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In this case report, we highlight the benefits of Medisca CopaSil application for scar healing in a horse having sustained second-degree burn injuries covering most of its back. The application of CopaSil started three months after sustaining the burn injury when silver sulfadiazine topical cream treatment showed no significant improvement. CopaSil is formulated with ingredients that may help in reducing inflammation and accelerate healing by modulating the immune response. After using CopaSil for six months, the horse's back was healed, and the hair began to regrow. The complete healing was achieved within six months, and full recovery was reported and confirmed by the horse's owner and pharmacist. This case report highlights the outcomes and benefits of CopaSil in improving the appearance of scars., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)

Metastasis is present in approximately 30% of patients diagnosed with renal cell carcinoma (RCC) and is associated with a 5-year survival rate of < 15%. Kidney injury molecule 1 (KIM-1), encoded by the HAVCR1 gene, is a proximal tubule cell-surface glycoprotein and a biomarker for early detection of RCC, but its pathophysiological significance in RCC remains unclear. We generated human and murine RCC cell lines either expressing or lacking KIM-1, respectively, and compared their growth and metastatic properties using validated methods. Surprisingly, KIM-1 expression had no effect on cell proliferation or subcutaneous tumour growth in immune deficient (Rag1 -/- ) Balb/c mice, but inhibited cell invasion and formation of lung metastasis in the same model. Further, we show that the inhibitory effect of KIM-1 on metastases was observed in both immune deficient and immune competent mice. Transcriptomic profiling identified the mRNA for the pro-metastatic GTPase, Rab27b, to be downregulated significantly in KIM-1 expressing human and murine RCC cells. Finally, analysis of The Cancer Genome Atlas (TCGA) data revealed that elevated HAVCR1 mRNA expression in the two most common types of RCC, clear cell and papillary RCC, tumours correlated with significantly improved overall patient survival. Our findings reveal a novel role for KIM-1 in inhibiting metastasis of RCC and suggests that tumour-associated KIM-1 expression may be a favourable prognostic factor.

Background: Despite reports that associate donor specific antibody (DSA) with rejection after liver transplantation, grafts are still allocated according to blood group (ABO) but not human leukocyte antigen (HLA) compatibility, possibly due to the absence of an easily discernible clinical association between adverse recipient outcome and DSA. Re-transplantation provides a test environment where the presence of preformed DSA is prevalent and its effect on outcome should be apparent., Methods: All patients undergoing a second liver transplantation with available pre-operative serum were included with the exception of ABO incompatible or multiple organ transplants. Banked sera were tested for anti-HLA antibodies with Luminex-based solid phase assays. Anti-HLA antibodies to the second donor (D2SA) were determined using antibodies specificity and HLA typing of 2nd liver donor., Results: Preformed HLA antibodies directed to second liver transplantation (D2SA) were found in 31 (39%) of the 79 patients that were included in the study. Primary and re-transplantation characteristics were similar in both subgroups except first graft survival which was significantly shorter in recipients who are negative for D2SA. Mean survival of the second graft was similar in D2SA+ and D2SA- cohorts [8.55 (range, 0.01-24.74) vs. 7.56 (range, 0-23.53) years respectively, P=0.574]. Mean patient survival after 2nd liver transplantation was similar in D2SA+ and D2SA- cohorts [9.11 (range, 0.01-24.74) vs. 8.10 (range, 0-23.53) years respectively, P=0.504]. Subgroup univariate analysis demonstrated no detrimental effect of class, locus, or strength of D2SA on survival of the second liver transplant. In multivariate cox regression model, neither class I D2DSA (HR =1.101, P=0.92) nor class II D2SA (HR =1.74, P=0.359) were significant risks of graft failure., Conclusions: Presence of D2SA was not found to be associated with inferior outcomes in this retrospective cohort study of liver re-transplantation suggesting that changes to the allocation system are not required., Competing Interests: Conflicts of Interest: Presented at American Transplant Congress 2018, Seattle, WA, USA. Data sharing: Anonymized subject level data will be available. Registered with www.clinicaltrials.gov NCT03815864.

Background: Fluid excess may place people undergoing surgery at risk for various complications. Hypertonic salt solution (HS) maintains intravascular volume with less intravenous fluid than isotonic salt (IS) solutions, but may increase serum sodium. This review was published in 2010 and updated in 2016., Objectives: To determine the benefits and harms of HS versus IS solutions administered for fluid resuscitation to people undergoing surgery., Search Methods: In this updated review we have searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 4, 2016); MEDLINE (January 1966 to April 2016); EMBASE (January 1980 to April 2016); LILACS (January 1982 to April 2016) and CINAHL (January 1982 to April 2016) without language restrictions. We conducted the original search on April 30th, 2007, and reran it on April 8th, 2016., Selection Criteria: We have included randomized clinical trials (RCTs) comparing HS to IS in people undergoing surgery, irrespective of blinding, language, and publication status., Data Collection and Analysis: Two independent review authors read studies that met our selection criteria. We collected study information and data using a data collection sheet with predefined parameters. We have assessed the impact of HS administration on mortality, organ failure, fluid balance, serum sodium, serum osmolarity, diuresis and physiologic measures of cardiovascular function. We have pooled the data using the mean difference (MD) for continuous outcomes. We evaluated heterogeneity between studies by I² percentage. We consider studies with an I² of 0% to 30% to have no or little heterogeneity, 30% to 60% as having moderate heterogeneity, and more than 60% as having high heterogeneity. In studies with low heterogeneity we have used a fixed-effect model, and a random-effects model for studies with moderate to high heterogeneity., Main Results: We have included 18 studies with 1087 participants of whom 545 received HS compared to 542 who received IS. All participants were over 18 years of age and all trials excluded high-risk patients (ASA IV). All trials assessed haematological parameters peri-operatively and up to three days post-operatively.There were three (< 1%) deaths reported in the IS group and four (< 1%) in the HS group, as assessed at 90 days in one study. There were no reports of serious adverse events. Most participants were in a positive fluid balance postoperatively (4.4 L IS and 2.5 L HS), with the excess significantly less in HS participants (MD -1.92 L, 95% confidence interval (CI) -2.61 to -1.22 L; P < 0.00001). IS participants received a mean volume of 2.4 L and HS participants received 1.49 L, significantly less fluid than IS-treated participants (MD -0.91 L, 95% CI -1.24 to -0.59 L; P < 0.00001). The maximum average serum sodium ranged between 138.5 and 159 in HS groups compared to between 136 and 143 meq/L in the IS groups. The maximum serum sodium was significantly higher in HS participants (MD 7.73, 95% CI 5.84 to 9.62; P < 0.00001), although the level remained within normal limits (136 to 146 meq/L).A high degree of heterogeneity appeared to be related to considerable differences in the dose of HS between studies. The quality of the evidence for the outcomes reported ranged from high to very low. The risk of bias for many of the studies could not be determined for performance and detection bias, criteria that we assess as likely to impact the study outcomes., Authors' Conclusions: HS reduces the volume of intravenous fluid required to maintain people undergoing surgery but transiently increases serum sodium. It is not known if HS affects survival and morbidity, but this should be examined in randomized controlled trials that are designed and powered to test these outcomes.

