Startseite Lebenswissenschaften 6-Phosphogluconate dehydrogenase inhibition arrests growth and induces apoptosis in gastric cancer via AMPK activation and oxidative stress
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6-Phosphogluconate dehydrogenase inhibition arrests growth and induces apoptosis in gastric cancer via AMPK activation and oxidative stress

  • Cheng Chen , Pan Du , Zhenguo Zhang EMAIL logo und Di Bao EMAIL logo
Veröffentlicht/Copyright: 23. Februar 2023
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Open Life Sciences
Aus der Zeitschrift Open Life Sciences Band 18 Heft 1

Abstract

Poor outcomes in advanced gastric cancer necessitate alternative therapeutic strategies. 6-Phosphogluconate dehydrogenase (6-PGDH), an enzyme that catalyzes the decarboxylation step in the oxidative pentose phosphate pathway, has been identified as a promising therapeutic target in many cancers. In this study, we systematically investigated the expression and function of 6-PGDH in gastric cancer. We found that 6-PGDH expression and activity were aberrantly elevated in gastric cancer tissues compared to their adjacent normal tissues. 6-PGDH knockdown using two independent shRNAs resulted in minimal 6-PGDH levels and activity, decreased growth, and enhanced gastric cancer cell sensitivity to 5-flurorouracil. However, 6-PGDH knockdown did not affect the cancer cells. Mechanistic studies showed that 6-PGDH inhibition disrupted lipid biosynthesis and redox homeostasis in gastric cancer, inhibited growth, and induced apoptosis. Notably, the in vitro findings were validated using an in vivo gastric cancer xenograft mouse model. This study established that 6-PGDH is broadly elevated in gastric cancer patients and that 6-PGDH inhibition can sensitize gastric cancer cells in response to chemotherapy.

Keywords: gastric cancer; 6-PGDH; redox homeostasis; AMPK; lipid biosynthesis

1 Introduction

Gastric cancer is the second most common cause of cancer-related death worldwide [1]. Treatment options for patients with gastric cancer include gastrectomy and chemotherapy [2]. 5-Flurorouracil (5-FU), alone or in combination with other conventional therapies, is the standard chemotherapy regimen. However, resistance, either acquired or primary, is the main cause of treatment failure [3]. The mechanisms of gastric cancer pathogenesis and chemoresistance are not clear and rely on multiple factors, such as deregulation of developmental pathways and cancer stem cell signaling (Wnt/β-catenin, Hedgehog, Notch, STAT3, and epithelial–mesenchymal transition) [4,5]. Recent studies have suggested altering the biosynthetic metabolism in gastric cancer, including anabolic biosynthesis and redox homeostasis, which might represent a promising therapeutic target.

Reduced levels of nicotinamide adenine dinucleotide phosphate (NADPH) is critical for redox defense and is the driving force of most biosynthetic enzymatic reactions, including DNA and lipids [6]. NADPH production is mediated by glutamine metabolism and the oxidative pentose phosphate pathway (PPP) [7]. 6-Phosphogluconate dehydrogenase (6-PGDH), a key enzyme in the oxidative PPP, is aberrantly activated and plays an important role in a variety of cancers. The repression of 6-PGDH results in altered metabolism, reduced cell growth and survival, and elevated reactive oxygen species (ROS) levels in colon, breast, liver, and thyroid cancers. Recent studies have also highlighted that 6-PGDH inhibition is selective for targeting cancer cells and reversing cancer resistance to chemotherapy [8–12].

In line with previous efforts, this work investigated the expression pattern and functions of 6-PGDH in gastric cancer, and attempted to determine the underlying mechanisms using patient samples and pre-clinical models in vitro and in vivo.

2 Materials and methods

2.1 Tissue specimens and cell culture

Surgical tissues from gastric cancer patients were used in this study. The frozen tissue specimens were used for RNA and protein extraction. Formalin-fixed, paraffin-embedded tissue specimens were used for immunohistochemical analysis. Two human gastric cancer cell lines, AGS and MKN-45, were obtained from the Cell Bank of the Type Culture Collection of the Chinese Academy of Sciences. AGS and MKN-45 cells were cultured in RPMI1640 and dulbecco’s modified eagle medium (Gibco, USA) supplemented with 10% fetal bovine serum (FBS) (Gibco, USA), respectively.

  1. Informed consent: Informed consent has been obtained from all individuals included in this study.

  2. Ethical approval: The research related to human use has been complied with all the relevant national regulations, institutional policies and in accordance with the tenets of the Helsinki Declaration, and has been approved by the ethics committee of Xiangyang Central Hospital (No. 2016-018).

2.2 Immunohistochemistry and western blot analysis

Tissue blocks were sectioned, dewaxed in xylene, and rehydrated prior to antigen retrieval using citrate buffer. The tissue sections were then washed with phosphate buffered saline (PBS), incubated with 1:500 diluted anti-6-PGDH antibody (Thermo Fisher Scientific #PA5-25362), the designated secondary antibody, and 3,3-diaminobenzidine, according to the standard staining protocol. Cell nuclei were counterstained with a hematoxylin solution (Sigma-Aldrich, USA). Immunostaining experiments were analyzed independently by two pathologists. Under a microscope (Zeiss, Germany), 6-PGDH protein expression was measured by multiplying the staining area by the intensity fraction of four random regions per section. The percentage of positive cells was scored as 1 (1–25%), 2 (26–50%), 3 (51–75%), or 4 (76–100%), and the staining intensity was scored as 0, 1, 2, or 3. Staining scores <6 and ≥6 were considered as low and high expression, respectively. For western blot analysis, cells were lysed using RIPA buffer (Thermo Fisher Scientific). Proteins were loaded and resolved using sodium dodecyl sulfate–polyacrylamide gel electrophoresis and analyzed by western blot using standard protocol. The primary antibodies used are listed as follows (1:1,000 dilution): anti-caspase 3 (ab32351, Abcam), anti-cleaved caspase 3 (ab32042, Abcam), anti-MIC-1 (8479, CST), anti-Bim (2933, CST), anti-β-actin (3700, CST), anti-p-AMPK (9158, CST), anti-AMPK (2537, CST), anti-ACC1 (4190, CST), anti-p-ACC1 (11818, CST), and anti-Nox2 (ab129068, Abcam). Rabbit secondary antibody (7074, CST, 1:2,000 dilution) and mouse secondary antibody (14709, CST, 1:2,000 dilution) were purchased from cell signaling. The molecular weight reflecting the location of target protein bound with its antibody was indicated in the figures.

2.3 6-PGDH enzyme activity assay

6-PGDH enzyme activity was assessed using total cell or tissue lysates and measured using a 6-PGDH assay kit (Abcam, #ab241016), according to the manufacturer’s instructions.

2.4 Real-time PCR

Total RNA from the tissue specimens was extracted using an mRNA isolation kit (Merck, #11741985001). The RNA concentration was determined spectrophotometrically at 260 nm. The reverse transcription reaction was performed using the iScript cDNA Synthesis Kit (Bio-Rad, #1708891). Quantitative real-time PCR was performed using the SYBR Green Supermix (Bio-Rad, #1708880). The sequences of the exon–exon junction primers for 6-PGDH were ATT CTC AAG TTC CAA GAC ACC G (forward) and GTG GTA AAA CAG GGC ATG GGA (reverse) [13].

The primers for β-actin are CTC CAT CCT GGC CTC GCT GT(forward) and GCT GTC ACC TTC ACC GTT CC (reverse). The primer concentrations were 10 mM. The specific reaction system is to add 5 µL of sybgreen, 1 µL of forward primer, 1 µL of reverse primer, and 3 µL of cDNA. The reaction thermal profiles were reaction at 50°C for 2 min (one time) and pre-denaturation at 95°C for 2 min (one time). Denaturation at 95°C for 15 s followed by annealing and extension at 60°C for 30 s (repeated for 40 cycles). The mRNA levels of 6-PGDH were quantified using a comparative CT method with β-actin levels for normalization.

