Modulation of hypoxia-inducible factor-1 signaling pathways in cancer angiogenesis, invasion, and metastasis by natural compounds: a comprehensive and critical review.

Tumor cells employ multiple signaling mediators to escape the hypoxic condition and trigger angiogenesis and metastasis. As a critical orchestrate of tumorigenic conditions, hypoxia-inducible factor-1 (HIF-1) is responsible for stimulating several target genes and dysregulated pathways in tumor invasion and migration. Therefore, targeting HIF-1 pathway and cross-talked mediators seems to be a novel strategy in cancer prevention and treatment. In recent decades, tremendous efforts have been made to develop multi-targeted therapies to modulate several dysregulated pathways in cancer angiogenesis, invasion, and metastasis. In this line, natural compounds have shown a bright future in combating angiogenic and metastatic conditions. Among the natural secondary metabolites, we have evaluated the critical potential of phenolic compounds, terpenes/terpenoids, alkaloids, sulfur compounds, marine- and microbe-derived agents in the attenuation of HIF-1, and interconnected pathways in fighting tumor-associated angiogenesis and invasion. This is the first comprehensive review on natural constituents as potential regulators of HIF-1 and interconnected pathways against cancer angiogenesis and metastasis. This review aims to reshape the previous strategies in cancer prevention and treatment.

The Exosome-Mediated PI3K/Akt/mTOR Signaling Pathway in Neurological Diseases.

As major public health concerns associated with a rapidly growing aging population, neurodegenerative diseases (NDDs) and neurological diseases are important causes of disability and mortality. Neurological diseases affect millions of people worldwide. Recent studies have indicated that apoptosis, inflammation, and oxidative stress are the main players of NDDs and have critical roles in neurodegenerative processes. During the aforementioned inflammatory/apoptotic/oxidative stress procedures, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway plays a crucial role. Considering the functional and structural aspects of the blood-brain barrier, drug delivery to the central nervous system is relatively challenging. Exosomes are nanoscale membrane-bound carriers that can be secreted by cells and carry several cargoes, including proteins, nucleic acids, lipids, and metabolites. Exosomes significantly take part in the intercellular communications due to their specific features including low immunogenicity, flexibility, and great tissue/cell penetration capabilities. Due to their ability to cross the blood-brain barrier, these nano-sized structures have been introduced as proper vehicles for central nervous system drug delivery by multiple studies. In the present systematic review, we highlight the potential therapeutic effects of exosomes in the context of NDDs and neurological diseases by targeting the PI3K/Akt/mTOR signaling pathway.

The pivotal role of JAK/STAT and IRS/PI3K signaling pathways in neurodegenerative diseases: Mechanistic approaches to polyphenols and alkaloids.

BACKGROUND: Neurodegenerative diseases (NDDs) are characterized by progressive neuronal dysfunctionality which results in disability and human life-threatening events. In recent decades, NDDs are on the rise. Besides, conventional drugs have not shown potential effectiveness to attenuate the complications of NDDs. So, exploring novel therapeutic agents is an urgent need to combat such disorders. Accordingly, growing evidence indicates that polyphenols and alkaloids are promising natural candidates, possessing several beneficial pharmacological effects against diseases. Considering the complex pathophysiological mechanisms behind NDDs, Janus kinase (JAK), insulin receptor substrate (IRS), phosphoinositide 3-kinase (PI3K), and signal transducer and activator of transcription (STAT) seem to play critical roles during neurodegeneration/neuroregeneration. In this line, modulation of the JAK/STAT and IRS/PI3K signaling pathways and their interconnected mediators by polyphenols/alkaloids could play pivotal roles in combating NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), stroke, aging, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), depression and other neurological disorders. PURPOSE: Thus, the present study aimed to investigate the neuroprotective roles of polyphenols/alkaloids as multi-target natural products against NDDs which are critically passing through the modulation of the JAK/STAT and IRS/PI3K signaling pathways. STUDY DESIGN AND METHODS: A systematic and comprehensive review was performed to highlight the modulatory roles of polyphenols and alkaloids on the JAK/STAT and IRS/PI3K signaling pathways in NDDs, according to the PRISMA guideline, using scholarly electronic databases, including Scopus, PubMed, ScienceDirect, and associated reference lists. RESULTS: In the present study 141 articles were included from a total of 1267 results. The results showed that phenolic compounds such as curcumin, epigallocatechin-3-gallate, and quercetin, and alkaloids such as berberine could be introduced as new strategies in combating NDDs through JAK/STAT and IRS/PI3K signaling pathways. This is the first systematic review that reveals the correlation between the JAK/STAT and IRS/PI3K axis which is targeted by phytochemicals in NDDs. Hence, this review highlighted promising insights into the neuroprotective potential of polyphenols and alkaloids through the JAK/STAT and IRS/PI3K signaling pathway and interconnected mediators toward neuroprotection. CONCLUSION: Amongst natural products, phenolic compounds and alkaloids are multi-targeting agents with the most antioxidants and anti-inflammatory effects possessing the potential of combating NDDs with high efficacy and lower toxicity. However, additional reports are needed to prove the efficacy and possible side effects of natural products.

