Sterol-regulatory element binding protein 1 (SREBP1), an intracellular cholesterol sensor located in the endoplasmic reticulum, regulates the intracellular cholesterol by the Insig-Srebp-Scap ...pathway. Over-expression of SREBP1 can cause dyslipidemia. SREBP1 can regulate the metabolic pathway, and then promote the proliferation of tumor cells. However, there is no relevant research of metastasis and invasion in the field of colorectal cancer (CRC).
Expression of SREBP1 was manipulated in CRC cell lines with low and high level SREBP1 expression by transfectiong with plasmids containing the SREBP1 gene, or by shRNA. The effect of SREBP1 on cell migration was assayed. The expression of SREBP1, p65 and MMP7 were detected by western blot. Human umbilical vein endothelial cell was used for detection of angiogenesis by adding the culture supernatant from HT29 and SW620. The level of reactive oxygen species (ROS) was detected by Dihydroethidium (DHE) staining. NF-κB inhibitor SN50 was used to test the relationship of SREBP1, NF-κB pathway and MMP7.
We found that the expression of SREBP1 in colon adenocarcinoma was significantly higher than that in noncancerous tissues, especially in the invasive tumor front including tumor budding. In vitro, SREBP1 over-expressed in colon cancer cell lines HT29 promoted angiogenesis in endothelial cells, increased ROS levels, phosphorylation of NF-κB-p65 and increases MMP7 expression. The effect of SREBP1 on expression of MMP7 was lost following treatment with the NF-κB inhibitor SN50.
Our results suggest that SREBP1 can promote the invasion and metastasis of CRC cells by means of promoting the expression of MMP7 related to phosphorylation of p65.
Objective
Common bile duct (CBD) stones can spontaneously pass through the papilla. This study explored factors associated with stone passage by comparing differences in the clinical features of ...stones retained in the CBD and excreted stones.
Methods
Data were retrospectively collected for all patients who were hospitalized in our center between March 2016 and May 2021 with clinical, laboratory, or imaging evidence of CBD stones. All patients underwent endoscopic retrograde cholangiopancreatography (ERCP) and were classified into two groups: group A (stones extracted by ERCP, n = 86) and group B (stones discharged before ERCP, n = 15). Demographic data, biochemical and radiological findings were compared between the groups.
Results
Stone size (0.82 vs. 0.33 cm), and levels of total bilirubin (58.2 vs. 28.8 μmol/L), gamma-glutamyl transpeptidase (416.7 vs. 193.9 U/L), alkaline phosphatase (191.9 vs. 123.1 U/L), carbohydrate antigen 19-9 (603.7 vs. 37.2 U/mL), and α-L-fucosidase (37.4 vs. 22.6 U/L) were significantly higher in group A than in group B. Logistic regression analyses showed that stone size was the only factor significantly associated with spontaneous passage of CBD stones.
Conclusions
CBD stones less than 0.33 cm in size may be self-expelled through the papilla.
In this article, we explore how incomplete spokes-character faces (versus complete spokes-character faces in application icon designs) make a positive impression on users, and we outline the boundary ...conditions. Across three studies, we find incomplete spokes-character faces to be an effective image icon tool. In study 1, we find that spokes-characters with incomplete faces improve users’ brand evaluations. In study 2, we find that incomplete spokes-character faces create perceptions of anthropomorphism, which lead to more favorable brand evaluations by enhancing the interpersonal closeness between the user and the brand. The results of study 3, however, show that the type of social exclusion (control vs. ignored vs. rejected) moderates the relationship between incomplete spokes-character faces in mobile application icons and brand evaluations.
•Analysis 51 ALS causative genes in a large ALS cohort from central-south of China.•Site of onset of ALS was influenced by rare damage variants and sex.•SOD1 gene was the most common mutated gene in ...China, followed by ATXN2 and NEK1.•Mutation spectrum of AD-ALS patients differed from that of sporadic ALS patients.
