The Effect of Curcumin on the Gut-Brain Axis: Therapeutic Implications.

The gut-brain axis describes the bidirectional communication between the gut, the enteric nervous system, and the central nervous system. The gut-brain axis has attracted increasing attention owing to its regulatory effect on dysbiosis and a wide range of related diseases. Several types of nutrients, such as curcumin, have been proposed as regulators of the dysbiotic state, and preclinical experiments have suggested that curcumin is not only beneficial but also safe. This review focuses on the interplay between curcumin and the gut microbiota. Moreover, it provides a comprehensive review of the crosstalk between the gut-brain axis and disease, whilst also discussing curcumin-mediated gut-brain axis-dependent and -independent signaling about modulation of gut microbiota dysbiosis. This will help to define the utility of curcumin as a novel therapeutic agent to regulate intestinal microflora dysbiosis.

Lavender (Lavandula angustifolia) syrup as an adjunct to standard care in patients with mild to moderate COVID-19: An open-label, randomized, controlled clinical trial.

Objective: ongoing COVID-19 pandemic has been associated with clinical signs characterized by fever, fatigue and cough. Our study aimed to assess the efficacy of a Persian medicine formulation, lavender syrup, as an add-on to standard care in patients with mild to moderate COVID-19. Materials and Methods: In this clinical trial which was conducted in Gorgan (Iran), 84 male and female COVID-19 outpatients were randomly allocated to either lavender syrup receiving 9 ml/twice/day for 21 days with standard conventional care or control groups. The primary objectives were to assess the improvement of clinical symptoms, while the secondary objectives were treatment satisfaction and anxiety levels which were evaluated once a week for 3 weeks. Results: Out of 84 participants, 81 were analyzed (41 in the add-on group). The comparison between groups for cough severity and anosmia showed a higher reduction in the lavender group. The effect size was 0.6 for cough relief. Other symptoms and the Hamilton total score decreased in both groups with no statistically significant differences between the groups. The lavender group showed greater patients' satisfaction score. Conclusion: Adjunctive therapy with lavender syrup could reduce cough and improve the quality of life in patients with COVID-19 patients.

Neuroprotective effect of Potentilla reptans L. root in the rat brain global ischemia/reperfusion model.

Stroke is the most common cause of death among neurological diseases. The protective effects of Potentilla reptans L. include antioxidative, anti-inflammatory, and antiapoptotic effects. In this study, the brain protection and beta-amyloid effects of P. reptans root extract were investigated in the rat brain ischemia/reperfusion (IR) model. Forty male Wistar rats were randomly divided into five groups (n = 8), including IR, sham, and three groups receiving P. reptans with concentrations of 0.025, 0.05, and 0.1 (g/kg/b.w.), which were injected daily for 7 days. For the IR model, the common carotid artery was occluded bilaterally for 8 min. All injections were intraperitoneal (IP). The shuttle box test was used to measure passive avoidance memory. Then the brain tissue was extracted for the histological examination of neuron counts and ß-amyloid plaques using a morphometric technique, and finally, Statistical Package for the Social Sciences software was used for statistical analysis of the data. Pretreatment with P. reptans improved memory impairment. Also, by examining the tissues of the CA1, CA3, and dentate gyrus areas of the hippocampus, it was observed that the number of plaques in the groups receiving P. reptans extract was reduced compared to the IR group, especially at the concentration of 0.05 g/kg/b.w. Also, P. reptans improved the number of neurons at all concentrations, in which the concentration of 0.05 g/kg/b.w. showed more effective therapeutic results. Taken together, we found that P. reptans root extract has beneficial effects on memory impairment, neuronal loss, and ß-amyloid accumulation.

Potentilla reptans L. preconditioning regulates H19 and MIAT long noncoding RNAs in H9C2 myoblasts Ischemia/Reperfusion model.

