Juglans regia L. Pellicle Extract

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1		Floriana D'Angeli	+ 2378 word(s)	2378	2021-05-11 11:06:45	\|
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This entry is adapted from the peer-reviewed paper 10.3390/antibiotics10020159

The difficulty to treat resistant strains-related hospital-acquired infections (HAIs) promoted the study of phytoextracts, known sources of bioactive molecules. Accordingly, in the present study, the pharmacological activities of Juglans regia (L.) pellicle extract (WPE) were investigated. The antiviral effect was tested against Herpes simplex virus type 1 and 2, Poliovirus 1, Adenovirus 2, Echovirus 9, Coxsackievirus B1 through the plaque reduction assay. The antibacterial and antifungal activities were evaluated against medically important strains, by the microdilution method.

antiviral antibacterial antifungal DPPH SOD-like antitumor polyphenols

1. Introduction

The emerging phenomenon of antimicrobial resistance (AMR) strongly limits the available therapeutic choices for the treatment of a large variety of infectious diseases, leading to an increased risk for severe infections, complications, and mortality ^[1]. Besides, AMR-related drug ineffectiveness can also significantly affect the success of major surgery and cancer chemotherapy ^[2]^[3]. Indeed, the precarious immune system of these patients promotes the development of opportunistic infections, which, in the absence of appropriate therapies, could result fatally. Thus, the concomitant presence of vulnerable individuals and the constant inclination to harboring pathogens make the hospital a high-risk environment for infectious diseases ^[4]. In this regard, the etiological agents responsible for hospital-acquired infections (HAIs) include bacteria, fungi, and viruses ^[5]. A recent surveillance study showed that most HAIs are provoked by Escherichia coli (18%), Staphylococcus aureus (12%), and Klebsiella spp. (9%), followed by Pseudomonas aeruginosa (8%), Enterococcus faecalis (8%), coagulase-negative staphylococci (7%), Enterobacter spp. (5%), Enterococcus faecium (4%), Proteus spp. (3.2%), and other Enterococcus spp. (3%). Moreover, this study revealed that a certain percentage of HAIs (6.3%) is due to fungal colonization and invasion, mainly to Candida albicans which account for 3.2% of the cases ^[6]. However, the concrete possibility to isolate antimicrobial-resistant strains among these pathogens could seriously compromise the efficacy of the treatment, with a consequent worsening of clinical conditions and, in extreme cases, even leading to a fatal outcome.

Regarding viruses, viral opportunistic infections occur when the host defenses are reduced, a condition frequently observed in hospitalized patients ^[7]. In this respect, the most common viruses involved in HAIs include Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), enteroviruses such as coxsackieviruses A and B, echoviruses, polioviruses, and adenoviruses ^[7]^[8]^[9].

In this context, much attention has been paid to the pharmacological role of natural extracts, as a source of bioactive compounds, able to hinder both pathogen and cancer cell physiology ^[8]. Concerning that, it has been shown that the crude extracts of the different tissues of walnut (kernel, shell, husk, bark, root, leaves, and septum) are endowed with outstanding pharmacological activities, including the anti-inflammatory, blood clotting, neuroprotective, antioxidant, antiproliferative, and antimicrobial properties ^[9]^[10]^[11]^[12]^[13]^[14]^[15].

In recent work, our group demonstrated a double effect of walnut septum extract, which was able to counteract both human glioblastoma cell survival and bacterial growth ^[16]. On the other hand, the biological effects of the edible portion covering the walnut kernel (pellicle) remain poorly investigated. In our previous paper, we characterized the chemical constituents of walnut pellicle extract (WPE), through ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-Ms/Ms) method. It is worth noting that the phytochemical profile of an extract can vary depending on the geographical area in which the relative plant has grown. Accordingly, J. regia chemical composition is strictly related to cultivar and climate area ^[17]. Indeed, our chemical analysis showed a high content of active compounds, mostly phenols, and hydrolyzable tannins. Interestingly, we also demonstrated the ability of WPE to inhibit the growth and biofilm formation of coagulase-negative staphylococci (CoNS). Furthermore, this extract proved to be effective in eradicating the biofilm previously formed by CoNS ^[18]. The promising results obtained led us to deepen the antimicrobial properties of this extract, by studying its effect on the most common etiological agents involved in HIAs.

