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Plants (Basel, Switzerland) May 2024is a perennial plant well known for its versatile medicinal properties, including hepatoprotective, antioxidant, anti-inflammatory, anti-tumor, estrogen-like, and...
is a perennial plant well known for its versatile medicinal properties, including hepatoprotective, antioxidant, anti-inflammatory, anti-tumor, estrogen-like, and antidepressant characteristics. It has been reported that plant age affects the quality of . This study aimed to explore the differential metabolome and transcriptome of 2-year (PN2) and 3-year-old (PN3) plant root samples. Principal component analysis of metabolome and transcriptome data revealed major differences between the two groups (PN2 vs. PN3). A total of 1813 metabolites and 28,587 genes were detected in this study, of which 255 metabolites and 3141 genes were found to be differential ( < 0.05) between PN2 vs. PN3, respectively. Among differential metabolites and genes, 155 metabolites and 1217 genes were up-regulated, while 100 metabolites and 1924 genes were down-regulated. The KEGG pathway analysis revealed differentially enriched metabolites belonging to class lipids ("13S-hydroperoxy-9Z, 11E-octadecadionic acid", "9S-hydroxy-10E, 12Z-octadecadionic acid", "9S-oxo-10E, 12Z-octadecadionic acid", and "9,10,13-trihydroxy-11-octadecadionic acid"), nucleotides and derivatives (guanine and cytidine), and phenolic acids (chlorogenic acid) were found to be enriched ( < 0.05) in PN3 compared to PN2. Further, these differentially enriched metabolites were found to be significantly ( < 0.05) regulated via linoleic acid metabolism, nucleotide metabolism, plant hormone signal transduction, and arachidonic acid metabolism pathways. Furthermore, the transcriptome analysis showed the up-regulation of key genes , , , gallate 1-beta-glucosyltransferase, and beta-D-glucosidase in various plants' secondary metabolic pathways and , , , , , , and genes observed in phytohormone signal transduction pathway that is involved in plant growth and development, and protection against the various stressors. This study concluded that the roots of a 3-year-old plant have better metabolome and transcriptome profiles compared to a 2-year-old plant with importantly enriched metabolites and genes in pathways related to metabolism, plant hormone signal transduction, and various biological processes. These findings provide insights into the plant's dynamic biochemical and molecular changes during its growth that have several implications regarding its therapeutic use.
PubMed: 38891250
DOI: 10.3390/plants13111441 -
Cells Jun 2024Tigilanol tiglate (TT, also known as EBC-46) is a novel, plant-derived diterpene ester possessing anticancer and wound-healing properties. Here, we show that TT-evoked...
Tigilanol tiglate (TT, also known as EBC-46) is a novel, plant-derived diterpene ester possessing anticancer and wound-healing properties. Here, we show that TT-evoked PKC-dependent S phosphorylation of the tyrosine kinase MET leads to subsequent degradation of tyrosine phosphorylated p-Y and p-Y MET species. PKC inhibition with BIM-1 blocked S phosphorylation of MET and led to MET cell surface accumulation. Treatment with metalloproteinase inhibitors prevented MET-ECD release into cell culture media, which was also blocked by PKC inhibitors. Furthermore, unbiased secretome analysis, performed using TMT-technology, identified additional targets of TT-dependent release of cell surface proteins from H357 head and neck cancer cells. We confirm that the MET co-signalling receptor syndecan-1 was cleaved from the cell surface in response to TT treatment. This was accompanied by rapid cleavage of the cellular junction adhesion protein Nectin-1 and the nerve growth factor receptor NGFR/TNFR16. These findings, that TT is a novel negative regulator of protumorigenic c-MET and NGFRp/TNFR16 signalling, as well as regulating Nectin-1-mediated cell adhesion, further contribute to our understanding of the mode of action and efficacy of TT in the treatment of solid tumours.
Topics: Humans; Proto-Oncogene Proteins c-met; Phosphorylation; Head and Neck Neoplasms; Cell Line, Tumor; Secretome; Diterpenes; Membrane Proteins; Signal Transduction; Syndecan-1; Nectins; Protein Kinase C
PubMed: 38891113
DOI: 10.3390/cells13110982 -
Immunity, Inflammation and Disease Jun 2024At present, neonatal hypoxic-ischemic encephalopathy (HIE), especially moderate to severe HIE, is a challenging disease for neonatologists to treat, and new...