2.5 Stable knockdown of 6-PGDH

A stable knockdown of endogenous human 6-PGDH was achieved using a lentiviral vector. pGIPZ shRNA 6-PGDH A was generated using 5′-AGG ACT GTC TCC AAA GTT G-3′, and pGIPZ shRNA 6-PGDH B was generated with 5′-GGT GGA TGA TTT CAT CGA GAA ACT CG-3′ targeting the coding region of the 6-PGDH transcript. The 6-PGDH-depleted AGS and MKN-45 cells were established by strictly following the protocol provided by Dharmacon GIPZ lentiviral shRNA Transfection Starter Kit and validated using western blot analysis.

2.6 Proliferation and DNA damage assays

For the proliferation assay, cells were seeded in a 96-well plate. After 24 h of 5-FU (Sigma, F6627) treatment, cell proliferation was determined using a BrdU Cell Proliferation Assay Kit (Abcam, #ab126556). DNA damage was determined using the DNA Damage Quantification Colorimetric Kit (Abcam, #ab284577), followed by absorbance measurements on a microplate reader.

2.7 Migration assay

Cell migration was assessed using the CytoSelect 24-well Cell Migration Assay Kit (Cell Biolabs Inc. #CBA-100). Briefly, 10,000 cells together with 5-FU in culture medium without FBS, were seeded into the insert of a transwell plate. The culture medium containing 10% FBS was placed in the lower chamber. After 6 h, the cells that spread on the upper surfaces of the filter (non-migrated cells) were wiped away using cotton swabs. The insert was stained, and the migrated cells were counted under a microscope.

2.8 Measurement of the NADPH/NAD+ ratio, ROS, and lipids

NADPH/NAD+ ratio was determined by measuring NADPH/NADP+ concentrations according to the protocol (BioAssay Systems, #ECNP-100). Briefly, NADPH and NADP+ were extracted from the cells and measured at 565 nm based on a glucose dehydrogenase cycling reaction, in which the formed NADPH reduces a formazan (MTT) reagent. The intensity of the product color is proportionate to the NADPH/NADP+ concentrations. The samples were then transferred to 96 plates for measuring the absorbance of 450 nm. The amount of oxidized NAD (NAD+) was presented subtracting NADH from NADtotal. The ratio of NAD/NADH in a sample was calculated by the equation: ratio = (NADtotal – NADH)/NADH. Intracellular ROS was measured using OxiSelect™ Intracellular ROS Assay Kit (Cell Biolabs, #STA-342). The amount of intracellular ROS was measured by detecting dichlorodihydrofluorescein, which is the cleavage product of carboxy-H2DCFDA by ROS. In all, cells were seeded in a plate. After 24 h of seeding, cells were washed with PBS and loaded with 10 mM carboxy-H2DCFDA for 30 min. The cells were harvested and resuspended in PBS. The mixtures were incubated at 30°C for 2 h. Cells were fixed by 2% paraformaldehyde. Untreated group served as control. Data were analyzed using Flow Jo Software (Version 10.1). According to the manufacturer’s instructions, the manufacturer’s Lipid Quantification Kit (Cell Biolabs, #STA-613) was used to quantify the lipids. The lipids in the tissue were extracted before total lipid measurements. The Lipid Quantification Kit’s enzymatic processes produced a dye that absorbs light at 540 nm. Each individual assay’s standard curve was created using the serial dilutions of the standard solution included in each kit. Create a standard curve and use the optical density values at specific absorbance wavelengths to best fit the corresponding standard concentrations, with R > 0.99 as the established standard for a linear function.

2.9 Xenograft mouse model

All animal experiments were approved by protocol No. 201706 and were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee. Mice were housed at the Animal Center of Hubei University of Arts and Sciences. The cells were injected subcutaneously into irradiated (240 cGy) immunodeficient mice. For a fair comparison, we inoculated the same mice with shRNA control cells on their left flank and shRNA 6-PGDH cells on the right flank. The tumor size was monitored for 4 weeks. When the tumor reached 1,000 mm3, the mice were euthanized using the gradual-fill method of CO2 euthanasia (the CO2 flow rate displaced 10–30% of the cage volume per minute). Tumors were dissected and tumor proteins were extracted using RIPA buffer.

  1. Ethical approval: The research related to animal use has been complied with all the relevant national regulations and institutional policies for the care and use of animals, and has been approved by the Institutional Animal Care and Use Committee of the Hubei University of Arts and Sciences (approval no. 2021074689).

2.10 Statistical analyses

Results were obtained from a minimum of three independent experiments in triplicate and are presented as mean ± standard deviation. Statistical analyses for comparisons of two categorical variables were conducted using the Mann–Whitney U-test. To ascertain each independent factor, one-way analysis of variance and subsequently unpaired Student’s t-tests were also conducted. Statistical significance was set at p < 0.05.

3 Results

3.1 Aberrant activation of 6-PGDH in gastric cancer

To identify the 6-PGDH expression pattern in normal gastric tissues and gastric cancer tissues, we used real-time PCR and immunohistochemistry approaches to determine the mRNA transcript and protein levels in 30 paired gastric cancer and adjacent normal gastric tissues obtained from subjects at different stages of disease (Table S1). Overall, we found that the average mRNA and protein levels of 6-PGDH were significantly increased by two-fold in gastric cancer tissues compared to normal gastric tissues (Figure 1a and b). However, 6-PGDH expression in individual patient samples demonstrated that ∼77% (23 of 30) of the tested patients had significantly elevated 6-PGDH expression in cancer tissues and ∼23% (7 out of 30) had comparable 6-PGDH expression levels between paired cancer and normal gastric tissues (Figure 1b and Table S2). In addition, 6-PGDH expression varied between normal and cancerous tissues. The highest fold-change between paired normal and cancerous gastric tissues was 3.5 (Table S2). We further found that increased expression was associated with increased enzyme activity (Figure 1c and Table S2). Furthermore, we found a significant positive correlation between the mRNA, protein, and activity levels of 6-PGDH (Figure S1) A total of 109 gastric cancer specimen cohorts were used to estimate 6-PGDH expression by immunohistochemistry staining. Overall survival (OS) is defined as the time from the end of the first operation to death. Time in therapeutic range (TTR) is defined as the time from the end of the first operation to the first recurrence. The OS and TTR for two subgroups (6-PGDHlow and 6-PGDHhigh) are presented in Figure S2. Here, we found that the 6-PGDHhigh subgroup had a significantly shorter OS (p < 0.001) and TTR (p < 0.001) than the 6-PGDHlow groups.

Figure 1 6-PGDH expression and activity are elevated in patients with gastric cancer. Scatter plot of mRNA (a), and enzyme activity (c) of 6-PGDH in gastric cancer tissues and adjacent normal gastric tissue obtained from gastric cancer patients (n = 30). The average expression and activity of 6-PGDH is significantly increased in gastric cancer tissue compared to normal gastric normal tissue. (b) Representative images of 6-PGDH immunohistochemistry in one patient with comparable 6-PGDH level between normal and cancer tissue and another patient with elevated 6-PGDH level in cancer tissue. Scale bar is 50 μm. * p < 0.05, compared to normal.
Figure 1

6-PGDH expression and activity are elevated in patients with gastric cancer. Scatter plot of mRNA (a), and enzyme activity (c) of 6-PGDH in gastric cancer tissues and adjacent normal gastric tissue obtained from gastric cancer patients (n = 30). The average expression and activity of 6-PGDH is significantly increased in gastric cancer tissue compared to normal gastric normal tissue. (b) Representative images of 6-PGDH immunohistochemistry in one patient with comparable 6-PGDH level between normal and cancer tissue and another patient with elevated 6-PGDH level in cancer tissue. Scale bar is 50 μm. * p < 0.05, compared to normal.

