Startseite Dopamine attenuates ethanol-induced neuronal apoptosis by stimulating electrical activity in the developing rat retina
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Dopamine attenuates ethanol-induced neuronal apoptosis by stimulating electrical activity in the developing rat retina

  • Junde Han , Shuli Ge , Kan Zhang , Jijian Zheng und Jing Dong EMAIL logo
Veröffentlicht/Copyright: 5. Juni 2025
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Aus der Zeitschrift Open Medicine Band 20 Heft 1

Abstract

Background

Prenatal alcohol exposure causes fetal alcohol spectrum disorders (FASD), primarily through alcohol-induced apoptosis. This study explores the link between ethanol-induced neuronal apoptosis and neural network electrical activity in developing rat retinal ganglion cells, and examines dopamine’s protective effects and influence on this activity.

Methods

The study employed a combination of immunohistochemical techniques, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and electrophysiological recordings to assess neuronal apoptosis and neural network activity in the developing rat retinal ganglion cell layer. Ethanol exposure was administered to model prenatal alcohol exposure, and dopamine was applied to evaluate its protective effects.

Results

Ethanol exposure was found to disrupt the spatiotemporal properties of synchronized spontaneous neural network electrical activity and partially induce neuronal apoptosis. Conversely, dopamine treatment increased the frequency of neural network electrical activity and attenuated ethanol-induced apoptosis.

Conclusion

The findings suggest that ethanol disrupts neural network activity and induces apoptosis in the developing nervous system, while dopamine exerts a protective effect by modulating neural network activity and reducing apoptosis. These results contribute to understanding the mechanisms underlying FASD and offer potential therapeutic avenues for prevention and treatment.

Keywords: developing neuron apoptosis; synchronized spontaneous neural network electrical activity; ethanol; dopamine; retina

1 Introduction

Alcohol exposure during pregnancy may lead to fetal alcohol syndrome (FAS), a severe form of FAS disorder, which includes a series of symptoms, such as craniofacial malformation, structural abnormalities of the nervous system, and long-term neurobehavioral disorders [1,2]. Up to 4.3–6.6% of young children have been affected by FAS in South Africa, which is similar to that in the United States and Western Europe [3–5]. The primary clinical manifestation of FAS is neurobehavioral disorders, and there is no definite conclusion about the precise mechanisms of FAS. Meanwhile, except for avoiding alcohol consumption, there are no effective clinical treatments for FAS.

Previous studies have reported that alcohol exposure during early pregnancy in both animals and humans causes irreversible damage to the central nervous system (CNS), such as the loss of neuronal mass and reduced brain volume [2,6,7]. Apoptosis of neurons and glia has been reported to occur in rodents or non-human primates due to single alcohol exposure during a period equivalent to the third trimester in humans [6,8]. Once alcohol-induced neuronal and glial apoptosis begins, a series of physiological and pathophysiological activities occur to compensate for the alcohol-induced injury and may result in permanent CNS damage. Thus, apoptosis is considered the primary mechanism resulting in FAS, and reducing alcohol-induced apoptosis may result in the prevention and treatment of FAS [9].

Ethanol-induced neuronal apoptosis in the developing neuronal system (brain, spinal cord, and retina) has been demonstrated to be associated with blocking N-methyl-d-aspartate (NMDA) receptors and activating gamma-aminobutyric acid (GABA) receptors [6,10]. Moreover, ethanol could induce an imbalance in the B-cell lymphoma 2 family, increasing mitochondrial membrane permeability and activating the endogenous apoptosis pathway [11]. In addition, the increased levels of reactive oxygen species, downregulation of the cyclic adenosine 3,5-monophosphate/protein kinase A (cAMP/PKA) pathway, and blockage of the insulin pathway are also associated with ethanol-induced neuronal apoptosis in developing neuronal systems [12–14]. However, the specific mechanism of ethanol-induced neuronal apoptosis remains unclear. In the developing nervous system, especially at the peak of synaptogenesis, accompanied by the maturation of the nervous system, cell signal transduction pathway, gene expression, and other physiological activity changes [15–17], the sequential switch of GABA, NMDA, and acetylcholine (Ach) receptors or subtype receptors regulates the spontaneous and rhythmic neural network activities to ensure the establishment of accurate neuronal connections and networks [18–20]. During the early development of the CNS, receptors, the synchronized spontaneous neural network electrical activity, and genes play an important role in apoptosis [21,22]. Previous studies have demonstrated that the blockade of the NMDA receptor, Ach receptor, or the synchronized spontaneous neural network electrical activity could induce neuronal apoptosis in the developing nervous system [22–25]. In addition, Feller et al. found that the application of the GABAa receptor agonist muscimol blocked the synchronized spontaneous neural network electrical activity in developing rat retina [26]. However, whether ethanol, which is an NMDA receptor antagonist, and GABA receptor agonists induce neuronal apoptosis by blocking spontaneous electrical activity in the developing nervous system remains unknown. Moreover, whether increasing the electric activity could attenuate ethanol-induced neuronal apoptosis is unclear.

In this study, the primary aim of utilizing dopamine is to investigate its protective role and underlying mechanisms in ethanol-induced apoptosis of neural cells in the developing rat retina. Dopamine, being a crucial neurotransmitter and neuromodulator, plays multiple roles in nervous system development, particularly in regulating neuronal survival, synaptic plasticity, and neural network activity [27]. Previous studies have indicated that dopamine, through activation of its receptors such as D1 and D2, can modulate intracellular signaling pathways including the cAMP/PKA pathway and calcium signaling, which are closely associated with neuronal survival and apoptosis [28]. Ethanol induces neuronal apoptosis via various mechanisms, including blocking NMDA receptors and activating GABA receptors, especially during critical developmental periods such as synaptogenesis and maturation of neural network activity. Disruptions in these receptors and spontaneous electrical activity may lead to neuronal apoptosis and abnormal network connections [29]. However, it remains unclear whether ethanol induces apoptosis by inhibiting spontaneous electrical activity and whether enhancing electrical activity can alleviate ethanol-induced apoptosis. Dopamine may exert its effects through several pathways: first, by activating its receptors to regulate neuronal electrical activity, thereby maintaining normal neural network function; second, by regulating the cAMP/PKA signaling pathway, antioxidant stress responses, or influencing mitochondrial function to mitigate the cellular homeostatic imbalances caused by ethanol [30]. Therefore, in this study, we aim to explore whether dopamine can alleviate ethanol-induced neuronal apoptosis by modulating spontaneous electrical activity or intracellular signaling pathways, thereby revealing its potential protective mechanisms in developmental neurological damage and providing new insights for the prevention and treatment of ethanol-related neurological developmental disorders.

