GSH-depleting metal-polyphenol-network nanoparticles with dual enzyme activities induce enhanced ferroptosis.

Ferroptosis is a non-apoptotic form of regulated cell death. The efficiency of ferroptosis is restrained in the tumor microenvironment (TME) by overexpression of glutathione (GSH) and insufficient production of hydrogen peroxide (H2O2). In this work, theranostic nanoparticles Ce-aMOFs@Fe3+-EGCG, termed MEFs, are developed by coating uniform Ce-based amorphous metal-organic frameworks (Ce-aMOFs) with epigallocatechin gallate (EGCG) and Fe3+. Fe3+ is chelated by the adjacent phenol hydroxyl groups in EGCG. In the tumor cell interior, overexpressed GSH and weak acidic medium degrade the coating to release Fe3+ and EGCG accompanied by exposure of Ce-aMOFs. Fe3+ and EGCG consume GSH along with turning Fe3+ into Fe2+. Ce-aMOFs act as a nanozyme possessing dual-enzymatic activities, i.e. superoxide dismutase (SOD)- and phosphatase-like activities. In the TME, Ce-aMOFs catalyze the conversion of endogenous superoxide (O2˙-) into H2O2, and Fe2+ catalyzes H2O2 to generate toxic hydroxyl radicals (˙OH), which may further induce tumor cell death through ferroptosis. In addition, the phosphatase-like activity of Ce-aMOFs may sustainably dephosphorylate NADPH and effectively inhibit intracellular biosynthesis of GSH. Therefore, MEFs ensure down-regulation of intracellular GSH levels and up-regulation of oxidative pressure, which enhance the ferroptosis effect.

The Role of Leukotriene B4 in Cow Metritis.

Introduction: Metritis is a common postpartum disease in dairy cows. As a mast cell (MC) mediator, leukotriene B4 (LTB4) is the strongest phagocyte chemokine. It is important in inflammation for the recruitment of immune cells to resist infection. This study investigated the effect of LTB4 in metritis. Material and Methods: Twenty Holstein cows 3 to 6 years old and at 6 to 10 days postpartum were selected, ten of which with postpartum metritis were the experimental group, and the other ten of which as healthy cows were the control group. The levels of LTB4, substance P (SP) and vasoactive intestinal peptide (VIP) were measured by ELISA, the expression of LTB4 receptor 2 (BLT2), matrix metalloproteinase (MMP)-2 and MMP-9 mRNA was measured by qPCR, and collagens I and IV were detected by immunohistochemical staining. Results: Concentrations of SP and LTB4 were significantly higher, but those of VIP were significantly lower in the experimental group than those in the control group. The expression of BLT2, MMP-2 and MMP-9 mRNA was significantly higher in the experimental group than that in the control group. The expression of collagen Ⅰ and collagen Ⅳ was significantly lower in the experimental group than that in the control group. Conclusion: In metritis, SP promotes the activation of MC and the synthesis and release of LTB4. Leukotriene B4 chemotactic immune cells promote the high expression of collagenase, which accelerated the hydrolysis of collagen, while the inhibitory effect of VIP on MC was weakened. This may further aggravate the damage to uterine tissue.

[Treatmen of distal femoral fracture of Müller type A with homeopathic bidirectional-traction reduction device unite with internal fixation].

OBJECTIVE: To investigate the effect of treatment of Müller A fracture of distal femur with small incision internal fixation assisted by homeopathic bidirectional-traction reduction device. METHODS: From January 2018 to December 2019, 22 patients (14 males and 8 females) with Müller type A distal femoral fractures were treated with homeopathic bidirectional-traction assisted reduction and minimally invasive small incision locking plate internal fixation;The age ranged from 29 to 58 years old with an average of (41.23±7.03) years. The time from injury to operation was 1 to 7 days with an average of (3.41±1.71) days. According to Müller classification, there were 4 cases of type A1, 10 cases of type A2, and 8 cases of type A3. The postoperative knee joint function was evaluated by Schatzker Lambert fracture criterion of distal femur. RESULTS: All the incisions healed in one stage without infection, osteomyelitis and other complications. All the fractures healed without malunion and nonunion. All of 22 patients were followed up for 12 to 18 months with an average of (14.50±2.02) months. The healing time was 3 to 6 months with an average of (4.64±1.14) months. According to Schatzker Lambert criteria for distal femoral fracture, 12 cases were excellent, 6 good, and 4 medium. CONCLUSION: It is an ideal method to treat Müller type A fracture of distal femur with homeopathic bidirectional-traction assisted reduction device and minimally invasive small incision locking plate internal fixation.