Background: Understanding the prognosis of hepatocellular carcinoma (HCC) informs plans for care. Tumor morphology and molecular markers have been correlated with outcomes. Three-dimensional tissue culture (3DTC) allows for direct in vitro measurement of a tumor's ability to grow and metastasize. The impact of chemotherapeutic agents, alone or in combinations, may also be measured., Methods: All patients with a presumed diagnosis of HCC were eligible for this study including those undergoing resection, chemoembolization and transplantation. Concomitant diseases and outcomes were recorded. One mm(3) HCC specimens were grown in multiwell plates containing gel media, without and with chemotherapeutic agents., Results: Tumors were sampled from 17 patients. Only 13 had HCC, all of whom had liver transplantation. Of the confirmed HCC patients, 6 (46%) are alive and disease free 82 months following transplantation, 1 (7%) is alive with recurrence of disease and 6 (46%) died, with a mean survival of 12 months post liver transplant. Ten of thirteen 3DTC samples grew, having an average migration distance of 108.3µm in the first 24 hours. Two of three patients who had prior chemoembolization had successful 3DTC. Migration distances (µm) were 188.8±104.3, 104.5±111.7 and 39.6±32.4 for tumors categorized as high, intermediate and low grade, respectively. Tumor migration was inhibited by irinotecan, paclitaxel and docetaxel (-68%±7%, -61%±19% and -60%±21%, respectively) whereas the effect was variable with 5 fluorouracil (5FU) and doxorubicin (-12%±51% and 9%±76%, respectively)., Conclusions: It is feasible to grow tissue from HCC in 3DTC to study the tumor's capacity to grow and migrate and its responsiveness to commonly used chemotherapeutic protocols.

Background: Sepsis is a severe condition characterized by multiple organ dysfunction resulting from an imbalanced host immune response to infections. miRNAs play a crucial role in regulating various biological processes. However, the precise role of miR-31 in the immunopathology of sepsis remains poorly understood. Methods: The concentration of hsa-miR-31-5p in patients with sepsis (both survivors and non-survivors) and healthy individuals was assayed. Using an experimental sepsis model of caecal ligation and puncture (CLP), the impact of mmu-miR-31-5p on survival, organ injury, and inflammation was evaluated. Additionally, the effect of mmu-miR-31-5p on macrophage polarization through Chi3l1 was investigated. Lastly, the therapeutic effects of miPEP31 on experimental sepsis were examined. Results: The results of miRNA sequencing (miRNA-seq) and quantitative polymerase chain reaction (q-PCR) analyses identified hsa-miR-31-5p as a potential biomarker for patients with sepsis, with non-survivors showing higher levels of hsa-miR-31-5p in peripheral blood mononuclear cells (PBMCs) compared to survivors. Functional studies conducted on peritoneal elucidated macrophages (PEMs) demonstrated that mmu-miR-31-5p inhibits M2 polarization in macrophages by downregulating Chi3l1. The utilization of miPEP31 as a therapeutic intervention had a substantial impact on reducing mortality rates, mitigating organ damage, inducing macrophage polarization towards the M2 phenotype, and suppressing the inflammatory response in murine models of severe sepsis. Conclusions: The suppression of miR-31 in sepsis plays a protective role in the host defense response by upregulating Chi3l1, highlighting the potential therapeutic efficacy of miPEP31 in sepsis treatment. [ABSTRACT FROM AUTHOR]

Sepsis is a systemic condition caused by a dysregulated host response to infection and often associated with excessive release of proinflammatory cytokines resulting in multi-organ failure (MOF), including cardiac dysfunction. Despite a number of effective supportive treatments (e.g. ventilation, dialysis), there are no specific interventions that prevent or reduce MOF in patients with sepsis. To identify possible intervention targets, we re-analyzed the publicly accessible Gene Expression Omnibus accession GSE131761 dataset, which revealed an increased expression of spleen tyrosine kinase (SYK) in the whole blood of septic patients compared to healthy volunteers. This result suggests a potential involvement of SYK in the pathophysiology of sepsis. Thus, we investigated the effects of the highly selective SYK inhibitor PRT062607 (15mg/kg; i.p.) on sepsis-induced cardiac dysfunction and MOF in a clinically-relevant, murine model of sepsis. PRT062607 or vehicle (saline) was administered to 10-weeks-old C57BL/6 mice at 1h after the onset of sepsis induced by cecal ligation and puncture (CLP). Antibiotics (imipenem/cilastatin; 2mg/kg; s.c.) and analgesic (buprenorphine; 0.05mg/kg; i.p.) were administered at 6h and 18h post-CLP. After 24h, cardiac function was assessed in vivo by echocardiography and, after termination of the experiments, serum and cardiac samples were collected to evaluate the effects of SYK inhibition on the systemic release of inflammatory mediators and the degree of organ injury and dysfunction. Our results show that treatment of CLP-mice with PRT062607 significantly reduces systolic and diastolic cardiac dysfunction, renal dysfunction and liver injury compared to CLP-mice treated with vehicle. In addition, the sepsis-induced systemic inflammation (measured as an increase in inflammatory cytokines and chemokines in the serum) and the cardiac activation of NF-kB (IKK) and the NLRP3 inflammasome were significantly reduced in CLP-mice treated with PRT062607. These results demonstrate, for the first time, that SYK inhibition 1h after the onset of sepsis reduces the systemic inflammation, cardiac dysfunction and MOF, suggesting a potential role of the activation of SYK in the pathophysiology of sepsis. Novel therapeutic strategies that inhibit SYK activity may be of benefit in patients with diseases associated with local or systemic inflammation including sepsis. [ABSTRACT FROM AUTHOR]

Our research team previously reported the immunomodulatory effects of kombucha fermentation liquid. This study investigated the protective effects of turmeric kombucha (TK) against lipopolysaccharide (LPS)-induced sepsis and its impact on the intestinal microbiota of mice. A turmeric culture medium without kombucha served as the control (TW). Non-targeted metabolomics analysis was employed to analyze the compositional differences between TK and TW. Qualitative analysis identified 590 unique metabolites that distinguished TK from TW. TK improved survival from 40 to 90%, enhanced thermoregulation, and reduced pro-inflammatory factor expression and inflammatory cell infiltration in the lung tissue, suppressing the NF-kB signaling pathway. TK also altered the microbiome, promoting Allobaculum growth. Our findings shed light on the protective effects and underlying mechanisms of TK in mitigating LPS-induced sepsis, highlighting TK as a promising anti-inflammatory agent and revealing new functions of kombucha prepared through traditional fermentation methods. [ABSTRACT FROM AUTHOR]

Preclinical mouse models are critical for understanding the pathophysiological response to infections and developing treatment strategies for sepsis. In keeping with ethical values, researchers follow guidelines to minimize the suffering of the mice. Weight loss is a criteria used as a humane end point, but there is no official recommendation for a maximum weight loss leading to euthanasia. To evaluate whether the thresholds used in daily practice are optimal, we performed a comprehensive retrospective analysis of data generated over 10 years with > 2300 mice used in models of infection with Listeria monocytogenes, Streptococcus pneumoniae, Candida albicans and H1N1 influenza virus. Weight loss segregated mice that survived from those that did not. Statistical analyses revealed that lowering the weight loss thresholds used (none, 30% or 20%) would have increased mortality rates due to the sacrifice of mice that survived infections (p < 0.01–0.001). Power calculations showed high variability and reduction of power as weight loss thresholds approached 20% for S. pneumoniae and L. monocytogenes models. Hence, weight loss thresholds need to be adapted to each model of infection used in a laboratory. Overall, weight loss is a valuable predictor of mortality that contributes to the robustness of composite scores. To our knowledge, this is the most extensive study exploring the relationship between weight loss threshold and sepsis outcome. It underscores the importance of the infection-model-specific evaluation of weight loss for use in clinical scores defining humane endpoints to minimize mouse suffering without compromising statistical power and scientific objectives. [ABSTRACT FROM AUTHOR]