2 Materials and methods

2.1 Animals

A total number of 69 postnatal Day 7 (P7) Sprague–Dawley rat pups were obtained from the Experimental Animal Center of Shanghai Sixth Hospital, Shanghai, China. Male and female rats were used in this study. All experimental procedures were reviewed and approved by the Animal Care Committee at the Shanghai Sixth Hospital, Shanghai Jiao Tong University School and complied with the guidelines of the Care and Use of Laboratory Animals published by the US National Institutes of Health and Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research. Every effort was made to minimize the number and discomfort of the animals during all experimental procedures.

2.2 Tissue preparation

Whole-mount rat retinas were obtained as previously described, with slight modifications [25]. Briefly, all eyeballs were dissected swiftly using fine scissors from experimental rat pups after being sacrificed by decapitation and transferred to an ice-cold (0‒4°C) bath of an artificial cerebrospinal fluid (ACSF) (composition in mM: sodium chloride 124, potassium chloride [KCl] 3.3, potassium dihydrogen phosphate 1.2, calcium dichloride with water 2.5, magnesium sulfate 2.4, sodium bicarbonate 26, and glucose 10). A 95% oxygen (O2)/5% carbon dioxide (CO2) gas mixture was continuously bubbled into the bath. Subsequently, an incision at the edge of the cornea and sclera (approximately one-fifth of the circumference) was manipulated using ophthalmology scissors to facilitate the exposure of the ACSF and drugs into the retina. Thereafter, the eyeballs were incubated in the ACSF (37°C) equilibrated with 95% O2/5% CO2 gas mixture until the experiment was completed. All procedures were performed within 6 h.

2.3 Drugs and reagents

All drugs were purchased from Sigma-Aldrich (St Louis, MO, USA), unless otherwise mentioned, and dissolved in ACSF. The following drugs were used: ethanol (Aladdin, Shanghai, China), dopamine, muscimol (GABAA receptor agonist), SR95531 (gabazine, GABAA/C receptor competitive antagonist), and picrotoxin (PTX) (GABAA receptor noncompetitive antagonist).

2.4 Electrophysiological experiments

Whole-mount rat retinas for patch-clamp recordings were obtained from P7 rat pups, as previously reported [31]. ON-alpha ganglion cells are often preferred for patch-clamp recordings at this stage due to their relatively earlier functional maturation and distinct physiological properties, which make them more suitable for studying early development in the retina. A piece of whole-mount retina was dissected from an eyeball; subsequently, the Müller cell end feet and connective tissues on the top of the ganglion cell layer (GCL) were removed with the ice-cold oxygenated ACSF. After a 30 min recovery at room temperature, the whole-mount retina was delivered and fixed to the backside of a heated bathing chamber with the sclera facet down by a small platinum ring with a nylon mesh. In the chamber, the retina was perfused constantly with the oxygenated ACSF (2–4 mL/min) at 32–35°C. Electrophysiological whole-cell patch-clamp recordings were obtained from GCL cells using Axopatch 700B amplifiers and pCLAMP 9 software (Axon Instruments, Inc., Union City, CA, USA) under an upright microscope equipped with a 40× water-immersion objective lens (BX50WI, Olympus USA, NY, USA). The borosilicate glass pipettes (B15023F, Wuhan microprobe Scientific Instrument, China) were pulled (P-97; Sutter, USA) with a resistance of 3–5 MΩ and filled with a pipette solution containing (in mM) the following: KCl 150, magnesium chloride 2, ethylene glycol tetraacetic acid 2, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid 10, and disodium adenosine 5′ triphosphate 2 at pH = 7.2, adjusted with a Tris base. After obtaining successful seals of 1 GΩ in 30 s or less, the current responses to pharmacological manipulations were recorded at a holding potential of –60 mV under the voltage clamp, filtered at 1 kHz, and sampled at 5 kHz.

2.5 Cleaved caspase-3 immunohistochemistry

After incubation with or without ethanol and/or GABAa agonist/antagonist in the ACSF (37°C) equilibrated with 95% O2/5% CO2 gas mixture for 5 h, the eyeballs were fixed in 4% paraformaldehyde for 1 h. Retinas were then dissected and fixed overnight. Following dehydration with an ethanol gradient, the fixed retinas were paraffin infiltrated and embedded in paraffin blocks for long-term preservation. Retinas were cut into 4–6 µm tissue slices using a paraffin slicing machine (Leica-2135, Leica, Germany). After dewaxing, hydration, and heat-induced epitope retrieval using a Tris/ethylenediaminetetraacetic acid buffer (pH 9.0) in a pressure cooker, retinal tissue sections were inactivated with 3% hydrogen peroxide and then incubated with a primary antibody (rabbit cleaved caspase-3 [AC3]; 1:300, #9661s, Cell Signaling Technology, Danvers, MA, USA) overnight at 4°C, followed by a secondary antibody (PV-9001, ZSGB-BIO, Beijing, China) at 37°C for 1 h. AC3 immunoreactivity was detected via a chromogenic reaction using 3,3′-diaminobenzidine (ZLI-9017, ZSGB-BIO, Beijing, China) oxidization. Finally, apoptotic neurons (brown stained) were counted under a light microscope.

2.6 Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay

According to the protocol of the TUNEL AP kit (Roche Applied Science, USA), retinal tissue sections were permeabilized with proteinase K for 15 min after deparaffinization and hydration, followed by treatment with 3% hydrogen peroxide to inactivate endogenous peroxidase. The retinal tissue sections were incubated with a terminal deoxynucleotidyl transferase reaction mix for 60 min at 37°C and 4′,6-diamidino-2-phenylindole for 5 min at room temperature. A confocal fluorescence microscope (Leica TCS SP8; Leica, Germany) was used to capture TUNEL-positive cells (red stained).

