Startseite Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
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Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics

  • Liping Su , Li Liu , Min Ji , Xiayun Hu , Min Liang , Ziyang Lu , Zhiguo Wang , Yaling Guan , Jinling Xiao , Mengjie Zhuang , Sensen Zhu , Long Yang EMAIL logo und Hongwei Pu EMAIL logo
Veröffentlicht/Copyright: 31. Juli 2023
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Aus der Zeitschrift Open Medicine Band 18 Heft 1

Abstract

Heroin can cause damage to many human organs, possibly leading to different types of arrhythmias and abnormal electrophysiological function of the heart muscle and the steady state of calcium-ion channels. We explored cardiomyocytes treated with heroin and the effect on calcium-ion channels. Transcriptomics and metabolomics were used to screen for differential genes and metabolite alterations after heroin administration to jointly analyze the effect of heroin on calcium channels in cardiomyocytes. Cardiomyocytes from primary neonatal rats were cultured in vitro and were treated with different concentrations of heroin to observe the changes in morphology and spontaneous beat frequency and rhythm by a patch clamp technique. Transcriptomic studies selected a total of 1,432 differentially expressed genes, 941 upregulated and 491 downregulated genes in rat cardiomyocytes from the control and drug intervention groups. Gene Ontology functional enrichment showed that 1,432 differential genes selected by the two groups were mainly involved in the regulation of the multicellular organismal process, response to external stimulus, myofibril, inflammatory response, muscle system process, cardiac muscle contraction, etc. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that these genes were mainly concentrated in cardiac muscle contraction, osteoclast differentiation, adrenergic signaling in cardiomyocytes, dilated cardiomyopathy, hypertrophic cardiomyopathy, and other important pathways. Metabolomic testing further suggested that cardiomyocyte metabolism was severely affected after heroin intervention. After the treatment with heroin, the L-type calcium channel current I–V curve was up-shifted, the peak value was significantly lower than that of the control group, action potential duration 90 was significantly increased in the action potential, resting potential negative value was lowered, and action potential amplitude was significantly decreased in cardiomyocytes. In this study, heroin could cause morphological changes in primary cardiomyocytes of neonatal rats and electrophysiological function. Heroin can cause myocardial contraction and calcium channel abnormalities, damage the myocardium, and change the action potential and L-type calcium channel.

Keywords: heroin; transcriptomics; action potential; L-calcium channel; arrhythmia

1 Introduction

In recent years, the abuse and addiction to heroin have become a serious public health concern in society. Heroin has a strong dependence and can cause various degrees of damage to many human organs [1]. A large number of studies have shown that heroin addiction has serious effects on the cardiovascular system, can induce various arrhythmias, and cause intracellular calcium overload, affecting the normal physiological function of the heart [2,3]. Cardiac electrophysiological activity is closely related to myocardial calcium channels, and calcium channels are regulated by various calcium-dependent regulatory proteins. Calcium ion (Ca2+) is an important second messenger in cells, which mainly maintains the normal electrophysiological function of the cell membrane and ensures the normal progress of various biological signal transduction pathways. Intracellular Ca2+ overload in cardiomyocytes is a major feature of cardiomyocyte injury. The prolongation of the action potential duration (APD) of ventricular myocytes can enhance intracellular calcium currents and change myocardial contractility. At the same time, changes in calcium related proteins can also cause abnormal changes in action potential, leading to the occurrence of cardiac arrhythmias. It plays an important role in the signal pathway mediated by opioid receptors [4,5]. Exploring the relationship between calcium ion and diacetylmorphine arrhythmia can provide new thinking for finding new drug targets and scientific prevention and treatment in clinical patients with diacetylmorphine arrhythmia.

2 Materials and methods

2.1 Materials

The 3-day-old SPF-class Sprague-Dawley (SD) neonatal rats were provided by the Experimental Animal Center of Xinjiang Medical University (Experimental animal ethical approval of the Medical Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University: K201907-06). Heroin was provided by the Anti-Drug Corps of Xinjiang Uygur Autonomous Region. Anti-cardiac troponin T(ab209813) was provided by Abcam company, USA, secondary antibody to mouse (goat polyclonal secondary antibody to mouse IgG H&L) was provided by Alexa Flour® 488, and ab150113 was provided by Abcam company, USA.

2.2 Cell culture

One hundred and twenty SD neonatal rats (1–3 days) were euthanatized, and their skin was disinfected with 75% alcohol under aseptic conditions. After cutting approximately half of the heart, the remaining heart was cut using an ophthalmic scissor into 7–8 petals along the tip of the heart in the radial shape. Then, 0.025% trypsin was added for digestion, and 0.6 mg/mL of type II collagenase was added for vibrating digestion for 7 min. Then, centrifugation was performed at 1,000 rpm for 5 min. The cells were counted and inoculated in a 100 mm culture dish at a cell density of 5 × 105 cells/mL. In this way, the proliferation of cardiac fibroblasts was inhibited. The cells were linked and beaten at the same frequency after being cultured for 5–6 days. Then, they could be used for subsequent experiments.

2.3 Immunofluorescence

The cultured primary cardiomyocytes were seeded or placed in a polylysine-pretreated laser confocal culture dish. The cells were fixed with 4% tissue cell fixative for 40 min at room temperature. Then, 0.3% Triton X-100 working solution was added to the culture dish for perforation, followed by incubation for 30 min. The anti-cardiac troponin T (1:500) was diluted with 0.3% Triton X-100 working solution. Bovine serum albumin was used for blockage for 1 h and incubated with the primary antibody overnight at 4℃. Then, it was rinsed with phosphate-buffered saline (PBS) three times for 5 min. The secondary antibody, which is the FITC-labeled goat anti-mouse IgG antibody (goat antibody to mouse IgG H&L [Alexa Flour® 488], 1:500), was incubated for 1 h at 37℃ in the dark. DAPI was used to stain the nucleus for 10 min. Under the confocal microscope, the purity of cardiomyocytes was identified and observed by taking five different visual fields. The expression of α-actin was observed at the excitation wavelength of 488 nm, and DAPI staining was observed under the excitation of ultraviolet wavelength. The positive cells were expressed, and the proportion of positive cells was counted by the two lasers that were superimposed at the same time.

