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Neurodegenerative diseases (NDDs) are on the rise in the world. Therefore, it is a critical issue to reveal the precise pathophysiological mechanisms and novel therapeutic strategies to deal with such conditions. Passing through different mechanisms, non-coding RNAs (ncRNAs) play a pivotal role in NDDs through various mechanisms, by changing the expression of some genes, interference with protein translation and alterations in some signaling pathways. It urges the need to introduce novel strategies and therapeutic agents with multi-targeting potentials. Phytochemicals are hopeful antioxidants and anti-inflammatory agents with promising modulatory roles on dysregulated signaling pathways and protein translation during NDDs. In this study, the role of ncRNAs (e.g. lncRNAs, miRNA, siRNAs and piRNAs) was highlighted in NDDs. This study also aimed to investigate the role of phytochemicals (phenolic compounds, alkaloids, terpenoids and sulfur compounds) in the modulation of ncRNAs during NDDs such as Alzheimer's disease, Parkinson's disease, epilepsy, depression and amyotrophic lateral sclerosis.

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.

Several signaling pathways and basic metabolites are responsible for the control of metabolism in both normal and cancer cells. As emerging hallmarks of cancer metabolism, the abnormal activities of these pathways are of the most noticeable events in cancer. This altered metabolism expedites the survival and proliferation of cancer cells, which have attracted a substantial amount of interest in cancer metabolism. Nowadays, targeting metabolism and cross-linked signaling pathways in cancer has been a hot topic to investigate novel drugs against cancer. Despite the efficiency of conventional drugs in cancer therapy, their associated toxicity, resistance, and high-cost cause limitations in their application. Besides, considering the numerous signaling pathways cross-linked with cancer metabolism, discovery, and development of multi-targeted and safe natural compounds has been a high priority. Natural secondary metabolites have exhibited promising anticancer effects by targeting dysregulated signaling pathways linked to cancer metabolism. The present review reveals the metabolism and cross-linked dysregulated signaling pathways in cancer. The promising therapeutic targets in cancer, as well as the critical role of natural secondary metabolites for significant anticancer enhancements, have also been highlighted to find novel/potential therapeutic agents for cancer treatment.

As the worldwide average life expectancy has grown, the prevalence of age-related neurodegenerative diseases (NDDs) has risen dramatically. A progressive loss of neuronal function characterizes NDDs, usually followed by neuronal death. Inflammation, apoptosis, oxidative stress, and protein misfolding are critical dysregulated signaling pathways that mainly orchestrate neuronal damage from a mechanistic point. Furthermore, in afflicted families with genetic anomalies, mutations and multiplications of α-synuclein and amyloid-related genes produce some kinds of NDDs. Overproduction of such proteins, and their excessive aggregation, have been proven in various models of neuronal malfunction and death. In this line, providing multi-target therapies carried by novel delivery systems would pave the road to control NDDs through simultaneous modulation of such dysregulated pathways. Phytochemicals are multi-target therapeutic agents, which employ several mechanisms towards neuroprotection. Besides, the blood–brain barrier (BBB) is a critical issue in managing NDDs since it inhibits the accessibility of drugs to the brain in sufficient concentration. Besides, discovering novel delivery systems is vital to improving the efficacy, bioavailability, and pharmacokinetic of therapeutic agents. Such novel formulations are also employed to improve the drug’s biodistribution, allow for the co-delivery of several medicines, and offer targeted intracellular delivery against NDDs. The present review proposes nanoformulations of phytochemicals and synthetic agents to combat NDDs by modulating neuroinflammation, neuroapoptosis, neuronal oxidative stress pathways and protein misfolding.

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.