2.7 Statistical analyses

AC3-positive cells were quantified from five discontinuous images that were randomly obtained using a light microscope (IX73, OLYMPUS, Japan), and TUNEL-positive cells were counted using a confocal fluorescence microscope (A1, Nikon, Japan) in each retina. The ratios of apoptotic cells in the GCL identified via AC3 immunoreactivity and the TUNEL assay were analyzed using Image-Pro Plus 6.0 (Media Cybernetics Company, USA). All data are presented as mean ± standard error of the mean. Data were analyzed using GraphPad Prism 5 or Origin 8.0. Differences between means of different groups were evaluated for statistical significance using the two-sample or unpaired Student’s t-tests to compare the frequency or amplitude of retinal waves following drug treatment. Non-normally distributed data were analyzed using the Mann–Whitney or Kruskal–Wallis tests. The level of statistical significance was set at p < 0.05.

  1. Informed consent: Informed consent was obtained from all participants.

  2. Ethical approval: This study was approved by the Ethics Committee of the Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University (Approval No.: 2022-2-21), and complied with the guidelines for the Care and Use of Laboratory Animals published by the US National Institutes of Health and the Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research.

3 Results

3.1 Muscimol blocked the synchronized spontaneous neural network electrical activity in the developing rat retinal GCL

Muscimol blocked the synchronized spontaneous neural network electrical activity in the developing rat retinal GCL. Using the whole-cell patch-clamp technique, we recorded the synchronized spontaneous neural network electrical activity in P7 rat retinal ganglion cells (Figure 1a). Application of muscimol (500 nM) completely blocked this activity (Figure 1b). This effect aligns with the reported transition of GABAa receptors from excitatory to inhibitory in the early developmental stage (<P7) [26,32]. GABAa receptors at this stage are excitable, allowing muscimol to depolarize retinal ganglion cells. However, sustained inward current by muscimol induced shunt conductance, causing a reversal in the resting potential and blocking the transfer of synchronized activity to the recorded cell (Figure 1b). After discontinuing muscimol application, the recorded cell gradually restored its ability to capture synchronized activity (red marks, Figure 1b). Additionally, bathing the GABAa antagonist SR95531 (5 μM) or the GABAa/c antagonist PTX (100 μM) prevented muscimol from activating the recorded cell (Figure 1c and d). In control experiments, muscimol completely blocked synchronized activity, but this effect was reversed by SR95531 or PTX in developing ganglion cells (Figure 2).

Figure 1 The effects of GABAa receptor agonist muscimol on the synchronized spontaneous neural network electricity activity in the developing rat retina GCL. The synchronized spontaneous neural network electricity activity were recorded by Whole-cell patch-clamp in P7 rat pups retina GCL (n = 6 retinas per group). (a) Synchronized spontaneous neural network electricity activity in the developing rat retinal GCL. (b) Puffing 500 nM muscimol around the recorded cell blocked the spontaneous and rhythmic neural network electricity activity transferring to the recording cell. The excitatory of the recoding cell restored and the neural network electricity activity were captured again (Red arrow mark) after stopping puffing muscimol. (c) and (d) The recording cell cannot be activated by muscimol puffing accompanied by bathing SR95531 (5 μM) or picrotoxin (PTX, 100 μM), antagonist of GABAa and GABAa/c respectively.
Figure 1

The effects of GABAa receptor agonist muscimol on the synchronized spontaneous neural network electricity activity in the developing rat retina GCL. The synchronized spontaneous neural network electricity activity were recorded by Whole-cell patch-clamp in P7 rat pups retina GCL (n = 6 retinas per group). (a) Synchronized spontaneous neural network electricity activity in the developing rat retinal GCL. (b) Puffing 500 nM muscimol around the recorded cell blocked the spontaneous and rhythmic neural network electricity activity transferring to the recording cell. The excitatory of the recoding cell restored and the neural network electricity activity were captured again (Red arrow mark) after stopping puffing muscimol. (c) and (d) The recording cell cannot be activated by muscimol puffing accompanied by bathing SR95531 (5 μM) or picrotoxin (PTX, 100 μM), antagonist of GABAa and GABAa/c respectively.

Figure 2 SR95531 and PTX reversed the effects of muscimol on the synchronized spontaneous neural network electricity activity. 5 μM SR95531 and 100 μM PTX (antagonist of GABAa and GABAa/c) reversed the effects of muscimol on the synchronized spontaneous neural network electricity activity in the developing rat retinal GCL (n = 6 retinas per group). (a) Bathing 500 nM muscimol blocked the spontaneous and rhythmic neural network electricity activity. (b) and (c) Both 5 μM SR95531 and 100 μM PTX reversed the effects of muscimol on the synchronized spontaneous neural network electricity activity. (d) and (e) The synchronized spontaneous neural network electricity activity cannot be blocked by bathing muscimol together with 5 μM SR95531 or 100 μM PTX.
Figure 2

SR95531 and PTX reversed the effects of muscimol on the synchronized spontaneous neural network electricity activity. 5 μM SR95531 and 100 μM PTX (antagonist of GABAa and GABAa/c) reversed the effects of muscimol on the synchronized spontaneous neural network electricity activity in the developing rat retinal GCL (n = 6 retinas per group). (a) Bathing 500 nM muscimol blocked the spontaneous and rhythmic neural network electricity activity. (b) and (c) Both 5 μM SR95531 and 100 μM PTX reversed the effects of muscimol on the synchronized spontaneous neural network electricity activity. (d) and (e) The synchronized spontaneous neural network electricity activity cannot be blocked by bathing muscimol together with 5 μM SR95531 or 100 μM PTX.

3.2 Muscimol induced neuronal apoptosis of the developing retinal GCL

Treatment with muscimol led to a significant increase in apoptotic cells in the GCL of the developing rat retina, as determined by immunocytochemistry and the TUNEL assay. Furthermore, both SR95531 and PTX attenuated muscimol-induced neuronal apoptosis in the developing retinal GCL (Figure 3). These findings, in conjunction with those from Figure 2, confirm that activation of GABAa receptors can induce neuronal apoptosis in the developing nervous system by blocking synchronized spontaneous neural network electrical activity.

