Post-translational protein lactylation modification in health and diseases: a double-edged sword.

As more is learned about lactate, it acts as both a product and a substrate and functions as a shuttle system between different cell populations to provide the energy for sustaining tumor growth and proliferation. Recent discoveries of protein lactylation modification mediated by lactate play an increasingly significant role in human health (e.g., neural and osteogenic differentiation and maturation) and diseases (e.g., tumors, fibrosis and inflammation, etc.). These views are critically significant and first described in detail in this review. Hence, here, we focused on a new target, protein lactylation, which may be a "double-edged sword" of human health and diseases. The main purpose of this review was to describe how protein lactylation acts in multiple physiological and pathological processes and their potential mechanisms through an in-depth summary of preclinical in vitro and in vivo studies. Our work aims to provide new ideas for treating different diseases and accelerate translation from bench to bedside.

[Open, multicenter, phase â £ clinical trial of Shenbei Guchang capsules in treatment of diarrhea type irritable bowel syndrome].

To evaluate the safety and effectiveness of Shenbei Guchang capsules in treatment of diarrhea type irritable bowel syndrome (yang deficiency of spleen and kidney) under widely used conditions, an open, multicenter, controlled, phase Ⅳ clinical trial was conducted in the drug clinical trial centers of 16 domestic hospitals. 2 123 patients from June 10, 2011 to November 29, 2012 were enrolled in the trial. Drug clinical trial was approved by Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital Ethics Committee before implementation. Before the start of trial, subjects were selected according to the research scheme and inclusion criteria, then they would step into the 14 d study after signing Informed Consent Form. All subjects were treated according to the research scheme, evaluated the conditions and filled in CFR sheet, to provide the evaluation data and information on safety and efficacy of Shenbei Guchang capsules. Shenbei Guchang capsules were used to treat diarrhea type irritable bowel syndrome in widely used conditions (2 123 cases), and 2 029 cases of them entered FAS set, cure+markedly effective in 1 921 cases, with a comprehensive curative effect rate of 94.68%; 2 010 cases of them entered PPS set, cure+markedly effective in 1 906 cases, with a comprehensive curative effect rate of 94.83%. The primary symptoms of IBS were abdominal pain and diarrhea. After treatment, both abdominal pain and diarrhea were improved, with significant differences (P<0.000 1). There were significant differences in traditional Chinese medicine symptom scores on both post-treatment day 7 and day 14 as compared with the conditions before treatment (P<0.000 1). 35 cases of adverse events occurred during the trial with an incidence of 1.65%, including 12 cases of drug-related adverse events (adverse reaction) with an incidence of 0.57%, mainly manifested as nausea, abdominal distension and dry mouth, most of which would be spontaneously relieved without any measures. No serious adverse events occurred. The commercially available Shenbei Guchang capsules are proved safe and effective for the treatment of diarrhea type irritable bowel syndrome (yang deficiency of spleen and kidney) under widely used conditions (2 123 cases), and can be continued for clinical promotion and application.

Astrocytic adenosine 5'-triphosphate release regulates the proliferation of neural stem cells in the adult hippocampus.

Astrocytes are key components of the niche for neural stem cells (NSCs) in the adult hippocampus and play a vital role in regulating NSC proliferation and differentiation. However, the exact molecular mechanisms by which astrocytes modulate NSC proliferation have not been identified. Here, we identified adenosine 5'-triphosphate (ATP) as a proliferative factor required for astrocyte-mediated proliferation of NSCs in the adult hippocampus. Our results indicate that ATP is necessary and sufficient for astrocytes to promote NSC proliferation in vitro. The lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficient ATP release from astrocytes. This deficiency led to a dysfunction in NSC proliferation that could be rescued via the administration of exogenous ATP. Moreover, P2Y1-mediated purinergic signaling is involved in the astrocyte promotion of NSC proliferation. As adult hippocampal neurogenesis is potentially involved in major mood disorder, our results might offer mechanistic insights into this disease.

Effectiveness and safety of Moluodan in the treatment of precancerous lesions of gastric cancer: A randomized clinical trial.

