Effect of Zusanli Acupoint Injection with Anisodamine on Postoperative Recovery Quality of Patients Undergoing Bariatric Surgery.

PURPOSE: To evaluate the influence of anisodamine injection at the Zusanli (ST36) on early postoperative recovery quality in patients who have undergone laparoscopic sleeve gastrectomy. MATERIALS AND METHODS: 141 patients undergoing laparoscopic sleeve gastrectomy were randomly divided into the control group (group C), the normal saline group (group S) and the anisodamine group (group A). Acupuncture point injections were administered after induction of general anesthesia. The quality of recovery-40 questionnaire (QoR-40) scores were documented preoperatively (D0) and on the 1st (D1), 3rd (D3) and 7th (D7) days postoperatively. Additional metrics included: the numerical rating scale (NRS) for pain, postoperative nausea and vomiting (PONV), assessment and analgesic consumption 24-h post-extubation and the initial postoperative times for ambulation and anal exhaust. Substance P (SP), ß-endorphin (ß-EP), motilin (MTL) and gastrin (GAS) were quantified at 24-h post-surgery. RESULTS: Compared with group C, group A demonstrated an elevation in QoR-40 scores and physical comfort dimensions during D1-3, and an increased pain scores during D1-7; group S exhibited an augmentation in QoR-40 scores and pain scores on D1 (p < 0.05). Compared with group S, group A improved QoR-40 scores on D1 and pain scores during D1-3 (p < 0.05). SP, ß-EP, MTL and GAS presented significant variances among the groups 24-h post-surgery (p < 0.05). There were significant differences between the groups in NRS pain scores and PONV scores at 24-h postoperatively, dosage of dizocin on the first postoperative day, and time to first anal defecation (p < 0.05). CONCLUSION: The administration of anisodamine via ST36 acupoint injections has been demonstrated to facilitate the recuperation of gastrointestinal functionality, to alleviate postoperative pain and nausea, and substantially to enhance the quality of early postoperative recovery.

Combined administration of anisodamine and neostigmine alleviated colitis by inducing autophagy and inhibiting inflammation.

Our previous work demonstrated that the anisodamine (ANI) and neostigmine (NEO) combination produced an antiseptic shock effect and rescued acute lethal crush syndrome by activating the α7 nicotinic acetylcholine receptor (α7nAChR). This study documents the therapeutic effect and underlying mechanisms of the ANI/NEO combination in dextran sulfate sodium (DSS)-induced colitis. Treating mice with ANI and NEO at a ratio of 500:1 alleviated the DSS-induced colitis symptoms, reduced body weight loss, improved the disease activity index, enhanced colon length, and alleviated colon inflammation. The combination treatment also enhanced autophagy in the colon of mice with DSS-induced colitis and lipopolysaccharide/DSS-stimulated Caco-2 cells. Besides, the ANI/NEO treatment significantly reduced INF-γ, TNF-α, IL-6, and IL-22 expression in colon tissues and decreased TNF-α, IL-1ß, and IL-6 mRNA levels in Caco-2 cells. Meanwhile, the autophagy inhibitor 3-methyladenine and ATG5 siRNA attenuated these effects. Furthermore, 3-methyladenine (3-MA) and the α7nAChR antagonist methyllycaconitine (MLA) weakened the ANI/NEO-induced protection on DSS-induced colitis in mice. Overall, these results indicate that the ANI/NEO combination exerts therapeutic effects through autophagy and α7nAChR in a DSS-induced colitis mouse model.

Anticancer effects of solasonine: Evidence and possible mechanisms.

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.

Ameliorative effect of anisodamine (654-1/654-2) against myocardial dysfunction induced by septic shock via the NF-κB/NLRP-3 or the PI3K-AKT/NF-κB pathway.

