Novel vaccine design based on genomics data analysis: A review.

Modification of pathogenic strains with the passage of time is responsible for evolution in the timeline of vaccine development for last 30 years. Recent advancements in computational vaccinology on the one hand and genome sequencing approaches on the other have generated new hopes in vaccine development. The aim of this review was to discuss the evolution of vaccines, their characteristics and limitations. In this review, we highlighted the evolution of vaccines, from first generation to the current status, pointing out how different vaccines have emerged and different approaches that are being followed up in the development of more rational vaccines against a wide range of diseases. Data were collected using Google Scholar, Web of Science, Science Direct, Web of Knowledge, Scopus and Science Hub, whereas computational tools such as NCBI, GeneMANIA and STRING were used to analyse the pathways of vaccine action. Innovative tools, such as computational tools, recombinant technologies and intra-dermal devices, are currently being investigated in order to improve the immunological response. New technologies enlightened the interactions of host proteins with pathogenic proteins for vaccine candidate development, but still there is a need of integrating transcriptomic and proteomic approaches. Although immunization with genomics data is a successful approach, its advantages must be assessed case by case and its applicability depends on the nature of the agent to be immunized, the nature of the antigen and the type of immune response required to achieve effective protection.

Alterations of B Cells in Immunosuppressive Phase of Septic Shock Patients.

OBJECTIVES: Septic shock is a subset of sepsis related to acute circulatory failure characterized by severe immunosuppression and high mortality. Current knowledge about B-cell status in the immunosuppressive phase of septic shock is sparse. The aim of this study was to investigate the alterations of B Cells in the immunosuppressive phase of septic shock. DESIGN: Prospective cohort study. SETTING: Adult ICUs at a university hospital. PATIENTS: Adult septic shock patients without any documented immune comorbidity. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The absolute counts of lymphocytes and B cells of 81 patients and 13 healthy controls, and serum immunoglobulin levels of 64 patients and 10 healthy controls were determined by clinical laboratory. The percentages and counts of B-cell subsets of 33 patients and 10 healthy controls and the immunoglobulin M expression on B-cell subsets of 20 patients and five healthy controls were quantified by flow cytometry. Immunoglobulin levels produced by B cells after stimulation in vitro of 20 patients and five healthy controls were tested by enzyme-linked immunosorbent assay. Redistribution and selective depletion of B-cell subsets in septic shock patients were discovered, and a decrease in immunoglobulin M levels was associated with a reduction in resting memory B-cell counts. These alterations were more pronounced in nonsurvivors compared with survivors. Additionally, receiver operating characteristic curve analysis showed that the data of B-cell subsets had the best predictive value for mortality risk. CONCLUSIONS: Severe B-cell abnormalities are present in the immunosuppressive phase of septic shock and are associated with prognosis.

Propensity to high-fat diet-induced obesity in mice is associated with the indigenous opportunistic bacteria on the interior of Peyer's patches.

Indigenous opportunistic bacteria on the interior of the Peyer's patches play a key role in the development of the mucosal immune, but their population composition has been ignored. The present study was conducted to test the hypothesis that the changes in the composition of indigenous opportunistic bacteria in the Peyer's patches are associated with obesity. C57BL/6J-male mice had been fed either a control diet or a high-fat diet. After 25 weeks, mice in high-fat diet exhibit either an obesity-prone (OP) or an obesity-resistant (OR) phenotype. Control diet group (CT) and OR group had a significant larger bacteria diversity than that in the OP group. Allobaculum and Lactobacillus were significantly decreased in high-fat diet induced OP mice compared with CT and OR mice, whereas Rhizobium and Lactococcus was significantly increased. The result of quantitative real-time PCR was consistent with that of 454 pyrosequencing. Significant correlations between mRNA expression of inflammation marks and the top 5 abundance genera bacteria on the interior of Peyer's patches were observed by Pearson's correlation analysis. Taken together, the indigenous opportunistic bacteria on the interior of Peyer's patches plays a major role in the development of inflammation for an occurrence of obesity.

