Attention Deficit Hyperactivity Disorder (ADHD) and Polyphenols: A Systematic Review.

Polyphenols are natural compounds also contained in daily consumed foods that show their efficacy in different clinical fields. Both pre-clinical and clinical studies demonstrated that polyphenols may manage neuroinflammation and oxidative stress processes tightly connected to neurodegenerative diseases and mental disorders. Thus, a neuroinflammatory state may influence the neurotransmitters pathways, such as the noradrenergic, glutamatergic, serotoninergic, and, in particular, dopaminergic ones, whose impairment is strongly associated with attention deficit hyperactivity disorder (ADHD). Therefore, the aim of the present systematic review is to provide an overview of the clinical outcomes' changes following ADHD treatment with polyphenols alone and in combination with the traditional drugs. This review was conducted according to PRISMA guidelines and recorded on PROSPERO with the number CRD42023438491; PubMed, Scopus, and Web of Science were used as search-engines to lead our research until June 2023. The inclusion criteria were articles written in English, including clinical, placebo-controlled, and case-control trials. We excluded reviews, metanalyses, background articles, and papers published in other languages. To avoid any bias, Rayyan software (COPYRIGHT © 2022 RAYYAN) was used to organize the work and manage the literature review. After screening, 10 studies were included, with a total of 556 patients that met the established inclusion criteria. The data obtained from these studies showed that polyphenols rebalanced oxidative stress pathways through different mechanisms, are effective for the treatment of ADHD both alone and in combination with traditional drugs, and are able to reduce symptoms as well as the side effects related to the use of conventional therapies. Finally, a positive effect of using polyphenols for ADHD prevention could be hypothesized.

Insights into the antiosteoporotic mechanism of the soy-derived isoflavone genistein: Modulation of the Wnt/beta-catenin signaling.

Bone remodeling is a process that involves osteoblasts, osteoclasts, and osteocytes, and different intracellular signaling, such as the canonical Wnt/ß-catenin pathway. Dysregulations of this pathway may also occur during secondary osteoporosis, as in the case of glucocorticoid-induced osteoporosis (GIO), which accelerates osteoblast and osteocyte apoptosis by reducing bone formation, osteoblast differentiation and function, accelerates in turn osteoblast, and osteocyte apoptosis. Genistein is a soy-derived nutrient belonging to the class of isoflavones that reduces bone loss in osteopenic menopausal women, inhibiting bone resorption; however, genistein may also favor bone formation. The aim of this study was to investigate whether estrogen receptor stimulation by genistein might promote osteoblast and osteocyte function during glucocorticoid challenge. Primary osteoblasts, collected from C57BL6/J mice, and MLO-A5 osteocyte cell line were used to reproduce an in vitro model of GIO by adding dexamethasone (1 µM) for 24 h. Cells were then treated with genistein for 24 h and quantitative Polymerase Chain Reaction (qPCR) and western blot were performed to study whether genistein activated the Wnt/ß-catenin pathway. Dexamethasone challenge reduced bone formation in primary osteoblasts and bone mineralization in osteocytes; moreover, canonical Wnt/ß-catenin pathway was reduced following incubation with dexamethasone in both osteoblasts and osteocytes. Genistein reverted these changes and this effect was mediated by both estrogen receptors α and ß. These data suggest that genistein could induce bone remodeling through Wnt/ß-catenin pathway activation.

Off-Target Effects of P2Y12 Receptor Inhibitors: Focus on Early Myocardial Fibrosis Modulation.

Several studies have demonstrated that, beyond their antithrombotic effects, P2Y12 receptor inhibitors may provide additional off-target effects through different mechanisms. These effects range from the preservation of endothelial barrier function to the modulation of inflammation or stabilization of atherosclerotic plaques, with an impact on different cell types, including endothelial and immune cells. Many P2Y12 inhibitors have been developed, from ticlopidine, the first thienopyridine, to the more potent non-thienopyridine derivatives such as ticagrelor which may promote cardioprotective effects following myocardial infarction (MI) by inhibiting adenosine reuptake through sodium-independent equilibrative nucleoside transporter 1 (ENT1). Adenosine may affect different molecular pathways involved in cardiac fibrosis, such as the Wnt (wingless-type)/beta (ß)-catenin signaling. An early pro-fibrotic response of the epicardium and activation of cardiac fibroblasts with the involvement of Wnt1 (wingless-type family member 1)/ß-catenin, are critically required for preserving cardiac function after acute ischemic cardiac injury. This review discusses molecular signaling pathways involved in cardiac fibrosis post MI, focusing on the Wnt/ß-catenin pathway, and the off-target effect of P2Y12 receptor inhibition. A potential role of ticagrelor was speculated in the early modulation of cardiac fibrosis, thanks to its off-target effect.

