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Introduction: The discovery of serine protease proprotein convertase subtilisin-kexin type 9 (PCSK9) has revolutionized pharmacological lipid-lowering treatments. The first PCSK9 antagonists (PCSK9-A), evolocumab and alirocumab, were approved in 2015. Targeting PCSK9 synthesis marked a major advancement in this field, leading to the development of inclisiran, a long-acting siRNA targeting PCSK9 mRNA. However, real-world safety data on this drug are still limited. Therefore, this study aims to provide a real-world safety evaluation of inclisiran, comparing its characteristics to those of PCSK9-As. Methods: A retrospective pharmacovigilance study was conducted using EudraVigilance (EV). Inclisiran-related individual case safety reports (I-ICSRs) from 01/01/2021 to 06/30/2023 were retrieved. ICSRs for evolocumab or alirocumab from 01/01/2015 to 06/30/2023 were collected as a reference group (RG). ADRs were classified using the MedDRA dictionary. Data were evaluated using descriptive and disproportionality analyses. Crude reporting odds ratio (ROR) with 95% confidence intervals (CI) were used as disproportionality measures. Results: Of the 15,236 ICSRs, 3.7% (n = 563) involved inclisiran, with the rest in the RG. Most I-ICSRs involved female patients (51.7%) aged 18 to 64 (52.8%). The most-reported ADRs for inclisiran were “general disorders and administration site conditions” (n = 347) and “investigations” (n = 277). Significant disproportionality was found in I-ICSRs compared to the RG for “Myalgia” (ROR: 2.43; 95% CI: 1.94–3.04), “Low-density lipoprotein increased” (ROR: 11.95; 95% CI: 9.10–15.52), and “Drug ineffective” (ROR: 6.37; 95% CI: 4.64–8.74). Conclusions: The inclisiran safety profile aligns with the existing literature and pre-commercial data. However, further studies are needed to fully understand the observed differences with PCSK9-As.

Aims: the aim of the study was to analyze glomerular filtration ratio (GFR) changes in diabetic patients assisted by General Practitioners (GPs) evaluating the risk factors related to glomerular function. Methods: patients with diabetes with at least three recorded values of creatinine were recruited in the study and GFR values were estimated. The quarterly percentage change in GFR for each patient was estimated. Nephrotoxic drugs were identified, and glucose-lowering drugs use was described. Linear regression analyses were performed to identify eGFR changes predictors. Results: a total of 545 patients with diabetes were selected. According to the last eGFR values 64 (11.7 %) patients were classified in G1 stage, 277 (50,8 %) in G2, 175 (32.1 %) in G3a, 25 (4.6 %) in G3b and only 4 (0.7 %) in G4. Patients treated with at least one glucose-lowering drugs were 479 (87.9 %), most of them with biguanides (67.0 %). At least one nephrotoxic drug prescription was recorded in 524 (96.1 %) patients; proton pump inhibitors (74.7 %) and NSAIDs (71.6 %) were the most prescription classes. Heart failure, diabetes duration and preserved GFR values were related to reduced eGFR values. Conclusions: patients with diabetes should be more carefully observed regardless of kidney risk factors and GFR values in clinical practice.

Obesity is considered one of the main risk factors for cardiovascular diseases. The browning process has been recently recognized as a promising anti-obesity therapy. Lycopene (LYC) and Garcinia cambogia fruit extract (GE) might be important resources for anti-obesity drugs; therefore, the aim of this study was to investigate the anti-obesity effects of LYC and GE on 3T3-L1 adipocytes and Zucker rats. Mouse 3T3-L1 pre-adipocytes were differentiated in mature adipocytes and then treated with LYC (0.5 μM), GE (30 mg/mL) or LYC + GE for 24 h. Moreover, male Zucker Crl:ZUC-Leprfa rats were randomly assigned to 5 groups of 10 animals to orally receive Vehicle (Ctrl), Orlistat (20 mg/kg), LYC (5 mg/kg), GE (1000 mg/kg) or LYC + GE for 28 days. LYC, GC extracts and even more LYC + GE stimulated the mRNA and protein expression of thermogenic genes UCP1, CIDEA and DIO2, significantly reduced lipid droplet size and increased lipid droplet number in adipocytes. UCP1 mRNA and protein expression was also increased in the visceral adipose tissue of the rats that received the dietary intake of LYC, GE and even more LYC + GE. Moreover, LYC + GE induced the reorganization of visceral fat depots that showed a great number of small adipocytes and a significant reduction in weight gain and food intake compared to the control group. The obtained results demonstrated that LYC + GE might be used as new approaches for obesity management in order to induce the browning process and achieve a metabolically active tissue instead of a tissue characterized by lipid depot accumulation.

Chronic venous insufficiency (CVI) represents a risk factor for cardiovascular events. The first-line treatment includes the use of compression stockings and lifestyle changes. Natural products, such as flavonoids, could be used to improve the effects of compression therapy due to their anti-inflammatory and anti-oxidant properties. This study aims to evaluate the effects of a dietary supplement containing baicalin, bromeline and escin in CVI patients. A retrospective cohort study was performed by using the medical records of CVI affected outpatients. Patients treated with the dietary supplement were defined as “users”. A modified Venous Clinical Severity Score (VCSS) was calculated, including pain, inflammation, vessels induration and skin pigmentation. All clinical variables were evaluated at baseline (T0), after 30 (T1) and 90(T2) days in “users” and “non-users”. Out of 62 patients, 30 (48.4%) were “users”. No difference was observed between groups at baseline. A lower VCSS value was recorded in “users” than that observed in “non-users” at T2 (7.0 (4.0–9.0) vs. 9.0 (5.0–10.0); p = 0.025). Vessels’ induration and pain significantly reduced in 53.3% and 43.3% of “users” and in 18.8% and 9.4% of “non-users”. Only “users” (33.3%) showed a reduction of the inflammatory signs as well as a decrease in malleolar circumference, from 29.0 (26.5–30.0) to 27.5 (26.0–28.5) (p < 000.1). A reduction of C-reactive Protein levels was found in “users” compared to “non-users” at T2 (1.0 (0.9–1.2) vs. 1.3 (1.0–1.5); p = 0.006). These findings suggest that implementation of a dietary supplement could improve the clinical outcomes of CVI patients.

Hypovolemic shock is a circulatory failure, due to a loss in the effective circulating blood volume, that causes tissue hypoperfusion and hypoxia. This condition stimulates reactive oxygen species (ROS) and pro-inflammatory cytokine production in different organs and also in the central nervous system (CNS). Levosimendan, a cardioprotective inodilator, and dobutamine, a β1-adrenergic agonist, are commonly used for the treatment of hypovolemic shock, thanks to their anti-inflammatory and antioxidant effects. For this reason, we aimed at investigating levosimendan and dobutamine’s neuroprotective effects in an “in vitro” model of lipopolysaccharide (LPS)-induced neuroinflammation. Human microglial cells (HMC3) were challenged with LPS (0.1 µg/mL) to induce an inflammatory phenotype and then treated with levosimendan (10 µM) or dobutamine (50 µM) for 24 h. Levosimendan and dobutamine significantly reduced the ROS levels and markedly increased Nrf2 and HO-1 protein expression in LPS-challenged cells. Levosimendan and dobutamine also decreased p-NF-κB expression and turned off the NLRP3 inflammasome together with its downstream signals, caspase-1 and IL-1β. Moreover, a reduction in TNF-α and IL-6 expression and an increase in IL-10 levels in LPS-stimulated HMC3 cells was observed following treatment. In conclusion, levosimendan and dobutamine attenuated LPS-induced neuroinflammation through NF-κB pathway inhibition and NLRP3 inflammasome activation via Nrf2/HO-1 signalling, suggesting that these drugs could represent a promising therapeutic approach for the treatment of neuroinflammation consequent to hypovolemic shock.

