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Purpose: Dimethyl fumarate (DMF), the first-line oral therapy for relapsing-remitting multiple sclerosis, is rapidly metabolized into monomethyl fumarate. The DMF oral administration provokes gastrointestinal discomfort causing treatment withdrawal. The present study aimed to develop an innovative formulation for DMF nasal administration. Lipid-polymer hybrid nanoparticles (LPNs) were developed to improve DMF stability, limiting gastrointestinal side effects and increasing brain bioavailability by nose-to-brain targeting application., Methods: DMF-loaded and unloaded LPNs with or without hyaluronic acid (HA) were prepared using the nanoprecipitation via magnetic/mechanical stirring technique. Particle morphology and surface properties were evaluated; drug content, viscosity, and mucoadhesion were determined. Physico-chemical stability of LPNs and DMF in the LPNs was also explored. In vitro DMF permeation experiments were performed utilizing the PermeaPad ® . The cytotoxicity and cellular uptake studies were performed using RPMI 2650 and SK-N-BE2 cell lines. DMF nose-to-brain delivery was evaluated by intranasally administering DMF-loaded LPNs to rats., Results: LPNs with average sizes of 120-250 nm and a negative zeta potential -17.3 to -43 mV were obtained, primarily influenced by the presence of HA. HA assured drug stability up to 60 days and promoting the in vitro permeation of DMF compared to the free-DMF. HA greatly improved the viscosity and mucoadhesive properties. LPNs with and without HA did not exhibit any cytotoxicity and showed a rapid cell uptake starting from 15 min to 2 h with a best internalization after 1 h of treatment in both epithelial and neuronal cell lines. Nasal administration of DMF-loaded LPNs allowed to quantify up to about 12 μg/mL of DMF in the rat cerebrospinal fluid., Conclusion: The results highlight the role of HA in improving LPNs properties and performance as carrier of DMF for nasal administration. In particular, LPNs appear able to enter neurons and monolayers of epithelial cells, allowing to promote the nose-to-brain DMF delivery., Competing Interests: The authors report no conflicts of interest in this work. The graphical abstract was created using BioRender software. Langellotto, M. (2024) https://BioRender.com/i91f605., (© 2025 Serri et al.)

Robotic surgery has become a popular method for treating ventral hernias due to its promising peri-operative outcomes. However, the long-term results of this approach are still unclear. In this study, 120 patients underwent robotic trans-abdominal retromuscular mesh placement (r-TARM) with a mean follow-up period of 18.1 months. This study aims to evaluate the feasibility of the robotic approach reporting peri-operative and midterm outcomes. Additionally, we examined possible risk factors that may contribute to the development of surgical site occurrences (SSOs). Between January 2021 and September 2023, 120 patients underwent r-TARM for midline hernias, including 39 primary, 71 incisional, and 10 recurrent cases. A retrospective analysis was performed. A logistic regression model was used to identify possible patient risk factors for SSO development. The average operative time was 153.5 ± 47.2 min, and there were no open or laparoscopic approach conversions. The mean length of hospital stay was 1.9 ± 0.9 days. We observed SSO in 16 patients (13.3%). One patient (0.8%) required angiographic embolization due to post-operative parietal bleeding. The mean follow-up time was 18.1 ± 7.8 months, and we observed hernia recurrence in only one (0.8%) patient. The logistic regression model did not identify any possible risk factors for SSO. r-TARM is a safe and effective method for treating ventral hernias not requiring posterior component separation. Our results indicate that patient and hernia characteristics were not predictive of SSO. Midterm outcomes are encouraging, though longer follow-up is needed., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Background: - Alcohol-induced pro-inflammatory activation might influence cellular and synaptic pathology, thus contributing to the behavioral phenotypes associated with alcohol use disorders. In the present study, the possible anti-inflammatory properties of N-[(4-trifluoromethyl)-benzyl]4-methoxybutyramide (GET73), a promising therapeutic agent for alcohol use disorder treatment, were evaluated in primary cultures of rat cortical microglia., Methods: - Primary cultures of cerebral cortex microglial cells were treated with 100 ng/ml lipopolysaccharide (LPS; 8 h, 37 °C) or 75 mM ethanol (EtOH; 4 days, 37 °C) alone or in the presence of GET73 (1-30 µM). At the end of the incubation period, multiparametric quantification of cytokines/chemokines was performed by using the xMAP technology and Luminex platform. Furthermore, cultured microglial cell viability following the treatment with EtOH and GET73, alone or in combination, has been measured by a colorimetric assay (i.e. MTT assay)., Results: - GET73 (10 and 30 µM) partially or fully prevented the LPS-induced increase of IL-6, IL-1β, RANTES/CCL5 protein and MCP-1/CCL2 levels. On the contrary, GET73 failed to attenuate the TNF-α level increase induced by LPS. Furthermore, GET73 treatment (10-30 µM) significantly attenuated or prevented the EtOH-induced increase of TNF-α, IL-6, IL-1β and MCP-1/CCL2 levels. Finally, at all the concentrations tested (1-30 µM), the GET73 treatment did not alter the EtOH-induced reduction of microglial cell viability., Conclusions: - The current results provide the first in vitro evidence of GET73 protective properties against EtOH-induced neuroinflammation. These data add more information on the complex and multifactorial profile of action of the compound, further supporting the significance of developing GET73 as a therapeutic tool for the treatment of individuals with alcohol use disorders., (© 2024. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

Treatment of incisional hernia is a rapidly evolving field of surgery, with actual trends being oriented toward retromuscular/preperitoneal mesh placement. The diffusion of robotic surgery is constantly growing in different surgical specialties and is gaining widespread acceptance for abdominal wall reconstruction. Recently, novel robotic platforms have entered into the market. In this study, we present the first transabdominal retromuscular incisional hernia repair performed with the new Hugo RAS™ system (Medtronic, Minneapolis, MN, USA). The surgical team had previous robotic experience and completed an official 2-day session running incisional hernia repair on human cadaver lab. Operating room setting and trocar layout were planned. The patient presented a 4 × 4 cm midline incisional hernia and was scheduled for transabdominal retromuscular incisional hernia repair at our Institution. A description of the operative room setup, robotic arm configuration and docking/tilt angles is provided. Docking time, operative time, and console time were 15, 95, and 75 min, respectively. All the surgical steps were completed without critical surgical errors or high-priority alarms. Neither intraoperative complications nor conversion to open surgery was recorded. Postoperative course was uneventful and the patient was discharged on postoperative day 2. The safety and the feasibility of these procedures will require further analysis and larger patients' sample sizes for procedural standardization and potential integration into minimally invasive abdominal wall reconstruction programs., (© 2024. Italian Society of Surgery (SIC).)