Heat-killed Lactobacillus murinus confers neuroprotection against dopamine neuronal loss by targeting NLRP3 inflammasome.

The intestinal flora has become very active in studies related to Parkinson's disease (PD) in recent years. The microbe-gut-brain axis is closely related to the maintenance of brain homeostasis as well as PD pathogenesis. Alterations in gut bacteria can contribute to neuroinflammation and dopamine (DA) neurodegeneration. Lactobacillus murinus, a gram-positive bacterium, is a commensal gut bacteria present in the mammalian gut and considered as a potential probiotic due to its beneficial effects, including anti-inflammatory and antibacterial actions. In this study, the effects of live L. murinus and heat-killed L. murinus on DA neuronal damage in rats and the underlying mechanisms were investigated. Data showed that heat-killed L. murinus ameliorated 6-hydroxydopamine-induced motor dysfunctions and loss of substantia nigra DA neurons, while no protection was shown in live L. murinus treatment. At the same time, heat-killed L. murinus reduced the activation of NLRP3 inflammasome in microglia and the secretion of pro-inflammatory factors, thus inhibiting the development of neuroinflammation. Furthermore, heat-killed L. murinus failed to display its original neuroprotective properties in NLRP3 inflammasome knockout mice. Together, heat-killed L. murinus conferred neuroprotection against DA neuronal loss via the inhibition of microglial NLRP3 inflammasome activation. These findings provide a promising potential for future applications of L. murinus, and also beneficial strategy for PD treatment.

Expression and clinical significance of VISTA, B7-H3, and PD-L1 in glioma.

Immune checkpoint (IC) therapy has led to a breakthrough in cancer treatment. However, the interaction of ICs is controversial in glioma. We detected features of ICs using transcriptome data and a multicolor immunofluorescence assay. We discovered that B7-H3 increased with grade and age and predicted worse overall survival (OS) at the transcriptional and proteomic levels. VISTA and PD-L1 were associated with OS and grade at the RNA level. At the protein level, VISTA was primarily expressed in tumor cells and TAMs. B7-H3 and VISTA were positively correlated with PD-L1. There was a strong correlation between PD-L1 and CD3 and between VISTA and IBA-1. PD-L1 was coexpressed with T cells. VISTA was coexpressed with TAMs. In T cells, we found a strong correlation in ICs, which worsened in TAMs and tumor cells. In conclusion, B7-H3 is a vital prognostic target for immunotherapy. We provided a potential mechanism for the immunosuppressive microenvironment in glioma.

Longitudinal Dynamics of Cellular Responses in Recovered COVID-19 Patients.

Safe and effective vaccines and therapeutics based on the understanding of antiviral immunity are urgently needed to end the COVID-19 pandemic. However, the understanding of these immune responses, especially cellular immune responses to SARS-CoV-2 infection, is limited. Here, we conducted a cohort study of COVID-19 patients who were followed and had blood collected to characterize the longitudinal dynamics of their cellular immune responses. Compared with healthy controls, the percentage of activation of SARS-CoV-2 S/N-specific T cells in recovered patients was significantly higher. And the activation percentage of S/N-specific CD8+ T cells in recovered patients was significantly higher than that of CD4+ T cells. Notably, SARS-CoV-2 specific T-cell responses were strongly biased toward the expression of Th1 cytokines, included the cytokines IFNγ, TNFα and IL2. Moreover, the secreted IFNγ and IL2 level in severe patients was higher than that in mild patients. Additionally, the number of IFNγ-secreting S-specific T cells in recovered patients were higher than that of N-specific T cells. Overall, the SARS-CoV-2 S/N-specific T-cell responses in recovered patients were strong, and virus-specific immunity was present until 14-16 weeks after symptom onset. Our work provides a basis for understanding the immune responses and pathogenesis of COVID-19. It also has implications for vaccine development and optimization and speeding up the licensing of the next generation of COVID-19 vaccines.

