TLR/mTOR inflammatory signaling pathway: novel insight for the treatment of schizophrenia.

The Toll-like receptor (TLR)/mammalian target of rapamycin (mTOR) signaling pathway is involved in the intracellular regulation of protein synthesis, specifically the ones that mediate neuronal morphology and facilitate synaptic plasticity. The activity of TLR/mTOR signaling has been disrupted, leading to neurodevelopment and deficient synaptic plasticity, which are the main symptoms of schizophrenia. The TLR receptor activates the mTOR signaling pathway and increases the elevation of inflammatory cytokines. Interleukin (IL)-6 is the most commonly altered cytokine, while IL-1, tumor necrosis factor, and interferon (IFN) also lead to SCZ. Anti-inflammatory and anti-oxidative agents such as celecoxib, aspirin, minocycline, and omega-3 fatty acids have shown efficiency against SCZ. As a result, inhibition of the inflammatory process could be suggested for the treatment of SCZ. So mTOR/TLR blockers represent the treatment of SCZ due to their inflammatory consequences. The objective of the present work was to find a novel anti-inflammatory agent that may block the mTOR/TLR inflammatory signaling pathways and might pave the way for the treatment of neuroinflammatory SCZ. Data were collected from experimental and clinical studies published in English between 1998 and October 2022 from Google Scholar, PubMed, Scopus, and the Cochrane library.

IDO/Kynurenine; novel insight for treatment of inflammatory diseases.

Inflammation and oxidative stress play pivotal roles in pathogenesis of many diseases including cancer, type 2 diabetes, cardiovascular disease, atherosclerosis, neurological diseases, and inflammatory diseases such as inflammatory bowel disease (IBD). Inflammatory mediators such as interleukins (ILs), interferons (INF-s), and tumor necrosis factor (TNF)-α are related to an extended chance of inflammatory diseases initiation or progression due to the over expression of the nuclear factor Kappa B (NF-κB), signal transducer of activators of transcription (STAT), nod-like receptor family protein 3 (NLRP), toll-like receptors (TLR), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR) pathways. These pathways are completely interconnected. Theindoleamine 2,3 dioxygenase (IDO) subset of the kynurenine (KYN) (IDO/KYN), is a metabolic inflammatory pathway involved in production of nicotinamide adenine dinucleotide (NAD + ). It has been shown that IDO/KYN actively participates in inflammatory processes and can increase the secretion of cytokines that provoke inflammatory diseases. Data were extracted from clinical and animal studies published in English between 1990-April 2022, which were collected from PubMed, Google Scholar, Scopus, and Cochrane library. IDO/KYN is completely associated with inflammatory-related pathways, thus leading to the production of cytokines such as TNF-α, IL-1ß, and IL-6, and ultimately development and progression of various inflammatory disorders. Inhibition of the IDO/KYN pathway might be a novel therapeutic option for inflammatory diseases. Herein, we gathered data on probable interactions of the IDO/KYN pathway with induction of some inflammatory diseases.

Statins: Beneficial Effects in Treatment of COVID-19.

The recent viral disease COVID-19 has attracted much attention. The disease is caused by SARS-CoV-19 virus which has different variants and mutations. The mortality rate of SARS-CoV-19 is high and efforts to establish proper therapeutic solutions are still ongoing. Inflammation plays a substantial part in the pathogenesis of this disease causing mainly lung tissue destruction and eventually death. Therefore, anti-inflammatory drugs or treatments that can inhibit inflammation are important options. Various inflammatory pathways such as nuclear factor Kappa B (NF-κB), signal transducer of activators of transcription (STAT), nod-like receptor family protein 3 (NLRP), toll-like receptors (TLRs), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR) pathways and mediators, such as interleukin (IL)-6, IL-1ß, tumor necrosis factor-α (TNF-α), and interferon-γ (INF-γ), cause cell apoptosis, reduce respiratory capacity and oxygen supply, eventually inducing respiratory system failure and death. Statins are well known for controlling hypercholesterolemia and may serve to treat COVID-19 due to their pleiotropic effects among which are anti-inflammatory in nature. In this chapter, the anti-inflammatory effects of statins and their possible beneficial effects in COVID-19 treatment are discussed. Data were collected from experimental and clinical studies in English (1998-October 2022) from Google Scholar, PubMed, Scopus, and the Cochrane Library.

Statins block mammalian target of rapamycin pathway: a possible novel therapeutic strategy for inflammatory, malignant and neurodegenerative diseases.

Inflammation plays a critical role in several diseases such as cancer, gastric, heart and nervous system diseases. Data suggest that the activation of mammalian target of rapamycin (mTOR) pathway in epithelial cells leads to inflammation. Statins, the inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), seem to be able to inhibit the mTOR. Statins are considered to have favorable effects on inflammatory diseases by reducing the complications caused by inflammation and by regulating the inflammatory process and cytokines secretion. This critical review collected data on this topic from clinical, in vivo and in vitro studies published between 1998 and June 2022 in English from databases including PubMed, Google Scholar, Scopus, and Cochrane libraries.

Current overview of opioids in progression of inflammatory bowel disease; pharmacological and clinical considerations.

Inflammatory bowel diseases (IBD) belong to a subgroup of persistent, long-term, progressive, and relapsing inflammatory conditions. IBD may spontaneously develop in the colon, resulting in tumor lesions in inflamed regions of the intestine, such as invasive carcinoma. The benefit of opioids for IBD treatment is still questionable, thereby we investigated databases to provide an overview in this context. This review demonstrates the controversial role of opioids in IBD therapy, their physiological and pharmacological functions in attenuating the IBD symptoms, and in improving inflammatory, oxidative stress, and the quality of life factors in IBD subjects. Data were extracted from clinical, in vitro, and in vivo studies in English, between 1995 and 2019, from PubMed, Google Scholar, Scopus, and Cochrane library. Based on recent reports, there are promising opportunities to target the opioid system and control the IBD symptoms. This study suggests a novel approach for future treatment of functional and inflammatory disorders such as IBD.

Curcumin as a therapeutic candidate for multiple sclerosis: Molecular mechanisms and targets.

Multiple sclerosis (MS) is a disease that has shown a considerable increase in prevalence in recent centuries. Current knowledge about its etiology is incomplete, and therefore it cannot be managed optimally utilizing targeted therapeutic regimens at each stage of the disease. MS progresses in different stages, beginning with a cascade of inflammation. The pivotal spark to initiate this cascade seems to be the migration of Th17 into the central nervous system across the blood-brain barrier (BBB) through the disrupted tight junctions. Coupling of interleukin (IL)-17 and IL-22 to their receptors in the BBB layer facilitates this migration. Subsequently, axon degeneration and the various manifestations of nerve-muscle disorders appear. Curcumin, a major component of turmeric, is derived from Curcuma longa, which belongs to the Zingiberaceae family. Numerous properties of curcumin have been identified recently, some of which can be effective in the treatment of MS, particularly the anti-inflammatory properties via inhibition of secretion of proinflammatory cytokines. In this paper, we will review the various properties and key effects of curcumin for the treatment of MS.

Therapeutic approaches for cholestatic liver diseases: the role of nitric oxide pathway.

Cholestasis describes bile secretion or flow impairment, which is clinically manifested with fatigue, pruritus, and jaundice. Neutrophils play a crucial role in many diseases such as cholestasis liver diseases through mediating several oxidative and inflammatory pathways. Data have been collected from clinical, in vitro, and in vivo studies published between 2000 and December 2021 in English and obtained from the PubMed, Google Scholar, Scopus, and Cochrane libraries. Although nitric oxide plays an important role in the pathogenesis of cholestatic liver diseases, excessive levels of NO in serum and affected tissues, mainly synthesized by the inducible nitric oxide synthase (iNOS) enzyme, can exacerbate inflammation. NO induces the inflammatory and oxidative processes, which finally leads to cell damage. We found that natural products such as baicalin, curcumin, resveratrol, and lycopene, as well as chemical likes ursodeoxycholic acid, dexamethasone, rosuvastatin, melatonin, and sildenafil, are able to markedly attenuate the NO production and iNOS expression, mainly through inducing the nuclear factor κB (NF-κB), Janus kinase and signal transducer and activator of transcription (JAK/STAT), and toll like receptor-4 (TLR4) signaling pathways. This study summarizes the latest scientific data about the bile acid signaling pathway, the neutrophil chemotaxis recruitment process during cholestasis, and the role of NO in cholestasis liver diseases. Literature review directed us to propose that suppression of NO and its related pathways could be a therapeutic option for preventing or treating cholestatic liver diseases.

Spinal Muscular Atrophy Treatment: The MTOR Regulatory Intervention.

Spinal muscular atrophy (SMA) is a hereditary disorder affecting neurons and muscles, resulting in muscle weakness and atrophy. Most SMA cases are diagnosed during infancy or early childhood, the most common inherited cause of infant mortality without treatment. Still, SMA might appear at older ages with milder symptoms. SMA patients demonstrate progressive muscle waste, movement problems, tremors, dysphagia, bone and joint deformations, and breathing difficulties. The mammalian target of rapamycin (mTOR), the mechanistic target of rapamycin, is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases encoded by the mTOR gene in humans. The mTOR phosphorylation, deregulation, and autophagy have shown dissimilarity amongst SMA cell types. Therefore, exploring the underlying molecular process in SMA therapy could provide novel insights and pave the way for finding new treatment options. This paper provides new insight into the possible modulatory effect of mTOR/ autophagy in SMA management.

Systematic Review on Herbal Preparations for Controlling Visceral Hypersensitivity in Functional Gastrointestinal Disorders.

BACKGROUND: Visceral hypersensitivity (VH) is an overreaction of the gastrointestinal (GI) tract to various stimuli and is characterized by hyperalgesia and/or allodynia. VH contributes to the etiology of many GI dysfunctions, particularly irritable bowel syndrome (IBS). Although the exact mechanisms underlying VH are yet to be found, inflammation and oxidative stress, psychosocial factors, and sensorimotor alterations may play significant roles in it. OBJECTIVE: In this review, we provide an overview of VH and its pathophysiological function in GI disorders. Adverse effects of synthetic drugs may make herbal agents a good candidate for pain management. Therefore, in this review, we will discuss the efficacy of herbal agents in the management of VH with a focus on their anti-inflammatory and antioxidant potentials. METHODS: Data were extracted from clinical and animal studies published in English between 2004 and June, 2020, which were collected from PubMed, Google Scholar, Scopus, and Cochrane Library. RESULTS: Overall, Radix, Melissia, Glycyrrhizae, Mentha, and Liquorice were the most efficient herbals for VH management in IBS and dyspepsia, predominantly through modulation of the mRNA expression of transient receptor potential vanilloid type-1 (TRPV1) and suppression of 5- hydroxytryptamine 3 (5-HT3) or the serotonin receptors. CONCLUSION: Considering the positive effects of herbal formulations in VH management, further research on novel herbal and/or herbal/chemical preparations is warranted.

LRRK2; Communicative Role in the Treatment of Parkinson's Disease and Ulcerative Colitis Overlapping.

BACKGROUND: Involvement of gastrointestinal inflammation in Parkinson's disease (PD) pathogenesis and movement have progressively emerged. Inflammation is involved in the etiology of both PD and inflammatory bowel disease (IBD). Transformations in leucine-rich recurrent kinase 2 (LRRK2) are among the best hereditary supporters of IBD and PD. Elevated levels of LRRK2 have been reported in stimulated colonic tissue from IBD patients and peripheral invulnerable cells from irregular PD patients; thus, it is thought that LRRK2 directs inflammatory cycles. OBJECTIVE: Since its revelation, LRRK2 has been seriously linked in neurons, albeit various lines of proof affirmed that LRRK2 is profoundly communicated in invulnerable cells. Subsequently, LRRK2 might sit at a junction by which stomach inflammation and higher LRRK2 levels in IBD might be a biomarker of expanded risk for inconsistent PD or potentially may address a manageable helpful objective in incendiary sicknesses that increment the risk of PD. Here, we discuss how PD and IBD share covering aggregates, especially regarding LRRK2 and present inhibitors, which could be a helpful objective in ongoing treatments. METHOD: English data were obtained from Google Scholar, PubMed, Scopus, and Cochrane library studies published between 1990-December 2022. RESULT: Inhibitors of the LRRK2 pathway can be considered as the novel treatment approaches for IBD and PD treatment. CONCLUSION: Common mediators and pathways are involved in the pathophysiology of IBD and PD, which are majorly correlated with inflammatory situations. Such diseases could be used for further clinical investigations.

Regulatory Mechanisms of Vanillic Acid in Cardiovascular Diseases: A Review.

Cardiovascular diseases (CVD) are the primary cause of death globally. Activation of oxidative stress and inflammatory pathways are contributory to the development of CVD. Pharmacological activities of vanillic acid have been investigated suggesting that they may have therapeutic utility clinically. Given its phenolic nature, the anti-inflammatory and antioxidant properties of vanillic acid have been shown to exert potent inhibitory activity against Adenosine Monophosphate-Activated Protein Kinase (AMPK), Nuclear Factor Kappa B (NF- κB), the Janus kinase (JAK)/signal transducer and activator of transcription (STAT), Nod-like receptor family protein (NLRP), Toll-like receptors (TLRs), Mitogen-Activated Signaling Proteins (MAPK) and Mammalian Target of Rapamycin (mTOR) signaling pathways. Vanillic acid has been shown to block pro-inflammatory cytokines and suppress inflammatory cascades. The inhibitory impact of vanillic acid on reactive oxygen species (ROS) and nitric oxygen synthase (iNOS) expression has also been demonstrated. Vanillic acid reduces oxidative-related markers such as superoxide dismutase (SOD), glutathione (GSH), Heme Oxygenase 1 (HO-1), and glutathione peroxidase (GSH-Px). Here, we review the cardioprotective effects and mechanisms of action of vanillic acid in CVD. Current potential applications of vanillic acid in CVD are discussed concerning preclinical and clinical studies.

Evaluation of acute and sub-chronic oral toxicities of Neoneaster in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Jaundice is a condition caused by the elevation of bilirubin level in the blood. Due to the neurological and neurodevelopmental sequalae of jaundice in newborns, the high cost of the treatment, and the side effects of the currently used therapies, novel therapeutically approaches are needed. Purgative manna (Shir-e-Khesht) has been used in Persian traditional medicine to reduce serum bilirubin levels of neonates. Neoneaster® is a natural health product formulated by a unique method from the manna of Cotoneaster nummularius Fisch. & C.A.Mey. for treating neonatal jaundice and managing constipation. The main component of Neoneaster®, mannitol, is an osmotic laxative which could increase intestinal transit and reduce the re-absorption of bilirubin in the enterohepatic cycle. AIM OF THE STUDY: We conducted this study to investigate acute and sub-chronic oral toxicities of Neoneaster in Wistar rats. MATERIALS AND METHODS: In the acute oral toxicity test, based on OECD 423 we administered Neoneaster to the Wistar rats at doses of 5, 50, 300, and 2000 mg/kg(OECD, 2002). Toxicological effects, including mortality and behavioral changes, were recorded for 14 days and compared to the control group. We also carried out histopathological assessments of the tissues of liver, heart, kidney, and spleen after this period. To evaluate sub-chronic toxicity, while administering 2000 mg/kg of Neoneaster daily to the Wistar rats, we recorded for changes in mortality and behavior for 45 days and compared these to the values of the control group. We also carried out biochemical, hematological, and histopathological assessments after this period. RESULTS: In both acute and sub-chronic oral toxicity tests, no mortalities, behavioral abnormalities, and histological signs of toxicity was observed in any of the administered doses in comparison to the control group. The percentage of weight gains in acute toxicity test and the weight gain in sub-chronic test were not significant (P>0/05). There were also no significant differences in hematological and biochemical markers (P>0/05). Based on our finding, Neoneaster can be classified as category 5 in the Globally Harmonized Chemical Classification and Labeling System (GHS) as its Lethal Dose 50 (LD50) is higher than 2000 mg/kg. CONCLUSIONS: This study suggests that Neoneaster is safe and can be classified as category 5 in the GHS system.

Management of Hemorrhagic Fever Viruses: Intervention of Natural and Synthetic Products.

BACKGROUND: Viral hemorrhagic fevers (VHFs) are a group of clinical syndromes caused by several different RNA virus families, including several members of the arenavirus, bunyavirus, filovirus, and flavivirus families. VHFs have high mortality rates, and they have been associated with vascular permeability, malaise, fever, variable degrees of hemorrhage, reduced plasma volume, and coagulation abnormalities. To treat such conditions, antigen-presenting cells target dysregulated immune reactions and productive infections. Monocytes and macrophages produce inflammatory cytokines that damage adaptive immunity, while infected dendritic cells fail to mature correctly, compromising adaptive immunity. Inflammation and uncontrolled virus replication are associated with vascular leakage and coagulopathy. OBJECTIVE: VHF infects both humans and animals and if not treated, causes hemorrhagic manifestations and lethal platelet dysfunction. Besides pharmacological and immunological solutions, the intervention of natural products for VHF management is of great interest. In this review, we gathered current data about the effectiveness of natural products for VHF management. METHODS: Data were extracted from Scopus, Google Scholar, PubMed, and Cochrane library in terms of clinical and animal studies published in English between 1981 to February 2022. RESULTS: Several plants from diverse families and species were identified with antiviral activity against VHF. The combination of botanical therapeutics and multitarget synergistic therapeutic effects is now the widely accepted explanation for the treatment of VHF. Most of these herbal therapeutics have shown promising immunomodulatory effects in vivo and in vitro VHF models. They can probably modulate the immune system in VHF-infected subjects mainly by interfering with certain inflammatory mediators involved in various infectious diseases. CONCLUSION: Natural, in particular, herbal sources can be valuable for the management of various VHFs and their related complications.

Licofelone Attenuates Acetic Acid-Induced Colitis in Rats Through Suppression of the Inflammatory Mediators.

Licofelone is a dual Cyclooxygenase 1,2 (COX1,2)/5-lipoxygenase) 5-LOX (inhibitor with analgesic and anti-inflammatory effects with possible functions on inflammatory bowel disease (IBD), which is a chronic recurrent condition with no particular treatment. This study evaluated the anti-inflammatory effects of licofelone on acetic acid-induced colitis in rats. Ten groups of male Wistar rats (n = 6) were used. Sham, control group, licofelone at doses of 2.5, 5, and 10 mg/kg, L-NG-nitro arginine methyl ester (L-NAME) (10 mg/kg, i.p.), aminoguanidine (AG) (100 mg/kg, i.p.), 30 min before using licofelone (10 mg/kg). Also, three groups received L-NAME, aminoguanidine, or dexamethasone. Macroscopic, microscopic, and biochemical analysis of myeloperoxidase (MPO), and nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß), superoxide dismutase (SOD), reactive oxygen species (ROS), and Toll-like receptor 4 (TLR-4) were assessed in colon tissue. Licofelone at a dose of 10 mg/kg attenuated colitis, increased SOD activity, and significantly reduced colonic levels of the abovementioned inflammatory factors. In addition, licofelone improved macroscopic and microscopic symptoms in the acetic acid-induced colitis model. Moreover, the concurrent use of nitric oxide synthase (NOS) inhibitors with 10 mg/kg of licofelone reversed the observed positive effects, demonstrating the function of nitric oxide in IBD pathogenesis and the probable mechanism for licofelone in the healing process of induced colitis. A reduced level of inflammatory factors confirmed the anti-inflammatory activity of licofelone as a dual COX1,2/5-LOX inhibitor. Furthermore, outcomes revealed the protective role of licofelone in treating experimental colitis. The findings are suggestive of the potential use of licofelone in IBD.

Juglone Mediates Inflammatory Bowel Disease Through Inhibition of TLR-4/NF KappaB Pathway in Acetic Acid-induced Colitis in Rats.

BACKGROUND: Juglone is a phenolic bioactive compound with antimicrobial, antitumour, antioxidant, and anti-inflammatory characteristics. Given its anti-inflammatory and antioxidant effects, it was selected for evaluation in the inflammatory bowel diseases (IBD) model. OBJECTIVE: The current study was performed to evaluate the therapeutic impacts of the juglone in acetic acid-induced colitis in male Wistar rats. METHODS: Juglone was extracted from Pterocarya fraxinifolia via maceration method. Colitis was induced in 36 male Wistar rats (n = 6), except in the sham group, 1 ml of acetic acid 4% was administered intrarectally. Twenty-four hours after induction of colitis, in 3 groups, juglone was administered orally (gavage) at 3 doses of 50, 100, and 150 mg/kg for 2 successive days (once a day). Other groups included the control group (only treated with acetic acid), sham group (normal saline), and standard group (Dexamethasone). To evaluate the inflammation sites, macroscopic and microscopic markers were assessed. The mRNA expression of interleukin (IL)-1ß, and tumor necrosis factor-alpha (TNF)-α were assessed by real-time PCR, while myeloperoxidase (MPO) was measured spectrophotometrically. ELISA assay kits were used to determine the colonic levels of SOD, ROS, NF-κB, and TLR-4. RESULTS: Macroscopic and microscopic assessments revealed that juglone significantly decreased colonic tissue damage and inflammation at 150 mg/kg. Juglone at 100, 150 mg/kg significantly decreased the TNF-α, MPO, and TLR-4 levels, as well as the SOD activity. All juglone-treated groups reduced the NF-κB levels compared to the control group (p < 0.001). The compound decreased the IL-1ß, and ROS levels at the concentration of 150 mg/kg. Juglone attenuated colitis symptoms, reduced inflammation cytokines, declined neutrophil infiltration, and suppressed IL- 1ß and TNF-α expressions in acetic acid-induced colitis rats. It may be proposed that juglone improved colitis in animal model through suppression of inflammatory parameters and downregulation of the NF-κB-TLR-4 pathway. CONCLUSION: Juglone exhibited anti-inflammatory and antioxidant effects in the experimental colitis model and could be a therapeutic candidate for IBD. Juglone should be a subject for further animal and clinical trials in IBD models and for safety concerns.

Ginger and its constituents: Role in treatment of inflammatory bowel disease.

Inflammatory bowel diseases (IBD), with obscure etiology, are rising and are of worldwide concern. Of the various components of IBD pathogenesis and progression, irritation appears to play a major part. Investigations on the molecular and cellular pathways that activate the IBD provide the focus for the development of useful therapies. Ginger (the rhizome of Zingiber officinale) has a broad spectrum of clinical applications due to its anti-inflammatory and anti-oxidative functions. Inflammation and oxidative stress are the key pathogenic factors in many diseases, including IBD. The most established components of ginger are phenolic compounds called gingerols. A wide range of pharmacological activities of the potential therapeutic benefit of Z. officinale have been detailed. In this regard, the anti-inflammatory activity of ginger has been documented by many researchers. It was shown that ginger is a potent inhibitor of the nuclear factor kappa B (NF-κB), signal transducer of activators of transcription (STATs), Nod-like receptor family proteins (NLRPs), toll-like receptors (TLRs), mitogen-activated protein kinase (MAPKs), and mTOR (mTOR) pathways, as well as inhibiting various pro-inflammatory cytokines. In the present report, the potential application of ginger in the management of IBD is reviewed in detail, with an emphasis on the relevant properties of ginger and its bioactive components. The significance of the functions, side effects, and delivery of ginger to the digestive system for particular application in IBD are also considered.

Transmembrane serine protease 2 and angiotensin-converting enzyme 2 anti-inflammatory receptors for COVID-19/inflammatory bowel diseases treatment.

Inflammatory bowel diseases (IBD) refer to a subgroup of chronic, progressive, long-term, and relapsing inflammatory disorders. IBD may spontaneously grow in the colon, and in severe cases may result in tumor lesions such as invasive carcinoma in inflamed regions of the intestine. Recent epidemiological reports indicate that old age and underlying diseases such as IBD contribute to severity and mortality in patients with coronavirus disease 2019 (COVID-19). Currently, the ongoing COVID-19 pandemic caused serious morbidity and mortality worldwide. It has also been shown that the transmembrane serine protease 2 is an essential factor for viral activation and viral engulfment. Generally, viral entry causes a 'cytokine storm' that induces excessive generation of proinflammatory cytokines/chemokines including interleukin (IL)-6, IL-2, IL-7, tumor necrosis factor-α, and interferon-γ. Future research could concentrate on developing inflammatory immunological responses that are efficient to encounter COVID-19. Current analysis elucidates the role of inflammation and immune responses during IBD infection with COVID-19 and provides a list of possible targets for IBD-regulated therapies in particular. Data from clinical, in vitro, and in vivo studies were collected in English from PubMed, Google Scholar, Scopus, and the Cochrane library until May 2021.

Ginger: A complementary approach for management of cardiovascular diseases.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. Inflammation and oxidative stress play critical roles in progression of various types of CVD. Broad pharmacological properties of ginger (the rhizome of Zingiber officinale) and its bioactive components have been reported, suggesting that they can be a therapeutic choice for clinical use. Consistent with its rich phenolic content, the anti-inflammatory and antioxidant properties of ginger have been confirmed in many studies. Ginger modifies many cellular processes and in particular was shown to have potent inhibitory effects against nuclear factor kappa B (NF-κB); signal transducer and activator of transcription; NOD-, LRR-, and pyrin domain-containing proteins; toll-like receptors; mitogen-activated protein kinase; and mammalian target of rapamycin signaling pathways. Ginger also blocks pro-inflammatory cytokines and the activation of the immune system. Ginger suppresses the activity of oxidative molecules such as reactive oxygen species, inducible nitric oxide synthase, superoxide dismutase, glutathione, heme oxygenase, and GSH-Px. In this report, we summarize the biochemical pathologies underpinning a variety of CVDs and the effects of ginger and its bioactive components, including 6-shogaol, 6-gingerol, and 10-dehydrogingerdione. The properties of ginger and its phenolic components, mechanism of action, biological functions, side effects, and methods for enhanced cell delivery are also discussed. Together with preclinical and clinical studies, the positive biological effects of ginger and its bioactive components in CVD support the undertaking of further in vivo and especially clinical studies.

The involvement of JAK/STAT signaling pathway in the treatment of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder in which inflammation and oxidative stress play key etiopathological role. The pathology of PD brain is characterized by inclusions of aggregated α-synuclein (α-SYN) in the cytoplasmic region of neurons. Clinical evidence suggests that stimulation of pro-inflammatory cytokines leads to neuroinflammation in the affected brain regions. Upon neuroinflammation, the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway, and other transcription factors such as nuclear factor κB (NF-κB), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), mammalian target of rapamycin (mTOR), and toll-like receptors (TLRs) are upregulated and induce the microglial activation, contributing to PD via dopaminergic neuron autophagy. Aberrant activation or phosphorylation of the components of JAK/STAT signaling pathway has been implicated in increased transcription of the inflammation-associated genes and many neurodegenerative disorders such as PD. Interferon gamma (IFN-γ), and interleukine (IL)-6 are two of the most potent activators of the JAK/STAT pathway, and it was shown to be elevated in PD. Stimulation of microglial cell with aggregated α-SYN results in production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and IL-1ß in PD. Dysregulation of the JAK/STAT in PD and its involvement in various inflammatory pathways make it a promising PD therapy approach. So far, a variety of synthetic or natural small-molecule JAK inhibitors (Jakinibs) have been found promising in managing a spectrum of ailments, many of which are in preclinical research or clinical trials. Herein, we provided a perspective on the function of the JAK/STAT signaling pathway in PD progression and gathered data that describe the rationale evidence on the potential application of Jakinibs to improve neuroinflammation in PD.

Targeting Mammalian Target of Rapamycin: Prospects for the Treatment of Inflammatory Bowel Diseases.

Inflammatory bowel disease (IBD) is a general term for a group of chronic and progressive disorders. Several cellular and biomolecular pathways are implicated in the pathogenesis of IBD, yet the etiology is unclear. Activation of the mammalian target of rapamycin (mTOR) pathway in the intestinal epithelial cells was also shown to induce inflammation. This review focuses on the inhibition of the mTOR signaling pathway and its potential application in treating IBD. We also provide an overview of plant-derived compounds that are beneficial for the IBD management through modulation of the mTOR pathway. Data were extracted from clinical, in vitro and in vivo studies published in English between 1995 and May 2019, which were collected from PubMed, Google Scholar, Scopus and Cochrane library databases. Results of various studies implied that inhibition of the mTOR signaling pathway downregulates the inflammatory processes and cytokines involved in IBD. In this context, a number of natural products might reverse the pathological features of the disease. Furthermore, mTOR provides a novel drug target for IBD. Comprehensive clinical studies are required to confirm the efficacy of mTOR inhibitors in treating IBD.