2.4 Cell morphology

A total of 10−4 mol/L heroin was used for the intervention with cardiomyocytes. The concentration of heroin was 0 mol/L (N group) and 10−4 mol/L (H group). After the PBS solution in equivalent volume was added to the normal group and acted for 24 h, the changes in morphology and spontaneous beat frequency and rhythm of cardiomyocytes were observed under an inverted fluorescence microscope at different concentrations of drug interference.

2.5 Sample intervention and collection

Cultured primary rat cardiomyocytes were divided into the normal control group (Con) and drug intervention group (Drug). The Drug group was given 10−4 mol/L heroin for 24 h according to the optimal drug action concentration determined by a previous experiment, and an equal amount of PBS was added to the Con group. After 24 h, the cells were collected in 1.5 mL Eppendorf tubes, repeating each group for subsequent transcriptomics and targeted metabolomics experiments based on the multiple reaction monitoring (MRM) method.

2.6 Transcriptomic detection and analysis

Transcriptomic detection and analysis involved the following steps.

(1) RNA extraction: the basic principle of extraction is to prevent RNA degradation in the process of extraction, maximize the efficiency of RNA extraction, and ensure the extraction of high-quality RNA with good integrity and high purity from the target sample. (2) Sample testing: high-quality RNA is the basis for the success of the whole project. We inspected the quality of the samples to ensure the accuracy of sequencing data, and the test results could only meet the requirements of sequencing and database construction. Sample test results are shown in the quality inspection report. (3) Library construction: after the sample test was qualified, magnetic beads with oligo (dT) were used to enrich the mRNA of eukaryotes. The fragmentation buffer was subsequently added to randomly interrupt the mRNA. Using mRNA as a template with six-base random primers (random hexamers), the second strand of cDNA was synthesized by buffer and dNTPs and DNA polymerase I, and the double-stranded cDNA was subsequently purified using AMPure XP beads. Purified double-stranded cDNA was then subjected to end repair, a tail addition, and sequencing joint ligation, followed by fragment size selection with AMPure XP beads. Finally, polymerase chain reaction enrichment was performed to obtain the final cDNA library. (4) Library quality control: after the library construction was completed, the insert length (insert size) and the effective concentration of the library were tested to ensure the library quality. (5) Computer sequencing: after the library inspection was qualified, different libraries were pooled according to the target data amount and computer sequencing. (6) Bioinformatics analysis included GO analysis, KEGG analysis, protein interaction network analysis, and transcription factor analysis.

2.7 Analysis of targeted metabolomics tests based on MRM

Energy metabolites were analyzed in rat cardiomyocytes based on the MRM method, and all samples were prepared as QC samples using QC samples to evaluate the stability and reproducibility of the data. The relative standard deviation (RSD) results of QC samples are shown in Figure 7, where the RSD is less than 30% energy metabolism, and the data are stable and reliable in the samples. The main steps are as follows: (1) Metabolite extraction: samples were removed at −80℃, and 1 mL of methanol acetonitrile solution (2:2:1, v/v) was added. The samples were vortexed for 60 s, underwent low-temperature sonication for 30 min twice, put at −20℃ for 1 h for protein precipitation, and centrifuged at 14,000 RCF at 4℃ for 20 min. The supernatant was frozen to get dry samples at −80℃. (2) Chromatography-mass spectrometry analysis: samples were separated using an Agilent 1290 Infinity LC ultra-HPLC system. Mass spectrometry was performed using a 5500 QTRAP mass spectrometer (AB SCIEX) in negative ion mode. (3) Data processing: the spectral peak area and retention time were extracted using MultiQuant software.

2.8 Cell patch clamp

After the treatment with 10−4 mol/L heroin for 24 and 48 h, the action potential and calcium channel current were detected. After the whole-cell recording mode was formed, the voltage clamp mode was changed to the current clamp mode, and the action potential was recorded. The patch clamp system was controlled by patch clamp amplifiers EPC10 and pCLAMP8.0 (Axon Instrument) software. The digital-to-analog converter performed I Ca-L to stimulate signal generation, feedback signal acquisition, and data analysis. The following solution formulation was used for detecting action potential: extracellular fluid: 140 mmol/L NaCl, 3.5 mmol/L KCl, 10 mmol/L HEPES, 10 mmol/L glucose, 1.25 mmol/L NaH2PO4, 1 mmol/L MgCl2, 2 mmol/L CaCl2, NaOH, and pH = 7.4. Intracellular fluid: 5 mmol/L NaCl, 140 mmol/L KCl, 0.1 mmol/L CaCl2, 1 mmol/L MgCl2, 10 mmol/L HEPES, 2 mmol/L Mg-ATP, KOH, and pH = 7.2. The following solution formulation was used for detecting calcium channels: extracellular fluid: 140 mmol/L TEA-Cl, 2 mmol/L MgCl2, 10 mmol/L HEPES, 10 mmol/L glucose, CsOH, and pH = 7.4. Intracellular fluid: 120 mmol/L CsCl, 1 mmol/L MgCl2, 10 mmol/L HEPES, 4 mmol/L Mg-ATP, CsOH, and pH = 7.2.

2.9 Statistical analysis

The statistical results concerning measurement data and enumeration data were tested by SPSS 23.0 software. Data were presented as the mean value ± standard error of the mean from at least three independent experiments performed in duplicate or triplicate. Statistical analysis was performed by one-way ANOVA with Bonferroni post hoc test, and the test level was set at α = 0.05.