Necrostatin-1 decreases necroptosis and inflammatory markers after intraventricular hemorrhage in mice.

Necrostatin-1, an inhibitor of necroptosis, can effectively inhibit necrotic apoptosis in neurological diseases, which results in the inhibition of inflammation, endoplasmic reticulum stress, and reactive oxygen species production and substantial improvement of neurological function. However, the effects of necrostatin-1 on intraventricular hemorrhage (IVH) remain unknown. In this study, we established a mouse model of IVH by injecting autologous blood into the lateral ventricle of the brain. We also injected necrostatin-1 into the lateral ventricle one hour prior to IVH induction. We found that necrostatin-1 effectively reduced the expression levels of the necroptosis markers receptor-interacting protein kinase (RIP)1, RIP3, mixed lineage kinase domain-like protein (MLKL), phosphorylated (p)-RIP3, and p-MLKL and the levels of interleukin-1ß , interleukin-6, and tumor necrosis factor-α in the surrounding areas of the lateral ventricle. However, necrostatin-1 did not reduce ependymal ciliary injury or brain water content. These findings suggest that necrostatin-1 can prevent local inflammation and microglial activation induced by IVH but does not greatly improve prognosis.

[Protective Effects of Akkermansia muciniphila and Amuc_1100 Protein on Rats on High-Fat Diet Combined with Streptozotocin Injection].

OBJECTIVE: To explore the protective effects of live or pasteurized Akkermansia muciniphila and Amuc_1100 protein on a rat model of diabetes mellitus induced by high-fat diet (HFD) combined with streptozotocin (STZ). METHODS: A total of 96 Sprague-Dawley (SD) rats were randomly assigned to 8 groups, including 6 experimental groups and 2 control groups, with 12 rats in each group. HFD combined with STZ injection was given to the rats to create a simulated model of the progression of diabetes mellitus type 2. In addition, the rats were treated with different doses of live or pasteurized Akkermansia muciniphila or Amuc_1100 protein by way of gavage for 8 weeks simultaneously. Plasma samples were collected to determine the level of parameters related to lipid and glucose metabolism, and inflammation mediators. Colon tissue specimens were collected for HE staining. Stool samples of the rats were collected for 16S rRNA gene sequencing. RESULTS: Compared with the HFD control group, rats in the group treated with Akkermansia muciniphila exhibited significantly lower body mass gain ( P<0.01) and lower plasma TNF-α level ( P<0.05). Administration of Akkermansia muciniphila or Amuc_1100 protein increased the number of goblet cells and mucin secretion. The ß diversity analysis of the samples showed no overall difference in the intervention groups. CONCLUSION: Oral administration of Akkermansia muciniphila can effectively ameliorate HFD-induced metabolic disorders, including body mass gain and systemic inflammation. Akkermansia muciniphila and Amuc_1100, to a certain degree, improved the gut barrier function. After eight weeks of intervention, there was no significant impact on the structure of the gut microbiota.

[A Comparative Study of Soil Environmental Standards for Agricultural Land Among Different Countries and Its Implication for China].

Soil environmental quality of agricultural land plays a determinate role in the quality of agricultural products, human health, and the safety of the ecosystem. In 2018, China issued the "soil environment quality risk control standard for soil contamination of agriculture land" (GB 15618-2018), which has been essential to soil pollution prevention and the control of agricultural land. In this study, a systematic and comparative analysis of soil environmental standards for the agricultural land of 17 countries or regions was conducted, including the framework, protection objective, derivation method, contaminant elements, analyses methods, and standard values, as well as the impact factors. The results showed that the number of contaminants of GB 15618-2018 was insufficient with the simple consideration of total concentrations. Meanwhile, there was a lack of the standardized derivation method. On such a basis, we put forward some suggestions to improve GB 15618-2018 in light of the aforementioned problems, including strengthening the research of soil environmental benchmark and background values; establishing the scientific and standardized derivation method; and improving the number, form, and availability of indicators for risk control. In the meantime, the regional and local background environmental concentration of soil was highly proposed as a supplement and optimization to soil screening values.

Immunization with Aß3-10-KLH vaccine improves cognitive function and ameliorates mitochondrial dysfunction and reduces Alzheimer's disease-like pathology in Tg-APPswe/PSEN1dE9 mice.

