Bruceine A alleviates alcoholic liver disease by inhibiting AIM2 inflammasome activation via activating FXR.

BACKGROUND: Alcoholic liver disease (ALD), a public health challenge worldwide caused by long-term persistent drinking, is life-threatening with minimal approved therapies. Hepatic steatosis accompanied by inflammation is an initial and inevitable stage in the complex progression of simple alcoholic liver injury to more severe liver diseases such as hepatitis, liver fibrosis, cirrhosis and liver cancer. PURPOSE: We aimed to identify the therapeutic role of Bruceine A (BA) in ALD whilst attempting to explore whether its protective effects depend specifically on the farnesoid X receptor (FXR). METHODS: Autodock was applied to detect the affinity between BA and FXR. Lieber-DeCarli liquid diet with 5 % ethanol (v/v) was adopted to establish the mouse ALD model. The lentivirus mediating FXR (LV-FXR) was injected into mice via the tail vein to establish FXR-overexpressed mice. FXR silencing or overexpression plasmids were transfected into AML-12 cells prior to ethanol stimulation. Quantitative real-time PCR, Western blotting and immunofluorescence assays were employed to determine the expression of related genes. We subjected liver sections to H&E and Oil Red O staining to evaluate the liver histological injury and the deposition of lipid droplets. RESULTS: BA significantly reduced body weight and liver-to-body weight ratios as well as biochemical indexes in mice. Ethanol-induced liver damage and lipid accumulation could be alleviated by BA treatment. BA bound to FXR by two hydrogen bonds. There was a positive correlation between BA administration and FXR expression. BA inhibited the expression of lipid synthesis genes and enhanced the expression of lipid metabolism genes by activating FXR, thus alleviating steatosis in ALD. Moreover, BA exerted an ameliorative effect against inflammation by inhibiting the activation of absent in melanoma 2 (AIM2) inflammasome by activating FXR. FXR overexpression possessed the ability to counter the accumulation of lipid and the activation of AIM2 inflammasome caused by ethanol. FXR deficiency exacerbated ethanol-induced liver steatosis and inflammation. The hepatoprotective effect of BA could be disrupted by FXR antagonist guggulsterone (GS) in vivo and FXR siRNA in vitro. CONCLUSION: BA alleviated alcoholic liver disease by inhibiting AIM2 inflammasome activation through an FXR-dependent mechanism. This study may potentially represent a new therapeutic approach for ALD.

A hybrid deep learning scheme for MRI-based preliminary multiclassification diagnosis of primary brain tumors.

Objectives: The diagnosis and treatment of brain tumors have greatly benefited from extensive research in traditional radiomics, leading to improved efficiency for clinicians. With the rapid development of cutting-edge technologies, especially deep learning, further improvements in accuracy and automation are expected. In this study, we explored a hybrid deep learning scheme that integrates several advanced techniques to achieve reliable diagnosis of primary brain tumors with enhanced classification performance and interpretability. Methods: This study retrospectively included 230 patients with primary brain tumors, including 97 meningiomas, 66 gliomas and 67 pituitary tumors, from the First Affiliated Hospital of Yangtze University. The effectiveness of the proposed scheme was validated by the included data and a commonly used data. Based on super-resolution reconstruction and dynamic learning rate annealing strategies, we compared the classification results of several deep learning models. The multi-classification performance was further improved by combining feature transfer and machine learning. Classification performance metrics included accuracy (ACC), area under the curve (AUC), sensitivity (SEN), and specificity (SPE). Results: In the deep learning tests conducted on two datasets, the DenseNet121 model achieved the highest classification performance, with five-test accuracies of 0.989 ± 0.006 and 0.967 ± 0.013, and AUCs of 0.999 ± 0.001 and 0.994 ± 0.005, respectively. In the hybrid deep learning tests, LightGBM, a promising classifier, achieved accuracies of 0.989 and 0.984, which were improved from the original deep learning scheme of 0.987 and 0.965. Sensitivities for both datasets were 0.985, specificities were 0.988 and 0.984, respectively, and relatively desirable receiver operating characteristic (ROC) curves were obtained. In addition, model visualization studies further verified the reliability and interpretability of the results. Conclusions: These results illustrated that deep learning models combining several advanced technologies can reliably improve the performance, automation, and interpretability of primary brain tumor diagnosis, which is crucial for further brain tumor diagnostic research and individualized treatment.

