Evaluation of the effectiveness of hesperidin and its derivatives in inhibiting human cancer MCF-7 cells and leshmania: an in vitro study

Mohammad Al-Halbosiy; Hanady Al Shmgani; Rakad Al-Jumaily; Baraa Abdulhameed; Lamees Jaed

doi:10.12688/f1000research.172260.1

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Research Article

Evaluation of the effectiveness of hesperidin and its derivatives in inhibiting human cancer MCF-7 cells and leshmania: an in vitro study

[version 1; peer review: awaiting peer review]

Mohammad Al-Halbosiy ¹, Hanady Al Shmgani ², Rakad Al-Jumaily³, Baraa Abdulhameed¹, Lamees Jaed²

Mohammad Al-Halbosiy ¹, Hanady Al Shmgani ², [...] Rakad Al-Jumaily³, Baraa Abdulhameed¹, Lamees Jaed²

PUBLISHED 16 Jan 2026

Author details Author details

¹ Al-Nahrain University/ Biotechnology research center, Baghdad, Iraq
² Biology Department, College of Education for Pure Sciences/Ibn al-Haitham, University of Baghdad, Baghdad ,Iraq, Baghdad, Iraq
³ Department of Biology, College of Science, University of Baghdad, Baghdad, Iraq, Baghdad, Iraq

Mohammad Al-Halbosiy
Roles: Formal Analysis, Methodology, Project Administration, Supervision, Writing – Review & Editing

Hanady Al Shmgani
Roles: Writing – Original Draft Preparation

Rakad Al-Jumaily
Roles: Data Curation, Investigation

Baraa Abdulhameed
Roles: Methodology

Lamees Jaed
Roles: Resources, Validation, Writing – Original Draft Preparation

OPEN PEER REVIEW

REVIEWER STATUS AWAITING PEER REVIEW

This article is included in the Fallujah Multidisciplinary Science and Innovation gateway.

Abstract

Background

Natural resources and their pharmaceutical products play an important role in disease management because of their potential for new drug discovery and historical traditional use in healthcare. This study aimed to investigate the effects of hesperidin and its derivatives on MCF-7 human breast cancer cells and leishmaniosis.

Methods

The colorimetric cell viability MTT assay was used to measure the efficacy of these compounds in inhibiting MCF-7 cell growth and the promastigote forms of Leishmania tropica. Cells treated with different concentrations (3.125, 6.25, 12.5, 25, 50, 100, and 200 μg/ml) of hesperidin and their derivative, derv.1(5-amino-1,3,4-thiadiazole-2-thiol), and derv. 2 (5-(methylthio)-1,3,4-thiadiazol-2-thiol) after 24 h exposure.

Results

The Results showed that hesperidin was the most effective in inhibiting MCF-7 cells, with a 58.3% inhibition rate at a concentration of 100 μg/ml, whereas the derivative (derv.2) exhibited the highest antileishmanial activity, with a 50.2% inhibition rate at the same concentration. The anticancer and antileishmanial effects were concentration-dependent, with inhibition rates decreasing at lower concentrations.

Conclusions

These findings indicate the potential role of hesperidin and its derivatives as anti-cancer and antileishmanial agents, suggesting new ways for further research into their medical applications.

Keywords

hesperidin, anti-cancer, antileishmanial, MCF-7 human breast cancer

Corresponding authors: Mohammad Al-Halbosiy, Hanady Al Shmgani

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2026 Al-Halbosiy M et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Al-Halbosiy M, Al Shmgani H, Al-Jumaily R et al. Evaluation of the effectiveness of hesperidin and its derivatives in inhibiting human cancer MCF-7 cells and leshmania: an in vitro study [version 1; peer review: awaiting peer review]. F1000Research 2026, 15:69 (https://doi.org/10.12688/f1000research.172260.1) First published: 16 Jan 2026, 15:69 (https://doi.org/10.12688/f1000research.172260.1) Latest published: 16 Jan 2026, 15:69 (https://doi.org/10.12688/f1000research.172260.1)