The role of taurine through endoplasmic reticulum in physiology and pathology.

Taurine is a sulfur-containing amino acid found in many cell organelles that plays a wide range of biological roles, including bile salt production, osmoregulation, oxidative stress reduction, and neuromodulation. Taurine treatments have also been shown to ameliorate the onset and development of many diseases, including hypertension, fatty liver, neurodegenerative diseases and ischemia-reperfusion injury, by exerting antioxidant, anti-inflammatory, and antiapoptotic effects. The endoplasmic reticulum (ER) is a dynamic organelle involved in a wide range of cellular functions, including lipid metabolism, calcium storage and protein stabilization. Under stress, the disruption of the ER environment leads to the accumulation of misfolded proteins and a characteristic stress response called the unfolded protein response (UPR). The UPR protects cells from stress and helps to restore cellular homeostasis, but its activation promotes cell death under prolonged ER stress. Recent studies have shown that ER stress is closely related to the onset and development of many diseases. This article reviews the beneficial effects and related mechanisms of taurine by regulating the ER in different physiological and pathological states, with the aim of providing a reference for further research and clinical applications.

Extension domain of amyloid processor protein inhibits amyloidogenic cleavage and balances neural activity in a traumatic brain injury mouse model.

BACKGROUND: Mechanisms underlying cognitive dysfunction following traumatic brain injury (TBI) partially due to abnormal amyloid processor protein (APP) cleavage and neural hyperactivity. Binding of the extension domain of APP (ExD17) to the GABAbR1 receptor results in reduced neural activity, which might play a role in the mechanisms of cognitive dysfunction caused by TBI. METHODS: Stretch-induced injury was utilized to establish a cell injury model in HT22 cells. The TBI model was created by striking the exposed brain tissue with a free-falling weight. Topical or intraperitoneal administration of ExD17 was performed. Cell viability was assessed through a cell counting kit-8 assay, while intracellular Ca2+ was measured using Fluo-4. Western blotting was used to investigate the expression of APP amyloidogenic cleavage proteins, GABAbR1, phospholipase C (PLC), PLCB3, and synaptic proteins. ELISA was performed to analyze the levels of Aß42. Seizures were assessed using electroencephalography (EEG). Behaviors were evaluated through the novel object recognition test, open field test, elevated plus maze test, and nest-building test. RESULTS: ExD17 improved cell viability and reduced intracellular calcium in the cell injury model. The treatment also suppressed the increased expression of APP amyloidogenic cleavage proteins and Aß42 in both cell injury and TBI models. ExD17 treatment reversed the abnormal expression of GABAbR1, GRIA2, p-PLCG1/PLCG1 ratio, and p-PLCB3/PLCB3 ratio. In addition, ExD17 treatment reduced neural activity, seizure events, and their duration in TBI. Intraperitoneal injection of ExD17 improved behavioral outcomes in the TBI mouse model. CONCLUSIONS: ExD17 treatment results in a reduction of amyloidogenic APP cleavage and neuroexcitotoxicity, ultimately leading to an improvement in the behavioral deficits observed in TBI mice.

The influences of green light on locomotion, growth and reproduction in the brown planthopper Nilaparvata lugens.

BACKGROUND: Light stimulation at a specific wavelength triggers various responses in insects and can be used for pest control. To develop efficient and ecofriendly photophysical pest control methods, the effects of green light on locomotion, growth (molting and eclosion) and reproduction in Nilaparvata lugens (Stål) (BPH), a major rice pest, were studied. Transcriptomics and transmission electron microscopy (TEM) were used to investigate the mechanisms involved. RESULTS: BPH adults showed disrupted daily locomotion patterns following green light treatment at night and exhibited abnormal locomotion peaks. Total 6-day locomotion of brachypterous adults was significantly greater than in the control group. The durations of growth stages 1-4 were all shorter under green light treatment than in the control, whereas the time from fourth molting to eclosion (stage 5) was significantly longer. When BPH adults under green light treatment began laying eggs, the egg hatching ratio (36.69%) was significantly lower than in the control (47.49%). Moreover, in contrast to the control, BPH molting and eclosion events tended to happen more at night. Transcriptome analysis proved that green light significantly affected the expression of genes involved in cuticular proteins, chitin deacetylase and chitinase, which are related to cuticular development. TEM observations confirmed abnormal cuticular development in nymph and adult BPHs (endocuticle, exocuticle and pore canals) under green light treatment. CONCLUSION: Green light treatment at night notably affected locomotion, growth and reproduction in BPH, thus providing a novel idea for controlling this pest. © 2023 Society of Chemical Industry.

