Phytochemical profiling, antioxidant, cytotoxic, and anti-inflammatory activities of Plectranthus rugosus extract and fractions: in vitro, in vivo, and in silico approaches.

BACKGROUND: Inflammation is a key biological reaction that comprises a complex network of signals that both initiate and stop the inflammation process. PURPOSE: This study targets to evaluate the anti-inflammatory potential of the leaves of the Plectranthus rugosus (P. rugosus) plant involving both in vitro and in vivo measures. The current available drugs exhibit serious side effects. Traditional medicines impart an essential role in drug development. P. rugosus is a plant used in traditional medicine of Tropical Africa, China, and Australia to treat various diseases. METHODS: Lipopolysaccharide (LPS), an endotoxin, kindles macrophages to discharge huge quantities of pro-inflammatory cytokines like TNF-α and IL-6. So, clampdown of macrophage stimulation may have a beneficial potential to treat various inflammatory disorders. The leaves of the P. rugosus are used for swelling purpose by local population; however, its use as an anti-inflammatory agent and associated disorders has no scientific evidence. RESULTS: The extracts of the plant Plectranthus rugosus ethanolic extract (PREE), Plectranthus rugosus ethyl acetate extract (PREAF), and the compound isolated (oleanolic acid) suppress the pro-inflammatory cytokines (IL-6 and TNF-α) and nitric oxide (NO), confirming its importance in traditional medicine. CONCLUSION: The pro-inflammatory cytokines are inhibited by P. rugosus extracts, as well as an isolated compound oleanolic acid without compromising cell viability.

Integrative transcriptome and single-cell sequencing technology analysis of the potential therapeutic benefits of oleanolic acid in liver injury and liver cancer.

BACKGROUND: Oleanolic acid has important hepatoprotective effects and inhibits liver tissue carcinogenesis. The aim of this study was to investigate the mechanism of action of oleanolic acid in inhibiting liver injury and liver cancer. METHOD: In this study, we applied differential gene analysis and gene enrichment analysis to identify the targets of oleanolic acid for the treatment of liver injury. And this study also applied Cibersort and GSVA methods to investigate the targets of oleanolic acid in liver injury. Based on oleanolic acid targets, we explored the major targets and further explored the role of the major targets in liver cancer. This study used the oncoPredict and the TIDE algorithm to predict the effect of oleanolic acid on drug resistance. Finally, the binding effect of oleanolic acid to relevant targets was explored using molecular docking techniques. RESULT: In this study, oleanolic acid was found to inhibit liver injury and promote liver regeneration mainly by promoting elevated expression of HMOX1. Oleanolic acid can inhibit oxidative stress and promotes Ferroptosis in liver injury. In liver cancer, we identified that the main target of oleanolic acid is HMOX1 and HDAC1. And we determined that HMOX1 promotes Ferroptosis in liver cancer. This reduced the sensitivity of liver cancer to targeted therapies and immunotherapy. Molecular docking showed high binding of oleanolic acid to HDAC1 and HMOX1. CONCLUSIONS: Oleanolic acid is an antioxidant by promoting high expression of HMOX1 and promotes the development of Ferroptosis in liver cancer and liver injury.

Advances in the anti-tumor potential of hederagenin and its analogs.

Hederagenin is a pentacyclic triterpenoid that is widely distributed as the main pharmaceutical ingredient in various medicinal plants. Similarly as other pentacyclic triterpenoids, hederagenin has various pharmacological effects such as anti-tumor, anti-inflammatory, anti-depressant, and anti-viral activities. In particular, the anti-tumor activity of hederagenin indicates its potential for development into highly effective chemotherapeutic agents. Studies revealed that hederagenin effectively suppresses the growth of various tumor cell lines in vitro and interacts with several molecular targets that play essential roles in various cellular signaling pathways. The compound suppresses transformation, inhibits proliferation, and induces apoptosis in tumor cells. In this review, we highlight research progress on the source, pharmacokinetics, pharmacological activity, and mechanism of action of hederagenin and the anti-tumor activity of its analogs by integrating and analyzing relevant domestic and international studies and providing a basis for their further development and application.

Potentials of Terpenoids as Inhibitors of Multiple Plasmodium falciparum Protein Drug Targets.

