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Rhamnocitrin (RH) is a bioactive flavonoid of Astragali Radix, which exerts a wide variety of pharmacological effects. However, there are no reports focusing on the therapeutical effects and mechanisms of RH against neuropathic pain (NP). In this study, systematic pharmacology and in vivo experimental approaches were employed to identify the potential targets of RH for treating oxaliplatin-induced NP. Our findings indicated that the therapeutical effect of RH might be closely associated with key genes, including MAPK3, MAPK1, SRC, PTGS2, EGFR, MMP9, and MMP2, as well as potential signaling pathways such as PI3K-Akt signaling pathway, EGFR tyrosine kinase inhibitor resistance, and Rap1 signaling pathway. The in vivo experimental findings demonstrated that RH could suppress oxidative stress, inflammatory response, and down-regulate MMP2 and MMP9 expressions to exert its therapeutic effects against NP. This study used network pharmacology and experimental validation to elucidate the potential targets and underlying mechanisms by which RH improves oxaliplatin-induced NP and offer new insight on drug development for NP.

Background: Recently, with new diagnosis criteria, metabolic associated fatty liver disease (MAFLD) was introduced to replace the diagnosis of nonalcoholic fatty liver disease (NAFLD). Considering that there weren’t sufficient studies on MAFLD in China, we aimed to explore the relationship between MAFLD and H. pylori infection, as well as the potential risk factors of MAFLD.Methods: In this cross-sectional study, 3449 subjects were enrolled from a Hospital Health Management Center of Shantou in China between July 2020 and October 2021. All participants included had underwent blood test, 13C urea breath test (13C-UBT) and abdominal ultrasound examination. The association between H. pylori infection and MAFLD were analyzed using logistic regression. Machine learning approach were applied to explore independent risk factors of MAFLD.Results: The overall prevalence of MAFLD was 39.4% in our study population. Of a total of 3449 participants, MAFLD was diagnosed in 1043 of 2254 males (46.3%) and 315 of 1195 females (26.4%). The prevalence of MAFLD increased with age and peaked at the 60-69-year age group (overall participants: 58.8%; male: 56.2%; female: 64.0%), and then declined slightly in the 70-above-year age group. The result of multivariable logistic regression revealed that H. pylori infection was not significantly correlated with MAFLD. Using logistic regression and LASSO regression, we identified age, overweight/obesity, T2DM, hypertension, UA, TG, HDL and ALT as independent risk factors of MAFLD.Conclusions: The prevalence of MAFLD in Shantou of south China was relatively high, and the prevalence was higher in males than in females. Our results showed that H. pylori infection wasn’t associated with the risk of MAFLD, when age, overweight/obesity, T2DM, hypertension, UA, TG, HDL and ALT were independent risk factors of MAFLD.

BACKGROUND AND AIM This meta-analysis aims to explore the risk of colorectal polyps among non-alcoholic fatty liver disease (NAFLD) patients. METHODS We searched PubMed, EMBASE, and Cochrane library databases using predefined search term to identify eligible studies (published up to 7 November 2019). Data from selected studies were extracted by using a standardized information collection form, and meta-analyses were performed using random-effects model. The statistical heterogeneity among studies (I2 ), subgroup analyses, meta-regression analyses, and the possibility of publication bias were assessed. RESULTS Twenty observational (12 cross-sectional, two case-control, and six cohort) studies met the eligibility criteria, involving 142 387 asymptomatic adults. In cross-sectional/case-control studies, NAFLD was found to be associated with an increased risk of colorectal polyps (odds ratio [OR] = 1.34; 95% confidence interval [CI] = 1.23-1.47) (including unclassified colorectal polyps, hyperplastic polyps, adenomas, and cancers) with statistically significant heterogeneity (I2 = 67.8%; P

