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Objective: Sepsis can have severe implications on lung function, leading to acute lung injury (ALI), a major contributor to sepsis-related mortality. Anisodamine hydrobromide (Ani HBr), a bioactive constituent derived from the root of Scopolia tangutica Maxim, a plant endemic to China, has demonstrated efficacy in treating septic shock. We aim to explore whether Ani HBr can alleviate sepsis-triggered ALI and elucidate the fundamental mechanisms involved., Materials and Method: The protective effects of Ani HBr were assessed in two models: in vitro , lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and in vivo , cecal ligation puncture (CLP)-induced sepsis. To measure the cell viability of RAW264.7 cells after Ani HBr treatment, we used the CCK-8 assay. We quantified the levels of pro-inflammatory cytokines expression using ELISA. We also measured the expression of pyrotosis indicators by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), Western blotting, and immunofluorescence., Results: Our study demonstrates that Ani HBr can alleviate pulmonary edema, bleeding, and excessive inflammation induced by CLP. Additionally, it exhibits protective effects against cytotoxicity induced by LPS in RAW264.7 macrophage cells. Furthermore, Ani HBr downregulates the mRNA and protein levels of NLRP3, Caspase-1, GSDMD, IL-18, and IL-1β in both animal models and cell cultures, thereby inhibiting pyroptosis in a similar mechanism to AC-YVAD-CMK (AYC)'s blockade of Caspase-1. Moreover, Ani HBr suppresses the production and release of proinflammatory cytokines., Conclusion: These findings suggest that Ani HBr could serve as a protective agent against sepsis-induced ALI by suppressing pyroptosis.

Solasonine (SS) and solamargine (SM) are alkaloids known for their antioxidant and anticancer properties, which can be further enhanced by encapsulating them in nanoparticles. This led to a study on the potential therapeutic benefits of SS and SM against bladder cancer when encapsulated in lipid-polymer hybrid nanoparticles (LPHNP). The LPHNP loaded with SS/SM were prepared using the emulsion and sonication method and their physical-chemical properties characterized. The biological effects of these nanoparticles were then tested in both 2D and 3D bladder cancer cell culture models, as well as in a syngeneic orthotopic mouse model based on the MB49 cell line and ethanol epithelial injury. The LPHNP-SS/SM had an average size of 130 nm, a polydispersity index of 0.22 and a positive zeta potential, indicating the presence of chitosan coating on the nanoparticle surface. The dispersion of LPHNP-SS/SM was found to be monodispersed with a span index of 0.539, as measured by nanoparticle tracking analysis (NTA). The recrystallization index, calculated from DSC data, was higher for the LPHNP-SS/SM compared to LPHNPs alone, confirming the presence of alkaloids within the lipid matrix. The encapsulation efficiency (EE%) was also high, with 91.08 % for SS and 88.35 % for SM. Morphological analysis by AFM and Cryo-TEM revealed that the nanoparticles had a spherical shape and core-shell structure. The study showed that the LPHNP-SS/SM exhibited mucoadhesive properties by physically interacting with mucin, suggesting a potential improvement in interaction with mucous membrane. Both the free and nanoencapsulated SS/SM demonstrated dose-dependent cytotoxicity against bladder cancer cell lines after 24 and 72 h of treatment. In 3D bladder cell culture, the nanoencapsulated SS/SM showed an IC 50 two-fold lower than free SS/SM. In vivo studies, the LPHNP-SS/SM displayed an antitumoral effect at high doses, leading to a significant reduction in bladder volume compared to the positive control. However, there were observed instances of systemic toxicity and liver damage, indicated by elevated levels of transaminases (TGO and TGP). Overall, these results indicate that the LPHNPs effectively encapsulated SS/SM, showing high encapsulation efficiency and stability, along with promising in vitro and in vivo antitumoral effects against bladder cancer. Further evaluation of its systemic toxicity effects is necessary to ensure its safety and efficacy for potential clinical application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