The present study aimed to evaluate the effect of the ethyl acetate fraction of P. reptans root (PEF) preconditioning on expressions of lncRNAs H19 and MIAT in H9C2 myoblasts I/R injury.H9C2 cells were treated with different concentrations ranging from (10-400 µg/ml) of PEF for 24 h, followed by simulation of I/R condition. For I/R experiments, H9C2 cells were subjected with the oxygen and glucose deprivation for 2 h.H9C2 cell viability was significantly enhanced by PEF preconditioning under I/R condition in a concentration-dependent manner up to 200 µg/ml as a EC50. The PEF significantly diminished the expression of lncRNA MIAT and rate of apoptosis against the I/R group. In addition, PEF pretreated before stimulation I/R condition increased H19 expression compared to the normal PEF group with no statistically significant differences between groups. Hence, the results suggest that PEF can protect cardiomyocytes during hypoxia-induced myocardial cell injury by targeting specific involved genes.

Bixin-loaded colloidal nanodelivery systems, techniques and applications.

Bixin is the cis-carotenoid from the seed of achiote tree or annatto. It is an approved liposoluble apocarotenoid by FDA as colorant and additive in the food industry. Nonetheless, bixin is unstable in the presence of oxygen, light, high pHs (alkali) and heat; thereby reducing its bioavailability/bioactivity, and also, with a low solubility in water. Some biopolymeric (e.g., nanofibers, nanogels, and nanotubes) and lipid-based nanocarriers (nanoliposomes, niosomes, hexosomes, nanoemulsions, solid-lipid nanoparticles, and nanostructured lipid carriers) have been introduced for bixin. Thus, this review focuses on the updated information regarding bixin-loaded nanodelivery platforms. Moreover, it provides a comprehensive review of bioavailability, physicochemical properties, and applications of nanoencapsulated-bixin as an additive, its release rate and safety issues. These findings will bring potential strategies for the usage of nanocarriers in managing bixin defaults to improve its broad application in various industries.

Impact of Phytochemicals on PPAR Receptors: Implications for Disease Treatments.

Peroxisome proliferator-activated receptors (PPARs) are members of the ligand-dependent nuclear receptor family. PPARs have attracted wide attention as pharmacologic mediators to manage multiple diseases and their underlying signaling targets. They mediate a broad range of specific biological activities and multiple organ toxicity, including cellular differentiation, metabolic syndrome, cancer, atherosclerosis, neurodegeneration, cardiovascular diseases, and inflammation related to their up/downstream signaling pathways. Consequently, several types of selective PPAR ligands, such as fibrates and thiazolidinediones (TZDs), have been approved as their pharmacological agonists. Despite these advances, the use of PPAR agonists is known to cause adverse effects in various systems. Conversely, some naturally occurring PPAR agonists, including polyunsaturated fatty acids and natural endogenous PPAR agonists curcumin and resveratrol, have been introduced as safe agonists as a result of their clinical evidence or preclinical experiments. This review focuses on research on plant-derived active ingredients (natural phytochemicals) as potential safe and promising PPAR agonists. Moreover, it provides a comprehensive review and critique of the role of phytochemicals in PPARs-related diseases and provides an understanding of phytochemical-mediated PPAR-dependent and -independent cascades. The findings of this research will help to define the functions of phytochemicals as potent PPAR pharmacological agonists in underlying disease mechanisms and their related complications.

Prediction of COVID-19 manipulation by selective ACE inhibitory compounds of Potentilla reptant root: In silico study and ADMET profile.