Senescence is a special state of tumor suppression induced by cell cycle arrest. However, releasing senescence-associated secretory phenotypes by senescent cells could provide tumorigenic conditions and epigenetic changes in neighboring cells. The conventional anticancer drugs activate therapy-induced senescence by several mechanisms which include an increase in mitochondrial biogenesis and reactive oxygen species, up-regulation of tumor suppressor proteins (e.g., p53, p21, p38, and p16) and modulation of dysregulated signaling mediators, including senescence-associated β-galactosidase, ataxia-telangiectasia mutated/ATM and Rad3-related, checkpoint kinase1/2, phosphatidylinositol 3-kinases/Akt, Ras/Raf pathway, and extracellular signal-regulated kinase/mitogen-activated protein kinase. On the other hand, conventional anticancer agents induce the secretion of procarcinogenic molecules, including inflammatory mediators, such as nuclear factor-κB, tumor necrosis factor-α, and interleukins, and angiogenic mediators, namely vascular endothelial growth factor, in the tumor microenvironment. This condition urges the need for finding novel alternative therapies, novel senolytics, senescence inducers and combination therapies in the regulation of senescence towards the regulation of multiple tumorigenic conditions. This comprehensive review highlights the therapeutic targets and signaling pathways in the senescence of tumor cells. The critical roles of anticancer drug-induced senescence, senolytics, and associated combined administrations are evaluated in the attenuation of cellular senescence pathways to achieve cancer prevention and efficient treatment. Current challenges/pitfalls, limitations, and future research are also discussed.

Despite the progression in targeting the complex pathophysiological mechanisms of neurodegenerative diseases (NDDs) and spinal cord injury (SCI), there is a lack of effective treatments. Moreover, conventional therapies suffer from associated side effects and low efficacy, raising the need for finding potential alternative therapies. In this regard, a comprehensive review was done regarding revealing the main neurological dysregulated pathways and providing alternative therapeutic agents following SCI. From the mechanistic point, oxidative stress and inflammatory pathways are major upstream orchestras of cross-linked dysregulated pathways (e.g., apoptosis, autophagy, and extrinsic mechanisms) following SCI. It urges the need for developing multitarget therapies against SCI complications. Polyphenols, as plant-derived secondary metabolites, have the potential of being introduced as alternative therapeutic agents to pave the way for treating SCI. Such secondary metabolites presented modulatory effects on neuronal oxidative stress, neuroinflammatory, and extrinsic axonal dysregulated pathways in the onset and progression of SCI. In the present review, the potential role of phenolic compounds as critical phytochemicals has also been revealed in regulating upstream dysregulated oxidative stress/inflammatory signaling mediators and extrinsic mechanisms of axonal regeneration after SCI in preclinical and clinical studies. Additionally, the coadministration of polyphenols and stem cells has shown a promising strategy for improving post-SCI complications.

Cardiovascular disease (CVD) is a major concern for health with high mortality rates around the world. CVD is often associated with partial or full occlusion of the blood vessel network. Changes in lifestyle can be useful for management early-stage disease but in the advanced stage, surgical interventions or pharmacological are needed to increase the blood flow through the affected tissue or to reduce the energy requirements. Regeneration medicine is a new science that has provided many different options for treating various diseases, especially in CVD over the years. Stem cell therapy, gene therapy, and tissue engineering are some of the powerful branches of the field that have given patients great hope in improving their condition. In this review, we attempted to examine the beneficial effects, challenges, and contradictory effects of angiogenesis in vivo, and in vitro models’ studies of CVD. We hope that this information will be able to help other researchers to design new effective structures and open new avenues for the treatment of CVD with the help of angiogenesis and regeneration medicine in the future.