P-glycoprotein (P-gp) mediated multidrug resistance (MDR) is the leading cause of chemotherapy failure since it causes the efflux of chemotherapeutic drugs from the cancer cells. Solasodine, a steroidal alkaloid and oxaspiro compound, present in the Solanaceae family showed significant cytotoxic effects on various cancer cells. However, the effect of solasodine on reversing P-gp mediated drug resistance is still unknown. Primarily in this study, the integrative network pharmacology analysis found 71 common targets between solasodine and cancer MDR, among them NF-κB was found as a potential target. The results of immunofluorescence analysis showed that solasodine significantly inhibits NF-κB-p65 nuclear translocation which caused downregulated P-gp expression in KBChR-8-5 cells. Further, solasodine binds to the active sites of the TMD region of P-gp and inhibits P-gp transport activity. Moreover, solasodine significantly promotes doxorubicin intracellular accumulation in the drug resistant cells. Solasodine reduced the fold resistance and synergistically sensitized doxorubicin's therapeutic effects in KBChR-8-5 cells. Additionally, the solasodine and doxorubicin combination treatment increased the apoptotic cell populations and G2/M phase cell cycle arrest in KBChR-8-5 cells. The MDR tumor bearing xenograft mice showed tumor-suppressing characteristics and P-gp downregulation during the combination treatment of solasodine and doxorubicin. These results indicate that solasodine targets NF-κB signaling to downregulate P-gp overexpression, inhibit P-gp transport activity, and enhance chemosensitization in MDR cancer cells. Considering its multifaceted impact, solasodine represents a potent natural fourth-generation P-gp modulator for reversing MDR in cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Three undescribed solalodine-type glycoalkaloids, named solanigrinoside A-C (1-3), and six known compounds (4-9) were isolated from the whole plants of Solanum nigrum. Their structures were elucidated based on analysis of HR-ESI-MS, 1D- and 2D-NMR spectral data, and comparison with those reported in literatures. The solanigrinoside A-C (1-3), solasodine (4), and 3-acetoxysolasodine (5) exhibited cytotoxic effects against LU-1, Hep-G2, and MCF-7 cells with IC 50 values in range from 4.6 μM to 56.2 μM. Compound 2 showed the significant cytotoxic activity with corresponding IC 50 values of 5.7 μM, 7.9 μM, and 4.6 μM, respectively., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Objective: To investigate the effect of solasonine, an active component of Solanum nigrum , on proliferation and apoptosis of non-small cell lung cancer PC9 cells., Methods: PC9 cells were treated with 2, 5, 10, 15, 20, or 25 μmol/L solasonine, and the changes in cell proliferation were examined using CCK-8 assay. Tetramethyl rhodamine ethyl ester (TMRE) was used to detect the changes in mitochondrial membrane potential, and caspase-3/7 detection kit and GreenNuc TM caspase-3/Annexin V-mCherry kit for live cell were used to analyze the changes in caspase-3 of the cells. Annexin V-FITC/PI double staining was employed to analyze the apoptosis rate of the cells. The effect of PTEN inhibitors on solasonine-induced cell apoptosis was examined by detecting apoptosis-related protein expressions using Western blotting., Results: Solasonine treatment for 24, 48, and 72 h significantly lowered the viability of PC9 cells. The cells treated with solasonine for 24 h showed significantly decreased mitochondrial membrane potential and increased cell apoptosis with enhanced caspase-3/7 and caspase-3 activities and expression of cleaved caspase-3. Solasonine treatment significantly decreased phosphorylation levels of PI3K and Akt, increased the protein expressions of PTEN and Bax, and lowered the expression of Bcl-2 protein in the cells., Conclusion: Solasonine inhibits proliferation and induces apoptosis of PC9 cells by regulating the Bcl-2/Bax/caspase-3 pathway and its upstream proteins.

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., Competing Interests: Declaration of competing interest The authors declare no conflict interest., (Copyright © 2023. Published by Elsevier B.V.)

Alkaloids are natural products that occur widely in many herbal plants. Anisodamine, widely present in the Solanaceae family, is an alkaloid extracted from the roots of the Anisodus tanguticus Maxim. It is an antagonist to M-choline receptors and exhibits diverse pharmacological effects, such as cholinolytic effect, calcium antagonist effect, anti-oxygenation effect. Anisodamine, a prominent constituent of the tropine alkaloid family, exhibits a range of pharmacological effects akin to those of atropine and scopolamine. owing to its low toxicity and moderate efficacy in clinical to wide applications, especially for varieties of shock treatment. However, there remains a dearth of research regarding the in vivo pharmacokinetics, mechanism of action, and toxicity of anisodamine. Consequently, this paper provides a comprehensive review of the anti-shock effects, toxicity, and pharmacokinetic characteristics of anisodamine to increase the understanding of its medicinal value, and provide reference and inspiration for the clinical application and further in-depth research of anisodamine., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

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., (Copyright © 2024. Published by Elsevier B.V.)

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., Competing Interests: Declaration of Competing Interest All authors declare that no conflict of interest exists., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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., Competing Interests: Conflicts of Interest Statement The authors declared no conflicts of interest., (Copyright © 2023. Published by Elsevier Masson SAS.)

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 (M pro ) 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 M pro . This study suggests that anisodamine is a potent antiviral agent for treating COVID-19., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare no conflict of interest, financial or otherwise., (Thieme. All rights reserved.)

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., (© 2021 John Wiley & Sons, Ltd.)

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 (YVO 4 :Eu 3+ :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 YVO 4 :Eu 3+ :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 YVO 4 :Eu 3+ :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 YVO 4 :Eu 3+ :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.

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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.

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/GSK3β 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., Competing Interests: The authors declare that they have no competing interests., (© 2021 Fan et al.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Qin, Xiang, Su, Sun and Liu.)

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 IC 50 = 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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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-1β 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 Ca 2+ /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.

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., (Copyright © 2020. Published by Elsevier Masson SAS.)

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., Competing Interests: The authors report no conflicts of interest regarding the publication of this article., (© 2020 Li et al.)

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-1β (IL-1β), 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-1β, 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.