Alzheimer's disease is a common cause of dementia, for which no disease-modifying therapy is yet available. Aß3-10-KLH, a vaccine for active immunization, has been shown to prevent pathological changes in young transgenic models of AD, but the effects of treatment with it and its effects on mitochondrial dysfunction remain unclear. We immunized 6-month-old Tg-APPswe/PSEN1dE9 mice with Aß3-10-KLH to analyze whether it is capable of eliminating amyloid-ß after its appearance. The vaccine effectively decreased amyloid-ß deposits, improved cognitive function and ameliorated mitochondrial dysfunction. These results indicate the potential of Aß3-10-KLH as a vaccine to treat AD.

Effect of isocenter deviation on volume modulated arc therapy plan results and gamma passing rate in the treatment of cervical cancer.

BACKGROUND: Isocenter deviation, often induced by small displacements of both the device and the patient, is a common error seen in radiotherapy. In this study, we investigated the impact of isocenter deviation on the results of the volumetric modulated arc therapy (VMAT) plan and dosimetric verification gamma passing rate in the treatment of cervical cancer. METHODS: The clinical data of 15 patients with cervical cancer who were treated with VMAT were retrospectively collected and analyzed. In this study, the isocenter site modification method was adopted. The VMAT plan with isocenter deviation adjustment was set as the experimental group, while the original plan was set as the control group. The impact of isocenter deviation on the results of the VMAT plan and dosimetric verification gamma passing rate was analyzed. Applying gamma analysis with different test criterions, the impact of isocenter deviation on the gamma passing rates was evaluated, and the sensitivity of different test criterions in identifying isocenter deviation was also analyzed. RESULTS: There was a significant difference in the average dose in the target area between experimental group and control group (P<0.05). In organs at risk (OAR) terms, isocenter deviations also caused significant differences in dose parameters between the two groups. Except that there was no significant difference in the rectal V40 between two groups when the isocenter deviation was greater than 3 mm in the y axis direction. With the increase in the isocenter deviation, there was a trend towards decreased gamma passing rates with different analysis criterions in the experimental group. The 2 mm/2% standard had the highest sensitivity for identifying isocenter deviation. CONCLUSIONS: Isocenter deviation has significant effects on the results of the volume rotation intensity modulation plan and dosimetric verification gamma passing rates in the treatment of cervical cancer. When the isocenter deviation was less than 3 mm, a higher gamma passing rate (>90%) could also be obtained under the condition of the 3 mm/3% test criterions. It is recommended that the 2 mm/2% test standard should be utilized in clinical practice.

Motility changes rather than EPS production shape aggregation of Chlamydomonas microsphaera in aquatic environment.

Microalgal aggregation is a key for both microalgae harvesting and water purification, where changes in extracellular polymeric substance (EPS) secretion and cell motility changes are of core importance. In this study, we investigated the aggregation process of Chlamydomonas microsphaera confronting resource limitation and chlorine disinfection, and tried to compare changes in the magnitude of EPS secretion and cell motility. Results show that the presence of mild chlorine solution (0.20%) dose stimulated microalgal aggregation (with an aggregated to planktonic cells ratio of 3.2), with extracellular protein concentration and mean cell velocity reaching a maximum of 43.43 ± 0.01 mg/L and 201 ± 35 µm/s, respectively. These values are 71% and 191% higher than those of the control. Comparably, nutrient availability had only a limited impact on microalgal aggregation and was associated with mild EPS secretion and cell motility. Correlation analysis revealed a strong positive impact of cell motility (mean velocity) on microalgae aggregation, with little effect on EPS excretion. Together, these quantitative estimations may shed light on understanding the mechanisms of microalgae aggregation in aqueous systems, which could help future design and practical operation of source water pretreatment or microalgae harvesting.

Dendrobium nobile Lindl alkaloid attenuates 6-OHDA-induced dopamine neurotoxicity.

