Home HK2 contributes to the proliferation, migration, and invasion of diffuse large B-cell lymphoma cells by enhancing the ERK1/2 signaling pathway
Article Open Access

HK2 contributes to the proliferation, migration, and invasion of diffuse large B-cell lymphoma cells by enhancing the ERK1/2 signaling pathway

  • Hongcan Zhao , Guoqian Xiang EMAIL logo , Tingjun Shao , Minmin Wang and Weijian Dai
Published/Copyright: October 14, 2023
Download Article (PDF)
Open Life Sciences
From the journal Open Life Sciences Volume 18 Issue 1

Abstract

Hexokinase 2 (HK2) has been associated with carcinogenic growth in numerous kinds of malignancies as essential regulators during the processing of glucose. This study aimed to explore the effects of HK2 on diffuse large B-cell lymphoma (DLBCL) cells via the ERK1/2 signaling. Expressions of HK2 and ERK1/2 were examined in DLBCL cell lines using quantitative reverse transcription polymerase chain reaction and western blotting. HK2 and ERK1/2 were attenuated through HK2 small-interfering RNA (siRNA) and ERK inhibitor FR180204, respectively, in U2932 and SU-DHL-4 cells. Cell Counting Kit-8, clone formation, transwell, and flow cytometry assays were used in evaluating the effects of HK2 and ERK1/2 on cell proliferation, migration, and apoptosis. Moreover, a xenograft model was created to assess the roles of HK2 in vivo. HK2 and ERK1/2 were evidently up-regulated in DLBCL cell lines. HK2 knockdown and FR180204 markedly suppressed the proliferation and clonogenesis of U2932 and SU-DHL-4 cells and promoted cell apoptosis in vitro. We also found that HK2 silencing suppressed tumor growth in vivo. Notably, HK2 knockdown inactivated the ERK1/2 signaling pathway both in vitro and in vivo. These data indicate that inhibition of HK2 may suppress the proliferation, migration, and invasion of DLBCL cells, partly via inhibiting the ERK1/2 signaling pathway.

Keywords: diffuse large B lymphoma; Hexokinase; ERK1/2; FR180204

1 Introduction

Lymphoma is a malignancy originating from the lymphatic hematopoietic system, with over 67 subtypes, including Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). Among these, HL includes 6 subtypes and NHL includes 61 subtypes; thus, most lymphomas are NHLs [1]. It is estimated that 544,000 new cases of NHL were detected worldwide in 2020, with roughly 260,000 people dying as a result of the disease [2]. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL, accounting for approximately 30–40% of all NHL cases [3]. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) are the first-line treatment options for DLBCL. Most patients experience remission after treatment, although approximately 10–15% of patients develop primary resistance and 20–25% of patients experience relapse following initial treatment [4,5]. Hence, establishing a prognostic evaluation system and finding new therapeutic targets for DLBCL represent rigorous clinical challenges for researchers.

DLBCL is a highly heterogeneous NHL, as reflected in its morphology, immunohistochemical phenotype, molecular genetics, involved sites, chemotherapy response, and survival rate [6,7,8]. Different subtypes are crucial for treatment selection and prognosis. Therefore, in recent years, the classification and prognosis of DLBCL have been extensively explored, and fruitful results have been obtained. As such, various types of assessment systems and markers closely related to DLBCL prognosis have been confirmed. These findings provided the basis for judging patient prognosis and selecting effective interventions for high-risk patients as well as for establishing individualized, precise, and standardized treatments. In addition, more comprehensive prognostic models can allow for the early identification of high-risk patients, enabling clinicians to select the appropriate treatment plan in advance and improve the remission rate and survival duration of patients. In this context, further exploration of the molecular changes and drug resistance mechanisms of DLBCL can contribute to the development of targeted drugs for this malignancy in the future, achieving significant therapeutic efficacy.

Hexokinases (HKs; or glucokinases) are involved in the first step of glucose metabolism, wherein glucose or glycogen is phosphorylated to glucose 6-phosphate. To date, four HK isoenzymes, namely HK1, HK2, HK3, and HK4, have been identified [9]. Of these, HK2 is primarily detected in embryos and is highly expressed in very few adult tissues, such as fat and skeletal muscles [10]. In recent years, many studies have shown that HK2 is highly expressed in breast cancer, liver cancer, glioma, and esophageal cancer and can promote tumor progression through energy metabolism and anti-apoptotic signaling pathways [9,11,12]. For instance, Bhalla et al. [13] found that HK2 is a key molecule that mediates hypoxia to promote DLBCL proliferation. Gao et al. [14] found that TNFα-YAP/p65 can synergistically regulate HK2 expression and promote breast cancer cell migration. Li et al. [15] and Zhang et al. [16] found that HK2 is closely related to the resistance of ovarian cancer to paclitaxel and cisplatin. Yuen et al. [17] reported that hypoxia can regulate the expression of Warburg effect-related molecules, including HK2, in cancer stem cells, thereby promoting malignant biological behaviors, such as tumor drug resistance [17]. In addition, Lu et al. [18] showed that the covalent lysine (K)-specific demethylase 1A (KDM1A) inhibitor ORY-1001 regulates the Warburg effect by controlling HK2 expression, which in turn inhibits lung cancer cell proliferation and clone formation but promotes apoptosis [18]. Agnihotri et al. [19] found that HK2 showed abnormally high expression in glioma and may serve as a potential therapeutic target [19]. By constructing a direct interacting protein network, HK2 was found to directly interact with EGFR, BUB3, and CircCDKN2B-AS1, which are proteins involved in the malignant progression of various tumors [20,21,22]. Therefore, HK2 likely promotes the malignant progression of DLBCL through signaling pathways other than energy metabolism. Specifically, ERK is an early member of the MAPK family, and its isomers ERK1 and ERK2 are involved in the regulation of cell proliferation, differentiation, apoptosis as well as other physiological processes [23]. From these reports, HK2 may be closely associated with malignant progression and serve as a potent therapeutic target for DLBCL.

