• Antioxidant Defense
• Curcumin
• Heat Stroke Treatment
• Hypothalamus Nerve Injury
• PAMAM Nanoparticles

• Curcumin/pharmacology
• Curcumin/chemistry
• Animals
• Heat Stroke/drug therapy
• Mice
• Nanoparticles/chemistry
• Male
• Blood-Brain Barrier/metabolism
• Blood-Brain Barrier/drug effects
• Disease Models, Animal
• Drug Carriers/chemistry
• Dendrimers/chemistry
• Dendrimers/pharmacology
• Brain/metabolism
• Brain/drug effects
• Cell Line
• Polyamines

• TSYC202301B146 "Tianshan Talents" high-level medical and health talent training program
• TSYC202301B146 "Tianshan Talents" high-level medical and health talent training program
• TSYC202301B146 "Tianshan Talents" high-level medical and health talent training program

• Animals
• Apoptosis
• Calcium/metabolism
• Caspase 3/metabolism
• Catechin/analogs & derivatives
• Glutamic Acid/metabolism
• Hippocalcin/genetics
• Hippocalcin/metabolism
• Infarction, Middle Cerebral Artery/complications
• Infarction, Middle Cerebral Artery/drug therapy
• Ischemic Stroke/metabolism
• Neurons/metabolism
• Neuroprotective Agents/pharmacology
• Neuroprotective Agents/therapeutic use
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Disease Models, Animal

• National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)

• Apoptosis
• Brain injury
• Calcitonin gene-related peptide
• Heatstroke

• Animals
• Rats
• Apoptosis
• Brain Injuries/metabolism
• Brain Injuries/pathology
• Calcitonin Gene-Related Peptide/pharmacology
• Calcitonin Gene-Related Peptide/metabolism
• Caspase 3
• Isoquinolines
• Proto-Oncogene Proteins c-bcl-2
• Rats, Sprague-Dawley
• Sulfonamides
• Heat Stroke/metabolism
• Heat Stroke/pathology

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.

To explore whether ulinastatin (UTI) can prevent VTE after brain tumor resection.

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.

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.

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.

• Ulinastatin
• Venous thromboembolism
• Brain tumor resection
• Randomized control trial
• Outcome

• Heat stress
• Heatstroke
• Intestine epithelial cells
• Necroptosis
• P53

• Mice
• Animals
• Toll-Like Receptor 3/metabolism
• Necroptosis
• Tumor Suppressor Protein p53/genetics
• Mice, Inbred C57BL
• Epithelial Cells/metabolism
• Intestines
• Mice, Knockout
• Heat Stroke
• Heat-Shock Response
• Adaptor Proteins, Vesicular Transport/metabolism
• Receptor-Interacting Protein Serine-Threonine Kinases/genetics
• Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
• Apoptosis

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.

To explore whether ulinastatin (UTI) can improve the outcome of severe AP.

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.

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.

The findings from the present research indicated that UTI can improve the clinical outcomes of patients with severe AP and has fewer adverse reactions.

• Ulinastatin
• 7-day mortality
• Severe acute pancreatitis
• Randomized controlled trial
• Outcome

• AQP4
• Brain injury
• Cell apoptosis
• Heat acclimation
• Proteomics
• Rat model

• 30-day mortality
• outcome
• rct
• severe multiple traumas
• ulinastatin

• Humans
• Multiple Organ Failure/drug therapy
• Multiple Organ Failure/etiology
• Glycoproteins/therapeutic use
• Urinary Tract Infections/drug therapy
• Multiple Trauma
• Double-Blind Method

Brain injury is the main cause of poor prognosis in heatstroke (HS) patients due to heat-stress-induced neuronal apoptosis. However, as a new cross-talk way among cells, whether microglial exosomal-microRNAs (miRNAs) are involved in HS-induced neuron apoptosis has not been elucidated.

We established a heatstroke mouse model and a heat-stressed neuronal cellular model on HT22 cell line. Then, we detected neuron apoptosis by histopathology and flow cytometry. The microglial exosomes are isolated by standard differential ultracentrifugation and characterized. Recipient neurons are treated with the control and HS exosomes, whereas in vivo, the exosomes were injected into the mice tail vein. The internalization of HS microglial exosomes by neurons was tracked. Apoptosis of HT22 was evaluated by flow cytometry and Western blot in vitro, TUNEL assay, and immunohistochemistry in vivo. We screened miR-466i-5p as the mostly upregulated microRNAs in HS exosomes by high-throughput sequencing and further conducted gene ontology (GO) pathway analysis. The effect and mechanism of HS exosomal miR-466i-5p on the induction of neuron apoptosis are demonstrated by nasal delivery of miR-466i-5p antagomir in vivo and transfecting miR-466i-5p mimics to HT22 in vitro.

HS induced an increase in neurons apoptosis. Microglial exosomes are identified and taken up by neurons, which induced HT22 apoptosis in vivo and vitro. HS significantly changed the miRNA profiles of microglial exosomes based on high-throughput sequencing. We selected miR-466i-5p as a target, and upregulated miR-466i-5p induced neurons apoptosis in vivo and vitro experiments. The effects are exerted by targeting Bcl-2, activating caspase-3 to induce neurons apoptosis.

