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Multi-Targeted Natural Products as Therapeutics

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Natural Products".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 26405

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Special Issue Editors

Dr. Elena Y. Enioutina

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Guest Editor

Division of Clinical Pharmacology, Pediatrics Department, School of Medicine, University of Utah, 295 Chipeta Way, Salt Lake City, Utah, USA
Interests: effectiveness and safety of natural products; herbal-drug interactions; pediatric clinical pharmacology

Dr. Kathleen M. Job

E-Mail Website
Guest Editor

Division of Clinical Pharmacology, Pediatrics Department, School of Medicine, University of Utah, 295 Chipeta Way, Salt Lake City, UT, USA
Interests: effectiveness and safety of natural products; herbal-drug interactions; pediatric clinical pharmacology

Prof. Dr. Catherine Sherwin

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Guest Editor

Department of Pediatrics, Boonshoft School of Medicine, Wright State University/Dayton Children’s Hospital, Dayton, OH 45404, USA
Interests: effectiveness and safety of natural products; herbal-drug interactions; pediatric clinical pharmacology

Special Issue Information

Dear Colleagues,

For centuries, humans have used medicinal herbs and other natural products to treat and prevent various diseases. In the 20th century, many new drugs approved by regulatory agencies worldwide were isolated from natural products. Consequently, medicinal herbs and other natural products represent a valuable resource and source for drug development.

Nowadays, we realize that the pathogenesis of many diseases is multifactorial. Therefore, successful treatment of these diseases should target several pathways for successful disease treatment. Conventional drugs, which are single-molecule medicines, usually target a single pathway or specific body function. Unlike conventional drugs, folk medicine traditionally uses one or more natural products to prepare extracts, infusions, and decoctions. A preparation from even one medicinal herb may contain hundreds, if not thousands, of bioactive molecules. These molecules target functions of different organs and systems and potentiate or antagonize the functions of the preparation's other bioactive molecules. For example, many, if not all, antibacterial and antiviral drugs also possess immunomodulatory properties. Another example is that anti-cancer remedies may activate or suppress various pathways involved in cancer development and progression.

In this Special Issue, we aim to summarize and examine the latest research findings, identifying natural products targeting multiple pathways and body functions that can lead to the successful treatment of multifactorial diseases.

On 28 September 2023, we chaired a webinar with the theme "Can phytomedicine target organ and system functions via multiple pathways?" (https://pharmaceuticals-2.sciforum.net/). Click the link to find the recordings of this webinar to watch, re-watch, and share with your colleagues!

Dr. Elena Y. Enioutina
Dr. Kathleen M. Job
Prof. Dr. Catherine Sherwin
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

natural products
medicinal herbs
marine products
animal products
bioactive compounds
multifactorial diseases
multi-targeting phytochemicals

Published Papers (14 papers)

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Research

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17 pages, 1574 KiB

Open AccessArticle

Proportion of Over-The-Counter Medicines Containing a Plant Component and Those with Synthetic Substances Administered among Children in a Bulgarian Population

by Bozhidarka Hadzhieva and Valentina Petkova-Dimitrova

Pharmaceuticals 2024, 17(2), 192; https://0-doi-org.brum.beds.ac.uk/10.3390/ph17020192 - 31 Jan 2024

Viewed by 726

Abstract

Over-the-counter medicines are intended to influence a number of symptoms and also to cure some human diseases without having to see the doctor. These medicines are used for self-medication and parents also give them to their children. The following fall within the scope of over-the-counter medicines: analgesics, antipyretics, antihistamines, decongestants, gastroprotectors, anti-cough medicines, and others. Their composition also includes one or a combination of medicinal plants. In addition to synthetic substances, some nonprescription medicines contain plant substances and their derivatives. Medicinal plants and their extracted derivatives are applicable in the therapies of a number of diseases. Considering the fact that over-the-counter medicines can be used among children from birth, the subject of our study is those whose composition includes biologically active plant substances. Within this study, we have established the number of nonprescription medicines containing a plant substance individually or in combination with another substance of the same kind and/or other substances, which have been included in a list published on the website of the Bulgarian Drug Agency. The objective of our study is to present the percentage of OTC medicines containing a plant substance intended to affect the symptoms of upper respiratory tract diseases and pain, which are used among children during different periods of their development. Some of these medicines also contain substances such as antihistamines (pheniramine maleate) and decongestants (pseudoephedrine, phenylephrine hydrochloride, dimetidine) that can cause various unwanted side effects. Considering the aforementioned aspects and also the peculiarities of childhood, we recommend that self-treatment be conducted only after consulting a health specialist. Full article

