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.

OBJECTIVE To investigate the effect and mechanism of Panax notoginseng saponins （PNS） on wound healing after anal fistula surgery in rats by regulating the hypoxia-inducible factor-1α （HIF-1α）/vascular endothelial growth factor （VEGF）/ vascular endothelial growth factor receptor-2 （VEGFR2） signaling pathway. METHODS SD rats were selected to establish a postoperative rat model of anal fistula by infecting wound with Escherichia coli. The model rats were randomly grouped into model group， PNS low-dose and high-dose groups （15， 30 mg/cm2）， high-dose of PNS+2-methoxyestradiol （2ME2） group （PNS 30 mg/cm2+HIF-1α inhibitor 2ME2 4 mg/kg）， with 10 rats in each group. Another 10 normal rats were selected for back hair removal treatment as the control group. Each drug group was injected with the corresponding drug solution intramuscularly or （and） intraperitoneally， once a day， for 3 weeks. After the last administration， the wound healing rate （excluding the control group）， microvascular density （MVD）， the expression of collagen Ⅰ and fibronectin （FN） in the wound tissue were detected in each group； the levels of angiogenic factors [VEGF， E-mail：842710813@qq.com angiopoietin-Ⅰ （Ang-Ⅰ）， Ang-Ⅱ] in serum， the levels of inflammatory factors [interleukin-6 （IL-6） and IL-2] in serum binggui7183@163.com and wound tissue as well as the expressions of the related proteins of HIF-1α/VEGF/VEGFR2 signaling pathway in the wound tissue of rats were also detected in each group. RESULTS The MVD， the expression of collagen Ⅰ and FN in the wound tissue， and the levels of IL-6 and IL-2 in serum and wound tissue of rats increased significantly in the model group， compared to the control group （P＜0.05）， while the serum levels of VEGF， Ang- Ⅰ and Ang-Ⅱ decreased significantly （P＜0.05）. The wound healing rate， the MVD in wound tissue， the serum levels of VEGF， Ang-Ⅰ and Ang-Ⅱ， the expressions of collagen Ⅰ and FN in the wound tissue， and protein expressions of HIF-1α， VEGF and VEGFR2 in the PNS low-dose and high-dose groups increased significantly， compared to the model group （P＜0.05）， while the levels of IL-6 and IL-2 in serum and wound tissue decreased significantly （P＜0.05）； the high-dose PNS had a stronger effect （P＜ 0.05）. 2ME2 could weaken the effect of PNS on above indicators of rats after anal fistula surgery （P＜0.05）. CONCLUSIONS PNS can promote the production of angiogenic factors and inhibit the production of pro-inflammatory factors， thereby promoting wound healing in rats after anal fistula surgery. The above effects are related to the activation of HIF-1α/VEGF/VEGFR2 signaling pathway.

BACKGROUND:Studies have shown that there is a close association between spinal cord injury and ferroptosis,and that tetramethylpyrazine has the function of regulating redox reactions. OBJECTIVE:To investigate the regulatory effect of tetramethylpyrazine on ferroptosis in rats with spinal cord injury and its mechanism. METHODS:Thirty-six female specific pathogen-free Sprague-Dawley rats were randomly divided into sham-operated group,model group and tetramethylpyrazine group,with 12 rats in each group.Animal models of spinal cord injury were established using the modified Allen's method in the latter two groups.No treatment was given in the sham-operated group,while rats in the model and tetramethylpyrazine groups were given intraperitoneal injection of normal saline and tetramethylpyrazine solution,once a day,for 28 days. RESULTS AND CONCLUSION:The Basso,Beattie&Bresnahan Locomotor Rating Scale score in the tetramethylpyrazine group was lower than that in the sham-operated group but higher than that in the model group after 14,21,and 28 days of treatment(P＜0.05).After 28 days of treatment,hematoxylin-eosin staining showed that in the model group,the spinal cord tissue of rats showed cavity formation,necrotic tissue and inflammatory infiltration with fibrous tissue formation;in the tetramethylpyrazine group,the area of spinal cord tissue defects was smaller,and inflammatory infiltration and fibrous tissue formation were less than those in the model group.After 28 days of treatment,Prussian blue staining showed that a large amount of iron deposition was seen in the spinal cord tissue of rats in the model group,and less iron deposition was seen in the spinal cord tissue of rats in the tetramethylpyrazine group than in the model group.After 28 days of treatment,the levels of glutathione and superoxide dismutase in the rat spinal cord tissue were decreased(P＜0.05)and the level of malondialdehyde was increased in the model group compared with the sham-operated group(P＜0.05);the levels of glutathione and superoxide dismutase in the rat spinal cord tissue were increased(P＜0.05)and the level of malondialdehyde was decreased in the tetramethylpyrazine group compared with the model group(P＜0.05).After 28 days of treatment,qRT-PCR and western blot assay showed that the mRNA and protein levels of glutathione peroxidase 4,ferritin heavy chain,and ferroportin in the rat spinal cord tissue in the model group were decreased compared with those in the sham-operated group(P＜0.05),while the mRNA and protein levels of glutathione peroxidase 4,ferritin heavy chain,and ferroportin in the rat spinal cord tissue in the tetramethylpyrazine group were increased compared with those in the model group(P＜0.05).Immunofluorescence staining showed that after 28 days of treatment,the neuronal nuclei positive staining in the spinal cord of rats was the most in the sham-operated group and the least in the model group.To conclude,tetramethylpyrazine can improve motor function and play a neuroprotective role in rats with spinal cord injury by regulating ferroptosis.