3.2 Functional effects of 6-PGDH in gastric cancer

To identify the functional effects of 6-PGDH on gastric cancer, we analyzed the growth, migration, and survival of gastric cancer cells after stable knockdown of 6-PGDH using two independent shRNAs. We also analyzed the sensitivity of 6-PGDH-depleted gastric cancer cells to 5-FU, which is the first-line chemotherapeutic agent for advanced gastric cancer [14]. AGS cells transduced with a lentiviral vector harboring 6-PGDH shRNA showed minimal levels of 6-PGDH expression and activity (Figure S3) and reduced cell proliferation (Figure 2a). In addition, 6-PGDH knockdown significantly enhanced the inhibitory effects of 5-FU on cell growth (Figure 2a). In contrast, 6-PGDH knockdown did not affect AGS cell migration or 5-FU sensitivity (Figure 2b). Of note, anti-proliferation and sensitization to chemotherapy induced by 6-PGDH depletion was not limited to AGS cells; MKN-45 responded in a similar manner (Figure S4a and b). Next, we analyzed apoptosis and DNA damage in the 6-PGDH-depleted cells. We found that 6-PGDH knockdown decreased caspase-3 and increased cleaved caspase-3 levels (Figure 3a), indicating that 6-PGDH knockdown induced apoptosis in gastric cancer cells. We observed decreased levels of anti-apoptotic protein Mcl-1 and increased levels of pro-apoptotic protein Bim (Figure 3a). Consistent with this finding, 6-PGDH depletion significantly increased DNA damage (Figure 3b, Figure S4c). In addition, the pan-caspase inhibitor Z-VAD-FMK significantly reversed DNA damage induced by 6-PGDH depletion in gastric cancer cells (Figure S5). These results clearly demonstrated increased apoptosis and DNA damage in gastric cancer cells after 6-PGDH inhibition. Notably, 6-PGDH inhibition further augmented the apoptosis and DNA damage induced by 5-FU. Similar results were obtained in MKN-45 cells with stable 6-PGDH knockdown, suggesting general functional effects of 6-PGDH on gastric cancer growth, survival, and chemosensitivity, but not migration.

Figure 2 6-PGDH knockdown inhibits gastric cancer cell growth and augments 5-FU’s inhibitory effects. (a) AGS cells with 6-PGDH knockdown displayed decreased proliferation and further growth inhibition after 5-FU treatment compared to control cells. (b) 6-PGDH knockdown did not affect AGS cell migration. The experiments were performed at least three times with triplicates. Proliferation was analyzed after 24 h drug treatment. Migration was analyzed after 6 h drug treatment. * p < 0.05, compared to shRNA control. ** p < 0.05, compared to 5-FU.
Figure 2

6-PGDH knockdown inhibits gastric cancer cell growth and augments 5-FU’s inhibitory effects. (a) AGS cells with 6-PGDH knockdown displayed decreased proliferation and further growth inhibition after 5-FU treatment compared to control cells. (b) 6-PGDH knockdown did not affect AGS cell migration. The experiments were performed at least three times with triplicates. Proliferation was analyzed after 24 h drug treatment. Migration was analyzed after 6 h drug treatment. * p < 0.05, compared to shRNA control. ** p < 0.05, compared to 5-FU.

Figure 3 6-PGDH knockdown induces gastric cancer cell apoptosis and augments 5-FU’s inhibitory effects. (a) Representative western blot image showing the decreased caspase 3, increased cleaved caspase 3, decreased Mcl-1, and increased Bim in 6-PGDH-depleted AGS cells. Western blot was performed at 72 h post-transfection. AGS cells with 6-PGDH knockdown displayed decreased proliferation and further growth inhibition after 5-FU treatment compared to control cells. (b) AGS cells with 6-PGDH knockdown displayed increased DNA damage compared to control group. The experiments were performed at least three times. * p < 0.05, compared to shRNA control. ** p < 0.05, compared to 5-FU.
Figure 3

6-PGDH knockdown induces gastric cancer cell apoptosis and augments 5-FU’s inhibitory effects. (a) Representative western blot image showing the decreased caspase 3, increased cleaved caspase 3, decreased Mcl-1, and increased Bim in 6-PGDH-depleted AGS cells. Western blot was performed at 72 h post-transfection. AGS cells with 6-PGDH knockdown displayed decreased proliferation and further growth inhibition after 5-FU treatment compared to control cells. (b) AGS cells with 6-PGDH knockdown displayed increased DNA damage compared to control group. The experiments were performed at least three times. * p < 0.05, compared to shRNA control. ** p < 0.05, compared to 5-FU.

3.3 6-PGDH inhibition disrupts biosynthesis and redox homeostasis in gastric cancer

To understand the underlying mechanisms of the 6-PGDH functional effects, we first assessed the NADPH/NADP+ ratio in 6-PGDH knockdown cells, as 6-PGDH is the major source of NADPH [15]. Not surprisingly, we observed a decreased NADPH/NADP+ ratio in 6-PGDH knockdown gastric cancer cells (Figure 4a), suggesting a decreased intracellular redox potential. Consistently, we found that 6-PGDH knockdown significantly increased ROS (Figure 4b) and NADPH oxidase 2 (Nox2) levels (Figure 4c and Figure S6). In addition, increased phosphorylation of AMP-activated protein kinase (AMPK) at T172 and acetyl-CoA carboxylase 1 (ACC1) at S79, and decreased lipid levels were detected in 6-PGDH knockdown cells (Figure 4d). This demonstrates that 6-PGDH knockdown leads to AMPK activation and a subsequent reduction of lipid synthesis. Addition of the anti-oxidant n-acetyl-L-cysteine (NAC) significantly reduced ROS levels in 6-PGDH knockdown cells but did not rescue the decreased lipid levels (Figure 5a and b). In contrast, addition of the AMPK inhibitor compound C significantly increased lipid levels in 6-PGDH knockdown cells but did not rescue increased ROS levels. Notably, the addition of NAC or compound C to 6-PGDH knockdown cells significantly rescued the decreased cell proliferation and increased cell apoptosis (Figure 5c and d). These results clearly demonstrate that 6-PGDH inhibition disrupts biosynthesis and redox homeostasis in gastric cancer cells by inhibiting growth and inducing apoptosis.

Figure 4 6-PGDH knockdown disrupts biosynthesis and redox homeostasis in gastric cancer cells. 6-PGDH knockdown significantly decreased NADPH/NADP+ ratio (a) and increased ROS (b) in AGS cells. (c) Representative western blot showing the increased Nox2, p-AMPK, and p-ACC1 level in 6-PGDH-depleted AGS cells. (d) 6-PGDH knockdown significantly decreased lipid synthesis in AGS cells. * p < 0.05, compared to shRNA 6-PGDH.
Figure 4

6-PGDH knockdown disrupts biosynthesis and redox homeostasis in gastric cancer cells. 6-PGDH knockdown significantly decreased NADPH/NADP+ ratio (a) and increased ROS (b) in AGS cells. (c) Representative western blot showing the increased Nox2, p-AMPK, and p-ACC1 level in 6-PGDH-depleted AGS cells. (d) 6-PGDH knockdown significantly decreased lipid synthesis in AGS cells. * p < 0.05, compared to shRNA 6-PGDH.

Figure 5 NAC and compound C reverse the decreased lipid biosynthesis and increased oxidative stress in 6-PGDH-depleted gastric cancer cells. (a) Addition of NAC but not compound C significantly rescued increased ROS in 6-PGDH-depleted cells. (b) Addition of compound C but not NAC significantly rescued decreased lipid level in 6-PGDH-depleted cells. Addition of NAC and compound C significantly rescued decreased growth (c) and increased apoptosis (d) in 6-PGDH-depleted cells. The experiments were performed at least three times with duplicates or triplicates. NAC at 3 mM and compound C at 10 μM were used. * p < 0.05, compared to shRNA 6-PGDH.
Figure 5

NAC and compound C reverse the decreased lipid biosynthesis and increased oxidative stress in 6-PGDH-depleted gastric cancer cells. (a) Addition of NAC but not compound C significantly rescued increased ROS in 6-PGDH-depleted cells. (b) Addition of compound C but not NAC significantly rescued decreased lipid level in 6-PGDH-depleted cells. Addition of NAC and compound C significantly rescued decreased growth (c) and increased apoptosis (d) in 6-PGDH-depleted cells. The experiments were performed at least three times with duplicates or triplicates. NAC at 3 mM and compound C at 10 μM were used. * p < 0.05, compared to shRNA 6-PGDH.

