Home Unleashing of cytotoxic effects of thymoquinone-bovine serum albumin nanoparticles on A549 lung cancer cells
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Unleashing of cytotoxic effects of thymoquinone-bovine serum albumin nanoparticles on A549 lung cancer cells

  • Bala Baskaran Durga EMAIL logo , Vinayagam Ramachandran , Bakthavatchalam Senthil , Vasthi Gnanarani Soloman , Mohamed Soliman Elshikh , Saeedah Musaed Almutairi , Zhi-Hong Wen and Yi-Hao Lo EMAIL logo
Published/Copyright: November 26, 2024
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Open Life Sciences
From the journal Open Life Sciences Volume 19 Issue 1

Abstract

This research examines the cytotoxic consequences of thymoquinone-loaded bovine serum albumin nanoparticles (TQ-BSA NPs) on the A549 lung cancer cell line. UV-visible (UV–Vis) spectroscopy, Fourier transform infrared spectrophotometer (FT-IR), scanning electron microscopy (SEM), and dynamic light scattering (DLS) were employed to verify the biogenic TQ-BSA NPs’ size, shape, and distribution. UV–Vis spectrophotometry indicated peaks at 200–300 nm, 500–600 nm, and a prominent peak at 700–800 nm, confirming the presence of TQ-BSA NPs. The polydispersity index, as confirmed by DLS, indicated a solvent distribution in water, accompanied by a zeta potential value of 126.2 ± 46.8 mV. The average size of TQ-BSA NPs was confirmed to be 187 ± 8 nm by SEM. TQ-BSA NPs reduce colony formation in the A549 lung cancer cell line in a dose-dependent manner relative to the control group. Protein expression analysis indicated that TQ-BSA NPs promoted programmed cell death by increasing pro-apoptotic levels and decreasing anti-apoptotic levels. TQ-BSA NPs demonstrated inhibition of cancer cell proliferation and promotion of apoptosis and exhibited significant efficacy against cancer cells at low concentrations. As a result, they have the makings of a promising chemotherapeutic agent for low-dose, long-term administration.

Graphical abstract

Keywords: A549 cells; thymoquinone; bovine serum albumin; cytotoxic; anticancer activity

1 Introduction

The World Health Organization defines wellness as a multidimensional state encompassing physical and mental well-being devoid of disease. Cancer ranks as the second leading non-communicable disease, following congestive heart failure, and continues to be a significant global issue. Pharmacokinetic challenges, including inadequate biodistribution, incomplete physicochemical characteristics, negative consequences, and a brief circulation half-life, restrict the therapeutic effectiveness of both established and experimental anticancer agents, consequently diminishing drug exposure to tumor cells [1,2]. In India, the most common types of cancer are breast, oral, cervical, lung, stomach, colon, and rectal cancers. Modifiable risk factors for cancer development are primarily influenced by environmental factors associated with lifestyle choices [3]. Research in the medical field emphasizes cancer diagnosis and treatment, along with the long-term health effects of therapeutic interventions [4].

Investigational cancer therapeutics face challenges in targeting specific sites within the body due to suboptimal physicochemical properties. The drugs exhibit side effects and have a short duration of action within the body [5]. These limitations result in impaired biodistribution attributed to unfavorable partitioning coefficients and inefficiencies in passive targeting. The medical field has shifted its focus to nanomedicine to tackle the therapeutic challenges posed by conventional drug delivery methods. This discipline employs the unique physical and chemical characteristics of nanomaterials to design and develop innovative drug distribution platforms, which may transform cancer treatment and address other diseases.

Plants are widely available, less expensive than conventional treatments, and commonly used as herbal remedies for various ailments [6]. Many plants contain antioxidant molecules, and natural antioxidants are becoming more and more popular than manufactured ones [7]. Normal oxygen and exogenous factor metabolism regularly produce reactive oxygen species (ROS) or free radicals [8]. Plant-based medicines continue to provide therapeutic options with fewer side effects, driving significant research interest [9,10]. These chemical processes may cause damage that reduces cell viability in vitro.

Albumin is one of the nanomaterials that has attracted significant interest in targeted medicine delivery. Its unique properties, such as drug loading capacity, water solubility, biodegradability, biocompatibility, and ability to transport both lipophilic and hydrophilic drugs, make it especially appealing [11]. Research has linked antioxidant-rich diets to a reduced incidence of chronic diseases, including cancer, neurodegeneration, and diabetes [12]. By aiding in the scavenging of free radicals, antioxidants shield cells from oxidative damage and mitigate the deleterious effects on proteins, lipids, and nucleic acids. Protein nanoparticles’ (NPs’) capacity to traverse physiological barriers and target tumor sites has garnered significant interest in pharmaceutical and nutraceutical research [13].

Nigella sativa seeds (N. sativa) have many bioactive compounds, such as the main ingredient thymoquinone (TQ) (2-isopropyl-5-methyl-1,4-benzoquinone), as well as monoterpenes like α-pinene and p-cymene, unique alkaloids like nigellone and nigellimine, and a saponin [14,15]. TQ has garnered considerable research interest owing to its extensive scope of pharmacological activities, such as antioxidant, anti-diabetic, anti-microbial, and hepatoprotective effects [15,16]. The anticancer potential of TQ is particularly well documented in terms of its other pharmacological benefits. Preclinical studies have demonstrated TQ pleiotropic properties, highlighting its role as an antioxidant, immunomodulator, and anticancer agent [17]. Studies have demonstrated that TQ treatment enhances immune function, reduces oxidative stress, and shields healthy cells from damage resulting from these stressors and cancer treatment [18]. Herbs and spices, such as N. sativa, exhibit anticancer properties that can effectively target tumor growth.

Bovine serum albumin nanoparticles (BSA NPs) can be produced using several techniques, such as thermal gelation, emulsification, and desolvation, and newer methods like nanospray and NP albumin-bound technology [19]. However, the desolvation method for BSA NP preparation is particularly effective for targeted drug delivery. This study aims to improve the anticancer efficacy of TQ-BSA NPs against the A549 lung cancer cell line.

2 Materials and methods

2.1 Cells and chemicals

A549 lung cancer cell lines were sourced from the American Type Culture Collection located in Manassas, VA, USA. The Dulbecco Modified Eagle’s Medium, fetal bovine serum, penicillin, and streptomycin were obtained from Hyclone (Logan, USA). Acridine orange/ethidium bromide (AO/EB), methyl thiazolyl diphenyl-tetrazolium bromide (MTT), and polyvinylidene fluoride (PVDF) membrane were obtained from Sigma Aldrich Co., USA. Primary rabbit polyclonal antibodies (Bcl-2, Bax, and Caspase-3) and secondary antibodies were obtained from Abcam, USA. All other chemicals and solvents utilized in this experiment were of analytical grade.

2.2 Synthesis of BSA NPs

BSA protein NPs were developed with a slight modification to the desolvation method. A total of 100 mg of BSA was measured and subsequently dissolved in 1.0 mL of a 10 mM NaCl solution at a pH of 7.0, utilizing 0.1 N sodium hydroxide (NaOH). NPs were synthesized by the continuous addition of 5.0 mL of ethanol as a solvent while stirring at 500 rpm at 37°C until the solution exhibited cloudiness. The opaque solution of NPs is stabilized through continuous agitation for 30 min, without the addition of further ethanol. Subsequently, 0.16 mL of 8% glutaraldehyde solution was applied to facilitate particle cross-linking.

2.2.1 Purification of BSA NPs

The NPs were purified via several cycles of differential centrifugation at 20,000 rpm for 8 min. The pellet was re-suspended in a 10 mM NaCl solution, and the supernatant was removed. Ultrasonication was conducted on each re-suspended stage at 10-min intervals [20].

2.2.2 Preparation of TQ-BSA NPs

The extraction of N. sativa seeds was performed using ethanol as the solvent, following previously established methods [21]. TQ-loaded NPs are synthesized by dissolving 20 mg of isolated TQ in 0.5 mL of ethanol and diluting it to 1.0 mL with Milli-Q water. Two hundred milligrams of BSA were dissolved in 1 mL of Milli-Q water and subsequently added slowly to the aforementioned solution. The precipitated solution was stirred at 500 rpm for 15 min. A few milliliters of ethanol were added gradually and stirred continuously for 30 min to obtain a clear solution. As a result, absolute ethanol, serving as the desolvating agent, was added gradually while maintaining continuous magnetic stirring at 500 rpm, leading to the prompt formation of a translucent suspension. The addition of 0.16 mL of 8% glutaraldehyde facilitates cross-linking with BSA NPs. To complete the reaction, the solution was maintained at room temperature with constant magnetic stirring at 500 rpm for 18 h. The resulting NP suspension underwent centrifugation for 20 min at 12,000 rpm. The procedure was conducted thrice to eliminate unbound medication, free glutaraldehyde, ethanol, and non-desolvated BSA. At each stage, NPs were reconstituted in approximately 10 mL of deionized water and underwent 5 min of ultrasonication. The NPs were subsequently dehydrated to yield a powder.

2.3 Characterization techniques

The morphology of the synthesized NPs was analyzed using scanning electron microscopy (SEM) with a Carl Zeiss scanning electron microscope. The absorption characteristics of the synthesized NPs were analyzed using a Shimadzu UV–Visible spectrophotometer (UV–Vis), with samples scanned over the range of 200–800 nm. The Fourier transform infrared spectrophotometer (FT-IR 8400S, Shimadzu, Tokyo, Japan) was employed to identify the chemical compounds present in synthesized NPs and drug-loaded NPs. The spectra were recorded in the absorption range of 400–4,000 cm⁻¹. The particle size and stability of BSA and drug-loaded NPs were analyzed using a dynamic light scattering (DLS) analyzer and zeta potential measurements with a Zeta-sizer (Malvern Instruments, Southborough, UK), respectively.

2.4 Assessment of the anti-carcinogenic effect of TQ-BSA NPs on the A549 lung cancer cell line using the MTT assay

The MTT assay was employed to assess the anti-carcinogenic effect by treating A549 cell lines with TQ-BSA NPs. The samples were combined into a 1 mL stock following filtration. Each of the 96-well plates contained 100 µL of diluted isolated chemical (TQ) along with drug-loaded TQ-BSA NPs. To assess the dose-dependent effects, TQ, TQ-BSA NPs, and cisplatin were evaluated at concentrations ranging from 3.125 to 100 μg/mL. The effectiveness of the samples was assessed by incubating 96-well plates at 36°C with 5% CO2, followed by examination after 24 h [22].

2.5 Staining with AO/EB

AO/EB staining was employed to detect alterations in apoptosis within cell membranes by examining nuclear changes and the formation of apoptotic bodies [23]. Treated and control cells were seeded in a six-well plate at a density of 3 × 104 cells per well, incubated for 24 h with different drug concentrations, and subsequently stained with a 1:1 acridine orange/ethidium bromide mixture. Cells were rinsed with phosphate-buffered saline (PBS) and analyzed using a 40× fluorescent microscope.