In the novel SARS-CoV-2 (COVID-19) as a global emergency event, the main reason of the cardiac injury from COVID-19 is angiotensin-converting enzyme 2 (ACE2) targeting in SARS-CoV-2 infection. The inhibition of ACE2 induces an increase in the angiotensin II (Ang II) and the angiotensin II receptor type 1 (AT1R) leading to impaired cardiac function or cardiac inflammatory responses. The ethyl acetate fraction of Potentilla reptans L. root can rescue heart dysfunction, oxidative stress, cardiac arrhythmias and apoptosis. Therefore, isolated components of P. reptans evaluated to identify natural anti-SARS-CoV-2 agents via molecular docking. In silico molecular docking study were carried out using the Auto Dock software on the isolated compounds of Potentilla reptans root. The protein targets of selective ACE and others obtained from Protein Data Bank (PDB). The best binding pose between amino acid residues involved in active site of the targets and compounds was discovered via molecular docking. Furthermore, ADMET properties of the compounds were evaluated. The triterpenoids of P. reptans showed more ACE inhibitory potential than catechin in both domains. They were selective on the nACE domain, especially compound 5. Also, the compound 5 & 6 had the highest binding affinity toward active site of nACE, cACE, AT1R, ACE2, and TNF-α receptors. Meanwhile, compound 3 showed more activity to inhibit TXA2. Drug likeness and ADMET analysis showed that the compounds passed the criteria of drug likeness and Lipinski rules. The current study depicted that P. reptans root showed cardioprotective effect in COVID-19 infection and manipulation of angiotensin II-induced side effects.

Effect of Lavender (Lavandula angustifolia L.) syrup on olfactory dysfunction in COVID-19 infection: A pilot controlled clinical trial.

OBJECTIVE: The effect of lavender syrup on COVID-19-induced olfactory dysfunction (OD) has been assessed in this study. MATERIALS AND METHODS: This pilot clinical trial was conducted in Gonbad-E-Kavoos (Golestan province, Iran). Twenty-three outpatients with COVID-19 and OD in lavender group took 9 ml of lavender syrup/bid for 3 weeks along with the standard COVID-19 treatments and 20 patients in control group took only standard COVID-19 treatments. The severity of OD was assessed by the visual analogue scale (VAS). Data analysis was performed by Friedman and Mann-Whitney tests using SPSS software. RESULTS: The mean± standard deviation of age was 36.6±9.1, and 42.6±10.4 years (p=0.05), and the duration of symptoms was 7.4±3.5, and 7.5±3.4 days (p=0.98) in the lavender and control group, respectively. The VAS score for OD decreased from 6.8±3.04 to 0.26±0.86 in the lavender group and from 5.3±3.4 to 1±2.61 in the control group. Although, VAS for OD was significantly decreased in both groups (p<0.001), the amount of VAS decrease was 6.6±2.9 scores in the lavender group, and 4.3±4 in the control group (p=0.03). No side effects were observed in the lavender group. CONCLUSION: The present study showed that lavender syrup is an effective treatment for COVID-19-induced OD. It is suggested to conduct further studies with larger sample size.

Taxonomical Investigation, Chemical Composition, Traditional Use in Medicine, and Pharmacological Activities of Boswellia sacra Flueck.

Aromatic oleo-gum-resin secreted from B. sacra, reputed as frankincense, is widely used in traditional medicine to treat Alzheimer's disease, gastric disorders, hepatic disorders, etc. Frankincense is also used in the cosmetic, perfume, and beverage and food industries. Frankincense is a rich resource for bioactive compounds, especially boswellic acids and derivatives. Although several reports have described frankincense's constituents and pharmacological activities, there is no comprehensive study that covers the valuable information on this species. Therefore, the current review will focus on the phytochemistry, traditional uses, and pharmacological activities of B. sacra.

Six new triterpenoids from the root of Potentilla reptans and their cardioprotective effects in silico.

Tormentic acid ester glucosides derivatives (1, 2 and 4), 3-oxoursane ester glycoside (3) and 11-methoxy-ursane ester glycosides (5, 6) as six new triterpenoids, along with catechin were isolated from the ethyl acetate fraction of Potentilla reptans root (Et) methanolic extract. The structures of the compounds were elucidated by 1D, 2D NMR, IR and MS spectroscopy. Additionally, isolated triterpenoid compounds (1-6) and catechin were evaluated for their cardioprotective effects via glycogen synthase kinase 3ß (GSK-3ß) and glucocorticoid regulated kinase-1 (SGK1) protein kinase inhibition by Molecular Docking. Compound 1 and catechin (compound 7) exhibited significant inhibitory effects against GSK-3ß and SGK1 protein kinases with a binding energy value -9.1 and -8.8 kcal/mol, respectively. Hence, Et can be a suitable natural candidate to protect cardiomyocytes injury.