The Absence of Gasdermin D Reduces Nuclear Autophagy in a Cecal Ligation and Puncture-Induced Sepsis-Associated Encephalopathy Mouse Model.

Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, which is a life-threatening condition resulting from a dysregulated host response to infection. Pyroptosis, a pro-inflammatory mode of lytic cell death mediated by GSDMD (Gasdermin D), is involved in the pathogenesis of SAE. While autophagy has been extensively studied in SAE, the role of nuclear autophagy is not yet well understood. In this study, we aimed to investigate the involvement of pyroptosis and neural nuclear autophagy in the pathogenesis of SAE. We analyzed a CLP (cecal ligation and puncture)-induced SAE model in wild-type and GSDMD-/- mice to gain insights into the underlying mechanisms. Here, we show that in sepsis, neural nuclear autophagy is extremely activated, and nuclear LaminB decreases and is accompanied by an increase in the ratio of LC3BII/I. These effects can be reversed in GSDMD-/- mice. The behavioral outcomes of septic wild-type mice are impaired by the evidence from the novel object recognition test (NORT) and open field test (OFT), but are improved in septic GSDMD-/- mice. In conclusion, our study demonstrates the activation of neural nuclear autophagy in SAE. The absence of GSDMD inhibits nuclear autophagy and improves the behavioral outcomes of SAE.

The role of taurine in male reproduction: Physiology, pathology and toxicology.

Taurine, a sulfur-containing amino acid, has a wide range of biological effects, such as bile salt formation, osmotic regulation, oxidative stress inhibition, immunomodulation and neuromodulation. Taurine has been proved to be synthesized and abundant in male reproductive organs. Recently, accumulating data showed that taurine has a potential protective effect on reproductive function of male animals. In physiology, taurine can promote the endocrine function of the hypothalamus-pituitary-testis (HPT) axis, testicular tissue development, spermatogenesis and maturation, delay the aging of testicular structure and function, maintain the homeostasis of the testicular environment, and enhance sexual ability. In pathology, taurine supplement may be beneficial to alleviate pathological damage of male reproductive system, including oxidative damage of sperm preservation in vitro, testicular reperfusion injury and diabetes -induced reproductive complications. In addition, taurine acts as a protective agent against toxic damage to the male reproductive system by exogenous substances (e.g., therapeutic drugs, environmental pollutants, radiation). Related mechanisms include reduced oxidative stress, increased antioxidant capacity, inhibited inflammation and apoptosis, restored the secretory activity of the HPT axis, reduced chromosomal variation, enhanced sperm mitochondrial energy metabolism, cell membrane stabilization effect, etc. Therefore, this article reviewed the protective effect of taurine on male reproductive function and its detailed mechanism, in order to provide reference for further research and clinical application.

Shifts in the diversity of root endophytic microorganisms across the life cycle of the ratooning rice Jiafuzhan.

