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1.
Int Immunopharmacol ; 133: 112133, 2024 May 30.
Article in English | MEDLINE | ID: mdl-38652962

ABSTRACT

There is an increasing tendency for sepsis patients to suffer from diaphragm atrophy as well as mortality. Therefore, reducing diaphragm atrophy could benefit sepsis patients' prognoses. Studies have shown that Anisodamine (Anis) can exert antioxidant effects when blows occur. However, the role of Anisodamine in diaphragm atrophy in sepsis patients has not been reported. Therefore, this study investigated the antioxidant effect of Anisodamine in sepsis-induced diaphragm atrophy and its mechanism. We used cecal ligation aspiration (CLP) to establish a mouse septic mode and stimulated the C2C12 myotube model with lipopolysaccharide (LPS). After treatment with Anisodamine, we measured the mice's bodyweight, diaphragm weight, fiber cross-sectional area and the diameter of C2C12 myotubes. The malondialdehyde (MDA) levels in the diaphragm were detected using the oxidative stress kit. The expression of MuRF1, Atrogin1 and JAK2/STAT3 signaling pathway components in the diaphragm and C2C12 myotubes was measured by RT-qPCR and Western blot. The mean fluorescence intensity of ROS in C2C12 myotubes was measured by flow cytometry. Meanwhile, we also measured the levels of Drp1 and Cytochrome C (Cyt-C) in vivo and in vitro by Western blot. Our study revealed that Anisodamine alleviated the reduction in diaphragmatic mass and the loss of diaphragmatic fiber cross-sectional area and attenuated the atrophy of the C2C12 myotubes by inhibiting the expression of E3 ubiquitin ligases. In addition, we observed that Anisodamine inhibited the JAK2/STAT3 signaling pathway and protects mitochondrial function. In conclusion, Anisodamine alleviates sepsis-induced diaphragm atrophy, and the mechanism may be related to inhibiting the JAK2/STAT3 signaling pathway.


Subject(s)
Diaphragm , Janus Kinase 2 , Muscular Atrophy , STAT3 Transcription Factor , Sepsis , Signal Transduction , Solanaceous Alkaloids , Animals , Janus Kinase 2/metabolism , STAT3 Transcription Factor/metabolism , Sepsis/drug therapy , Sepsis/complications , Solanaceous Alkaloids/therapeutic use , Solanaceous Alkaloids/pharmacology , Mice , Signal Transduction/drug effects , Diaphragm/drug effects , Diaphragm/pathology , Diaphragm/metabolism , Male , Cell Line , Muscular Atrophy/drug therapy , Muscular Atrophy/etiology , Disease Models, Animal , Lipopolysaccharides , Mice, Inbred C57BL , Oxidative Stress/drug effects , Tripartite Motif Proteins/metabolism , Tripartite Motif Proteins/genetics , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Antioxidants/pharmacology , Antioxidants/therapeutic use , Muscle Proteins/metabolism , SKP Cullin F-Box Protein Ligases/metabolism , SKP Cullin F-Box Protein Ligases/genetics , Muscle Fibers, Skeletal/drug effects , Muscle Fibers, Skeletal/pathology , Muscle Fibers, Skeletal/metabolism , Atrophy
2.
Fitoterapia ; 175: 105916, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38527590

ABSTRACT

Six previously unreported solanidane steroidal alkaloids, namely lyrasolanosides A-F, were isolated from Solanum lyratum. In addition, five known steroidal alkaloids were also identified. The structures of these compounds were determined through the use of NMR, HRESIMS,UV, IR and ECD analysis. To assess their bioactivities, the cytotoxic effects of the six previously unreported compounds were evaluated on A549 cells. The results revealed that lyrasolanoside B (2) exhibited the highest potency among them. Lyrasolanoside B (2) exhibited significant inhibition of cell migration, invasion, and adhesion dramatically. Mechanistically, it was found to suppress the activity of JAK2/STAT3 signaling pathway by downregulating the expression of phosphorylated JAK2/STAT3 in an exosome-dependent manner. In addition, lyrasolanoside B (2) was found to significantly upregulate the expression of E-cadherin and downregulate the expression of N-cadherin and vimentin. These findings indicate that lyrasolanoside B (2) inhibits the metastasis of A549 cells by suppressing exosome-mediated EMT. These findings suggest that lyrasolanoside B (2) may inhibit the metastasis of lung cancer by regulating A549-derived exosomes.


Subject(s)
Solanum , Humans , A549 Cells , Molecular Structure , Solanum/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/isolation & purification , Cell Movement/drug effects , Phytochemicals/pharmacology , Phytochemicals/isolation & purification , Solanaceous Alkaloids/pharmacology , Solanaceous Alkaloids/isolation & purification , Signal Transduction/drug effects , Alkaloids/pharmacology , Alkaloids/isolation & purification , China
3.
Biomed Pharmacother ; 171: 116146, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38198952

ABSTRACT

The effectiveness and safety of traditional Chinese medicine's active ingredients in anti-tumor effects have attracted widespread attention worldwide. Solasonine is the main anti-tumor component of the traditional Chinese medicine Solanum nigrum L, which can inhibit tumor cell proliferation, induce apoptosis, induce ferroptosis in tumor cells, and inhibit of tumor cell metastasis, thereby inhibiting tumor progression. Therefore, we summarized anti-tumor mechanisms and targets of solasonine to provide new ideas and theoretical basis for its further development and application.


