Gentiopicroside and swertiamarin induce non-selective oxidative stress-mediated cytotoxic effects in human peripheral blood mononuclear cells.

Gentiopicroside (Gp) and swertiamarin (Sm), secoiridoid glycosides commonly found in plants of the Gentianaceae family, differ in one functional group. They exhibit promising cytotoxic effects in cancer cell lines and overall protective outcomes, marking them as promising molecules for developing novel pharmaceuticals. To investigate potential variations in cellular sensitivity to compounds of similar molecular structures, we analyzed the mode of Gp and Sm induced cell death in human peripheral blood mononuclear cells (PBMCs) after 48 h of treatment. The lowest tested concentration that significantly reduces cell viability, 50 µM, was applied. Oxidative stress parameters were estimated by measuring the levels of prooxidative/antioxidative balance, lipid peroxidation products, and 8-oxo-7,8-dihydro-2-deoxyguanosine, while gene expression of DNA repair enzymes was evaluated by employing quantitative real-time PCR. Cellular morphology was analyzed by fluorescent microscopy, and immunoblot analysis of apoptosis and necroptosis-related proteins was used to assess the type of cell death induced by the treatments. The discriminatory impact of Gp/Sm treatments on apoptosis and necroptosis-induced cell death was evaluated by monitoring the cell survival in co-treatment with specific cell death inhibitors. Obtained results show greater cytotoxicity of Gp than Sm suggesting that variations in the molecular structures of the tested compounds can substantially affect their biological effects. Gp/Sm co-treatment with apoptosis and necroptosis inhibitors revealed a distinct, albeit non-specific mechanism of PBMCs cell death. Although the therapeutic may not directly cause a specific type of cell death, its extent can be pivotal in assessing the safety of therapeutic application and developing phytopharmaceuticals with improved features. Since phytopharmaceuticals affect all exposed cells, identification of cytotoxic mechanisms on PBMCs after Gp and Sm treatment is important for addressing the formulation and dosage of potential phytopharmaceuticals.

Swertiamarin relieves radiation-induced intestinal injury by limiting DNA damage.

Radiotherapy is the conventional treatment for pelvic abdominal tumors. However, it can cause some damage to the small intestine and colorectal, which are very sensitive to radiation. Radiation-induced intestinal injury (RIII) affects the prognosis of radiotherapy, causing sequelae of loss of function and long-term damage to patients' quality of life. Swertiamarin is a glycoside that has been reported to prevent a variety of diseases including but not limited to diabetes, hypertension, atherosclerosis, arthritis, malaria, and abdominal ulcers. However, its therapeutic effect and mechanism of action on RIII have not been established. We investigated whether swertiamarin has a protective effect against RIII. In this article, we use irradiator to create cellular and mouse models of radiation damage. Preventive administration of swertiamarin could reduce ROS and superoxide anion levels to mitigate the cellular damage caused by radiation. Swertiamarin also attenuated RIII in mice, as evidenced by longer survival, less weight loss and more complete intestinal barrier. We also found an increase in the relative abundance of primary bile acids in irradiated mice, which was reduced by both FXR agonists and swertiamarin, and a reduction in downstream interferon and inflammatory factors via the cGAS-STING pathway to reduce radiation-induced damage.

Exploring the potential of semi-synthetic Swertiamarin analogues for GLUT facilitation and insulin secretion in NIT-1 cell lines: a molecular docking and in-vitro study.

Synthesis, characterisation, and anti-diabetic potential of swertiamarin analogues against DPP-4 enzymatic inhibition was done prior to this study. However, swertiamarin and its analogues inhibited DPP-4 enzyme significantly. Semisynthetic swertiamarin analogues have been studied for antidiabetic potential and mechanism of action utilising molecular docking and in-vitro techniques. The mechanism of action for swertiamarin analogues was determined by in-silico molecular docking studies using glucose-transporters, GLUT-1 (PDB ID: 4PYP), GLUT-3 (PDB ID: 7SPS), and GLUT-4 (PDB ID: 7WSM) along with in-vitro glucose uptake and glucose-induced insulin secretion assays. These studies found that synthesised swertiamarin analogues SNIPERSV3, SNIPERSV4, and SNIPERSV7 shown better docking score against different GLUTs and better anti-diabetic effects on glucose uptake and insulin secretion in NIT-1 cell line than standard glibenclamide and swertiamarin. Thus, swertiamarin analogues might be studied for diabetes therapy in the future.