3.4 6-PGDH inhibition arrests gastric cancer growth and disrupts biosynthesis and redox homeostasis in an in vivo mouse model

To investigate whether the data obtained using the cell culture system were reproducible in vivo, we performed functional and mechanistic studies using a xenograft tumor model. We subcutaneously injected 6-PGDH knockdown cells into immunodeficient mice and monitored tumor growth for ∼4 weeks. We observed a significantly smaller size and the delayed growth of tumors formed by 6-PGDH knockdown cells compared to the control (Figure 6). In line with our in vitro data, we observed a significant decrease in the NADPH/NADP+ ratio in 6-PGDH knockdown tumors compared to that in the control (Figure 7a). Western blot analysis of tumor lysates demonstrated increased p-AMPK and p-ACC1 levels (Figure 7b), suggesting increased AMPK activation in 6-PGDH knockdown tumors. Taken together, we demonstrated that 6-PGDH inhibition arrests gastric cancer growth and disrupts biosynthesis and redox homeostasis in vivo.

Figure 6 6-PGDH knockdown inhibits gastric cancer growth in vivo. (a) Images showing dissected tumors in mice injected with AGS cells with 6-PGDH knockdown. Two stable AGS cell lines with 6-PGDH knockdown (b and c) displayed significantly growth arrest in mice. We inoculated the same mice with shRNA control cells on its left flank and shRNA 6-PGDH cells on its right flank. Therefore, both shRNA 6-PGDH A and B have their own shRNA control, respectively. * p < 0.05, compared to shRNA control.
Figure 6

6-PGDH knockdown inhibits gastric cancer growth in vivo. (a) Images showing dissected tumors in mice injected with AGS cells with 6-PGDH knockdown. Two stable AGS cell lines with 6-PGDH knockdown (b and c) displayed significantly growth arrest in mice. We inoculated the same mice with shRNA control cells on its left flank and shRNA 6-PGDH cells on its right flank. Therefore, both shRNA 6-PGDH A and B have their own shRNA control, respectively. * p < 0.05, compared to shRNA control.

Figure 7 6-PGDH knockdown disrupts biosynthesis and redox homeostasis in vivo. 6-PGDH shRNA tumors display decreased NADPH/NADP+ ratio (a) and increased p-AMPK and p-ACC1 level (b). * p < 0.05, compared to shRNA control.
Figure 7

6-PGDH knockdown disrupts biosynthesis and redox homeostasis in vivo. 6-PGDH shRNA tumors display decreased NADPH/NADP+ ratio (a) and increased p-AMPK and p-ACC1 level (b). * p < 0.05, compared to shRNA control.

4 Discussion

Although previously unstudied in gastric cancer, substantial evidence has emphasized the important roles of 6-PGDH in multiple aspects of cancer cells, from cancer initiation to metastasis, and resistance to drug treatment [16], suggesting an interesting therapeutic target for the investigation of gastric cancer. Indeed, our findings are consistent with previous reports and provide the first evidence that 6-PGDH is overexpressed and hyperactivated in most gastric cancer patients, and that 6-PGDH inhibition is active against gastric cancer by disrupting lipid biosynthesis and redox homeostasis.

6-PGDH expression and activity have been reported to be elevated in cancer cells compared to normal cells [17,18], and cancer cells after prolonged treatment of chemotherapy drugs [19]. Focusing on 30 paired gastric normal and cancer tissue samples, we found that the mRNA and protein levels of 6-PGDH were increased two-fold in gastric cancer tissues regardless of disease stage, age, tumor sites, and histology (Figure 1 and Table S1). Notably, 6-PGDH hyperactivation occurred in most, but not all, gastric cancer patients (Figure 1b, Table S2), suggesting that 6-PGDH hyperactivation is not a universal feature but only present in a particular group of patients with gastric cancer. Four major mechanisms that regulate 6-PGDH hyperactivation in cancer have been reported: YTH domain family 2 promotes 6-PGDH mRNA translation by directly binding to the m6A modification site [20], nuclear factor erythroid 2-related factor 2 activates 6-PGDH via a well-conserved anti-oxidant response element [21], epidermal growth factor receptor phosphorylates and activates 6-PGDH by Fyn [18], and direct structural interactions with malic enzyme1 [22]. These factors are worth investigating to further understand the regulation of 6-PGDH in gastric cancer.

We next showed that 6-PGDH hyperactivation was correlated with gastric cancer progression. In particular, loss-of-function studies demonstrated that growth and survival, but not migration stimulation, play prominent roles with 6-PGDH in gastric cancer (Figures 2 and 3). This is supported by previous findings that 6-PGDH inhibition suppresses proliferation and induces cell death in leukemia, ovarian, and breast cancers [23–25]. Although 6-PGDH promotes migration and invasion of lung and cervical cancer cells [9,26], 6-PGDH inhibition did not affect the migration of gastric cancer cells (Figure 2b). The important role of 6-PGDH in gastric cancer growth was clearly demonstrated in a xenograft mouse model (Figure 6). In addition, 6-PGDH protected gastric cancer cells from chemotherapy-induced toxicity (Figures 2 and 3), which is consistent with the reported roles of 6-PGDH in the development of chemoresistance in cervical, lung, and ovarian cancers [19,25]. Selective and potent pharmacological inhibitors of 6-PGDH, such as physcion and S-nitrosation, have been developed, and their anticancer activities have been validated in some cancers [27]. Our functional studies using a genetic approach serve as a proof-of-concept to demonstrate the critical role of 6-PGDH in gastric cancer. Further studies should be conducted on the cytotoxic effects of 6-PGDH inhibitors alone and in combination with chemotherapy against gastric cancer, along with the toxicological profiles of these inhibitors. In addition to the antitumor effect of 6-PGDH inhibitors, their toxicity to normal tissues should also be seriously considered in clinical practice. 6-PGDH is a crucial PPP enzyme involving the production of NADPH that enables cells to combat the oxidative stress via the glutathione system. It has been reported that excessive oxidative stress can lead to toxicity in liver and kidney [28,29]. Therefore, 6-PGDH inhibitors may cause liver and kidney damage at least when used as anticancer agents. Further experiments should be performed to determine this issue and explore how to decrease the harmful effects of 6-PGDH inhibition on normal tissues.

Consistent with the identified role of 6-PGDH in metabolic reprogramming and redox homeostasis [30] our work showed that 6-PGDH is important for the coordination between lipid biosynthesis and redox homeostasis to promote gastric cancer growth in vitro and in vivo, at least in part by controlling the intracellular levels of NADPH and activating AMPK (Figures 4 and 5). Overall, our mechanistic studies demonstrated that (1) 6-PGDH knockdown led to AMPK activation and subsequent reduction of lipid synthesis, (2) 6-PGDH knockdown decreased the NADPH/NADP+ ratio, (3) 6-PGDH knockdown resulted in oxidative stress, (4) AMPK activation/lipid biosynthesis disruption and oxidative stress were independent events in 6-PGDH-depleted gastric cancer cells, and (5) both disrupted lipid synthesis and increased oxidative stress contributed to the inhibition of growth and survival by 6-PGDH depletion. Based on the results obtained from rescue studies, we speculate that increased oxidative stress and reduced lipid synthesis play equal roles in inhibiting gastric cancer cells. In addition, we speculate that oxidative stress is a consequence of a decreased NADPH/NADP+ ratio. Previous work demonstrated that 6-PGDH and AMPK coordinate cancer cell metabolism [31], and our work agrees with and further extends the previous work by adding NADPH to the list of cancer cell metabolism regulators. To maintain a high proliferation rate and promote survival during stress, cancer cells are known to be more dependent on [32] supplementation than normal cells for redox hemostasis, lipid oxidation, and biomolecular synthesis. With regards to NADPH, intracellular redox homeostasis plays critical roles in various cellular processes and signaling pathways during carcinogenesis and tumor progression [33]. In particular, the predominant roles of oxidative stress and lipid synthesis are cell growth and survival, rather than migration. This may explain why 6-PGDH inhibition did not affect cell migration. 6-PGDH inhibition decreased the NADPH/NADP+ ratio, increased ROS, activated AMPK, decreased ACC1 activity, and reduced lipid synthesis (Figures 4 and 5), suggesting that 6-PGDH is an attractive therapeutic target for gastric cancer.

