Combining ulinastatin with TIENAM improves the outcome of sepsis induced by cecal ligation and puncture in mice by reducing inflammation and regulating immune responses.

Despite the high mortality associated with sepsis, effective and targeted treatments remain scarce. The use of conventional antibiotics such as TIENAM (imipenem and cilastatin sodium for injection, TIE) is challenging because of the increasing bacterial resistance, which diminishes their efficacy and leads to adverse effects. Our previous studies demonstrated that ulinastatin (UTI) exerts a therapeutic impact on sepsis by reducing systemic inflammation and modulating immune responses. In this study, we examined the possibility of administering UTI and TIE after inducing sepsis in a mouse model using cecal ligation and puncture (CLP). We assessed the rates of survival, levels of inflammatory cytokines, the extent of tissue damage, populations of immune cells, microbiota in ascites, and important signaling pathways. The combination of UTI and TIE significantly improved survival rates and reduced inflammation and bacterial load in septic mice, indicating potent antimicrobial properties. Notably, the survival rates of UTI+TIE-treated mice increased from 10 % to 75 % within 168 h compared to those of mice that were subjected to CLP. The dual treatment successfully regulated the levels of inflammatory indicators (interleukin [IL]-6, IL-1ß, and tumor necrosis factor [TNF]-α) and immune cell numbers by reducing B cells, natural killer cells, and TNFR2+ Treg cells and increasing CD8+ T cells. Additionally, the combination of UTI and TIE alleviated tissue damage, reduced bacterial load in the peritoneal cavity, and suppressed the NF-κB signaling pathway. Our findings indicate that UTI and TIE combination therapy can significantly enhance sepsis outcomes by reducing inflammation and boosting the immune system. The results offer a promising therapeutic approach for future sepsis treatment.

Ulinastatin shortens the length of ICU stay in critical patients with organ failure: A 7-year real-world study.

BACKGROUND: Ulinastatin has been applied in a series of diseases associated with inflammation but its clinical effects remain somewhat elusive. OBJECTIVE: We aimed to investigate the potential effects of ulinastatin on organ failure patients admitted to the intensive care unit (ICU). METHODS: This is a single-center retrospective study on organ failure patients from 2013 to 2019. Patients were divided into two groups according to using ulinastatin or not during hospitalization. Propensity score matching was applied to reduce bias. The outcomes of interest were 28-day all-cause mortality, length of ICU stay, and mechanical ventilation duration. RESULTS: Of the 841 patients who fulfilled the entry criteria, 247 received ulinastatin. A propensity-matched cohort of 608 patients was created. No significant differences in 28-day mortality between the two groups. Sequential organ failure assessment (SOFA) was identified as the independent risk factor associated with mortality. In the subgroup with SOFA ≤ 10, patients received ulinastatin experienced significantly shorter time in ICU (10.0 d [interquartile range, IQR: 7.0∼20.0] vs 15.0 d [IQR: 7.0∼25.0]; p = .004) and on mechanical ventilation (222 h [IQR:114∼349] vs 251 h [IQR: 123∼499]; P = .01), but the 28-day mortality revealed no obvious difference (10.5% vs 9.4%; p = .74). CONCLUSION: Ulinastatin was beneficial in treating patients in ICU with organ failure, mainly by reducing the length of ICU stay and duration of mechanical ventilation.

An Applied Study of Ulinastatin in Pain Management After Hip Replacement: Impact on Opioid Use.

Background: Due to the global prevalence of opioid drugs, postsurgical prescriptions can lead to substantial opioid consumption, highlighting the increasing need for alternative medications. Alternative medicines can markedly lessen the usage of opioids after surgery, but the variety and notable side effects of these alternatives require meticulous experimental support. Objective: This study explored the efficacy and safety of ulinastatin for alleviating postsurgical pain, for reducing the need for opioids, and for inclusion in conventional treatment methods. Methods: A total of 108 patients undergoing elective hip replacement were randomly allocated into either the experimental group (56 cases, standard pain relief treatment plus 60 IU ulinastatin) or the control group (40 cases, standard pain relief treatment). The main outcomes measured were the total consumption of opioids at 24, 48, and 72 h postoperatively. Secondary outcomes comprised patient-reported pain indices and levels of satisfaction with pain control. The frequency of adverse events evaluated medication safety. Results: There were no statistically significant differences in age, sex, or underlying diseases between the two groups. Over 24 hours, opioid consumption was higher in the standard treatment group (66.6 mg; mean difference [MD]: 4.43 mg; 95% CI: 57.6-75.5) than in the intervention group (54.5 mg; MD: 1.91 mg; 95% CI: 50.7-58.3). The standard treatment group exhibited a notably higher incidence of adverse reactions. However, there was no disparity in post-discharge satisfaction between the groups, with an odds ratio of 1.058 (95% CI: 0.62-1.82; P > 0.05). Additionally, significant differences in C-reactive protein levels were observed immediately and 6 h after surgery between the two groups. Conclusion: Within 72 h post-surgery, ulinastatin was effective in substantially reducing the use of opioids while maintaining adequate pain control. Ulinastatin may be beneficial for postoperative pain management and for reducing the risks associated with opioid use. Registered: ClinicalTrials.gov ChiCTR2300072126.