Protective effect of Enicostemma axillare - Swertiamarin on oxidative stress against nicotine-induced liver damage in SD rats.

OBJECTIVE: The current investigation was aimed to determine the hepatoprotective benefits of Swertiamarin (ST) administration against nicotine-induced hepatotoxicity in SD rats. MATERIAL AND METHODS: A total of 48 adult male SD rats were allocated into six groups using a fully randomised approach. As a control, group I was given oral (PO) normal saline. For 65 days, the animals in groups II, III, IV, V and VI received 2.5mg/kg/day of nicotine intraperitoneally (IP), 100mg/kg/day of ST orally (PO), 200mg/kg/day of ST orally (PO), 2.5mg/kg/day of nicotine (IP)+100mg/kg/day of ST (PO), and 2.5mg/kg/day of nicotine (IP)+200mg/kg/day of ST (PO), respectively. Animals were killed on 66thday, liver tissue was removed and used for histopathological analysis as well as biochemical testing (oxidative stress parameters and liver function enzymes). RESULTS: When compared to control animals, the animals in group II showed a substantial rise in their aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine levels (P˂0.001). Furthermore, compared to control animals, these animals displayed enhanced hepatic oxidative stress as indicated by significantly higher Malondialdehyde (MDA) levels (P˂0.001) and lower levels of Catalase (CAT), Glutathione (GSH), Glutathione peroxidase (GSH-Px) and Superoxide dismutase (SOD) (P˂0.001). Further, more histological anomalies were seen in the liver of nicotine-treated rats compared to control rats, including significant vacuolization, poor tissue architecture, the growth of pycnotic nuclei, and dilated sinusoids. Contrary to nicotine-treated rats, the co-administration of ST and nicotine was observed to prevent the abnormalities caused by nicotine (groups V and VI). CONCLUSION: The results of the current study show that nicotine can seriously harm liver tissue and that swertiamarin can prevent the harmful effects of nicotine on rat liver. Future research is necessary to delve deeply into the mechanisms behind swertiamarin protective impact against nicotine-induced hepatotoxicity.

Identification and validation of targets of swertiamarin on idiopathic pulmonary fibrosis through bioinformatics and molecular docking-based approach.

BACKGROUND: Swertiamarin is the main hepatoprotective component of Swertiapatens and has anti-inflammatory and antioxidation effects. Our previous study showed that it was a potent inhibitor of idiopathic pulmonary fibrosis (IPF) and can regulate the expressions of α-smooth muscle actin (α-SMA) and epithelial cadherin (E-cadherin), two markers of the TGF-ß/Smad (transforming growth factor beta/suppressor of mothers against decapentaplegic family) signaling pathway. But its targets still need to be investigated. The main purpose of this study is to identify the targets of swertiamarin. METHODS: GEO2R was used to analyze the differentially expressed genes (DEGs) of GSE10667, GSE110147, and GSE71351 datasets from the Gene Expression Omnibus (GEO) database. The DEGs were then enriched with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis for their biological functions and annotated terms. The protein-protein interaction (PPI) network was constructed to identify hub genes. The identified hub genes were predicted for their bindings to swertiamarin by molecular docking (MD) and validated by experiments. RESULTS: 76 upregulated and 27 downregulated DEGs were screened out. The DEGs were enriched in the biological function of cellular component (CC) and 7 cancer-related signaling pathways. Three hub genes, i.e., LOX (lysyl oxidase), COL5A2 (collagen type V alpha 2 chain), and CTGF (connective tissue growth factor) were selected, virtually tested for the interactions with swertiamarin by MD, and validated by in vitro experiments. CONCLUSION: LOX, COL5A2, and CTGF were identified as the targets of swertiamarin on IPF.

Mangiferin from Enicostemma littorale Blume with in silico and in vitro anti-inflammatory potential.