In conclusion, our work establishes that 6-PGDH is aberrantly activated in most gastric cancer patients, and that 6-PGDH inhibition is active against gastric cancer in vivo by targeting NADPH and AMPK-related cell metabolism. These discoveries are critical preclinical steps toward investigating 6-PGDH pharmacological inhibitors in combination to achieve chemosensitization in gastric cancer.

# These two authors contributed to this work equally and are co-first authors.

  1. Funding information: This work was supported by Wuhan Science Foundation (2017006).

  2. Author contributions: C.C. and D.B. designed the experiments. Z.Z. and P.D. performed each of the tests and collated the data. Z.Z. and C.C. analyzed the results and prepared the manuscript. D.B. revised the manuscript.

  3. Conflict of interest: Authors state no conflict of interest.

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

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Received: 2022-05-29
Revised: 2022-09-08
Accepted: 2022-09-21
Published Online: 2023-02-23

© 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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  225. Untargeted metabolomics reveals sour jujube kernel benefiting the nutritional value and flavor of Morchella esculenta
  226. Mycobiota in Slovak wine grapes: A case study from the small Carpathians wine region
  227. Elemental analysis of Fadogia ancylantha leaves used as a nutraceutical in Mashonaland West Province, Zimbabwe
  228. Microbiological transglutaminase: Biotechnological application in the food industry
  229. Influence of solvent-free extraction of fish oil from catfish (Clarias magur) heads using a Taguchi orthogonal array design: A qualitative and quantitative approach
  230. Chromatographic analysis of the chemical composition and anticancer activities of Curcuma longa extract cultivated in Palestine
  231. The potential for the use of leghemoglobin and plant ferritin as sources of iron
  232. Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM
  233. Bioengineering and Biotechnology
  234. Biocompatibility and osteointegration capability of β-TCP manufactured by stereolithography 3D printing: In vitro study
  235. Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study
  236. Agriculture
  237. Biofertilizer and NPSB fertilizer application effects on nodulation and productivity of common bean (Phaseolus vulgaris L.) at Sodo Zuria, Southern Ethiopia
  238. On correlation between canopy vegetation and growth indexes of maize varieties with different nitrogen efficiencies
  239. Exopolysaccharides from Pseudomonas tolaasii inhibit the growth of Pleurotus ostreatus mycelia
  240. A transcriptomic evaluation of the mechanism of programmed cell death of the replaceable bud in Chinese chestnut
  241. Melatonin enhances salt tolerance in sorghum by modulating photosynthetic performance, osmoregulation, antioxidant defense, and ion homeostasis
  242. Effects of plant density on alfalfa (Medicago sativa L.) seed yield in western Heilongjiang areas
  243. Identification of rice leaf diseases and deficiency disorders using a novel DeepBatch technique
  244. Artificial intelligence and internet of things oriented sustainable precision farming: Towards modern agriculture
  245. Animal Sciences
  246. Effect of ketogenic diet on exercise tolerance and transcriptome of gastrocnemius in mice
  247. Combined analysis of mRNA–miRNA from testis tissue in Tibetan sheep with different FecB genotypes
  248. Isolation, identification, and drug resistance of a partially isolated bacterium from the gill of Siniperca chuatsi
  249. Tracking behavioral changes of confined sows from the first mating to the third parity
  250. The sequencing of the key genes and end products in the TLR4 signaling pathway from the kidney of Rana dybowskii exposed to Aeromonas hydrophila
  251. Development of a new candidate vaccine against piglet diarrhea caused by Escherichia coli
  252. Plant Sciences
  253. Crown and diameter structure of pure Pinus massoniana Lamb. forest in Hunan province, China
  254. Genetic evaluation and germplasm identification analysis on ITS2, trnL-F, and psbA-trnH of alfalfa varieties germplasm resources
  255. Tissue culture and rapid propagation technology for Gentiana rhodantha
  256. Effects of cadmium on the synthesis of active ingredients in Salvia miltiorrhiza
  257. Cloning and expression analysis of VrNAC13 gene in mung bean
  258. Chlorate-induced molecular floral transition revealed by transcriptomes
  259. Effects of warming and drought on growth and development of soybean in Hailun region
  260. Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves
  261. Comparative analysis of the rhizosphere microbiome and medicinally active ingredients of Atractylodes lancea from different geographical origins
  262. Distinguish Dianthus species or varieties based on chloroplast genomes
  263. Comparative transcriptomes reveal molecular mechanisms of apple blossoms of different tolerance genotypes to chilling injury
  264. Study on fresh processing key technology and quality influence of Cut Ophiopogonis Radix based on multi-index evaluation
  265. An advanced approach for fig leaf disease detection and classification: Leveraging image processing and enhanced support vector machine methodology
  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
https://doi.org/10.1515/biol-2022-0514
Schlagwörter für diesen Artikel
gastric cancer; 6-PGDH; redox homeostasis; AMPK; lipid biosynthesis
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Biomedical Sciences
  2. Systemic investigation of inetetamab in combination with small molecules to treat HER2-overexpressing breast and gastric cancers
  3. Immunosuppressive treatment for idiopathic membranous nephropathy: An updated network meta-analysis
  4. Identifying two pathogenic variants in a patient with pigmented paravenous retinochoroidal atrophy
  5. Effects of phytoestrogens combined with cold stress on sperm parameters and testicular proteomics in rats
  6. A case of pulmonary embolism with bad warfarin anticoagulant effects caused by E. coli infection
  7. Neutrophilia with subclinical Cushing’s disease: A case report and literature review
  8. Isoimperatorin alleviates lipopolysaccharide-induced periodontitis by downregulating ERK1/2 and NF-κB pathways
  9. Immunoregulation of synovial macrophages for the treatment of osteoarthritis
  10. Novel CPLANE1 c.8948dupT (p.P2984Tfs*7) variant in a child patient with Joubert syndrome
  11. Antiphospholipid antibodies and the risk of thrombosis in myeloproliferative neoplasms
  12. Immunological responses of septic rats to combination therapy with thymosin α1 and vitamin C
  13. High glucose and high lipid induced mitochondrial dysfunction in JEG-3 cells through oxidative stress
  14. Pharmacological inhibition of the ubiquitin-specific protease 8 effectively suppresses glioblastoma cell growth
  15. Levocarnitine regulates the growth of angiotensin II-induced myocardial fibrosis cells via TIMP-1
  16. Age-related changes in peripheral T-cell subpopulations in elderly individuals: An observational study
  17. Single-cell transcription analysis reveals the tumor origin and heterogeneity of human bilateral renal clear cell carcinoma
  18. Identification of iron metabolism-related genes as diagnostic signatures in sepsis by blood transcriptomic analysis
  19. Long noncoding RNA ACART knockdown decreases 3T3-L1 preadipocyte proliferation and differentiation
  20. Surgery, adjuvant immunotherapy plus chemotherapy and radiotherapy for primary malignant melanoma of the parotid gland (PGMM): A case report
  21. Dosimetry comparison with helical tomotherapy, volumetric modulated arc therapy, and intensity-modulated radiotherapy for grade II gliomas: A single‑institution case series
  22. Soy isoflavone reduces LPS-induced acute lung injury via increasing aquaporin 1 and aquaporin 5 in rats
  23. Refractory hypokalemia with sexual dysplasia and infertility caused by 17α-hydroxylase deficiency and triple X syndrome: A case report
  24. Meta-analysis of cancer risk among end stage renal disease undergoing maintenance dialysis
  25. 6-Phosphogluconate dehydrogenase inhibition arrests growth and induces apoptosis in gastric cancer via AMPK activation and oxidative stress
  26. Experimental study on the optimization of ANM33 release in foam cells
  27. Primary retroperitoneal angiosarcoma: A case report
  28. Metabolomic analysis-identified 2-hydroxybutyric acid might be a key metabolite of severe preeclampsia
  29. Malignant pleural effusion diagnosis and therapy
