Paciente varón de tres años con sibilancias y tos crónica / Three-Year-Old Male with Wheezing and Chronic Cough

Se presenta el caso de un niño de 3 años con diagnóstico de asma, rinitis alérgica, características craneofaciales dismórficas e infecciones respiratorias altas y bajas recurrentes, manejado como asma desde un inicio. Como parte del estudio de comorbilidades, se decide realizar una prueba del sudor que sale en rango intermedio y más tarde se encuentra una mutación, donde se obtiene un resultado positivo para una copia que se asocia a fibrosis quística. Se revisará el caso, así como el diagnóstico, clínica y tratamiento del síndrome metabólico relacionado con el regulador de conductancia transmembrana de fibrosis quística (CRMS).

We present the case of a 3-year-old boy with a diagnosis of asthma, allergic rhinitis, dysmorphic craniofacial characteristics and recurrent upper and lower respiratory infections, managed as asthma from the beginning. As part of the study of comorbidi-ties, it was decided to carry out a sweat test that came out in the intermediate range and later one mutation was found, where a positive result was obtained for a copy that is associated with cystic fibrosis. The case will be reviewed, as well as the diagnosis, symptoms and treatment of the metabolic syndrome related to the cystic fibrosis trans-membrane conductance regulator (CRMS).

Effects of alfentanil on myocardial fibrosis in rats with acute myocardial infarction by regulating the SphK1/S1P signaling pathway / 中国药房

OBJECTIVE To explore the effects of alfentanil （ALF） on myocardial fibrosis in rats with acute myocardial infarction （AMI） by regulating sphingosine kinase 1 （SphK1）/sphingosine 1-phosphate （S1P） signaling pathway. METHODS Male SD rats were collected to construct AMI model by the ligation of anterior descending branch of left coronary artery. The successfully modeled rats were randomly divided into AMI model group （Model group）， ALF low-dose group （ALF-L group， 0.25 mg/kg ALF）， ALF high-dose group （ALF-H group， 0.5 mg/kg ALF）， high dose of ALF+SphK1 activator group （ALF-H+K6PC-5 group， 0.5 mg/kg ALF+1 μg/g K6PC-5）. At the same time， a sham operation group （Sham group） was set up to perform only chest opening/closing operations without ligating the anterior descending branch of left coronary artery， with 15 rats in each group. Rats in each drug group were intraperitoneally injected with the corresponding drug solution， once a day， for 4 consecutive weeks. Twelve hours after the last medication， cardiac function indicators [left ventricular systolic pressure （LVSP）， left ventricular ejection fraction （LVEF）， left ventricular systolic diameter （LVSD）， left ventricular fractional shortening （LVFS）] of rats were detected in each group； the condition of myocardial infarction， pathological changes in myocardial tissue， and degree of fibrosis were observed； serum levels of brain natriuretic peptide （BNP） and cardiac troponin Ⅰ （cTnⅠ） in rats were detected. The protein expressions of collagen Ⅰ ， collagen Ⅲ ， matrix metalloproteinase-2 （MMP-2）， SphK1 and S1P were alsodetected in the myocardial tissue of rats. RESULTS Compared with the Sham group， the arrangement of myocardial cells in the Model group was disordered， with a large number of inflammatory cells infiltrating. The levels of LVSP， LVFS and LVEF in the Model group were significantly reduced （P＜0.05）； LVSD level， myocardial infarction area， collagen volume fraction， serum levels of BNP and cTnⅠ， the protein expressions of collagen Ⅰ， collagen Ⅲ， MMP-2， SphK1 and S1P in myocardial tissue were significantly increased or enlarged （P＜0.05）. Compared with the Model group， the pathological changes and degree of fibrosis in the myocardial tissue of rats in each dose group of ALF were improved or relieved， while the quantitative indicators of rats in the ALF-H group were significantly improved and significantly better than those in ALF-L group （P＜0.05）. K6PC-5 could significantly reverse the improvement effect of high-dose ALF on the above quantitative indicators in rats （P＜0.05）. CONCLUSIONS ALF can reduce myocardial fibrosis and improve cardiac function in AMI rats， and the effect may be related to the inhibition of the SphK1/S1P signaling pathway.

Myricetin attenuates renal fibrosis by activating Nrf2/HO-1 pathway to inhibit oxidative stress / 药学学报