Parkinson's disease (PD) is one of the most common central nervous system (CNS) degenerative disease and is characterized by a progressive loss of midbrain substantia nigra dopamine (DA) neurons. Dendrobium nobileLindl alkaloid (DNLA) is an active component extracted from D. nobile Lindl, which is a traditional Chinese herb. The various pharmacological effects of D. nobile are beneficial for human health. Recently, DNLA-mediated neuroprotective effects have been reported. However, the neuroprotection of DNLA on 6-hydroxydopamine (6-OHDA)-induced DA neurotoxicity is still unknown. This study aimed to explore the neuroprotective effects of DNLA on DA neurotoxicity induced by 6-OHDA. In PD rat model, continuous intragastric administration of DNLA (20 mg/kg) for 7 days significantly ameliorated 6-OHDA-induced DA neurons loss in the midbrain substantia nigra. In addition, primary rat midbrain neuron-glia cocultures were used to explore the mechanisms underlying DNLA-related DA neuroprotection. The studies on neuron-glia cocultures revealed that neuroprotective effects of DNLA (2.5 ng/mL) were mediated by inhibiting the release of proinflammatory cytokines. Taken together, DNLA holds neuroprotective effect on 6-OHDA-induced neurons neurodegeneration by selectively inhibiting the production of proinflammatory factors and could be a potential compound for PD treatment.

Ellagic Acid Protects Dopamine Neurons via Inhibition of NLRP3 Inflammasome Activation in Microglia.

Neuroinflammation plays a crucial role in the pathological process of Parkinson's disease (PD). Nod-like receptor protein 3 (NLRP3) inflammasome was highly located in microglia and involved in the process of neuroinflammation. Activation of the NLRP3 inflammasome has been confirmed to contribute to the progression of PD. Thus, inhibition of NLRP3 inflammasome activation could be an important breakthrough point on PD therapy. Ellagic acid (EA) is a natural polyphenol that has been widely found in soft fruits, nuts, and other plant tissues with anti-inflammatory, antioxidant, and neuroprotective properties. However, the mechanisms underlying EA-mediated anti-inflammation and neuroprotection have not been fully elucidated. In this study, a lipopolysaccharide- (LPS-) induced rat dopamine (DA) neuronal damage model was performed to determine the effects of EA on the protection of DA neurons. In addition, the DA neuronal MN9D cell line and microglial BV-2 cell line were employed to explore whether EA-mediated neuroprotection was through an NLRP3-dependent mechanism. Results indicated that EA ameliorated LPS-induced DA neuronal loss in the rat substantia nigra. Further, inhibition of microglial NLRP3 inflammasome signaling activation was involved in EA-generated neuroprotection, as evidenced by the following observations. First, EA reduced NLRP3 inflammasome signaling activation in microglia and subsequent proinflammatory cytokines' excretion. Second, EA-mediated antineuroinflammation and further DA neuroprotection from LPS-induced neurotoxicity were not shown upon microglial NLRP3 siRNA treatment. In conclusion, this study demonstrated that EA has a profound effect on protecting DA neurons against LPS-induced neurotoxicity via the suppression of microglial NLRP3 inflammasome activation.

Corrigendum: Combination Treatment of Icariin and L-DOPA Against 6-OHDA-Lesioned Dopamine Neurotoxicity.

[This corrects the article DOI: 10.3389/fnmol.2018.00155.].

Esophageal Histological Precursor Lesions and Subsequent 8.5-Year Cancer Risk in a Population-Based Prospective Study in China.

INTRODUCTION: Data on the associations between esophageal histological lesions and risk of esophageal squamous cell carcinoma (ESCC) in general populations are limited. We aimed to investigate these associations in a large Chinese general population to inform future Chinese ESCC screening guidelines. METHODS: We performed endoscopic screening of 21,111 participants aged 40-69 years from 3 high-risk areas of China in 2005-2009, and followed the cohort through 2016. Cumulative incidence and mortality rates of ESCC were calculated by baseline histological diagnosis, and hazard ratios of ESCC, overall and by age and sex, were assessed using the Cox proportional hazards models. RESULTS: We identified 143 new ESCC cases (0.68%) and 62 ESCC deaths (0.29%) during a median follow-up of 8.5 years. Increasing grades of squamous dysplasia were associated with the increasing risk of ESCC incidence and mortality. The cumulative ESCC incidence rates for severe dysplasia/carcinoma in situ, moderate dysplasia (MD), and mild dysplasia were 15.5%, 4.5%, and 1.4%, respectively. Older individuals (50-69 years) had 3.1 times higher ESCC incidence than younger individuals (40-49 years), and men had 2.4 times higher ESCC incidence than women. DISCUSSION: This study confirmed that increasing grades of squamous dysplasia are associated with increasing risk of ESCC and that severe dysplasia and carcinoma in situ require clinical treatment. This study suggests that in high-risk areas of China, patients with endoscopically worrisome MD should also receive therapy, the first screening can be postponed to 50 years, and endoscopic surveillance intervals for unremarkable MD and mild dysplasia can be lengthened to 3 and 5 years, respectively.