Objective:To analyze the clinical characteristics of invasive intervention-related intestinal fistula in patients with acute pancreatitis (AP).Methods:We retrospectively analyzed the clinical data of 177 moderately severe acute pancreatitis (MSAP) or severe acute pancreatitis (SAP) patients who received invasive intervention in Peking Union Medical College Hospital from January 2003 to December 2022. Patients were divided into fistula group and non-fistula group based on the presence or absence of fistula after or during receiving invasive interventions. The age, gender, etiology, systemic inflammatory response syndrome(SIRS), impairment of organ function, revised Atlanta classification, bedside index of severity of acute pancreatitis(BISAP), Balthazar CT classification, extra-pancreatic involvement and secondary infection of local complications, indications, timing and modalities of invasive interventions, length of hospitalization, length of intensive care and outcomes were recorded. The differences on clinical characteristics were compared between the two groups.Results:Intestinal fistulae were found in 21(11.9%) cases during or after invasive intervention, including 8 during or after percutaneous drainage and 13 during or after surgeries. 51 cases received endoscopic drainage or debridement and no intestinal fistula occurred after endoscopic management. Compared to patients without fistula, the median age was younger in the fistula group (36 vs 45 years, P=0.014), and the occurrence of SIRS (95.2% vs 59.6%, P=0.001), extra-pancreatic invasion (100.0% vs 67.3%, P=0.002), and secondary infection (71.4% vs 36.5%, P=0.002) were higher. Patients with fistula had a longer median length of hospitalization (71 vs 40 days, P=0.016) and intensive care (8 vs 0 days, P=0.002). All patients in the fistula group had peri-pancreatic, abdominal and retroperitoneal involvement seen on imaging or intraoperatively. The intestinal fistulae mainly occurred in the colon ( n=13, 61.9%) and the duodenum ( n=6, 28.6%). The confirmed diagnosis of fistulae was based on transfistula imaging ( n=11) or digestive tract imaging ( n=5). Among 13 cases with colonic fistulae, nonsurgical treatment was preferred in 9 cases, and surgeries of fistula repairmen or proximal ostomy were preferred in 4 cases. Among 8 cases with non-colonic fistulae, nonsurgical treatment was preferred in 7 cases, and only 1 case repaired the fistula immediately during the intraoperative detection. Conclusions:Intestinal fistula is an important complication of severe AP, and it is closely associated with invasive interventions. Improved invasive intervention strategies may help prevent intestinal fistula formation; timely and effective management of intestinal fistula may help avoid complications and shorten hospitalization.

Objective:To analyze clinical characteristics of primary pancreatic lymphoma (PPL) patients.Methods:Clinical features of 22 patients diagnosed as PPL admitted to Peking Union Medical College Hospital from January 2002 to May 2023 were analyzed retrospectively.Results:The median age was 56.4±13.3 years. The median time from onset to diagnosis was 1.0 (1.0, 3.0) months. The main clinical manifestations were abdominal pain (15/22), weight loss (14/22) and jaundice (10/22). Elevated lactate dehydrogenase (LDH) was observed in 15/20 (75%) patients. Only 2 (2/9, 22.2%) patients had increased CA199 levels and 2 (2/9, 22.2%) patients had increased CEA levels. The maximum tumor diameter was 5.0 (3.8, 6.9) cm. Contrast-enhanced CT mostly showed low enhancement lesions. Major pancreatic duct dilatation were rare on CT scan (4/20). Fifteen patients were confirmed by pancreatic pathology, of which 8 were obtained by surgery, 4 were obtained by CT or ultrasound-guided percutaneous biopsy, and 3 were obtained by EUS-FNA. The main pathological type was diffuse large B-cell lymphoma (14/22). 19 patients received chemotherapy, and 6 patients died with a median follow-up of 5.0 (1.5, 35.5) months.Conclusions:PPL is rare and easy to be misdiagnosed. Elevated LDH levels, normal tumor markers, and non-dilatation of main pancreatic duct are important diagnostic clues. It is important to obtain pathology by EUS-FNA and other methods for definite diagnosis.