(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)

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17 pages, 1938 KiB

Open AccessArticle

In Vitro Screening of Antimicrobial and Anti-Coagulant Activities, ADME Profiling, and Molecular Docking Study of Citrus limon L. and Citrus paradisi L. Cold-Pressed Volatile Oils

by Assia Hamdi, Mabrouk Horchani, Hichem Ben Jannet, Mejdi Snoussi, Emira Noumi, Nouha Bouali, Adel Kadri, Flavio Polito, Vincenzo De Feo and Hayet Edziri

Pharmaceuticals 2023, 16(12), 1669; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16121669 - 30 Nov 2023

Viewed by 1274

Abstract

Citrus, which belongs to the Rutaceae family, is a very widespread genus in the Mediterranean Basin. In Tunisia, various parts of these spontaneous or cultivated plants are used in common dishes or in traditional medicine. The purpose of this work was to investigate C. limon and C. paradisi essential oil (EO). The samples were studied for their chemical composition using SPME/MS, as well as their antibacterial and antifungal activities. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) methods were used to evaluate the anticoagulant potentialities. The obtained results show that both essential oils are rich in monoterpenes hydrocarbons, whereby limonene is the main compound in C. paradisi EO (86.8%) and C. limon EO (60.6%). Moreover, C. paradisi EO contains β-pinene (13.3%), sabinene (2.2%) and α-pinene (2.1%). The antibacterial assay of the essential oils showed important bactericidal and fungicidal effects against all strains tested. In fact, the MICs values of C. limon EO ranged from 0.625 to 2.5 mg/mL against all Gram-positive and Gram-negative bacteria, and from 6.25 to 12.5 mg/mL for Candida spp. strains, while C. paradisi EO was more active against all bacteria with low MICs values ranging from 0.192 to 0.786 mg/mL, and about 1.5 mg/mL against Candida species. Both tested Citrus EOs exhibited interesting anticoagulant activities as compared to heparin. The molecular docking approach was used to study the binding affinity and molecular interactions of all identified compounds with active sites of cytidine deaminase from Klebsiella pneumoniae (PDB: 6K63) and the C (30) carotenoid dehydrosqualene synthase from Staphylococcus aureus (PDB: 2ZCQ). The obtained results show that limonene had the highest binding score of −4.6 kcal.mol⁻¹ with 6K63 enzyme, and −6.7 kcal.mol⁻¹ with 2ZCQ receptor. The ADME profiling of the major constituents confirmed their important pharmacokinetic and drug-like properties. Hence, the obtained results highlight the potential use of both C. limon and C. paradisi essential oils as sources of bioactive compounds with antibacterial, antifungal, and anti-coagulant activities. Full article

(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)

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14 pages, 1434 KiB

Open AccessArticle

Modulation of Hepatic Functions by Chicory (Cichorium intybus L.) Extract: Preclinical Study in Rats

by Lubov V. Krepkova, Alexandra N. Babenko, Svetlana V. Lemyaseva, Olga L. Saybel, Catherine M. Sherwin and Elena Y. Enioutina

Pharmaceuticals 2023, 16(10), 1471; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16101471 - 16 Oct 2023