Introduction

Natural resources and their pharmaceutical products play an important role in the management of diseases with almost no adverse effects. Many studies have revealed that natural substances or their main components can enhance health in different ways, such as decreasing inflammation and oxidative stress, managing diseases, including autoimmune disease and cancer, and regulating the pathways of cell signaling.¹ The utilization of agriculture and/or its waste products for producing bioactive products is gaining traction because of its cost-effectiveness and potential to address waste disposal issues. This approach offers a sustainable alternative, as highlighted by research focusing on environmental implications.² Hesperidin (HSP) is a bioflavonoid found mainly in citrus fruits, particularly in peels. It functions as a protective agent and is produced by secondary plant metabolism. It exhibits various biological activities, including antioxidant, antibacterial, anti-inflammatory, and antitumor effects. Beyond citrus, HSP is also present in plant genera, such as Lamiaceae, Fabaceae, and Betulaceae. Its classification as a glycoside flavone underscores its role in plant defense and potential health benefits.^3,4

Cancer is characterized by uncontrolled division of cells, leading to the formation of tumors that can invade other tissues and metastasize at the speed at which cancer develops and becomes dangerous varies, with some cancers progressing rapidly while others take years. Treatments often target uncontrolled growth of cells. Breast cancer, the most common cancer in women, has a significant impact on mortality and morbidity.^5,6 Many studies have confirmed the role of natural products in preventing the development of breast cancer by promoting cancer cell apoptosis, inhibiting proliferation and metastasis of cancer cells, and avoiding signal transduction.^7,8 However, many biomolecules found in the human diet, including flavonoids, can act as chemopreventers and reduce cancer cell growth. Many mechanisms have been suggested to explain the effect of these biomolecules, such as apoptosis and cell-cycle arrest, in addition to their antioxidant qualities.⁹

Leishmaniasis is a parasitic disease caused by protozoan parasites of the Leishmania genus, transmitted through the bite of infected female phlebotomine sand flies. It is a neglected tropical disease (NTD) with a wide spectrum of clinical manifestations, ranging from self-healing cutaneous lesions to life-threatening visceral forms.¹⁰ The disease is endemic in tropical and subtropical regions and remains a significant public health challenge, particularly in resource-limited settings requiring integrated control strategies to reduce its burden.

Hesperidin, as well as many natural flavonoids, show low water solubility and few lipophilic molecules, hindering their ability to cross the cell membrane. To overcome these limitations, in our previous study, novel HSP derivatives were developed and synthesized that exhibited promising anticytotoxic and antioxidant properties.¹¹ In this study, we investigated the effects of HSP and its derivatives on MCF-7 human breast cancer cells, and their potential efficacy against leishmaniasis.

To overcome these limitations, new HSP derivatives have been developed and synthesized. Two novel HSP derivatives were successfully synthesized and described in our previous study, which exhibited promising anticytotoxic and antioxidant activities.¹¹ This study investigated the effects of hesperidin and its derivatives on MCF-7 human breast cancer cells and on leishmaniosis.

Materials and methods

Chemicals

Hesperidin (Catalogue no. H5006; ≥80%), and 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) (Catalogue no. 475989) were purchased from Sigma Aldrich (St. Louis, MO, USA). Roswell Park Memorial Institute (RPMI) 1640 medium, fetal bovine serum (FBS), and antibiotic–antimycotic solution were procured from Gibco (Gaithersburg, MD, USA).

Preparation and synthesis of HSP derivatives

The two derivatives used in this study were prepared and synthesized as described in our previous study.¹¹ The purity of the recrystallized compounds was assessed via thin-layer chromatography (TLC), and their structure was verified through physical properties and spectral analyses. The open capillary tube method was used to determine the melting point of the samples. IR spectra were obtained using Fourier-Transform Infrared (FTIR) spectroscopy and H-NMR spectra were acquired on a Bruker AVN 300 MHz spectrometer. Electron impact mass spectrometry (EIMS) analysis was performed using a Shimadzu-GC-MS-QP2010 Ultra System.