Background and Objectives: Tirbanibulin 1% ointment is a novel synthetic anti-proliferative agent that inhibits tubulin polymerization. It is approved for treating actinic keratosis (AK) on the face and scalp in adults. It has demonstrated good efficacy, an adequate safety profile and excellent patient adherence in the phase 3 clinical trials, however data about its real-life efficacy and safety are lacking. Here we report the experience of the dermatology unit of the University Hospital of Messina. Materials and Methods: We performed a spontaneous open-label, prospective non-randomized study to assess the effectiveness and safety of tirbanibulin 1% ointment for the treatment of 228 AKs in 38 consecutive patients—28 males (73%) and 10 females (26%)—aged between 52 and 92 years (mean age: 72 ± 8.92 years). Results: Total clearance was recorded in 51% of lesions, while partial clearance was recorded in 73% of lesions. An excellent tolerability profile and high compliance rate were observed, with no treatment discontinuation due to the onset of adverse events. Conclusion: Our real-life experience confirms the effectiveness and safety of tirbanibulin ointment for the treatment of AKs.

Inflammatory bowel diseases (IBDs) encompass ulcerative colitis (UC) and Crohn’s disease (CD), both of which are inflammatory ailments affecting the gastrointestinal tract [...]

Cadmium (Cd) represents a public health risk due to its non-biodegradability and long biological half-life. The main target of Cd is the kidney, where it accumulates. In the present narrative review, we assessed experimental and clinical data dealing with the mechanisms of kidney morphological and functional damage caused by Cd and the state of the art about possible therapeutic managements. Intriguingly, skeleton fragility related to Cd exposure has been demonstrated to be induced both by a direct Cd toxic effect on bone mineralization and by renal failure. Our team and other research groups studied the possible pathophysiological molecular pathways induced by Cd, such as lipid peroxidation, inflammation, programmed cell death, and hormonal kidney discrepancy, that, through further molecular crosstalk, trigger serious glomerular and tubular injury, leading to chronic kidney disease (CKD). Moreover, CKD is associated with the presence of dysbiosis, and the results of recent studies have confirmed the altered composition and functions of the gut microbial communities in CKD. Therefore, as recent knowledge demonstrates a strong connection between diet, food components, and CKD management, and also taking into account that gut microbiota are very sensitive to these biological factors and environmental pollutants, nutraceuticals, mainly present in foods typical of the Mediterranean diet, can be considered a safe therapeutic strategy in Cd-induced kidney damage and, accordingly, could help in the prevention and treatment of CKD.

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.

Beta (β)-blockers (BB) are useful in reducing morbidity and mortality in patients with heart failure (HF) and concomitant chronic obstructive pulmonary disease (COPD). Nevertheless, the use of BBs could induce bronchoconstriction due to β2-blockade. For this reason, both the ESC and GOLD guidelines strongly suggest the use of selective β1-BB in patients with HF and COPD. However, low adherence to guidelines was observed in multiple clinical settings. The aim of the study was to investigate the BBs use in older patients affected by HF and COPD, recorded in the REPOSI register. Of 942 patients affected by HF, 47.1% were treated with BBs. The use of BBs was significantly lower in patients with HF and COPD than in patients affected by HF alone, both at admission and at discharge (admission, 36.9% vs. 51.3%; discharge, 38.0% vs. 51.7%). In addition, no further BB users were found at discharge. The probability to being treated with a BB was significantly lower in patients with HF also affected by COPD (adj. OR, 95% CI: 0.50, 0.37–0.67), while the diagnosis of COPD was not associated with the choice of selective β1-BB (adj. OR, 95% CI: 1.33, 0.76–2.34). Despite clear recommendations by clinical guidelines, a significant underuse of BBs was also observed after hospital discharge. In COPD affected patients, physicians unreasonably reject BBs use, rather than choosing a β1-BB. The expected improvement of the BB prescriptions after hospitalization was not observed. A multidisciplinary approach among hospital physicians, general practitioners, and pharmacologists should be carried out for better drug management and adherence to guideline recommendations.

Background: Antibiotics are prescribed for children both in hospital and community settings, particularly at preschool age. Italy shows a high rate of inappropriate antibiotic prescriptions which may represent a serious problem in the hospital scenario. Thus, the aim of this study was to investigate appropriateness of antibiotic prescribing in the context of different paediatric subspecialties in a hospital setting.Methods: Antibiotics prescribing was retrospectively analysed in paediatric patients (0–18 years) admitted in the emergency paediatrics, general paediatrics, paediatric nephrology and rheumatology units between January and December 2019. Patients were stratified by age in neonates, infants, toddlers, children and adolescents. Assessments were conducted by trained local assessors and appropriateness was classified as appropriate, inappropriate and not assessable.Results: Empirical antibiotics were mainly prescribed following a diagnosis of respiratory, gastrointestinal and/or urinary infection. A total of 825 antibiotic prescriptions were recorded in the three subspecialties; 462 antibiotic prescriptions (56%) out of 825 were assessed as inappropriate and 55 prescriptions (6.7%) were not assessable. Inappropriateness considerably varied within subspecialties: the risk of inappropriate antibiotic prescribing was higher in emergency paediatrics and general paediatric than in children, according to age. Ceftriaxone and clarithromycin were the most inappropriate prescribed antibiotics in the emergency paediatrics whereas amoxicillin/clavulanic acid represented the most inappropriate antibiotic prescribed in general paediatrics.Conclusion: The present data may be useful in order to reduce inappropriate antibiotic prescribing in the paediatric setting; antibiotic stewardship and clinical improvement programs in hospital paediatric care are strongly recommended.