This paper investigates the effect of myricetin (MYR) on renal fibrosis induced by unilateral ureteral obstruction (UUO) and common bile duct ligation (CBDL) in mice and its mechanism. The animal experiment has been approved by the Ethics Committee of China Pharmaceutical University (NO: 2022-10-020). Thirty-five ICR mice were divided into control, UUO, UUO+MYR, CBDL and CBDL+MYR groups. H&E and Masson staining were used to detect pathological changes in kidney tissues. Western blot (WB) was used to detect the expression of fibrosis-related proteins in renal tissue, and total superoxide dismutase (SOD) activity detection kit (WST-8) was used to detect the changes of total SOD in renal tissue of CBDL mice. In vitro, HK-2 cells and transforming growth factor beta 1 (TGF-β1, 10 ng·mL-1) were used to induce fibrotic model, and high glucose (30 mmol·L-1) was used to induce oxidative stress model, and then treated with different concentrations of MYR, WB was used to detect the expression of fibrosis and oxidative stress-related proteins, while NIH/3T3 cells were treated with different concentrations of MYR, and their effects on cell proliferation were detected by 5-bromo-2′-deoxyuridine (Brdu). The results showed that the renal lesions in UUO group and CBDL group were severe, collagen deposition was obvious, the expression of collagen-Ⅰ (COL-Ⅰ), α-smooth muscle actin (α-SMA), fibronectin (FN), vimentin and plasminogen activator inhibitor-1 (PAI-1) protein was up-regulated, and the activity of SOD enzyme in CBDL group was significantly decreased. MYR partly reversed the above changes after treatment. MYR inhibited the proliferation of NIH/3T3 cells but had no effect on the proliferation of HK-2 cells, and decreased the upregulation of PAI-1, FN and vimentin in HK-2 cells stimulated by TGF-β1. MYR can also up-regulate the down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in HK-2 cells stimulated by high glucose. To sum up, MYR can improve renal fibrosis in vivo and in vitro, probably by inhibiting the proliferation of fibroblasts and activating Nrf2/HO-1 signal pathway to inhibit oxidative stress.

Value of MRI biliary score and liver/muscle ratio in evaluating the pathological grade of liver fibrosis / 临床肝胆病杂志

ObjectiveTo investigate the value of biliary score and hepatic signal intensity-to-muscle signal intensity ratio （HMR） obtained by multiphase contrast-enhanced MRI scan using Gd-EOB-DTPA in evaluating the pathological grade of liver fibrosis. MethodsA retrospective analysis was performed for the MRI and clinical data of 51 patients with chronic hepatitis B liver fibrosis in Wuming Hospital Affiliated to Guangxi Medical University from January 2020 to May 2023. The 51 patients with liver fibrosis were divided into low-grade group （S1-S2） and high-grade group （S3-S4）. GE Architact 3.0T MR scanner was used to perform MRI scans， including routine plain scan and contrast-enhanced scan at arterial phase， portal venous phase， delayed phase， hepatobiliary phase， and excretory phase， and biliary score and HMR were measured for the patients with different grades of liver fibrosis. The t-test was used for comparison of continuous data between groups， and the chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups. The receiver operating characteristic （ROC） curve was plotted to evaluate the value of MRI indicators in determining the pathological grade of liver fibrosis. ResultsAmong the 51 patients with liver fibrosis， there were 30 patients in the low-grade group and 21 in the high-grade group. Compared with the high-grade group， the low-grade group had significantly higher biliary score （3.67±0.55 vs 2.57±0.75， t=6.05， P<0.001） and HMR at portal venous phase （2.38±0.76 vs 1.97±0.18， t=2.41， P=0.020）， delayed phase （2.48±0.70 vs 1.99±0.27， t=3.09， P=0.003）， and hepatobiliary phase （4.10±0.63 vs 3.16±0.47， t=5.81， P<0.001）. The above indicators had an area under the ROC curve （AUC） of 0.86， 0.79， 0.82， and 0.88， respectively， in distinguishing low- and high-grade liver fibrosis， with a positive rate of 70%， 63.3%， 83.3%， and 96.7%， respectively， and a negative rate of 90%， 95.2%， 74.1%， and 100%， respectively， in the diagnosis of high-grade liver fibrosis. Biliary score combined HMR had an AUC of 0.95， with a positive rate of 85.7% and a negative rate of 96.7%. ConclusionBiliary score and HMR at hepatobiliary phase obtained by multiphase contrast-enhanced MRI scan using Gd-EOB-DTPA has a relatively high diagnostic efficacy in distinguishing between low- and high-grade liver fibrosis and a certain guiding value for the diagnosis and treatment of liver fibrosis in clinical practice.

Pathogenesis of Idiopathic Pulmonary Fibrosis and Modulating Effect of Chinese Medicine： A Review / 中国实验方剂学杂志

Idiopathic pulmonary fibrosis （IPF）， as a progressive lung disease， has a poor prognosis and no reliable and effective therapies. IPF is mainly treated by organ transplantation and administration of chemical drugs， which are ineffective and induce side effects， failing to meet the clinical needs. Therefore， developing safer and more effective drugs has become an urgent task， which necessitates clear understanding of the pathogenesis of IPF. The available studies about the pathogenesis of IPF mainly focus on macrophage polarization， epithelial-mesenchymal transition （EMT）， oxidative stress， and autophagy， while few studies systematically explain the principles and links of the pathogeneses. According to the traditional Chinese medicine theory， Qi deficiency and blood stasis and Qi-Yang deficiency are the key pathogeneses of IPF. Therefore， the Chinese medicines or compound prescriptions with the effects of replenishing Qi and activating blood， warming Yang and tonifying Qi， and eliminating stasis and resolving phlegm are often used to treat IPF. Modern pharmacological studies have shown that such medicines play a positive role in inhibiting macrophage polarization， restoring redox balance， inhibiting EMT， and regulating cell autophagy. However， few studies report how Chinese medicines regulate the pathways in the treatment of IPF. By reviewing the latest articles in this field， we elaborate on the pathogenesis of IPF and provide a comprehensive overview of the mechanism of the active ingredients or compound prescriptions of Chinese medicines in regulating IPF. Combining the pathogenesis of IPF with the modulating effects of Chinese medicines， we focus on exploring systemic treatment options for IPF， with a view to providing new ideas for the in-depth study of IPF and the research and development of related drugs.