2.6 Agarose gel electrophoresis

Agarose gel electrophoresis was employed to distinguish DNA fragments according to their size. The negatively charged DNA migrates through the pores of an agarose gel toward the positively charged end when an electrical current is applied, with smaller fragments moving more quickly than larger fragments. The resulting bands can subsequently be visualized with ultraviolet (UV) light. Agarose gel was prepared and poured onto the gel plate without bubble formation. It was allowed to cool for 20 min, after which the combs were removed, and the cellotapes were uncovered. After mixing 5 μL (100–200 ng) of the DNA sample with the dye and loading it into the well using a pipette or capillary tube, the black negative terminal is connected to the top end of the gel, referred to as the cathode, while the red positive terminal is connected to the bottom end of the gel, known as the anode. Electrophoresis commences upon activating the DC power supply at a voltage of 5 V/cm. Upon the tracking dye (bromophenol blue) advancing 1 cm from the bottom end, the current is deactivated, the power supply is removed, and the gel is subsequently stained with 0.5 μg/mL ethidium bromide in sterile distilled water within a plastic tray for 30–45 min. The gel is rinsed with distilled water and subsequently transferred onto the UV transilluminator. The UV light is activated, allowing for the visualization of DNA bands, and a photograph is captured using an orange filter.

2.7 Protein immunoblot analysis

A protease inhibitor (1 mM phenylmethylsulfonyl fluoride) was added to 0.01 M Tris-HCl buffer (pH 7.4) for lysing the cell lines treated with TQ-BSA NPs. Protein concentrations were quantified using the Lowry method, and 50 μg of protein from each sample was subjected to SDS-PAGE electrophoresis on 10% polyacrylamide gels. Proteins were transferred to a PVDF membrane and incubated overnight at 4°C with primary antibodies (Bax, Bcl-2, and caspase 3), followed by incubation with horseradish peroxidase-conjugated secondary antibodies. Protein bands were identified through enhanced chemiluminescence [24].

2.8 Flow cytometry analysis

Fluorescence-activated cell sorting (FACS) was employed for cell cycle analysis. The cells were stained using fluorescein isothiocyante (FITC)-Annexin V (BD FACS Aria II BSL-2) to assess cell death at different stages of the cell cycle. Cells were treated with the IC50 concentrations of isolated TQ and TQ-BSA NPs (62.15 and 24.56 µg/mL, respectively). After treatment, the cells were collected and resuspended in PBS, and cold ethanol was gradually added to reach a final concentration of 70%. The cells were then incubated in an ice-cold environment for 2 h. Following this, the cells were washed with PBS and resuspended in staining buffer containing 100 µg/mL RNase A, 50 µg/mL propidium iodide, and 0.1% Triton X-100. The suspension was left at 4°C overnight. The fluorescence intensity of the nuclei was measured, and the data were analyzed using flow cytometry software [25].

2.9 Statistical analysis

Data were analyzed using SPSS 23 software, employing Duncan’s multiple range test (DMRT) for post hoc comparisons. The results are presented as mean ± standard deviation, with a significance level of p < 0.05. All experiments were conducted by three independent investigators to ensure the reliability of the findings.

3 Results

3.1 UV–Vis spectroscopy of the prepared BSA and TQ-BSA NPs

The UV–Vis spectra of pure BSA, BSA NPs, and TQ-BSA NPs are depicted in Figure 1a. The absorption spectra for BSA and BSA NPs were observed within the range of 200 to 800 nm, whereas the TQ-BSA NPs exhibited an extended absorption range, spanning from 200 to 1,000 nm.

Figure 1 (a) UV–Vis analysis of pure BSA, BSA NPs, and TQ-BSA NPs. (b) FTIR spectra of synthesized BSA nanoparticle and (c) TQ-BSA NPs.
Figure 1

(a) UV–Vis analysis of pure BSA, BSA NPs, and TQ-BSA NPs. (b) FTIR spectra of synthesized BSA nanoparticle and (c) TQ-BSA NPs.

3.2 FT-IR analysis of synthesized BSA and TQ-BSA NPs

The FTIR spectrum of pure BSA showed characteristic peaks at 3350.88, 2927.40, 1714.53, 1455.16, and 1242.62 cm⁻¹, as displayed in Figure 1b. In contrast, the FTIR spectrum of TQ-BSA NPs exhibited peaks at 3781.34, 2926.77, 1720.18, 1451.07, and 1247.44 cm⁻¹, as shown in Figure 1c and detailed in Table 1. These differences indicate the successful formation of TQ-BSA NPs.

Table 1

Characteristic band of BSA NPs and TQ-BSA NPs in FT-IR analysis

Peak value Bond Functional group
BSA NPs
3776.59 O–H-stretching Alcohol
3350.88 NH-stretching amide A
2927.40 NH-stretching Amide B
1714.53 C═O stretching Amide A
1455.16 C–N stretching N–H bending vibration Amide I
1242.62 C–N stretching N–H bending vibration Amide II
1172.71 C═O stretching Amide III
1047.83 C–N stretching Amides
926.03 ═C–H bend Alkenes
720.77 C═C bending Alkenes
TQ-BSA NPs
3781.34 O–H stretching Alcohol
3372.98 NH stretching Aliphatic 1° amide
2926.77 NH–stretching Amide a
2859.30 CH stretching Aldehyde
2354.57 CH stretching Alkanes
1720.18 C═O stretching vibration Amide I
1656.46 NH bending Acids
1451.07 OH bending Alcohol
1247.44 C–O stretching Alkyl aryl carrier
1053.97 CO–O–CO stretching Anhydride
715.33 C–Cl compound Halo compound

3.3 DLS of synthesized BSA and TQ-BSA NPs

The DLS measurements of the synthesized NPs showed a single sharp peak representing the size distribution, as illustrated in Figure 2a and b. This indicates a uniform particle size distribution for both BSA and TQ-BSA NPs.

Figure 2 (a) and (b) By performing DLS analysis, the intensity size distribution of BSA NPs and TQ-BSA NPs was identified. (c) and (d) Zeta potential analysis of BSA NPs and TQ-BSA NPs. (e) and (f) SEM analysis of BSA NPs and TQ-BSA NPs.
Figure 2

(a) and (b) By performing DLS analysis, the intensity size distribution of BSA NPs and TQ-BSA NPs was identified. (c) and (d) Zeta potential analysis of BSA NPs and TQ-BSA NPs. (e) and (f) SEM analysis of BSA NPs and TQ-BSA NPs.

3.4 Zeta potential analysis of synthesized BSA and TQ-BSA NPs

The Zeta potential reflects the potential difference between the surrounding layer of dispersed particles and their electric double layer at the sliding plane. As shown in Figure 2c, the BSA NPs exhibited a surface charge of −4.5 ± 1.2 mV when dispersed in water. In contrast, the TQ-BSA NPs, when dispersed in water, displayed a significantly higher zeta potential value of 126.2 ± 46.8 mV, as depicted in Figure 2d. These values indicate the electrostatic stability and surface charge characteristics of the NPs.

3.5 SEM analysis of the synthesized BSA and TQ-BSA NPs

SEM images (Figure 2e and f) analysis was performed on the synthesized BSA NPs and the formulated TQ–BSA NPs. The average size of the synthesized BSA NPs is less than 200 nm, while TQ–BSA NPs had an average size of 187 ± 8 nm.

3.6 Determine the drug encapsulation efficiency for TQ-BSA NPs

Our experiment investigated a NP-based drug delivery system. We measured how well the NPs (likely made from BSA) bound to the drug molecule (TQ) and how much drug they could carry. The system achieved its highest efficiency (43.2%) with the drug TQ-BSANP.

3.7 In vitro cytotoxicity assay for TQ, BSA NPs, and TQ-BSA NPs

The in vitro cytotoxicity of TQ and TQ-BSA NPs was evaluated against the A549 lung adenocarcinoma cell line using the MTT assay to assess cell viability and proliferation. The A549 cancer cells were treated with various concentrations of cisplatin, a commercially used anticancer drug, and incubated for 24 h as a standard comparison. The anti-proliferative activity of isolated TQ, cisplatin, and TQ-BSA NPs was measured after a 24-h incubation, with the results presented in Table 2 and Figure 3. These data allow for the comparison of the cytotoxic efficacy of the NPs against a recognized chemotherapeutic agent.

Table 2

In vitro cytotoxicity assay of isolated TQ and TQ-BSA Nps

Concentration (μg/mL) Cytotoxicity (%)
Isolated TQ BSA-TQ NPs Cisplatin
3.125 2.20 ± 0.17a 37.80 ± 0.98a 42.05 ± 0.91a
6.25 5.75 ± 0.61b 43.78 ± 0.97b 48.84 ± 0.61b
12.50 13.24 ± 0.77c 47.98 ± 1.62c 60.99 ± 0.55c
25.00 24.44 ± 0.75d 55.09 ± 1.78d 67.77 ± 0.30d
50.00 44.47 ± 0.89e 60.04 ± 1.08e 75.82 ± 0.41e
100.00 76.30 ± 0.42f 70.06 ± 1.03f 96.39 ± 0.15f
IC50 (μg/mL) 62.15 24.56 2.46
R 2 0.990 0.892 0.913

Cytotoxicity values are expressed as Mean ± SD (N = 3). The data was analyzed by one-way ANOVA test, using IBM SPSS Version 20.0. Mean values within the column followed by different letters are statistically significant (p < 0.05) from each other concentration, and the same letters are statistically non-significant (p > 0.05) are compared by ANOVA, Duncan’s multiple range test (DMRT), and significant level alpha 0.05.

Figure 3 In vitro cytotoxicity assay of isolated TQ and TQ-BSA NPs. Microscopic examination at a magnification of 20× was employed to assess cellular morphology and proliferation.
Figure 3

In vitro cytotoxicity assay of isolated TQ and TQ-BSA NPs. Microscopic examination at a magnification of 20× was employed to assess cellular morphology and proliferation.

Visual inspection of the extracted TQ revealed no apparent changes in its chemical composition following treatment, as indicated by minimal to no alterations in concentration. Conversely, the treated cancer cell line displayed dose-dependent morphological alterations, with the highest percentage of cell death observed at increasing dose levels, as depicted in Figure 3. Consistent with free TQ treatment, the TQ-BSA NP-exposed cancer cell line displayed a concentration-dependent response in terms of cellular morphology. Increasing NP concentrations (3.125, 6.25, 12.5, 25, 50, 100 μg/mL) resulted in a statistically significant reduction in the viability of the cell population, as evidenced by a pronounced alteration in cellular morphology in Figure 3. Our investigation revealed that TQ-BSA NPs contributed to an increase in the rate of cell death at every concentration, just as the commercial medication cisplatin. Microscopic examination at a magnification of 20× was employed to assess cellular morphology and proliferation in Figure 3.