Apoptotic suppression is important for rapid tumor growth, and apoptosis involves the expression and regulation of several genes, signaling pathways, and proteins. The Bcl-2 protein family constitutes many pro- and anti-apoptotic proteins [24]. However, the link between HK2 and lymphoma, specifically DLBCL, remains unclear, and its roles in the proliferation and metastasis of this malignancy from a prognostic viewpoint have rarely been reported. In the present study, we confirmed that HK2 is upregulated in DLBCL cells. HK2 knockdown inhibited the proliferation, migration, and invasion of DLBCL cells in vitro and restricted tumor growth in vivo, and these effects were associated with the suppression of the ERK1/2 signaling pathway. These findings offer novel insights into the oncogenic roles of HK2 in DLBCL, which may further our understanding of the pathogenesis of and therapeutical strategies for this malignancy.

2 Materials and methods

2.1 Cell culture and transfection

Human normal B-cell line HMy2.CIR was preserved in our laboratory and DLBCL TMD8, OCI-Ly3, U2932, OCI-Ly1, OCI-Ly7, SU-DHL-4, and SU-DHL-6 cells were purchased from the American Type Culture Collection (Manassas, VA, USA). HMy2.CIR, OCI-Ly3, and OCI-Ly7 cells were cultured in Iscove’s modified Dulbecco’s medium (IMDM) (Gibco, USA) containing 10% fetal bovine serum (FBS), 100 μg mL−1 streptomycin, and 100 U mL−1 penicillin (HyClone). The rest of the cells were maintained in RPMI 1640 medium with 10% FBS. All cells were cultivated in a humidified incubator at 37℃ with 5% CO2. To knockdown HK2 in the cells, siRNA sequences against HK2 (si-HK2 #1: 5′-GGAGATGGAGAAAGGGCTT-3′; si-HK2 #2: 5′-GCGCATCAAGGAGAACAAA-3′) or negative control (si-NC: 5′-AGACTTCCTCACCTCCTTCT-3′) were synthesized by Genepharm Co. Ltd. (Shanghai, China). All transfections were performed using Lipofectamine 3000 (Invitrogen, USA) according to the manufacturer’s procedures. The transfection efficiency was assessed with quantitative reverse transcription polymerase chain reaction (qRT-PCR).

2.2 Cell proliferation assay

Forty-eight hours after transfection, 3 × 103 HK-2-silenced U2932 and SU-DHL-4 cells were seeded into 96‐well plates. Moreover, the ERK inhibitor F180204 (5 μm) was supplemented to the medium, and then, the Cell Counting Kit-8 (CCK-8) solution (Sigma-Aldrich, USA) was added to each well after 24, 48, 72, and 96 h of incubation. Next, absorbance at 450 nm was recorded using a microplate reader (Molecular Devices, USA). For cell colony assay, 6 × 102 HK-2-silenced or F180204-treated U2932 and SU-DHL-4 cells were cultured on 6-well plates for 14 days. Thereafter, the cells were fixed and stained with 0.1% crystal violet for 30 min. Finally, cell colonies comprising over 50 cells were photographed and counted under a light microscope (AE2000, Motic).

2.3 Cell apoptosis assay

Annexin V-FITC apoptosis detection kit was purchased from Beyotime (Shanghai, China) to assess the apoptosis of HK-2-silenced or F180204-treated U2932 and SU-DHL-4 cells following the manufacturer’s instructions. After being harvested and centrifuged, the cells were incubated with 500 μL of Annexin V-FITC-binding solution and then stained with 5 μL of Annexin V-FITC and 10 μL of PI. Thereafter, apoptosis was evaluated using a flow cytometer and analyzed with FlowJo (V10.8.1, BD Biosciences, USA).

2.4 Transwell assays

For cell migration assay, 1 × 104 HK-2-silenced or F180204-treated U2932 and SU-DHL-4 cells were cultured with 200 μL of a serum-free medium in the upper chamber of a transwell system (Corning, NY, USA). For cell invasion assay, the transwell chambers were pretreated with Matrigel™, and an equal number of cells were inoculated in the upper chamber. Then, 500 μL of RPMI 1640 medium containing 20% FBS was added to the lower chambers. After removing non-adherent cells in the upper chamber with cotton-tipped swabs, the cells that invaded and migrated to the lower chambers were fixed with 4% paraformaldehyde and stained with 0.1% crystal violet. Finally, the invading and migrating cells were captured and counted under a light microscope.

2.5 qRT-PCR assays

Total RNA from HMy2.CIR and DLBCL cells was extracted with TRIzol® reagent (Invitrogen) and reverse-transcribed into cDNA using the Transcriptor First-Strand cDNA Synthesis Kit (Takara Biotechnology, Dalian, China). Subsequently, PCR amplification was performed using SYBR Premix Ex Taq II Kit (Takara) on a CFX Connect Real-Time PCR Detection System (Bio-Rad, USA) to measure the expression levels of HK2. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as an internal control. The primers used in the present study were synthesized by Sangon Biotech (Shanghai, China): HK2 forward 5′-GAGCCACCACTCACCCTACT-3′; HK2 reverse 5′-CCAGGCATTCGGCAATGTG-3′; GAPDH forward 5′-TGTGGGCATCAATGGATTTGG-3′; and GAPDH reverse 5′-ACACCATGTATTCCGGGTCAAT-3′. The relative expression levels of HK2 were calculated using the 2−ΔΔCt method [25].

