Hypoxia-inducible lipid droplet-associated protein (HILPDA) and cystathionine ß-synthase (CBS) co-contribute to protecting intestinal epithelial cells from Staphylococcus aureus via regulating lipid droplets formation.

Despite Staphylococcus aureus (S. aureus) being a highly studied zoontic bacterium, its enteropathogenicity remains elusive. Herein, our findings demonstrated that S. aureus infection led to the accumulation of lipid droplets (LDs) in intestinal epithelial cells, accompanied by marked elevation inflammatory response that ultimately decreases intracellular bacterial load. The aforestated phenomenon may be partly attributed to the up-regulation of hypoxia-inducible lipid droplet-associated protein (HILPDA) and the concomitant down-regulation of cystathionine ß-synthase (CBS) protein. Moreover, S. aureus infection up-regulated the expression of HILPDA, thereby promoting LDs accumulation, and down-regulated that of CBS, consequently inhibiting microsomal triglyceride transfer protein (MTTP) expression. This process may suppress the transport of LDs to the extracellular environment, further contributing to the formation of intracellular LDs. In summary, the results of this study provide significant insights into the intricate mechanisms through which the host organism combats pathogens and maintains the balance of sulfur and lipid metabolism. These findings not only enhance our understanding of the host's defense mechanisms but also offer promising avenues for the development of novel strategies to combat intestinal infectious diseases.

A General Strategy toward Self-assembled Nanovaccine Based on Cationic Lentinan to Induce Potent Humoral and Cellular Immune Responses.

Adjuvants play a critical role in the induction of effective immune responses by vaccines. Here, a self-assembling nanovaccine platform that integrates adjuvant functions into the delivery vehicle is prepared. Cationic Lentinan (CLNT) is mixed with ovalbumin (OVA) to obtain a self-assembling nanovaccine (CLNTO nanovaccine), which induces the uptake and maturation of bone marrow dendritic cells (BMDCs) via the toll-like receptors 2/4 (TLR2/4) to produce effective antigen cross-presentation. CLNTO nanovaccines target lymph nodes (LNs) and induce a robust OVA-specific immune response via TLR and tumor necrosis factor (TNF) signaling pathways, retinoic acid-inducible gene I (RIG-I) receptor, and cytokine-cytokine receptor interactions. In addition, CLNTO nanovaccines are found that promote the activation of follicular helper T (Tfh) cells and induce the differentiation of germinal center (GC) B cells into memory B cells and plasma cells, thereby enhancing the immune response. Vaccination with CLNTO nanovaccine significantly inhibits the growth of ovalbumin (OVA)-expressing B16 melanoma cell (B16-OVA) tumors, indicating its great potential for cancer immunotherapy. Therefore, this study presents a simple, safe, and effective self-assembling nanovaccine that induces helper T cell 1 (Th1) and helper T cell (Th2) immune responses, making it an effective vaccine delivery system.

A critical role for host-derived cystathionine-ß-synthase in Staphylococcus aureus-induced udder infection.

Cystathionine-ß-synthase (CBS) catalyzes the first step of the transsulfuration pathway. The role of host-derived CBS in Staphylococcus aureus (S. aureus)-induced udder infection remains elusive. Herein, we report that S. aureus infection enhances the expression of CBS in mammary epithelial cells in vitro and in vivo. A negative correlation is present between the expression of CBS and inflammation after employing a pharmacological inhibitor/agonist of CBS. In addition, CBS achieves a fine balance between eliciting sufficient protective innate immunity and preventing excessive damage to cells and tissues preserving the integrity of the blood-milk barrier (BMB). CBS/H2S reduces bacterial load by promoting the generation of antibacterial substances (ROS, RNS) and inhibiting apoptosis, as opposed to relying solely on intense inflammatory reactions. Conversely, H2S donor alleviate inflammation via S-sulfhydrating HuR. Finally, CBS/H2S promotes the expression of Abcb1b, which in turn strengthens the integrity of the BMB. The study described herein demonstrates the importance of CBS in regulating the mammary immune response to S. aureus. Increased CBS in udder tissue modulates excessive inflammation, which suggests a novel target for drug development in the battle against S. aureus and other infections.

