OBJECTIVE To study the safety of Shuangshu decoction in rats and its efficacy in improving functional dyspepsia （FD） in rats. METHODS In safety test， 40 rats were divided into blank control group， Shuangshu decoction low-dose， medium- dose and high-dose groups [108， 216， 324 g/（kg·d）， calculated by raw medicine， the same applies below]； they were given relevant medicine intragastrically， for continuous 14 days. The mortality and toxic reactions of rats were recorded， and the organ indexes of the liver， kidney， spleen， lung and heart of rats were calculated； the pathological morphological changes in the liver， kidney， spleen， lung， heart， stomach， duodenum， and colon were observed to evaluate the acute toxicity of Shuangshu decoction. Another 40 rats were grouped and administered in the same way for 30 consecutive days. The mortality and toxic reactions of the rats were recorded， and the corresponding organ indexes were calculated. The pathological morphological changes in the corresponding organs were observed， and blood routine and serum biochemical indicators were measured， in order to assess the subacute toxicity of Shuangshu decoction. In pharmacodynamic experiments: 50 rats were divided into blank control group， model group， and Shuangshu decoction low-， medium-， and high-dose groups （9.45， 18.9， 37.8 g/kg）， with 10 rats in each group. Except for blank control group， rats in all other groups were used to establish the FD rat model by subcutaneous injection of loperamide （3.5 mg/kg）. Rats in each group were administered the corresponding drug solution/normal saline intragastrically， once a day， for 14 consecutive days. After the last medication， fecal moisture content， intestinal propulsion rate， gastric emptying rate and serum level of motilin were all detected， and interstitial cell of Cajal （ICC） ultrastructure of rats was observed in colon tissue. RESULTS The safety experiments showed that no death occurred in each dose group， and no significant difference was found in organ coefficient， routine blood and serum biological index， compared to blank control group （P＞0.05）； no abnormality was found in organ appearance and pathological sections. The results of the pharmacodynamic experiments showed that， compared with the blank control group， the fecal moisture content， gastric emptying rate， intestinal propulsion rate， and serum motilin levels in the model group were significantly decreased （P＜0.05）； in the colonic tissue， the mitochondria in the ICC exhibited severe swelling with the disappearance of cristae， and the endoplasmic reticulum was dilated. Compared with model group， the rats in Shuangshu decoction high-dose group showed significant increases in the above quantitative indicators （P＜ 0.05）； additionally， there was a large number of mitochondria in the ICC of the colonic tissue， with clear cristae and regular arrangement. CONCLUSIONS Shuangshu decoction is safe and has a beneficial improving effect on FD rats； its mechanism of action may be related to the regulation of gastrointestinal hormone expression to promote gastric emptying and intestinal propulsion， as well as the repair of mitochondrial structure in ICCs to restore gastrointestinal function.

Objective To systematically review the effectiveness of perioperative oral probiotics in hepatic resection patients,and provide evidence-based clinical evidence.Methods PubMed,Cochrane Library,Web of Science,EMbase,SinoMed,WanFang Data,CNKI and VIP databases were electronically searched to collect randomized controlled trials(RCTs)on perioperative oral probiotics in hepatectomized patients from inception to June 30,2023.Two reviewers independently screened literature,extracted data and assessed the risk of bias of the included studies.Meta-analysis was performed by RevMan 5.4 software.Results A total of 10 RCTs were included,including 715 patients.The Meta-analysis showed that compared to placebo or blank controls,the incidence of postoperative infections in oral probiotic patients(RR=0.60,95％CI 0.48 to 0.74,P＜0.001),serum endotoxin levels(MD=-0.88,95％CI-1.53 to-0.22,P=0.009),cumulative antibiotic use(MD=-1.48,95％CI-2.17 to-0.78,P＜0.001),AST levels(MD=-9.68,95％CI-11.36 to-8.01,P＜0.001),ALT levels(MD=-21.24,95％CI-34.81 to-7.68,P=0.002),TBiL levels(SMD=-0.70,95％CI-0.95 to-0.45,P＜0.001),CRP levels(SMD=-0.52,95％CI-0.91 to-0.13,P=0.009),procalcitonin levels(MD=-0.19,95％CI-0.32 to-0.05,P=0.006),IL-6 levels(MD=-7.30,95％CI-14.26 to-0.33,P=0.04),and the first flatus time(MD=-1.16,95％CI-1.51 to-0.82,P＜0.001),hospital stay(MD=-0.62,95％CI-0.83 to-0.41,P＜0.001),hospitalisation costs(SMD=-0.65,95％CI-0.95 to-0.34,P＜0.001)were lower.Conclusion Current evidence shows that perioperative oral probiotics can significantly reduce the postoperative infection rate and decrease the release of inflammatory factors in liver resection patients,promote the recovery of postoperative hepatic and gastrointestinal functions,and shorten the length of hospital stay and costs.Due to the limited quality and quantity of the included studies,more high quality studies are needed to verify the above conclusion.