The diversity of root endophytic microorganisms, which is closely related to plant life activities, is known to vary with the plant growth stage. This study on the ratooning rice Jiafuzhan explored the diversity of the root endophytic bacteria and fungi and their dynamics during the plant life cycle. By sequencing the 16S ribosomal ribonucleic acid (16S rRNA) and internal transcribed spacer (ITS) genes, 12,154 operational taxonomic units (OTUs) and 497 amplicon sequence variants (ASVs) were obtained, respectively. The root endophytic microorganisms of rice in the seedling, tillering, jointing, heading, and mature stages of the first crop and at 13, 25, and 60 days after regeneration (at the heading, full heading, and mature stages of the second crop, respectively) were analyzed using diversity and correlation analyses. There were significant differences in the α-diversity and ß-diversity of root endophytic bacteria and fungi in the growth stage. Additionally, linear discriminant analysis (LDA) effect size (LEfSe) analysis revealed biomarker bacteria for each growth stage, but biomarker fungi did not exist in every stage. Moreover, the correlation analysis showed that the bacterial and fungal biomarkers interacted with each other. Furthermore, the nitrogen-fixing genus Bradyrhizobium existed in all growth stages. These findings indicate the pattern of root endophytic microorganisms of ratooning rice at different growth stages, and they provide new insights into the high yield of the second crop of ratooning rice (in light of the abundance of various bacteria and fungi).

Estrogen plays an important role by influencing the NLRP3 inflammasome.

The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is an important part of the natural immune system that plays an important role in many diseases. Estrogen is a sex hormone that plays an important role in controlling reproduction and regulates many physiological and pathological processes. Recent studies have indicated that estrogen is associated with disease progression. Estrogen can ameliorate some diseases (e. g, sepsis, mood disturbances, cerebral ischemia, some hepatopathy, Parkinson's disease, amyotrophic lateral sclerosis, inflammatory bowel disease, spinal cord injury, multiple sclerosis, myocardial ischemia/reperfusion injury, osteoarthritis, and renal fibrosis) by inhibiting the NLRP3 inflammasome. Estrogen can also promote the development of diseases (e.g., ovarian endometriosis, dry eye disease, and systemic lupus erythematosus) by upregulating the NLRP3 inflammasome. In addition, estrogen has a dual effect on the development of cancers and asthma. However, the mechanism of these effects is not summarized. This article reviewed the progress in understanding the effects of estrogen on the NLRP3 inflammasome and its mechanisms in recent years to provide a theoretical basis for an in-depth study.

Effects of Lycopene Attenuating Injuries in Ischemia and Reperfusion.

Tissue and organ ischemia can lead to cell trauma, tissue necrosis, irreversible damage, and death. While intended to reverse ischemia, reperfusion can further aggravate an ischemic injury (ischemia-reperfusion injury, I/R injury) through a range of pathologic processes. An I/R injury to one organ can also harm other organs, leading to systemic multiorgan failure. A type of carotenoid, lycopene, has been shown to treat and prevent many diseases (e.g., rheumatoid arthritis, cancer, diabetes, osteoporosis, male infertility, neurodegenerative diseases, and cardiovascular disease), making it a hot research topic in health care. Some recent researches have suggested that lycopene can evidently ameliorate ischemic and I/R injuries to many organs, but few clinical studies are available. Therefore, it is essential to review the effects of lycopene on ischemic and I/R injuries to different organs, which may help further research into its potential clinical applications.

Inhibition of Ferroptosis Attenuates Glutamate Excitotoxicity and Nuclear Autophagy in a CLP Septic Mouse Model.

ABSTRACT: Sepsis-associated encephalopathy (SAE) often manifests in severe diffuse cerebral dysfunction due to an aberrant systemic immune response to infection. The underlying pathophysiology of SAE is not entirely understood but is likely a multifactorial process that involves disruption in cell death mechanism. Ferroptosis is a novel form of programmed cell death characterized by iron accumulation and lipid peroxidation, leading to inflammatory cascade and glutamate release. We hypothesized that ferroptosis is involved in the glutamate-mediated excitotoxic neuron injury during the uncontrolled neural inflammatory process of SAE. Inhibiting ferroptosis with ferrostatin-1 (Fer-1) could alleviate glutamate excitotoxicity and reduce neuron death of SAE, potentially improving prognosis. We found that in the cecal ligation and puncture (CLP) sepsis model, ferroptosis occurred increasingly in the cerebrum, characterized by glutathione-dependent antioxidant enzyme glutathione peroxidase 4 (GPX4) inactivation, transferrin upregulation, mitochondria shrink and malondialdehyde (MDA) increased. Fer-1 treatment downregulated cerebral ferroptosis and alleviated glutamate excitotoxicity via dampening system xc-(SXC) and glutamate receptor N-methyl-D-asperate receptor subunit 2. Combined with an observed reduction in calcium transporter PLCG and PLCB activation, these processes ultimately protected the integrities of synapses and neurons during SAE. Fer-1 treatment also rescued sepsis-induced nuclear autophagy and improved the behaviors of tail suspension test and novel object recognition test in septic mice. Conclusively, our results suggested that inhibition of ferroptosis could attenuate glutamate excitotoxicity and SAE outcomes.

