Ocotillol-Type Pseudoginsenoside-F11 Alleviates Lipopolysaccharide-Induced Acute Kidney Injury through Regulation of Macrophage Function by Suppressing the NF-κB/NLRP3/IL-1ß Signaling Pathway.

Acute kidney injury (AKI) is characterized by a sudden decline in renal function. The inflammatory response is the fundamental pathologic alteration throughout AKI, regardless of the various causal factors. Macrophages are the main immune cells involved in the inflammatory microenvironment in AKI. Consequently, targeting macrophages might become a novel strategy for the treatment of AKI. In this study, we demonstrated that pseudoginsenoside-F11 (PF11), a distinctive component of Panax quinquefolius L., regulated macrophage function and protected renal tubular epithelial cells TCMK-1 from lipopolysaccharide (LPS) in vitro. PF11 also alleviated renal injuries in an LPS-induced AKI mouse model, decreased the levels of inflammatory cytokines, reduced macrophage inflammatory infiltration, and promoted the polarization of M1 macrophages to M2c macrophages with suppression of the nuclear factor-κB/NOD-like receptor thermal protein domain-associated protein 3/interleukin-1ß (NF-κB/NLRP3/IL-1ß) signaling pathway. To further investigate whether this nephroprotective effect of PF11 is mediated by macrophages, we performed macrophage depletion by injection of clodronate liposomes in mice. Macrophage depletion abolished PF11's ability to protect against LPS-induced kidney damage with downregulating the NF-κB/NLRP3/IL-1ß signaling pathway. In summary, this is the first study providing data on the efficacy and mechanism of PF11 in the treatment of AKI by regulating macrophage function.

Sulfotransferase homolog 2 receptors blockade on monocyte subsets along with their inflammatory cytokines for septic lung injury.

PURPOSE OF THE STUDY: To observe the dynamic changes in monocyte subsets during septic lung injury and to assess the anti-inflammatory role of the sulfotransferase homolog 2 (ST2) receptor. MATERIALS AND METHODS: Dynamic changes of monocyte subsets from patients with septic lung injury and mice post-cecal ligation and puncture (CLP) were monitored. ST2 receptors on mice monocytes and concentrations of IL-33, IL-1ß, IL-12, and IL-27 from peripheral blood or culture supernatant were detected. RESULTS: CD14lowCD16- (Mo0) and CD14++CD16+ (Mo2) monocyte subsets were significantly expanded in patients with sepsis-related acute respiratory distress syndrome. In sepsis model mice, monocyte counts, particularly of Ly6Cint and CDLy6Cint+hi monocytes, were significantly increased. The mean optical density value of TNF-α after CLP mainly increased after 24 h, whereas that of IL-6 was significantly increased at all time points assessed after CLP. The levels of IL-1ß, IL-12, IL-27, and IL-33 increased to variable degrees at 6, 12, 24, and 48h after CLP, and ST2+ monocytes were significantly expanded in sepsis model mice compared to sham-operated mice. ST2 receptor blockade suppressed IL-1ß and IL-12 production in cell culture. CONCLUSIONS: Changes in monocyte subsets expressing the ST2 receptor play an important role in septic lung injury by modulating inflammatory cytokine secretion.

Cancer-Related Therapeutic Potential of Epimedium and Its Extracts.

Epimedium is a Chinese herb known as "yin and yang fire," first mentioned in the Compendium of Materia Medica. Many of the proprietary Chinese medicines used in clinical practice contain Epimedium as an ingredient, and its main active constituents include icariin, icaritin, and icariside II, among others. In addition to its traditional use in treating fatigue and sexual problems, modern research has confirmed that the main bioactive compounds in Epimedium have pharmacological effects such as antidepressant, antibacterial, antiviral, antioxidant, and anti-inflammatory properties, as well as inhibiting bone destruction, promoting bone growth, improving immune regulation and protecting the cardio-cerebral vascular system. With the continuous development of extraction and purification techniques, the development and use of bioactive compounds in Epimedium have significantly progressed, and the anticancer effect has received widespread attention. Since natural herbs have few side effects on the human body and do not easily develop drug resistance, they have long been the direction of research in cancer treatment. This review summarizes the latest research on the anticancer effects of Epimedium and its extracts, describes the bioactive compounds, pharmacological efficacy, and antitumor mechanism of Epimedium, and gives a new view on the administration and development of Epimedium.