The bioassay-guided fractionation of the extract of aerial parts of Enicostemma littorale resulted in two fractions 3 and 4 with moderate and potent antioxidant activity, respectively. The purification of fraction 3 gave swertiamarin (1), while the LCMS profile of fraction 4 unveiled the presence of another constituent along with swertiamarin. The extensive purification of fraction 4 led to the unusual isolation of mangiferin (2) from E. littorale. The uncommon isolation of mangiferin from E. littorale motivated us to conduct its in silico and in vitro screening as an anti-inflammatory agent. Both studies have proved mangiferin to be a promising anti-inflammatory molecule with a binding energy of -9.17 kcal/mol against Cyclooxygenase-2 protein and IC50 of 146.07 nanomolar. This study is the first report of the isolation of mangiferin, a xanthone glycoside from E. littorale.Communicated by Ramaswamy H. Sarma.

Chromatographic analysis of selected phytosterols from Cyathea and their characterization by in silico docking to potential therapeutic targets.

Separation and quantification of lupeol, stigmasterol and swertiamarin in ethanolic extracts of selected Cyathea species have been developed using HPTLC and an attempt is made to explore the biopotential of phytochemicals against various proteins by computational analysis. Compounds were separated using the specific mobile phase and the developed plates were sprayed with respective spraying reagents. The 3D structure of the receptor proteins viz., 1VSN, 5BNQ, 6HN8, 7DN4 and 3TJU, and the 3D SDF structures of ligands like lupeol, stigmasterol and swertiamarin were retrieved from the Protein Data Bank (PDB) and NCBI-Pub Chem Compound database respectively. The Argus 4.0.1 is computer generated drug design screening software is employed to analyze the binding affinity of test compounds against the selected proteins in the form of E-values versus potential drug targets. The docking result was saved and visualized using Discovery Studio Visualizer. The terpenoid band with Rf value 0.79 depicted the presence of lupeol in C. gigantea (0.04%) and C. crinita (0.02%). The steroid band with Rf value 0.41 confirmed the presence of stigmasterol with varied frequency viz., C. nilgirensis (0.33%), C. gigantea (0.29%) and C. crinita (0.52%). Lupeol, stigmasterol and swertiamarin showed the interaction against the studied proteins viz., 1VSN, 5BNQ, 6HN8, 7DN4, 3TJU with varied energy values and interacting residues. The results of the virtual screening and molecular docking analysis suggest that the phytochemical compounds of Cyathea species viz., lupeol and stigmasterol were identified as possible lead molecules to fight against cancer and cytotoxicity.

Lomatogonium rotatum extract alleviates diabetes mellitus induced by a high-fat, high-sugar diet and streptozotocin in rats.

BACKGROUND: Lomatogonium rotatum (LR) is traditionally used in Mongolian folk medicine as a hypoglycemic agent, but its evidence-based pharmacological effects and me-chanisms of action have not been fully elucidated. AIM: To emphasize the hypoglycemic action mechanism of LR in a type 2 diabetic rat model and examine potential biomarkers to obtain mechanistic understanding regarding serum metabolite modifications. METHODS: A high-fat, high-sugar diet and streptozotocin injection-induced type 2 diabetic rat model was established. The chemical composition of the LR was identified by high performance liquid chromatography. LR extract administrated as oral gavage at 0.5 g/kg, 2.5 g/kg, and 5 g/kg for 4 wk. Anti-diabetic effects of LR extract were evaluated based on histopathological examination as well as the measurement of blood glucose, insulin, glucagon-like peptide 1 (GLP-1), and lipid levels. Serum metabolites were analyzed using an untargeted metabolomics approach. RESULTS: According to a chemical analysis, swertiamarin, sweroside, hesperetin, coumarin, 1.7-dihydroxy-3,8-dimethoxyl xanthone, and 1-hydroxy-2,3,5 trimethoxanone are the principal active ingredients in LR. An anti-diabetic experiment revealed that the LR treatment significantly increased plasma insulin and GLP-1 levels while effectively lowering blood glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and oral glucose tolerance test compared to the model group. Furthermore, untargeted metabolomic analysis of serum samples detected 236 metabolites, among which 86 were differentially expressed between the model and the LR group. It was also found that LR considerably altered the levels of metabolites such as vitamin B6, mevalonate-5P, D-proline, L-lysine, and taurine, which are involved in the regulation of the vitamin B6 metabolic pathway, selenium amino acid metabolic pathway, pyrimidine metabolic pathway, and arginine and proline metabolic pathways. CONCLUSION: These findings indicated that LR may have a hypoglycemic impact and that its role may be related to changes in the serum metabolites and to facilitate the release of insulin and GLP-1, which lower blood glucose and lipid profiles.