Besides, since opportunistic infections can significantly affect the clinical outcome of oncologic patients, it could be useful to find novel antimicrobial agents also able to prevent cancer cell proliferation. Accordingly, the cytotoxic effect of WPE was evaluated on two tumoral (human colorectal adenocarcinoma cell line Caco-2 and human breast cancer cell line MCF7) and one primary (human foreskin fibroblast cell line HFF1) cell lines. Finally, by DPPH and the Folin–Ciocalteau assays, we analyzed the antioxidant properties and the total phenol content of WPE, respectively.

2. Cytotoxicity on HEp-2 and Vero Cell Lines

The 50% cytotoxic doses (CD₅₀) of WPE on HEp-2 and VERO cells were 25.00 and 28.00 µg/mL, respectively (Table 1). The non-cytotoxic doses were used to perform the antiviral evaluation.

Table 1. Antiviral activity of walnut pellicle extract.

	CD₅₀ ^a		ID₅₀ ^b
	HEp-2	VERO	HSV-1	HSV-2	ECHO 9	Polio 1	Coxsackie B1	Adeno 2
WPE (µg/mL) ^c	25.00	28.00	10.00	8.00	ORC ^d	ORC	ORC	ORC
Acyclovir (µg/mL)	>600.00	>600.00	0.12	0.36	ORC	ORC	ORC	ORC

^a CD₅₀, concentration which inhibited 50% cell growth compared to control cultures; ^b ID₅₀, the concentration which inhibited 50% virus plaque formation and virus-induced cytopathogenicity. Values are mean ± S.D. (maximal S.D. estimated) for three separate assays. ^c WPE: walnut pellicle extract. ^d ORC: out of range of concentration.

3. Antiviral Activity

Results obtained from our screening demonstrated that WPE had an inhibitory effect on HSV-1 and HSV-2 replication at doses below the CD₅₀. The ID₅₀ values were found to be 10 and 8 µg/mL for HSV-1 and HSV-2, respectively. The antiviral effect of WPE was compared to acyclovir, to which HSV-1 and HSV-2 showed an ID₅₀ of 0.12 and 0.36 µg/mL, respectively. WPE was ineffective against Echovirus 9 (ECHO 9), Poliovirus 1 (Polio 1), Coxsackievirus B1 (Coxsackie B1), and Adenovirus 2 (Adeno 2) (Table 1). The study of the effect of the compound on neutralization of viral infectivity demonstrated that WPE had not virucidal activity against all the viruses tested.

4. Antibacterial Activity

Based on minimal inhibitory concentration (MIC) values, which ranged from 8.59 to 275.00 µg/mL, the Gram-positive strains were more sensitive to WPE than the Gram-negative ones. It is worth noting that WPE, at the concentration of 275.00 µg/mL, was able to inhibit the growth of five clinical strains resistant to ciprofloxacin (E. faecium 018/040, E. coli 024/040, E. coli 025/040, Klebsiella pneumoniae (K. pneumoniae) 035/040 and P. aeruginosa 028/040). The results of the antibacterial activity are shown in Table 2.

Table 2. Antibacterial activity of walnut pellicle extract against Gram-positive and Gram-negative strains.