BACKGROUND
At present, neonatal hypoxic-ischemic encephalopathy (HIE), especially moderate to severe HIE, is a challenging disease for neonatologists to treat, and new alternative/complementary treatments are urgently needed. The neuroinflammatory cascade triggered by hypoxia-ischemia (HI) insult is one of the core pathological mechanisms of HIE. Early inhibition of neuroinflammation provides long-term neuroprotection. Plant-derived monomers have impressive anti-inflammatory effects. Aloesin (ALO) has been shown to have significant anti-inflammatory and antioxidant effects in diseases such as ulcerative colitis, but its role in HIE is unclear. To this end, we conducted a series of experiments to explore the potential mechanism of ALO in preventing and treating brain damage caused by HI insult.
MATERIALS AND METHODS
Hypoxic-ischemic brain damage (HIBD) was induced in 7-day-old Institute of Cancer Research (ICR) mice, which were then treated with 20 mg/kg ALO. The neuroprotective effects of ALO on HIBD and the underlying mechanism were evaluated through neurobehavioral testing, infarct size measurement, apoptosis detection, protein and messenger RNA level determination, immunofluorescence, and molecular docking.
RESULTS
ALO alleviated the long-term neurobehavioral deficits caused by HI insult; reduced the extent of cerebral infarction; inhibited cell apoptosis; decreased the levels of the inflammatory factors interleukin (IL)-1β, IL-6, and tumor necrosis factor-α; activated microglia and astrocytes; and downregulated the protein expression of members in the TLR4 signaling pathway. In addition, molecular docking showed that ALO can bind stably to TLR4.
CONCLUSION
ALO ameliorated HIBD in neonatal mice by inhibiting the neuroinflammatory response mediated by TLR4 signaling.
Topics: Animals; Toll-Like Receptor 4; Hypoxia-Ischemia, Brain; Mice; Animals, Newborn; Neuroprotective Agents; Neuroinflammatory Diseases; Mice, Inbred ICR; Disease Models, Animal; Signal Transduction; Apoptosis; Anti-Inflammatory Agents; Molecular Docking Simulation
PubMed: 38888378
DOI: 10.1002/iid3.1320 -
PloS One 2024Phenolic acids still gain significant attention due to their potential antimicrobial and cytotoxic properties. In this study, we have investigated the antimicrobial of...
Phenolic acids still gain significant attention due to their potential antimicrobial and cytotoxic properties. In this study, we have investigated the antimicrobial of six phenolic acids, namely chlorogenic, caffeic, p-coumaric, rosmarinic, gallic and tannic acids in the concentration range 0.5-500 μM, against Escherichia coli and Lactobacillus rhamnosus. The antimicrobial activity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay. Additionally, the cytotoxic effects of these phenolic acids on two cancer cell lines, the colorectal adenocarcinoma Caco-2 cell line and Dukes' type C colorectal adenocarcinoma DLD-1 cell line was examined. To further understand the molecular properties of these phenolic acids, quantum chemical calculations were performed using the Gaussian 09W program. Parameters such as ionization potential, electron affinity, electronegativity, chemical hardness, chemical softness, dipole moment, and electrophilicity index were obtained. The lipophilicity properties represented by logP parameter was also discussed. This study provides a comprehensive evaluation of the antimicrobial and cytotoxic activity of six phenolic acids, compounds deliberately selected due to their chemical structure. They are derivatives of benzoic or cinnamic acids with the increasing number of hydroxyl groups in the aromatic ring. The integration of experimental and computational methodologies provides a knowledge of the molecular characteristics of bioactive compounds and partial explanation of the relationship between the molecular structure and biological properties. This knowledge aids in guiding the development of bioactive components for use in dietary supplements, functional foods and pharmaceutical drugs.
Topics: Humans; Hydroxybenzoates; Caco-2 Cells; Cell Line, Tumor; Escherichia coli; Anti-Infective Agents; Microbial Sensitivity Tests; Gallic Acid; Cinnamates; Caffeic Acids; Coumaric Acids
PubMed: 38885237
DOI: 10.1371/journal.pone.0299372 -
Journal of Pharmacy & Bioallied Sciences Apr 2024Cancer, diabetes, and wounds are critical health challenges affecting millions of people worldwide. Cancer arises from the transformation of normal cells into tumor...