Subject(s)
Neoplasms , Solanaceous Alkaloids , Humans , Solanaceous Alkaloids/pharmacology , Apoptosis , Medicine, Chinese Traditional
4.
Biomed Pharmacother ; 161: 114522, 2023 May.
Article in English | MEDLINE | ID: mdl-37002581

ABSTRACT

Anisodamine is an anticholinergic drug extracted and isolated from the Anisodus tanguticus (Maxim.) Pascher of the Solanaceae family which is also a muscarinic receptor antagonist. Owing to the lack of natural sources of anisodamine, synthetic products are now used. Using ornithine and arginine as precursor compounds, putrescine is catalyzed by different enzymes and then undergoes a series of reactions to produce anisodamine. It has been used clinically to protect cardiac function and treat septic shock, acute pancreatitis, calculous renal colic, bronchial asthma, blood circulation disturbances, jaundice, analgesia, vertigo, acute poisoning, and other conditions.This review describes the relevant pharmacokinetic parameters. Anisodamine is poorly absorbed in the gastrointestinal tract, and it is not as effective as intravenous administration. For clinical medication, intravenous infusion should be used rather than rapid intravenous injection. With the advancement of research in recent years, the application scope of anisodamine has expanded, with significant developments and application values surging.This review systematically describes the sources, pharmacokinetics, pharmacological effects and clinical application of anisodamine, in order to provide a basis for clinical use.


Subject(s)
Pancreatitis , Solanaceous Alkaloids , Humans , Acute Disease , Pancreatitis/drug therapy , Solanaceous Alkaloids/pharmacology , Solanaceous Alkaloids/therapeutic use , Cholinergic Antagonists
5.
Drug Res (Stuttg) ; 72(6): 327-335, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35724671

ABSTRACT

Insulin resistance (IR) is a condition in which target cells become insensitive to normal insulin concentrations in order to deliver glucose. The goal of this study was to see if solasodine combined with coenzyme Q10 could help rats with insulin resistance caused by a high-fat diet (HFD) by regulating the expression of IRS-I and PPAR-γ proteins.One of the six groups (n=6) got a conventional diet for 16 weeks as a control (normal), the HFD was given to the other five groups for 16 weeks, which further classified as-one group as HFD control while others treated with pioglitazone (10 mg/kg), coenzyme Q10 (50 mg/kg), solasodine (50 mg/kg) and combination of solasodine and coenzyme Q10i.e. SDQ10 (total 50 mg/kg) for the last 4 weeks orally once daily. Blood and tissue samples were collected by the end of study period for the biochemical and histological studies. As a result, HFD fed rats exhibited a significant increase in food and energy intake, body mass index, kidney and pancreas weight, fasting glucose, glycosylated haemoglobin, insulin level, liver enzyme ALT and AST and decrease antioxidant activity of superoxide dismutase and catalase. HFD received animals also produced a lower level of p-IRS1 and PPAR-y protein expression in western blot analysis. SDQ10 in combination successfully restored the above-mentioned complexity of insulin resistance caused by aHFD. Besides, increasesthe antioxidant activity of superoxide dismutase and catalase and normalized the architecture of kidney, pancreas and adipose tissue as well astreatment with SDQ10 raised the level of p-IRS1 and PPAR-y protein in liver tissue. As a result, supplementing with solasodine and coenzyme Q10 reversed the effect of the HFD on p-IRS1 and PPAR-y protein in liver tissue while also alleviating insulin resistance symptoms.


Subject(s)
Insulin Resistance , Insulins , Solanaceous Alkaloids , Ubiquinone , Animals , Antioxidants/pharmacology , Blood Glucose , Catalase/metabolism , Diet, High-Fat/adverse effects , Insulin/metabolism , Insulin Receptor Substrate Proteins , Insulins/metabolism , Insulins/pharmacology , Liver/metabolism , PPAR gamma/metabolism , Rats , Solanaceous Alkaloids/pharmacology , Superoxide Dismutase/metabolism , Ubiquinone/analogs & derivatives , Ubiquinone/pharmacology
6.
Biochem Biophys Res Commun ; 616: 8-13, 2022 08 06.
Article in English | MEDLINE | ID: mdl-35636257

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provoked a pandemic of acute respiratory disease, namely coronavirus disease 2019 (COVID-19). Currently, effective drugs for this disease are urgently warranted. Anisodamine is a traditional Chinese medicine that is predicted as a potential therapeutic drug for the treatment of COVID-19. Therefore, this study aimed to investigate its antiviral activity and crucial targets in SARS-CoV-2 infection. SARS-CoV-2 and anisodamine were co-cultured in Vero E6 cells, and the antiviral activity of anisodamine was assessed by immunofluorescence assay. The antiviral activity of anisodamine was further measured by pseudovirus entry assay in HEK293/hACE2 cells. Finally, the predictions of crucial targets of anisodamine on SARS-CoV-2 were analyzed by molecular docking studies. We discovered that anisodamine suppressed SARS-CoV-2 infection in Vero E6 cells, and reduced the SARS-CoV-2 pseudovirus entry to HEK293/hACE2 cells. Furthermore, molecular docking studies indicated that anisodamine may target SARS-CoV-2 main protease (Mpro) with the docking score of -6.63 kcal/mol and formed three H-bonds with Gly143, Cys145, and Cys44 amino acid residues at the predicted active site of Mpro. This study suggests that anisodamine is a potent antiviral agent for treating COVID-19.