Senescence suppresses tumor growth, while also developing a tumorigenic state in the nearby cells that is mediated by senescence-associated secretory phenotypes (SASPs). The dual function of cellular senescence stresses the need for identifying multi-targeted agents directed towards the promotion of cell senescence in cancer cells and suppression of the secretion of pro-tumorigenic signaling mediators in neighboring cells. Natural secondary metabolites have shown favorable anticancer responses in recent decades, as some have been found to target the senescence-associated mediators and pathways. Furthermore, phenolic compounds and polyphenols, terpenes and terpenoids, alkaloids, and sulfur-containing compounds have shown to be promising anticancer agents through the regulation of paracrine and autocrine pathways. Plant secondary metabolites are potential regulators of SASPs factors that suppress tumor growth through paracrine mediators, including growth factors, cytokines, extracellular matrix components/enzymes, and proteases. On the other hand, ataxia-telangiectasia mutated, ataxia-telangiectasia and Rad3-related, extracellular signal-regulated kinase/mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, nuclear factor-κB, Janus kinase/signal transducer and activator of transcription, and receptor tyrosine kinase-associated mediators are main targets of candidate phytochemicals in the autocrine senescence pathway. Such a regulatory role of phytochemicals on senescence-associated pathways are associated with cell cycle arrest and the attenuation of apoptotic/inflammatory/oxidative stress pathways. The current systematic review highlights the critical roles of natural secondary metabolites in the attenuation of autocrine and paracrine cellular senescence pathways, while also elucidating the chemopreventive and chemotherapeutic capabilities of these compounds. Additionally, we discuss current challenges, limitations, and future research indications.

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

Background As common, progressive, and chronic causes of disability and death, neurodegenerative diseases (NDDs) significantly threaten human health, while no effective treatment is available. Given the engagement of multiple dysregulated pathways in neurodegeneration, there is an imperative need to target the axis and provide effective/multi-target agents to tackle neurodegeneration. Recent studies have revealed the role of phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) in some diseases and natural products with therapeutic potentials. Purpose This is the first systematic and comprehensive review on the role of plant-derived secondary metabolites in managing and/or treating various neuronal disorders via the PI3K/Akt/mTOR signaling pathway. Study design and methods A systematic and comprehensive review was done based on the PubMed, Scopus, Web of Science, and Cochrane electronic databases. Two independent investigators followed the PRISMA guidelines and included papers on PI3K/Akt/mTOR and interconnected pathways/mediators targeted by phytochemicals in NDDs. Results Natural products are multi-target agents with diverse pharmacological and biological activities and rich sources for discovering and developing novel therapeutic agents. Accordingly, recent studies have shown increasing phytochemicals in combating Alzheimer's disease, aging, Parkinson's disease, brain/spinal cord damages, depression, and other neuronal-associated dysfunctions. Amongst the emerging targets in neurodegeneration, PI3K/Akt/mTOR is of great importance. Therefore, attenuation of these mediators would be a great step towards neuroprotection in such NDDs. Conclusion The application of plant-derived secondary metabolites in managing and/or treating various neuronal disorders through the PI3K/Akt/mTOR signaling pathway is a promising strategy towards neuroprotection.

Neurodegenerative diseases are questions that modern therapeutics can still not answer. Great milestones have been achieved regarding liver, heart, skin, kidney and other types of organ transplantations but the greatest drawback is the adequate supply of these organs. Furthermore, there are still a few options available in the treatment of neurodegenerative diseases. With great advances in medical science, many health problems faced by humans have been solved, and their quality of life is improving. Moreover, diseases that were incurable in the past have now been fully cured. Still, the area of regenerative medicine, especially concerning neuronal regeneration, is in its infancy. Presently allopathic drugs, surgical procedures, organ transplantation, stem cell therapy forms the core of regenerative therapy. However, many times, the currently used therapies cannot completely cure damaged organs and neurodegenerative diseases. The current review focuses on the concepts of regeneration, hurdles faced in the path of regenerative therapy, neurodegenerative diseases and the idea of using peptides, cytokines, tissue engineering, genetic engineering, advanced stem cell therapy, and polyphenolic phytochemicals to cure damaged tissues and neurodegenerative diseases.