3 Results

3.1 Purity identification for primarily cultured cardiomyocytes of neonatal rats

The passaged-7 primarily cultured cardiomyocytes were identified by laser confocal microscopy. The expression of α-actin, which is a classical biomarker specific to cardiomyocytes, was detected in the primary cardiomyocytes. After the primary antibody FITC-labeled goat anti-mouse IgG combined with the myocardial cell-specific protein cardiac troponin T in the cytoplasm, the grid-like or filamentous-green fluorescence (Figure 1b) was excited by a 488 nm laser. DAPI dying was used to locate the nucleus, and it formed circular or elliptical blue fluorescence (Figure 1a) excited by the ultraviolet laser. The overlap figures showed the intact morphological structure of primary cardiomyocytes with various forms, including triangles, fusiforms, and polygons. The actin protein was filamentously distributed and interwoven into a network in the cells (Figure 1c). Five randfluorescent fields were selected from each dish, and cells expressing blue and green fluorescence were identified as positive cells. The number of blue fluorescence was recorded as the total number of cells, and the proportion of positive cells was calculated. The results showed that the purity of the primary cultured rat cardiomyocytes was >90%, which could be used in subsequent experiments.

Figure 1 Identification results of primary cardiomyocytes. (a) Anti-cardiac troponin T cytoplasm stained green; (b) DAPI nuclei are blue; and (c) A + B synthesis.
Figure 1

Identification results of primary cardiomyocytes. (a) Anti-cardiac troponin T cytoplasm stained green; (b) DAPI nuclei are blue; and (c) A + B synthesis.

3.2 Morphological changes in cardiomyocytes treated with different concentrations of heroin

When the cardiomyocytes of primary neonatal rats were continuously cultured for 3 days, spontaneous pulsation occurred, and the pulsation frequency was slower. Then, the cells were cultured for 7 days, and most cells recovered to spontaneous pulsation, while some of the cardiomyocytes were connected into pieces and beaten with a regular rhythm. In the control group with PBS, the quantities of cultured cardiomyocytes were large, and their morphology was intact. Additionally, the cell morphology was diverse and triangular, long fusiform, and polygonal, with a clear structure, intact membrane, and bright membrane edge, and the nucleus was round or similar to round. The size was normal, the nuclear membrane was smooth, and the cells were connected to each other by pseudopods (Figure 2a). With the intervention of heroin, the number of cardiomyocytes sharply decreased, the cell membrane shrank, the pseudopods decreased, the nuclear structure was blurred, and the cell debris appeared in the cells (Figure 2b).

Figure 2 Morphological changes in myocardial cells after heroin intervention for 24 h. (a) Normal primary cardiomyocyte group; (b) Diacetylmorphine intervention group.
Figure 2

Morphological changes in myocardial cells after heroin intervention for 24 h. (a) Normal primary cardiomyocyte group; (b) Diacetylmorphine intervention group.

3.3 Transcriptomic screening for differential genes and signaling pathway changes before and after heroin intervention

A total of 1,432 differentially expressed genes were selected in the normal control group, 941 were upregulated and 491 were downregulated in the normal control and drug intervention groups, respectively. The direct embodiment of the gene expression level was the abundance of its transcripts, and the higher the transcript abundance, the higher the gene expression level. FPKM values for each gene in each sample were calculated using feature Counts software. FPKM represented the number of alignments to transcript per kilobase per million alignment fragments, eliminating the effect of gene length and sequencing quantity differences on the calculated gene expression. The calculated gene expression levels could be directly used to compare the gene expression differences between different samples. Table 1 shows the statistics of the number of different genes at different expression levels. A volcano plot can visually show the distribution of differential genes and their expression levels in the two groups (Figure 3). Differential gene clustering could be used to judge the changes in different genes between different groups. According to the similarity of the expression of genes in each sample, the genes were clustered to visually show the expression of genes in different samples to obtain information related to biological problems. As could be seen from the cluster map, most genes were significantly up or downregulated before and after the heroin intervention (Figure 4). We used p adj. of <0.05 and log 2 foldchange of >1 as the differential significance criterion. The top 30 significantly differentially expressed genes between the two groups were selected, and the analysis results are shown in Table 2. Gene Ontology (GO) functional enrichment showed that 1,432 differential genes selected by the two groups were mainly involved in the regulation of the multicellular organismal process, response to external stimulus, defense response, developmental process, myofibril, inflammatory response, circulatory system process, muscle system process, cardiac muscle contraction, cardiac muscle tissue development, etc. (Figure 5). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of 1,432 differential genes screened out the top 20 most significant differential signaling pathways. Cardiac muscle contraction, osteoclast differentiation, adrenergic signaling in cardiomyocytes, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and other important pathways were significantly upregulated. The NOD-like receptor signaling pathway, influenza A, TNF signaling pathway, Kaposi sarcoma-associated herpesvirus infection, herpes simplex virus 1 infection, and other important pathways were significantly downregulated (Figure 6; Table 3).

Table 1

Statistics of number of genes with different expression levels

Sample 0 ≤ FPKM ＜ 1 1 ≤ FPKM ＜ 5 5 ≤ FPKM ＜ 10 10 ≤ FPKM ＜ 30 30 ≤ FPKM ＜ 50 50 ≤ FPKM
Con-1 20,798 (59.56%) 4,699 (13.46%) 2,632 (7.54%) 4,018 (11.51%) 1,150 (3.29%) 1,621 (4.64%)
Con-2 20,831 (59.66%) 4,817 (13.8%) 2,586 (7.41%) 3,917 (11.22%) 1,111 (3.18%) 1,656 (4.74%)
Con-3 20,822 (59.63%) 4,769 (13.66%) 2,565 (7.35%) 3,982 (11.4%) 1,136 (3.25%) 1,644 (4.71%)
Drug-1 20,393 (58.4%) 5,135 (14.71%) 2,447 (7.01%) 4,071 (11.66%) 1,177 (3.37%) 1,695 (4.85%)
Drug-2 20,443 (58.55%) 5,148 (14.74%) 2,454 (7.03%) 4,017 (11.5%) 1,150 (3.29%) 1,706 (4.89%)
Drug-3 20,407 (58.44%) 5,073 (14.53%) 2,480 (7.1%) 4,106 (11.76%) 1,175 (3.37%) 1,677 (4.8%)
Figure 3 Volcano plot of the differential gene expression distribution. The abscissa indicates the fold change of gene expression in different experimental groups or in different samples; the ordinate indicates the statistically significant degree of gene expression change. Scatters in the plot represent individual genes, black dots indicate genes with no significant differences, red dots indicate upregulated genes with significant differences, and green dots indicate downregulated genes with significant differences.
Figure 3

