Intra-peritoneal lavage of Zingiber officinale rhizome and its active constituent gingerol impede inflammation, angiogenesis, and fibrosis following post-operative peritoneal adhesion in male rats.

Post-operative peritoneal adhesions (PA) are a common and important clinical problem. In this study, we focused on the ameliorative efficacy of ginger and gingerol compounds on surgical-induced peritoneal adhesion, and their strategies that disrupted the PA formation pathways to suppress their incidence. First, liquid chromatography-mass spectrometry (LC-MS) was established to separate and identify several chemical groups of ginger rhizome extract. In the next steps, male Wistar albino rats were randomly selected and divided into various groups, namely sham, control, ginger extract (0.6, 1.8, 5 %w/v), and gingerol (0.05, 0.1, 0.3, and 1 %w/v). Finally, we investigated the macroscopic parameters such as wound healing, body weight as well as spleen height and weight. In addition, visual peritoneal adhesion assessment was performed via Nair et al and Adhesion Scoring Scheme. Moreover, the microscopic parameters and biological assessment was performed via and immunoassays. The present findings revealed significant improvement in wound healing and reduction of the adhesion range, as Nair et al. and Adhesion Scoring Scheme scoring, in both the ginger and gingerol groups compared to the PA group (P < 0.05). Whereas, gingerol (0.3 % w/v) was able to increase the body weight in rats (P < 0.0001) at end stage of experiment. Also, inflammation, angiogenesis, and fibrosis were significantly decreased due to the downregulation of interleukin (IL)-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß1, vascular endothelial growth factor (VEGF), respectively, in the ginger and gingerol groups compared to the PA group (P < 0.05). In contrast, the levels of IL-10 were increased in the ginger and gingerol groups compared to the control group (P < 0.01). Our results proved that ginger rhizome and gingerol, as novel therapeutic compounds, could be used to prevent PA for their beneficial anti-inflammatory as well as anti-fibrosis properties in clinical trials. However, further clinical studies are required to approve the effectiveness of ginger and gingerol.

Protective effects of functional foods against Parkinson's disease: A narrative review on pharmacology, phytochemistry, and molecular mechanisms.

In Persian Medicine (PM), PD (brain-based tremor) is a known CNS disorder with several therapeutic and preventive options. In their medical textbooks and pharmacopeias, Persian great scientists such as Rhazes (854-925 AD), Avicenna (980-1037 AD), and Jorjani (1042-1136 AD), have discussed pharmacological and nutritional strategies for the prevention, slowing progression, and treatment of PD. In the present study, we surveyed plant- and animal-based foods recommended by PM for the prevention and treatment of CNS-related tremors. In vivo and in-vitro pharmacological evidence supporting the beneficial effects of PM-recommended foods in prevention and alleviating PD, major active phytochemicals along with the relevant mechanisms of action were studied. Several PM plants possess potent antioxidant, antiinflammatory, and PD preventing properties. Garlic and allicin, cabbage and isothiocyanates, chickpea seed and its O-methylated isoflavones biochanin A and formononetin, cinnamon, and cinnamaldehyde, saffron and its crocin, crocetin, and safranal, black cumin and its thymoquinone, black pepper and piperine, pistachio and genistein and daidzein, and resveratrol are among the most effective dietary itemsagainst PD. They act through attenuating neurotoxin-induced memory loss and behavioral impairment, oxidative stress, and dopaminergic cell death. PM-recommended foods can help alleviate PD progression and also discovering and developing new neuroprotective anti-PD pharmaceuticals.

A mechanistic insight into the biological activities of urolithins as gut microbial metabolites of ellagitannins.