  30. Effect of spaceflight on the phenotype and proteome of Escherichia coli
  31. Comparison of immunotherapy combined with stereotactic radiotherapy and targeted therapy for patients with brain metastases: A systemic review and meta-analysis
  32. Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation
  33. Association between the VEGFR-2 -604T/C polymorphism (rs2071559) and type 2 diabetic retinopathy
  34. The role of IL-31 and IL-34 in the diagnosis and treatment of chronic periodontitis
  35. Triple-negative mouse breast cancer initiating cells show high expression of beta1 integrin and increased malignant features
  36. mNGS facilitates the accurate diagnosis and antibiotic treatment of suspicious critical CNS infection in real practice: A retrospective study
  37. The apatinib and pemetrexed combination has antitumor and antiangiogenic effects against NSCLC
  38. Radiotherapy for primary thyroid adenoid cystic carcinoma
  39. Design and functional preliminary investigation of recombinant antigen EgG1Y162–EgG1Y162 against Echinococcus granulosus
  40. Effects of losartan in patients with NAFLD: A meta-analysis of randomized controlled trial
  41. Bibliometric analysis of METTL3: Current perspectives, highlights, and trending topics
  42. Performance comparison of three scaling algorithms in NMR-based metabolomics analysis
  43. PI3K/AKT/mTOR pathway and its related molecules participate in PROK1 silence-induced anti-tumor effects on pancreatic cancer
  44. The altered expression of cytoskeletal and synaptic remodeling proteins during epilepsy
  45. Effects of pegylated recombinant human granulocyte colony-stimulating factor on lymphocytes and white blood cells of patients with malignant tumor
  46. Prostatitis as initial manifestation of Chlamydia psittaci pneumonia diagnosed by metagenome next-generation sequencing: A case report
  47. NUDT21 relieves sevoflurane-induced neurological damage in rats by down-regulating LIMK2
  48. Association of interleukin-10 rs1800896, rs1800872, and interleukin-6 rs1800795 polymorphisms with squamous cell carcinoma risk: A meta-analysis
  49. Exosomal HBV-DNA for diagnosis and treatment monitoring of chronic hepatitis B
  50. Shear stress leads to the dysfunction of endothelial cells through the Cav-1-mediated KLF2/eNOS/ERK signaling pathway under physiological conditions
  51. Interaction between the PI3K/AKT pathway and mitochondrial autophagy in macrophages and the leukocyte count in rats with LPS-induced pulmonary infection
  52. Meta-analysis of the rs231775 locus polymorphism in the CTLA-4 gene and the susceptibility to Graves’ disease in children
  53. Cloning, subcellular localization and expression of phosphate transporter gene HvPT6 of hulless barley
  54. Coptisine mitigates diabetic nephropathy via repressing the NRLP3 inflammasome
  55. Significant elevated CXCL14 and decreased IL-39 levels in patients with tuberculosis
  56. Whole-exome sequencing applications in prenatal diagnosis of fetal bowel dilatation
  57. Gemella morbillorum infective endocarditis: A case report and literature review
  58. An unusual ectopic thymoma clonal evolution analysis: A case report
  59. Severe cumulative skin toxicity during toripalimab combined with vemurafenib following toripalimab alone
  60. Detection of V. vulnificus septic shock with ARDS using mNGS
  61. Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
  62. The influence and mechanistic action of sperm DNA fragmentation index on the outcomes of assisted reproduction technology
  63. Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review
  64. ctDNA as a prognostic biomarker in resectable CLM: Systematic review and meta-analysis
  65. Diagnosis of primary amoebic meningoencephalitis by metagenomic next-generation sequencing: A case report
  66. Phylogenetic analysis of promoter regions of human Dolichol kinase (DOLK) and orthologous genes using bioinformatics tools
  67. Collagen changes in rabbit conjunctiva after conjunctival crosslinking
  68. Effects of NM23 transfection of human gastric carcinoma cells in mice
  69. Oral nifedipine and phytosterol, intravenous nicardipine, and oral nifedipine only: Three-arm, retrospective, cohort study for management of severe preeclampsia
  70. Case report of hepatic retiform hemangioendothelioma: A rare tumor treated with ultrasound-guided microwave ablation
  71. Curcumin induces apoptosis in human hepatocellular carcinoma cells by decreasing the expression of STAT3/VEGF/HIF-1α signaling
  72. Rare presentation of double-clonal Waldenström macroglobulinemia with pulmonary embolism: A case report
  73. Giant duplication of the transverse colon in an adult: A case report and literature review
  74. Ectopic thyroid tissue in the breast: A case report
  75. SDR16C5 promotes proliferation and migration and inhibits apoptosis in pancreatic cancer
  76. Vaginal metastasis from breast cancer: A case report
  77. Screening of the best time window for MSC transplantation to treat acute myocardial infarction with SDF-1α antibody-loaded targeted ultrasonic microbubbles: An in vivo study in miniswine
  78. Inhibition of TAZ impairs the migration ability of melanoma cells
  79. Molecular complexity analysis of the diagnosis of Gitelman syndrome in China
  80. Effects of maternal calcium and protein intake on the development and bone metabolism of offspring mice
  81. Identification of winter wheat pests and diseases based on improved convolutional neural network
  82. Ultra-multiplex PCR technique to guide treatment of Aspergillus-infected aortic valve prostheses
  83. Virtual high-throughput screening: Potential inhibitors targeting aminopeptidase N (CD13) and PIKfyve for SARS-CoV-2
  84. Immune checkpoint inhibitors in cancer patients with COVID-19
  85. Utility of methylene blue mixed with autologous blood in preoperative localization of pulmonary nodules and masses
  86. Integrated analysis of the microbiome and transcriptome in stomach adenocarcinoma
  87. Berberine suppressed sarcopenia insulin resistance through SIRT1-mediated mitophagy
  88. DUSP2 inhibits the progression of lupus nephritis in mice by regulating the STAT3 pathway
  89. Lung abscess by Fusobacterium nucleatum and Streptococcus spp. co-infection by mNGS: A case series
  90. Genetic alterations of KRAS and TP53 in intrahepatic cholangiocarcinoma associated with poor prognosis
  91. Granulomatous polyangiitis involving the fourth ventricle: Report of a rare case and a literature review
  92. Studying infant mortality: A demographic analysis based on data mining models
  93. Metaplastic breast carcinoma with osseous differentiation: A report of a rare case and literature review
  94. Protein Z modulates the metastasis of lung adenocarcinoma cells
  95. Inhibition of pyroptosis and apoptosis by capsaicin protects against LPS-induced acute kidney injury through TRPV1/UCP2 axis in vitro
  96. TAK-242, a toll-like receptor 4 antagonist, against brain injury by alleviates autophagy and inflammation in rats
  97. Primary mediastinum Ewing’s sarcoma with pleural effusion: A case report and literature review
  98. Association of ADRB2 gene polymorphisms and intestinal microbiota in Chinese Han adolescents
  99. Tanshinone IIA alleviates chondrocyte apoptosis and extracellular matrix degeneration by inhibiting ferroptosis
  100. Study on the cytokines related to SARS-Cov-2 in testicular cells and the interaction network between cells based on scRNA-seq data
  101. Effect of periostin on bone metabolic and autophagy factors during tooth eruption in mice
  102. HP1 induces ferroptosis of renal tubular epithelial cells through NRF2 pathway in diabetic nephropathy
  103. Intravaginal estrogen management in postmenopausal patients with vaginal squamous intraepithelial lesions along with CO2 laser ablation: A retrospective study
  104. Hepatocellular carcinoma cell differentiation trajectory predicts immunotherapy, potential therapeutic drugs, and prognosis of patients
  105. Effects of physical exercise on biomarkers of oxidative stress in healthy subjects: A meta-analysis of randomized controlled trials
  106. Identification of lysosome-related genes in connection with prognosis and immune cell infiltration for drug candidates in head and neck cancer
  107. Development of an instrument-free and low-cost ELISA dot-blot test to detect antibodies against SARS-CoV-2
  108. Research progress on gas signal molecular therapy for Parkinson’s disease
  109. Adiponectin inhibits TGF-β1-induced skin fibroblast proliferation and phenotype transformation via the p38 MAPK signaling pathway
