Current Molecular Pharmacology - Volume 15, Issue 1, 2022

Sports-related traumatic brain injury (TBI) is one of the common neurological maladies experienced by athletes. Earlier, the term ‘punch drunk syndrome’ was used in the case TBI of boxers and now this term is replaced by chronic traumatic encephalopathy (CTE). Sports-related brain injury can either be short-term or long-term. A common instance of brain injury encompasses subdural hematoma, concussion, cognitive dysfunction, amnesia, headache, vision issue, axonopathy, or even death, if it remains undiagnosed or untreated. Further, chronic TBI may lead to pathogenesis of neuroinflammation and neurodegeneration via tauopathy, the formation of neurofibrillary tangles, and damage to the blood-brain barrier, microglial, and astrocyte activation. Thus, altered pathological, neurochemical, and neurometabolic attributes lead to the modulation of multiple signaling pathways and cause neurological dysfunction. Available pharmaceutical interventions are based on one drug one target hypothesis and are thereby unable to cover altered multiple signaling pathways. However, in recent times, pharmacological intervention of nutrients and nutraceuticals have been explored as they exert a multifactorial mode of action and maintain over homeostasis of the body. There are various reports available showing the positive therapeutic effect of nutraceuticals in sport-related brain injury. Therefore, in the current article, we have discussed the pathology, neurological consequence, sequelae, and perpetuation of sports-related brain injury. Further, we have discussed various nutraceutical supplements as well as available animal models to explore the neuroprotective effect/ upshots of these nutraceuticals in sports-related brain injury.

Alzheimer’s disease (AD) is one of the common chronic neurological disorders and associated with cognitive dysfunction, depression and progressive dementia. The presence of β-amyloid or senile plaques, hyper-phosphorylated tau proteins, neurofibrillary tangle, oxidative-nitrative stress, mitochondrial dysfunction, endoplasmic reticulum stress, neuroinflammation and derailed neurotransmitter status are the hallmarks of AD. Currently, donepezil, memantine, rivastigmine and galantamine are approved by the FDA for symptomatic management. It is well-known that these approved drugs only exert symptomatic relief and possess poor patient-compliance. Additionally, various published evidence showed the neuroprotective potential of various nutraceuticals via their antioxidant, anti-inflammatory and anti-apoptotic effects in the preclinical and clinical studies. These nutraceuticals possess a significant neuroprotective potential and hence, can be a future pharmacotherapeutic for the management and treatment of AD. However, nutraceuticals suffer from certain major limitations such as poor solubility, low bioavailability, low stability, fast hepatic- metabolism and larger particle size. These pharmacokinetic attributes restrict their entry into the brain via the blood-brain barrier. Therefore, to overcome such issues, various nanoformulations of nutraceuticals have been developed, that allow their effective delivery into the brain owing to reduced particle size, increased lipophilicity, increased bioavailability and avoidance of fast hepatic metabolism. Thus, in this review, we have discussed the etiology of AD, focusing on the pharmacotherapeutics of nutraceuticals with preclinical and clinical evidence, discussed pharmaceutical limitations and regulatory aspects of nutraceuticals to ensure safety and efficacy. We have further explored various nanoformulations of nutraceuticals as a novel approach to overcome the existing pharmaceutical limitations and for effective delivery into the brain.

Sports deserve a special place in human life to impart healthy and refreshing wellbeing. However, sports activities, especially contact sports, renders athlete vulnerable to brain injuries. Athletes participating in a contact sport like boxing, rugby, American football, wrestling, and basketball are exposed to traumatic brain injuries (TBI) or concussions. The acute and chronic nature of these heterogeneous injuries provides a spectrum of dysfunctions that alters the neuronal, musculoskeletal, and behavioral responses of an athlete. Many sports-related brain injuries go unreported, but these head impacts trigger neurometabolic disruptions that contribute to long-term neuronal impairment. The pathophysiology of post-concussion and its underlying mechanisms are undergoing intense research. It also shed light on chronic disorders like Parkinson's disease, Alzheimer's disease, and dementia. In this review, we examined post-concussion neurobehavioral changes, tools for early detection of signs, and their impact on the athlete. Further, we discussed the role of nutritional supplements in ameliorating neuropsychiatric diseases in athletes.