2.6 Western blotting

Total protein was extracted from HMy2.CIR and DLBCL cells using ice-cold RIPA lysis buffer (Solarbio, Beijing, China) supplemented with proteinase inhibitors (Beyotime, China). Next, protein concentration was assessed using the BCA protein assay kit (Beyotime, China). Equal amounts (25 μg) of protein extracts were separated with 10% sodium dodecyl sulfate–polyacrylamide gel electrophoresis and transferred onto polyvinylidene fluoride (PVDF) membranes (Millipore, Burlington, MA, USA). The PVDF membranes were blocked with 5% nonfat milk for 2 h at room temperature, following incubation with the primary antibodies against HK2 (1:1,000, BF0283, Affinity), ERK1/2 (1:2,500, AF0155, Affinity), phospho-ERK1/2 (Thr202/Tyr204) (1:1,000, AF1015, Affinity), Bax (1:2,000, ab182733, Abcam), Bcl-2 (1:1,000, AF6139, Affinity), caspase-3 (1:500, ab13847, Abcam), E-cadherin (1:2,000, 20874-1-AP, ProteinTech), N-cadherin (1:1,000, AF6139, Affinity), and GAPDH (1:5,000, AF7021, Affinity) at 4°C overnight. After washing three times with TBST, the membranes were incubated with an anti-rabbit or anti-mouse HRP-conjugated secondary antibody for 1 h. Finally, bands were detected using an enhanced chemiluminescence (Beyotime, China) system and analyzed using ImageJ (v1.8.0, National Institutes of Health, USA).

2.7 Tumor xenograft models

To identify the roles of HK2 in DLBCL tumor growth in vivo, a xenograft mouse model was established in the present study. In brief, 5 × 106 HK2-knockdown U2932 cells and the corresponding control cells were subcutaneously injected into the flanks of 4-week-old BALB/c nude mice (Shanghai SLAC Laboratory Animals Ltd., China). Tumor volume was recorded every 5 days using a vernier caliper and calculated using the formula: volume (mm3) = width2 × length/2. After 30 days, the xenografts were collected and weighed. Additionally, the xenograft tissues were subjected to hematoxylin and eosin (HE) staining, terminal-deoxynucleoitidyl transferase-mediated nick end labeling (TUNEL) assay, and immunohistochemical (IHC) analysis.

  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 was approved by the Ethics Committee of Zhejiang Eyong Pharmaceutical Research and Development Center (certificate no. SYXK (Zhe) 2021-0033, Hangzhou, China).

2.8 HE staining, TUNEL assay, and IHC analysis

For HE staining, the xenograft tissues were fixed, dehydrated, paraffin-embedded, sectioned, and stained with HE (Solarbio, China). HE-stained images were captured using a microscope at 200× magnification. For the TUNEL assay, 4-μm-thick paraffin-embedded xenograft tissue sections were dewaxed, rehydrated, incubated with proteinase K, incubated in 3% H2O2, permeabilized with 0.5% Triton X-100, and incubated with a TUNEL reaction mixture for 1 h at 37°C in the dark. Next, the sections were incubated with 3,3′-diaminobenzidine (DAB; Beyotime, China) for 5 min, and then, nuclei were counterstained with hematoxylin (Solarbio, China). TUNEL staining was investigated, and photographs were scanned using a microscope at 400× magnification. For IHC analysis, the xenograft tissues were fixed, paraffin-embedded, sectioned, dewaxed, exposed to antigens, and quenched for endogenous peroxidase activity. Then, the sections were incubated with 10% goat serum for 30 min at room temperature, followed by anti-Ki67 (1:100, AF0198, Affinity), anti-caspase 3 (1:100, 19677-1-AP, ProteinTech), anti-N-cadherin (1:7,500, 66219-1-Ig, ProteinTech), anti-HK2 (1:100, DF6176, Affinity), anti-E-cadherin (1:200, ab231303, Abcam), and anti-p-ERK (1:200, 4370T, Cell Signaling Technology) overnight at 4°C. Thereafter, the sections were washed with PBS and incubated with an appropriate HRP-labeled secondary antibody for 30 min at 37°C. The slides were visualized using DAB staining and hematoxylin counterstaining. Finally, images were obtained with a microscope at 200× magnification and semi-quantitatively analyzed using ImageJ.

2.9 Statistical analysis

All results are presented as mean ± standard deviation. Statistical analysis was performed using Student’s unpaired t-test. A P < 0.05 was considered statistically significant.

3 Results

3.1 HK2 upregulation in DLBCL cell lines and its association with DLBC prognosis

To elucidate the roles of HK2 in the progression of DLBCL, the human normal B-cell line HMy2.CIR and the DLBCL cells TMD8, OCI-Ly3, U2932, OCI-Ly1, OCI-Ly7, SU-DHL-4, and SU-DHL-6 were used, and the expression levels of HK2 in these cells were explored with qPCR and western blotting. Both transcript and protein expression levels of HK2 were significantly higher in DLBCL cells than those in HMy2.CIR cells, particularly U2932 and SU-DHL-4 cells (Figure 1a–d). Therefore, HK2 silencing was investigated in U2932 and SU-DHL-4 cell lines. Interestingly, HK2 levels increased gradually with the progression of cancer stages in patients with DLBCL (Figure 1e). Furthermore, higher HK2 expression in patients with DLBCL was associated with worse overall survival, although no significant difference was noted in the UALCAN database [26] (Figure 1f). Therefore, HK2 may act as a potential therapeutic target for DLBCL.