Benznidazole (BNZ) serves as the primary drug for treating Chagas Disease and is listed in the WHO Model List of Essential Medicines for Children. Herein, a new child-friendly oral BNZ delivery platform is developed in the form of supramolecular eutectogels (EGs). EGs address BNZ's poor oral bioavailability and provide a flexible twice-daily dose in stick-pack format. This green and sustainable formulation strategy relies on the gelation of drug-loaded Natural Deep Eutectic Solvents (NaDES) with xanthan gum (XG) and water. Specifically, choline chloride-based NaDES form stable and biocompatible 5 mg/mL BNZ-loaded EGs. Rheological and Low-field NMR investigations indicate that EGs are viscoelastic materials comprised of two co-existing regions in the XG network generated by different crosslink distributions between the biopolymer, NaDES and water. Remarkably, the shear modulus and relaxation spectrum of EGs remain unaffected by temperature variations. Upon dilution with simulated gastrointestinal fluids, EGs results in BNZ supersaturation, serving as the primary driving force for its absorption. Interestingly, after oral administration of EGs to rats, drug bioavailability increases by 2.6-fold, with a similar increase detected in their cerebrospinal fluid. The noteworthy correlation between in vivo results and in vitro release profiles confirms the efficacy of EGs in enhancing both peripheral and central BNZ oral bioavailability., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Giorgia Nucci reports financial support was provided by Fondazione Famiglia Parmiani, Bologna. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated., Methods: Pregnant Sprague-Dawley rats were treated with MAM (22 mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6 mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed., Results: A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats., Conclusions: The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia., (© 2024. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

Ferulic acid (Fer) and geraniol (Ger) are natural compounds whose antioxidant and anti-inflammatory activity confer beneficial properties, such as antibacterial, anticancer, and neuroprotective effects. However, the short half-lives of these compounds impair their therapeutic activities after conventional administration. We propose, therefore, a new prodrug (Fer-Ger) obtained by a bio-catalyzed ester conjugation of Fer and Ger to enhance the loading of solid lipid microparticles (SLMs) designed as Fer-Ger delivery and targeting systems. SLMs were obtained by hot emulsion techniques without organic solvents. HPLC-UV analysis evidenced that Fer-Ger is hydrolyzed in human or rat whole blood and rat liver homogenates, with half-lives of 193.64 ± 20.93, 20.15 ± 0.75, and 3.94 ± 0.33 min, respectively, but not in rat brain homogenates. Studies on neuronal-differentiated mouse neuroblastoma N2a cells incubated with the reactive oxygen species (ROS) inductor H 2 O 2 evidenced the Fer-Ger ability to prevent oxidative injury, despite the fact that it appears ROS-promoting. The amounts of Fer-Ger encapsulated in tristearin SLMs, obtained in the absence or presence of glucose, were 1.5 ± 0.1%, allowing the control of the prodrug release (glucose absence) or to sensibly enhance its water dissolution rate (glucose presence). These new "green" carriers can potentially prolong the beneficial effects of Fer and Ger or induce neuroprotection as nasal formulations.

Bioluminescence and fluorescence resonance energy transfer (BRET and FRET) together with the proximity ligation method revealed the existence of G-protein-coupled receptors, Ionotropic and Receptor tyrosine kinase heterocomplexes, e.g., A2AR-D2R, GABAA-D5R, and FGFR1-5-HT1AR heterocomplexes. Molecular integration takes place through allosteric receptor-receptor interactions in heteroreceptor complexes of synaptic and extra-synaptic regions. It involves the modulation of receptor protomer recognition, signaling and trafficking, as well as the modulation of behavioral responses. Allosteric receptor-receptor interactions in hetero-complexes give rise to concepts like meta-modulation and protein modulation. The introduction of receptor-receptor interactions was the origin of the concept of meta-modulation provided by Katz and Edwards in 1999, which stood for the fine-tuning or modulation of nerve cell transmission. In 2000-2010, Ribeiro and Sebastiao, based on a series of papers, provided strong support for their view that adenosine can meta-modulate (fine-tune) synaptic transmission through adenosine receptors. However, another term should also be considered: protein modulation, which is the key feature of allosteric receptor-receptor interactions leading to learning and consolidation by novel adapter proteins to memory. Finally, it must be underlined that allosteric receptor-receptor interactions and their involvement both in brain disease and its treatment are of high interest. Their pathophysiological relevance has been obtained, especially for major depressive disorder, cocaine use disorder, and Parkinson's disease.

Background: Research implicates inflammation in the vicious cycle between depression and obesity, yet few longitudinal studies exist. The rapid weight loss induced by bariatric surgery is known to improve depressive symptoms dramatically, but preoperative depression diagnosis may also increase the risk for poor weight loss. Therefore, we investigated longitudinal associations between depression and inflammatory markers and their effect on weight loss and clinical outcomes in bariatric patients., Methods: This longitudinal observational study of 85 patients with obesity undergoing bariatric surgery included 41 cases with depression and 44 controls. Before and 6 months after surgery, we assessed depression by clinical interview and measured serum high-sensitivity C-reactive protein (hsCRP) and inflammatory cytokines, including interleukin (IL)-6 and IL-10., Results: Before surgery, depression diagnosis was associated with significantly higher serum hsCRP, IL-6, and IL-6/10 ratio levels after controlling for confounders. Six months after surgery, patients with pre-existing depression still had significantly higher inflammation despite demonstrating similar weight loss to controls. Hierarchical regression showed higher baseline hsCRP levels predicted poorer weight loss ( β = -0.28, p = 0.01) but had no effect on depression severity at follow-up ( β = -0.02, p = 0.9). Instead, more severe baseline depressive symptoms and childhood emotional abuse predicted greater depression severity after surgery ( β = 0.81, p < 0.001; and β = 0.31, p = 0.001, respectively)., Conclusions: Depression was significantly associated with higher inflammation beyond the effect of obesity and other confounders. Higher inflammation at baseline predicted poorer weight loss 6 months after surgery, regardless of depression diagnosis. Increased inflammation, rather than depression, may drive poor weight loss outcomes among bariatric patients.

Paraoxonase (PON) enzymes (PON1, PON2 and PON3) exert antioxidant properties through arylesterase, lactonase and paraoxonase activities. Increasing findings suggested their potential involvement, particularly PON1 and PON2, in Alzheimer's disease (AD), a neurodegenerative pathology characterized by early oxidative stress. Specifically, decreased serum PON1-arylesterase and lactonase activities seem to be associated with an increased brain oxidative damage in early AD, leading to hypothesize that PON activity alterations might be an early event in AD. To address this hypothesis, the levels of 4-hydroxynonenal (4-HNE; i.e. a marker of oxidative stress damage) along with the protein expression and enzymatic activity of PON1 and PON2 have been investigated in the brain and serum of young [Postnatal day (PD)8-10, 20-25 and 60-65] asymptomatic 3xTg-AD female mice, one of the most used transgenic models of AD. At PD 8-10, there were no differences in hippocampus and prefrontal cortex (PFC) 4-HNE expression levels between 3xTg-AD mice compared to controls (Non-Tg mice). On the other hand, significant increased levels of 4-HNE were detected in PD 20-30 3xTg-AD mice hippocampus, while a significant reduction was observed in 3xTg-AD group at PD 60-65. In the PFC, 4-HNE levels were significantly reduced in 3xTg-AD mice brain at PD 20-30, while no differences in 4-HNE levels were detected at PD 60-65. No significant differences in arylesterase and lactonase activities were observed in the plasma of 3xTg-AD and Non-Tg mice at the different considered ages. Compared to Non-Tg mice, a reduction of brain arylesterase activity was found in 3xTg-AD female at PD 20-30 and PD 60-65, but it was significant only in the younger group. Finally, a similar trend was observed also for PON1 and PON2 protein levels, with both significantly, and solely, decreased in 3xTg-AD mice brain at PD 20-30. Overall, these findings suggest that the altered oxidative stress homeostasis in the 3xTg-AD female mice may be related to an early reduction in activity and expression of PONs enzymes most likely via a reduced brain arylesterases activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Psychotic disorders have been reported in long-term users of synthetic cannabinoids. This study aims at investigating the long-lasting effects of repeated JWH-018 exposure., Experimental Approach: Male CD-1 mice were injected with vehicle, JWH-018 (6 mg·kg -1 ), the CB 1 -antagonist NESS-0327 (1 mg·kg -1 ) or co-administration of NESS-0327 and JWH-018, every day for 7 days. After 15 or 16 days washout, we investigated the effects of JWH-018 on motor function, memory, social dominance and prepulse inhibition (PPI). We also evaluated glutamate levels in dialysates from dorsal striatum, striatal dopamine content and striatal/hippocampal neuroplasticity focusing on the NMDA receptor complex and the neurotrophin BDNF. These measurements were accompanied by in vitro electrophysiological evaluations in hippocampal preparations. Finally, we investigated the density of CB 1 receptors and levels of the endocannabinoid anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and their main synthetic and degrading enzymes in the striatum and hippocampus., Key Results: The repeated treatment with JWH-018 induced psychomotor agitation while reducing social dominance, recognition memory and PPI in mice. JWH-018 disrupted hippocampal LTP and decreased BDNF expression, reduced the synaptic levels of NMDA receptor subunits and decreased the expression of PSD95. Repeated exposure to JWH-018, reduced hippocampal CB 1 receptor density and induced a long-term alteration in AEA and 2-AG levels and their degrading enzymes, FAAH and MAGL, in the striatum., Conclusion and Implications: Our findings suggest that repeated administration of a high dose of JWH-018 leads to the manifestation of psychotic-like symptoms accompanied by alterations in neuroplasticity and change in the endocannabinoid system., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Robotic surgery may offer significant advantages for treating extraperitoneal rectal cancer. Although laparoscopy has been shown to be safe and effective, laparoscopic total mesorectal excision (TME) remains technically challenging and is still performed in selected centers. Robotic anterior resection (RAR) may overcome the drawback of conventional laparoscopy, providing high-quality surgery with favorable oncological outcomes. Moreover, recent data show how RAR offers clinical and oncological benefits when affording difficult TMEs, such as low and advanced rectal tumors, in terms of complication rate, specimen quality, recurrence rate, and survival. This series aims to review the most recent and relevant literature, reporting mid- and long-term oncological outcomes and focusing on minimally invasive RAR for low rectal cancer.