Volcano plot of the differential gene expression distribution. The abscissa indicates the fold change of gene expression in different experimental groups or in different samples; the ordinate indicates the statistically significant degree of gene expression change. Scatters in the plot represent individual genes, black dots indicate genes with no significant differences, red dots indicate upregulated genes with significant differences, and green dots indicate downregulated genes with significant differences.

Figure 4 Differential gene cluster map. Each column represents one sample, and each row represents one gene. Red indicates upregulation and blue downregulation. Above is the dendrogram of the sample clusters, two The closer the sample branches are, the closer the expression pattern of all different genes between these two samples is. The dendrogram of the gene clusters is shown on the left, two The closer the gene branches are, the closer their expression level is.
Figure 4

Differential gene cluster map. Each column represents one sample, and each row represents one gene. Red indicates upregulation and blue downregulation. Above is the dendrogram of the sample clusters, two The closer the sample branches are, the closer the expression pattern of all different genes between these two samples is. The dendrogram of the gene clusters is shown on the left, two The closer the gene branches are, the closer their expression level is.

Table 2

Differential genes (Con vs Drug)

Number Expression changes Name p value Expression changes Name p value
1 Up Reg3b 0.00000 Down Symbol 0.00000
2 Up Nppb 0.00000 Down Ptx3 0.00000
3 Up Nppa 0.00000 Down Prg4 0.00000
4 Up Hmox1 0.00000 Down Rasl12 0.00000
5 Up Lyz2 0.00000 Down Fzd1 0.00000
6 Up Rcan1 0.00000 Down Apol9a 0.00000
7 Up Gdf15 0.00000 Down Htr2a 0.00000
8 Up Myh7 0.00000 Down Mx2 0.00000
9 Up Zfand2a 0.00000 Down Ackr3 0.00000
10 Up Tcp11l2 0.00000 Down Jak2 0.00000
11 Up Xirp1 0.00000 Down Lox 0.00000
12 Up Gclc 0.00000 Down Irf7 0.00000
13 Up Myl3 0.00000 Down F3 0.00000
14 Up Mybpc3 0.00000 Down AABR07059663.1 0.00000
15 Up Myl2 0.00000 Down Tgm2 0.00000
16 Up Cybb 0.00000 Down Parp9 0.00000
17 Up Slc7a11 0.00000 Down Samd9 0.00000
18 Up Mtss1 0.00000 Down Cxcl6 0.00000
19 Up Tnnc1 0.00000 Down 3-Mar 0.00000
20 Up Atp1b1 0.00000 Down Prickle1 0.00000
21 Up Casq2 0.00000 Down Lgals3bp 0.00000
22 Up Fhl1 0.00000 Down Il6 0.00000
23 Up Popdc2 0.00000 Down Lrrc32 0.00000
24 Up Parm1 0.00000 Down Ahr 0.00000
25 Up Pcf11 0.00000 Down Grem1 0.00000
26 Up Sorbs2 0.00000 Down Cd55 0.00000
27 Up Ankrd1 0.00000 Down Ugdh 0.00000
28 Up Osgin1 0.00000 Down AABR07058464.1 0.00000
29 Up Actn2 0.00000 Down Pde7a 0.00000
30 Up Art3 0.00000 Down Adamts15 0.00000
Figure 5 Bar graph of GO enrichment for differential genes.
Figure 5

Bar graph of GO enrichment for differential genes.

Figure 6 KEGG enrichment bubble plot of the differentially expressed genes.
Figure 6

KEGG enrichment bubble plot of the differentially expressed genes.

Table 3

Differential signaling pathways (Con vs Drug)

