Despite therapy with potent antiviral agents, chronic hepatitis B (CHB) patients remain at high risk of hepatocellular carcinoma (HCC). While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis, the specific metabolites modulating HCC risk in CHB patients are largely unknown. Here, we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case-control design nested within a large-scale, prospective cohort. Metabolomics analysis reveals a reduction in long-chain acylcarnitines (LCACs) in the baseline plasma of patients with HCC development. LCACs preferentially inhibit the proliferation of HCC cells in vitro at a physiological concentration and prevent the occurrence of HCC in vivo without hepatorenal toxicity. Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A, which upregulates histone H3 Lys14 acetylation at the promoter region of KLF6 gene and thereby activates KLF6/p21 pathway. Indeed, blocking LCAC metabolism attenuates the difference in KLF6/p21 expression induced by baseline plasma of HCC/non-HCC patients. The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control. These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.

OBJECTIVE To study the inhibitory effect of ethyl acetate extract from Mimosa pudica root （ethyl acetate extract for short） on acute myeloid leukemia in mice. METHODS Different concentrations of ethyl acetate extract （0.062 5， 0.125， 0.25， 0.5 mg/mL） were used to treat acute myelomonocytic leukemia cell lines WEHI-3， and their effects on cell viability were investigated. Fifty BALB/C mice were randomly divided into blank control group， model group， positive control group （5- fluorouracil， 13 mg/kg）， and ethyl acetate extract low-dose and high-dose groups （50， 200 mg/kg）， with 10 mice in each group. Except for the blank control group， the leukemia model was constructed by intraperitoneal injection of WEHI-3 cells in other groups， and from the second day of modeling， corresponding drugs/water were orally administered once a day for 14 consecutive days. After the last administration， the liver and spleen indexes of mice were measured， and liver tissue pathological morphology observation， hematological analysis， and white blood cell differentiation detection were performed； the levels of cytokine [interleukin-2 （IL-2）， IL-3， interferon-γ （IFN-γ）， tumor necrosis factor-α （TNF-α）] in serum were determined； the levels of leukocyte surface markers [cluster of differentiation 3 （CD3）， CD19， CD11b， CD107b （Mac-3）] in whole blood were all detected. RESULTS After treated with 0.062 5-0.5 mg/mL ethyl acetate， the inhibition rate of cell proliferation were increased significantly （P＜0.05）. After intervention with high-dose ethyl acetate， the liver and spleen index， serum level of TNF-α， the levels of CD11b and Mac-3 in blood were significantly reduced （P＜0.05）， while serum levels of IL-2， IL-3 and IFN-γ， and the levels of CD3 and CD19 in blood were increased significantly （P＜0.05）. Occasional lymphocyte infiltration was present in the liver parenchyma， with almost no infiltration of inflammatory cells； hematology improvement and weakened white blood cell differentiation were found. CONCLUSIONS The ethyl acetate extract of M. pudica root can inhibit the proliferation of WEHI-cells， and improve symptoms in acute myeloid leukemia mice， the mechanism of which may be associated with enhancing the immune function.

OBJECTIVE To study the inhibitory effect of ethyl acetate extract from Mimosa pudica root （ethyl acetate extract for short） on acute myeloid leukemia in mice. METHODS Different concentrations of ethyl acetate extract （0.062 5， 0.125， 0.25， 0.5 mg/mL） were used to treat acute myelomonocytic leukemia cell lines WEHI-3， and their effects on cell viability were investigated. Fifty BALB/C mice were randomly divided into blank control group， model group， positive control group （5- fluorouracil， 13 mg/kg）， and ethyl acetate extract low-dose and high-dose groups （50， 200 mg/kg）， with 10 mice in each group. Except for the blank control group， the leukemia model was constructed by intraperitoneal injection of WEHI-3 cells in other groups， and from the second day of modeling， corresponding drugs/water were orally administered once a day for 14 consecutive days. After the last administration， the liver and spleen indexes of mice were measured， and liver tissue pathological morphology observation， hematological analysis， and white blood cell differentiation detection were performed； the levels of cytokine [interleukin-2 （IL-2）， IL-3， interferon-γ （IFN-γ）， tumor necrosis factor-α （TNF-α）] in serum were determined； the levels of leukocyte surface markers [cluster of differentiation 3 （CD3）， CD19， CD11b， CD107b （Mac-3）] in whole blood were all detected. RESULTS After treated with 0.062 5-0.5 mg/mL ethyl acetate， the inhibition rate of cell proliferation were increased significantly （P＜0.05）. After intervention with high-dose ethyl acetate， the liver and spleen index， serum level of TNF-α， the levels of CD11b and Mac-3 in blood were significantly reduced （P＜0.05）， while serum levels of IL-2， IL-3 and IFN-γ， and the levels of CD3 and CD19 in blood were increased significantly （P＜0.05）. Occasional lymphocyte infiltration was present in the liver parenchyma， with almost no infiltration of inflammatory cells； hematology improvement and weakened white blood cell differentiation were found. CONCLUSIONS The ethyl acetate extract of M. pudica root can inhibit the proliferation of WEHI-cells， and improve symptoms in acute myeloid leukemia mice， the mechanism of which may be associated with enhancing the immune function.

