Solasonine Research Articles

Solasonine ameliorates cerebral ischemia-reperfusion injury via suppressing TLR4/MyD88/NF-κB pathway and activating AMPK/Nrf2/HO-1 pathway

Solasonine (SS), the main active ingredient of Solanum nigrum L., has been reported to possess a variety of pharmacological properties. A recent study demonstrated a neuroprotective effect of SS in a mouse nerve injury model. However, its protective effects on cerebral ischemia/reperfusion injury (CIRI) remain to be elucidated. We investigated herein the in vitro and in vivo neuroprotective effects of SS. Primary hippocampal neurons were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) to construct an in vitro model while rats were treated with middle cerebral artery occlusion/reperfusion (MCAO/R) to establish an in vivo CIRI model. The results showed that SS reduced OGD/R-induced inflammatory responses of neurons by blocking secretion of TNF-α, IL-1β and IL-6. Moreover, SS ameliorated OGD/R-induced oxidative stress in neurons by decreasing the level of ROS and MDA and increasing the activity of SOD and GPx. We also found that SS protected neurons from OGD/R-induced apoptosis by down-regulating bax and cleaved caspase-3 and up-regulating bcl-2. The in vivo results revealed that SS administration reduced the infarct volume and alleviated the neurological deficit of MCAO/R rats as well as diminished neuronal damages in these rats. Our investigation on the underlying mechanisms indicated that the neuroprotective effect of SS on CIRI may be associated with the TLR4/MyD88/NF-κB and AMPK/Nrf2/HO-1 pathways. Taken together, these findings demonstrate that SS ameliorates CIRI via suppressing TLR4/MyD88/NF-κB pathway and activating AMPK/Nrf2/HO-1 pathway.

Solasonine Inhibits Cancer Stemness and Metastasis by Modulating Glucose Metabolism via Wnt/β-Catenin/Snail Pathway in Osteosarcoma.

Solasonine (SS) is a natural glycoalkaloid compound that has been reported to possess a significant anticancer function. However, its anticancer effects and related mechanisms in osteosarcoma (OS) have not been studied. This study sought to investigate the impact of SS on the growth of OS cells. OS cells were treated with different concentrations of SS for 24[Formula: see text]h, and the results showed that SS attenuated the survival of OS cells in a dose-dependent manner. Additionally, SS suppressed cancer stem-like properties and epithelial-mesenchymal transition (EMT) by inhibiting aerobic glycolysis in OS cells in an ALDOA-dependent manner. Additionally, SS reduced the levels of Wnt3a, [Formula: see text]-catenin, and Snail in OS cells in vitro. Furthermore, Wnt3a activation reversed the SS-induced inhibition of glycolysis in OS cells. Collectively, this study discovered a novel effect of SS in inhibiting aerobic glycolysis, in addition to cancer stem-like features and EMT, implying that SS could be a therapeutic candidate for OS treatment.

Anticancer activity of glycoalkaloids from Solanum plants: A review.

Cancer is still one of the main causes of death worldwide. For this reason, new compounds that have chemotherapeutic potential have been identified. One such group of substances is Solanaceae glycoalkaloids (GAs). They are natural compounds produced by plants widely used in traditional medicine for healing many disorders. Among others, GAs exhibit significant antitumor properties, for example, a strong inhibitory effect on cancer cell growth. This activity can result in the induction of tumor cell apoptosis, which can occur via different molecular pathways. The molecular mechanisms of the action of GAs are the subject of intensive research, as improved understanding could lead to the development of new cancer therapies. The genetic basis for the formation of neoplasms are mutations in protooncogenes, suppressors, and apoptosis-controlling and repair genes; therefore, substances with antineoplastic properties may affect the levels of their expression or the levels of their expression products. Therapeutic compounds can be applied separately or in combination with other drugs to increase the efficiency of cancer therapy; they can act on the cell through various mechanisms at different stages of carcinogenesis, inducing the process of apoptosis, blocking cell proliferation and migration, and inhibiting angiogenesis. This review summarizes the newest studies on the anticancer properties of solanine (SN), chaconine (CH), solasonine (SS), solamargine (SM), tomatine (TT) and their extracts from Solanum plants.

