*2.2. Materials*

Raspberry was provided from Guishanhong Agricultural Development Co. Ltd., (Guiyang, Guizhou, China). The leaves, fruit pulp, and seeds of raspberry were separated, vacuum freeze-dried to remove the water, and then ground in a mechanic micromill (BJFSJ-150G, Shanghai, China) to fine powder, respectively. All samples were stored at −20 ◦C until use.

#### *2.3. Extraction of Phenolic Compounds*

One gram of the above sample powder was soaked with 10 mL of different extractions solvents (50% ethanol (EtOH), 100% EtOH, 50% methanol, 100% methanol, ethyl acetate and acetone), and then sonicated for 30 min at 40◦C, 320 W. The mixture was subsequently filtered through a Whatman No. 1 paper.

#### *2.4. Determination of Total Phenolic Content (TPC) and Flavonoid Content (TFC)*

TPC was measured according to the Folin–Ciocalteau method with gallic acid as the standard [15]. TPC were expressed as mg gallic acid equivalents (GAE)/g sample in dry weight (DW). TFC was determined based on the aluminium chloride colorimetric method with rutin as the standard [16]. TFC were expressed as mg rutin equivalents (RE)/g sample in DW.

#### *2.5. Phenolic Compositions Analysis by HPLC-ESI-HR-qTOF-MS*/*MS*

The phenolic compositions of the three parts extracts' (extracted by 50% methanol) of raspberry were separated by using an HPLC system (Agilent 1200, CA, USA) equipped with a Diode Array Detector (DAD, Aglient, CA, USA). The analytical column was 250 mm × 4.6 mm, Zorbax Eclipse C18 plus column (5 μm, Aligent, CA, USA). Acetonitrile including 0.1% formic acid (phase A) and water including 0.1% formic acid (phase B) were used as the mobile phases. The gradient elution program was 0–5 min, 15% A; 5–20 min, 15–25% A; 20–30 min, 25–35% A; 30–40 min, 35–50% A; 40–50 min, 80% A; 50–55 min, 15% A, with a flow rate of 0.8 mL/min. The injection volume was 10 μL, temperature of the column was set to 30◦C, and the UV/DAD were monitored from 200 to 600 nm. The HR-qTOF-MS/MS analysis was performed with a high-resolution time-of-flight (HR-qTOF) mass detector (maXis, Bruker, Billerica, MA, USA) in the negative or positive mode (4.0 kV). Mass spectra were recorded over the mass range *m*/*z* 100 to 1000. The acquired MS data were processed by Bruker Daltonics DataAnalysis software. The contents of the analytes were expressed as mg per g DW (Table S1).

#### *2.6. Antioxidant Activities Assays*

#### 2.6.1. DPPH Radical Scavenging Activity Assay

DPPH assay was measured based on the method described earlier [17]. The absorbance at 517 nm was recorded by a microplate reader (SpectraMax M5 Molecular Device, CA, USA). Trolox or Vc solution (5–100 μg/mL) were served as positive controls. The results were expressed as the percentage of inhibition in the following Equation (1).

$$\text{DPPH radical scanning activity} \left( \% \right) \ = \left( 1 - \frac{A\_s - A\_b}{A\_c} \right) \times 100 \tag{1}$$

where *As* = the absorbance of the sample extracts with DPPH solution, *Ab* = the absorbance of the sample extracts without DPPH solution, *Ac* = the absorbance of DPPH solution.

#### 2.6.2. ABTS Cation Radical Scavenging Activity Assay

ABTS assay was determined according to the method of Wang et al. (2017) [18]. The absorbance at 517 nm was recorded by the microplate reader. Trolox or Vc solution (5–100 μg/mL) was served as positive controls. The scavenging activity (%) was calculated by Equation (2).

$$\text{ABTS}^+ \text{ radical scanning activity} \left(\% \right) \ = \left(1 - \frac{A\_\delta - A\_b}{A\_\varepsilon} \right) \times 100 \tag{2}$$

where *As* = the absorbance of the extracts with ABTS+ solution, *Ab* = the absorbance of the extracts without ABTS+ solutionl, *Ac* = the absorbance of ABTS+ solution.

#### 2.6.3. Hydroxyl (OH−) Radical Scavenging Activity Assay

The scavenging activity of OH− radicals was measured based on the method described by Liu et al., 2017 [19]. The reaction mixture included 100 μL of the extracts' dilutions, 100 μL of 6 mM Fe2SO4

solution, and 100 μL of 2.4 mM H2O2. After 10 min of incubation at 25◦C, the mixture was incubated with 100 μL of 6 mM salicylic acid at 25 ◦C for 30 min, then the absorbance at 510 nm was measured. A Trolox or Vc solution (5–100 μg/mL) served as the positive control.

