Multiple drug-delivery strategies to enhance the pharmacological and toxicological properties of Mefenamic acid.

OBJECTIVE: To improve the biological and toxicological properties of Mefenamic acid (MA), the galactosylated prodrug of MA named MefeGAL was included in polymeric solid dispersions (PSs) composed of poly(glycerol adipate) (PGA) and Pluronic® F68 (MefeGAL-PS). MefeGAL-PS was compared with polymeric solid formulations of MA (MA-PS) or a mixture of equal ratio of MefeGAL/MA (Mix-PS). METHODS: The in vitro and in vivo pharmacological and toxicological profiles of PSs have been investigated. In detail, we evaluated the anti-inflammatory (carrageenan-induced paw edema test), analgesic (acetic acid-induced writhing test) and ulcerogenic activity in mice after oral treatment. Additionally, the antiproliferative activity of PSs was assessed on in vitro models of colorectal and non-small cell lung cancer. RESULTS: When the PSs were resuspended in water, MefeGAL's, MA's and their mixture's apparent solubilities improved due to the interaction with the polymeric formulation. By comparing the in-vivo biological performance of MefeGAL-PS with that of MA, MefeGAL and MA-PS, it was seen that MefeGAL-PS exhibited the same sustained and delayed analgesic and anti-inflammatory profile as MefeGAL but did not cause gastrointestinal irritation. The pharmacological effect of Mix-PS was present from the first hours after administration, lasting about 44 hours with only slight gastric mucosa irritation. In-vitro evaluation indicated that Mix-PS had statistically significant higher cytotoxicity than MA-PS and MefeGAL-PS. CONCLUSIONS: These preliminary data are promising evidence that the galactosylated prodrug approach in tandem with a polymer-drug solid dispersion formulation strategy could represent a new drug delivery route to improve the solubility and biological activity of NSAIDs.

Nephrology Partnership for Advancing Technology in Healthcare (N-PATH) program: the teachers' perspective.

The N-PATH (Nephrology Partnership for Advancing Technology in Healthcare) program concluded with the 60th European Renal Association 2023 Congress in Milan, Italy. This collaborative initiative aimed to provide advanced training in interventional nephrology to young European nephrologists. Funded by Erasmus+ Knowledge Alliance, N-PATH addressed the global burden of chronic kidney disease (CKD) and the shortage of nephrologists. CKD affects >850 million people worldwide, yet nephrology struggles to attract medical talent, leading to unfilled positions in residency programs. To address this, N-PATH focused on enhancing nephrology education through four specialized modules: renal expert in renal pathology (ReMAP), renal expert in vascular access (ReVAC), renal expert in medical ultrasound (ReMUS) and renal expert in peritoneal dialysis (RePED). ReMAP emphasized the importance of kidney biopsy in nephrology diagnosis and treatment, providing theoretical knowledge and hands-on training. ReVAC centred on vascular access in haemodialysis, teaching trainees about different access types, placement techniques and managing complications. ReMUS recognized the significance of ultrasound in nephrology, promoting interdisciplinary collaboration and preparing nephrologists for comprehensive patient care. RePED addressed chronic peritoneal dialysis, offering comprehensive training in patient selection, prescription, monitoring, complications and surgical techniques for catheter insertion. Overall, N-PATH's strategy involved collaborative networks, hands-on training, mentorship, an interdisciplinary approach and the integration of emerging technologies. By bridging the gap between theoretical knowledge and practical skills, N-PATH aimed to revitalize interest in nephrology and prepare proficient nephrologists to tackle the challenges of kidney diseases. In conclusion, the N-PATH program aimed to address the shortage of nephrologists and improve the quality of nephrology care in Europe. By providing specialized training, fostering collaboration and promoting patient-centred care, N-PATH aimed to inspire future nephrology professionals to meet the growing healthcare demands related to kidney diseases and elevate the specialty's status within the medical community.

Quantitative ADC: An Additional Tool in the Evaluation of Prostate Cancer?

