The changes of the peripheral CD4+ lymphocytes and inflammatory cytokines in Patients with COVID-19.

To investigate the clinical value of changes in the subtypes of peripheral blood lymphocytes and levels of inflammatory cytokines in patients with COVID-19, the total numbers of lymphocytes and CD4+ lymphocytes and the ratio of CD4+/CD8+ lymphocytes were calculated and observed in different groups of patients with COVID-19. The results show that the lymphocytopenia in patients with COVID-19 was mainly manifested by decreases in the CD4+ T lymphocyte number and the CD4+/CD8+ ratio. The decreased number of CD4+ T lymphocytes and the elevated levels of TNF-α and IL-6 were correlated with the severity of COVID-19 disease.

Discovery of Novel Aryl Carboxamide Derivatives as Hypoxia-Inducible Factor 1α Signaling Inhibitors with Potent Activities of Anticancer Metastasis.

In order to discover novel hypoxia-inducible factor 1 (HIF-1) inhibitors for the cancer metastasis treatment, 68 new aryl carboxamide compounds were synthesized and evaluated for their inhibitory effect by dual luciferase-reporter assay. Based on five rounds of investigation on structure-activity relationships step by step, compound 30m was discovered as the most active inhibitor (IC50 = 0.32 µM) with no obvious cytotoxicity (CC50 > 50 µM). It effectively attenuated hypoxia-induced HIF-1α protein accumulation and reduced transcription of vascular epidermal growth factor in a dose-dependent manner, which was further demonstrated by its inhibitory potency on capillary-like tube formation, angiogenesis of zebrafish as well as cellular migration and invasion. Importantly, compound 30m exhibited antimetastatic potency in breast cancer lung metastasis in the mice model, indicating its promising therapeutic potential for prevention and treatment of tumor metastasis. These results definitely merit attention for further rational design of more efficient HIF-1 inhibitors in the future.

Anti-inflammatory and organ protective effect of insulin in scalded MODS rats without controlling hyperglycemia.

BACKGROUND: Insulin, as an anti-inflammatory drug, could not be freely used in patients who experienced trauma according to the degree of inflammation, because of the side effect of hypoglycemia. In vivo experimental evidence is lacking concerning whether the effect is dosage dependent and whether it relies on controlling hyperglycemia. METHODS: By adjusting the dosage ratio of glucose and insulin, different dosages of insulin were used to treat severely scalded MODS rats to achieve uncontrolled or controlled hyperglycemia. One hundred forty rats with severe scalded were randomly divided into a hyperglycemia-controlled group, hyperglycemia-uncontrolled group, and control group. The levels of inflammation response indexes and major organ dysfunction indexes were measured and compared between groups. RESULTS: The blood indexes of inflammatory response and major organ dysfunction did not show statistical difference between hyperglycemia-controlled groups (A) and uncontrolled groups (B) in the same dosage of insulin (all P>0.05). The blood indexes of inflammatory response and major organ dysfunction demonstrated statistical difference in different dosages of insulin with hyperglycemia-controlled groups (A1-A3 groups) and hyperglycemia-uncontrolled groups (B1-B3 groups) (all P<0.01). The higher dosage of insulin, the better effect of anti-inflammation and organ protection it would demonstrate with or without controlling hyperglycemia. CONCLUSIONS: The effect of anti-inflammation and organ protection of insulin is dosage dependent in vivo; it does not rely on controlling hyperglycemia. Temporary traumatic hyperglycemia itself might not be detrimental to the body. Adjusting the ratio of insulin and glucose could provide a novel train of thought for freely treating patients with severe traumatic injury with different dosages of insulin according to the degree of inflammation.

Clinical application of a novel diagnostic scheme including pancreatic ß­cell dysfunction for traumatic multiple organ dysfunction syndrome.