BACKGROUND: Septic shock, an extremely dangerous condition that causes impairment of organ function, always largely contributes to mortality in intensive care units. The impact of septic shock-induced organ damage on morbidity and mortality is substantially influenced by myocardial dysfunction. However, it remains unclear whether and in what manner anisodamine (654-1/654-2) ameliorates myocardial dysfunction caused by septic shock. PURPOSE: This study is the pioneering investigation and validation about the protective efficacy of anisodamine (654-1/654-2) against LPS-induced myocardial dysfunction in septic shock rats. It also aims to explore the differences in the underlying molecular mechanisms of both drugs. METHODS: A septic shock model was established in SD rats by after tail vein administration of LPS. 64 rats were distributed into eight groups, such as LPS group, control group, LPS+654-1 group (1.25, 2.5, and 5 mg/kg), and LPS+654-2 group (1.25, 2.5, and 5 mg/kg). The hemodynamics, echocardiography, immunohistochemical analysis, TEM, TUNEL assay, and H&E staining were utilized to assess the septic shock model and myocardial function. Lactic acid, inflammatory markers (IL-1ß, IL-6, and TNF-α), endothelial injure markers (SDC-1, HS and TM) and myocardial injury markers (CK, c-TNT and NT-pro BNP) were assessed using ELISA or biochemical kits. Additionally, the mechanisms of 654-1/654-2 were analyzed using RNA-seq and bioinformatics, and validated using western blotting and RT-PCR. RESULTS: Administration of 654-1/654-2 significantly restored hemodynamics and improved myocardial and endothelial glycocalyx injury in septic shock rats. Furthermore, 654-1/654-2 dose-dependently reduced plasma levels of lactic acid, inflammatory cytokines, and markers of endothelial and myocardial injury. Analyses using RNA-seq, WB and RT-PCR techniques indicated that 654-1/654-2 could mitigate myocardial and endothelial injury by inhibiting the NF-κB and NLRP-3 pathways, and activating the PI3K-AKT pathway. CONCLUSIONS: These findings demonstrated that 654-1/654-2 could alleviate myocardial damage in septic shock rats. Specifically, 654-1 inhibited the NF-κB/NLRP-3 pathway, whereas 654-2 promoted the PI3K-AKT pathway and inhibited the NF-κB pathway, effectively mitigating the inflammatory response and cell apoptosis.

Update on the sources, pharmacokinetics, pharmacological action, and clinical application of anisodamine.

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.

Solasodine suppress MCF7 breast cancer stem-like cells via targeting Hedgehog/Gli1.

BACKGROUND: Recently, a novel therapy to treat cancer has been to target cancer stem-like cells (CSCs). The aim of this study was to investigate the effect of solasodine, a steroidal alkaloid isolated from Solanum incanum L., on MCF7 CSCs and to understand the compound's underlying mechanism of action. METHOD: A tumorsphere formation assay was used to evaluate the effects of solasodine on the proliferation and self-renewal ability of MCF7 CSCs. The level of expression of proteins associated with cancer stemness markers and Hh signaling mediators was determined. The interaction between solasodine and Gli1 was calculated by molecular docking and further demonstrated by cellular thermal shift assay. RESULTS: Solasodine significantly decreased the proliferation of MCF7 tumorspheres and showed a stronger cytotoxicity on breast cancer cells with higher levels of Gli1 expression. The results showed that the levels of CD44 and ALDH1 expression were suppressed. Furthermore, expression of CD24 was enhanced by solasodine, via a mechanism that involved dampening Gli1 expression and blocking the nuclear translocation of this protein in MCF7 tumorspheres. Computational studies predicted that solasodine showed a high affinity with the Gli1 zinc finger domain that resulted from hydrogen-bonds to the THR243 and ASP216 amino acids residues. In addition, solasodine specifically bound with Gli1 and enhanced Gli1 protein stability in MCF7 cells. CONCLUSION: Here, our findings indicated that solasodine can directly suppresses Hh/Gli1 signaling, and is a novel anticancer candidate that targets CSCs.

Evaluation of a Chaotrope and Kosmotrope in the Multivariate Optimization of PHW-ATPE of Solasodine from Leaves of Solanum mauritianum.

A hyphenated pressurized hot water­aqueous two-phase extraction (PHW-ATPE) method was applied to extract solasodine from Solanum mauritianum (S. mauritianum). A central composite design (CCD) was applied to determine the optimal conditions for the extraction of solasodine. The parameters evaluated included the percentage concentration of salt (NaCl or Na2CO3) and temperature. The fit of the central composite design response surface model for PHW-ATPE to the data generated a model with a good quadratic fit (R2 = 0.901). The statistically significant (p < 0.05) parameters, such as the linear and quadratic effects of the concentration of salt (%) powder, had a significant impact on the extraction of solasodine. The application of multiply charged salts such as Na2CO3 (kosmotrope) was shown to be a comparably better extractant of solasodine than NaCl (chaotrope) due to the salting-out effect. The optimized conditions for extraction of solasodine with NaCl or Na2CO3 were a temperature of 80 °C at a salt concentration of 20%. The maximum extraction of solasodine was 300.79 mg kg−1 and 162.34 mg kg−1 for Na2CO3 and NaCl, respectively.

Orally administered solasodine, a steroidal glycoalkaloid, suppresses ovalbumin-induced exaggerated Th2-immune response in rat model of bronchial asthma.

Bronchial asthma is a chronic lung disorder, that affects an estimated 262 million people worldwide, thereby, causing a large socio-economic burden. Drug molecules from natural sources have exhibited a good promise in providing an alternative therapy in many chronic ailments. Solasodine, a glycoalkaloid has received an immense interest due to its large pharmacological and industrial value, however, its usefulness in asthma control has not been investigated till date. In this work, solasodine was tested for its ability to reverse several characteristics of bronchial asthma induced by intraperitoneal injection of ovalbumin (OVA) and aluminium hydroxide in experimental rats. Treating asthmatic animals with solasodine (1 mg/kg b.w. or 10 mg/kg b.w.) or dexamethasone (2.5 mg/kg b.w.) reversed OVA-induced airway hyperresponsiveness, infiltration of inflammatory cells and histamine levels in the airways. Furthermore, as compared to OVA-control rats, allergen-induced elevated levels of IgE, nitrites, nitric oxide, and pro-inflammatory mediators, including TNF-α, IL-1ß, LTD-4, and Th2-cytokines, particularly, IL-4, IL-5 were remarkably reduced in both bronchoalveolar lavage fluid and blood. These findings are supported by significant protection offered by various treatments against OVA-induced airway inflammation and mast cell degranulation in mesenteric tissues. Further, In-silico molecular docking studies performed to determine inhibitory potential of solasodine at IL-4 and IL-5, demonstrated strong affinity of phytocompound for these receptors than observed with antagonists previously reported. Results of current study imply that solasodine has therapeutic promise in allergic asthma, presumably due to its ability to prevent mast cell degranulation and consequent generation of histamine and Th2-associated cytokines in airways.

Chitosan and anisodamine enhance the immersion immune efficacy of inactivated Elizabethkingia miricola vaccine in black spotted frogs.

Black spotted frogs have rich nutrition and delicious meat, and its market consumption has increased year by year. However, outbreaks of the diseases have caused huge losses to the breeding industry. The crooked head disease caused by Elizabethkingia miricola (E. miricola) is highly contagious and lethal, and there is no effective treatment method. Vaccination is the most promising strategy to prevent infectious diseases. Immersion vaccination has attracted many researchers because of its simplicity of operation in preventing infectious diseases. In addition, immersion vaccines can be more effective when used with adjuvants. In this study, we prepared inactivated E. miricola with 0.3% formaldehyde, and the black spotted frogs were vaccinated by soaking in inactivated E. miricola vaccine, anisodamine + vaccine mixture, ß-glucan + vaccine mixture, chitosan + vaccine mixture for 60 min. PBS was used as a control. After being challenged by E. miricola, the survival rate of anisodamine + vaccine (57%) and chitosan + vaccine group (63%) was significantly higher than that of the control group (17%). By analyzing pathological sections, we found that the chitosan + vaccine and anisodamine + vaccine groups protected the brain, eye, liver and kidney tissues of the black spotted frogs compared to the control group, which was consistent with the trend of survival rate. In addition, chitosan + vaccine and anisodamine + vaccine groups had better effects on LZM, TSOD and C3 in serum than control group. Meanwhile, the numbers of the percentage of leukocytes/haemocytes in the peripheral blood of immunized black spotted frogs increased. The anisodamine + vaccine group (5.3%) and chitosan + vaccine (5.38%) group were significantly higher than the blank control group (2.24%), which indicate that the two groups induced a more significant immune response and were more resistant to bacterial invasion. The tissue bacterial loads in liver, brain, kidney and eye were significantly lower in the anisodamine + vaccine and chitosan + vaccine groups than that of the control group. This study explored and demonstrated the good efficiency of chitosan and anisodamine as adjuvants for immunization by immersion and provided a reference for improving the efficiency of immunization by immersion.

Observation of Clinical Efficacy of Anisodamine and Chlorpromazine in the Treatment of Intractable Hiccup after Stroke.