Background: The lack of a reliable scoring system that predicts the development of septic shock and death precludes comparison of disease and/or treatment outcomes in animal models of sepsis. We developed a murine sepsis score (MSS) that evaluates seven clinical variables, and sought to assess its validity and reliability in an experimental mouse model of polymicrobial sepsis., Methods: Stool collected from the cecum of C57BL/6 (B6) mice was dissolved in 0.9% normal saline (NS) and filtered, resulting in a fecal solution (FS) which was injected intraperitoneally into B6 mice. Disease severity was monitored by MSS during the experimental timeline. Blood and tissue samples were harvested for the evaluation of inflammatory changes after sepsis induction. The correlation between pro-inflammatory markers and MSS was assessed by the Spearman rank correlation coefficient., Results: Mice injected with FS at a concentration of 90 mg/mL developed polymicrobial sepsis with a 75% mortality rate at 24 hours. The MSS was highly predictive of sepsis progression and mortality, with excellent discriminatory power, high internal consistency (Cronbach alpha coefficient = 0.92), and excellent inter-rater reliability (intra-class coefficient = 0.96). An MSS of 3 had a specificity of 100% for predicting onset of septic shock and death within 24 hours. Hepatic dysfunction and systemic pro-inflammatory responses were confirmed by biochemical and cytokine analyses where the latter correlated well with the MSS. Significant bacterial dissemination was noted in multiple organs. Furthermore, the liver, spleen, and intestine demonstrated histopathological evidence of injury., Conclusions: The MSS reliably predicts disease progression and mortality in an animal model of polymicrobial sepsis. More importantly, it may be used to assess and compare outcomes among various experimental models of sepsis, and serve as an ethically acceptable alternative to death as an endpoint.

Despite recent therapeutic advances, including the introduction of novel cytostatic drugs and therapeutic antibodies, many cancer patients will experience recurrent or metastatic disease. Current treatment options, particularly for those patients with metastatic breast, prostate, or skin cancers, are complex and have limited curative potential. Recent clinical trials, however, have shown that cell-based therapeutic vaccines may be used to generate broad-based, antitumor immune responses. Dendritic cells (DC) have proved to be the most efficacious cellular component for therapeutic vaccines, serving as both the adjuvant and antigen delivery vehicle. At present it is not possible to noninvasively determine the fate of DC-based vaccines after their administration to human subjects. In this study, we demonstrate that in vitro-generated mouse DC can be readily labeled with superparamagnetic iron oxide nanoparticles, Feridex, without altering cell morphology, or their phenotypic and functional maturation. Feridex-labeling enables the detection of DC in vivo after their migration to draining lymph nodes using a 1.5 T clinical magnetic resonance scanner. In addition, we report a semiquantitative approach for analysis of magnetic resonance images and show that the Feridex-induced signal void volume, and fractional signal loss, correlates with the delivery and migration of small numbers of in vitro-generated DC. These findings, together with ongoing preclinical studies, are key to gaining information critical for improving the efficacy of therapeutic vaccines for the treatment cancer, and potentially, chronic infectious diseases.

Background: Thyroid storm (TS), a life-threatening condition that can damage multiple organs, has limited therapeutic options. Hypercytokinemia is a suggested background, but the pathological condition is unclear and there are no appropriate animal models. We aimed to develop a TS mouse model by administration of triiodothyronine and lipopolysaccharide, and then to examine the effects of ghrelin on this model. Methods: We evaluated the use of serum IL-6 levels as a representative marker of hypercytokinemia in patients with TS. To establish the mouse model, preliminary experiments were conducted to determine the non-lethal doses of triiodothyronine and lipopolysaccharide when administered individually. As a TS model, C57BL/6 mice were administered with triiodothyronine 1.0 mg/kg (subcutaneously, once daily for seven consecutive days) and lipopolysaccharide 0.5 mg/kg (intraperitoneally, on day 7) to develop a lethal model with approximately 30% survival on day 8. We assessed the survival ratio, mouse sepsis scores and blood biomarkers (IL-6, metanephrine, alanine aminotransferase) and evaluated the effects of ghrelin 300 µg/kg on these parameters in TS model. Results: Serum IL-6 was increased in patients with TS compared with those with Graves' disease as the diseased control (18.2 vs. 2.85 pg/mL, P <.05, n = 4 each). The dosage for the murine TS model was triiodothyronine 1.0 mg/kg and lipopolysaccharide 0.5 mg/kg. The TS model group had increased mouse sepsis score, serum IL-6, metanephrine and alanine aminotransferase. In this model, the ghrelin improved the survival rate to 66.7% (P <.01, vs. 0% [saline-treated group]) as well as the mouse sepsis score, and it decreased the serum IL-6 and metanephrine. Conclusion: We established an animal model of TS that exhibits pathophysiological states similar to human TS with induction of serum IL-6 and other biomarkers by administration of T3 and LPS. The results suggest the potential effectiveness of ghrelin for TS in humans. [ABSTRACT FROM AUTHOR]

Sepsis is a potentially fatal clinical condition that results from an immune imbalance in the host during an infection. It presents systemic alterations due to excessive activation of pro-inflammatory mediators that contribute to inflammation, formation of reactive species, and tissue damage. Anti-inflammatory mediators are then extensively activated to regulate this process, leading to immune exhaustion and, consequently, immunosuppression of the host. Considering the biological activities of the nutraceutical Agaricus brasiliensis (A. brasiliensis), such as immunomodulatory, antioxidant, and antitumor activities, the present study investigated the therapeutic potential of the lipid fraction of A. brasiliensis (LF) in a model of lethal sepsis in mice (Mus musculus), induced by cecal ligation and perforation (CLP). The results showed that treatment of septic animals with LF or LF associated with ertapenem (LF-Erta) reduced systemic inflammation, promoting improvement in clinical parameters and increased survival. The data show a reduction in pro-inflammatory and oxidative stress markers, regulation of the anti-inflammatory response and oxidizing agents, and increased bacterial clearance in the peritoneal cavity and liver. Thus, it can be concluded that LF as a treatment, and in conjunction with antibiotic therapy, has shown promising effects as a hepatoprotective, antioxidant, antimicrobial, and immunomodulatory agent. [ABSTRACT FROM AUTHOR]

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Introduction: Sepsis is a serious complaint caused by a dysregulated host response to infection. It is one of the most common causes of admission to intensive care units. Acute kidney injury (AKI) is the most frequent complication of sepsis in critically ill patients and often requires renal replacement therapy. Despite decades of sepsis research, no specific therapies for sepsis emerged. Morin is a flavonoid that is abundant in the plants of the Moraceae famil, and has protective effect against many diseases that are mostly affected by inflammation and overproduction of oxidative stress, including a range of nephrotoxicity models rather than septic-induced AKI. Aim of the Study: Thus, the present study was carried out to evaluate the effect of morin on the survival rate, clinical symptoms, renal histological alterations, and the immunoreactivity of the cell survival marker BCl2 in septic-induced AKI. Methods: sepsis-induced AKI was induced in mice by a single intraperitoneal injection of lipopolysaccharides (LPS;5mg/kg). Treatment with morin (50 mg/kg bw) started 5 hours after LPS challenge, then for 2 more days. Results: The results showed that LPS-injected mice had low survival rate (44% vs 100% in normal control) and showed several clinical signs including;hypoactivity, lethargy, loss of appetite, ruffled fur, high breathing rate, hind limb paralysis, and closed eyes. On the other hand, morin-treated animals showed significantly higher survival rate than that of the septic control group (90% vs 44%), recovery from the signs of sepsis, enhancement of the histology of kidney. In addition, morin decreased the immunoreactivity of the cell surviving marker BCl2. Conclusion: these findings indicate that morin has a notable therapeutic effect against sepsis-associated AKI and may be a useful therapeutic option for increasing the survival rates of septic patients or even for preventing its associated renal complications. [ABSTRACT FROM AUTHOR]

