported three or more risk factors, and the proportion was 26.2% among participants who were positive according to both HRFQ and FIT. Among all participants who were preliminarily screened positive, the multivariable results showed that those who were married (OR = 1.58, 95% CI: 1.12, 2.25, p = 0.01), had chronic diarrhea (OR = 1.34, 95% CI: 1.00, 1.78, p = 0.047), and had a positive FIT (OR = 1.60, 95% CI: 1.21, 2.10, p < 0.001 for patients who were negative according to HRFQ but positive according to FIT; OR = 2.12, 95% CI: 1.33, 2.78, p = 0.002 for patients who were positive for both HRFQ and FIT) were more likely to adhere to colonoscopy, while participants with a history of cancer (OR: 0.50, 95% CI: 0.31, 0.79, p = 0.003) were less likely to adhere to colonoscopy. The results among participants who were tested positive according to only HRFQ were similar to those among all participants who were tested positive according to HRFQ or FIT. However, among participants who were tested positive according to only FIT, we only found that those who were married (OR = 2.52, 95% CI: 1.08, 5.90, p = 0.033) had a higher odds of adhering to colonoscopy, while those with a history of diabetes (OR = 0.35, 95% CI: 0.13, 0.96, p = 0.042) were less likely to adhere to colonoscopy. CONCLUSION: Our findings provide evidence supporting the development of tailored interventional strategies that aim to improve adherence to colonoscopy for individuals with a high risk of colorectal neoplasms. Both barriers and facilitators associated with adherence to colonoscopy should be considered in supportive systems and health policies. However, further well-designed prospective studies are warranted to confirm our findings.

Factors associated with positive predictive value of preliminary screening in a two-step screening strategy for colorectal neoplasms in China.

BACKGROUND: The positive predictive value (PPV) of high risk factor questionnaire (HRFQ) plus fecal immunochemical test (FIT) as preliminary screening strategy for colorectal-related neoplasia is relatively low. We aim to explore independent factors associated with PPVs of HRFQ combined FIT for selecting high risk individuals for colonoscopy. METHODS: A total of 6971 residents were enrolled in a community-based screening program. Participants who had positive results of HRFQ and/or FIT and subsequently received colonoscopy were involved. The associations of socio-demographic factors, lifestyle behaviors, and high risk factors of colorectal cancer with PPVs of HRFQ, FIT, and their combination were evaluated by multivariable logistic regression models. RESULTS: Among 572 involved cases, 249 (43.5%) colorectal neoplasms were detected by colonoscopy, including 71 advanced adenoma (12.4%) and 9 colorectal cancer (CRC) (1.6%). The PPVs of preliminary screening were 43.5% for total colorectal neoplasms, 14.0% for advanced neoplasm, and 1.6% for CRC. Adding positive HRFQ to FIT could improve the PPV from 3.5 to 8.0% for detecting CRC. Preliminarily screened positive individuals who were males [adjusted odds ratio (AOR): 1.95, 95% CI 1.31, 2.90; p < 0.001], elders (> 60 years) (AOR: 1.70, 95% CI 1.17, 2.46; p = 0.005), or ex-/current smokers (AOR: 3.04, 95% CI 1.31, 7.09; p = 0.10) had higher odds of PPVs of detecting colorectal neoplasms. CONCLUSIONS: Combining HRFQ and FIT could largely improve PPVs for screening advanced neoplasm and CRC. Gender and age-specific FIT cut-off values as well as initiating ages for CRC screening might be recommended to improve the accuracy and effectiveness of current screening algorithm.

Soybean isoflavones protect SH-SY5Y neurons from atrazine-induced toxicity by activating mitophagy through stimulation of the BEX2/BNIP3/NIX pathway.