Figure 3 GABAa receptor agonist muscimol induced neuronal apoptosis in the developing retina GCL. Rat retinas were incubated with or without 500 nM muscimol for 5 hrs in the absence or presence of 5 μM SR95531 or 100 μM PTX (n = 5 retinas per group). (a) Photomicrograph of Caspase-3 positive cells (brown color) in the rat retinal GCL, scale bar, 50 μm. (b) Photomicrograph of TUNEL-positive cells (red color) in the rat retinal GCL, scale bar, 25 μm. (c) The ratio of Caspase-3 positive cells in the retinal GCL in different groups. (d) The percentages of TUNEL-positive cells in the rat retina GCL. Ctl: Control; Muscimol: 500 nM muscimol; Muscimol + PTX: 500 nM muscimol + 100 μM PTX; Muscimol + SR95531: 500 nM muscimol + 5 μM SR95531. Compared with the muscimol, the mean ratio of Caspase-3 positive cells are significantly different from the control and the Muscimol + PTX and Muscimol + SR95531 (** p < 0.01 compared with the control, ## p < 0.01 compared with the Muscimol).
Figure 3

GABAa receptor agonist muscimol induced neuronal apoptosis in the developing retina GCL. Rat retinas were incubated with or without 500 nM muscimol for 5 hrs in the absence or presence of 5 μM SR95531 or 100 μM PTX (n = 5 retinas per group). (a) Photomicrograph of Caspase-3 positive cells (brown color) in the rat retinal GCL, scale bar, 50 μm. (b) Photomicrograph of TUNEL-positive cells (red color) in the rat retinal GCL, scale bar, 25 μm. (c) The ratio of Caspase-3 positive cells in the retinal GCL in different groups. (d) The percentages of TUNEL-positive cells in the rat retina GCL. Ctl: Control; Muscimol: 500 nM muscimol; Muscimol + PTX: 500 nM muscimol + 100 μM PTX; Muscimol + SR95531: 500 nM muscimol + 5 μM SR95531. Compared with the muscimol, the mean ratio of Caspase-3 positive cells are significantly different from the control and the Muscimol + PTX and Muscimol + SR95531 (** p < 0.01 compared with the control, ## p < 0.01 compared with the Muscimol).

3.3 Effects of ethanol and dopamine on the synchronized spontaneous neural network electrical activity in the developing rat retina

Our previous study demonstrated that ethanol induces neuronal apoptosis in the developing rat retina in a dose-dependent manner [33]. Here, we investigated the effects of ethanol on the spatiotemporal properties of synchronized spontaneous neural network electrical activity in the GCL of the developing rat retina. Ethanol (200 mM) significantly prolonged the interval of synchronized spontaneous network activity, increasing it from 1.39 ± 0.12 to 2.08 ± 0.16 min (control vs ethanol, F = 10, p < 0.01; Figure 4a). Importantly, this effect was not accompanied by changes in amplitude (data not shown). The GABAA antagonist SR95531 did not reverse the effects of ethanol on the synchronized spontaneous network activity. Under these conditions, the interval remained elevated at 2.23 ± 0.17 min compared to 1.30 ± 0.07 min in the control (control vs ethanol + SR95531, F = 6, p < 0.01; Figure 4b). Previous research has shown that dopamine increases the frequency of synchronized spontaneous network activity [34]. We assessed the impact of dopamine on ethanol-induced changes in the synchronized spontaneous network activity in the GCL. Dopamine significantly reduced the interval of spontaneous and rhythmic electrical activity in both the absence and presence of ethanol. Under control conditions, dopamine decreased the interval from 1.37 ± 0.05 to 0.35 ± 0.01 min (control vs dopamine, n = 6, p < 0.01; Figure 4d). Similarly, in the presence of ethanol, dopamine further reduced the interval from 1.37 ± 0.06 to 0.37 ± 0.01 min (control vs ethanol + dopamine, n = 6, p < 0.01; Figure 4e and f).

Figure 4 Effects of ethanol and dopamine on the synchronized spontaneous neural network electricity activity in the developing rat retina. Rat retinas were bathed with or without 200 nM ethanol in the absence or presence of 5 μM SR95531 or 10 μM dopamine (n = 6 retinas per group except the EtOH). (a) 200 nM ethanol decreased the frequency of the synchronized spontaneous network activity (n = 6 retinas). (b) 5 μM SR95531 cannot reverse the effects of ethanol on the synchronized spontaneous neural network electricity activity. (c) 5 μM SR95531 had no effect on the synchronized spontaneous neural network electricity activity. (d) and (e) 10 μM dopamine increased the frequency of the synchronized spontaneous network activity bathing with or without ethanol. (f) and (g) Interval of the synchronized spontaneous neural network electricity activity after bathing with or without ethanol in the absence or presence of SR95531 or Dopamine. Ctl: Control; EtOH: 200 nM ethanol; EtOH + SR95531: 200 nM ethanol + 5 μM SR95531; SR95531: 5 μM SR95531. EtOH + Dopamine: 200 nM ethanol + 10 μM dopamine; Dopamine: 10 μM dopamine. (** p < 0.01 compared with the control, && p < 0.01 compared with the EtOH + Dopamine).
Figure 4

Effects of ethanol and dopamine on the synchronized spontaneous neural network electricity activity in the developing rat retina. Rat retinas were bathed with or without 200 nM ethanol in the absence or presence of 5 μM SR95531 or 10 μM dopamine (n = 6 retinas per group except the EtOH). (a) 200 nM ethanol decreased the frequency of the synchronized spontaneous network activity (n = 6 retinas). (b) 5 μM SR95531 cannot reverse the effects of ethanol on the synchronized spontaneous neural network electricity activity. (c) 5 μM SR95531 had no effect on the synchronized spontaneous neural network electricity activity. (d) and (e) 10 μM dopamine increased the frequency of the synchronized spontaneous network activity bathing with or without ethanol. (f) and (g) Interval of the synchronized spontaneous neural network electricity activity after bathing with or without ethanol in the absence or presence of SR95531 or Dopamine. Ctl: Control; EtOH: 200 nM ethanol; EtOH + SR95531: 200 nM ethanol + 5 μM SR95531; SR95531: 5 μM SR95531. EtOH + Dopamine: 200 nM ethanol + 10 μM dopamine; Dopamine: 10 μM dopamine. (** p < 0.01 compared with the control, && p < 0.01 compared with the EtOH + Dopamine).