PURPOSE: The resistance of parasite to readily affordable antimalarial drugs, the high cost of currently potent drugs, and the resistance of vector mosquitoes to insecticides threaten the possibility of malaria eradication in malaria endemic areas. Due to the fact that quinine and artemisinin were isolated from plants sources, researchers have been encouraged to search for new antimalarials from medicinal plants. This is especially the case in Africa where a large percentage of the population depends on medicinal plant to treat malaria and other ailments. METHOD: In this study, we evaluated previously characterized Plasmodium-cidal compounds obtained from the African flora to identify their likely biochemical targets, for an insight into their possible antimalarial chemotherapy. Molecular docking study was first conducted, after which remarkable compounds were submitted for molecular dynamic (MD) simulations studies. RESULTS: From a total of 38 Plasmodium-cidal compounds docked with confirmed Plasmodium falciparum protein drug targets [plasmepsin II (PMII), histo-aspartic protein (HAP) and falcipain-2 (FP)], two pentacyclic triterpene, cucurbitacin B and 3 beta-O-acetyl oleanolic acid showed high binding affinity relative to artesunate. This implies their capacity to inhibit the three selected P. falciparum target proteins, and consequently, antimalarial potential. From the MD simulations studies and binding free energy outcomes, results confirmed that the two compounds are stable in complex with the selected antimalarial targets; they also showed excellent binding affinities during the 100 ns simulation. CONCLUSION: These results showed that cucurbitacin B and 3 beta-O-acetyl oleanolic acid are potent antimalarials and should be considered for further studies.

Network pharmacology study of the mechanism underlying the therapeutic effect of Zhujing pill and its main component oleanolic acid against diabetic retinopathy.

Diabetic retinopathy (DR) is the leading cause of blindness in the working population worldwide, with few effective drugs available for its treatment in the early stages. The Zhujing pill (ZJP) is well-established to enhance the early symptoms of DR, but the mechanism underlying its therapeutic effect remains unclear. In the present study, we used systems biology and multidirectional pharmacology to screen the main active ingredients of ZJP and retrieved DrugBank and Genecards databases to obtain 'drug-disease' common targets. Using bioinformatics analysis, we obtained the core targets, and potential mechanisms of action of ZJP and its main components for the treatment of DR. Molecular docking was used to predict the binding sites and the binding affinity of the main active ingredients to the core targets. The predicted mechanism was verified in animal experiments. We found that the main active ingredient of ZJP was oleanolic acid, and 63 common 'drug-disease' targets were identified. Topological analysis and cluster analysis based on the protein-protein interaction network of the Metascape database screened the core targets as PRKCA, etc. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that these core targets were significantly enriched in the pro-angiogenic pathway of the VEGF signaling pathway. Molecular docking and surface plasmon resonance revealed that ZJP and its main active component, oleanolic acid had the highest binding affinity with PKC-α, the core target of the VEGF signaling pathway. Animal experiments validated that ZJP and oleanolic acid could improve DR.

Oleanolic acid and ursolic acid: therapeutic potential in neurodegenerative diseases, neuropsychiatric diseases and other brain disorders.

Brain disorders such as neurodegenerative diseases and neuropsychiatric diseases have become serious threatens to human health and quality of life. Oleanolic acid (OA) and ursolic acid (UA) are pentacyclic triterpenoid isomers widely distributed in various plant foods and Chinese herbal medicines. Accumulating evidence indicates that OA and UA exhibit neuroprotective effects on multiple brain disorders. Therefore, this paper reviews researches of OA and UA on neurodegenerative diseases, neuropsychiatric diseases and other brain disorders including ischemic stroke, epilepsy, etc, as well as the potential underlying molecular mechanisms.

Present and Future Prospects of the Anti-cancer Activities of Saikosaponins.

Since their discovery, saikosaponins (SSs) have been found to play an important role in treating a variety of cancers via diverse mechanisms of action. This review summarizes the current research status and prospects of the anti-cancer activities of SSs, providing novel insights into the limitations of current studies. In addition, it discusses whether SSs can be applied in immunotherapy and the possible mechanisms by which SSs may facilitate immunotherapy. The research is significant to understanding the anti-cancer potents of SSs in the development of SSs-based therapeutic strategies and clinical practice.

Ursolic acid and its isomer oleanolic acid are responsible for the anti-dementia effects of Ocimum sanctum in olfactory bulbectomized mice.