Correction: Mannino et al. Beta-Caryophyllene Exhibits Anti-Proliferative Effects through Apoptosis Induction and Cell Cycle Modulation in Multiple Myeloma Cells. Cancers 2021, 13, 5741.

In the original publication [...].

Beta-Caryophyllene, a Plant-Derived CB2 Receptor Agonist, Protects SH-SY5Y Cells from Cadmium-Induced Toxicity.

Cadmium (Cd) is a transition heavy metal that is able to accumulate in the central nervous system and may induce cell death through reactive oxygen species (ROS)-mediated mechanisms and inactivating the antioxidant processes, becoming an important risk factor for neurodegenerative diseases. The antioxidant effects of cannabinoid receptor modulation have been extensively described, and, in particular, ß-Caryophyllene (BCP), a plant-derived cannabinoid 2 receptor (CB2R) agonist, not only showed significant antioxidant properties but also anti-inflammatory, analgesic, and neuroprotective effects. Therefore, the aim of the present study was to evaluate BCP effects in a model of Cd-induced toxicity in the neuroblastoma SH-SY5Y cell line used to reproduce Cd intoxication in humans. SH-SY5Y cells were pre-treated with BCP (25, 50, and 100 µM) for 24 h. The day after, cells were challenged with cadmium chloride (CdCl2; 10 µM) for 24 h to induce neuronal toxicity. CdCl2 increased ROS accumulation, and BCP treatment significantly reduced ROS production at concentrations of 50 and 100 µM. In addition, CdCl2 significantly decreased the protein level of nuclear factor erythroid 2-related factor 2 (Nrf2) compared to unstimulated cells; the treatment with BCP at a concentration of 50 µM markedly increased Nrf2 expression, thus confirming the BCP anti-oxidant effect. Moreover, BCP treatment preserved cells from death, regulated the apoptosis pathway, and showed a significant anti-inflammatory effect, thus reducing the pro-inflammatory cytokines increased by the CdCl2 challenge. The results indicated that BCP preserved neuronal damage induced by Cd and might represent a future candidate for protection in neurotoxic conditions.

Oral Cavity Squamous Cell Carcinoma: An Update of the Pharmacological Treatment.

Oral cavity squamous cell carcinoma (OCSCC) represents a serious health and socio-economic problem in different geographical areas of the world. It is characterized by a high rate of mortality, recurrence and metastasis. Despite the therapeutic strategies implemented for its management and resolution, currently the survival estimate for locally advanced disease is about 50%. The available therapeutic options comprise surgery and pharmacological treatment. Recently, an increased emphasis has been placed on the drugs that might be of benefit in this life-threatening disease. Therefore, the aim of this present review was to offer a general survey of the current available pharmacological treatment for OCSCC. The PubMed database was used to retrieve the papers using "OCSCC" as the search terms. We limited our search to the last 5 years to give a more updated and recent picture of the state of the art, including preclinical and clinical investigations. We found that 77 out of 201 papers were on the surgical treatment of OCSCC, 43 out of 201 focused on the radiotherapy and 81 out of 201 underwent evaluation for the aim of our review. We excluded the case reports, editorial letters, observational studies and papers written in languages other than English. A total of 12 articles were included in the final review. Our results showed that nanotechnologies use to enhance the efficacy of anticancer drugs such as: cisplatin, paclitaxel, cetuximab, EGFR antagonists, MEK1/2 and immune check inhibitors combination could have promising anti-cancer activity. However, the paucity of available data on drugs suggests the urgent need to improve the pharmacological armamentarium for OCSCC treatment.

Effects of genistein aglycone in glucocorticoid induced osteoporosis: A randomized clinical trial in comparison with alendronate.