To analyze the mutational spectrum of known ALS causative genes in China ALS patients. We comprehensively analyzed 51 ALS causative genes by combining different sequencing technologies in 753 unrelated ALS patients from Central South China. The mean age at onset (AAO) was 53.7±11.4 years. The AAO was earlier in the autosomal dominant (AD) ALS patients than in the sporadic ALS (sALS) patients. Bulbar onset was more frequent in females than in males. SOD1 was the most frequently mutated gene in the AD-ALS and the sALS patients, followed by the ATXN2 and FUS genes in the AD-ALS patients and the NEK1 and CACNA1H genes in the sALS patients. Patients with RDVs in the SOD1 or FUS genes had an earlier AAO than the mean AAO of all the patients, while the patients with RDVs in the NEK1 gene showed later onset. SOD1 gene was the most commonly mutated gene in ALS patients in China, followed by ATXN2 and NEK1. The phenotype might be determined synergistically by sex and genetic variants.
Cytochrome P450 3A (CYP3A), the most important class of drug-metabolizing enzymes, participates in the metabolism of half of clinically used drugs. The CYP3A index reactions of dogs, one of the most ...widely used preclinical nonrodent species, are still poorly understood. This work evaluated the activity and selectivity of 10 CYP3A index reactions, including midazolam (MDZ) 1'- and 4-hydroxylation, alprazolam (APZ) and triazolam (TRZ)
- and 4-hydroxylation, testosterone (T) 6
-hydroxylation, lithocholate (LCA) 6
-hydroxylation, deoxycholate (DCA) 1
- and 5
-hydroxylation, with quantitative reaction phenotyping and kinetic analysis in human and canine recombinant CYP enzymes (rCYPs). In human studies, all reactions are reconfirmed as mixed index reactions of CYP3A with minor contributions from non-CYP3A isoforms. In canine studies, all reactions are also primarily catalyzed by CYP3A12 with lower contributions from CYP3A26. However, the canine CYP2B11 appreciably contributes to the hydroxylation of benzodiazepines except for APZ 4-hydroxylation. The canine CYP3A isoforms have lower activity than human isoforms toward T 6
-hydroxylation and LCA 6
-hydroxylation and both substrates undergo non-CYP3A catalyzed side reactions. DCA 1
- and 5
-hydroxylation are validated as the CYP3A index reactions in both humans and dogs with limited non-CYP3A contributions and side reactions. In conclusion, this work provides a comprehensive overview for the selectivity and activity of in vitro CYP3A index reactions in humans and dogs. The validated CYP3A index reactions between humans and dogs may benefit future practices in drug metabolism and drug interaction studies. SIGNIFICANCE STATEMENT: Dogs are one of the most important nonrodent animals with limited studies of cytochrome P450 enzymes than humans. This work provides the most comprehensive quantitative data to date for the selectivity and activity of CYP3A index reactions in humans and dogs. The canine CYP2B11 was found to appreciably contribute to hydroxylation of midazolam, alprazolam and triazolam, the well-known probes for human CYP3A. Deoxycholate 1
- and 5
-hydroxylation are validated as the CYP3A index reactions in both humans and dogs.
The salience network plays an important role in detecting stimuli related to behavior and integrating neural processes. The aim of this study was to investigate changes in functional connectivity of ...the salience network in insomnia patients. Independent component analysis combined with a dual regression approach was used to examine functional connectivity differences in the salience network between patients with insomnia (n = 33) and healthy controls (n = 33). Pearson correlation analysis was used to analyze the relationship between differences in functional connectivity and the clinical characteristics of insomnia patients. Compared to healthy controls, insomnia patients showed increased functional connectivity in the dorsal anterior cingulate cortex within the salience network, as well as greater connectivity between the salience network and other brain regions including the dorsolateral prefrontal cortex, superior frontal gyrus, sensorimotor area and brain stem. The correlation analysis showed that increased functional connectivity between the salience network and left dorsolateral prefrontal cortex was positively correlated with Pittsburgh Sleep Quality Index score. Increased functional connectivity between salience network and several brain regions may be related to hyperarousal in insomnia patients. The connectivity between salience network and dorsolateral prefrontal cortex may potentially be used as a neuroimaging biomarker of sleep quality.