PFKFB3-Meditated Glycolysis via the Reactive Oxygen Species-Hypoxic Inducible Factor 1α Axis Contributes to Inflammation and Proliferation of Staphylococcus aureus in Epithelial Cells.

Mastitis caused by antibiotic-resistant strains of Staphylococcus aureus is a significant concern in the livestock industry due to the economic losses it incurs. Regulating immunometabolism has emerged as a promising approach for preventing bacterial inflammation. To investigate the possibility of alleviating inflammation caused by S aureus infection by regulating host glycolysis, we subjected the murine mammary epithelial cell line (EpH4-Ev) to S aureus challenge. Our study revealed that S aureus can colonize EpH4-Ev cells and promote inflammation through hypoxic inducible factor 1α (HIF1α)-driven glycolysis. Notably, the activation of HIF1α was found to be dependent on the production of reactive oxygen species (ROS). By inhibiting PFKFB3, a key regulator in the host glycolytic pathway, we successfully modulated HIF1α-triggered metabolic reprogramming by reducing ROS production in S aureus-induced mastitis. Our findings suggest that there is a high potential for the development of novel anti-inflammatory therapies that safely inhibit the glycolytic rate-limiting enzyme PFKFB3.

The therapeutic potential for targeting CSE/H2S signaling in macrophages against Escherichia coli infection.

Macrophages play a pivotal role in the inflammatory response to the zoonotic pathogen E. coli, responsible for causing enteric infections. While considerable research has been conducted to comprehend the pathogenesis of this disease, scant attention devoted to host-derived H2S. Herein, we reported that E. coli infection enhanced the expression of CSE in macrophages, accompanied by a significantly increased inflammatory response. This process may be mediated by the involvement of excessive autophagy. Inhibition of AMPK or autophagy with pharmacological inhibitors could alleviate the inflammation. Additionally, cell model showed that the mRNA expression of classic inflammatory factors (Il-1ß, Il-6), macrophage polarization markers (iNOS, Arg1) and ROS production was significantly down-regulated after employing CSE specific inhibitor PAG. And PAG is capable of inhibiting excessive autophagy through the LKB1-AMPK-ULK1 axis. Interestingly, exogenous H2S could suppress inflammation response. Our study emphasizes the importance of CSE in regulating the macrophage-mediated response to E. coli. Increased CSE in macrophages leads to excessive inflammation, which should be considered a new target for drug development to treat intestinal infection.

Prognostic and immunological role of FDX1 in pan-cancer: an in-silico analysis.

Previous research has demonstrated that ferredoxin 1 (FDX1) contributes to the accumulation of toxic lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and results in cuproptotic cell death. However, the role that FDX1 plays in human cancer prognosis and immunology is still not well understood. The original data was obtained from TCGA and GEO databases and integrated using R 4.1.0. The TIMER2.0, GEPIA, and BioGPS databases were used to explore FDX1 expression. The impact of FDX1 on prognosis was analyzed using the GEPIA and Kaplan-Meier Plotter databases. External validation will be performed using the PrognoScan database. FDX1 expression in different immune and molecular subtypes of human cancers was evaluated using the TISIDB database. The correlation between FDX1 expression and immune checkpoints (ICP), microsatellite instability (MSI), and tumor mutational burden (TMB) in human cancers was analyzed using R 4.1.0. The TIMER2.0 and GEPIA databases were used to study the relationship between FDX1 expression and tumor-infiltrating immune cells. With the c-BioPortal database, we investigated the genomic alterations of FDX1. Pathway analysis and assessment of the sensitivity potential of FDX1-related drugs were also performed. Using the UALCAN database, we analyzed the differential expression of FDX1 in KIRC (kidney renal clear cell carcinoma) with different clinical features. Coexpression networks of FDX1 were analyzed using LinkedOmics. In general, FDX1 was expressed differently in different types of cancer in humans. Expression of FDX1 was strongly correlated with patient prognosis, ICP, MSI, and TMB. FDX1 was also participated in immune regulation and the tumor microenvironment. Coexpression networks of FDX1 were primarily involved in oxidative phosphorylation regulation. Pathway analysis revealed that the expression of FDX1 was correlated to cancer-related and immune-related pathways. FDX1 has the potential to serve as a biomarker for pan-cancer prognosis and immunology, as well as a novel target for tumor therapy.