Inhibition of the C3a receptor attenuates sepsis-induced acute lung injury by suppressing pyroptosis of the pulmonary vascular endothelial cells.

Acute lung injury (ALI) is the leading cause of bacterial sepsis-related death because of disrupted pulmonary endothelial barrier, resulting in protein-rich pulmonary oedema, an influx of pro-inflammatory cells and refractory hypoxaemia. Several studies have reported that C3a levels are significantly higher in organs with sepsis and their peripheral organs and are closely associated with organ dysfunction and poor prognosis in sepsis. However, the role of the C3a complement in sepsis ALI remains unclear. Therefore, this study aimed to investigate the important role and mechanism of C3a in preventing the occurrence of pyroptosis (a pro-inflammatory form of cell death) to protect the lung endothelial cells (ECs) in sepsis-induced ALI. A septic mouse model was established with cecal ligation and puncture (CLP), which demonstrated that C3a mediated EC pyroptosis through its C3aR receptor. Furthermore, inhibition of the C3a-C3aR axis could block both NLRP3/caspase-1 and caspase-11 pathways, thus preventing pulmonary EC from pyroptosis. These results indicate that inhibition of the C3A-C3AR complement axis can inhibit pulmonary vascular EC pyroptosis, a potential target for the treatment of ALI.

Effects of Genistein on Common Kidney Diseases.

Genistein is a naturally occurring phytoestrogen (soy or soybean products) that is classified as an isoflavone, and its structure is similar to that of endogenous estrogens; therefore, genistein can exert an estrogen-like effect via estrogen receptors. Additionally, genistein is a tyrosine kinase inhibitor, which enables it to block abnormal cell growth and proliferation signals through the inhibition of tyrosine kinase. Genistein is also an angiogenesis inhibitor and an antioxidant. Genistein has effects on kidney cells, some of the kidney's physiological functions, and a variety of kidney diseases. First, genistein exerts a protective effect on normal cells by reducing the inflammatory response, inhibiting apoptosis, inhibiting oxidative stress, inhibiting remodeling, etc., but after cell injury, the protective effect of genistein decreases or even has the opposite effect. Second, genistein can regulate renin intake to maintain blood pressure balance, regulate calcium uptake to regulate Ca2+ and Pi balances, and reduce vasodilation to promote diuresis. Third, genistein has beneficial effects on a variety of kidney diseases (including acute kidney disease, kidney cancer, and different chronic kidney diseases), such as reducing symptoms, delaying disease progression, and improving prognosis. Therefore, this paper reviews animal and human studies on the protective effects of genistein on the kidney in vivo and in vitro to provide a reference for clinical research in the future.

Inhibition of PFKFB Preserves Intestinal Barrier Function in Sepsis by Inhibiting NLRP3/GSDMD.