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., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Liver cancer, of which human hepatocellular carcinoma (HCC) is the most common type, represents the second most common cause of death from cancer worldwide. To date, treatments remain mostly ineffective and efforts are made to discover new molecules or therapeutic strategies against HCC. Mortalin, an hsp70 chaperone protein, is overexpressed in various cancer, including HCC. Mortalin sequesters p53 into the cytoplasm, thereby inhibiting its translocation to the nucleus and consequently, its cellular functions. Inhibition of mortalin-p53 interactions, which should activate the apoptotic process and the subsequent cell death, has thus been proposed as an anticancer strategy. In silico screening of a database of 354 natural compounds identified solasonine, a steroidal glycoalkaloid from Solanaceae, as a potent inhibitor of p53-mortalin interactions. Pharmacological studies confirmed that solasonine was able to inhibit efficiently mortalin-p53 interaction in HCC HepG2 cell line that expresses both mortalin and p53. This resulted in p53 translocation to the nucleus. Solasonine-induced apoptosis and cell death of HCC cell lines either expressing p53 (HepG2) or not (Hep3b), indicating that apoptotic activities of solasonine can be mediated not only through p53-dependent but also p53-independent pathways. The cytotoxic effects of solasonine correlated in part with its apoptotic properties and differed in the two HCC cell lines, being reversed by pifithrin-α, an inhibitor of p53 functions, in HepG2 cells but not in Hep3b cells. Nonapoptotic cell death was also observed, notably in Hep3b cells., (© 2019 Société Française de Pharmacologie et de Thérapeutique.)

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, (NH 4 ) 2 SO 4 , 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.

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.

Solamargine, a derivative from the steroidal solasodine in Solanum species, has exhibited anticancer activities in numerous types of cancer; however, its role in gastric cancer (GC) remains unknown. In the present study, it was demonstrated that Solamargine suppressed the viability of five gastric cancer cell lines in a dose‑dependent manner and induced notable alterations in morphology. Treatment with Solamargine promoted cell apoptosis (P<0.01). Solamargine increased the expression of long noncoding RNA (lnc) p53 induced transcript and lnc nuclear paraspeckle assembly transcript 1 (NEAT1)&#95;2 (P<0.01) in GC by reducing the phosphorylation of extracellular signal‑regulated kinase (Erk)1/2 mitogen‑activated protein kinase (MAPK). To gain insight into the potential mechanism, an Erk1/2 inhibitor (U0126) was applied. The results revealed that lncNEAT1&#95;2 expression levels increased, which was consistent with the effects of Solamargine. Downregulation of lncNEAT1&#95;2 in GC cells revealed no effect on the expression levels of total Erk1/2 and, and counteracted the effect of Solamargine. Solamargine was observed to increase the expression of lncNEAT1&#95;2 via the Erk1/2 MAPK signaling pathway. Of note, the knockdown of lncNEAT1&#95;2 reduced the inhibitory effect of Solamargine (P<0.05). Additionally, experiments in vivo and in primary GC cells from patients demonstrated that Solamargine significantly suppressed tumor growth (P<0.05). In vivo analysis of a xenograft mouse model further supported that Solamargine could induce the apoptosis of cancer cells in tumor tissue as observed by a terminal deoxynucleotidyl transferase‑mediated dUTP‑biotin nick end labeling and H&E staining (P<0.05). Experiments in primary GC cells from patients verified the anti‑tumor effect of Solamargine. In summary, the findings of the present study indicated that Solamargine inhibited the progression of GC by regulating lncNeat1&#95;2 via the MAPK pathway.

Fe3O4-magnetic liposome (MLP) can deliver drugs to target tissues and can increase drug efficacy. The present study aimed to investigate the effects of solamargine (SM) and Fe3O4-SM in pancreatic cancer (PC). Cell viability was detected using a Cell Counting kit‑8 assay. Apoptosis and cell cycle progression was tested using a flow cytometry assay. A scratch assay was used to examine cell metastasis. Quantitative polymerase chain reaction, western blot analysis or immunohistochemical analysis were performed to determine the expression of target factors. Magnetic resonance imagining (MRI) and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labelling were conducted to detect tumor growth and apoptosis in vivo, respectively. It was demonstrated that Fe3O4-SM inhibited cancer cell growth via a slow release of SM over an extended period of time. SM was revealed to induce apoptosis and cell cycle arrest. Furthermore, SM decreased the expression of X-linked inhibitor of apoptosis, Survivin, Ki‑67, proliferating cell nuclear antigen and cyclin D1, but increased the activity of caspase-3. It was also observed that SM inhibited tumor cell metastasis by modulating the expression of matrix metalloproteinase (MMP)-2 and TIMP metallopeptidase inhibitor-2. Furthermore, the phosphorylation of protein kinase B and mechanistic target of rapamycin was suppressed by SM. Notably, the effect of SM was enhanced by Fe3O4-SM. The malignant growth of PC was decreased by SM in vivo. Furthermore, the expression of Ki‑67 was decreased by SM and Fe3O4-SM. Additionally, cell apoptosis was increased in the Fe3O4-SM group, compared with the SM group. The present study illustrated the antitumor effect and action mec-hanism produced by SM. Additionally, it was demonstrated that Fe3O4-SM was more effective than SM in protecting against PC.