OBJECTIVE: To investigate the clinical potential and safety of Moluodan to reverse gastric precancerous lesions. METHODS: Patients aged 18-70 years diagnosed with moderate-to-severe atrophy and/or moderate-to-severe intestinal metaplasia, with or without low-grade dysplasia, and negative for Helicobacter pylori were recruited in this randomized, double-blind, parallel-controlled trial. The primary outcome was the improvement of global histological diagnosis at 1-year follow-up endoscopy using the operative link for gastritis assessment, the operative link for gastric intestinal metaplasia assessment, and the disappearance rate of dysplasia. RESULTS: Between November 3, 2017 and January 27, 2021, 166 subjects were randomly assigned to the Moluodan group, 168 to the folic acid group, 84 to the combination group, and 84 to the high-dose Moluodan group. The improvement in global histological diagnosis was achieved in 60 (39.5%) subjects receiving Moluodan, 59 (37.8%) receiving folic acid, 26 (32.1%) receiving the combined drugs, and 36 (47.4%) receiving high-dose Moluodan. Moluodan was non-inferior to folic acid (95% confidence interval: -9.2 to 12.5; P = 0.02). High-dose Moluodan had a trend for better protective efficacy, though there was no statistical significance. The disappearance rate of dysplasia was 82.8% in the Moluodan group, which was superior to folic acid (53.9%; P = 0.006). No drug-related serious adverse events were observed. CONCLUSIONS: One pack of Moluodan three times daily for 1 year was safe and effective in reversing gastric precancerous lesions, especially dysplasia. Doubling its dose showed a better efficacy trend.

The only proposed T-cell epitope derived from the TEL-AML1 translocation is not naturally processed.

Adoptive therapy with T-cell receptor (TCR)-engineered T cells is a promising approach in cancer treatment. While usage of T cells specific for tumor-associated antigens (TAAs) can lead to serious side effects because of autoimmunity, targeting true tumor-specific mutations, such as the products of translocations in leukemias, should reduce such a risk. A potentially ideal target might be the chimeric protein TEL-AML1, which results from the chromosomal translocation 12;21 and represents the most common fusion gene in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Within the fusion region of TEL-AML1, a single epitope has been described by reverse immunology as immunogenic in HLA-A*0201 restriction settings. As a potential source of TCRs specific for this TEL-AML1 epitope, we have used mice expressing a human TCR-αß repertoire and human MHC class I. Surprisingly, we have found that, although a specific functional CD8(+) T-cell response against this peptide could be evoked, the described epitope was in fact not endogenously processed. Analyses done with a potent antigen-presenting cell line, as well as with purified human proteasomes, support the conclusion that this peptide cannot be proposed as a potential target in immunotherapy of ALL in HLA-A*0201-restricted fashion.

Insight into increased risk of portal vein thrombosis in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the leading chronic liver diseases with increased morbidity and mortality rates for extrahepatic diseases (including cardiovascular disease, portal vein thrombosis, etc.). There is an increased risk of thrombosis in both the portal and systemic circulation in patients with NAFLD, independent of traditional liver cirrhosis. However, increased portal pressure, the most critical factor, is frequently observed in NAFLD patients, predisposing them to portal vein thrombosis (PVT). It has been reported that there is an 8.5% incidence of PVT among patients with non-cirrhotic NAFLD in a prospective cohort study. Based on the prothrombotic status of NAFLD itself, patients combined with cirrhosis may accelerate the development of PVT and lead to a poor prognosis. Moreover, PVT has been shown to complicate the procedure and adversely affect the outcome during liver transplantation surgery. NAFLD is in a prothrombotic state, and its underlying mechanisms have not been fully understood so far. Particularly noteworthy is that gastroenterologists currently overlook the higher risk of PVT in NAFLD. We investigate the pathogenesis of NAFLD complicated with PVT from the perspective of primary, secondary, and tertiary hemostasis, and also summarize relevant studies in humans. Some treatment options that may affect NAFLD and its PVT are also explored to improve patient-oriented outcomes.

Artificial intelligence empowers the second-observer strategy for colonoscopy: a randomized clinical trial.