Figure 1 HK2 was overexpressed in DLBCL cell lines. (a) HK2 expression in normal (Hmy2.CIR) and DLBCL (TMD8, OCI-Ly3, U2932, OCI-Ly1, OCI-Ly7, SU-DHL-4, and SU-DHL-6) cells were measured using qRT-PCR. (b–d) Protein expression levels of HK2, p-ERK1/2, and ERK1/2 were assessed using western blotting. The University of Alabama at Birmingham Cancer (UALCAN) data analysis portal was used to analyze (e) the expression levels of HK2 at individual cancer stages and (f) overall survival of patients with DLBCL. *P < 0.05 and **P < 0.01 versus the Hmy2.CIR group. ▲ P < 0.05 Stage 1-versus-Stage 4 (P-value: 2.502100 × 10−2). ABC-DLBCL: activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL); GCB-DLBCL: Germinal center B-cell-like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL).
Figure 1

HK2 was overexpressed in DLBCL cell lines. (a) HK2 expression in normal (Hmy2.CIR) and DLBCL (TMD8, OCI-Ly3, U2932, OCI-Ly1, OCI-Ly7, SU-DHL-4, and SU-DHL-6) cells were measured using qRT-PCR. (b–d) Protein expression levels of HK2, p-ERK1/2, and ERK1/2 were assessed using western blotting. The University of Alabama at Birmingham Cancer (UALCAN) data analysis portal was used to analyze (e) the expression levels of HK2 at individual cancer stages and (f) overall survival of patients with DLBCL. *P < 0.05 and **P < 0.01 versus the Hmy2.CIR group. ▲ P < 0.05 Stage 1-versus-Stage 4 (P-value: 2.502100 × 10−2). ABC-DLBCL: activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL); GCB-DLBCL: Germinal center B-cell-like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL).

3.2 HK2 knockdown inhibits U2932 and SU-DHL-4 cell proliferation

To further identify its effects, we knocked down HK2 in U2932 and SU-DHL-4 cells. As shown in Figure 2a, RT-PCR analysis revealed that si-HK2 #1 and si-HK2 #2 significantly silenced HK2 levels compared with si-NC in U2932 and SU-DHL-4 cells, and the silencing effect was particularly strong for si-HK2 #1. Therefore, we selected si-HK2 #1 for subsequent experiments. HK2 silencing significantly suppressed U2932 and SU-DHL-4 cell proliferation and colony formation (Figure 2b and c). Similar inhibitory effects of the ERK inhibitor FR180204 were noted on DLBCL cell growth.

Figure 2 HK2 knockdown inhibits U2932 and SU-DHL-4 cell proliferation in vitro. (a) HK2 was knocked down in U2932 and SU-DHL-4 cells using siRNAs. (b) The viability of HK2-silenced and FR180204-treated (5 μM) U2932 and SU-DHL-4 cells was assessed using the CCK-8 assays. (c) Colony formation assays were used to assess the clone numbers of HK2-silenced and FR180204-treated U2932 and SU-DHL-4 cells. *P < 0.05 and **P < 0.01 versus the si-NC group.
Figure 2

HK2 knockdown inhibits U2932 and SU-DHL-4 cell proliferation in vitro. (a) HK2 was knocked down in U2932 and SU-DHL-4 cells using siRNAs. (b) The viability of HK2-silenced and FR180204-treated (5 μM) U2932 and SU-DHL-4 cells was assessed using the CCK-8 assays. (c) Colony formation assays were used to assess the clone numbers of HK2-silenced and FR180204-treated U2932 and SU-DHL-4 cells. *P < 0.05 and **P < 0.01 versus the si-NC group.

3.3 HK2 knockdown inhibits U2932 and SU-DHL-4 cell mobility

Transwell migration and invasion assays revealed that the number of migrating and invading cells was decreased in HK2-knockdown and FR180204-treated groups compared with those in the si-NC group (Figure 3a). Epithelial–mesenchymal transformation (EMT) contributes to cancer cell migratory and invasive abilities; therefore, we measured the expression levels of EMT-related proteins. Western blotting demonstrated that HK2 knockdown and FR180204 treatment increased E-cadherin levels but decreased N-cadherin levels in U2932 and SU-DHL-4 cells (Figure 3b).

Figure 3 HK2 knockdown inhibits U2932 and SU-DHL-4 cell migration and invasion in vitro. (a) Transwell assays were used to analyze the effects of HK2 knockdown on the migration and invasion of U2932 and SU-DHL-4 cells. (b) Western blotting was used to assess the expression levels of E-cadherin and N-cadherin in HK2-silenced and FR180204-treated U2932 and SU-DHL-4 cells. *P < 0.05 and **P < 0.01 versus the si-NC group.
Figure 3

HK2 knockdown inhibits U2932 and SU-DHL-4 cell migration and invasion in vitro. (a) Transwell assays were used to analyze the effects of HK2 knockdown on the migration and invasion of U2932 and SU-DHL-4 cells. (b) Western blotting was used to assess the expression levels of E-cadherin and N-cadherin in HK2-silenced and FR180204-treated U2932 and SU-DHL-4 cells. *P < 0.05 and **P < 0.01 versus the si-NC group.