The findings demonstrate that a higher dose concentration has superior anti-carcinogenic efficacy, leading to the maximum killing of cancer cells. Present isolated TQ, TQ-BSA NPs, and Cisplatin significantly reduced cell viability as compared to control at 100% cell viability (p < 0.05) and significant difference from the concentration using the DMRT statistic (p < 0.05). As expected, TQ-BSA NPs exhibit significantly increased cytotoxicity against cancer cell lines, with an IC50 of 24.56 µg/mL after a 24-h incubation period. In comparison, the isolated TQ reveals 76.30 ± 0.42% of cell death at a concentration of 100 µg after a 24-h incubation period (IC50 = 62.15 µg/mL), while the commercial drug (Cisplatin) treated cancer cell line displays an IC50 value of 2.46 µg/mL after a 24 h incubation period in Table 2. TQ, TQ-BSA NPs, and Cisplatin exhibited a significant dose-dependent cytotoxicity on A549 cell (R 2 = 0.990, 0.892, and 0.913) in Table 2. Previously, Yu et al. reported Cisplatin IC50 (μg/mL) on A549 2.458 (2.330–2.639) in close agreement with the present study.

3.8 Protein expression studies for BSA NPs and TQ-BSA NPs

The protein expression levels of Bcl-2, Bax, and caspase-3 in A549 cells treated with TQ-BSA NPs are shown in Figure 4a and b. The expression of pro-apoptotic proteins caspase-3 and Bax was progressively increased, while the anti-apoptotic protein Bcl-2 was gradually decreased with treatment at the IC50 concentrations of isolated TQ and TQ-BSA NPs (62.15 and 24.56 µg/mL, respectively), as depicted in Figure 4a and b. The effects observed at the IC50 concentrations of isolated TQ and TQ-BSA NPs were significantly different compared to the control, indicating the potential of these NPs to induce apoptosis.

Figure 4 (a) The protein expression changes of Bax, Bcl-2, and caspase-3 in the A549 cell line by Western blot analysis. (b) Densitometric analysis of Bax, Bcl-2, and caspase-3 value were represented as the means ± SD. *p < 0.05 control vs TQ, *p < 0.05 TQ-BSA NPs vs TQ. (c) Lane 1: M – molecular weight of marker of 1 kb ladder, Lane 2: S – sample after 24 h of treatment. (d, e, and f) AO/EB staining A549 cells were labeled by AO/EB 24 h after loading of TQ and TQ-BSA NPs es and were examined under a fluorescent microscope.
Figure 4

(a) The protein expression changes of Bax, Bcl-2, and caspase-3 in the A549 cell line by Western blot analysis. (b) Densitometric analysis of Bax, Bcl-2, and caspase-3 value were represented as the means ± SD. *p < 0.05 control vs TQ, *p < 0.05 TQ-BSA NPs vs TQ. (c) Lane 1: M – molecular weight of marker of 1 kb ladder, Lane 2: S – sample after 24 h of treatment. (d, e, and f) AO/EB staining A549 cells were labeled by AO/EB 24 h after loading of TQ and TQ-BSA NPs es and were examined under a fluorescent microscope.

3.9 Analysis of DNA fragments using agarose gel electrophoresis

As a biological marker for apoptosis, DNA fragmentation analysis was employed biochemically to distinguish between necrotic and apoptotic cells. DNA is taken out of a homogenate of lysed cells and electrophoresed on an agarose gel in this experiment. After subjecting lung adenocarcinoma (A549) cells to BSA loaded with TQ, the cell DNA was extracted and placed onto a 2% agarose gel. The results indicate that there is a connection of some kind between the DNA ladder pattern and the chromatin that was recovered from cancer cells that had been exposed to NPs in Figure 4c.

3.10 AO/EB staining

The AO/EB double labeling technique was employed to enhance the detection of apoptotic cell death in cells treated with TQ-BSA NPs. Apoptosis was identified by observing changes in nuclear color. In control (normal) cells, the circular nucleus was uniformly distributed at the center of the cell. Cells treated with the IC50 concentrations of isolated TQ and TQ-BSA NPs (62.15 and 24.56 µg/mL, respectively), as determined from the MTT assay, were stained with AO and EB. The late apoptotic cells emitted orange fluorescence, which indicated that they were permeable to both AO and EB. In contrast, green fluorescence was associated with viable cells, as these were only permeable to AO and impermeable to EB. These observations are presented in Figure 4d–f.

3.11 Flow cytometer analysis for BSA NPs and TQ-BSA NPs

Flow cytometry was used to assess the fluorescence intensity corresponding to the uptake of NPs by A549 lung adenocarcinoma cells. The fluorescence intensity of FITC-BSA in each treatment group was quantitatively analyzed based on the number of NPs per vesicle or cell. The data, illustrated in Figure 5a–f, indicated that the relative fluorescence values ranged from 6 to 18, demonstrating a time-dependent increase in NP internalization within the A549 cells. This suggests effective uptake of the NPs over the incubation period.

Figure 5 (a)–(c) Flow cytometry analysis of the cytotoxic effect of TQ-BSA NPs in A549 cells. The cells were treated with TQ (62.15 µg/mL) and TQ-BSA NPs (24.56 µg/mL) for 24 h. (d)–(f) the results of the quadrant investigation of fluorescence intensity of A549 cells in Annexin V FITC and PI channels were observed.
Figure 5

(a)–(c) Flow cytometry analysis of the cytotoxic effect of TQ-BSA NPs in A549 cells. The cells were treated with TQ (62.15 µg/mL) and TQ-BSA NPs (24.56 µg/mL) for 24 h. (d)–(f) the results of the quadrant investigation of fluorescence intensity of A549 cells in Annexin V FITC and PI channels were observed.

4 Discussion

4.1 UV–Vis spectrophotometer

The UV–Vis spectra of Figure 1a of pure BSA peak formed possibly due to the occurrence of amino acid chains, in addition to its feeble absorption because of aromatic amino acids (phenylalanine and tyrosine). BSA NPs peak slightly shifts due to alteration in the protein backbone which substantiates that BSA develops into a nano-sized molecule. It is noteworthy that this brings up the absorption range that is reduced in formulated TQ-BSA NPs where almost five peak changes were observed, and absorption shifts fall between the range of 200–300 nm, 500–600 nm, and major of 700–800 nm in Figure 1a. This clearly states that during nanoparticle synthesis, certain modifications of the backbone of amino acids enhance the interaction of the drug with the aromatic amino acid (phenylalanine and tyrosine) for completion of TQ-BSA NPs.

The results of the study on salicylic acid-loaded protein nanomaterials provide supportive evidence for the findings from UV-Vis spectroscopy, indicating that the drug-binding site on BSA is a lipophilic pocket composed of positively charged surfaces. This configuration readily binds with negatively charged drug molecules, resulting in significant alterations in the absorption spectra of the sample, effectively demonstrating that the drug binds to the protein base for the successful formation of drug-loaded nanoparticles (NPs) [26,27]. Our results have corroborated these findings.

4.2 FT-IR analysis

The FT-IR spectrum of pure BSA exhibited characteristic peaks at 3350.88, 2927.40, 1714.53, 1455.16, and 1242.62 cm⁻¹, as shown in Figure 1b. These peaks correspond to the stretching vibrations of OH groups, while amides A and I are associated with NH and C═O stretching vibrations, respectively. Amide II reflects a combination of N–H in-plane bending and C–N stretching vibrations [28]. The synthesis of NPs induces conformational changes that interact with the chemical environment, resulting in slight shifts in the characteristic bonds of the amide functional groups.

The synthesized BSA NPs displayed all the expected prominent spectral peaks, as detailed in Table 1. Key bonding sites include alcohol O–H stretching at 3781.34 cm⁻¹, amide A NH stretching at 2926.77 cm⁻¹, amide I C═O stretching at 1720.18 cm⁻¹, amide II representing the coupling of N–H bending and C–N stretching at 1451.07 cm⁻¹, and amide III corresponding to N–H in-plane bending and C–N stretching at 1247.44 cm⁻¹, as depicted in Figure 1c. Additional peaks observed in the spectra of BSA NPs included NH stretching of aliphatic 1-amines at 3372.98 cm⁻¹, CH stretching from aldehydes at 2859.30 cm⁻¹, CH stretching from alkanes at 2354.57 cm⁻¹, NH bending of acids at 1655.46 cm⁻¹, CO–O–CO stretching at 1053.97 cm⁻¹, and anhydride C–Cl at 715.33 cm⁻¹. Notably, halo compounds were generated only in drug-loaded NPs [29]. These findings confirm the successful synthesis of TQ-BSA NPs, as detailed in Table 1. The results were compared with previous FTIR studies of protein NPs [30,31].

4.3 DLS and zeta potential

The size distribution of the prepared NPs, as determined by the DLS method, is shown in Figure 2a and b. The scattering of light by dispersed NPs is proportional to the sixth power of their radii. When the particles are approximately one-tenth the wavelength of the incident light (λ/10), the scattered light retains the same energy as the incident light, resulting in elastic scattering that is not angle-dependent (Rayleigh scattering).

The DLS analysis revealed that the prepared BSA NPs exhibited a sharp single peak, indicating their purity and uniform nanosize. Similarly, the drug-loaded BSA NPs also displayed a distinct, sharp peak, confirming their uniformity, purity, and diameter of 187.9 nm. In contrast, the size distribution of the TQ-BSA NPs demonstrated a diameter range within the acceptable limits, along with a polydispersity index (PDI) of less than 0.5%. Previous studies have shown that a low PDI is crucial for ensuring highly monodispersed particles in drug delivery applications [32]. Thus, the DLS results suggest that TQ-BSA NPs are highly effective for cancer treatment.

The zeta potential reflects the potential difference between the layer of dispersed particles surrounding electrophoretically mobile particles and their electric double layer at the sliding plane. Previous research has indicated that the addition of glutaraldehyde and variations in pH can significantly influence the surface charge of NPs, subsequently affecting the electrostatic potential and dispersion stability of BSA NPs in solution [26]. As illustrated in Figure 2c, the zeta potential measurement for BSA NPs showed a surface charge of −4.5 ± 1.2 mV when dispersed in water, which is relatively lower than values reported in previous studies. This reduction in surface charge may be attributed to alterations in the secondary structure of the NPs, leading to decreased surface charges during NP assembly.

Zeta potential serves as an indicator of the colloidal stability of NP suspensions. NPs with high absolute zeta potential values–whether strongly positive or negative–are generally more stable due to the increased electrostatic repulsion between particles, which helps prevent aggregation. In this study, the zeta potential of TQ-BSA NPs was measured at 126.2 ± 46.8 mV (Figure 2d), indicating a strong positive charge. This suggests that the NPs possess good stability and are less prone to aggregation. Such a favorable zeta potential enhances the NPs’ ability to maintain a stable state by inhibiting aggregation [32].

In biological environments, including blood and cell culture media, NPs often interact with a variety of proteins and ions. A high zeta potential can help prevent protein halo formation, aggregation, or destabilization caused by salts or serum proteins, thereby preserving the NPs’ functionality. The strong positive charge of TQ-BSA NPs implies that the formulation is likely to remain stable in biological fluids, enhancing their bioavailability. Therefore, based on various studies, it can be concluded that the synthesized NPs demonstrate excellent stability for drug delivery applications.

