Physalis alkekengi L. var. franchetii (Mast.) Makino: Comparison
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The calyxes and fruits of Physalis alkekengi L. var. franchetii (Mast.) Makino (P. alkekengi), a medicinal and edible plant, are frequently used as heat-clearing and detoxifying agents in thousands of Chinese medicine prescriptions. For thousands of years in China, they have been widely used in clinical practice to treat throat disease, hepatitis, and bacillary dysentery.

  • the calyxes and fruits of P. alkekengi
  • structural analysis
  • quality control
  • pharmacology
  • pharmacokinetics

1. Introduction

P. alkekengi is a perennial plant (Figure 1a) belonging to the genus Physalis of the family Solanaceae. The calyxes and fruits of P. alkekengi (known as Jindenglong in Chinese) (Figure 1b) are distributed in Europe and Asia. The use of the calyxes and fruits of this plant was first recorded in the prestigious monograph Shennong Bencao Jing in China [1]. Subsequently, it was included as an important traditional Chinese medicine (TCM) in the Ben Cao Gang Mu and pharmacopoeia [2]. Calyxes are green, self-expanded into an oocyst shape, slightly concave at the base, 2.5–5 cm in length, 2.5–3.5 cm in diameter, have thin leathery skin, and are orange-red or fire-red when mature (Figure 1c). Fruits are spherical, orange-red, and 10–15 mm in diameter (Figure 1d). This plant has been used for >2000 years in China, and its activities have been defined as “heat-clearing and detoxifying, relieving sore throat to reducing phlegm and inducing diuresis for treating strangurtia” in TCM theory [3][4]. In clinical practice, P. alkekengi is often used in combination with other TCMs for the treatment of cough, excessive phlegm, pharyngitis, sore throat, dysuria, pemphigus, eczema, and jaundice [5]. Currently, the 12 TCM formulae and modern pharmaceutical preparations of the calyxes and fruits of P. alkekengi are listed in the Pharmacopoeia of the People’s Republic of China and used in folk medicine [6]. For example, qing guo ointment, a TCM formula composed of seven medicinal herbal plants (i.e., the calyxes and fruits of P. alkekengi, Cannarii Fructus, Sophorae Tonkinensis Radix et Rhizoma, Sterculiae Lychnophorae Semen, Trichosanthis Radix, Ophiopogonis Radix, and Chebulae Fructus), is effective for clearing the throat and quenching thirst, treating aphasia and hoarseness, and relieving sore throat, dry mouth, and dry tongue [1].
/media/item_content/202202/62046ff1e21f6molecules-27-00695-g001.pngFigure 1. Images of P. alkekeng. (a) The whole plant; (b) Calyxes and fruits; (c) Calyxes; (d) Fruits.
In the last decades, reviews concerning research progress on the calyxes and fruits of P. alkekengi have been published, mainly focusing on the chemical components, traditional uses, toxicology, and pharmacological activities [6]; however, thus far, there are no reports on structural analysis, quality control, and pharmacokinetics. In recent years, new pharmacological activities have been discovered, and the main active ingredients in P. alkekengi are physalins and flavonoids [7]. Therefore, we herein provide a literature review on the structural analysis of physalins and flavonoids in the calyxes and fruits of P. alkekengi. We have also prepared a comprehensive and up-to-date report for the known pharmacological activities. In addition, the quality control and pharmacokinetics studies are summarized in detail. We hope that the current review will provide a theoretical basis and valuable data for future in-depth studies and the development of useful applications.

2. Pharmacology

Pharmacological experiments showed that the various crude extracts and compounds isolated from P. alkekengi have diverse biological activities (e.g., anti-inflammatory, anti-tumor, immunosuppressive, anti-microbial, anti-leishmanial, anti-asthmatic, anti-diabetic, etc.). In addition, the mechanisms of action of the anti-inflammatory and anti-tumor activities were also reported. The main pharmacological activities of crude extracts and compounds are shown in Table 1.
Table 1. Pharmacological effects of P. alkekengi.
Pharmacological Activity Animal/Cell Models Constituent/Extract Detail Dosage Reference
Anti-inflammatory activity LPS-induced 264.7 cells Physalins A, O, L, G Isophysalin A Induced NO production 20 μM [8]
  IFN-γ-stimulated macrophages