Bacterial Strains ^b	Source	MIC ^a (µg/mL)		I.C. ^e
		WPE ^c	Cip ^d
		Range [0.53–275.00]	[0.06–32.00]
Gram-positive
E. faecalis 012/040	Abscess	8.59	0.50	S
E. faecium 019/040	Catheter cystitis	8.59	1.00	S
S. epidermidis 007/040	Osteomyelitis	8.59	0.031	S
S. epidermidis ATCC 14990	Standard	8.59	0.125	S
E. faecalis 015/040	Abscess	17.18	0.25	S
S. aureus 002/040	Endophtalmitis	17.18	0.25	S
S. aureus 004/040	Pneumonia	17.18	0.25	S
E. faecalis 013/040	Septicemia	34.37	0.50	S
S. aureus 005/040	Endophtalmitis	34.37	0.50	S
E. faecalis ATCC 29212	Standard	68.75	0.50	S
E. faecalis 014/040	Pneumonia	68.75	1.00	S
E. faecium 018/040	Catheter cystitis	275.00	8.00	R
S. aureus ATCC 29213	Standard	275.00	0.50	S
S. epidermidis 009/040	Endophtalmitis	275.00	0.015	S
E. faecium 017/040	Cholecystitis	>275.00	>32.00	R
E. faecium 020/040	Cholecystitis	>275.00	16.00	R
E. faecium ATCC 700221	Standard	>275.00	>32.00	R
S. aureus 003/040	Pneumonia	>275.00	4.00	R
S. epidermidis 008/040	Septicemia	>275.00	8.00	R
S. epidermidis 010/040	Septicemia	>275.00	8.00	R
Gram-negative
E. coli 024/040	Cystitis	275.00	4.00	R
E. coli 025/040	Cystitis	275.00	8.00	R
K. pneumoniae 035/040	Nephritis	275.00	4.00	R
P. aeruginosa 028/040	Septicemia	275.00	4.00	R
P. aeruginosa 029/040	Pneumonia	275.00	0.125	S
P. mirabilis 038/040	Cystitis	275.00	0.015	S
P. mirabilis ATCC 7002	Standard	275.00	0.25	S
E. coli 022/040	Septicemia	>275.00	0.015	S
E. coli 023/040	Septicemia	>275.00	>32.00	R
E. coli ATCC 35218	Standard	>275.00	0.015	S
K. pneumoniae 032/040	Nephritis	>275.00	4.00	R
K. pneumoniae 033/040	Pneumonia	>275.00	32.00	R
K. pneumoniae 034/040	Pneumonia	>275.00	8.00	R
K. pneumoniae ATCC 700630	Standard	>275.00	0.25	S
P. aeruginosa 027/040	Septicemia	>275.00	0.06	S
P. aeruginosa 030/040	Pneumonia	>275.00	16.00	R
P. aeruginosa ATCC 27853	Standard	>275.00	0.25	S
P. mirabilis 037/040	Cystitis	>275.00	1.00	S
P. mirabilis 039/040	Cystitis	>275.00	0.015	S
P. mirabilis 040/040	Cystitis	>275.00	8.00	R

^a MIC: Minimal Inhibitory Concentration; ^b Strain numbers refer to an internal directory for bacteria. ^c WPE: walnut pellicle extract; ^d Cip: Ciprofloxacin; ^e I.C.: Interpretive criteria for Ciprofloxacin (CLSI M100-S28): ≤1 Susceptible (S); 2 Intermediate (I); ≥4 Resistant (R).

5. Discussion

Hospital-acquired infections represent a serious complication, often arising during the convalescence period in a medical facility ^[19]. It has been reported that HAIs amount to the first cause of death among hospitalized patients. To prevent these injurious events, the Centers for Disease Control and Prevention (CDC) constantly monitor the clinical practices correlated to an increased risk for microorganism contamination and invasion, including ventilator-associated pneumonia, catheter-associated urinary tract infections, bloodstream infections, and surgical site infections ^[20]. These illnesses can be caused by different pathogens, belonging to bacteria, fungi, or virus’s family. Accordingly, infectious diseases can significantly compromise the clinical outcome of the patients, including the oncologic ones. The increasing development of resistant mechanisms to the most commonly used drug promoted the research of new bioactive chemical compounds from phytoextracts. Concerning that literature data demonstrated the antimicrobial and the antiproliferative effects of walnut extracts ^[11]^[16]^[21]^[22]^[23]. However, despite the great attention paid to J. regia extracts, the knowledge on the biological effects of the edible pellicle is still limited.

In our previous work, we proved an antibacterial and antibiofilm activity of the present extract against CoNS. Furthermore, by UPLC-Ms/Ms, we chemically analyzed the phytoextract, revealing the presence of several biologically active molecules (Table 5) ^[18]. These results led us to hypothesize further antimicrobial properties. Indeed, in the present study, we found that WPE exerts an interesting activity against HSV-1 and HSV-2, with a concentration-dependent antiviral effect. It was demonstrated that natural extracts rich in polyphenols are capable to directly block virus attachment to host-cell ^[24]^[25] or interfering with the early phases of the replicative cycle ^[26]. Accordingly, the anti-herpes effect may be attributed to a synergistic effect of different compounds, belonging to phenols, flavonoids, and sterols. For example, among flavonoids, rutin and quercetin exerted potent anti-herpetic activity, both showing an EC₅₀ of 5 μM against HSV-1, although only quercetin inhibited HSV-2 infection, with an EC₅₀ of 35 μM ^[27]^[28]. A number of reports highlighted the antiviral role of quercetin against HSV. Hung et al. demonstrated the ability of quercetin to inhibit HSV-1 infection of Vero cells ^[29]. A further study showed that this molecule is able to modulate the expression of HSV proteins, such as the viral glycoprotein D (gD), an essential protein for the attachment of virus on host cell membrane during the infectious process, and ICP0, a viral protein expressed in the early phases of the HSV-1 replication cycle. Furthermore, the authors also demonstrated that quercetin acts at the genic level, downregulating the correlated gene-replication such as ICP0, UL13, and UL52 ^[30]. The WPE contains other compounds ^[18], including protocatechuic acid, myricetin ^[31], gallic acid, ellagic acid, kaempferol ^[32], and β-sitosterol ^[33], which were also associated with the anti-HSV activity. Interestingly, an in-silico analysis showed that tris-juglone, one of the previously determined constituents of WPE (Table 3) ^[18], showed antiviral activity against the SARS-CoV-2 virus by inhibiting cathepsin L, a lysosomal cysteine endopeptidase involved in the activation of heparinase ^[34]. The indirect block of this enzyme reduces the egress of the virus from the host cell. Since cathepsin L plays the same role in HSV-2, we can hypothesize that the HSV-inhibitory effect of WPE could be similarly mediated by tris-juglone ^[35].

