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Immune checkpoint inhibitors can enhance the anti-tumor effect of T cells by blocking the negative regulatory signal of T cells, and meanwhile, they may also cause the imbalance of immune tolerance or normal immune hyperfunction, thus leading to immune hepatitis. This article mainly reviews the therapeutic mechanism of immune checkpoint inhibitors, their mechanism in causing the adverse reaction of liver injury, related risk factors, and incidence rate and summarizes the treatment methods for liver injury caused by immune checkpoint inhibitors. It is believed that while promoting anti-tumor immunity, immune checkpoint inhibitors may cause non-homogeneous immune-related liver injury due to the specificity of non-tumor tissue targets, and the main purpose of treatment is to restore immune homeostasis. Therefore, the management of patients using immune checkpoint inhibitors often requires a balance between treatment window, toxicity, and treatment of specific injury, as well as multidisciplinary collaboration.
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Objective:To evaluate the role of NIMA-related kinase 7 (NEK7)/Nod-like receptor family pyrin domain-containing protein 3 (NLRP3) signaling pathway in sepsis-associated encephalopathy in mice.Methods:A total of 150 healthy adult male C57BL/6 mice, aged 8-12 weeks, weighing 20-25 g, were divided into 5 groups ( n=30 each) by a random number table method: sham operation group (Sham group), sepsis group (CLP group), sepsis+ NLRP3 inhibitor MCC950 group (CLP+ MCC950 group), sepsis+ NEK7 siRNA group (CLP+ NEK7 siRNA group), and sepsis+ NC siRNA group (CLP+ NC siRNA group). Sepsis was induced by classic cecal ligation and puncture (CLP) in anesthetized animals.MCC950 10 mg/kg was intraperitoneally injected for 3 consecutive days after operation in CLP+ MCC950 group, while the equal volume of normal saline was given instead in Sham group.Immediately after operation and on 3rd day after operation, NEK7 siRNA 3 nmol/20 g was injected into the ventricle in CLP+ NEK7 siRNA group, and the equal dose of NC siRNA was injected into the ventricle instead in Sham group.The survival of mice was recorded on 4th postoperative day.On 4th and 7th days after operation, 10 mice in each group were selected for Y maze space recognition experiment.On 7th day after operation, 5 mice in each group were randomly sacrificed and hippocampal tissues were taken for determination of the contents of interleukin-1beta (IL-1β), interleukin-18 (IL-18) and tumor necrosis factor-alpha (TNF-α) (by enzyme-linked immunosorbent assay), and 6 mice in each group were sacrificed and hippocampal tissues were taken for determination of the expression of NEK7, NLRP3, cleaved-caspase-1 and apoptosis-associated speck-like protein containing a caspase-1 recruitment domain (ASC) (by Western blot). Results:The survival rates were 100%, 50%, 73%, 60% and 53% in Sham, CLP, CLP+ MCC950, CLP+ NEK7 siRNA, and CLP+ NC siRNA groups, respectively, on day 4 after surgery.Compared with Sham group, the frequency of entries into novel arm was significantly reduced, and the time spent in the novel arm was shortened at 4th and 7th days after operation, and the contents of IL-1β, IL-18 and TNF-α in hippocampus were increased, and the expression of NEK7, NLRP3, cleaved-caspase-1 and ASC was up-regulated at 7th day after operation in CLP group ( P<0.05). Compared with CLP group, the frequency of entries into novel arm was significantly increased, and the time spent in the novel arm was prolonged at 4th and 7th days after operation, and the contents of IL-1β, IL-18 and TNF-α in hippocampus were decreased at 7th day after operation in CLP+ MCC950 and CLP+ NEK7 siRNA groups, the expression of NLRP3, cleaved-caspase-1 and ASC was significantly down-regulated at 7th day after operation in CLP+ MCC950 group, the expression of NEK7, NLRP3, cleaved-caspase-1 and ASC was significantly down-regulated in CLP+ NEK7 siRNA group ( P<0.05), and no significant change was found in the parameters mentioned above in CLP+ NC siRNA group ( P>0.05). Conclusions:NEK7/NLRP3 signaling pathway is involved in SAE in mice, and the underlying mechanism may be related to promotion of inflammatory responses.