Background: In colonoscopy screening for colorectal cancer, human vision limitations may lead to higher miss rate of lesions; artificial intelligence (AI) assistance has been demonstrated to improve polyp detection. However, there still lacks direct evidence to demonstrate whether AI is superior to trainees or experienced nurses as a second observer to increase adenoma detection during colonoscopy. In this study, we aimed to compare the effectiveness of assistance from AI and human observer during colonoscopy. Methods: A prospective multicenter randomized study was conducted from 2 September 2019 to 29 May 2020 at four endoscopy centers in China. Eligible patients were randomized to either computer-aided detection (CADe)-assisted group or observer-assisted group. The primary outcome was adenoma per colonoscopy (APC). Secondary outcomes included polyp per colonoscopy (PPC), adenoma detection rate (ADR), and polyp detection rate (PDR). We compared continuous variables and categorical variables by using R studio (version 3.4.4). Results: A total of 1,261 (636 in the CADe-assisted group and 625 in the observer-assisted group) eligible patients were analysed. APC (0.42 vs 0.35, P = 0.034), PPC (1.13 vs 0.81, P < 0.001), PDR (47.5% vs 37.4%, P < 0.001), ADR (25.8% vs 24.0%, P = 0.464), the number of detected sessile polyps (683 vs 464, P < 0.001), and sessile adenomas (244 vs 182, P = 0.005) were significantly higher in the CADe-assisted group than in the observer-assisted group. False detections of the CADe system were lower than those of the human observer (122 vs 191, P < 0.001). Conclusions: Compared with the human observer, the CADe system may improve the clinical outcome of colonoscopy and reduce disturbance to routine practice (Chictr.org.cn No.: ChiCTR1900025235).

[Recent progress in neurobiological mechanisms of depression].

Revealing the neurobiological mechanism of depression has always been a big challenge in the field of neuroscience. Not only are depressive syndromes heterogeneous and their aetiologies diverse, but also some symptoms are impossible to reproduce in animal models. Nevertheless, great progress has been made on the understanding and treatment of depression in recent years. In this review, we focus on key leading hypotheses in the neurobiological mechanism of depression, examine their strengths and weaknesses critically, and also highlight new insights that promise to extend the understanding of depression and its treatment.

CO2 Is Beneficial to Gut Microbiota Homeostasis during Colonoscopy: Randomized Controlled Trial.

BACKGROUND: Many studies have reported minor complications and disturbance of the gut microbiota after colonoscopy. Compared with air, carbon dioxide (CO2) insufflation could decrease minor complications, but its impact on gut microbiota remains unknown. METHODS: Thirty-eight healthy subjects were assessed and twenty were randomized to receive either CO2 or air insufflation during colonoscopy. Neither the participants nor the staff involved in the follow-up knew which gas was used. Minor complications were assessed using symptom scores. Fecal samples were collected at eight time-points for microbiome analysis by full-length 16S rRNA gene amplicon analysis. RESULTS: Baseline characteristics were similar in both groups. The recovery of minor complications after colonoscopy was faster in the CO2 group (the day of the colonoscopy) than in the air group (the day after the colonoscopy). There was no significant reduction in alpha diversity (species richness) of the first stool after colonoscopy in the CO2 group (115.0 ± 32.81 vs. 97.4 ± 42.31, p = 0.28) compared with the air group (123.8 ± 37.25 vs. 84.8 ± 31.67, p = 0.04). However, there were no differences in beta diversity between the groups. Linear discriminant analysis effect size (LEfSe) analysis indicated that anaerobic probiotics such as Bacteroides caccae, Bacteroides finegoldii and Bacteroides thetaiotaomicron were more abundant in the CO2 group than in the air group within 14 days after colonoscopy. On the contrary, the content of Escherichiacoli, Ruminococcus torques and Ruminococcus guavus was higher in the air group. CONCLUSIONS: CO2 is beneficial to gut microbiota homeostasis during colonoscopy in healthy subjects. The effects in patients with different diseases need to be further studied.

Traditional Chinese Medicine in Treatment of COVID-19 and Viral Disease: Efficacies and Clinical Evidence.