Number Changes ID KEGG pathway Test Ref p value FDR
1 Up rno04260 Cardiac muscle contraction 16 86 0.00000 0.00001
2 Up rno04380 Osteoclast differentiation 19 123 0.00000 0.00001
3 Up rno04261 Adrenergic signaling in cardiomyocytes 19 146 0.00000 0.00014
4 Up rno05414 DCM 14 92 0.00001 0.00040
5 Up rno05140 Leishmaniasis 12 70 0.00001 0.00042
6 Up rno04610 Complement and coagulation cascades 13 85 0.00001 0.00054
7 Up rno05410 HCM 13 88 0.00002 0.00068
8 Up rno04662 B cell receptor signaling pathway 12 77 0.00002 0.00071
9 Up rno05150 Staphylococcus aureus infection 13 91 0.00003 0.00076
10 Up rno04145 Phagosome 18 167 0.00004 0.00108
11 Up rno04061 Viral protein interaction with cytokine and cytokine receptor 12 84 0.00006 0.00127
12 Up rno04666 Fc gamma R-mediated phagocytosis 12 91 0.00012 0.00257
13 Up rno05152 Tuberculosis 17 168 0.00015 0.00298
14 Up rno05221 Acute myeloid leukemia 10 68 0.00018 0.00325
15 Up rno04010 MAPK signaling pathway 24 295 0.00023 0.00391
16 Up rno05202 Transcriptional misregulation in cancer 17 184 0.00045 0.00716
17 Up rno04960 Aldosterone-regulated sodium reabsorption 7 39 0.00049 0.00731
18 Up rno04514 Cell adhesion molecules 15 156 0.00064 0.00900
19 Up rno04670 Leukocyte transendothelial migration 12 111 0.00079 0.01048
20 Up rno05412 Arrhythmogenic right ventricular cardiomyopathy 9 74 0.00155 0.01947
1 Down rno04621 NOD-like receptor signaling pathway 14 168 0.00000 0.00037
2 Down rno05164 Influenza A 13 156 0.00000 0.00045
3 Down rno04668 TNF signaling pathway 10 111 0.00003 0.00204
4 Down rno05167 Kaposi sarcoma-associated herpesvirus infection 12 192 0.00017 0.00862
5 Down rno05168 Herpes simplex virus 1 infection 16 321 0.00020 0.00862
6 Down rno05160 Hepatitis C 10 150 0.00035 0.01139
7 Down rno05165 Human papillomavirus infection 16 339 0.00037 0.01139
8 Down rno05161 Hepatitis B 10 154 0.00044 0.01176
9 Down rno05162 Measles 9 137 0.00078 0.01863
10 Down rno04622 RIG-I-like receptor signaling pathway 6 64 0.00097 0.02082
11 Down rno04620 Toll-like receptor signaling pathway 7 90 0.00113 0.02210
12 Down rno04350 TGF-beta signaling pathway 7 95 0.00155 0.02567
13 Down rno05169 Epstein-Barr virus infection 11 212 0.00149 0.02567
14 Down rno04623 Cytosolic DNA-sensing pathway 5 53 0.00251 0.03859
15 Down rno04060 Cytokine-cytokine receptor interaction 12 265 0.00288 0.04126
16 Down rno04512 ECM-receptor interaction 6 87 0.00466 0.06256
17 Down rno04072 Phospholipase D signaling pathway 8 151 0.00576 0.07284
18 Down rno04657 IL-17 signaling pathway 6 94 0.00678 0.08096
19 Down rno05146 Amoebiasis 6 99 0.00867 0.09815
20 Down rno04933 AGE-RAGE signaling pathway in diabetic complications 6 101 0.00953 0.10243

3.4 Metabolomic changes in cardiomyocytes after heroin intervention

The results of targeted metabolomics analysis based on the MRM methods revealed significant changes in multiple metabolites in SD rat cardiomyocytes following the heroin intervention, such as cis-aconitate, citrate, isocitrate, lactate, adenosine 5′-triphosphate (ATP), phosphoenolpyruvate (all the p-values were less than 0.05, and the difference was statistically significant). These metabolites are mainly related to mitochondrial oxidative phosphorylation. We found that the production of ATP was significantly reduced after diacetylmorphine intervention, suggesting that diacetylmorphine may affect the oxidative phosphorylation process of mitochondria, interfere with ATP production and then affect the myocardial contractile function (Figures 7–9).

Figure 7 The RSD distribution of the QC samples.
Figure 7

The RSD distribution of the QC samples.

Figure 8 Results of the hierarchical clustering of the metabolites.
Figure 8

Results of the hierarchical clustering of the metabolites.

Figure 9 Trend diagram of group metabolite expression levels.
Figure 9 Trend diagram of group metabolite expression levels.
Figure 9

Trend diagram of group metabolite expression levels.

3.5 Action potential of myocardial cells

After 7 days of isolated culturing, the cardiomyocytes of the neonatal rats were treated with 10−4 mol/L heroin for 24 and 48 h, and the action potential was significantly changed compared with the N group. Compared with the normal control group, after the action of 10−4 mol/L heroin for 24 h, the APA and RP significantly decreased, and the APD was significantly prolonged, with the results being statistically significant (p < 0.05) (Figures 10 and 11). After 48 h of action, the negative value of the RP lowered, the APA significantly decreased, and the APD was significantly prolonged, with statistically significant results (p < 0.05) (Figures 10 and 11). The results showed that 10−4 mol/L heroin could change the AP of cardiomyocytes, decrease the RP and APA, increase the APD, and increase the APD with the extension of the action time.

Figure 10 Action potential of cardiomyocytes in different groups. Action potential of cardiomyocytes in control group, heroin intervened for 24 and 48 h.
Figure 10

Action potential of cardiomyocytes in different groups. Action potential of cardiomyocytes in control group, heroin intervened for 24 and 48 h.

Figure 11 The changes in action potential in control group and 10−4 mol/L heroin intervention 24 and 48 h group. (a) RP and APA values of each group; (b) Statistical chart of APD for each group.
Figure 11

The changes in action potential in control group and 10−4 mol/L heroin intervention 24 and 48 h group. (a) RP and APA values of each group; (b) Statistical chart of APD for each group.

3.6 L-type calcium channel current of cardiomyocytes

The activation potential of the normal control group was −40 mV, the maximum peak potential was −10 mV, and the inversion potential was +30 mV. The interference of 10−4 mol/L heroin for 24 h significantly up-shifted the current–voltage curve. The peak pA/pF decreased from −14.469 ± 3.611 to −4.966 ± 0.771 (p < 0.05). The current–voltage curve was significantly up-shifted by 48 h of interference, and the peak pA/pF decreased from −14.469 ± 3.611 to −3.757 ± 2.060 (p < 0.05). The membrane potential was plotted based on peak pA/pF, and the I–V curve of I ca was plotted. After the interference of heroin, the Ca2+ current was significantly changed in the I–V curve compared with the control group, and I–V curve was significantly up-shifted, but the curve shape was unchanged (Table 4, Figure 12a–d), indicating that heroin only affected I ca-L current but did not change the electrophysiological properties of the Ca2+ channel.