Viewed by 1140

Abstract

The liver is important in detoxifying organisms from xenobiotics, supporting immune functions, and metabolizing lipids and glucose. In addition, a growing number of drug-induced liver injuries and diseases associated with liver dysfunction make the development of phytodrugs targeting multiple liver functions particularly crucial. Therefore, we investigated the effects of a novel chicory extract prepared from aerial parts of the wild Cichorium intybus L. plant (CE) on liver enzymes and on lipid and glucose metabolism in rats with acute liver injury or hyperlipidemia. A single subcutaneous injection of mercury chloride induced an acute liver injury. Hyperlipidemia was induced by a single intraperitoneal injection of Tween-80 or by feeding rats with cholesterol and mercazolil for 28 days. Under varying regimens, the experimental rats received 100 mg/kg b.w. or 500 mg/kg b.w. of CE. CE treatment ameliorated acute liver injury by reducing liver enzyme activity, bilirubin, glucose, and lipid levels. Treatment of hyperlipidemic rats with CE effectively reduced serum lipid and glucose levels. The data obtained in this study suggest that chicory-based phytodrugs may be used to effectively treat acute liver injury and for the prophylaxis or treatment of diseases such as hyperlipidemia, type 2 diabetes, and metabolic syndrome. Clinical trials are needed to prove the effectiveness of chicory extract in human patients. Full article

(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)

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16 pages, 1787 KiB

Open AccessArticle

Galangal–Cinnamon Spice Mixture Blocks the Coronavirus Infection Pathway through Inhibition of SARS-CoV-2 M^Pro, Three HCoV-229E Targets; Quantum-Chemical Calculations Support In Vitro Evaluation

by Doaa G. El-Hosari, Wesam M. Hussein, Marwa O. Elgendy, Sara O. Elgendy, Ahmed R. N. Ibrahim, Alzhraa M. Fahmy, Afnan Hassan, Fatma Alzahraa Mokhtar, Modather F. Hussein, Mohamed E. A. Abdelrahim and Eman G. Haggag

Pharmaceuticals 2023, 16(10), 1378; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16101378 - 28 Sep 2023

Cited by 3 | Viewed by 2152

Abstract

Natural products such as domestic herbal drugs which are easily accessible and cost-effective can be used as a complementary treatment in mild and moderate COVID-19 cases. This study aimed to detect and describe the efficiency of phenolics detected in the galangal–cinnamon mixture in the inhibition of SARS-CoV-2’s different protein targets. The potential antiviral effect of galangal–cinnamon aqueous extract (GCAE) against Low Pathogenic HCoV-229E was assessed using cytopathic effect inhibition assay and the crystal violet method. Low Pathogenic HCoV-229E was used as it is safer for in vitro laboratory experimentation and due to the conformation and the binding pockets similarity between HCoV-229E and SARS-CoV-2 M^Pro. The GCAE showed a significant antiviral effect against HCoV-229E (IC₅₀ 15.083 µg/mL). Twelve phenolic compounds were detected in the extract with ellagic, cinnamic, and gallic acids being the major identified phenolic acids, while rutin was the major identified flavonoid glycoside. Quantum-chemical calculations were made to find molecular properties using the DFT/B3LYP method with 6-311++G(2d,2p) basis set. Quantum-chemical values such as EHOMO, ELUMO, energy gap, ionization potential, chemical hardness, softness, and electronegativity values were calculated and discussed. Phenolic compounds detected by HPLC-DAD-UV in the GCAE were docked into the active site of 3 HCoV-229E targets (PDB IDs. 2ZU2, 6U7G, 7VN9, and 6WTT) to find the potential inhibitors that block the Coronavirus infection pathways from quantum and docking data for these compounds. There are good adaptations between the theoretical and experimental results showing that rutin has the highest activity against Low Pathogenic HCoV-229E in the GCAE extract. Full article

(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)

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24 pages, 8132 KiB

Open AccessFeature PaperArticle

Quality, Safety and Biological Studies on Campylanthus glaber Aerial Parts

by Katelene Lima, Maryam Malmir, Sérgio P. Camões, Kamrul Hasan, Samuel Gomes, Isabel Moreira da Silva, Maria Eduardo Figueira, Joana P. Miranda, Rita Serrano, Maria Paula Duarte and Olga Silva

Pharmaceuticals 2023, 16(10), 1373; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16101373 - 28 Sep 2023