Nomogram including indirect bilirubin for the prediction of post-stroke depression at 3 months after mild acute ischemic stroke onset.

Background: Post-stroke depression (PSD) has been proven to be associated with stroke severity. Thus, we hypothesized that the prevalence of PSD would be lower in patients with mild stroke. We aim to explore predictors of depression at 3 months after mild acute ischemic stroke (MAIS) onset and to develop a practical and convenient prediction model for the early identification of patients at high risk. Methods: A total of 519 patients with MAIS were consecutively recruited from three hospitals in Wuhan city, Hubei province. MAIS was defined as a National Institute of Health Stroke Scale (NIHSS) score of ≤5 at admission. Meeting the DSM-V diagnostic criteria and a 17-item Hamilton Rating Scale for Depression (HAMD-17) score of >7 at their 3-month follow-up were considered the primary outcomes. A multivariable logistic regression model was used to determine the factors adjusted for potential confounders, and all independent predictors were brought into the construction of a nomogram to predict PSD. Results: The prevalence of PSD is up to 32% at 3 months after MAIS onset. After adjusting for potential confounders, indirect bilirubin (p = 0.029), physical activity (p = 0.001), smoking (p = 0.025), hospitalization days (p = 0.014), neuroticism (p < 0.001), and MMSE (p < 0.001) remained independently and significantly related with PSD. The concordance index (C-index) of the nomogram jointly constructed by the aforementioned six factors was 0.723 (95% CI: 0.678-0.768). Conclusion: The prevalence of PSD seems equally high even if the ischemic stroke is mild, which calls for great concern from clinicians. In addition, our study found that a higher level of indirect bilirubin can lower the risk of PSD. This finding may provide a potential new approach to PSD treatment. Furthermore, the nomogram including bilirubin is convenient and practical to predict PSD after MAIS onset.

AMPK/Drp1 pathway mediates Streptococcus uberis-Induced mitochondrial dysfunction.

Excessive production of reactive oxygen species (ROS) leads to oxidative stress in host cells and affects the progress of disease. Mitochondria are an important source of ROS and their dysfunction is closely related to ROS production. S. uberis is a common causative agent of mastitis. The expression of key enzymes of the mitochondrial apoptotic pathway is increased in mammary epithelial cells after S. uberis stimulation, while expression of proteins related to mitochondrial function is decreased. Drp1, a key protein associated with mitochondrial function, is activated upon infection. Accompanied by mitochondria-cytosol translocation of Drp1, Fis1 expression is significantly upregulated while Mfn1 expression is downregulated implying that the balance of mitochondrial dynamics is disrupted. This leads to mitochondrial fragmentation, decreased mitochondrial membrane potential, higher levels of mROS and oxidative injury. The AMPK activator AICAR inhibits the increased phosphorylation of Drp1 and the translocation of Drp1 to mitochondria by salvaging mitochondrial function in an AMPK/Drp1 dependent manner, which has a similar effect to Drp1 inhibitor Mdivi-1. These data show that AMPK, as an upstream negative regulator of Drp1, ameliorates mitochondrial dysfunction induced by S. uberis infection.

FABP4-mediated lipid droplet formation in Streptococcus uberis-infected macrophages supports host defence.

Foamy macrophages containing prominent cytoplasmic lipid droplets (LDs) are found in a variety of infectious diseases. However, their role in Streptococcus uberis-induced mastitis is unknown. Herein, we report that S. uberis infection enhances the fatty acid synthesis pathway in macrophages, resulting in a sharp increase in LD levels, accompanied by a significantly enhanced inflammatory response. This process is mediated by the involvement of fatty acid binding protein 4 (FABP4), a subtype of the fatty acid-binding protein family that plays critical roles in metabolism and inflammation. In addition, FABP4 siRNA inhibitor cell models showed that the deposition of LDs decreased, and the mRNA expression of Tnf, Il1b and Il6 was significantly downregulated after gene silencing. As a result, the bacterial load in macrophages increased. Taken together, these data demonstrate that macrophage LD formation is a host-driven component of the immune response to S. uberis. FABP4 contributes to promoting inflammation via LDs, which should be considered a new target for drug development to treat infections.