A comparative analysis of sivelestat sodium hydrate and ulinastatin combination therapy in the treatment of sepsis with acute respiratory distress syndrome.

OBJECTIVE: This comparative analysis aimed to investigate the efficacy of Sivelestat Sodium Hydrate (SSH) combined with Ulinastatin (UTI) in the treatment of sepsis with acute respiratory distress syndrome (ARDS). METHODS: A control group and an observation group were formed with eighty-four cases of patients with sepsis with ARDS, with 42 cases in each group. The control group was intravenously injected with UTI based on conventional treatment, and the observation group was injected with SSH based on the control group. Both groups were treated continuously for 7 days, and the treatment outcomes and efficacy of both groups were observed. The Murray Lung Injury Score (MLIS), Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II) were compared. Changes in respiratory function, inflammatory factors, and oxidative stress indicators were assessed. The occurrence of adverse drug reactions was recorded. RESULTS: The total effective rate in the observation group (95.24%) was higher than that in the control group (80.95%) (P < 0.05). The mechanical ventilation time, intensive care unit (ICU) hospitalization time, and duration of antimicrobial medication in the observation group were shorter and multiple organ dysfunction syndrome incidence was lower than those in the control group (P < 0.05). The mortality rate of patients in the observation group (35.71%) was lower than that in the control group (52.38%), but there was no statistically significant difference between the two groups (P > 0.05). MLIS, SOFA, and APACHE II scores in the observation group were lower than the control group (P < 0.05). After treatment, respiratory function, inflammation, and oxidative stress were improved in the observation group (P < 0.05). Adverse reactions were not significantly different between the two groups (P > 0.05). CONCLUSION: The combination of SSH plus UTI improves lung injury and pulmonary ventilation function, and reduces inflammation and oxidative stress in patients with sepsis and ARDS.

Effect of Oxygen-Glucose Deprivation of Microglia-Derived Exosomes on Hippocampal Neurons: A Study on miR-124 and Inflammatory Cytokines.

Stroke is a cerebrovascular disease that threatens human health. Developing safe and effective drugs and finding therapeutic targets has become an urgent scientific problem. The aim of this study was to investigate the effect of oxygen-glucose deprivation of the microglia-derived exosome on hippocampal neurons and its relationship to miR-124 in the exosome. We incubated hippocampal neurons with exosomes secreted by oxygen-glucose deprivation/ reoxygenation (OGD/R) microglia. The levels of glutamic acid (GLU) and gamma-aminobutyric acid (GABA) in the culture supernatant were detected by ELISA. CCK-8 was used to measure neuronal survival rates. The mRNA levels of TNF-α and IL-6 were detected by RT-qPCR to evaluate the effect of exosomes on neurons. RT-qPCR was then used to detect miR-124 in microglia and their secreted exosomes. Finally, potential targets of miR-124 were analyzed through database retrieval, gene detection with dual luciferase reporters, and western blotting experiments. The results showed that the contents of GLU, TNF-α and IL-6 mRNA increased in the supernatant of cultured hippocampal neurons, the content of GABA decreased, and the survival rate of neurons decreased. Oxygen-glucose deprivation increases miR-124 levels in microglia and their released exosomes. miR-124 acts as a target gene on cytokine signaling suppressor molecule 1(SOCS1), while miR-124 inhibitors reduce the expression of TNF-α and IL-6 mRNA in neurons. These results suggest that oxygen- and glucose-deprived microglia regulate inflammatory cytokines leading to reduced neuronal survival, which may be achieved by miR-124 using SOCS1 as a potential target.

The Preventive Effect of Urinary Trypsin Inhibitor on Postoperative Cognitive Dysfunction, on the Aspect of Behavior, Evaluated by Y-Maze Test, via Modulation of Microglial Activity.