Patients with end-stage liver disease after liver transplantation constantly suffer from malnutrition due to primary diseases and transplantation-related factors. Malnutrition will worsen clinical condition of the patients, increase the incidence of complication, length of hospital stay and medical expense after transplantation, and lower the survival rate. Sufficient nutritional support at all stages of liver transplantation is of significance. Accurate assessment of nutritional status and timely intervention are prerequisites for perioperative nutritional treatment in liver transplantation. In this article, the latest nutritional risk screening indexes and evaluation tools, nutritional support methods and other perioperative nutritional intervention measures for liver transplantation were reviewed, aiming to deepen the understanding and cognition of perioperative nutritional therapy for liver transplantation and provide reference for improving nutritional status and clinical prognosis of liver transplant recipients.

PiT2 is an inorganic phosphate (Pi) transporter whose mutations are linked to primary familial brain calcification (PFBC). PiT2 mainly consists of two ProDom (PD) domains and a large intracellular loop region (loop7). The PD domains are crucial for the Pi transport, but the role of PiT2-loop7 remains unclear. In PFBC patients, mutations in PiT2-loop7 are mainly nonsense or frameshift mutations that probably cause PFBC due to C-PD1131 deletion. To date, six missense mutations have been identified in PiT2-loop7; however, the mechanisms by which these mutations cause PFBC are poorly understood. Here, we found that the p.T390A and p.S434W mutations in PiT2-loop7 decreased the Pi transport activity and cell surface levels of PiT2. Furthermore, we showed that these two mutations attenuated its membrane localization by affecting adenosine monophosphate-activated protein kinase (AMPK)- or protein kinase B (AKT)-mediated PiT2 phosphorylation. In contrast, the p.S121C and p.S601W mutations in the PD domains did not affect PiT2 phosphorylation but rather impaired its substrate-binding abilities. These results suggested that missense mutations in PiT2-loop7 can cause Pi dyshomeostasis by affecting the phosphorylation-regulated cell-surface localization of PiT2. This study helps understand the pathogenesis of PFBC caused by PiT2-loop7 missense mutations and indicates that increasing the phosphorylation levels of PiT2-loop7 could be a promising strategy for developing PFBC therapies.
Humans ; Cell Membrane ; Mutation, Missense ; Phosphates/metabolism* ; Sodium-Phosphate Cotransporter Proteins, Type III/genetics*

Primary familial brain calcification (PFBC) is an inherited neurodegenerative disorder mainly characterized by progressive calcium deposition bilaterally in the brain, accompanied by various symptoms, such as dystonia, ataxia, parkinsonism, dementia, depression, headaches, and epilepsy. Currently, the etiology of PFBC is largely unknown, and no specific prevention or treatment is available. During the past 10 years, six causative genes (SLC20A2, PDGFRB, PDGFB, XPR1, MYORG, and JAM2) have been identified in PFBC. In this review, considering mechanistic studies of these genes at the cellular level and in animals, we summarize the pathogenesis and potential preventive and therapeutic strategies for PFBC patients. Our systematic analysis suggests a classification for PFBC genetic etiology based on several characteristics, provides a summary of the known composition of brain calcification, and identifies some potential therapeutic targets for PFBC.
Animals ; Brain Diseases/therapy* ; Xenotropic and Polytropic Retrovirus Receptor ; Brain/pathology*