Subject(s)
COVID-19 Drug Treatment , COVID-19 , Coronavirus 3C Proteases , SARS-CoV-2 , Solanaceous Alkaloids , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/virology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/drug effects , Coronavirus 3C Proteases/metabolism , HEK293 Cells , Humans , Molecular Docking Simulation , Peptide Hydrolases , Protease Inhibitors/pharmacology , Solanaceous Alkaloids/pharmacology , Viral Nonstructural Proteins/chemistry
7.
J Appl Toxicol ; 42(6): 1067-1077, 2022 06.
Article in English | MEDLINE | ID: mdl-34967033

ABSTRACT

Anisodamine is one of the major components of the tropine alkaloid family and is widely used in the treatment of pain, motion sickness, pupil dilatation, and detoxification of organophosphorus poisoning. As a muscarinic receptor antagonist, the low toxicity and moderate drug effect of anisodamine often result in high doses for clinical use, making it important to fully investigate its toxicity. In this study, zebrafish embryos were exposed to 1.3-, 2.6-, and 5.2-mM anisodamine for 7 days to study the toxic effects of drug exposure on pigmentation, mineral density, craniofacial area, and eye development. The results showed that exposure to anisodamine at 1.3 mM resulted in cranial malformations and abnormal pigmentation in zebrafish embryos; 2.6- and 5.2-mM anisodamine resulted in significant eye development defects and reduced bone density in zebrafish embryos. The associated toxicities were correlated with functional development of neural crest cells through gene expression (col1a2, ddb1, dicer1, mab21l1, mab21l2, sox10, tyrp1b, and mitfa) in the dose of 5.2-mM exposed group. In conclusion, this study provides new evidence of the developmental toxicity of high doses of anisodamine in aqueous solutions to organisms and provides a warning for the safe use of this drug.


Subject(s)
Solanaceous Alkaloids , Zebrafish , Animals , Embryo, Nonmammalian , Minerals/metabolism , Minerals/pharmacology , Pigmentation , Solanaceous Alkaloids/metabolism , Solanaceous Alkaloids/pharmacology , Solanaceous Alkaloids/therapeutic use , Zebrafish/genetics , Zebrafish Proteins/genetics
8.
J Toxicol Environ Health A ; 85(4): 131-142, 2022 02 16.
Article in English | MEDLINE | ID: mdl-34612163

ABSTRACT

Melanoma is the most aggressive type of skin cancer, and thus it is important to develop new drugs for its treatment. The present study aimed to examine the antitumor effects of solamargine a major alkaloid heteroside present in Solanum lycocarpum fruit. In addition solamargine was incorporated into nanoparticles (NP) of yttrium vanadate functionalized with 3-chloropropyltrimethoxysilane (YVO4:Eu3+:CPTES:SM) to determine antitumor activity. The anti-melanoma assessment was performed using a syngeneic mouse melanoma model B16F10 cell line. In addition, systemic toxicity, nephrotoxic, and genotoxic parameters were assessed. Solamargine, at doses of 5 or 10 mg/kg/day administered subcutaneously to male C57BL/6 mice for 5 days, decreased tumor size and frequency of mitoses in tumor tissue, indicative of a decrease in cell proliferation. Treatments with YVO4:Eu3+:CPTES:SM significantly reduced the number of mitoses in tumor tissue, associated with no change in tumor size. There were no apparent signs of systemic toxicity, nephrotoxicity, and genotoxicity initiated by treatments either with solamargine alone or plant alkaloid incorporated into NP. The animals treated with YVO4:Eu3+:CPTES:SM exhibited significant increase in spleen weight accompanied by no apparent histological changes in all tissues examined. In addition, animals treated with solamargine (10 mg/kg/day) and YVO4:Eu3+:CPTES:SM demonstrated significant reduction in hepatic DNA damage which was induced by tumor growth. Therefore, data suggest that solamargine may be considered a promising candidate in cancer therapy with no apparent toxic effects.


Subject(s)
Antineoplastic Agents/pharmacology , Melanoma, Experimental/drug therapy , Solanaceous Alkaloids/pharmacology , Animals , Antineoplastic Agents/toxicity , Cell Line, Tumor , DNA Damage , Liver/drug effects , Male , Mice , Mice, Inbred C57BL , Mitosis/drug effects , Nanoparticles/administration & dosage , Silanes/chemistry , Solanaceous Alkaloids/toxicity , Yttrium/chemistry
9.
J Ethnopharmacol ; 280: 114473, 2021 Nov 15.
Article in English | MEDLINE | ID: mdl-34343650