Coronavirus disease 2019 (COVID-19) remains an uncontained, worldwide pandemic. While battling the disease in China, the Chinese government has actively promoted the use of traditional Chinese medicine, and many studies have been conducted to determine the efficacy of traditional Chinese medicine for treating COVID-19. The present review discusses the effectiveness and safety of traditional Chinese medicine in curing COVID-19 and provides clinical evidence from all confirmed cases in China. Applications of traditional Chinese medicine and specific recipes for treating other viral infections, such as those caused by severe acute respiratory syndrome coronavirus and influenza A viruses (including H1N1), are also discussed. Studies have reported that traditional Chinese medicine treatment plays a significant role in improving clinical symptoms. Therefore, further investigation may be of high translational value in revealing novel targeted therapies for COVID-19.

Diagnostic Performance of FibroTouch Ultrasound Attenuation Parameter and Liver Stiffness Measurement in Assessing Hepatic Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

INTRODUCTION: To evaluate the diagnostic performance of ultrasound attenuation parameter (UAP) and liver stiffness measurement (LSM) by FibroTouch for diagnosis of hepatic steatosis and fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: We recruited 237 patients undergoing FibroTouch and liver biopsy within 2 weeks. The pathological findings of liver biopsy were scored by Nonalcoholic Steatohepatitis Clinical Research Network, and the diagnostic accuracy of UAP for steatosis and LSM for fibrosis was evaluated by area under the receiver operating characteristic curve (AUROC). The impacts of histological parameters on UAP and LSM were analyzed, and diagnostic performance of FibroTouch UAP and LSM was compared with other noninvasive biomarkers. RESULTS: The success rate of FibroTouch examination was 96.51%. The AUROC of UAP for diagnosis of steatosis ≥S1, ≥S2, and S3 was 0.88, 0.93, and 0.88, and the cutoff values were 244, 269, and 296 dB/m, respectively. The AUROC of LSM for the diagnosis of fibrosis stages ≥F2, ≥F3, and F4 was 0.71, 0.71, and 0.77, and the cutoff values were 9.4, 9.4, and 11 kPa, respectively. Multiple regression analysis showed that LSM was positively correlated with degree of fibrosis and NAFLD activity score. UAP was positively correlated with liver steatosis. The diagnostic performance of UAP for steatosis was significantly superior to that of the hepatic steatosis index. DISCUSSION: FibroTouch has a low failure rate with moderate to high diagnostic performance for discriminating the steatosis degree and fibrosis stage and is suitable for clinical evaluation and monitoring of patients with NAFLD.

Combined lithotripsy of mechanical clamping and electrohydraulics in facilitating endoscopic management of refractory residual biliary calculi after surgery.

Although postoperative cholangioscopy (POC) guided electrohydraulic lithotripsy (EHL) is considered to be a conventional technique for residual biliary calculi, its efficacy still needs to be improved to fit in the managemet of refractory calculi. This study evaluated the efficacy and safety of combined lithotripsy of mechanical clamping and electrohydraulics in fragmentation and removal of refractory calculi. Totally, 281 patients, who suffered from residual biliary calculi after hepatectomy and underwnet POC from August 2016 to June 2018 were involved. The first 128 patients were subjected to conventional EHL, and later consective 153 to combined lithotripsyof mechanical clamping and EHL. Perioperative data, technical information, treatment outcomes and follow-up results were collected. Clinical characteristics were statistically comparable (P > 0.05). The overall POC interventional sessions (2.0 ± 0.65 vs. 2.9 ± 1.21 sessions), average operating time (99.1 ± 34.88 vs. 128.6 ± 72.87 minutes), incidence of intraoperative hemobilia (4.58% vs. 10.93%), cholangitis (6.54% vs. 14.06%), postoperative complications (10.45% vs. 21.87%), T-tube retaining time after first POC (20.7 ± 5.35 vs. 28.1 ± 8.28 days), and treatment costs ($2375 ± 661.72 vs. $3456.7 ± 638.07) were significantly lower in the combined lithotripsy group than those in the EHL group (P < 0.05). There were no differences between the two groups in calculi recurrence at half-a year, or one year follow-up. In conclusion, combined lithotripsy of mechanical clamping and electrohydraulics can safely and effectively benefit postoperative patients along with refractory residual biliary calculi.