FXR overexpression prevents hepatic steatosis through inhibiting AIM2 inflammasome activation in alcoholic liver disease.

BACKGROUND AND PURPOSE: Alcoholic liver disease (ALD), a metabolic liver disease caused by excessive alcohol consumption, has attracted increasing attention due to its high prevalence and mortality. Up to date, there is no effective and feasible treatment method for ALD. This study was to investigate whether Farnesoid X receptor (FXR, NR1H4) can alleviate ALD and whether this effect is mediated by inhibiting absent in melanoma 2 (AIM2) inflammasome activation. METHODS: The difference in FXR expression between normal subjects and ALD patients was analyzed using the Gene Expression Omnibus (GEO) database. Lieber-DeCarli liquid diet with 5% ethanol (v/v) (EtOH) was adopted to establish the mouse ALD model. Liver histopathological changes and the accumulation of lipid droplets were assessed by H&E and Oil Red O staining. Quantitative real-time PCR, Western blotting analysis and immunofluorescence staining were utilized to evaluate the expression levels of related genes and proteins. DCFH-DA staining was adopted to visualize reactive oxidative species (ROS). RESULTS: FXR was distinctly downregulated in liver tissues of patients with steatosis compared to normal livers using the GEO database, and in ethanol-induced AML-12 cellular steatosis model. FXR overexpression ameliorated hepatic lipid metabolism disorder and steatosis induced by ethanol by inhibiting the expression of genes involved in lipid synthesis and inducing the expression of genes responsible for lipid metabolism. Besides, FXR overexpression inhibited ethanol-induced AIM2 inflammasome activation and alleviated oxidative stress and ROS production during ethanol-induced hepatic steatosis. However, when FXR was knocked down, the results were completely opposite. CONCLUSIONS: FXR attenuated lipid metabolism disorders and lipid degeneration in alcohol-caused liver injury and alleviated oxidative stress and inflammation by inhibiting AIM2 inflammasome activation.

Farnesoid X receptor overexpression prevents hepatic steatosis through inhibiting AIM2 inflammasome activation in nonalcoholic fatty liver disease.

Oxidative stress-mediated activation of inflammasome has a significant effect on the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Farnesoid X receptor (NR1H4, FXR) has been implicated in biological function and many diseases, including NAFLD. The regulatory effect of FXR on oxidative stress and whether this process is related with the activation of absent melanoma 2 (AIM2) inflammasome in NAFLD remain unclear. In the present research, we confirmed that FXR in the livers of steatosis patients is significantly reduced compared with normal liver tissue by using the Gene Expression Omnibus (GEO) database and a palmitic acid (PA) - mediated steatosis model in AML-12 cells. Under the premise of ensuring the same food intake as the control group, overexpression of FXR in mice attenuated HFD-mediated weight gain and liver steatosis, facilitated lipid metabolism, improved fatty acid ß-oxidation, lipolysis, and reduced fatty acid synthesis and intake, which also inhibited the activation of AIM2 inflammasome. Overexpression of FXR alleviated PA-induced triglyceride (TG) accumulation, imbalance of lipid homeostasis, and the activation of AIM2 inflammasome in hepatic steatosis cells, while FXR knockdown appeared the opposite effects. FXR overexpression suppressed PA- and HFD-induced oxidative stress, but FXR siRNA demonstrated the opposite influence. The decreased ROS generation may be the reason why FXR weakens AIM2 activation when a fatty acid overload occurs. In conclusion, our results confirm that other than regulating lipid homeostasis and blocking NLRP3 inflammasome activation, FXR improves hepatic steatosis by a novel mechanism that inhibits oxidative stress and AIM2 inflammasome activation.