Atrazine (ATR) is a widely used herbicide that can induce the degeneration of dopaminergic (DAergic) neurons in the substantia nigra, resulting in a Parkinson's disease-like syndrome. Despite the high risk of environmental exposure, few studies have investigated strategies for the prevention of ATR neurotoxicity. Our previous studies demonstrated that ATR can impair mitochondrial function, leading to metabolic failure. Cells maintain mitochondrial quality through selective autophagic elimination, termed mitophagy. Soybean isoflavones (SI) possess multiple beneficial bioactivities, including preservation of mitochondria function, so it was hypothesized that SI can protect neurons against ATR toxicity by promoting mitophagy. Pretreatment of SH-SY5Y neurons with SI prevented ATR-induced metabolic failure and cytotoxicity as assessed by intracellular ATP, Na+-K+-ATPase activity, mitochondrial membrane potential, and cell viability assays. The neuroprotective efficacy of SI was superior to the major individual components genistein, daidzein, and glycitein. Ultrastructural analyses revealed that ATR induced mitochondrial damage, while SI promoted the sequestration of damaged mitochondria into autophagic vesicles. Soybean isoflavones also induced mitophagy as evidenced by upregulated expression of BNIP3/NIX, BEX2, and LC3-II, while co-treatment with the mitophagy inhibitor Mdivi-1 blocked SI-mediated neuroprotection and prevented SI from reversing ATR-induced BEX2 downregulation. Furthermore, BEX2 knockdown inhibited SI-induced activation of the BNIP3/NIX pathway, mitophagy, and neuroprotection. These findings suggest that SI protects against ATR-induced mitochondrial dysfunction and neurotoxicity by activating the BEX2/BNIP3/NIX pathway.

Theacrine, a Potent Antidepressant Purine Alkaloid from a Special Chinese Tea, Promotes Adult Hippocampal Neurogenesis in Stressed Mice.

Daily intake of tea has been known to relate to a low risk of depression. In this study, we report that a special variety of tea in China, Camellia assamica var. kucha (kucha), possesses antidepressant effects but with less adverse effects as compared to traditional tea Camellia sinensis. This action of kucha is related to its high amount of theacrine, a purine alkaloid structurally similar to caffeine. We investigated the antidepressant-like effects and mechanisms of theacrine in chronic water immersion restraint stress and chronic unpredictable mild stress mice models. PC12 cells and primary hippocampal neural stem cells were treated with stress hormone corticosterone (CORT) to reveal the potential antidepression mechanism of theacrine from the perspective of adult hippocampus neurogenesis. Results of behavioral and neurotransmitter analysis showed that intragastric administration of theacrine significantly counteracted chronic stress-induced depression-like disorders and abnormal 5-hydroxytryptamine (5-HT) metabolism with less central excitability. Further investigation from both in vivo and in vitro experiments indicated that the antidepressant mechanism of theacrine was associated with promoting adult hippocampal neurogenesis, via the modulation of the phosphodiesterase-4 (PDE4)/cyclic adenosine monophosphate (cAMP)/cAMP response-element binding (CREB)/brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) pathway. Collectively, our findings could promote the prevalence of kucha as a common beverage with uses for health care and contribute to the development of theacrine as a potential novel antidepressant medicine.

Oxygenated phosphatidylethanolamine navigates phagocytosis of ferroptotic cells by interacting with TLR2.

During cancer therapy, phagocytic clearance of dead cells plays a vital role in immune homeostasis. The nonapoptotic form of cell death, ferroptosis, exhibits extraordinary potential in tumor treatment. However, the phagocytosis mechanism that regulates the engulfment of ferroptotic cells remains unclear. Here, we establish a novel pathway for phagocytic clearance of ferroptotic cells that is different from canonical mechanisms by using diverse ferroptosis models evoked by GPX4 dysfunction/deficiency. We identified the oxidized phospholipid, 1-steaoryl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH), as a key eat-me signal on the ferroptotic cell surface. Enriching the plasma membrane with SAPE-OOH increased the efficiency of phagocytosis of ferroptotic cells by macrophage, a process that was suppressed by lipoprotein-associated phospholipase A2. Ligand fishing, lipid blotting, and cellular thermal shift assay screened and identified TLR2 as a membrane receptor that directly recognized SAPE-OOH, which was further confirmed by TLR2 inhibitors and gene silencing studies. A mouse mammary tumor model of ferroptosis verified SAPE-OOH and TLR2 as critical players in the clearance of ferroptotic cells in vivo. Taken together, this work demonstrates that SAPE-OOH on ferroptotic cell surface acts as an eat-me signal and navigates phagocytosis by targeting TLR2 on macrophages.

Protective role of serpina3c as a novel thrombin inhibitor against atherosclerosis in mice.