Value of urinary KIM-1 and NGAL combined with serum Cys C for predicting acute kidney injury secondary to decompensated cirrhosis.

Urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and serum cystatin C (Cys C) are biomarkers of acute kidney injury (AKI). However, the efficacy of combining these indices to diagnose decompensated cirrhosis is unknown. This study involved 150 patients divided into AKI and non-AKI, and healthy individuals. Urinary KIM-1 and NGAL, serum Cys and creatine, and glomerular filtration rate (GFR) were compared based on Child-Pugh liver function class. Urinary KIM-1 and NGAL concentrations and serum Cys C levels were significantly higher in patients with AKI secondary to decompensated cirrhosis than in those with AKI not secondary to decompensated cirrhosis (p < 0.01). These were significantly associated with higher kidney injury index stages (p < 0.01) and negatively correlated with GFR in secondary AKI patients. Urinary KIM-1 and NGAL and serum Cys C increased significantly and GFR decreased as Child-Pugh class of decompensated cirrhosis significantly increased (p < 0.05). SCr levels were significantly increased in Child-Pugh class C patients (p < 0.05). Urinary KIM-1, urinary NGAL, serum Cys C, and the combined detection factor, as screening indices, could aid in the early diagnosis of AKI secondary to decompensated cirrhosis.

Preparation of Rhodium(III) complexes with 2(1H)-quinolinone derivatives and evaluation of their in vitro and in vivo antitumor activity.

A series of 2(1H)-quinolinone derivatives and their rhodium (III) complexes were designed and synthesized. All the rhodium (III) complexes exhibited higher in vitro cytotoxicity for Hep G2, HeLa 229, MGC80-3, and NCI-H460 human tumor cell lines than their ligands and cisplatin, and among them complex 9 was found to be selectively cytotoxic to tumor cells. Further investigation revealed that complex 9 caused cell cycle arrest at the G2/M phase and induced apoptosis, and inhibited the proliferation of Hep G2 cells by impeding the phosphorylation of epidermal growth factor receptor (EGFR) and its downstream enzymes. Complex 9 also up-regulated the proapoptotic proteins Bak, Bax, and Bim, which altogether activated caspase-3/9 to initiate cell apoptosis. Notably, complex 9 effectively inhibited tumor growth in the NCI-H460 xenograft mouse model with less adverse effect than cisplatin.

A ß-carboline derivative-based nickel(ii) complex as a potential antitumor agent: synthesis, characterization, and cytotoxicity.

A novel nickel(ii) complex of 6-methoxy-1-pyridine-ß-carboline (4a) was synthesized and characterized. The cytotoxicities of the complex towards six cancer cell lines, including MGC-803, Hep G2, T24, OS-RC-2, NCI-H460, and SK-OV-3, and human normal liver cell line HL-7702 were investigated. The IC50 values for MGC-803, Hep G2, T24, OS-RC-2, NCI-H460 and SK-OV-3 were generally in the micromolar range (3.77-15.10 µM), lower than those of ligand 4 and cisplatin. Furthermore, 4a (6 µM) significantly induced cell cycle arrest at the S phase, and caused the down-regulation of p-AKT, cyclin E, cyclin A and CDK2 and the up-regulation of p27. Various experiments showed that 4a induced apoptosis, activated caspase-3, increased the levels of reactive oxygen species (ROS) and enhanced the intracellular [Ca2+]c levels in MGC-803. In addition, the expression of intrinsic apoptotic proteins, including cytochrome c and apaf-1, increased. Further intrinsic apoptosis was triggered via executive molecular caspase-9 and caspase-3. In short, 4a exerted its cytotoxic activity primarily through inducing cell cycle arrest at the S phase and intrinsic apoptosis.

Efficacy and safety of high-dose dual therapy for Helicobacter pylori rescue therapy: A systematic review and meta-analysis.