3.4 Effects of dopamine on ethanol-induced neuronal apoptosis in the developing rat retina

Ethanol-induced neuronal apoptosis in the GCL of developing rat retina was similar to that observed in our previous study [33]. In this study, after 5 h of exposure to 200 mM ethanol, neuronal apoptosis occurred significantly in the developing rat retinal GCL. The ratio of neuronal apoptosis was upregulated from 2.21 ± 0.29 to 5.82 ± 0.55% (Figure 5a and c, n = 25, p < 0.01) after 5 h of incubation with ethanol by immunochemistry and 13.23 ± 1.42 to 28.65 ± 1.25% (Figure 5b and d, n = 25, p < 0.01) by the TUNEL assay. SR95531 did not alleviate ethanol-induced or physiological neuronal apoptosis, by both immunochemistry and the TUNEL assay. Dopamine, which can increase the frequency of the spontaneous and rhythmic network electrical activity, attenuated the physiological neuronal apoptosis from 2.21 ± 0.29 to 1.15 ± 0.024% (n = 25, P = 0.03) by immunochemistry and 13.23 ± 1.42 to 5.06 ± 0.49% (n = 25, p < 0.01) by the TUNEL assay (Figure 5). In addition, the ratio of ethanol-induced neuronal apoptosis was downregulated from 5.82 ± 0.55 to 2.23 ± 0.37% (n = 25, p < 0.01) and 28.65 ± 1.25 to 11.95 ± 1.32% by immunochemistry and the TUNEL assay (n = 25, p < 0.01), respectively, after co-incubation with dopamine (Figure 5).

Figure 5 Effects of dopamine on the ethanol-induced neuronal-apoptosis in the developing rat retina. Rat retinas were incubated with or without 200 nM ethanol in the absence or presence of 5 μM SR95531 or 10 μM dopamine for 5 hrs (n = 5 retinas per group). (a) Photomicrograph of Caspase-3 positive cells (brown color) in the rat retinal GCL, scale bar, 50 μm. (b) Photomicrograph of TUNEL-positive cells (red color) in the rat retinal GCL, scale bar, 25 μm. (c) The ratio of Caspase-3 positive cells in the retinal GCL in different groups. (d) The percentages of TUNEL-positive cells in the rat retinal GCL. (* p < 0.05, ** p < 0.01 compared with the control, ## p < 0.01 compared with the SR95531, $$ p < 0.01 compared with the EtOH).
Figure 5

Effects of dopamine on the ethanol-induced neuronal-apoptosis in the developing rat retina. Rat retinas were incubated with or without 200 nM ethanol in the absence or presence of 5 μM SR95531 or 10 μM dopamine for 5 hrs (n = 5 retinas per group). (a) Photomicrograph of Caspase-3 positive cells (brown color) in the rat retinal GCL, scale bar, 50 μm. (b) Photomicrograph of TUNEL-positive cells (red color) in the rat retinal GCL, scale bar, 25 μm. (c) The ratio of Caspase-3 positive cells in the retinal GCL in different groups. (d) The percentages of TUNEL-positive cells in the rat retinal GCL. (* p < 0.05, ** p < 0.01 compared with the control, ## p < 0.01 compared with the SR95531, $$ p < 0.01 compared with the EtOH).

4 Discussion

In this study, we observed that muscimol inhibited synchronized spontaneous neural network electrical activity and stimulated neuronal apoptosis in the developing rat retinal GCL. This finding confirms that blocking synchronized spontaneous neural network electrical activity can induce neuronal apoptosis in the developing nervous system. Ethanol disrupts the synchronized spontaneous neural network electrical activity by altering its spatiotemporal properties, which may be associated with ethanol-induced neuronal apoptosis in the developing rat retinal GCL. Additionally, SR95531 was unable to reverse the effect of ethanol on synchronized spontaneous neural network electrical activity and neuronal apoptosis. Conversely, dopamine increased the frequency of synchronized spontaneous neural network activity, both in the presence and absence of ethanol, and attenuated both physiological and ethanol-induced apoptosis.

During the early stages of neural system development, the sequential activation of GABA, NMDA, and ACh receptors or their subtypes regulates spontaneous and rhythmic neural network electrical activity [18–20]. This study revealed that ethanol-induced neuronal apoptosis was partially mediated by disrupting the spatiotemporal properties of synchronized spontaneous neural network electrical activity. Although ethanol can block NMDA receptors and activate GABA receptors [35], previous studies have shown that the effects of ethanol on GABAa receptors are associated with an enhancement of GABA-stimulated Cl– flux, increased GABA neuronal activity, and GABA release [36–38]. This may explain why ethanol cannot completely block neural network electrical activity, unlike muscimol, by reversing the resting potential. Furthermore, the synchronized spontaneous neural network electrical activity transitions from a cholinergic drive to a glutamatergic drive, primarily occurring between postnatal Days 7–9 (P7–P9) in rats (nicotinic ACh receptors for <P7 and NMDA glutamate receptors for >P9). Therefore, ethanol cannot fully block network electrical activities by solely blocking NMDA receptors. The precise mechanism by which ethanol disrupts the spatiotemporal properties of synchronized spontaneous neural network electrical activity remains to be explored in future studies.

A previous study demonstrated that the spatiotemporal properties of neural network activity are regulated by a cAMP/PKA cascade [34]. In this study, dopamine effectively attenuated ethanol-induced neuronal apoptosis by stimulating neural network electrical activity. Additionally, our prior research indicated that dopamine reduces ethanol-induced apoptosis through the cAMP/PKA pathway [33]. Consequently, it can be concluded that dopamine attenuates ethanol-induced neuronal apoptosis by stimulating neural network electrical activity via activation of the cAMP/PKA cascade. However, the exact molecular mechanisms underlying this process require further investigation.

