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Fig. 1 · Structure
Cat. No.
A10634
CAS No.
20702-77-6
Formula
C28H36O15
Mol. Weight
612.6

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Neohesperidin dihydrochalcone (Nhdc)

Cat. No. A10634 CAS 20702-77-6
Neohesperidin dihydrochalcone (Nhdc) is a flavonoid sweetening agent with potent antioxidant activity.

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Biological Activity

Bioactivity / Mechanism

Neohesperidin dihydrochalcone (NHDC) competitively inhibited human cathepsin S in a purified-enzyme assay (Ki 8 ± 1 μM at pH 5.5). Inhibition was weaker at pH 7.4 (Ki 40 ± 6 μM), and related cathepsins B, L and K were less sensitive under the reported acidic assay conditions. [1]

Literature-reported observations and conditions; not Adooq-tested protocols or general treatment recommendations.

In Vitro Studies

In primary human epidermal keratinocytes, 24 h NHDC exposure at 100–500 μM reduced cathepsin S expression and supernatant activity, with no significant WST-1 viability loss reported. These findings concern a cell model from one donor. [1]

NHDC effects on adipocyte lipid accumulation differed between protocols. One 3T3-L1 study reported reduced lipid accumulation at 50–100 μM and associated changes in PI3K/AKT/mTOR and AMPK phosphorylation. Another reported increased lipid deposition at 500 μM. The studies do not establish why the responses differ or support a universal lipid-lowering effect. [2,3]

Competitive inhibition of human cathepsin S

Biochemical assay · Purified human cathepsin S with fluorogenic Z-FR-AMC substrate; cathepsins B, L and K comparators [1]

NHDC competitively and reversibly inhibited Cat S, with weaker inhibition at neutral pH and of related cathepsins.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Cathepsin S inhibition at pH 5.5Ki 8 ± 1 μM[1]
Cathepsin S inhibition at pH 7.4Ki 40 ± 6 μM[1]
Inhibition of related human cathepsins at pH 5.5Ki Cat L: 144 ± 22 μM; Cat B: 167 ± 11 μM; Cat K: 61 ± 16 μM[1]

Literature-Reported Treatment Conditions

Treatment concentration
NHDC 0–100 μM; Figure 1A: 0, 5, 25, 50 and 100 μM
Exposure duration
10 min preincubation for inhibition assays; stability tested over 0–120 min
Method
Fluorometric substrate hydrolysis at 37 °C; Lineweaver–Burk, Dixon and nonlinear analyses
Reported limits
Stock solvent is not specified in the reviewed flavonoid/enzyme methods. Ki uncertainty type is not assigned here.
Methods and source locations

Compound reported in the paper: Neohesperidin dihydrochalcone; Compound label in the paper: NHDC

Evidence concerns the named NHDC material tested by the authors; it does not validate an Adooq lot or establish clinical efficacy.

Table 1 (continued), p.100; Figure 1A–C, p.101; Results p.98; Materials pp.106–107

Cathepsin S inhibition at pH 5.5: Z-FR-AMC hydrolysis; reported Ki, not IC50 or treatment dose — Table 1, row 13 (p.100); Results p.98; Figure 1A

Cathepsin S inhibition at pH 7.4: Reported pH-dependent kinetic inhibition — Results, Competitive inhibition of Cat S by NHDC, p.98; Enzyme inhibition studies, p.107

Inhibition of related human cathepsins at pH 5.5: Fluorogenic substrate inhibition; comparative enzyme panel — Results p.98; Figure 1C; Enzyme inhibition studies p.107

Cathepsin S expression and activity in human keratinocytes

Cell-based study · Primary normal human epidermal keratinocytes (NHEK) from abdominal skin of one healthy 26-year-old donor [1]

After 24 h exposure, NHDC lowered Cat S mRNA/protein and supernatant activity; the authors reported no significant WST-1 viability loss at 100 or 500 μM.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Cat S expression and secreted activity versus untreated cellsdirection Decreased Cat S mRNA and protein; decreased supernatant activity[1]
WST-1 cell viability versus untreated cellsdirection No significant decrease at 100 or 500 μM[1]

Literature-Reported Treatment Conditions

Treatment concentration
100 and 500 μM
Exposure duration
24 h
Method
Cell treatment followed by RT-qPCR (RPS16 normalization), lysate ELISA, supernatant Z-Leu-Arg-AMC hydrolysis and WST-1
Reported limits
No treatment stock solvent was identified in the reviewed cell-culture methods.
Methods and source locations

Compound reported in the paper: Neohesperidin dihydrochalcone; Compound label in the paper: NHDC

Evidence concerns the named NHDC material tested by the authors; it does not validate an Adooq lot or establish clinical efficacy.