Table 3. Chemical compounds identified from walnut pellicle extract through UPLC-Ms/Ms ^[18] and related pharmacological activities.

Chemical Name	Chemical Class	RT * (min)	m/z (g/mol)	Pharmacological Activities
Protocatechuic acid	Benzoic acid and Phenol derivatives	35.09	154.027	Antiviral ^[31] Antibacterial ^[36] Antioxidant ^[37]
Gallic acid	Benzoic acid and Phenol derivatives	18.60	170.021	Antiviral ^[32] Antibacterial ^[38] Antioxidant ^[37]
Ferulic acid	Cinnamic acids and derivatives	36.20	194.058	Antibacterial ^[38] Antioxidant ^[39]
Sinapate	Cinnamic acids and derivatives	n.r.	224.210	Antibacterial, Antifungal, Antitumor ^[40]
Palmitic acid	Fatty acids	12.43	256.240	Antioxidant ^[41]^[42] Antitumor ^[43]
Oleic acid	Fatty acids	37.24	282.256	Antioxidant ^[41]^[42] Antitumor ^[43]
Ellagic acid	Tannins	33.20	302.006	Antiviral ^[32] Antioxidant ^[44] Antitumor ^[45]
Quercetin	Flavonoids	33.97	302.043	Antiviral ^[27]^[28] Antibacterial ^[46] Antifungal ^[47] Antioxidant ^[39] Antitumor ^[45]
Myricetin	Flavonoids	33.78	318.038	Antiviral ^[31] Antifungal ^[47] Antitumor ^[45]
Chlorogenic acid	Cinnamate ester derivatives	39.49	354.095	Antioxidant ^[48]
Beta-sitosterol	Steroids and steroid derivatives	33.89	411.386	Antiviral ^[33]
Kaempferol-arabinoside	Flavonoids	n.r.	418.080	Antiviral ^[32]
Tocopherol	Prenol lipids	36.07	430.381	Antioxidant ^[41]
Avicularin	Flavonoids	20.08	434.085	Antifungal ^[49] Antitumor ^[50]
Tris-juglone	Phenanthrenes and derivatives	36.94	516.048	Anti-SARS-CoV-2 (in-silico analysis) ^[34]
(+)-Procyanidin B2	Flavonoids	38.25	578.520	Antibacterial, Antioxidant, Antitumor ^[51]
Rutin	Flavonoids	45.11	610.153	Antibacterial ^[52] Antiviral ^[27]^[28]^[29] Antifungal ^[47] Antioxidant ^[39] Antitumor ^[45]

Notes: * RT: retention time; n.r.: not reported. The retention time of the compounds was not reported, due to their low concentrations in the extract.

Furthermore, WPE was more efficient in reducing bacterial growth of Gram-positive strains compared to those Gram-negative, as indicated by the lower MIC values. This dissimilar effect reflects differences in the cell wall composition between the two bacterial groups ^[16]^[53]. Indeed, Gram-negative bacteria are characterized by a highly selective external membrane to the passage of the molecules, which makes these bacteria more resistant to drugs ^[53]^[54]^[55]. Nevertheless, as reported by Saraiva et al., since several bacteria strains showed MIC values under the concentration of 500 µg/mL, WPE can be considered an active antimicrobial agent ^[56].