Deoxycholic acid (DCA, 3
, 12
-dihydroxy-5
-cholan-24-oic acid) is the major circulating secondary bile acid, which is synthesized by gut flora in the lower gut and selectively oxidized by CYP3A into ...tertiary metabolites, including 1
,3
,12
-trihydroxy-5
-cholan-24-oic acid (DCA-1
-ol) and 3
,5
,12
-trihydroxy-5
-cholan-24-oic acid (DCA-5
-ol) in humans. Since DCA has the similar exogenous nature and disposition mechanisms as xenobiotics, this work aimed to investigate whether the tertiary oxidations of DCA are predictive of in vivo CYP3A activities in beagle dogs. In vitro metabolism of midazolam (MDZ) and DCA in recombinant canine CYP1A1, 1A2, 2B11, 2C21, 2C41, 2D15, 3A12, and 3A26 enzymes clarified that CYP3A12 was primarily responsible for either the oxidation elimination of MDZ or the regioselective oxidation metabolism of DCA into DCA-1
-ol and DCA-5
-ol in dog liver microsomes. Six male dogs completed the CYP3A intervention studies including phases of baseline, inhibition (ketoconazole treatments), recovery, and induction (rifampicin treatments). The oral MDZ clearance after a single dose was determined on the last day of the baseline, inhibition, and induction phases, and subjected to correlation analysis with the tertiary oxidation ratios of DCA detected in serum and urine samples. The results confirmed that the predosing serum ratios of DCA oxidation, DCA-5
-ol/DCA, and DCA-1
-ol/DCA were significantly and positively correlated both intraindividually and interindividually with oral MDZ clearance. It was therefore concluded that the tertiary oxidation of DCA is predictive of CYP3A activity in beagle dogs. Clinical transitional studies following the preclinical evidence are promising to provide novel biomarkers of the enterohepatic CYP3A activities. SIGNIFICANCE STATEMENT: Drug development, clinical pharmacology, and therapeutics are under insistent demands of endogenous CYP3A biomarkers that avoid unnecessary drug exposure and invasive sampling. This work has provided the first proof-of-concept preclinical evidence that the CYP3A catalyzed tertiary oxidation of deoxycholate, the major circulating secondary bile acid synthesized in the lower gut by bacteria, may be developed as novel in vivo biomarkers of the enterohepatic CYP3A activities.
Identifying the progress of kidney injury may aid the effective treatment and intervention. Herein, we developed a fluorescent biosensor array for instantaneous and accurate identification of the ...kidney injury progression via “doubled” signals. The multichannel biosensor array consisted of polydopamine-polyethyleneimine (PDA-PEI) and multicolor-labelled different length of DNAs including AAAAA-Cyanine7 (5A-Cy7), AAAAAAAAAA-Texas Red (10A-Texas Red), and AAAAAAAAAAAAAAAAAAAA-VIC (20A-VIC). Facing to the variety of protein in urine with alterable charge accompanied with different progress of kidney injury, the composition of urine replaces the DNA signal molecules, forming their special fluorescence patterns. Taking the size of protein into consideration, the original three variables induced by the protein charge were extended to six variables induced by the two factors of protein particle size and charge difference, which could provide a more accurate strategy to identify the progress of kidney injury. Notably, this strategy not only opened up new perspective for identification the progress of kidney injury via the size and charge of urine protein, but also improved the resolving power of sensor array by increasing the number of sensor elements for extending their potential application to various diseases.
Graphical abstract
Background
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder. Mitochondrial dysfunction is involved in the complex pathophysiology of ALS; however, the role of ...mitochondrial DNA (mtDNA) variants in ALS is poorly understood. We aimed to elucidate the role of mtDNA variants in the pathogenesis of ALS.
Methods
The mitochondrial haplogroups of 585 ALS patients and 371 healthy controls were determined; 38 ALS patients and 42 controls underwent long-range polymerase chain reaction combined with next-generation sequencing technology to analyze whole mitochondrial genome variants.
Results
A higher percentage of variants accumulated in ALS patients than in controls. Analysis of coding region variations that were further stratified by mtDNA genes revealed that nonsynonymous variants were more vulnerable in ALS patients than in controls, particularly in the
ND4L
,
ND5
, and
ATP8
genes. Moreover, pathogenic nonsynonymous variants tended to over-represent in ALS patients. Unsurprisingly, nonsynonymous variants were not related to the phenotype. Haplogroup analysis did not found evidence of association between haplogroups with the risk of ALS, however, patients belonging to haplogroup Y and M7c were prone to develop later onset of ALS.
Conclusions
This is the first study to profile mtDNA variants in ALS patients from mainland China. Our results suggest that an increase in the number of nonsynonymous variants is linked to the pathogenesis of ALS. Moreover, haplogroup Y and M7c may modulate the clinical expression of ALS. Our findings provide independent, albeit limited, evidence for the role of mtDNA in the pathogenesis of ALS.
PDF