Efficacy and complications of inoperable malignant distal biliary obstruction treatment by metallic stents: fully covered or uncovered?

Obstructive jaundice caused by malignant distal biliary obstruction is a common clinical symptom in patients with inoperable biliary-pancreatic cancer. Endoscopic retrograde cholangiopancreatography (ERCP)-guided stent implantation is an effective treatment for obstructive jaundice. Internal stent drainage is more physiologic and associated with a better quality of life than external stent drainage methods such as percutaneous transhepatic gallbladder drainage or percutaneous transhepatic cholangiodrainage. Self-expanding metallic stents, which may be covered and uncovered, are commonly used. However, some uncertainties remain regarding the selection of metallic stents, including drainage patency time, clinical effect, stent migration, and post-operative complications such as pancreatitis, bleeding, and cholecystitis. This review aims to summarize the current progress and controversies surrounding the use of covered or uncovered metallic stents in inoperable common biliary obstruction via ERCP.

Dosimetric comparison of four radiotherapy techniques for stage III non­small cell lung cancer.

The present study was implemented to compare the dosimetric parameters of the target dose coverage and critical structures in the treatment planning of four radiotherapy techniques [namely, three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), hybrid IMRT (h-IMRT) and volumetric-modulated arc therapy (VMAT)] for stage III non-small cell lung cancer (NSCLC) qualified plans for medical physicists, therapists and physicians. A total of 40 patients confirmed to have stage IIIA or IIIB NSCLC were enrolled, and four plans were designed for each patient. The prescription dose to the planning target volume (PTV) was assigned as 60 Gy in 30 fractions. The conformity index (CI), heterogeneity index (HI) and parameters of organs at risk (OARs) were calculated. For the PTV, the CI for VMAT was found to be the highest of all the four techniques (P<0.05), whereas the HI for the h-IMRT technique was found to be the lowest (P<0.05). Concerning the OARs, for the percentage of lung volume receiving a dose >5 Gy (lung V5), the highest value was obtained with VMAT (P<0.05), whereas for lung V30 and heart V30, the VMAT and IMRT techniques were found to be better compared with 3D-CRT and h-IMRT (P<0.05). For esophagus V50, the maximal dose (Dmax) and mean dose for the IMRT technique displayed the best results (P<0.05), and in the case of the spinal cord, the Dmax with VMAT showed a significant advantage over the other techniques (P<0.05). The treatment monitor units (MUs) in IMRT were found to be the largest (P<0.05), whereas the treatment time with VMAT was the shortest (P<0.05). For smaller PTVs, VMAT was the technique that provided the optimal dose distribution and sparing of the heart. Compared with 3D-CRT alone, adding 20% IMRT to the 3D-CRT base plan was shown to improve the plan quality, and IMRT and VMAT, as techniques, had better dose coverage and sparing of OARs. Furthermore, for patients in whom the lung V5 could be kept low enough, VMAT potentially offered a good alternative to the technique to IMRT, thereby offering additional possibilities for sparing of other OARs, and decreasing the MUs and treatment time.

Residual behavior and dietary risk assessment of albendazole as fungicide in citrus orchards.

Albendazole is a broad-spectrum fungicide that shows great potential in controlling fungal diseases in citrus. To quantify the dissipation behavior, residue distribution, and dietary risk of albendazole in citrus, we developed an UPLC-MS/MS analysis protocol. The average recovery rate of albendazole in whole citrus and citrus pulp ranged from 74 to 105% with an RSD of 3 to 8%, and a limit of quantification of 0.01 mg kg-1. The degradation half-lives were 2.8-3.0 and 5.7-17.0 days in whole citrus and citrus pulp, respectively, and the final residues of albendazole were <0.059 mg kg-1 with a risk quotient of <1. This study not only demonstrates that the dietary risk of albendazole in citrus is negligible, but also provides empirical data to establish the maximum residual limit (MRL) for the safe application of albendazole in citrus orchards to meet the requirements for food safety as well as international trade.