Pyxinol Fatty Acid Ester Derivatives J16 against AKI by Selectively Promoting M1 Transition to M2c Macrophages.

Acute kidney injury (AKI) is a common, multicause clinical condition that, if ignored, often progresses to chronic kidney disease (CKD) and end-stage kidney disease, with a mortality rate of 40-50%. However, there is a lack of universal treatment for AKI. Inflammation is the basic pathological change of early kidney injury, and inflammation can exacerbate AKI. Macrophages are the primary immune cells involved in the inflammatory microenvironment of kidney disease. Therefore, regulating the function of macrophages is a crucial breakthrough for the AKI intervention. Our team chemically modified pyxinol, an ocotillol-type ginsenoside, to prepare PJ16 with higher solubility and bioavailability. In vitro, using a model of macrophages stimulated by LPS, it was found that PJ16 could regulate macrophage function, including inhibiting the secretion of inflammatory factors, promoting phagocytosis, inhibiting M1 macrophages, and promoting M1 transition to the M2c macrophage. Further investigation revealed that PJ16 may shield renal tubular epithelial cells (HK-2) damaged by LPS in vitro. Based on this, PJ16 was validated in the animal model of unilateral ureteral obstruction, which showed that it improves renal function and inhibits renal tissue fibrosis by decreasing inflammatory responses, reducing macrophage inflammatory infiltration, and preferentially upregulating M2c macrophages. In conclusion, our study is the first to show that PJ16 resists AKI and fibrosis by mechanistically regulating macrophage function by modulating the phenotypic transition from M1 to M2 macrophages, mainly M2c macrophages.

Assessing the Role of Gaseous Chlorine Dioxide in Modulating the Postharvest Ripening of Keitt Mangoes through the Induction of Ethylene Biosynthesis.

Consumer acceptance of Keitt mangoes (Mangifera indica L.) is significantly affected by their slow postharvest ripening. This work used gaseous chlorine dioxide (ClO2(g)) to prepare the ready-to-eat Keitt mango and explored the potential mechanisms for the mango ripening. Harvested mangoes were treated with 20 mg·L-1 of ClO2(g) or ethephon for 3 h (25 °C) and left in a climatic chamber with a temperature of 25 ± 1 °C and a relative humidity of 85 ± 5% for 4 d. The results showed that ClO2(g) treatment significantly promoted the orange coloration of mango flesh compared to the untreated control group. Moreover, ClO2(g) treatment significantly elevated the total soluble solids, total soluble sugar, and total carotenoids content of mangoes, whereas the firmness and titratable acidity were reduced. ClO2(g)-treated mangoes reached the edible window on day 2, as did mangoes treated with ethephon at the same concentration, except that the sweetness was prominent. The residual ClO2 level of the mangoes was <0.3 mg/kg during the whole storage time, which is a safe level for fruit. In addition, ClO2(g) significantly advanced the onset of ethylene peaks by 0.5 days and increased its production between days 0.5 and 2 compared to the control group. Consistently, the genes involved in ethylene biosynthesis including miACS6, miACO1, and miACO were upregulated. In sum, ClO2(g) can be a potential technique to reduce the time for harvested mango to reach the edible window, and it functions in modulating postharvest ripening by inducing ethylene biosynthesis.

Establishing a Proteomics-Based Signature of AKR1C3-Related Genes for Predicting the Prognosis of Prostate Cancer.