Objective:To observe the protective effects of Zhiganqing Prescription on the liver of C57BL/6J non-alcoholic fatty liver disease (NAFLD) mice induced by high fat diet and its effects on PI3K/Akt/FoxO1 signaling pathway, insulin resistance (IR) and gluconogenesis.Methods:A total of 48 8-week-old male C57BL/6J mice were divided into control group ( n=8) and modeling group ( n=40) according to random number table method. The control group was fed with ordinary diet, and the model group was fed with high-fat diet. The NAFLD model was established after 8 weeks of feeding. The modeling group was divided into model group, Pioglitazone group, Zhiganqing Prescription low-, medium-, and high-dosage group ( n=8 in each group) according to random number table method, and drug intervention lasted for 8 weeks. The body mass of mice was measured regularly during administration. Fasting blood glucose (FBG) levels were measured at 0 and 8 weeks of administration, and oral glucose tolerance tests (OGTT) were conducted. After the experiment, serum levels of GPT, GOT, TC, TG, LDL-C, HDL-C, FINS and C-P were detected and HOMA-IR was calculated. The pathological morphology of liver was observed by HE and PAS staining. The expression levels of PI3K and p-Akt were detected by IHC staining. The protein expression levels of PI3K, Akt, p-Akt, FoxO1, p-FoxO1, G6PC and PCK1 were detected by Western blot. Results:Compared with model group, the body weight of mice in each administration group decreased at 4, 6 and 8 weeks ( P<0.05 or P<0.01). At the 8th week of administration, the levels of FBG and OGTT AUC in each administration group decreased ( P<0.05 or P<0.01), the levels of GPT, TC, TG and LDL-C decreased ( P<0.01), and the GOT levels in Zhiganqing Prescription medium- and high-dosage groups decreased ( P<0.01). The HDL-C level in Zhiganqing Prescription medium-dosage group decreased ( P<0.05 or P<0.01), and the HOMA-IR level in Zhiganqing Prescription low- and medium-dosage groups decreased ( P<0.05 or P<0.01). The levels of FINS and C-P in each administration group increased ( P<0.05 or P<0.01), and the expressions of PI3K protein and p-Akt/Akt, p-FoxO1 /FoxO1 protein in liver tissues increased ( P<0.05 or P<0.01). The protein expressions of G6PC and PCK1 decreased ( P<0.05 or P<0.01). Conclusion:Zhiganqing Prescription can effectively control the body mass, blood glucose, liver function and blood lipids of NAFLD mice, improve IR and gluconeogenesis, the mechanism of which may be related to the activation of PI3K/Akt/FoxO1 signaling pathway.

Objective To observe the echocardiographic manifestations of infective endocarditis(IE)complicated with valve damage in children.Methods Totally 104 children with IE were retrospectively enrolled and divided into non-damage group(n=34),mild damage group(n=39)and dysfunction group(n=31)according to whether complicated with valve damage and damage's degree.The general and echocardiographic data were compared among groups,and the echocardiographic characteristics of IE complicated with valve damage in children were analyzed.Results Significant difference of the proportion of combining with other congenital heart diseases(excluding bicuspid aortic malformations),the incidence of embolization events during hospital stay,also of endocarditis of left cardiac system were found among groups(all P＜0.05).Pairwise comparison showed that in non-damage group,the proportion of combining with other congenital heart diseases was higher,while the incidence of endocarditis of left cardiac system was lower than those in both mild damage group and dysfunction group(all P＜0.05).The incidence of embolization events during hospital stay in non-damage group was lower than that in dysfunction group(P＜0.05).Among 70 cases of IE complicated with valve damage,mitral valve(30/70,42.86％)was the most common involved valve,mostly presented as valve stenosis(63/70,90.00％).No significant difference of valve involvement site,valve structural lesions nor the incidence of valve stenosis was found between mild damage group and dysfunction group(all P＞0.05).Conclusion IE complicated with valve damage in children mostly involved left cardiac system,and the risk of embolization events was higher than that of IE children without valve damage.Echocardiography could be used as an important method for evaluating the site of valve involvement and the degree of damage.

ObjectiveTo investigate the effects of cathodic transcranial direct current stimulation (ctDCS) on upper limb and finger dysfunction after right brain injury (RBI). MethodsFrom October, 2020 to May, 2022, 40 RBI patients in Beijing Bo'ai Hospital were randomly divided into control group and experimental group, with 20 patients in each group. All the patients accepted conventional drug treatment, conventional rehabilitation treatment and functional occupational therapy. The cathode electrode was placed in the M1 area of the uninjured side of brain, then the control group received sham stimulation and the experimental group received stimulation, for four weeks. They were assessed with Fugl-Meyer Assessment-Upper Extremities (FMA-UE) and -Finger, and the modified Barthel Index (MBI) before and after treatment. ResultsAfter treatment, the scores of FMA-UE, FMA-Finger and MBI improved in the two groups (t > 5.627, P < 0.001), and improved more in the experimental group than in the control group (t > 2.161, P < 0.05). ConclusionctDCS can effectively improve the motor function of upper limbs and fingers of RBI patients, and improve the ability of activities of daily living.