Additionally, NP size is a crucial factor influencing cellular uptake. Research indicates that NPs less than 200 nm in size are optimal for internalization by cancer cells, such as the A549 lung cancer cell line. This size range facilitates the exploitation of receptor-mediated endocytosis pathways, which are more efficient for NPs of this dimension. If TQ-BSA NPs fall within this range, they are expected to exhibit higher uptake efficiency, contributing to their therapeutic efficacy. Smaller NPs (<200 nm) also tend to have improved tumor penetration and are more likely to accumulate at tumor sites via the enhanced permeability and retention effect, which is vital for enhancing drug delivery in cancer therapy. A more detailed discussion of the size data obtained from DLS could further elucidate how the size of TQ-BSA NPs might influence their ability to reach and be retained within the tumor microenvironment.

4.4 SEM analysis

As shown in Figure 2e and f, SEM analysis was conducted on the synthesized BSA NPs and the formulated TQ-BSA NPs. This analysis confirms that both types of NPs exhibit a similar spherical morphology. Furthermore, it demonstrates that the surfaces of both BSA and TQ-BSA NPs are largely smooth. The average size of the synthesized BSA NPs is less than 200 nm, while the average size of the drug-loaded NPs is 187 ± 8 nm. This finding is consistent with the DLS results, validating that both techniques yield comparable results. The shape and surface morphology of NPs, as observed through SEM, significantly influence their interaction with cells. Spherical particles are generally internalized more efficiently than other shapes, such as rods or discs. If the SEM results confirm that TQ-BSA NPs are spherical, this could enhance their interaction with the A549 cell line, improving their capacity to deliver TQ effectively. The presence of an uneven surface, noted in previous studies, is also linked to increased drug encapsulation efficiency [26,33].

The size and morphology of the NPs directly affect the drug release profile. Smaller NPs typically facilitate faster drug release due to their larger surface area-to-volume ratio, while larger NPs may offer a slower release, potentially allowing for sustained therapeutic effects. According to research findings, if the synthesized nanocarrier is smaller than 200 nm, it can positively interact with tumor tissues, enhancing the permeability and retention effect, which allows the NPs to remain in circulation longer. Given that the TQ-BSA NPs fall within this size range and contribute to a stable system, they are deemed reliable for drug delivery applications.

4.5 Anticancer activity

For biomedical applications, it is essential that the synthesized NPs are compatible with living organisms. The in vitro cytotoxicity of TQ and TQ-BSA NPs was evaluated against the A549 lung adenocarcinoma cell line using the MTT assay. The MTT results indicated that TQ, TQ-BSA NPs, and cisplatin significantly decreased cell viability compared to the control group, which maintained 100% viability. Similar findings were reported by Ghazy and Hanafy and Salim et al., who assessed the cytotoxicity of Cetuximab and Propolis-loaded serum albumin NPs against various cancer cell lines, including Caco-2, breast, and lung cancer cells [34,35].

The cytotoxicity of TQ-BSA NPs against the A549 cell line was notably significant, revealing a dose-dependent decrease in cell viability with increasing concentrations of TQ, TQ-BSA NPs, and cisplatin. The IC50 values were determined as follows: TQ (62.15 µg/mL), TQ-BSA NPs (24.56 µg/mL), and cisplatin (2.46 µg/mL), as detailed in Table 2. The observed suppression of clonogenic potential in treated cells suggests the anti-tumorigenic potential of TQ-BSA NPs. Previous studies have shown similar cytotoxic effects for catechin and epicatechin-BSA NPs and cisplatin against A549 cell lines, supporting the current findings [36,37].

Understanding whether TQ-BSA NPs induce apoptosis through intrinsic (mitochondrial) or extrinsic (death receptor) pathways is critical, as this would provide insights into their mechanisms of action. Without detailing these pathways, the discussion remains speculative. Elucidating the specific apoptotic pathways could reveal whether key proteins such as caspases, Bcl-2, Bax, and cytochrome c are activated during the apoptotic cascade. Mechanistic clarity is essential since different apoptotic pathways can have varied therapeutic implications. For instance, the intrinsic pathway typically involves mitochondrial damage, whereas the extrinsic pathway relies on receptor–ligand interactions [24,38].

Our current findings suggest that high doses of resveratrol-BSA NPs primarily activate a non-caspase-dependent pathway mediated by apoptosis-inducing factor (AIF), followed by a necrotic programmed cell death pathway [39]. Previous in vitro and in vivo studies have indicated that caspase activation plays a significant role in the cytotoxicity of drug-loaded NPs. While some studies suggest that TQ induces cell death in human colon cancer cells via a caspase-independent mechanism [40], treatments with agents like thyroid substitute-BSA NPs can lead to cytochrome c release and subsequent caspase-3 activation.

Our results demonstrate that treatment with TQ-BSA NPs led to a gradual decrease in Bcl-2 expression, coupled with an increase in Bax and caspase-3 expression, correlating with the IC50 concentrations of the NPs (Figure 4a and b). Previous studies have indicated that AIFs can cause cell death through caspase-independent mechanisms [41]. Mitochondrial apoptosis factors contribute to nuclear condensation, triggering cell death through significant chromatin fragmentation [42]. Previous research also supports the notion that TQ and TQ-loaded cubosomes enhance caspase-3 activation in treated cells [43].

Our findings suggest that TQ-BSA NPs induce the translocation of AIF from the mitochondria to the nucleus in A549 cells. The release of AIF protein after treating A549 cells with apoptogenic agents has been shown to concentrate around and partially translocate into the nuclei. Caspase-3 inhibitors can halt chromatin condensation, AIF migration, and DNA fragmentation [44]. Our data indicate that AIF translocation, rather than caspase activation, may primarily drive DNA fragmentation following TQ-BSA NP treatment, as demonstrated by the fact that pan-caspase inhibition prevented treatment-induced apoptotic cell death. These findings align with prior studies exploring the apoptotic pathways mediated by TQ-BSA NPs.

The essential regulatory processes involved in mitochondrial membrane depolarization include the activation of Bax and its subsequent translocation into the mitochondria. For instance, following treatment with macrophage inflammatory protein supernatant, Bax translocates to the mitochondria within 2 h. The upregulation of mitochondrial Bax is associated with a decrease in AIF and cytochrome c levels. AIF and cytochrome c must be released from the mitochondria for Bax to bind effectively. To our knowledge, this is the first study to investigate the signaling pathway by which TQ-BSA NPs induce apoptosis in A549 cells via a caspase-independent mechanism.

Further research is necessary to fully understand the signaling pathways that lead to TQ-BSA NP-induced apoptotic death in lung cancer A549 cells. TQ may also represent a potential candidate for chemoprevention and chemotherapy, as it can exhibit similar activity at much lower doses than conventional chemotherapy agents. Notably, TQ-BSA NPs showed potent effects on A549 cells. Previous reports indicate that the release of Ca²⁺ from the endoplasmic reticulum plays a crucial role in AIF release from the mitochondria, which is associated with the Bcl family member Bax. Our findings suggest that the apoptosis induced by TQ-BSA NPs in A549 cells may involve AIF release, along with mitochondrial membrane potential changes and modifications in Bax expression [45,46].

Recent insights into the mechanism by which TQ induces cell death in human lung tumors have revealed that TQ typically disrupts signaling through the AKT/phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways [47]. TQ consistently inhibits the activity of nuclear factor-κB (RelA/p65) and downstream transcription factors, such as AP-1 [48]. It is believed that TQ affects the transcription of genes involved in apoptosis, including cyclins, cyclin-dependent kinases, Bcl-2, Bax, and apoptosis inhibitors [49]. These results align with our findings, suggesting that TQ-BSA NPs promote apoptosis in the A549 cell line via a mitochondrial-mediated apoptotic mechanism through the inhibition of Bcl-2 protein release, which increases mitochondrial membrane permeability.

Investigating the interactions between various pro-apoptotic and anti-apoptotic proteins involved in mitochondrial-mediated apoptosis will be essential for fully elucidating the action mechanism of TQ-BSA NPs on the A549 cell line. The ability of cytotoxic chemotherapy drugs to induce apoptosis and cancer cell death underlies their clinical use [50]. Importantly, this process does not elicit inflammatory responses, as the cells undergo apoptosis. Given the alarming rise in lung cancer incidence, there is an urgent need for revolutionary anticancer therapies that minimize adverse effects on healthy cells [51]. Hence, the potential of BSA NPs to induce apoptosis in invasive breast cancer cell lines was explored. Morphological changes were assessed using inverted phase-contrast microscopy, along with DNA fragmentation tests and AO/EtBr staining after 24 h. The results indicate that BSA NPs can induce apoptosis in breast cancer cells, likely through the production of pro-apoptotic signaling molecules that stimulate cellular death by increasing ROS levels [52].

It is believed that oxidative stress-inducing agents primarily target cancer cells, which exhibit higher ROS levels than normal cells [53]. The findings provide evidence for the pro-oxidant nature of TQ-BSA NPs, as they enhance ROS levels in cancer cells, consistent with previous reports [54,55]. Prior studies have also indicated that Baicalin-loaded folic acid-modified albumin NPs can trigger apoptosis and oxidative stress in MCF-7 cells [56]. The excessive internalization of NPs may lead to dysfunction that accelerates apoptosis [57]. Further investigation is warranted to determine the optimal treatment strategy.

5 Conclusion

In summary, TQ-BSA NPs were successfully synthesized and characterized, and their targeted anticancer activity against the A549 lung adenocarcinoma cell line was investigated. Characterization results confirmed the formation of spherical NPs with an average size of 187 ± 8 nm. Anticancer assays demonstrated the effectiveness of TQ-BSA NPs in reducing cell viability in the A549 cell line. Moreover, TQ-BSA NPs induced programmed cell death by promoting pro-apoptotic factors and downregulating anti-apoptotic factors. TQ, the active therapeutic component, exhibited significant efficacy against lung cancer cells when encapsulated in BSA NPs and administered at low doses, indicating its potential as an anticancer agent utilizing BSA as a nanocarrier.

While the in vitro findings provide valuable insights, further research is essential to thoroughly investigate the pharmacokinetic properties of these biological agents in preclinical and clinical settings. Such studies will facilitate the development of innovative treatment strategies in oncology, including the formulation of anticancer drugs that minimize adverse effects, even with prolonged use.

# First author’s equal contribution.

Acknowledgments

This study was supported by Zuoying Armed Forced General Hospital (grant KAFGH-ZY-A-109015) and the Ministry of Science and Technology, Taiwan (NSTC-113-2314-B-283-001). The authors extend their appreciation to the Researchers supporting project number (RSP2024R470), King Saud University, Riyadh, Saudi Arabia.

  1. Funding information: This study was supported by Zuoying Armed Forced General Hospital (grant KAFGH-ZY-A-109015) and the Ministry of Science and Technology, Taiwan (NSTC-113-2314-B-283-001). Researchers supporting project number (RSP2024R470), King Saud University, Riyadh, Saudi Arabia.

  2. Author contributions: Bala Baskaran Durga, Bakthavatchalam Senthil, Yi-Hao Lo and Vasthi Gnanarani Soloman: conceptualization, data curation, formal analysis, writing – original draft, writing – review & editing, Vasthi Gnanarani Soloman and Mohamed Soliman Elshikh: project administration, visualization, Zhi-Hong Wen: data curation, validation, Saeedah Musaed Almutairi: methodology, investigation, validation, Ramachandran Vinayagam, and Yi-Hao Lo: supervision, writing – review & editing.