Cancer, diabetes, and wounds are critical health challenges affecting millions of people worldwide. Cancer arises from the transformation of normal cells into tumor cells, leading to uncontrolled growth and potential spread to other parts of the body. Diabetes is a chronic metabolic disorder characterized by elevated blood sugar levels, and wounds can result from various injuries and diseases. In this study, we investigated the therapeutic potential of for its anticancer, antidiabetic, and wound healing activities. The anticancer activity of the ethanolic extract of was evaluated using the MTT (3- [4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay, which showed a concentration-dependent decrease in cell proliferation and growth. The extract exhibited promising anticancer potential, which could help control cancer progression. For the antidiabetic activity, we assessed α-amylase inhibition using a colorimetric method. The extract demonstrated substantial α-amylase inhibitory activity, comparable with the standard metformin. This indicates its potential in reducing postprandial blood sugar spikes in diabetic patients. In the wound healing activity, a scratch assay was performed to measure cell migration and growth. The results showed that extract promoted wound closure similar to the control. The extract's wound healing properties suggest its potential use in managing various types of wounds. Phytochemical analysis confirmed the presence of key bioactive compounds in both ethanolic and aqueous extracts of , supporting the observed therapeutic effects. In conclusion, holds promise as a potential source of novel therapeutic agent for cancer, diabetes, and wound management. The results from this study provide valuable insights into the plant's pharmacological activities and may pave the way for the development of new herbal-based treatments for these conditions.
PubMed: 38882727
DOI: 10.4103/jpbs.jpbs_545_23 -
Drug Design, Development and Therapy 2024Traditional Chinese medicine (TCM) therapy is an important means to treat hepatocellular carcinoma (HCC), (Latin name: ; Chinese name: Huangqi, HQ) and (Latin name: ;...
PURPOSE
Traditional Chinese medicine (TCM) therapy is an important means to treat hepatocellular carcinoma (HCC), (Latin name: ; Chinese name: Huangqi, HQ) and (Latin name: ; Chinese name: Baizhu, BZ) (HQBZ), a classic herb pair, is often used in combination to HCC. However, the main components and potential mechanisms of HQBZ therapy in HCC remain unclear. This study aimed to identify the potential active ingredients and molecular mechanisms of action of HQBZ in HCC treatment.
METHODS
The HQBZ-Compound-Target-HCC network and HQBZ-HCC transcriptional regulatory network were constructed to screen the core active compound components and targets of HQBZ therapy for HCC. Molecular docking techniques are used to verify the stability of binding core active compound components to targets. GO and KEGG enrichment analysis were used to explore the signaling pathway of HQBZ in HCC treatment, the mechanism of HQBZ treatment of HCC was verified based on in vivo H22 tumor bearing mice and in vitro cell experiments.
RESULTS
Network pharmacology and molecular docking studies showed that HQBZ treatment of HCC was related to the targeted regulation of IL-6 and STAT3 by the active compound biatractylolide, KEGG pathway enrichment analysis suggest that HQBZ may play a role in the treatment of HCC through IL-6/STAT3 signaling pathway. In vitro experiment results proved that HQBZ could regulate IL-6/STAT3 signaling pathway transduction on CD8T cells, inhibit CD8T cell exhaustion and restore the function of exhausted CD8T cells. In vivo experiment results proved that HQBZ can regulate IL-6/STAT3 signaling pathway transduction in H22 liver cancer model mouse tumor tissue, increased the proportion of tumor infiltrating CD8T cells.
CONCLUSION
This study found that HQBZ may play a therapeutic role in HCC by targeting IL-6 and STAT3 through biatractylolide, its mechanism of action is related to regulating IL-6/STAT3 signaling pathway, reversing T cell failure and increasing tumor infiltration CD8T cells.
Topics: Carcinoma, Hepatocellular; Liver Neoplasms; Animals; Humans; Drugs, Chinese Herbal; Network Pharmacology; Mice; STAT3 Transcription Factor; Atractylodes; Antineoplastic Agents, Phytogenic; Molecular Docking Simulation; Astragalus Plant; Cell Proliferation; Liver Neoplasms, Experimental; Interleukin-6; Medicine, Chinese Traditional; Drug Screening Assays, Antitumor
PubMed: 38882048
DOI: 10.2147/DDDT.S459593 -
Frontiers in Pharmacology 2024(Willd. ex Schult.) DC. (Rubiaceae) is traditionally used by Amazonian indigenous groups to treat inflammatory diseases. To date, there are no systematic reviews and...
BACKGROUND
(Willd. ex Schult.) DC. (Rubiaceae) is traditionally used by Amazonian indigenous groups to treat inflammatory diseases. To date, there are no systematic reviews and meta-analyses on the use of for inflammation control in animals supporting the traditional knowledge about this species. This study was conducted to evaluate the effect of extracts in modulating inflammatory mediators and to determine which types of inflammatory diseases can be treated by this species.