Polyphenolic phytoconstituents have been widely in use worldwide for ages and are categorised as secondary metabolites of plants. The application of polyphenols such as quercetin, resveratrol, curcumin as nutritional supplements has been researched widely. The use of polyphenols and specifically quercetin, for improving memory and mental endurance has shown significant effects among rats. Even though similar results have not been resonated among humans, but preclinical results have encouraged researchers to explore other polyphenols to study the effects as supplements among athletes. The phytopharmacological research has elucidated the use of natural polyphenols to prevent and treat various physiological and metabolic disorders owing to their free radical scavenging properties, anti-inflammatory, anti-cancer, and immunomodulatory effects. In- -spite of the tremendous pharmacological profile, one of the most dominant problem regarding the use of polyphenolic compounds is their low bioavailability. Nanonization is considered as one of the most prominent approaches among many. This article aims to review and discuss the molecular mechanisms of recently developed nanocarrier-based drug delivery systems for polyphenols and their application as drugs and supplements. Nanoformulations of natural polyphenols as bioactive agents, such as quercetin, kaempferol, fisetin, rutin, hesperetin, and naringenin epigalloccatechin- 3-gallate, genistein, ellagic acid, gallic acid, chlorogenic acid, ferulic acid, curcuminoids, and stilbenes is expected to have better efficacy. These delivery systems are expected to provide higher penetrability of polyphenols at cellular levels and exhibit a controlled release of the drugs. It is widely accepted that natural polyphenols do demonstrate significant therapeutic effects. However, the hindrances in their absorption, specificity, and bioavailability can be overcome using nanotechnology.

Diabetic neuropathy is an incapacitating chronic pathological condition that encompasses a large group of diseases and manifestations of nerve damage. It affects approximately 50% of patients with diabetes mellitus. Autonomic, sensory, and motor neurons are affected. Disabilities are severe, along with poor recovery and diverse pathophysiology. Physical exercise and herbal- based therapies have the potential to decrease the disabilities associated with diabetic neuropathy. Aerobic exercises like walking, weight lifting, the use of nutraceuticals and herbal extracts are found to be effective. Literature from the public domain was studied emphasizing various beneficial effects of different exercises, herbal and nutraceuticals for their therapeutic action in diabetic neuropathy. Routine exercises and administration of herbal and nutraceuticals, either the extract of plant material containing the active phytoconstituent or isolated phytoconstituent at safe concentration, have been shown to have promising positive action in the treatment of diabetic neuropathy. Exercise has shown promising effects on vascular and neuronal health. It has proven to be well effective in the treatment as well as prevention of diabetic neuropathy by various novel mechanisms, including Herbal and nutraceuticals therapy. They primarily show the anti-oxidant effect, secretagogue, anti-inflammatory, analgesic, and neuroprotective action. Severe adverse events are rare with these therapies. The current review investigates the benefits of exercise and nutraceutical therapies in the treatment of diabetic neuropathy.

Background: Neurodegenerative disorders belong to different classes of progressive/ chronic conditions that affect the peripheral/central nervous system. It has been shown through studies that athletes who play sports involving repeated head trauma and sub-concussive impacts are more likely to experience neurological impairments and neurodegenerative disorders in the long run. Aims: The aim of the current narrative review article is to provide a summary of various nutraceuticals that offer promise in the prevention or management of sports-related injuries, especially concussions and mild traumatic brain injuries. Methods: This article reviews the various potential nutraceutical agents and their possible mechanisms in providing a beneficial effect in the injury recovery process. A thorough survey of the literature was carried out in the relevant databases to identify studies published in recent years. In the present article, we have also highlighted the major neurological disorders along with the associated nutraceutical(s) therapy in the management of disorders. Results: The exact pathological mechanism behind neurodegenerative conditions is complex as well as idiopathic. However, mitochondrial dysfunction, oxidative stress as well as intracellular calcium overload are some common reasons responsible for the progression of these neurodegenerative disorders. Owing to the multifaceted effects of nutraceuticals (complementary medicine), these supplements have gained importance as neuroprotective. These diet-based approaches inhibit different pathways in a physiological manner without eliciting adverse effects. Food habits and lifestyle of an individual also affect neurodegeneration. Conclusion: Studies have shown nutraceuticals (such as resveratrol, omega-3-fatty acids) to be efficacious in terms of their neuroprotection against several neurodegenerative disorders and to be used as supplements in the management of traumatic brain injuries. Protection prior to injuries is needed since concussions or sub-concussive impacts may trigger several pathophysiological responses or cascades that can lead to long-term complications associated with CNS. Thus, the use of nutraceuticals as prophylactic treatment for neurological interventions has been proposed.