Viewed by 908

Abstract

In Cabo Verde, several endemic species are used in traditional medicine. However, no scientific studies have been conducted on the quality, efficacy, and safety of most of these plants. This study focused on establishing the botanical and chemical identification parameters required for a quality monograph of Campylanthus glaber Benth. aerial parts, a medicinal plant of Cabo Verde traditionally used to treat fever and muscular pain. In addition, in vitro antioxidant and antihyperglycemic activity, cytotoxicity, and genotoxicity were assessed for this medicinal plant. Optical microscopy, LC/UV-DAD-ESI/MS, and colorimetric assays were used for botanical, chemical, and biological studies, respectively. Cytotoxicity was assessed by the MTT assay with HepG2 cells, and genotoxicity by the Ames test. Microscopically, the xeromorphic leaf of C. glaber presents a thick cuticle (13.6–25.5 µm), thick-walled epidermal cells, anomocytic-type stomata, glandular trichomes (stalk length = 49.4–120.8 µm), and idioblasts containing calcium oxalate microcrystals. The chemical screening of aqueous and hydroethanolic extracts of this medicinal plant revealed the presence of organic acids, iridoids, phenylethanoids, and flavonoids as the main classes of marker compounds, with malic acid, citric acid, and verbascoside being the main marker compounds identified. Both extracts showed similar LC/UV-DAD/ESI-MS qualitative profiles and DPPH radical scavenger activity (IC₅₀ = 130.9 ± 1.4; 134.3 ± 3.1 µg/mL). The hydroethanolic extract inhibited both α-amylase and α-glucosidase enzymes in a dose-dependent manner. Both extracts showed no cytotoxicity (up to 1000 µg/mL) by the MTT assay and no genotoxic potential with or without metabolic activation up to 5 mg /plate. The results obtained are an important contribution to the monographic quality assessment of C. glaber aerial parts and suggest that this medicinal plant may be safe and potentially used as an herbal drug raw material for pharmaceutical purposes. Full article

(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)

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18 pages, 5200 KiB

Open AccessArticle

Synergistic Antihyperglycemic and Antihyperlipidemic Effect of Polyherbal and Allopolyherbal Formulation

by Yahya Alhamhoom, Syed Sagheer Ahmed, Rupesh Kumar M., MD. Salahuddin, Bharathi D. R., Mohammed Muqtader Ahmed, Syeda Ayesha Farhana and Mohamed Rahamathulla

Pharmaceuticals 2023, 16(10), 1368; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16101368 - 27 Sep 2023

Viewed by 1090

Abstract

Polyherbal formulation (PHF) enhances therapeutic efficacy and minimizes side effects by reducing individual herb dosages. Allopolyherbal formulation (APHF) combines polyherbal extracts with allopathic medication, effectively reducing the latter’s required dose and mitigating associated adverse effects. The current study intends to assess the anti-diabetic effects of PHF and APHF in-vivo. Dried raw powders of Cassia auriculata leaf, Centella asiatica leaf, and Zingiber officinale rhizome were extracted by cold maceration process using 70% ethanol. These extracts were combined in three different ratios to make PHF. PHF was subjected to qualitative and quantitative phytochemical investigations. APHF has been prepared by combining a potent ratio of PHF with metformin in three different ratios. The compatibility of APHF has been confirmed by differential scanning calorimetry (DSC). In vivo activity was also evaluated in streptozotocin-induced diabetic albino rats. PHF (3 different ratios at a dose of 200–400 mg/kg b.w), APHF (combination of PHF and metformin in 3 different ratios, 200 + 22.5, 200 + 45, and 200 + 67.5 mg/kg b.w), and metformin (90 mg/kg b.w) were administered to albino rats for 21 consecutive days. Blood glucose levels were estimated on the 1st, 7th, 14th, and 21st days of treatment. On the 21st day, blood was collected by cardiac puncture for biochemical analysis. The liver and pancreas were isolated and subjected to histopathological analysis. PHF and APHF showed significant anti-diabetic and antihyperlipidemic efficacy. In comparison to PHF, APHF had the most promising action. The current study demonstrated that PHF and APHF are safe and efficacious drugs in the treatment of diabetes mellitus as they help to replace or lower the dose of metformin, thereby decreasing the risks of metformin. Full article