This study aims to clarify the bioactive constituents responsible for the anti-dementia effects of Ocimum sanctum Linn. ethanolic extract (OS) using olfactory bulbectomized (OBX) mice, an animal model of dementia. The effects of OS or its extract further fractionated with n-hexane (OS-H), ethyl acetate (OS-E), and n-butanol (OS-B) on the spatial cognitive deficits of OBX mice were elucidated by the modified Y-maze tests. The effects of the major constituents of the most active OS fraction were also elucidated using the reference drug donepezil. The administration of OS and OS-E ameliorated the spatial cognitive deficits caused by OBX, whereas OS-H or OS-B had no effect. Two major constituents, ursolic acid (URO) and oleanolic acid (OLE), and three minor constituents were isolated from OS-E. URO (6 and 12 mg/kg) and OLE (24 mg/kg) attenuated the OBX-induced cognitive deficits. URO (6 mg/kg) and donepezil reversed the OBX-induced down-regulation of vascular endothelial growth factor (VEGF) and choline acetyltransferase expression levels in the hippocampus. URO inhibited the ex vivo activity of acetylcholinesterase with similar efficacy to donepezil. URO inhibited the in vitro activity of acetylcholinesterase (IC50 = 106.5 µM), while the effects of OS, OS-E, and other isolated compounds were negligible. These findings suggest that URO and OLE are responsible for the anti-dementia action of OS extract, whereas URO possesses a more potent anti-dementia effect than its isomer OLE. The effects of URO are, at least in part, mediated by normalizing the function of central cholinergic systems and VEGF protein expression.

Wilforlide A ameliorates the progression of rheumatoid arthritis by inhibiting M1 macrophage polarization.

Rheumatoid arthritis (RA) is an autoimmune disease with increased M1 macrophages. The classical activated M1 macrophages produce various cytokines to control inflammation. Wilforlide A is a natural product that displays anti-inflammatory activities. However, the effect of Wilforlide A on RA progression and the potential mechanisms are unclear. Herein, the collagen-induced arthritis (CIA) mouse was used as an experimental model of RA. The administration of Wilforlide A reduced clinical scores, joint swelling and histological damage in ankle joints of RA mice. The secreted pro-inflammatory factors (MCP1, GM-CSF and M-CSF) and M1 biomarker iNOS in synovium were inhibited by Wilforlide A. In vitro, macrophages deriving from THP-1 cells were stimulated with LPS/IFN-γ to mimic M1 polarization. Similarly, Wilforlide A blocked macrophages polarizing towards M1 subsets. The in vitro results demonstrated that Wilforlide A suppressed LPS/IFN-γ-induced TLR4 upregulation, IκBα degradation and NF-κB p65 activation. In addition, TAK242 (a TLR4 inhibitor) treatment caused a similar inhibitory effect on M1 polarization with Wilforlide A, whereas it was less than the combination of TAK242 and Wilforlide A. Therefore, this work supports that Wilforlide A ameliorates M1 macrophage polarization in RA, which is partially mediated by TLR4/NF-κB signaling pathway inactivation.

Using network pharmacology and molecular docking verification to explore the mechanism of ursolic acid in the treatment of osteoporosis.

Whether ursolic acid is an effective drug in treatment of osteoporosis (OP) and how it exhibit activity effect on OP is unclear. To investigated the potential molecular mechanism of ursolic acid in the treatment of OP and figured out its possible mechanism is necessary. The target genes of ursolic acid were screened by using the database of traditional chinese medicine systems pharmacology, PubMed database and UniProt database. OP-related target genes were searched by GeneCards database, and utilized online mapping tool to obtain common target genes of component-disease. String database was used to construct a protein-protein interaction (PPI) network of component-disease common target genes and perform topological analysis to screen core target genes. DAVID database was performed gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for component-disease shared target genes. Using the core target protein as the receptor and ursolic acid as the ligand, the molecular docking was performed using AutoDockVina 1.1.2 software. A total of 52 ursolic acid-related target genes and 4657 OP-related target genes were excavated, with a total of collective 43 target genes. The above-mentioned PPI network with shared target genes contains 43 nodes and 510 edges, with an average node degree value of 23.32. A total of 24 core target genes were obtained, mainly including tumor protein p53 (TP53), vascular endothelial growth factor A (VEGFA), interleukin-6 (IL6), tumor necrosis factor (TNF), caspase3 (CASP3), matrix metallo protein (MMP9), transcription factor AP-1 (JUN), activator of transcription 3 (STAT3), mitogen-activated protein kinase 8 (MAPK8), and prostaglandin endoperoxidase 2 (PTGS2), respectively. According to KEGG enrichment analysis, there are 126 treatment of OP signaling pathway were enriched. GO enrichment analysis revealed that 313 biological processes were identified. The molecular docking result showed that the binding energies were all lower than -5 kcal/mol, indicating strong binding activity to the protein by the 6 core target gene. The therapeutic effect of ursolic acid on OP may be achieved by regulating TP53, JUN, IL6, VEGFA, CASP3, and MAPK8 genes, respectively. It exhibits possible biological function in the treatment of OP mainly involve positive regulation of apoptotic process, response to drug, incytoplasm, cytosol, protein binding, identical protein binding. Its mechanism may related to multiple therapeutic targets and signaling pathways such as cancer pathway, hepatitis B, and TNF signaling pathway.