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Fungal and bacterial infections remain a major problem worldwide, requiring the development of effective therapeutic strategies. Solanum mammosum L. (Solanaceae) ("teta de vaca") is used in traditional medicine in Peru to treat fungal infections and respiratory disorders via topical application. However, the mechanism of action remains unknown, particularly in light of its chemical composition. MATERIALS AND METHODS: The antifungal activity of TDV was determined against Trichophyton mentagrophytes and Candida albicans using bioautography-TLC-HRMS to rapidly identify the active compounds. Then, the minimum inhibitory concentration (MIC) of the fruit crude extract and the active compound was determined to precisely evaluate the antifungal activity. Additionally, the effects of the most active compound on the formation of Pseudomonas aeruginosa biofilms and pyocyanin production were evaluated. Finally, a LC-HRMS profile and a molecular network of TDV extract were created to characterize the metabolites in the fruits' ethanolic extract. RESULTS: Bioautography-TLC-HRMS followed by isolation and confirmation of the structure of the active compound by 1D and 2D NMR allowed the identification solamargine as the main compound responsible for the anti-Trichophyton mentagrophytes (MIC = 64 µg mL-1) and anti-Candida albicans (MIC = 64 µg mL-1) activities. In addition, solamargine led to a significant reduction of about 20% of the Pseudomonas aeruginosa biofilm formation. This effect was observed at a very low concentration (1.6 µg mL-1) and remained fairly consistent regardless of the concentration. In addition, solamargine reduced pyocyanin production by about 20% at concentrations of 12.5 and 50 µg mL-1. Furthermore, the LC-HRMS profiling of TDV allowed us to annotate seven known compounds that were analyzed through a molecular network. CONCLUSIONS: Solamargine has been shown to be the most active compound against T. mentoagrophytes and C. albicans in vitro. In addition, our data show that this compound affects significantly P. aeruginosa pyocyanin production and biofilm formation in our conditions. Altogether, these results might explain the traditional use of S. mammosum fruits to treat a variety of fungal infections and respiratory disorders.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Solanaceous Alkaloids/pharmacology , Solanum/chemistry , Anti-Bacterial Agents/isolation & purification , Antifungal Agents/isolation & purification , Arthrodermataceae/drug effects , Biofilms/drug effects , Candida albicans/drug effects , Microbial Sensitivity Tests , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Pseudomonas aeruginosa/drug effects , Pyocyanine/metabolism , Solanaceous Alkaloids/isolation & purification
10.
Pharmazie ; 76(5): 220-224, 2021 05 01.
Article in English | MEDLINE | ID: mdl-33964996

ABSTRACT

Anisodamine exerts significant protective effect on ischemia/reperfusion (I/R) injury in various organs. However, little is known about the mechanisms of anisodamine in renal I/R injury. Activation of extracellular regulated protein kinases (ERK) pathway promotes the repair of renal epithelial cells following oxidant injury. The present study investigated whether the renoprotective role of anisodamine against renal I/R injury in rats was associated with the activation of ERK signaling pathway. Male Sprague-Dawley (SD) rats were separated into the following groups: Sham-operated group, I/R group, anisodamine-treated group, PD98059 (MEK-1/ERK inhibitor)-treated group and anisodamine plus PD98059-treated group. A rat model of renal I/R was established by excising the right kidney and then clamping the left renal pedicle for 45 min followed by reperfusion for 24 h. Serum and renal tissue samples were obtained for assays of the associated morphological, molecular and biochemical parameters. Treatment with anisodamine ameliorated renal I/R injury, as evidenced by improvements of renal histology and kidney function, a decrease in paller's score and apoptosis index. Anisodamine also upregulated the phosphorylation levels of ERK1/2 and its downstream targets, including 90 ribosomal S6 kinase (p90rsk) and Bad, as well as the expression of antiapoptotic Bcl-2 protein, downregulated the expression levels of proapoptotic proteins Bax and cleaved-caspase-3, whereas these effects were greatly abolished by administration of PD98059. In conclusion, the results suggest that anisodamine prevents renal I/R injury in rats as a result of an activation of the ERK signaling pathway and anti-apoptotic properties.


Subject(s)
Acute Kidney Injury/drug therapy , Apoptosis/drug effects , MAP Kinase Signaling System/drug effects , Reperfusion Injury/drug therapy , Solanaceous Alkaloids/pharmacology , Acute Kidney Injury/pathology , Animals , Apoptosis Regulatory Proteins/metabolism , Epithelial Cells/drug effects , Flavonoids/pharmacology , Kidney/drug effects , Kidney/metabolism , Male , Models, Animal , Phosphorylation , Rats , Rats, Sprague-Dawley , Reperfusion Injury/pathology , Signal Transduction/drug effects
11.
Drug Des Devel Ther ; 15: 1509-1519, 2021.
Article in English | MEDLINE | ID: mdl-33888977