Aldo-keto reductase family 1 member C3 (AKR1C3) plays an important role in prostate cancer (PCa) progression, particularly in castration-resistant prostate cancer (CRPC). It is necessary to establish a genetic signature associated with AKR1C3 that can be used to predict the prognosis of PCa patients and provide important information for clinical treatment decisions. AKR1C3-related genes were identified via label-free quantitative proteomics of the AKR1C3-overexpressing LNCaP cell line. A risk model was constructed through the analysis of clinical data, PPI, and Cox-selected risk genes. Cox regression analysis, Kaplan-Meier (K-M) curves, and receiver operating characteristic (ROC) curves were used to verify the accuracy of the model, and two external datasets were used to verify the reliability of the results. Subsequently, the tumor microenvironment and drug sensitivity were explored. Moreover, the roles of AKR1C3 in the progression of PCa were verified in LNCaP cells. MTT, colony formation, and EdU assays were conducted to explore cell proliferation and drug sensitivity to enzalutamide. Migration and invasion abilities were measured using wound-healing and transwell assays, and qPCR was used to assess the expression levels of AR target genes and EMT genes. CDC20, SRSF3, UQCRH, INCENP, TIMM10, TIMM13, POLR2L, and NDUFAB1 were identified as AKR1C3-associated risk genes. These risk genes, established using the prognostic model, can effectively predict the recurrence status, immune microenvironment, and drug sensitivity of PCa. Tumor-infiltrating lymphocytes and several immune checkpoints that promote cancer progression were higher in high-risk groups. Furthermore, there was a close correlation between the sensitivity of PCa patients to bicalutamide and docetaxel and the expression levels of the eight risk genes. Moreover, through in vitro experiments, Western blotting confirmed that AKR1C3 enhanced SRSF3, CDC20, and INCENP expression. We found that PCa cells with a high expression of AKR1C3 have high proliferation ability and high migration ability and were insensitive to enzalutamide. AKR1C3-associated genes had a significant role in the process of PCa, immune responses, and drug sensitivity and offer the potential for a novel model for prognostic prediction in PCa.

STEMI in an adolescent boy due to anomalous left main coronary artery arising from the right sinus of Valsalva: Case report and brief review of the literature.

Congenital anomalous origin of coronary artery is a rare cardiovascular malformation and the most common anomaly is the left circumflex (LCX) arising from the right sinus of Valsalva (RSV). Other forms include both coronary arteries from RSV, the left anterior descending coronary artery from RSV, and a single coronary artery from the left sinus of Valsalva. Despite being rare, anomalous origin of left main coronary artery (LMCA) from RSV carries a high risk of sudden cardiac death. Here, we report a case of 13-year-old boy with chest pain and acute extensive anterior ST-segment elevation myocardial infarction (STEMI) who was initially diagnosed as acute myocarditis in the emergency department. A bedside echocardiogram showed severe global hypokinesia of left ventricle (LV) and normal right ventricle (RV) function. Coronary computed tomography angiography (CCTA) examination showed LMCA originated from the RSV. The patient underwent coronary artery bypass grafting surgery and was discharged without complications. A timely correct diagnosis of an anomalous coronary artery is critical in symptomatic patients, CCTA plays an important role in clinical decision making.

The Use of Star Anise-Cinnamon Essential Oil as an Alternative Antibiotic in Prevention of Salmonella Infections in Yellow Chickens.