Adverse side effects of conventional chemotherapy, acquired resistance and fatal tumor metastasis of human colorectal cancer (CRC) are propelling the exploration for novel selective anticarcinogens. Solasodine is a main active component isolated from Solanum incanum L that exhibited a potent stemness and invasion inhibitory effect on human colorectal cancer HCT116 cells. Colony Spheroid formation assay showed that solasodine dose-dependently prohibited HCT116 cell stemness. CD133, CD44, Nanog, Oct-4 and Sox-2 were inhibited by solasodine to reverse stemness and similar mechanism was stimulated in vivo. Transwell and scratch wound assays revealed that solasodine impeded HCT116 cell invasion and migration potential strengthened by TGF-β1. Moreover, solasodine attenuated TGF-β1-induced EMT and decreased MMPs while in vivo study showed the same trend. The results of this study implied that solasodine may be a novel therapeutic drug for CRC treatment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Solanine A is a novel steroidal alkaloid isolated from Solanum nigrum Linn., a medicinal and edible plant which is widely used for treating various inflammatory diseases. In this study, we found that solanine A markedly suppressed the production of nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) in lipopolysaccharide/interferon-γ (LPS/IFNγ)-stimulated RAW264.7 cells, and attenuated xylene, carrageenan and agar-induced inflammation in mice. The mRNA levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and -1β (IL-1β), as well as C-X-C motif chemokine ligand-9 (CXCL9), were significantly decreased by solanine A. Furthermore, solanine A also suppressed LPS/IFNγ-induced protein expression of iNOS and COX2. Mechanistically, solanine A inhibited the nuclear translocation of nuclear factor-κB (NF-κB) through the prevention of NF-κB p65 and inhibitory κB-α (IκBα) phosphorylation and IκBα degradation, and it also suppressed activation of extracellular regulated protein kinases (ERK), signal transducers and activators of transcription-1 (STAT1) and serine/threonine protein kinase Akt in LPS/IFNγ-stimulated RAW264.7 macrophages and agar-induced granuloma model in mice. Taken together, solanine A exhibits a potent anti-inflammatory activity in LPS/IFNγ- activated macrophages and animal models of inflammation through inhibition of NF-κB, ERK1/2, Akt and STAT1 signaling pathways, suggesting that solanine A may be a valuable leading compound in the treatment of inflammatory diseases., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: The present study investigates the hepato- and DNA-protective effects of standardized extracts of Cleome brachycarpa (cabralealactone), Solanum incanum (solasodin), and Salvadora oleioides (salvadorin) in rats., Materials and Methods: Hepatotoxicity was induced with intraperitoneal injection of carbon tetrachloride (CCl 4 ) (1 mL/kg b.wt.) once a week for 12 weeks. The hepato- and DNA protective effects of the extracts in different combinations were compared with that of a standard drug Clavazin (200 mg/kg b.wt.). Tissue alanine aminotransferase, alpha-fetoprotein, tumor necrosis factor alpha (TNF-α), isoprostanes-2α, malondialdehyde, and 8-hydroxydeoxyguanosine, the significant hallmarks of oxidative stress, were studied., Results: Histopathological findings of the liver sections from the rat group which received CCl 4 +cabralealactone, solasodin, and salvadorin demonstrated improved centrilobular hepatocyte regeneration with moderate areas of congestion and infiltration comparable with Clavazin. For in silico study, the identified compounds were subjected to molecular docking with cyclooxygenase-2 and TNF-α followed by a molecular dynamics study, which indicated their potential as anti-inflammatory agents., Conclusion: Cabralealactone, solasodin, and salvadorin confer some hepatoprotective and DNA-damage protective effects against CCl 4 -induced toxicity. They successfully restored the normal architecture of hepatocytes and have the potential to be used as inhibitor to main culprits, that is, cyclooxygenase-2 and TNF-α. They can combat oxidative stress and liver injuries both as mono and combinational therapies. However, combination therapy has more ameliorating effects., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Solanum aculeastrum fruits are used by some cancer sufferers as a form of alternative treatment. Scientific literature is scarce concerning its anticancer activity, and thus the aim of the study was to assess the in vitro anticancer and P-glycoprotein inhibitory potential of extracts of S. aculeastrum fruits. Furthermore, assessment of the combinational effect with doxorubicin was also done., Methods: The crude extract was prepared by ultrasonic maceration. Liquid-liquid extraction yielded one aqueous and two organic fractions. Bioactive constituents were isolated from the aqueous fraction by means of column chromatography, solid phase extraction and preparative thin-layer chromatography. Confirmation of bioactive constituent identity was done by nuclear magnetic resonance and ultra-performance liquid chromatography mass spectrometry. The crude extract and fractions were assessed for cytotoxicity and P-glycoprotein inhibition in both cancerous and non-cancerous cell lines using the sulforhodamine B and rhodamine-123 assays, respectively., Results: Both the crude extract and aqueous fraction was cytotoxic to all cell lines, with the SH-SY5Y neuroblastoma cell line being most susceptible to exposure (IC 50  = 10.72 μg/mL [crude], 17.21 μg/mL [aqueous]). Dose-dependent P-glycoprotein inhibition was observed for the crude extract (5.9 to 18.9-fold at 100 μg/mL) and aqueous fraction (2.9 to 21.2 at 100 μg/mL). The steroidal alkaloids solamargine and solanine were identified. While solanine was not bioactive, solamargine displayed an IC 50 of 15.62 μg/mL, and 9.1-fold P-glycoprotein inhibition at 100 μg/mL against the SH-SY5Y cell line. Additive effects were noted for combinations of doxorubicin against the SH-SY5Y cell line., Conclusions: The crude extract and aqueous fraction displayed potent non-selective cytotoxicity and noteworthy P-glycoprotein inhibition. These effects were attributed to solamargine. P-glycoprotein inhibitory activity was only present at concentrations higher than those inducing cytotoxicity, and thus does not appear to be the likely mechanism for the enhancement of doxorubicin's cytotoxicity. Preliminary results suggest that non-selective cytotoxicity may hinder drug development, however, further assessment of the mode of cell death is necessary to determine the route forward.