Intestinal barrier dysfunction is associated with the occurrence and development of sepsis. Further, aerobic glycolysis plays an essential role in inflammation and cell death. This study is aimed at investigating the protective effect and mechanism of PFKFB3 inhibition on intestinal barrier dysfunction in sepsis mice. Sepsis mouse models were established by cecal ligation and puncture (CLP) in wild-type mice and Gsdmd-/- mice. The results showed that the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in the small intestines was significantly upregulated in sepsis. 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), the specific inhibitor of PFKFB3, and Gsdmd gene knockout significantly inhibited the inflammatory response and cell death caused by sepsis, thus alleviating intestinal damage and barrier dysfunction. 3PO was also shown to significantly inhibit oxidative stress and NLRP3/caspase-1/GSDMD-dependent cell pyroptosis in the small intestines. The in vitro studies revealed that 3PO reduced NLRP3/caspase-1/GSDMD-dependent cell pyroptosis by inhibiting ROS. Taken together, our results suggest that PFKFB3 is involved in inflammation, oxidative stress, and pyroptosis during sepsis and enhances intestinal damage, which may provide important clues about the potential targets to be exploited in this highly lethal disease.

Effects of Lipoic Acid on Ischemia-Reperfusion Injury.

Ischemia-reperfusion (I/R) injury often occurred in some pathologies and surgeries. I/R injury not only harmed to physiological functions of corresponding organ and tissue but also induced multiple tissue or organ dysfunctions (even these in distant locations). Although the reperfusion of blood attenuated I/R injury to a certain degree, the risk of secondary damages was difficult to be controlled and it even caused failures of these tissues and organs. Lipoic acid (LA), as an endogenous active substance and a functional agent in food, owns better safety and effects in our body (e.g., enhancing antioxidant activity, improving cognition and dementia, controlling weight, and preventing multiple sclerosis, diabetes complication, and cancer). The literature searching was conducted in PubMed, Embase, Cochrane Library, Web of Science, and SCOPUS from inception to 20 May 2021. It had showed that endogenous LA was exhausted in the process of I/R, which further aggravated I/R injury. Thus, supplements with LA timely (especially pretreatments) may be the prospective way to prevent I/R injury. Recently, studies had demonstrated that LA supplements significantly attenuated I/R injuries of many organs, though clinic investigations were short at present. Hence, it was urgent to summarize these progresses about the effects of LA on different I/R organs as well as the potential mechanisms, which would enlighten further investigations and prepare for clinic applications in the future.

Willingness and influential factors of parents of 3-6-year-old children to vaccinate their children with the COVID-19 vaccine in China.

The impact of Coronavirus disease 2019 (COVID-19) on children aged 3-6 can be severe. Vaccination for COVID-19 is one of the most important primary preventative measures to reduce disease transmission. Parents are hesitant to vaccinate their children against COVID-19 because it was reported in the news that some adults have had adverse reactions to the vaccine. This study aims to investigate the willingness of Chinese parents of 3-6 year old children to vaccinate them with the COVID-19 vaccine and identify what factors influence their decisions. A survey was conducted using a two-stage stratified random sampling method from December 2020 to February 2021. We used univariate analysis and multivariate binary logistic analysis to explore potential factors that may determine the acceptance of the COVID-19 vaccine. Of the 468 parents who participated, 86.75% were willing to vaccinate their children with the COVID-19 vaccine. Parents who were female (OR = 2.591; 95% CI: 0.432-4.689), recognized their children in the high-risk category (OR = 2.494; 95% CI:1.244-5.002), often followed-up with COVID-19 vaccine-related information (OR = 9.065; 95% CI: 3.220-28.654), believed in the safety of the COVID-19 vaccine (OR = 3.068; 95% CI: 1.313-7.168), or thought the COVID-19 vaccine could prevent COVID-19 (OR = 13.750; 95% CI: 2.516-75.140) were more willing to vaccinate their children. To ease parents' hesitation about vaccines, the authority organization should release updated information on the safety and reliability of vaccines, target gender-specific health education for parents, and ask the media to report scientifically support information.

Microbial L-asparaginase for Application in Acrylamide Mitigation from Food: Current Research Status and Future Perspectives.

