Research

Jump to: Review

16 pages, 2712 KiB

Open AccessArticle

Multidirectional Effects of Terpenoids from Sorbus intermedia (EHRH.) PERS Fruits in Cellular Model of Benign Prostate Hyperplasia

by Agnieszka Sołtys, Agnieszka Galanty, Karolina Grabowska, Paweł Paśko, Paweł Zagrodzki and Irma Podolak

Pharmaceuticals 2023, 16(7), 965; https://doi.org/10.3390/ph16070965 - 05 Jul 2023

Cited by 1 | Viewed by 1067

Abstract

Benign prostatic hyperplasia (BPH) is a common urological disease affecting aging men. Its pathogenesis is regarded as complex and multifactorial, with sex hormones and inflammation as key contributory factors. In the current study, we investigated the anti-BPH potential of terpenoids present in the [...] Read more.

Benign prostatic hyperplasia (BPH) is a common urological disease affecting aging men. Its pathogenesis is regarded as complex and multifactorial, with sex hormones and inflammation as key contributory factors. In the current study, we investigated the anti-BPH potential of terpenoids present in the fruits of Sorbus intermedia (EHRH.) PERS. Not only the effects on testosterone-stimulated normal prostate epithelial PNT2 cells, namely suppression of 5-α-reductase activity, PSA secretion, and cell proliferation, were determined but also the inhibitory activity on heat-induced protein denaturation, hyaluronidase, as well as IL-6, TNF-α, and NO release in LPS-treated macrophages. Sorbus terpenoids significantly inhibited 5-α-reductase activity and reduced PSA secretion in PNT2 cells, reversing the stimulatory effect of testosterone. PNT2 cell proliferation was also found to be attenuated. Subsequently, all compounds reduced the release of pro-inflammatory mediators in RAW 264.7 cells. In addition, ursolic acid (UA) and its aldehyde (UAL) were the most potent hyaluronidase inhibitors of all compounds, with IC₅₀ values of 225.75 µg/mL and 369.77 µg/mL, respectively. For better understanding and interpretation of the overall effect of Sorbus terpenoids on different aspects of BPH pathogenesis and development, cluster analysis was applied. Full article

(This article belongs to the Special Issue Plant-Derived Anti-inflammatory Agents: Molecular Pharmacology and Further Studies)

► Show Figures

Figure 1

16 pages, 2238 KiB

Open AccessArticle

Margaritaria nobilis L.f. (Phyllanthaceae) Ethanolic Extract: Low Acute Oral Toxicity and Antinociceptive Activity

by Fabiana Menezes S. Camara, Brenda Costa da Conceição, Eloise Karoline S. Cardoso, Johan Carlos C. Santiago, Carlos Alberto B. Albuquerque, Washington L. Pereira, Marta C. Monteiro, Consuelo Y. Yoshioka e Silva, Milton Nascimento da Silva, Cristiane F. Maia and Eneas A. Fontes-Junior

Pharmaceuticals 2023, 16(5), 689; https://doi.org/10.3390/ph16050689 - 03 May 2023

Viewed by 1725

Abstract

Margaritaria nobilis L.f. (Phyllanthaceae), a native Brazilian tree occurring mainly in the Amazon, is used in folk medicine for the treatment of abscesses (bark) and cancer-like symptoms (leaves). The present study evaluates the safety of its acute oral administration and its effects on [...] Read more.

Margaritaria nobilis L.f. (Phyllanthaceae), a native Brazilian tree occurring mainly in the Amazon, is used in folk medicine for the treatment of abscesses (bark) and cancer-like symptoms (leaves). The present study evaluates the safety of its acute oral administration and its effects on nociception and plasma leakage. The chemical constitution of the leaf’s ethanolic extract is determined by ultra-performance liquid chromatography–high-resolution mass spectrometry (LC-MS. Its acute oral toxicity is evaluated in female rats at a dose of 2000 mg/kg, evaluating the occurrence of deaths and Hippocratic, behavioral, hematological, biochemical, and histopathological changes, as well as food and water consumption and weight gain. Antinociceptive activity is evaluated in male mice with acetic-acid-induced peritonitis (APT) and formalin (FT) tests. An open field (OF) test is performed to verify possible interferences in the animals’ consciousness or locomotion. LC-MS analysis shows the presence of 44 compounds classified as phenolic acid derivatives, flavonoids and O-glycosylated derivatives, and hydrolyzable tannins. No deaths or significant behavioral, histological, or biochemical changes are observed in the toxicity assessment. In nociception tests, M. nobilis extract significantly reduces abdominal contortions in APT, demonstrating selectivity for inflammatory components (FT second phase), not interfering in neuropathic components (FT first phase) or consciousness and locomotion levels in OF. Additionally, M. nobilis extract inhibits plasma acetic-acid-induced leakage. These data demonstrate the low toxicity of M. nobilis ethanolic extract, as well as its effectiveness in modulating inflammatory nociception and plasma leakage, possibly related to the flavonoids and tannins present in its composition. Full article