ObjectiveTo explore the mechanism of Renshen Baidusan in repairing intestinal mucosa in ulcerative colitis （UC） by regulating autophagy to scavenge peroxides. MethodThe mouse model of UC was induced by free drinking of 3.0% dextran sulphate sodium （DSS） solution. Sixty male C57BL/6J mice were randomized into normal， model， mesalazine （0.3 g·kg^-1）， and high-， medium-， and low-dose （12.35， 8.22， 4.11 g·kg^-1， respectively） Renshen Baidusan groups （n=10）. The mice were administrated with corresponding drugs by gavage for 7 consecutive days. The colon tissue was stained with hematoxylin-eosin （HE） to reveal the pathological changes， and Alcian blue-Periodic acid Scheff （PAS/AB） staining was employed to observe the goblet cell changes. The fluorescence expression of reactive oxygen species （ROS） in the colon tissue was detected by the immunofluorescence assay. The activity of superoxide dismutase （SOD） and the content of malondialdehyde （MDA） were measured by the biochemical methods. Western blot was employed to determine the expression levels of proliferating cell nuclear antigen （PCNA）， microtubule-associated protein 1 light chain 3 （LC3）， leucine-rich repeat-containing G protein-coupled receptor 5 （LGR5）， and p62. ResultDestroyed mucosal epithelial structure， intestinal gland destruction， loss of goblet cells， and massive infiltration of inflammatory cells appeared in the model group. Compared with the normal group， the model group showed increased tissue damage injury （TDI） score of the colon tissue， decreased SOD activity and LC3Ⅱ/Ⅰ， PCNA value， and elevated levels of p62， MDA， ROS， and LGR5 （P<0.05）. Compared with the model group， different doses of Renshen Baidusan decreased the TDI score， promoted the generation of new goblet cells， elevated the levels of PCNA， LGR5， SOD， and LC3Ⅱ/Ⅰ， and lowered the levels of p62， MDA， and ROS （P<0.05）. Moreover， the low dose group showed the best performance （P<0.05）. ConclusionRenshen Baidusan can promote intestinal epithelial repair by activating intestinal autophagy， alleviating oxidative stress， and promoting intestinal stem cell proliferation and differentiation.

ObjectiveTo summarize the history and modern clinical application of Renshen Baidusan. MethodThe bibliometric method was used to retrieve the relevant publications of Renshen Baidusan from the ancient book database and China National Knowledge Infrastructure （CNKI）. The publications were screened according to the inclusion and exclusion criteria. The information of dynasty， book title， function， dosage and so on was extracted， on the basis of which the history， composition， dosage， decocting method， original medicinal plants， processing， and modern clinical application of this prescription were analyzed. ResultRenshen Baidusan was first recorded in the Formulary of the Bureau of Taiping People's Welfare Pharmacy， consisting of Bupleuri Radix， Glycyrrhizae Radix et Rhizoma， Platycodonis Radix， Ginseng Radix et Rhizoma， Chuanxiong Rhizoma， Poria， Aurantii Fructus， Peucedani Radix， Notopterygii Rhizoma et Radix， Angelicae Pubescentis Radix， Zingiberis Rhizoma Recens， and Menthae Haplocalycis Herba and with the effect of dispersing cold， removing dampness， reinforcing Qi， and relieving exterior. Later generations of physicians used this prescription on the basis of the record in Formulary of the Bureau of Taiping People's Welfare Pharmacy to treat cold （frequency of 112， 22.63%） and seasonal cold （frequency of 83， 16.77%）. Renshen Baidusan is widely used in modern clinical practice to treat respiratory diseases （frequency of 42， 17.65%）， skin diseases （frequency of 34， 14.29%）， and infectious diseases （frequency of 33， 13.87%）. This prescription is often modified to treat the syndrome of internal deficiency and external contraction， or external contraction of wind， cold and damp pathogens without deficiency of healthy Qi， which fully embodies the concept of treating different diseases with the same method in traditional Chinese medicine. ConclusionThe textual research reveals the key information of the classical prescription Renshen Baidusan， providing a basis for the subsequent development and application of compound preparations.