A solution of the first derivative, [drev.1] (5-amino-1,3,4-thiadiazole-2-thiol), was added dropwise to the HSP solution (0.133 g, 1 mmol) in glacial acetic acid (10 ml). The reaction mixture was refluxed for 18 h (monitored by TLC, CHCL₃, MeOH 1:1). The resulting precipitate was collected, washed with water, and recrystallized from aqueous DMF to yield a white amorphous solid (78%, mp 219-221°C). The second derivative was prepared as above with some medication (HSP 5-(methylthio)-1,3,4-thiadiazol-2-thiol [drev.2]; the modifications included thioether linkage at the 5-position of thiadiazole ring, shorter reaction time to 12 h, ethanol recrystallization solvent, and melting point 205-207°C.

Anticancer activity

The percentage of breast cancer growth inhibition was determined using the colorimetric MMT assay. The MCF-7 cell line (Michigan Cancer Foundation 7) is a widely used human breast cancer model, derived from a 69-year-old woman’s metastatic adenocarcinoma, we obtained it from the biotechnology research center/Al-Nahrain University, Baghdad, Iraq. Briefly, MCF-7 cells were seeded at a density of 1×10⁶ cells/ml in a 96-well plate. The test compound (hesperidin) was derived. 1 and derive. 2) were dissolved in an aqueous solution at concentrations of 3.15, 6.25, 12.5, 25, 50, and 100 μg/ml. Subsequently, 100 μL of each concentration was added to the respective well, followed by incubation at 37°C for 24 h. After incubation, 10 μL MTT solution (5 mg/ml) was added to each well and incubated for an additional 4h. To solubilize the formazan crystals, 50 μL of dimethyl sulfoxide (DMSO) was added to each well, followed by a 10-minute incubation. Untreated cell culture medium served as a negative control. All experiments were conducted in triplicates. The absorbance was measured at 620 nm using an ELISA reader, and the mean absorbance values for each replicate group were calculated. Cell viability (expressed as a percentage) and the inhibition ratio were determined using standard formulae, as follows¹²:

IG % = (Ac - As / Ac) \times 100

Ac = optical density of control, As = optical density of samples.

Antileishmanial activity assessment

The antileishmanial activity of hesperidin and its derivatives (derive.1 and derive.2) was evaluated against the promastigote form of Leishmania tropica.¹³ The L. tropica strain was obtained from and maintained at the Biotechnology Research Center, Al-Nahrain University. Promastigotes were cultured in RPMI-1640 medium supplemented with L-glutamine (20 mM), 10% fetal bovine serum, 100 U/ml penicillin, and 50 μg/ml streptomycin, all treated samples then incubated at 22-26°C.

Cell viability was assessed using the colorimetric MTT assay, as described in anticancer section above. L. tropica promastigotes (1 × 10⁶ cells/mL, 100 μL/well) were seeded into a 96-well tissue culture plate. The test compounds (hesperidin and Derv. 1, and Derv. 2) were dissolved in aqueous solutions at concentrations of 3.125, 6.25, 12.5, 25, 50, and 100 μg/mL, respectively. Subsequently. The following equation was used to determine cell growth inhibition:

IG % = (Ac - As / Ac) \times 100

Where AC = optical density of control, As = optical density of samples.

Statistical analysis

The experimental data were analyzed using SPSS (SPSS 23.0, SPSS Ins. III., USA). Significant differences were assessed using One-Way Analysis of variance (ANOVA), and P values ≤ 0.05 were considered significant.

Results and Discussion

MTT assay was used to measure the viability of MCF-7 breast cancer cells. Cells were treated with different concentrations (3.125, 6.25, 12.5, 25, 50, and 100 μg/ml) of hesperidin and its derivatives (derv.1 and 2) for 24 h. The Results of hesperidin exposure showed the best percentage of inhibition at 48.9% and 57.3% at the highest concentrations (50 and 100 μg/ml), respectively, compared to derv.1 (39.3% and 37.5%) and derv.2 (36.8% and 35%), respectively, as shown in Table 1. Also a considerable variance reveled between the 25 and 12.5 μg/ml with the lowest concentrations (6.25 and 3.125 μg/ml) among the different of hesperidin and their derv.1 and 2 ( Table 1).