Correlation between Macrophage Polarization and PD-L1-Related Tumor Microenvironmental Alteration and Metastasis in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis; nearly 80% patients have regional or distant metastasis when diagnosed. Tumor microenvironment (TME) alteration and epithelial-to-mesenchymal transition (EMT) have been reported to play a key role in cancer metastasis. However, the correlation between TME and EMT was poorly studied in PDAC. This study aims to explore the correlation between EMT markers and TME alteration, mainly including macrophage polarization and PD-L1 expression change, in primary and metastatic PDAC tissues by immunohistochemistry. The results indicated that macrophage polarization was found in metastases with the number of M1 macrophages (CD86+) decreased and M2 (CD163+) increased, though PD-L1 expression did not have a significant alteration. Compared to primary tumors, E-cadherin was significantly lower, while snail was higher, while no difference was found with N-cadherin and ZEB1. Correlation analysis indicated that snail, but not ZEB1, E-cadherin, or N-cadherin, was highly correlated with macrophage polarization. To conclude, the number of CD86+ M1 macrophages was increased while CD163+ M2 macrophages decreased in metastases, with no significant alteration of PD-L1 expression compared to primary tumors. EMT markers-Snail and E-cadherin-but not ZEB1 or N-cadherin, were found to be higher/lower in metastases, which mean that EMT played an important role in PDAC metastasis. Further analysis indicated that snail was highly correlated with M1 to M2 macrophage polarization, which prompted that EMT may be one reason for macrophage polarization induced TME alteration in PDAC metastasis.

Neoadjuvant Therapy for Pancreatic Ductal Adenocarcinoma: Where Do We Go?

The incidence of pancreatic ductal adenocarcinoma (PDAC) has been on the rise in recent years; however, its clinical diagnosis and treatment remain challenging. Although surgical resection remains the only chance for long-term patient survival, the likelihood of initial resectability is no higher than 20%. Neoadjuvant therapy (NAT) in PDAC aims to transform the proportion of inoperable PDACs into operable cases and reduce the likelihood of recurrence to improve overall survival. Ongoing phase 3 clinical trial aims to validate the role of NAT in PDAC therapy, including prolongation of survival, increased R0 resection, and a higher proportion of negative lymph nodes. Controversies surrounding the role of NAT in PDAC treatment include applicability to different stages of PDAC, chemotherapy regimens, radiation, duration of treatment, and assessment of effect. This review aims to summarize the current progress and controversies of NAT in PDAC.

ORM 1 as a biomarker of increased vascular invasion and decreased sorafenib sensitivity in hepatocellular carcinoma.

This study aimed to clarify the role of Orosomucoid 1 (ORM1) in the development and therapy resistance in hepatocellular carcinoma (HCC). The mRNA expression level of ORM1 was analyzed via integrative analysis of Gene Express Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. The protein expression level of ORM1 in our cohort was determined using immunohistochemistry. Correlation analysis was used to investigate the relationship between ORM1 expression and clinical parameters. The Cell Counting Kit-8 assay was used to clarify the role of ORM1 in HCC malignant behaviors, including cell growth and sorafenib sensitivity, in vitro. The results indicated that ORM1 was significantly downregulated in the hepatic cancer cells compared to that in the non-cancerous cells. However, it was upregulated in microvascular invasion samples, especially in the cancer embolus compared to that in the surrounding tumor cells. Though Kaplan-Meier analysis did not show an association of ORM1 expression with the overall survival rates of HCC patients, univariate analysis indicated that ORM1 expression was highly correlated with tumor grade and stage. An in vitro assay also revealed that downregulation of ORM1 led to the suppression of tumor growth and enhancement of sorafenib sensitivity without epithelial-to-mesenchymal transition (EMT) alteration, which was consistent with our bioinformatic analysis. Hence, ORM1 played a key role in HCC tumorigenesis and may serve as a potential target for the development of therapeutics against HCC in the future.