Regulation of ydiV-induced biological characteristics permits Escherichia coli evasion of the host STING inflammatory response.

Mammary gland-derived Escherichia coli (E. coli) is an important pathogen causing dairy cow mastitis. YdiV, with EAL-like domains, inhibits flagellum biogenesis and motility and affects c-di-GMP (eubacterial signaling molecule) concentration changes in bacteria. However, the pathophysiological role of ydiV in host-pathogen cross-talk still needs to be elucidated. In this study, firstly constructed the ydiV mutant (NJ17ΔydiV) and ydiV complementary (cNJ17ΔydiV) E. coli strains to infect mouse mammary epithelial cells (EpH4-Ev) and macrophages (RAW264.7), as well as mouse mammary glands, respectively. Then biological characteristics, adaptor molecules in related signaling pathways, proinflammatory cytokines and the extent of host cell damage was evaluated. Compared with E. coli NJ17 infected mice, the bacterial load in the mammary gland of NJ17ΔydiV was significantly lower and the extent of the damage was alleviated. Notably, the deletion of ydiV significantly aggravated cell damage in RAW264.7 cells and compared with the wild-type strain, NJ17ΔydiV significantly activated the STING/TBK1/IRF3 pathway in macrophages. In EpH4-Ev cells, although STING did not sense E. coli NJ17 invasion, IRF3 was activated by the NJ17ΔydiV strain. Taken together, ydiV deletion significantly affects a variety of biological characteristics and induces severe cell damage, while the STING/TBK1/IRF3 pathway actively participated in pathogen elimination in the host. This study highlights a new role for ydiV in E. coli infection and provides a foundation for further studies to better understand host-bacteria interactions and potential prophylactic strategies for infectious diseases.

The Deletion of yeaJ Gene Facilitates Escherichia coli Escape from Immune Recognition.

Mammary gland-derived Escherichia coli is an important pathogen causing dairy cow mastitis. Mammary gland mucosal immunity against infectious E. coli mainly depends on recognition of pathogen-associated molecular patterns by innate receptors. Stimulator of interferon (IFN) gene (STING) has recently been the dominant mediator in reacting to bacterial intrusion and preventing inflammatory disorders. In this study, we first proved that the diguanylate cyclase YeaJ relieves mouse mammary gland pathological damage by changing E. coli phenotypic and host STING-dependent innate immunity responses. YeaJ decreases mammary gland circular vacuoles, bleeding, and degeneration in mice. In addition, YeaJ participates in STING-IRF3 signaling to regulate inflammation in vivo. In vitro, YeaJ decreases damage to macrophages (RAW264.7) but not to mouse mammary epithelial cells (EpH4-Ev). Consistent with the results in mouse mammary glands, YeaJ significantly activates the STING/TBK1/IRF3 pathway in RAW264.7 macrophages as well. In conclusion, the deletion of yeaJ facilitates E. coli NJ17 escape from STING-dependent innate immunity recognition in vitro and in vivo. This study highlights a novel role for YeaJ in E. coli infection, which provides a better understanding of host-bacterium interactions and potential prophylactic strategies for infections. IMPORTANCE E. coli is the etiological agent of environmental mastitis in dairy cows, which causes massive financial losses worldwide. However, the pathophysiological role of YeaJ in the interaction between E. coli and host remains unclear. We found that YeaJ significantly influences various biological characteristics and suppresses severe inflammatory response as well as greater damage. YeaJ alleviates damage to macrophages (RAW264.7) and mouse mammary gland. Moreover, these effects of YeaJ are achieved at least partial by mediating the STING-IRF3 signaling pathway. In conclusion, the deletion of yeaJ facilitates E. coli NJ17 escape from STING-dependent innate immunity recognition in vitro and in vivo. This study is the basis for further research to better understand host-bacterium interactions and provides potential prophylactic strategies for infections.