We demonstrate the effect of microglial exosomal miR-466i-5p on neurons apoptosis and reveal potentially Bcl-2/caspase-3 pathway in heatstroke.

• Animals
• Mice
• Apoptosis/genetics
• Brain Injuries/pathology
• Caspase 3/metabolism
• Heat Stroke/genetics
• Hippocampus/metabolism
• Microglia/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neurons/metabolism
• Proto-Oncogene Proteins c-bcl-2/metabolism

• Natural Science Foundation of Guangdong Province

Spontaneous intracerebral hemorrhage (ICH) is still a major public health problem, with high mortality and disability. Ulinastatin (UTI) was purified from human urine and has been reported to be anti-inflammatory, organ protective, and antioxidative stress. However, the neuroprotection of UTI in ICH has not been confirmed, and the potential mechanism is unclear. In the present study, we aimed to investigate the neuroprotection and potential molecular mechanisms of UTI in ICH-induced early brain injury in a C57BL/6 mouse model.

The neurological score, brain water content, neuroinflammatory cytokine levels, oxidative stress levels, and neuronal damage were evaluated.

UTI treatment markedly increased the neurological score, alleviated brain edema, decreased the levels of the inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and NF-κB, decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and upregulated the levels of glutathione (GSH), superoxide dismutase (SOD), and Nrf2. This finding indicated that UTI-mediated inhibition of neuroinflammation and oxidative stress alleviated neuronal damage after ICH. The neuroprotective capacity of UTI is partly dependent on the ROS/MAPK/Nrf2 signaling pathway.

UTI improves neurological outcomes in mice and reduces neuronal death by protecting against neural neuroinflammation and oxidative stress.

Spontaneous intracerebral hemorrhage (ICH) is a major public health problem with a huge economic burden worldwide. Ulinastatin (UTI), a serine protease inhibitor, has been reported to be anti-inflammatory, immune regulation, and organ protection by reducing reactive oxygen species production, and inflammation. Necroptosis is a programmed cell death mechanism that plays a vital role in neuronal cell death after ICH. However, the neuroprotection of UTI in ICH has not been confirmed, and the potential mechanism is unclear. The present study aimed to investigate the neuroprotection and potential molecular mechanisms of UTI in ICH-induced EBI in a C57BL/6 mouse model.

The neurological score, brain water content, neuroinflammatory cytokine levels, and neuronal damage were evaluated. The anti-inflammation effectiveness of UTI in ICH patients also was evaluated.

UTI treatment markedly increased the neurological score, alleviate the brain edema, decreased the inflammatory cytokine TNF-α, interleukin‑1β (IL‑1β), IL‑6, NF‑κB levels, and RIP1/RIP3, which indicated that UTI-mediated inhibition of neuroinflammation, and necroptosis alleviated neuronal damage after ICH. UTI also can decrease the inflammatory cytokine of ICH patients. The neuroprotective capacity of UTI is partly dependent on the MAPK/NF-κB signaling pathway.

UTI improves neurological outcomes in mice and reduces neuronal death by protecting against neural neuroinflammation, and necroptosis.

Traumatic brain injury (TBI) remains a major public health problem and cause of death. Ulinastatin (UTI), a serine protease inhibitor, has been reported to have an anti-inflammatory effect and play a role in immunoregulation and organ protection by reducing reactive oxygen species (ROS) production, oxidative stress and inflammation. However, the neuroprotective of UTI in TBI has not been confirmed. Therefore, this study aimed to investigate the neuroprotection and potential molecular mechanisms of UTI in TBI-induced EBI in a C57BL/6 mouse model.

The neurological score and brain water content were evaluated. Enzyme-linked immunosorbent assay was used to detect neuroinflammatory cytokine levels, ROS and malondialdehyde detection to evaluate oxidative stress levels, and TUNEL staining and western blotting to examine neuronal damages and their related mechanisms.

Treatment with UTI markedly increased the neurological score; alleviated brain oedema; decreased the inflammatory cytokine tumour necrosis factor a, interleukin-1β (IL-1β), IL-6 and nuclear factor kappa B (NF-kB) levels; inhibited oxidative stress; decreased caspase-3 and Bax protein expressions; and increased the Bcl-2 levels, indicating that UTI-mediated inhibition of neuroinflammation, oxidative stress and apoptosis ameliorated neuronal death after TBI. The neuroprotective capacity of UTI is partly dependent on the TLR4/NF-kB/p65 signalling pathway.

Therefore, this study reveals that UTI improves neurological outcomes in mice and reduces neuronal death by protecting against neural neuroinflammation, oxidative stress and apoptosis.