Rolling Bearing Fault Diagnosis Based on Markov Transition Field and Residual Network.

Data-driven rolling-bearing fault diagnosis methods are mostly based on deep-learning models, and their multilayer nonlinear mapping capability can improve the accuracy of intelligent fault diagnosis. However, problems such as gradient disappearance occur as the number of network layers increases. Moreover, directly taking the raw vibration signals of rolling bearings as the network input results in incomplete feature extraction. In order to efficiently represent the state characteristics of vibration signals in image form and improve the feature learning capability of the network, this paper proposes fault diagnosis model MTF-ResNet based on a Markov transition field and deep residual network. First, the data of raw vibration signals are augmented by using a sliding window. Then, vibration signal samples are converted into two-dimensional images by MTF, which retains the time dependence and frequency structure of time-series signals, and a deep residual neural network is established to perform feature extraction, and identify the severity and location of the bearing faults through image classification. Lastly, experiments were conducted on a bearing dataset to verify the effectiveness and superiority of the MTF-ResNet model. Features learned by the model are visualized by t-SNE, and experimental results indicate that MTF-ResNet showed better average accuracy compared with several widely used diagnostic methods.

USP22 regulates lipidome accumulation by stabilizing PPARγ in hepatocellular carcinoma.

Elevated de novo lipogenesis is considered to be a crucial factor in hepatocellular carcinoma (HCC) development. Herein, we identify ubiquitin-specific protease 22 (USP22) as a key regulator for de novo fatty acid synthesis, which directly interacts with deubiquitinates and stabilizes peroxisome proliferator-activated receptor gamma (PPARγ) through K48-linked deubiquitination, and in turn, this stabilization increases acetyl-CoA carboxylase (ACC) and ATP citrate lyase (ACLY) expressions. In addition, we find that USP22 promotes de novo fatty acid synthesis and contributes to HCC tumorigenesis, however, this tumorigenicity is suppressed by inhibiting the expression of PPARγ, ACLY, or ACC in in vivo tumorigenesis experiments. In HCC, high expression of USP22 positively correlates with PPARγ, ACLY or ACC expression, and associates with a poor prognosis. Taken together, we identify a USP22-regulated lipogenesis mechanism that involves the PPARγ-ACLY/ACC axis in HCC tumorigenesis and provide a rationale for therapeutic targeting of lipogenesis via USP22 inhibition.

Geometric Evolvement, Simulation, and Test of a Bionic Lateral PDC Reamer Bit Inspired by Capra sibirica Horn.

PDC (polycrystalline diamond compact) bit is the key equipment for drilling holes inside the rock in oil and mining industry. Inspired by the shape and structure of Capra sibirica horn, a bionic lateral PDC reamer bit with variable lateral reaming radius was developed. Side view of Capra sibirica horn was employed for fitting the horn shape curve based on picture processing method. PDC teeth were arranged on the horn shape blade imitating the transverse ridges on the horn to cut the rock material, found with only 30% utilization rate of the total teeth and load concentration of the last tooth. A bionic blade curve evolved from the Capra sibirica horn was defined with geometric method for the lateral reamer bit; the utilization rate of the teeth on the bionic blade curve was improved to 90% with uniformly distributed reaming load. Multigroup simulations were conducted with the finite element method; the effects of bit revolution speed and rotation feed speed of the bionic blade to reaming load were emphatically studied. Concrete sample was reamed indoors from 240 mm to 407 mm in diameter, and the bionic lateral PDC reamer bit was approved by the test result.