METHODS
We conducted a systematic review and meta-analysis of preclinical studies published before 26 July 2023, identified in PubMed, Embase, and Scopus. Four independent reviewers extracted the data and assessed the risks of bias. The effects of on inflammatory diseases and the inflammatory mediators involved were extracted from the studies. Standardized mean differences (SMD) and 95% confidence intervals (95%CI) of the outcomes were estimated. The meta-analyses were conducted using RevMan 5.4 (Cochrane Collaboration). This protocol was registered in PROSPERO (CRD42023450869).
RESULTS
Twenty-four of 523 studies were included. extracts decreased the cytokines interleukin (IL)-6 (SMD: -0.72, 95%CI: -1.15, -0.29, = 0.001) and transcription factor nuclear factor -B (NF-κB) (SMD: -1.19, 95%CI: -1.89, -0.48, = 0.001). However, the extracts did not significantly alter IL-1 (SMD: -0.16, 95%CI: -0.87, +0.56, = 0.67), IL-10 (SMD: -0.05, 95%CI:-0.35, 0.45, = 0.80), or tumor necrosis factor- (TNF-α) levels (SMD: 0.18, 95%CI: -0.25, 0.62, = 0.41).
CONCLUSION
Many extracts of stem bark, roots, and leaves of , mostly aqueous and hydroethanolic, exhibited anti-inflammatory and/or immunomodulatory activities and low toxicity. The extracts decreased NF-κB and IL-6. These findings suggest that this species has the potential to treat inflammatory diseases in which these markers are increased, according to the ethnopharmacological use. These activities are not related to a specific class of compounds.
UNLABELLED
https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=450869, Identifier CRD42023450869.
PubMed: 38881881
DOI: 10.3389/fphar.2024.1378408 -
Frontiers in Pharmacology 2024Sodium nitrite (NaNO) is a widely used food ingredient, although excessive concentrations can pose potential health risks. In the present study, we evaluated the...
Sodium nitrite (NaNO) is a widely used food ingredient, although excessive concentrations can pose potential health risks. In the present study, we evaluated the deterioration effects of NaNO additives on hematology, metabolic profile, liver function, and kidney function of male Wistar rats. We further explored the therapeutic potential of supplementation with root ethanolic extract (SCREE) to improve NaNO-induced hepatorenal toxicity. In this regard, 65 adult male rats were divided into eight groups; Group 1: control, Groups 2, 3, and 4 received SCREE in 200, 400, and 600 mg/kg body weight, respectively, Group 5: NaNO (6.5 mg/kg body weight), Groups 6, 7 and 8 received NaNO (6.5 mg/kg body weight) in combination with SCREE (200, 400, and 600 mg/kg body weight), respectively. Our results revealed that the NaNO-treated group shows a significant change in deterioration in body and organ weights, hematological parameters, lipid profile, and hepatorenal dysfunction, as well as immunohistochemical and histopathological alterations. Furthermore, the NaNO-treated group demonstrated a considerable increase in the expression of TNF-α cytokine and tumor suppressor gene P53 in the kidney and liver, while a significant reduction was detected in the anti-inflammatory cytokine IL-4 and the apoptosis suppressor gene BCL-2, compared to the control group. Interestingly, SCREE administration demonstrated the ability to significantly alleviate the toxic effects of NaNO and improve liver function in a dose-dependent manner, including hematological parameters, lipid profile, and modulation of histopathological architecture. Additionally, SCREE exhibited the ability to modulate the expression levels of inflammatory cytokines and apoptotic genes in the liver and kidney. The phytochemical analysis revealed a wide set of primary metabolites in SCREE, including phenolics, flavonoids, vitamins, alkaloids, saponins and tannins, while the untargeted UPLC/T-TOF-MS/MS analysis identified 183 metabolites in both positive and negative ionization modes. Together, our findings establish the potential of SCREE in mitigating the toxic effects of NaNO by modulating metabolic, inflammatory, and apoptosis. Together, this study underscores the promise of SCREE as a potential natural food detoxifying additive to counteract the harmful impacts of sodium nitrite.
PubMed: 38881874
DOI: 10.3389/fphar.2024.1378249 -
Frontiers in Pharmacology 2024(Bunge) Kitag. ex H.Hara, a member of the Asclepiadaceae family, has a rich history as a traditional Chinese medicinal plant used to treat digestive disorders....
(Bunge) Kitag. ex H.Hara inhibits pancreatic cancer progression by inducing caspase-dependent apoptosis and suppressing TGF-β-mediated epithelial-mesenchymal transition.