Polydatin: Pharmacological Mechanisms, Therapeutic Targets, Biological Activities, and Health Benefits.

Polydatin is a natural potent stilbenoid polyphenol and a resveratrol derivative with improved bioavailability. Polydatin possesses potential biological activities predominantly through the modulation of pivotal signaling pathways involved in inflammation, oxidative stress, and apoptosis. Various imperative biological activities have been suggested for polydatin towards promising therapeutic effects, including anticancer, cardioprotective, anti-diabetic, gastroprotective, hepatoprotective, neuroprotective, anti-microbial, as well as health-promoting roles on the renal system, the respiratory system, rheumatoid diseases, the skeletal system, and women's health. In the present study, the therapeutic targets, biological activities, pharmacological mechanisms, and health benefits of polydatin are reviewed to provide new insights to researchers. The need to develop further clinical trials and novel delivery systems of polydatin is also considered to reveal new insights to researchers.

Targeting lactate metabolism and glycolytic pathways in the tumor microenvironment by natural products: A promising strategy in combating cancer.

Anticancer drugs are not purely effective because of their toxicity, side effects, high cost, inaccessibility, and associated resistance. On the other hand, cancer is a complex public health problem that could intelligently adopt different signaling pathways and alter the body's metabolism to escape from the immune system. One of the cancer strategies to metastasize is modifying pH in the tumor microenvironment, ranging between 6.5 and 6.9. As a powerful determiner, lactate is responsible for this acidosis. It is involved in immune stimulation, including innate and adaptive immunity, apoptotic-related factors (Bax/Bcl-2, caspase), and glycolysis pathways (e.g., GLUT-1, PKM2, PFK, HK2, MCT-1, and LDH). Lactate metabolism, in turn, is interconnected with several dysregulated signaling mediators, including PI3K/Akt/mTOR, AMPK, NF-κB, Nrf2, JAK/STAT, and HIF-1α. Because of lactate's emerging and critical role, targeting lactate production and its transporters is important for preventing and managing tumorigenesis. Hence, exploring and developing novel promising anticancer agents to minimize human cancers is urgent. Based on numerous studies, natural secondary metabolites as multi-target alternative compounds with health-promoting properties possess more high effectiveness and low side effects than conventional agents. Besides, the mechanism of multi-targeted natural sources is related to lactate production and cancer-associated cross-talked factors. This review focuses on targeting the lactate metabolism/transporters, and lactate-associated mediators, including glycolytic pathways. Besides, interconnected mediators to lactate metabolism are also targeted by natural products. Accordingly, plant-derived secondary metabolites are introduced as alternative therapies in combating cancer through modulating lactate metabolism and glycolytic pathways.

The antinociceptive mechanisms of melatonin: role of L-arginine/nitric oxide/cyclic GMP/KATP channel signaling pathway.

Pain is one of the most common medical challenges, reducing life quality. Despite the progression in pain management, it has remained a clinical challenge, which raises the need for investigating novel antinociceptive drugs with correspondence signaling pathways. Besides, the precise antinociceptive mechanisms of melatonin are not revealed. Accordingly, owing to the critical role of L-arginine/nitric oxide (NO)/cyclic GMP (cGMP)/KATP in the antinociceptive responses of various analgesics, the role of this signaling pathway is evaluated in the antinociceptive effects of melatonin. Male NMRI mice were intraperitoneally pretreated with the injection of L-arginine (NO precursor, 100 mg/kg), N(gamma)-nitro-L-arginine methyl ester [L-NAME, NO synthase (NOS) inhibitor, 30 mg/kg], S-nitroso-N-acetylpenicillamine (SNAP, NO donor, 1 mg/kg), sildenafil (phosphodiesterase inhibitor, 0.5 mg/kg), and glibenclamide (KATP channel blocker, 10 mg/kg) alone and before the administration of the most effective dose of melatonin amongst the intraperitoneal doses of 50, 100, and 150 mg/kg. The formalin test (2%, 25 µL, intra-plantarly) was done following the melatonin administration, then the nociceptive responses of mice were evaluated during the early phase for 5 min and the late phase for 15 min. The results showed that 100 mg/kg dose of melatonin carried out the most antinociceptive effects. While the antinociceptive effect of melatonin was increased by L-arginine, SNAP, and sildenafil, it was significantly reduced by L-NAME and glibenclamide in both phases of the formalin test, with no relation to the sedative effects of melatonin evaluated by the inclined plane test. In conclusion, the antinociceptive effect of melatonin is mediated through the L-arginine/NO/cGMP/KATP pathway.