Objective: This study is aimed at investigating the clinical efficacy of anisodamine combined with chlorpromazine on intractable hiccups after stroke. Methods: 150 patients admitted to Affiliated Hospital of the Hebei University of Engineering from 2017 to 2021 were selected as the research objects, all of which received the computed tomography (CT) examination. During CT examination, intelligent algorithms were used to segment the images. An unsupervised multilayer image threshold segmentation algorithm was proposed by using Kullback-Leibler (K-L) divergence and the modified particle swarm optimization (MPSO) algorithm. All patients were divided into three groups, with each group of 50 patients. Patients in the control group (group A) took the calcium tablets, vitamin C tablets, and vitamin B1 tablets orally. Patients in the control group (group B) received the acupoint injection of anisodamine, and those in the observation group (group C) received the acupoint injection of anisodamine combined with chlorpromazine. The therapeutic effect and patient satisfaction of the three groups were compared. Results: The two-dimensional (2D) K-L divergence was applied for the multilayer segmentation of images, which was helpful to obtain accurate images. The MPSO algorithm was adopted to reduce the computational complexity. The total efficiency of group C was 98%, that of group B was 56%, and that of group A was 22%. The total efficiency and satisfaction rate of group C were signally better than those of group A and group B (P < 0.05). Conclusion: The combination of 2D K-L divergence and MPSO algorithm could improve the accuracy of multilayer image segmentation and CT imaging. Acupoint injection of anisodamine combined with chlorpromazine had better efficacy than the injection of anisodamine alone for the treatment of intractable hiccups after stroke, with high safety and clinical promotion value.

Co-Adjuvancy of Solasodine & CoQ10 Against High Fat Diet-Induced Insulin Resistance Rats Via Modulating IRS-I and PPAR-γ Proteins Expression.

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.

Solasonine induces apoptosis of the SGC-7901 human gastric cancer cell line in vitro via the mitochondria-mediated pathway.

Solasonine, a steroidal glycoalkaloid isolated from the herbal plant Solanum nigrum Linn., has shown active against multiple human cancers; however, there is little knowledge on the activity of solasonine against gastric cancer until now. This study aimed to examine the effect of solasonine on the biological behaviours of human gastric cancer SGC-7901 cells. The results showed that solasonine suppressed SGC-7901 cell proliferation in a dose-dependent manner. Solasonine treatment mainly induced the cell cycle arrest at G2 phase in SGC-7901 cells. Treatment with solasonine resulted in significant down-regulation of Bcl-2 and Caspase-3 protein expression and reduced Bax and Bcl-xL protein expression in SGC-7901 cells. Solasonine shows a comparable inhibitory effect on the proliferation of human gastric cancer SGC-7901 cells with cisplatin, and solasonine induces of SGC-7901 cell apoptosis through triggering the endoplasmic reticulum stress pathway and the mitochondrial pathway. Our data indicate that solasonine may be a promising agent for the treatment of gastric cancer.

Anisodamine potently inhibits SARS-CoV-2 infection in vitro and targets its main protease.

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.

Anisodamine Enhances Macrophage M2 Polarization through Suppressing G9a-Mediated Interferon Regulatory Factor 4 Silencing to Alleviate Lipopolysaccharide-Induced Acute Lung Injury.

Acute lung injury (ALI) is a serious inflammatory lung disease. Imbalances in the polarization of classically activated (M1) and alternatively activated (M2) macrophages are closely related to ALI. Anisodamine has a promising therapeutic effect for septic shock. Nevertheless, the role of anisodamine in progression of ALI remains to be investigated. Our results showed that anisodamine significantly reduced lung damage, myeloperoxidase (MPO) activity, lung wet/dry ratio, total cell number, and protein concentrations in bronchoalveolar lavage fluid and decreased interleukin (IL)-6 level and the levels of M1 phenotypic markers, whereas it increased IL-10 level and the levels of M2 phenotypic markers in mice with a nasal instillation of lipopolysaccharide (LPS). Bone marrow-derived macrophages (BMDMs) were stimulated or transfected with LPS plus anisodamine or LPS plus G9a short hairpin RNA. Anisodamine and downregulation of G9a both promoted BMDM M2 polarization caused by IL-4 treatment and inhibited M1 polarization resulting from LPS treatment. Chromatin immunoprecipitation assay revealed that anisodamine inhibited G9a-mediated methylation and expression suppression on interferon regulatory factory 4 (IRF4). Overexpression of G9a or silence of IRF4 reversed the improvement effect of anisodamine on lung tissue injury, evidenced by an increase of MPO activity and the restoration of LPS-induced alterations of M1 and M2 polarization. In conclusion, anisodamine protected against LPS-induced ALI, during which anisodamine suppressed the LPS-stimulated alterations of macrophage M1 and M2 polarization through inhibiting G9a-mediated methylation of IRF4, suggesting that anisodamine was a potential therapeutic drug to alleviate ALI. SIGNIFICANCE STATEMENT: Anisodamine treatment was able to attenuate lung injury and pulmonary edema caused by lipopolysaccharide (LPS) stimulation, and the specific mechanism was that anisodamine reversed the LPS-induced alterations of M1 and M2 polarization by inhibiting G9a-mediated methylation and expression suppression of interferon regulatory factor 4, which suggests that anisodamine has the potential to alleviate acute lung injury.