Background::Adamantinomatous craniopharyngioma (ACP) is the commonest pediatric sellar tumor. No effective drug is available and interpatient heterogeneity is prominent. This study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles, imaging findings, and histological features, in order to predict the response to anti-inflammatory treatment and immunotherapies.Methods::Totally 142 Chinese cases diagnosed with craniopharyngiomas were profiled, including 119 ACPs and 23 papillary craniopharyngiomas. Whole-exome sequencing (151 tumors, including recurrent ones), RNA sequencing (84 tumors), and DNA methylome profiling (95 tumors) were performed. Consensus clustering and non-negative matrix factorization were used for subgrouping, and Cox regression were utilized for prognostic evaluation, respectively.Results::Three distinct molecular subgroups were identified: WNT, ImA, and ImB. The WNT subgroup showed higher Wnt/β-catenin pathway activity, with a greater number of epithelial cells and more predominantly solid tumors. The ImA and ImB subgroups had activated inflammatory and interferon response pathways, with enhanced immune cell infiltration and more predominantly cystic tumors. Mitogen-activated protein kinases (MEK/MAPK) signaling was activated only in ImA samples, while IL-6 and epithelial-mesenchymal transition biomarkers were highly expressed in the ImB group, mostly consisting of children. The degree of astrogliosis was significantly elevated in the ImA group, with severe finger-like protrusions at the invasive front of the tumor. The molecular subgrouping was an independent prognostic factor, with the WNT group having longer event-free survival than ImB (Cox, P = 0.04). ImA/ImB cases were more likely to respond to immune checkpoint blockade (ICB) therapy than the WNT group ( P <0.01). In the preliminary screening of subtyping markers, CD38 was significantly downregulated in WNT compared with ImA and ImB ( P = 0.01). Conclusions::ACP comprises three molecular subtypes with distinct imaging and histological features. The prognosis of the WNT type is better than that of the ImB group, which is more likely to benefit from the ICB treatment.

OBJECTIVE To investigate the improvement effects of Arisaema Cum Bile on Parkinson’s disease （PD） model mice and its potential mechanism. METHODS Sixty male C57BL/6J mice were randomly divided into normal group， model group， Arisaema Cum Bile low-dose group [0.39 g/（kg·d）]， Arisaema Cum Bile high-dose group [1.56 g/（kg·d）] and positive control drug Levodopa tablet group [80 mg/（kg·d）]， with 12 mice in each group. Except that normal group was given constant volume of normal saline， other groups were given 1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine [MPTP，35 mg/（kg·d）] intraperitoneally for 5 consecutive days to induce subacute PD model； after modeling， they were given relevant medicine continuously for 7 d； rod climbing test and line suspension test were performed 1 d before modeling， on the 5th day of modeling and after the last medication. The number of tyrosine hydroxylase （TH）-positive neurons in the substantia nigra of mice were measured by immunofluorescence； the levels of interleukin 1β （IL-1β） and tumor necrosis factor α（ TNF-α） in serum and the levels of IL- E-mail：qhwang668@sina.com 1β， TNF-α， cyclooxygenase-2 （COX-2） and inducible nitric oxide synthase （iNOS） in the substantia nigra of mice were measured by enzyme-linked immunosorbent assay. The expression levels of cAMP-dependent protein kinase catalytic subunit α （PKA C-α）， glutathione peroxidase 4 （GPX4） and ferritin heavy chain polypeptide 1 （FTH1） proteins in the substantia nigra of mice was measured by Western blot. RESULTS After last medicine， compared with the normal group， mice in the model group had significantly longer pole-climbing time （P＜0.01）， significantly lower line suspension scores （P＜0.01）， significantly fewer TH-positive neurons in the substantia nigra （P＜0.01）， significantly higher serum concentrations of IL-1β and TNF-α and nigrostriatal concentrations of IL-1β， TNF-α， COX-2 and iNOS （P＜0.01）， while lower protein expression levels of GPX4， PKA C-α and FTH1 in the substantia nigra （P＜0.05 or P＜0.01）. Compared with the model group， the above indexes of mice were significantly returned in Arisaema Cum Bile high-dose group （P＜0.05 or P＜ 0.01）. CONCLUSIONS Arisaema Cum Bile can improve motor impairment and reduce apoptosis of nigrostriatal TH neurons in MPTP-induced PD mice， and has neuroprotective effects on model mice； this may be related to its inhibition of neuroinflammation and the inhibition of ferroptosis by up-regulating PKA signaling pathway.