Candida species are also responsible for healthcare-related infections both in immunocompetent and immunocompromised hosts ^[57]^[58]. Although new synthetic drugs are generally active against resistant Candida species, their administration can cause toxicity, interactions with other drugs, and inadequate bioavailability ^[59]^[60]^[61]. Experimental evidence supported the anticandidal activity of different extracts from J. regia, including leaf, bark, and root ^[62]^[63]^[64]^[65]. In agreement with these data, our findings showed an antifungal activity of WPE against different Candida species, with MICs ranging from 17.18 to 275.00 µg/mL. This effect could be attributed to the presence of the flavonoids quercetin, myricetin, and rutin ^[47]. Besides, in our previous chromatographic analysis, we identified the flavonol avicularin. This compound was isolated from Juglans sinensis leaves ^[66]. Da Silva Sa et al. demonstrated that this compound is able to inhibit C. albicans growth in concentrations of 2 to 16 µg/mL ^[49]. Concerning non-albicans Candida species, the extract was less efficient in reducing the growth of these pathogens. This effect could be due to both a reduced permeability of these yeasts to natural extracts and to their higher capacity to produce biofilm ^[67]^[68].

Taken together, these results clearly showed good antimicrobial effects of WPE, revealing its efficacy against different pathogens. In the oncologic field, the development of opportunistic infections is considered a common side effect of chemotherapy ^[69]. According to this concept, we evaluated the potential antiproliferative action of the extract, by treating two different cancer cell lines (MCF-7 and Caco-2 cells) and a primary fibroblast cell line (HFF-1) with increasing concentrations of WPE, for 24 h, 48 h, and 72 h. Interestingly, after a prolonged period (48 h and 72 h) the treatment with WPE significantly reduced Caco-2 cell viability in a dose-dependent manner. Considering that the pellicle of walnut is edible, being concomitantly ingested with the fruit and that the gastrointestinal tract is the most exposed district to the action of dietary ingredients, it is possible to hypothesize a benefic effect of this portion of the walnut, rich in polyphenols, at the intestinal level ^[70]. In this respect, literature data showed the ability of a large variety of classes of dietary polyphenols, including rutin, quercetin, myricetin, ellagic acid ^[45], and avicularin ^[50], all present in our extract, to affect glucose transport in Caco-2 cells via both facilitated transport proteins (GLUT 1 and 2) and sodium-dependent glucose transporter 1 (SGLT1). Several natural extracts, usually rich in these molecules, were also found to inhibit glucose uptake in Caco-2 cells through these mechanisms ^[50]^[71]. Being the main cellular energetic source, glucose plays a key role also in cancer cell growth ^[72]. It has been demonstrated that the inhibition of glucose uptake is able to arrest cancer progression ^[73]. Therefore, in our case, the cytotoxic effect of WPE on Caco-2 cells could be attributed to the reduced glucose internalization, mediated by the synergistic action of polyphenolic compounds. Conversely, the inefficacy of WPE on MCF-7 cells confirmed the results obtained in our previous studies, which showed a greater drug resistance of these cells, induced by the breast cancer resistance protein (BCRP) expression ^[74]. Notably, WPE did not determine any cytotoxic effect on the primary HFF-1 cells.

The protective role of WPE was further explored by evaluating its potential scavenger activity against reactive oxygen species (ROS). As expected, the extract inhibited superoxide anion formation similarly to the SOD enzyme, also showing the ability to bleach the stable DPPH radical. The free radical-scavenging activity is strictly related to the high content of phenols and flavonoids, as determined by the Folin–Ciocalteu method (Table 4). These results are consistent with other studies focusing on J. regia pellicle extracts, which revealed a high amount of phenols and flavonoids, mostly in yellow pellicle than in red ones ^[75]^[76].

Table 4. Antioxidant activity and total phenolic and flavonoid contents of walnut pellicle extract.

Sample	SOD-like Activity	DPPH Test	Total Phenolic	Total Flavonoids
Sample	IC₅₀ (μg/mL)		Gallic Acid (mg/g)	Catechin (mg/g)
WPE ^a	80 ± 0.51	48.35 ± 1.7	0.377 ± 0.01	0.292 ± 0.08
SOD ^b	50 mU ± 0.85	-	-	-
Trolox	-	15 mM ± 0.62	-	-

^a WPE: walnut pellicle extract; ^b SOD: superoxide dismutase.

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Floriana D'Angeli

Carlo Genovese

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