This experimental study was designed to evaluate the effect of ulinastatin, a urinary trypsin inhibitor, on postoperative cognitive dysfunction (POCD) in rats under general anesthesia with isoflurane, on the aspect of behavior, as evaluated using a Y-maze test and focusing on microglial activity. Ulinastatin (50,000 U/mL) and normal saline (1 mL) were randomly (1:1) administered intraperitoneally to the ulinastatin and control groups, respectively, before general anesthesia. Anesthesia with isoflurane 1.5 volume% was maintained for 2 h. The Y-maze test was used to evaluate cognitive function. Neuronal damage using caspase-1 expression, the degree of inflammation through cytokine detection, and microglial activation with differentiation of the phenotypic expression were evaluated. Twelve rats were enrolled in the study and evenly allocated into the two groups, with no dropouts from the study. The Y-maze test showed similar results in the two groups before general anesthesia (63 ± 12% in the control group vs. 64 ± 12% in the ulinastatin group, p = 0.81). However, a significant difference was observed between the two groups after general anesthesia (17 ± 24% in the control group vs. 60 ± 12% in the ulinastatin group, p = 0.006). The ulinastatin group showed significantly lower expression of caspase-1. Pro-inflammatory cytokine levels were significantly lower in the ulinastatin group than in the control group. The ulinastatin group had a significantly lower microglial activation (41.74 ± 10.56% in the control group vs. 4.77 ± 0.56% in the ulinastatin, p < 0.001), with a significantly lower activation of M1 phenotypes (52.19 ± 7.83% in the control group vs. 5.58 ± 0.76% in the ulinastatin group, p < 0.001). Administering ulinastatin before general anesthesia prevented neuronal damage and cognitive decline after general anesthesia, in terms of the aspect of behavior, as evaluated by the Y-maze test. The protective effect of ulinastatin was associated with the inhibition of microglial activation, especially the M1 phenotype.

The effect of ulinastatin on acute kidney injury in patients undergoing off-pump cardiac bypass surgery.

BACKGROUND: Ulinastatin, an anti-inflammatory and antioxidant trypsin inhibitor, has shown potential in mitigating acute kidney injury (AKI) and reducing serum creatinine levels after various surgeries. This retrospective study aimed to evaluate the effects of ulinastatin on AKI in patients undergoing off-pump coronary artery bypass (OPCAB) surgery. METHODS: We hypothesized that the administration of ulinastatin could prevent AKI in OPCAB. Electrical medical records were reviewed to identify OPCAB patients between January 2015 and June 2020. The utilization of ulinastatin was randomly determined and applied during this period. Acute kidney injury was defined according to the KDIGO guideline, and its incidence was compared between the ulinastatin administration group and the control group. To investigate the effect of ulinastatin on renal function, multivariate logistic regression analysis was used to calculate propensity scores for each group. RESULTS: A total 454 OPCAB were performed, and after following inclusion and exclusion process, 100 patients were identified in the ulinastatin group and 303 patients in the control group. Using 1:2 propensity score matching, we analyzed 100 and 200 patients in the ulinastatin and control groups. The incidence of AKI was similar between the groups (2.5% for the control group, 2.0% for the ulinastatin group, p > 0.999). However, the serum creatinine value on the first post-operative day were significantly lower in the ulinastatin group compared to the control group (0.774 ± 0.179 mg/dL vs 0.823 ± 0.216 mg/dL, P = 0.040), while no significant differences were observed for the other time points (P > 0.05). The length of ICU stay day was significantly shorter in the ulinastatin group (2.91 ± 2.81 day vs 5.22 ± 7.45 day, respectively, P < 0.001). CONCLUSIONS: Ulinastatin did not have a significant effect on the incidence of AKI; it demonstrated the ability to reduce post-operative serum creatine levels at first post-operative day and shorten the length of ICU stay.

Effects of ulinastatin combined with dexmedetomidine on cognitive dysfunction and emergence agitation in elderly patients who underwent total hip arthroplasty.

BACKGROUND: With the continuous growth of the modern elderly population, the risk of fracture increases. Hip fracture is a common type of fracture in older people. Total hip arthroplasty (THA) has significant advantages in relieving chronic pain and promoting the recovery of hip joint function. AIM: To investigate the effect of ulinastatin combined with dexmedetomidine (Dex) on the incidences of postoperative cognitive dysfunction (POCD) and emergence agitation in elderly patients who underwent THA. METHODS: A total of 397 patients who underwent THA from February 2019 to August 2022. We conducted a three-year retrospective cohort study in Shaanxi Provincial People's Hospital. Comprehensive demographic data were obtained from the electronic medical record system. We collected preoperative, intraoperative, and postoperative data. One hundred twenty-nine patients who were administered Dex during the operation were included in the Dex group. One hundred fifty patients who were intravenously injected with ulinastatin 15 min before anesthesia induction were included in the ulinastatin group. One hundred eighteen patients who were administered ulinastatin combined with Dex during the operation were included in the Dex + ulinastatin group. The patients' perioperative conditions, hemodynamic indexes, postoperative Mini-Mental State Examination (MMSE) scores, Ramsay score, incidence of POCD, and serum inflammatory cytokines were evaluated. RESULTS: There was a significant difference in the 24 h visual analogue scale score among the three groups, and the score in the Dex + ulinastatin group was the lowest (P < 0.05). Compared with the Dex and ulinastatin group, the MMSE scores of the Dex + ulinastatin group were significantly increased at 1 and 7 d after the operation (all P < 0.05). Compared with those in the Dex and ulinastatin groups, incidence of POCD, levels of serum inflammatory cytokines in the Dex + ulinastatin group were significantly decreased at 1 and 7 d after the operation (all P < 0.05). The observer's assessment of the alertness/sedation score and Ramsay score of the Dex + ulinastatin group were significantly different from those of the Dex and ulinastatin groups on the first day after the operation (all P < 0.05). CONCLUSION: Ulinastatin combined with Dex can prevent the occurrence of POCD and emergence agitation in elderly patients undergoing THA.