Urolithins are the gut metabolites produced from ellagitannin-rich foods such as pomegranates, tea, walnuts, as well as strawberries, raspberries, blackberries, and cloudberries. Urolithins are of growing interest due to their various biological activities including cardiovascular protection, anti-inflammatory activity, anticancer properties, antidiabetic activity, and antiaging properties. Several studies mostly based on in vitro and in vivo experiments have investigated the potential mechanisms of urolithins which support the beneficial effects of urolithins in the treatment of several diseases such as Alzheimer's disease, type 2 diabetes mellitus, liver disease, cardiovascular disease, and various cancers. It is now obvious that urolithins can involve several cellular mechanisms including inhibition of MDM2-p53 interaction, modulation of mitogen-activated protein kinase pathway, and suppressing nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity. Antiaging activity is the most appealing and probably the most important property of urolithin A that has been investigated in depth in recent studies, owing to its unique effects on activation of mitophagy and mitochondrial biogenesis. A recent clinical trial showed that urolithin A is safe up to 2,500 mg/day and can improve mitochondrial biomarkers in elderly patients. Regarding the importance of mitochondria in the pathophysiology of many diseases, urolithins merit further research especially in clinical trials to unravel more aspects of their clinical significance. Besides the nutritional value of urolithins, recent studies proved that urolithins can be used as pharmacological agents to prevent or cure several diseases. Here, we comprehensively review the potential role of urolithins as new therapeutic agents with a special focus on the molecular pathways that have been involved in their biological effects. The pharmacokinetics of urolithins is also included.

Efficacy of Covexir® (Ferula foetida oleo-gum) treatment in symptomatic improvement of patients with mild to moderate COVID-19: A randomized, double-blind, placebo-controlled trial.

The SARS-CoV-2 COVID-19 pandemic has emerged as an unprecedented emergency state in healthcare system and global challenge. In recent decade, the function of exogenous H2 S in the treatment of respiratory diseases has been investigated using H2 S-donor agents. Ferula foetida is a medicinal plant that is traditionally used in respiratory diseases including asthma and viral respiratory diseases. The oleo-gum of this plant is a rich source of several organic sulfides including thiophenes, disulfides and polysulfide derivatives, which can act as H2 S-donor agents. The purpose of this study was to investigate the efficacy of Covexir® (F. foetida oleo-gum) treatment as a rich source of H2 S-donor compounds in clinical presentations of patients with COVID-19. The efficacy of Covexir® was evaluated in a randomized, double-blind, placebo-controlled trial in outpatients with COVID-19. Covexir® could significantly inhibit cough when compared to the placebo group (p < .01 and p < 001, respectively). Moreover, there was a significant difference (p < 001) between the two groups in dyspnea symptom at follow-up interval of 7 day after receiving Covexir®. Furthermore, on days 3 and 7, statistically significant differences were observed in myalgia, anorexia, anosmia, and sense of taste severity between two groups. Our findings revealed that Covexir® was very safe in the treatment of COVID-19 patients with mild to moderate symptoms and it can be recommended to improve clinical presentations of patients with COVID-19 such as cough, shortness of breath, myalgia, anorexia, anosmia, and sense of taste.

The effects of phytochemicals and herbal bio-active compounds on tumour necrosis factor-α in overweight and obese individuals: a clinical review.

Obesity is abnormal fat accumulation in the body which acts as a risk factor for various cardiometabolic states. Adipose tissue in excess can release inflammatory factors, including TNF-α and IL-6, and suppress adiponectin production. TNF-α increases the levels of IL-6 and acute phase reactants such as C-reactive protein. Inflammation has a crucial role in developing and progressing various cardiometabolic diseases and a wide range of obesity-related complications. It has been shown that TNF-α has a significant role in the development of insulin resistance. Recently, a growing body of evidence has focused on herbal medicine, phytochemicals and natural bioactive compounds as inexpensive, relatively easy accessible agents with low adverse effects to reduce inflammatory markers such as TNF-α and simultaneously decrease insulin resistance, glucose intolerance, and dyslipidemia in obesity. The main focus of the current review is to summarize the results of the studies, which assessed the effects of phytochemicals and herbal bio-active compounds on serum TNF-α in subjects with overweight or obesity. This review suggests that herbal medicine have favorable effects on the reduction of TNF-α concentration; however, the results were not uniform for different products. Among the reviewed plants, ginger, ginseng, resveratrol, and flaxseed had more promising effects.

Perspective on the application of medicinal plants and natural products in wound healing: A mechanistic review.