5 Limitations and future directions

Several limitations exist in the present study. First, the exact mechanism of ethanol-induced disruption of the spatiotemporal properties of neural network electrical activity was not explored. Second, the study did not investigate how dopamine increases neural network electrical activity, thereby exerting a protective effect. Furthermore, this study focused exclusively on the neuroapoptosis induced by ethanol treatment at P7 in the rat GCL. Future research is needed to explore the effects of ethanol and dopamine on other regions of the developing brain.

6 Clinical implications

These findings have potential translational implications for clinical practice. Specifically, targeting dopamine pathways may offer a therapeutic strategy to mitigate ethanol-induced neuronal damage during early development. Given the protective effects of dopamine on neuronal apoptosis and neural network activity, pharmacological interventions or therapies that enhance dopamine signaling could be developed to treat or prevent ethanol-induced neurotoxicity in vulnerable populations, such as infants or individuals with fetal alcohol spectrum disorders. Future studies should explore the feasibility and efficacy of such interventions in preclinical models and clinical settings.

7 Conclusion

In this study, we found that ethanol induced neuronal apoptosis in the developing rat retinal GCL by discombobulating the spatiotemporal properties of the synchronized spontaneous neural network electrical activity. Dopamine increased the frequency of the neural network electrical activity and attenuated ethanol-induced apoptosis.

# Junde Han and Shuli Ge contributed equally to this article.

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Acknowledgments

We would like to thank Editage (www.editage.cn) for English language editing.

  1. Funding information: This study was supported by the National Natural Science Foundation of China (Beijing, China) (Grant numbers 81771218 and 81271263 to Jijian Zheng and 81701045 to Jing Dong).

  2. Author contributions: Junde Han: methodology, investigation, writing – original draft preparation; Shuli Ge: data analysis and figure manipulation; Kan Zhang: software and visualization; Jijian Zheng and Jing Dong: study concepts, writing – reviewing and editing.

  3. Conflict of interest: The authors state that there are no financial, personal, or professional conflicts of interests that may hinder this work.

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

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Received: 2024-06-25
Revised: 2025-04-10
Accepted: 2025-04-25
Published Online: 2025-06-05