3.4 HK2 knockdown promotes cell apoptosis of U2932 and SU-DHL-4

As shown in Figure 4a, HK2 knockdown and FR180204 treatment significantly promoted U2932 and SU-DHL-4 cell apoptosis. Next, we investigated whether HK2 affected U2932 and SU-DHL-4 cell apoptosis by regulating the expression of apoptosis-related proteins. HK2 knockdown increased protein levels of Bax and caspase-3 but decreased protein levels of Bcl-2 in U2932 and SU-DHL-4 cells. To examine the vital role of the ERK signaling pathway in DLBCL pathogenesis, we further assessed whether HK2 regulated this pathway. Western blotting revealed that p-ERK levels were significantly decreased in U2932 and SU-DHL-4 cells with HK2 knockdown (Figure 4b). Moreover, analogous effects were observed following the FR180204 treatment of U2932 and SU-DHL-4 cells. Additionally, hypoxia-inducible transcription factor 1α (HIF-1α) could bind with the promoter of HK2 and promote its transcription to increase glycolytic flux for promoting tumor survival and growth [27,28]. Western blot analysis showed that HK2 knockdown and FR180204 treatment rescued the HIF-1α and Ki67 proteins in U2932 and SU-DHL-4 cells (Figure 4c). These findings demonstrated that HK2 may serve as a positive regulator of the ERK pathway in DLBCL.

Figure 4 HK2 knockdown promotes U2932 and SU-DHL-4 cell apoptosis in vitro. (a) Flow cytometry assay was employed to measure U2932 and SU-DHL-4 cell apoptosis. (b) Representative blots and statistical analysis of Bax, Bcl-2, caspase-3, ERK1/2, and p-ERK1/2 in HK2-silenced and FR180204-treated U2932 and SU-DHL-4 cells. (c) Representative blots and statistical analysis of HIF-1α and Ki67 in HK2-silenced and FR180204-treated U2932 and SU-DHL-4 cells. *P < 0.05 and **P < 0.01 versus the si-NC group.
Figure 4

HK2 knockdown promotes U2932 and SU-DHL-4 cell apoptosis in vitro. (a) Flow cytometry assay was employed to measure U2932 and SU-DHL-4 cell apoptosis. (b) Representative blots and statistical analysis of Bax, Bcl-2, caspase-3, ERK1/2, and p-ERK1/2 in HK2-silenced and FR180204-treated U2932 and SU-DHL-4 cells. (c) Representative blots and statistical analysis of HIF-1α and Ki67 in HK2-silenced and FR180204-treated U2932 and SU-DHL-4 cells. *P < 0.05 and **P < 0.01 versus the si-NC group.

3.5 HK2 knockdown inhibits DLBCL tumor growth in vivo

To confirm the role of HK2 in tumor growth in vivo, U2932 cells with HK2 knockdown and the corresponding negative controls were subcutaneously injected into the flanks of BALB/c nude mice. In the tumor model, HK2 silencing led to a lower growth rate of the xenograft compared with normal HK2 expression (Figure 5a and b). Coincidently, xenograft tissues from mice injected with HK2-silenced cells showed a lower weight than those from mice injected with si-NC cells (Figure 5c). Additionally, HK2 knockdown promoted xenograft tissue necrosis and apoptosis compared, as shown by HE and TUNEL staining, respectively (Figure 5d and e). Furthermore, the IHC analysis of xenograft tissues revealed that Ki67, N-cadherin, HK2, and p-ERK expression was decreased, while caspase-3 and E-cadherin expression was increased in the HK2-knockdown group (Figure 5f). Moreover, the results of Western blotting also demonstrated that knockdown of HK2 could markedly suppress the expression of Bcl-2 and p-ERK and increase the expression of Bax in tumor tissues (Figure 5g). To conclude, these data confirmed that HK2 could promote tumor growth in vivo and may have an effect on the ERK signaling pathway.

Figure 5 HK2 knockdown suppresses DLBCL tumor growth in vivo. (a) Representation of tumor tissues of the xenograft in nude mice. (b) The tumor growth rate and (c) weight were markedly decreased in HK2-knockdown cell-treated nude mice. (d) Pathologic changes and (e) apoptosis of tumor tissues were measured with hematoxylin and eosin staining (scale bar = 100 μm) and TUNEL assay (scale bar = 50 μm), respectively. (f) Ki67, caspase 3, N-cadherin, HK-2, E-cadherin, and p-ERK expression in the xenografts was measured using IHC staining (scale bar = 100 μm). (g) Expression levels of Bax, Bcl-2, p-ERK, and ERK were measured using Western blotting. *P < 0.05 and **P < 0.01 versus the si-NC group.
Figure 5

HK2 knockdown suppresses DLBCL tumor growth in vivo. (a) Representation of tumor tissues of the xenograft in nude mice. (b) The tumor growth rate and (c) weight were markedly decreased in HK2-knockdown cell-treated nude mice. (d) Pathologic changes and (e) apoptosis of tumor tissues were measured with hematoxylin and eosin staining (scale bar = 100 μm) and TUNEL assay (scale bar = 50 μm), respectively. (f) Ki67, caspase 3, N-cadherin, HK-2, E-cadherin, and p-ERK expression in the xenografts was measured using IHC staining (scale bar = 100 μm). (g) Expression levels of Bax, Bcl-2, p-ERK, and ERK were measured using Western blotting. *P < 0.05 and **P < 0.01 versus the si-NC group.