The aim of the present study was to investigate the cardioprotective effects of anisodamine against myocardial ischemia/reperfusion (I/R) injury and the molecular mechanisms involved. The present results demonstrated that anisodamine attenuated myocardial infarct sizes, decreased the levels of creatine kinase and lactate dehydrogenase, whereas it increased the left ventricular (LV) systolic pressure, the LV end‑diastolic pressure, and the LV pressure maximum rising and falling rates in a myocardial I/R rat model. In addition, anisodamine was revealed to suppress oxidative stress, inflammatory factor production and myocardial cell apoptosis, as demonstrated by the downregulation of caspase‑3 and apoptosis regulator BAX protein expression. The production of reactive oxygen species was decreased and the protein expression of inducible nitric oxide synthase (iNOS) was downregulated, whereas the expression of endothelial NOS was enhanced. In addition, the activity of nicotinamide‑adenine dinucleotide phosphate oxidase (Nox) was suppressed and the expression of Nox4 was downregulated in rats with myocardial I/R injury. In conclusion, the results of the present study suggested that anisodamine exerted a cardioprotective effect against myocardial I/R injury in rats, through the inhibition of oxidative stress, the suppression of inflammatory processes and the inhibition of myocardial cell apoptosis.

Anisodamine protects against free radical-induced cellular damage. This study aimed to investigate the protective effect of anisodamine on rhabdomyolysis-induced acute kidney injury (RIAKI). C57BL/6 J mice, TXNIP -/- and NLRP3 -/- (both were C57BL/6 J background) mice were used to construct RIAKI model. Anisodamine administration was performed on RIAKI mice only. Mice were divided into control, TXNIP-KD (knock down), LNPR3-KD, and anisodamine group (n = 15 in each group). The renal injury, renal function, renal tubular cells apoptosis and expression of Caspase-1, ASC, endoplasmic reticulum (ER) stress markers IRE-1α, CHOP, and ATF4, and interleukin (IL-1α, IL-1β, and IL-18) were detected. The knock down of TXNIP or NLRP3 expression in mice showed protective effect against RIAKI pathogenesis, as compared with the RIAKI mice. The expression of Caspase-1, ASC, and interleukins, renal injury, renal tubular cells apoptosis in TXNIP-KD and LNPR3-KD mice were significantly inhibited in comparison with the RIAKI mice. Moreover, anisodamine treatment reduced expression of ER stress markers IRE-1α, CHOP, and ATF4, TXNIP and NLRP3, as well as ACS, Caspase-1, IL-1α, IL-1β, and IL-18, showing moderate protective effect on the changes of above factors comparing with TXNIP or NLRP3 knock down. This study declared that anisodamine showed protective effect on RIAKI model may by inhibiting ER stress associated TXNIP/NLRP3 inflammasome.

Antifungal activity of some natural molecules can be abated or blocked by efflux pumps in Candida albicans, which restricts the discovery of potential antifungal agents. Here we found that the steroidal alkaloid solasodine is active against C. albicans efflux pump-deficient strains but inert towards the wild type. However, the glucosylated solasodine-3-O-β-d-glucopyranoside exhibits antifungal activity towards the wild type strain. Further investigation revealed that the entry of solasodine into C. albicans cells is blocked by efflux pumps. Glucosylation provides an alternative access not disturbed by efflux pumps. Once inside cells, the carried glucosylated solasodine is cleaved into the active molecule solasodine by the glucosidase, which is located in cytoplasm membrane and exhibits selective activity against hydrolyzing glucosyl natural products but not against other monosaccharide-substituted products. This glucosidase is not encoded by orf19.4031, considered homologous to steryl-β-glucosidase encoded by the gene EGH1 in Saccharomyces cerevisiae. Our study reveals that glucosylation is an alternative approach for introducing potential antifungal activity into C. albicans cells and overcoming the drug-resistance resulting from hyperactivation of efflux pumps., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The increasing incidence of fungal infections and emergence of drug resistance underlie the constant search for new antifungal agents and exploration of their modes of action. The present study aimed to investigate the antifungal mechanisms of solasodine-3-O-β-d-glucopyranoside (SG) isolated from the medicinal plant Solanum nigrum L. In vitro, SG displayed potent fungicidal activity against both azole-sensitive and azole-resistant Candida albicans strains in Spider medium with its MICs of 32 μg/ml. Analysis of structure and bioactivity revealed that both the glucosyl residue and NH group were required for SG activity. Quantum dot (QD) assays demonstrated that the glucosyl moiety was critical for SG uptake into Candida cells, as further confirmed by glucose rescue experiments. Measurement of the fluorescence intensity of 2',7'-dichlorofluorescin diacetate (DCFHDA) by flow cytometry indicated that SG even at 64 μg/ml just caused a moderate increase of reactive oxygen species (ROS) generation by 58% in C. albicans cells. Observation of vacuole staining by confocal microscopy demonstrated that SG alkalized the intracellular vacuole of C. albicans and caused hyper-permeability of the vacuole membrane, resulting in cell death. These results support the potential application of SG in fighting fungal infections and reveal a novel fungicidal mechanism., (Copyright © 2017. Published by Elsevier Ltd.)