Caffeine intake is associated with a reduced risk developing non-alcoholic fatty liver disease (NAFLD), but the underlying molecular mechanisms remain to be fully elucidated. We report here that caffeine markedly improved high fat diet-induced NAFLD in mice resulting in a 10-fold increase in circulating IL-6 levels, leading to STAT3 activation in the liver. Interestingly, the expression of IL-6 mRNA was not increased in the liver, but increased substantially in the muscles of caffeine-treated mice. Caffeine was found to stimulate IL-6 production in cultured myotubes but not in hepatocytes, adipocytes, or macrophages. The inhibition of p38/MAPK abrogated caffeine-induced IL-6 production in muscle cells. Caffeine failed to improve NAFLD in IL-6 and hepatocyte-specific STAT3 knockout mice, indicating that the IL-6/STAT3 pathway is vital for the hepatoprotective effects of caffeine in NAFLD. The possibility that IL-6/STAT3-mediated hepatic autophagosome induction and hepatocytic oxygen consumption are involved in the anti-NAFLD effects of caffeine cannot be excluded, based on the findings presented here. Our results reveal that caffeine ameliorates NAFLD via crosstalk between muscle IL-6 production and liver STAT3 activation.

Exercise prevents depression through peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α)-mediated activation of a particular branch of the kynurenine pathway. From kynurenine (KYN), two independent metabolic pathways produce neurofunctionally different metabolites, mainly in somatic organs: neurotoxic intermediate metabolites via main pathway and neuroprotective end product, kynurenic acid (KYNA) via the branch. Elevated levels of KYN have been found in patients with depression. Herein, we investigated whether and how caffeine prevents depression, focusing on the kynurenine pathway. Mice exposed to chronic mild stress (CMS) exhibited depressive-like behaviours with an increase and decrease in plasma levels of pro-neurotoxic KYN and neuroprotective KYNA, respectively. However, caffeine rescued CMS-exposed mice from depressive-like behaviours and restored the plasma levels of KYN and KYNA. Concomitantly, caffeine induced a key enzyme converting KYN into KYNA, namely kynurenine aminotransferase-1 (KAT1), in murine skeletal muscle. Upon caffeine stimulation murine myotubes exhibited KAT1 induction and its upstream PGC-1α sustainment. Furthermore, a proteasome inhibitor, but not translational inhibitor, impeded caffeine sustainment of PGC-1α, suggesting that caffeine induced KAT1 by inhibiting proteasomal degradation of PGC-1α. Thus, caffeine protection against CMS-induced depression may be associated with sustainment of PGC-1α levels and the resultant KAT1 induction in skeletal muscle, and thereby consumption of pro-neurotoxic KYN.

This study aimed to explore the efficacy of percutaneous transforaminal endoscopic discectomy (PTED) unilateral and bilateral approach for bilateral decompression in the treatment of degenerative lumbar spinal stenosis (DLSS) and their effects on quality of life. Altogether 119 patients with DLSS admitted to our hospital from May 2012 to February 2014 were enrolled in this study. Patients in Group A (62 cases) were treated with PTED bilateral approach for bilateral decompression, while those in Group B (57 cases) were treated with PTED unilateral approach for bilateral decompression. The therapeutic effect and incidence of complications in the two groups were observed. Visual Analogue Scale (VAS) was used to assess the pain degree of the lower limbs. Oswestry Disability Index (ODI) was used to assess the improvement of neurological function. 36-ltem Short Form Health Survey (SF-36) developed by the Institute of Medicine was used to assess the quality of life. There were no significant differences between Group A and Group B in operative time, intraoperative blood loss, hospitalization time, the effective rate of treatment, and the incidence of complications (P>0.05). The recovery time of lumbar function in Group A was significantly shorter than that in Group B (P