Acute (i.e., wasting) pediatric malnutrition consistently elevates blood glucocorticoid levels, but neither the magnitude of the rise in concentration nor its kinetics is clear. Male and female C57BL/6J mice, initially 19 days old, and CBA/J mice, initially 23 days old, consumed a complete purified diet either ad libitum (age-matched control) or in restricted daily quantities (mimicking marasmus), or they consumed a purified isocaloric low-protein diet ad libitum (mimicking incipient kwashiorkor). Serum levels of corticosterone were assessed by double antibody radioimmunoassay after 3, 6, and 14 days (C57BL/6J strain) or after 6 and 14 days in the genetically distant CBA/J strain. Age-matched control groups of both strains exhibited mean corticosterone levels of 5-30 ng/ml, whereas the acutely malnourished groups exhibited mean levels of this hormone that were elevated by more than an order of magnitude as early as 3 days after initiation of weight loss. This outcome was confirmed in a second experiment in which the serum corticosterone level of C57BL/6J weanlings was examined by competitive binding enzyme immunoassay 3 and 14 days after initiation of the dietary protocols. Therefore, deficits of protein and/or energy in weanling murine systems relevant to acute pediatric malnutrition elicit early elevations in blood glucocorticoid levels to a magnitude reminiscent of critical illness and multiple trauma. The key to this novel finding was an exsanguination method that permitted accurate assessment of the blood corticosterone level of the healthy, quiescent mouse. Overall, the results of this investigation provide a new perspective on the glucocorticoids as part of the early hormonal response to acute weanling malnutrition coincident with the shift toward catabolic metabolism and the initiation of depression in cellular immune competence.

The rise of antimicrobial resistance in ESKAPEE pathogens poses significant clinical challenges, especially in polymicrobial infections. Bacteriophage-derived endolysins offer promise in combating this crisis, but face practical hurdles. Our study focuses on engineering endolysins from a Klebsiella pneumoniae phage, fusing them with ApoE23 and COG133 peptides. We assessed the resulting chimeric proteins' bactericidal activity against ESKAPEE pathogens in vitro. ApoE23-Kp84B (CHU-1) reduced over 3 log units of CFU for A. baumannii, E. faecalis, K. pneumoniae within 1 h, while COG133-Kp84B (CHU-2) showed significant efficacy against S. aureus. COG133-L1-Kp84B, with a GS linker insertion in CHU-2, exhibited outstanding bactericidal activity against E. cloacae and P. aeruginosa. Scanning electron microscopy revealed alterations in bacterial morphology after treatment with engineered endolysins. Notably, CHU-1 demonstrated promising anti-biofilm and anti-persister cell activity against A. baumannii and E. faecalis but had limited efficacy in a bacteremia mouse model of their coinfection. Our findings advance the field of endolysin engineering, facilitating the customization of these proteins to target specific bacterial pathogens. This approach holds promise for the development of personalized therapies tailored to combat ESKAPEE infections effectively. [ABSTRACT FROM AUTHOR]

Community-acquired respiratory infection is the commonest cause of sepsis presenting to emergency departments. Yet current experimental animal models simulate peritoneal sepsis with intraperitoneal (I.P.) injection of lipopolysaccharide (LPS) as the predominant route. We aimed to compare the progression of organ injury between I.P. LPS and intranasal (I.N.) LPS in order to establish a better endotoxemia murine model of respiratory sepsis. Eight weeks old male BALB/c mice received LPS-Escherichia coli doses at 0.15, 1, 10, 20, 40 and 100 mg per kg body weight (e.g. LPS-10 is a dose of 10 mg/kg body weight). Disease severity was monitored by a modified Mouse Clinical Assessment Score for Sepsis (M-CASS; range 0–21). A M-CASS score ≥ 10 or a weight reduction of ≥ 20%, was used as a criterion for euthanasia. The primary outcome was the survival rate (either no death or no need for euthanasia). The progression of disease was specified as M-CASS, body weight, blood glucose, histopathological changes to lung, liver, spleen, kidney, brain and heart tissues. Survival rate in I.P. LPS-20 mice was 0% (2/3 died; 1/3 euthanized with M-CASS > 10) at 24 h. Survival rate in all doses of I.N. LPS was 100% (20/20; 3–4 per group) at 96 h. 24 h mean M-CASS post-I.P. LPS-10 was 6.4/21 significantly higher than I.N. LPS-10 of 1.7/21 (Unpaired t test, P < 0.05). Organ injury was present at 96 h in the I.P. LPS-10 group: lung (3/3; 100%), spleen (3/3; 100%) and liver (1/3; 33%). At 24 h in the I.P. LPS-20 group, kidney injury was observed in the euthanized mouse. At 96 h in the post-I.N. LPS-20 group, only lung injury was observed in 2/3 (67%) mice (Kruskal-Wallis test with Dunn's, P < 0.01). At 24 h in the post-I.N. LPS-100 group all (4/4) mice had evidence of lung injury. Variable doses of I.N. LPS in mice produced lung injury but did not produce sepsis. Higher doses of I.P. LPS induced multi-organ injury but not respiratory sepsis. Lethal models of respiratory virus, e.g., influenza A, might provide alternative avenues that can be explored in future research. [ABSTRACT FROM AUTHOR]

Immunotherapies have revolutionized cancer treatment. These treatments rely on immune cell activation in tumours, which limits the number of patients that respond. Inflammatory molecules, like lipopolysaccharides (LPS), can activate innate immune cells, which convert tumour microenvironments from cold to hot, and increase therapeutic efficacy. However, systemic delivery of lipopolysaccharides (LPS) can induce cytokine storm. In this work, we developed immune‐controlling Salmonella (ICS) that only produce LPS in tumours after colonization and systemic clearance. We tuned the expression of msbB, which controls production of immunogenic LPS, by optimizing its ribosomal binding sites and protein degradation tags. This genetic system induced a controllable inflammatory response and increased dendritic cell cross‐presentation in vitro. The strong off state did not induce TNFα production and prevented adverse events when injected into mice. The accumulation of ICS in tumours after intravenous injection focused immune responses specifically to tumours. Tumour‐specific expression of msbB increased infiltration of immune cells, activated monocytes and neutrophils, increased tumour levels of IL‐6, and activated CD8 T cells in draining lymph nodes. These immune responses reduced tumour growth and increased mouse survival. By increasing the efficacy of bacterial anti‐cancer therapy, localized production of LPS could provide increased options to patients with immune‐resistant cancers. [ABSTRACT FROM AUTHOR]