There are no available antivirals for many viruses or strains, while current antivirals are limited by toxicity and drug resistance. Therefore, alternative strategies, such as RNA interference (RNAi) are required. RNAi suppresses gene expression of any mRNA, making it an attractive candidate for antiviral therapeutics. Studies have evaluated siRNAs in a range of viruses, with some showing promising results. However, issues with stability and delivery of siRNAs remain. These issues may be minimized by modifying the siRNA structure, using an efficient delivery vector and targeting multiple regions of a virus's genome in a single dose. Finding these solutions could accelerate the progress of RNAi-based antivirals. This review highlights selected examples of antiviral siRNAs, limitations of RNAi and strategies to overcome these limitations

Prostate cancer (PC) is a rapidly increasing ailment worldwide. The previous decade has observed a rapid advancement in PC therapies that was evident from the number of FDA approvals during this phase. Androgen deprivation therapies (ADT) have traditionally remained a mainstay for the management of PCs, but the past decade has experienced the emergence of newer classes of drugs that can be used with or without the administration of ADT. FDA approved poly (ADP-ribose) polymerase inhibitors (PARPi) such as olaparib and rucaparib after successful clinical trials against gene-mutated metastatic castration-resistant prostate cancer. Furthermore, drugs like apalutamide, darolutamide and enzalutamide with androgen-targeted mechanism of action have manifested superior results in non-metastatic castration-resistant prostate cancer (nmCRPC), metastatic castration- sensitive prostate cancer (mCSPC), and metastatic castration-resistant prostate cancer (m- CRPC) respectively with or without previously administered docetaxel. Relugolix, an oral gonadotropin- releasing hormone antagonist and a combination of abiraterone acetate plus prednisone were also approved by FDA after a successful trial in advanced PC and mCRPC respectively. This review aims to analyze the FDA-approved agents in PC during last decade and provide a summary of their clinical trials. It also presents an overview of the ongoing progress of prospective molecules still under trial.

Heat Shock Proteins (HSPs) are important molecular chaperones that facilitate many functions of the cells. They also play a pivotal role in cell survival, especially in the presence of stressors, including nutritional deprivation, lack of oxygen, fever, alcohol, inflammation, oxidative stress, heavy metals, as well as conditions that cause injury and necrosis. In the face of a painful stimulus encounter, many factors could be associated with pain that may include nitric oxide, excitatory amino acids, reactive oxygen species (ROS) formation, prostaglandins, and inflammatory cytokines. One influential factor affecting pain reduction is the expression of HSPs that act as a ROS scavenger, regulate the inflammatory cytokines, and reduce pain responses subsequently. Hence, we assembled information on the painkilling attributes of HSPs. In this field of research, new painkillers could be developed by targetting HSPs to alleviate pain and widen our grasp of pain in pathological conditions and neurological diseases.

Background: As one of the effective pharmacological constituents of Ginseng Radix et Rhizoma, ginsenoside Rh2 (Rh2) exerts a remarkable anticancer effect on various cancer cell lines in vitro and strongly inhibits tumor growth in vivo without severe toxicity. Objective: This article reviewed existing evidence supporting the anticancer effects of Rh2 to classify and conclude previous and current knowledge on the mechanisms and therapeutic effects of Rh2, as well as to promote the clinical application of this natural product. Conclusion: This article reviewed the anticancer efficacies and mechanisms of Rh2, including the induction of cell cycle arrest and programmed cell death, repression of metastasis, alleviation of drug resistance, and regulation of the immune system. Finally, this paper discussed the research and application prospects of Rh2.

Background: High-quality of the oocyte is crucial for embryo development and the success of human-assisted reproduction. The postovulatory aged oocytes lose developmental competence with mitochondrial dysfunction and oxidative stress. Coenzyme Q10 (CoQ10) is widely distributed in the membranes of cells and has an important role in the mitochondrial respiration chain against oxidative stress and modulation of gene expression. Objective: The objective of this study is to investigate the functions and mechanisms of CoQ10 on delaying postovulatory oocyte aging. Methods: Quantitative real-time PCR and Immunofluorescence staining were used to determine the expression patterns of the biogenesis genes of CoQ10 in postovulatory aged oocytes compared with fresh oocytes. The mitochondrial function, apoptosis, reactive oxygen species (ROS) accumulation and spindle abnormalities were investigated after treatment with 10 μM CoQ10 in aged groups. SIRT4 siRNA or capped RNA was injected into oocytes to investigate the function of SIRT4 on postovulatory oocyte aging and the relationship between CoQ10 and SIRT4. Results: Multiple CoQ10 biosynthesis enzymes are insufficient, and a supplement of CoQ10 can improve oocyte quality and elevate the development competency of postovulatory aged oocytes. CoQ10 can attenuate the aging-induced abnormalities, including mitochondrial dysfunction, ROS accumulation, spindle abnormalities, and apoptosis in postovulatory aged oocytes. Furthermore, SIRT4, which was first found to be up-regulated in postovulatory aged oocytes, decreased following CoQ10 treatment. Finally, knockdown of SIRT4 can rescue aging-induced dysfunction of mitochondria, and the efficiency of CoQ10 rescuing dysfunction of mitochondria can be weakened by SIRT4 overexpression. Conclusion: Supplement of CoQ10 protects oocytes from postovulatory aging by inhibiting SIRT4 increase.