Protective role of nutraceuticals against myocarditis.

Myocarditis is an inflammatory disease of the myocardium that mostly affects young adults. The disease is commonly caused by viral infection, medications, autoimmune disorders, and inflammatory conditions. Nearly 50% of the cases of myocarditis are due to post-viral immune response in a setting of an identifiable or non-identifiable infection. The clinical manifestation is nonspecific ranging from asymptomatic courses to sudden death in infants and young patients. This review describes the properties of phytochemicals as plant-derived active ingredients which can be used in the prevention and treatment of myocarditis and its associated risk factors. Meanwhile, it has illustrated epidemiological analyses, mechanism of action, and the metabolism of phytochemicals in animal and human clinical trials. We also mentioned the precise mechanism of action by which phytochemicals elicit their anti-viral, anti-inflammatory, antioxidant, and immunomodulatory effects and how they regulate signal transduction pathways. Nevertheless, comprehensive clinical trials are required to study the properties of phytochemicals in vivo, in vitro, and in silico for a proper management of myocarditis. Our findings indicate that phytochemicals function as potent adjunctive therapeutic drugs in myocarditis and its related complications.

Anticancer Activity of Ethnopharmacological Plants of Golestan Province/Iran against AGS, HT-29 and KYSE-30 Cell Lines through Promoting the Apoptosis and Immunomodulatory Effects.

The anticancer and immunomodulatory effects of medicinal plants from Golestan province, as a promising source of cancer therapy against gastrointestinal cancer cell lines, were investigated in this study. The ethanolic root/aerial part extracts of 9 medicinal plants were screened for their cytotoxicity against normal mouse fibroblast cells (L-929) and three human cancer cell lines including gastric adenocarcinoma (AGS), colorectal adenocarcinoma (HT-29), and esophagus adenocarcinoma (KYSE-30) by performing MTT assay to determine the IC50 of the extracts. The in-vitro antioxidant activity, total phenolic (TPC), and total flavonoid content (TFC) of extracts was evaluated. Flow cytometry and Real-Time PCR were used for apoptosis assay and evaluation of expression of some genes involved in cell signaling; TLR-4, AKT, ERK1/2, and NFκB. Out of the 9 plant extracts screened, Arctiumlappa root (ALR), showed the most potent cytotoxicity against AGS, KYSE-30, and HT-29 cells with IC50 values of 10, 200, and 2030 µg/mL, respectively. In addition, ALR exerts high TPC (215.8 ± 0.3 mg GAE/g), TFC (69.03 ± 0.7 mg QUE/g) and high radical scavenging activity with IC50 (1250 ± 0.1 µg/mL) in DPPH method. Also, ALR stimulates TLR-4 signaling, increased apoptosis, and decreased cancer cell attachment to the surface compared to the untreated cells. This plant, with a strong cytotoxic effect on cancer cells as well as increased apoptosis and its effect on molecules involved in TLR4 signaling as the immunomodulatory effect can be a suitable candidate for in-vivo studies in the future for cancer therapy.

Potentilla reptans L. postconditioning protects reperfusion injury via the RISK/SAFE pathways in an isolated rat heart.