The purpose of this research is the sociological explanation of the beliefs, behaviors and sexual understanding of young people. With a combined approach, this research used the phenomenology method to discover the problem and the survey method for the exploratory study of sexual tendencies. Factors and concepts obtained from in-depth interviews were tested in the form of a design model and survey. The phenomenology section included 19 young people who were selected by chain sampling. For data analysis, Collaizi -method was used, and the validity and reliability of the study was checked by the Lincoln-Guba method. In the survey, the population of Tehran university students and the sample size of 400 people were selected using Cochran's formula. In data analysis, one-way variance analysis, regression and path analysis were used. Concepts in the form of typology were extracted from the phenomenological findings, which include extramarital sexual relations, cohabitation, intercourse, sexual diversity, simultaneous relationships with several people, sexual interactions as leisure behavior, girls as a stimulus and precursor, representation of the body. as physical-social capital and the fluidity of young people's relationships. The results of multivariate regression and path analysis showed that the decline of religious values is effective directly and through the influence on the individualism of sexual orientation. Media affects sexual tendencies directly and through influencing individualism and consumerism. The reference group has an effect on both consumerism and directly the sexual orientation of young people. Filial piety in the family power structure and social trust has an effect on sexual tendencies.. [ABSTRACT FROM AUTHOR]

Prolonged labor can lead to infection, fetal distress, asphyxia, and life-threatening harm to both the mother and the baby. Surfactant protein A (SP-A) was shown to contribute to the maintenance of pregnancy and timing of term labor. SP-A modulates the stoichiometric expression of the SP-R210L and SP-R210S isoforms of the SP-R210 receptor on alveolar macrophages (AMs). Lack of SP-R210L dysregulates macrophage inflammatory responses. We asked whether SP-A alters normal and inflammation-induced parturition through SP-R210 using SP-A- and SP-R210L-deficient mice. Labor and delivery of time-pregnant mice were monitored in real time using a time-lapse infrared camera. Intrauterine injection with either vehicle or Escherichia coli lipopolysaccharide (LPS) on embryonic (E) day 18.5 post coitus was used to assess the effect of gene disruption in chorioamnionitis-induced labor. We report that either lack of SP-A or disruption of SP-R210L delays parturition by 0.40 and 0.55 days compared with controls, respectively. LPS induced labor at 0.60, 1.01, 0.40, 1.00, and 1.31 days earlier than PBS controls in wild type (WT), SP-A-deficient, littermate controls, heterozygous, and homozygous SP-R210L-deficient mice, respectively. Lack of SP-A reduced litter size in PBS-treated mice, whereas the total number of pups delivered was similar in all LPS-treated mice. The number of live pups, however, was significantly reduced by 50%–70% in SP-A and SP-R210L-deficient mice compared with controls. Differences in gestational length were not associated with intrauterine growth restriction. The present findings support the novel concept that the SP-A/SP-R210 pathway modulates timely labor and delivery and supports fetal lung barrier integrity during fetal-to-neonatal transition in term pregnancy. NEW & NOTEWORTHY: To our knowledge, this study is the first to report that SP-A prevents delay of labor and inflammation-induced stillbirth through the receptor SP-R210L. [ABSTRACT FROM AUTHOR]

The human gastrointestinal system is a complex ecosystem crucial for well-being. During sepsis-induced gut injury, the integrity of the intestinal barrier can be compromised. Lipopolysaccharide (LPS), an endotoxin from Gram-negative bacteria, disrupts the intestinal barrier, contributing to inflammation and various dysfunctions. The current study explores the protective effects of limonene, a natural compound with diverse biological properties, against LPS-induced jejunal injury in mice. Oral administration of limonene at dosages of 100 and 200 mg/kg was used in the LPS mouse model. The Murine Sepsis Score (MSS) was utilized to evaluate the severity of sepsis, while serum levels of urea and creatinine served as indicators of renal function. Our results indicated that LPS injection induced renal function deterioration, evidenced by elevated serum urea and creatinine levels compared to control mice. However, pretreatment with limonene at doses of 100 and 200 mg/kg mitigated this decline in renal function, evidenced from the reduced levels of serum urea and creatinine. Limonene demonstrated anti-inflammatory effects by reducing pro-inflammatory cytokines (TNF-α, IL-1β, COX-2), suppressing the TLR4/NF-κB/AP-1 but not IRF3 signaling pathways, and modulating oxidative stress through Nrf2 activation. The results suggest that limonene holds promise as a potential therapeutic agent for mitigating intestinal inflammation and preserving gastrointestinal health. [ABSTRACT FROM AUTHOR]

Substance P (SP), encoded by the TAC1/Tac1 gene, acts as a significant mediator in dysregulated systemic inflammatory response and associated organ injury in sepsis by activating the neurokinin-1 receptor (NK1R). This study investigated the impact of SP-NK1R signaling on ferroptosis in the liver and lungs of mice with sepsis. Sepsis was induced by caecal ligation puncture (CLP) surgery in mice. The SP-NK1R signaling was suppressed by Tac1 gene deletion, NK1R blockade, and a combination of these two approaches. The physiological conditions of mice were recorded. The profile of the SP-NK1R cascade, inflammatory response, ferroptosis, and tissue histology were investigated in the liver and lungs. Several manifestations of sepsis occurred in Tac1+/+ mice during the development of sepsis. Notably, hypothermia became significant four hours after the induction of sepsis. In the liver and lungs of mice subjected to CLP surgery, the concentrations of SP and NK1R were upregulated. Additionally, the concentrations of pro-inflammatory mediators, including cytokines (IL-1β, IL-6, and TNF-α) and chemokines (MCP-1 and MIP-2), were increased. Moreover, ferroptosis was elevated, as evidenced by increased concentrations of iron and MDA and reduced concentrations of GSH, Nrf2, and Gpx4. Suppressing the SP-NK1R cascade significantly mitigated CLP-surgery-induced alterations in mice. Importantly, these three approaches used to suppress SP-NK1R signaling showed similar effects on protecting mice against sepsis. In conclusion, increased SP-mediated acute inflammatory response and injury in the liver and lungs in mice with CLP-surgery-induced sepsis was associated with elevated ferroptosis. The detrimental effect of SP on sepsis was predominantly mediated by NK1R. Therefore, the suppression of increased SP-NK1R signaling and ferroptosis may be a promising adjuvant therapeutic candidate for sepsis and associated acute liver and lung injury. [ABSTRACT FROM AUTHOR]