Solasonine alleviates high glucose-induced podocyte injury through increasing Nrf2-medicated inhibition of NLRP3 activation.

The worldwide high prevalence of diabetic nephropathy is one of the common causes of renal failure in diabetic patients. Hyperglycemia-caused podocyte injury is considered as a major contributor to diabetic kidney disease, accompanied by a chronic inflammatory condition. Pyroptosis, a characterized inflammatory form of programmed cell death, is believed to be involved in the pathogenesis of diabetic nephropathy. Solasonine (SS) is a natural alkaloid and received attention as a potential anticancer agent. However, its protective effect against hyperglycemia-caused podocyte injury remains to be determined. Our study found that SS alleviates cell apoptosis, and reduces pyroptosis and oxidative damage in high glucose (HG)-treated MPC5 podocytes. Pro-inflammatory cytokines, including interleukin (IL)-1β and IL-18, and caspase-1 activity were markedly suppressed by SS in HG-treated MPC5 podocytes. SS also reduced HG-induced oxidative damage in MPC5 podocytes. Nrf2 expression was activated by SS in vitro under a HG condition. In addition, Nrf2 silencing attenuated the protective effect of SS against apoptosis, pro-inflammatory cytokines release, caspase-1 activity, and oxidative damage in MPC5 podocytes under a HG condition. Taken together, our findings revealed for the first time that SS alleviated high glucose-induced podocyte apoptosis, pyroptosis, and oxidative damage via regulating the Nrf2/NLRP3 signaling pathway. Our results indicate that SS has the potential as a therapeutic agent for podocyte injury in diabetic nephropathy.

Solasonine relieves sevoflurane-induced neurotoxicity via activating the AMP-activated protein kinase/FoxO3a pathway.

Solasonine (SS), the main active ingredient of Solanumnigrum L, has been reported to boast extensive anti-tumor, anti-oxidant, and anti-inflammatory properties. This study is committed to exploring whether solasonine can alleviate neurotoxicity resulting from sevoflurane. The mouse hippocampal neuron cell line HT22 was treated with sevoflurane and/or solasonine of different doses. The proliferation, inflammation, oxidative stress response, and apoptosis of HT22 cells were examined. The AMP-activated protein kinase (AMPK)/FoxO3a signaling pathway was ascertained through Western blot and cellular immunofluorescence. In in-vivo experiments, Morris water maze figured out the changes in learning and memory abilities of mice treated with 8 mg/kg solasonine and exposed to SEV. Sevoflurane induced apoptosis and hampered proliferation in HT22 cells. It also aggravated the release of inflammatory factors and oxidative stress mediators. Solasonine weakened neuron damage mediated by sevoflurane in a concentration-dependent pattern. Mechanically, sevoflurane clogged AMPK/FoxO3a signaling pathway activation, which was strengthened by solasonine. AMPK inhibition greatly influenced solasonine's protective effect on HT22 cells. Invivo, solasonine prominently ameliorated learning and memory disorders and nerve damage in mice exposed to sevoflurane. Solasonine alleviates sevoflurane-induced neurotoxicity through activating the AMPK/FoxO3a signaling pathway.

Targeted uptake of folic acid-functionalized polymeric nanoparticles loading glycoalkaloidic extract in vitro and in vivo assays

Solanum lycocarpum fruits contain two major glycoalkaloids (GAs), solamargine (SM) and solasonine (SS). These compounds are reported as cytotoxic. However, they have poor water solubility and low bioavailability. To overcome these disadvantages and getting an efficient formulation the current study aimed to develop, characterize, and test the effectiveness of a nanotechnology-based strategy using poly(D,L-lactide) (PLA) nanoparticles functionalized with folate as delivery system of glycoalkaloidic extract (AE) for bladder cancer therapy. The strategic of adding folic acid into nanoformulations can increase the selectivity of the compounds to the cancer cells reducing the side effects. Our results revealed the successful preparation of AE-loaded folate-targeted nanoparticles (NP-F-AE) with particle size around 177 nm, negative zeta potential, polydispersity index <0.20, and higher efficiency of encapsulation for both GAs present in the extract (>85 %). To investigate the cellular uptake, the fluorescent dye coumarin-6 was encapsulated into the nanoparticle (NP-F-C6). The cell studies showed high uptake of nanoparticles by breast (MDA-MB-231) and bladder (RT4) cancer cells, but not for normal keratinocytes cells (HaCaT) indicating the target uptake to cancer cells. The cytotoxicity of nanoparticles was evaluated on RT4 2D culture model showing 2.16-fold lower IC50 than the free AE. Furthermore, the IC50 increased on the RT4 spheroids compared to 2D model. The nanoparticles penetrated homogeneously into the urotheliumof porcine bladder. These results showed that folate-conjugated polymeric nanoparticles are potential carriers for targeted glycoalkaloidic extract delivery to bladder cancer cells.