CircRNA Circ_0120051 Inhibits the Fibrotic Phenotype of Myocardial Fibroblasts via Targeting miR-144-3p/IDH2 Axis / 中山大学学报(医学科学版)

ObjectiveTo investigate the regulatory effect of circular RNA circ_0120051 on the fibrotic phenotype of cardiac fibroblasts and the potential mechanism involved. MethodsThe expression of circ_0120051 and its host gene of solute carrier family 8 member A1（SLC8A1） mRNA in the myocardium of healthy organ donors （n=24） and heart failure （HF） patients （n=21） were assessed by real-time quantitative polymerase chain reaction （RT-qPCR） assay. RNA stability of circ_0120051 was identified by RNase R exonuclease digestion assay. The cytoplasmic and nuclear distribution of circ_0120051 in human cardiomyocyte AC16 was detected by RT-qPCR assay. The expression of fibrosis-related genes in mouse cardiac fibroblasts （mCFs） with adenovirus-mediated overexpression of circ_0120051 was detected by RT-qPCR and Western blot assay， respectively. The effect of overexpression of circ_0120051 on the migration activity of mCFs was evaluated by wound-healing assay. RNA co-immunoprecipitation （RIP） was conducted to detect the interaction between circ_0120051 and miR-144-3p. The binding site of miR-144-3p in the 3'-UTR of isocitrate dehydrogenase 2 （Idh2） mRNA was identified by the dual luciferase reporter gene assay. ResultsCirc_0120051 was significantly up-regulated in the myocardium of HF patients， while the mRNA expression of its host gene SLC8A1 was not changed. Circ_0120051 was mainly located in the cytoplasm of human AC16 cells. Results of RNase R exonuclease digestion revealed that circ_0120051 possesses the characteristic stability of circular RNA compared to the linear SLC8A1 mRNA. Overexpression of circ_0120051 could inhibit the expression of fibrosis-related gene in mCFs and mCFs migration. RIP assay confirmed the specific interaction between circ_0120051 and miR-144-3p. Transfection of miR-144-3p mimic could efficiently promote the expression of fibrosis-related genes in mCFs and reverse the inhibitory effect of circ_0120051 on the fibrotic phenotype of mCFs. Results of the dual luciferase reporter gene assay confirmed the interaction between miR-144-3p and the 3'-UTR of Idh2. Transfection of miR-144-3p transcriptionally inhibited Idh2 expression， and overexpression of circ_0120051 enhanced IDH2 expression in mCFs. MiR-144-3p mimic and Idh2 small interfering RNA （siRNA） could consistently reverse the inhibitory effects of circ_0120051 on fibrosis-related genes expression in mCFs and mCFs migration. ConclusionsCirc_0120051 inhibits the fibrotic phenotype of cardiac fibroblasts via sponging miR-144-3p to enhance the target gene of IDH2 expression.

Nuclear factor-KB signaling pathway and gender differences in alcoholic liver fibrosis / 解剖学报

Objective To investigate the relationship between nuclear factor(NF)-κB signaling pathway and gender differences in alcoholic liver fibrosis. Methods C57BL/6 N mice at 7-8 weeks of age were randomly divided into: male normal group, male model group, female normal group and female model group of 20 mice each. The normal group was fed with control liquid diet for 8 weeks, and the model group was fed with alcoholic liquid diet for 8 weeks combined with 31.5% ethanol gavage (5g/kg twice a week) to establish an alcoholic liver fibrosis model. The mice were executed at the end of 8 weekends, and the alanine aminotransferase (ALT), aspartate aminotransferase (AST) activity, estradiol (E

Novel mechanisms driving renal tubulointerstitial fibrosis / 中国临床药理学与治疗学

Renal fibrosis, especially tubulointerstitial fibrosis, is the most common pathway of all chronic kidney diseases progressing to end-stage renal diseases. Several adaptive reactions occur in renal tubular epithelial cells after chronic injury, such as changes in glycolipid metabolism, unfolded protein response, autophagy and senescence, epithelial-to-mesenchymal transition and G2/M cell cycle arrest. Maladaptive repair mechanisms can induce tubulointerstitial fibrosis. This article will discuss the molecular mechanism of these adaptive responses of renal tubular epithelial cells driving renal tubulointerstitial fibrosis, and provide a basis for exploring new drug targets for renal tubulointerstitial fibrosis.

Progress in the potential therapeutic mechanism of mesenchymal stem cell-derived exosomes for liver fibrosis / 中国临床药理学与治疗学

Liver fibrosis is pathological in most chronic liver diseases. Exosomes secreted by mesenchymal stem cells (MSCs) can regulate liver fibrosis through mechanisms such as inhibition of inflammatory response and proliferation of activated hepatic stellate cells, regulation of immune cells and metabolism. Therefore, MSC-derived exosomes can be used as a cell-free therapy for chronic liver disease, expanding new ideas for the treatment of chronic liver disease. Recent researches on MSC-derived exosomes in the treatment of liver fibrosis are reviewed in this article.