ABSTRACT

BACKGROUND: Increasing evidences have revealed that solasodine, isolated from Solanum sisymbriifolium fruits, has multiple functions such as anti-oxidant, anti-tumor and anti-infection. However, its role in pancreatic cancer has not been well studied. METHODS: To explore the role of solasodine in pancreatic cancer, human pancreatic cell lines including SW1990 and PANC1 were treated with different concentrations of solasodine for 48 h, and cell viability was evaluated by MTT assay, cell invasion and migration were evaluated by Transwell assay. The effect of solasodine on the apoptosis of SW1990 and PANC1 cells was detected by flow cytometry. To further explore the antitumor effect of solasodine in vivo, an SW1990 tumor-bearing mouse model was constructed. The effects of solasodine on cytokines in the serum of SW1990 tumor-bearing mice were also evaluated by ELISA assay. RESULTS: Specifically, in vitro, solasodine could significantly inhibit the proliferation of pancreatic cancer cell lines SW1990 and PANC1 cells. Flow cytometric analysis indicated that solasodine could induce apoptosis of SW1990 and PANC1 cells. Western blot assay indicated that solasodine could significantly inhibit the activation of Cox-2/Akt/GSK3ß signal pathway. Meanwhile, the release of Cytochrome c from mitochondria to cytoplasm which can raise the caspases cascade (C-caspase 3 and C-caspase 9) was significantly enhanced by solasodine. In vivo, the results showed that solasodine had potent anti-tumor activities with a lower cytotoxicity. In addition, the serum TNF-α, IL-2 and IFN-γ levels in SW1990 tumor-bearing mice after the treatment of solasodine was significantly increased. CONCLUSION: Taken together, our results suggested that the solasodine could prevent the progression of pancreatic cancer by inhibiting proliferation and promoting apoptosis, as well as stimulating immunity, suggesting that solasodine might be a potential therapeutic strategy for pancreatic cancer.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Fruit/chemistry , Pancreatic Neoplasms/drug therapy , Solanaceous Alkaloids/pharmacology , Solanum/chemistry , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Apoptosis/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Conformation , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Solanaceous Alkaloids/chemistry , Solanaceous Alkaloids/isolation & purification , Tumor Cells, Cultured
12.
J Steroid Biochem Mol Biol ; 205: 105776, 2021 01.
Article in English | MEDLINE | ID: mdl-33130020

ABSTRACT

Solasodine analogues containing a seven-membered F ring with a nitrogen atom placed at position 22a were prepared from diosgenin or tigogenin in a four-step synthesis comprising of the simultaneous opening of the F-ring and introduction of cyanide in position 22α, activation of the 26-hydroxyl group as mesylate, nitrile reduction, and N-cyclization. Solasodine, six obtained 22a(N)-homo analogues, as well as four 26a-homosolasodine derivatives and their open-chain precursors (13 in total) were tested as potential inhibitors of acetyl- and butyryl-cholinesterases and showed activity at micromolar concentrations. The structure-activity relationship study revealed that activities against studied esterases are affected by the structure of E/F rings and the substitution pattern of ring A. The most potent compound 8 acted as non-competitive inhibitors and exerted IC50 = 8.51 µM and 7.05 µM for eeAChE and eqBChE, respectively. Molecular docking studies revealed the hydrogen bond interaction of 8 with S293 of AChE; further rings are stabilized via hydrophobic interaction (ring A) or interaction with Y341 and W286 (rings B and C). Biological experiments showed no neurotoxicity of differentiated SH-SY5Y cells. More importantly, results from neuroprotective assay based on glutamate-induced cytotoxicity revealed that most derivatives had the ability to increase the viability of differentiated SH-SY5Y cells in comparison to galantamine and lipoic acid assayed as standards. The newly synthesized solasodine analogues are able to inhibit and to bind cholinesterases in noncompetitive mode of inhibition and exhibited neuroprotection potential of differentiated neuroblastoma cells after Glu-induced toxicity.


Subject(s)
Cholinesterase Inhibitors/chemistry , Neuroprotective Agents/chemistry , Neurotoxicity Syndromes/drug therapy , Solanaceous Alkaloids/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/pharmacology , Cholinesterases/chemistry , Cholinesterases/drug effects , Diosgenin/chemistry , Humans , Molecular Docking Simulation , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacology , Neurotoxicity Syndromes/enzymology , Neurotoxicity Syndromes/pathology , Nitrogen/chemistry , Solanaceous Alkaloids/chemical synthesis , Solanaceous Alkaloids/pharmacology , Structure-Activity Relationship
13.
Biomed Pharmacother ; 129: 110282, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32531676

ABSTRACT

Solasonine is a compound isolated from Solanum melongena that has anti-infection properties, and promotes neurogenesis. However, the use of solasonine for the treatment of hepatocellular carcinoma (HCC) has not yet been reported. So, the aim of this study was to assess the efficacy of solasonine for the treatment of HCC. The effects of solasonine were tested using the HCC cell lines HepG2 and HepRG. Metabolomics analysis was conducted to assess the effects of solasonine on tumor growth of nude mice xenografts using HepG2 cells. The data demonstrated that solasonine significantly suppressed proliferation of HepG2 and HepRG cells. A mouse xenograft model of HepG2 tumor formation confirmed that solasonine suppressed tumor volume and weight, and inhibited HCC cell migration and invasion, as determined with the Transwell and scratch wound assays. To further reveal the underlying regulatory mechanism, metabolomics analysis was performed. The results revealed the effects of solasonine on glutathione metabolism, including glutathione peroxidase 4 (GPX4) and glutathione synthetase (GSS). The glutathione-dependent lipid hydroperoxidase GPX4 prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions, and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death. Solasonine increased lipid ROS levels in HepG2 cells by suppression of GPX4 and GSS. However, the use of a ferroptosis inhibitor reversed solasonine-induced ROS production and cell apoptosis. Taken together, these results demonstrate that solasonine promotes ferroptosis of HCC cells via GPX4-induced destruction of the glutathione redox system.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Carcinoma, Hepatocellular/drug therapy , Ferroptosis/drug effects , Glutathione/metabolism , Liver Neoplasms/drug therapy , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Solanaceous Alkaloids/pharmacology , Animals , Carcinoma, Hepatocellular/enzymology , Carcinoma, Hepatocellular/pathology , Cell Movement/drug effects , Cell Proliferation/drug effects , Glutathione Synthase/metabolism , Hep G2 Cells , Humans , Liver Neoplasms/enzymology , Liver Neoplasms/pathology , Mice, Inbred BALB C , Mice, Nude , Neoplasm Invasiveness , Oxidation-Reduction , Reactive Oxygen Species/metabolism , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
14.
Drug Des Devel Ther ; 14: 1609-1620, 2020.
Article in English | MEDLINE | ID: mdl-32425506