Prostate cancer is one of the most common tumors among the male population. Magnetic resonance imaging (MRI), standardized by the PI-RADS version 2.1 scoring system, has a fundamental role in detecting prostate cancer and evaluating its aggressiveness. Diffusion-weighted imaging sequences and apparent diffusion coefficient values, in particular, are considered fundamental for the detection and characterization of lesions. In 2016 the International Society of Urological Pathology introduced a new anatomopathological 5-grade scoring system for prostate cancer. The aim of this study is to evaluate the correlation between quantitative apparent diffusion coefficient values (ADC) derived from diffusion-weighted imaging (DWI) sequences and the International Society of Urological Pathology (ISUP) and PI-RADS groups. Our retrospective study included 143 patients with 154 suspicious lesions, observed on prostate magnetic resonance imaging and compared with the histological results of the biopsy. We observed that ADC values can aid in discriminating between not clinically significant (ISUP 1) and clinically significant (ISUP 2-5) prostate cancers. In fact, ADC values were lower in ISUP 5 lesions than in negative lesions. We also found a correlation between ADC values and PI-RADS groups; we noted lower ADC values in the PI-RADS 5 and PI-RADS 4 groups than in the PI-RADS 3 group. In conclusion, quantitative apparent diffusion coefficient values can be useful to assess the aggressiveness of prostate cancer.

Chemopreventive effect of a milk whey by-product derived from Buffalo (Bubalus bubalis) in protecting from colorectal carcinogenesis.

BACKGROUND: Several studies show that natural foods are a source of compounds with anticancer properties that affect the gut microbiota and its metabolites. In the present study, we investigate the effect of a delactosed buffalo milk whey by-product (DMW) on colorectal carcinogenesis. METHODS: The effect of DMW on colorectal carcinoma (CRC) was investigated in the established mouse model of azoxymethane (AOM)-induced colon carcinoma, which closely resembles the human clinical condition of CRC. The effect of DMW on CRC immortalized cell lines was also evaluated to further identify the antineoplastic mechanism of action. RESULTS: Pretreatment of AOM-treated mice with DMW significantly (P < 0.05) reduced the percentage of mice bearing both aberrant crypt foci with more than four crypts (which are early precancerous lesions that progress to CRC) and tumors. In addition, DMW completely counteracted the effect of AOM on protein expression of caspase-9, cleaved caspase-3 and poly ADP-ribose polymerase in colonic tissue. Administration of DMW alone (i.e. without AOM) resulted in changes in the composition of the gut microbiota, leading to enrichment or depletion of genera associated with health and disease, respectively. DMW was also able to restore AOM-induced changes in specific genera of the gut microbiota. Specifically, DMW reduced the genera Atopobiaceae, Ruminococcus 1 and Lachnospiraceae XPB1014 and increased the genera Parabacteroides and Candidatus Saccharimonas, which were increased and reduced, respectively, by AOM. Blood levels of butyric acid and cancer diagnostic markers (5-methylcytidine and glycerophosphocholine), which were increased by AOM treatment, were reduced by DMW. Furthermore, DMW exerted cytotoxic effects on two human CRC cell lines (HCT116 and HT29) and these effects were associated with the induction of apoptotic signaling. CONCLUSIONS: Our results suggest that DMW exerts chemopreventive effects and restores the gut microbiota in AOM-induced CRC, and induces cytotoxic effect on CRC cells. DMW could be an important dietary supplement to support a healthy gut microbiota and reduce the prevalence of CRC in humans. Video Abstract.

The Beneficial Effects of Ultramicronized Palmitoylethanolamide in the Management of Neuropathic Pain and Associated Mood Disorders Induced by Paclitaxel in Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication of antineoplastic drugs, particularly paclitaxel (PTX). It can affect the quality of patients' lives and increase the risk of developing mood disorders. Although several drugs are recommended, they yielded inconclusive results in clinical trials. The aim of the present work is to investigate whether the palmitoylethanolamide (PEA) would reduce PTX-induced CIPN and associated mood disorders. Moreover, the role PPAR-α and the endocannabinoid system will also be investigated. CIPN was induced by intraperitoneally injection of PTX (8 mg/kg) every other day for a week. PEA, 30 mg/kg, was orally administrated in a bioavailable form (i.e., ultramicronized PEA, um-PEA) one hour after the last PTX injection, for 7 days. In the antagonism experiments, AM281 (1 mg/kg) and GW6471 (2 mg/kg) were administrated 30 min before um-PEA. Our results demonstrated that um-PEA reduced the development of hypersensitivity with the effect being associated with the reduction in spinal and hippocampal pro-inflammatory cytokines, as well as antidepressive and anxiolytic effects. Moreover, the PPAR-α and CB1 receptor antagonists blocked the behavioral and antinociceptive effects of um-PEA. Our findings suggest that um-PEA is a promising adjunct in CIPN and associated mood disorders through the activation of PPAR-α, which influences the endocannabinoid system.