In vitro and in silico screening of novel typhoid drugs from endangered herb (Enicostema axillare).

In the present study, antibacterial activity of swertiamarin from Enicostema axillare (Lam) was checked against three different human gram-negative pathogens namely Salmonella typhi, Klebsiella pneumoniae and Shigella flexneri. Minimum inhibitory concentration assay revealed low dose and efficient activity of swertiamarin on the above said pathogens. Though swertiamarin is a well-studied and characterized compound, there is no experimental proof available for its antibacterial activity. To gain more insight about the antibacterial efficiency of swertiamarin against typhoid causing S. typhi, a comparative molecular docking of S. typhi OmpF (3NSG) was performed with swertiamarin and other typhoid drugs available in the market which exposed better activity strength of swertiamarin compared with that of the other drugs. Further, molecular dynamics of S. typhi OmpF-swertiamarin shows good flexibility and stability at 100 ns. The outcome of this work will definitely provide an idea of using very low dose of swertiamarin as a potent and promising drug against typhoid fever.Communicated by Ramaswamy H. Sarma.

Cardioprotective Role of Swertiamarin, a Plant Glycoside Against Experimentally Induced Myocardial Infarction via Antioxidant and Anti-inflammatory Functions.

The study examined the protective effects of swertiamarin on rats with experimentally induced myocardial infarction. Three to six week-old male albino Wistar rats were used in this study and experimental myocardial infarction (MI) was induced using isoproterenol. Our results showed that swertiamarin restored the alteration in heart weight, body weight, and heart weight/tibia length ratio of MI-induced rats to basal levels significantly (p < 0.05). Swertiamarin significantly (p < 0.05) restored the levels of cardiac pathophysiological marker creatine kinase (CKMB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine transaminase (ALT), and cardiac troponin I (cTn-1) to near normalcy in MI-induced rats. Levels of oxidative stress markers malondialdehyde (MDA), protein carbonyls (PC), and levels of Vitamin C and Vitamin E were significantly (p < 0.05) reverted to near basal levels in MI-induced rats by swertiamarin. Levels of the antioxidant glutathione (GSH) and antioxidant enzymes which include superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-s-transferase (GST), glutathione reductase (GR), and plasma total antioxidant capacity (TAC) were (p < 0.05) brought to near normalcy in MI-induced rats by swertiamarin. Levels of sodium (Na), potassium (k), and calcium (Ca) ATPases were significantly (p < 0.05) restored to near normalcy in MI-induced rats by swertiamarin. Status of pro-inflammatory cytokines including tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and histological aberrations were also significantly (p < 0.05) restored to near normalcy in MI-induced rats by swertiamarin. Together, our results concluded that swertiamarin exerts significant cardioprotective functions in experimental MI in rats.

Swertiamarin attenuates paraquat-induced pulmonary epithelial-like cell apoptosis via NOX4-mediated regulation of redox and mitochondrial function

Abstract The aim of the present study was to investigate the effect of swertiamarin (STM) in attenuating paraquat (PQ)-induced human lung alveolar epithelial-like cell (A549) apoptosis and the underlying mechanisms. A549 cells were pretreated with different concentrations of STM for 2 hr and then cultured with or without PQ (700 µM) for 24 hr. Cell survival was determined using the CCK8 assay. Morphological changes, MDA content, inflammatory factors, fibrogenesis parameters, apoptosis rates, redox status and mitochondrial membrane potential (MMP) were evaluated. The expression of several genes involved in the modulation of redox status was measured by Western blotting. Cell viability and MMP were decreased, but the apoptosis rate and DCFH oxidation were elevated by PQ exposure. STM pretreatment notably increased cell viability and MMP and reduced the apoptosis rate and DCFH oxidation. Furthermore, TLR4- NOX4 signaling was significantly inhibited by STM. The downregulation of NOX4 by siRNA exerted the same protective effects as STM. This study provides the first evidence that STM attenuates PQ-induced pulmonary epithelial-like cell apoptosis via NOX4-mediated regulation of redox and mitochondrial function

Swertiamarin ameliorates diet-induced obesity by promoting adipose tissue browning and oxidative metabolism in preexisting obese mice.