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

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

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Received: 2024-06-06
Revised: 2024-09-20
Accepted: 2024-10-10
Published Online: 2024-11-26

© 2024 the author(s), published by De Gruyter

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

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  22. Sirtuin 5 regulates acute myeloid leukemia cell viability and apoptosis by succinylation modification of glycine decarboxylase
  23. Apigenin 7-glucoside impedes hypoxia-induced malignant phenotypes of cervical cancer cells in a p16-dependent manner
  24. KAT2A changes the function of endometrial stromal cells via regulating the succinylation of ENO1
  25. Current state of research on copper complexes in the treatment of breast cancer
  26. Exploring antioxidant strategies in the pathogenesis of ALS
  27. Helicobacter pylori causes gastric dysbacteriosis in chronic gastritis patients
  28. IL-33/soluble ST2 axis is associated with radiation-induced cardiac injury
  29. The predictive value of serum NLR, SII, and OPNI for lymph node metastasis in breast cancer patients with internal mammary lymph nodes after thoracoscopic surgery
  30. Carrying SNP rs17506395 (T > G) in TP63 gene and CCR5Δ32 mutation associated with the occurrence of breast cancer in Burkina Faso
  31. P2X7 receptor: A receptor closely linked with sepsis-associated encephalopathy
  32. Probiotics for inflammatory bowel disease: Is there sufficient evidence?
  33. Identification of KDM4C as a gene conferring drug resistance in multiple myeloma
  34. Microbial perspective on the skin–gut axis and atopic dermatitis
  35. Thymosin α1 combined with XELOX improves immune function and reduces serum tumor markers in colorectal cancer patients after radical surgery
  36. Highly specific vaginal microbiome signature for gynecological cancers
  37. Sample size estimation for AQP4-IgG seropositive optic neuritis: Retinal damage detection by optical coherence tomography
  38. The effects of SDF-1 combined application with VEGF on femoral distraction osteogenesis in rats
  39. Fabrication and characterization of gold nanoparticles using alginate: In vitro and in vivo assessment of its administration effects with swimming exercise on diabetic rats
  40. Mitigating digestive disorders: Action mechanisms of Mediterranean herbal active compounds
  41. Distribution of CYP2D6 and CYP2C19 gene polymorphisms in Han and Uygur populations with breast cancer in Xinjiang, China
  42. VSP-2 attenuates secretion of inflammatory cytokines induced by LPS in BV2 cells by mediating the PPARγ/NF-κB signaling pathway
  43. Factors influencing spontaneous hypothermia after emergency trauma and the construction of a predictive model
  44. Long-term administration of morphine specifically alters the level of protein expression in different brain regions and affects the redox state
  45. Application of metagenomic next-generation sequencing technology in the etiological diagnosis of peritoneal dialysis-associated peritonitis
  46. Clinical diagnosis, prevention, and treatment of neurodyspepsia syndrome using intelligent medicine
  47. Case report: Successful bronchoscopic interventional treatment of endobronchial leiomyomas
  48. Preliminary investigation into the genetic etiology of short stature in children through whole exon sequencing of the core family
  49. Cystic adenomyoma of the uterus: Case report and literature review
  50. Mesoporous silica nanoparticles as a drug delivery mechanism
  51. Dynamic changes in autophagy activity in different degrees of pulmonary fibrosis in mice
  52. Vitamin D deficiency and inflammatory markers in type 2 diabetes: Big data insights
  53. Lactate-induced IGF1R protein lactylation promotes proliferation and metabolic reprogramming of lung cancer cells
  54. Meta-analysis on the efficacy of allogeneic hematopoietic stem cell transplantation to treat malignant lymphoma
  55. Mitochondrial DNA drives neuroinflammation through the cGAS-IFN signaling pathway in the spinal cord of neuropathic pain mice
  56. Application value of artificial intelligence algorithm-based magnetic resonance multi-sequence imaging in staging diagnosis of cervical cancer
  57. Embedded monitoring system and teaching of artificial intelligence online drug component recognition
  58. Investigation into the association of FNDC1 and ADAMTS12 gene expression with plumage coloration in Muscovy ducks
  59. Yak meat content in feed and its impact on the growth of rats
  60. A rare case of Richter transformation with breast involvement: A case report and literature review
  61. First report of Nocardia wallacei infection in an immunocompetent patient in Zhejiang province
  62. Rhodococcus equi and Brucella pulmonary mass in immunocompetent: A case report and literature review
  63. Downregulation of RIP3 ameliorates the left ventricular mechanics and function after myocardial infarction via modulating NF-κB/NLRP3 pathway
  64. Evaluation of the role of some non-enzymatic antioxidants among Iraqi patients with non-alcoholic fatty liver disease
  65. The role of Phafin proteins in cell signaling pathways and diseases
  66. Ten-year anemia as initial manifestation of Castleman disease in the abdominal cavity: A case report
  67. Coexistence of hereditary spherocytosis with SPTB P.Trp1150 gene variant and Gilbert syndrome: A case report and literature review
  68. Utilization of convolutional neural networks to analyze microscopic images for high-throughput screening of mesenchymal stem cells
  69. Exploratory evaluation supported by experimental and modeling approaches of Inula viscosa root extract as a potent corrosion inhibitor for mild steel in a 1 M HCl solution
  70. Imaging manifestations of ductal adenoma of the breast: A case report
  71. Gut microbiota and sleep: Interaction mechanisms and therapeutic prospects
  72. Isomangiferin promotes the migration and osteogenic differentiation of rat bone marrow mesenchymal stem cells
  73. Prognostic value and microenvironmental crosstalk of exosome-related signatures in human epidermal growth factor receptor 2 positive breast cancer
  74. Circular RNAs as potential biomarkers for male severe sepsis
  75. Knockdown of Stanniocalcin-1 inhibits growth and glycolysis in oral squamous cell carcinoma cells
  76. The expression and biological role of complement C1s in esophageal squamous cell carcinoma
  77. A novel GNAS mutation in pseudohypoparathyroidism type 1a with articular flexion deformity: A case report
  78. Predictive value of serum magnesium levels for prognosis in patients with non-small cell lung cancer undergoing EGFR-TKI therapy
  79. HSPB1 alleviates acute-on-chronic liver failure via the P53/Bax pathway
  80. IgG4-related disease complicated by PLA2R-associated membranous nephropathy: A case report
  81. Baculovirus-mediated endostatin and angiostatin activation of autophagy through the AMPK/AKT/mTOR pathway inhibits angiogenesis in hepatocellular carcinoma
  82. Metformin mitigates osteoarthritis progression by modulating the PI3K/AKT/mTOR signaling pathway and enhancing chondrocyte autophagy
  83. Evaluation of the activity of antimicrobial peptides against bacterial vaginosis
  84. Atypical presentation of γ/δ mycosis fungoides with an unusual phenotype and SOCS1 mutation
  85. Analysis of the microecological mechanism of diabetic kidney disease based on the theory of “gut–kidney axis”: A systematic review
  86. Omega-3 fatty acids prevent gestational diabetes mellitus via modulation of lipid metabolism
  87. Refractory hypertension complicated with Turner syndrome: A case report
  88. Interaction of ncRNAs and the PI3K/AKT/mTOR pathway: Implications for osteosarcoma
  89. Association of low attenuation area scores with pulmonary function and clinical prognosis in patients with chronic obstructive pulmonary disease
  90. Long non-coding RNAs in bone formation: Key regulators and therapeutic prospects
  91. The deubiquitinating enzyme USP35 regulates the stability of NRF2 protein
  92. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as potential diagnostic markers for rebleeding in patients with esophagogastric variceal bleeding
  93. G protein-coupled receptor 1 participating in the mechanism of mediating gestational diabetes mellitus by phosphorylating the AKT pathway
  94. LL37-mtDNA regulates viability, apoptosis, inflammation, and autophagy in lipopolysaccharide-treated RLE-6TN cells by targeting Hsp90aa1
  95. The analgesic effect of paeoniflorin: A focused review
  96. Chemical composition’s effect on Solanum nigrum Linn.’s antioxidant capacity and erythrocyte protection: Bioactive components and molecular docking analysis
  97. Knockdown of HCK promotes HREC cell viability and inner blood–retinal barrier integrity by regulating the AMPK signaling pathway
  98. The role of rapamycin in the PINK1/Parkin signaling pathway in mitophagy in podocytes
  99. Laryngeal non-Hodgkin lymphoma: Report of four cases and review of the literature
  100. Clinical value of macrogenome next-generation sequencing on infections
  101. Overview of dendritic cells and related pathways in autoimmune uveitis
  102. TAK-242 alleviates diabetic cardiomyopathy via inhibiting pyroptosis and TLR4/CaMKII/NLRP3 pathway
  103. Hypomethylation in promoters of PGC-1α involved in exercise-driven skeletal muscular alterations in old age
  104. Profile and antimicrobial susceptibility patterns of bacteria isolated from effluents of Kolladiba and Debark hospitals
  105. The expression and clinical significance of syncytin-1 in serum exosomes of hepatocellular carcinoma patients
  106. A histomorphometric study to evaluate the therapeutic effects of biosynthesized silver nanoparticles on the kidneys infected with Plasmodium chabaudi
  107. PGRMC1 and PAQR4 are promising molecular targets for a rare subtype of ovarian cancer
  108. Analysis of MDA, SOD, TAOC, MNCV, SNCV, and TSS scores in patients with diabetes peripheral neuropathy
  109. SLIT3 deficiency promotes non-small cell lung cancer progression by modulating UBE2C/WNT signaling
  110. The relationship between TMCO1 and CALR in the pathological characteristics of prostate cancer and its effect on the metastasis of prostate cancer cells
  111. Heterogeneous nuclear ribonucleoprotein K is a potential target for enhancing the chemosensitivity of nasopharyngeal carcinoma
  112. PHB2 alleviates retinal pigment epithelium cell fibrosis by suppressing the AGE–RAGE pathway
  113. Anti-γ-aminobutyric acid-B receptor autoimmune encephalitis with syncope as the initial symptom: Case report and literature review
  114. Comparative analysis of chloroplast genome of Lonicera japonica cv. Damaohua
  115. Human umbilical cord mesenchymal stem cells regulate glutathione metabolism depending on the ERK–Nrf2–HO-1 signal pathway to repair phosphoramide mustard-induced ovarian cancer cells
  116. Electroacupuncture on GB acupoints improves osteoporosis via the estradiol–PI3K–Akt signaling pathway
  117. Renalase protects against podocyte injury by inhibiting oxidative stress and apoptosis in diabetic nephropathy
