Intrathecal Administration of Melatonin Ameliorates the Neuroinflammation- Mediated Sensory and Motor Dysfunction in A Rat Model of Compression Spinal Cord Injury.

BACKGROUND: Spinal cord injury (SCI), often characterized by sensory-motor dysfunction, is a major debilitating disorder of the central nervous system. As no useful treatment for post- SCI complications has been approved thus far, finding novel treatments is of great importance. OBJECTIVE: Considering the promising effects of melatonin (MEL) against destructive mechanisms in other models of brain damage, in the current study, we evaluated its ameliorative effects on sensory- motor outcomes, inflammatory mediators, histological changes and other post-SCI complications. METHODS: Rats in SCI and MEL groups underwent laminectomy followed by a severe compression injury by an aneurysm clip. Then, intrathecal treatment with vehicle (5% dimethyl sulfoxide) or MEL was carried out post-injury. Acetone drop, von Frey, inclined plane, and BBB tests as well as weight changes and auricle temperature, were used to evaluate the neuropathic pain, motor function, and other post-SCI complications. The effects of MEL on the activity of MMP-2 and MMP-9 were assessed using the gelatin zymography method every week till day 28 post-SCI. Histopathological assessments were performed on days 14, 21, and 28. RESULTS: MEL treatment resulted in decreased motor dysfunction, mechanical and cold allodynia, auricle temperature, and also ameliorated weight loss. Moreover, MEL suppressed MMP-9 activity while increasing that of MMP-2 post-SCI, indicating its anti-neuroinflammatory effects. Also, MEL significantly preserved white matter myelinated areas and the number of sensory neurons post-SCI. CONCLUSION: The results suggest MEL as a promising candidate for medical therapies with advantageous effects on improving functional recovery through suppressing inflammatory mediators, and attenuating spinal tissue damages.

Ginger and Heart Health: From Mechanisms to Therapeutics.

BACKGROUND: As a major cause of morbidity and mortality, cardiovascular diseases (CVDs) are globally increasing. In spite of recent development in the management of cardiovascular complications, CVDs have remained a medical challenge. Numerous conventional drugs are used to play cardioprotective roles; however, they are associated with several side effects. Considering the rich phytochemistry and fewer side effects of herbal medicines, they have gained particular attention to develop novel herbal drugs with cardioprotective potentials. Amongst natural entities, ginger is an extensively used and well-known functional food and condiment, possessing plentiful bioactivities, like anti-inflammatory, antioxidant, and antimicrobial properties in several disorders management. OBJECTIVE: The current review deliberated phytochemical properties as well as the ginger/ginger constituents' biological activities and health benefits in several diseases, with particular attention to cardiovascular complications. METHODS: A comprehensive search was conducted using multiple databases, including Scopus, PubMed, Medline, Web of Science, national database (Irandoc and SID), and related articles in terms of the health benefits and cardioprotective effects of ginger/ginger constituents. These data were collected from inception until August 2019. RESULTS: In recent years, several herbal medicines were used to develop new drugs with more potency and also minor side effects. Amongst natural entities, ginger is used as a traditional medicine in several diseases. The crude extract, along with related pungent active constituents, is mostly attributed to heart health. The cardioprotective effects of ginger are contributed to its cardiotonic, anti- hypertensive, anti-hyperlipidemia, and anti-platelet effects. The signaling pathways and molecular mechanisms of ginger regarding its cardioprotective effects are also clarified. CONCLUSION: This study revealed the biological activities, health benefits, and cardioprotective properties of ginger/ginger constituents along with related mechanisms of action, which gave new insights to show new avenues in the treatment of CVDs.

Effect of Antihypertensive Drugs on Cognition and Behavioral Symptoms of Patients with Alzheimer's Disease: A Meta-analysis.

BACKGROUND: It has been found that there is a link between hypertension and elevated risk of Alzheimer's Disease (AD). Herein, a meta-analysis based on Randomized Clinical Trials (RCTs) was used to assess the effect of antihypertensive drugs on cognition and behavioral symptoms of AD patients. METHODS: The three databases, PubMed/Medline, Scopus, and Cochrane Library, were searched up to March 2020. The quality of the studies included in the meta-analysis was evaluated by the Jadad score. Clinical Global Impression of Change (CGIC) included in two studies, Mini-Mental State Examination (MMSE) included in three studies, and Neuropsychiatric Inventory (NPI) in three studies were the main outcomes in this systematic review. RESULTS: Out of 1506 studies retrieved in the databases, 5 RCTs were included and analyzed in the meta-analysis. The pooled mean differences of CGIC, MMSE, and NPI in patients with AD receiving antihypertensive drugs compared to placebo were -1.76 with (95% CI = -2.66 to -0.86; P=0.0001), 0.74 (95% CI = 0.20 to 1.28; P= 0.007), and -9.49 (95% CI = -19.76 to 0.79; P = 0.07), respectively. CONCLUSION: The findings of the present meta-analysis show that antihypertensive drugs may improve cognition and behavioral symptoms of patients with AD. However, more well-designed RCTs with similar drugs are needed to achieve more conclusive results.