Obesity is a risk factor for many metabolic diseases. Efficient therapeutic strategies are urgently needed. Swertiamarin (STM) prevents obesity and the associated insulin resistance and inflammation. However, the therapeutic effects of STM on preexisting obesity remain unclear. Therefore, in this study we aim to investigate the effects of STM on energy expenditure and fat browning in mice with preexisting obesity. C57BL/6J mice are fed with a high-fat diet (HFD) for 8 weeks to induce obesity and then gavaged (or not) with STM for 10 weeks. The whole-body energy metabolism of mice is examined by indirect calorimetry. The results show that after 10 weeks of treatment, STM markedly prevents HFD-induced weight gain, chronic inflammation, insulin resistance, and hepatic steatosis. STM promotes oxygen consumption and energy expenditure. The level of uncoupling protein 1 is enhanced in the brown and white adipose tissues of STM-treated mice. STM increases the phosphorylation of AMP-activated protein kinase and the expressions of genes involved in fat oxidation, reducing fat deposition in skeletal muscles. Meanwhile, STM does not affect the intestinal microbiotic composition. Overall, STM supplementation may serve as a potential therapy for obesity.

Effect of novel therapeutic medicine swertiamarin from Enicostema axillare in zebrafish infected with Salmonella typhi.

Herbal treatments have been practiced by humans over centuries and therefore possess time-proven safety. However, it is crucial to evaluate the toxic effects of herbal medicine to confirm their safety, particularly when developing therapeutic drugs. Use of laboratory animals such as mice, rat, and rabbits was considered as gold standard in herbal toxicity assessments. However, in the last few decades, the ethical consideration of using higher vertebrates for toxicity testing has become more controversial. As a possible alternative model involving lower vertebrates such as zebra fish were introduced. Hence in the present study, swertiamain compound isolated from E. axillare was assessed for it antimicrobial activity in zebra fish larvae againt S. typhi. The cumulative mortality rate and bacterial localization in zebra fish larvae were studied. Biochemical markers assays were performed to find the preventive role of the compound during the typhoid infection. The results showed that zebra fish can be successfully used as a model to study typhoid infection and the anti-bacterial compound swertiamarin used in this study clears the bacterial load and pathogenic symptoms to a great extent.

Swertiamarin-mediated immune modulation/adaptation confers protection against Plasmodium berghei.

Aims: Development of resistance by the malaria parasite, a systemic inflammatory and infectious pathogen, has raised the need for novel efficacious antimalarials. Plant-derived natural compounds are known to modulate the immune response and eradicate the infectious pathogens. Therefore we carried out experiments with swertiamarin to dissect its anti-inflammatory and immunomodulatory potential. Materials & methods: We carried out studies in Swiss albino mice that received infectious challenge with Plasmodium berghei and swertiamarin treatment in a prophylactic manner. Results & conclusion: Oral administration of swertiamarin prior to infectious challenge with P. berghei in experimental mice showed delayed parasite development as compared with untreated control. IFN-γ and IL-10 appeared to be adapted/modulated by regular swertiamarin treatment. Further, withdrawal of swertiamarin pressure did not affect parasite replication. However, the short half-life of swertiamarin limited its long-lasting therapeutic effect, requiring higher and frequent dosing schedules.

Swertiamarin, an active iridoid glycoside from Swertia pseudochinensis H. Hara, protects against alpha-naphthylisothiocyanate-induced cholestasis by activating the farnesoid X receptor and bile acid excretion pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Swertiamarin (SW), which belongs to iridoid glycosides, is one of the main components of Swertia plants in Gentianaceae family, including Swertia pseudochinensis H. Hara and Swertia mileensis T. N. Ho et W. L. Shi. There are mainly used in traditional Chinese medicine for the treatment of hepatic and biliary disease such as jaundice. AIM OF THIS STUDY: This experiment aimed to explore the protective mechanism of SW on cholestasis induced by alpha-naphthylisothiocyanate in rats. MATERIALS AND METHODS: Healthy rats were randomly divided into the control, model (ANIT, 50 mg/kg), ursodeoxycholic acid (UDCA, 80 mg/kg), and low-dose (SW, 80 mg/kg), medium-dose (SW, 100 mg/kg), and high-dose (SW, 150 mg/kg) groups. The hepatic protective effect of SW was preliminarily evaluated by measurement of serum biochemical indicators and liver morphological evaluation. Moreover, metabolomics and proteomics analysis were used to explore the protective mechanism of SW on cholestasis. The expression of related proteins was determined by Western blot and polymerase chain reaction, and the important proteins were verified by cell experiments in vitro. RESULTS: SW (100 mg/kg) can reduce the serum levels of the model group. The hepatocyte of the medium-dose treatment group was arranged neatly without evident inflammation. SW can partially reverse the changes in cholestasis metabolites, such as taurocholic acid, SM (d18:1/16:0), all-trans-retinoic acid and other products of rats. The main metabolic pathways affected were primary bile acid synthesis, glycerophospholipid metabolism, sphingolipid metabolism and retinol metabolism. SW medium-dose treatment group showed effective reversal of 25 related proteins and it can remarkably reduce the contents of NTCP and CYP27A1 in rat liver and increase the protein expressions of CYP7A1, CYP8B1, bile salt export pump, multidrug resistance-associated protein and FXR. CONCLUSIONS: SW can alleviate ANIT-induced cholestasis, which by activating the farnesoid X receptor and bile acid excretion pathway.