OBJECTIVE To explore the effects of pterostilbene （PTE） on wound healing in diabetic skin ulcer model rats and its mechanism. METHODS Ten SD rats were grouped into control group； after diabetic skin ulcer model of other rats was induced by giving high-fat and high-sugar diet+intraperitoneal injection of streptozotocin+cutting off the skin and subcutaneous tissue in the marked area of the back， model rats were randomly divided into model group， PTE low-dose group （40 mg/kg）， PTE high-dose group （80 mg/kg）， PTE high-dose+PP2 group （80 mg/kg PTE+2 mg/kg SRC inhibitor PP2）， with 10 rats in each group. On the second day after modeling， the rats in each drug group were intraperitoneally injected with corresponding drug solutions， while the rats in control group and model group were intraperitoneally injected with normal saline， once a day， for 14 consecutive days. The wound healing rate of rats in each group was measured on the 7th and 14th day of administration； the contents of interleukin-1β （IL-1β）， IL-6， tumor necrosis factor-α （TNF-α） and vascular endothelial growth factor （VEGF） in the serum of rats were detected； the pathological changes of wound granulation tissue were observed， and the expressions of SRC/mitogen-activated protein kinase kinase （MEK）/extracellular signal-regulated kinase （ERK） signaling pathway-related proteins in wound granulation tissue were detected. RESULTS Compared with control group， the wound healing rate， serum content of VEGF， the phosphorylation levels of SRC， MEK1/2 and ERK1/2 were decreased significantly （P＜0.05）， while serum contents of IL- 1β， IL-6 and TNF-α were increased significantly （P＜0.05）； there was obvious infiltration of inflammatory cells in the wound granulation tissue， and the number of new blood vessels decreased. Compared with model group， above indexes of PTE low-dose and high-dose groups were improved significantly （P＜0.05）， and the pathological injury of granulation tissue in wound was improved. PP2 significantly reversed the improvement effects of PTE on the above indexes （P＜0.05）. CONCLUSIONS PTE can promote the wound healing of diabetic skin ulcer model rats， the mechanism of which may be related to activating SRC/MEK/ERK signaling pathway.

Background::To date, there is no effective medicine to treat coronavirus disease 2019 (COVID-19), and the antiviral efficacy of arbidol in the treatment for COVID-19 remained equivocal and controversial. The purpose of this study was to evaluate the efficacy and safety of arbidol tablets in the treatment of COVID-19.Methods::This was a prospective, open-label, controlled and multicenter investigator-initiated trial involving adult patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients were stratified 1:2 to either standard-of-care (SOC) or SOC plus arbidol tablets (oral administration of 200 mg per time, three times a day for 14 days). The primary endpoint was negative conversion of SARS-CoV-2 within the first week. The rates and 95% confidential intervals were calculated for each variable.Results::A total of 99 patients with laboratory-confirmed SARS-CoV-2 infection were enrolled; 66 were assigned to the SOC plus arbidol tablets group, and 33 to the SOC group. The negative conversion rate of SARS-CoV-2 within the first week in patients receiving arbidol tablets was significantly higher than that of the SOC group (70.3% [45/64] vs. 42.4% [14/33]; difference of conversion rate 27.9%; 95% confidence interval [CI], 7.7%-48.1%; P = 0.008). Compared to those in the SOC group, patients receiving arbidol tablets had a shorter duration of clinical recovery (median 7.0 days vs. 12.0 days; hazard ratio [HR]: 1.877, 95% CI: 1.151-3.060, P = 0.006), symptom of fever (median 3.0 days vs. 12.0 days; HR: 18.990, 95% CI: 5.350-67.410, P < 0.001), as well as hospitalization (median 12.5 days vs. 20.0 days; P < 0.001). Moreover, the addition of arbidol tablets to SOC led to more rapid normalization of declined blood lymphocytes (median 10.0 days vs. 14.5 days; P > 0.05). The most common adverse event in the arbidol tablets group was the elevation of transaminase (5/200, 2.5%), and no one withdrew from the study due to adverse events or disease progression. Conclusions::SOC plus arbidol tablets significantly increase the negative conversion rate of SARS-CoV-2 within the first week and accelerate the recovery of COVID-19 patients. During the treatment with arbidol tablets, we find no significant serious adverse events.Trial registration::Chinese Clinical Trial Registry, NCT04260594, www.clinicaltrials.gov/ct2/show/NCT04260594?term= NCT04260594&draw=2&rank=1