Purpose: Robotic surgery offers new possibilities in repairing complex hernias with a minimally invasive approach. This study aimed to analyze our preliminary results., Methods: Between November 2015 and February 2020, 150 patients underwent robotic reconstruction for abdominal wall defects (77 primary and 73 incisional). A retrospective analysis of a prospectively maintained database was conducted to evaluate the short-term outcomes., Results: The mean operative time was 176.9 ± 72.1 min. No conversion to open or laparoscopic approach occurred. The mean hospital length of stay was 2.6 ± 1.6. According to Clavien-Dindo classification, two (grade III) complications following retromuscular mesh placement (1.3%) occurred. One patient (0.7%) required surgical revision due to small bowel occlusion following an intraparietal hernia. The 30-day readmission rate was 0.6%, and the mortality was nihil., Conclusions: Robotic surgery is valuable for safely completing challenging surgical procedures like complex abdominal wall reconstruction, with low conversion and complication rates. A stepwise approach to the different surgical techniques is essential to optimize the outcomes and maximize the benefits of the robotic approach., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Phytochemicals, produced as secondary plant metabolites, have shown interesting potential therapeutic activities against neurodegenerative diseases and cancer. Unfortunately, poor bioavailability and rapid metabolic processes compromise their therapeutic use, and several strategies are currently proposed for overcoming these issues. The present review summarises strategies for enhancing the central nervous system's phytochemical efficacy. Particular attention has been paid to the use of phytochemicals in combination with other drugs (co-administrations) or administration of phytochemicals as prodrugs or conjugates, particularly when these approaches are supported by nanotechnologies exploiting conjugation strategies with appropriate targeting molecules. These aspects are described for polyphenols and essential oil components, which can improve their loading as prodrugs in nanocarriers, or be part of nanocarriers designed for targeted co-delivery to achieve synergistic anti-glioma or anti-neurodegenerative effects. The use of in vitro models, able to simulate the blood-brain barrier, neurodegeneration or glioma, and useful for optimizing innovative formulations before their in vivo administration via intravenous, oral, or nasal routes, is also summarised. Among the described compounds, quercetin, curcumin, resveratrol, ferulic acid, geraniol, and cinnamaldehyde can be efficaciously formulated to attain brain-targeting characteristics, and may therefore be therapeutically useful against glioma or neurodegenerative diseases.

Poorly soluble drugs must be appropriately formulated for clinical use to increase the solubility, dissolution rate, and permeation across the intestinal epithelium. Polymeric and lipid nanocarriers have been successfully investigated for this aim, and their physicochemical properties, and in particular, the surface chemistry, significantly affect the pharmacokinetics of the drugs after oral administration. In the present study, PLGA nanoparticles (SS13NP) and solid lipid nanoparticles (SS13SLN) loaded with SS13, a BCS IV model drug, were prepared. SS13 bioavailability following the oral administration of SS13 (free drug), SS13NP, or SS13SLN was compared. SS13NP had a suitable size for oral administration (less than 300 nm), a spherical shape and negative zeta potential, similarly to SS13SLN. On the contrary, SS13NP showed higher physical stability but lower encapsulation efficiency (54.31 ± 6.66%) than SS13SLN (100.00 ± 3.11%). When orally administered (0.6 mg of drug), SS13NP showed higher drug AUC values with respect to SS13SLN (227 ± 14 versus 147 ± 8 µg/mL min), with higher C max (2.47 ± 0.14 µg/mL versus 1.30 ± 0.15 µg/mL) reached in a shorter time (20 min versus 60 min). Both formulations induced, therefore, the oral bioavailability of SS13 (12.67 ± 1.43% and 4.38 ± 0.39% for SS13NP and SS12SLN, respectively) differently from the free drug. These in vivo results confirm that the chemical composition of nanoparticles significantly affects the in vivo fate of a BCS IV drug. Moreover, PLGA nanoparticles appear more efficient and rapid than SLN in allowing drug absorption and transport to systemic circulation., (© 2022. Controlled Release Society.)

Background: This Italian multicentric retrospective study aimed to investigate the possible changes in outcomes of patients undergoing surgery for gastrointestinal cancers during the COVID-19 pandemic., Method: Our primary endpoint was to determine whether the pandemic scenario increased the rate of patients with colorectal, gastroesophageal, and pancreatic cancers resected at an advanced stage in 2020 compared to 2019. Considering different cancer staging systems, we divided tumors into early stages and advanced stages, using pathological outcomes. Furthermore, to assess the impact of the COVID-19 pandemic on surgical outcomes, perioperative data of both 2020 and 2019 were also examined., Results: Overall, a total of 8250 patients, 4370 (53%) and 3880 (47%) were surgically treated during 2019 and 2020 respectively, in 62 Italian surgical Units. In 2020, the rate of patients treated with an advanced pathological stage was not different compared to 2019 (P = 0.25). Nevertheless, the analysis of quarters revealed that in the second half of 2020 the rate of advanced cancer resected, tented to be higher compared with the same months of 2019 (P = 0.05). During the pandemic year 'Charlson Comorbidity Index score of cancer patients (5.38 ± 2.08 vs 5.28 ± 2.22, P = 0.036), neoadjuvant treatments (23.9% vs. 19.5%, P < 0.001), rate of urgent diagnosis (24.2% vs 20.3%, P < 0.001), colorectal cancer urgent resection (9.4% vs. 7.37, P < 0.001), and the rate of positive nodes on the total nodes resected per surgery increased significantly (7 vs 9% - 2.02 ± 4.21 vs 2.39 ± 5.23, P < 0.001)., Conclusions: Although the SARS-CoV-2 pandemic did not influence the pathological stage of colorectal, gastroesophageal, and pancreatic cancers at the time of surgery, our study revealed that the pandemic scenario negatively impacted on several perioperative and post-operative outcomes., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Evidence on the efficacy of minimally invasive (MI) segmental resection of splenic flexure cancer (SFC) is not available, mostly due to the rarity of this tumor. This study aimed to determine the survival outcomes of MI and open treatment, and to investigate whether MI is noninferior to open procedure regarding short-term outcomes., Methods: This nationwide retrospective cohort study included all consecutive SFC segmental resections performed in 30 referral centers between 2006 and 2016. The primary endpoint assessing efficacy was the overall survival (OS). The secondary endpoints included cancer-specific mortality (CSM), recurrence rate (RR), short-term clinical outcomes (a composite of Clavien-Dindo > 2 complications and 30-day mortality), and pathological outcomes (a composite of lymph nodes removed ≧12, and proximal and distal free resection margins length ≧ 5 cm). For these composites, a 6% noninferiority margin was chosen based on clinical relevance estimate., Results: A total of 606 patients underwent either an open (208, 34.3%) or a MI (398, 65.7%) SFC segmental resection. At univariable analysis, OS and CSM were improved in the MI group (log-rank test p = 0.004 and Gray's tests p = 0.004, respectively), while recurrences were comparable (Gray's tests p = 0.434). Cox multivariable analysis did not support that OS and CSM were better in the MI group (p = 0.109 and p = 0.163, respectively). Successful pathological outcome, observed in 53.2% of open and 58.3% of MI resections, supported noninferiority (difference 5.1%; 1-sided 95%CI - 4.7% to ∞). Successful short-term clinical outcome was documented in 93.3% of Open and 93.0% of MI procedures, and supported noninferiority as well (difference - 0.3%; 1-sided 95%CI - 5.0% to ∞)., Conclusions: Among patients with SFC, the minimally invasive approach met the criterion for noninferiority for postoperative complications and pathological outcomes, and was found to provide results of OS, CSM, and RR comparable to those of open resection., (© 2022. The Author(s).)