Type 2 diabetes mellitus (T2DM) severely increases the probability of developing coronary artery disease (CAD), and diabetic patients with CAD should be considered at very high cardiovascular risk. The complexity of this clinical scenario makes very hard the appropriateness of the pharmacological treatment in the real world. To investigate the implementation of guideline recommendations for the treatment of patients affected by CAD with or without T2DM, a retrospective observational study was carried out between 2018 and 2020, by using the computerized clinical medical record of 10 general practitioners (GPs) including 13,206 subjects. A total of 926 patients (7.0%) were affected by CAD and 393 (42.4%) of them were also diabetic. LDLc, SBP, DBP, and FPG were recorded in 77.4%, 65.4%, 66.5%, and 82.6% of patients, respectively. Comorbidities (median; IQR = 8; 6–10 vs. 5; 3–7: p < 0.001) were significantly high in diabetic patients. Specialist counselling has been observed in 59.9% of diabetic and 57% of non-diabetic patients (p = 0.400). Antithrombotic drugs, statins, β-blockers, or RAASs were prescribed in 67.2%, 59.6%, and 75.9% of patients, respectively. Overall, 462 (49.9%) patients used the treatment suggested by guidelines. Dyslipidemia, hypertension, atherosclerosis, and specialist counselling were predictors of suggested drugs use both in diabetic and non-diabetic patients. Diabetes was not an independent factor related to the likelihood to be properly treated, according to the guidelines. Glucose lowering drugs were prescribed in 69.5% of diabetic patients, but only 39 (14.3%) were treated with the proper GLP-1 or SGLT2-i, whereas 45 patients (16.5%) received the improper sulphonylureas. Our results showed that a “non-ideal” therapeutic approach was adopted in patients affected by diabetes and CAD. ADA and ESC guidelines recommend the use of at least one hypoglycemic agent belonging to the GLP-1 or SGLT2-i class in diabetic patients with high/very high cardiovascular risk, regardless of the glycemic target (HbA1c

This study aimed to evaluate the management of high cardiovascular risk (CVr) in the patients with diabetes by exploring the prescribing behavior in a setting of general practitioners (GPs). A retrospective cohort study was carried out using the data recorded between 2018 and 2020 in the clinical database of 10 GPs. Diabetes was defined using the International Classification of Diseases (ICD-9-CM) coding (250*) or using the laboratory parameters (hyperglycemia condition: ≥126 mg/dL). A cohort was described stratifying by demographic, clinical and therapeutic characteristics, and laboratory tests. Both the CVr and statin prescriptions were evaluated; adherence to statin therapy (medication possession ratio, MPR ≥ 80) was calculated in accordance with the low-density lipoprotein cholesterol (LDL-C) target. The multivariate logistic regression models with adjusted odds ratios (ORs) and the corresponding 95% Confidence Intervals (CIs) were calculated to identify the predictors of lipid modifying agents use and achieved target therapy; moreover, glucose-lowering drugs use was evaluated. Out of 13,206 people screened, 1,851 (14.0%) patients were affected by diabetes mellitus (DM), and 1,373 were identified at high/very high CVr. Of them, 1,158 (84.3%) had at least one measurement of LDL-C, and 808 (58.8%) received a prescription with at least one lipid-lowering drug (LLD). The patients at high/very high CVr treated or not treated with LLD, reached the LDL-C target in 24.0 and 10.3%, respectively (p < 0.001). Furthermore, 34.6% of patients treated with high intensity LLDs and adherent to therapy showed the LDL-C values below the therapeutic target. Out of 1,373 patients at high/very high CVr, 958 (69.8%) had at least one prescription of glucose-lowering drugs. Of them, 52.0% (n = 498) were prescribed not in agreement with the current guidelines. More specifically, 392 patients (40.9%) were treated with metformin only, while the remaining 106 (11.1%) were treated with metformin together with hypoglycemic agents other than glucagon-like peptide-1 receptor agonists (GLP1-RA) or sodium-glucose-transporter 2 (SGLT2) inhibitors. Our results suggest the urgent need to improve the management of patients with diabetes at high and very high CVr in the real life, to reduce the burden of diabetes on the health system.

Proteasome inhibition is a promising strategy for the treatment of multiple myeloma; unfortunately, this disease is often associated with an increasing chemoresistance. One novel approach may be to target the immunoproteasome, a proteasomal isoform mainly present in cells of hematopoietic origin. We investigated the activity of a panel of amides against immunoproteasome core particles as potential agents for the treatment of multiple myeloma (MM). Amide 6 showed an ideal profile since it was able to inhibit both the chymotrypsin-like activities of the immunoproteasome with Ki values of 4.90 µM and 4.39 µM for β1i and β5i, respectively, coupled with an EC50 =17.8 µM against MM.1R cells. Compound 6 inhibited also ubiquitinated protein degradation and was able to act on different phases of MM cell cycle reducing the levels of cyclin A/CDK1, cyclin B/CDK1 and cyclin D/CDK4/6 complexes, which turns in cell cycle arrest.

Lycopene is a carotenoid found in tomatoes that has potent antioxidant activity. The Mediterranean diet is particularly rich in lycopene, which has well-known beneficial effects on cardiovascular health. We tested the effects of lycopene extract in a group of 20 ApoE knockout mice, fed with a high fat western diet for 14 weeks. Starting from week 3 and up to week 14, the mice were randomly divided into two groups that received lycopene (n = 10) by oral suspension every day at the human equivalent dose of 60 mg/day (0.246 mg/mouse/day), or the vehicle solution (n = 10). The lycopene administration reduced triglycerides and cholesterol blood levels starting from week 6 and continuing through to the end of the experiment (p < 0.001). This reduction was mediated by an enhanced liver expression of PPAR-α and AMPK-α and reduced SREBP levels (p < 0.0001). As a histological red-out, the extent of atherosclerotic plaques and the intima–media thickness in the aorta were significantly reduced by lycopene. In this context, lycopene augmented the Nrf-2 positivity staining in the endothelium, thereby confirming that its antioxidant activity was mediated by this nuclear factor. The positive results obtained in this pre-clinical model further support the use of lycopene extracts to reduce atherosclerosis.

Immunosuppressant drugs (ISDs) are routinely used in clinical practice to maintain organ transplant survival. However, these drugs are characterized by a restricted therapeutic index, a high inter- and intra-individual pharmacokinetic variability, and a series of severe adverse effects. In particular, genetic factors have been estimated to play a role in this variability because of polymorphisms regarding genes encoding for enzymes and transporters involved in the ISDs pharmacokinetic. Several studies showed important correlations between genetic polymorphisms and ISDs blood levels in transplanted patients; therefore, this review aims to summarize the pharmacogenetics of approved ISDs. We used PubMed database to search papers on pharmacogenetics of ISDs in adults or pediatric patients of any gender and ethnicity receiving immunosuppressive therapy after kidney transplantation. We utilized as search term: “cyclosporine or tacrolimus or mycophenolic acid or sirolimus or everolimus and polymorphism and transplant”. Our data showed that polymorphisms in CYP3A5, CYP3A4, ABCB1, and UGT1A9 genes could modify the pharmacokinetics of immunosuppressants, suggesting that patient genotyping could be a helpful strategy to select the ideal ISDs dose for each patient.