Table 4

Changes in I ca-L current density in control group and 10−4 mol/L heroin intervention 24 and 48 h group (pA/pF) ( x ¯ ± s, n = 6)

Voltage clamping Con group 10−4 mol/L, 24 h 10−4 mol/L, 48 h
−50 mV 0.463 ± 0.919 −0.114 ± 0.369 0.801 ± 0.478
−40 mV −0.678 ± 2.175 −1.034 ± 0.815 0.123 ± 0.643
−30 mV −4.702 ± 4.855 −1.908 ± 0.400 −0.633 ± 0.777
−20 mV −10.683 ± 6.695 −3.258 ± 0.750 −2.471 ± 0.785
−10 mV −14.469 ± 3.611 −4.461 ± 0.270* −3.757 ± 2.060*
0 mV −13.322 ± 0.276 −4.966 ± 0.771* −3.081 ± 1.502*
10 mV −6.952 ± 1.227 −3.875 ± 0.974* −0.875 ± 0.550*
20 mV −2.897 ± 1.460 −1.852 ± 1.260 2.468 ± 1.190
30 mV 0.459 ± 3.810 −0.098 ± 0.929 3.027 ± 0.490
40 mV 3.188 ± 4.457 1.207 ± 0.549 3.789 ± 0.359
50 mV 5.114 ± 4.392 1.992 ± 0.187 4.233 ± 0.211

Vs: Compared with Con group, *p < 0.05.

Figure 12 Changes in I ca-L I−V curve and Ca2+ current intervened by heroin. (a) Changes in I ca-L I−V curve in 10−4 mol/L heroin intervened group at different times. (b) Ca2+ current of cardiomyocytes after 10−4 mol/L heroin intervention 24 h. (c) Ca2+ current of cardiomyocytes after 10−4 mol/L heroin intervention 48 h. (d) Ca2+ current of cardiomyocytes after heroin intervention in different times.
Figure 12

Changes in I ca-L I−V curve and Ca2+ current intervened by heroin. (a) Changes in I ca-L I−V curve in 10−4 mol/L heroin intervened group at different times. (b) Ca2+ current of cardiomyocytes after 10−4 mol/L heroin intervention 24 h. (c) Ca2+ current of cardiomyocytes after 10−4 mol/L heroin intervention 48 h. (d) Ca2+ current of cardiomyocytes after heroin intervention in different times.

4 Discussion

Heroin (chemical name: diacetylmorphine) is an opiate, a naturally occurring alkaloid extracted from the seedpod of the Papaver somniferum. After long-term use, it will cause not only serious damage to the immune function but also damage vital organs, such as the heart, brain, liver, and kidney [6]. The hypothesis of myocardial damage related to heroin includes striated muscle atrophy, hypoxia, acidosis, and vasoconstriction substance released by muscle necrosis or allergic reactions [7]. Therefore, further investigation regarding the exact mechanism of cardiovascular damage caused by heroin in the medical field is urgently needed. Diacetylmorphine can lead to the occurrence of arrhythmia and can cause the change in spontaneous beating frequency of cardiac myocytes, but the specific mechanism is still unclear and needs further investigation.

Ca2+ signaling plays a very important role in the opioid receptor-mediated signaling pathways in which many opioid receptor subtypes attaching to the myocardial cell membrane exist [8,9,10]. Opioid receptors are activated by opioids to protect against myocardial ischemia-reperfusion injury [11,12,13]. Ca2+, which acts as the second intracellular messenger, participates in various biological processes and activates multiple intracellular signaling molecules, which are more closely related to CaM, activated CaMKII, and calcineurin. CaMKII plays an important role in intracellular calcium homeostasis and regulation of the release and reabsorption of Ca2+ by sarcoplasmic reticulum receptor and sarcoplasmic reticulum Ca2+-ATPase and complete the excitation-contraction coupling of cardiomyocytes. When any process of calcium release, uptake, or storage is abnormal, will affect the Ca2+ circulation in myocardial cells, and then affect the Ca2+ balance in cardiomyocytes [8,9,14]. In the experiment of diacetylmorphine interfering with isolated myocardial cells, it was found that the decrease in spontaneous beating frequency of myocardial cells may be related to the depletion of Ca2+ stored in myocardial cells by diacetylmorphine, resulting in Ca2+ imbalance. However, the specific mechanism remains to be further explored.

Heroin, which belongs to the exogenous morphine opioid receptor agonist, competitively combines with the opioid receptor of the myocardial cell membrane to inhibit the formation and release of endogenous endorphin in the myocardium after entering the body, and it is different from synthetic morphine or opioid receptor agonists organ injury by its fat solubility, action local, action speed, withdrawal symptoms, response intensity, duration, and metabolic rate [10,15,16,17]. Therefore, it is unscientific to explain the toxic effects of heroin by using the study results on opioids. A previous study has found that an increase in spontaneous beat frequency in cardiomyocytes could be induced by heroin. The studies have shown that heroin could cause a significant increase in free Ca2+ concentration in cardiomyocytes depending on the dosage, and the isolated, cultured cardiomyocytes underwent calcium overload for a short period of time under the interference of heroin, but it could quickly drop to normal levels [18]. Verapamil, which significantly inhibits heroin-induced calcium overload in cardiomyocytes, can reduce cell death [19]. In animal experiments, the heart rate and amplitude of rats have been reduced by heroin, and this mechanism might be related to the storage of Ca2+ in depleted cardiomyocytes [20]. It indicated that heroin could transiently increase the levels of Ca2+ in cardiomyocytes, which could produce a transient positive inotropic effect. Additionally, a significant negative inotropic effect occurred after Ca2+ was depleted in the sarcoplasmic reticulum.

In this study, heroin could induce cardiomyocyte injury, and the patch-clamp technique detected cell electrophysiological function. It was found that the APD90 of cardiomyocytes was significantly extended by heroin. The APD increased, the negative value of RP and the APA decreased, while the L-Ca2+ channel current peak significantly decreased, with a statistically significant difference (p < 0.05).