Background: Since the introduction of minimally invasive surgery, new techniques like transabdominal preperitoneal (TAPP) repair have progressively gained acceptance for the treatment of groin hernia. Laparoscopic TAPP (LTAPP) is recommended for bilateral repairs. Likewise, the introduction of robotic platforms has promised additional surgical benefits for robotic TAPP (RTAPP), which are yet to be confirmed. This study compared multicenter data obtained from patients undergoing bilateral inguinal hernia repair with RTAPP, performed during the preliminary learning curve period, versus conventional LTAPP., Materials and Methods: All consecutive bilateral inguinal hernia patients from four Italian centers between June 2015 and July 2020 were selected. A propensity score model was used to compare patients treated with LTAPP versus RTAPP, considering sex, age, body mass index, current smoking status, overall comorbidity, hernia classification (primary or recurrent), and associated procedures as covariates. After matching, intraoperative details and postoperative outcomes were evaluated., Results: In total, 275 LTAPP and 40 RTAPP were performed. After matching, 80 and 40 patients were allocated to the LTAPP and RTAPP cohorts, respectively. No intraoperative complications or conversion to open surgery occurred. However, a longer operative time was recorded in the RTAPP group (79 ± 21 versus 98 ± 29 min; p < 0.001). Postoperative visual analog scale (VAS) pain scores (p = 0.13) did not differ and complication rates were similar. There were no clinical recurrences in either group, with mean follow-up periods of 52 ± 14 (LTAPP) and 35 ± 8 (RTAPP) months. A statistical difference in length of hospital stay was found between the groups (1.05 ± 0.22 vs 1.50 ± 0.74 days; p < 0.001)., Conclusion: In this patient population, outcomes for bilateral inguinal hernia repair appear comparable for RTAPP and LTAPP, except for a shorter recovery after laparoscopic surgery. A longer operative time for robotic surgery could be attributable to the learning curve period of each center., (© 2022. The Author(s).)

Eugenol, cinnamaldehyde and D-limonene, the main components of natural essential oils, are endowed with antioxidant and anti-inflammatory properties which allow them to induce beneficial effects on intestinal, cardiac and neuronal levels. In order to characterize their pharmacokinetic profiles and aptitude to permeate in the central nervous system after intravenous and oral administration to rats, new analytical procedures, easily achievable with HPLC-UV techniques, were developed. The terminal half-lives of these compounds range from 12.4 ± 0.9 (D-limonene) and 23.1 ± 1.6 min (cinnamaldehyde); their oral bioavailability appears relatively poor, ranging from 4.25 ± 0.11% (eugenol) to 7.33 ± 0.37% (cinnamaldehyde). Eugenol evidences a marked aptitude to permeate in the cerebrospinal fluid (CSF) of rats following both intravenous and oral administrations, whereas cinnamaldehyde appears able to reach the CSF only after intravenous administration; limonene is totally unable to permeate in the CSF. Eugenol was therefore recruited for in vitro studies of viability and time-/dose-dependent dopamine release in neuronal differentiated PC12 cells (a recognized cellular model mimicking dopaminergic neurons), evidencing its ability to increase cell viability and to induce dopamine release according to a U-shaped time-course curve. Moreover, concentration-response data suggest that eugenol may induce beneficial effects against Parkinson's disease after oral administration.

Introduction: Inguinal hernia repair is one of the most commonly performed surgical procedures in general surgery. Despite surgical advances, recurrence and chronic pain are still major issues after this intervention. Aim of our study was to retrospectively assess and compare outcomes of robotic versus laparoscopic repair of recurrent inguinal hernia. Methods: All patients who underwent recurrent inguinal hernia repair between 2014 and 2021 in five different institutions were included in our study. Baseline data on age, gender, body mass index, comorbidities, smoking habit, and anticoagulant therapy were retrospectively collected from prospectively maintained databases. Operative time, length of stay, and early and late complications were compared between the robotic and the laparoscopic approach. Results: Forty-eight patients underwent recurrent inguinal hernia repair between January 2014 and December 2021. Twenty-three patients underwent a robotic procedure, whereas 25 were submitted to the laparoscopic intervention. Overall mean follow-up was 26.2 months. There was no significant difference in the baseline characteristics of the two groups. Acceptable and comparable rates of peri- and postoperative outcomes were recorded. However, postoperative visual analog scale score and incidence of chronic pain were lower after the robotic rather than after the laparoscopic approach. (2.9 versus 3.8 P  = .002; 20% versus 0%; P  = .02, respectively). Conclusions: Minimally invasive repair of recurrent inguinal hernia is safe and feasible; robotic surgery is associated with low rate of postoperative and chronic pain without a significant increase in operative time.

Cortisone is a metabolite belonging to the corticosteroid class that is used pharmaceutically directly as a drug or prodrug. In addition to its large consumption, its use is linked to several side effects, so pharmaceutical research aims to develop effective drugs with low or no side effects, alternative compounds to cortisone are part of an active investment in ongoing research on drug discovery. Since biotransformation can be considered a source of new molecules with potential therapeutic use, the present work focuses on a preliminary in vitro study aimed at evaluating the mutagenic, anti-inflammatory, antioxidant and neuroprotective activity of SCA and SCB molecules obtained from the biotransformation of cortisone using Rh. Rhodnii strain DSM 43960. The results obtained are very encouraging due to the safety of biotransformed compounds with reference to genotoxicity checked by Ames test, to the very high antioxidant capacity and to the anti-inflammatory activity. In fact, thecompounds inhibited both the TNFα-stimulated expression and secretion of NFkB target cytokines, and COX activity, and can activate the glucocorticoid receptor. Finally SCA and SCB exhibited neuroprotective properties., (© 2022. The Author(s).)