Table 1. Percentage of inhibition of MCF-7 cell line by using the hesperidin and their derivative (derv.1 and 2) during 24 hours of exposure.

Conc. μg/ml	Hesperidin		Hesperidin derv.1		Hesperidin derv.2
Conc. μg/ml	Mean ± SD	GI%	Mean ± SD	GI%	Mean ± SD	GI%
100	0.196 ± 0.002	57.39	0.139 ± 0.057	39.3	0.144 ± 0.038	36.8
50	0.234 ± 0.018	48.9	0.143 ± 0.003	37.5	0.148 ± 0.007	35
25	0.262 ± 0.058	43	0.149 ± 0.006	34.9	0.155 ± 0.011	32
12.5	0.293 ± 0.039	36.3	0.178 ± 0.013	22.1	0.185 ± 0.019	18.8
6.25	0.376 ± 0.016	18.3	0.190 ± 0.004	17	0.197 ± 0.003	13.5
3.125	0.419 ± 0.140	8.9	0.212 ± 0.044	7.4	0.218 ± 0.024	4.4
Control	0.460 ± 0.002	-	0.229 ± 0.013	-	0.228 ± 0.019	-

The results in Table 2 indicate the antileishmanial activity of hesperidin and its derivative (derv.1 and 2) against promastigote forms of Leishmania tropica. Cells were treated with different concentrations (3.125, 6.25, 12.5, 25, 50, and 100 μg/ml) of hesperidin and derv.1 and 2 during 24 h of exposure. The Results of derv.2 exposure showed the highest percentage of inhibition of 35.7% and 50.2% at the highest concentrations (50 and 100 μg/ml), respectively, in comparison to hesperidin (30.1% and 24.7%) and derv.1 (33.3% and 25.2%), respectively, as shown in Table 2. In addition, considerable variance was observed at 25 μg/ml concentration between derv.2 (32.6%) and hesperidin (16%) and derv.1 (17.6%). However, no differences were observed at the lowest concentrations (6.25 and 3.125 μg/ml) among the hesperidin and their derv.1 and 2 ( Table 2).

Table 2. Percentage of inhibition of promastigote forms of Leishmania tropica by using the hesperidin and their derivative (derv.1 and 2) during 24 hours of exposure.

Conc. μg/ml	Hesperidin		Hesperidin derv.1		Hesperidin derv.2
Conc. μg/ml	Mean ± SD	GI%	Mean ± SD	GI%	Mean ± SD	GI%
100	0.304 ± 0.007	30.3	0.132 ± 0.002	33.3	0.230 ± 0.019	50.2
50	0.328 ± 0.049	24.7	0.148 ± 0.006	25.2	0.297 ± 0.005	35.6
25	0.366 ± 0.019	16	0.163 ± 0.007	17.6	0.311 ± 0.011	32.6
12.5	0.395 ± 0.009	9.4	0.180 ± 0.001	9	0.378 ± 0.005	18.2
6.25	0.412 ± 0.011	5.5	0.189 ± 0.005	4.5	0.421 ± 0.029	8.8
3.125	0.485 ± 0.026	0	0.201 ± 0.004	0	0.478 ± 0.001	0
Control	0.436 ± 0.022	-	0.198 ± 0.004	-	0.462 ± 0.002	-

The investigation of natural products and their semi-synthetic derivatives remains the cornerstone of pharmaceutical discovery, offering a rich reservoir of chemical scaffolds with diverse biological activities. This study contributes to this field by evaluating the anticancer and antileishmanial potential of the flavonoid hesperidin and two of its synthesized thiadiazole derivatives. These findings provide compelling preliminary evidence that the structural modification of a natural compound can selectively enhance its bioactivity against different pathogenic targets.