4 Discussion

DLBCL is the most common lymphoid malignancy in approximately 30% of all NHL cases worldwide [29]. Although remarkable progress had been achieved in the recent several years and nearly 60–70% of all DLBCL patients experience satisfactory clinical outcomes, the potential mechanism of DLBCL remains obscure [4]. Hence, promising targets must be investigated to deepen our understanding of the physiological and pathological processes of DLBCL. Recent studies have illustrated that HK2 is closely associated with the pathology of B-cell malignant lymphoma. For instance, Nakajima et al. [30] reported that HK2 levels were significantly elevated in B-cell lymphoma cells through c-MYC and HIF; HK2 was further overexpressed under a hypoxic microenvironment, triggering cisplatin resistance in B-cell lymphoma [30]. More importantly, HK2 inhibition by the HDAC inhibitor panobinostat remarkably ameliorated the cisplatin resistance of B-cell lymphoma cell lines [30]. Similarly, Bhalla et al. [13] reported that HK2 may serve as a hub metabolic driver to promote the DLBCL phenotype under hypoxic stress. From these findings, HK2 can be implicated in the carcinogenesis of DLBCL.

In the present study, HK2 was significantly upregulated in DLBCL cell lines, and high HK2 expression was associated with DLBCL prognosis to a certain extent, consistent with previous reports [13,30,31]. Subsequently, we knocked down HK2 expression in U2932 and SU-DHL-4 cells and assessed its effects on cell viability, proliferation, apoptosis, migration, and invasion. HK2 knockdown significantly inhibited the proliferation, migration, and invasion but promoted the apoptosis of U2932 and SU-DHL-4 cells. Furthermore, in vivo experiments suggested that HK2 knockdown significantly inhibited the growth of tumors derived from U2932 cells. These results were consistent with the conclusion of a previous genetic knockdown experiment that HK2 is a direct contributor to DLBCL development [13]. Interestingly, in a conditional knockout mouse model, HK2 mediated KRas-driven lung carcinoma and ErbB2-driven generation and maintenance of breast cancer, and HK2 downregulation inhibited lung cancer in vitro and in vivo as well as the malignant biological behavior of breast cancer [32]. Additionally, HK2 is valuable as a prognostic biomarker in patients with DLBCL and may be useful as a tool to assess disease risk [33]. Taken together, our findings and previous reports suggest that HK2 acts as a tumor metabolic driver in the DLBCL phenotype.

To further explore the molecular mechanism underlying HK2-mediated effects on DLBCL cell proliferation, apoptosis, migration, and invasion, we analyzed downstream effectors. ERK1 and ERK2, which are key protein kinases in Ras-Raf-MEK-ERK-MAPK signaling, are associated with apoptosis, cell proliferation, and immune response in cancer, and ERK inhibitors have been used in early clinical trials to treat various advanced/metastatic solid tumors [34]. Hicks et al. [35] found that combined BRAF (dabrafenib) and ERK1/2 (SCH772984) inhibition synergistically attenuated cell growth and promoted cell apoptosis in thyroid cancer. Furthermore, Cui et al. [36] showed that FR180204, an ERK inhibitor, effectively reversed cell growth in HK2-overexpressing SiHa-HK2 and HeLa-HK2 cells. In the present study, FR180204 significantly inhibited U2932 and SU-DHL-4 cell proliferation, migration, and invasion but promoted cell apoptosis. Consistently, increased E-cadherin, Bax, and caspase-3 protein levels and decreased N-cadherin and Bcl-2 protein levels were observed in HK2-knockdown and FR180204-treated U2932 and SU-DHL-4 cells. Additionally, decreased p-ERK1/2 protein levels were observed in U2932 and SU-DHL-4 cells and xenograft tumor tissues derived from HK2-knockdown U2932 cells. Taken together, these results suggest that HK2 overexpression activates ERK1/2 signaling in U2932 and SU-DHL-4 cells. However, the present study has a limitation. Further research is warranted to confirm the potential molecular regulatory mechanism through which HK2 upregulates ERK1/2 expression in DLBCL cell lines.

5 Conclusions

The present study demonstrated that HK2 knockdown inactivates ERK1/2 signaling to inhibit cell proliferation, migration, and invasion but promotes cell apoptosis in vitro and in vivo by inducing E-cadherin, Bax, and caspase-3 protein expression and suppressing Ki67, N-cadherin, and Bcl-2 protein expression in DLBCL.

  1. Funding information: This work was supported by Zhejiang Medical and Health Technology (No. 2020361961).

  2. Author contributions: H.C.Z. and G.Q.X. designed the study. H.C.Z., T.J.S., M.M.W., and W.J.D. performed the experiments and analyzed the results. H.C.Z. wrote the manuscript. H.C.Z. and G.Q.X. edited the manuscript and provided critical comments. All authors have read and approved the final 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.