The Ameliorative Effects of Saikosaponin in Thioacetamide-Induced Liver Injury and Non-Alcoholic Fatty Liver Disease in Mice.

Liver disorders are a major health concern. Saikosaponin-d (SSd) is an effective active ingredient extracted from Bupleurum falcatum, a traditional Chinese medicinal plant, with anti-inflammatory and antioxidant properties. However, its hepatoprotective properties and underlying mechanisms are unknown. We investigated the effects and underlying mechanisms of SSd treatment for thioacetamide (TAA)-induced liver injury and high-fat-diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in male C57BL/6 mice. The SSd group showed significantly higher food intake, body weight, and hepatic antioxidative enzymes (catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD)) and lower hepatic cyclooxygenase-2 (COX-2), serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and fibroblast growth factor-21 (FGF21) compared with controls, as well as reduced expression of inflammation-related genes (nuclear factor kappa B (NF-κB) and inducible nitric oxide synthase (iNOS)) messenger RNA (mRNA). In NAFLD mice, SSd reduced serum ALT, AST, triglycerides, fatty acid-binding protein 4 (FABP4) and sterol regulatory element-binding protein 1 (SREBP1) mRNA, and endoplasmic reticulum (ER)-stress-related proteins (phosphorylated eukaryotic initiation factor 2α subunit (p-eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP). SSd has a hepatoprotective effect in liver injury by suppressing inflammatory responses and acting as an antioxidant.

Anti-dengue activity of super critical extract and isolated oleanolic acid of Leucas cephalotes using in vitro and in silico approach.

BACKGROUNDS: Leucas cephalotes is a common ethnomedicinal plant widely used by traditional healers for the treatment of Malaria and other types of fever. Oleanolic acid and its derivatives have been reported for various types of pharmacological activities, such as anti-inflammatory, antioxidant, anticancer, hepatoprotective, anti-HIV and anti-HCV activity. METHODS: L.cephalotes plant extracts were prepared by supercritical fluid extraction (SFE) method and oleanolic acid was isolated by preparatory thin-layer chromatography. The compound was identified and characterize by using ultraviolet-visible spectroscopy (UV-VIS), Fourier transform infra-Red spectroscopy (FT-IR) and high-performance thin-layer chromatography (HPTLC). The structure of the compound was elucidated by proton nuclear magnetic resonance (1HNMR) and carbon nuclear magnetic resonance (1CNMR) and the purity checked by differential scanning calorimetry (DSC). The MTT assay was used to determine the toxicity of plant extract and oleanolic acid using a microplate reader at 595 nm. The anti-dengue activity of plant extract and oleanolic acid was tested in vitro and in silico using real-time RT-PCR. RESULTS: The optimum yield of the extract was obtained at 40 °C temperature and 15Mpa pressure. The maximum non-toxic dose (MNTD) of plant extract and oleanolic acid were found as 46.87 µg/ml and 93.75 µg/ml, respectively in C6/36 cell lines. UV spectrophotometer curve of the isolated compound was overlapped with standard oleanolic acid at 232 nm. Superimposed FT-IR structure of the isolated compound was indicated the same spectra at 3433, 2939, 2871, 1690, 1500,1463, 1387, 1250, 1209, 1137 and 656 position as per marker compound. HPTLC analysis showed the retention factor of L. cephalotes extract was 0.19 + 0.06 as similar to the standard oleanolic acid chromatogram. The NMR structure of the isolated compound was identified as similar to the marker oleanolic acid structure. DSC analysis revealed the purity of isolated oleanolic acid was 98.27% with a melting point of 311.16 °C. Real-time RT PCR results revealed that L. cephalotes supercritical extract and isolated oleanolic acid showed 100 and 99.17% inhibition against the dengue - 2 virus when treated with MNTD value of plant extract (46.87 µg/ml) and the test compound (93.75 µg/ml), respectively. The molecular study demonstrated the binding energy of oleanolic acid with NS1and NS5 (non-structural protein) were - 9.42 & -8.32Kcal/mol, respectively. CONCLUSIONS: The SFE extract L. cephalotes and its active compound, oleanolic acid inhibiting the activity of dengue-2 serotype in the in vitro and in silico assays. Thus, the L.cephalotes plant could be an excellent source for drug design for the treatment of dengue infection.