Wound is defined as any injury to the body such as damage to the epidermis of the skin and disturbance to its normal anatomy and function. Since ancient times, the importance of wound healing has been recognized, and many efforts have been made to develop novel wound dressings made of the best material for rapid and effective wound healing. Medicinal plants play a great role in the wound healing process. In recent decades, many studies have focused on the development of novel wound dressings that incorporate medicinal plant extracts or their purified active compounds, which are potential alternatives to conventional wound dressings. Several studies have also investigated the mechanism of action of various herbal medicines in wound healing process. This paper attempts to highlight and review the mechanistic perspective of wound healing mediated by plant-based natural products. The findings showed that herbal medicines act through multiple mechanisms and are involved in various stages of wound healing. Some herbal medicines increase the expression of vascular endothelial growth factor (VEGF) and transforming growth factor-ß (TGF-ß) which play important role in stimulation of re-epithelialization, angiogenesis, formation of granulation tissue, and collagen fiber deposition. Some other wound dressing containing herbal medicines act as inhibitor of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and inducible nitric oxide synthase (iNOS) protein expression thereby inducing antioxidant and anti-inflammatory properties in various phases of the wound healing process. Besides the growing public interest in traditional and alternative medicine, the use of herbal medicine and natural products for wound healing has many advantages over conventional medicines, including greater effectiveness due to diverse mechanisms of action, antibacterial activity, and safety in long-term wound dressing usage.

Metabolic differences of two Ferula species as potential sources of galbanum: An NMR-based metabolomics study.

INTRODUCTION: Ferula gummosa Boiss. and Ferula galbaniflua Boiss. & Buhse (Apiaceae) are two important Iranian plants that are considered as potential sources of galbanum (barijeh). Galbanum is traditionally used for treating different diseases including flatulence and memory impairment. OBJECTIVE: According to a phylogenetic analysis of the nrDNA ITS sequence and the Flora Iranica, F. gummosa has been considered as a synonym of F. galbaniflua. However, F. galbaniflua and F. gummosa grow in two different geographical locations and have different metabolic patterns. Some researchers believe that F. gummosa and F. galbaniflua are two distinct species. To discriminate these species, we compared metabolic profiles of F. gummosa and F. galbaniflua samples. METHODS: 1 H-NMR-based metabolomics analysis was used for classification of F. gummosa and F. galbaniflua samples collected from northeast Iran. The acquired data were analyzed using hierarchical cluster analysis (HCA), partial least squares discriminant analysis (PLS-DA) and orthogonal projection to latent structures discriminant analysis (OPLS-DA). RESULTS: The result showed a clear separation between the two species that may be related to the quantity and diversity of their metabolites. Ferula gummosa had higher mogoltacin levels, while F. galbaniflua had higher feselol levels. Ligupersin A and conferdione were significantly detected in F. gummosa, whereas sterol compounds were significantly detected in F. galbaniflua. CONCLUSION: Our findings indicate that clear metabolomics discrimination of F. gummosa and F. galbaniflua makes their chemotaxonomic classification possible.

Non-antibiotic adjunctive therapy: A promising approach to fight tuberculosis.

Tuberculosis (TB) is currently a clinical and public health problem. There is a concern about the emergence and development of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) species. Additionally, the lack of effective vaccines is another limitation to control the related infections. To overcome these problems various approaches have been pursued such as finding novel drug candidates with a new mechanism of action or repurposing conventional antibiotics. However, these strategies are still far from clinical application. Hence, the use of adjunctive therapy has been suggested for TB. In this paper, we review non-antibiotic adjunctive treatment options for TB. Natural products, vitamins, micronutrients, and trace elementals, as well as non-antibiotic drugs, are examples of agents which have been used as adjunctive therapies. The use of these adjunctive therapies has been shown to improve disease outcomes and reduce the adverse effects of antibiotic drugs. Employing these agents, either alone or in combination with antibiotics, might be considered as a promising approach to control TB infections and achieve better clinical outcomes. However, supportive evidence from randomized controlled trials is still scant and merits further investigations.

Antibacterial activity of flavonoids and their structure-activity relationship: An update review.