The most potent anticancer activity against MCF-7 human breast cancer cells was exhibited by the parent compound, hesperidin, which achieved 58.3% inhibition at 100 μg/ml with concentration-dependent inhibition of MCF-7 cell growth by hesperidin. This observation aligns with a substantial body of literature documenting the chemopreventive and antitumor properties of flavonoids by inducing apoptosis and inhibiting proliferation in cancer cells through mechanisms such as cell cycle arrest, often at the G1/S or G2/M checkpoints, and exhibiting potent antioxidant and anti-inflammatory effects that indirectly suppress tumor promotion and progression.¹⁴ The superior efficacy of HSP over its derivatives (derv.1 and 2) in inhibiting MCF-7 cells suggests that the pure structure may be more conducive to interacting with cancer cell pathways, possibly with its glycoside flavone backbone.¹⁵ However, the fact that the thiadiazole derivatives (derv.1 and derv.2) showed lower efficacy against MCF-7 cells than the parent hesperidin is a critical finding. This suggests that the specific structural motifs of hesperidin, particularly its glycosylated rutinose moiety and characteristic flavanone skeleton, are crucial for its interaction with molecular targets in breast cancer cells. The introduction of the 1,3,4-thiadiazole ring, while potentially beneficial for other biological activities, may have altered the pharmacokinetics of the molecule (e.g., reducing cellular uptake) or its affinity for key oncogenic targets such as protein kinases or estrogen receptors to which MCF-7 cells are responsive. Currently, anticancer research on natural compounds has focused on the induction of apoptosis in cancer cells.¹⁶ Hesperidin induces apoptosis in cancer cells through the intrinsic mitochondrial pathway, characterized by the upregulation of pro-apoptotic proteins (e.g., Bax) and downregulation of anti-apoptotic proteins (e.g., Bcl-2).¹⁷ Siddiqui et al.¹⁸ indicated that hesperidin has a promising impact on the treatment of cancer due to its high efficacy and fewer side effects than non-natural drugs. The concentration-dependent effect observed in both assays was consistent with the pathway principles of natural compounds, where higher doses typically produce higher therapeutic results.¹⁹ However, the decline in efficacy at lower concentrations highlights the need for further optimization to enhance potency, while minimizing potential side effects. Moreover, other studies in which minor modifications significantly altered compound efficacy. Moreover, studies have suggested some mechanisms of HSP and its derivatives in anticancer and antileishmanial activities, such as induction of apoptosis through mitochondrial dysfunction or modulation of signaling pathways via PI3K/AKT and MAPK.^20,21

Enhanced antileishmanial activity of derivative derv.2

In contrast to the anticancer results, the derivative derv.2 (5-(methylthio)-1,3,4-thiadiazol-2-thiol) demonstrated antileishmanial activity against the promastigote forms of Leishmania tropica. This significant observation underscores the principle of selective bioactivity through rational chemical modifications. The 1,3,4-thiadiazole nucleus is a privileged structure in medicinal chemistry that is renowned for its broad-spectrum antimicrobial, antifungal, and antiparasitic properties. The results showed that derv.2 was the most effective, as it achieved a 50.2% inhibition rate at 100 μg/m, outperforming both HSP and derv.1. This suggests that the thioether linkage at the 5-position of the thiadiazole ring in derv.2 may enhance its activity against Leishmania by improving membrane permeability or targeting specific enzymes.²² Increasing lipophilicity is another suggested mechanism: the methylthio (-SCH3) group in derv.2 likely increases the lipophilicity of the compounds compared to polar glycosylated hesperidin and amino-substituted derv.1. This enhanced lipophilicity facilitates passive diffusion across the unique and complex cell membrane of the leishmania parasite, which is rich in glycosylphosphatidylinositols and other lipids.²³ The fact that derv.2 was more effective against the parasite than the parent compound suggests the potential for selective toxicity. The unique biochemical pathways in leishmania (e.g., the trypanothione system) present targets that are absent in human cells, which could be more susceptible to the novel thiadiazole derivative.²⁴

The consistent observation of concentration-dependent anticancer and antileishmanial activities strengthens the validity of the findings. This indicated that the effects were specific and not due to general cytotoxicity at high concentrations. The divergent structure-activity relationship revealed that hesperidin is optimal for anticancer activity, and its thiadiazole derivative (derv.2) is superior for antileishmanial activity is of paramount importance. This suggests that a single natural product can serve as a platform for generating multiple lead compounds optimized for distinct therapeutic indications.