Figure 4A–D and caption, p.104; NHEK Results pp.100–101; Cell culture and expression/activity methods pp.108–109

Cat S expression and secreted activity versus untreated cells: Figure 4: n = 3; protein/activity assays in duplicate. Caption describes median values ± SD and Mann–Whitney U testing. No bar heights converted to exact values. — Figure 4B–D and caption; NHEK Results pp.100–101

WST-1 cell viability versus untreated cells: WST-1; n = 3; untreated cells normalized to 100% — Figure 4A and caption; NHEK Results p.100

Lipid accumulation and signaling in differentiating 3T3-L1 cells

Cell-based study · Murine 3T3-L1 preadipocytes differentiated into adipocytes [2]

NHDC at 50 or 100 μM reduced Oil Red O lipid accumulation. At 50 μM, viability was unchanged and phosphorylation ratios for PI3K, AKT and mTOR decreased while AMPK phosphorylation increased. These are pathway associations, not direct enzyme inhibition.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Oil Red O lipid accumulation relative to NHDC controlreported reduction 50 μM: 11.7% reduction; 100 μM: 15.4% reduction (both p < 0.01)[2]
MTT viability after 50 μM NHDCdirection No significant difference from control[2]
Phosphorylated/total protein ratiosdirection p-PI3K/PI3K, p-AKT/AKT and p-mTOR/mTOR decreased; p-AMPK/AMPK increased[2]

Literature-Reported Treatment Conditions

Treatment concentration
30, 50 and 100 μM for lipid accumulation; 50 μM for viability and signaling
Exposure duration
8 days
Method
Exposure during differentiation; Oil Red O, MTT and immunoblot assays
Vehicle
0.2% DMSO in culture medium for NHDC
Reported limits
Exact reagent purity and independent lot characterization were not supplied in Section 2.1.
Methods and source locations

Compound reported in the paper: Neohesperidin dihydrochalcone; Compound label in the paper: NHDC

Evidence concerns the named NHDC material tested by the authors; it does not validate an Adooq lot or establish clinical efficacy.

Sections 2.1, 2.7–2.11, 3.4 and 3.6; Figures 4 and 6

Oil Red O lipid accumulation relative to NHDC control: Oil Red O; mean ± SEM, n = 3; no significant reduction at 30 μM shown by shared Figure 4 letters — Section 3.4; Figure 4A/B(a) and caption

MTT viability after 50 μM NHDC: MTT after 8 days; mean ± SEM, n = 3 — Sections 2.9 and 3.4; Figure 4C(a)

Phosphorylated/total protein ratios: Western blots with β-actin loading control; n = 3, mean ± SEM; unpaired Student t-test — Sections 2.10, 3.6; Figure 6A/B

Increased lipid deposition at 500 μM NHDC

Cell-based study · Differentiating murine 3T3-L1 adipocytes; differentiated untreated and non-differentiated controls; DHCA comparator [3]

At 500 μM, NHDC significantly increased relative Oil Red O lipid deposition compared with differentiated untreated controls. DHCA decreased deposition, so the metabolite result cannot be assigned to NHDC.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Relative Oil Red O lipid depositionmean ± SEM Differentiated control: 3.96 ± 0.06; NHDC: 4.53 ± 0.08 arbitrary units[3]

Literature-Reported Treatment Conditions

Treatment concentration
500 μM
Exposure duration
Exposure during differentiation; Section 2.5 describes a day-8 workflow, whereas Figure 3 caption says 10 days after differentiation
Method
Oil Red O at 490 nm, normalized to initial cell number and non-differentiated control
Reported limits
Vehicle not specified in the reviewed methods; exact duration is internally inconsistent and remains unresolved.
Methods and source locations

Compound reported in the paper: Neohesperidin dihydrochalcone; Compound label in the paper: NHDC

Evidence concerns the named NHDC material tested by the authors; it does not validate an Adooq lot or establish clinical efficacy.

Sections 2.1, 2.5, 2.8 and 3.3; Figure 3 and caption

Relative Oil Red O lipid deposition: Non-differentiated group set to 1; n = 4; one-way ANOVA/Tukey, different letters p < 0.05 — Section 3.3; Figure 3 and caption

In Vivo Studies

In male db/db mice, NHDC at 100 mg/kg by oral gavage, 5 days/week for 4 weeks, reduced subcutaneous and total adipose tissue weight. Final body weight and weight gain were not significantly reduced versus PBS control. Plasma insulin increased, and oral glucose-tolerance AUC did not improve significantly. [2]

Adipose tissue and metabolic outcomes in db/db mice

Animal study · Male C57BLKS/J db/db mice; randomized groups, n = 9 each; modified AIN-93G diet [2]