Steroidal glycoalkaloids (SGAs) are plant secondary metabolites known to be toxic to animals and humans and that have putative roles in defense against pests. The proposed mechanisms of SGA toxicity are sterol-mediated disruption of membranes and inhibition of cholinesterase activity in neurons. It has been suggested that phytopathogenic microorganisms can overcome SGA toxicity by enzymatic deglycosylation of SGAs. Here, we have explored SGA-mediated toxicity toward the invasive oomycete Phytophthora infestans, the causative agent of the late blight disease in potato and tomato, as well as the potential for SGA deglycosylation by this species. Our growth studies indicate that solanidine, the nonglycosylated precursor of the potato SGAs α-chaconine and α-solanine, has a greater physiological impact than its glycosylated forms. All of these compounds were incorporated into the mycelium, but only solanidine could strongly inhibit the growth of P. infestans in liquid culture. Genes encoding several glycoside hydrolases with potential activity on SGAs were identified in the genome of P. infestans and were shown to be expressed. However, we found no indication that deglycosylation of SGAs takes place. We present additional evidence for apparent host-specific adaptation to potato SGAs and assess all results in terms of future pathogen management strategies.

Cancers are usually treated by anticancer agents that are toxic for both normal and cancer cells, so these drugs have major side effects and they are not suitable and enough effective for cancer prevention. Solamargine, a steroidal alkaloid glycoside found in Solanum species such as Solanum nigrum, displayed several therapeutic activities. We aim to review the use of solamargine in experimental cancer studies. Articles published in biology journals between 1975 and 2017 were retrieved from PubMed, Scopus, and Web of Science using relevant keywords. The scientific papers mainly focusing on solamargine with therapeutic efficacies against cancers were identified and tabulated. In addition, the reliability of experimental findings was determined under "Risk of Bias" criteria. The author manually reviewed 33 articles; 27 articles were found concerning the anti-cancer potential in cancer cells. Solamargine has been found to possess anticancer activities via its effect on a variety of biological pathways including cell survival pathways, tumor suppressor pathways, caspase activation pathway, mitochondrial pathways, death receptor pathways, protein kinase pathways, and signal pathways, which promote invasion/migration and multi drug resistance. Solamargine can be an anticancer agent candidate when complementary scientific evidences become available. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Solasodine, a naturally occurring aglycone of glycoalkaloid in eggplant (Solanum melongena), was found to inhibit proliferation in various tumor cells. However, the effect of solasodine on cancer cell metastasis remains unclear. This study investigates the suppression mechanism of solasodine on motility of human lung cancer cell A549 in vitro. Results show that solasodine reduces viability of A549 cells. Treatment with non-toxic doses of solasodine suppresses markedly cell invasion. Solasodine reduces the mRNA level of matrix metalloproteinase-2 (MMP-2), MMP-9 and extracellular inducer of matrix metalloproteinase (EMMPRIN), but increases the expression of reversion-inducing cysteine-rich protein with kazal motifs (RECK), as well as tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2. Immunoblotting assays indicate that solasodine is effective in suppressing PI3K and Akt phosphorylation. Moreover, solasodine downregulates oncogenic microRNA-21 (miR-21), which has been known to target RECK. Downregulation of miR-21 by miR-21 inhibitor increases RECK expression and decreases cell invasion, suggesting that downregulation of miR-21 by solasodine may contribute to elevate RECK expression and subsequently inhibiting cell invasion. Taken together, the results reveal that inhibition of A549 cell invasion by solasodine may be, at least in part, through blocking MMP expression. Solasodine also reduces PI3K/Akt signaling pathways and downregulates expression of miR-21. These findings demonstrate an attractive therapeutic potential for solasodine in lung cancer anti-metastatic therapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Lung cancer is the most common cancer and the leading cause of cancer deaths worldwide. We previously showed that solamargine, one natural phytochemicals from traditional plants, inhibited the growth of lung cancer cells through inhibition of prostaglandin E2 (PGE 2 ) receptor EP4. However, the potential downstream effectors of EP4 involving in the anti-lung cancer effects of solamargine still remained to be determined. In this study, we further verified that solamargine inhibited growth of non-small-cell lung cancer (NSCLC) cells in multiple cell lines. Mechanistically, solamargine increased phosphorylation of ERK1/2. Moreover, solamargine inhibited the protein expression of DNA methyltransferase 1 (DNMT1) and c-Jun, which were abrogated in cells treated with MEK/ERK1/2 inhibitor (PD98059) and transfected with exogenously expressed DNMT1 gene, respectively. Interestingly, overexpressed DNMT1 gene antagonized the effect of solamargine on c-Jun protein expression. Intriguingly, overexpressed c-Jun blocked solamargine-inhibited lung cancer cell growth, and feedback resisted the solamargine-induced phosphorylation of ERK1/2. A nude mouse xenograft model implanted with lung cancer cells in vivo confirmed the results in vitro. Collectively, our results show that solamargine inhibits the growth of human lung cancer cells through reduction of EP4 protein expression, followed by increasing ERK1/2 phosphorylation. This results in decrease in DNMT1 and c-Jun protein expressions. The inter-correlations between EP4, DNMT1 and c-Jun and feedback regulation of ERK1/2 by c-Jun contribute to the overall responses of solamargine in this process. This study uncovers an additional novel mechanism by which solamargine inhibits growth of human lung cancer cells., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Solasodine, a steroidal alkaloid isolated from solanaceous species, exhibits anticancer activities on several cell lines. This study aimed to explore the antitumor potential of solasodine on ovarian cancer cells. The MTT assay, lactate dehydrogenase release assay, Hoechst 33342 staining, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine staining assay, and Annexin V/PI assay were conducted to investigate the antiproliferation and apoptosis-inducing effects of solasodine. Monodansylcadaverine staining was performed to label the acidic puncta on ovarian cancer HEY cells. A wound healing assay and Transwell assay were carried out to determine whether solasodine elicits an antimetastatic effect on HEY cells. A gelatin zymography assay was applied to detect the enzymatic activities of matrix metalloproteinases. Western blot was employed to examine relevant protein expression. Results revealed that solasodine inhibited cell viabilities in a time- and dose-dependent manner, triggered apoptotic body formation, reduced cell mitochondrial membrane potential, and interfered with autolysosome degradation in ovarian cancer cells. Solasodine also suppressed the migration and invasion of HEY cells by downregulating matrix metalloproteinase expression and activities. This study could be used as a basis for further studies on the molecular mechanisms of the antiproliferation, apoptosis-inducing, autophagy-modifying, and antimetastatic activities of solasodine., (Georg Thieme Verlag KG Stuttgart · New York.)