Objective:To assess the effect of intra-aortic balloon pump (IABP) on in-hospital mortality in patients with cardiac arrest undergoing extracorporeal cardiopulmonary resuscitation (ECPR).Methods:A retrospective study was performed on 696 patients with intra-hospital cardiac arrest undergoing ECPR from Samsung Medical Center in Korea between January 2004 and December 2013. According to whether IABP was used, the patients were divided into ECPR group and ECPR+IABP group. Cox regression and propensity score matching (PSM) were used to examine the correlation between IABP usage and in-hospital mortality, and standardized mean difference ( SMD) was used to check the degree of PSM. Survival analysis of in-hospital mortality was performed by the Kaplan-Meier method, and further analyzed by the Log-Rank test. Using the propensity score as weights, multiple regression model and inverse probability weighting (IPW) model were used for sensitivity analysis. In-hospital mortality, extracorporeal membrane oxygenation (ECMO) withdrawal success rate and neurological function prognosis were compared between the two groups. Results:A total of 199 patients with cardiac arrest undergoing ECPR were included, including 120 males and 79 females, and the average age was (60.0±16.8) years. Thirty-one patients (15.6%) were treated with ECPR and IABP, and 168 patients (84.4%) only received ECPR. The total hospitalized mortality was 68.8% (137/199). The 1 : 1 nearest neighbor matching algorithm was performed with the 0.2 caliper value. The following variables were selected to generate propensity scores, including age, gender, race, marital status, insurance, admission type, service unit, heart rate, mean arterial pressure, respiratory rate, pulse oxygen saturation, white blood cell count. After the propensity score matching, 24 pairs of patients were successfully matched, with the average age of (63.0±12.8) years, including 31 males and 17 females. The in-hospital mortality was 72.6% (122/168) and 48.4% (15/31) in the ECPR group and the ECPR+IABP group [hazard ratio ( HR) = 0.48, 95% confidence interval (95% CI) was 0.28-0.82, P = 0.007]. Multiple regression model, adjusted propensity score, PSM and IPW model showed that the in-hospital mortality in the ECPR+IABP group was significantly lower compared with the ECPR group ( HR = 0.44, 0.50, 0.16 and 0.49, respectively, 95% CI were 0.24-0.79, 0.28-0.91, 0.06-0.39 and 0.31-0.77, all P < 0.05). The combined application of IABP could improve the ECMO withdrawal success rate [odds ratio ( OR) = 8.95, 95% CI was 2.72-29.38, P < 0.001] and neurological prognosis ( OR = 4.06, 95% CI was 1.33-12.40, P = 0.014) in adult cardiac arrest patients. Conclusion:In patients with cardiac arrest using ECPR, the combination of IABP was independently associated with lower in-hospital mortality, higher ECMO withdrawal success rate and better neurological prognosis.