Taurine Reprograms Mammary-Gland Metabolism and Alleviates Inflammation Induced by Streptococcus uberis in Mice.

Streptococcus uberis (S. uberis) is an important pathogen causing mastitis, which causes continuous inflammation and dysfunction of mammary glands and leads to enormous economic losses. Most research on infection continues to be microbial metabolism-centric, and many overlook the fact that pathogens require energy from host. Mouse is a common animal model for studying bovine mastitis. In this perspective, we uncover metabolic reprogramming during host immune responses is associated with infection-driven inflammation, particularly when caused by intracellular bacteria. Taurine, a metabolic regulator, has been shown to effectively ameliorate metabolic diseases. We evaluated the role of taurine in the metabolic regulation of S. uberis-induced mastitis. Metabolic profiling indicates that S. uberis exposure triggers inflammation and metabolic dysfunction of mammary glands and mammary epithelial cells (the main functional cells in mammary glands). Challenge with S. uberis upregulates glycolysis and oxidative phosphorylation in MECs. Pretreatment with taurine restores metabolic homeostasis, reverses metabolic dysfunction by decrease of lipid, amino acid and especially energy disturbance in the infectious context, and alleviates excessive inflammatory responses. These outcomes depend on taurine-mediated activation of the AMPK-mTOR pathway, which inhibits the over activation of inflammatory responses and alleviates cellular damage. Thus, metabolic homeostasis is essential for reducing inflammation. Metabolic modulation can be used as a prophylactic strategy against mastitis.

A Massive Right Hemisphere Infarction After Autologous Fat Grafting for Facial Filling.

ABSTRACT: Cerebral fat embolism following facial autologous fat injection is a rare and serious complication. There are limited long-term follow-up data on the motion, cognitive and mental outcomes of surviving patients with cerebral fat embolism following facial autologous fat injection. In this study, the authors reported a patient with a 22-year-old woman with a massive right hemisphere infarction following facial autologous fat injection had normal cognitive function, independent living ability, and social function at 5 years follow-up visit, even though computed tomography showed her entire right cerebral hemisphere had atrophied with softening lesions.

Taurine Alleviates Streptococcus uberis-Induced Inflammation by Activating Autophagy in Mammary Epithelial Cells.

Streptococcus uberis infection can cause serious inflammation and damage to mammary epithelial cells and tissues that can be significantly alleviated by taurine. Autophagy plays an important role in regulating immunity and clearing invasive pathogens and may be regulated by taurine. However, the relationships between taurine, autophagy, and S. uberis infection remain unclear. Herein, we demonstrate that taurine augments PTEN activity and inhibits Akt/mTOR signaling, which decreases phosphorylation of ULK1 and ATG13 by mTOR and activates autophagy. Activating autophagy accelerates the degradation of intracellular S. uberis, reduces intracellular bacterial load, inhibits over-activation of the NF-κB pathway, and alleviates the inflammation and damage caused by S. uberis infection. This study increases our understanding of the mechanism through which taurine regulates autophagy and is the first to demonstrate the role of autophagy in S. uberis infected MAC-T cells. Our study also provides a theoretical basis for employing nutritional elements (taurine) to regulate innate immunity and control S. uberis infection. It also provides theoretical support for the development of prophylactic strategies for this important pathogen.

A web based dynamic MANA Nomogram for predicting the malignant cerebral edema in patients with large hemispheric infarction.