Integrative Multiomics Profiling Unveils the Protective Function of Ulinastatin against Dextran Sulfate Sodium-Induced Colitis.

Ulcerative colitis is an inflammatory bowel disease with multiple pathogeneses. Here, we aimed to study the therapeutic role of ulinastatin (UTI), an anti-inflammatory bioagent, and its associated mechanisms in treating colitis. Dextran sulfate sodium was administrated to induce colitis in mice, and a subgroup of colitis mice was treated with UTI. The gut barrier defect and inflammatory manifestations of colitis were determined via histological and molecular experiments. In addition, transcriptomics, metagenomics, and metabolomics were employed to explore the possible mechanisms underlying the effects of UTI. We found that UTI significantly alleviated the inflammatory manifestations and intestinal barrier damage in the mice with colitis. Transcriptome sequencing revealed a correlation between the UTI treatment and JAK-STAT signaling pathway. UTI up-regulated the expression of SOCS1, which subsequently inhibited the phosphorylation of JAK2 and STAT3, thus limiting the action of inflammatory mediators. In addition, 16S rRNA sequencing illustrated that UTI maintained a more stable intestinal flora, protecting the gut from dysbiosis in colitis. Moreover, metabolomics analysis demonstrated that UTI indeed facilitated the production of some bile acids and short-chain fatty acids, which supported intestinal homeostasis. Our data provide evidence that UTI is effective in treating colitis and support the potential use of UTI treatment for patients with ulcerative colitis.

The impact of ulinastatin on wound infection and healing in patients with burn wounds: A meta-analysis.

Burn injuries result in localised tissue damage and precipitate systemic responses; routine clinical treatments, which typically include metabolic nutritional support and anti-infection therapies, do not yield optimal outcomes. Therefore, we aimed to systematically evaluate the effects of ulinastatin on wound infection and healing in patients with burns to provide reliable evidence-based recommendations for burn treatment. An electronic search of the Web of Science, PubMed, Cochrane Library, Embase, Wanfang, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure databases, supplemented by manual searches, was conducted from database inception to October 2023 to collect randomised controlled trials (RCTs) assessing the efficacy of ulinastatin for the treatment of burns. Two researchers screened all retrieved articles according to the inclusion and exclusion criteria; the included studies were evaluated for quality, and the relevant data were extracted. Stata 17.0 software was employed for data analysis. Overall, 8 RCTs with 803 patients were included, with 404 and 399 in the ulinastatin and conventional treatment groups, respectively. The analysis revealed that wound infections (odds ratio [OR] = 0.08, 95% CI: 0.02-0.35, p = 0.001) and complications (OR = 0.21, 95% CI: 0.10-0.42, p < 0.001) were significantly lower, and wound healing time (standardised mean differences [SMD] = -1.31, 95% CI: -2.05 to -0.57, p = 0.001) was significantly shorter, in the ulinastatin groups than in the control group. This meta-analysis revealed that ulinastatin can effectively reduce the incidence of wound infections and complications and significantly shorten the duration of wound healing in patients with burns, thereby promoting early recovery in these patients.

Ulinastatin in combination with aprotinin improves systemic inflammation in patients undergoing cardiac surgery with cardiopulmonary bypass.