Previous studies have demonstrated that, in addition to inducing structural changes in thyroid follicles, cadmium (Cd) increased the number of C cells. We examined the effects of myo-inositol (MI), seleno-L-methionine (Se), MI + Se, and resveratrol on C cells of mice exposed to cadmium chloride (Cd Cl2), as no data are currently available on the possible protective effects of these molecules. In contrast, we have previously shown this protective effect against CdCl2 on the thyroid follicles of mice. Ninety-eight C57 BL/6J adult male mice were divided into 14 groups of seven mice each: (i) 0.9% NaCl (vehicle; 1 ml/kg/day i.p.); (ii) Se (0.2 mg/kg/day per os); (iii) Se (0.4 mg/kg/day per os); (iv) MI (360 mg/kg/day per os); (v) Se (0.2 mg/kg/day) + MI; (vi) Se (0.4 mg/kg/day) + MI; (vii) resveratrol (20 mg/kg); (viii) CdCl2 (2 mg/kg/day i.p.) + vehicle; (ix) CdCl2 + Se (0.2 mg/kg/day); (x) CdCl2 + Se (0.4 mg/kg/day); (xi) CdCl2 + MI; (xii) CdCl2 + Se (0.2 mg/kg/day) + MI; (xiii) CdCl2 + Se (0.4 mg/kg/day) + MI; (xiv) CdCl2 + resveratrol (20 mg/kg). After 14 days, thyroids were processed for histological, immunohistochemical, and morphometric evaluation. Compared to vehicle, Cd significantly decreased follicle mean diameter, increased CT-positive cells number, area and cytoplasmic density, and caused the disappearance of TUNEL-positive C cells, namely, the disappearance of C cells undergoing apoptosis. Se at either 0.2 or 0.4 mg/kg/day failed to significantly increase follicular mean diameter, mildly decreased CT-positive cells number, area and cytoplasmic density, and was ineffective on TUNEL-positive C cells. Instead, MI alone increased significantly follicular mean diameter and TUNEL-positive cells number, and decreased significantly CT-positive cells number, area and cytoplasmic density. MI + Se 0.2 mg/kg/day or MI + Se 0.4 mg/kg/day administration improved all five indices more markedly. Indeed, follicular mean diameter and TUNEL-positive cells number increased significantly, while CT-positive cells number, area and cytoplasmic density decreased significantly. Thus, all five indices overlapped those observed in vehicle-treated mice. Resveratrol improved significantly all the considered parameters, with a magnitude comparable to that of MI alone. In conclusion, the association Myo + Se is effective in protecting the mouse thyroid from the Cd-induced hyperplasia and hypertrophy of C cells. This benefit adds to that exerted by Myo + Se on thyrocytes and testis.

Fuchs endothelial corneal dystrophy (FECD) is a bilateral, hereditary syndrome characterized by progressive irreversible injury in the corneal endothelium; it is the most frequent cause for corneal transplantation worldwide. Oxidative stress induces the apoptosis of corneal endothelial cells (CECs), and has a crucial function in FECD pathogenesis. The stimulation of the adenosine A2A receptor (A2Ar) inhibits oxidative stress, reduces inflammation and modulates apoptosis. Polydeoxyribonucleotide (PDRN) is a registered drug that acts through adenosine A2Ar. Thus, the goal of this study was to assess the effect of PDRN in an in vitro FECD model. Human Corneal Endothelial Cells (IHCE) were challenged with H2O2 (200 μM) alone or in combination with PDRN (100 μg/mL), PDRN plus ZM241385 (1 μM) as an A2Ar antagonist, and CGS21680 (1 μM) as a well-known A2Ar agonist. H2O2 reduced the cells’ viability and increased the expression of the pro-inflammatory markers NF-κB, IL-6, IL-1β, and TNF-α; by contrast, it decreased the expression of the anti-inflammatory IL-10. Moreover, the pro-apoptotic genes Bax, Caspase-3 and Caspase-8 were concurrently upregulated with a decrease of Bcl-2 expression. PDRN and CGS21680 reverted the negative effects of H2O2. Co-incubation with ZM241385 abolished the effects of PDRN, indicating that A2Ar is involved in the mode of action of PDRN. These data suggest that PDRN defends IHCE cells against H2O2-induced damage, potentially as a result of its antioxidant, anti-inflammatory and antiapoptotic properties, suggesting that PDRN could be used as an FECD therapy.

Children represent one of the most susceptible groups to adverse drug reactions (ADRs), as a consequence of physiological growth and maturation of different organ systems. The aim of this study was to characterize the frequency, preventability and seriousness of ADRs recorded in the Pediatric Emergency Department (ED) of the University hospital of Messina, in Sicily. All the suspected adverse reactions to drugs and vaccines collected from 2012 to 2018 were selected and then analyzed. Only adverse drug reactions (ADRs) with a probable or possible causality assessment were included, according to the Naranjo Algorithm and the World Health Organization criteria; the preventability assessment using Schumock and Thornton criteria was also carried out. The Medical Dictionary for Regulatory Activities (MedDRA) was used to group ADRs. Of 75,935 admissions to the Pediatric ED, 120 were due to suspected ADRs. The rate of hospital admission due to ADRs (75.8%) was significantly greater than that of patients without ADRs (11.9%). Among pediatric patients with ADRs the median (Q1–Q3) age was 29.5 (12–73.25) months. Most of ADRs were observed in infants and children (43.3% and 41.7%, respectively vs adolescents, 15%). In addition, in children with ADRs, females [41 (14–105)] were older than males [23 (11–45)] (p=0.044). Most adverse reactions were serious (75.8%) and 20.8% were preventable or probably preventable; however, the majority of serious ADRs (93.4%) resulted without sequelae. The reactions were found to be as probable (54.2%) or possible (45.8%). Vaccines (n=63), antibacterials (n=31) and anti-inflammatory medicines (n=14) were the most frequently drugs involved. Organ toxicity mapping due to vaccines was general disorders and administration site conditions (65.1%), nervous disorders (50.2%), cutaneous disorders (35%), followed by gastrointestinal disorders (20.6%). Cutaneous disorders (76%) gastrointestinal (20.7%), general (15.5%), and nervous disorders (8.6%) were the organ toxicity mapping due to drugs. Active pharmacovigilance has an essential role in supporting the development of strategies aimed at intervention to reduce admissions due to ADRs. Our data suggest that ADRs represent the first cause of hospitalization to the Pediatric Emergency Department. Furthermore, according to the literature, vaccines and antibiotics are the most frequent cause of adverse drug reactions in children.

Inflammatory Bowel Disease (IBD) comprises a group of disorders, in particular Crohn’s disease (CD) and ulcerative colitis (UC), characterized by chronic inflammation affecting the gastrointestinal tract. The treatment of these conditions is primarily based on anti-inflammatory drugs, although the use of biological drugs with lower side effects quickly increased in the last decade. However, the presence of certain polymorphisms in the population may determine a different outcome in response to therapy, reflecting the heterogeneity of the efficacy in patients. Considering that several studies showed important correlations between genetic polymorphisms and response to biological treatments in IBD patients, this systematic review aims to summarize the pharmacogenetics of biologicals approved for IBD, thus highlighting a possible association between some polymorphisms and drug response. With this purpose, we reviewed PubMed papers published over the past 21 years (2000–2021), using as the search term “drug name and IBD or CD or UC and polymorphisms” to underline the role of pharmacogenetic tests in approaching the disease with a targeted therapy.