Introduction: Cannabis abuse during adolescence is a risk factor for cognitive impairments in psychiatric disorders later in life. To date, the possible causal relationship between cannabinoids, kynurenic acid (KYNA; i.e., a neuroactive metabolite of tryptophan degradation) and cognition has not been investigated in adolescence. Early exposure to delta 9-tetrahydrocannabinol (THC; i.e., the main psychotropic component of cannabis) causes enduring cognitive deficits, which critically involve impaired glutamatergic function in the prefrontal cortex (PFC). In addition, prenatal cannabis exposure results in enduring increases in PFC KYNA levels. Based on these findings, the effects of chronic THC exposure in rats, during another critical period of neurodevelopment particularly sensitive to perturbation by exogenous stimuli, such as adolescence, have been investigated., Methods: Male Wistar rats were chronically treated with vehicle or ascending intraperitoneal (i.p.) doses of THC starting on postnatal day (PND) 35 until PND 45. In adulthood (PND 75), cognitive assessment (Y-maze) and extracellular KYNA/glutamate levels were measured in the PFC by in vivo microdialysis, before and after a challenge with KYN (5 mg/kg i.p., the biological precursor of KYNA). By using the selective, brain-penetrable KAT II inhibitor PF-04859989, we then examined whether blockade of KYNA neosynthesis prevents the cognitive impairment., Results: Compared to vehicle-treated controls, extracellular basal KYNA levels were higher in the PFC of adult rats chronically exposed to THC in adolescence ( p < 0.01). No changes were observed in extracellular glutamate levels. Following a challenge with KYN, extracellular KYNA levels similarly increased in both groups (i.e., vehicle- and THC-treated; p < 0.001 and p < 0.01, respectively). Chronic adolescent THC exposure negatively affected short-term memory (reduced spontaneous alternation), in adult animals ( p < 0.001), while PF-04859989 (30 mg/kg i.p.) restored the cognitive impairment ( p < 0.05)., Discussion: We propose that the observed alterations in PFC KYNA signaling might be involved in the cognitive dysfunction induced by the exposure to THC during the adolescence. In the translational realm, these experiments raise the prospect of prevention of KYNA neosynthesis as a possible novel approach to counteract some of the detrimental long-term effects of adolescence cannabis use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Beggiato, Ieraci, Zuccarini, Di Iorio, Schwarcz and Ferraro.)

Ferulic acid (Fer) is known for its antioxidant and anti-inflammatory activities, which are possibly useful against neurodegenerative diseases. Despite the ability of Fer to permeate the brain, its fast elimination from the body does not allow its therapeutic use to be optimized. The present study proposes the preparation and characterization of tristearin- or stearic acid-based solid lipid microparticles (SLMs) as sustained delivery and targeting systems for Fer. The microparticles were produced by conventional hot emulsion techniques. The synthesis of the methyl ester of Fer (Fer-Me) allowed its encapsulation in the SLMs to increase. Fer-Me was hydrolyzed to Fer in rat whole blood and liver homogenate, evidencing its prodrug behavior. Furthermore, Fer-Me displayed antioxidant and anti-inflammatory properties. The amount of encapsulated Fer-Me was 0.719 ± 0.005% or 1.507 ± 0.014% in tristearin or stearic acid SLMs, respectively. The tristearin SLMs were able to control the prodrug release, while the stearic acid SLMs induced a significant increase of its dissolution rate in water. Jointly, the present results suggest that the tristearin SLMs loaded with Fer-Me could be a potential formulation against peripheral neuropathic pain; conversely, the stearic acid SLMs could be useful for Fer-Me uptake in the brain after nasal administration of the formulation.

Background: Robotic surgery may facilitate complex procedures such as right colectomy with complete mesocolic excision (CME) and shorten the learning curve. This study aimed to compare senior and junior surgeons' results in performing robotic right colectomy (RRC) with CME and intracorporeal anastomosis for right colon cancer., Materials and Methods: Between January 2015 and April 2020, a total of 161 patients underwent RRC with CME. After propensity score matching, two groups of 31 patients for each surgeon were formed. Intraoperative, postoperative and pathological outcomes were the variables assessed., Results: No statistically significant difference was recorded between the two groups. The senior surgeon experienced 16.1% minor complications (Clavien-Dindo I-II) and 3.2% major complications (Clavien-Dindo III-IV), while the novice surgeon reported 19.3% and 3.2% rates of minor and major adverse events, respectively., Conclusions: After a structured training protocol, a novice may obtain comparable results to an expert in performing RRC with CME., (© 2022 John Wiley & Sons Ltd.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer RF declared a past co-authorship with authors KF and DOBE to the handling editor.

Background and Aim: Bariatric surgery (BS) is a pillar for the treatment of morbid obesity and its related comorbidities. However, it might be associated with long-term deficiencies and absorption issues. Adherence to micronutrient supplementation is a crucial aspect in the management of these patients., Aim: The aim of the present survey was to evaluate the adherence to micronutrient supplementation in a cohort of Italian patients submitted to BS (BS patients) and to identify predictors of adherence using a self-administered, anonymous, internet-based instrument., Methods: Patients who underwent BS over the last decade in a single center were invited to participate to a self-administered, anonymous, internet-based survey consisting of a 23 items structured questionnaire evaluating: a. demographic information b. Bariatric procedures performed; c. Indication to BS; d. Lapse of time since last BS, e. Frequency of follow up visits post-surgery, f. Perception of well-being post BS; g. Adherence to micronutrient supplementation; h. Changes in their quality of life and self-esteem., Results: We received an automatic notification of delivery from 1100 out of 1600 BS patients and 290 (81.4% female, mean age 39.5 ± 10.1 years) completed the questionnaire. The main reported bariatric procedures were: Sleeve Gastrectomy (59%), Roux-en-Y Gastric Bypass (31%) and Adjustable Gastric Banding (7.2%). Only 33.1% of the sample acknowledged to have taken all recommended medication regularly. BS patients who underwent malabsorptive procedures and had their last follow up visit more than 5 years earlier, had a higher risk of being nonadherent to micronutrient supplementation. Conversely, BS patients in their forties seemed more likely to adhere to treatment recommendations. Losing more weight was the only independent risk factors for nonadherence to micronutrient supplementation, independently from patient's perception of wellbeing., Conclusion: After BS, several clinical and psychosocial factors might predict nonadherence to micronutrient supplementation.

Several studies showed that D-Limonene can improve metabolic parameters of obese mice via various mechanisms, including intestinal microbiota modulation. Nevertheless, its effective doses often overcome the acceptable daily intake, rising concerns about toxicity. In this study we administered to C57BL/6 mice for 84 days a food supplement based on D-Limonene, adsorbed on dietary fibers (FLS), not able to reach the bloodstream, to counteract the metabolic effects of a high-fat diet (HFD). Results showed that daily administration of D-Limonene (30 and 60 mg/kg body weight) for 84 days decreased the weight gain of HFD mice. After 84 days we observed a statistically significant difference in weight gain in the group of mice receiving the higher dose of FLS compared to HFD mice (35.24 ± 4.56 g vs. 40.79 ± 3.28 g, p < 0.05). Moreover, FLS at both doses tested was capable of lowering triglyceridemia and also fasting glycemia at the higher dose. Some insights on the relevant fatty acid changes in hepatic tissues were obtained, highlighting the increased polyunsaturated fatty acid (PUFA) levels even at the lowest dose. FLS was also able to positively modulate the gut microbiota and prevent HFD-associated liver steatosis in a dose-dependent manner. These results demonstrate that FLS at these doses can be considered non-toxic and could be an effective tool to counteract diet-induced obesity and ameliorate metabolic profile in mice.

The minimally invasive treatment of rectal cancer with Total Mesorectal Excision is a complex and challenging procedure due to technical and anatomical issues which could impair postoperative, oncological and functional outcomes, especially in a defined subgroup of patients. The results from recent randomized controlled trials comparing laparoscopic versus open surgery are still conflicting and trans-anal bottom-up approaches have recently been developed. Robotic surgery represents the latest consistent innovation in the field of minimally invasive surgery that may potentially overcome the technical limitations of conventional laparoscopy thanks to an enhanced dexterity, especially in deep narrow operative fields such as the pelvis. Results from population-based multicenter studies have shown the potential advantages of robotic surgery when compared to its laparoscopic counterpart in terms of reduced conversions, complication rates and length of stay. Costs, often advocated as one of the main drawbacks of robotic surgery, should be thoroughly evaluated including both the direct and indirect costs, with the latter having the potential of counterbalancing the excess of expenditure directly related to the purchase and maintenance of robotic equipment. Further prospectively maintained or randomized data are still required to better delineate the advantages of the robotic platform, especially in the subset of most complex and technically challenging patients from both an anatomical and oncological standpoint.