LPS-stimulated macrophages		 Physalins B, F, G Reduced NO production; inhibited TNF-α, IL-6, IL-12 2 μg/mL [9]
  C57BL/6 mice Physalins B, F Suppressed the increase in TNF-α; increased vascular permeability; prevented neutrophil influx 20 mg/kg [10]
  LPS-induced 264.7 cells Physalin B Decreased the levels of TNF-α, IL-6, IL-1β 0.25, 0.5, 1.0 μM [11]
  LPS/IFN-γ-induced macrophages

IL-4/IL-13-induced macrophages

LPS-induced C57BL/6 mice		 Physalin D In vitro: activated signal transducer and activator of STAT6 pathway; suppressed STAT1 activation; blocked STAT1 nuclear translocation

In vivo: reduced inducible iNOS cell number; increased CD206+ cell number		 5 μM [12]
  LPS-stimulated RAW 264.7 cells Physalin E Inhibited the generation of TNF-α, IL-6, NF-κB p65; reduced the degradation of I-kappa B protein 12.5, 25, 50 μM [13]
  TPA-induced acute ear edema in mice

Oxazolone-induced chronic dermatitis in mice		 Physalin E Reduced ear edema response and myeloperoxidase activity; suppressed increase in ear thickness and levels of TNF-α and IFN-γ 0.125, 0.25, 0.5 mg/ear [14]
  DBA/1 mice Physalin F Decreased paw edema and joint inflammation 60 mg/kg [15]
  LPS-induced macrophages Physalin X

Aromaphysalin B		 Inhibited NO production IC50 = 68.50, 29.69 μM, respectively [16]
  LPS-induced macrophages Physalins B, F, H, V, D1, VII, I

Isophysalin B		 Inhibited NO production IC50 = 0.32–4.03, 12.83–34.19 μM, respectively. [17]
  LPS-induced macrophages Physalins A, B, F

Ombuine

Luteolin		 Inhibited NO production IC50 = 2.57 ± 1.18, 0.84 ± 0.64, 0.33 ± 0.17, 2.23 ± 0.19, 7.39 ± 2.18 µM, respectively. [18]
  LPS/IFN-γ-stimulated macrophages

ICR mice		 Luteolin In vitro: suppressed the production of IL-6, IL-12, and TNF-α

In vivo: inhibited paw edema		 20 μM

20 mg/kg		 [19]
  KF-8 cells Apigenin

Lutelin		 Inhibited NF-κB activation and the expression of CCL2/MCP-1 and CXCL1/KC 20 μM [20]
  LPS-induced macrophages Kaempferol

Quercetin		 Inhibited STAT-1 and NF-κB activation, iNOS protein and mRNA expression, and NO production 100 μM [21][22]
  LPS-stimulated THP-1 cells

ICR mice		 70% ethanol extract In vitro: reduced the production of NO, PGE2, TNF-α, IL-1, iNOS, and COX-2

In vivo: reduced ear edema; induced granulomatous tissue formation		 500 μg/mL [23]
  Wistar rats Methanol extract Reduced the paw volume 500 mg/kg [24]
  LPS-induced macrophages Physanosides B Inhibited NO production IC50 = 9.93 μM [25]
  LPS-induced macrophages (6S,9R)-roseoside Inhibited NO production IC50 = 7.31 μM [26]
Anti-tumor activity HepG2 cells Physalin A Activated the Nrf2–ARE pathway and its target genes 20 μM [26]
  Non-small cell lung cancer

BALB /c mice		 Physalin A In vitro: suppressed both constitutive and induced STAT3 activity

In vivo: suppressed tumor xenograft growth		 5,10, 15 μM

40, 80 mg/kg		 [27]
  Human melanoma A375-S2 cells Physalin A Activated transmembrane death receptor;