Based on World Health Organization reports, resistance of bacteria to well-known antibiotics is a major global health challenge now and in the future. Different strategies have been proposed to tackle this problem including inhibition of multidrug resistance pumps and biofilm formation in bacteria and development of new antibiotics with novel mechanism of action. Flavonoids are a large class of natural compounds, have been extensively studied for their antibacterial activity, and more than 150 articles have been published on this topic since 2005. Over the past decade, some promising results were obtained with the antibacterial activity of flavonoids. In some cases, flavonoids (especially chalcones) showed up to sixfold stronger antibacterial activities than standard drugs in the market. Some synthetic derivatives of flavonoids also exhibited remarkable antibacterial activities with 20- to 80-fold more potent activity than the standard drug against multidrug-resistant Gram-negative and Gram-positive bacteria (including Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus). This review summarizes the ever changing information on antibacterial activity of flavonoids since 2005, with a special focus on the structure-activity relationship and mechanisms of actions of this broad class of natural compounds.

The Protective Role of Phenolic Compounds Against Doxorubicin-induced Cardiotoxicity: A Comprehensive Review.

Although doxorubicin (DOX) is among the most widely used anticancer agents, its clinical application is hampered owing to its cardiotoxicity. Adjuvant therapy with an antioxidant has been suggested as a promising strategy to reduce DOX-induced adverse effects. In this context, many phenolic compounds have been reported to protect against DOX-induced cardiotoxicity. The cardioprotective effects of phenolic compounds are exerted via multiple mechanisms including inhibition of reactive oxygen species generation, apoptosis, NF-κB, p53, mitochondrial dysfunction, and DNA damage. In this review, we present a summary of the in vitro, in vivo, and clinical findings on the protective mechanisms of phenolic compounds against DOX-induced cardiotoxicity.

Highly Oxygenated Sesquiterpene Lactones from Cousinia aitchisonii and their Cytotoxic Properties: Rhaserolide Induces Apoptosis in Human T Lymphocyte (Jurkat) Cells via the Activation of c-Jun n-terminal Kinase Phosphorylation.

Infrared-guided chromatographic fractionation of sesquiterpene lactones from the extracts of Cousinia aitchisonii and Cousinia concolor led to the isolation of five pure compounds. A new sesquiterpene lactone, namely, aitchisonolide, and two known sesquiterpene lactones (desoxyjanerin and rhaserolide) were isolated from C. aitchisonii and two known lignans (arctiin and arctigenin) from C. concolor. The structures of these compounds were elucidated by one-dimensional and two-dimensional nuclear magnetic resonance techniques, as well as high-resolution mass spectrometry. The purified and characterized compounds were subjected to cytotoxicity assay. The sesquiterpene lactones desoxyjanerin and rhaserolide showed significant cytotoxic activities against five different cancer cell lines and the normal human embryonic kidney cell line. Rhaserolide was chosen to evaluate the possible mechanism of action. Western blot analysis revealed that rhaserolide could induce apoptosis in Jurkat cells via the activation of c-Jun n-terminal kinase phosphorylation.

Investigation of the antibacterial activity and efflux pump inhibitory effect of co-loaded piperine and gentamicin nanoliposomes in methicillin-resistant Staphylococcus aureus.

OBJECTIVE: Antibiotic resistance has stimulated the research for developing novel strategies that can prevent bacterial growth. Methicillin-resistant Staphylococcus aureus (MRSA), regarded as one of the most serious antibiotic-resistant bacteria which has been conventionally recognized as a nosocomial pathogen. MATERIALS AND METHODS: Nanoliposomal formulations of piperine and gentamicin were prepared by dehydration-rehydration (DRV) method and characterized for size, zeta potential and encapsulation efficiency. Antibactericidal activities of liposomal and free forms were evaluated against MRSA ATCC 43300 by the determination of minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and fractional inhibitory concentration index (FICI). The time-kill studies were carried out to evaluate the potency of antibacterial agents. The effect of piperine on bacterial efflux pumps was also investigated. RESULTS: MIC values of gentamicin and piperine were 32 and 100 µg/mL, respectively. Synergetic effects were observed by the combination of gentamicin and piperine and FICI was determined to be 0.5. Following incorporation of gentamicin into liposomal gentamicin and liposomal combination, the MIC values were reduced 16- and 32-fold, respectively. MBC values of gentamicin reduced 4 and 8 times following incorporation into gentamicin and combination liposomes, respectively. In comparison with vancomycin, liposomal combination was more effective in bacterial inhibition and killing. Liposomal combination was the most effective preparations in time-kill study. Our findings indicated that liposomal piperine was able to inhibit the efflux pump sufficiently. CONCLUSION: The results of this study revealed that liposomal combination is a powerful nano-antibacterial agent to eradicate MRSA infection. This dual-loaded formulation was an effective approach for eradication of MRSA.