The role of adenosine A2A receptor (A2AR) and striatal-enriched protein tyrosine phosphatase (STEP) interactions in the striatal-pallidal GABA neurons was recently discussed in relation to A2AR overexpression and cocaine-induced increases of brain adenosine levels. As to phosphorylation, combined activation of A2AR and metabotropic glutamate receptor 5 (mGluR5) in the striatal-pallidal GABA neurons appears necessary for phosphorylation of the GluA1 unit of the AMPA receptor to take place. Robert Yasuda (J Neurochem 152: 270-272, 2020) focused on finding a general mechanism by which STEP activation is enhanced by increased A2AR transmission in striatal-pallidal GABA neurons expressing A2AR and dopamine D2 receptor. In his Editorial, he summarized in a clear way the significant effects of A2AR activation on STEP in the dorsal striatal-pallidal GABA neurons which involves a rise of intracellular levels of calcium causing STEP activation through its dephosphorylation. However, the presence of the A2AR in an A2AR-fibroblast growth factor receptor 1 (FGFR1) heteroreceptor complex can be required in the dorsal striatal-pallidal GABA neurons for the STEP activation. Furthermore, Won et al. (Proc Natl Acad Sci USA 116: 8028-8037, 2019) found in mass spectrometry experiments that the STEP splice variant STEP 61 can bind to mGluR5 and inactivate it. In addition, A2AR overexpression can lead to increased formation of A2AR-mGluR5 heterocomplexes in ventral striatal-pallidal GABA neurons. It involves enhanced facilitatory allosteric interactions leading to increased Gq-mediated mGluR5 signaling activating STEP. The involvement of both A2AR and STEP in the actions of cocaine on synaptic downregulation was also demonstrated. The enhancement of mGluR5 protomer activity by the A2AR protomer in A2AR-mGluR5 heterocomplexes in the nucleus accumbens shell appears to have a novel significant role in STEP mechanisms by both enhancing the activation of STEP and being a target for STEP 61 ., (© 2021. The Author(s).)

Cyclodextrins (CDs) are oligosaccharides widely used in the pharmaceutical field. In this review, a detailed examination of the literature of the last two decades has been made to understand the role of CDs in nasal drug delivery systems. In nasal formulations, CDs are used as pharmaceutical excipients, as solubilizers and absorption promoters, and as active ingredients due to their several biological activities (antiviral, antiparasitic, anti-atherosclerotic, and neuroprotective). The use of CDs in nasal formulations allowed obtaining versatile drug delivery systems intended for local and systemic effects, as well as for nose-to-brain transport of drugs. In vitro and in vivo models currently employed are suitable to analyze the effects of CDs in nasal formulations. Therefore, CDs are versatile pharmaceutical materials, and due to the continual synthesis of new CDs derivatives, the research on the new nasal applications is an interesting field evolving in the coming years, to which Italian research will still contribute.

The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor-receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1-15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor-receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.

Rectal prolapse is a condition that can cause significant social impairment and negatively affects quality of life. Surgery is the mainstay of treatment, with the aim of restoring the anatomy and correcting the associated functional disorders. During recent decades, laparoscopic abdominal procedures have emerged as effective tools for the treatment of rectal prolapse, with the advantages of faster recovery, lower morbidity, and shorter length of stay. Robotic surgery represents the latest evolution in the field of minimally invasive surgery, with the benefits of enhanced dexterity in deep narrow fields such as the pelvis, and may potentially overcome the technical limitations of conventional laparoscopy. Robotic surgery for the treatment of rectal prolapse is feasible and safe. It could reduce complication rates and length of hospital stay, as well as shorten the learning curve, when compared to conventional laparoscopy. Further prospectively maintained or randomized data are still required on long-term functional outcomes and recurrence rates.

Recently, many studies have shown that plant metabolites, such as geraniol (GER), may exert anti-inflammatory effects in neurodegenerative diseases and, in particular, Parkinson's disease (PD) models. Unfortunately, delivering GER to the CNS via nose-to-brain is not feasible due to its irritant effects on the mucosae. Therefore, in the present study β-cyclodextrin (βCD) and its hydrophilic derivative hydroxypropyl-beta-cyclodextrin (HPβCD) were selected as potential carriers for GER nose-to-brain delivery. Inclusion complexes were formulated and the biocompatibility with nasal mucosae and drug bioavailability into cerebrospinal fluid (CSF) were studied in rats. It has been demonstrated by DTA, FT-IR and NMR analyses that both the CDs were able to form 1:1 GER-CD complexes, arising long-term stable powders after the freeze-drying process. GER-HPβCD-5 and GER-βCD-2 complexes exhibited comparable results, except for morphology and solubility, as demonstrated by SEM analysis and phase solubility study, respectively. Even though both complexes were able to directly and safely deliver GER to CNS, GER-βCD-2 displayed higher ability in releasing GER in the CSF. In conclusion, βCD complexes can be considered a very promising tool in delivering GER into the CNS via nose-to-brain route, preventing GER release into the bloodstream and ensuring the integrity of the nasal mucosa., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Technical and oncological aspects are still debated when dealing with minimally-invasive right colectomy. Main controversial issues still remain about whether the anastomosis should be performed intra- or extracorporeally and if a complete mesocolic excision (CME) should be carried out. We report the feasibility of robotic right colectomy with CME and intracorporeal anastomosis (IA) for right sided colon cancer. Data from patients who underwent robotic right colectomy with IA and CME from January 2015 to April 2020 were prospectively collected and retrospectively analyzed. Intraoperative outcomes and complications (minor I-II and major III-IV according to Clavien-Dindo classification), conversion rate, 30-day postoperative outcomes and pathological outcomes were the variables assessed. A total of 161 patients undergoing robotic right colectomy for cancer met the inclusion criteria. Mean operative time was 185 min, no intraoperative complications were observed, and the conversion rate was 3.7% (6 patients requiring elective conversions). Overall, mean postoperative stay was 4.9 days and the overall 30-day complication rate was 16.1%. 20 patients (12.4%) had minor complications, while major postoperative complications occurred in six patients (3.7%). Anastomotic leak was recorded in one patient (0.6%) and the 30-day re-admission rate was 0.6%. Mean number of harvested lymph nodes was 21.9. Patients requiring conversion experienced two minor complications, with a mean length of stay of 7 days. Robotic right colectomy with CME and IA is feasible and it is associated with good intraoperative and short-term postoperative clinical outcomes.