Background: Cyclophosphamide (CP) as an alkylating compound has been widely applied to treat cancer and autoimmune diseases. CP is observed to be nephrotoxic in humans and animals because it produces reactive oxygen species. Gallic Acid (GA), a polyhydroxy phenolic compound, is reported to exhibit antioxidant and anti-inflammatory effects. Objective: The current research aimed at evaluating the GA effect on CP-related renal toxicity. Methods: In total, 35 male mice were assigned to 5 groups. Group1: receiving normal saline, group 2: CP group, receiving one CP injection (200 mg/kg; i.p.) on day 6. Groups 3 and 4: GA+CP, GA (10 and 30 mg/kg; p.o.; respectively) received through six consecutive days plus CP on the 6th day 2 hr after the last dose of GA, group 5: received GA (30 mg/kg; p.o.) for six consecutive days. Then on day 7, blood samples were collected for determining Creatinine (Cr), serum kidney injury molecule-1 (KIM-1), Blood Urea Nitrogen (BUN), and Neutrophil Gelatinase-Associated Lipocalin (NGAL) concentrations. Malondialdehyde (MDA), Nitric Oxide (NO) concentration, Catalase (CAT), Superoxide Dismutase (SOD), Glutathione (GSH), Glutathione Peroxidase (GPx) activities, and IL-1β, TNF-α levels were assessed in renal tissue. Results: CP administration significantly increases KIM-1, NGAL, Cr, BUN, MDA, NO, IL-1β, and TNF-α level. It also decreases GSH concentration, SOD, GPx, and CAT function. Pretreatment with GA prevented these changes. Histopathological assessments approved the GA protective effect. Conclusion: Our results showed that GA is possibly effective as a protective agent in cyclophosphamide- associated toxicities.

Background: Methotrexate (MTX) is used potently for a wide range of diseases. However, hepatic intoxication by MTX hinders its clinical use. Objectives: The present study was conducted to investigate the diallyl disulfide (DADS) ability to ameliorate MTX-induced hepatotoxicity. Methods: Thirty-two rats were randomly divided into four groups: normal control, DADS (50 mg/kg/day, orally), MTX (single i.p. injection of 20 mg/kg) and DADS+MTX. Liver function biomarkers, histopathological examinations, oxidative stress, inflammation, and apoptosis biomarkers were investigated. Besides, an in vitro cytotoxic activity study was conducted to explore the modulatory effects of DADS on MTX cytotoxic activity using Caco-2, MCF-7, and HepG2 cells. Results: DADS significantly reduced the increased serum activities of ALT, AST, ALP, and LDH. These results were confirmed by the alleviation of liver histopathological changes. It restored the decreased GSH content and SOD activity, while significantly decreased MTX-induced elevations in both MDA and NO2 - contents. The hepatoprotective effects were mechanistically mediated through the up-regulation of hepatic Nrf-2 and the down-regulation of Keap-1, P38MAPK, and NF- ΚB expression levels. In addition, an increase in Bcl-2 level with a decrease in the expression of both Bax and caspase-3 was observed. The in vitro study showed that DADS increased MTX antitumor efficacy. Conclusion: DADS potently alleviated MTX-induced hepatotoxicity through the modulation of Keap-1/Nrf-2, P38MAPK/NF-ΚB and apoptosis signaling pathways and effectively enhanced the MTX cytotoxic effects, which could be promising for further clinical trials.