L-asparaginase (E.C.3.5.1.1) hydrolyzes L-asparagine to L-aspartic acid and ammonia, which has been widely applied in the pharmaceutical and food industries. Microbes have advantages for L-asparaginase production, and there are several commercially available forms of L-asparaginase, all of which are derived from microbes. Generally, L-asparaginase has an optimum pH range of 5.0-9.0 and an optimum temperature of between 30 and 60 °C. However, the optimum temperature of L-asparaginase from hyperthermophilic archaea is considerable higher (between 85 and 100 °C). The native properties of the enzymes can be enhanced by using immobilization techniques. The stability and recyclability of immobilized enzymes makes them more suitable for food applications. This current work describes the classification, catalytic mechanism, production, purification, and immobilization of microbial L-asparaginase, focusing on its application as an effective reducer of acrylamide in fried potato products, bakery products, and coffee. This highlights the prospects of cost-effective L-asparaginase, thermostable L-asparaginase, and immobilized L-asparaginase as good candidates for food application in the future.

The effects of metformin on autophagy.

Metformin is the first-line option for treating newly diagnosed diabetic patients and also involved in other pharmacological actions, including antitumor effect, anti-aging effect, polycystic ovarian syndrome prevention, cardiovascular action, and neuroprotective effect, etc. However, the mechanisms of metformin actions were not fully illuminated. Recently, increasing researches showed that autophagy is a vital medium of metformin playing pharmacological actions. Nevertheless, results on the effects of metformin on autophagy were inconsistent. Apart from few clinical evidences, more data focused on kinds of no-clinical models. First, many studies showed that metformin could induce autophagy via a number of signaling pathways, including AMPK-related signaling pathways (e.g. AMPK/mTOR, AMPK/CEBPD, MiTF/TFE, AMPK/ULK1, and AMPK/miR-221), Redd1/mTOR, STAT, SIRT, Na+/H+ exchangers, MAPK/ERK, PK2/PKR/AKT/ GSK3ß, and TRIB3. Secondly, some signaling pathways were involved in the process of metformin inhibiting autophagy, such as AMPK-related signaling pathways (AMPK/NF-κB and other undetermined AMPK-related signaling pathways), Hedgehog, miR-570-3p, miR-142-3p, and MiR-3127-5p. Thirdly, two types of signaling pathways including PI3K/AKT/mTOR and endoplasmic reticulum (ER) stress could bidirectionally impact the effectiveness of metformin on autophagy. Finally, multiple signal pathways were reviewed collectively in terms of affecting the effectiveness of metformin on autophagy. The pharmacological effects of metformin combining its actions on autophagy were also discussed. It would help better apply metformin to treat diseases in term of mediating autophagy.

MicroRNA-150 inhibits myeloid-derived suppressor cells proliferation and function through negative regulation of ARG-1 in sepsis.

AIMS: Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The majority of sepsis-related deaths occur during late sepsis, which presents as a state of immunosuppression. Myeloid-derived suppressor cells (MDSCs) have been reported to promote immunosuppression during sepsis. Here we aim to understand the role of microRNAs in regulating MDSCs proliferation and immunosuppression function during sepsis. MAIN METHODS: Murine sepsis model was established using cecal ligation and puncture (CLP). A microarray was used to identify microRNAs with differential expression in murine sepsis. The effect of microRNA-150 on MDSCs proliferation and function was then evaluated. 140 multiple trauma patients from Tongji Hospital and 10 healthy controls were recruited. Peripheral blood samples were taken and the serum level of miR-150 was measured. KEY FINDINGS: In the murine model of sepsis, MDSCs expansion was noted in the spleen and bone marrow, while expression of miR-150 in MDSCs decreased. Replenishing miR-150 inhibited the expansion of MDSCs in both monocytic and polymorphonuclear subpopulations, as well as decreasing the immunosuppressive function of MDSCs, through down-regulation of ARG1. Both pro-inflammatory cytokine IL-6 and anti-inflammatory cytokines TGF-ß and IL-10 were reduced by miR-150. In human, the serum level of miR-150 was down-regulated in septic patients and elevated in non-septic trauma patients compared to healthy controls. SIGNIFICANCE: Our study showed that MiR-150 is down-regulated during sepsis. Replenishing miR-150 reduces the immunosuppression function of MDSCs by down-regulating ARG1 in late sepsis. MiR-150 might serve as a potential therapeutic option for sepsis.