OBJECTIVE: To investigate the impact of ulinastatin combined with protease inhibitors on serum inflammatory factors in patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: A retrospective analysis was conducted on 86 patients who underwent cardiac surgery with cardiopulmonary bypass at Xi'an Gaoxin Hospital from May 2019 to June 2021. Based on the administration of drugs by a micro-infusion pump after anesthesia induction and before skin incision, the patients were divided into an observation group (receiving ulinastatin at a dose of 12,000 U/kg and protease inhibitors at a dose of 4 million units) with 46 cases and a control group (receiving protease inhibitors at a dose of 2 million units) with 40 cases. Peripheral blood leukocyte count, neutrophil percentage, interleukin (IL)-6, tumor necrosis factor (TNF)-α, serum creatine kinase isoenzyme (CK-MB), and serum cardiac troponin I (cTnI) levels were measured and compared between the two groups before surgery, 1 hour after surgery, and 24 hours after surgery. The positive inotropic drug usage, duration of postoperative mechanical ventilation, and incidence of complications were also compared between the two groups. Finally, an analysis was conducted to identify independent risk factors affecting patient prognosis. RESULTS: The peripheral blood white blood cell (WBC) count, neutrophil percentage, serum inflammatory factor level, CK-MB, and cTnI of the two groups of patients at 1 h and 24 h after the operation were significantly higher than those before the operation. However, the observation group had significantly lower levels of peripheral blood WBC count, neutrophil percentage, serum inflammatory factors, CK-MB, and cTnI compared to the control group (all P<0.05). Additionally, the observation group had significantly lower dopamine dosage and a shorter duration of mechanical ventilation compared to the control group (all P<0.05). The incidence of complications was lower in the observation group compared to the control group (P<0.05). TNF-α, cTnI, and treatment regimen were identified as independent risk factors associated with adverse patient prognosis. CONCLUSION: The perioperative use of ulinastatin combined with protease inhibitors in patients undergoing cardiac surgery with cardiopulmonary bypass is beneficial in suppressing systemic inflammatory response, improving cardiopulmonary function, and reducing the incidence of complications. These findings suggest its clinical utility.

Effects of ulinastatin therapy in deep vein thrombosis prevention after brain tumor surgery: A single-center randomized controlled trial.

BACKGROUND: Venous thromboembolism (VTE) is a common neurosurgical complication after brain tumor resection, and its prophylaxis has been widely studied. There are no effective drugs in the clinical management of venous thromboembolism, and there is an absence of evidence-based medicine concerning the treatment of severe multiple traumas. AIM: To explore whether ulinastatin (UTI) can prevent VTE after brain tumor resection. METHODS: The present research included patients who underwent brain tumor resection. Patients received UTIs (400,000 IU) or placebos utilizing computer-based random sequencing (in a 1:1 ratio). The primary outcome measures were the incidence of VTE, coagulation function, pulmonary emboli, liver function, renal function, and drug-related adverse effects. RESULTS: A total of 405 patients were evaluated between January 2019 and December 2021, and 361 of these were initially enrolled in the study to form intention-to-treat, which was given UTI (n = 180) or placebo (n = 181) treatment in a random manner. There were no statistically significant differences in baseline clinical data between the two groups. The incidence of VTE in the UTI group was remarkably improved compared with that in the placebo group. UTI can improve coagulation dysfunction, pulmonary emboli, liver function, and renal function. No significant difference was identified between the two groups in the side effects of UTI-induced diarrhea, vomiting, hospital stays, or hospitalization costs. The incidence of allergies was higher in the UTI group than in the placebo group. CONCLUSION: The findings from the present research indicated that UTI can decrease the incidence of VTE and clinical outcomes of patients after brain tumor resection and has fewer adverse reactions.

The role of TLR4/MyD88/NF-κB in the protective effect of ulinastatin on the intestinal mucosal barrier in mice with sepsis.

OBJECTIVE: To investigate the effect of the TLR4/MyD88/NF-κB (Toll-like receptor 4/myeloid differentiation factor/nuclear factor kappa B) signalling pathway on the protective effect of ulinastatin on the intestinal mucosal barrier in mice with sepsis. METHODS: A mouse model of sepsis was established by classical caecal ligation and perforation. Forty-four SPF C57BL/6 mice were randomly divided into the following four groups with 11 mice in each group: the control group (Con group), ulinastatin group (Uti group), Uti + LPS (lipopolysaccharide, LPS) group (Uti + LPS group) and LPS group. Mice in the Con group and Uti group received saline or ulinastatin injected 2 h after modelling; Mice in the Uti + LPS group received LPS injected 0 h after modelling, other procedures were the same as in the Uti group; Mice in the LPS group received LPS only. At 48 h after surgery, the levels of TNF-α (tumour necrosis factor-α, TNF-α), IL-6 (interleukin-6, IL-6) and IL-1ß (interleukin-1ß, IL-1ß) in vein, and the expression of TLR4, MyD88 and NF-κB mRNA in small intestinal mucosa tissues using ELISA and RT‒PCR. RESULTS: The pathological specimens showed increased inflammatory injury in the Con and LPS groups, while these injuries and changes improved in the Uti group. The scores of intestinal mucosal injury at 48 h of Uti injection were significantly lower than those of the Con group (P < 0.001), while the scores of intestinal mucosal injury of Uti + LPS were significantly higher than those of the Uti group (P = 0.044). The expression of TNF-α, IL-6 and IL-1ß in the Uti decreased significantly at 48 h after surgery than that in the Con group (P = 0.001, P = 0.014, P = 0.004), while the expression of TNF-α, IL-6 and IL-1ß in the Uti + LPS group increased significantly after surgery than that in the Uti group (P = 0.026, P = 0.040, P = 0.039). The expression of TLR4, MyD88 and NF-κB mRNA in the Uti group decreased significantly compared with that in the Con group (P = 0.001, P = 0.021, P = 0.007), while the expression of TLR4, MyD88 and NF-κB mRNA in the Uti + LPS group was higher than that in the Uti group (P = 0.023, P = 0.040, P = 0.045). CONCLUSION: These findings indicate that the protective effect of ulinastatin on the intestinal mucosal barrier against sepsis may be mediated through the TLR4/MyD88/NF-κB pathway.