BACKGROUND: For large hemispheric infarction (LHI), malignant cerebral edema (MCE) is a life-threatening complication with a mortality rate approaching 80%. Establishing a convenient prediction model of MCE after LHI is vital for the rapid identification of high-risk patients as well as for a better understanding of the potential mechanism underlying MCE. METHODS: One hundred forty-two consecutive patients with LHI within 24 h of onset between January 1, 2016 and August 31, 2019 were retrospectively reviewed. MCE was defined as patient death or received decompressive hemicraniectomy (DHC) with obvious mass effect (≥ 5 mm midline shift or Basal cistern effacement). Binary logistic regression was performed to identify independent predictors of MCE. Independent prognostic factors were incorporated to build a dynamic nomogram for MCE prediction. RESULTS: After adjusting for confounders, four independent factors were identified, including previously known atrial fibrillation (KAF), midline shift (MLS), National Institutes of Health Stroke Scale (NIHSS) and anterior cerebral artery (ACA) territory involvement. To facilitate the nomogram use for clinicians, we used the "Dynnom" package to build a dynamic MANA (acronym for MLS, ACA territory involvement, NIHSS and KAF) nomogram on web ( http://www.MANA-nom.com ) to calculate the exact probability of developing MCE. The MANA nomogram's C-statistic was up to 0.887 ± 0.041 and the AUC-ROC value in this cohort was 0.887 (95%CI, 0.828 ~ 0.934). CONCLUSIONS: Independent MCE predictors included KAF, MLS, NIHSS, and ACA territory involvement. The dynamic MANA nomogram is a convenient, practical and effective clinical decision-making tool for predicting MCE after LHI in Chinese patients.

Nomograms to predict 2-year overall survival and advanced schistosomiasis-specific survival after discharge: a competing risk analysis.

BACKGROUND: The prognosis of patients with advanced schistosomiasis is poor. Pre-existing prognosis studies did not differentiate the causes of the deaths. The objectives were to evaluate the 2-year overall survival (OS) and advanced schistosomiasis-specific survival (ASS) in patients with advanced schistosomiasis after discharge through competing risk analysis and to build predictive nomograms. METHODS: Data was extracted from a previously constructed database from Hubei province. Patients were enrolled from September 2014 to January 2015, with follow up to January 2017. OS and ASS were primary outcome measures. Nomograms for estimating 2-year OS and ASS rates after discharge were established based on univariate and multivariate Cox regression model and Fine and Gray's model. Their predictive performances were evaluated using C-index and validated in both internal and external validation cohorts. RESULTS: The training cohort included 1487 patients with advanced schistosomiasis. Two-year mortality rate of the training cohort was 8.27% (123/1487). Competing events accounted for 26.83% (33/123). Older age, splemomegaly clinical classification, abnormal serum DBil, AST, ALP and positive HBsAg were significantly associated with 2-year OS. Older age, splemomegaly clinical classification, abnormal serum AST, ALP and positive HBsAg were significantly associated with 2-year ASS. The established nomograms were well calibrated, and had good discriminative ability, with a C-index of 0.813 (95% CI 0.803-0.823) for 2-year OS prediction and 0.834 (95% CI 0.824-0.844) for 2-year ASS prediction. Their predictive performances were well validated in both internal and external validation cohorts. CONCLUSION: The effective predictors of 2-year OS and ASS were discovered through competing risk analysis. The nomograms could be used as convenient predictive tools in clinical practice to guide follow-up and aid accurate prognostic assessment.

Lactobacillus reuteri maintains intestinal epithelial regeneration and repairs damaged intestinal mucosa.

Little is known about the regulatory effect of microbiota on the proliferation and regeneration of ISCs. Here, we found that L. reuteri stimulated the proliferation of intestinal epithelia by increasing the expression of R-spondins and thus activating the Wnt/ß-catenin pathway. The proliferation-stimulating effect of Lactobacillus on repair is further enhanced under TNF -induced intestinal mucosal damage, and the number of Lgr5+ cells is maintained. Moreover, compared to the effects of C. rodentium on the induction of intestinal inflammation and crypt hyperplasia in mice, L. reuteri protected the intestinal mucosal barrier integrity by moderately modulating the Wnt/ß-catenin signaling pathway to avoid overactivation. L. reuteri had the ability to maintain the number of Lgr5+ cells and stimulate intestinal epithelial proliferation to repair epithelial damage and reduce proinflammatory cytokine secretion in the intestine and the LPS concentration in serum. Moreover, activation of the Wnt/ß-catenin pathway also induced differentiation toward Paneth cells and increased antimicrobial peptide expression to inhibit C. rodentium colonization. The protective effect of Lactobacillus against C. rodentium infection disappeared upon application of the Wnt antagonist Wnt-C59 in both mice and intestinal organoids. This study demonstrates that Lactobacillus is effective at maintaining intestinal epithelial regeneration and homeostasis as well as at repairing intestinal damage after pathological injury and is thus a promising alternative therapeutic method for intestinal inflammation.