Inflammation-Independent Antinociceptive Effects of DF2755A, a CXCR1/2 Selective Inhibitor: A New Potential Therapeutic Treatment for Peripheral Neuropathy Associated to Non-Ulcerative Interstitial Cystitis/Bladder Pain Syndrome.

Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic bladder disease of unknown etiology characterized by urinary frequency and episodic and chronic pain. Analgesic treatments for IC/BPS are limited, especially for patients with non-Hunner (non-ulcerative) type IC who usually have poor overall outcomes. Here, we demonstrate that oral treatment with DF2755A, a potent and selective inhibitor of chemokine receptors CXCR1/2, can prevent and reverse peripheral neuropathy associated to non-Hunner IC/BPS by directly inhibiting chemokine-induced excitation of sensory neurons. We tested DF2755A antinociceptive effects in a cyclophosphamide (CYP)-induced non-ulcerative IC rat model characterized by severe peripheral neuropathy in the absence of bladder inflammatory infiltrate, urothelial hyperplasia, and hemorrhage. Treatment with DF2755A prevented the onset of peripheral neuropathy and reversed its development in CYP-induced IC rats, showing a strong and long-lasting anti-hyperalgesic effect. Ex vivo and in vitro studies showed that DF2755A treatment strongly inhibited the expression of CXCR2 agonists, CXCL1/KC, and CXCL5 and of transient receptor potential vanilloid 1 (TRPV1) compared to vehicle, suggesting that its effects can be due to the inhibition of the nociceptive signaling passing through the CXCL1/CXCR1-2 axis and TRPV1. In conclusion, our results highlight the key pathophysiological role played by the CXCL1/CXCR1-2 axis and TRPV1 in the onset and development of peripheral neuropathy in non-Hunner IC and propose DF2755A as a potential therapeutic approach for the treatment of not only inflammatory painful conditions but also neuropathic ones and in particular non-Hunner IC/BPS.

Paclitaxel binds and activates C5aR1: A new potential therapeutic target for the prevention of chemotherapy-induced peripheral neuropathy and hypersensitivity reactions.

Chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSRs) are among the most frequent and impairing side effects of the antineoplastic agent paclitaxel. Here, we demonstrated that paclitaxel can bind and activate complement component 5a receptor 1 (C5aR1) and that this binding is crucial in the etiology of paclitaxel-induced CIPN and anaphylaxis. Starting from our previous data demonstrating the role of interleukin (IL)-8 in paclitaxel-induced neuronal toxicity, we searched for proteins that activate IL-8 expression and, by using the Exscalate platform for molecular docking simulations, we predicted the high affinity of C5aR1 with paclitaxel. By in vitro studies, we confirmed the specific and competitive nature of the C5aR1-paclitaxel binding and found that it triggers intracellularly the NFkB/P38 pathway and c-Fos. In F11 neuronal cells and rat dorsal root ganglia, C5aR1 inhibition protected from paclitaxel-induced neuropathological effects, while in paclitaxel-treated mice, the absence (knock-out mice) or the inhibition of C5aR1 significantly ameliorated CIPN symptoms-in terms of cold and mechanical allodynia-and reduced the chronic pathological state in the paw. Finally, we found that C5aR1 inhibition can counteract paclitaxel-induced anaphylactic cytokine release in macrophages in vitro, as well as the onset of HSRs in mice. Altogether these data identified C5aR1 as a key mediator and a new potential pharmacological target for the prevention and treatment of CIPN and HSRs induced by paclitaxel.