Mechanism Assay of Honeysuckle for Heat-Clearing Based on Metabolites and Metabolomics.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as cyclooxygenase (Cox)-1/2 inhibitor, have emerged as potent antipyretics and analgesics. However, few herbs with Cox-1/2 inhibitory activity are commonly used for heat-clearing in China. Although these are known to have antipyretic activity, there is a lack of molecular data supporting their activity. Using the traditional Chinese medicine herb honeysuckle (Hon) as an example, we explored key antipyretic active compounds and their mechanisms of action by assessing their metabolites and metabolomics. Mitogen-activated protein kinase (MAPK) 3 and protein kinase B (AKT) 1 were suggested as key targets regulated primarily by chlorogenic acid (CA) and swertiamarin (SWE). CA and SWE synergistically inhibited the production of interleukin (IL)-1 and IL-6, alleviated generation of prostaglandin E2, and played an antipyretic role equivalent to honeysuckle extract at the same dose contents within 3 h. Collectively, these findings indicated that lipopolysaccharide-induced fever can be countered by CA with SWE synergistically, allowing the substitution of a crude extract of complex composition with active compounds. Our findings demonstrated that, unlike the traditional NSAIDs, the Hon extract showed a remote and indirect mechanism for alleviating fever that depended on the phosphatidylinositol-3-kinase-AKT and MAPK pathways by regulating the principal mediator of inflammation.

Proteomic Analysis of Swertiamarin-treated BV-2 Cells and Possible Implications in Neuroinflammation.

The purpose of this study was to explore the neuroprotective role of swertiamarin on neuro-inflammation, and analyzed its potential mechanism by proteomics. We used LPS to induce a inflammatory model on BV-2 cells, then 10, 25, 50 µg/mL swertiamarin was used to treat the LPS pretreated BV-2 cells. We used ELISA to detect the effect of swertiamarin on the expression of inflammation related indicators such as IL-1ß, il-6, IL-18 and TNF-α. The proteomics based on TMT-LC-MS/MS analysis was performed to explore the anti-inflammatory effects of swertiamarin by bioinformatics analysis. We found swertiamain was able to inhibit pro-inflammatory cytokines secretion in a does dependent manner, including IL-1ß, IL-6, IL-18 and TNF-α. These results were further verified by western blot. The proteomics analysis results suggested that the potential bioprocessings which regulated by swertiamarin mainly involved in cellular response to carbon monoxide, strand displacement, palmitoleoyltransferase activity, D2 dopamine receptor binding, RNA polymerase II transcription cofactor activity. The present study may provide a promising approach to treat and prevent neuro-inflammation diseases. It is preliminarily indicated that swertiamarin will play an important role in clinical anti-neuroinflammation process in the future.

Synthesis, molecular docking and ADMET prediction of novel swertiamarin analogues for the restoration of type-2 diabetes: an enzyme inhibition assay.