Allosteric modulators of G protein coupled receptors (GPCRs), including GABA B Rs (GABA B Rs), are promising therapeutic candidates. While several positive allosteric modulators (PAM) of GABA B Rs have been characterized, only recently the first negative allosteric modulator (NAM) has been described. In the present study, we report the characterization of COR758, which acts as GABA B R NAM in rat cortical membranes and CHO cells stably expressing GABA B Rs (CHO-GABA B ). COR758 failed to displace the antagonist [ 3 H]CGP54626 from the orthosteric binding site of GABA B Rs showing that it acts through an allosteric binding site. Docking studies revealed a possible new allosteric binding site for COR758 in the intrahelical pocket of the GABA B1 monomer. COR758 inhibited basal and GABA B R-stimulated O-(3-[ 35 Sthio)-triphosphate ([ 35 S]GTPγS) binding in brain membranes and blocked the enhancement of GABA B R-stimulated [ 35 S]GTPγS binding by the PAM GS39783. Bioluminescent resonance energy transfer (BRET) measurements in CHO-GABA B cells showed that COR758 inhibited G protein activation by GABA and altered GABA B R subunit rearrangements. Additionally, the compound altered GABA B R-mediated signaling such as baclofen-induced inhibition of cAMP production in transfected HEK293 cells, agonist-induced Ca 2+ mobilization as well as baclofen and the ago-PAM CGP7930 induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in CHO-GABA B cells. COR758 also prevented baclofen-induced outward currents recorded from rat dopamine neurons, substantiating its property as a NAM for GABA B Rs. Altogether, these data indicate that COR758 inhibits G protein signaling by GABA B Rs, likely by interacting with an allosteric binding-site. Therefore, COR758 might serve as a scaffold to develop additional NAMs for therapeutic intervention., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Complete mesocolic excision (CME) for right colectomy increase the technical complexity of a laparoscopic approach especially when an intracorporeal anastomosis (IA) is associated. The robotic platform, with its intrinsic technical advantages, could potentially overcome the limitations of conventional laparoscopy. This study aimed to describe the robotic bottom-up technique and to evaluate short-terms outcomes of robotic right colectomy (RRC) with CME and IA., Methods: Data from patients who underwent RRC for cancer with bottom-up suprapubic approach from October 2016 to April 2020 were prospectively collected and retrospectively analyzed. Intraoperative outcomes and complications, conversion rate, 30-day postoperative outcomes, incisional hernia rate and pathological outcomes were the variables assessed., Results: A total of 109 patients were submitted to bottom-up suprapubic approach for RRC with CME and IA during the study period. Mean operative time was 179 min, no intraoperative complications were observed, and the conversion rate was 3.6%. Mean postoperative stay was 4.6 days and the overall 30-day complication rate was 15.6%. Thirteen patients (12%) had minor complications, while major postoperative complications occurred in 4 patients (3.6%). Anastomotic leak was recorded in 1 patient (0.9%) and the 30-day re-admission rate was 0.9%. Mean number of harvested lymph nodes was 22.6. Incisional hernia rate at the specimen extraction site was 0.9%., Conclusions: Bottom-up approach for RRC with CME and IA carries a low rate of conversions, intraoperative and short-term postoperative complications.

Background: This study aimed to evaluate the impact of the robotic approach on the minimally invasive elective treatment of diverticular disease., Methods: Data from patients who underwent elective robotic colectomy for diverticular disease from January 2015 to February 2020 were prospectively collected and retrospectively analysed. Intraoperative and 30-day postoperative outcomes were the variables assessed., Results: A total of 80 patients (71% with prior complicated diverticulitis) met the inclusion criteria. Mean operative time was 241 min, one intraoperative complication (1.2%) was observed, the conversion rate was 2.5%. Mean hospital stay was 6.4 days and overall 30-day complication rate was 22.5%. Fourteen patients (17.5%) had minor complications, while major postoperative complications occurred in four patients (5%). Anastomotic leak rate was 3.9% and the 30-day readmission rate was 3.7%., Conclusions: Robotic colectomy for diverticular disease has proven to be feasible and safe, with low intraoperative complications, conversion, and anastomotic leak rates., (© 2020 John Wiley & Sons Ltd.)

Background: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is the second most frequently performed bariatric procedure worldwide; however, long-term results are not frequently reported., Objectives: To evaluate the outcomes of LRYGB on weight loss and co-morbidities in a single center 15 years after the operation., Setting: Tertiary-care referral hospital., Methods: From February 2000 to December 2003, 105 patients (86 women; mean age 39.9 ± 17.4; mean body mass index [BMI] 47.2 ± 6.4 kg/m 2 ; 78 with BMI < 50 kg/m 2 and 27 with BMI ≥ 50 kg/m 2 ) underwent LRYGB. Retrospective analyses of a prospectively maintained database were carried out to evaluate weight loss; resolution of co-morbidities, including type 2 diabetes mellitus (T2D), hypertension (HTN), and dyslipidemia; complications; and nutritional status., Results: The follow-up rate at 15 years was 87.6%. Mean excess weight loss was 58.6 ± 27%, with 74.1% of patients achieving a total weight loss ≥ 20%. According to the Biron et al. criteria, an inadequate outcome was found in 11/21 (52.4%) of patients with an initial BMI ≥ 50 kg/m 2 versus 21/64 (32.8%) of patients with a preoperative BMI < 50 kg/m 2 (P = .001). Both groups experienced gradual weight regain (WR); specifically, 34.1% of patients regained more than 15% of their lowest postoperative weight. The rates of reoperations due to early and late surgical complications were 3.8% and 9.5%, respectively. T2D was resolved in 50% of patients, HTN in 61.1%, and dyslipidemia in 58.3%. Iron deficiency anemia (53%) was the most common postoperative nutritional finding., Conclusion: LRYGB provides satisfactory weight loss and resolution of co-morbidities up to 15 years. WR was a common finding. A significant proportion of patients with a preoperative BMI ≥ 50 kg/m 2 did not achieve a favorable weight loss outcome. Indications to perform LRYGB in this group of patients should be definitively reconsidered., (Copyright © 2020 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

The widespread distribution of heteroreceptor complexes with allosteric receptor-receptor interactions in the CNS represents a novel integrative molecular mechanism in the plasma membrane of neurons and glial cells. It was proposed that they form the molecular basis for learning and short-and long-term memories. This is also true for drug memories formed during the development of substance use disorders like morphine and cocaine use disorders. In cocaine use disorder it was found that irreversible A2AR-D2R complexes with an allosteric brake on D2R recognition and signaling are formed in increased densities in the ventral enkephalin positive striatal-pallidal GABA antireward neurons. In this perspective article we discuss and propose how an increase in opioid heteroreceptor complexes, containing MOR-DOR, MOR-MOR and MOR-D2R, and their balance with each other and A2AR-D2R complexes in the striatal-pallidal enkephalin positive GABA antireward neurons, may represent markers for development of morphine use disorders. We suggest that increased formation of MOR-DOR complexes takes place in the striatal-pallidal enkephalin positive GABA antireward neurons after chronic morphine treatment in part through recruitment of MOR from the MOR-D2R complexes due to the possibility that MOR upon morphine treatment can develop a higher affinity for DOR. As a result, increased numbers of D2R monomers/homomers in these neurons become free to interact with the A2A receptors found in high densities within such neurons. Increased numbers of A2AR-D2R heteroreceptor complexes are formed and contribute to enhanced firing of these antireward neurons due to loss of inhibitory D2R protomer signaling which finally leads to the development of morphine use disorder. Development of cocaine use disorder may instead be reduced through enkephalin induced activation of the MOR-DOR complex inhibiting the activity of the enkephalin positive GABA antireward neurons. Altogether, we propose that these altered complexes could be pharmacological targets to modulate the reward and the development of substance use disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Borroto-Escuela, Wydra, Fores-Pons, Vasudevan, Romero-Fernandez, Frankowska, Ferraro, Beggiato, Crespo-Ramirez, Rivera, Rocha, Perez de la Mora, Stove, Filip and Fuxe.)

The role of mycobacterial efflux pumps in drug-resistant tuberculosis has been widely reported. Recently, a new compound, named SS13, has been synthesized, and its activity as a potential efflux inhibitor has been demonstrated. In this work, the chemical-physical properties of the SS13 were investigated; furthermore, a formulative study aimed to develop a formulation suitable for oral administration was performed. SS13 shows nonintrinsic antitubercular activity, but it increases the antitubercular activity of all the tested drugs on several strains. SS13 is insoluble in different simulated gastrointestinal media; thus, its oral absorption could be limited. Solid lipid nanoparticles (SLNs) were, therefore, developed by using two different lipids, Witepsol and/or Gelucire. Nanoparticles, having a particle size (range of 200-450 nm with regards to the formulation composition) suitable for intestinal absorption, are able to load SS13 and to improve its permeation through the intestinal mucosa compared to the pure compound. The cytotoxicity is influenced by the concentration of nanoparticles administered. These promising results support the potential application of these nanocarriers for increasing the oral permeation of SS13 in multidrug-resistant tuberculosis management.