Cadmium (Cd) represents a public health risk due to its non-biodegradability and long biological half-life. The main target of Cd is considered the kidney, where it accumulates. No effective treatment for Cd poisoning is available so that several therapeutic approaches were proposed to prevent damages after Cd exposure. We evaluated the effects of a flavonoid-rich extract of bergamot juice (BJe), alone or in association with curcumin (Cur) and resveratrol (Re), in the kidney of mice exposed to cadmium chloride (CdCl2). Male mice were administered with CdCl2 and treated with Cur, Re, or BJe alone or in combination for 14 days. The kidneys were processed for biochemical, structural and morphometric evaluation. Cd treatment significantly increased urea nitrogen and creatinine levels, along with tp53, Bax, Nos2 and Il1b mRNA, while reduced that of Bcl2, as well as glutathione (GSH) content and glutathione peroxidase (GPx) activity. Moreover, Cd caused damages to glomeruli and tubules, and increased Nrf2, Nqo1 and Hmox1 gene expression. Cur, Re and BJe at 40 mg/kg significantly improved all parameters, while BJe at 20 mg/kg showed a lower protective effect. After treatment with the associations of the three nutraceuticals, all parameters were close to normal, thus suggesting a new potential strategy in the protection of renal functions in subjects exposed to environmental toxicants.

The normal wound healing process is characterized by a complex, highly integrated cascade of events, requiring the interactions of many cell types, including inflammatory cells, fibroblasts, keratinocytes and endothelial cells, as well as the involvement of growth factors and enzymes. However, several diseases such as diabetes, thermal injury and ischemia could lead to an impaired wound healing process characterized by wound hypoxia, high levels of oxygen radicals, reduced angiogenesis, decreased collagen synthesis and organization. Polydeoxyribonucleotide (PDRN) has been used to improve wound healing through local and systemic administration thanks to its ability to promote cell migration and growth, angiogenesis, and to reduce inflammation on impaired wound healing models in vitro, in vivo and clinical studies. In light of all these observations, the aim of this review is to provide a full overview of PDRN applications on skin regeneration. We reviewed papers published in the last 25 years on PubMed, inserting “polydeoxyribonucleotide and wound healing” as the main search term. All data obtained proved the ability of PDRN in promoting physiological tissue repair through adenosine A2A receptor activation and salvage pathway suggesting that PDRN has proven encouraging results in terms of healing time, wound regeneration and absence of side effects.

Obesity is a worldwide chronic metabolic disease characterized by an abnormal fat accumulation and represents one of the main risk factors for several diseases. White adipose tissue is the primary site for energy storage in the form of triglycerides, whereas brown adipose tissue does not store energy-providing lipids but rather dissipates it by producing heat. White-to-brown adipocyte trans-differentiation could represent a new target of anti-obesity strategies and result in fat reduction. Previous studies indicated that adenosine receptor activation induces trans-differentiation of white adipocytes to brown adipocytes. The aim of this study was to evaluate the effects of polydeoxyribonucleotide (PDRN), an A2Ar receptor agonist, in an in vitro model of browning. Mouse 3T3-L1 pre-adipocytes were differentiated in mature adipocytes with specific culture media and then treated with PDRN (10 µg/mL), PDRN + ZM241385 (1 µM), CGS21680 (1 µM) and CGS + ZM241385 for 24 h. Cell viability was studied by MTT assay, and browning induction was evaluated by Oil Red O staining and by RT-qPCR to study gene expression of browning markers. PDRN, as well as CGS21680, reduced the accumulation of lipids, cell volume and lipid droplet size; increased the expression of UCP1, PRDM16 and DIO2, considered as browning markers; and reduced the expression of FASn and FABP4, considered as whitening markers. In addition, PDRN decreased leptin expression and enhanced adiponectin mRNA levels. All these effects were abrogated when PDRN was co-incubated with the A2Ar antagonist ZM241385. In conclusion, these results suggest that PDRN is able to induce the white-to-brown adipose differentiation through A2Ar stimulation. Since PDRN is a safe drug already available in the market for other therapeutic indications, its “anti-obesity” potential warrants investigation in a clinical scenario.

Introduction: Drug combination is widely used to treat chronic inflammatory diseases. A similar strategy might be worth of interest to design plant-derived natural products to treat inflammatory conditions. Curcumin is a natural phenolic compound which shares anti-inflammatory activity with both flavocoxid, a flavonoid mixture of baicalin and catechin, and β-caryophyllene, a bicyclic sesquiterpene. The aim of this study was to investigate the synergy potential of curcumin with both flavocoxid and β-caryophyllene in human articular chondrocytes triggered with lipopolysaccharide (LPS), in an experimental in vitro model of osteoarthritis.Materials and Methods: Human articular chondrocytes were stimulated with LPS alone or in combination with different treatments. Total RNA was extracted 4 h after treatment to study interleukin 1β (IL-1β), NF-κB, and STAT3 mRNA expression. A drug combination study was designed choosing 5 doses to demonstrate a synergistic effect of compounds, according to Chou and Talalay method. A median-effect equation was applied and finally, the combination index (CI) was used to clarify the nature of the compounds interaction (synergistic versus additive versus antagonistic inhibitory effects); CI < 1, CI = 1, and CI > 1 indicated synergistic, additive, and antagonistic effects, respectively.Results: LPS prompted IL-1β expression. Curcumin, flavocoxid and β-caryophyllene suppressed IL-1β expression with different IC50. A synergistic action for the reduction of the inflammatory phenotype in human chondrocytes was observed for the combination curcumin-flavocoxid with a percentage from 10% to 90%, and for the combination curcumin-β-caryophyllene from 50% to 90%. IC50 doses of either flavocoxid, β-caryophyllene and curcumin alone or in combination were safe and did not affect cell vitality. Moreover, the same IC50 doses reduced the transcription factors NF-κB and STAT3 mRNA expression and interestingly the effects of the combinations were greater than the natural products alone, thus suggesting that the site where the synergy takes place could be at the signal transduction level.Discussion: The results suggest that curcumin synergizes with either flavocoxid or β-caryophyllene, exerting an anti-inflammatory activity and thus strongly suggesting the potential of a dual combination of these compounds for the management of osteoarthritis and unmasking a new feature of these natural products.

It is known that cadmium damages testis structure and functionality. We examined the effects of nutraceuticals such as a flavonoid-rich extract of bergamot juice (BJe), alone or in association with curcumin (Cur) and resveratrol (Re), on mice testicular dysfunction caused by cadmium chloride (CdCl2). Controversial data on the protective effects of Cur and Re are available, while no evidence on the possible role of BJe exists. Adult male C57 BL/6J mice were administered with CdCl2 and treated with Cur, Re, or BJe alone or in combination for 14 days. Then, testes were removed and processed for molecular, structural, and immunohistochemical analyses. CdCl2 increased the mRNA of IL-1β, TNF-α, p53, and BAX while reduced that of Bcl-2 and induced tubular lesions and apoptosis of germinal cells. Cur, Re, and BJe at 40 mg/kg significantly improved all of these parameters and events, although BJe at 20 mg/kg showed a lower protective effect. The association of Cur, Re, and BJe at both doses of 50/20/20 and 100/20/40 mg/kg brought each parameter close to those of the control. Our results indicate that the nutraceuticals employed in this study and their associations exert a positive action against Cd-induced testicular injury, suggesting a possible protection of testis functionality in subjects exposed to environmental toxicants.