  110. The G protein-coupled receptor-related gene signatures for predicting prognosis and immunotherapy response in bladder urothelial carcinoma
  111. α-Fetoprotein contributes to the malignant biological properties of AFP-producing gastric cancer
  112. CXCL12/CXCR4/CXCR7 axis in placenta tissues of patients with placenta previa
  113. Association between thyroid stimulating hormone levels and papillary thyroid cancer risk: A meta-analysis
  114. Significance of sTREM-1 and sST2 combined diagnosis for sepsis detection and prognosis prediction
  115. Diagnostic value of serum neuroactive substances in the acute exacerbation of chronic obstructive pulmonary disease complicated with depression
  116. Research progress of AMP-activated protein kinase and cardiac aging
  117. TRIM29 knockdown prevented the colon cancer progression through decreasing the ubiquitination levels of KRT5
  118. Cross-talk between gut microbiota and liver steatosis: Complications and therapeutic target
  119. Metastasis from small cell lung cancer to ovary: A case report
  120. The early diagnosis and pathogenic mechanisms of sepsis-related acute kidney injury
  121. The effect of NK cell therapy on sepsis secondary to lung cancer: A case report
  122. Erianin alleviates collagen-induced arthritis in mice by inhibiting Th17 cell differentiation
  123. Loss of ACOX1 in clear cell renal cell carcinoma and its correlation with clinical features
  124. Signalling pathways in the osteogenic differentiation of periodontal ligament stem cells
  125. Crosstalk between lactic acid and immune regulation and its value in the diagnosis and treatment of liver failure
  126. Clinicopathological features and differential diagnosis of gastric pleomorphic giant cell carcinoma
  127. Traumatic brain injury and rTMS-ERPs: Case report and literature review
  128. Extracellular fibrin promotes non-small cell lung cancer progression through integrin β1/PTEN/AKT signaling
  129. Knockdown of DLK4 inhibits non-small cell lung cancer tumor growth by downregulating CKS2
  130. The co-expression pattern of VEGFR-2 with indicators related to proliferation, apoptosis, and differentiation of anagen hair follicles
  131. Inflammation-related signaling pathways in tendinopathy
  132. CD4+ T cell count in HIV/TB co-infection and co-occurrence with HL: Case report and literature review
  133. Clinical analysis of severe Chlamydia psittaci pneumonia: Case series study
  134. Bioinformatics analysis to identify potential biomarkers for the pulmonary artery hypertension associated with the basement membrane
  135. Influence of MTHFR polymorphism, alone or in combination with smoking and alcohol consumption, on cancer susceptibility
  136. Catharanthus roseus (L.) G. Don counteracts the ampicillin resistance in multiple antibiotic-resistant Staphylococcus aureus by downregulation of PBP2a synthesis
  137. Combination of a bronchogenic cyst in the thoracic spinal canal with chronic myelocytic leukemia
  138. Bacterial lipoprotein plays an important role in the macrophage autophagy and apoptosis induced by Salmonella typhimurium and Staphylococcus aureus
  139. TCL1A+ B cells predict prognosis in triple-negative breast cancer through integrative analysis of single-cell and bulk transcriptomic data
  140. Ezrin promotes esophageal squamous cell carcinoma progression via the Hippo signaling pathway
  141. Ferroptosis: A potential target of macrophages in plaque vulnerability
  142. Predicting pediatric Crohn's disease based on six mRNA-constructed risk signature using comprehensive bioinformatic approaches
  143. Applications of genetic code expansion and photosensitive UAAs in studying membrane proteins
  144. HK2 contributes to the proliferation, migration, and invasion of diffuse large B-cell lymphoma cells by enhancing the ERK1/2 signaling pathway
  145. IL-17 in osteoarthritis: A narrative review
  146. Circadian cycle and neuroinflammation
  147. Probiotic management and inflammatory factors as a novel treatment in cirrhosis: A systematic review and meta-analysis
  148. Hemorrhagic meningioma with pulmonary metastasis: Case report and literature review
  149. SPOP regulates the expression profiles and alternative splicing events in human hepatocytes
  150. Knockdown of SETD5 inhibited glycolysis and tumor growth in gastric cancer cells by down-regulating Akt signaling pathway
  151. PTX3 promotes IVIG resistance-induced endothelial injury in Kawasaki disease by regulating the NF-κB pathway
  152. Pancreatic ectopic thyroid tissue: A case report and analysis of literature
  153. The prognostic impact of body mass index on female breast cancer patients in underdeveloped regions of northern China differs by menopause status and tumor molecular subtype
  154. Report on a case of liver-originating malignant melanoma of unknown primary
  155. Case report: Herbal treatment of neutropenic enterocolitis after chemotherapy for breast cancer
  156. The fibroblast growth factor–Klotho axis at molecular level
  157. Characterization of amiodarone action on currents in hERG-T618 gain-of-function mutations
  158. A case report of diagnosis and dynamic monitoring of Listeria monocytogenes meningitis with NGS
  159. Effect of autologous platelet-rich plasma on new bone formation and viability of a Marburg bone graft
  160. Small breast epithelial mucin as a useful prognostic marker for breast cancer patients
  161. Continuous non-adherent culture promotes transdifferentiation of human adipose-derived stem cells into retinal lineage
  162. Nrf3 alleviates oxidative stress and promotes the survival of colon cancer cells by activating AKT/BCL-2 signal pathway
  163. Favorable response to surufatinib in a patient with necrolytic migratory erythema: A case report
  164. Case report of atypical undernutrition of hypoproteinemia type
  165. Down-regulation of COL1A1 inhibits tumor-associated fibroblast activation and mediates matrix remodeling in the tumor microenvironment of breast cancer
  166. Sarcoma protein kinase inhibition alleviates liver fibrosis by promoting hepatic stellate cells ferroptosis
  167. Research progress of serum eosinophil in chronic obstructive pulmonary disease and asthma
  168. Clinicopathological characteristics of co-existing or mixed colorectal cancer and neuroendocrine tumor: Report of five cases
  169. Role of menopausal hormone therapy in the prevention of postmenopausal osteoporosis
  170. Precisional detection of lymph node metastasis using tFCM in colorectal cancer
  171. Advances in diagnosis and treatment of perimenopausal syndrome
  172. A study of forensic genetics: ITO index distribution and kinship judgment between two individuals
  173. Acute lupus pneumonitis resembling miliary tuberculosis: A case-based review
  174. Plasma levels of CD36 and glutathione as biomarkers for ruptured intracranial aneurysm
  175. Fractalkine modulates pulmonary angiogenesis and tube formation by modulating CX3CR1 and growth factors in PVECs
  176. Novel risk prediction models for deep vein thrombosis after thoracotomy and thoracoscopic lung cancer resections, involving coagulation and immune function
  177. Exploring the diagnostic markers of essential tremor: A study based on machine learning algorithms
  178. Evaluation of effects of small-incision approach treatment on proximal tibia fracture by deep learning algorithm-based magnetic resonance imaging
  179. An online diagnosis method for cancer lesions based on intelligent imaging analysis
  180. Medical imaging in rheumatoid arthritis: A review on deep learning approach
  181. Predictive analytics in smart healthcare for child mortality prediction using a machine learning approach
  182. Utility of neutrophil–lymphocyte ratio and platelet–lymphocyte ratio in predicting acute-on-chronic liver failure survival
  183. A biomedical decision support system for meta-analysis of bilateral upper-limb training in stroke patients with hemiplegia
  184. TNF-α and IL-8 levels are positively correlated with hypobaric hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats
  185. Stochastic gradient descent optimisation for convolutional neural network for medical image segmentation
  186. Comparison of the prognostic value of four different critical illness scores in patients with sepsis-induced coagulopathy
  187. Application and teaching of computer molecular simulation embedded technology and artificial intelligence in drug research and development
  188. Hepatobiliary surgery based on intelligent image segmentation technology