Background Patients suffering from gastrointestinal cancer comprise a large group receiving home hospice care in China, however, little is known about the prediction of their survival time. This study aimed to develop a gastrointestinal cancer-specific non-lab nomogram predicting survival time in home-based hospice. Methods We retrospectively studied the patients with gastrointestinal cancer from a home-based hospice between 2008 and 2018. General baseline characteristics, disease-related characteristics, and related assessment scale scores were collected from the case records. The data were randomly split into a training set (75%) for developing a predictive nomogram and a testing set (25%) for validation. A non-lab nomogram predicting the 30-day and 60-day survival probability was created using the least absolute shrinkage and selection operator (LASSO) Cox regression. We evaluated the performance of our predictive model by means of the area under receiver operating characteristic curve (AUC) and calibration curve. Results A total of 1618 patients were included and divided into two sets: 1214 patients (110 censored) as training dataset and 404 patients (33 censored) as testing dataset. The median survival time for overall included patients was 35 days (IQR, 17–66). The 5 most significant prognostic variables were identified to construct the nomogram among all 28 initial variables, including Karnofsky Performance Status (KPS), abdominal distention, edema, quality of life (QOL), and duration of pain. In training dataset validation, the AUC at 30 days and 60 days were 0.723 (95% CI, 0.694–0.753) and 0.733 (95% CI, 0.702–0.763), respectively. Similarly, the AUC value was 0.724 (0.673–0.774) at 30 days and 0.725 (0.672–0.778) at 60 days in the testing dataset validation. Further, the calibration curves revealed good agreement between the nomogram predictions and actual observations in both the training and testing dataset. Conclusion This non-lab nomogram may be a useful clinical tool. It needs prospective multicenter validation as well as testing with Chinese clinicians in charge of hospice patients with gastrointestinal cancer to assess acceptability and usability.

Additional file 1: Supplementary Table 1. The distribution of GI cancers for the training and testing dataset.

The effect of metformin on human esophageal normal and carcinoma cells remains poorly understood. We aim to investigate the different antiproliferation effects and underlying distinct molecular mechanisms between these two types of cells. Human esophageal squamous cell carcinoma cell line, EC109, and normal esophageal epithelial cell line, HEEC, were used in the experiment. The cell survival rate was determined by cell counting kit-8 (CCK-8). Cell apoptosis was analyzed by flow cytometry. The mRNA and protein levels of signal transducer and activator of transcription 3 (Stat3) were detected by real-time quantitative PCR and western blot. Interleukin-6 (IL-6) was added to activate Stat3. The level of intracellular reactive oxygen species (ROS) was assessed by a DCFH-DA fluorescent probe. Metformin had more significant inhibitory effects on cell proliferation in EC109 cells than HEECs. Metformin induced apoptosis of EC109 cells in a dose-dependent manner instead of HEECs. The expression of Stat3 in both mRNA and protein levels was higher in EC109 cells than HEECs. Further study revealed that metformin may attenuate the phosphorylation of the Stat3 and the Bcl-2 expression, which was restored by IL-6 partly in EC109 cells but not HEECs. On the contrary, metformin increased the level of ROS in both the cell lines, but this intracellular ROS variation had no effect on apoptosis. Metformin has different functional roles on the apoptosis in esophageal carcinoma cells and normal esophageal cells. Therefore, the Stat3/Bcl-2 pathway-mediated apoptosis underlies the cell-type-specific drug sensitivity, suggesting metformin possesses a therapeutic activity and selectivity on esophageal cancer.

Previous studies have suggested that metformin, a biguanide family member widely used as an oral antidiabetic drug, may inhibit proliferation and induce apoptosis in certain types of cancer cell. However, the molecular mechanisms underlying metformin-associated anticancer effects, and in particular antimetastatic effects, remain to be fully understood. The present study assessed the efficacy of metformin in inhibiting the migration and invasion of the esophageal carcinoma cell line EC109, and evaluated the effect of metformin on the protein kinase B (AKT) signaling pathway. EC109 cells were treated with 0, 5, 10 or 20 mM metformin during the logarithmic growth phase. A Transwell assay and western blot analysis revealed that metformin inhibited the migration and invasion of EC109 cells, nuclear factor-κB activation, matrix metallopeptidase 9 and N-cadherin expression in a phosphorylated-AKT dependent manner. These results suggested that metformin inhibits the migration and invasion of human esophageal carcinoma cells by suppressing AKT phosphorylation and regulating the expression of migration- and invasion-associated genes.