(This article belongs to the Special Issue Plant-Derived Anti-inflammatory Agents: Molecular Pharmacology and Further Studies)

► Show Figures

Graphical abstract

17 pages, 4097 KiB

Open AccessArticle

The First Anti-Snakebite and Hepatoprotective Characterization of a Trypsin Kunitz-like Inhibitor (EcTI) from the Plant Enterolobium contortisiliquum; A Case of Two Soul Mates Meeting

by Caroline R. C. Costa, Mariana N. Belchor, Airam Roggero, Laila L. Moraes, Ricardo Samelo, Isabelly Annunciato, Camila R. Bonturi, Maria L. V. Oliva, Sergio F. Sousa, Marcos A. de Oliveira and Marcos H. Toyama

Pharmaceuticals 2023, 16(4), 632; https://doi.org/10.3390/ph16040632 - 21 Apr 2023

Viewed by 1505

Abstract

Snake venom serine protease (SVSP) interferes with the regulation and control of important biological reactions in homeostasis and can be classified as an activator of the fibrinolytic system and platelet aggregation. Our group has recently isolated a new serine protease from Crotalus durissus [...] Read more.

Snake venom serine protease (SVSP) interferes with the regulation and control of important biological reactions in homeostasis and can be classified as an activator of the fibrinolytic system and platelet aggregation. Our group has recently isolated a new serine protease from Crotalus durissus terrificus total venom (Cdtsp-2). This protein exhibits edematogenic capacity and myotoxic activity. A Kunitz-like EcTI inhibitor protein with a molecular mass of 20 kDa was isolated from Enterolobium contortisiliquum and showed high trypsin inhibition. Thus, the objective of this work is to verify the possible inhibition of the pharmacological activities of Cdtsp-2 by the Kutinz-type inhibitor EcTI. To isolate Cdtsp-2 from total C. d. terrificus venom, we used three-step chromatographic HPLC. Using the mice paw edema model, we observed an edematogenic effect, myotoxicity and hepatotoxicity caused by Cdtsp-2. In vitro and in vivo experiments showed that the alterations in hemostasis caused by Cdtsp-2 are crucial for the development of marked hepatotoxicity and that EcTI significantly inhibits the enzymatic and pharmacological activities of Cdtsp-2. Kunitz-like inhibitor may be a viable alternative for the development of ancillary treatments against the biological activities of venoms. Full article

(This article belongs to the Special Issue Plant-Derived Anti-inflammatory Agents: Molecular Pharmacology and Further Studies)

► Show Figures

Figure 1

18 pages, 3493 KiB

Open AccessArticle

In Silico Evaluation of Quercetin Methylated Derivatives on the Interaction with Secretory Phospholipases A2 from Crotalus durissus terrificus and Bothrops jararacussu

by Mariana Novo Belchor, Caroline Ramos da Cruz Costa, Airam Roggero, Laila L. F. Moraes, Ricardo Samelo, Isabelly Annunciato, Marcos Antonio de Oliveira, Sergio F. Sousa and Marcos Hikari Toyama

Pharmaceuticals 2023, 16(4), 597; https://doi.org/10.3390/ph16040597 - 15 Apr 2023

Cited by 2 | Viewed by 1262

Abstract

Quercetin derivatives have already shown their anti-inflammatory potential, inhibiting essential enzymes involved in this process. Among diverse pro-inflammatory toxins from snake venoms, phospholipase A2 is one of the most abundant in some species, such as Crotalus durissus terrificus and Bothrops jararacussu from the [...] Read more.