Senescence, caused by cell-cycle arrest, is a hallmark of aging. Senescence has also been described in embryogenesis, wound healing, and acute injuries. Sepsis is characterized by a dysregulated host response to infection, leading to organ dysfunction and mortality. Most of the pathophysiology of human sepsis is recapitulated in the mouse model of polymicrobial sepsis, developed by cecal ligation and puncture (CLP). In this report, we demonstrate a rapid onset of cellular senescence in the liver of mice subjected to CLP-induced sepsis, characterized by the upregulation of p21, p53, and other senescence markers, including SA-βgal. Using RNAscope, confocal microscopy, and flow cytometry, we further confirm the emergence of p21-expressing senescence phenotype in the liver 24 h after sepsis induction. Senescence was observed in several cell types in the liver, including hepatocytes, endothelial cells, and macrophages. We determined the landscape of senescence phenotype in murine sepsis by single-cell sequencing, which further ascertained that this cell fate is not confined to any particular cell type but displays a heterogeneous distribution. Furthermore, we observed a significant reduction in mortality following sepsis when mice were treated with senolytics, a combination of dasatinib and quercetin, before the CLP surgery. Our experiments unequivocally demonstrated a rapid development of cellular senescence with sepsis and, for the first time, described the senescence landscape in the sepsis liver and the possible role of senescent cells in the worsening outcome following sepsis., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Sepsis and septic shock are life-threatening systemic inflammatory conditions and among the most frequent causes of morbidity and mortality globally. Preclinical evidence has identified a number of diazepine-based compounds with therapeutic potential in inflammatory diseases. However, the potential anti-inflammatory properties of diazepines in the overwhelming immune response during sepsis have been rarely examined. Thus, the current study aimed to identify a new diazepine compound with therapeutic potential in sepsis. Assessing the inflammatory response of macrophages to Lipopolysaccharides (LPS) in vitro identified 2-[7-(trifluoromethyl)-2,3-dihydro-1H-1,4-diazepin-5-yl]phenol (2-TDDP) as a potential anti-inflammatory agent. It reduced secretion of Interleukin-1β (IL-1β), IL-6, IL-12p70, IL-18, Tumor necrosis factor-α (TNF-α), Interferon-γ (IFN-γ), IFN-β, and increased the secretion of IL-10. In a mouse model of LPS-induced endotoxin shock, 2-TDDP reduced mortality and attenuated inflammation-induced tissue injury in the spleen, liver, kidney, and lung. This was accompanied by reduced serum levels of IL-1β, IL-6, IL-12p70, TNF-α, IFN-γ, IFN-β, and increased levels of IL-10. Importantly, 2-TDDP suppressed the Toll-like receptor 4 (TLR4)/Nuclear factor-κB (NF-κB) and TLR4/Interferon regulatory factor 3 (IRF3) signaling pathways through a reduction in the expression of TLR4, Myeloid differentiation primary response 88 (MyD88), P65, and TNF receptor-associated factor 3 (Traf3). Moreover, 2-TDDP suppressed the expression of CD86, Programmed death-ligand 1 (PD-L1) and C5a receptor (C5aR), but not Major histocompatibility complex II (MHCII). Analysis of splenic lymphocyte populations revealed a decrease in the number of CD4 + , CD8 + , and B cells. Collectively, these findings introduced the dihydrodiazepine 2-TDDP as a new anti-inflammatory agent with potent therapeutic potential in endotoxin shock, paving an avenue for future clinical application., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Approximately 40 to 60% of patients with sepsis develop sepsis-induced cardiomyopathy (SIC), which is associated with a substantial increase in mortality. We have found that molecular hydrogen (H2) inhalation improved the survival rate and cardiac injury in septic mice. However, the mechanism remains unclear. This study aimed to explore the regulatory mechanism by which hydrogen modulates autophagy and its role in hydrogen protection of SIC. Methods: Cecal ligation and puncture (CLP) was used to induce sepsis in adult C57BL/6J male mice. The mice were randomly divided into 4 groups: Sham, Sham + 2% hydrogen inhalation (H2), CLP, and CLP + H2 group. The 7-day survival rate was recorded. Myocardial pathological scores were calculated. Myocardial troponin I (cTnI) levels in serum were detected, and the levels of autophagy- and mitophagy-related proteins in myocardial tissue were measured. Another four groups of mice were also studied: CLP, CLP + Bafilomycin A1 (BafA1), CLP + H2, and CLP + H2 + BafA1 group. Mice in the BafA1 group received an intraperitoneal injection of the autophagy inhibitor BafA1 1 mg/kg 1 h after operation. The detection indicators remained the same as before. Results: The survival rate of septic mice treated with H2 was significantly improved, myocardial tissue inflammation was improved, serum cTnI level was decreased, autophagy flux was increased, and mitophagy protein content was decreased (P < 0.05). Compared to the CLP + H2 group, the CLP + H2 + BafA1 group showed a decrease in autophagy level and 7-day survival rate, an increase in myocardial tissue injury and cTnI level, which reversed the protective effect of hydrogen (P < 0.05). Conclusion: Hydrogen exerts protective effect against SIC, which may be achieved through the promotion of autophagy and mitophagy. [ABSTRACT FROM AUTHOR]

The impact of various fatty acid types on adaptive immunity remains uncertain, and their roles remain unelucidated. Stearoyl-CoA desaturase (Scd) is a D-9 desaturase, which is a key rate-limiting enzyme for the conversion of saturated fatty acids (SFA) to monounsaturated fatty acids (MUFA) in the fatty acid de novo synthesis. Scd-1 converts stearic acid (SA) and palmitic acid (PA) to oleic acid (OA) and palmitoleic acid (PO), respectively. In this study, through a series of experiments, we showed that Scd-1 and its resulting compound, OA, have a substantial impact on the transformation of CD8+ naïve T cells into effector T cells. Inactivation of Scd-1 triggers the specialization of CD8+ T cells into the Teff subset, enhancing the effector function and mitochondrial metabolism of Teff cells, and OA can partially counteract this. A deeper understanding of lipid metabolism in immune cells and its impact on cell function can lead to new therapeutic approaches for controlling the immune response and improving prognosis. [ABSTRACT FROM AUTHOR]

The Helios protein (encoded by the IKZF2 gene) is a member of the Ikaros transcription family and it has recently been proposed as a promising biomarker for systemic lupus erythematosus (SLE) disease progression in both mouse models and patients. Helios is beginning to be studied extensively for its influence on the T regulatory (Treg) compartment, both CD4+ Tregs and KIR+/Ly49+ CD8+ Tregs, with alterations to the number and function of these cells correlated to the autoimmune phenomenon. This review analyzes the most recent research on Helios expression in relation to the main immune cell populations and its role in SLE immune homeostasis, specifically focusing on the interaction between T cells and tolerogenic dendritic cells (tolDCs). This information could be potentially useful in the design of new therapies, with a particular focus on transfer therapies using immunosuppressive cells. Finally, we will discuss the possibility of using nanotechnology for magnetic targeting to overcome some of the obstacles related to these therapeutic approaches. [ABSTRACT FROM AUTHOR]

The tolerance model rests on the thesis of a physiologically regulated, albeit unsustainable, systemic attempt to adapt to the catabolic challenge posed by acute prepubescent malnutrition even in its severe forms. The model centers on the immunological component of the attempt, positing reorientation toward a non-inflammatory form of competence in place of the classic paradigm of immunological attrition and exhaustion. The foundation of the model was laid in 1990, and sixteen years later it was articulated formally on the basis of a body of evidence centered on T cell cytokines and interventions with cytokine and hormonal mediators. The benefit originally suggested was a reduced risk of autoimmune pathologies consequent to the catabolic release of self-antigens, hence the designation highlighting immune tolerance. Herein, the emergence of the tolerance model is traced from its roots in the recognition that acute malnutrition elicits an endocrine-based systemic adaptive attempt. Thereafter, the growth of the evidence base supporting the model is outlined, and its potential to shed new light on existing information is tested by application to the findings of a published clinical study of acutely malnourished children. Finally, some knowledge gaps pertinent to the model are identified and its potential for growth consonant with evolving perceptions of immunobiology is illustrated. [ABSTRACT FROM AUTHOR]