Paraneoplastic Wong-Type Dermatomyositis Associated with Gynecological Malignancy.

Although dermatomyositis is known to be a possible paraneoplastic syndrome, often in the setting of gynecological cancers, Wong-type dermatomyositis-a rare variant of dermatomyositis-has not been clearly associated with internal malignancies to date. There is only one report from Japan of a woman who developed Wong-type dermatomyositis together with the recurrence of uterine cancer. We report the case of a Caucasian patient who presented with infrequent Wong-type dermatomyositis with positive anti-TIF1γ antibodies; screening for internal malignancies revealed fallopian tube carcinoma.

Biological Profile of Two Gentiana lutea L. Metabolites Using Computational Approaches and In Vitro Tests.

Natural products have been the main source of bioactive molecules for centuries. We tested the biological profile of two metabolites extracted from Gentiana lutea L. by means of computational techniques and in vitro assays. The two molecules (loganic acid and gentiopicroside) were tested in silico using an innovative technique, named Inverse Virtual Screening (IVS), to highlight putative partners among a panel of proteins involved in inflammation and cancer events. A positive binding with cyclooxygenase-2 (COX-2), alpha-1-antichymotrypsin, and alpha-1-acid glycoprotein emerged from the computational experiments and the outcomes from the promising interaction with COX-2 were confirmed by Western blot, highlighting the reliability of IVS in the field of the natural products.

Giant nevus comedonicus of the entire lower left limb protecting from the associated bullous pemphigoid: A hypothetical role of NEK9 mutation?

We present the case of a 92-year-old woman, with bullous pemphigoid (BP) and a concomitant nevus comedonicus (NC) presenting as an asymptomatic, linear lesion of the entire lower left limb, formed by multiple comedones. Dermoscopy of the NC and histopathology confirmed the clinical and dermoscopic suspect of giant congenital nevus comedonicus. The two entities presented no overlap. In this article, we speculate that a mutation of the NEK9 gene, associated with NC, probably altering the normal follicular differentiation in NC lesions, may hypothetically also influence the expression of BPAG2 in NC. This might possibly influence a protective role of NC lesions towards BP. Undoubtedly, genetic studies would be needed to confirm or reject the proposed hypothesis.

Effects of Chronic Oral Probiotic Treatment in Paclitaxel-Induced Neuropathic Pain.

Chemotherapy-induced peripheral neuropathy (CIPN) represents one of the most prevalent and potentially disabling side effects due to the use of anticancer drugs, one of the primary neuropathies detected is peripheral neuropathy induced by administration of taxanes, including paclitaxel. It has been demonstrated that gut microbiota is crucial for the therapeutic effect of chemotherapeutic drugs for inhibiting tumor growth and contributed to the pathogenesis of the CIPN. The use of nutraceuticals has receiving growing attention from the research community due to their phytochemical, biological, and pharmacological properties. It has been demonstrated that probiotic formulations may both reduce inflammation and modulate the expression of pain receptors. Our studies tested the efficacy of a probiotic formulation, SLAB51, in preventing paclitaxel-induced neuropathy. Interestingly, our probiotic formulation was able to keep the gut integrity, preserving its functionality, in CIPN-mice, moreover, it prevented the mechanical and cold hypersensitivity induced in paclitaxel-mice. Additionally, ex-vivo analysis showed that in CIPN-mice the pro-biotic treatment increased the expression of opioid and cannabinoid receptors in spinal cord, it prevented in the reduction in nerve fiber damage in the paws and modulated the serum proinflammatory cytokines concentration. On basis of these data, the use of this specific probiotic formulation may represent a valid adjuvant agent to paclitaxel, useful and not toxic for long-lasting therapies.

Engineering Boron Hot Spots for the Site-Selective Installation of Iminoboronates on Peptide Chains.