Abnormal vascular smooth muscle cell (VSMC) proliferation is a critical step in the development of atherosclerosis. Serpina3c is a serine protease inhibitor (serpin) that plays a key role in metabolic diseases. The present study aimed to investigate the role of serpina3c in atherosclerosis and regulation of VSMC proliferation and possible mechanisms. Serpina3c is down-regulated during high-fat diet (HFD)-induced atherosclerosis. An Apoe-/-/serpina3c-/--double-knockout mouse model was used to determine the role of serpina3c in atherosclerosis after HFD for 12 weeks. Compared with Apoe-/- mice, the Apoe-/-/serpina3c-/- mice developed more severe atherosclerosis, and the number of VSMCs and macrophages in aortic plaques was significantly increased. The present study revealed serpina3c as a novel thrombin inhibitor that suppressed thrombin activity. In circulating plasma, thrombin activity was high in the Apoe-/-/serpina3c-/- mice, compared with Apoe-/- mice. Immunofluorescence staining showed thrombin and serpina3c colocalization in the liver and aortic cusp. In addition, inhibition of thrombin by dabigatran in serpina3c-/- mice reduced neointima lesion formation due to partial carotid artery ligation. Moreover, an in vitro study confirmed that thrombin activity was also decreased by serpina3c protein, supernatant and cell lysate that overexpressed serpina3c. The results of experiments showed that serpina3c negatively regulated VSMC proliferation in culture. The possible mechanism may involve serpina3c inhibition of ERK1/2 and JNK signaling in thrombin/PAR-1 system-mediated VSMC proliferation. Our results highlight a protective role for serpina3c as a novel thrombin inhibitor in the development of atherosclerosis, with serpina3c conferring protection through the thrombin/PAR-1 system to negatively regulate VSMC proliferation through ERK1/2 and JNK signaling.

Case Report: One-Year Delay in the Effect of Conversion Surgery Therapy for Advanced Hepatocellular Carcinoma After Systemic Therapy.

Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed malignancy and the third leading cause of cancer-related deaths worldwide. A 58-year-old man visited his local hospital due to abdominal discomfort and was diagnosed with lung metastasis. After admission to our hospital in April 2020, he received two cycles of transcatheter arterial embolization (TAE), hepatic arterial infusion chemotherapy (HAIC-Folfox), sorafenib, and camrelizumab every 3 weeks. Due to the end of HAIC treatment, he underwent drug-eluting transcatheter arterial chemoembolization (dTACE) once, sorafenib, and camrelizumab. However, because of worsening liver function, we interrupted TACE and only gave sorafenib and camrelizumab in August 2020. Although he received systemic therapy, the tumors still rapidly progressed and we considered the possibility of tumor resistance. Subsequently, regorafenib was given. In September, the patient underwent conventional TACE (cTACE) once, regorafenib, and camrelizumab. After half a year of comprehensive treatment, the treatment effect was not satisfactory, and he returned to the local hospital to received regorafenib every day and camrelizumab once every 3 weeks. The patient found that the tumor and lung metastasis had shrunk significantly after 1 year of the initial diagnosis, then he was admitted to our hospital and received surgery treatment, and now he has survived disease-free for 6 months.

Human Milk sn-2 Palmitate Triglyceride Rich in Linoleic Acid Had Lower Digestibility but Higher Absorptivity Compared with the sn-2 Palmitate Triglyceride Rich in Oleic Acid in Vitro.

The digestion and absorption of different structural lipids in human milk may be different. Hence, by simulating in vitro infant digestion and Caco-2 cells to explore the effects of 1-oleoyl-2-palmitoyl-3-linoleoylglycerol (OPL)/1,3-dilinoleoyl-2-palmitoylglycerol (LPL)/1,3-dioleoyl-2-palmitoylglycerol (OPO) and their mixtures (M) (OPL/LPL/OPO in M1, M2, and M3 were 1.5/0.5/1, 1.2/1.2/1, and 0.5/0.2/1, respectively) on digestion and absorption. The digestibility of the OPO group was higher than those of the OPL and LPL groups, and the M3 group was higher than the M1 and M2 groups. The synthesis and transport of triglycerides in Caco-2 cells in OPL and LPL groups were higher than the OPO group, and the M1 group was significantly higher than that of M3. The expression of FABP1, PPARα, and MTT protein in OPL and M1 groups was significantly higher than OPO and M3, respectively. There are differences in the digestion and absorption of differently structured lipids from this study.