Glucocorticoid-induced osteoporosis (GIO) complicates the clinical management of patients subjected to long-term glucocorticoid use. This study explored the effects of genistein on bone loss in a randomized double-blind alendronate-controlled trial in postmenopausal women with GIO. 200 postmenopausal women (taking at least 5 mg of prednisone equivalents) since 3 months, or more, and expected to continue for at least other 12 months, were randomized to receive genistein (54 mg/day daily) or alendronate (70 mg once a week) for 24 months. Both groups received also Calcium and Vitamin D3 supplementation. Median bone mineral density (BMD) at the antero-posterior lumbar spine significantly increased from 0.75 g/cm2 at baseline to 0.77 g/cm2 at 1 year and 0.79 g/cm2 at 2 years in alendronate-treated patients and from 0.77 g/cm2 at baseline to 0.79 g/cm2 at 12 months and to 0.80 g/cm2 at 24 months in genistein recipients. No difference was observed between the two treatments. Median BMD at the femoral neck increased from 0.67 g/cm2 at baseline to 0.68 g/cm2 at 1 year and 0.69 g/cm2 at 2 years in alendronate-treated patients and from 0.68 g/cm2 at baseline to 0.70 g/cm2 at 12 months and to 0.71 g/cm2 at 24 months in genistein recipients. No difference was observed between alendronate and genistein groups in BMD. Regarding bone markers genistein and alendronate statistically decreased c-terminal telopeptide, while osteocalcin, bone-ALP, and sclerostin showed greater changes in genistein treated patients. This randomized clinical trial suggests that genistein aglycone represents an additional therapeutic option for patients with GIO.

Anti-oxidant and anti-inflammatory effects of ellagic and punicic acid in an in vitro model of cardiac fibrosis.

Cardiac fibrosis is a pathological process characterized by an excessive deposition of extracellular matrix (ECM) and an increased production of fibrillar collagen in the cardiac interstitium, mainly caused by the activation of cardiac fibroblasts and their transition into myofibroblasts. Oxidative stress is deeply implicated in the pathogenesis of cardiac fibrosis both directly and via its involvement in the tumor growth factor ß1 (TGF-ß1) signaling. Ellagic acid (EA) and punicic acid (PA) are the main components of the Punica granatum L (pomegranate) fruit and seed oil respectively, whose antioxidant, anti-inflammatory and anti-fibrotic effects have been previously described. Therefore, the aim of this study was to investigate the effects of EA or PA or EA+PA in an in vitro model of cardiac fibrosis. Immortalized Human Cardiac Fibroblasts (IM-HCF) were stimulated with 10 ng/ml of TGF-ß1 for 24 h to induce a fibrotic damage. Cells were then treated with EA (1 µM), PA (1 µM) or EA+PA for additional 24 h. Both EA and PA reduced the pro-fibrotic proteins expressions and the intracellular reactive oxygen species (ROS) accumulation. The anti-oxidant activity was also observed by Nrf2 activation with the consequent TGF-ß1-Smad2/3-MMP2/9 and Wnt/ß-catenin signaling inhibition, thus reducing collagen production. EA and PA significantly inhibit NF-κB pathway and, consequently, TNF-α, IL-1ß and IL-6 levels: the greater effect was observed when EA and PA were used in combination. These results suggest that EA, PA and in particular EA+PA might be effective in reducing fibrosis through their antioxidant and anti-inflammatory properties by the modulation of different molecular pathways.

Vitiligo and Mental Health: Natural Compounds' Usefulness.

Vitiligo is an autoimmune dermatosis frequently associated with other comorbidities, such as mental health disorders. It is unclear if vitiligo triggers mental disorders or if mental disorders trigger vitiligo, but each one affects and worsen the other, if present at the same time. Both mental health disorders and vitiligo present a multifactorial pathogenesis and often require prolonged periods of therapy, sometimes with poor results. Given the possible link of common pathogenetic factors and the need of integrated therapies, the aim of this review is to look at natural compounds as possible supplements for both conditions. The results yielded show a possible role of these supplements in ameliorating both conditions, thus helping these patients to achieve a better quality of life and reduce the need for prolonged therapies. The limitations regarding the relative lack of in vivo studies, and the increasing need to lighten the burden of these chronic diseases, suggests that it is mandatory to proceed with further trials.

Wnt Signaling Pathways: From Inflammation to Non-Melanoma Skin Cancers.