Salmonella is capable of harming human and animal health, and its multidrug resistance (MDR) has always been a public health problem. In addition, antibiotic-free or antibiotic-reduced policies have been implemented in poultry production. Therefore, the search for antibiotic alternatives is more urgent than ever before. The aim of this study was to assess the antibacterial activity of star anise-cinnamon essential oil (SCEO) in vitro and its prophylactic effect against the infections of Salmonella pullorum, Salmonella give, and Salmonella kentucky in vivo. The results demonstrated that SCEO is effective against Salmonella pullorum, Salmonella give, and Salmonella kentucky in vitro. Supplementation with SCEO could significantly decrease the infections of Salmonella pullorum and Salmonella give, whereas it could slightly but not significantly decrease the infection of Salmonella kentucky, while also significantly alleviating the body weight (BW) loss caused by the infections of Salmonella pullorum, Salmonella give, and Salmonella kentucky in Yellow chickens. The SCEO had the best prophylactic effect against the infection of Salmonella give in Yellow chickens, followed by the infection of Salmonella pullorum and the infection of Salmonella kentucky. The SCEO, used as an antibiotic alternative, could be an effective prevention strategy against the infections of Salmonella pullorum, Salmonella give, and Salmonella kentucky in Yellow chickens.

ARID1A Is a Prognostic Biomarker and Associated with Immune Infiltrates in Hepatocellular Carcinoma.

Objective: ARID1A has been discovered as a potential cancer biomarker. But its role in hepatocellular carcinoma (HCC) is subject to considerable dispute. Methods: The relationship between ARID1A and clinical factors was investigated. Clinicopathological variables related to overall survival in HCC subjects were identified using Cox and Kaplan-Meier studies. The connection between immune infiltrating cells and ARID1A expression was investigated using the tumor Genome Atlas (TCGA) dataset for gene set enrichment analysis (GSEA). Finally, a cell experiment was used to confirm it. Results: The gender and cancer topography (T) categorization of HCC were linked to increased ARID1A expression. Participants with advanced levels of ARID1A expression had a worse prognosis than someone with lower levels. ARID1A was shown to be a risk indicator of overall survival on its own. ARID1A expression is inversely proportional to immune cell infiltration. In vitro, decreasing ARID1A expression substantially slowed the cell cycle and decreased HCC cell proliferation, migration, and invasion. Conclusion: The expression of ARID1A could be used to predict the outcome of HCC. It is closely related to tumor immune cell infiltration.

The effect of oregano essential oil on the prevention and treatment of Salmonella pullorum and Salmonella gallinarum infections in commercial Yellow-chicken breeders.

In order to prevent pullorum disease and fowl typhoid in breeders, the use of oregano essential oil (OEO) was tested for the prevention and treatment of infections of multidrug-resistant Salmonella pullorum (SP) and Salmonella gallinarum (SG) in commercial Yellow-chicken breeders. In the challenge-protection experiment, commercial Hongguang-Black 1-day-old breeder chicks were randomly divided into four groups, including A (challenged, preventive dose), B (challenged, treatment dose), C (challenged, untreated), and D (unchallenged, untreated). Group A was supplemented with 200 µL/L OEO in the drinking water during the whole trial (1-35 days of age) and group B was supplemented with 400 µL/L OEO during 8-12 days of age, while groups C and D were kept as untreated controls. At 7 days of age, birds of groups A, B, and C were divided into two subgroups with equal number of birds (A1-A2, B1-B2, and C1-C2), and then subgroups A1, B1, and C1 were challenged with SP, while subgroups A2, B2, and C2 were challenged with SG. Clinical symptoms and death were observed and recorded daily. Every week during the experiment, serum antibodies against SP and SG of all the groups were detected by the plate agglutinate test (PAT). At the age of 35 days, all birds were weighed and necropsied, lesions were recorded and the challenging pathogens were isolated. The results showed that the positive rates of SP and SG isolation in groups A1, A2 and B1, B2 were significantly lower (P < 0.05) than those of groups C1 and C2, respectively, while groups A1 and A2 were slightly lower (P > 0.05) than those of groups B1 and B2. The average body weight (BW) of groups A1 and A2 were significantly higher (P < 0.05) than those of groups B1, B2 and C1, C2, respectively, but there was no significant difference (P > 0.05) with that of group D. The r-value between PAT positive and the recovery rates of Salmonella was 0.99, which means they are highly positively correlated. The results of this study demonstrated that the prevention dose (200µL/L) and the treatment dose (400 µL/L) of OEO supplemented in the drinking water could all effectively decrease infections of SP and SG and that the effect of the prevention was greater than that of the treatment and finally that the prevention could also significantly reduce the BW decline of birds challenged with SP and SG.