Anticancer effects of oleanolic acid on human melanoma cells.

Owing to the ineffectiveness of the currently used therapies against melanoma, there has been a shift in focus toward alternative therapies involving the use of natural compounds. This study assessed the anticancer effects of oleanolic acid (OA) and its ability to induce apoptosis in A375SM and A375P melanoma cells in vivo. Compared to the control group, viability of A375P and A375SM cells decreased following OA treatment. In OA-treated A375SM and A375P cells, 4',6-diamidino-2-phenylindole staining showed an increase in the apoptotic body, and flow cytometry revealed increased number of apoptotic cells compared to that in the control group. OA-treated A375SM cells exhibited an increased expression of the apoptotic proteins, cleaved poly (ADP-ribose) polymerase (PARP) and B-cell lymphoma (Bcl)-2-associated X protein (Bax) as well as decreased expression of the antiapoptotic protein Bcl-2 compared to that in the control group. In OA-treated A375P cells, expression patterns of cleaved PARP and Bcl-2 were similar to those in OA-treated A375SM cells; however, no difference was reported in the expression of Bax compared to that in the control group. Additionally, OA-treated melanoma cells showed decreased expression of phospho-nuclear factor-κB (p-NF-κB), phospho-inhibitor of nuclear factor-κBα (p-IκBα), and phospho-IκB kinase αß than that in the control group. Moreover, immunohistochemistry showed a comparatively decreased level of p-NF-κB in the OA-treated group than that in the control group. Xenograft analysis confirmed the in vivo anticancer effects of OA against A375SM cells. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay revealed an increased number of TUNEL-positive cells in the OA-treated group compared to that in the control group. In conclusion, the study results suggest that OA induces apoptosis of A375SM and A375P cells in vitro and apoptosis of A375SM cells in vivo. Furthermore, the in vitro and in vivo anticancer effects were mediated by the NF-κB pathway.

Synergistic Antioxidant Effects of Araloside A and L-Ascorbic Acid on H2O2-Induced HEK293 Cells: Regulation of Cellular Antioxidant Status.

Araloside A is a pentacyclic triterpenoid saponin, and L-ascorbic acid is a globally recognized antioxidant. In this study, coadministered araloside A and L-ascorbic acid were found to have a strong synergistic antioxidant effect, and correlations between cellular antioxidant indexes and free radical scavenging ability were found. Individual and combined pretreatment with araloside A and L-ascorbic acid increased both cell viability and antioxidant enzyme activity and inhibited the release of lactate dehydrogenase (LDH); the accumulation of malondialdehyde (MDA), lipid peroxidation (LPO) products, and H2O2; and the production of intracellular reactive oxygen species (ROS), protein carbonyls, and 8-hydroxy-2-deoxy guanosine (8-OHdG). Free radical scavenging ability was positively correlated with superoxide dismutase (SOD) and catalase (CAT) activity, the glutathione (GSH)/oxidized glutathione (GSSG) ratio, and total antioxidant capacity (T-AOC). Our study is the first investigation of araloside A and L-ascorbic acid coadministration for the treatment of diseases caused by oxidative stress. The synergistic antioxidant effects of araloside A and L-ascorbic acid support their potential as functional food ingredients for the elimination of oxidative stress-induced adverse reactions.

Olive leaf extract prevents obesity, cognitive decline, and depression and improves exercise capacity in mice.