References

[1] Thandra KC, Barsouk A, Saginala K, Padala SA, Barsouk A, Rawla P. Epidemiology of Non-Hodgkin’s Lymphoma. Med Sci (Basel). 2021 Jan 30;9(1):5.10.3390/medsci9010005Search in Google Scholar PubMed PubMed Central

[2] Mafra A, Laversanne M, Gospodarowicz M, Klinger P, De Paula Silva N, Piñeros M, et al. Global patterns of non-Hodgkin lymphoma in 2020. Int J Cancer. 2022;151(9):1474–81.10.1002/ijc.34163Search in Google Scholar PubMed

[3] Sehn LH, Salles G. Diffuse large B-cell Lymphoma. N Engl J Med. 2021 Mar 4;384(9):842–58.10.1056/NEJMra2027612Search in Google Scholar PubMed PubMed Central

[4] He MY, Kridel R. Treatment resistance in diffuse large B-cell lymphoma. Leukemia. 2021;35(8):2151–65.10.1038/s41375-021-01285-3Search in Google Scholar PubMed

[5] Suzuki T, Maruyama D, Miyagi-Maeshima A, Nomoto J, Tajima K, Ito Y, et al. Clinicopathological analysis of primary refractory diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone chemoimmunotherapy. Cancer Med. 2021;10(15):5101–9.10.1002/cam4.4062Search in Google Scholar PubMed PubMed Central

[6] Ganapathi KA, Brown LE, Prakash S, Bhargava P. New developments in non-Hodgkin lymphoid malignancies. Pathology. 2021;53(3):349–66.10.1016/j.pathol.2021.01.002Search in Google Scholar PubMed

[7] Berendsen MR, Stevens WBC, van den Brand M, van Krieken JH, Scheijen B. Molecular genetics of relapsed diffuse large B-cell lymphoma: Insight into mechanisms of therapy resistance. Cancers (Basel). 2020;12(12):3553.10.3390/cancers12123553Search in Google Scholar PubMed PubMed Central

[8] Susanibar-Adaniya S, Barta SK. Update on Diffuse large B cell lymphoma: A review of current data and potential applications on risk stratification and management. Am J Hematol. 2021;96(5):617–29.10.1002/ajh.26151Search in Google Scholar PubMed PubMed Central

[9] Guo D, Meng Y, Jiang X, Lu Z. Hexokinases in cancer and other pathologies. Cell Insight. 2023;2(1):100077.10.1016/j.cellin.2023.100077Search in Google Scholar PubMed PubMed Central

[10] Ciscato F, Ferrone L, Masgras I, Laquatra C, Rasola A. Hexokinase 2 in cancer: A prima donna playing multiple characters. Int J Mol Sci. 2021;22(9):4716.10.3390/ijms22094716Search in Google Scholar PubMed PubMed Central

[11] Ma J, Fan Y, Feng T, Chen F, Xu Z, Li S, et al. Correction: HOTAIR regulates HK2 expression by binding endogenous miR-125 and miR-143 in oesophageal squamous cell carcinoma progression. Oncotarget. 2019;10(21):2112.10.18632/oncotarget.26801Search in Google Scholar PubMed PubMed Central

[12] Jiao L, Zhang HL, Li DD, Yang KL, Tang J, Li X, et al. Regulation of glycolytic metabolism by autophagy in liver cancer involves selective autophagic degradation of HK2 (hexokinase 2). Autophagy. 2018;14(4):671–84.10.1080/15548627.2017.1381804Search in Google Scholar PubMed PubMed Central

[13] Bhalla K, Jaber S, Nahid MN, Underwood K, Beheshti A, Landon A, et al. Author Correction: Role of hypoxia in diffuse large B-cell Lymphoma: Metabolic repression and selective translation of HK2 facilitates development of DLBCL. Sci Rep. 2018;8(1):7221.10.1038/s41598-018-25251-9Search in Google Scholar PubMed PubMed Central

[14] Gao Y, Yang Y, Yuan F, Huang J, Xu W, Mao B, et al. TNFα-YAP/p65-HK2 axis mediates breast cancer cell migration. Oncogenesis. 2017;6(9):e383.10.1038/oncsis.2017.83Search in Google Scholar PubMed PubMed Central

[15] Li Z, Tang X, Luo Y, Chen B, Zhou C, Wu X, et al. NK007 helps in mitigating paclitaxel resistance through p38MAPK activation and HK2 degradation in ovarian cancer. J Cell Physiol. 2019;234(9):16178–90.10.1002/jcp.28278Search in Google Scholar PubMed

[16] Zhang XY, Zhang M, Cong Q, Zhang MX, Zhang MY, Lu YY, et al. Hexokinase 2 confers resistance to cisplatin in ovarian cancer cells by enhancing cisplatin-induced autophagy. Int J Biochem Cell Biol. 2018;95:9–16.10.1016/j.biocel.2017.12.010Search in Google Scholar PubMed

[17] Yuen CA, Asuthkar S, Guda MR, Tsung AJ, Velpula KK. Cancer stem cell molecular reprogramming of the Warburg effect in glioblastomas: a new target gleaned from an old concept. CNS Oncol. 2016;5(2):101–8.10.2217/cns-2015-0006Search in Google Scholar PubMed PubMed Central

[18] Lu Z, Guo Y, Zhang X, Li J, Li L, Zhang S, et al. ORY-1001 suppresses cell growth and induces apoptosis in lung cancer through triggering HK2 mediated warburg effect. Front Pharmacol. 2018;9:1411.10.3389/fphar.2018.01411Search in Google Scholar PubMed PubMed Central

[19] Agnihotri S, Mansouri S, Burrell K, Li M, Mamatjan Y, Liu J, et al. Ketoconazole and posaconazole selectively target HK2-expressing Glioblastoma cells. Clin Cancer Res. 2019;25(2):844–55.10.1158/1078-0432.CCR-18-1854Search in Google Scholar PubMed PubMed Central

[20] Xu MJ, Johnson DE, Grandis JR. EGFR-targeted therapies in the post-genomic era. Cancer Metastasis Rev. 2017;36(3):463–73.10.1007/s10555-017-9687-8Search in Google Scholar PubMed PubMed Central