(Bunge) Kitag. ex H.Hara, a member of the Asclepiadaceae family, has a rich history as a traditional Chinese medicinal plant used to treat digestive disorders. However, its potential anti-cancer effects in pancreatic cancer remain largely unexplored. This study delves into the intricate anti-pancreatic cancer mechanisms of (Bunge) Kitag. ex H.Hara aqueous extract (CPAE) by elucidating its role in apoptosis induction and the inhibition of invasion and migration. A comprehensive set of methodologies was employed to assess CPAE's impact, including cell viability analyses using MTT and colony formation assays, flow cytometry for cell cycle distribution and apoptosis assessment, scratch-wound and Matrigel invasion assays for migration and invasion capabilities, and immunoblotting to measure the expression levels of key proteins involved in apoptosis and metastasis. Additionally, a murine xenograft model was established to investigate CPAE's anti-cancer potential. CPAE exhibited time- and dose-dependent suppression of proliferation and colony formation in pancreatic cancer cells. Notably, CPAE induced apoptosis and G2/M phase arrest, effectively activating the caspase-dependent PARP pathway. At non-cytotoxic doses, CPAE significantly curtailed the metastatic abilities of pancreatic cells, effectively suppressing epithelial-mesenchymal transition (EMT) and downregulating the TGF-β1/Smad2/3 pathway. experiments underscored CPAE's ability to inhibit tumor proliferation. This study illuminates the multifaceted anti-proliferative, pro-apoptotic, anti-invasive, and anti-migratory effects of CPAE, both and . CPAE emerges as a promising herbal medicine for pancreatic cancer treatment, with its potential mediated through apoptosis induction via the caspase-dependent PARP pathway and MET suppression via the TGF-β1/Smad2/3 signaling pathway at non-cytotoxic doses. These findings advocate for further exploration of CPAE's therapeutic potential in pancreatic cancer.
PubMed: 38881872
DOI: 10.3389/fphar.2024.1284371 -
Cell Communication and Signaling : CCS Jun 2024Multidrug resistance (MDR) limits successful cancer chemotherapy. P-glycoprotein (P-gp), BCRP and MRP1 are the key triggers of MDR. Unfortunately, no MDR modulator was...
BACKGROUND
Multidrug resistance (MDR) limits successful cancer chemotherapy. P-glycoprotein (P-gp), BCRP and MRP1 are the key triggers of MDR. Unfortunately, no MDR modulator was approved by FDA to date. Here, we will investigate the effect of BI-2865, a pan-KRAS inhibitor, on reversing MDR induced by P-gp, BCRP and MRP1 in vitro and in vivo, and its reversal mechanisms will be explored.
METHODS
The cytotoxicity of BI-2865 and its MDR removal effect in vitro were tested by MTT assays, and the corresponding reversal function in vivo was assessed through the P-gp mediated KBv200 xenografts in mice. BI-2865 induced alterations of drug discharge and reservation in cells were estimated by experiments of Flow cytometry with fluorescent doxorubicin, and the chemo-drug accumulation in xenografts' tumor were analyzed through LC-MS. Mechanisms of BI-2865 inhibiting P-gp substrate's efflux were analyzed through the vanadate-sensitive ATPase assay, [I]-IAAP-photolabeling assay and computer molecular docking. The effects of BI-2865 on P-gp expression and KRAS-downstream signaling were detected via Western blotting, Flow cytometry and/or qRT-PCR. Subcellular localization of P-gp was visualized by Immunofluorescence.
RESULTS
We found BI-2865 notably fortified response of P-gp-driven MDR cancer cells to the administration of chemo-drugs including paclitaxel, vincristine and doxorubicin, while such an effect was not observed in their parental sensitive cells and BCRP or MRP1-driven MDR cells. Importantly, the mice vivo combination study has verified that BI-2865 effectively improved the anti-tumor action of paclitaxel without toxic injury. In mechanism, BI-2865 prompted doxorubicin accumulating in carcinoma cells by directly blocking the efflux function of P-gp, which more specifically, was achieved by BI-2865 competitively binding to the drug-binding sites of P-gp. What's more, at the effective MDR reversal concentrations, BI-2865 neither varied the expression and location of P-gp nor reduced its downstream AKT or ERK1/2 signaling activity.
CONCLUSIONS
This study uncovered a new application of BI-2865 as a MDR modulator, which might be used to effectively, safely and specifically improve chemotherapeutic efficacy in the clinical P-gp mediated MDR refractory cancers.
Topics: Humans; Animals; Drug Resistance, Neoplasm; Drug Resistance, Multiple; Mice; Cell Line, Tumor; ATP Binding Cassette Transporter, Subfamily B, Member 1; Xenograft Model Antitumor Assays; Mice, Nude; Doxorubicin; Mice, Inbred BALB C; Female
PubMed: 38872211
DOI: 10.1186/s12964-024-01698-4