Solamargine induces autophagy-mediated apoptosis and enhances bortezomib activity in multiple myeloma.

Multiple myeloma (MM) is an incurable plasma cell malignancy with a poor survival rate. Conventional chemotherapeutic agent-induced adverse events, including toxicity, neuropathy or drug resistance, significantly decrease the patients' quality of life and can even lead to interruption of treatment. Therefore, novel therapeutic drugs and strategies are urgently needed to improve MM therapy and patient outcomes. Here, we show that solamargine (SM), a steroidal alkaloid glycoside isolated from a Chinese herb Solanum nigrum L., exhibits promising anti-MM activity. In particular, SM suppressed the viability of MM cell lines (ARP-1 and NCI-H929) in a concentration- and time-dependent manner, inducing apoptosis in these cells. RNA-seq analysis showed that treatment with SM led to the upregulation of genes associated with cell death and autophagy in H929 cells. Further, we found that treatment with SM activated autophagy in the MM cells, as incubation with 3-Methyladenine, an inhibitor of autophagy, significantly alleviated SM-triggered apoptosis and inhibition of viability in MM cells. Interestingly, we also observed a synergistic effect between SM and bortezomib (BTZ), a common chemotherapeutic agent for MM, in both MM cells and human bone marrow CD138+ primary myeloma cells. We also confirmed the single-agent efficacy of SM and the synergistic effects between SM and BTZ in an MM xenograft mouse model. Collectively, these findings indicate that SM exerts an anti-MM effect, at least in part, by activating cell autophagy and reveal that SM alone or in combination with BTZ is a potential therapeutic strategy for treating MM.

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

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

Solamargine induces hepatocellular carcinoma cell apoptosis and autophagy via inhibiting LIF/miR-192-5p/CYR61/Akt signaling pathways and eliciting immunostimulatory tumor microenvironment.

Hepatocellular carcinoma (HCC) is well-known to be a highly prevalent malignant tumor, but the treatment of this pathological state has been still challenging. Solamargine (SM), a traditional Chinese herb-derived compound, has been widely reported to possess multiple antitumor properties. However, whether SM plays a vital role in HCC therapy and how it exerts an antitumor effect remains unclear. Thus, in this study, we demonstrated that SM inhibited the proliferation of HCC and effectively induced HCC cell apoptosis and autophagy in vitro and in vivo. Mechanistically, the oncogenic factor LIF was aberrantly elevated in HCC tissues and down-regulated by SM in HCC cells, as well as subsequently the overexpression of LIF could restore the anti-HCC effects of SM via miR-192-5p/CYR61/Akt signaling pathways. Additionally, SM could repolarize tumor associated macrophages by LIF/p-Stat3 to inhibit the growth and epithelial-mesenchymal transition of HCC, and simultaneously affected other immune cell populations in the immune (tumor) microenvironment by regulating macrophages, such as MDSCs, DCs and T cell populations. Together, these findings exploit the potential use of SM against HCC and shed light on exploring SM as a potent candidate drug for the future HCC therapeutics.

Khasianine ameliorates psoriasis-like skin inflammation and represses TNF-α/NF-κB axis mediated transactivation of IL-17A and IL-33 in keratinocytes.