TLR2 Signaling Pathway Combats Streptococcus uberis Infection by Inducing Mitochondrial Reactive Oxygen Species Production.

Mastitis caused by Streptococcus uberis (S. uberis) is a common and difficult-to-cure clinical disease in dairy cows. In this study, the role of Toll-like receptors (TLRs) and TLR-mediated signaling pathways in mastitis caused by S. uberis was investigated using mouse models and mammary epithelial cells (MECs). We used S. uberis to infect mammary glands of wild type, TLR2-/- and TLR4-/- mice and quantified the adaptor molecules in TLR signaling pathways, proinflammatory cytokines, tissue damage, and bacterial count. When compared with TLR4 deficiency, TLR2 deficiency induced more severe pathological changes through myeloid differentiation primary response 88 (MyD88)-mediated signaling pathways during S. uberis infection. In MECs, TLR2 detected S. uberis infection and induced mitochondrial reactive oxygen species (mROS) to assist host in controlling the secretion of inflammatory factors and the elimination of intracellular S. uberis. Our results demonstrated that TLR2-mediated mROS has a significant effect on S. uberis-induced host defense responses in mammary glands as well as in MECs.

Role of Toll-like receptor 2 against Streptococcus uberis infection in primary mouse mammary epithelial cells.

Mammary epithelial cells (MECs) play an important role against Streptococcus uberis infection which is one of the main causes of bovine mastitis and a potential threat to human health. Toll-like receptors (TLRs) and their mediated signaling pathways are critical in both innate and infection responses, yet their roles in anti-S. uberis infection in MECs remains poorly defined. In this work we investigated the regulatory mechanisms of TLR2 in inflammatory responses, where WT and TLR2-/- mice were euthanized at 15-18 days gestation, and mammary gland tissues were collected aseptically. The mouse MECs (MMECs) were isolated by combined digestion with type I collagenase, hyaluronidase and trypsin. We challenged MMECs with S. uberis and quantified antioxidant capacity as well as reactive oxygen species (ROS), proinflammatory cytokines and cell damage at different times. The loss of TLR2 function in MMECs results in more serious cell damage, increased cell adhesion, and significantly decreased ROS and mitochondrial ROS (mROS) with bactericidal function in response to S. uberis infection. Moreover, it was observed that the antioxidant capacity declined, and the production of TLR2-mediated cytokines (except CXC ligand 15) also were reduced. We demonstrated that TLR2 can mediate cellular anti-infective processes in MMECs by regulating the production of ROS and mROS and the secretion of cytokines. The results suggest an unpredicted role of TLR2 in MMECs in response to S. uberis infection.

Predictors of malignant cerebral edema in cerebral artery infarction: A meta-analysis.

Malignant cerebral edema (MCE) is a life-threatening complication of acute cerebral stroke. To date, the focus has been on symptomatic treatment, rather than on prevention. Therefore, to identify high-risk patients and explore potential therapeutic approaches, we investigated the possible predictors of MCE. Specifically, we performed a meta-analysis to identify the potential predictors of MCE in patients with acute cerebral infarction. We searched the MEDLINE, Embase, Cochrane, China National Knowledge Infrastructure, Wanfang Data, and VIP databases from their inception to July 2018 for cohort and case control studies on the predictors of MCE in patients with cerebral infarction. Forty-seven eligible studies containing a total of 45,826 patients were included. Our results suggest that the risk of MCE is higher in case of severe clinical symptoms and large infarct volumes. Additionally, male sex, older age, and a history of stroke and smoking were protective factors against MCE in cerebral infarction patients. Furthermore, thrombolytic therapy and recanalization substantially decreased the risk of MCE in patients with acute stroke. Higher admission temperature (in the subgroup with admission ≤12 h after onset), higher admission blood pressure, and admission leukocytes were also MCE predictors. Our findings facilitate the early prediction of MCE and may contribute to potential therapeutic approaches.