Clinical Efficacy of Ulinastatin Combined with Azithromycin in the Treatment of Severe Pneumonia in Children and the Effects on Inflammatory Cytokines and Oxidative Stress: A Retrospective Cohort Study.

Purpose: This retrospective cohort study aimed to evaluate the clinical efficacy of ulinastatin (UTI) and azithromycin (AZM) combination therapy in treating severe pneumonia in children and its impact on inflammatory cytokines and oxidative stress. Patients and Methods: This retrospective cohort study was conducted from January 1, 2019, to January 1, 2021, involving pediatric patients diagnosed with severe mycoplasma pneumonia (SMPP). The pediatric patients were divided into two groups: those receiving UTI and AZM combination therapy (treatment group) and those receiving azithromycin alone (control group). We compared the two groups regarding clinical data, disease outcomes, inflammatory cytokines, and oxidative stress levels. Results: Baseline characteristics did not significantly differ between the two groups. UTI, in combination with AZM, significantly improved blood oxygen levels, inflammatory infection markers, and relevant clinical symptoms in patients with SMPP on the 3rd day of treatment. Additionally, it significantly reduced the levels of inflammatory cytokines TNF-a, IL-6, IL-1ß, and IL-10, as well as oxidative stress markers GSH and SOD. Conclusion: Combining UTI and AZM can rapidly alleviate clinical symptoms and effectively control the progression of patients with SMPP. Therefore, this treatment approach deserves consideration for clinical promotion and utilization.

Ulinastatin ameliorates podocyte ferroptosis via regulating miR-144-3p/SLC7A11 axis in acute kidney injury.

Ferroptosis is a newly discovered form of cell death characterized by intracellular iron accumulation and subsequent lipid peroxidation, which has been identified in various pathological processes, such as acute kidney injury (AKI). Ulinastatin (UTI), known as an antioxidant and anti-inflammatory, has been reported to prevent kidney injury. Here, we investigated the protective effects of UTI on LPS-induced podocyte ferroptosis in vivo and in vitro. Conditionally immortalized mouse podocyte was exposed to LPS in the presence or absence of UTI in vitro for 48 h. The levels of reactive oxygen species (ROS) and intracellular Fe2+ were detected to value the effect of UTI treatment on the podocyte cell ferroptosis. We also evaluated the influence of UTI on kidney injury in vivo. LPS-induced mice were treated with vehicle or UTI at 50 U/g/d for 6 wk. We identified the important function of UTI in repressing ferroptosis and ameliorating podocyte injury. The treatment of UTI reduced accumulation of Fe2+ and lipid ROS in podocyte. The cell proliferation was induced by UTI compared with the LPS-treated group in vitro. UTI attenuated the podocyte cytoskeletal as well. Regarding the mechanism, we found that UTI upregulated solute carrier family 7 member 11 (SLC7A11) expression by reducing miR-144-3p in the cells. The overexpression of miR-144-3p blocked the protective role of UTI in podocyte ferroptosis. MiR-144-3p/SLC7A11 axis was involved in UTI-mediated podocyte cell proliferation in vitro. Furthermore, the treatment of UTI repressed podocyte injury and proteinuria in vivo, and the level of miR-144-3p was decreased while SLC7A11 expression was increased in comparison with the model mice. UTI prevents LPS-induced podocyte ferroptosis and subsequent renal dysfunction through miR-144-3p/SLC7A11 axis. These findings might provide a potential novel therapeutic option for AKI and other renal diseases affecting podocyte.

Ulinastatin combined with somatostatin enhances disease control and modulates serum inflammatory factors in patients with severe pancreatitis.