Fuchs endothelial corneal dystrophy (FECD) is characterized by the gradual deterioration of corneal endothelial cells (CECs) and is the most common cause of corneal transplantation worldwide. CECs apoptosis caused by oxidative stress plays a pivotal role in the pathogenesis of FECD. Antioxidant compounds have been of considerable significance as a candidate treatment in the management of corneal diseases. Based on these findings, the objective of this study was to evaluate the effects of an aloe extract with antioxidant properties, in an “in vitro” model of FECD. Human corneal epithelial (HCE) cells were preincubated with aloe extract 100 μg/mL, two hours before hydrogen peroxide (H2O2) stimulus. H2O2 challenge significantly reduced the cell viability, increased the generation of Reactive Oxygen Species (ROS) and malondialdehyde levels. Moreover, m-RNA expression and activity of Nrf-2, Catalase and Superoxide dismutase (SOD) were reduced together with an enhanced expression of IL-1β, tumor necrosis factor-α (TNF-α), IL-6, and cyclooxygenase 2 (COX-2). Furthermore, Bcl-2, Caspase-3 and Caspase-8 expression were down-regulated while Bax was up-regulated by H2O2 stimulus. Aloe extract blunted the oxidative stress-induced inflammatory cascade triggered by H2O2 and modulated apoptosis. Aloe extract defends HCE cells from H2O2-induced injury possibly due its antioxidant and anti-inflammatory activity, indicating that eye drops containing aloe extract may be used as an adjunctive treatment for FECD.

Flavocoxid is a blended extract containing baicalin and catechin with potent antioxidant and anti-inflammatory properties due to the inhibition of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) enzymes, nuclear factor-κB (NF-κB), tumor necrosis factor (TNF)-alpha, and the mitogen-activated protein kinases (MAPKs) pathways. This phase 1/2 study was designed to assess the safety and tolerability of flavocoxid in patients with Duchenne muscular dystrophy (DMD). Thirty-four patients were recruited: 17 were treated with flavocoxid at an oral dose of 250 or 500 mg, according to body weight, for one year; 17 did not receive flavocoxid and served as controls. The treatment was well tolerated and nobody dropped out. Flavocoxid induced a significant reduction in serum interleukin (IL)-1 beta and TNF-alpha only in the group of DMD boys on add-on therapy (flavocoxid added to steroids for at least six months). The decrease in IL-1 beta was higher in younger boys. The serum H2O2 concentrations significantly decreased in patients treated with flavocoxid alone with a secondary reduction of serum glutathione peroxidase (GPx) levels, especially in younger boys. The exploratory outcome measures failed to show significant effects but there was a trend showing that the younger boys who received treatment were faster at performing the Gowers’ maneuver, while the older boys who received treatment were faster at doing the 10-m walk test (10MWT). Therefore, a double-blind, placebo-controlled study for at least two/three years is warranted to verify flavocoxid as a steroid substitute or as add-on therapy to steroids.

Inflammatory bowel diseases (IBDs) are chronic conditions that can benefit from the combined treatment of adenosine receptor agonists and hyaluronic acid (HA), which, binding the CD44, has pro-survival effects. Therefore, this study investigated the effects of a mixture of polynucleotides and HA in an experimental model of dinitrobenzenesulfonic acid (DNBS)-induced colitis. A group of 40 rats received a single intra-colonic instillation of DNBS, and after 6 h, animals were randomized to receive daily: (i) saline solution; (ii) polynucleotides (Poly; 8 mg/kg); (iii) polynucleotides (8 mg/kg) plus hyaluronic acid (HA; 15 mg/kg); and (iv) hyaluronic acid (HA; 15 mg/kg). Rats in the control group (n = 10) received saline solution only. Seven days after induction, animals receiving Poly plus HA showed reduced clinical signs, weight loss and colon shortening, ameliorated macroscopic and histological damage, and apoptosis. Moreover, the combined treatment reduced the positivity in the colonic infiltrate of CD3 positive T cells, CD20 positive B cells and CD44. Furthermore, Poly plus HA reduced colonic myeloperoxidase activity and malondialdehyde, indicating a dampening of the inflammatory infiltrate and oxidation products. Our research demonstrated that a combined treatment of polynucleotides with hyaluronic acid had a protective effect in a model of ulcerative colitis, suggesting that this association deserves further attention for the treatment of IBDs.

Oral surgery has undergone dramatic developments in recent years due to the use of biomaterials. The aim of the present review is to provide a general overview of the current biomaterials used in oral surgery and to comprehensively outline their impact on post-operative wound healing. A search in Medline was performed, including hand searching. Combinations of searching terms and several criteria were applied for study identification, selection, and inclusion. The literature was searched for reviews published up to July 2020. Reviews evaluating the clinical and histological effects of biomaterials on post-operative wound healing in oral surgical procedures were included. Review selection was performed by two independent reviewers. Disagreements were resolved by a third reviewer, and 41 reviews were included in the final selection. The selected papers covered a wide range of biomaterials such as stem cells, bone grafts, and growth factors. Bioengineering and biomaterials development represent one of the most promising perspectives for the future of oral surgery. In particular, stem cells and growth factors are polarizing the focus of this ever-evolving field, continuously improving standard surgical techniques, and granting access to new approaches.

Rheumatoid arthritis (RA) is a systemic disease that leads to joint destruction. During the last decade, the therapy of RA has been principally based on biological drugs. Although the efficacy of biological therapy has been established, patients demonstrated a high heterogeneity in clinical response to treatment. Several genetic polymorphisms play a part in the different response to biological drugs. This review summarizes the pharmacogenetics of biological agents approved for clinical RA treatment. We reviewed PubMed papers published over the past 20 years (2000–2020), inserting as the search term “rheumatoid arthritis and polymorphisms”. Despite some studies showing important correlations between genetic polymorphisms and response to biological therapy in RA patients, most of these findings are still lacking and inconsistent. The personalized treatment according to a pharmacogenetics approach is promising but the available pharmacogenetics data on biological treatment in RA are not adequate and reliable to recommend pharmacogenetic tests before starting biological therapy in RA patients.

Human gingival fibroblasts (GF) and human oral mucosa epithelial cells (EC) with an inflammatory phenotype represent a valuable experimental paradigm to explore the curative activity of agents to be used in oral mucositis. The role of cannabinoid receptor 2 (CB2) has not yet been investigated in oral mucositis. The aim of this study was to evaluate the therapeutic potential of β-Caryophyllene (BCP), a CB2 agonist, in an in vitro model of oral mucositis. GF and EC were stimulated with LPS (2 µg/mL) alone or in combination with BCP; a group of LPS challenged GF and EC were treated with BCP and AM630, a CB2 antagonist. LPS increased the inflammatory cytokines TNF-α, IL-1β, IL-6 and IL-17A whereas it decreased the anti-inflammatory cytokine IL-13. The upstream signals were identified in an augmented expression of NF-κB and STAT-3 and in reduced mRNA levels of PPARγ and PGC-1α. BCP blunted the LPS-induced inflammatory phenotype and this effect was reverted by the CB2 antagonist AM630. These results suggest that CB2 receptors are an interesting target to develop innovative strategies for oral mucositis and point out that BCP exerts a marked curative effect in a preclinical model of oral mucositis which deserves to be confirmed in a clinical setting.