#### 2.6.4. Ferric Reducing/Antioxidant Power (FRAP) Assay

The FRAP assay was measured according to the method reported by Wong, Li, Cheng, and Chen (2006) [20]. A standard curve was constructed using the FeSO4·7H2O (0–1000 μM) as the reference standard. The FRAP values were expressed in mM ferrous sulfate equivalents Fe(II)SE/g sample in DW (mM Fe(II)SE/g DW).

#### *2.7. Type II Diabetes Related Enzyme Inhibition Properties*

#### 2.7.1. α-Glucosidase Inhibition Activity Assay

The inhibitory activity of α-glucosidase was performed as the previous reported method with modifications [21]. Briefly, 100 μL of the extracts' dilutions and 100 μL of 1 U/mL α-glucosidase in 0.1 M phosphate buffer solution (pH 6.8) was mixed and pre-incubated at 37 ◦C for 10 min. Then, 100 μL of 5 mM *p*-NPG solution was added, and the reaction solution was incubated for another 20 min. The reaction was terminated by adding 500 μL of 0.2 M Na2CO3 solution. The absorbance at 405 nm was recorded. Acarbose was used as a positive control. The inhibitory potency (%) was calculated by Equation (3).

$$
\alpha-\text{Glucosidase inhibitory potency} \left( \% \right) \, = \left[ 1 - \frac{\Delta As}{\Delta Ac} \right] \times 100 \tag{3}
$$

where ΔAs = Aextract+enzyme − Aextract, ΔAc = Abuffer+enzyme − Abuffer.

#### 2.7.2. α-Amylase Inhibition Activity Assay

The inhibitory activity of α-amylase was carried out according to the literature with slight modification [22]. An amount of 200 μL of the extracts' dilutions were mixed with 200 μL of α-amylase (0.5 mg/mL in PBS, pH = 6.8), and the mixture was pre-incubated at 37 ◦C for 15 min. Then, 400 μL of 2 mg/mL soluble starch solution was added to start the hydrolysis at 37 ◦C for 10 min. Afterwards, 1 mL of DNS reagen<sup>t</sup> was added to stop the hydrolysis reaction, and the mixture was placed in boiling water bath for 5 min. When being cooled to room temperature, the absorbance at 540 nm was measured. The solution without α-amylase was used as the blank. The inhibitory potency (%) was calculated by Equation (4).

$$
\alpha-\text{Amylase inhibitory potency } \left(\%\right) \, = \left[1-\frac{\Delta As}{\Delta Ac}\right] \times 100\tag{4}
$$

where ΔAs = Aextract+enzyme − Aextract, ΔAc = Abuffer+enzyme − Abuffer.

#### *2.8. Molecular Docking Analysis*

The 2D conformers of the main phenolic standards (gallic acid, ellagic acid, and procyanidin C3) and acarbose (an anti-diabetic drug) were drawn by Chem 3D software, and the PDB formats of the α-glucosidase (PDB ID:3A4A) and α-amylase (PDB ID:1PPI) were downloaded from RCSB PDB (http://www.rcsb.org/pdb/home/home.do) [23]. Because the structural information of α-glucosidase from *S. cerevisiae* was not available, the homology structural (isomaltase, PDB ID: 3A4A) with high similarity of α-glucosidase was used as the template to perform the α-glucosidase docking analysis [23]. The molecular docking analysis of the main phenolic standards and acarbose to digestive enzymes was performed by the Surflex-Dock Geom (SFXC) mode using SYBYL-X 2.0 software package (Tripos, Inc., St. Louis, MO, USA). The docking procedure of small molecules to digestive enzymes is referred to in the literature [24]. Subsequently, a docking score file was generated and saved as the SD format. A C-Score (≥ 4) was selected as the credible results for the next docking analysis. The relevant docking parameters (e.g., T-Score, PMF-Score, D-Score, CHEM-Score, amino acid residues with active site, and

hydrogen bond distances, etc.) may be used to reveal the inhibition mechanism of small molecules to digestive enzymes. The Surflex-Dock scoring function is a weighted sum of non-linear functions involving van der Waals surface distances between the appropriate pairs of exposed enzyme and ligand atoms.