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Objective To study the effects of thyroid hormone (TH) on synaptophysin (syn) expression in rat cortex and hippocampus during developing period. Methods The experimental animals were divided into four groups: (1) Hypothyroidism group: the pregnant maternal rats had been given 0.02% methimazole(MM)water since 5 days, the infant rats suffered from innate hypothyroidism. (2)T4 substitution group: innate 0 days. (4)Normal control group: The pregnant rats were given a normol diet and water, yielding infant rats used as normal matched control. The expression of synaptophysin mRNA were measured by in site hybridization. Results (1) In the normal control group synaptophysin expression showed a characteristics layer distribution in the cortex and hippocampus. The expression was very low at O day, the peak of expression was at 4 days. During the following days, the expression was reduced gradually, reaching nearly the level in the adulthood by 30 days. (2)Synaptophysin expressions in hypothyroidism group were significantly lower than those in normal control group(P＜0. 01). In hypothyroidism group the peak of synaptophysin expression was delayed by 3 days, attaining the high peak on 7 days. (3) Synaptophysin expressions in T4 substitution group were significantly higher than those in hypothyroidism group at 4 days, 7 days, 14 days, 21 days, and 30 days, but were still lower than the levels in normal group(P＜0.05 or P＜0.01, except 7 days synaptophysin expression at hippocampus DG,P＞0.05). (4)Synaptophysin expressions in T4 hyperthyroidism group were significantly higher than those in normal control group at 14 days、21 days、30 days(P＜0.05 or P＜0. 01). Conclusion The results suggested that reduced thyroid hormone, T4 substitution, and T4 hyperthyroidism led to the changes of synaptophysin expression in the rat cortex and hippocampus, resulting in an adverse effect on synapses occurrence and related nerve circuit establishment,with appearance of peerless neuronal place or mistaken nerve thoroughfare, thus hindering the development and function of the brain. Timely T4 substitution therapy is an important way to correct the disturbance in synapses development of the central nervous system due to deficient thyroid hormone.
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Objective Using hypothyroid,hyperthyroid and normol control rats model,we investigated mRNA expression of the nerve-growth-factor and its receptor TrkA in hippocampus and parietal cortex at 14,21,28days of ages,to offer a possible neurobiological explanation about mechanism of thyroid hormone modulating NGF and its receptor TrkA.Methods For hypothyroid group,rats were reared with 0.02% methimazol water from 5~6 day of gestation to the day when they were sacrificed;for hyperthyroid group,rats were daily intraperitoneal injected of 0.4?g/g body weight tiiodothyronin from beginning of delivery;for normal control rats were reared a normol diet and water.NGF mRNA and TrkAmRNA were measured by in site hybridization.Results The peak of mRNA expression of NGF and TrkA is at P21and P28 respectively,.The mRNA expression of NGF and TrkA in hypothyroid rats was significantly lower than that in age-matched euthyroid at P14,P21,P28(P
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Objective To study the effect of phosphodiesterase inhibitor pentoxifylline (PTX) on type 1 diabetes in NOD mice and its possible mechanism.Methods Blood glucose, urinary glucose, insulitis and incidence of diabetes were investigated in NOD mice treated with PTX, insulitis was observed by HE staining and the expressions of IFN ?, TNF ?, IL 10 in pancreas were measured by RT PCR technique. Results The incidence of diabetes in the PTX group was 30.0% which was significantly lower than 67.9% in the control group (P
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The choline acetyltransferase (CHAT) and the molecular forms of acetyl-cholinesterase (ACHE) activites in various brain regions of 20-day-old hypothyroid and hyper-thyroid rats were measured. The results provided the following information: 1) CHAT and ACHE activities were directly interrelated with thyroid hormones. 2) In both hypothyroid and hyperthyroid rats the nonextractable ACHE activity was distinctly decreased in every brain region, suggesting that both conditions were affected in the critical period of cholinergic synaptic development. 3) The ratio of membrane-bound ACHE to soluble ACHE decreased;it showed that thyroid hormone deficiency might distrub development and maturation of cholinergic neurons. 4) In most regions of the central nervous system,the CHAT seemed to be more affected than ACHE by thyroid hormones.