Prostate cancer is the second most common cause of cancer-related deaths worldwide. The mucin 1 (MUC1) oncoprotein is highly expressed in human prostate cancers with aggressive features. However, the role for MUC1 in occurrence and progression of castration-resistant prostate cancer (CRPC) remained elusive. In this study, we showed that solamargine, a major steroidal alkaloid glycoside, inhibited the growth of CRPC cells, which was enhanced in the presence of metformin. Furthermore, we found that solamargine increased phosphorylation of AMPKα, whereas reducing the protein expression and promoter activity of MUC1. A greater effect was observed in the presence of metformin. In addition, solamargine reduced NF-κB subunit p65 protein expression. Exogenously expressed p65 resisted solamargine-reduced MUC1 protein and promoter activity. Interestingly, exogenously expressed MUC1 attenuated solamargine-stimulated phosphorylation of AMPKα and, more importantly reversed solamargine-inhibited cell growth. Finally, solamargine increased phosphorylation of AMPKα, while inhibiting MUC1, p65 and tumor growth were observed in vivo. Overall, our results show that solamargine inhibits the growth of CRPC cells through AMPKα-mediated inhibition of p65, followed by reduction of MUC1 expression in vitro and in vivo. More importantly, metformin facilitates the antitumor effect of solamargine on CRPC cells.

The major obstacle limiting the efficacy of current Smoothened (Smo) inhibitors is the primary and acquired resistance mainly caused by Smo mutations and Gli amplification. In this context, developing Hh inhibitors targeting Gli, the final effector of this signaling pathway, may combat the resistance. In this study we found that solasonine, a natural glycoalkaloid compound, significantly inhibited the hedgehog (Hh) pathway activity. Meanwhile, solasonine may obviously inhibit the alkaline phosphatase (ALP) activity in C3H10T1/2 cells, concomitantly with reductions of the mRNA expression of Gli1 and Ptch1 . However, we found that solasonine exhibited no effect on the transcriptional factors activities provoked by TNF-α and PGE2, thus suggesting its selectivity against Hh pathway activity. Furthermore, we identified that solasonine inhibited the Hh pathway activity by acting on its transcriptional factor Gli using a series of complementary data. We also observed that solasonine obviously inhibited the Gli-luciferase activity provoked by ectopic expression of Smo mutants which may cause the resistance to the current Smo inhibitors. Our study suggests that solasonine may significantly inhibit the Hh pathway activity by acting on Gli, therefore indicating the possibility to use solasonine as a lead compound to develop anticancer drugs for combating the resistance of current Smo inhibitors.

The key step in the concise syntheses of calystegine B2 and its C-2 epimer calystegine B3 was the construction of cycloheptanone 8via an intramolecular Nozaki-Hiyama-Kishi (NHK) reaction of 9, an aldehyde containing a Z-vinyl iodide. Vinyl iodide 9 was obtained by the Stork olefination of aldehyde 10, derived from carbohydrate starting materials. Calystegines B2 (3) and B3 (4) were synthesized from d-xylose and l-arabinose derivatives respectively in 11 steps in excellent overall yields (27% and 19%).