In conclusion, this study highlights the dual potential of HSP and derv. (1) and (2) as anticancer and antileishmanial agents, respectively. While HSP shows promise against MCF-7 cells, its derivative derv.2 emerges as a more effective antileishmanial candidate. These findings pave the way for further research on structural optimization, mechanistic studies, and preclinical trials to develop these compounds as viable therapeutic options.

Data availability

Zenodo. Evaluation of the effectiveness of hesperidin and its derivatives in inhibiting human cancer MCF-7 cells and leshmania: an in vitro study. https://doi.org/10.5281/zenodo.17793855.²⁵

This project contains the following underlying data

• Table 1: Raw data Excel sheet. The values behind the means, standard deviations and other measures reported in MCF-7 cell line percentage inhibition by hesperidin and their derivatives
• Table 2: Raw data Excel sheet. The values behind the means, standard deviations and other measures reported in Leishmania tropica cell line percentage inhibition by hesperidin and their derivatives.

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

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Author details Author details

¹ Al-Nahrain University/ Biotechnology research center, Baghdad, Iraq
² Biology Department, College of Education for Pure Sciences/Ibn al-Haitham, University of Baghdad, Baghdad ,Iraq, Baghdad, Iraq
³ Department of Biology, College of Science, University of Baghdad, Baghdad, Iraq, Baghdad, Iraq

Mohammad Al-Halbosiy
Roles: Formal Analysis, Methodology, Project Administration, Supervision, Writing – Review & Editing

Hanady Al Shmgani
Roles: Writing – Original Draft Preparation

Rakad Al-Jumaily
Roles: Data Curation, Investigation

Baraa Abdulhameed
Roles: Methodology

Lamees Jaed
Roles: Resources, Validation, Writing – Original Draft Preparation

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

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https://doi.org/10.12688/f1000research.172260.1

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Al-Halbosiy M, Al Shmgani H, Al-Jumaily R et al. Evaluation of the effectiveness of hesperidin and its derivatives in inhibiting human cancer MCF-7 cells and leshmania: an in vitro study [version 1; peer review: awaiting peer review]. F1000Research 2026, 15:69 (https://doi.org/10.12688/f1000research.172260.1)

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[1] 1. Anywar GU, Kakudidi E, Oryem-Origa H, et al.: Cytotoxicity of Medicinal Plant Species Used by Traditional Healers in Treating People Suffering From HIV/AIDS in Uganda. Front. Toxicology. 2022; 4: 832780. PubMed Abstract | Publisher Full Text | Free Full Text

[2] 2. Guo J, Zhang Y, Fang J, et al.: Reduction and Reuse of Forestry and Agricultural Bio-Waste through Innovative Green Utilization Approaches: A Review. Forests. 2024; 15(8): 1372. Publisher Full Text

[3] 3. Ogunro OB: An updated and comprehensive review of the health benefits and pharmacological activities of hesperidin. Biochem. Biophys. Res. Commun. 2025 Jul 30; 772: 151974. Epub 2025 May 11. PubMed Abstract | Publisher Full Text

[4] 4. Al-Kubaisi ZA, Al-Shmgani HS, Salman MJ: Evaluation of in vivo and in vitro protective effects of quercetin on lipopolysaccharide-induced inflammation and cytotoxicology. Research Journal of Pharmacy and Technology. 2020; 13(8): 3897–3903. Publisher Full Text

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Evaluation of the effectiveness of hesperidin and its derivatives in inhibiting human cancer MCF-7 cells and leshmania: an in vitro study

Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Materials and methods

Chemicals

Preparation and synthesis of HSP derivatives

Anticancer activity

Antileishmanial activity assessment

Statistical analysis

Results and Discussion

Table 1. Percentage of inhibition of MCF-7 cell line by using the hesperidin and their derivative (derv.1 and 2) during 24 hours of exposure.

Table 2. Percentage of inhibition of promastigote forms of Leishmania tropica by using the hesperidin and their derivative (derv.1 and 2) during 24 hours of exposure.

Enhanced antileishmanial activity of derivative derv.2

Data availability

References

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