I–V curve shifted up, but it did not change the shape of the curve. It indicated that the external calcium influx decreased, the repolarization time increased, and the APD significantly increased under the interference of heroin. The possible mechanism might be related to the depletion of Ca2+ stored in cardiomyocytes by heroin, and it is consistent with the results in heart rate and amplitude of electrocardiogram in rats induced by heroin in animal experiments [21]. In this study, the frequency of spontaneous beating in cardiomyocytes was slowed down by heroin. Heroin realized signal transduction by stimulating any opioid receptors on the surface of the myocardial cell membrane, whereas the mechanism of changes caused in the muscle force of myocardial cell remains to be further studied.

Calcium ions play an important role in the excitatory contraction coupling of the heart. The voltage-dependent L-type channel may be opened because of depolarization of the myocardial cell membrane and produces a transient calcium gradient to trigger the release of calcium ions from the sarcoplasmic reticulum [22]. The mechanisms by which diacetylmorphine induces myocardial toxicity are complex and multifactorial, including interference with cardiomyocyte energy metabolism and intracellular calcium processing, ROS production, neurohormonal stress, and induction of cardiomyocyte apoptosis. Under normoxic conditions, more than 95% of the ATP produced in the heart comes from oxidative phosphorylation in the mitochondria. Perturbations during ATP production may directly affect the contractile function of the myocardium [23]. In this study, the morphology and electrophysiological function of cardiomyocytes were changed under the interference of heroin. Cardiomyocyte transcriptomics and metabolomics also significantly varied, and myocardial contractile signaling pathways were also significantly altered, after diacetylmorphine intervention, many metabolites are significantly altered, these metabolites are mainly related to the mitochondrial oxidative phosphorylation. We found that the production of ATP was significantly reduced after diacetylmorphine intervention, suggesting that diacetylmorphine may affect the oxidative phosphorylation process of mitochondria, interfere with ATP production and then affect the myocardial contractile function, suggesting that heroin can significantly affect cardiomyocyte metabolic processes and then affect cardiac contractility. A series of activities, such as myocardial relaxation and contraction, were closely related to intracellular calcium ion contents. Heroin could induce abnormal changes in calcium ion contents and electrophysiological function in cardiomyocytes. Thus, calcium channels play a certain role in the process of myocardial rhythm abnormalities induced by heroin. In summary, heroin can damage the myocardium to a certain degree and cause changes in the action potential and L-type calcium channel, as well as the change in the electrophysiological function of cardiomyocytes. Our data are basically consistent with the results of animal experiments.

5 Conclusion

In this study, we found through transcriptomic and metabolomics studies that heroin can cause myocardial contraction and calcium channel abnormalities, damage the myocardium, and change the action potential and L-type calcium channel. These results will also provide molecular targets for finding and establishing a new therapeutic scheme for clinical diagnosis and prevention.

# Authors contributed equally.

Acknowledgement

Not applicable.

  1. Funding information: This work was supported by the National Science Foundation of China (NSFC), China (Grant numbers: 81860049 and 82160055) and Science and Nature Foundation of Xinjiang Uyghur Autonomous Region (Grant number: 2020D01C257); State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases Fund (Grant no. SKL-HIDCA-2022-JZ7).

  2. Author contributions: Liping Su, Li Liu, Min Ji, and Xiayun Hu conceived and designed the study; Liping Su, Xiayun Hu, Ziyang Lu, YAling Guan, and Jinling Xiao performed the experiments; Li Liu, Min Ji, Mengjie Zhuang, and Sensen Zhu analyzed the data; Min Liang and Zhiguo Wang interpreted the data; Hongwei Pu wrote the manuscript; Long yang, Hongwei Pu, and Liping Su gave final approval of the version to be published. All authors read and approved the manuscript.

  3. Conflict of interest: The authors declare that they have no competing interest.

  4. Data availability statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2022-10-09
Revised: 2023-06-11
Accepted: 2023-07-04
Published Online: 2023-07-31