Obesity is a risk factor for development of metabolic diseases and cognitive decline; therefore, obesity prevention is of paramount importance. Neuronal mitochondrial dysfunction induced by oxidative stress is an important mechanism underlying cognitive decline. Olive leaf extract contains large amounts of oleanolic acid, a transmembrane G protein-coupled receptor 5 (TGR5) agonist, and oleuropein, an antioxidant. Activation of TGR5 results in enhanced mitochondrial biogenesis, which suggests that olive leaf extract may help prevent cognitive decline through its mitochondrial and antioxidant effects. Therefore, we investigated olive leaf extract's effects on obesity, cognitive decline, depression, and endurance exercise capacity in a mouse model. In physically inactive mice fed a high-fat diet, olive leaf extract administration suppressed increases in fat mass and body weight and prevented cognitive declines, specifically decreased working memory and depressive behaviors. Additionally, olive leaf extract increased endurance exercise capacity under atmospheric and hypoxic conditions. Our study suggests that these promising effects may be related to oleanolic acid's improvement of mitochondrial function and oleuropein's increase of antioxidant capacity.

Preventing the onset of diabetes-induced chronic kidney disease during prediabetes: The effects of oleanolic acid on selected markers of chronic kidney disease in a diet-induced prediabetic rat model.

BACKGROUND: The prevalence of prediabetes correlates with increased incidence of chronic kidney disease (CKD). This study was aimed at investigating the effects of oleanolic acid (OA) on markers associated with CKD in the prediabetic rat model. METHODS: Prediabetes was induced by exposing male Sprague Dawley rats (150-180 g) to high-fat high- carbohydrate (HFHC) diet for 20 weeks. The prediabetic animals were further subdivided according to their treatment and treated for 12 weeks with either OA (80 mg/kg p.o) or metformin (500 mg/kg p.o) both with and without dietary intervention. 24 h fluid intake and urine output were measured every fourth week of the treatment period while the urine samples were also used for podocin quantification through PCR. The animals were then sacrificed with urine, plasma and kidneys being harvested for biochemical analysis including the measurement of aldosterone, kidney-injury-molecule-1(KIM-1), blood and urine electrolytes, estimated glomerular filtration rate (eGFR), and albumin/creatinine (Alb/Cr) ratio. RESULTS: This study observed that OA could reduce oxidative stress in the kidney while restoring plasma aldosterone and KIM-1 as well as urine electrolytes which were found to be augmented in prediabetic animals. This also correlated with normalization of GFR and Alb/Cr ratio in the OA-treated groups in both the absence and presence of dietary intervention. CONCLUSIONS: These findings suggest that OA can ameliorate renal complications in a prediabetic rat model. However, more research is needed for the elucidation of molecular mechanisms behind these effects.

Momordin Ic induces G0/1 phase arrest and apoptosis in colon cancer cells by suppressing SENP1/c-MYC signaling pathway.

Momordin Ic (MI) is a natural pentacyclic triterpenoid enriched in various Chinese natural medicines such as the fruit of Kochia scoparia (L.) Schrad. Studies have shown that MI presents antitumor properties in liver and prostate cancers. However, the activity and potential mechanisms of MI against colorectal cancer remain elusive. Here, we showed that MI inhibited cell proliferation with G0/1 phase cell cycle arrest in colon cancer cells. Moreover, it was observed that MI increased apoptosis compared to untreated cells. Further investigation showed that the SUMOylation of c-Myc was enhanced by MI and led to the down-regulated protein level of c-Myc, which is involved in regulating cell proliferation and apoptosis. SENP1 has been demonstrated to be critical for the SUMOylation of c-Myc. Meanwhile, knockdown of SENP1 by siRNA abolished the effects of MI on c-Myc level and cell viability in colon cancer cells. Together, these results revealed that MI exerted an anti-tumor activity in colon cancer cells via SENP1/c-Myc signaling pathway. These finding provide an insight into the potential of MI for colon cancer therapy.

Saikosaponin a contributed to CCIN treatment by promoting neutrophil bactericidal activity via activation CBL-dependent ERK pathway.