The Reciprocal Interaction Between LncRNA CCAT1 and miR-375-3p Contribute to the Downregulation of IRF5 Gene Expression by Solasonine in HepG2 Human Hepatocellular Carcinoma Cells.

Solasonine (SS), a natural glycoalkaloid component, has been shown to have potent inhibitory activity and cytotoxicity against many cancer types. However, the precise mechanisms underlying this, particularly in hepatocellular carcinoma (HCC) are poorly understood. In this study, we showed that SS inhibited growth of HCC cells. Mechanistically, we observed that SS increased the expression of miR-375-3p, whereas reducing levels of long non-coding RNAs (lncRNAs) CCAT1 was noticed in HepG2 HCC and other cells. In addition, we found that SS repressed transcription factors, SP1 and interferon regulatory factor 5 (IRF5), protein expressions. There was a reciprocal interaction among miR-375-3p, CCAT1, and SP1. Moreover, SS inhibited IRF5 promoter activity, which was not observed in cells transfected with excessive expressed SP1 vectors. Interestingly, exogenously expressed IRF5 was shown to reverse expressions of SS-inhibited CCAT1 and induced-miR-375-3p; and neutralized SS-inhibited growth of HCC cells. Similar results were also found in vivo mouse model. Collectively, our results show that SS inhibits HepG2 HCC growth through the reciprocal regulation between the miR-375-3p and lncRNA CCAT1, and this results in transcription factor SP1-mediated reduction of IRF5 expression. The regulations and interactions among miR-375-3p, CCAT1, SP1, and IRF5 axis unveil a novel molecular mechanism underlying the anti-HCC growth by SS. IRF5 may be a potential target for treatment of HCC.

IN VITRO Anticancer Activity and Physicochemical Properties of SOLANUM LYCOCARPUM Alkaloidic Extract Loaded in Natural Lipid-Based Nanoparticles

Bladder cancer (BC) is the 9th most common cancer in the worldwide. BC's treatment is still a challenging goal. Thereby, the screening of natural compounds as solasonine (SS) and solamargine (SM) that exhibit antitumor activity is interesting to BC therapy. This work aimed to develop natural lipid-based nanoparticles (NLN) as carrier system of S. lycocarpum's fruits alkaloidic extract (AE), rich in SS and SM, and to evaluate its antitumor activity in bladder cancer cells. The NLN-AE exhibited 56 nm of diameter, low polydispersity index with shelf life estimated of 12 months, measured by LUMiSizer®. NLN-AE showed low recrystallization index with high encapsulation efficiency of SS (86%) and SM (89%). A sustained release profile was verified after 36 h. The free AE exhibited antitumor activity in bladder cancer cells. The cell viability decreased 5.4 fold when AE was encapsulated in NLN. Thus, NLN-AE has higher anti-proliferative activity than the free AE.

In vitro and in vivo evaluation of the delivery of topical formulations containing glycoalkaloids of Solanum lycocarpum fruits

The glycoalkaloids solasonine (SN) and solamargine (SM) have been studied for their antiparasitic, antifungal, and anticancer properties, especially in vitro and in vivo against non-melanoma skin cancer. Thus, the alkaloidic extract of Solanum lycocarpum, which contains approximately 45% each of SN and SM, was used to define the best experimental conditions for in vitro and in vivo assays. The in vitro assays were performed with the Franz cell diffusion porcine skin model to evaluate the effects of different pHs and the presence of monoolein, ethoxydiglycol or ethanol penetration enhancers on the skin penetration and retention of SN and SM after 3, 6, 9 and 12h of exposure. The in vivo assay was performed on hairless mice with the formulation selected in the in vitro assays. The results showed that pH 6.5 was optimal for SM penetration. The formulation containing 5% alkaloidic extract, 5% propylene glycol, 5% monoolein and a hydroxyethyl cellulose gel base (Natrosol®) (pH 6.5) was optimal for the delivery of SN and SM into the skin, and this formulation is potentially useful for the topical therapy of several skin disorders.

Antiproliferative activity of Solanum lycocarpum alkaloidic extract and their constituents, solamargine and solasonine, in tumor cell lines

Natural products are some of the important sources of new anticancer drugs. The Brazilian flora is considered one of the most diverse in the word, although not many large-scale pharmacological and phytochemical studies have been conducted to date. With this in mind, in the present study we evaluated the antiproliferative activity of Solanum lycocarpum fruit glycoalkaloid extract (SL) and its major compounds, solamargine (SM) and solasonine (SS), against different tumor cell lines: murine melanoma (B16F10), human colon carcinoma (HT29), human breast adenocarcinoma (MCF-7), human cervical adenocarcinoma (HeLa), human hepatocellular liver carcinoma (HepG2) and human glioblastoma (MO59J, U343 and U251). The antiproliferative activity was evaluated using XTT assay and results were expressed as IC50. The most pronounced antiproliferative activity was observed for SM, with IC50 values ranging from 4.58 to 18.23 μg/mL. The lowest IC50 values were observed against HepG2, being 9.60 μg/mL for SL, 4.58 μg/mL for SM and 6.01 μg/mL for SS. Thus, SL, SM and SS demonstrated antiproliferative activity against the tumor cell lines tested, and were most effective against the HepG2 cell line.

Antigenotoxicity of Solanum lycocarpum glycoalkaloid extract and its majority compounds, solamargine and solasonine, in V79 cells

Solanum lycocarpum A. St.-Hil. (Solanaceae) are commonly used in traditional medicine for the treatment of diabetes and obesity, as well as for controlling cholesterol levels. Solasonine and solamargine are two major glycoalkaloids found in at least 100 Solanum species. In this sense, the aim of the present study was to evaluate the cytotoxic, genotoxic and antigenotoxic potential of S. lycocarpum fruits glycoalkaloid extract (SL), solamargine (SM) and solasonine (SS), in V79 cells. Cytotoxicity was evaluated by the colony forming assay. Genotoxic and antigenotoxic potential were evaluated by comet assay. Different concentrations of SL (4, 8, 16 and 32 µg/mL), SM (7.1µg/mL) and SS (14.4 µg/mL) were used for the evaluation of their genotoxic potential in V79 cells. In the antigenotoxicity assay, the different concentrations of SL, SM and SS were combined with methyl methanesulfonate (MMS). SL, SM and SS were cytotoxic at concentrations up to 32µg/mL, 7.1µg/mL and 14.4 µg/mL, respectively. The comet assay revealed that SL, SM and SS displayed no genotoxic activity, but they significantly reduced the extent of DNA damage induced by MMS.

A validated HPLC analytical method for the analysis of solasonine and solamargine in in vitro skin penetration studies

To assess topical delivery studies of glycoalkaloids, an analytical method by HPLC-UV was developed and validated for the determination of solasonine (SN) and solamargine (SM) in different skin layers, as well as in a topical formulation. The method was linear within the ranges 0.86 to 990.00 µg/mL for SN and 1.74 to 1000.00 µg/mL for SM (r = 0.9996). Moreover, the recoveries for both glycoalkaloids were higher than 88.94 and 93.23% from skin samples and topical formulation, respectively. The method developed is reliable and suitable for topical delivery skin studies and for determining the content of SN and SM in topical formulations.

A Validated Reverse Phase HPLC Analytical Method for Quantitation of Glycoalkaloids inSolanum lycocarpumand Its Extracts

Solanum lycocarpum (Solanaceae) is native to the Brazilian Cerrado. Fruits of this species contain the glycoalkaloids solasonine (SN) and solamargine (SM), which display antiparasitic and anticancer properties. A method has been developed for the extraction and HPLC-UV analysis of the SN and SM in different parts of S. lycocarpum, mainly comprising ripe and unripe fruits, leaf, and stem. This analytical method was validated and gave good detection response with linearity over a dynamic range of 0.77–1000.00 μg mL−1 and recovery in the range of 80.92–91.71%, allowing a reliable quantitation of the target compounds. Unripe fruits displayed higher concentrations of glycoalkaloids (1.04% ± 0.01 of SN and 0.69% ± 0.00 of SM) than the ripe fruits (0.83% ± 0.02 of SN and 0.60% ± 0.01 of SM). Quantitation of glycoalkaloids in the alkaloidic extract gave 45.09% ± 1.14 of SN and 44.37% ± 0.60 of SM, respectively.

Simultaneous determination of three steroidal glycoalkaloids in Solanum xanthocarpum by high performance thin layer chromatography

A new high-performance thin-layer chromatographic (HPTLC) method has been developed for the simultaneous quantitation of three bioactive steroidal glycoalkaloid (SGA) markers, solasonine (SN), solamargine (SM) and khasianine (KN) in the plant Solanum xanthocarpum. Extraction efficiency of targeted SGAs from plant matrix using methanol and acidified methanol were studied using percolation, ultrasonication and microwave techniques. The separation was achieved on silica gel 60F 254 TLC plates using chloroform–methanol–water as mobile phase. The quantitation of SGAs was carried out using the densitometric reflection/absorption mode at 520 nm after post chromatographic derivatization using Dragendorff's reagent. The method was validated for peak purity, precision, accuracy, robustness, limit of detection (LOD) and quantitation (LOQ). Method specificity was confirmed using retention factor ( R f), Vis spectral correlation and electrospray ionization mass spectra (ESI-MS) of marker compounds in the sample track.

Effects of glycoalkaloids from Solanum plants on cucumber root growth

The phytotoxic effect of four glycoalkaloids and two 6- O-sulfated glycoalkaloid derivatives were evaluated by testing their inhibition of cucumber root growth. The bioassays were performed using both compounds singly and in equimolar mixtures, respectively. Cucumber root growth was reduced by chaconine (C), solanine (S), solamargine (SM) and solasonine (SS) with IC 50 values of 260 (C), 380 (S), 530 (SM), and 610 μM (SS). The inhibitory effect was concentration-dependent. 6- O-sulfated chaconine and 6- O-sulfated solamargine had no inhibitory effects, which indicated that the carbohydrate moieties play an important role in inhibiting cucumber root growth. The equimolar mixtures of paired glycoalkaloids, both chaconine/solanine and solamargine/solasonine, produced synergistic effects on inhibition of cucumber root growth. By contrast, mixtures of unpaired glycoalkaloids from different plants had no obviously synergistic effects. The growth inhibited plant roots lacked hairs, which implied that inhibition was perhaps at the level of root hair growth.

Steroid alkaloid glycosides from Solanum coccineum

In addition to solamargine, isoanguivine and solasonine, two new steroid alkaloid glycosides, xylosyl-solamargine and xylosyl-β-solamarine, have been isolated from the aerial parts of Solanum coccineum, the structures of which have been elucidated as (25R)-3β-{O-β- d- xylopyranosyl-(1 → 2)-O-α- l- rhamnopyranosyl-(1 → 4)-O-[α- l- rhamnopyranosyl-(1 → 2)]-β- d- glucopyranosyloxy}-22αN- spirosol-5-ene and (25S)-3β-O-β- d- xylopyranosyl-(1 → 2)-O-α- l- rhamnopyranosyl-(1 → 4)-O-[α- l- rhamnopyranosyl-(1 → 2)]-β - d- glucopyranosyloxy}-22βN- spirosol-5-ene .

Steroid alkaloid glycosides from Solanum robustum

Solamargine, solasonine, N-hydroxyrobustine and a new glycoalkaloid, N-hydroxysolamargine, has been isolated from the leaves of Solanum robustum, the structure of which has been elucidated as (25R)-3β{O-α- l-rhamnopyranosyl -(1→2)-O-[α- l-rhamnopyranosyl-(1→4)]-β-[spd -glucopyranosyloxy -22αN -spirosol-5-en-N-ol.