Alzheimer’s disease (AD) is a progressive neuronal/cognitional dysfunction, leading to disability and death. Despite advances in revealing the pathophysiological mechanisms behind AD, no effective treatment has yet been provided. It urges the need for finding novel multi-target agents in combating the complex dysregulated mechanisms in AD. Amongst the dysregulated pathophysiological pathways in AD, oxidative stress seems to play a critical role in the pathogenesis progression of AD, with a dominant role of nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap1)/antioxidant responsive elements (ARE) pathway. In the present study, a comprehensive review was conducted using the existing electronic databases, including PubMed, Medline, Web of Science, and Scopus, as well as related articles in the field. Nrf2/Keap1/ARE has shown to be the upstream orchestrate of oxidative pathways, which also ameliorates various inflammatory and apoptotic pathways. So, developing multi-target agents with higher efficacy and lower side effects could pave the road in the prevention/management of AD. The plant kingdom is now a great source of natural secondary metabolites in targeting Nrf2/Keap1/ARE. Among natural entities, phenolic compounds, alkaloids, terpene/terpenoids, carotenoids, sulfur-compounds, as well as some other miscellaneous plant-derived compounds have shown promising future accordingly. Prevailing evidence has shown that activating Nrf2/ARE and downstream antioxidant enzymes, as well as inhibiting Keap1 could play hopeful roles in overcoming AD. The current review highlights the neuroprotective effects of plant secondary metabolites through targeting Nrf2/Keap1/ARE and downstream interconnected mediators in combating AD.

It has been reported that the antiestrogen Tamoxifen induces liver tumors in rats and genotoxic effects in vitro through DNA interaction. So, it can be proposed that its structural analogue, Clomifene, also can bind to DNA. To test this hypothesis, the DNA binding properties of Clomifene have been studied by absorption spectroscopy, fluorescence spectroscopy, cellular uptake, cell viability, cell proliferation and molecular modeling techniques. Evidences are provided that Clomifene could interact with DNA via minor groove interaction mode. The negative ΔG value implied that the interaction occurred between DNA and Clomifene spontaneously. Also, the positive ΔH and positive ΔS values indicated that the binding of Clomifene with DNA is mainly entropy driven and the enthalpy is unfavorable parameter. This also suggests that the hydrophobic interaction plays a major role in the binding with overall binding constant of K=5.645×107M-1 at 298K. From the results of docking, it can be concluded that Hydrogen bonds is also one of the most important interactions. The increase in entropy of system after binding might be due to the destruction of the DNA structure.

Cardiovascular disease is an important cause for morbidity and mortality worldwide. Flavonoids, such as naringin, and naringenin are important natural phytochemicals in the treatment or prevention of various disorders such as obesity, cardiac diseases, diabetes, and metabolic syndrome. Naringin and naringenin have significant therapeutic potential in several diseases through anti-oxidative, anti-inflammatory, and anti-apoptotic actions; these flavonoids play a protective role in human pathophysiology. In this review, based on the latest evidence, we present a summary of the impact of naringin, and naringenin on cardiovascular disease, and analyze and discuss the basic roles of naringin and naringenin and their mechanisms of actions in cardiovascular disease and other vascular dysfunction. The data collected in this review may serve as a comprehensive reference for the effects of naringin, and naringenin in cardiovascular disease, which may be beneficial for further research and for the design of naringin and naringenin analogs as new therapeutic options for cardiovascular diseases.

In this study, the interaction of clomiphene (CLO), a non-steroidal and ovulatory stimulant drug employed in the treatment of infertility, with human serum albumin (HSA), the most abundant plasma transport protein, was investigated using spectrofluorometric, FT-IR, UV-Vis, and molecular modeling methods. The obtained results indicated that the binding of CLO to HSA led to intense fluorescence quenching of HSA via a static quenching mechanism, and that the process of CLO binding to HSA was enthalpy driven. By using experimental and theoretical methods, it was confirmed that as a result of binding CLO, slight conformational changes in HSA occurred. Also, the negative ΔH of interaction indicated that the binding of CLO with HSA was mainly enthalpy driven. The experimental and computational results suggested that hydrogen bonds and van der Waals interactions played a major role in the binding, with overall binding constants of K = 3.67 × 109 M−1 at 286 K and 6.52 × 105 mol L−1 at 310 K. Moreover, the results of molecular modeling showed that Asp234, Phe228, Leu327, and Arg209 in HSA had the highest interaction energies with the ligand.