Cyclooxygenase-2 (COX-2) can exert pro-inflammatory effects in nonalcoholic steatohepatitis (NASH). The aim of this study was to determine if the inhibition of COX-2 attenuates hepatocyte apoptosis in steatohepatitis and to examine the underlying molecular mechanism. Male wild type C57BL6/J mice and COX-2 knock out (COX-2-/-) mice were fed a methionine choline deficient (MCD) diet for 3 weeks. The wild type mice were also treated with celecoxib or a combination of celecoxib and a Akt specific inhibitor, miltefosine (MTF). After that, liver histology, serum alanine aminotransferase (ALT) levels, hepatic triglyceride (TG) levels, hepatocyte apoptosis, phosphorylated Akt (Ser473, pAkt) and p53 protein levels in mice livers were assessed. Celecoxib attenuated the severity of liver steatohepatitis and reduced the number of apoptotic cells, accompanied by increasing the activity of Akt and decreasing expression of p53. On the contrary, MTF can abrogate the effects of celecoxib on anti-apoptosis and anti-steatohepatitis. Moreover, the effects on the COX-2-/- mice that were fed the MCD diet were similar to that for celecoxib. The findings suggested that suppressing COX-2 can improve steatohepatitis by inhibiting hepatocyte apoptosis in mice via regulating the Akt/p53 pathway. Celecoxib treatment may be a favorable treatment option for NASH.

Metformin is used as a first-line therapy for type 2 diabetes, with reports of its usefulness for the prevention and control of several types of cancers. This study investigated the effects of metformin on hepatocellular carcinoma (HCC). The human HCC cell lines HepG2 and PLC/PRF/5 were cultured and treated with metformin or 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an activator of adenosine monophosphate (AMP)-activated protein kinase. Changes in cell viability and cell cycle distribution were evaluated by MTT and flow cytometry, respectively. Apoptosis was assessed by fluorescent-dye staining. An HCC model was established in 6- to 8-week-old BALB/c-nu mice by subcutaneous injection of PLC/PRF/5 cells. After 1 week, mice were treated intragastrically with metformin or vehicle. Tumor xenograft tissues were examined using immunohistochemistry for evaluation of the the expression of cyclin D1, p21CIP and p27KIP. HCC cells and tissues from the in vitro and in vivo experiments, respectively, were subjected to protein extraction and western blotting. We found that metformin treatment reduced HCC cell viability in a dose-dependent manner similar to AICAR treatment. In addition, metformin treatment induced HCC cell cycle arrest at G1/G0 phase and apoptosis. Intragastric treatment of the mouse PLC/PRF/5 cell xenograft model with metformin showed that metformin not only blocked tumor progression, but also reduced tumor morbidity. Treatment with metformin upregulated the expression of p21CIP and p27KIP, but downregulated cyclin D1 levels, both in vitro and in vivo. Metformin treatment also upregulated the expression of phosphorylated AMPK protein in xenograft tissues. These findings indicate that metformin warrants further evaluation as a novel therapeutic and preventive strategy against HCC.

White adipose tissue (WAT) is important for the maintenance of metabolic homeostasis, and metabolic syndrome is sometimes associated with WAT dysfunction in humans and animals. WAT reportedly plays a key, beneficial role in the maintenance of glucose and lipid homeostasis during de novo lipogenesis (DNL). Pu’erh tea extract (PTE) can inhibit harmful, ectopic DNL in the liver, thus protecting against hepatosteatosis, in mice with diet-induced obesity. We examined whether PTE could induce DNL in WAT and consequently protect against hepatosteatosis. C57BL/6 male mice were fed a high-fat diet (HFD) with/without PTE for 16 weeks. Systemic insulin sensitivity was determined using HOMA-IR, insulin- and glucose-tolerance tests, and WAT adipogenesis was evaluated by histological analysis. Adipogenesis-, inflammation-, and DNL-related gene expression in visceral AT (VAT) and subcutaneous AT (SAT) was measured using quantitative reverse transcription-PCR. Regression analysis was used to investigate the association between DNL in WAT and systemic insulin resistance or hepatosteatosis. Pu’erh tea extract significantly reduced the gain of body weight and SAT, but not VAT adiposity, in mice fed the high-fat diet and induced adipogenesis in VAT. The expression of DNL-related genes, including Glut4, encoding an important insulin-regulated glucose transporter (GLUT4), were highly elevated in VAT. Moreover, PTE inhibited VAT inflammation by simultaneously downregulating inflammatory molecules and inducing expression of Gpr120 that encodes an anti-inflammatory and pro-adipogenesis receptor (GPR-120) that recognizes unsaturated long-chain fatty acids, including DNL products. The expression of DNL-related genes in VAT was inversely correlated with hepatosteatosis and systemic insulin resistance. Activation of DNL in VAT may explain PTE-mediated alleviation of hepatosteatosis symptoms and systemic insulin resistance.