ABSTRACT

INTRODUCTION: Hepatocellular carcinoma (HCC) is a primary liver cancer with a 5-year incidence of over 70%. Anisodamine (ANI), an alkaloid extracted from Anisodus, has a good therapeutic effect in septic shock and morphine addiction. Our study designed to investigate the anticancer effect of anisodamine (ANI) on HCC. MATERIALS AND METHODS: HepG2 cells were subcutaneously injected into BALB/C nude mice and the tumor tissue was subcutaneously inoculated to construct the transplanted tumor. Mice were randomly divided into 10 groups (n = 5): control group, ANI-10 group, ANI-50 group, ANI-200 group, ANI-200+pcDNA-NLRP3 group, ANI-200+EV group, sh-NLRP3 group, ANI-200 + sh-NLRP3 group, normal group and normal+ANI-200 group. RESULTS: Studies indicated that ANI inhibited the growth of HCC xenografts and reduced liver damage in a dose-dependent manner. Besides, ANI increased the survival rate of tumor-bearing mice and suppressed the expression of NLRP3 in a dose-dependent manner. It is worth noting that NLRP3 overexpression reversed the inhibitory effect of ANI on HCC xenografts. In addition, TUNEL analysis showed that ANI-induced apoptosis of tumor cells, and NLRP3 overexpression reversed the inhibitory effect of ANI on HCC. Moreover, ANI further regulated the levels of IFN-γ, TNF-α, IL-4 and IL-27. Notably, low expression of NLRP3 enhanced the inhibitory effect of ANI on the development of HCC xenografts in mice. DISCUSSION: These findings indicate that ANI suppressed the growth of HCC cells, induced apoptosis and regulated the levels of inflammatory factors by inhibiting NLRP3 inflammasome activation.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Carcinoma, Hepatocellular/drug therapy , Inflammasomes/drug effects , Liver Neoplasms/drug therapy , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Solanaceous Alkaloids/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Proliferation/drug effects , Cytokines/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Hep G2 Cells , Humans , Injections, Subcutaneous , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Liver Neoplasms, Experimental/drug therapy , Liver Neoplasms, Experimental/metabolism , Liver Neoplasms, Experimental/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Solanaceous Alkaloids/administration & dosage , Structure-Activity Relationship , Tumor Cells, Cultured
15.
Naunyn Schmiedebergs Arch Pharmacol ; 393(9): 1715-1728, 2020 09.
Article in English | MEDLINE | ID: mdl-32388600

ABSTRACT

The present research work was designed to examine the neuroprotective effect of ethanolic extract of Solanum virginianum Linn. (SV) in chronic construction injury (CCI) of sciatic nerve-induced neuropathic pain in rats. The extract was initially standardized by high-performance thin-layer chromatography using solasodine as a biomarker and was then subjected to assess the degree of mechanical allodynia, thermal allodynia, mechanical hyperalgesia, thermal hyperalgesia and biochemical evaluations. Administration of SV (100 and 200 mg/kg; p.o.) and pregabalin (10 mg/kg; p.o.) as a reference standard significantly debilitated hyperalgesia and allodynia and notably restored the altered antioxidant level and pro-inflammatory cytokine (IL-1ß and TNF-α) expression in a dose-dependent manner. Further, to appraise the mechanistic approach of solasodine, docking simulation studies were done on the 3D structure of the voltage-gated N-type calcium channel (Cav 2.2), R-type calcium channel (Cav 2.3) and sodium channel (Nav 1.7), and the results revealed that solasodine properly positioned into Phe 19, Leu 32, Met 51 and Met 71 (FLMM pocket) of Cav 2.2 and Cav 2.3 and being a competitor of Ca2+/N-lobe it may inactivate these calcium channels but did not bind into the desired binding pocket of Nav 1.7. Thus, the study confirmed the role of solasodine as a major biomarker for the observed neuroprotective nature of Solanum virginianum.