Spinal cord injury (SCI) is a complex clinical and progressive condition characterized by neuronal loss, axonal destruction and demyelination. In the last few years, adenosine receptors have been studied as a target for many diseases, including neurodegenerative conditions. The aim of this study was to investigate the effects of an adenosine receptor agonist, PDRN, in an experimental model of SCI. Moreover, since adenosine receptors stimulation may also activate the Wnt pathway, we wanted to study PDRN effects on Wnt signaling following SCI. Spinal trauma was induced by extradural compression of spinal cord at T5-T8 level in C57BL6/J mice. Animals were randomly assigned to the following groups: Sham (n = 10), SCI (n = 14), SCI+PDRN (8 mg/kg/i.p.; n = 14), SCI+PDRN+DMPX (8 and 10 mg/kg/i.p., respectively; n = 14). DMPX was used as an adenosine receptor antagonist to evaluate whether adenosine receptor block might prevent PDRN effects. PDRN systemically administered 1 h following SCI, protected from tissue damage, demyelination, and reduced motor deficits evaluated after 10 days. PDRN also reduced the release of the pro-inflammatory cytokines TNF-α and IL-1β, reduced BAX expression and preserved Bcl-2. Furthermore, PDRN stimulated Wnt/β-catenin pathway and decreased apoptotic process 24 h following SCI, whereas DMPX administration prevented PDRN effects on Wnt/β-catenin signaling. These results confirm PDRN anti-inflammatory activity and demonstrate that a crosstalk between Wnt/β-catenin signaling is possible by adenosine receptors activation. Moreover, these data let us hypothesize that PDRN might promote neural repair through axonal regeneration and/or neurogenesis.

Glucocorticoid-induced osteoporosis (GIO) is a secondary cause of bone loss. Bisphosphonates approved for GIO, might induce jaw osteonecrosis; thus additional therapeutics are required. Adenosine receptor agonists are positive regulators of bone remodeling, thus the efficacy of adenosine receptor stimulation for treating GIO was tested. In a preventive study GIO was induced in Sprague-Dawley rats by methylprednisolone (MP) for 60 days. Animals were randomly assigned to receive polydeoxyribonucleotide (PDRN), an adenosine A2 receptor agonist, or PDRN and DMPX (3,7-dimethyl-1-propargylxanthine, an A2 antagonist), or vehicle (0.9% NaCl). Another set of animals was used for a treatment study, following the 60 days of MP-induction rats were randomized to receive (for additional 60 days) PDRN, or PDRN and DMPX (an adenosine A2 receptor antagonist), or zoledronate (as control for gold standard treatment), or vehicle. Control animals were administered with vehicle for either 60 or 120 days. Femurs were analyzed after treatments for histology, imaging, and breaking strength analysis. MP treatment induced severe bone loss, the concomitant use of PDRN prevented the developing of osteoporosis. In rats treated for 120 days, PDRN restored bone architecture and bone strength; increased b-ALP, osteocalcin, osteoprotegerin and stimulated the Wnt canonical and non-canonical pathway. Zoledronate reduced bone resorption and ameliorated the histological features, without significant effects on bone formation. Our results suggest that adenosine receptor stimulation might be useful for preventing and treating GIO.

Treatment for traumatic brain injury (TBI) remains elusive despite compelling evidence from animal models for a variety of therapeutic targets. The activation of the NLRP3 (Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome has been proposed as key point in the brain damage associated with TBI. NLRP3 was tested as potential target for reducing neuronal loss and promoting functional recovery in a mouse model of TBI. Male NLRP3-/- (n = 20) and wild type (n = 27) mice were used. A closed TBI model was performed and inflammatory and apoptotic markers were evaluated. A group of WT mice also received BAY 11-7082, a NLRP3 inhibitor, to further evaluate the role of this pathway. At 24 h following TBI NLRP3-/- animals demonstrated a preserved cognitive function as compared to WT mice, additionally brain damage was less severe and the inflammatory mediators were reduced in brain lysates. The administration of BAY 11-7082 in WT animals subjected to TBI produced overlapping results. At day 7 histology revealed a more conserved brain structure with reduced damage in TBI NLRP3-/- animals compared to WT. Our data indicate that the NLRP3 pathway might be exploited as molecular target for the short-term sequelae of TBI.

PDRN is a proprietary and registered drug that possesses several activities: tissue repairing, anti-ischemic, and anti-inflammatory. These therapeutic properties suggest its use in regenerative medicine and in diabetic foot ulcers. PDRN holds a mixture of deoxyribonucleotides with molecular weights ranging between 50 and 1,500 KDa, it is derived from a controlled purification and sterilization process of Oncorhynchus mykiss (Salmon Trout) or Oncorhynchus keta (Chum Salmon) sperm DNA. The procedure guarantees the absence of active protein and peptides that may cause immune reactions. In vitro and in vivo experiments have suggested that PDRN most relevant mechanism of action is the engagement of adenosine A2A receptors. Besides engaging the A2A receptor, PDRN offers nucleosides and nucleotides for the so called “salvage pathway.” The binding to adenosine A2A receptors is a unique property of PDRN and seems to be linked to DNA origin, molecular weight and manufacturing process. In this context, PDRN represents a new advancement in the pharmacotherapy. In fact adenosine and dipyridamole are non-selective activators of adenosine receptors and they may cause unwanted side effects; while regadenoson, the only other A2A receptor agonist available, has been approved by the FDA as a pharmacological stress agent in myocardial perfusion imaging. Finally, defibrotide, another drug composed by a mixture of oligonucleotides, has different molecular weight, a DNA of different origin and does not share the same wound healing stimulating effects of PDRN. The present review analyses the more relevant experimental and clinical evidences carried out to characterize PDRN therapeutic effects.

Cadmium (Cd) impairs blood-testis barrier (BTB). Polydeoxyribonucleotide (PDRN), an adenosine A2A agonist, has positive effects on male reproductive system. We investigated the effects of PDRN on the morphological and functional changes induced by Cd in mice testes. Adult Swiss mice were divided into four groups: controls administered with 0.9% NaCl (1 ml/kg, i.p., daily) or with PDRN (8 mg/kg, i.p. daily), animals challenged with Cd chloride (CdCl2; 2 mg/kg, i.p, daily) and animals challenged with CdCl2 (2 mg/kg, i.p., daily) and treated with PDRN (8 mg/kg, i.p., daily). Experiments lasted 14 days. Testes were processed for biochemical, structural, and ultrastructural evaluation and hormones were assayed in serum. CdCl2 increased pERK 1/2 expression and Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) levels; it decreased testosterone (TE) and inhibin-B levels and induced structural damages in extratubular compartment and in seminiferous epithelium, with ultrastructural features of BTB disruption. Many TUNEL-positive germ cells were present. CdCl2 increased tubular TGF-β3 immunoreactivity and reduced claudin-11, occludin, and N-cadherin immunoreactivity. PDRN administration reduced pERK 1/2 expression, FSH, and LH levels; it increased TE and inhibin-B levels, ameliorated germinal epithelium changes and protected BTB ultrastructure. Few TUNEL-positive germ cells were present and the extratubular compartment was preserved. Furthermore, PDRN decreased TGF-β3 immunoreactivity and enhanced claudin-11, occludin, and N-cadherin immunoreactivity. We demonstrate a protective effect of PDRN on Cd-induced damages of BTB and suggest that PDRN may play an important role against Cd, particularly against its harmful effects on gametogenesis.