Four weeks of NHDC reduced subcutaneous and total adipose tissue weight but did not significantly reduce final body weight or weight gain. Plasma insulin increased; OGTT AUC was unchanged.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Subcutaneous and total adipose tissue weightsmean ± SEM Subcutaneous: control 2.46 ± 0.47 g; NHDC 1.27 ± 0.16 g. Total: control 5.66 ± 0.49 g; NHDC 4.42 ± 0.20 g.[2]
Final body weight and body weight gainmean ± SEM Final: control 37.75 ± 1.02 g; NHDC 35.23 ± 0.64 g. Gain: control 9.80 ± 0.67 g; NHDC 8.01 ± 0.69 g. Neither NHDC comparison significant.[2]
Plasma insulin versus PBS controlmean ± SEM Control: 1.77 ± 0.28 ng/dL; NHDC: 2.95 ± 0.36 ng/dL[2]
OGTT and fasting glucose time coursedirection OGTT AUC: no significant difference; fasting glucose reduction at week 2 was not sustained as a significant group separation at later plotted weeks[2]

Conditions shared by the study groups

Route
Oral gavage
Frequency
5 days per week
Treatment course
4 weeks
Vehicle
PBS
Study groups and reported outcomes
Group / doseComparatorObserved resultReference
PBS control—Comparator values retained in measurements.[2]
NHDC
100 mg/kg body weight		PBS gavage controlLower subcutaneous/total adipose weight; no significant weight-gain reduction; higher plasma insulin.[2]
PBS control
Model: Male C57BLKS/J db/db mice; n = 9 per group
Reported limits: No blinding details identified in the reviewed animal-study methods.
NHDC
Model: Male C57BLKS/J db/db mice; n = 9 per group
Reported limits: No blinding details identified in the reviewed animal-study methods.
Methods and source locations

Compound reported in the paper: Neohesperidin dihydrochalcone; Compound label in the paper: NHDC

Evidence concerns the named NHDC material tested by the authors; it does not validate an Adooq lot or establish clinical efficacy.

Sections 2.1–2.4, 2.11 and 3.1–3.2; Table 3; Figure 2

Subcutaneous and total adipose tissue weights: n = 9/group; Table 3 different letters indicate p < 0.05 in pairwise comparisons; overall ANOVA p = 0.0247 and 0.0299, respectively — Table 3; Section 3.1

Final body weight and body weight gain: n = 9/group; identical a superscripts for control and NHDC. Overall gain ANOVA significance includes GNHDC and is not evidence of NHDC significance. — Table 3; Section 3.1

Plasma insulin versus PBS control: n = 9/group; units reproduced exactly from Table 3; NHDC increased insulin, reported p < 0.01 in Results — Table 3; Section 3.1

OGTT and fasting glucose time course: OGTT after 2 weeks; mean ± SEM, n = 9/group; no numerical values inferred from curves — Sections 2.3 and 3.2; Figure 2D/E and caption

PBS control · Section 2.2; Table 3; Figure 2

NHDC · Section 2.2; Table 3; Figure 2

Specifications

Manufacturer Adooq Bioscience
CAS Number 20702-77-6
Formula C28H36O15
Molecular Weight 612.6
Synonyms Nhdc
SMILES
C[C@H]1[C@@H]([C@H]([C@H]([C@@H](O1)O[C@@H]2[C@H]([C@@H]([C@H](O[C@H]2OC3=CC(=C(C(=C3)O)C(=O)CCC4=CC(=C(C=C4)OC)O)O)CO)O)O)O)O)O

Storage & Solubility

In Vitro Solubility

Reported Solubility

SolventReported Solubility
DMSO 94 mg/mL (153.45 mM)
Water Insoluble
Ethanol 94 mg/mL (153.45 mM)

Preparing Stock Solutions

Stock preparation is unavailable for this product molecular weight.

Calculated stock concentrations do not establish solvent solubility. Refer to the reported solubility data for experimental guidance.

Storage

Store powder at -20°C, keep desiccated.
In powder form, the chemical is stable for 36 months.
In solution, store at -20°C and use within 1 month to prevent loss of potency. Aliquot to avoid multiple freeze/thaw cycles.

Research References

  1. [1] J. Sage, J. Renault, R. Domain, et al. Modulation of the expression and activity of cathepsin S in reconstructed human skin by neohesperidin dihydrochalcone Matrix Biology (2022). PMID: 35167945 DOI: 10.1016/j.matbio.2022.02.003 Source material
  2. [2] Minseo Kwon, Yerin Kim, Jihye Lee, et al. Neohesperidin Dihydrochalcone and Neohesperidin Dihydrochalcone-O-Glycoside Attenuate Subcutaneous Fat and Lipid Accumulation by Regulating PI3K/AKT/mTOR Pathway In Vivo and In Vitro Nutrients (2022). PMID: 35268062 DOI: 10.3390/nu14051087 Source material
  3. [3] Sooyeon Choi, Seungmin Yu, Jonghun Lee, et al. Effects of Neohesperidin Dihydrochalcone (NHDC) on Oxidative Phosphorylation, Cytokine Production, and Lipid Deposition Foods (2021). PMID: 34207068 DOI: 10.3390/foods10061408 Source material

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