  118. Review: Dicranostigma leptopodum: A peculiar plant of Papaveraceae
  119. Combination effect of flavonoids attenuates lung cancer cell proliferation by inhibiting the STAT3 and FAK signaling pathway
  120. Renal microangiopathy and immune complex glomerulonephritis induced by anti-tumour agents: A case report
  121. Correlation analysis of AVPR1a and AVPR2 with abnormal water and sodium and potassium metabolism in rats
  122. Gastrointestinal health anti-diarrheal mixture relieves spleen deficiency-induced diarrhea through regulating gut microbiota
  123. Myriad factors and pathways influencing tumor radiotherapy resistance
  124. Exploring the effects of culture conditions on Yapsin (YPS) gene expression in Nakaseomyces glabratus
  125. Screening of prognostic core genes based on cell–cell interaction in the peripheral blood of patients with sepsis
  126. Coagulation factor II thrombin receptor as a promising biomarker in breast cancer management
  127. Ileocecal mucinous carcinoma misdiagnosed as incarcerated hernia: A case report
  128. Methyltransferase like 13 promotes malignant behaviors of bladder cancer cells through targeting PI3K/ATK signaling pathway
  129. The debate between electricity and heat, efficacy and safety of irreversible electroporation and radiofrequency ablation in the treatment of liver cancer: A meta-analysis
  130. ZAG promotes colorectal cancer cell proliferation and epithelial–mesenchymal transition by promoting lipid synthesis
  131. Baicalein inhibits NLRP3 inflammasome activation and mitigates placental inflammation and oxidative stress in gestational diabetes mellitus
  132. Impact of SWCNT-conjugated senna leaf extract on breast cancer cells: A potential apoptotic therapeutic strategy
  133. MFAP5 inhibits the malignant progression of endometrial cancer cells in vitro
  134. Major ozonated autohemotherapy promoted functional recovery following spinal cord injury in adult rats via the inhibition of oxidative stress and inflammation
  135. Axodendritic targeting of TAU and MAP2 and microtubule polarization in iPSC-derived versus SH-SY5Y-derived human neurons
  136. Differential expression of phosphoinositide 3-kinase/protein kinase B and Toll-like receptor/nuclear factor kappa B signaling pathways in experimental obesity Wistar rat model
  137. The therapeutic potential of targeting Oncostatin M and the interleukin-6 family in retinal diseases: A comprehensive review
  138. BA inhibits LPS-stimulated inflammatory response and apoptosis in human middle ear epithelial cells by regulating the Nf-Kb/Iκbα axis
  139. Role of circRMRP and circRPL27 in chronic obstructive pulmonary disease
  140. Investigating the role of hyperexpressed HCN1 in inducing myocardial infarction through activation of the NF-κB signaling pathway
  141. Characterization of phenolic compounds and evaluation of anti-diabetic potential in Cannabis sativa L. seeds: In vivo, in vitro, and in silico studies
  142. Quantitative immunohistochemistry analysis of breast Ki67 based on artificial intelligence
  143. Ecology and Environmental Science
  144. Screening of different growth conditions of Bacillus subtilis isolated from membrane-less microbial fuel cell toward antimicrobial activity profiling
  145. Degradation of a mixture of 13 polycyclic aromatic hydrocarbons by commercial effective microorganisms
  146. Evaluation of the impact of two citrus plants on the variation of Panonychus citri (Acari: Tetranychidae) and beneficial phytoseiid mites
  147. Prediction of present and future distribution areas of Juniperus drupacea Labill and determination of ethnobotany properties in Antalya Province, Türkiye
  148. Population genetics of Todarodes pacificus (Cephalopoda: Ommastrephidae) in the northwest Pacific Ocean via GBS sequencing
  149. A comparative analysis of dendrometric, macromorphological, and micromorphological characteristics of Pistacia atlantica subsp. atlantica and Pistacia terebinthus in the middle Atlas region of Morocco
  150. Macrofungal sporocarp community in the lichen Scots pine forests
  151. Assessing the proximate compositions of indigenous forage species in Yemen’s pastoral rangelands
  152. Food Science
  153. Gut microbiota changes associated with low-carbohydrate diet intervention for obesity
  154. Reexamination of Aspergillus cristatus phylogeny in dark tea: Characteristics of the mitochondrial genome
  155. Differences in the flavonoid composition of the leaves, fruits, and branches of mulberry are distinguished based on a plant metabolomics approach
  156. Investigating the impact of wet rendering (solventless method) on PUFA-rich oil from catfish (Clarias magur) viscera
  157. Non-linear associations between cardiovascular metabolic indices and metabolic-associated fatty liver disease: A cross-sectional study in the US population (2017–2020)
  158. Knockdown of USP7 alleviates atherosclerosis in ApoE-deficient mice by regulating EZH2 expression
  159. Utility of dairy microbiome as a tool for authentication and traceability
  160. Agriculture
  161. Enhancing faba bean (Vicia faba L.) productivity through establishing the area-specific fertilizer rate recommendation in southwest Ethiopia
  162. Impact of novel herbicide based on synthetic auxins and ALS inhibitor on weed control
  163. Perspectives of pteridophytes microbiome for bioremediation in agricultural applications
  164. Fertilizer application parameters for drip-irrigated peanut based on the fertilizer effect function established from a “3414” field trial
  165. Improving the productivity and profitability of maize (Zea mays L.) using optimum blended inorganic fertilization
  166. Application of leaf multispectral analyzer in comparison to hyperspectral device to assess the diversity of spectral reflectance indices in wheat genotypes
  167. Animal Sciences
  168. Knockdown of ANP32E inhibits colorectal cancer cell growth and glycolysis by regulating the AKT/mTOR pathway
  169. Development of a detection chip for major pathogenic drug-resistant genes and drug targets in bovine respiratory system diseases
  170. Exploration of the genetic influence of MYOT and MB genes on the plumage coloration of Muscovy ducks
  171. Transcriptome analysis of adipose tissue in grazing cattle: Identifying key regulators of fat metabolism
  172. Comparison of nutritional value of the wild and cultivated spiny loaches at three growth stages
  173. Transcriptomic analysis of liver immune response in Chinese spiny frog (Quasipaa spinosa) infected with Proteus mirabilis
  174. Disruption of BCAA degradation is a critical characteristic of diabetic cardiomyopathy revealed by integrated transcriptome and metabolome analysis
  175. Plant Sciences
  176. Effect of long-term in-row branch covering on soil microorganisms in pear orchards
  177. Photosynthetic physiological characteristics, growth performance, and element concentrations reveal the calcicole–calcifuge behaviors of three Camellia species
  178. Transcriptome analysis reveals the mechanism of NaHCO3 promoting tobacco leaf maturation
  179. Bioinformatics, expression analysis, and functional verification of allene oxide synthase gene HvnAOS1 and HvnAOS2 in qingke
  180. Water, nitrogen, and phosphorus coupling improves gray jujube fruit quality and yield
  181. Improving grape fruit quality through soil conditioner: Insights from RNA-seq analysis of Cabernet Sauvignon roots
  182. Role of Embinin in the reabsorption of nucleus pulposus in lumbar disc herniation: Promotion of nucleus pulposus neovascularization and apoptosis of nucleus pulposus cells
  183. Revealing the effects of amino acid, organic acid, and phytohormones on the germination of tomato seeds under salinity stress
  184. Combined effects of nitrogen fertilizer and biochar on the growth, yield, and quality of pepper
  185. Comprehensive phytochemical and toxicological analysis of Chenopodium ambrosioides (L.) fractions
  186. Impact of “3414” fertilization on the yield and quality of greenhouse tomatoes
  187. Exploring the coupling mode of water and fertilizer for improving growth, fruit quality, and yield of the pear in the arid region
  188. Metagenomic analysis of endophytic bacteria in seed potato (Solanum tuberosum)
  189. Antibacterial, antifungal, and phytochemical properties of Salsola kali ethanolic extract
  190. Exploring the hepatoprotective properties of citronellol: In vitro and in silico studies on ethanol-induced damage in HepG2 cells
  191. Enhanced osmotic dehydration of watermelon rind using honey–sucrose solutions: A study on pre-treatment efficacy and mass transfer kinetics
  192. Effects of exogenous 2,4-epibrassinolide on photosynthetic traits of 53 cowpea varieties under NaCl stress
  193. Comparative transcriptome analysis of maize (Zea mays L.) seedlings in response to copper stress
  194. An optimization method for measuring the stomata in cassava (Manihot esculenta Crantz) under multiple abiotic stresses
  195. Fosinopril inhibits Ang II-induced VSMC proliferation, phenotype transformation, migration, and oxidative stress through the TGF-β1/Smad signaling pathway
  196. Antioxidant and antimicrobial activities of Salsola imbricata methanolic extract and its phytochemical characterization
  197. Bioengineering and Biotechnology
  198. Absorbable calcium and phosphorus bioactive membranes promote bone marrow mesenchymal stem cells osteogenic differentiation for bone regeneration
  199. New advances in protein engineering for industrial applications: Key takeaways
  200. An overview of the production and use of Bacillus thuringiensis toxin
  201. Research progress of nanoparticles in diagnosis and treatment of hepatocellular carcinoma
  202. Bioelectrochemical biosensors for water quality assessment and wastewater monitoring
  203. PEI/MMNs@LNA-542 nanoparticles alleviate ICU-acquired weakness through targeted autophagy inhibition and mitochondrial protection
  204. Unleashing of cytotoxic effects of thymoquinone-bovine serum albumin nanoparticles on A549 lung cancer cells
  205. Erratum
  206. Erratum to “Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM”
  207. Erratum to “Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation”
  208. Retraction
  209. Retraction to “MiR-223-3p regulates cell viability, migration, invasion, and apoptosis of non-small cell lung cancer cells by targeting RHOB”
  210. Retraction to “A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis”
  211. Special Issue on Advances in Neurodegenerative Disease Research and Treatment
  212. Transplantation of human neural stem cell prevents symptomatic motor behavior disability in a rat model of Parkinson’s disease
  213. Special Issue on Multi-omics
  214. Inflammasome complex genes with clinical relevance suggest potential as therapeutic targets for anti-tumor drugs in clear cell renal cell carcinoma
  215. Gastroesophageal varices in primary biliary cholangitis with anti-centromere antibody positivity: Early onset?
https://doi.org/10.1515/biol-2022-1000
Keywords for this article
A549 cells; thymoquinone; bovine serum albumin; cytotoxic; anticancer activity
Creative Commons
BY 4.0