Swertiamarin is a lead, biologically active compound obtained from Enicostemma littorale Blume and known to be identified for the anti-diabetic activity. Present work comprises the synthesis and structural optimization of seven novel swertiamarin analogues and those were not being reported elsewhere till date. Swertiamarin was isolated, followed by modifications that have been accomplished amidst fluorinating, acetylating and oxidizing agents and also performed chromatographic purity and characterization of analogues. Furthermore, the swertiamarin analogues were screened for dipeptidyl peptidase IV (DPP-IV) enzyme inhibition with in silico studies. Besides, the pharmacokinetics and toxicity of analogues were predicted using ADMET software. In a nutshell, the compounds such as SNIPERSV-4 and SNIPERSV-7 have to pose good initial activity (∼48%) in comparison to standard DPP-IV inhibitor (Sitagliptin). The identified analogues were active against DPP-IV enzyme in preliminary screenings, and these findings would be beneficial for the new age researchers also for the therapy of diabetes.

Investigation of phytoconstituents of Enicostemma littorale as potential glucokinase activators through molecular docking for the treatment of type 2 diabetes mellitus.

Glucokinase (GK) is an enzyme involved in synthesising glucose into glucose-6 phosphate and serves a crucial function in glucose sensing. Therefore, agents that induce GK activation could be used to treat T2DM. The present work has been carried out to investigate the GK activation potential of phytoconstituents of Enicostemma littorale through molecular docking. All the phytoconstituents have been screened through the Lipinski rule of 5, Veber's rule, and ADMET properties. From these initial screening, only Apigenin, Ferulic acid, Genkwanin, p-coumaric acid, Protocatechuic acid, Syringic acid, and Vanillic acid have been selected to perform molecular docking studies. The binding free energy and binding mode of the native ligand in the allosteric site of the enzyme have been considered the reference for the other molecules' validation. The native ligand has exhibited - 7.2 kcal/mol binding free energy, whereas; it has formed four hydrogen bonds with THR-228, LYS-169, ASP-78, and GLY-81. Based on these findings, the interactions of phytoconstituents have been justified. Apigenin, genkwanin, and swertiamarin exhibited - 8.7, - 7.5, and - 8.3 kcal/mol binding free energy, respectively, which indicates better enzyme activation than the native ligand. Swertiamarin has formed 08 hydrogen bonds with allosteric amino acid residues, which confirms the excellent enzyme activation by these phytoconstituents. We concluded that if we can isolate and consume the exact active phytoconstituents (GK activators) from this plant, we can use them effectively to treat T2DM. More GK activators can be developed by considering them as a natural lead moiety.

Swertiamarin mitigates nephropathy in high-fat diet/streptozotocin-induced diabetic rats by inhibiting the formation of advanced glycation end products.

CONTEXT: The molecular mechanism by which Swertiamarin (SM) prevents advanced glycation end products (AGEs) induced diabetic nephropathy (DN) has never been explored. OBJECTIVE: To evaluate the effect of SM in preventing the progression of DN in high fat diet-streptozotocin-induced diabetic rats. MATERIALS AND METHODS: After 1 week of acclimatisation, the rats were divided randomly into five groups as follows: (1) Control group, which received normal chow diet; (2) High-fat diet (HFD) group which was fed diet comprising of 58.7% fat, 27.5% carbohydrate and 14.4% protein); (3) Aminoguanidine (AG) group which received HFD + 100 mg/k.b.w.AG (intraperitoneal); (4) Metformin (Met) group which received HFD + 70 mg/k.b.w. the oral dose of Met and (5) SM group which was supplemented orally with 50 mg/k.b.w.SM along with HFD. After 12 weeks all HFD fed animals were given a single 35 mg/k.b.w. dose of streptozotocin with continuous HFD feeding for additional 18 weeks. Later, various biochemical assays, urine analyses, histopathological analysis of kidneys, levels of AGEs, expression of various makers, and in-silico analysis were performed. RESULTS: The diabetic group demonstrated oxidative stress, increased levels of AGEs, decreased renal function, fibrosis in the renal tissue, higher expression of the receptor for advanced glycation end products (RAGE), which were ameliorated in the SM treated group. In-silico analysis suggests that SM can prevent the binding of AGEs with RAGE. CONCLUSIONS: SM ameliorated DN by inhibiting the oxidative stress induced by AGEs.HighlightsSM reduces the levels of hyperglycaemia-induced advanced glycation end products in serum and renal tissue.SM prevents renal fibrosis by inhibiting the EMT in the kidney tissue.The in-silico analysis proves that SM can inhibit the binding of various AGEs with RAGE, thereby inhibiting the AGE-RAGE axis.