OBJECTIVE: This study was designed to explore the effects of ulinastatin combined with somatostatin on disease control and serum inflammatory factors in patients with severe pancreatitis. METHODS: The data of 80 patients with severe pancreatitis treated in the First Affiliated Hospital of Jiangxi Medical College from May 2020 to April 2022 were analyzed retrospectively. Among them, 36 patients treated with somatostatin alone (3 mg somatostatin added in 50 mL normal saline) on the basis of standard treatment were assigned to a control group, and the other 44 patients treated with both ulinastatin (100,000 U of ulinastatin injection added in 250 mL 5% glucose solution) and somatostatin (3 mg somatostatin added in 50 mL normal saline) were enrolled into a study group. The levels of serum inflammatory factors (interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and soluble intercellular adhesion molecule-1 (sICAM-1)), biochemical indexes (C-reactive protein, white blood cell count, and serum amylase) and gastrointestinal function indexes (motilin and gastrin) in the two groups were analyzed and compared before and after treatment. Additionally, the alleviation of clinical symptoms, treatment response and occurrence of adverse reactions were compared between the two groups. The mortality rate of patients within 1 month after the treatment was evaluated, and the risk factors affecting the prognosis were analyzed through logistics regression. RESULTS: Before treatment, there was no significant difference between the two groups in the levels of IL-1ß, IL-6 and sICAM-1 (P>0.05), while after treatment, the levels of all three factors decreased significantly in both groups (P<0.0001), with more notable decreases in the study group than those in the control group (P<0.0001). Before treatment, the two groups were not significantly different in the levels of C-reactive protein, white blood cell count, and serum amylase (P>0.05), while after treatment, all the three levels decreased notably in both groups (P<0.0001), with notably lower levels in the study group than those in the control group (P<0.0001). Before treatment, the levels of motilin and gastrin in the two groups were not significantly different (P>0.05), while after treatment, motilin increased significantly and gastrin decreased significantly in both groups (P<0.0001), and the study group showed a notably higher motilin level and a notably lower gastrin level than the control group (P<0.0001). The study group experienced a significantly earlier disappearance time of abdominal distension and abdominal pain and a significantly shorter hospitalization time than the control group (P<0.0001). Moreover, the study group showed a notably higher overall response rate than the control group (P=0.029), and presented a notably lower incidence of adverse reactions than the control group (P=0.036). According to univariate analysis, age, onset time, Acute Physiology and Chronic Health Evaluation II score and therapeutic regimen were the factors impacting the patients' prognosis. According to logistics regression analysis, therapeutic regimen was an independent risk factor affecting the prognosis. CONCLUSION: Compared with somatostatin alone, ulinastatin combined with somatostatin is more effective in the treatment of severe pancreatitis. The combination can substantially alleviate the inflammatory response and improve the gastrointestinal function and clinical symptoms of patients, without increasing adverse reactions. Therefore, ulinastatin combined with somatostatin is worthy of clinical promotion.

Expression of Angiopoietin-2 in Lung Tissue of Juvenile SD Rats with Lipopolysaccharide-Induced Acute Lung Injury and the Role of Ulinastatin.

This study aimed to observe the expression of angiopoietin-2 (Ang-2) in the lung tissue of juvenile SD rats with lipopolysaccharide (LPS)-induced acute lung injury (ALI) and to clarify the role of ulinastatin (UTI). Ninety 18-21-day-old juvenile SD male rats were randomly divided into five groups (n = 18). ALI rat model was established by intraperitoneal injection of LPS (LPS 10 mg/kg), while the control group was given the same dose of normal saline. The UTI intervention group was given the injection of UTI (5000 U/mL) immediately after the injection of LPS, which was divided into UTI low-dose group (LPS + 5 ml/kg UTI), UTI medium-dose group (LPS + 10 ml/kg UTI), and UTI high-dose group (LPS + 20 ml/kg UTI).The respiratory status of each group of rats was observed, and six rats were randomly selected to be killed in each group at 6, 12, and 24 h, and the lung tissues were dissected and retained. The pathological changes of the lung tissues were observed by hematoxylin-eosin (HE) staining, the expression levels and locations of Ang-2 and vascular endothelial growth factor (VEGF) in lung tissue were observed by immunohistochemical staining, and the expressions of genes and proteins of Ang-2 and VEGF were detected by quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. Three hours after intraperitoneal injection, rats in the model group developed shortness of breath and the developed respiratory distress progressed over time. The lung pathological changes in the model group were obvious compared with those in the control group, and gradually worsened with time, and the pathological changes of lung in the rats in the UTI intervention group were reduced compared with those in the model group. At different time points, the expressions of Ang-2 and VEGF in the lung tissue of rats in the model group were higher than those in the control group, and were lower in the UTI intervention group than those in the model group. The expressions of Ang-2 and VEGF protein were lower in the low-dose group of UTI group than those in the high-dose group of UTI group at different time points (P < 0.05), and the expressions of Ang-2 and VEGF protein in the low-dose group of UTI were significantly lower than those in the medium-dose group at 12 h and 24 h (P < 0.05). The expression of Ang-2 was increased in the lung tissue of juvenile SD rats with LPS-induced ALI, and was associated with the degree of lung injury. UTI might attenuate LPS-induced ALI by inhibiting the expression of Ang-2 in lung tissue, and the low dose was more obvious than the medium and high dose.

Ulinastatin inhibits the metastasis of nasopharyngeal carcinoma by involving uPA/uPAR signaling.