Induced poptosis via apoptotic (intrinsic and extrinsic) pathway; up-regulated p53-NOXA-mediated ROS generation		 15 μM [28]
  Human HT1080 fibrosarcoma cells Physalin A Upregulated CASP3, CASP8 expression IC50 = 10.7 ± 0.91 μM [29]
  Human melanoma A375-S2 cells Physalin A Repressed the production of RNS and ROS; triggered the expression of iNOS and NO 15 μM [30]
  Non-small cell lung cancer Physalin A Induced G2/M cell cycle arrest; increased the amount of intracellular ROS IC50 = 28.4 μM [31]
  Prostate cancer cells (CWR22Rv1, C42B) Physalins A, B Inhibited the growth of two cells; activated the JNK and ERK pathway IC50 = 14.2, 9.6 μM, respectively [32]
  Non-small cell lung cancer Physalin B Exhibited anti-proliferative and apoptotic activity; downregulated the CDK1/CCNB1 complex; upregulated p21 5, 10, 20 μmol/L [33]
  Human melanoma A375 cells Physalin B Activated the expression of the NOXA, BCL2 associated X (Bax), and CASP3 3 μg/mL [34]
  Human HCT116 colon cancer cells Physalin B Activated the ERK, JNK, and p38 MAPK pathways; increased ROS generation IC50 = 1.35 μmol/L [35]
  Human DLD-1 colon cancer cells Physalin B Inhibited TNFα-induced NF-κB activation; induced the proapoptotic protein NOXA generation 5 μM [36]
  Breast cancer cells (MCF-7, MDA-MB-231, T-47D) Physalin B Induced cell cycle arrest at G2/M phase; promoted the cleavage of PARP, CASP3, CASP7, and CASP9; inactivated Akt and P13K phosphorylation 2.5, 5, 10 μM [37]
  TNF-α-stimulated HeLa cells Physalins B, C, F Inhibited the phosphorylation and degradation of IκBα and NF-κB activation IC50 = 6.07, 6.54, 2.53 μM, respectively [38]
  Tumor cells (A549, K562) (17S,20R,22R)-5β,6β-epoxy-18,20-dihydroxy-1-ox-

owitha-2,24-dienolide

withaphysalin B		 Suppressed the PI3K/Akt/mTOR signaling pathway IC50 = 1.9–4.3 μM [39]
  Tumor cells (B-16, HCT-8, PC3, MDA-MB-435, MDA-MB-231, MCF-7, K562, CEM, HL-60)

Swiss mice		 Physalins B, D In vitro: displayed activity against several cancer cell lines

In vivo: inhibited the proliferation of cells; reduced Ki67 staining		 0.58–15.18, 0.28–2.43 μg/mL, respectively

10, 25 mg/kg		 [40]
  Human cancer cells (C4-2B, 22Rv1, 786-O, A-498, ACHN, A375-S2) Physalins B, F Showed anti-proliferative activities IC50 = 0.24–3.17 μM [17]
  Human T cell leukemia Jurkat cells Physalins B, F Inhibited PMA-induced NF-κB and TNF-α-induced NF-κB activation 8, 16 µM, respectively [41]
  HEK293T cells

BALB/c-nu/nu mice		 Physalin F In vitro: decreased TOPFlash reporter activity; promoted the proteasomal degradation of β-catenin

In vivo: downregulated β-catenin		 4 μM

10, 20 mg/kg		 [42]
  T-47D cells Physalin F Activated the CASP3 and c-myc pathways IC50 = 3.60 μg/mL [43]
  Human renal, carcinoma cells (A498, ACHN, UO-31) Physalin F Induced cell apoptosis through the ROS-mediated mitochondrial pathway; suppressed NF-κB activation 1, 3, 10 μg/mL [44]
  PC-3 cancer cell lines 7β-ethoxyl-isophysalin C Showed apparent moderate activities IC50 = 8.26 µM [45]
  Human osteosarcoma cells Physakengose G Inhibited the epidermal growth factor receptor/mTOR (EGFR/mTOR) pathway; blocked autophagic flux through lysosome dysfunction 5, 10, 20 μM [46]
Immunosuppressive activity Trypanosoma cruzi (T. cruzi)-infected insects Physalin B Decreased number of T. cruzi Dm28c and T. cruzi transmission; inhibited the development of parasites 1 mg/mL

20 ng

57 ng/cm2		 [47]
  H14 Trypanosoma rangeli-infected Rhodnius prolixus larvae Physalin B Reduced the production of hemocyte microaggregation and NO 0.1, 1 μg/mL [48]
  T. cruzi trypomastigotes