Activation of PGC-1α via isoliquiritigenin-induced downregulation of miR-138-5p alleviates nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), a metabolic disease, has received wide attention worldwide. However, there is no approved effective drug for NAFLD treatment. In the study, H&E and Oil Red O staining were employed to detect liver histopathological changes and the accumulation of lipid droplets. Quantitative real-time PCR, Western blot, bioinformatics, luciferase assay, immunofluorescence staining, reactive oxygen species (ROS), and siRNA were used to further elucidate the mechanism of isoliquiritigenin (ISL) against NAFLD. The results showed that ISL significantly reduced the liver-to-body weight ratios and biochemical index. And the staining results showed that ISL remarkedly ameliorated liver histopathological changes of NAFLD. Furthermore, ISL significantly increased the levels of PPARα, CPT1α, and ACADS, which were involved in lipid metabolism, and inhibited the ROS, TNF-α, IL-1ß, and IL-6 expression by activating PGC-1α. Bioinformatics and luciferase assay analysis confirmed that miR-138-5p might bind to PGC-1α mRNA in NAFLD. Importantly, the expression of miR-138-5p was increased in the NAFLD, which was significantly decreased by ISL. In addition, the miR-138-5p inhibitor also promoted lipid metabolism and inhibited inflammatory response in NAFLD via PGC-1α activation. The above results demonstrate that ISL alleviates NAFLD through modulating miR-138-5p/PGC-1α-mediated lipid metabolism and inflammatory reaction in vivo and in vitro.

Differential Expression of COL1A1, COL1A2, COL6A3, and SULF1 as Prognostic Biomarkers in Gastric Cancer.

BACKGROUND: Gastric cancer (GC) is among the most prevalent cancers globally. As such, there is a need to explore the mechanism underlying its pathogenesis and identify potential biomarkers for its prognosis. METHODS: ONCOMINE was used to screen differentially expressed genes between GC and normal gastric mucosa. GEPIA was used to analyze the expression and correlation of candidate genes in tumor node metastasis (TNM) stage. STRING was used to construct protein interaction network. Kaplan-Meier plotter was used to analyze survival. TIMER was used to evaluate the association between candidate genes and immune cell infiltration. RESULTS: From the ONCOMINE database, we found COL1A1, COL1A2, COL6A3, and SULF1 genes were significantly upregulated in stomach adenocarcinomas. There was a considerable correlation between the expression of COL1A1 (p = 0.029), COL1A2 (p = 0.004), COL6A3 (p = 0.002), SULF1 (p = 0.001), and the TNM stage. COL1A1 was positively correlated with ERBB2 (R = -0.037, p = 0.46), while the other three genes were negatively correlated with ERBB2 (p > 0.05). The Kaplan-Meier plotter showed that low transcriptional levels of COL1A1 (p = 0.0020), COL1A2 (p = 0.0015), COL6A3 (p = 0.0015), and SULF1 (p = 0.0016) in gastric cancer patients were remarkably related to longer overall survival. In addition, there was a close relationship between chemokine expression and infiltration of the six immune cell types: B cells, macrophages, CD4+ T cells, CD8+ T cells, dendritic cells, and neutrophils, implying that the genes acted as indicators of both prognosis and immune status. CONCLUSION: Our findings implicate COL1A1, COL1A2, COL6A3, and SULF1 as candidate biomarkers for the prognosis of gastric cancer.

Yangonin modulates lipid homeostasis, ameliorates cholestasis and cellular senescence in alcoholic liver disease via activating nuclear receptor FXR.