© 2025 the author(s), published by De Gruyter

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

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https://doi.org/10.1515/med-2025-1205
Schlagwörter für diesen Artikel
developing neuron apoptosis; synchronized spontaneous neural network electrical activity; ethanol; dopamine; retina
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Research Articles
  2. Network pharmacological analysis and in vitro testing of the rutin effects on triple-negative breast cancer
  3. Impact of diabetes on long-term survival in elderly liver cancer patients: A retrospective study
  4. Knockdown of CCNB1 alleviates high glucose-triggered trophoblast dysfunction during gestational diabetes via Wnt/β-catenin signaling pathway
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  7. Development and validation of headspace gas chromatography with a flame ionization detector method for the determination of ethanol in the vitreous humor
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  9. Predictive value of plasma sB7-H3 and YKL-40 in pediatric refractory Mycoplasma pneumoniae pneumonia
  10. Antiangiogenic potential of Elaeagnus umbellata extracts and molecular docking study by targeting VEGFR-2 pathway
  11. Comparison of the effectiveness of nurse-led preoperative counseling and postoperative follow-up care vs standard care for patients with gastric cancer
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  17. Lysophosphatidic acid 2 alleviates deep vein thrombosis via protective endothelial barrier function
  18. Transcription factor A, mitochondrial promotes lymph node metastasis and lymphangiogenesis in epithelial ovarian carcinoma
  19. Serum PM20D1 levels are associated with nutritional status and inflammatory factors in gastric cancer patients undergoing early enteral nutrition
  20. Hydromorphone reduced the incidence of emergence agitation after adenotonsillectomy in children with obstructive sleep apnea: A randomized, double-blind study
  21. Vitamin D replacement therapy may regulate sleep habits in patients with restless leg syndrome
  22. The first-line antihypertensive nitrendipine potentiated the therapeutic effect of oxaliplatin by downregulating CACNA1D in colorectal cancer
  23. Health literacy and health-related quality of life: The mediating role of irrational happiness
  24. Modulatory effects of Lycium barbarum polysaccharide on bone cell dynamics in osteoporosis
  25. Mechanism research on inhibition of gastric cancer in vitro by the extract of Pinellia ternata based on network pharmacology and cellular metabolomics
  26. Examination of the causal role of immune cells in non-alcoholic fatty liver disease by a bidirectional Mendelian randomization study
  27. Clinical analysis of ten cases of HIV infection combined with acute leukemia
  28. Investigating the cardioprotective potential of quercetin against tacrolimus-induced cardiotoxicity in Wistar rats: A mechanistic insights
  29. Clinical observation of probiotics combined with mesalazine and Yiyi Baitouweng Decoction retention enema in treating mild-to-moderate ulcerative colitis
  30. Diagnostic value of ratio of blood inflammation to coagulation markers in periprosthetic joint infection
  31. Sex-specific associations of sex hormone binding globulin and risk of bladder cancer
  32. Core muscle strength and stability-oriented breathing training reduces inter-recti distance in postpartum women
  33. The ERAS nursing care strategy for patients undergoing transsphenoidal endoscopic pituitary tumor resection: A randomized blinded controlled trial
  34. The serum IL-17A levels in patients with traumatic bowel rupture post-surgery and its predictive value for patient prognosis
  35. Impact of Kolb’s experiential learning theory-based nursing on caregiver burden and psychological state of caregivers of dementia patients
  36. Analysis of serum NLR combined with intraoperative margin condition to predict the prognosis of cervical HSIL patients undergoing LEEP surgery
  37. Commiphora gileadensis ameliorate infertility and erectile dysfunction in diabetic male mice
  38. The correlation between epithelial–mesenchymal transition classification and MMP2 expression of circulating tumor cells and prognosis of advanced or metastatic nasopharyngeal carcinoma
  39. Tetrahydropalmatine improves mitochondrial function in vascular smooth muscle cells of atherosclerosis in vitro by inhibiting Ras homolog gene family A/Rho-associated protein kinase-1 signaling pathway
  40. A cross-sectional study: Relationship between serum oxidative stress levels and arteriovenous fistula maturation in maintenance dialysis patients
  41. A comparative analysis of the impact of repeated administration of flavan 3-ol on brown, subcutaneous, and visceral adipose tissue
  42. Identifying early screening factors for depression in middle-aged and older adults: A cohort study
  43. Perform tumor-specific survival analysis for Merkel cell carcinoma patients undergoing surgical resection based on the SEER database by constructing a nomogram chart
  44. Unveiling the role of CXCL10 in pancreatic cancer progression: A novel prognostic indicator
  45. High-dose preoperative intraperitoneal erythropoietin and intravenous methylprednisolone in acute traumatic spinal cord injuries following decompression surgeries
  46. RAB39B: A novel biomarker for acute myeloid leukemia identified via multi-omics and functional validation
  47. Impact of peripheral conditioning on reperfusion injury following primary percutaneous coronary intervention in diabetic and non-diabetic STEMI patients
  48. Clinical efficacy of azacitidine in the treatment of middle- and high-risk myelodysplastic syndrome in middle-aged and elderly patients: A retrospective study
  49. The effect of ambulatory blood pressure load on mitral regurgitation in continuous ambulatory peritoneal dialysis patients
  50. Expression and clinical significance of ITGA3 in breast cancer
  51. Single-nucleus RNA sequencing reveals ARHGAP28 expression of podocytes as a biomarker in human diabetic nephropathy
  52. rSIG combined with NLR in the prognostic assessment of patients with multiple injuries
  53. Toxic metals and metalloids in collagen supplements of fish and jellyfish origin: Risk assessment for daily intake
  54. Exploring causal relationship between 41 inflammatory cytokines and marginal zone lymphoma: A bidirectional Mendelian randomization study
  55. Gender beliefs and legitimization of dating violence in adolescents
  56. Effect of serum IL-6, CRP, and MMP-9 levels on the efficacy of modified preperitoneal Kugel repair in patients with inguinal hernia
  57. Effect of smoking and smoking cessation on hematological parameters in polycythemic patients
  58. Pathogen surveillance and risk factors for pulmonary infection in patients with lung cancer: A retrospective single-center study
  59. Necroptosis of hippocampal neurons in paclitaxel chemotherapy-induced cognitive impairment mediates microglial activation via TLR4/MyD88 signaling pathway
  60. Celastrol suppresses neovascularization in rat aortic vascular endothelial cells stimulated by inflammatory tenocytes via modulating the NLRP3 pathway
  61. Cord-lamina angle and foraminal diameter as key predictors of C5 palsy after anterior cervical decompression and fusion surgery
  62. GATA1: A key biomarker for predicting the prognosis of patients with diffuse large B-cell lymphoma
  63. Influencing factors of false lumen thrombosis in type B aortic dissection: A single-center retrospective study
  64. MZB1 regulates the immune microenvironment and inhibits ovarian cancer cell migration
  65. Integrating experimental and network pharmacology to explore the pharmacological mechanisms of Dioscin against glioblastoma
  66. Trends in research on preterm birth in twin pregnancy based on bibliometrics
  67. Four-week IgE/baseline IgE ratio combined with tryptase predicts clinical outcome in omalizumab-treated children with moderate-to-severe asthma
  68. Single-cell transcriptomic analysis identifies a stress response Schwann cell subtype
  69. Acute pancreatitis risk in the diagnosis and management of inflammatory bowel disease: A critical focus
  70. Effect of subclinical esketamine on NLRP3 and cognitive dysfunction in elderly ischemic stroke patients
  71. Interleukin-37 mediates the anti-oral tumor activity in oral cancer through STAT3
  72. CA199 and CEA expression levels, and minimally invasive postoperative prognosis analysis in esophageal squamous carcinoma patients
  73. Efficacy of a novel drainage catheter in the treatment of CSF leak after posterior spine surgery: A retrospective cohort study
  74. Comprehensive biomedicine assessment of Apteranthes tuberculata extracts: Phytochemical analysis and multifaceted pharmacological evaluation in animal models
  75. Relation of time in range to severity of coronary artery disease in patients with type 2 diabetes: A cross-sectional study
  76. Dopamine attenuates ethanol-induced neuronal apoptosis by stimulating electrical activity in the developing rat retina
  77. Correlation between albumin levels during the third trimester and the risk of postpartum levator ani muscle rupture
  78. Factors associated with maternal attention and distraction during breastfeeding and childcare: A cross-sectional study in the west of Iran
  79. Mechanisms of hesperetin in treating metabolic dysfunction-associated steatosis liver disease via network pharmacology and in vitro experiments
  80. The law on oncological oblivion in the Italian and European context: How to best uphold the cancer patients’ rights to privacy and self-determination?
  81. The prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index for survival in patients with colorectal cancer