Background: The area of Milazzo-Valle del Mela (Sicily, Italy) is considered at high risk of environmental crisis by regional authorities. Objective: To measure oxidative-stress, DNA repair and detoxification genes in school children living near the industrial area and in age-matched controls. Methods: The parent study was a biomonitoring investigation evaluating heavy metal urine levels in 226 children aged 12–14 years, living in the high risk area, and in 29 age-matched controls living 45 km far from the industrial site. In the present study 67 exposed adolescents and 29 controls were included. Samples were analyzed for urinary 8-hydroxydeoxyguanosine (8OHdG) levels, and gene expression of OGG1 (DNA repair gene), NQO1, ST13, and MT1A (detoxifying genes). Results: Urinary cadmium was higher (p = 0.0004) in exposed [geometric mean, 0.46 µg/L; 25th–75th percentile: 0.3–0.56] than in control adolescents [geometric mean, 0.26 µg/L; 25th–75th percentile: 0.2–0.3]. Chromium was also significantly elevated in exposed [geometric mean, 1.52 µg/L; 25th–75th percentile: 1.19–1.93] compared with controls [geometric mean, 1.25 µg/L; 25th–75th percentile: 1.05–1.48; p = 0.02]. Urinary 8-OHdG concentration was greater in exposed than in controls (71.49 vs 61.87 µg/L, p = 0.02), and it was correlated with cadmium levels (r = 0.46, p

β-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist that tempers inflammation. An interaction between the CB2 receptor and peroxisome proliferator-activated receptor gamma (PPAR-γ) has been suggested and PPAR-γ activation exerts anti-arthritic effects. The aim of this study was to characterize the therapeutic activity of BCP and to investigate PPAR-γ involvement in a collagen antibody induced arthritis (CAIA) experimental model. CAIA was induced through intraperitoneal injection of a monoclonal antibody cocktail and lipopolysaccharide (LPS; 50 μg/100 μL/ip). CAIA animals were then randomized to orally receive either BCP (10 mg/kg/100 μL) or its vehicle (100 μL of corn oil). BCP significantly hampered the severity of the disease, reduced relevant pro-inflammatory cytokines, and increased the anti-inflammatory cytokine IL-13. BCP also decreased joint expression of matrix metalloproteinases 3 and 9. Arthritic joints showed increased COX2 and NF-ĸB mRNA expression and reduced expression of the PPARγ coactivator-1 alpha, PGC-1α, and PPAR-γ. These conditions were reverted following BCP treatment. Finally, BCP reduced NF-ĸB activation and increased PGC-1α and PPAR-γ expression in human articular chondrocytes stimulated with LPS. These effects were reverted by AM630, a CB2 receptor antagonist. These results suggest that BCP ameliorates arthritis through a cross-talk between CB2 and PPAR-γ.

Activation of the adenosine receptor pathway has been demonstrated to be effective in improving tissue remodelling and blunting the inflammatory response. Active colitis is characterized by an intense inflammatory reaction resulting in extensive tissue damage. Symptomatic improvement requires both control of the inflammatory process and repair and remodelling of damaged tissues. We investigated the ability of an A2A receptor agonist, polydeoxyribonucleotide (PDRN), to restore tissue structural integrity in two experimental colitis models using male Sprague-Dawley rats. In the first model, colitis was induced with a single intra-colonic instillation of dinitro-benzene-sulfonic acid (DNBS), 25mg diluted in 0.8ml 50% ethanol. After 6 hrs, animals were randomized to receive either PDRN (8mg/kg/i.p.), or PDRN + the A2A antagonist (DMPX; 10mg/kg/i.p.), or vehicle (0.8 ml saline solution) daily. In the second model, dextran sodium sulphate (DSS) was dissolved in drinking water at a concentration of 8%. Control animals received standard drinking water. After 24 hrs animals were randomized to receive PDRN or PDRN+DMPX as described above. Rats were sacrificed 7 days after receiving DNBS or 5 days after DSS. In both experimental models of colitis, PDRN ameliorated the clinical symptoms and weight loss associated with disease as well as promoted the histological repair of damaged tissues. Moreover, PDRN reduced expression of inflammatory cytokines, myeloperoxydase activity, and malondialdheyde. All these effects were abolished by the concomitant administration of the A2a antagonist DMPX. Our study suggests that PDRN may represent a promising treatment for improving tissue repair during inflammatory bowel diseases.

Cecal ligation and puncture (CLP) is an experimental polymicrobial sepsis induced systemic inflammation that leads to acute organ failure. Aim of our study was to evaluate the effects of SP600125, a specific c-Jun NH2-terminal kinase (JNK) inhibitor, to modulate the early and late steps of the inflammatory cascade in a murine model of CLP-induced sepsis. CB57BL/6J mice were subjected to CLP or sham operation. Animals were randomized to receive either SP600125 (15 mg/kg) or its vehicle intraperitoneally 1 hour after surgery and repeat treatment every 24 hours. To evaluate survival, a group of animals was monitored every 24 hours for 120 hours. Two other animals were sacrificed 4 or 18 hours after surgical procedures; lung and liver samples were collected for biomolecular and histopathologic analysis. The expression of p-JNK, p-ERK, TNF-α, HMGB-1, NF-κB, Ras, Rho, Caspase 3, Bcl-2, and Bax was evaluated in lung and liver samples; SP600125 improved survival, reduced CLP induced activation of JNK, NF-κB, TNF-α, and HMGB-1, inhibited proapoptotic pathway, preserved Bcl-2 expression, and reduced histologic damage in both lung and liver of septic mice. SP600125 protects against CLP induced sepsis by blocking JNK signalling; therefore, it can be considered a therapeutic approach in human sepsis.

Flavonoids, from Scutellaria baicalensis (Chinese skullcap) and Acacia catechu (black catechu), have been shown to exert a variety of therapeutic effects, including anti-inflammatory, antiviral, antibacterial, and anticancer activities. Flavocoxid is a mixed extract containing baicalin and catechin and it acts as a dual balanced inhibitor of cyclooxygenase-1 (COX-1) and COX-2 peroxidase enzyme activities with a significant inhibition of 5-lipoxygenase (5-LOX) enzyme activity in vitro. Flavocoxid downregulates gene or protein expression of several inflammatory markers and exerts also strong antioxidant activity in several experimental models. Controlled clinical trials and a postmarketing study have clearly shown that flavocoxid is as effective as naproxen in managing the signs and symptoms of osteoarthritis of the knee and it has better upper gastrointestinal, renal, and respiratory safety profile than naproxen. Flavocoxid may therefore provide a potential therapeutic approach to the treatment of chronic inflammatory conditions.