Quercetin derivatives have already shown their anti-inflammatory potential, inhibiting essential enzymes involved in this process. Among diverse pro-inflammatory toxins from snake venoms, phospholipase A2 is one of the most abundant in some species, such as Crotalus durissus terrificus and Bothrops jararacussu from the Viperidae family. These enzymes can induce the inflammatory process through hydrolysis at the sn-2 position of glycerophospholipids. Hence, elucidating the main residues involved in the biological effects of these macromolecules can help to identify potential compounds with inhibitory activity. In silico tools were used in this study to evaluate the potential of quercetin methylated derivatives in the inhibition of bothropstoxin I (BthTX-I) and II (BthTX-II) from Bothrops jararacussu and phospholipase A2 from Crotalus durissus terrificus. The use of a transitional analogous and two classical inhibitors of phospholipase A2 guided this work to find the role of residues involved in the phospholipid anchoring and the subsequent development of the inflammatory process. First, main cavities were studied, revealing the best regions to be inhibited by a compound. Focusing on these regions, molecular docking assays were made to show main interactions between each compound. Results reveal that analogue and inhibitors, Varespladib (Var) and p-bromophenacyl bromide (BPB), guided quercetins derivatives analysis, revealing that Leu2, Phe5, Tyr28, glycine in the calcium-binding loop, His48, Asp49 of BthTX-II and Cdtspla2 were the main residues to be inhibited. 3MQ exhibited great interaction with the active site, similar to Var results, while Q anchored better in the BthTX-II active site. However, strong interactions in the C-terminal region, highlighting His120, seem to be crucial to decreasing contacts with phospholipid and BthTX-II. Hence, quercetin derivatives anchor differently with each toxin and further in vitro and in vivo studies are essential to elucidate these data. Full article

(This article belongs to the Special Issue Plant-Derived Anti-inflammatory Agents: Molecular Pharmacology and Further Studies)

► Show Figures

Figure 1

15 pages, 1645 KiB

Open AccessArticle

New Approaches on the Anti-Inflammatory and Cardioprotective Properties of Taraxacum officinale Tincture

by Alexandra Epure, Alina E. Pârvu, Laurian Vlase, Daniela Benedec, Daniela Hanganu, Ovidiu Oniga, Ana-Maria Vlase, Irina Ielciu, Anca Toiu and Ilioara Oniga

Pharmaceuticals 2023, 16(3), 358; https://doi.org/10.3390/ph16030358 - 26 Feb 2023

Cited by 3 | Viewed by 1759

Abstract

The present research investigated the in vivo anti-inflammatory and cardioprotective activities, as well as the antioxidant potential of Taraxacum officinale tincture (TOT), in relation to the polyphenolic composition. Chromatographic and spectrophotometric techniques were used to determine the polyphenolic profile of TOT and the [...] Read more.

The present research investigated the in vivo anti-inflammatory and cardioprotective activities, as well as the antioxidant potential of Taraxacum officinale tincture (TOT), in relation to the polyphenolic composition. Chromatographic and spectrophotometric techniques were used to determine the polyphenolic profile of TOT and the antioxidant activity was preliminarily assessed in vitro by DPPH• and FRAP spectrophotometric methods. The in vivo anti-inflammatory and cardioprotective activities were studied in rat turpentine-induced inflammation and in rat isoprenaline-induced myocardial infarction (MI) models. The main polyphenolic compound identified in TOT was cichoric acid. The oxidative stress determinations showed the capacity of the dandelion tincture not only to decrease the total oxidative stress (TOS), the oxidative stress index (OSI), and the total antioxidant capacity (TAC), but also the malondialdehide (MDA), thiols (SH), and nitrites/nitrates (NOx) levels both in inflammation and MI models. In addition, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatin kinase-MB (CK-MB), and nuclear factor kappa B (NF-κB) parameters were decreased by the administration of the tincture. The results show that T. officinale could be considered a valuable source of natural compounds with important benefits in pathologies linked to oxidative stress. Full article

(This article belongs to the Special Issue Plant-Derived Anti-inflammatory Agents: Molecular Pharmacology and Further Studies)