Articles in the same Issue

  1. Biomedical Sciences
  2. Constitutive and evoked release of ATP in adult mouse olfactory epithelium
  3. LARP1 knockdown inhibits cultured gastric carcinoma cell cycle progression and metastatic behavior
  4. PEGylated porcine–human recombinant uricase: A novel fusion protein with improved efficacy and safety for the treatment of hyperuricemia and renal complications
  5. Research progress on ocular complications caused by type 2 diabetes mellitus and the function of tears and blepharons
  6. The role and mechanism of esketamine in preventing and treating remifentanil-induced hyperalgesia based on the NMDA receptor–CaMKII pathway
  7. Brucella infection combined with Nocardia infection: A case report and literature review
  8. Detection of serum interleukin-18 level and neutrophil/lymphocyte ratio in patients with antineutrophil cytoplasmic antibody-associated vasculitis and its clinical significance
  9. Ang-1, Ang-2, and Tie2 are diagnostic biomarkers for Henoch-Schönlein purpura and pediatric-onset systemic lupus erythematous
  10. PTTG1 induces pancreatic cancer cell proliferation and promotes aerobic glycolysis by regulating c-myc
  11. Role of serum B-cell-activating factor and interleukin-17 as biomarkers in the classification of interstitial pneumonia with autoimmune features
  12. Effectiveness and safety of a mumps containing vaccine in preventing laboratory-confirmed mumps cases from 2002 to 2017: A meta-analysis
  13. Low levels of sex hormone-binding globulin predict an increased breast cancer risk and its underlying molecular mechanisms
  14. A case of Trousseau syndrome: Screening, detection and complication
  15. Application of the integrated airway humidification device enhances the humidification effect of the rabbit tracheotomy model
  16. Preparation of Cu2+/TA/HAP composite coating with anti-bacterial and osteogenic potential on 3D-printed porous Ti alloy scaffolds for orthopedic applications
  17. Aquaporin-8 promotes human dermal fibroblasts to counteract hydrogen peroxide-induced oxidative damage: A novel target for management of skin aging
  18. Current research and evidence gaps on placental development in iron deficiency anemia
  19. Single-nucleotide polymorphism rs2910829 in PDE4D is related to stroke susceptibility in Chinese populations: The results of a meta-analysis
  20. Pheochromocytoma-induced myocardial infarction: A case report
  21. Kaempferol regulates apoptosis and migration of neural stem cells to attenuate cerebral infarction by O‐GlcNAcylation of β-catenin
  22. Sirtuin 5 regulates acute myeloid leukemia cell viability and apoptosis by succinylation modification of glycine decarboxylase
  23. Apigenin 7-glucoside impedes hypoxia-induced malignant phenotypes of cervical cancer cells in a p16-dependent manner
  24. KAT2A changes the function of endometrial stromal cells via regulating the succinylation of ENO1
  25. Current state of research on copper complexes in the treatment of breast cancer
  26. Exploring antioxidant strategies in the pathogenesis of ALS
  27. Helicobacter pylori causes gastric dysbacteriosis in chronic gastritis patients
  28. IL-33/soluble ST2 axis is associated with radiation-induced cardiac injury
  29. The predictive value of serum NLR, SII, and OPNI for lymph node metastasis in breast cancer patients with internal mammary lymph nodes after thoracoscopic surgery
  30. Carrying SNP rs17506395 (T > G) in TP63 gene and CCR5Δ32 mutation associated with the occurrence of breast cancer in Burkina Faso
  31. P2X7 receptor: A receptor closely linked with sepsis-associated encephalopathy
  32. Probiotics for inflammatory bowel disease: Is there sufficient evidence?
  33. Identification of KDM4C as a gene conferring drug resistance in multiple myeloma
  34. Microbial perspective on the skin–gut axis and atopic dermatitis
  35. Thymosin α1 combined with XELOX improves immune function and reduces serum tumor markers in colorectal cancer patients after radical surgery
  36. Highly specific vaginal microbiome signature for gynecological cancers
  37. Sample size estimation for AQP4-IgG seropositive optic neuritis: Retinal damage detection by optical coherence tomography
  38. The effects of SDF-1 combined application with VEGF on femoral distraction osteogenesis in rats
  39. Fabrication and characterization of gold nanoparticles using alginate: In vitro and in vivo assessment of its administration effects with swimming exercise on diabetic rats
  40. Mitigating digestive disorders: Action mechanisms of Mediterranean herbal active compounds
  41. Distribution of CYP2D6 and CYP2C19 gene polymorphisms in Han and Uygur populations with breast cancer in Xinjiang, China
  42. VSP-2 attenuates secretion of inflammatory cytokines induced by LPS in BV2 cells by mediating the PPARγ/NF-κB signaling pathway
  43. Factors influencing spontaneous hypothermia after emergency trauma and the construction of a predictive model
  44. Long-term administration of morphine specifically alters the level of protein expression in different brain regions and affects the redox state
  45. Application of metagenomic next-generation sequencing technology in the etiological diagnosis of peritoneal dialysis-associated peritonitis
  46. Clinical diagnosis, prevention, and treatment of neurodyspepsia syndrome using intelligent medicine
  47. Case report: Successful bronchoscopic interventional treatment of endobronchial leiomyomas
  48. Preliminary investigation into the genetic etiology of short stature in children through whole exon sequencing of the core family
  49. Cystic adenomyoma of the uterus: Case report and literature review
  50. Mesoporous silica nanoparticles as a drug delivery mechanism
  51. Dynamic changes in autophagy activity in different degrees of pulmonary fibrosis in mice
  52. Vitamin D deficiency and inflammatory markers in type 2 diabetes: Big data insights
  53. Lactate-induced IGF1R protein lactylation promotes proliferation and metabolic reprogramming of lung cancer cells
  54. Meta-analysis on the efficacy of allogeneic hematopoietic stem cell transplantation to treat malignant lymphoma
  55. Mitochondrial DNA drives neuroinflammation through the cGAS-IFN signaling pathway in the spinal cord of neuropathic pain mice
  56. Application value of artificial intelligence algorithm-based magnetic resonance multi-sequence imaging in staging diagnosis of cervical cancer
  57. Embedded monitoring system and teaching of artificial intelligence online drug component recognition
  58. Investigation into the association of FNDC1 and ADAMTS12 gene expression with plumage coloration in Muscovy ducks
  59. Yak meat content in feed and its impact on the growth of rats
  60. A rare case of Richter transformation with breast involvement: A case report and literature review
  61. First report of Nocardia wallacei infection in an immunocompetent patient in Zhejiang province
  62. Rhodococcus equi and Brucella pulmonary mass in immunocompetent: A case report and literature review
  63. Downregulation of RIP3 ameliorates the left ventricular mechanics and function after myocardial infarction via modulating NF-κB/NLRP3 pathway
  64. Evaluation of the role of some non-enzymatic antioxidants among Iraqi patients with non-alcoholic fatty liver disease
  65. The role of Phafin proteins in cell signaling pathways and diseases
  66. Ten-year anemia as initial manifestation of Castleman disease in the abdominal cavity: A case report
  67. Coexistence of hereditary spherocytosis with SPTB P.Trp1150 gene variant and Gilbert syndrome: A case report and literature review
  68. Utilization of convolutional neural networks to analyze microscopic images for high-throughput screening of mesenchymal stem cells
  69. Exploratory evaluation supported by experimental and modeling approaches of Inula viscosa root extract as a potent corrosion inhibitor for mild steel in a 1 M HCl solution
  70. Imaging manifestations of ductal adenoma of the breast: A case report
  71. Gut microbiota and sleep: Interaction mechanisms and therapeutic prospects
  72. Isomangiferin promotes the migration and osteogenic differentiation of rat bone marrow mesenchymal stem cells
  73. Prognostic value and microenvironmental crosstalk of exosome-related signatures in human epidermal growth factor receptor 2 positive breast cancer
  74. Circular RNAs as potential biomarkers for male severe sepsis
  75. Knockdown of Stanniocalcin-1 inhibits growth and glycolysis in oral squamous cell carcinoma cells
  76. The expression and biological role of complement C1s in esophageal squamous cell carcinoma
  77. A novel GNAS mutation in pseudohypoparathyroidism type 1a with articular flexion deformity: A case report
  78. Predictive value of serum magnesium levels for prognosis in patients with non-small cell lung cancer undergoing EGFR-TKI therapy
  79. HSPB1 alleviates acute-on-chronic liver failure via the P53/Bax pathway
  80. IgG4-related disease complicated by PLA2R-associated membranous nephropathy: A case report
  81. Baculovirus-mediated endostatin and angiostatin activation of autophagy through the AMPK/AKT/mTOR pathway inhibits angiogenesis in hepatocellular carcinoma
  82. Metformin mitigates osteoarthritis progression by modulating the PI3K/AKT/mTOR signaling pathway and enhancing chondrocyte autophagy
  83. Evaluation of the activity of antimicrobial peptides against bacterial vaginosis
  84. Atypical presentation of γ/δ mycosis fungoides with an unusual phenotype and SOCS1 mutation
  85. Analysis of the microecological mechanism of diabetic kidney disease based on the theory of “gut–kidney axis”: A systematic review
  86. Omega-3 fatty acids prevent gestational diabetes mellitus via modulation of lipid metabolism
  87. Refractory hypertension complicated with Turner syndrome: A case report
  88. Interaction of ncRNAs and the PI3K/AKT/mTOR pathway: Implications for osteosarcoma
  89. Association of low attenuation area scores with pulmonary function and clinical prognosis in patients with chronic obstructive pulmonary disease
  90. Long non-coding RNAs in bone formation: Key regulators and therapeutic prospects
  91. The deubiquitinating enzyme USP35 regulates the stability of NRF2 protein
  92. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as potential diagnostic markers for rebleeding in patients with esophagogastric variceal bleeding
  93. G protein-coupled receptor 1 participating in the mechanism of mediating gestational diabetes mellitus by phosphorylating the AKT pathway
  94. LL37-mtDNA regulates viability, apoptosis, inflammation, and autophagy in lipopolysaccharide-treated RLE-6TN cells by targeting Hsp90aa1
  95. The analgesic effect of paeoniflorin: A focused review
  96. Chemical composition’s effect on Solanum nigrum Linn.’s antioxidant capacity and erythrocyte protection: Bioactive components and molecular docking analysis
  97. Knockdown of HCK promotes HREC cell viability and inner blood–retinal barrier integrity by regulating the AMPK signaling pathway
  98. The role of rapamycin in the PINK1/Parkin signaling pathway in mitophagy in podocytes
  99. Laryngeal non-Hodgkin lymphoma: Report of four cases and review of the literature
  100. Clinical value of macrogenome next-generation sequencing on infections
  101. Overview of dendritic cells and related pathways in autoimmune uveitis
  102. TAK-242 alleviates diabetic cardiomyopathy via inhibiting pyroptosis and TLR4/CaMKII/NLRP3 pathway
  103. Hypomethylation in promoters of PGC-1α involved in exercise-driven skeletal muscular alterations in old age
  104. Profile and antimicrobial susceptibility patterns of bacteria isolated from effluents of Kolladiba and Debark hospitals
  105. The expression and clinical significance of syncytin-1 in serum exosomes of hepatocellular carcinoma patients
  106. A histomorphometric study to evaluate the therapeutic effects of biosynthesized silver nanoparticles on the kidneys infected with Plasmodium chabaudi
  107. PGRMC1 and PAQR4 are promising molecular targets for a rare subtype of ovarian cancer
  108. Analysis of MDA, SOD, TAOC, MNCV, SNCV, and TSS scores in patients with diabetes peripheral neuropathy
