Acute liver failure (ALF) is a life-threatening condition associated with macrophage-mediated inflammatory responses. Effective therapies and drugs are still lacking to date. Here, we reveal that a derivative of xanthohumol, CAM12203, alleviates lipopolysaccharide (LPS) + d-galactosamine (D-GalN)-induced ALF through limiting macrophage-mediated inflammation, with the most significant impact on interleukin-1β (IL-1β) transcription. Through biotin labeling-mediated pull-down and LC-MS/MS analysis, diacylglycerol kinase ζ (DGKζ), a lipid-metabolizing kinase, is identified as the direct target of CAM12203. Mechanistically, DGKζ is induced in macrophages upon inflammatory stimuli and is upregulated observed on clinical liver failure samples. Its product phosphatidic acid (PA) boosts phospholipase C (PLC)-inositol 1,4,5-trisphosphate (IP₃)-Ca²⁺ signaling and subsequent janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) cascade, ultimately promoting IL-1β production and liver failure. DGKζ knockdown/ablation or inhibition significantly impairs the DGKζ-STAT3-IL-1β pathway along with ALF progression. Finally, CAM12203 is confirmed to be a new DGKζ inhibitor and acts against inflammation in a DGKζ-reliant manner. Taken together, CAM12203 inhibits IL-1β transcription in macrophages by binding to DGKζ and blocking the DGKζ-STAT3 axis, thereby exerting an ameliorative effect on ALF. These results not only highlight CAM12203 as a promising lead compound for ALF treatment, but also define DGKζ as a novel therapeutic target.

Cerebral small vessel disease is a group of heterogeneous diseases with stroke and cognitive impairment as the main clinical features.It can be divided into sporadic type and hereditary type.Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) belongs to hereditary cerebral small vessel disease.It has been reported in China,Japan,Spain,Greece,and other countries.The diagnosis mainly depends on characteristic clinical symptoms,imaging features,and genetic testing.CARASIL manifests as diffuse white matter abnormal signal and subcortical multiple infarcts on MRI,and it caused by HTRA1 gene mutation.

Medulla oblongata is precise in structure and the blood supply is complicated. After its infarction, it is easy to be misdiagnosed or missed because of its various clinical manifestations and lack of specificity. This article reviews the pathogenesis, clinical manifestations, and prognosis of medullary infarction in different sites.

Objective To investigate the effect of blood hemoperfusion with resin adsorption connected in series to continuous veno-venous hemofiltration ( HP + CVVH) on plasma cytokines such as TNF-α,IL-1β,IL-6 as well as cellular immunity and prognosis of patients with multiple organ dysfunction syndromes (MODS). Methods It was a prospective,randomized clinical trial.A total of 30 patients diagnosed as MODS were randomly (random number) divided into routine treatment + HP + CVVH group (treatment group) and routine treatment + CVVH group (control group).In treatment group,patients received blood hemoperfusion with resin adsorption for 2 hours,and then CVVH for 10 hours every day for 3days.In control group,patients received CVVH for 12 hours every day for 3 days.The plasma samples of patients in treatment group were obtained 0 h,2 h,12 h,24 h,26 h,36 h,48 h,50 h,60 h,5 days,7 days and 10 days after renal replacement therapy.The plasma samples of patients in control group were obtained 0 h,12 h,24 h,36 h,48 h,60 h,5 days,7 days and 10 days after renal replacement therapy.All of these patients were monitored with APACHE Ⅱ score,T-lymphocytes subpopulations,blood lactate acid concentration,heart rate,respiration rate and oxygenation index. Results Plasma levels of TNF-α,IL-1β and IL-6 decreased dramatically after HP (P ＜ 0.01 ) and T-lymphocytes subpopulations CD3+,CD4 +,CD8 + and CD4 +/CD8 + increased after both HP + CVVH and CVVH.The differences in plasma levels of TNF-α,IL-1βand IL-6 of patients between two groups were not noticeably obvious at the intervals of 12 h,36 h,and 50 h after renal replacement therapy. But on the 5 th day after renal replacement therapy,plasma levels of TNF-α,IL-1βand IL-6 of patients in HP + CVVH group were lower than those in control group (P ＜ 0. 05 ).There were 5 fatal patients in HP + CVVH group and 6 patients died off in CVVH group during 28 days after treatment.Conclusions Both HP + CVVH and CVVH could lower the levels of plasma TNF-α,IL-1β and IL-6,and improve cellular immunity and clinical symptoms as well as signs.Compared with CVVH,plasma levels of TNF-α,IL- 1β and IL-6 were lower on the 5th day and increase rate of 28-day survival in HP + CVVH group.