BACKGROUND: Despite granulocyte colony-stimulating factor (GCSF) is widely used in clinical, cancer chemotherapy induced neutropenia (CCIN) infection and infection-related mortality is high for lack of functionally mature neutrophils. Generating functional neutrophils is new therapeutic approaches to reduce CCIN-associated infection and mortality. Saikosaponin a (SSA) is one of the major bioactive components of Radix Bupleuri (RB) and exerts immunoregulatory effects. PURPOSE: The present study aims to investigate the efficacy and mechanism of SSA in CCIN therapy. METHODS: SSA was applied both in vitro and in vivo to assess the efficacy of CCIN therapy. The differentiation of neutrophils was measured by Nitroblue tetrazolium (NBT) reduction assay and Giemsa staining assay. The neutrophil differentiation related real-time transcription factors were detected by quantitative PCR (RT-qPCR) and Western Blot. Bacteria killing assay was used to assess the ability of fighting infection. Network pharmacology was employed to explore the mechanism network, and the predicted pathways were validated by Western Blot. RESULTS: We found that SSA contributed to generate functional mature neutrophils which capable of fighting infection both in vitro and in vivo. Network pharmacology prediction showed 55 pathways were predicted involved in SSA against CCIN. Further validation showed that CBL-ERK1/2 pathway was activated by SSA, which could upregulate PU.1 and CEBPß expression leading to neutrophil differentiation. CONCLUSIONS: Our findings suggest a natural regimen SSA regenerates microbicidal neutrophils to effectively reduce CCIN-associated infection via activating CBL-ERK1/2 pathway, providing a rationale for future therapeutic approaches.

The effects of Nigella sativa on respiratory, allergic and immunologic disorders, evidence from experimental and clinical studies, a comprehensive and updated review.

Nigella sativa (N. sativa) seed had been used traditionally due to several pharmacological effects. The updated experimental and clinical effects of N. sativa and its constituents on respiratory, allergic and immunologic disorders are provided in this comprehensive review article. Various databases including PubMed, Science Direct and Scopus were used. The preventive effects of N. sativa on pulmonary diseases were mainly due to its constituents such as thymoquinone, thymol, carvacrol and alpha-hederin. Extracts and constituents of N. sativa showed the relaxant effect, with possible mechanisms indicating its bronchodilatory effect in obstructive pulmonary diseases. In experimental animal models of different respiratory diseases, the preventive effect of various extracts and constituents of N. sativa was demonstrated by mechanisms such as antioxidant, immunomodulatory and antiinflammatory effects. Bronchodilatory and preventive effects of the plant and its components on asthma, COPD and lung disorders due to exposure to noxious agents as well as on allergic and immunologic disorders were also shown in the clinical studies. Various extracts and constituents of N. sativa showed pharmacological and therapeutic effects on respiratory, allergic and immunologic disorders indicating possible remedy effect of that the plant and its effective substances in treating respiratory, allergic and immunologic diseases.

Computational assessment of saikosaponins as adjuvant treatment for COVID-19: molecular docking, dynamics, and network pharmacology analysis.

Saikosaponins are major biologically active triterpenoids, usually as glucosides, isolated from Traditional Chinese Medicines (TCM) such as Bupleurum spp., Heteromorpha spp., and Scrophularia scorodonia with their antiviral and immunomodulatory potential. This investigation presents molecular docking, molecular dynamics simulation, and free energy calculation studies of saikosaponins as adjuvant therapy in the treatment for COVID19. Molecular docking studies for 23 saikosaponins on the crystal structures of the extracellular domains of human lnterleukin-6 receptor (IL6), human Janus Kinase-3 (JAK3), and dehydrogenase domain of Cylindrospermum stagnale NADPH-oxidase 5 (NOX5) were performed, and selected protein-ligand complexes were subjected to 100 ns molecular dynamics simulations. The molecular dynamics trajectories were subjected to free energy calculation by the MM-GBSA method. Molecular docking and molecular dynamics simulation studies revealed that IL6 in complex with Saikosaponin_U and Saikosaponin_V, JAK3 in complex with Saikosaponin_B4 and Saikosaponin_I, and NOX5 in complex with Saikosaponin_BK1 and Saikosaponin_C have good docking and molecular dynamics profiles. However, the Janus Kinase-3 is the best interacting partner for the saikosaponin compounds. The network pharmacology analysis suggests saikosaponins interact with the proteins CAT Gene CAT (Catalase) and Checkpoint kinase 1 (CHEK1); both of these enzymes play a major role in cell homeostasis and DNA damage during infection, suggesting a possible improvement in immune response toward COVID-19.