Glucose uptake in the brain decreases because of normal aging but this decline is accelerated in Alzheimer's disease (AD) patients. In fact, positron emission tomography (PET) studies have shown that metabolic reductions in AD patients occur decades before the onset of symptoms, suggesting that metabolic deficits may be an upstream event in at least some late-onset cases. A decrease in availability of glucose content induces a considerable impairment/downregulation of glycosylation, which is an important post-translational modification. Glycosylation is an important and highly regulated mechanism of secondary protein processing within cells and it plays a crucial role in modulating stability of proteins, as carbohydrates are important in achieving the proper three-dimensional conformation of glycoproteins. Moreover, glycosylation acts as a metabolic sensor that links glucose metabolism to normal neuronal functioning. All the proteins involved in β-amyloid (Aβ) precursor protein metabolism have been identified as candidates of glycosylation highlighting the possibility that Aβ metabolism could be regulated by their glycosylation. Within this framework, the present review aims to summarize the current understanding on the role of glycosylation in the etiopathology of AD, emphasizing the idea that glucose metabolic pathway may represent an alternative therapeutic option for targeting AD. From this perspective, the pharmacological modulation of glycosylation levels may represent a 'sweet approach' to treat AD targeting new mechanisms independent of the amyloid cascade and with comparable impacts in familial and sporadic AD.

The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism has been correlated with increased predisposition to develop cognitive and psychiatric disorders, and with a reduced response to some therapeutic treatments. However, the mechanisms underlying these impairments are currently not completely understood. Remarkably, kynurenine pathway alterations have also been implicated in cognitive and psychiatric disorders. Moreover, recent evidence suggests that physical exercise may promote beneficial effects by controlling kynurenine metabolism in the muscle. The aim of the present study was to assess whether the kynurenine pathway was differentially regulated in sedentary and exercising wild-type (BDNF Val/Val ) and homozygous knock-in BDNF Val66Met (BDNF Met/Met ) mice. We found that plasma and hippocampal levels of kynurenic acid and the hippocampal mRNA levels of IDO1 and KAT2 protein levels were increased in BDNF Met/Met mice and were not modulated by physical exercise. On the contrary, KAT1 protein levels in the gastrocnemius muscle were reduced, whereas MCP1 mRNA in the gastrocnemius muscle and GFAP protein in the hippocampus were increased in BDNF Met/Met mice compared to BDNF Val/Val mice, and reduced by physical exercise. Physical exercise increased plasmatic kynurenine levels only in BDNF Met/Met mice, and protein levels of KAT1 and KAT4 in the gastrocnemius muscle and hippocampus respectively, regardless of the genotype. Finally, we found that physical exercise was able to enhance the hippocampal-dependent memory only in the BDNF Val/Val mice. Overall our results showing an overactivation of the kynurenine pathway in the BDNF Met/Met mice may suggest a possible mechanism underlying the cognitive deficits reported in the BDNF Val66Met carriers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Palmitoylethanolamide (PEA) is an endogenous lipid mediator that, also by blunting astrocyte activation, demonstrated beneficial properties in several in vitro and in vivo models of Alzheimer's disease (AD). In the present study, we used astrocyte-neuron co-cultures from 3xTg-AD mouse (i.e. an animal model of AD) cerebral cortex to further investigate on the role of astrocytes in PEA-induced neuroprotection. To this aim, we evaluated the number of viable cells, apoptotic nuclei, microtubule-associated protein-2 (MAP2) positive cells and morphological parameters in cortical neurons co-cultured with cortical astrocytes pre-exposed, or not, to Aβ 42 (0.5 μM; 24 h) or PEA (0.1 μM; 24 h). Pre-exposure of astrocytes to Aβ 42 failed to affect the viability, the number of neuronal apoptotic nuclei, MAP2 positive cell number, neuritic aggregations/100 μm, dendritic branches per neuron, the neuron body area, the length of the longest dendrite and number of neurites/neuron in 3xTg-AD mouse astrocyte-neuron co-cultures. Compared to neurons from wild-type (non-Tg) mouse co-cultures, 3xTg-AD mouse neurons co-cultured with astrocytes from this mutant mice displayed higher number of apoptotic nuclei, lower MAP2 immunoreactivity and several morphological changes. These signs of neuronal suffering were significantly counteracted when the 3xTg-AD mouse cortical neurons were co-cultured with 3xTg-AD mouse astrocytes pre-exposed to PEA. The present data suggest that in astrocyte-neuron co-cultures from 3xTg-AD mice, astrocytes contribute to neuronal damage and PEA, by possibly counteracting reactive astrogliosis, improved neuronal survival. These findings further support the role of PEA as a possible new therapeutic opportunity in AD treatment., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Spinal cord injury (SCI) is an incurable condition, in which a cascade of cellular and molecular events triggered by inflammation and excitotoxicity impairs endogenous regeneration, namely remyelination and axonal outgrowth. We designed a treatment solution based on an implantable biomaterial (electrospun poly (l-lactic acid) [PLLA]) loaded with ibuprofen and triiodothyronine (T3) to counteract inflammation, thus improving endogenous regeneration. In vivo efficacy was tested by implanting the drug-loaded PLLA in the rat model of T8 contusion SCI. We observed the expected recovery of locomotion beginning on day 7. In PLLA-implanted rats (i.e., controls), the recovery stabilized at 21 days post-lesion (DPL), after which no further improvement was observed. On the contrary, in PLLA + ibuprofen (Ibu) + T3 (PLLA-Ibu-T3) rats a further recovery and a significant treatment effect were observed, also confirmed by the gait analysis on 49 DPL. Glutamate release at 24 h and 8 DPL was reduced in PLLA-Ibu-T3- compared to PLLA-implanted rats, such as the estimated lesion volume at 60 DPL. The myelin- and 200-neurofilament-positive area fraction was higher in PLLA-Ibu-T3-implanted rats, where the percentage of astrocytes was significantly reduced. The implant of a PLLA electrospun scaffold loaded with Ibu and T3 significantly improves the endogenous regeneration, leading to an improvement of functional locomotion outcome in the SCI.

Cannabis remains one of the most widely used illicit drugs during pregnancy. The main psychoactive component of marijuana (Δ 9 -tetrahydrocannabinol, THC) is correlated with untoward physiological effects in the offspring. Neurobehavioral and cognitive impairments have been reported in longitudinal studies on children and adolescents prenatally exposed to marijuana, and a link to psychiatric disorders has been proposed. Interestingly, the deleterious effects of prenatal cannabis use are similar to those observed in adult rats prenatally exposed to (L)-kynurenine, the direct bioprecursor of the neuroactive metabolite kynurenic acid (KYNA). We therefore investigated whether alterations in KYNA levels in the rat brain might play a role in the long-term consequences of prenatal cannabinoid exposure. Pregnant Wistar rats were treated daily with THC [5 mg/kg, p.o.] from gestational day (GD)5 through GD20. Using in vivo microdialysis in the medial prefrontal cortex, adult animals were then used to determine the extracellular levels of KYNA and glutamate. Compared to controls, extracellular basal KYNA levels were higher, and basal glutamate levels were lower, in prenatally THC-exposed rats. These rats also showed abnormal short-term memory. Following an additional acute challenge with a low dose of kynurenine (5 mg/kg i.p.) in adulthood, the increase in extracellular KYNA levels in the mPFC was more pronounced in in prenatally THC-exposed rats. These effects could be causally related to the cognitive dysfunction seen in prenatally THC-exposed rats. In the translational realm, these experiments raise the prospect of prevention of KYNA neosynthesis as a promising novel approach to combat some of the detrimental long-term effects of prenatal cannabis use., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)