[21] Li J, Hu B, Wang T, Huang W, Ma C, Zhao Q, et al. Correction to: c-Src confers resistance to mitotic stress through inhibition of DMAP1/Bub3 complex formation in pancreatic cancer. Mol Cancer. 2019;18(1):172.10.1186/s12943-019-1067-2Search in Google Scholar PubMed PubMed Central

[22] Zhang Y, Zhao L, Yang S, Cen Y, Zhu T, Wang L, et al. CircCDKN2B-AS1 interacts with IMP3 to stabilize hexokinase 2 mRNA and facilitate cervical squamous cell carcinoma aerobic glycolysis progression. J Exp Clin Cancer Res. 2020;39(1):281.10.1186/s13046-020-01793-7Search in Google Scholar PubMed PubMed Central

[23] Barbosa R, Acevedo LA, Marmorstein R. The MEK/ERK network as a therapeutic target in human cancer. Mol Cancer Res. 2021;19(3):361–74.10.1158/1541-7786.MCR-20-0687Search in Google Scholar PubMed PubMed Central

[24] Khodavirdipour A, Jamshidi F, Nejad HR, Zandi M, Zarean R. To study the anti-cancer effects of Shigella Flexneri in AspC-1 Pancreatic Cancer Cell Line in Approach to Bax and bcl-2 Genes. J Gastrointest Cancer. 2021;52(2):593–9.10.1007/s12029-020-00433-9Search in Google Scholar PubMed

[25] Maren NA, Duduit JR, Huang D, Zhao F, Ranney TG, Liu W. Stepwise Optimization of Real-Time RT-PCR Analysis. Methods Mol Biol. 2023;2653:317–32.10.1007/978-1-0716-3131-7_20Search in Google Scholar PubMed

[26] Chandrashekar DS, Karthikeyan SK, Korla PK, Patel H, Shovon AR, Athar M, et al. UALCAN: An update to the integrated cancer data analysis platform. Neoplasia. 2022;25:18–27.10.1016/j.neo.2022.01.001Search in Google Scholar PubMed PubMed Central

[27] Kierans SJ, Taylor CT. Regulation of glycolysis by the hypoxia-inducible factor (HIF): implications for cellular physiology. J Physiol. 2021 Jan;599(1):23–37.10.1113/JP280572Search in Google Scholar PubMed

[28] Cao L, Wang M, Dong Y, Xu B, Chen J, Ding Y, et al. Circular RNA circRNF20 promotes breast cancer tumorigenesis and Warburg effect through miR-487a/HIF-1α/HK2. Cell Death Dis. 2020;11(2):145.10.1038/s41419-020-2336-0Search in Google Scholar PubMed PubMed Central

[29] Hawkes EA, Barraclough A, Sehn LH. Limited-stage diffuse large B-cell lymphoma. Blood. 2022;139(6):822–34.10.1182/blood.2021013998Search in Google Scholar PubMed

[30] Nakajima K, Kawashima I, Koshiisi M, Kumagai T, Suzuki M, Suzuki J, et al. Glycolytic enzyme hexokinase II is a putative therapeutic target in B-cell malignant lymphoma. Exp Hematol. 2019;78(46–55):e3.10.1016/j.exphem.2019.09.023Search in Google Scholar PubMed

[31] Jalali S, Ansell SM. The potential role of glycogen metabolism in diffuse large B-cell lymphoma. Leuk Lymphoma. 2020;61(5):1028–36.10.1080/10428194.2019.1702185Search in Google Scholar PubMed

[32] Han X, Ren C, Lu C, Qiao P, Yang T, Yu Z. Deubiquitination of MYC by OTUB1 contributes to HK2 mediated glycolysis and breast tumorigenesis. Cell Death Differ. 2022;29(9):1864–73.10.1038/s41418-022-00971-8Search in Google Scholar PubMed PubMed Central

[33] Jin J, Gui A, Chen G, Liu Y, Xia Z, Liu X, et al. Hexokinase II expression as a prognostic marker in diffuse large B-cell lymphoma: pre- and post-rituximab era. Int J Hematol. 2022;116(3):372–80.10.1007/s12185-022-03358-0Search in Google Scholar PubMed

[34] Roskoski R Jr. Targeting ERK1/2 protein-serine/threonine kinases in human cancers. Pharmacol Res. 2019;142:151–68.10.1016/j.phrs.2019.01.039Search in Google Scholar PubMed

[35] Hicks HM, McKenna LR, Espinoza VL, Pozdeyev N, Pike LA, Sams SB, et al. Inhibition of BRAF and ERK1/2 has synergistic effects on thyroid cancer growth in vitro and in vivo. Mol Carcinog. 2021;60(3):201–12.10.1002/mc.23284Search in Google Scholar PubMed

[36] Cui N, Li L, Feng Q, Ma HM, Lei D, Zheng PS. Hexokinase 2 promotes cell growth and tumor formation through the Raf/MEK/ERK signaling pathway in cervical cancer. Front Oncol. 2020;10:581208.10.3389/fonc.2020.581208Search in Google Scholar PubMed PubMed Central

Received: 2023-04-03
Revised: 2023-07-19
Accepted: 2023-08-19
Published Online: 2023-10-14

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

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

Articles in the same Issue

  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”
https://doi.org/10.1515/biol-2022-0726
Keywords for this article
diffuse large B lymphoma; Hexokinase; ERK1/2; FR180204
Creative Commons
BY 4.0

Articles in the same Issue

  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”
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 5.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/biol-2022-0726/html
Scroll to top button