► Show Figures

Figure 1

18 pages, 4673 KiB

Open AccessArticle

Therapeutic Effect of Costunolide in Autoimmune Hepatitis: Network Pharmacology and Experimental Validation

by Zheng Huang, Shangshu Nie, Shuhui Wang, Han Wang, Jin Gong, Wei Yan, Dean Tian and Mei Liu

Pharmaceuticals 2023, 16(2), 316; https://doi.org/10.3390/ph16020316 - 17 Feb 2023

Cited by 3 | Viewed by 1955

Abstract

Novel treatments for autoimmune hepatitis (AIH) are highly demanded due to the limitations of existing therapeutic agents. Costunolide is a promising candidate due to its anti-inflammatory and hepatoprotective function, but its effect in AIH remains obscure. In this study, we integrated network pharmacology [...] Read more.

Novel treatments for autoimmune hepatitis (AIH) are highly demanded due to the limitations of existing therapeutic agents. Costunolide is a promising candidate due to its anti-inflammatory and hepatoprotective function, but its effect in AIH remains obscure. In this study, we integrated network pharmacology and experimental validation to reveal the effect and mechanism of costunolide in AIH. A total of 73 common targets of costunolide and AIH were obtained from databases. Pathway enrichment analysis indicated that PI3K-AKT pathway was the core pathway of costunolide in AIH. Protein–protein interaction network analysis and molecular docking revealed that SRC and IGF1R might play critical roles. In two murine AIH models, costunolide significantly attenuated liver injury, inflammation, and fibrosis reflected by the liver gross appearance, serum transaminases, necrosis area, spleen index, immune cell infiltration, and collagen deposition. Western blot and immunohistochemistry confirmed that phosphorylated AKT, SRC, and IGF1R were upregulated in AIH models, and costunolide administration could inhibit the phosphorylation of these proteins. In summary, costunolide significantly ameliorates murine AIH. The therapeutic effect might work by suppressing the activation of PI3K-AKT pathway and inhibiting the phosphorylation of SRC and IGF1R. Our research reveals the potent therapeutic effect of costunolide in AIH and the potential role of SRC and IGF1R in AIH for the first time, which may further contribute to the novel drug development for AIH and other autoimmune diseases. Full article

(This article belongs to the Special Issue Plant-Derived Anti-inflammatory Agents: Molecular Pharmacology and Further Studies)

► Show Figures

Figure 1

16 pages, 4784 KiB

Open AccessArticle

Exploring the Effective Components and Mechanism of Action of Japanese Ardisia in the Treatment of Autoimmune Hepatitis Based on Network Pharmacology and Experimental Verification

by Tian Fu, Yifei Chen, Junkui Li, Peili Zhu, Huajuan He, Wei Zhang, Ken Kin Lam Yung and Wei Wu

Pharmaceuticals 2022, 15(12), 1457; https://doi.org/10.3390/ph15121457 - 24 Nov 2022

Viewed by 1536

Abstract

Japanese Ardisia is widely used as a hepatoprotective and anti-inflammatory agent in China. However, the active ingredients in Japanese Ardisia and their potential mechanisms of action in the treatment of autoimmune hepatitis (AIH) are unknown. The pharmacodynamic substance and mechanism of action of [...] Read more.