The regulatory effect of morphine postconditioning in left stellate ganglion on remodeling after myocardial infarction / 中国药理学通报

Aim To investigate the regulatory effect of morphine postconditioning in the LSG on remodeling after myocardial infarction. Methods SD rats were randomly divided into four groups: sham operation group (Sham), myocardial infarction group (MI), myocardial infarction + saline group (Control) and myocardial infarction + morphine postconditioning group (MI + Morphine) . The rat MI model was constructed by ligating the left anterior descending coronary artery, and then morphine was given to the LSG by percutaneous posterior approach. After four weeks, the changes of cardiac function in rats were detected by ultrasound. Masson staining was used to detect fibrosis changes; the expression of Collagen I and Collagen III protein was detected by Western blot. The mRNA expression of ANP and BNP was detected by RT-qPCR. The expression of JJLOR in LSG was detected by immunofluorescence. The concentration of catecholamine in plasma and myocardial tissue was detected by ELISA. Results Compared with the sham group, the cardiac function of the MI group was significantly impaired, the myocardial tissue showed significant fibrosis changes, and the concentration of catecholamine in plasma and myocardial tissue significantly increased. Compared with the control group, the MI + Morphine group reduced myocardial fibrosis collagen deposition in rats after MI, inhibited the expression of ANP and BNP in myocardial tissue, reduced the concentration of catecholamine, and improved the cardiac function of MI rats. Immunofluorescence results showed that JJLOR was expressed in LSG after MI and increased after morphine postconditioning. Conclusions This study shows that morphine postconditioning in the LSG has a protective effect on myocardial remodeling after myocardial infarction. The mechanism may be related to the activation of JJLOR in the LSG by morphine and the reduction of catecholamine release from sympathetic nerve endings.

Effects of 2-dodecyl-6-methoxycyclohexa-2,5-diene-l ,4-dione on resisting hepatic fibrosis induced by CC14 in rats and its mechanisms via TGF-pi/Smads signaling pathway / 中国药理学通报

Aim To investigate the effects of 2-dode-cyl-6-methoxycyclohexa-2 , 5-diene-l, 4-dione ( DM-DD) on resisting hepatic fibrosis induced by carbon tetrachloride ( CC14 ) in rats and the underlying mechanisms , with a specific focus on the TGF-pi/Smads signaling pathway. Methods The hepatic fibrosis model was replicated using 50% CC14. Various parameters, including levels of aspartate transferase ( AST) , ala-nine transferase ( ALT ) , albumin/globulin ( A/G ) , total protein (TP) , total bilirubin (T-BIL) , hyaluron-ic acid ( HA ) , laminin ( LN ) , collagen type Ж ( Col Ж) , and collagen type IV(ColIV) in the blood, were measured. Liver tissue lesions and fiber formation were observed using HE and Masson staining. The expression levels of a smooth muscle actin (a-SMA) , collagen type I ( Col I ) , transformed growth factor (TGF-pi), Smad2, and Smad7 proteins were assessed using immunohistochemistry. a-SMA, Coll, TGF-pi, and Smad7 mRNA levels in liver tissue were measured by RT-PCR. Additionally, the expression levels of TGF-pi, Smad4, and Smad7 proteins in liver tissue were determined by Western blot. Results In comparison to the normal control group, the model group exhibited significantly elevated levels of AST, ALT, TP, T-BIL, HA, LN, Col Ш and Col IV in serum. But A/G level notably decreased. Successful modeling was confirmed by the presence of extensive fiber formations observed through HE and Massonstaining in liver tissue. The DMDD administration group demonstrated a notable decrease levels of AST, ALT, TP, T-BIL, HA, LN, Col III, and CollV, but A/G was significantly elevated when compared to the model group. Furthermore, a-SMA, Coll, TGF-f31, Smad2 and Smad4 mRNA and protein levels in the DMDD administration group were significantly reduced, while Smad7 significantly declined. HE and Masson staining results reflected a marked reduction in fibrous hyper-plasia. Conclusion DMDD exhibits a protective effect against CCl4-induced hepatic fibrosis, and its mechanism appears to be associated with the TGF-fJl/ Smads signaling pathway.

Effect of LAG3 deficiency on natural killer cell function and hepatic fibrosis in mice infected with Echinococcus multilocularis / 中国血吸虫病防治杂志