BALB/c mice macrophages		 Physalin B

Physalin F		 Displayed strongest effects against epimastigote forms of T. cruzi IC50 = 5.3 ± 1.9, 5.8 ± 1.5 μM, respectively

IC50 = 0.68 ± 0.01, 0.84 ± 0.04 μM, respectively		 [49]
  Con A-induced spleen cells

CBA mice		 Physalins B, F, G In vitro: inhibited MLR and IL-2 production

In vivo: prevented the rejection of allogeneic heterotopic heart transplant		 2 μg/mL

1 mg/mouse/day		 [50]
  Human T-cell lymphotropic virus type 1 (HTLV-1)-infected subjects Physalin F Inhibited spontaneous proliferation; reduced the levels of IL-2, IL-6, IL-10, TNF-α, and IFN-γ 10 μM [51]
  T cells

BALB/c mice		 Physalin H In vitro: suppressed proliferation and MLR

In vivo: inhibited delayed-type hypersensitivity reactions and T-cell response		 IC50 = 0.69, 0.39 μg/mL, respectively

IC50 = 2.75 or 3.61 μg/mL		 [52]
  ICR mice Polysaccharides Enhanced specific antibody titers immunoglobulin G (IgG), IgG1, and IgG2b, as well as the concentration of IL-2 and IL-4 40 µg/mice [53]
Anti-microbial activity Gram-positive bacteria: Staphylococcus epidermidis (S. epidermidis), Enterococcus faecalis (E. faecalis), Staphylococcus aureus (S. aureus), Bacillus subtilis (B. subtilis), Bacillus cereus (B. cereus) Methanol extract

Dichloromethane extract

Physalin D		 Displayed moderate antibacterial activity MIC = 32–128 µg/mL [54]
  Escherichia coli (E. coli), B. subtilis Physalins B, J, P Showed high antibacterial activity MIC = 12.5–23.7, 23.23–24.34, 22.8–27.98 µg/mL, respectively [55]
  Mycobacterium tuberculosis H37Rv Trichlormethane extract

Physalins B, D		 Showed antibacterial activity MIC = 32, >128, 32 µg/mL, respectively [56]
  Lactobacillus delbrueckii (L. delbrueckii),

E. coli		 70% ethanol extract Promoted the growth of L. delbrueckii; inhibited the growth of E. coli 0.78–1.56 mg/mL [57]
  Gram-positive bacteria: S. aureus, S. epidermidis, Staphylococcus saprophyticus (S. saprophyticus), Enterococcus faecium (E. faecium)

Gram-negative bacteria: Pseudomonas aeruginosa (P. aeruginosa), Streptococcus pneumoniae (S. pneumoniae), E. coli		 70% ethanol extract Showed antibacterial activity MIC = 0.825–1.65 mg/mL [23]
  S. aureus, B. subtilis, P. aeruginosa, E. coli Physakengoses B, E, F, G, H, K, L, M, N, O Showed potent inhibitory effects MIC = 2.16–14.9 μg/mL [58][59]
Anti-leishmanial Leishmania-infected macrophages

Leishmania amazonensis

-infected BALB/c mice		 Physalins B, F In vitro: reduced the percentage of macrophages

In vivo: reduced the lesion size, the parasite load, and histopathological alterations		 IC50 = 0.21 and 0.18 μM, respectively [60]
Others Kunming mice Water extract Decreased the expression of white blood cells and eosinophils, IL-5, IFN-γ, Th1, and Th2 0.25, 5, 1 g/mL [61]
  3T3-L1 pre-adipocyte cells

HepG2 cells

Male Sprague–Dawley (SD) rats		 Ethyl acetate extract In vitro: relieved oxidative stress; inhibited α-glucosidase activity.

In vivo: decreased FBG, TC, and TG		 300 mg/kg [62]
  Alloxan-induced mice Polysaccharides Decreased FBG and GSP; increased FINS; upregulated the PI3K, Akt, and GLUT4 mRNA 200, 400, 800 mg/kg [63]
  High-fat diet-fed and streptozotocin-induced diabetic SD rats Ethyl acetate extract Reduced the FBG, TC, TG, and GSP; increased FINS 300, 600 mg/kg [64]
  Wistar rats

Albino mice		 Aqueous methanolic extract Reduced the intensity of gastric mucosal damage; inhibited pain sensation 500 μg/mL

500 mg/kg		 [24]
  LPS-induced acute lung injury in BALB/c mice 70% ethanol extract Reduced the release of TNF-α and the accumulation of oxidation products; decreased the levels of NF-κB, phosphorylated-p38, ERK, JNK, p53, CASP3, and COX-2 500 mg/kg [65]
  4% dextran sulfate sodium--induced colitis in BALB/c mice Physalin B Reduced MPO activity; suppressed the activation of NF-κB, STAT3, arrestin beta 1 (ARRB1), and NLR family pyrin domain containing 3 (NLRP3) 10, 20 mg/kg [11]
  N2a/APPsw cells Physalin B Downregulated β-amyloid (Aβ) secretion and the expression of beta-secretase 1 (BACE1) 3 μmol/L [66]
  DPPH

TBA		 Physalin D Exhibited antioxidant activity IC50 ≥ 10 ± 2.1 µg/mL [54]
  Plasmodium berghei-infected mice Physalins B, D, F, G Caused parasitemia reduction and delay 50, 100 mg/kg [67]
  High glucose-induced primary mouse hepatocytes

Oleic acid-induced HepG2 cells

Kunming mice		 75% ethanol extract

Luteolin-7-O-β-d-glucopyranoside		 In vitro: decreased the levels of TG in HepG2 cells

In vivo: decreased the levels of TC and TG		 50, 100 μg/mL, respectively

1 or 2 g/kg,

0.54 g/kg, respectively		 [68]
  SD mice Luteolin Increased NO; activated PI3K/Akt/NO signaling pathway; enhanced the activity of endothelial NOS 7.5 µg/mL [69]
  SD rats Luteolin Conferred a cardioprotective effect; ameliorated Ca2+ overload 7.5, 15, 30 μmol/L [70]

2.1. Anti-Inflammatory Activity

Studies involving in vitro and in vivo models of lipopolysaccharide-stimulated (LPS-stimulated) THP-1 cells, mouse ear-swelling, rat cotton pellet granuloma, and rat hind paw edema have confirmed that ethanol and methanol extracts from P. alkekengi calyxes exert anti-inflammatory effects. The extracts achieve these effects by inhibiting the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) [23][53]. As active ingredients isolated from P. alkekengi, physalins A, B, D, E, F, H, G, L, O, V, D1, X, VII, and I, isophysalin A, isophysalin B, and aromaphysalin B showed anti-inflammatory activity. At a concentration of 20 µM, physalins A, O, L, and G and isophysalin A inhibited the LPS-induced NO production by blocking TNF-α [8][9]. Physalins B, E, F, G, H, V, X, D1, VII, and I, isophysalin B, and aromaphysalin B reduced the levels of proinflammatory mediators NO, TNF-α, IL-6, IL-12, and interferon-γ (IFN-γ) in LPS-stimulated and IFN-γ-stimulated macrophages, RAW 264.7 cells, and 12-O-tetradecanoylphorbol-13-acetate (TPA)- and oxazolo-induced dermatitis. These effects occurred through upregulation of the signal transducer and activator of transcription 6 (STAT6) and downregulation of nuclear factor-κB (NF-κB) and the STAT1 signaling pathway [9][10][12][13][14][16][17]. The anti-inflammatory effects of four flavonoids (i.e., luteolin, apigenin, kaempferol, and quercetin) were related to inhibition of the production of NO, IL-6, IL-12, TNF-α, STAT-1, and NF-κB, the expression of C–C motif chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) and C–X–C motif chemokine ligand 1/KC (CXCL1/KC), and paw edema [18][19][20][21]. Ombuine inhibited the production of NO in LPS-damaged macrophage cells, with a half maximal inhibitory concentration (IC50) value of 2.23 ± 0.19 µM [18].

2.2. Anti-Tumor Activity

Recently, in vitro experimental studies showed the anti-tumor activity of physalins in non-small cell lung cancer, human melanoma A375-S2 cells, and tumor cell lines (A549, K562). The results indicated that physalins A and B have strong anti-tumor activity and induced G2/M cell cycle arrest in non-small cell lung cancer and A375-S2 cells. The mechanism involved in this effect is related to the inhibition of Janus kinase 2 (JAK2) phosphorylation, JAK3 phosphorylation, both constitutive and induced STAT3, reactive nitrogen species (RNS), reactive oxygen species (ROS), and cyclin-dependent kinase 1/cyclin B1 (CDK1/CCNB1) complex, as well as the promotion of the p53-NADPH oxidase activator- (p53-NOXA), p38-NF-κB, and p38 mitogen-activated protein kinase/ROS (MAPK/ROS) pathways [27][28][30][31][33][34]. Physalin A also increased the content of detoxifying enzyme in HepG2 cells, induced apoptosis in HT1080 cells, and inhibited growth in prostate cancer cells (CWR22Rv1 and C42B). These effects occurred by activating the nuclear factor erythroid 2-related factor 2–antioxidant response element (Nrf2–ARE), death receptor apoptotic, JUN N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) signaling pathway; the IC50 values were 20, 10.7, 14.2, and 1.9–4.3 μM, respectively [26][28][29][32]. In addition, six types of cancer cells (i.e., prostate, human HCT116 colon, human DLD-1 colon, breast, TNF-α-stimulated HeLa, and human T cell leukemia Jurkat) were treated with physalin B. The treatment inhibited the activation of TNF-α-induced NF-κB and phorbol 12-myristate 13-acetate (PMA)-induced NF-κB pathways, whereas it promoted the activation of ERK, JNK, p38 MAPK, and P53 pathways [38][35][36][37][41]. Physalin F decreased the TOPFlash reporter activity, inhibited the effects on T-47D cells, and induced cell apoptosis via ROS-mediated mitochondrial pathways [42][43][44].
In vivo, physalins A and F clearly inhibited tumor growth by downregulating β-catenin in xenograft tumor-bearing mice [27][42]. At 10 mg/kg and 25 mg/kg, respectively, physalins B and D inhibited tumor proliferation in mice bearing sarcoma 180 tumor cells [40]. In short, the anti-tumor activity of P. alkekengi and its constituents was associated with the downregulation of JAK/STAT3, TNF-α-induced NF-κB, PMA-induced NF-κB, and phosphoinositide-3-kinase-Akt-mechanistic target of the rapamycin (PI3K/Akt/mTOR) signaling pathway. Moreover, it was linked to the upregulation of the death receptor apoptotic, p53-NOXA, p38-NF-κB, p38 MAPK/ROS, p21, and Nrf2 signaling pathway. The signaling pathways are given in Figure 2.
/media/item_content/202202/62047086c17bamolecules-27-00695-g005.pngFigure 2. Signaling pathways involved in the antitumor activity of P. alkekengi and its constituents.

2.3. Immunosuppressive Activity

The immunosuppressive activity of P. alkekengi mainly focused on immune cells and Trypanosoma infection. Previous studies utilizing concanavalin A (Con A)-activated spleen cells suggested that physalin B inhibited Con A-induced lymphoproliferation, mixed lymphocyte reaction (MLR), and IL-2 production [50]. Yu et al. [52] found that physalin H also significantly inhibited the proliferation of Con A-induced T cells and MLR in vitro, with IC50 values of 0.69 and 0.39 μg/mL, respectively. In vivo, physalin H dose-dependently inhibited CD4+ T cell-mediated delayed-type hypersensitivity reactions and antigen-specific T-cell response in ovalbumin-immunized mice, with IC50 values of 3.61 μg/mL for 48 h and 2.75 μg/mL for 96 h. The mechanisms may be related to the modulation of T-helper 1/T-helper 2 (Th1/Th2) cytokine balance, inhibition of T cell activation, and proliferation and induction of HO-1 in T cells. Moreover, at the concentration of 40 µg, polysaccharides from fruits of P. alkekengi showed good immunosuppressive effects in mice [53]. Physalin B decreased the number of T. cruzi Dm28c and T. cruzi transmission in the gut at doses of 1 mg/mL (oral administration), 20 ng (topical application), and 57 ng/cm2 (contact treatment), and suppressed epimastigote forms of T. cruzi, with an IC50 value of 5.3 ± 1.9 μM [47][49]. At a concentration of 1 μg/mL, physalin B significantly increased the mortality rate (78.1%) among Rhodnius prolixus larvae infected with Trypanosoma rangeli [48]. Physalin F prevented the rejection of allogeneic heterotopic heart transplants in vivo in a concentration-dependent manner. Moreover, it inhibited the spontaneous proliferation of peripheral blood mononuclear cells in patients with human T-cell lymphotropic virus type 1-related (HTLV1-related) myelopathy at 10 μM, suggesting its potential for treatments of pathologies in the inhibition of immune responses [50][51].

2.4. Antibacterial Activity

In vitro, at the concentration of 100 μg/mL, physalin D isolated from P. alkekengi was found to be effective against Staphylococcus epidermidis (S. epidermidis), Enterococcus faecalis (E. faecalis), Staphylococcus aureus (S. aureus), and Bacillus subtilis (B. subtilis) [54]. Yang et al. [55] reported that physalins B, J, and P exhibited a good antibacterial activity against Escherichia coli (E. coli) and B. subtilis. Additionally, trichlormethane, ethanol, methanol, or aqueous extracts from P. alkekengi were also active against some Gram-positive and Gram-negative bacteria [23][56][57][58]. Janua’rio et al. [56] found that the crude trichlormethane extract (fraction A1-29-12) inhibited the Mycobacterium tuberculosis H37RV strain at a minimum concentration of 32 μg/mL. Li et al. [57] found that the 70% ethanol extract stimulated the growth of probiotic bacteria (Lactobacillus delbrueckii) and inhibited that of pathogenic bacteria (E. coli) in a dose-dependent manner. Moreover, a study indicated that physakengoses also have potent antibacterial activity against S. aureus, B. subtilis, and Pseudomonas aeruginosa (P. aeruginosa). The minimum inhibitory concentration (MIC) values of physakengoses B, E, F, G, and H for S. aureus were 9.72 ± 2.83, 9.81 ± 1.48, 5.32 ± 1.47, 6.57 ± 0.86, and 5.78 ± 0.96 μg/mL, respectively. For B. subtilis, these values were 8.89 ± 1.63, 5.59 ± 0.85, 3.50 ± 1.49, 8.78 ± 1.67, and 3.57 ± 1.02 µg/mL, respectively. For P. aeruginosa, these values were 14.91 ± 2.56, 13.12 ± 2.42, 5.79 ± 1.15, 4.51 ± 3.02, and 3.21 ± 0.95 μg/mL, respectively [58]. Zhang et al. showed that physakengoses K, L, M, N, and O had potent antibacterial activity, with MIC values ranging from 2.16 to 12.76 mg/mL [59]. However, the mechanism involved in the antibacterial activity of P. alkekengi has not been reported yet, warranting further research. The antibacterial activity is illustrated in Figure 3.
/media/item_content/202202/620470b46575bmolecules-27-00695-g006.pngFigure 3. Schematic representation of antibacterial activity of P. alkekengi and its constituents.

2.5. Antileishmanial Activity

Physalins exhibit potent antileishmanial activity against the cutaneous leishmaniasis [71][72]. Guimarães et al. [60] reported that physalins B and F exerted in vivo antileishmanial effects in BALB/c mice infected with Leishmania amazonensis (L. amazonensis); in vitro, they demonstrated an effect against intracellular amastigotes of Leishmania. In vitro, physalins B and F inhibited the infection of macrophages with L. amazonensis, with IC50 values of 0.21 and 0.18 μM, respectively. Physalin F markedly reduced the lesion size and number of parasites in vivo. However, physalin D did not show this activity. This effect was associated with the inhibition of NO and proinflammatory cytokines (e.g., IL-12 and TNF-α) by physalins B and F; however, physalin D lacked immunomodulatory/anti-inflammatory activity [9][50]. Meanwhile, the results suggest that anti-inflammatory and antileishmanial activities by physalins play a role in the treatment of cutaneous leishmaniasis.

2.6. Others

The anti-asthmatic activity of physalins has been increasingly reported over the years. In an in vitro study, following the oral administration of a water extract from P. alkekengi, the number of white blood cells and eosinophils in mice, as well as the expression of IL-5 and IFN-γ in lung tissue, were reduced. These findings indicated its potency as a drug for the treatment of allergic asthma in children [61]. Moreover, some studies showed that luteolin effectively inhibited inflammation in asthmatic models [73]. The relevant mechanisms may be related to the inhibition of iNOS/NO signaling. Thus, more studies are required to explain the mechanisms involved in the anti-asthmatic activity of the P. alkekengi extract.
Thus far, most scientific investigations on the anti-diabetic activity of P. alkekengi have been carried out using the fruits, aerial parts, and polysaccharides obtained from the calyxes of P. alkekengi. For the fruits and aerial parts, the ethyl acetate extract effectively decreased the levels of fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), and glycated serum protein, whereas it significantly increased those of fasting insulin (FINS) [62][64]. Moreover, polysaccharides showed anti-hyperglycemic activity on alloxan-induced mice. Although research is currently at a preliminary stage, the possible mechanisms are related to the enhancement of PI3K, Akt, and glucose transporter type 4 (GLUT4) mRNA expression, as well as the inhibition of FNG and GSP expression, indicating that they are promising candidates for the development of new anti-diabetic agents [63].
The anti-ulcer and anti-Helicobacter pylori effects are newly discovered pharmacological effects of P. alkekengi. Wang et al. reported that the P. alkekengi extract showed anti-Helicobacter pylori and gastroprotective activities by reducing the intensity of gastric mucosal damage and mitigating pain sensation [24]. It was recently reported that the 70% ethanol extract of P. alkekengi treated LPS-induced acute lung injury by: (1) reducing the release of TNF-α and the accumulation of oxidation products; (2) decreasing the levels of NF-κB, phosphorylated-p38, ERK, JNK, p53, caspase 3 (CASP3), and COX-2; and (3) enhancing the translocation of Nrf2 from the cytoplasm to the nucleus [65]. It was also shown that the mechanism of P. alkekengi, which is involved in the improvement of oxidative stress damage and inflammatory response induced by acute lung injury, was related to the inhibition of NF-κB and the MAPK signaling pathway and the transduction of the apoptotic pathway, as well as the activation of the Nrf2 signaling pathway. Physalin B could be used in the treatment of dextran sulfate sodium-induced colitis in BALB/c mice by suppressing multiple inflammatory signaling pathways [11]. In addition, physalin B is effective against Alzheimer’s disease through downregulation of β-amyloid (Aβ) secretion and beta-secretase 1 (BACE1) expression by activating forkhead box O1 (FoxO1) and inhibiting STAT3 phosphorylation [66]. In the diphenyl-2-picrylhydrazyl (DPPH) and thiobarbituric acid (TBA) test, physalin D showed antioxidant activity, with an IC50 value ≥10 ± 2.1 μg/mL [54]. Physalins B, D, F, and G showed low anti-plasmodial activity; nevertheless, physalin D markedly caused parasitemia and a delay in mortality in mice infected with Plasmodium berghei [67]. Furthermore, a study demonstrated that 75% ethanol extract of calyxes and fruits of P. alkekengi significantly decreased the serum’s total cholesterol and TG levels in vivo. Moreover, luteolin-7-O-β-d-glucopyranoside isolated from P. alkekengi decreased the TG levels induced by oleic acid in HepG2 cells and by high glucose in primary mouse hepatocytes, thereby exhibiting hypolipidemic activity [68]. Luteolin effectively relaxed the blood vessels and preserved the rat heart, mainly through activation of the PI3K/Akt/NO signaling pathway and enhancement of the activity of endothelial NOS, as well as amelioration of the Ca2+ overload in rat cardiomyocytes [69][70].

3. Summary

In summary, P. alkekengi is an excellent, abundant, inexpensive, and edible drug. The synthesis of the main active components of P. alkekengi must be further analyzed using additional biological and chemical techniques to further expand their potential applications. In addition, the quantitative analysis of the chemical constituents of P. alkekengi should be employed for the purpose of standardization and quality control of extracts. Lastly, additional in vivo animal research and clinical trials are needed to determine whether various applications of P. alkekengi are effective and safe in a larger population.

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