Anisodamine was isolated from the medicinal herb, it was used in the treatment of gastrointestinal smooth muscle spasm, infective toxic shock and organophosphorus intoxication. But there is no report about anisodamine with α-glucosidase inhibitory activity. In order to find novel α-glucosidase inhibitors, a series of α-substituted arylacetates derivatives have been synthesized based on the active unit of anisodamine. In α-glucosidase assay, compound 9 in Schiff base form and compound 22 in ester form show strong inhibition against α-glucosidase with IC50 value of 46.81μM and 83.76μM, respectively. Compounds 9 and 22 exhibit comparable good antidiabetic activities as commercial drug Glimepiride. In addition, Schiff bases of α-substituted arylacetates show antitumor activities against human cancer cell lines, where compound 9 with thiourea moiety performs the best antitumor activity. We anticipate that our research will provide potential candidate scaffolds for antidiabetic drug design., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Steroidal glycoalkaloids present in Solanaceae are toxic compounds biosynthesised for the protection of the plants. However, many health benefits of these compounds have been reported so far. One of their promising targets might be cancer, as demonstrated in a large number of studies. However, the main mechanism of action seems to be unclear. It could include the induction of apoptosis or trigger a necrosis with a subsequent inflammatory response. The relatively high systemic toxicity of steroidal compounds is another effect that must be taken into account in anticancer research. The main aim of this work was to summarise the recent progress in the investigation of the mechanisms of their antitumour action and to discuss their potential., (Georg Thieme Verlag KG Stuttgart · New York.)

Context: The persistence of fascioliasis in many developing countries urges the search for simple, cheap, and effective substances. In this view, plants provide interesting molluscicidal activities thanks to the secondary metabolites they produce. The genus Solanum is known for its potent effect on vector snails., Objective: The molluscicidal activity of Solanum elaeagnifolium Cav. (Solanaceae) seeds against Galba truncatula Müll. (Lymnaeidae), intermediate host of Fasciola hepatica L. (Fasciolidae), was evaluated., Materials and Methods: Solanum elaeagnifolium seeds were powdered and successively extracted using n-hexane, methylene chloride, acetone, and methanol, for 20 h each. After filtration, solvents were evaporated. An acid-base treatment was conducted on seed methanolic extract to isolate total alkaloids and β-solamarine. Total saponins fraction was obtained after successive macerations and evaporations. The molluscicidal activity was evaluated by subjecting snails, in groups of 10, for 48 h to 500 mL of extracts, fractions, and pure product aqueous solutions, each containing amounts, ranging from 1 to 50 mg of plant material in 5 mg increments., Results: The methanolic extract of seeds, β-solamarine isolated for the first time from this plant and total saponins fraction showed very potent activities on snails, giving respective median lethal concentrations (LC50) of 1.18, 0.49, and 0.94 mg/L. Total alkaloids fraction obtained from the methanolic extract was less active giving an LC50 value of 14.67 mg/L., Discussion and Conclusion: This study emphasizes that glycoalkaloids and saponins of Solanum elaeagnifolium are potent molluscicidal agents. Seed methanolic extract, β-solamarine, and total saponins fraction may be used as molluscicides.

The synthesis of 1α-hydroxysolasodine from diosgenin was attempted. The Pd/C catalyst mediated dehydrogenation of diosgenin generated the 1,4,6-trien-3-one (3), which was reacted with Ac2O in pyridine in the presence of a catalytic amount of POCl3 followed by hydrolysis to give the 22-hydroxyfurostan (4) in 65% yield. Conversion of the primary 26-OH group into the azide and simultaneously 22-OH dehydration were achieved in one step by Mitsunobu reaction. Treatment of the (25R)-26-azidofurosta-1,4,6,20(22)-tetraen-3-one (5) with chlorotrimethylsilane (TMSCl)/NaI/MeCN and cyclisation in situ provided the (22R,25R)-spirosola-1,4,6-trien-3-one (6) in good yield. Stereoselective and regioselective epoxidation of trienone (6) with 30% H2O2 and 5% NaOH in methanol gave the 1α,2α-epoxy-(22R,25R)-spirosola-4,6-dien-3-one (7). Birch reduction of the epoxide (7) with Li/NH3 in THF followed by the treatment with NH4Cl, however, failed to generate the expected 1α-hydroxysolasodine, but provided a tetrahydrofuran ring opening product, (22S,25R)-1α,16β-dihydroxy-22,26-epiminocholest-4-en-3-one (8). Compounds 3 and 5-8 as well as solasodine were evaluated for their cell growth inhibitory activities against human prostate cancer PC3, human cervical carcinoma Hela, and human hepatoma HepG2 cells. At the concentration of 10 μM, only epoxide 7 displayed moderate inhibitory rates towards these cells (40-54%)., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Anisodamine is an ancient Chinese medicine derived from Tibet as a belladonna alkaloid, which is usually used for improvement of blood circulation in patients with organ phosphorus poisoning or shock. In this study, for the first time, we report its cardioprotective effects on preventing ischemia/reperfusion (I/R) injury of patients with acute myocardial infarction (AMI), and decreasing the myocardial infarction area and severity in heart of Sprague-Dawley (SD) rats. Our results suggest a potential molecular mechanism of anisodamine against the I/R injury in cardiomyocytes is associated with its anti-apoptotic effect. Anisodamine treatment decreases the expression of caspase-3 and caspase-8, and increases Bcl-2/Bax ratio in cardiomyocytes. Our data suggest that anisodamine can provide significant cardioprotection against I/R injury, potentially through the suppression of cardiomyocytes apoptosis.