Boronic acids (BAs) are a promising bioconjugation function to design dynamic materials as they can establish reversible covalent bonds with oxygen/nitrogen nucleophiles that respond to different pH, ROS, carbohydrates and glutathione levels. However, the dynamic nature of these bonds also limits the control over the stability and site-selectivity of the bioconjugation, which ultimately leads to heterogeneous conjugates with poor stability under physiological conditions. Here we disclose a new strategy to install BAs on peptide chains. In this study, a "boron hot spot" based on the 3-hydroxyquinolin-2(1H)-one scaffold was developed and upon installation on a peptide N-terminal cysteine, enables the site-selective formation of iminoboronates with 2-formyl-phenyl boronic acids (Ka of 58128±2 m-1 ). The reaction is selective in the presence of competing lysine ϵ-amino groups, and the resulting iminoboronates, displayed improved stability in buffers solutions and a cleavable profile in the presence of glutathione. Once developed, the methodology was used to prepare cleavable fluorescent conjugates with a laminin fragment, which enabled the validation of the 67LR receptor as a target to deliver cargo to cancer HT29 cells.

Narrow-band imaging: a useful tool for early recognition of oral lichen planus malignant transformation?

BACKGROUND: Oral lichen planus (OLP) lesions have an overall malignant transformation rate of 1.37%. In patients with chronic disease, the diagnosis of malignancy relies on histopathological examination guided by clinical suspicion. Narrow-band imaging (NBI) is a promising endoscopic technique which, using a filtered light with specific wavelengths, can highlight microvascular abnormalities associated with subclinical neoplastic changes of the upper aerodigestive tract epithelium. OBJECTIVES: This study aimed to analyse the value of NBI in selecting patients for biopsy before the emergence of clinical changes, allowing early detection of oral malignancies arising from OLP. MATERIALS AND METHODS: A prospective study was conducted, enrolling 32 consecutive patients with a histological diagnosis of OLP with no previous diagnosis of oral cancer or other oral inflammatory diseases. Patients with suspicious NBI lesions underwent biopsies, while other patients were included in the follow-up. RESULTS: Two patients were judged positive at NBI evaluation and squamous cell carcinoma was diagnosed after histological examination. None of the other patients developed clinical features of malignancies during follow-up. CONCLUSION: NBI evaluation may increase the accuracy of detection of subclinical neoplastic transformation in OLP lesions and further encourage clinicians to perform biopsies in selected cases.

Paracetamol-Galactose Conjugate: A Novel Prodrug for an Old Analgesic Drug.

Paracetamol has been one of the most commonly used and prescribed analgesic drugs for more than a hundred years. Despite being generally well tolerated, it can result in high liver toxicity when administered in specific conditions, such as overdose, or in vulnerable individuals. We have synthesized and characterized a paracetamol galactosylated prodrug (PARgal) with the aim of improving both the pharmacodynamic and pharmacological profile of paracetamol. PARgal shows a range of physicochemical properties, solubility, lipophilicity, and chemical stability at differing physiological pH values and in human serum. PARgal could still be preclinically detected 2 h after administration, meaning that it displays reduced hepatic metabolism compared to paracetamol. In overdose conditions, PARgal has not shown any cytotoxic effect in in vitro analyses performed on human liver cells. Furthermore, when tested in an animal pain model, PARgal demonstrated a sustained analgesic effect up to the 12th hour after oral administration. These findings support the use of galactose as a suitable carrier in the development of prodrugs for analgesic treatment.

DF2726A, a new IL-8 signalling inhibitor, is able to counteract chemotherapy-induced neuropathic pain.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of several anti-neoplastics and a main cause of sensory disturbances in cancer survivors, negatively impacting patients' quality of life. Peripheral nerve degeneration or small fibre neuropathy is generally accepted as the underlying mechanism in the development of CIPN. Recent evidence has contributed to clarify the determinant role of cytokines and chemokines in the process leading to neuronal hyperexcitability. Exposure to oxaliplatin triggers alterations in peripheral neuropathic pathways previously linked to IL-8 pathway. We investigated a novel selective inhibitor of IL-8 receptors, DF2726A, and showed its effects in counteracting CINP pathways, extending the relevance of the activation of IL-8 pathway to the class of platinum chemotherapeutics. Based on our results, we suggest that DF2726A might be a promising candidate for clinical treatment of CIPN conditions due to its efficacy and optimized pharmacokinetic/pharmacodynamic profile.