ETHNO-PHARMACOLOGICAL RELEVANCE: Khasianine is recently identified as a bioactive compound from Solanum nigrum L. (SNL) which is a traditional Chinese herb (named LongKui in China) and has been clinically applied for treating psoriasis in China but with limited knowledge about the active ingredients. AIM OF THE STUDY: This study tried to explore the bioactivity of Khasianine and showed that Khasianine possessed highly anti-inflammatory bioactivity which rapidly alleviated psoriasis-like mice skin inflammation. MATERIALS AND METHODS: Imiquimod induced psoriasis-like mouse model, and human keratinocytes were employed in this study. In vivo, immunohistochemistry and immunofluorescence were performed to evaluate the pathological improvement in psoriatic lesions after Khasianine treatment. In vitro, tumor necrosis factor α (TNF-α) treated HaCaT cells with or without Khasianine, were used to analyze the expression and cellular location of NF-κB p65, the expression of IL-17A and IL-33, and the binding intensity of NF-κB p65 on the promoter of IL-17A and IL-33 to understand the molecular mechanism of Khasianine mediated anti-inflammatory effect. RESULTS: Khasianine reduced infiltration of CD4+ T helper cells (Th cells) and macrophages in mice psoriatic lesions. Immunohistochemistry analysis revealed that Khasianine reduced TNF-α levels in lesions and suppressed NF-κB p65 activation as well as expression of IL-17A and IL-33 in mice epidermal keratinocytes. Further studies in human keratinocytes demonstrated that Khasianine inhibited TNF-α-induced transcriptional activation (transactivation) of NF-κB p65 such as evicting NF-κB p65 binding from the promoter regions of IL-17A and IL-33 and preventing NF-κB nuclear translocation. CONCLUSIONS: Our results suggested that Khasianine is a potent anti-inflammatory compound with the bioactivity of NF-κB inhibition and is a promising candidate for psoriasis topical therapy.

Pharmacokinetics, oral bioavailability and metabolic analysis of solasodine in mice by dried blood spot LC-MS/MS and UHPLC-Q-Exactive MS.

Solasodine, a major ingredient in Solanaceae family, has various biological functions such as inducing neurogenesis, anticonvulsant and anti-tumor. Its risk assessment has also drawn public attention. However, little is known about its oral bioavailability and metabolic process. In this study, an liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the quantification of solasodine in mice dried blood spot (DBS) samples. To block nonspecific adsorption, DBS samples were pretreated with bovine serum albumin (BSA) and then extracted with ethyl acetate. This method was applied to a pharmacokinetic and bioavailability study of solasodine. The absolute bioavailability was only 1.28%. Thereafter, its metabolites in mice were characterized using an ultra-performance liquid chromatography Q-Exactive high-resolution mass spectrometer (UHPLC-QE-HRMS). Several isomeric metabolites were well separated and differentiated using their retention time, fragmentation pathways and correspondingly fragmentation rules of solasodine. As a result, 21 metabolites were characterized including 16 phase I and 5 phase II metabolites. The proposed metabolic pathways showed that solasodine mainly experienced oxidation, dehydration, dehydrogenation and sulfation. These results could help us to better understand the efficacy and safety of solasodine.

Solamargine inhibits the growth of hepatocellular carcinoma and enhances the anticancer effect of sorafenib by regulating HOTTIP-TUG1/miR-4726-5p/MUC1 pathway.

Hepatocellular carcinoma (HCC) is one of the most common primary malignancies. Drug resistance has significantly prevented the clinical application of sorafenib (SF), a first-line targeted medicine for the treatment of HCC. Solamargine (SM), a natural alkaloid, has shown potential antitumor activity, but studies about antitumor effect of SM are obviously insufficient in HCC. In the present study, we found that SM significantly inhibited the growth of HCC and enhanced the anticancer effect of SF. In brief, SM significantly inhibited the growth of HepG2 and Huh-7 cells. The combination of SM and SF showed a synergistic antitumor effect. Mechanistically, SM downregulated the expression of long noncoding RNA HOTTIP and TUG1, followed by increasing the expression of miR-4726-5p. Moreover, miR-4726-5p directly bound to the 3'-UTR region of MUC1 and decreased the expression of MUC1 protein. Overexpression of MUC1 partially reversed the inhibitory effect of SM on HepG2 and Huh-7 cells viability, which suggested that MUC1 may be the key target in SM-induced growth inhibition of HCC. More importantly, the combination of SM and SF synergistically restrained the expression of MUC1 protein. Taken together, our study revealed that SM inhibited the growth of HCC and enhanced the anticancer effect of SF through HOTTIP-TUG1/miR-4726-5p/MUC1 signaling pathway. These findings will provide potential therapeutic targets and strategies for the treatment of HCC.