Subject(s)
Analgesics/pharmacology , Hyperalgesia/prevention & control , Molecular Docking Simulation , Neuralgia/prevention & control , Pain Threshold/drug effects , Plant Extracts/pharmacology , Sciatic Neuropathy/drug therapy , Solanaceous Alkaloids/pharmacology , Solanum , Analgesics/isolation & purification , Analgesics/metabolism , Animals , Behavior, Animal/drug effects , Binding Sites , Binding, Competitive , Calcium Channels, N-Type/drug effects , Calcium Channels, N-Type/metabolism , Disease Models, Animal , Ethanol/chemistry , Female , Hyperalgesia/metabolism , Hyperalgesia/physiopathology , Male , Neuralgia/metabolism , Neuralgia/physiopathology , Plant Extracts/isolation & purification , Plant Extracts/metabolism , Protein Binding , Rats, Wistar , Sciatic Neuropathy/metabolism , Sciatic Neuropathy/physiopathology , Solanaceous Alkaloids/isolation & purification , Solanaceous Alkaloids/metabolism , Solanum/chemistry , Solvents/chemistry
16.
J Recept Signal Transduct Res ; 40(1): 58-66, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31997696

ABSTRACT

Purpose: Anisodamine (An) has anti-inflammatory effects, but its role in acute pancreatitis is still unknown. This study aimed to explore the action mechanism of An pretreatment in lipopolysaccharide (LPS)-induced pancreatic acinar cells, hoping to provide a research basis for the disease treatment.Materials and methods: Pancreatic acinar cells were pretreated with An at different concentrations and then induced by LPS. The viability and apoptosis of the treated cells were measured by Cell Counting Kit-8 and flow cytometry. The releases of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-18 were measured by enzyme-linked immunosorbent assay. The expressions of thioredoxin-interacting protein (TXNIP), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), NOD-like receptor protein 3 (NLRP3), Caspase-1, p65, and inhibitor of kappa B alpha (IκBα) in the treated cells were detected by Western blot and quantitative real-time polymerase chain reaction assay.Results: LPS promoted apoptosis of pancreatic acinar cells, suppressed cell viability, increased TNF-α, IL-1ß, and IL-18 releases and the expression levels of TXNIP, ASC, NLRP3, Caspase-1, p-p65, and p-IκBα, however, such effects of LPS could be alleviated by An pretreatment with the strongest effect when the concentration of An was set at 100 µg/mL. Moreover, overexpressed NLRP3 aggravated the effects of LPS in pancreatic acinar cells, which could be reversed by pretreatment of 100 µg/mL An.Conclusion: An pretreatment attenuated LPS-induced apoptosis and inflammatory response of pancreatic acinar cells through suppressing NLRP3 and inactivating NF-κB signaling pathway, thus, it could be explored as a potential therapy for treating acute pancreatitis.


Subject(s)
Acinar Cells/metabolism , Acinar Cells/pathology , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pancreas/pathology , Signal Transduction , Solanaceous Alkaloids/pharmacology , Acinar Cells/drug effects , Animals , Apoptosis/drug effects , Cell Line , Inflammation/pathology , Lipopolysaccharides , Rats , Signal Transduction/drug effects
17.
Front Immunol ; 11: 595342, 2020.
Article in English | MEDLINE | ID: mdl-33633726

ABSTRACT

The outbreak of coronavirus disease 2019 (COVID-19) underlined the urgent need for alleviating cytokine storm. We propose here that activating the cholinergic anti-inflammatory pathway (CAP) is a potential therapeutic strategy. However, there is currently no approved drugs targeting the regulatory pathway. It is evident that nicotine, anisodamine and some herb medicine, activate the CAP and exert anti-inflammation action in vitro and in vivo. As the vagus nerve affects both inflammation and specific immune response, we propose that vagus nerve stimulation by invasive or non-invasive devices and acupuncture at ST36, PC6, or GV20, are also feasible approaches to activate the CAP and control COVID-19. It is worth to investigate the efficacy and safety of the strategy in patients with COVID-19.


Subject(s)
COVID-19/therapy , Cytokine Release Syndrome/therapy , Neuroimmunomodulation/immunology , Vagus Nerve Stimulation/methods , Vagus Nerve/immunology , Acupuncture , Anti-Inflammatory Agents/pharmacology , Cytokines/blood , Drugs, Chinese Herbal/pharmacology , Humans , Inflammation/therapy , Nicotine/pharmacology , SARS-CoV-2 , Solanaceous Alkaloids/pharmacology
18.
J Cell Mol Med ; 23(11): 7749-7761, 2019 11.
Article in English | MEDLINE | ID: mdl-31475459

ABSTRACT

Solamargine (SM) has been shown to have anti-cancer properties. However, the underlying mechanism involved remains undetermined. We showed that SM inhibited the growth of non-small cell lung cancer (NSCLC) cells, which was enhanced in cells with silencing of long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR), while it overcame by overexpression of HOTAIR. In addition, SM increased the expression of miR-214-3p and inhibited 3-phosphoinositide-dependent protein kinase-1 (PDPK1) gene expression, which was strengthened by miR-214-3p mimics. Intriguingly, HOTAIR could directly bind to miR-214-3p and sequestered miR-214-3p from the target gene PDPK1. Intriguingly, overexpression of PDPK1 overcame the effects of SM on miR-214-3p expressions and neutralized the SM-inhibited cell growth. Similar results were observed in vivo. In summary, our results showed that SM-inhibited NSCLC cell growth through the reciprocal interaction between HOTAIR and miR-214-3p, which ultimately suppressed PDPK1 gene expression. HOTAIR effectively acted as a competing endogenous RNA (ceRNA) to stimulate the expression of target gene PDPK1. These complex interactions and feedback mechanisms contribute to the overall effect of SM. This unveils a novel molecular mechanism underlying the anti-cancer effect of SM in human lung cancer.