Ellagic acid protects dopamine neurons from rotenone-induced neurotoxicity via activation of Nrf2 signalling.

Parkinson's disease (PD) is the second most prevalent central nervous system (CNS) degenerative disease. Oxidative stress is one of key contributors to PD. Nuclear factor erythroid-2-related factor 2 (Nrf2) is considered to be a master regulator of many genes involved in anti-oxidant stress to attenuate cell death. Therefore, activation of Nrf2 signalling provides an effective avenue to treat PD. Ellagic acid (EA), a natural polyphenolic contained in fruits and nuts, possesses amounts of pharmacological activities, such as anti-oxidant stress and anti-inflammation. Recent studies have confirmed EA could be used as a neuroprotective agent in neurodegenerative diseases. Here, mice subcutaneous injection of rotenone (ROT)-induced DA neuronal damage was performed to investigate EA-mediated neuroprotection. In addition, adult Nrf2 knockout mice and different cell cultures including MN9D-enciched, MN9D-BV-2 and MN9D-C6 cell co-cultures were applied to explore the underlying mechanisms. Results demonstrated EA conferred neuroprotection against ROT-induced DA neurotoxicity. Activation of Nrf2 signalling was involved in EA-mediated DA neuroprotection, as evidenced by the following observations. First, EA activated Nrf2 signalling in ROT-induced DA neuronal damage. Second, EA generated neuroprotection with the presence of astroglia and silence of Nrf2 in astroglia abolished EA-mediated neuroprotection. Third, EA failed to produce DA neuroprotection in Nrf2 knockout mice. In conclusion, this study identified EA protected against DA neuronal loss via an Nrf2-dependent manner.

[Effects of Akkermansia muciniphila on the Proliferation, Apoptosis and Insulin Secretion of Rat Islet Cell Tumor Cells].

OBJECTIVE: To investigate the effects of Akkermansia muciniphila ( A. muciniphila) on the proliferation, apoptosis and insulin secretion of rat pancreatic islet cell tumor cells (INS-1). METHODS: INS-1 cells were divided into three groups, normal, repair, and protect groups, and subsequently every group was subjected with A. muciniphila metabolites, live A. muciniphilaorpasteurized A. muciniphila for 48 h. A group that did not treat with anything was set as blank control. After intervention, the cell viability was determined by MTT method, the insulin secretion level stimulated by glucose was determined by ELISA, the expressions of the genes involved in insulin secretion and apoptosis were tested by qRT-PCR, and the expression of apoptosis related protein Bax was evaluated by Western blot. RESULTS: There was no significant change in INS-1 cell morphology after co-incubation with 3 types of A. Muciniphila interventions for 48 h. The proliferative activity of INS-1 cells was decreased in the repair group that treated with live A. muciniphila than that of control ( P<0.005). A. muciniphila intervention had no effect on insulin secretion in INS-1 cells in normal, repair or protection group ( P>0.05). A. muciniphila secretions promoted the expression of glucose transporter 2 ( Glut2) in 3 groups and the expression of glucokinase ( GCK) in repair group ( P<0.05). The expression of Baxof the INS-1 cell in the normal group was decreased after intervented with 3 kinds of A. muciniphila intervention materials ( P<0.001).The expression of Bax gene of the INS-1 cell in the repair group that treated with dead A. muciniphilawas decreased ( P<0.05). The expression of Bax protein of INS-1 cells that treated with A. muciniphila interventions was decreased. CONCLUSION: A. muciniphila can promote the expression of insulin secretion-related genes in INS-1 cells, inhibit the expression of apoptotic genes and apoptosis protein Bax.This research provides a new direction for applying A. muciniphila in improving type 2 diabetes.