Structural and biochemical analysis of 1-Cys peroxiredoxin ScPrx1 from Saccharomyces cerevisiae mitochondria.

BACKGROUND: ScPrx1 is a yeast mitochondrial 1-Cys peroxiredoxins (Prx), a type of Prx enzyme which require thiol-containing reducing agents to resolve its peroxidatic cysteine. ScPrx1 plays important role in protection against oxidative stress. Mitochondrial thioredoxin ScTrx3 and glutathione have been reported to be the physiological electron donor for ScPrx1. However, the mechanism underlying their actions, especially the substrate recognition of ScPrx1 requires additional elucidation. METHODS: The structure of ScPrx1 was obtained through crystallization experiments. The oligomeric state of ScPrx1 was monitored by Blue-Native PAGE. Mutations were generated by the QuikChange PCR-based method. The ScPrx1 activity assay was carried out by measuring the change of 340 nm absorption of the NADPH oxidation. RESULTS: ScPrx1 exist as a homodimer in solution. The structure adopts a typical Prx-fold core which is preceded by an N-terminal ß-hairpin and has a C-terminal extension. Mutations (Glu94Ala, Arg198Ala and Trp126) close to the active site could enhance the catalytic efficiency of ScPrx1 while His83Ala and mutations on α4-ß6 region exhibited reduced activity. The biochemical data also show that the deletion or mutations on ScPrx1 C-terminal have 2-4.56 fold increased activity. CONCLUSION: We inferred that conformational changes of ScPrx1 C-terminal segment were important for its reaction, and the α4-ß6 loop regions around the ScPrx1 active sites were important for the catalytic function of ScPrx1. Collectively, these structural features provides a basis for understanding the diverse reductant species usage in different 1-Cys Prxs.

Protein Crystallography and Site-Direct Mutagenesis Analysis of the Poly(ethylene terephthalate) Hydrolase PETase from Ideonella sakaiensis.

Unlike traditional recycling strategies, biodegradation is a sustainable solution for disposing of poly(ethylene terephthalate) (PET) waste. PETase, a newly identified enzyme from Ideonella sakaiensis, has high efficiency and specificity towards PET and is, thus, a prominent candidate for PET degradation. On the basis of biochemical analysis, we propose that a wide substrate-binding pocket is critical for its excellent ability to hydrolyze crystallized PET. Structure-guided site-directed mutagenesis revealed an improvement in PETase catalytic efficiency, providing valuable insight into how the molecular engineering of PETase can optimize its application in biocatalysis.

Growth/no growth boundary of Clostridium perfringens from spores in cooked meat: A logistic analysis.

Clostridium perfringens is a major foodborne health hazard that can cause acute gastroenteritis in consumers, and is often associated with cooked meat and poultry products. Improper cooling after cooking may allow this pathogen to grow in a product, producing an enterotoxin that causes food poisoning. This study was conducted to evaluate the effect of common ingredients, including sodium tripolyphosphate (STPP), sodium lactate (NaL), and sodium chloride (NaCl), on the germination and outgrowth of C. perfringens spores in meat products. The growth/no growth test was conducted in Shahidi Ferguson Perfringens agar mixed with STPP (0-2500ppm), NaL (0-4%), and NaCl (0-4%) in microplates. Turbidity measurements at 600nm were compared before and after anaerobic incubation at 46°C to evaluate growth and no growth conditions. The dichotomous responses were analyzed by logistic regression to develop a model for estimating the growth probability of C. perfringens. The probability model was used to define the threshold of growth (probability >0.1 or 0.2) of C. perfringens and validated using inoculated ground beef under optimum temperature. Inoculated ground beef was mixed with different combinations of STPP, NaL, and NaCl to observe growth or no growth of C. perfringens, and the probability was calculated from the formulation. If the threshold of growth was set to 0.2, the accuracy of the growth and no growth predictions was 95.7%, with 4.3% over-prediction of growth events (fail-safe). The results from this study suggested that proper combinations of STPP, NaL, and NaCl could be used to control the growth of C. perfringens in cooked beef under the optimum temperature. The results may also suggest that proper combinations of STPP, NaL, and NaCl in cooked meat and poultry products could be used to prevent the growth of C. perfringens during cooling.