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
https://doi.org/10.1515/med-2023-0765
Schlagwörter für diesen Artikel
heroin; transcriptomics; action potential; L-calcium channel; arrhythmia
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Research Articles
  2. Exosomes derived from mesenchymal stem cells overexpressing miR-210 inhibits neuronal inflammation and contribute to neurite outgrowth through modulating microglia polarization
  3. Current situation of acute ST-segment elevation myocardial infarction in a county hospital chest pain center during an epidemic of novel coronavirus pneumonia
  4. circ-IARS depletion inhibits the progression of non-small-cell lung cancer by circ-IARS/miR-1252-5p/HDGF ceRNA pathway
  5. circRNA ITGA7 restrains growth and enhances radiosensitivity by up-regulating SMAD4 in colorectal carcinoma
  6. WDR79 promotes aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) by the suppression of SIRT4
  7. Up-regulation of collagen type V alpha 2 (COL5A2) promotes malignant phenotypes in gastric cancer cell via inducing epithelial–mesenchymal transition (EMT)
  8. Inhibition of TERC inhibits neural apoptosis and inflammation in spinal cord injury through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis
  9. 3D-printed polyether-ether-ketone/n-TiO2 composite enhances the cytocompatibility and osteogenic differentiation of MC3T3-E1 cells by downregulating miR-154-5p
  10. Propofol-mediated circ_0000735 downregulation restrains tumor growth by decreasing integrin-β1 expression in non-small cell lung cancer
  11. PVT1/miR-16/CCND1 axis regulates gastric cancer progression
  12. Silencing of circ_002136 sensitizes gastric cancer to paclitaxel by targeting the miR-16-5p/HMGA1 axis
  13. Short-term outcomes after simultaneous gastrectomy plus cholecystectomy in gastric cancer: A pooling up analysis
  14. SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways
  15. Molecular mechanism by which the Notch signaling pathway regulates autophagy in a rat model of pulmonary fibrosis in pigeon breeder’s lung
  16. lncRNA TPT1-AS1 promotes cell migration and invasion in esophageal squamous-cell carcinomas by regulating the miR-26a/HMGA1 axis
  17. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis
  18. Glycoprotein non-metastatic melanoma B interacts with epidermal growth factor receptor to regulate neural stem cell survival and differentiation
  19. Treatments for brain metastases from EGFR/ALK-negative/unselected NSCLC: A network meta-analysis
  20. Association of osteoporosis and skeletal muscle loss with serum type I collagen carboxyl-terminal peptide β glypeptide: A cross-sectional study in elder Chinese population
  21. circ_0000376 knockdown suppresses non-small cell lung cancer cell tumor properties by the miR-545-3p/PDPK1 pathway
  22. Delivery in a vertical birth chair supported by freedom of movement during labor: A randomized control trial
  23. UBE2J1 knockdown promotes cell apoptosis in endometrial cancer via regulating PI3K/AKT and MDM2/p53 signaling
  24. Metabolic resuscitation therapy in critically ill patients with sepsis and septic shock: A pilot prospective randomized controlled trial
  25. Lycopene ameliorates locomotor activity and urinary frequency induced by pelvic venous congestion in rats
  26. UHRF1-induced connexin26 methylation is involved in hearing damage triggered by intermittent hypoxia in neonatal rats
  27. LINC00511 promotes melanoma progression by targeting miR-610/NUCB2
  28. Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis of serum metabolomic characteristics in people with different vitamin D levels
  29. Role of Jumonji domain-containing protein D3 and its inhibitor GSK-J4 in Hashimoto’s thyroiditis
  30. circ_0014736 induces GPR4 to regulate the biological behaviors of human placental trophoblast cells through miR-942-5p in preeclampsia
  31. Monitoring of sirolimus in the whole blood samples from pediatric patients with lymphatic anomalies
  32. Effects of osteogenic growth peptide C-terminal pentapeptide and its analogue on bone remodeling in an osteoporosis rat model
  33. A novel autophagy-related long non-coding RNAs signature predicting progression-free interval and I-131 therapy benefits in papillary thyroid carcinoma
  34. WGCNA-based identification of potential targets and pathways in response to treatment in locally advanced breast cancer patients
  35. Radiomics model using preoperative computed tomography angiography images to differentiate new from old emboli of acute lower limb arterial embolism
  36. Dysregulated lncRNAs are involved in the progress of myocardial infarction by constructing regulatory networks
  37. Single-arm trial to evaluate the efficacy and safety of baclofen in treatment of intractable hiccup caused by malignant tumor chemotherapy
  38. Genetic polymorphisms of MRPS30-DT and NINJ2 may influence lung cancer risk
  39. Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis
  40. Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma
  41. Upregulation of lncRNA LANCL1-AS1 inhibits the progression of non-small-cell lung cancer via the miR-3680-3p/GMFG axis
  42. CircRANBP17 modulated KDM1A to regulate neuroblastoma progression by sponging miR-27b-3p
  43. Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9
  44. Downregulation of RBM17 enhances cisplatin sensitivity and inhibits cell invasion in human hypopharyngeal cancer cells
  45. HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway
  46. The association between sleep duration, quality, and nonalcoholic fatty liver disease: A cross-sectional study
  47. Myostatin silencing inhibits podocyte apoptosis in membranous nephropathy through Smad3/PKA/NOX4 signaling pathway
  48. A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis
  49. Impact of omicron wave and associated control measures in Shanghai on health management and psychosocial well-being of patients with chronic conditions
  50. Clinicopathological characteristics and prognosis of young patients aged ≤45 years old with non-small cell lung cancer
  51. TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia
  52. The dose limits of teeth protection for patients with nasopharyngeal carcinoma undergoing radiotherapy based on the early oral health-related quality of life
  53. miR-30b-5p targeting GRIN2A inhibits hippocampal damage in epilepsy
  54. Long non-coding RNA AL137789.1 promoted malignant biological behaviors and immune escape of pancreatic carcinoma cells
  55. IRF6 and FGF1 polymorphisms in non-syndromic cleft lip with or without cleft palate in the Polish population
  56. Comprehensive analysis of the role of SFXN family in breast cancer
  57. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy
  58. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression
  59. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway
  60. Downregulation of KIAA1199 alleviated the activation, proliferation, and migration of hepatic stellate cells by the inhibition of epithelial–mesenchymal transition
  61. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment
  62. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3
  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
  64. Tectorigenin alleviates the apoptosis and inflammation in spinal cord injury cell model through inhibiting insulin-like growth factor-binding protein 6
  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
  66. F-box and WD repeat domain containing 7 inhibits the activation of hepatic stellate cells by degrading delta-like ligand 1 to block Notch signaling pathway
  67. Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
  68. Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway
  69. Effect of miR-499-5p/SOX6 axis on atrial fibrosis in rats with atrial fibrillation
  70. Cholesterol induces inflammation and reduces glucose utilization
  71. circ_0004904 regulates the trophoblast cell in preeclampsia via miR-19b-3p/ARRDC3 axis
  72. NECAB3 promotes the migration and invasion of liver cancer cells through HIF-1α/RIT1 signaling pathway
  73. The poor performance of cardiovascular risk scores in identifying patients with idiopathic inflammatory myopathies at high cardiovascular risk
  74. miR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4
  75. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis
  76. α-Hederin regulates macrophage polarization to relieve sepsis-induced lung and liver injuries in mice
  77. Changes of microbiota level in urinary tract infections: A meta-analysis
  78. Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions
  79. Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies – (lessons learned from) a prospective study
  80. Outcomes of low-risk birth care during the Covid-19 pandemic: A cohort study from a tertiary care center in Lithuania
  81. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway
  82. Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
  83. Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme
  84. Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes
  85. An economic evaluation of fine-needle cytology as the primary diagnostic tool in the diagnosis of lymphadenopathy
  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
  87. Network pharmacology combined with molecular docking and experimental validation to reveal the pharmacological mechanism of naringin against renal fibrosis
  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
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Heruntergeladen am 3.10.2025 von https://www.degruyterbrill.com/document/doi/10.1515/med-2023-0765/html
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