Background: Idiopathic pulmonary fibrosis (IPF) is a serious disease with a high mortality rate. Activation of transforming growth factor (TGF)-β1 production and signalling are considered the cornerstone in the epithelial-mesenchymal transition (EMT) process. EMT plays a central role in the development of fibrosis in many organs including the lungs. Activated platelets are an important source of TGF-β1 and play a pivotal role in EMT and fibrosis process. The antiplatelet, ticagrelor was previously found to inhibit the EMT in different types of cancer cells, but its ability to serve as an anti-pulmonary fibrosis (PF) agent was not previously investigated. Objective: In this study, we aim to investigate the potential ability of ticagrelor to ameliorate bleomycin-induced fibrosis in rats. Methods: PF was induced in rats by intratracheal BLM at a dose of 3 mg/kg. The effect of daily 20 mg/kg oral ticagrelor on different histological and biochemical parameters of fibrosis was investigated Results: Our results revealed that ticagrelor can alleviate lung fibrosis. We found that ticagrelor inhibited TGF-β1 production and suppressed Smad3 activation and signaling pathway with subsequent inhibition of Slug and Snail. In addition, ticagrelor antagonized PI3K/AKT/mTOR pathway signaling. Moreover, ticagrelor inhibited the EMT that was revealed by its ability to up-regulate the epithelial markers as E-cadherin (E-cad) and to decrease the expression of the mesenchymal markers as vimentin (VIM) and alpha-smooth muscle actin (α-SMA). Conclusion: Our results suggest that the P2Y12 inhibitor, ticagrelor may have a therapeutic potential in reducing the progression of PF.

Background: Diabetes mellitus (DM) affects the musculoskeletal system through its metabolic perturbations. Exercise modulates blood sugar levels and increases the body’s sensitivity to insulin in patients with DM. Objective: This study aimed to investigate the potential effects of combined quercetin and coenzyme Q10 (CoQ10) supplements with or without exercise on the histological, biochemical and molecular structures of diabetic rat’s skeletal muscle Methods: A total of 64 adult male albino rats were divided into six groups: control, trained nondiabetic, non-trained diabetic, diabetic rats treated with combined CoQ10 and quercetin, diabetic rats with treadmill training, and diabetic rats treated with treadmill training and CoQ10 and quercetin. Blood and skeletal muscle samples were obtained from all groups for routine histological examination and biochemical determination of cytokine levels and protein activities. Quantitative real-time polymerase chain reaction (qRT-PCR) and morphometric analysis of PAS and Bax expressions were also performed. Results: Biochemical analysis revealed improvement in all studied parameters with combined Co- Q10 and quercetin than exercise training alone. Combined treatment and exercise showed significant improvement in all parameters especially interleukin 6 and malondialdehyde. Fibronectin type III domain-containing protein 5 (FNDC5) expression and irisin levels increased in all trained groups but combined treatment with exercise significantly increased their levels than exercise alone. Histological analysis revealed improvement after exercise or combined treatment; however, when exercise was combined with CoQ10 and quercetin, marked improvement was observed. Conclusion: the combination of CoQ10 and quercetin could be promising in preserving musculoskeletal function in patients with DM concomitantly with physical exercise.

Background: Liver cancer ranks as the 7th and 5th leading cause of cancer morbidity worldwide in men and women, respectively. Hepatocellular Carcinoma (HCC) is the most common type of liver cancer and is associated with an increasing global burden of Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH). Objective: The present study aimed to investigate the possible chemopreventive effect of etoricoxib on diethylnitrosamine (DENA) and 2-acetylaminofluorene (2AAF)-induced HCC in male Wistar rats. Methods: HCC was induced by DENA (150 mg/kg/week; i.p) for 2 weeks, then 2AAF (20 mg/kg; p.o) every other day for three successive weeks. Etoricoxib (0.6 mg/kg, p.o.) was given to DENA/ 2AAF-administered rats for 20 weeks. Results: Etoricoxib significantly suppressed alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19.9) as liver tumor biomarkers. It also decreased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin levels while increased serum albumin levels. Besides, it alleviated DENA/2AAF-induced histopathological abrasions and inflammatory cell infiltration. Furthermore, etoricoxib showed a potent antioxidant effect, supported by a significant lipid peroxide reduction and elevation in superoxide dismutase activity and GSH content. In addition, Etoricoxib significantly down-regulated the protein expression of interleukin 1 beta (IL-1β), tumor necrosis factor α (TNFα), nuclear Factor-kappa B (NF-ΚB), phosphorylated nuclear Factor-kappa B (p-NF-ΚB), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2). Conclusion: In conclusion, the current results proved that etoricoxib possesses an anticarcinogenic effect via its antioxidant, anti-inflammatory, and modulation of NF-ΚB/COX-2/PGE2 signaling.