OBJECTIVE: Although some studies have reported >90% success with high-dose dual proton pump inhibitor (PPI)-amoxicillin dual therapy for Helicobacter pylori (H. pylori) eradication, the efficacy of this therapy remains controversial. We aimed to re-evaluate the efficacy and safety of high-dose dual therapy on H. pylori eradication. METHODS: We searched PubMed, the Cochrane Library, and EMBASE for randomized clinical trials (RCTs) evaluating the efficacy of high-dose PPI-amoxicillin dual therapy as the rescue therapy on H. pylori eradication. Treatment effect was determined with a fixed-effect model using the inverse variance method and was expressed as risk ratio (RR) with 95% confidence interval (CI). RESULTS: Because of significant statistical heterogeneity (χ2  15.98, I2  = 69%) among the six studies that qualified, four RCTs that included 473 patients with H. pylori infection after eradication failure were assessed. The meta-analysis showed that high-dose dual therapy and guideline-recommended rescue therapies achieved similar efficacy (81.3% vs 81.5%, RR 1.00 [95% CI 0.93-1.08], intention-to-treat analysis), compliance (95.3% vs 95.4%, RR 1.00 [95% CI 0.97-1.03]), and side effects (17.9% vs 19.7%, RR 0.88 [95% CI 0.62-1.25]). CONCLUSIONS: High-dose PPI-amoxicillin dual therapy is comparable to recommended rescue therapies for H. pylori infection. More researches are needed to determine the efficacy of high-dose dual therapy as a first-line therapy.

siRNA targeting YAP gene inhibits gastric carcinoma growth and tumor metastasis in SCID mice.

Yes-associated protein (YAP) is constitutively activated in numerous types of cancer, including gastric carcinoma. The aim of the present study was to investigate the effects of YAP silencing on proliferation, apoptosis, metastasis and angiogenesis in a gastric orthotopic implantation cancer model of severe combined immunodeficiency mice. Small-hairpin RNA (shRNA) targeting the YAP gene was employed to inhibit YAP expression. SGC7901 cells transfected with YAP shRNA demonstrated significantly decreased gastric cancer growth and metastasis in the orthotopic implantation mouse model. Silencing of YAP additionally promoted tumor cell apoptosis, and inhibited tumor cell proliferation and angiogenesis. Notably, YAP shRNA also downregulated the expression of TEA domain family member 1, cyclinD1, vascular endothelial growth factor and fibroblast growth factor-2. The results of the present study suggested that YAP may have a significant role in the proliferation, metastasis and angiogenesis of gastric cancer. RNA interference-mediated silencing of YAP may provide an opportunity to develop a novel treatment strategy for gastric cancer.

Influencing factors of immediate angiographic results in intracranial aneurysms patients after endovascular treatment.

The purpose of this study was to analyze influencing factors associated with immediate angiographic results in intracranial aneurysms patients after endovascular treatment (EVT), providing theoretical evidence and guidance for clinical treatment of intracranial aneurysms. Totally 529 patients met the inclusive criteria, consisting of 338 males and 191 females. Gender; age; history of hypertension, diabetes, and smoking; intracranial atherosclerosis; rupture status, size and location, features of aneurysmal neck, shapes; vasospasm; treatment modality; and degree of aneurysm occlusion were all carefully and completely recorded. All data were investigated in univariate and multivariate logistic regression model to determine whether they were correlated with the degree of aneurysm occlusion. According to aneurysm size, aneurysms were classified as micro-miniature, miniature, and large aneurysms. There were 451 narrow-neck aneurysms and 78 wide-neck aneurysms. Totally 417 were regular and 112 were irregular. And 125 were un-ruptured aneurysms; 404 were ruptured aneurysms. The modalities of treatment were as follows: embolization with coil (n = 415), stent-assisted coil embolization (n = 89), and balloon-assisted coil embolization (n = 25). Univariate analysis showed that aneurysm size, feature of aneurysm neck, shape, and rupture status might affect the immediate occlusion after EVT. Multivariate logistic regression analysis indicated that ruptured aneurysm, tiny aneurysm, and wide-neck aneurysm were independent influencing factors of complete occlusion of intracranial aneurysm. Aneurysm rupture status, size, feature of aneurysmal neck, and shape might be the independent influencing factors of immediate angiographic results in intracranial aneurysm patients after EVT. Un-ruptured, micro-miniature, narrow-neck, and regular-shaped aneurysms were more probable to be occluded completely.