Biological properties and molecular targets of umbelliprenin--a mini-review.

7-Prenyloxycoumarins are a group of secondary metabolites found mainly in plants belonging to the families Rutaceae and Apiaceae. Auraptene, umbelliprenin (UM), and 7-isopentenyloxycoumarin are some examples of prenylated coumarins. UM occurs in various edible plant species including celery, coriander, angelica, lemon, and particularly, Ferula species. Although UM was isolated more than 50 years ago, its biological activities have been studied since the last two decades. Besides anticancer activities, biological activities including anti-inflammatory, antioxidant, and antileishmanial activities have been reported from this natural compound. The present mini-review deals with the biological activities and mechanism of actions reported for UM.

Sesquiterpene lactones from Ferula oopoda and their cytotoxic properties.

Two new sesquiterpene lactones, namely feruhodin A and feruhodin B, together with six known compounds, daucoeudesmanolactone, dehydrooopodin, oopodin, badkhysin, 7-demethylplastochromenol, and scoparone, were isolated from the roots of Ferula oopoda. The structures of these compounds were elucidated by 1D and 2D NMR techniques as well as high-resolution mass spectrometry. Cytotoxic effects of these compounds were evaluated against two human cancer cell lines including MCF7and K562 using the Alamar blue assay. The results showed that dehydrooopodin possessed significant cytotoxic effects with IC50 values of 15 and 5 µM against MCF7 and K562, respectively.

Adlumiceine methyl ester, a new alkaloid from Fumaria vaillantii.

A new alkaloid, adlumiceine methyl ester (1), together with two known alkaloids, parfumine (2) and N-methylhydrastine methyl ester (3), was isolated from aerial parts of Fumaria vaillantii. The structures of compounds were determined by 1D/2D NMR and MS data. All three compounds were tested for cytotoxic activity against PC3 and MCF7 cell lines using Alamar blue assay. The tested compounds showed no significant cytotoxic activity (IC50>50 µM) against PC3 and MCF7 cell lines.

C19-diterpene alkaloids from Delphinium turkmenum lipsky.

The genus Delphinium is a rich source of diterpene alkaloids. Chemical investigation on an alkaloid rich extract of the whole parts of Delphinium turkmenum resulted in the isolation of three C19-diterpene alkaloids (1-3) and a palmitic acid derivative (4). The chemical structures were elucidated by analysis of 1D and 2D-NMR and comparison the data with those reported in the literature. Notably, all isolated compounds were reported for the first time from D. turkmenum.

Evaluation of Urolithin A Efficacy in Heart Failure Patients with Reduced Ejection Fraction: A Randomized, Double-blind, Crossover, Placebo-controlled Clinical Trial.

BACKGROUND: Mitochondrial dysfunction and impaired mitophagy are integral to myocyte loss and the progression of heart failure. Urolithin A (UA), a microbiota-produced metabolite of ellagitannins and ellagic acid, is a known stimulator of mitophagy and mitochondrial biogenesis that has shown cardioprotective effects in experimental models. METHODS: A randomized, double-blind, placebo-controlled 2×2 crossover trial was conducted on 10 patients with HF with reduced ejection fraction (HFrEF). The trial design involved two 4- week intervention periods of UA (500 mg BID) and placebo, separated by a 2-week washout phase. The patients underwent two-dimensional echocardiogram examination as well as blood sampling at the beginning and end of each period. RESULTS: All patients completed the study. The results failed to reveal any significant effect of UA supplementation on echocardiographic measures (LVEF, LVEDD, LVESV, and TAPSE). Plasma concentrations of pro-BNP, glucose, and CRP (p >0.05) were also not altered. Serum HDL-C levels were increased with UA compared with placebo (+6.46±2.33 mg/dL, p =0.026), whereas other lipid indices (LDL-C, triglycerides, total cholesterol, and VLDL-C) remained unchanged (p >0.05). CONCLUSION: The results of the present study do not support any positive effect of UA supplementation in improving echocardiographic and biochemical indices of HFrEF. Further studies with higher doses of UA and longer supplementation duration are encouraged to be conducted. CLINICAL TRIAL REGISTRATION NUMBER: IRCT20210216050375N1.