  109. SLIT3 deficiency promotes non-small cell lung cancer progression by modulating UBE2C/WNT signaling
  110. The relationship between TMCO1 and CALR in the pathological characteristics of prostate cancer and its effect on the metastasis of prostate cancer cells
  111. Heterogeneous nuclear ribonucleoprotein K is a potential target for enhancing the chemosensitivity of nasopharyngeal carcinoma
  112. PHB2 alleviates retinal pigment epithelium cell fibrosis by suppressing the AGE–RAGE pathway
  113. Anti-γ-aminobutyric acid-B receptor autoimmune encephalitis with syncope as the initial symptom: Case report and literature review
  114. Comparative analysis of chloroplast genome of Lonicera japonica cv. Damaohua
  115. Human umbilical cord mesenchymal stem cells regulate glutathione metabolism depending on the ERK–Nrf2–HO-1 signal pathway to repair phosphoramide mustard-induced ovarian cancer cells
  116. Electroacupuncture on GB acupoints improves osteoporosis via the estradiol–PI3K–Akt signaling pathway
  117. Renalase protects against podocyte injury by inhibiting oxidative stress and apoptosis in diabetic nephropathy
  118. Review: Dicranostigma leptopodum: A peculiar plant of Papaveraceae
  119. Combination effect of flavonoids attenuates lung cancer cell proliferation by inhibiting the STAT3 and FAK signaling pathway
  120. Renal microangiopathy and immune complex glomerulonephritis induced by anti-tumour agents: A case report
  121. Correlation analysis of AVPR1a and AVPR2 with abnormal water and sodium and potassium metabolism in rats
  122. Gastrointestinal health anti-diarrheal mixture relieves spleen deficiency-induced diarrhea through regulating gut microbiota
  123. Myriad factors and pathways influencing tumor radiotherapy resistance
  124. Exploring the effects of culture conditions on Yapsin (YPS) gene expression in Nakaseomyces glabratus
  125. Screening of prognostic core genes based on cell–cell interaction in the peripheral blood of patients with sepsis
  126. Coagulation factor II thrombin receptor as a promising biomarker in breast cancer management
  127. Ileocecal mucinous carcinoma misdiagnosed as incarcerated hernia: A case report
  128. Methyltransferase like 13 promotes malignant behaviors of bladder cancer cells through targeting PI3K/ATK signaling pathway
  129. The debate between electricity and heat, efficacy and safety of irreversible electroporation and radiofrequency ablation in the treatment of liver cancer: A meta-analysis
  130. ZAG promotes colorectal cancer cell proliferation and epithelial–mesenchymal transition by promoting lipid synthesis
  131. Baicalein inhibits NLRP3 inflammasome activation and mitigates placental inflammation and oxidative stress in gestational diabetes mellitus
  132. Impact of SWCNT-conjugated senna leaf extract on breast cancer cells: A potential apoptotic therapeutic strategy
  133. MFAP5 inhibits the malignant progression of endometrial cancer cells in vitro
  134. Major ozonated autohemotherapy promoted functional recovery following spinal cord injury in adult rats via the inhibition of oxidative stress and inflammation
  135. Axodendritic targeting of TAU and MAP2 and microtubule polarization in iPSC-derived versus SH-SY5Y-derived human neurons
  136. Differential expression of phosphoinositide 3-kinase/protein kinase B and Toll-like receptor/nuclear factor kappa B signaling pathways in experimental obesity Wistar rat model
  137. The therapeutic potential of targeting Oncostatin M and the interleukin-6 family in retinal diseases: A comprehensive review
  138. BA inhibits LPS-stimulated inflammatory response and apoptosis in human middle ear epithelial cells by regulating the Nf-Kb/Iκbα axis
  139. Role of circRMRP and circRPL27 in chronic obstructive pulmonary disease
  140. Investigating the role of hyperexpressed HCN1 in inducing myocardial infarction through activation of the NF-κB signaling pathway
  141. Characterization of phenolic compounds and evaluation of anti-diabetic potential in Cannabis sativa L. seeds: In vivo, in vitro, and in silico studies
  142. Quantitative immunohistochemistry analysis of breast Ki67 based on artificial intelligence
  143. Ecology and Environmental Science
  144. Screening of different growth conditions of Bacillus subtilis isolated from membrane-less microbial fuel cell toward antimicrobial activity profiling
  145. Degradation of a mixture of 13 polycyclic aromatic hydrocarbons by commercial effective microorganisms
  146. Evaluation of the impact of two citrus plants on the variation of Panonychus citri (Acari: Tetranychidae) and beneficial phytoseiid mites
  147. Prediction of present and future distribution areas of Juniperus drupacea Labill and determination of ethnobotany properties in Antalya Province, Türkiye
  148. Population genetics of Todarodes pacificus (Cephalopoda: Ommastrephidae) in the northwest Pacific Ocean via GBS sequencing
  149. A comparative analysis of dendrometric, macromorphological, and micromorphological characteristics of Pistacia atlantica subsp. atlantica and Pistacia terebinthus in the middle Atlas region of Morocco
  150. Macrofungal sporocarp community in the lichen Scots pine forests
  151. Assessing the proximate compositions of indigenous forage species in Yemen’s pastoral rangelands
  152. Food Science
  153. Gut microbiota changes associated with low-carbohydrate diet intervention for obesity
  154. Reexamination of Aspergillus cristatus phylogeny in dark tea: Characteristics of the mitochondrial genome
  155. Differences in the flavonoid composition of the leaves, fruits, and branches of mulberry are distinguished based on a plant metabolomics approach
  156. Investigating the impact of wet rendering (solventless method) on PUFA-rich oil from catfish (Clarias magur) viscera
  157. Non-linear associations between cardiovascular metabolic indices and metabolic-associated fatty liver disease: A cross-sectional study in the US population (2017–2020)
  158. Knockdown of USP7 alleviates atherosclerosis in ApoE-deficient mice by regulating EZH2 expression
  159. Utility of dairy microbiome as a tool for authentication and traceability
  160. Agriculture
  161. Enhancing faba bean (Vicia faba L.) productivity through establishing the area-specific fertilizer rate recommendation in southwest Ethiopia
  162. Impact of novel herbicide based on synthetic auxins and ALS inhibitor on weed control
  163. Perspectives of pteridophytes microbiome for bioremediation in agricultural applications
  164. Fertilizer application parameters for drip-irrigated peanut based on the fertilizer effect function established from a “3414” field trial
  165. Improving the productivity and profitability of maize (Zea mays L.) using optimum blended inorganic fertilization
  166. Application of leaf multispectral analyzer in comparison to hyperspectral device to assess the diversity of spectral reflectance indices in wheat genotypes
  167. Animal Sciences
  168. Knockdown of ANP32E inhibits colorectal cancer cell growth and glycolysis by regulating the AKT/mTOR pathway
  169. Development of a detection chip for major pathogenic drug-resistant genes and drug targets in bovine respiratory system diseases
  170. Exploration of the genetic influence of MYOT and MB genes on the plumage coloration of Muscovy ducks
  171. Transcriptome analysis of adipose tissue in grazing cattle: Identifying key regulators of fat metabolism
  172. Comparison of nutritional value of the wild and cultivated spiny loaches at three growth stages
  173. Transcriptomic analysis of liver immune response in Chinese spiny frog (Quasipaa spinosa) infected with Proteus mirabilis
  174. Disruption of BCAA degradation is a critical characteristic of diabetic cardiomyopathy revealed by integrated transcriptome and metabolome analysis
  175. Plant Sciences
  176. Effect of long-term in-row branch covering on soil microorganisms in pear orchards
  177. Photosynthetic physiological characteristics, growth performance, and element concentrations reveal the calcicole–calcifuge behaviors of three Camellia species
  178. Transcriptome analysis reveals the mechanism of NaHCO3 promoting tobacco leaf maturation
  179. Bioinformatics, expression analysis, and functional verification of allene oxide synthase gene HvnAOS1 and HvnAOS2 in qingke
  180. Water, nitrogen, and phosphorus coupling improves gray jujube fruit quality and yield
  181. Improving grape fruit quality through soil conditioner: Insights from RNA-seq analysis of Cabernet Sauvignon roots
  182. Role of Embinin in the reabsorption of nucleus pulposus in lumbar disc herniation: Promotion of nucleus pulposus neovascularization and apoptosis of nucleus pulposus cells
  183. Revealing the effects of amino acid, organic acid, and phytohormones on the germination of tomato seeds under salinity stress
  184. Combined effects of nitrogen fertilizer and biochar on the growth, yield, and quality of pepper
  185. Comprehensive phytochemical and toxicological analysis of Chenopodium ambrosioides (L.) fractions
  186. Impact of “3414” fertilization on the yield and quality of greenhouse tomatoes
  187. Exploring the coupling mode of water and fertilizer for improving growth, fruit quality, and yield of the pear in the arid region
  188. Metagenomic analysis of endophytic bacteria in seed potato (Solanum tuberosum)
  189. Antibacterial, antifungal, and phytochemical properties of Salsola kali ethanolic extract
  190. Exploring the hepatoprotective properties of citronellol: In vitro and in silico studies on ethanol-induced damage in HepG2 cells
  191. Enhanced osmotic dehydration of watermelon rind using honey–sucrose solutions: A study on pre-treatment efficacy and mass transfer kinetics
  192. Effects of exogenous 2,4-epibrassinolide on photosynthetic traits of 53 cowpea varieties under NaCl stress
  193. Comparative transcriptome analysis of maize (Zea mays L.) seedlings in response to copper stress
  194. An optimization method for measuring the stomata in cassava (Manihot esculenta Crantz) under multiple abiotic stresses
  195. Fosinopril inhibits Ang II-induced VSMC proliferation, phenotype transformation, migration, and oxidative stress through the TGF-β1/Smad signaling pathway
  196. Antioxidant and antimicrobial activities of Salsola imbricata methanolic extract and its phytochemical characterization
  197. Bioengineering and Biotechnology
  198. Absorbable calcium and phosphorus bioactive membranes promote bone marrow mesenchymal stem cells osteogenic differentiation for bone regeneration
  199. New advances in protein engineering for industrial applications: Key takeaways
  200. An overview of the production and use of Bacillus thuringiensis toxin
  201. Research progress of nanoparticles in diagnosis and treatment of hepatocellular carcinoma
  202. Bioelectrochemical biosensors for water quality assessment and wastewater monitoring
  203. PEI/MMNs@LNA-542 nanoparticles alleviate ICU-acquired weakness through targeted autophagy inhibition and mitochondrial protection
  204. Unleashing of cytotoxic effects of thymoquinone-bovine serum albumin nanoparticles on A549 lung cancer cells
  205. Erratum
  206. Erratum to “Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM”
  207. Erratum to “Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation”
  208. Retraction
  209. Retraction to “MiR-223-3p regulates cell viability, migration, invasion, and apoptosis of non-small cell lung cancer cells by targeting RHOB”
  210. Retraction to “A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis”
  211. Special Issue on Advances in Neurodegenerative Disease Research and Treatment
  212. Transplantation of human neural stem cell prevents symptomatic motor behavior disability in a rat model of Parkinson’s disease
  213. Special Issue on Multi-omics
  214. Inflammasome complex genes with clinical relevance suggest potential as therapeutic targets for anti-tumor drugs in clear cell renal cell carcinoma
  215. Gastroesophageal varices in primary biliary cholangitis with anti-centromere antibody positivity: Early onset?
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