Canonical and non-canonical Wnt signaling pathways are involved in cell differentiation and homeostasis, but also in tumorigenesis. In fact, an exaggerated activation of Wnt signaling may promote tumor growth and invasion. We summarize the most intriguing evidence about the role of Wnt signaling in cutaneous carcinogenesis, in particular in the pathogenesis of non-melanoma skin cancer (NMSC). Wnt signaling is involved in several ways in the development of skin tumors: it may modulate the inflammatory tumor microenvironment, synergize with Sonic Hedgehog pathway in the onset of basal cell carcinoma, and contribute to the progression from precancerous to malignant lesions and promote the epithelial-mesenchymal transition in squamous cell carcinoma. Targeting Wnt pathways may represent an additional efficient approach in the management of patients with NMSC.

Biglycan Involvement in Heart Fibrosis: Modulation of Adenosine 2A Receptor Improves Damage in Immortalized Cardiac Fibroblasts.

Cardiac fibrosis is a common pathological feature of different cardiovascular diseases, characterized by the aberrant deposition of extracellular matrix (ECM) proteins in the cardiac interstitium, myofibroblast differentiation and increased fibrillar collagen deposition stimulated by transforming growth factor (TGF)-ß activation. Biglycan (BGN), a small leucine-rich proteoglycan (SLRPG) integrated within the ECM, plays a key role in matrix assembly and the phenotypic control of cardiac fibroblasts. Moreover, BGN is critically involved in pathological cardiac remodeling through TGF-ß binding, thus causing myofibroblast differentiation and proliferation. Adenosine receptors (ARs), and in particular A2AR, may play a key role in stimulating fibrotic damage through collagen production/deposition, as a consequence of cyclic AMP (cAMP) and AKT activation. For this reason, A2AR modulation could be a useful tool to manage cardiac fibrosis in order to reduce fibrotic scar deposition in heart tissue. Therefore, the aim of the present study was to investigate the possible crosstalk between A2AR and BGN modulation in an in vitro model of TGF-ß-induced fibrosis. Immortalized human cardiac fibroblasts (IM-HCF) were stimulated with TGF-ß at the concentration of 10 ng/mL for 24 h to induce a fibrotic phenotype. After applying the TGF-ß stimulus, cells were treated with two different A2AR antagonists, Istradefylline and ZM241385, for an additional 24 h, at the concentration of 10 µM and 1 µM, respectively. Both A2AR antagonists were able to regulate the oxidative stress induced by TGF-ß through intracellular reactive oxygen species (ROS) reduction in IM-HCFs. Moreover, collagen1a1, MMPs 3/9, BGN, caspase-1 and IL-1ß gene expression was markedly decreased following A2AR antagonist treatment in TGF-ß-challenged human fibroblasts. The results obtained for collagen1a1, SMAD3, α-SMA and BGN were also confirmed when protein expression was evaluated; phospho-Akt protein levels were also reduced following Istradefylline and ZM241385 use, thus suggesting that collagen production involves AKT recruited by the A2AR. These results suggest that A2AR modulation might be an effective therapeutic option to reduce the fibrotic processes involved in heart pathological remodeling.

Corrigendum: Pharmacological activity and clinical use of PDRN.

[This corrects the article DOI: 10.3389/fphar.2017.00224.].

Corrigendum: Polydeoxyribonucleotide, an adenosine-A2A receptor agonist, preserves blood testis barrier from cadmium-induced injury.

[This corrects the article DOI: 10.3389/fphar.2016.00537.].

Corrigendum: Update on genistein and thyroid: an overall message of safety.

[This corrects the article DOI: 10.3389/fendo.2012.00094.].

Corrigendum: Adenosine receptor stimulation improves glucocorticoid-induced osteoporosis in a rat model.

[This corrects the article DOI: 10.3389/fphar.2017.00558.].

Corrigendum: Activation of A2A receptor by PDRN reduces neuronal damage and stimulates WNT/ß-catenin driven neurogenesis in spinal cord injury.

[This corrects the article DOI: 10.3389/fphar.2018.00506.].

Corrigendum: Exploiting curcumin synergy with natural products using quantitative analysis of dose-effect relationships in an experimental in vitro model of osteoarthritis.

[This corrects the article DOI: 10.3389/fphar.2019.01347.].