Synthesis, biosynthesis and biological activities of galbanic acid - A review.

Abstract Context: Galbanic acid (GA) is a biologically active sesquiterpene coumarin from Ferula species (Apiaceae). This compound showed various biological properties including anticancer, cancer chemopreventive, anticoagulant, antiviral, and antileishmanial activities. Objectives: This article is a review on the synthesis, biosynthesis, and biological activities of GA. In addition, we discussed gaps in our knowledge about GA that deserve future research. In this article, we also evaluated the drug-likeness of GA in silico. Methods: All relevant databases were searched for the terms "galbanic acid", "methyl galbanate", "Ferula" and "sesquiterpene coumarin" without limitation, up to May 2013. Information on GA was collected via electronic search using Pubmed, Scopus, Web of Science, and Sciencedirect. All physicochemical parameters used for the prediction of drug-likeness were calculated using MarvinSketch (version 5.11, academic package, ChemAxon). Results: This compound showed various biological properties including anticancer, cancer chemopreventive, anticoagulant, antiviral and antileishmanial activities. GA can inhibit the growth of prostate cancer cells via decreasing androgen receptor abundance. In silico physicochemical studies on GA showed that this compound has drug-like properties, the parameters that are important to predict potential of a compound for being a future drug. Conclusion: GA is a valuable natural product with various biological activities. New discoveries with GA are to be expected.

The combination of polyphenols and phospholipids as an efficient platform for delivery of natural products.

Although nature is a rich source of potential drugs and drug leads, the widespread application of natural products (NPs) is limited due to their poor absorption when administered orally. A strategy of using phytosome has emerged as a promising technique to increase the bioavailability of NPs. Here, a comprehensive computational investigation is performed to explore the nature of interactions in the formation of phytosomes between phosphatidylcholine (PC) and a series of polyphenols (PP), including epigallocatechin-3-gallate (Eg), luteolin (Lu), quercetin (Qu), and resveratrol (Re). Our quantum mechanical calculation revealed that the intermolecular hydrogen bonds (HBs) of phosphate and glycerol parts of PC with the polyphenol compounds are the main driving force in the formation of phytosomes. The strongest HB (with energy HB = - 108.718 kJ/mol) is formed between the Eg molecule and PC. This hydrogen bond results from the flexible structure of the drug which along with several van der Waals (vdW) interactions, makes Eg-PC the most stable complex (adsorption energy = - 164.93 kJ/mol). Energy decomposition analysis confirms that the electrostatic interactions (hydrogen bond and dipole-diploe interactions) have a major contribution to the stabilization of the studied complexes. The obtained results from the molecular dynamics simulation revealed that the formation of phytosomes varies depending on the type of polyphenol. It is found that the intermolecular hydrogen bonds between PP and PC are a key factor in the behavior of the PP-PC complex in the self-aggregation of phytosome. In Eg-PC, Lu-PC, and Qu-PC systems, the formation of strong hydrogen bonds (HBCP < 0 and ∇2ρBCP > 0) between PP and PC protects the PP-PC complexes from degradation. The steered molecular dynamics simulation results have a good agreement with experimental data and confirm that the phytosome platform facilitates the penetration of PP compounds into the membrane cells.

Curcumin-loaded mesoporous silica nanoparticles for drug delivery: synthesis, biological assays and therapeutic potential - a review.

Curcumin-loaded mesoporous silica nanoparticles (MSNs) have shown promise as drug delivery systems to address the limited pharmacokinetic characteristics of curcumin. Functionalization with folic acid and PEGylation enhance anticancer activity, biocompatibility, stability, and permeability. Co-delivery with other drugs results in synergistically enhanced cytotoxic activity. Environment-responsive MSNs prevent undesirable drug leakage and increase selectivity towards target tissues. This review summarizes the methods of Cur-loaded MSN synthesis and functionalization and their application in various diseases, and also highlights the potential of Cur-loaded MSNs as a promising drug delivery system.