Mosaic variants resulting from postzygotic mutations are prevalent in the human genome and play important roles in human diseases. However, except for cancer-related variants, there is no collection of postzygotic mosaic variants in noncancer disease-related and healthy individuals. Here, we present MosaicBase, a comprehensive database that includes 6698 mosaic variants related to 266 noncancer diseases and 27,991 mosaic variants identified in 422 healthy individuals. Genomic and phenotypic information of each variant was manually extracted and curated from 383 publications. MosaicBase supports the query of variants with Online Mendelian Inheritance in Man (OMIM) entries, genomic coordinates, gene symbols, or Entrez IDs. We also provide an integrated genome browser for users to easily access mosaic variants and their related annotations for any genomic region. By analyzing the variants collected in MosaicBase, we find that mosaic variants that directlycontribute to disease phenotype show features distinct from those of variants in individuals with mild or no phenotypes, in terms of their genomic distribution, mutation signatures, and fraction of mutant cells. MosaicBase will not only assist clinicians in genetic counseling and diagnosis but also provide a useful resource to understand the genomic baseline of postzygotic mutations in the general human population. MosaicBase is publicly available at http://mosaicbase.com/ or http://49.4.21.8:8000.

Objective To evaluate the effect of activating adenylate-activated protein kinase (AMPK) on sepsis in aged mice and the relationship with autophagy.Methods Experiment [Twentyeight SPF female C57BL/6 mice,aged 16-19 months,weighing 25-35 g,were divided into sepsis group (group S,n=14) and sepsis plus AMPK agonist AICAR group (S+A group,n=14) by using a random number table method.In group S+A,AICAR 0.5 ml (dissolved in 5％ dimethyl sulfoxide) was administered by intragastric gavage.In group S,5％ dimethyl sulfoxide 0.5 ml was injected by intragastric gavage once a day for 7 consecutive days.The body weight of each mouse before and after administration was recorded.Sepsis was induced by intraperitoneal injection with cecal slurry 200 μl at the end of administration.Nine mice were selected in each group and observed for 7 days after establishing the model,and the survival rates were recorded.At 24 h after establishing the model,5 mice were sacrificed in each group,and spleen tissues were obtained for determination of the expression of AMPK,phosphorylated AMPK (p-AMPK),microtubule-associated protein 1 light chain 3 Ⅰ (LC3 Ⅰ) and LC3 Ⅱ (by Western blot).The ratios of p-AMPK/AMPK and LC3 Ⅱ/LC3 Ⅰ were calculated.Experiment Ⅱ Ten SPF female C57BL/6 mice,aged 16-19 months,weighing 25-35 g,were studied.The peritoneal macrophages obtained from 5 mice were extracted,cultured primarily and then randomized into control group (group C,n =5) and EG-FP E.Coli group (group E,n=5) using a random number table method.AICAR 0.5 ml was injected by intragastric gavage once a day for 7 consecutive days in the other 5 mice.The peritoneal macrophages were extracted after the end of intragastric administration,cultured primarily and then divided into 2 groups (n=5 each) using a random number table method:AICAR plus EGFP E.Coli group (group A+E) and AICAR plus autophagy inhibitor 3-methyladenine plus EGFP E.Coli group (group A+M+E).In group A+M+E,5 mmol/L 3-methyladenine 100 μl was added,and the cells were incubated for 1 h.EGFP expressingE.Coli was then added,and the cells were incubated for 1 h in E,A+E and A+E+M groups.Flow cytometry was used to detect the phagocytic ability of macrophages.Results Experiment Ⅰ The body weight was significantly lower after the end of administration than before administration in group S+A (P＜0.05).Compared with group S,the body weight was significantly decreased at the end of administration,the survival rate was increased at 7 days after establishing the model,the expression of LC3 Ⅱ in spleen tissues was up-regulated and the ratios of p-AMPK/AMPK and LC3 Ⅱ/LC3 Ⅰ were increased in group S+A (P＜0.05).Experiment Ⅱ Compared with group C,the phagocytic ability of macrophages was significantly enhanced in the other three groups (P＜0.05).Compared with group E,the phagocytic ability of macrophages was significantly enhanced in group A+E (P＜0.05),and no significant change was found in the phagocytic ability of macrophages in group A+M+E (P＞0.05).Compared with group A+E,the phagocytic ability of macrophages was significantly weakened in group A+M +E (P＜0.05).Conclusion Activating AMPK can increase the survival rate of aged mice with sepsis,and the mechanism is associated with enhancing autophagy of macrophages.