Japanese Ardisia is widely used as a hepatoprotective and anti-inflammatory agent in China. However, the active ingredients in Japanese Ardisia and their potential mechanisms of action in the treatment of autoimmune hepatitis (AIH) are unknown. The pharmacodynamic substance and mechanism of action of Japanese Ardisia in the treatment of AIH were investigated using network pharmacology and molecular docking technology in this study. Following that, the effects of Japanese Ardisia were evaluated using the concanavalin A (Con A)-induced acute liver injury rat model. The active ingredients and targets of Japanese Ardisia were searched using the Traditional Chinese Medicine Systems Pharmacology database, and hepatitis-related therapeutic targets were identified through GeneCards and Online Mendelian Inheritance in Man databases. A compound–target network was then constructed using Cytoscape software, and enrichment analysis was performed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Molecular docking technology was used to simulate the docking of key targets, and the AIH rat model was used to validate the expression of key targets. Nineteen active chemical components and 143 key target genes were identified. GO enrichment analysis revealed that the treatment of AIH with Japanese Ardisia mainly involved DNA–binding transcription factor binding, RNA polymerase II-specific DNA transcription factor binding, cytokine receptor binding, receptor-ligand activity, ubiquitin-like protein ligase binding, and cytokine activity. In the KEGG enrichment analysis, 165 pathways were identified, including the lipid and atherosclerotic pathway, IL-17 signaling pathway, TNF signaling pathway, hepatitis B pathway, and the AGE–RAGE signaling pathway in diabetic complications. These pathways may be the key to effective AIH treatment with Japanese Ardisia. Molecular docking showed that quercetin and kaempferol have good binding to AKT1, IL6, VEGFA, and CASP3. Animal experiments demonstrated that Japanese Ardisia could increase the expression of AKT1 and decrease the expression of CASP3 protein, as well as IL-6, in rat liver tissues. This study identified multiple molecular targets and pathways for Japanese Ardisia in the treatment of AIH. At the same time, the effectiveness of Japanese Ardisia in treating AIH was verified by animal experiments. Full article

(This article belongs to the Special Issue Plant-Derived Anti-inflammatory Agents: Molecular Pharmacology and Further Studies)

► Show Figures

Figure 1

17 pages, 1314 KiB

Open AccessArticle

Accessing Lipophilicity and Biomimetic Chromatography Profile of Biologically Active Ingredients of Botanicals Used in the Treatment of Inflammatory Bowel Disease

by Mario-Livio Jeličić, Daniela Amidžić Klarić, Jelena Kovačić, Donatella Verbanac and Ana Mornar

Pharmaceuticals 2022, 15(8), 965; https://doi.org/10.3390/ph15080965 - 04 Aug 2022

Cited by 4 | Viewed by 1732

Abstract

In the present study, various procedures have been compared for the determination of lipophilicity, hydrophobicity, and plasma protein binding of curcuminoids, boswellic acids, andrographolides, and piperine as biologically active ingredients of botanicals used in IBD treatment. Our results have shown that IAM-HPLC assay [...] Read more.

In the present study, various procedures have been compared for the determination of lipophilicity, hydrophobicity, and plasma protein binding of curcuminoids, boswellic acids, andrographolides, and piperine as biologically active ingredients of botanicals used in IBD treatment. Our results have shown that IAM-HPLC assay is the most suitable one for lipophilicity determination of all analytes regardless of their class and botanical source. HSA-HPAC and AGP-HPAC assays revealed that all investigated compounds have a higher affinity for HSA which is the most abundant protein in human plasma. The high affinity of biologically active compounds to all biological structures (phospholipids and proteins) admonishes that their small portion is available for therapeutic effects in IBD patients. Our experimental research is complemented by various theoretical approaches based on different algorithms for pharmacokinetic properties prediction. The similarities between experimental and calculated values were evaluated using PCA and CA as a statistical tool. The statistical analysis implies that plasma protein binding is a complex process, and theoretical approaches still cannot fully replace experimental ones. Full article

(This article belongs to the Special Issue Plant-Derived Anti-inflammatory Agents: Molecular Pharmacology and Further Studies)

► Show Figures

Graphical abstract

21 pages, 5851 KiB

Open AccessArticle

Malva parviflora Leaves and Fruits Mucilage as Natural Sources of Anti-Inflammatory, Antitussive and Gastro-Protective Agents: A Comparative Study Using Rat Models and Gas Chromatography

by Ahmed E. Altyar, Ans Munir, Saiqa Ishtiaq, Muhammad Rizwan, Khizar Abbas, Osama Kensara, Sameh S. Elhady, Waleed Y. Rizg, Fadia S. Youssef and Mohamed L. Ashour

Pharmaceuticals 2022, 15(4), 427; https://doi.org/10.3390/ph15040427 - 31 Mar 2022

Cited by 7 | Viewed by 2966

Abstract

Malva parviflora L., Little mallow, has been traditionally used as an alternative food source. It acts as a medicinal herb containing a potential source of mucilage thus herein; we aimed to assess the toxicity, anti-inflammatory, antitussive and gastro-protective actions of M. parviflora mucilage [...] Read more.