Medicinal plants for diabetes associated neurodegenerative diseases: A systematic review of preclinical studies.

Diabetes mellitus is a metabolic defect with many complications for the patients. Deaths due to diabetes and its complications are increasing, and one of the most serious consequences are the neurological disorders. Chemical treatments have irreversible side effect and therefore the aim of this study is to evaluate the medicinal plants used for treatment of cognitive impairments and neurodegenerative diseases associated with diabetes in 2004-2020 period. Electronic databases used were PubMed, Scopus and Cochrane library. The keywords used were "diabetes," "plant," "herb," "neurodegenerative," "neurodegeneration," "cognitive," "cognition," "Alzheimer," "dementia." The non-English articles, repetitive articles and review studies were excluded. From total of 3,590 results, 58 articles are included in the study. The results show that many chemical treatments considered for this disease simply control hyperglycemia, but cannot improve the complications of diabetes. Herbal medicine could be more effective due to the high antioxidant activity of some medicinal plants. Biologically active substances of medicinal plants can improve the neurological disorders caused by diabetes via several pathways. The most important pathway is related to antioxidant properties. Other pathways include antiinflammatory, anti-apoptotic, neurotoxicity inhibition, neuronal death, increasing the uptake of glucose by cells and improve neurotransmitters levels involved in learning and memory.

Targeting Mitogen-Activated Protein Kinases by Natural Products: A Novel Therapeutic Approach for Inflammatory Bowel Diseases.

An increase in the prevalence of Inflammatory Bowel Diseases (IBD) as a multifactorial intestinal chronic inflammation as well as the absence of a certain cure, has created an innovative era in the management of IBD by molecule/pathway-based anti-inflammatory approaches. There are credible documentations that demonstrate Mitogen-Activated Protein Kinases (MAPK) acts as IBD regulator. Upon the activation of MAPK signalling pathway, the transcription and expression of various encoding inflammatory molecules implicated in IBD are altered, thereby exacerbating the inflammation development. The current pharmacological management of IBD, including drug and biological therapies are expensive, possess temporary relief and some adverse effects. In this context, a variety of dietary fruits or medicinal herbs have received worldwide attention versus the development of IBD. Infact, natural ingredients, such as Flavaglines, Fisetin, Myricitrin, Cardamonin, Curcumin, Octacosanol and Mangiferin possess protective and therapeutic effects against IBD via modulation of different segments of MAPK signaling pathway. This review paper calls attention to the role of MAPK signaling triggered by natural products in the prevention and treatment of IBD.

Targeting AMPK signaling pathway by natural products for treatment of diabetes mellitus and its complications.

Diabetes affects a large population of the world. Lifestyle, obesity, dietary habits, and genetic factors contribute to this metabolic disease. A target pathway to control diabetes is the 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. AMPK is a heterotrimeric protein with α, ß, and γ subunits. In several studies, AMPK activation enhanced glucose uptake into cells and inhibited intracellular glucose production. Impairment of AMPK activity is present in diabetes, according to some studies. Drugs used in the treatment of diabetes, such as metformin, are also known to act through regulation of AMPK. Thus, drugs that activate and regulate AMPK are potential candidates for the treatment of diabetes. In addition, many patients encounter important adverse effects, like hypoglycemia, while using allopathic drugs. As a result, the investigation of plant-derived natural drugs that lack adverse side effects and treat diabetes is necessary. Natural products like berberine, quercetin, resveratrol, and so forth have shown significant potential in regulating and activating the AMPK pathway which can lead to manage diabetes mellitus and its complications.

The Protective Effect of Melissa officinalis L. in Visceral Hypersensitivity in Rat Using 2 Models of Acid-induced Colitis and Stress-induced Irritable Bowel Syndrome: A Possible Role of Nitric Oxide Pathway.

BACKGROUND/AIMS: The aim of present study is to estimate the effects of Melissa officinalis L. (MO) on visceral hypersensitivity (VH), defecation pattern and biochemical factors in 2 experimental models of irritable bowel syndrome (IBS) and the possible role of nitric oxide. METHODS: Two individual models of IBS were induced in male Wistar-albino rats. In the acetic acid model, the animals were exposed to rectal distension and abdominal withdrawal reflex, and the defecation patterns were determined. In the restraint stress model, the levels of TNF-α, myeloperoxidase, lipid peroxidation, and antioxidant powers were determined in the (removed) colon. Rats had been treated with MO, L-NG-nitroarginine methyl ester (L-NAME), aminoguanidine (AG), MO + AG, or MO + L-NAME in the mentioned experimental models. RESULTS: Hypersensitive response to rectal distension and more stool defecation in control rats have been observed in comparison to shams. MO-300 significantly reduced VH and defecation frequency in comparison to controls. VH and defecation pattern did not show significant change in AG + MO and L-NAME + MO groups compared to controls. Also, significant reduction in TNF-α, myeloperoxidase, thiobarbituric acid reactive substances (TBARS), and an increase in antioxidant power in MO-300 group was recorded compared to controls. AG + MO and L-NAME + MO groups showed a reverse pattern compared to MO-300 group. CONCLUSIONS: MO can ameliorate IBS by modulating VH and defecation patterns. Antioxidant and anti-inflammatory properties along with its effect on the nitrergic pathway seem to play important roles in its pharmacological activity.