(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)

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19 pages, 5252 KiB

Open AccessArticle

Inhibition of TRPA1, Endoplasmic Reticulum Stress, Human Airway Epithelial Cell Damage, and Ectopic MUC5AC Expression by Vasaka (Adhatoda vasica; Malabar Nut) Tea

by Tosifa A. Memon, Lili Sun, Marysol Almestica-Roberts, Cassandra E. Deering-Rice, Philip J. Moos and Christopher A. Reilly

Pharmaceuticals 2023, 16(6), 890; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16060890 - 17 Jun 2023

Viewed by 1381

Abstract

This study tested whether a medicinal plant, Vasaka, typically consumed as a tea to treat respiratory malaise, could protect airway epithelial cells (AECs) from wood smoke particle-induced damage and prevent pathological mucus production. Wood/biomass smoke is a pneumotoxic air pollutant. Mucus normally protects the airways, but excessive production can obstruct airflow and cause respiratory distress. Vasaka tea pre- and co-treatment dose-dependently inhibited mucin 5AC (MUC5AC) mRNA induction by AECs treated with wood smoke particles. This correlated with transient receptor potential ankyrin-1 (TRPA1) inhibition, an attenuation of endoplasmic reticulum (ER) stress, and AEC damage/death. Induction of mRNA for anterior gradient 2, an ER chaperone/disulfide isomerase required for MUC5AC production, and TRP vanilloid-3, a gene that suppresses ER stress and wood smoke particle-induced cell death, was also attenuated. Variable inhibition of TRPA1, ER stress, and MUC5AC mRNA induction was observed using selected chemicals identified in Vasaka tea including vasicine, vasicinone, apigenin, vitexin, isovitexin, isoorientin, 9-oxoODE, and 9,10-EpOME. Apigenin and 9,10-EpOME were the most cytoprotective and mucosuppressive. Cytochrome P450 1A1 (CYP1A1) mRNA was also induced by Vasaka tea and wood smoke particles. Inhibition of CYP1A1 enhanced ER stress and MUC5AC mRNA expression, suggesting a possible role in producing protective oxylipins in stressed cells. The results provide mechanistic insights and support for the purported benefits of Vasaka tea in treating lung inflammatory conditions, raising the possibility of further development as a preventative and/or restorative therapy. Full article

(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)

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Review

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19 pages, 2938 KiB

Open AccessReview

Unveiling the Potential of Ent-Kaurane Diterpenoids: Multifaceted Natural Products for Drug Discovery

by Shadrack Kibet, Njogu M. Kimani, Syombua S. Mwanza, Cynthia M. Mudalungu, Cleydson B. R. Santos and Chrysantus M. Tanga

Pharmaceuticals 2024, 17(4), 510; https://0-doi-org.brum.beds.ac.uk/10.3390/ph17040510 - 16 Apr 2024

Viewed by 477

Abstract

Natural products hold immense potential for drug discovery, yet many remain unexplored in vast libraries and databases. In an attempt to fill this gap and meet the growing demand for effective drugs, this study delves into the promising world of ent-kaurane diterpenoids, a class of natural products with huge therapeutic potential. With a dataset of 570 ent-kaurane diterpenoids obtained from the literature, we conducted an in silico analysis, evaluating their physicochemical, pharmacokinetic, and toxicological properties with a focus on their therapeutic implications. Notably, these natural compounds exhibit drug-like properties, aligning closely with those of FDA-approved drugs, indicating a high potential for drug development. The ranges of the physicochemical parameters were as follows: molecular weights—288.47 to 626.82 g/mol; number of heavy atoms—21 to 44; the number of hydrogen bond donors and acceptors—0 to 8 and 1 to 11, respectively; the number of rotatable bonds—0 to 11; fraction Csp3—0.65 to 1; and TPSA—20.23 to 189.53 Å². Additionally, the majority of these molecules display favorable safety profiles, with only 0.70%, 1.40%, 0.70%, and 46.49% exhibiting mutagenic, tumorigenic, reproduction-enhancing, and irritant properties, respectively. Importantly, ent-kaurane diterpenoids exhibit promising biopharmaceutical properties. Their average lipophilicity is optimal for drug absorption, while over 99% are water-soluble, facilitating delivery. Further, 96.5% and 28.20% of these molecules exhibited intestinal and brain bioavailability, expanding their therapeutic reach. The predicted pharmacological activities of these compounds encompass a diverse range, including anticancer, immunosuppressant, chemoprotective, anti-hepatic, hepatoprotectant, anti-inflammation, antihyperthyroidism, and anti-hepatitis activities. This multi-targeted profile highlights ent-kaurane diterpenoids as highly promising candidates for further drug discovery endeavors. Full article