Objective To investigate the effect of LAG-3 deficiency (LAG3-/-) on natural killer (NK) cell function and hepatic fibrosis in mice infected with Echinococcus multilocularis. Methods C57BL/6 mice, each weighing (20 ± 2) g, were divided into the LAG3-/- and wild type (WT) groups, and each mouse in both groups was inoculated with 3 000 E. multilocularis protoscoleces via the hepatic portal vein. Mouse liver and spleen specimens were collected 12 weeks post-infection, sectioned and stained with sirius red, and the hepatic lesions and fibrosis were observed. Mouse hepatic and splenic lymphocytes were isolated, and flow cytometry was performed to detect the proportions of hepatic and splenic NK cells, the expression of CD44, CD25 and CD69 molecules on NK cell surface, and the secretion of interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), interleukin (IL)-4, IL-10 and IL-17A. Results Sirius red staining showed widening of inflammatory cell bands and hyperplasia of fibrotic connective tissues around mouse hepatic lesions, as well as increased deposition of collagen fibers in the LAG3-/-group relative to the WT group. Flow cytometry revealed lower proportions of mouse hepatic (6.29% ± 1.06% vs. 11.91% ± 1.85%, P < 0.000 1) and splenic NK cells (4.44% ± 1.22% vs. 5.85% ± 1.10%, P > 0.05) in the LAG3-/- group than in the WT group, and the mean fluorescence intensity of CD44 was higher on the surface of mouse hepatic NK cells in the LAG3-/- group than in the WT group (t = −3.234, P < 0.01), while no significant differences were found in the mean fluorescence intensity of CD25 or CD69 on the surface of mouse hepaticNK cells between the LAG3-/- and WT groups (both P values > 0.05). There were significant differences between the LAG3-/- and WT groups in terms of the percentages of IFN-γ (t = −0.723, P > 0.05), TNF-α (t = −0.659, P > 0.05), IL-4 (t = −0.263, P > 0.05), IL-10 (t = −0.455, P > 0.05) or IL-17A secreted by mouse hepatic NK cells (t = 0.091, P > 0.05), and the percentage of IFN-γ secreted by mouse splenic NK cells was higher in the LAG3-/- group than in the WT group (58.40% ± 1.64% vs. 50.40% ± 4.13%; t = −4.042, P < 0.01); however, there were no significant differences between the two groups in terms of the proportions of TNF-α (t = −1.902, P > 0.05), IL-4 (t = −1.333, P > 0.05), IL-10 (t = −1.356, P > 0.05) or IL-17A secreted by mouse splenic NK cells (t = 0.529, P > 0.05). Conclusions During the course of E. multilocularis infections, LAG3-/- promotes high-level secretion of IFN-γ by splenic NK cells, which may participate in the reversal the immune function of NK cells, resulting in aggravation of hepatic fibrosis.

Dynamic observation on capillarization of liver sinusoidal endothelial cells induced by Echinococcus multilocularis infection / 中国血吸虫病防治杂志

Objective To investigate the capillarization of liver sinusoidal endothelial cells (LSECs) and its association with hepatic fibrosis during the development of alveolar echinococcosis, so as to provide the basis for unraveling the mechanisms underlying the role of LSEC in the development and prognosis of hepatic injuries and hepatic fibrosis caused by alveolar echinococcosis. Methods Forty C57BL/6 mice at ages of 6 to 8 weeks were randomly divided into a control group and 1-, 2- and 4-week infection groups, of 10 mice in each group. Each mouse in the infection groups was intraperitoneally injected with 2 000 Echinococcus multilocularis protoscoleces, while each mouse in the control group was given an equal volume of phosphate-buffered saline using the same method. All mice were sacrificed 1, 2 and 4 weeks post-infection and mouse livers were collected. The pathological changes of livers were observed using hematoxylin-eosin (HE) staining, and hepatic fibrosis was evaluated through semi-quantitative analysis of Masson’s trichrome staining-positive areas. The activation of hepatic stellate cells (HSCs) and extracellular matrix (ECM) deposition were examined using immunohistochemical staining of α-smooth muscle actin (α-SMA) and collagen type I alpha 1 (COL1A1), and the fenestrations on the surface of LSECs were observed using scanning electron microscopy. Primary LSECs were isolated from mouse livers, and the mRNA expression of LSEC marker genes Stabilin-1, Stabilin-2, Ehd3, CD209b, GATA4 and Maf was quantified using real-time fluorescence quantitative PCR (qPCR) assay. Results Destruction of local liver lobular structure was observed in mice 2 weeks post-infection with E. multilocularis protoscoleces, and hydatid cysts, which were surrounded by granulomatous tissues, were found in mouse livers 4 weeks post-infection. Semi-quantitative analysis of Masson’s trichrome staining showed a significant difference in the proportion of collagen fiber contents in mouse livers among the four groups (F = 26.060, P < 0.001), and a higher proportion of collagen fiber contents was detected in mouse livers in the 4-week infection group [(11.29 ± 2.58)%] than in the control group (P < 0.001). Immunohistochemical staining revealed activation of a few HSCs and ECM deposition in mouse livers 1 and 2 weeks post-infection, and abundant brown-yellow stained α-SMA and COL1A1 were deposited in the lesion areas in mouse livers 4 weeks post-infection, which spread to surrounding tissues. Semi-quantitative analysis revealed significant differences in α-SMA (F = 7.667, P < 0.05) and COL1A1 expression (F = 6.530, P < 0.05) in mouse levers among the four groups, with higher α-SMA [(7.13 ± 3.68)%] and COL1A1 expression [(13.18 ± 7.20)%] quantified in mouse livers in the 4-week infection group than in the control group (both P values < 0.05). Scanning electron microscopy revealed significant differences in the fenestration frequency (F = 37.730, P < 0.001) and porosity (F = 16.010, P < 0.001) on the surface of mouse LSECs among the four groups, and reduced fenestration frequency and porosity were observed in the 1-[(1.22 ± 0.48)/μm2 and [(3.05 ± 0.91)%] and 2-week infection groups [(3.47 ± 0.10)/μm2 and (7.57 ± 0.23)%] groups than in the control group (all P values < 0.001). There was a significant difference in the average fenestration diameter on the surface of mouse LSECs among the four groups (F = 15.330, P < 0.001), and larger average fenestration diameters were measured in the 1-[(180.80 ± 16.42) nm] and 2-week infection groups [(161.70 ± 3.85) nm] than in the control group (both P values < 0.05). In addition, there were significant differences among the four groups in terms of Stabilin-1 (F = 153.100, P < 0.001), Stabilin-2 (F = 57.010, P < 0.001), Ehd3 (F = 31.700, P < 0.001), CD209b (F = 177.400, P < 0.001), GATA4 (F = 17.740, P < 0.001), and Maf mRNA expression (F = 72.710, P < 0.001), and reduced mRNA expression of Stabilin-1, Stabilin-2, Ehd3, CD209b, GATA4 and Maf genes was quantified in three infection groups than in the control group (all P values < 0.001). Conclusions E. multilocularis infections may induce capillarization of LSECs in mice, and result in a reduction in the expression of functional and phenotypic marker genes of LSECs, and capillarization of LSECs occurs earlier than activation of HSC and development of hepatic fibrosis.

Role of Macrophage Activation and Polarization in Myocardial Fibrosis and Intervention of Traditional Chinese Medicine / 中国实验方剂学杂志

Myocardial fibrosis （MF） is a common pathological manifestation of various heart diseases. Due to the non-renewable nature of myocardial cells， the occurrence of MF represents irreversible damage to the myocardium. Previous studies have suggested that fibroblast-mediated collagen deposition is the main mechanism of MF. Recent studies have found that there is an immune regulation mechanism in the heart itself， and macrophage activation/polarization plays an important role in MF. With the deepening of traditional Chinese medicine research， scholars have found that traditional Chinese medicine can interfere with MF by regulating the renin-angiotensin-aldosterone system （RAAS） system and the inflammatory process， repairing the extracellular matrix， managing oxidative stress， and maintaining the balance of autophagy. This process is closely related to the activation and M1/M2 polarization of macrophages. Throughout the MF process， macrophage activation is beneficial， but excessive activation will be harmful. In the early stage of MF， appropriate M1 macrophage polarization is conducive to activating immunity and removing harmful substances. In the middle and late stages of MF， appropriate M2 macrophage polarization is conducive to remodeling the damaged myocardium. If macrophage activation is excessive/insufficient， or the balance of M1/M2 macrophage polarization is broken， the effect changes from improvement to destruction. Traditional Chinese medicines that regulate the activation/polarization of macrophages have the effects of replenishing Qi and nourishing Yin， as well as regulating Qi and activating blood， but there are also some heat-clearing， dampness-drying， and detoxification products. Therefore， the occurrence of MF may be caused by Qi and Yin deficiency， damp heat accumulation， and Qi stagnation and blood stasis. By summarizing the biological processes involved in macrophage activation/polarization in MF， this paper expounded on the research progress of traditional Chinese medicine in regulating macrophage activation and M1/M2 polarization from different angles to improve MF， so as to provide a reference for the treatment of MF with traditional Chinese medicine.

Regulatory effect and mechanism of macrophage polarization in liver fibrosis / 临床肝胆病杂志

Liver fibrosis is the healing reaction of chronic liver injury caused by various factors such as viral infection， alcohol， and chemical substances and is a key link in the progression of chronic liver diseases to liver cirrhosis and liver cancer. Liver macrophages are considered important mediators of liver injury and repair， and the polarization trend of macrophages has a bidirectional regulatory effect on liver fibrosis. This article reviews the role of different phenotypes of liver macrophages in the development and progression of liver fibrosis， in order to provide new ideas for the prevention and treatment of fibrosis.

Role of podoplanin in hepatic stellate cell activation and liver fibrosis / 临床肝胆病杂志

ObjectiveTo investigate the role and mechanism of podoplanin （PDPN） in hepatic stellate cell （HSC） activation and liver fibrosis. MethodsLiver biopsy samples were collected from 75 patients with chronic hepatitis B who attended Department of Infectious Diseases， Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine， for the first time from September 2019 to June 2022， and RT-PCR and immunohistochemistry were used to measure the expression of PDPN in liver tissue of patients in different stages of liver fibrosis. A total of 12 male C57/BL6 mice were randomly divided into control group and model group. The mice in the model group were given intraperitoneal injection of 10% CCl4， and those in the control group were injected with an equal volume of olive oil， for 6 weeks. HE staining and Sirius Red staining were used to observe liver histopathological changes； primary mouse liver cells were separated to measure the mRNA expression of PDPN in various types of cells； primary mouse HSCs were treated with PDPN protein， followed by treatment with the NF-‍κB inhibitor BAY11-708， to measure the expression of inflammatory factors in HSCs induced by PDPN. The independent-samples t test was used for comparison of normally distributed continuous data between two groups； a one-way analysis of variance was used for comparison between multiple groups， and the least significant difference t-test was used for further comparison between two groups. The Spearman correlation analysis was used to investigate data correlation. ResultsAs for the liver biopsy samples， there was a relatively low mRNA expression level of PDPN in normal liver， and there was a significant increase in the mRNA expression level of PDPN in liver tissue of stage S3 or S4 fibrosis （all P<0.001）. Immunohistochemical staining showed that PDPN was mainly expressed in the fibrous septum and the hepatic sinusoid， and the PDPN-positive area in S4 liver tissue was significantly higher than that in S0 liver tissue （t=8.892， P=0.001）. In normal mice， PDPN was mainly expressed in the hepatic sinusoid， and there was a significant increase in the expression of PDPN in CCl4 model mice （t=0.95， P<0.001）， mainly in the fibrous septum. RT-PCR showed a significant increase in the mRNA expression of PDPN in the CCl4 model mice （t=11.25， P=0.002）. Compared with hepatocytes， HSCs， Kupffer cells， and bile duct endothelial cells， hepatic sinusoidal endothelial cells showed a significantly high expression level of PDPN （F=20.56， P<0.001）. Compared with the control group， the primary mouse HSCs treated by PDPN protein for 15 minutes showed significant increases in the mRNA expression levels of the inflammation-related factors TNFα， CCL3， CXCL1， and CXCR1 （all P<0.05）， and there were significant reductions in the levels of these indicators after treatment with BAY11-7082 （all P<0.05）. ConclusionThere is an increase in the expression of PDPN mainly in hepatic sinusoidal endothelial cells during liver fibrosis， and PDPN regulates HSC activation and promotes the progression of liver fibrosis via the NF-κB signaling pathway.

Effect of human umbilical cord mesenchymal stem cells in treatment of mice with liver fibrosis and its mechanism / 临床肝胆病杂志

ObjectiveTo investigate the effect of human umbilical cord mesenchymal stem cells （hUCMSCs） in the treatment of mice with liver fibrosis and its mechanism. MethodsA total of 18 specific pathogen-free C57BL/6 mice， aged 6 weeks， were selected and divided into control group （n=6）， carbon tetrachloride （CCl4） model group （CCl4 group， n=6）， and hUCMSCs treatment group （MSC group， n=6） using a random number table. The mice in the CCl4 group and the MSC group were given intraperitoneal injection of CCl4 solution to establish a mouse model of liver fibrosis， while those in the control group were injected with the same dose of corn oil， and the mice in the MSC group were injected with hUCMSCs via the caudal vein during the injection of CCl4. At the end of week 8， mouse serum was collected， and the mice were sacrificed to collect and fix the liver. Enzyme-linked immunosorbent assay was used to measure the levels of inflammatory factors； an automatic biochemical detector was used to measure liver function parameters； HE staining， Masson staining， Sirius Red staining， and α-SMA immunofluorescence assay were used to evaluate liver fibrosis. Hepatic stellate cells （HSCs） stimulated by TGF-β were co-cultured with hUCMSCs in the medium with or without chitinase-3 like-protein-1 （CHI3L1）， and Western blot was used to measure the expression levels of proteins. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the Dunnett’s t-test was used for further comparison between two groups. ResultsMasson staining and Sirius Red staining showed that the CCl4 group had a significantly higher degree of fibrosis than the control group （both P<0.05）， and the MSC group had significant alleviation of fibrosis compared with the CCl4 group （both P<0.05）. Compared with the control group， the CCl4 group had significant increases in the levels of interleukin-1β， interleukin-6 （IL-6）， aspartate aminotransferase （AST）， alanine aminotransferase （ALT）， and alkaline phosphatase （ALP） （all P<0.05）， and compared with the CCl4 group， the MSC group had significant reductions in the levels of IL-6， AST， ALT， and ALP （all P<0.05）. The CCl4 group had significantly higher expression levels of CHI3L1 and α-SMA than the control group and the MSC group （all P<0.05）. The cell culture experiment showed that the MSC+HSC group had a significantly higher expression level of Bax than the HSC group and the MSC+CHI3L1 group （both P<0.05）， suggesting that CHI3L1 reversed the pro-apoptotic effect of MSC on activated HSCs. ConclusionThis study shows that hUCMSCs can improve liver fibrosis in mice， possibly by inhibiting CHI3L1 to promote the apoptosis of HSCs.

Application value of two-dimensional shear wave elastography and serological models in the staging of liver fibrosis in patients with chronic hepatitis B / 临床肝胆病杂志

ObjectiveTo investigate the value of two-dimensional shear wave elastography （2D-SWE） or serological models used alone or in combination in determining the stage of liver fibrosis in patients with chronic hepatitis B. MethodsA retrospective analysis was performed for the clinical data of 327 patients with chronic hepatitis B who were admitted to Mengchao Hepatobiliary Hospital of Fujian Medical University from August 2020 to August 2022 and underwent 2D-SWE and liver histopathological examination， including sex， age， serological markers， and 2D-SWE results. According to the degree of liver fibrosis， they were divided into S0-S1， S≥2， S≥3， and S=4 groups， and the serological models were calculated based on serological markers. A Spearman correlation analysis was used to investigate the correlation of 2D-SWE and serological models with liver fibrosis stage； the receiver operating characteristic curve was plotted with the results of liver histopathology as the standard to compare the efficiency of each parameter used alone or in combination in determining the stage of liver fibrosis； the Delong test was used to investigate the difference between different methods. ResultsLiver stiffness measurement measured by 2D-SWE was strongly correlated with the stage of liver fibrosis （r=0.741， P<0.001）， and as for the serological model， six markers （APRI， FIB-4， GPR， GP， RPR， and S index）， other than AAR， were positively correlated with the stage of liver fibrosis （all P<0.001）. 2D-SWE had an area under the ROC curve （AUC） of 0.878， 0.932， and 0.942， respectively， in the diagnosis of S≥2， S≥3， and S=4 liver fibrosis （all P<0.001）， with an optimal cut-off value of 6.9 kPa， 7.9 kPa， and 9.4 kPa， respectively. Among the serological models， APRI had the largest AUC of 0.788 and 0.875， respectively， in the diagnosis of S≥2 and S=4 liver fibrosis， and S index had the largest AUC of 0.846 in the diagnosis of S≥3 liver fibrosis. In the diagnosis of S≥2， S≥3， and S=4 liver fibrosis， 2D-SWE combined with APRI increased the AUC values to 0.887， 0.938， and 0.950， respectively， and 2D-SWE combined with S index increased the AUC values to 0.879， 0.935， and 0.941， respectively， while there were no significant differences between 2D-SWE and the above combinations （P>0.05）. Conclusion2D-SWE has a better diagnostic efficacy than the above seven serological models in determining liver fibrosis stage. The serological models have a certain diagnostic value， among which APRI and S index have a relatively high diagnostic value. There is no significant difference between 2D-SWE and 2D-SWE combined with serological models， and such combinations cannot significantly improve diagnostic efficiency. Therefore， further studies are needed to explore new combinations of diagnostic methods.

Ameliorative effect and mechanism of Sanwei ganlu on hepatic fibrosis in rats / 中国药房

OBJECTIVE To investigate the ameliorative effects and mechanism of Sanwei ganlu on hepatic fibrosis in rats. METHODS The rats were randomly divided into normal group， model group， silibinin group （positive control， 50 mg/kg）， and Sanwei ganlu low-dose， medium-dose， and high-dose groups （80， 250， 800 mg/kg）. Except for normal group， hepatic fibrosis rat models were established by intraperitoneal injection of CCl4 in the other groups of rats. Starting from the 6th week of modeling administration， they were given normal saline or corresponding drugs intragastrically at the same time. At the end of the ninth-week experiment， liver and spleen indexes of rats were calculated； the pathological structure and fibrosis changes of liver tissue were observed by HE， Masson and Sirus Red staining. The contents of alanine transaminase （ALT）， aspartate transaminase （AST）， procollagen type Ⅲ （PC Ⅲ）， collagen type Ⅳ （COL-Ⅳ）， interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α） and IL-1β in serum， and hyaluronic acid （HA） and laminin （LN） in liver tissue were all detected. RESULTS Compared with the model group， the liver injury and collagen fiber deposition of rats were improved to different extents in Sanwei ganlu groups and silibinin group； the contents of ALT， AST， PC Ⅲ， COL-Ⅳ， IL-6， TNF-α and IL-1β in serum as well as the contents of HA and LN in liver tissue significantly decreased （P＜0.05 or P＜0.01）. CONCLUSIONS Sanwei ganlu can alleviate the progression of hepatic fibrosis in rats， possibly by inhibiting the synthesis of collagen fiber， reducing transaminase content， down-regulating the levels of HA， LN， PC Ⅲ and COL-Ⅳ， and reducing the inflammatory response.

Intervention effect and mechanism of breviscapine on hepatic fibrosis in rats / 中国药房

OBJECTIVE To investigate the intervention effect and potential mechanism of breviscapine on hepatic fibrosis （HF） in rats based on the transforming growth factor-β（1 TGF-β1）/Smad2/extracellular signal-regulated protein kinase 1（ERK1） and Kelch-like epichlorohydrin-associated protein 1（Keap1）/nuclear factor-erythroid 2-related factor 2（Nrf2）/heme oxygenase-1（HO-1） pathways. METHODS Totally 60 rats were randomly divided into normal control group， model group， breviscapine low-dose， medium-dose and high-dose groups （5.4， 10.8， 21.6 mg/kg）， and colchicine group （positive control， 0.45 mg/kg）， with 10 rats in each group， half male and half female. Except for the normal control group， HF model of the other groups was induced by carbon tetrachloride. Subsequently， each drug group was given corresponding medicine by gavage once a day for 28 days. The liver appearance of rats in each group was observed and their liver coefficients were calculated. The levels of alanineaminotransferase （ALT） and aspartate aminotransferase （AST）in serum， those of ALT， AST， superoxide dismutase （SOD），malondialdehyde （MDA） and glutathione peroxidase （GSH- Px） in liver tissue were detected. The liver tissue inflammatory and fibrotic changes were observed. The protein and mRNA expressions of TGF-β1， Smad2， ERK1， Nrf2， Keap1 and HO-in liver tissue were detected. RESULTS Compared with the normal control group， the model group showed large areas of white nodular lesions in the liver， obvious inflammatory cell infiltration and collagen fiber deposition. The body weight， the levels of SOD and GSH-Px in liver tissue， the protein and mRNA expressions of Nrf2 and HO-1 were significantly lowered in the model group （P＜0.05）； the liver coefficient， the percentage of Masson staining positive area， ALT and AST levels of serum and liver tissue， MDA level of liver tissue， the protein and mRNA expressions of TGF-β1， Smad2， ERK1 and Keap1 were significantly increased （P＜0.05）. Compared with the model group， the liver lesions of rats in each drug group were improved， and the above quantitative indexes were generally reversed （P＜0.05）. CONCLUSIONS Breviscapine has a good intervention effect on HF rats， which may be related to inhibiting TGF-β1/Smad2/ERK1 pathway for anti-fibrosis and regulating Keap1/Nrf2/HO-1 pathway to inhibit oxidative stress.