Subject(s)
3-Phosphoinositide-Dependent Protein Kinases/antagonists & inhibitors , 3-Phosphoinositide-Dependent Protein Kinases/genetics , Gene Expression Regulation, Neoplastic/drug effects , Lung Neoplasms/genetics , MicroRNAs/genetics , RNA, Long Noncoding/metabolism , Solanaceous Alkaloids/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Humans , Lung Neoplasms/pathology , Mice, Nude , MicroRNAs/metabolism , RNA, Long Noncoding/genetics
19.
BMC Nephrol ; 20(1): 223, 2019 06 17.
Article in English | MEDLINE | ID: mdl-31208365

ABSTRACT

BACKGROUND: Anisodamine is used for the treatment of reperfusion injury in various organs. In this study, we investigated the effectiveness and mechanisms of action of anisodamine in promoting recovery from glycerol-induced acute kidney injury (AKI). METHODS: We compared the protective effects of atropine and anisodamine in the rat model of glycerol-induced AKI. We examined signaling pathways involved in oxidative stress, inflammation and apoptosis, as well as expression of kidney injury molecule-1 (KIM-1). Renal injury was assessed by measuring serum creatinine and urea, and by histologic analysis. Rhabdomyolysis was evaluated by measuring creatine kinase levels, and oxidative stress was assessed by measuring malondialdehyde (MDA) and superoxide dismutase (SOD) levels in kidney tissues. Inflammation was assessed by quantifying interleukin 6 (IL-6) and CD45 expression. Apoptosis and necrosis were evaluated by measuring caspase-3 (including cleaved caspase 3) and RIP3 levels, respectively. RESULTS: Glycerol administration resulted in a higher mean histologic damage score, as well as increases in serum creatinine, urea, creatine kinase, reactive oxygen species (ROS), MDA, IL-6, caspase-3 and KIM-1 levels. Furthermore, glycerol reduced kidney tissue SOD activity. All of these markers were significantly improved by anisodamine and atropine. However, the mean histologic damage score and levels of urea, serum creatinine, creatine kinase, ROS and IL-6 were lower in the anisodamine treatment group compared with the atropine treatment group. CONCLUSION: Pretreatment with anisodamine ameliorates renal dysfunction in the rat model of glycerol-induced rhabdomyolytic kidney injury by reducing oxidative stress, the inflammatory response and cell death.


Subject(s)
Acute Kidney Injury/chemically induced , Acute Kidney Injury/prevention & control , Glycerol/toxicity , Oxidative Stress/drug effects , Reactive Oxygen Species/antagonists & inhibitors , Solanaceous Alkaloids/therapeutic use , Acute Kidney Injury/metabolism , Animals , Free Radical Scavengers/pharmacology , Free Radical Scavengers/therapeutic use , Male , Oxidative Stress/physiology , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Solanaceous Alkaloids/pharmacology , Solvents/toxicity , Treatment Outcome
20.
Molecules ; 24(12)2019 Jun 21.
Article in English | MEDLINE | ID: mdl-31234274

ABSTRACT

Background: Solasodine is a major bioactive ingredient in Solanum nigrum L. that has strong pharmacological characteristics. Therefore, the development of a simple and effective extraction method for obtaining solasodine is highly important. This study aims to provide a rapid and effective method for extracting solasodine from Solanum nigrum L. by microwave-assisted aqueous two-phase extraction (MAATPE). Methods: First, the high-performance liquid chromatography (HPLC) conditions were established for the detection of solasodine. Then, the aqueous two-phase system (ATPS) compositions were examined. On the basis of the results of single-factor experiments, for a better yield, response surface methodology (RSM) was used to optimize influential factors including the extraction temperature, extraction time and liquid-to-solid ratio. Results: The maximum extraction yield of 7.11 ± 0.08 mg/g was obtained at 44 °C, an extraction time of 15 min, and a liquid-to-solid ratio of 42:1 mL/g in the ATPS consisting of EtOH solvent, (NH4)2SO4, and water (28:16:56, w/w/w). The extraction yield of the alkaloid obtained using this method was markedly higher than those of microwave-assisted extraction (MAE) and ultrasonic-assisted extraction (UAE). Conclusions: In this work, solasodine was extracted by MAATPE for the first time and a high yield was obtained. MAATPE is a simple, rapid, and green technique for extraction from medical plants. Thus, the present study will enable the development of a feasible extraction method of active alkaloids from Solanum nigrum L.


Subject(s)
Chromatography, High Pressure Liquid/methods , Fruit/chemistry , Solanaceous Alkaloids/chemistry , Solanum nigrum/chemistry , Liquid-Liquid Extraction , Microwaves , Plant Extracts/chemistry , Plant Extracts/pharmacology , Solanaceous Alkaloids/pharmacology , Water/chemistry
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