(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)

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28 pages, 7614 KiB

Open AccessReview

Multitargeted Herbal Prescription So Shiho Tang: A Scoping Review on Biomarkers for the Evaluation of Therapeutic Effects

by Nguyen Khoi Song Tran, Ji Hwan Lee, Myong Jin Lee, Jun Yeon Park and Ki Sung Kang

Pharmaceuticals 2023, 16(10), 1371; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16101371 - 27 Sep 2023

Cited by 1 | Viewed by 1018

Abstract

Alternative medicines, especially herbal remedies, have been employed to treat infections and metabolism-related chronic inflammation because their safety and multidimensional therapeutic potential outweigh those of synthetic drugs. So Shiho Tang (SSHT), a well-known Oriental prescription (Xiao Chai Hu Tang in Chinese) composed of seven herbs, is traditionally prescribed to treat various viral infections and chronic metabolic disorders in Asia with or without the support of other natural medicines. To provide a general background on how SSHT is used as a medicinal alternative, we conducted a scoping review using the PubMed database system. Among the 453 articles, 76 studies used aqueous extracts of SSHT alone. This result included seven clinical studies and 69 basic studies: cell-based, animal-based, and ex vivo studies. The in vitro and clinical reports mainly focus on hepatic infection and hepatocarcinoma, and the documentation of in vivo tests of SSHT presents a wide range of effects on cancer, fibrosis, inflammation, and several metabolic disorder symptoms. Additionally, among the seven clinical records, two reverse-effect case studies were reported in middle-aged patients. In brief, this systematic review provides general knowledge on the natural remedy SSHT and its potential in phytotherapeutic primary health care. Full article

(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)

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19 pages, 681 KiB

Open AccessReview

Mitigation of Insulin Resistance by Natural Products from a New Class of Molecules, Membrane-Active Immunomodulators

by Elzbieta Izbicka and Robert T. Streeper

Pharmaceuticals 2023, 16(7), 913; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16070913 - 21 Jun 2023

Viewed by 2114

Abstract

Insulin resistance (IR), accompanied by an impaired cellular glucose uptake, characterizes diverse pathologies that include, but are not limited to, metabolic disease, prediabetes and type 2 diabetes. Chronic inflammation associated with deranged cellular signaling is thought to contribute to IR. The key molecular players in IR are plasma membrane proteins, including the insulin receptor and glucose transporter 4. Certain natural products, such as lipids, phenols, terpenes, antibiotics and alkaloids have beneficial effects on IR, yet their mode of action remains obscured. We hypothesized that these products belong to a novel class of bioactive molecules that we have named membrane-active immunomodulators (MAIMs). A representative MAIM, the naturally occurring medium chain fatty acid ester diethyl azelate (DEA), has been shown to increase the fluidity of cell plasma membranes with subsequent downstream effects on cellular signaling. DEA has also been shown to improve markers of IR, including blood glucose, insulin and lipid levels, in humans. The literature supports the notion that DEA and other natural MAIMs share similar mechanisms of action in improving IR. These findings shed a new light on the mechanism of IR mitigation using natural products, and may facilitate the discovery of other compounds with similar activities. Full article

(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)

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27 pages, 2549 KiB

Open AccessReview

Hypericum perforatum L. and the Underlying Molecular Mechanisms for Its Choleretic, Cholagogue, and Regenerative Properties

by Ala Mohagheghzadeh, Parmis Badr, Abdolali Mohagheghzadeh and Shiva Hemmati

Pharmaceuticals 2023, 16(6), 887; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16060887 - 15 Jun 2023

Cited by 1 | Viewed by 2576

Abstract

Any defects in bile formation, secretion, or flow may give rise to cholestasis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. As the pathogenesis of hepatic disorders is multifactorial, targeting parallel pathways potentially increases the outcome of therapy. Hypericum perforatum has been famed for its anti-depressive effects. However, according to traditional Persian medicine, it helps with jaundice and acts as a choleretic medication. Here, we will discuss the underlying molecular mechanisms of Hypericum for its use in hepatobiliary disorders. Differentially expressed genes retrieved from microarray data analysis upon treatment with safe doses of Hypericum extract and intersection with the genes involved in cholestasis are identified. Target genes are located mainly at the endomembrane system with integrin-binding ability. Activation of α5β1 integrins, as osmo-sensors in the liver, activates a non-receptor tyrosine kinase, c-SRC, which leads to the insertion of bile acid transporters into the canalicular membrane to trigger choleresis. Hypericum upregulates CDK6 that controls cell proliferation, compensating for the bile acid damage to hepatocytes. It induces ICAM1 to stimulate liver regeneration and regulates nischarin, a hepatoprotective receptor. The extract targets the expression of conserved oligomeric Golgi (COG) and facilitates the movement of bile acids toward the canalicular membrane via Golgi-derived vesicles. In addition, Hypericum induces SCP2, an intracellular cholesterol transporter, to maintain cholesterol homeostasis. We have also provided a comprehensive view of the target genes affected by Hypericum’s main metabolites, such as hypericin, hyperforin, quercitrin, isoquercitrin, quercetin, kaempferol, rutin, and p-coumaric acid to enlighten a new scope in the management of chronic liver disorders. Altogether, standard trials using Hypericum as a neo-adjuvant or second-line therapy in ursodeoxycholic-acid-non-responder patients define the future trajectories of cholestasis treatment with this product. Full article

(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)

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18 pages, 1616 KiB

Open AccessReview

Natural Products Targeting PI3K/AKT in Myocardial Ischemic Reperfusion Injury: A Scoping Review

by Syarifah Aisyah Syed Abd Halim, Norhashima Abd Rashid, Choy Ker Woon and Nahdia Afiifah Abdul Jalil

Pharmaceuticals 2023, 16(5), 739; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16050739 - 12 May 2023

Cited by 4 | Viewed by 1693

Abstract

This scoping review aimed to summarize the effects of natural products targeting phosphoinositide-3-kinases/serine/threonine kinase (PI3K/AKT) in myocardial ischemia-reperfusion injury (MIRI). The review details various types of natural compounds such as gypenoside (GP), gypenoside XVII (GP-17), geniposide, berberine, dihydroquercetin (DHQ), and tilianin which identified to reduce MIRI in vitro and in vivo by regulating the PI3K/AKT signaling pathway. In this study, 14 research publications that met the inclusion criteria and exclusion criteria were shortlisted. Following the intervention, we discovered that natural products effectively improved cardiac functions through regulation of antioxidant status, down-regulation of Bax, and up-regulation of Bcl-2 and caspases cleavage. Furthermore, although comparing outcomes can be challenging due to the heterogeneity in the study model, the results we assembled here were consistent, giving us confidence in the intervention’s efficacy. We also discussed if MIRI is associated with multiple pathological condition such as oxidative stress, ERS, mitochondrial injury, inflammation, and apoptosis. This brief review provides evidence to support the huge potential of natural products used in the treatment of MIRI due to their various biological activities and drug-like properties. Full article

(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)

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28 pages, 1609 KiB

Open AccessReview

Natural Ingredients to Improve Immunity

by Amin Gasmi, Mariia Shanaida, Oleksandra Oleshchuk, Yuliya Semenova, Pavan Kumar Mujawdiya, Yana Ivankiv, Olena Pokryshko, Sadaf Noor, Salva Piscopo, Stepan Adamiv and Geir Bjørklund