Malva parviflora L., Little mallow, has been traditionally used as an alternative food source. It acts as a medicinal herb containing a potential source of mucilage thus herein; we aimed to assess the toxicity, anti-inflammatory, antitussive and gastro-protective actions of M. parviflora mucilage extracted from its leaves (MLM) and fruit (MFM). Toxicity studies were investigated by in vitro hemolytic assay whereas acute anti-inflammatory and antitussive activities were assessed by carrageenan-induced paw edema and sulphur dioxide induced cough model in rats, respectively. Gastro-protective effects were studied using ethanol induced acute and chronic gastric ulcer rat models. Their metabolic profiles were determined using gas chromatography. The results revealed that MLM and MFM were non-toxic towards human erythrocytes and their lethal doses were found to be greater than 5 g/kg. Pretreatment with MLM (500 mg/kg) and MFM (500 mg/kg) significantly reduced the carrageenan-induced paw thickness (p < 0.001). Maximum edema inhibition (%) was observed at 4 h in diclofenac sodium (39.31%) followed by MLM (27.35%) and MFM (15.68%). Animals pretreated with MLM (500 mg/kg) significantly lower the cough frequency in SO₂ gas induced cough models in contrast to control. Moreover, MLM at doses of 250 and 500 mg/kg reduced the ethanol induced gastric mucosal injuries in acute gastric ulcer models presenting ulcer inhibition of 23.04 and 38.74%, respectively. The chronic gastric ulcer model MFM (500 mg/kg) demonstrated a remarkable gastro-protective effect showing 63.52% ulcer inhibition and results were closely related to standard drug sucralfate. In both models, MLM and MFM decreased gastric juice volume and total acidity in addition to an increased gastric juice pH and gastric mucous content justifying an anti-secretary role of this mucilage that was further confirmed by histopathological examination. Meanwhile, GC analyses of the mucilage revealed their richness with natural as well as acidic monosaccharides. It is concluded that MLM and MFM can be used therapeutically for the management of inflammation, cough and gastric ulcer. Full article

(This article belongs to the Special Issue Plant-Derived Anti-inflammatory Agents: Molecular Pharmacology and Further Studies)

► Show Figures

Figure 1

Review

Jump to: Research

22 pages, 1331 KiB

Open AccessReview

Effects of Natural Product-Derived Compounds on Inflammatory Pain via Regulation of Microglial Activation

by Joon Park, Changho Lee and Yun Tai Kim

Pharmaceuticals 2023, 16(7), 941; https://doi.org/10.3390/ph16070941 - 29 Jun 2023

Cited by 2 | Viewed by 1718

Abstract

Inflammatory pain is a type of pain caused by tissue damage associated with inflammation and is characterized by hypersensitivity to pain and neuroinflammation in the spinal cord. Neuroinflammation is significantly increased by various neurotransmitters and cytokines that are expressed in activated primary afferent [...] Read more.

Inflammatory pain is a type of pain caused by tissue damage associated with inflammation and is characterized by hypersensitivity to pain and neuroinflammation in the spinal cord. Neuroinflammation is significantly increased by various neurotransmitters and cytokines that are expressed in activated primary afferent neurons, and it plays a pivotal role in the development of inflammatory pain. The activation of microglia and elevated levels of pro-inflammatory cytokines are the hallmark features of neuroinflammation. During the development of neuroinflammation, various intracellular signaling pathways are activated or inhibited in microglia, leading to the regulation of inflammatory proteins and cytokines. Numerous attempts have been conducted to alleviate inflammatory pain by inhibiting microglial activation. Natural products and their compounds have gained attention as potential candidates for suppressing inflammatory pain due to verified safety through centuries of use. Many studies have also shown that natural product-derived compounds have the potential to suppress microglial activation and alleviate inflammatory pain. Herein, we review the literature on inflammatory mediators and intracellular signaling involved in microglial activation in inflammatory pain, as well as natural product-derived compounds that have been found to suppress microglial activation. This review suggests that natural product-derived compounds have the potential to alleviate inflammatory pain through the suppression of microglial activation. Full article

(This article belongs to the Special Issue Plant-Derived Anti-inflammatory Agents: Molecular Pharmacology and Further Studies)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Plant-Derived Anti-inflammatory Agents: Molecular Pharmacology and Further Studies

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI