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Cancers of the gastrointestinal tract (GIT) are the most common human malignancies. The prevalence of esophageal Cancer, pancreatic ductal adenocarcinoma, gastric Cancer, hepatocellular carcinoma, colorectal Cancer and gallbladder Cancer are on the rise now a days. Despite advances in cancer treatment, increasing reports are focusing on finding novel therapies with lower side effects and higher potency. From the mechanistic point of view, several dysregulated factors are behind the pathophysiology of GIT cancers. Multiple studies have shown molecular targeted therapies in various GIT cancers, including epidermal growth factor receptor pathway (EGFR), vascular endothelial growth factor pathway (VEGF), Wnt/β-catenin pathway, and insulin-like growth factor receptor (IGFR).The aforementioned mediators are the critical targets of the existence of monoclonal antibodies and small molecules in treating GIT cancers. Accordingly, providing the exact dysregulated mechanisms behind GIT cancers could pave the road in the treatment of cancers. This chapter reveals dysregulated signaling pathways and potential therapeutic agents in the treatment of GIT cancer.

Background Withania somnifera (WS), also known as Ashwagandha, is commonly used in Ayurveda and other traditional medicine systems. WS has seen growing, worldwide use by the public due to its reputation as an adaptogen. This popularity has elicited increased scientific study of its biological effects, including a potential application for neuropsychiatric and neurodegenerative disorders. Objective This review aims to provide a comprehensive summary of preclinical and clinical studies examining the neuropsychiatric effects of WS, specifically its application in stress, anxiety, depression, and insomnia. Methods Reports of human trials and animal studies of WS were collected primarily from the PubMed, Scopus, and Google Scholar databases. Results WS root and leaf extracts exhibited noteworthy anti-stress and anti-anxiety activity in animal and human studies. WS also improved symptoms of depression and insomnia, though fewer studies investigated these applications. WS may alleviate these conditions predominantly through modulation of the hypothalamic-pituitary-adrenal and sympathetic-adrenal medullary axes, as well as through GABAergic and serotonergic pathways. While some studies link specific withanolide components to its neuropsychiatric benefits, there is evidence for the presence of additional, yet unidentified, active compounds in WS. Conclusion While benefits were seen in the reviewed studies, significant variability in the WS extracts examined prevents a consensus on the optimum WS preparation or dosage to treat neuropsychiatric conditions. WS appears generally safe for human use; however, it will be important to investigate potential herb-drug interactions involving WS if used alongside pharmaceutical interventions. Further elucidation of active compounds of WS is also needed.

Growing studies are revealing the critical manifestations of influenza, dengue virus (DENV) infection, Zika virus (ZIKV) disease, and Ebola virus disease (EVD) as emerging infectious diseases. However, their corresponding mechanisms of major complications headed for neuronal dysfunction are not entirely understood. From the mechanistic point of view, inflammatory/oxidative mediators are activated during emerging infectious diseases towards less cell migration, neurogenesis impairment, and neuronal death. Accordingly, the virus life cycle and associated enzymes, as well as host receptors, cytokine storm, and multiple signaling mediators, are the leading players of emerging infectious diseases. Consequently, chemokines, interleukins, interferons, carbohydrate molecules, toll-like receptors (TLRs), and tyrosine kinases are leading orchestrates of peripheral and central complications which are in near interconnections. Some of the resulting neuronal manifestations have attracted much attention, including inflammatory polyneuropathy, encephalopathy, meningitis, myelitis, stroke, Guillain-Barré syndrome (GBS), radiculomyelitis, meningoencephalitis, memory loss, headaches, cranial nerve abnormalities, tremor, and seizure. The complex pathophysiological mechanism behind the aforementioned complications urges the need for finding multi-target agents with higher efficacy and lower side effects. In recent decades, the natural kingdom has been highlighted as promising neuroprotective natural products in modulating several dysregulated signaling pathways/mediators. The present study provides neuronal manifestations of some emerging infectious diseases and underlying pathophysiological mechanisms. Besides, a mechanistic-based strategy is developed to introduce candidate natural products as promising multi-target agents in combating major dysregulated pathways towards neuroprotection in influenza, DENV infection, ZIKV disease, and EVD.

Due to the complicated pathogenic pathways of coronavirus disease 2019 (COVID-19), related medicinal therapies have remained a clinical challenge. COVID-19 highlights the urgent need to develop mechanistic pathogenic pathways and effective agents for preventing/treating future epidemics. As a result, the destructive pathways of COVID-19 are in the line with clinical symptoms induced by severe acute coronary syndrome (SARS), including lung failure and pneumonia. Accordingly, revealing the exact signaling pathways, including inflammation, oxidative stress, apoptosis, and autophagy, as well as relative representative mediators such as tumor necrosis factor-α (TNF-α), nuclear factor erythroid 2-related factor 2 (Nrf2), Bax/caspases, and Beclin/LC3, respectively, will pave the road for combating COVID-19. Prevailing host factors and multiple steps of SARS-CoV-2 attachment/entry, replication, and assembly/release would be hopeful strategies against COVID-19. This is a comprehensive review of the destructive signaling pathways and host–pathogen interaction of SARS-CoV-2, as well as related therapeutic targets and treatment strategies, including potential natural products-based candidates J.E. gratefully acknowledges funding from CONICYT (PAI/ACADEMIA N°79160109) SI

Neurological disorders are the major and increasing cause of disability and death. Despite the progressions in the management of neurological diseases, revealing related medicinal therapies remained a clinical challenge, due to their less efficacy and different adverse effects. Besides, several cellular and molecular mechanisms are underlying the progression of neurodegeneration. Increasing our knowledge on these complexes signaling pathways, along with the lack of efficient therapeutic compound, raise the need to develop novel multitarget drugs to stop the progression of neurodegenerative diseases through different mechanisms. Among these destructive signaling pathways, oxidative stress, inflammation, and apoptosis play major roles. Being the auspicious source of antioxidant, antiinflammatory, and antiapoptotic agents, carotenoids have been potential neuroprotective constituents, and there is increasing evidence demonstrating the negative correlation of carotenoids with neurodegenerative diseases. As a red-orange carotenoid possessing unique structure linked to its superior antioxidant activity, astaxanthin (AST) is a promising and multitarget agent. There is also growing attention regarding the potential neuroprotective activity of AST. In the present chapter, we provide the beneficial neuroprotective effects of carotenoids with a particular focus on AST and related pharmacological mechanisms of action to show new avenue in the prevention and treatment of neurodegenerative diseases.

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.