Pharmaceuticals 2023, 16(4), 528; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16040528 - 01 Apr 2023

Cited by 9 | Viewed by 5918

Abstract

The immune system protects the body from infectious agents such as bacteria, viruses, or fungi. Once encountered with pathogens or antigens, the innate and adaptive arms of the immune system trigger a strong immune response to eliminate them from the system and protect the body. Thus, well-balanced immunity is pivotal for maintaining human health, as an insufficient level of immune defense leads to infections and tumors. In contrast, the excessive functioning of the immune system causes the development of autoimmune diseases and allergies. Strong immunity requires adequate nutrition, dietary interventions, and sufficient intake of certain vitamins (vitamin C, vitamin D, and folic acid) and minerals (magnesium, zinc, and selenium). Therefore, nutritional and micronutrient deficiencies lead to compromised immunity. Several natural ingredients have shown potent immunomodulatory properties. The immune-enhancing properties of many plants and fungi are due to containing bioactive phytoconstituents such as polyphenols, terpenoids, β-glucans, vitamins, etc. Probiotics and prebiotics can be used as innovative tools to reduce intestinal inflammation and downregulate hypersensitivity reactions. Plant sources of melatonin, a multifunctional molecule with proven anti-inflammatory and immunomodulatory properties, have been discovered relatively recently. The bioactive compounds augment the immune response by directly increasing the cytotoxic activity of natural killer cells, macrophages, and neutrophils. Many phytoconstituents prevent cell damage due to their powerful antimicrobial, antioxidant, and anti-inflammatory properties. The present review attempts to understand the molecular mechanisms underlying the immune-enhancing properties of some bioactive compounds from plants, fungi, animals, microorganisms, and other natural sources. Full article

(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)

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37 pages, 705 KiB

Open AccessSystematic Review

Mechanistic Evidence of Andrographis paniculata (Burm. f.) Wall. ex Nees, Pelargonium sidoides DC., Echinacea Species and a Combination of Hedera helix L., Primula veris L./Primula elatior L. and Thymus vulgaris L./Thymus zygis L. in the Treatment of Acute, Uncomplicated Respiratory Tract Infections: A Systematic Literature Review and Expert Interviews

by Liesbeth B. M. Veldman, Eefje Belt-Van Zoen and Erik W. Baars

Pharmaceuticals 2023, 16(9), 1206; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16091206 - 24 Aug 2023

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Abstract

Reducing inappropriate antibiotic (AB) use by using effective non-antibiotic treatments is one strategy to prevent and reduce antimicrobial resistance (AMR). Andrographis paniculata (Burm. f.) Wall. ex Nees, Pelargonium sidoides DC., Echinacea species and a combination of ivy (Hedera helix L.), primrose (Primula veris L./Primula elatior L.) and thyme (Thymus vulgaris L./Thymus zygis L.) have promising clinical effects in uncomplicated, acute upper respiratory tract infections (URTI) treatment. However, mechanistic evidence of these herbal treatments is lacking. The objective of this Pstudy is to provide an overview of mechanistic evidence for these effects. Thirty-eight databases were searched. Included studies were mechanistic studies (in vitro, animal, and human studies and reviews) on these herbs; published before June 2021. Non-mechanistic studies or studies on combinations of herbs other than ivy/primrose/thyme were excluded. Furthermore, three experts in traditional, complementary and integrative healthcare (TCIH) research and pharmacognosy were interviewed to collect additional expert knowledge. The results show that A. paniculata acts through immunomodulation and antiviral activity, possibly supplemented by antibacterial and antipyretic effects. P. sidoides acts through antiviral, indirect antibacterial, immunomodulatory and expectorant effects. Echinacea species likely act through immunomodulation. The combination of ivy/primrose/thyme combines secretolytic and spasmolytic effects from ivy with antibacterial effects from thyme. Studies on primrose were lacking. This mechanistic evidence supports the difference-making evidence from clinical studies, contributes to evidence-based recommendations for their use in URTI treatment, and guides future mechanistic studies on URTI treatments. Full article

(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)

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