BACKGROUND: Our previous study indicated that Potentilla reptans root has a preconditioning effect by its antioxidant and anti-apoptotic effects in an isolated rat heart ischemia/reperfusion (IR) model. In the present study, we investigated the post-conditioning cardio-protective effects of Potentilla reptans and its active substances. METHODS: The ethyl acetate fraction of P. reptans root (Et) was subjected to an IR model under 30 min of ischemia and 100 min of reperfusion. To investigate the postconditioning effect, Et was perfused for 15 min at the early phase of reperfusion. RISK/SAFE pathway inhibitors, 5HD and L-NAME, were applied individually 10 min before the ischemia, either alone or in combination with Et during the early reperfusion phase. The hemodynamic factors and ventricular arrhythmia were calculated during the reperfusion. Oxidative stress, apoptosis markers, GSK-3ß and SGK1 proteins were assessed at the end of experiments. RESULTS: Et postconditioning (Etpost) significantly reduced the infarct size, arrhythmia score, ventricular fibrillation incidence, and enhanced the hemodynamic parameters by decreasing the MDA level and increasing expression of Nrf2, SOD and CAT activities. Meanwhile, Etpost increased the BCl-2/BAX ratio and decreased Caspase-3 expression. The cardioprotective effect of Etpost was abrogated by L-NAME, Wortmannin (a PI3K/Akt inhibitor), and AG490 (a JAK/STAT3 inhibitor). Finally, Etpost reduced the expression of GSK-3ß and SGK1 proteins pertaining to the IR group. CONCLUSION: P. reptans reveals the post-conditioning effects via the Nrf2 pathway, NO release, and the RISK/SAFE pathway. Also, Etpost decreased apoptotic indexes by inhibiting GSK-3ß and SGK1 expressions. Hence, our data suggest that Etpost can be a suitable natural candidate to protect cardiomyocytes during reperfusion injury.

Anti-atherosclerotic Effects of Spice-Derived Phytochemicals.

Cardiovascular diseases are the leading cause of death in the world. Atherosclerosis is characterized by oxidized lipid deposition and inflammation in the arterial wall and represents a significant problem in public health and medicine. Some dietary spices have been widely used in many countries; however, the mechanism of their action as it relates to the prevention and treatment of atherosclerosis is still poorly understood. In this review, we focus on the properties of various spice-derived active ingredients used in the prevention and treatment of atherosclerosis, as well as associated atherosclerotic risk factors. We provide a summary of the mechanisms of action, epidemiological analyses, and studies of various components of spice used in the clinic, animal models, and cell lines related to atherosclerosis. Most notably, we focused on mechanisms of action by which these spice-derived compounds elicit their lipid-lowering, anti-inflammatory, antioxidant, and immunomodulatory properties, as well as their involvement in selected biochemical and signal transduction pathways. It is suggested that future research should aim to design well-controlled clinical trials and more thoroughly investigate the role of spices and their active components in the prevention/treatment of atherosclerosis. Based on this literature review, it appears that spices and their active components are well tolerated and have few adverse side effects and, therefore, provide a promising adjunctive treatment strategy for patients with atherosclerosis.

Preconditioning and anti-apoptotic effects of Metformin and Cyclosporine-A in an isolated bile duct-ligated rat heart.

Despite all previous studies relating to the mechanism of cirrhotic cardiomyopathy (CCM), the role of cirrhosis on Ischemic Preconditioning (IPC) has not yet been explored. The present study strives to assess the cardioprotective role of IPC in bile duct ligated (BDL) rats as well as the cardioprotective role of Cyclosporin-A (CsA) and Metformin (Met) in CCM. Cirrhosis was induced by bile duct ligation (BDL). Rats' hearts were isolated and attached to a Langendorff Apparatus. The pharmacological preconditioning with Met and CsA was done before the main ischemia. Myocardial infarct size, hemodynamic and electrophysiological parameters, biochemical markers, and apoptotic indices were determined at the end of the experiment. Infarct size, apoptotic indices, arrhythmia score, and incidence of VF decreased significantly in the IPC group in comparison with the I/R group. These significant decreases were abolished in the IPC (BDL) group. Met significantly decreased the infarct size and apoptotic indices compared with I/R (BDL) and normal groups, while CsA led to similar decreases except in the level of caspase-3 and -8. Met and CsA decreased and increased the arrhythmia score and incidence of VF in the BDL groups, respectively. Functional recovery indices decreased in the I/R (BDL) and IPC (BDL) groups. Met improved these parameters. Therefore, the current study depicted that the cardioprotective effect of Met and CsA on BDL rats is mediated through the balance between pAMPK and apoptosis in the mitochondria.

Targeting autophagy in cardiac ischemia/reperfusion injury: A novel therapeutic strategy.

Acute myocardial infarction (AMI) is one of the leading causes of morbidity worldwide. Myocardial reperfusion is known as an effective therapeutic choice against AMI. However, reperfusion of blood flow induces ischemia/reperfusion (I/R) injury through different complex processes including ion accumulation, disruption of mitochondrial membrane potential, the formation of reactive oxygen species, and so forth. One of the processes that gets activated in response to I/R injury is autophagy. Indeed, autophagy acts as a "double-edged sword" in the pathology of myocardial I/R injury and there is a controversy about autophagy being beneficial or detrimental. On the basis of the autophagy effect and regulation on myocardial I/R injury, many studies targeted it as a therapeutic strategy. In this review, we discuss the role of autophagy in I/R injury and its targeting as a therapeutic strategy.

Cardioprotective and anti-apoptotic effects of Potentilla reptans L. root via Nrf2 pathway in an isolated rat heart ischemia/reperfusion model.

BACKGROUND: Previous studies have shown that proanthocyanidins have cardioprotective effects which are mediated via the release of nitric oxide (NO) ultimately resulting in increasing the antioxidant activity. We have investigated to show whether 1) the total extract and ethyl acetate fraction (Et) of Potentilla reptans root have an ischemic preconditioning (IPC) effect, 2) P. reptans has antioxidant and cardioprotective effects mediated by nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and scavenging of reactive oxygen species (ROS), 3) NO, caspase-3 and Bcl-2/Bax are involved in the IPC effect of P. reptans. METHODS: Male Wistar rats were divided into 10 groups. The isolated hearts were subjected to 30 min of ischemia and 100 min of reperfusion. The P. reptans was applied before the main ischemia. The infarct size was estimated by triphenyl-tetrazolium chloride staining. The hemodynamic parameters and ventricular arrhythmias were calculated during the reperfusion. Antioxidant markers and immunohistochemistry assays were determined at the end of the protocol. RESULTS: The Et significantly decreased the infarct size, arrhythmia scores, ventricular fibrillation incidence, and enhanced the hemodynamic parameters in a concentration-dependent manner against the ischemia/reperfusion group. SOD and CAT activity were increased and MDA level was decreased in response to the Et. Meanwhile, Et attenuated the suppression of Nrf2 expression and reduced the apoptotic indexes. The cardioprotective effect of P. reptans was abrogated by L-NAME. CONCLUSIONS: P. reptans demonstrated that the cardioprotective preconditioning effects via NO release, Nrf2 pathway, and antioxidant activity lead to a decrease in the apoptotic index.

Hydro-alcoholic extract of Matricaria recutita exhibited dual anti-spasmodic effect via modulation of Ca2+ channels, NO and PKA2-kinase pathway in rabbit jejunum.

OBJECTIVE: Several studies have shown the antispasmodic activity of Matricariarecutita without detailing the underlying mechanism(s). The present study was designed to determine whether the antispasmodic mechanisms of M. recutita extract mediated via histaminergic/cholinergic receptors, Ca2+channels, activation of PKA2 and NO release in isolated rabbit jejunum. MATERIALS AND METHODS: The concentration- dependent (3 × 10-3-1.3 × 10-2 mg/ml) antispasmodic effect of the hydro-alcoholic extract of M. recutita flowers was studied in isolated rabbit jejunum. The isolated jejunum preparations were divided into seven groups, including the pharmacological probes that modulate cholinergic, histaminergic, and nitrergic receptors, as well as PKA2. RESULTS: M. recutita inhibited spontaneous smooth muscle contractility of the jejunum in a concentration-dependent manner (3 × 10-3-1.3 × 10-2 mg/ml) and reduced both K+- and Ca2+-induced contractions, which is similar to the effect of verapamil. The antispasmodic effect of M. recutita was inhibited by H89 (a PKA2 inhibitor). The myorelaxant effect of M. recutita increased in the presence of ACh/His and H89. CONCLUSION: M. recutita evoked antispasmodic and spasmolytic effects mediated through different signaling pathways. Our results have shown this dual inhibitory effect is mediated by blocking Ca2+ channels, activating His and ACh receptors, releasing NO, and activating PKA2.