• Ca2+
• apoptosis
• endoplasmic reticulum stress
• heat stress

Gut microbiome, as the largest and most important micro-ecosystem, plays a critical role in health. The purpose of this study was to evaluate whether heat stress modulates the composition and diversity of the gut microbiome in rats. The heat stress model was prepared in rats with the heating temperature maintained at 35–38°C. Cecum contents were collected after heat stress for 3 h and days 1, 3 and 7. Total DNA was extracted for 16 S rRNA sequencing and analysis of intestinal microbiome composition and diversity. The study showed that the composition of the intestinal microbiome of heat stress group was changed. And the heat stress modulated key phylotypes of gut microbiota at the level of phylum and genus. In particular, the genus of Lactobacillus and Bacteroides were significantly reduced, whereas the Oscillospira and Clostridium were increased by heat stress. Meanwhile, the rats under the heat stress encountered the change in carbohydrate metabolism, amino acid metabolism, and membrane transport to defense against stress. Taken together, the composition and structure of gut microbiome were affected by heat stress and some key phylotypes were also significantly altered. We conclude that the heat stress could impact multiple biological functions, via altering the gut microbiome.

• Gut microbiome
• Heat stress
• Metabolism
• Rats

Background: Exertional heat stroke (EHS) is a life-threatening injury that can lead to acute kidney injury (AKI). The clinical characteristics of and risk factors for EHS complicated with AKI have been poorly documented.

Methods: A retrospective study with EHS admitted to the intensive care unit (ICU) from January 2008 to June 2019 was performed. Data including baseline clinical information at admission, main organ dysfunction, 90-day mortality and total cost of hospitalization were collected.

Results: A total of 187 patients were finally included, of which 82 (43.9%) had AKI. AKI patients had more severe organ injury and higher total hospitalization costs than non-AKI patients. Multivariate logistic analysis showed that lymphocyte, neutrophil, D-dimer and myoglobin (MB) ≥ 1,000 ng/ml were independent risk factors for AKI caused by EHS. In addition, SOFA score [hazard ratio (HR) 4.1, 95% confidence interval (95% CI) 1.6–10.8, P = 0.004] and GCS score (HR 3.2, 95% CI 1.2–8.4 P = 0.017) were the risk factor for 90-day mortality in patients with EHS complicated with AKI, with an area under the curve (AUC) of 0.920 (95% CI 0.842–0.998, P < 0.001) and 0.851 (95% CI 0.739–0.962, P < 0.001), respectively. Survival analysis showed that the 90-day mortality in AKI patients was significantly high (P < 0.0001) and the mortality rate of patients with AKI stage 2 was the highest than other stages.

Conclusions: EHS complicated with AKI is associated with higher hospitalization costs and poorly clinical outcomes. MB ≥1,000 ng/ml, Inflammation, coagulation were associated with the occurrence and development of AKI. Early treatment strategies based reducing the SOFA and GCS score may be pivotal for improving the prognosis of EHS.

• SOFA
• acute kidney injury
• heatstroke
• mortality
• risk factors

Heatstroke is a life-threatening illness that is characterised by a core body temperature >40^°C and central nervous system dysfunction. Acute kidney injury (AKI) is a common complication of heatstroke, and the mitochondrial apoptotic pathway has been demonstrated to be one of the leading causes of tissue damage and cell death in AKI. Curcumin is a phenol that is extracted from turmeric and demonstrates anti-apoptotic properties. To test if curcumin can protect the kidney from injury caused by heat stress, the effect of curcumin administration on renal injury and apoptosis of renal tissue was examined in a rat model of dry-heat environment. A total of 50 Sprague-Dawley rats were randomly divided into five groups (n=10): Standard temperature control, dry-heat control and curcumin treatment groups (50, 100 and 200 mg/kg groups). After exposure to a dry-heat environment for 150 min, the rats were anesthetized and euthanized. Blood, urine and renal tissue were collected to quantify the expression of specific mitochondrial apoptosis-related molecules. Curcumin pre-treatment decreased blood urea nitrogen and serum creatinine, urinary kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin levels compared with the dry-heat control group. Curcumin was also revealed to downregulate c-Jun N-terminal kinases (JNK), cytochrome c, caspase-3 and caspase-9 expression upon treatment with 100 and 200 mg/kg curcumin, which may result in inhibition of the mitochondrial apoptotic pathway in renal cells. The current study revealed that Curcumin may to have potential for preventing heatstroke-induced AKI.

• acute kidney injury
• curcumin
• heatstroke
• mitochondrial apoptotic pathway
• rat model

• Cardiac fibroblasts
• Dual specificity phosphatase 1
• Inflammatory mediators
• Rolipram
• Sepsis induced cardiomyopathy

• Animals
• Anti-Inflammatory Agents/pharmacology
• Cardiomyopathies/etiology
• Cardiomyopathies/metabolism
• Cardiomyopathies/physiopathology
• Cardiomyopathies/prevention & control
• Cells, Cultured
• Cytokines/genetics
• Cytokines/metabolism
• Disease Models, Animal
• Dual Specificity Phosphatase 1/genetics
• Dual Specificity Phosphatase 1/metabolism
• Endotoxemia/complications
• Endotoxemia/drug therapy
• Endotoxemia/metabolism
• Fibroblasts/drug effects
• Fibroblasts/metabolism
• Inflammation Mediators/metabolism
• Male
• Mice, Inbred C57BL
• Rolipram/pharmacology
• Signal Transduction
• Stroke Volume/drug effects
• Ventricular Function, Left/drug effects

• 81571940; 81741125 National Natural Science Foundation of China