Naringenin and its Nano-formulations for Fatty Liver: Cellular Modes of Action and Clinical Perspective.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease mainly caused by high-fat diets and sudden feed changes, vitamin and energy deficiency, and inflammatory processes. Fatty liver leads to cirrhosis, hepatocellular carcinoma as well as liver failure. Lifestyle-modifying such as weight loss and a healthy diet have an inverse correlation with the risk of fatty liver. The promising effect of a diet rich in vegetables and fruits against fatty liver has been evidenced by several empirical studies focused on flavonoids. Among naturally occurring flavonoids, naringenin is one of the most important flavonoids which can be isolated from some edible fruits, especially citrus species. METHODS: In the present review, we discuss the effects of naringenin and its nano-formulations against fatty liver disease and the proposed molecular mechanism of action. A large number of studies attributed to naringenin anti-inflammatory, antioxidant and insulin-like actions, as well as different types of effects on sex hormone metabolism and lipid metabolism. Naringenin-loaded nanoparticles have been used to solve the limited stability, solubility, bioavailability and pharmacological activity of naringenin and, consequently, to improve its therapeutic effects. RESULTS AND DISCUSSION: Naringenin exerts diverse biological actions including the decrease of biomarkers of lipid peroxidation and protein carbonylation, increase of antioxidant defenses, scavenging of reactive oxygen species and modulation of signaling pathways related to fatty acid metabolism which can favor the oxidation of fatty acid, lower lipid accumulation in the liver and thereby prevent fatty liver.

The Role of Visceral Hypersensitivity in Irritable Bowel Syndrome: Pharmacological Targets and Novel Treatments.

Irritable bowel syndrome (IBS) is the most common disorder referred to gastroenterologists and is characterized by altered bowel habits, abdominal pain, and bloating. Visceral hypersensitivity (VH) is a multifactorial process that may occur within the peripheral or central nervous systems and plays a principal role in the etiology of IBS symptoms. The pharmacological studies on selective drugs based on targeting specific ligands can provide novel therapies for modulation of persistent visceral hyperalgesia. The current paper reviews the cellular and molecular mechanisms underlying therapeutic targeting for providing future drugs to protect or treat visceroperception and pain sensitization in IBS patients. There are a wide range of mediators and receptors participating in visceral pain perception amongst which substances targeting afferent receptors are attractive sources of novel drugs. Novel therapeutic targets for the management of VH include compounds which alter gut-brain pathways and local neuroimmune pathways. Molecular mediators and receptors participating in pain perception and visceroperception include histamine-1 receptors, serotonin (5-hydrodytryptamine) receptors, transient receptor potential vanilloid type I, tachykinins ligands, opioid receptors, voltage-gated channels, tyrosine receptor kinase receptors, protease-activated receptors, adrenergic system ligands, cannabinoid receptors, sex hormones, and glutamate receptors which are discussed in the current review. Moreover, several plant-derived natural compounds with potential to alleviate VH in IBS have been highlighted. VH has an important role in the pathology and severity of complications in IBS. Therefore, managing VH can remarkably modulate the symptoms of IBS. More preclinical and clinical investigations are needed to provide efficacious and targeted medicines for the management of VH.

The role of dietary polyphenols in the management of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is an idiopathic chronic, relapsing inflammation of the bowel which is caused by dysregulation of the mucosal immune system. Polyphenols as the secondary plant metabolites universally present in vegetables and fruits and are the most abundant antioxidants in the human diet. There is evidence demonstrating the beneficial health effects of dietary polyphenols. This review criticizes the potential of commonly used polyphenols including apple polyphenol, bilberry anthocyanin, curcumin, epigallocatechin-3-gallate (EGCG) and green tea polyphenols, naringenin, olive oil polyphenols, pomegranate polyphenols and ellagic acid, quercetin, as well as resveratrol specifically in IBD with an emphasis on cellular mechanisms and pharmaceutical aspects. Scientific research confirmed that dietary polyphenols possess both protective and therapeutic effects in the management of IBD mediated via down-regulation of inflammatory cytokines and enzymes, enhancing antioxidant defense, and suppressing inflammatory pathways and their cellular signaling mechanisms. Further preclinical and clinical studies are needed in order to understand safety, bioavailability and bioefficacy of dietary polyphenols in IBD patients.