BACKGROUND: Alcoholic liver disease (ALD) is a progressive disease beginning with simple steatosis but can progress to alcoholic steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. The morbidity of ALD is on the rise and has been a large burden on global healthcare system. It is unfortunately that there are currently no approved therapeutic drugs against ALD. Hence, it is of utmost urgency to develop the efficacious therapies. The ability of many molecular targets against ALD is under investigation. Farnesoid X receptor (FXR), a member of the ligand-activated transcription factor superfamily, has been recently demonstrated to have a crucial role in the pathogenesis and progression of ALD. PURPOSE: The purpose of the study is to determine whether Yangonin (YAN), a FXR agonist previously demonstrated by us, exerts the hepatoprotective effects against ALD and further to clarify the mechanisms in vitro and in vivo. STUDY DESIGN: The alcoholic liver disease model induced by Lieber-Decarli liquid diet was established with or without Yan treatment. METHODS: We determined the liver to body weight ratios, the body weight, serum and hepatic biochemical indicators. The alleviation of the liver histopathological progression was evaluated by H&E and immunohistochemical staining. Western blot and quantitative real-time PCR were used to demonstrate YAN treatment-mediated alleviation mechanisms of ALD. RESULTS: The data indicated that YAN existed hepatoprotective activity against ALD via FXR activation. YAN improved the lipid homeostasis by decreasing hepatic lipogenesis and increasing fatty acid ß-oxidation and lipoprotein lipolysis through modulating the related protein. Also, YAN ameliorated ethanol-induced cholestasis via inhibiting bile acid uptake transporter Ntcp and inducing bile acid efflux transporter Bsep and Mrp2 expression. Besides, YAN improved bile acid homeostasis via inducing Sult2a1 expression and inhibiting Cyp7a1 and Cyp8b1 expression. Furthermore, YAN attenuated ethanol-triggered hepatocyte damage by inhibiting cellular senescence marker P16, P21 and Hmga1 expression. Also, YAN alleviated ethanol-induced inflammation by down-regulating the inflammation-related gene IL-6, IL-1ß and TNF-α expression. Notably, the protective effects of YAN were cancelled by FXR siRNA in vitro and FXR antagonist GS in vivo. CONCLUSIONS: YAN exerted significant hepatoprotective effects against liver injury triggered by ethanol via FXR-mediated target gene modulation.

Safety and efficacy of S1 monotherapy or combined with nab-paclitaxel in advanced elderly pancreatic cancer patients: A meta-analysis.

OBJECTIVE: To evaluate the therapeutic efficacy and safety of S1 monotherapy or combination with nab-paclitaxel for the treatment of elderly patients with metastatic or locally advanced pancreatic adenocarcinoma. METHOD: PubMed, Embase, Cochrane Central Library, China Biology Medicine, and China National Knowledge Infrastructure databases were searched without time limits according to the inclusion criteria. RevMan (Version 5.3) software was used for data extraction and meta-analysis. Objective response rate (ORR) and disease control rate (DCR) were used to evaluate therapeutic effects while side effects including leukopenia, thrombocytopenia, neurotoxicity, vomit, and alopecia were extracted for evaluation. There was no need for ethical review in this study because no ethical experiments were conducted and all data used were public data. All relevant data are within the paper and its Supporting Information files. RESULTS: Four retrospective studies comprising 308 elderly patients with metastatic or locally advanced pancreatic adenocarcinoma were included in the analysis. One hundred fifty-one patients underwent S1 monotherapy and 157 received S1 combined nab-paclitaxel. Meta-analysis indicated that compared with S1 monotherapy, S1 combined with nab-paclitaxel had higher ORR (OR 2.25, 95% CI: 1.42-3.55; P = .0005) and DCR (OR 2.94, 95% CI: 1.55-5.58; P = .0009). The adverse reaction of leukopenia was higher in the combined therapy group (OR 1.85, 95% CI: 1.09-3.13, P = .02), but no significant difference was found in thrombocytopenia, neurotoxicity, vomiting, and alopecia between the 2 groups (P > .05). CONCLUSION: Nab-paclitaxel plus S1 was more efficient in terms of ORR and DCR than S1 monotherapy in elderly pancreatic ductal adenocarcinoma patients while the side effect was controllable with a higher probability of leukopenia. Thus, combined nab-paclitaxel and S1 could be safely used in elderly patients.

Luteolin ameliorates LPS-induced acute liver injury by inhibiting TXNIP-NLRP3 inflammasome in mice.