  189. Value of brain injury-related indicators based on neural network in the diagnosis of neonatal hypoxic-ischemic encephalopathy
  190. Analysis of early diagnosis methods for asymmetric dementia in brain MR images based on genetic medical technology
  191. Early diagnosis for the onset of peri-implantitis based on artificial neural network
  192. Clinical significance of the detection of serum IgG4 and IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy
  193. Forecast of pain degree of lumbar disc herniation based on back propagation neural network
  194. SPA-UNet: A liver tumor segmentation network based on fused multi-scale features
  195. Systematic evaluation of clinical efficacy of CYP1B1 gene polymorphism in EGFR mutant non-small cell lung cancer observed by medical image
  196. Rehabilitation effect of intelligent rehabilitation training system on hemiplegic limb spasms after stroke
  197. A novel approach for minimising anti-aliasing effects in EEG data acquisition
  198. ErbB4 promotes M2 activation of macrophages in idiopathic pulmonary fibrosis
  199. Clinical role of CYP1B1 gene polymorphism in prediction of postoperative chemotherapy efficacy in NSCLC based on individualized health model
  200. Lung nodule segmentation via semi-residual multi-resolution neural networks
  201. Evaluation of brain nerve function in ICU patients with Delirium by deep learning algorithm-based resting state MRI
  202. A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis
  203. Markov model combined with MR diffusion tensor imaging for predicting the onset of Alzheimer’s disease
  204. Effectiveness of the treatment of depression associated with cancer and neuroimaging changes in depression-related brain regions in patients treated with the mediator-deuterium acupuncture method
  205. Molecular mechanism of colorectal cancer and screening of molecular markers based on bioinformatics analysis
  206. Monitoring and evaluation of anesthesia depth status data based on neuroscience
  207. Exploring the conformational dynamics and thermodynamics of EGFR S768I and G719X + S768I mutations in non-small cell lung cancer: An in silico approaches
  208. Optimised feature selection-driven convolutional neural network using gray level co-occurrence matrix for detection of cervical cancer
  209. Incidence of different pressure patterns of spinal cerebellar ataxia and analysis of imaging and genetic diagnosis
  210. Pathogenic bacteria and treatment resistance in older cardiovascular disease patients with lung infection and risk prediction model
  211. Adoption value of support vector machine algorithm-based computed tomography imaging in the diagnosis of secondary pulmonary fungal infections in patients with malignant hematological disorders
  212. From slides to insights: Harnessing deep learning for prognostic survival prediction in human colorectal cancer histology
  213. Ecology and Environmental Science
  214. Monitoring of hourly carbon dioxide concentration under different land use types in arid ecosystem
  215. Comparing the differences of prokaryotic microbial community between pit walls and bottom from Chinese liquor revealed by 16S rRNA gene sequencing
  216. Effects of cadmium stress on fruits germination and growth of two herbage species
  217. Bamboo charcoal affects soil properties and bacterial community in tea plantations
  218. Optimization of biogas potential using kinetic models, response surface methodology, and instrumental evidence for biodegradation of tannery fleshings during anaerobic digestion
  219. Understory vegetation diversity patterns of Platycladus orientalis and Pinus elliottii communities in Central and Southern China
  220. Studies on macrofungi diversity and discovery of new species of Abortiporus from Baotianman World Biosphere Reserve
  221. Food Science
  222. Effect of berrycactus fruit (Myrtillocactus geometrizans) on glutamate, glutamine, and GABA levels in the frontal cortex of rats fed with a high-fat diet
  223. Guesstimate of thymoquinone diversity in Nigella sativa L. genotypes and elite varieties collected from Indian states using HPTLC technique
  224. Analysis of bacterial community structure of Fuzhuan tea with different processing techniques
  225. Untargeted metabolomics reveals sour jujube kernel benefiting the nutritional value and flavor of Morchella esculenta
  226. Mycobiota in Slovak wine grapes: A case study from the small Carpathians wine region
  227. Elemental analysis of Fadogia ancylantha leaves used as a nutraceutical in Mashonaland West Province, Zimbabwe
  228. Microbiological transglutaminase: Biotechnological application in the food industry
  229. Influence of solvent-free extraction of fish oil from catfish (Clarias magur) heads using a Taguchi orthogonal array design: A qualitative and quantitative approach
  230. Chromatographic analysis of the chemical composition and anticancer activities of Curcuma longa extract cultivated in Palestine
  231. The potential for the use of leghemoglobin and plant ferritin as sources of iron
  232. Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM
  233. Bioengineering and Biotechnology
  234. Biocompatibility and osteointegration capability of β-TCP manufactured by stereolithography 3D printing: In vitro study
  235. Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study
  236. Agriculture
  237. Biofertilizer and NPSB fertilizer application effects on nodulation and productivity of common bean (Phaseolus vulgaris L.) at Sodo Zuria, Southern Ethiopia
  238. On correlation between canopy vegetation and growth indexes of maize varieties with different nitrogen efficiencies
  239. Exopolysaccharides from Pseudomonas tolaasii inhibit the growth of Pleurotus ostreatus mycelia
  240. A transcriptomic evaluation of the mechanism of programmed cell death of the replaceable bud in Chinese chestnut
  241. Melatonin enhances salt tolerance in sorghum by modulating photosynthetic performance, osmoregulation, antioxidant defense, and ion homeostasis
  242. Effects of plant density on alfalfa (Medicago sativa L.) seed yield in western Heilongjiang areas
  243. Identification of rice leaf diseases and deficiency disorders using a novel DeepBatch technique
  244. Artificial intelligence and internet of things oriented sustainable precision farming: Towards modern agriculture
  245. Animal Sciences
  246. Effect of ketogenic diet on exercise tolerance and transcriptome of gastrocnemius in mice
  247. Combined analysis of mRNA–miRNA from testis tissue in Tibetan sheep with different FecB genotypes
  248. Isolation, identification, and drug resistance of a partially isolated bacterium from the gill of Siniperca chuatsi
  249. Tracking behavioral changes of confined sows from the first mating to the third parity
  250. The sequencing of the key genes and end products in the TLR4 signaling pathway from the kidney of Rana dybowskii exposed to Aeromonas hydrophila
  251. Development of a new candidate vaccine against piglet diarrhea caused by Escherichia coli
  252. Plant Sciences
  253. Crown and diameter structure of pure Pinus massoniana Lamb. forest in Hunan province, China
  254. Genetic evaluation and germplasm identification analysis on ITS2, trnL-F, and psbA-trnH of alfalfa varieties germplasm resources
  255. Tissue culture and rapid propagation technology for Gentiana rhodantha
  256. Effects of cadmium on the synthesis of active ingredients in Salvia miltiorrhiza
  257. Cloning and expression analysis of VrNAC13 gene in mung bean
  258. Chlorate-induced molecular floral transition revealed by transcriptomes
  259. Effects of warming and drought on growth and development of soybean in Hailun region
  260. Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves
  261. Comparative analysis of the rhizosphere microbiome and medicinally active ingredients of Atractylodes lancea from different geographical origins
  262. Distinguish Dianthus species or varieties based on chloroplast genomes
  263. Comparative transcriptomes reveal molecular mechanisms of apple blossoms of different tolerance genotypes to chilling injury
  264. Study on fresh processing key technology and quality influence of Cut Ophiopogonis Radix based on multi-index evaluation
  265. An advanced approach for fig leaf disease detection and classification: Leveraging image processing and enhanced support vector machine methodology
  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
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Heruntergeladen am 27.1.2026 von https://www.degruyterbrill.com/document/doi/10.1515/biol-2022-0514/html
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