Emodin (1,3,8-trihydroxy-6-methylanthraquinone), a natural anthraquinone derivative found in several herbal medicines, is highly active in suppressing the proliferation of various tumor cells such as breast, hepatocellular, and lung cancer cells under in vitro conditions. The mechanism of emodin-induced apoptosis in esophagus carcinoma cells, EC-109, is not completely understood. In this study, EC-109 cells treated with emodin underwent rapid apoptosis as judged by morphological changes and flow cytometry analysis. The addition of emodin to EC-109 cells led to the inhibition of growth in a time- and dose-dependent manner. Fluorescence measurements of cells indicated that the intracellular pH (pHi) decreased significantly by 0.47–0.78 units. The results obtained from flow cytometry suggested that bursts of reactive oxygen species took place after the application of emodin. The present study indicates that emodin may be a strong anticancer drug against esophagus cancer cells by causing various early events leading to growth inhibition, including the production of reactive oxygen species and decrease of pHi, which may result in cellular apoptosis.

Rationale:Glosssopharyngeal neuralgia (GPN) is a painful syndrome characterized by paroxysmal neuropathic pain in the pharynx, tonsil, posterior base of tongue, inner ear, and mandibular angle. The traditional therapies of GPN, including medication and surgical operation, are not always effe

FET family proteins consist of fused in sarcoma/translocated in liposarcoma (FUS/TLS), Ewing's sarcoma (EWS), and TATA-binding protein-associated factor 15 (TAF15). Mutations in the copper/zinc superoxide dismutase (SOD1), TAR DNA-binding protein 43 (TDP-43), and FET family proteins are associated with the development of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. There is currently no cure for this disease and few effective treatments are available. Epidemiological studies indicate that the consumption of tea is associated with a reduced risk of developing neurodegenerative diseases. The results of this study revealed that components of a pu-erh tea extract (PTE) interacted with FET family proteins but not with TDP-43 or SOD1. PTE induced the degradation of FET family proteins but had no effects on TDP-43 or SOD1. The most frequently occurring ALS-linked FUS/TLS mutant protein, R521C FUS/TLS, was also degraded in the presence of PTE. Furthermore, ammonium chloride, a lysosome inhibitor, but not lactacystin, a proteasome inhibitor, reduced the degradation of FUS/TLS protein by PTE. PTE significantly reduced the incorporation of R521C FUS/TLS into stress granules under stress conditions. These findings suggest that PTE may have beneficial health effects, including preventing the onset of FET family protein-associated neurodegenerative diseases and delaying the progression of ALS by inhibiting the cytoplasmic aggregation of FET family proteins.

Esophageal squamous cell carcinomas (ESCC) have become a severe threat to health and the current treatments for ESCC are frequently not effective. Recent epidemiological studies suggest that the anti-hyperglycemic agent metformin may reduce the risk of developing cancer, including ESCC, among diabetic patients. However, the antitumor effects of metformin on ESCC and the mechanisms underlying its cell cycle regulation remain elusive. The findings reported herein show that the anti-proliferative action of metformin on ESCC cell lines is partially mediated by AMPK. Moreover, we observed that metformin induced G0/G1 phase arrest accompanied by the up-regulation of p21CIP1 and p27KIP1. In vivo experiments further showed that metformin inhibited tumor growth in a ESCC xenograft model. Most importantly, the up-regulation of AMPK, p53, p21CIP1, p27KIP1 and the down-regulation of cyclinD1 are involved in the anti-tumor action of metformin in vivo. In conclusion, metformin inhibits the growth of ESCC cells both in cell cultures and in an animal model. AMPK, p53, p21CIP1, p27KIP1 and cyclinD1 are involved in the inhibition of tumor growth that is induced by metformin and cell cycle arrest in ESCC. These findings indicate that metformin has the potential for use in the treatment of ESCC.