BACKGROUND: Chemical liver injury is one of the main causes of acute liver failure and death. To date, however, treatment strategies for acute liver injury have been limited. Therefore, there is an urgent need to find new therapeutic targets and effective drugs. NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome is a complex of multiple proteins that has been shown to induce cell death under inflammatory and stress pathologic conditions and is thought to provide new targets for the treatment of a variety of diseases. PURPOSE: The purpose of this study was to investigate whether luteolin has a protective effect on the liver and further elucidate whether it is realized through the thioredoxin interacting protein (TXNIP)-NLRP3 axis. STUDY DESIGN: Acute hepatic injury in mice caused by intraperitoneal injection of lipopolysaccharide (LPS) was treated with or without luteolin. METHODS: Male C57BL/6 mice and mouse primary hepatocytes were selected. TXNIP protein knockdown was achieved by siRNA, qPCR and Western blot were performed to explore the mechanism of luteolin in alleviating acute liver injury. RESULTS: The results indicated that luteolin had a markedly protective effect on acute liver injury induced by LPS in mice by inhibiting the TXNIP-NLRP3 axis. Luteolin inhibits NLRP3 inflammasome activation by suppressing TXNIP, apoptosis associated speck-like protein containing a CARD domain (ASC), caspase-1, interleukin-1ß (IL-1ß) and IL-18 to reduce liver injury. In addition, luteolin inhibits LPS-induced liver inflammation by inhibiting the production of inflammation-related gene tumor necrosis factor-α (TNF-α), IL-10, and IL-6. What's more, luteolin alleviated LPS-induced hepatocyte injury by inhibiting oxidative stress and regulating MDA, SOD, and GSH levels. However, the protective effect of luteolin on acute LPS-induced liver injury in mice was blocked by si-TXNIP in vitro. CONCLUSIONS: These combined data showed that luteolin may alleviate LPS-induced liver injury through the TXNIP-NLPR3 axis, providing new therapeutic targets and therapeutic drugs for subsequent studies.

Dissipation behavior, residue distribution, and dietary risk assessment of fluopimomide and dimethomorph in taro using HPLC-MS/MS.

Dimethomorph is a morpholine broad-spectrum fungicide and effectively controls taro blight, cucumber downy mildew, rice blast disease, and others. Fluopimomide is a newly developed broad-spectrum fungicide to primarily control oomycetes and rhizoctonia diseases. Taro, one of the earliest cultivated crops, is a staple food in Africa, Oceania, and Asia. Recently, a commercial suspension concentrate formulation containing 15% fluopimomide and 25% dimethomorph has been registered in China, the second largest taro producer in the world. The objective of this study was to develop a high-performance liquid chromatography tandem mass spectrometry method to detect the residues of fluopimomide and dimethomorph concurrently in taro samples. The results showed that the average recoveries of fluopimomide and dimethomorph ranged from 83 to 108%, and relative standard deviations (RSD) ranged from 1 to 11%. The limit of quantitation (LOQ) was 0.01 mg kg-1 for the two compounds. The dissipation results demonstrated that both fluopimomide and dimethomorph in taro degraded rapidly in taro fields, and the residues of the two fungicides were below the LOQ within 14 days post-application. The final residue levels of fluopimomide and dimethomorph in taro were lower than 0.066 mg kg-1 28 days post-application. For dietary risk assessments, the dietary structure of different genders and age of people in China exposure risk assessment and whole diet exposure risk assessment shows that the risk quotient (RQ) values were substantially lower than 100%, suggesting that the long-term risks of fluopimomide/dimethomorph mixed formulation in taro at the recommended dosage were negligible. In summary, our combined results from the dissipation behaviors, terminal residues, and dietary risk assessments provide the critical empirical data for the establishment of the maximum residue levels (MRLs) of the two broad-spectrum fungicides in taro, a traditional food for African, Oceanic, and South Asian cultures.