Purpose: Innate immune activation plays a critical role in the onset and progression of many diseases. While positron emission tomography (PET) imaging provides a non-invasive means to visualize and quantify such immune responses, most available tracers are not specific for innate immune cells. To address this need, we developed [18F]OP-801 by radiolabeling a novel hydroxyl dendrimer that is selectively taken up by reactive macrophages/microglia and evaluated its ability to detect innate immune activation in mice following lipopolysaccharide (LPS) challenge. Procedures: OP-801 was radiolabeled in two steps: [18F]fluorination of a tosyl precursor to yield [18F]3-fluoropropylazide, followed by a copper-catalyzed click reaction. After purification and stability testing, [18F]OP-801 (150-250 μCi) was intravenously injected into female C57BL/6 mice 24 h after intraperitoneal administration of LPS (10 mg/kg, n=14) or saline (n=6). Upon completing dynamic PET/CT imaging, mice were perfused, and radioactivity was measured in tissues of interest via gamma counting or autoradiography. Results: [18F]OP-801 was produced with >95% radiochemical purity, 12–52 μCi/μg specific activity, and 4.3±1.5% decay-corrected yield. Ex vivo metabolite analysis of plasma samples (n=4) demonstrated high stability in mice (97±3% intact tracer >120 min post-injection). PET/CT images of mice following LPS challenge revealed higher signal in organs known to be inflamed in this context, including the liver, lung, and spleen. Gamma counting confirmed PET findings, showing significantly elevated signal in the same tissues compared to saline-injected mice: the liver (p=0.009), lung (p=0.030), and spleen (p=0.004). Brain PET/CT images (summed 50–60 min) revealed linearly increasing [18F]OP-801 uptake in the whole brain that significantly correlated with murine sepsis score (r=0.85, p<0.0001). Specifically, tracer uptake was significantly higher in the brain stem, cortex, olfactory bulb, white matter, and ventricles of LPS-treated mice compared to saline-treated mice (p<0.05). Conclusion: [18F]OP-801 is a promising new PET tracer for sensitive and specific detection of activated macrophages and microglia that warrants further investigation. [ABSTRACT FROM AUTHOR]

The article focuses on the essential role of vitamin C in the tricarboxylic acid cycle for the production of anti-inflammatory itaconate. Topics include the involvement of vitamin C in metabolic pathways, the anti-inflammatory properties of itaconate, and the potential implications for therapeutic interventions targeting redox balance.

Pyroptosis is a cell death process that causes inflammation and contributes to numerous diseases. Pyroptosis is mediated by caspase-1 family proteases that cleave the pore-forming protein gasdermin D, causing plasma membrane rupture and release of pathogenic cellular contents. We previously identified muscimol as a small molecule that prevents plasma membrane rupture during pyroptosis via an unidentified mechanism. Here, we show that muscimol has reversible activity to prevent cellular lysis without affecting earlier pyroptotic events. Although muscimol is a well-characterized agonist for neuronal GABAA receptors, muscimol protection is not altered by GABAA receptor antagonists or recapitulated by other GABAA agonists, suggesting that muscimol acts via a novel mechanism. We find that muscimol blocks oligomerization of ninjurin-1, which is required for plasma membrane rupture downstream of gasdermin D pore formation. Our structure-activity relationship studies reveal distinct molecular determinants defining inhibition of pyroptotic lysis compared to GABAA binding. In addition, we demonstrate that muscimol reduces lethality during LPS-induced septic shock. Together, these findings demonstrate that ninjurin-1-mediated plasma membrane rupture can be pharmacologically modulated and pave the way toward identification of therapeutic strategies for pathologic conditions associated with pyroptosis. The small molecule muscimol blocks oligomerization of ninjurin-1, which is required for plasma membrane rupture downstream of gasdermin D pore formation during pyroptotic lysis, and reduces lethality in mice during LPS-induced septic shock. [ABSTRACT FROM AUTHOR]

Sepsis is one of the major complications of surgery resulting in high morbidity and mortality, but there are no specific therapies for sepsis-induced organ dysfunction. Data obtained under Gene Expression Omnibus accession GSE131761 were re-analyzed and showed an increased gene expression of Janus Kinase 2 (JAK2) and Signal Transducer and Activator of Transcription 3 (STAT3) in the whole blood of post-operative septic patients. Based on these results, we hypothesized that JAK/STAT activation may contribute to the pathophysiology of septic shock and, hence, investigated the effects of baricitinib (JAK1/JAK2 inhibitor) on sepsis-induced cardiac dysfunction and multiple-organ failure (MOF). In a mouse model of post-trauma sepsis induced by midline laparotomy and cecal ligation and puncture (CLP), 10-week-old male (n=32) and female (n=32) C57BL/6 mice received baricitinib (1mg/kg; i.p.) or vehicle at 1h or 3h post-surgery. Cardiac function was assessed at 24h post-CLP by echocardiography in vivo, and the degree of MOF was analyzed by determination of biomarkers in the serum. The potential mechanism underlying both the cardiac dysfunction and the effect of baricitinib was analyzed by western blot analysis in the heart. Trauma and subsequent sepsis significantly depressed the cardiac function and induced multiple-organ failure, associated with an increase in the activation of JAK2/STAT3, NLRP3 inflammasome and NF-κβ pathways in the heart of both male and female animals. These pathways were inhibited by the administration of baricitinib post the onset of sepsis. Moreover, treatment with baricitinib at 1h or 3h post-CLP protected mice from sepsis-induced cardiac injury and multiple-organ failure. Thus, baricitinib may be repurposed for trauma-associated sepsis. [ABSTRACT FROM AUTHOR]

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BACKGROUND: Sepsis-associated encephalopathy (SAE) is a critical disease caused by sepsis. In addition to high mortality, SAE can also adversely affect life quality and lead to significant socioeconomic costs. This review aims to explore the development of evaluation animal models of SAE, giving insight into the direction of future research in terms of its pathophysiology and therapy. METHODS: We performed a literature search from January 1, 2000, to December 31, 2022, in MEDLINE, PubMed, EMBASE, and Web of Science using related keywords. Two independent researchers screened all the accessible articles based on the inclusion and exclusion criteria and collected the relevant data of the studies. RESULTS: The animal models for sepsis are commonly induced through cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) injection. SAE can be evaluated using nervous reflex scores and sepsis evaluation during the acute phase, or through Morris water maze (MWM), openfield test, fear condition (FC) test, inhibitory avoidance, and other tests during the late phase. CONCLUSION: CLP and LPS injection are the most common methods for establishing SAE animal models. Nervous reflexs cores, MWM, FC test, and inhibitory avoidance are widely used in SAE model analysis. Future research should focus on establishing a standardized system for SAE development and analysis. [ABSTRACT FROM AUTHOR]

Background: Childhood malnutrition can have devastating consequences on health, behavior, and cognition. Edible insects are sustainable low cost high protein and iron nutritious foods that can prevent malnutrition. However, it is unclear whether insect-based diets may help prevent changes to brain neurochemistry associated with malnutrition. Materials and Methods: Weanling male Sprague–Dawley rats were malnourished by feeding a low protein-iron diet (LPI, 5% protein and ∼2 ppm Fe) for 3 weeks or nourished by feeding a sufficient protein-iron diet (SPI, 15% protein 20 ppm FeSO4) for the duration of the study. Following 3 weeks of LPI diet, three subsets of the malnourished rats were placed on repletion diets supplemented with cricket, palm weevil larvae, or the SPI diet for 2 weeks, while the remaining rats continued the LPI diet for an additional 2 weeks. Monoamine-related neurochemicals (e.g. serotonin (5-HT), dopamine (DA), norepinephrine) and select monoamine metabolites were measured in the hypothalamus, hippocampus, striatum, and prefrontal cortex using Ultra High-Performance Liquid Chromatography. Results: Five weeks of LPI diets disrupted brain monoamines, most notable in the hypothalamus. Two weeks supplementation with cricket and palm weevil larvae diets prevented changes to measures of 5-HT and DA turnover in the hippocampus and hypothalamus. Moreover, these insect diets prevented the malnutrition-induced imbalance of 5-HT and DA metabolites in the hippocampus, striatum, and hypothalamus. Conclusion: Edible insects such as cricket and palm weevil larvae could be sustainable nutrition intervention to prevent behavioral and cognitive impairment associated abnormal brain monoamine activities that results from early life malnutrition. [ABSTRACT FROM AUTHOR]