A novel diagnostic scheme that includes pancreatic ß­cell dysfunction analysis for the diagnosis of traumatic multiple organ dysfunction syndrome (MODS) was investigated to assist in the early diagnosis and detection of MODS. Early intervention and treatment of MODS has been associated with a reduced mortality rate. A total of 2,876 trauma patients (including patients post­major surgery) were admitted to the intensive care unit of the authors' hospital between December 2010 and December 2015 and enrolled in the present study. There were 205 cases where the patient succumbed to their injuries. In addition to the conventional diagnostic scheme for traumatic MODS, indexes of pancreatic ß­cell dysfunction [fasting blood­glucose (FBG), homeostatic model assessment­ß and (blood insulin concentration 30 min following glucose loading­fasting insulin concentration)/(blood glucose concentration 30 min following glucose loading­FBG concentration)] were included to establish an improved diagnostic scheme for traumatic MODS. The novel scheme was subsequently used in clinical practice alongside the conventional scheme and its effect was evaluated. The novel scheme had a significantly higher positive number of MODS diagnoses for all trauma patients compared with the conventional scheme (12.48 vs. 8.87%; P<0.01). No significant difference was identified in the final percentage of positive of MODS diagnoses for trauma­associated mortality patients between the novel (88.30%) and the conventional scheme (86.34%). The novel scheme had a significantly higher positive number of MODS diagnoses for trauma­associated mortality patients 3 days prior to patients succumbing to MODS compared with the conventional scheme (80.98 vs. 64.39%; P<0.01). The consensus of the MODS diagnosis of all trauma patients between the novel scheme and the conventional scheme was 100%; however, out of the patients diagnosed as positive by novel scheme 71.03% were positive by the conventional scheme. The consensus between the final MODS diagnosis and the MODS diagnosis 3 days prior to patients succumbing to their injuries between the novel scheme and the conventional scheme was 100%; however, out of the patients diagnosed as positive by novel scheme 97.79 were positive by the conventional scheme of the 205 patients who succumbed to MODS and out of the patients diagnosed as positive for MODS by novel scheme 3 days prior to succumbing, 79.52% were positive by the conventional scheme. The results of the present study demonstrated that the novel diagnostic scheme using the relevant indexes of pancreatic ß­cell dysfunction for diagnosis of traumatic MODS, was able to diagnose MODS early without excessively extending the diagnostic scope. Its clinical application should be promoted.

Effects of insulin combined with ethyl pyruvate on inflammatory response and oxidative stress in multiple-organ dysfunction syndrome rats with severe burns.

BACKGROUND: Inflammation response and oxidative stress promote the occurrence and development of multiple-organ dysfunction syndrome (MODS). METHODS: Eighty MODS rats with third-degree burns were divided randomly into 4 groups: insulin, ethyl pyruvate (EP), insulin combined with EP, and control. Blood levels of glucose, alanine aminotransferase (ALT), creatine (CRE), creatine kinase (CK), tumor necrosis factor α (TNF-α), high-mobility group box 1 (HMGB-1), malondialdehyde (MDA), and total antioxidant capacity (TAC) before as well as 1, 3, 5, and 7 days after burns were measured. RESULTS: Blood levels of ALT, CRE, CK, TNF-α, HMGB-1, and MDA in INS, EP, and INS+EP groups at different time points were significantly lower, and TAC was significantly higher than that in the control group (C) (P<.01). These parameters in the INS+EP group were significantly lower, and TAC was significantly higher than that in INS and EP groups (P<.01). Blood levels of TNF-α, HMGB-1, and TAC in the INS group at different time points after burns were significantly lower, and MDA was significantly higher than that in the EP group (P<.01). CONCLUSIONS: Insulin combined with EP can effectively reduce the inflammatory response, oxidative stress, and main organ dysfunctions in MODS rats after severe burns. The therapeutic effect of insulin combined with EP is superior to single-agent treatment. The insulin anti-inflammatory effect is better than that of pyruvic acid ethyl ester, and the ethyl pyruvate antioxidation effect is better than that of insulin. The insulin can treat inflammation, whereas EP can reduce oxidative stress in MODS rats.

Protective effect of glucose-insulin-potassium (GIK) on intestinal tissues after severe burn in experimental rats.

Intestinal barrier damage after scald and burns, other trauma or major operations result in severe intestinal infections that cause serious consequences. Therefore, it is important to develop methods to protect intestinal barrier after severe burns. This study used rats that had full-thickness burn of approximately 30% of the total body surface area to investigate the effect and mechanism of glucose-insulin-potassium (GIK) and provide experimental evidence for application of GIK in protecting the intestine after burns or other trauma and major surgeries. The results show that the degree of intestinal damage and plasma diamine oxidase (DAO) levels in GIK (the concentrations of glucose, insulin, sodium chloride and potassium chloride were 100 g l(-1), 70 U l(-1), 9 g l(-1) and 5 g l(-1), respectively) and insulin (30 IU l(-1)) treatment groups were significantly lower than that in control group; the status of anti-inflammatory and pro-inflammatory cytokines and the ratio between them in GIK and insulin groups also significantly improved compared to those in control group; intestinal tumour necrosis factor-alpha (TNFα), nuclear factor-kappaB (NF-κB) and interleukin-10 (IL-10) messenger RNA (mRNA) expression and IL10/TNFα in GIK and insulin groups 2 days after the injury were also improved significantly compared to those in control group. All the indices including body weight detected in GIK group were improved to those in insulin group. Taken together, these results show that GIK and insulin show protective effect on intestine after severe burn, which may relate to controlling hyperglycaemia and regulating intestinal expression of NFκB and pro-inflammatory and anti-inflammatory cytokine genes by GIK and insulin; the protective effect of GIK on intestinal tissue after severe burn is superior to that of using insulin alone, which may attribute to improving the nutritional status by glucose supplement and the relatively higher dose of insulin in the GIK group.