Bilirubin has good anti-inflammatory， antioxidant and immunomodulatory effects， but its poor water solubility and low bioavailability greatly limit its clinical application. Researchers have developed bilirubin into various nanoparticles， which effectively eliminate the limitation of low solubility of bilirubin with the advantage of dosage form， so that they can maximize its pharmacological activities such as anti-inflammatory， anti-oxidation and immune regulation. Bilirubin nanoparticles have great application potential in a variety of gastrointestinal diseases， liver and kidney diseases， skin diseases， autoimmune diseases， islet transplantation and targeted therapy of tumors （both as a direct anti-tumor drug and as a drug delivery system）. The study of bilirubin nanoparticles will promote the clinical application of bilirubin and the development of related new drugs.

It was a retrospective cohort study. Eighty maintenance hemodialysis (MHD) patients with corona virus disease 2019 (COVID-19) were enrolled, among whom 48 patients survived and 32 died. The clinical data between the survival and death groups were compared. The Cox regression model was used to analyze the risk factors of death in MHD patients with COVID-19, and a survival prediction model was constructed. The results showed that age, lesion-cumulative number of lung segments, C-reactive protein, procalcitonin, serum ferritin, interleukin-6, D-dimer, serum phosphorus, and proportions of males, diabetes and hypoxemia in the death group were higher than those in the survival group (all P<0.05). Increased age ( HR=1.039, 95% CI 1.007-1.072, P=0.017), diabetes ( HR=2.688, 95% CI 1.018-6.991, P=0.046), increased C-reactive protein ( HR=1.006, 95% CI 1.001-1.011, P=0.012), and increased serum phosphorus ( HR=1.573, 95% CI 1.015-2.438, P=0.043) were independent influencing factors of death in MHD patients with COVID-19. The survival prediction model was established based on age, diabetes, C-reactive protein and blood phosphorus. The area under the receiver operating characteristic curve of the combined model for survival time at 7-day, 14-day, and 21-day were 0.751 (95% CI 0.690-0.811), 0.768 (95% CI 0.712-0.824), and 0.780 (95% CI 0.729-0.831), respectively. The concordance index of cross- validation as internal validation was 0.797 (95% CI 0.757-0.837). Increased age, diabetes, elevated C-reactive protein and elevated blood phosphorus are independent risk factors of COVID-19 death in MHD patients, and the survival prediction model built by those factors has good efficacy.

Traditional Chinese medicine has the characteristics of multiple components， pathways， and targets in the treatment of fracture healing， and has good therapeutic advantages and potential for fractures with complex pathological mechanisms. Based on this， the author summarized the mechanism of promoting fracture healing by the monomer components and compound formulas of traditional Chinese medicine and found that visfatin A， puerarin， and others can activate the mitogen-activated protein kinase （MAPK） signaling pathway； Xugudan， Guben zenggu formula and others can activate bone morphogenetic protein （BMP） signaling pathway； baicalin， Achyranthes bidentata polysaccharides and others can activate Wnt/β -catenin signaling pathway； apigenin， notoginsenoside and others can activate receptor activator of nuclear factor-κB （NF-κB）/receptor activator of NF-κB ligand/osteoprotegerin （RANK/RANKL/OPG） signaling pathway； Compound huoxue jiegu capsule， Jiangu granule and others can inhibit phosphoinositide 3-kinase/protein kinase B （PI3K/AKT） signaling pathway； icariin can activate Notch signaling pathway； Taohong siwu decoction， crocin and others can activate Hippo signaling pathway； jujuboside A and osthole can inhibit NF-κB signaling pathway， and thus promote fracture healing.