  82. Factors affecting the measurements of peripheral oxygen saturation values in healthy young adults
  83. Comparison and correlations between findings of hysteroscopy and vaginal color Doppler ultrasonography for detection of uterine abnormalities in patients with recurrent implantation failure
  84. The effects of different types of RAGT on balance function in stroke patients with low levels of independent walking in a convalescent rehabilitation hospital
  85. Causal relationship between asthma and ankylosing spondylitis: A bidirectional two-sample univariable and multivariable Mendelian randomization study
  86. Correlations of health literacy with individuals’ understanding and use of medications in Southern Taiwan
  87. Correlation of serum calprotectin with outcome of acute cerebral infarction
  88. Comparison of computed tomography and guided bronchoscopy in the diagnosis of pulmonary nodules: A systematic review and meta-analysis
  89. Curdione protects vascular endothelial cells and atherosclerosis via the regulation of DNMT1-mediated ERBB4 promoter methylation
  90. The identification of novel missense variant in ChAT gene in a patient with gestational diabetes denotes plausible genetic association
  91. Molecular genotyping of multi-system rare blood types in foreign blood donors based on DNA sequencing and its clinical significance
  92. Exploring the role of succinyl carnitine in the association between CD39⁺ CD4⁺ T cell and ulcerative colitis: A Mendelian randomization study
  93. Dexmedetomidine suppresses microglial activation in postoperative cognitive dysfunction via the mmu-miRNA-125/TRAF6 signaling axis
  94. Analysis of serum metabolomics in patients with different types of chronic heart failure
  95. Diagnostic value of hematological parameters in the early diagnosis of acute cholecystitis
  96. Pachymaran alleviates fat accumulation, hepatocyte degeneration, and injury in mice with nonalcoholic fatty liver disease
  97. Decrease in CD4 and CD8 lymphocytes are predictors of severe clinical picture and unfavorable outcome of the disease in patients with COVID-19
  98. METTL3 blocked the progression of diabetic retinopathy through m6A-modified SOX2
  99. The predictive significance of anti-RO-52 antibody in patients with interstitial pneumonia after treatment of malignant tumors
  100. Exploring cerebrospinal fluid metabolites, cognitive function, and brain atrophy: Insights from Mendelian randomization
  101. Development and validation of potential molecular subtypes and signatures of ocular sarcoidosis based on autophagy-related gene analysis
  102. Widespread venous thrombosis: Unveiling a complex case of Behçet’s disease with a literature perspective
  103. Uterine fibroid embolization: An analysis of clinical outcomes and impact on patients’ quality of life
  104. Discovery of lipid metabolism-related diagnostic biomarkers and construction of diagnostic model in steroid-induced osteonecrosis of femoral head
  105. Serum-derived exomiR-188-3p is a promising novel biomarker for early-stage ovarian cancer
  106. Enhancing chronic back pain management: A comparative study of ultrasound–MRI fusion guidance for paravertebral nerve block
  107. Peptide CCAT1-70aa promotes hepatocellular carcinoma proliferation and invasion via the MAPK/ERK pathway
  108. Electroacupuncture-induced reduction of myocardial ischemia–reperfusion injury via FTO-dependent m6A methylation modulation
  109. Hemorrhoids and cardiovascular disease: A bidirectional Mendelian randomization study
  110. Cell-free adipose extract inhibits hypertrophic scar formation through collagen remodeling and antiangiogenesis
  111. HALP score in Demodex blepharitis: A case–control study
  112. Assessment of SOX2 performance as a marker for circulating cancer stem-like cells (CCSCs) identification in advanced breast cancer patients using CytoTrack system
  113. Risk and prognosis for brain metastasis in primary metastatic cervical cancer patients: A population-based study
  114. Comparison of the two intestinal anastomosis methods in pediatric patients
  115. Factors influencing hematological toxicity and adverse effects of perioperative hyperthermic intraperitoneal vs intraperitoneal chemotherapy in gastrointestinal cancer
  116. Endotoxin tolerance inhibits NLRP3 inflammasome activation in macrophages of septic mice by restoring autophagic flux through TRIM26
  117. Lateral transperitoneal laparoscopic adrenalectomy: A single-centre experience of 21 procedures
  118. Petunidin attenuates lipopolysaccharide-induced retinal microglia inflammatory response in diabetic retinopathy by targeting OGT/NF-κB/LCN2 axis
  119. Procalcitonin and C-reactive protein as biomarkers for diagnosing and assessing the severity of acute cholecystitis
  120. Factors determining the number of sessions in successful extracorporeal shock wave lithotripsy patients
  121. Development of a nomogram for predicting cancer-specific survival in patients with renal pelvic cancer following surgery
  122. Inhibition of ATG7 promotes orthodontic tooth movement by regulating the RANKL/OPG ratio under compression force
  123. A machine learning-based prognostic model integrating mRNA stemness index, hypoxia, and glycolysis‑related biomarkers for colorectal cancer
  124. 10.1515/med-2025-1282
  125. Review Articles
  126. The effects of enhanced external counter-pulsation on post-acute sequelae of COVID-19: A narrative review
  127. Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments
  128. Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment: A systematic review
  129. Review of mechanisms and frontier applications in IL-17A-induced hypertension
  130. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus
  131. The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis
  132. The application of augmented reality in robotic general surgery: A mini-review
  133. The effect of Greek mountain tea extract and wheat germ extract on peripheral blood flow and eicosanoid metabolism in mammals
  134. Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation
  135. Plant polyphenols, terpenes, and terpenoids in oral health
  136. Laboratory medicine between technological innovation, rights safeguarding, and patient safety: A bioethical perspective
  137. End-of-life in cancer patients: Medicolegal implications and ethical challenges in Europe
  138. The maternal factors during pregnancy for intrauterine growth retardation: An umbrella review
  139. Intra-abdominal hypertension/abdominal compartment syndrome of pediatric patients in critical care settings
  140. PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy
  141. Screening of Group B Streptococcus in pregnancy: A systematic review for the laboratory detection
  142. Giant borderline ovarian tumours – review of the literature
  143. Leveraging artificial intelligence for collaborative care planning: Innovations and impacts in shared decision-making – A systematic review
  144. Cholera epidemiology analysis through the experience of the 1973 Naples epidemic
  145. Risk factors of frailty/sarcopenia in community older adults: Meta-analysis
  146. Case Reports
  147. Delayed graft function after renal transplantation
  148. Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
  149. Diverse electrophysiological demyelinating features in a late-onset glycogen storage disease type IIIa case
  150. Giant right atrial hemangioma presenting with ascites: A case report
  151. Laser excision of a large granular cell tumor of the vocal cord with subglottic extension: A case report
  152. EsoFLIP-assisted dilation for dysphagia in systemic sclerosis: Highlighting the role of multimodal esophageal evaluation
  153. Rapid Communication
  154. Biological properties of valve materials using RGD and EC
  155. Letter to the Editor
  156. Role of enhanced external counterpulsation in long COVID
  157. Expression of Concern
  158. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  159. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  160. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  161. Corrigendum
  162. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  163. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  164. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  165. Retraction
  166. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  167. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  168. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  169. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  170. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  171. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  172. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  173. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  174. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  175. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  176. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  177. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  178. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  179. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  180. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  181. Special Issue Diabetes
  182. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  183. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  184. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  185. A review of brain research on T2DM-related cognitive dysfunction
  186. Special Issue Biomarker Discovery and Precision Medicine
  187. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
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Heruntergeladen am 21.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/med-2025-1205/html
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