Differential expression and localization of dentin matrix protein 1 (DMP1) fragments in mouse submandibular glands.

It has been demonstrated that dentin matrix protein 1 (DMP1) is an essential regulator in the formation of bone and tooth. In addition to the mineralized tissues, DMP1 is also expressed in the non-mineralized tissues such as kidney, brain and salivary glands. Some studies have shown that the expression of DMP1 is significantly elevated in cancerous glands, while details about the expression and localization patterns of DMP1 in these glandular tissues still remain largely unknown. In this study, with multiple approaches, we systematically analyzed the expression and localization of DMP1 in mouse submandibular glands (SMGs). The results showed that although DMP1 was expressed in both female and male mouse SMGs, the mRNA levels of DMP1 in male mice were higher than those in female mice after the appearance of granular convoluted tubule (GCT). In mouse SMGs, DMP1 was primarily present as the 46 kDa C-terminal fragment and the 37 kDa N-terminal fragment. The C-terminal fragment was mainly localized in the nuclei of acinar and ductal cells, while the N-terminal fragment was restricted to the cytoplasm of ductal cells. This study showed the expression of DMP1 in the GCT of male mice, a novel finding different from the result of previous reports. Collectively, the differential localization patterns of DMP1 fragments indicate that different forms of DMP1 may play distinct roles in the SMGs.

Inactivation of a novel FGF23 regulator, FAM20C, leads to hypophosphatemic rickets in mice.

Family with sequence similarity 20,-member C (FAM20C) is highly expressed in the mineralized tissues of mammals. Genetic studies showed that the loss-of-function mutations in FAM20C were associated with human lethal osteosclerotic bone dysplasia (Raine Syndrome), implying an inhibitory role of this molecule in bone formation. However, in vitro gain- and loss-of-function studies suggested that FAM20C promotes the differentiation and mineralization of mouse mesenchymal cells and odontoblasts. Recently, we generated Fam20c conditional knockout (cKO) mice in which Fam20c was globally inactivated (by crossbreeding with Sox2-Cre mice) or inactivated specifically in the mineralized tissues (by crossbreeding with 3.6 kb Col 1a1-Cre mice). Fam20c transgenic mice were also generated and crossbred with Fam20c cKO mice to introduce the transgene in the knockout background. In vitro gain- and loss-of-function were examined by adding recombinant FAM20C to MC3T3-E1 cells and by lentiviral shRNA-mediated knockdown of FAM20C in human and mouse osteogenic cell lines. Surprisingly, both the global and mineralized tissue-specific cKO mice developed hypophosphatemic rickets (but not osteosclerosis), along with a significant downregulation of osteoblast differentiation markers and a dramatic elevation of fibroblast growth factor 23 (FGF23) in the serum and bone. The mice expressing the Fam20c transgene in the wild-type background showed no abnormalities, while the expression of the Fam20c transgene fully rescued the skeletal defects in the cKO mice. Recombinant FAM20C promoted the differentiation and mineralization of MC3T3-E1 cells. Knockdown of FAM20C led to a remarkable downregulation of DMP1, along with a significant upregulation of FGF23 in both human and mouse osteogenic cell lines. These results indicate that FAM20C is a bone formation "promoter" but not an "inhibitor" in mouse osteogenesis. We conclude that FAM20C may regulate osteogenesis through its direct role in facilitating osteoblast differentiation and its systemic regulation of phosphate homeostasis via the mediation of FGF23.