Distant metastasis is the primary reason for treatment failure in patients with nasopharyngeal carcinoma (NPC). In this study, we investigated the effect of ulinastatin (UTI) on NPC metastasis and its underlying mechanism. Highly-metastatic NPC cell lines S18 and 58F were treated with UTI and the effect on cell proliferation, migration, and invasion were determined by MTS and Transwell assays. S18 cells with luciferase-expressing (S18-1C3) were injected into the left hind footpad of nude mice to establish a model of spontaneous metastasis from the footpad to popliteal lymph node (LN). The luciferase messenger RNA (mRNA) was measured by quantitative polymerase chain reaction (qPCR), and the metastasis inhibition rate was calculated. Key molecular members of the UTI-related uPA, uPAR, and JAT/STAT3 signaling pathways were detected by qPCR and immunoblotting. UTI suppressed the migration and infiltration of S18 and 5-8F cells and suppressed the metastasis of S18 cells in vivo without affecting cell proliferation. uPAR expression decreased from 24 to 48 h after UTI treatment. The antimetastatic effect of UTI is partly due to the suppression of uPA and uPAR. UTI partially suppresses NPC metastasis by downregulating the expression of uPA and uPAR.

Ulinastatin ameliorated streptozotocin-induced diabetic nephropathy: Potential effects via modulating the components of gut-kidney axis and restoring mitochondrial homeostasis.

Growing evidence supports the role of the gut-kidney axis and persistent mitochondrial dysfunction in the pathogenesis of diabetic nephropathy (DN). Ulinastatin (UTI) has a potent anti-inflammatory effect, protecting the kidney and the gut barrier in sepsis, but its effect on DN has yet to be investigated. This study aimed to assess the potential mitigating effect of UTI on DN and investigate the possible involvement of gut-kidney axis and mitochondrial homeostasis in this effect. Forty male Wistar rats were divided equally into four groups: normal; UTI-treated control; untreated DN; and UTI-treated DN. At the end of the experiment, UTI ameliorated DN by modulating the gut-kidney axis as it improved serum and urinary creatinine, urine volume, creatinine clearance, blood urea nitrogen, urinary albumin, intestinal morphology including villus height, crypt depth, and number of goblet cells, with upregulating the expression of intestinal tight-junction protein claudin-1, and counteracting kidney changes as indicated by significantly decreasing glomerular tuft area and periglomerular and peritubular collagen deposition. In addition, it significantly reduced intestinal and renal nuclear factor kappa B (NF-κB), serum Complement 5a (C5a), renal monocyte chemoattractant protein-1 (MCP-1), renal intercellular adhesion molecule 1 (ICAM1), and renal signal transducer and activator of transcription 3 (STAT3), mitochondrial dynamin related protein 1 (Drp1), mitochondrial fission 1 protein (FIS1), mitochondrial reactive oxygen species (ROS), renal hydrogen peroxide (H2O2), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels. Furthermore, it significantly increased serum short chain fatty acids (SCFAs), and mitochondrial ATP levels and mitochondrial transmembrane potential. Moreover, there were significant correlations between measured markers of gut components of the gut-kidney axis and renal function tests in UTI-treated DN group. In conclusion, UTI has a promising therapeutic effect on DN by modulating the gut-kidney axis and improving renal mitochondrial dynamics and redox equilibrium.

Ulinastatin in the treatment of severe acute pancreatitis: A single-center randomized controlled trial.

BACKGROUND: Severe acute pancreatitis (AP) is one of the most common diseases of the gastrointestinal tract and carries a significant financial burden with high disability and mortality. There are no effective drugs in the clinical management of severe AP, and there is an absence of evidence-based medicine concerning the treatment of severe AP. AIM: To explore whether ulinastatin (UTI) can improve the outcome of severe AP. METHODS: The present research included patients who were hospitalized in intensive critical care units (ICUs) after being diagnosed with severe AP. Patients received UTI (400000 IU) or placebos utilizing computer-based random sequencing (in a 1:1 ratio). The primary outcome measures were 7-d mortality, clinical efficacy, inflammatory response, coagulation function, infection, liver function, renal function, and drug-related adverse effects were evaluated. RESULTS: A total of 181 individuals were classified into two groups, namely, the placebo group (n = 90) and the UTI group (n = 91). There were no statistically significant differences in baseline clinical data between the two groups. The 7-d mortality and clinical efficacy in the UTI group were remarkably improved compared with those in the placebo group. UTI can protect against hyperinflammation and improve coagulation dysfunction, infection, liver function, and renal function. UTI patients had markedly decreased hospital stays and hospitalization expenditures compared with the placebo group. CONCLUSION: The findings from the present research indicated that UTI can improve the clinical outcomes of patients with severe AP and has fewer adverse reactions.