Purpose: This is the first of three parts of the clinical practice guideline from the European Society of Intensive Care Medicine (ESICM) on resuscitation fluids in adult critically ill patients. This part addresses fluid choice and the other two will separately address fluid amount and fluid removal., Methods: This guideline was formulated by an international panel of clinical experts and methodologists. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was applied to evaluate the certainty of evidence and to move from evidence to decision., Results: For volume expansion, the guideline provides conditional recommendations for using crystalloids rather than albumin in critically ill patients in general (moderate certainty of evidence), in patients with sepsis (moderate certainty of evidence), in patients with acute respiratory failure (very low certainty of evidence) and in patients in the perioperative period and patients at risk for bleeding (very low certainty of evidence). There is a conditional recommendation for using isotonic saline rather than albumin in patients with traumatic brain injury (very low certainty of evidence). There is a conditional recommendation for using albumin rather than crystalloids in patients with cirrhosis (very low certainty of evidence). The guideline provides conditional recommendations for using balanced crystalloids rather than isotonic saline in critically ill patients in general (low certainty of evidence), in patients with sepsis (low certainty of evidence) and in patients with kidney injury (very low certainty of evidence). There is a conditional recommendation for using isotonic saline rather than balanced crystalloids in patients with traumatic brain injury (very low certainty of evidence). There is a conditional recommendation for using isotonic crystalloids rather than small-volume hypertonic crystalloids in critically ill patients in general (very low certainty of evidence)., Conclusions: This guideline provides eleven recommendations to inform clinicians on resuscitation fluid choice in critically ill patients., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

The article focuses on the bidirectional relationship between gut microbiota dysbiosis and chronic obstructive pulmonary disease (COPD), emphasizing the complex interplay between the gut and lungs. Topics include the impact of gut environment on lung inflammation, COPD-related changes influencing gut microbiota, and the potential for dietary interventions in COPD management.

Background: Sepsis poses a serious threat to human life and health, with limited options for current clinical treatments. Acupuncture plays an active role in treating sepsis. However, previous studies have focused on the neuromodulatory effect of acupuncture, neglecting its network modulatory effect. Exosomes, as a new way of intercellular communication, may play an important role in transmitting acupuncture information. This paper explores the possibility of electroacupuncture-driven endogenous circulating serum exosomes and their carried miRNAs as a potential treatment for sepsis. Methods: The sepsis mouse model was established by intraperitoneal injection of lipopolysaccharide (LPS) (12 mg/kg, 24 mg/kg), and EA (continuous wave, 10 Hz, intensity 5) or intraperitoneal injection of Acupuncture Exosomes (Acu-exo) were performed before the model establishment. The therapeutic effect was evaluated by survival rate, ELISA, H&E staining and lung wet/dry weight ration (W/D). In vivo imaging of small animals was used to observe the accumulation of Acu-exo in various organs of sepsis mice. LPS was used to induce macrophages in cell experiments, and the effect of Acu-exo on macrophage inflammatory cytokines was observed. In addition, The miRNA sequencing method was further used to detect the serum exosomes of normal and EA-treated mice, and combined with network biology analysis methods to screen possible key targets. Results: EA and Acu-exo reduced the W/D and lung tissue damage in sepsis mice, down-regulated the expression of serum inflammatory cytokines TNF-α and IL-6, and increased the survival rate of sepsis mice. In vivo imaging of small animals found that Acu-exo were accumulated in the lungs of sepsis mice. Cell experiments proved that Acu-exo down-regulated the expression of inflammatory cytokines TNF-α, IL-6 and IL-1β to alleviate the inflammatory response induced by LPS in macrophages. MiRNA sequencing revealed 53 differentially expressed miRNAs, and network biology analysis revealed the key targets of Acu-exo in sepsis treatment. Conclusion: Electroacupuncture-driven endogenous circulating serum exosomes and their carried miRNAs may be a potential treatment for sepsis. [ABSTRACT FROM AUTHOR]

Background: Despite widespread study of dendritic cell (DC)-based cancer immunotherapies, the in vivo postinjection fate of DC remains largely unknown. Due in part to a lack of quantifiable imaging modalities, this is troubling as the amount of DC migration to secondary lymphoid organs correlates with therapeutic efficacy. Magnetic particle imaging (MPI) has emerged as a suitable modality to quantify in vivo migration of superparamagnetic iron oxide (SPIO)-labeled DC. Herein, we describe a popliteal lymph node (pLN)-focused MPI scan to quantify DC in vivo migration accurately and consistently. Methods: Adenovirus (Ad)-transduced SPIO+ (Ad SPIO+) and SPIO+ C57BL/6 bone marrow-derived DC were generated and assessed for viability and phenotype, then fluorescently labeled and injected into mouse hind footpads (n = 6). Two days later, in vivo DC migration was quantified using whole animal, pLN-focused, and ex vivo pLN MPI scans. Results: No significant differences in viability, phenotype and in vivo pLN migration were noted for Ad SPIO+ and SPIO+ DC. Day 2 pLN-focused MPI quantified DC migration in all instances while whole animal MPI only quantified pLN migration in 75% of cases. Ex vivo MPI and fluorescence microscopy confirmed that pLN MPI signal was due to originally injected Ad SPIO+ and SPIO+ DC. Conclusion: We overcame a reported limitation of MPI by using a pLN-focused MPI scan to quantify pLN-migrated Ad SPIO+ and SPIO+ DC in 100% of cases and detected as few as 1000 DC (4.4 ng Fe) in vivo. MPI is a suitable preclinical imaging modality to assess DC-based cancer immunotherapeutic efficacy. Relevance statement: Tracking the in vivo fate of DC using noninvasive quantifiable magnetic particle imaging can potentially serve as a surrogate marker of therapeutic effectiveness. Key points: • Adenoviral-transduced and iron oxide-labeled dendritic cells are in vivo migration competent. • Magnetic particle imaging is a suitable modality to quantify in vivo dendritic cell migration. • Magnetic particle imaging focused field of view overcomes dynamic range limitation. [ABSTRACT FROM AUTHOR]

Sepsis remains a major challenge owing to its severe adverse effects and high mortality, against which specific pharmacological interventions with high efficacy are limited. Mitigation of hyperactive inflammatory responses is a key factor in enhancing the likelihood of survival in patients with sepsis. The Aloe genus has several health benefits, including anti-inflammatory properties. The toxicological implications of aloe-emodin (AE), extracted from various Aloe species, remain uncertain in clinical contexts. However, AE has been shown to inhibit inflammatory responses in lipopolysaccharide-induced mice, indicating its potential as a therapeutic approach for sepsis treatment. Nonetheless, there is a paucity of data regarding the therapeutic benefits of AE in the widely recognized cecal ligation and puncture (CLP)-induced sepsis model, which is commonly used as the gold standard model for sepsis research. This study demonstrates the potential benefits of AE in the treatment of CLP-induced sepsis and investigates its underlying mechanism, along with the efficacy of postoperative AE treatment in mice with CLP-induced sepsis. The results of this study suggest that AE can mitigate sepsis in mice by diminishing systemic inflammation and regulating the gut microbiota. The study provides novel insights into the molecular mechanisms underlying the anti-inflammatory effects of AE. [ABSTRACT FROM AUTHOR]