OBJECTIVE To investigate the protective effect and potential mechanism of Arisaema Cum Bile on acute liver injury induced by carbon tetrachloride （CCl4） in mice. METHODS Fifty mice were randomly divided into normal group， model group， positive control group （Biphenyl diester dropping pills， 150 mg/kg）， Arisaema Cum Bile low-dose and high-dose groups （0.78， 2.34 g/kg）， with 10 mice in each group. The mice in each group were given relevant medicine intragastrically， once a day， for 7 consecutive days. Two hours after the last administration， those groups were given intraperitoneal injection of 0.2% CCl4-olive oil solution to induce acute liver injury model except for normal group. Seventeen hours after intraperitoneal injection， the serum levels of alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， interleukin-6 （IL-6）， tumor necrosis factor-α（TNF- α）， and malondialdehyde （MDA）， superoxide dismutase （SOD） in liver tissue were measured with kit method. The hepatic index was detected. The pathological changes of liver tissue were observed by HE staining， and the degree of liver injury was scored quantitatively. The mRNA expressions of TNF-α and IL-6 in liver tissue were detected by real-time fluorescence quantitative PCR； the protein expressions of Janus kinase 2 （JAK2）， signal transducer and activator of transcription protein 3 （STAT3） and nuclear factor-κB p65 （NF-κB p65） in liver tissue were detected by Western blot assay. RESULTS Compared with normal group，the levels of ALT， AST， IL-6， TNF-α and MDA， the hepatic index were increased significantly （P＜0.05）， while the level of SOD was decreased significantly （P＜0.05）； the mRNA E-mail：qhwang668@sina.com expressions of IL-6 and TNF-α， and the protein expressions of JAK2， STAT3 and NF-κB p65 were up-regulated significantly （P＜0.05）； the pathological observation of liver tissue showed that the structure of hepatic cord was seriously disordered， there were many inflammatory cells infiltration of liver cells， and the liver injury score was significantly increased （P＜0.05）. Compared with model group， pathological changes and above indexes in mice were improved significantly in Arisaema Cum Bile low-dose and high-dose groups （P＜0.05）. CONCLUSIONS Arisaema Cum Bile has a protective effect on CCl4-induced acute liver injury in mice， which may be related to the inhibition of inflammatory response mediated by JAK2/STAT3/NF-κB signal pathway and antioxidant stress.

OBJECTIVE：To identify Panax notoginseng and its processed products . METHODS ：The fingerprint was established by HPLC. Using ginsenoside Rb 1 as reference ，HPLC fingerprints of 15 batches of P. notoginseng and its processed products were drawn and the similarity evaluation was conducted by using the Similarity Evaluation System for TCM Chromatographic Fingerprints（2012 edition）. The common peaks were confirmed by comparing with substance control. SPSS 21.0 and SIMCA 14.1 software were used to perform cluster analysis ，principal component analysis and orthogonal partial least squares-discriminant analysis；taking the variable importance projection （VIP）value greater than 1 as the standard ，the differential marker components causing the quality difference between P. notoginseng and its processed products were screened. IR fingerprints of P. notoginseng and its processed products were established by OMNIC 8.2.0 software，and the spectral similarity was evaluated ；double index sequence analysis was used to analyze absorption peaks of IR fingerprints of 15 batches of P. notoginseng and its processed products. RESULTS ：There were 16 common peaks in the fingerprints of 15 batches of P. notoginseng ， and the similarities were 0.911-1.000；there were 25 common peaks in the fingerprints of processed products ，and the similaritieswere 0.862-1.000. They had 12 identical common peaks ，and wang668@sina.com three of them were ident ified as sanchinoside R 1，ginsenoside Rg1 and ginsenoside Rb 1. Results of cluster analysi s showed that when the distance was 10，15 batches of P. notoginseng could be clustered into two categories ，SW1-SW5 into one category ，SH1-SH5 and SQ 1-SQ5 into one category ，ZW1-ZW5，ZH1-ZH5 and ZQ1-ZQ5 of 15 batches of processed products could be clustered into one category. When the distance was 5，15 batches of P. notoginseng could be clustered into three categories ，SW1-SW5 into one category ，SH2-SH5 and SQ 2 into one category ，SQ1， SQ3-SQ5 and SH 1 into one category. Fifteen batches of processed products could be clustered into two categories ，ZW1-ZW5 into one category ，ZH1-ZH5 and ZQ 1-ZQ5 into one category. The results of principal component analysis showed that the cumulative variance contribution rate of the first two principal components was 80.104％ . The results of orthogonal partial least squares-discriminant analysis showed that the VIP values of the five peaks were greater than 1，which were peak H ，peak G ，peak J，peak F （ginsenoside Rg 1）and peak I. The similarity of IR fingerprints of 15 batches of P. notoginseng and its processed products were 0.889 7-1.000 0 and 0.972 8-1.000 0；the common peak rates were 80％-100％，and the variation peak rates were 0-17.65％ and 0-18.75％，respectively. By comparing the wave numbers of absorption peaks ，it was found that there were differences between P. notoginseng at 3 440 and 1 450 cm－1 and processed products at 1 530 and 575 cm－1. CONCLUSIONS ：Established HPLC fingerprint and IR fingerprint have good similarity ，and could effectively distinguish P. notoginseng and its processed products. P. notoginseng and its processed products from different habitats have high common peak rate and low variation rate ，and their chemical components are different ；peak H ，peak G ，peak J ，ginsenoside Rg 1 and peak I are differential marker components causing the quality difference between P. notoginseng and processed products.